Cognition and Addiction

Cognition and Addiction
A Researcher’s Guide from Mechanisms

Towards Interventions
Edited by
Antonio Verdejo-Garcia
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, United Kingdom
525 B Street, Suite 1650, San Diego, CA 92101, United States
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
Copyright © 2020 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including
photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher.
Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with
organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.
elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may
be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding,
changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any
information, methods, compounds, or experiments described herein. In using such information or methods they should be
mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any
injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or
operation of any methods, products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
ISBN: 978-0-12-815298-0
For information on all Academic Press publications visit our

website at https://www.elsevier.com/books-and-journals
Publisher: Nikki Levy

Acquisition Editor: Joslyn Chaiprasert-Paguio
Editorial Project Manager: Tracy Tufaga
Production Project Manager: Mohana Natarajan
Cover Designer: Greg Harris
Typeset by TNQ Technologies
I have been dedicated to edit this book during the last couple of years, but the
knowledge and collaborations that have made it possible span over 15 years.
Thus, I would like to dedicate this book to my mentors: Professors Miguel
Perez-Garcı́a, Antoine Bechara, and Karen Bolla and to the many colleagues and
friends (and colleagues who became friends) with whom I have shared amazing
research and life adventures in Granada, Barcelona, Iowa, Baltimore, Cambridge,
and Melbourne. To my parents, for fighting to give me a university education and
teaching me to always decide by myself. Huge thanks to my wife, Natalia, for
being an inspiration and spring of energy for so many personal and career
choicesdI look up to you every single day.
Antonio Verdejo-Garcı́a,
Melbourne, May 2019
Contributors
Merideth A. Addicott, Department of Psychiatry, Uni- Nicolas Cabé, Normandie Univ, UNICAEN, PSL Uni-
versity of Arkansas for Medical Science, Little Rock, versité de Paris, EPHE, INSERM, U1077, CHU de
AR, United States Caen, GIP Cyceron, Neuropsychologie et Imagerie de la
Robin L. Aupperle, Laureate Institute for Brain Research, Mémoire Humaine, Caen, France
Tulsa, OK, United States Zhipeng Cao, School of Psychology, University College
Alex Baldacchino, Division of Populations and Health Dublin, Dublin, Ireland
Science, St Andrews Medical School, University of Adrian Carter, Turner Institute for Brain and Mental
St Andrews, St Andrews, Fife, United Kingdom Health, Monash University, Melbourne, VIC, Australia;
Joël Billieux, Addictive and Compulsive Behaviours UQ Centre for Clinical Research, University of
Laboratory, Institute for Health and Behaviours, Uni- Queensland, Brisbane, QLD, Australia
versity of Luxembourg, Esch-sur-Alzette, Luxembourg Natalie Castellanos-Ryan, Universite de Montreal, CHU
Marilisa Boffo, Addiction Development and Psychopathol- Ste Justine, Montreal, QC, Canada
ogy (ADAPT) Laboratory, Department of Psychology, Luke Clark, Centre for Gambling Research at UBC,
University of Amsterdam, Amsterdam, The Netherlands; Department of Psychology, University of British
Department of Psychology, Education and Child Columbia, Vancouver, BC, Canada
Studies, Erasmus University Rotterdam, Rotterdam, Patricia Conrod, Universite de Montreal, CHU Ste Jus-
The Netherlands tine, Montreal, QC, Canada
Matthias Brand, General Psychology: Cognition and Fleur Davey, Research and Development Department,
Center for Behavioral Addiction Research (CeBAR), NHS Fife, Dunfermline, Fife, United Kingdom
University of Duisburg-Essen, Duisburg, Germany;
Erwin L. Hahn Institute for Magnetic Resonance Imaging, Andrew Dawson, Turner Institute for Brain and Mental
Essen, Germany Health, Monash University, Melbourne, VIC, Australia
Damien Brevers, Laboratory of Psychological Medicine Logan T. Dowdle, Department of Psychiatry and Behav-
and Addictology, Faculty of Medicine, Brugmann- ioral Sciences, College of Medicine, Medical University
Campus, Université Libre de Bruxelles, Brussels, of South Carolina. Charleston, SC, United States
Belgium; Research in Psychology Applied to Motor Timothy C. Durazzo, Stanford University and Palo Alto
Learning, Faculty of Motor Sciences, Erasme Campus, VA Medical Center, Stanford, CA, United States
Université Libre de Bruxelles, Brussels, Belgium Hamed Ekhtiari, Laureate Institute for Brain Research,
Gabriel Brooks, Centre for Gambling Research at UBC, Tulsa, OK, United States
Department of Psychology, University of British Mario Ferrari, Centre for Gambling Research at UBC,
Columbia, Vancouver, BC, Canada Department of Psychology, University of British
S.J. Brooks, School of Natural Sciences and Psychology, Columbia, Vancouver, BC, Canada
Liverpool John Moores University, Liverpool, United Matt Field, Department of Psychology, University of
Kingdom; Department of Neuroscience, Uppsala Uni- Sheffield, Sheffield, South Yorkshire, United Kingdom
versity, Uppsala, Sweden
S. Funk, Department of Psychology, University of Cape
M. Aryana Bryan, Center on Mindfulness and Integrative Town, Cape Town, South Africa
Health Intervention Development, University of Utah,
Salt Lake City, UT, United States
xv
xvi Contributors
Gloria Garcia-Fernandez, School of Psychological Daniel H. Lench, Department of Psychiatry and Behavioral
Sciences and Turner Institute for Brain and Mental Sciences, College of Medicine, Medical University of
Health, Monash University, Melbourne, VIC, Aus- South Carolina. Charleston, SC, United States
tralia; Faculty of Psychology, University of Oviedo, Angéline Maillard, Normandie Univ, UNICAEN, PSL
Oviedo, Spain Université de Paris, EPHE, INSERM, U1077, CHU de
Eric L. Garland, Center on Mindfulness and Integrative Caen, GIP Cyceron, Neuropsychologie et Imagerie de la
Health Intervention Development, University of Utah, Mémoire Humaine, Caen, France
Salt Lake City, UT, United States Pierre Maurage, Laboratory for Experimental Psychopa-
Rita Z. Goldstein, Departments of Psychiatry and Neuro- thology, Psychological Science Research Institute,
science, Icahn School of Medicine at Mount Sinai, New Université Catholique de Louvain, Louvain-la-Neuve,
York, NY, United States Belgium
Raul Gonzalez, Center for Children and Families, Dieter J. Meyerhoff, University of California San Fran-
Department of Psychology, Florida International Uni- cisco and San Francisco VA Medical Center, San
versity, Miami, FL, United States Francisco, CA, United States
Renee D. Goodwin, Department of Epidemiology and Scott J. Moeller, Department of Psychiatry, Stony Brook
Biostatistics, School of Public Health, The City Uni- University School of Medicine, Stony Brook, NY,
versity of New York, New York, NY, United States; United States
Department of Epidemiology, Mailman School of Catharine Montgomery, School of Natural Sciences and
Public Health, Columbia University, New York, NY, Psychology, Liverpool John Moores University,
United States Liverpool, United Kingdom
Anna E. Goudriaan, Amsterdam UMC, Department of Laura O’Halloran, School of Psychology, Trinity College
Psychiatry, University of Amsterdam, the Netherlands; Dublin, Dublin, Ireland
Amsterdam Institute for Addiction Research; Arkin
Mental Health; Department of Quality of Care and Ileana Pacheco-Colón, Center for Children and Families,
Research and Jellinek, Amsterdam, The Netherlands Department of Psychology, Florida International Uni-
versity, Miami, FL, United States
Wayne Hall, UQ Centre for Clinical Research, University
of Queensland, Brisbane, QLD, Australia; Centre for Martin P. Paulus, Laureate Institute for Brain Research,
Youth Substance Abuse Research, University of Tulsa, OK, United States
Queensland, Brisbane, QLD, Australia; National Tomás Paus, Bloorview Research Institute, Holland
Addiction Centre, Kings College London, London, Bloorview Kids Rehabilitation Hospital, Toronto, ON,
WC2R 2LS, United Kingdom Canada; Departments of Psychology and Psychiatry,
Adam W. Hanley, Center on Mindfulness and Integrative University of Toronto, Toronto, ON, Canada
Health Intervention Development, University of Utah, MacKenzie R. Peltier, Yale School of Medicine, Depart-
Salt Lake City, UT, United States ment of Psychiatry, New Haven, CT, United States; VA
Colleen A. Hanlon, Department of Psychiatry and Connecticut Healthcare System, West Haven, CT, United
Behavioral Sciences, College of Medicine, Medical States
University of South Carolina, Charleston, SC, United Brian Pennie, School of Psychology, Trinity College
States Dublin, Dublin, Ireland
Matthew O. Howard, University of North Carolina at Anne Lise Pitel, Normandie Univ, UNICAEN, PSL Uni-
Chapel Hill, Chapel Hill, NC, United States versité de Paris, EPHE, INSERM, U1077, CHU de
Andrew Jones, Department of Psychological Sciences, Caen, GIP Cyceron, Neuropsychologie et Imagerie de la
University of Liverpool, Liverpool, Merseyside, United Mémoire Humaine, Caen, France
Kingdom Marc N. Potenza, Departments of Psychiatry and Neuro-
Daniel L. King, School of Psychology, The University of science and Child Study Center, Yale School of Med-
Adelaide, Adelaide, SA, Australia; College of Educa- icine, New Haven, CT, United States; The Connecticut
tion, Psychology and Social Work, Flinders University, Council on Problem Gambling, Wethersfield, CT,
Adelaide, SA, Australia United States; The Connecticut Mental Health Center,
New Haven, CT, United States
Jacob W. Koudys, University of Toronto, Toronto, ON,
Canada
Contributors xvii
Boris B. Quednow, Experimental and Clinical Pharma- Douglas Steele, Institute of Neuroscience, Ninewells
copsychology, Department of Psychiatry, Psychotherapy Hospital Medical School, University of Dundee,
and Psychosomatics, Psychiatric Hospital, University of Dundee, Tayside, United Kingdom
Zurich, Zurich, Switzerland; Neuroscience Centre Ryan M. Sullivan, Department of Psychiatry, Stony Brook
Zurich, University of Zurich and Swiss Federal Institute University School of Medicine, Stony Brook, NY,
of Technology (ETH) Zurich, Zurich, Switzerland United States; Department of Psychology, University of
C. Rabier, Department of Psychology, University of Cape Wisconsin-Milwaukee, Milwaukee, WI, United States
Town, Cape Town, South Africa Serenella Tolomeo, Division of Populations and Health
Kavya Raj, Turner Institute for Brain and Mental Health, Science, St Andrews Medical School, University of St
Monash University, Melbourne, VIC, Australia Andrews, St Andrews, Fife, United Kingdom
Tonisha Kearney Ramos, Department of Psychiatry and Tess den Uyl, Addiction Development and Psychopathol-
Behavioral Sciences, College of Medicine, Medical ogy (ADAPT) Laboratory, Department of Psychology,
University of South Carolina, Charleston, SC, United University of Amsterdam, Amsterdam, The Netherlands
States Alireza Valyan, Allameh Tabataba’i University, Tehran,
Tara Rezapour, Institute for Cognitive Science Studies, Iran
Tehran, Iran; Iranian National Center for Addiction Antonio Verdejo-Garcia, School of Psychological Sci-
Studies, Tehran University of Medical Sciences, ences and Turner Institute for Brain and Mental Health,
Tehran, Iran Monash University, Melbourne, VIC, Australia
Carl A. Roberts, Institute of Psychology, Health and Fausto Viader, Normandie Univ, UNICAEN, PSL Uni-
Society, University of Liverpool, Liverpool, United versité de Paris, EPHE, INSERM, U1077, CHU de
Kingdom Caen, GIP Cyceron, Neuropsychologie et Imagerie de la
Adam J. Rubenis, Turning Point Alcohol and Drug Mémoire Humaine, Caen, France
Centre, Melbourne, VIC, Australia Robert Whelan, School of Psychology, Trinity College
Anthony C. Ruocco, University of Toronto, Toronto, ON, Dublin, Dublin, Ireland
Canada Reinout W. Wiers, Addiction Development and Psychopa-
H.B. Schiöth, Department of Neuroscience, Uppsala thology (ADAPT) Laboratory, Department of Psychology,
University, Uppsala, Sweden University of Amsterdam, Amsterdam, The Netherlands
Ryan Smith, Laureate Institute for Brain Research, Tulsa, Oulmann Zerhouni, UFR Sciences Psychologiques et
OK, United States Sciences de l’Éducation (SPSE), Université Paris Nan-
Mehmet Sofuoglu, Yale School of Medicine, Department terre, Nanterre, France
of Psychiatry, New Haven, CT, United States; VA Anna Zilverstand, Department of Psychiatry, University
Connecticut Healthcare System, West Haven, CT, of Minnesota, Minneapolis, MN, United States
United States
Biographies
Antonio Verdejo-García has a PhD in Psychology research center, and the University of Granada, and he
(Addiction Neuropsychology, University of Granada, is the Chair of the Neuroscience Interest Group of the
2006) and a Masters in Psychological and Biomedical International Society of Addiction Medicine.
Aspects of Health and Illness (University of Granada, Professor Verdejo-García has led numerous studies on
2002). After his PhD, he continued specialized training the cognitive and neural substrates of substance and
in addiction neuroscience in highly prestigious research behavioral addictions, and new cognitive training and
centers: Johns Hopkins Medical Institute (Neurology), remediation interventions for treating substance use dis-
IMIM-Hospital del Mar (Pharmacology) and the University orders. He is internationally recognized as an expert in this
of Cambridge (Behavioural and Clinical Neuroscience field, as evinced by several international Editorial Board
Institute). positions including top-ranked addiction journals. He has
Currently, Antonio Verdejo-García is an Australian published more than 200 peer-reviewed articles, and his
Medical Research Future Fund Fellow and holds a Full work has attracted over 10,000 citations and has been
ProfessoreResearch appointment at the Turner Institute for translated into clinical trials of neurocognitive interventions
Brain and Mental Health (Monash University), where he is and policy recommendations regarding application of
the Deputy Lead of the Addiction and Mental Health neuroscience principles for the prevention and treatment of
Program. He also holds honorary appointments at Turning addictions.
Point, Australia’s leading national addiction treatment and
xix
Foreword
Since the seminal paper of Dr. Leshnerdthen the director variations of this model with new perspectives for treatment.
of the National Institute on Drug Abusedin Science In the Chapters 14e16, similar reviews are presented for
in 1997, addiction is generally regarded to be a bio- gambling and gaming disorders.
psychosocial disorder with strong genetic and neuro- In addition to their role as risk factors in the develop-
biological underpinnings and a chronic-intermittent course ment of addiction, cognitive impairments are often a
with periods of recovery followed by relapse and often with consequence of chronic, excessive drug use with negative
serious psychosocial deterioration. Based on animal studies effects on the course of the disorder and on treatment
and human genetic and neuroimaging studies, Dr. Leshner effectiveness. In the Chapters 8e13, reviews on the
concluded that addiction is a brain disease and that addicted consequences of drug use are presented for the different
people are patients who deserve (reimbursed) treatment. substances of abuse, including alcohol, tobacco, cannabis,
According to the underlying biopsychosocial model, cocaine, MDMA, and opioids. These chapters invariably
addiction is the outcome of a preexisting hyperactive brain show not only that drug use may lead to cognitive
reward system in combination with a deficient cognitive impairments but also that (sustained) abstinence will lead to
control system in combination with neuroplastic changes partial or complete recovery of cognitive functions and
caused by continued drug use. Originally, the model was probably to better long-term outcomes of treatment.
predominantly presented in terms of dysfunctional brain Treatment is the focus of the next part of the book
structures and neurotransmitter abnormalities with rela- (Chapters 17e23). In a series of highly informative reviews,
tively little attention to the cognitive representations of the authors show that there are currently many more treat-
these abnormalities. As a consequence, the link between the ment options than motivational interviewing and cognitive
neurobiological abnormalities and the behavioral mani- behavioral treatment, including cognitive bias modification,
festations of addictions was incomplete, and the search for working memory training, inhibition control training,
new treatments was mainly directed to the discovery of goal management training, mindfulness-based relapse
new medications against relapse. Recent developments in prevention (MBRP), transcranial magnetic stimulation, and
our knowledge about the neurocognitive aspects of the the use of cognition-enhancing medications. With the
development of addictive behaviors, the neurocognitive exception of approach bias modification and MBRP, these
consequences of chronic drug use, and the potential new interventions need to be tested in large-phase III trials,
treatments directed at improvement of preexisting and but most of them show great promise and will redirect
drug-induced neurocognitive deficits have created new treatment from talking to training and from face-to-face
hope for patients with an addiction. interventions to online treatments. In the last two chapters of
This is the first book that provides a comprehensive the book (Chapters 29 and 30), the authors provide an in-
review of what we now know about cognition and addic- tegrated review of both existing and new treatment options
tion. An impressive lineup of experts presents a broad and and a theory-based proposal for optimal combinations of
in-depth overview of what is known about the cognitive cognitive interventions based on a thorough understanding
underpinnings of addiction, neurocognitive approaches to of the underlying cognitive models.
treatment and future research perspectives. Chapters 24e28 are more contemplative in nature and
The book starts with a well-balanced presentation of make the reader think about population neuroscience, the
what we know about preexisting (genetic and learned) use of cognitive information in combination with genetics,
cognitive processes that are responsible for the change from the cognitive effects of reduced consumption versus
recreational drug use to goal-driven, drug seeking and finally complete abstinence, and finally the (limited) impact of
ending in chronic compulsive and habitual addictive scientific knowledge about cognition and addiction on
behaviors leading to physical and/or psychosocial decline policy development.
(Chapters 1e7). In addition to the well-known dual-process This book is a remarkable set of reviews and position
model, the authors present extensions and/or integrated papers presented as chapters edited by one of the best
xxi
xxii Foreword
scientists in the field of cognition and addiction. Thanks to interested in the topic. I therefore highly recommend this
his broad and in-depth knowledge of the field and his book to everybody in the field.
ability to recruit the best experts on such diverse topics; Wim van den Brink, MD PhD
this book is currently by far the best introduction to Em. Professor of Psychiatry and Addiction,
cognition and addiction for neuroscience and psychology Amsterdam University Medical Centers,
students and researchers and for clinical psychologists, Amsterdam, The Netherlands
psychiatrists, neurologists, and for all other people
Acknowledgments
The Editor (Antonio Verdejo-García) is funded by an acknowledge Professor Wim van den Brink, a trailblazer
Australian Medical Research Future Fund, Next Generation addiction researcher and inspirational figure for many (back
Clinical Researchers CDF2 Fellowship (MRFF 1141214) then) young researchers in cognition and addiction and a
and wish to acknowledge this support, trusting that the tireless supporter of early career scientists, for writing the
book will contribute to the fellowship legacy by training a foreword of the book. Last not least, sincere acknowledg-
new generation of addiction researchers. The Editor would ments to the Elsevier editorial team including Joslyn
also like to acknowledge all the contributors for generously Chaiprasert-Paguio, who planted the first seed of this book,
sharing their unique knowledge and limited timedthey and Tracy Tufaga, who has invaluably helped to make it
make up an outstanding cast and are the ones who give true grow.
value to this book. The Editor would also like to specially
xxiii
Introduction
Cognition refers to mental processes and encompasses gambling addictions, and the cognitive sequela asso-
“all forms of knowing and awareness, such as ciated with the chronic use of different substances, such
conceiving, remembering, judging, imagining, and as alcohol, cannabis, stimulants and opioids, and
problem solving” (APA Dictionary of Psychology). gambling modalities. The cognitive profiles associated
Addiction is a mental health condition and, not surp- with different drugs and addictive behaviors are dis-
risingly, is associated with cognitive biases and deficits. cussed in the context of current topics and contro-
The last 20 years have witnessed an unprecedented versies, such as the therapeutic effects of cannabinoids,
expansion in the understanding of the cognitive the aftermath of the synthetic opioid crisis, or the
underpinnings of addiction vulnerability and chronicity. advent of online gambling and gaming activities
This growth has been fueled by theoretical and techno- (Curran et al., 2016; Karilla et al., 2018; Kardefelt-
logical advancement. Neurobehavioral models of addi- Winther et al., 2017). Section (3) introduces novel
ction have shed light on the cognitive mechanisms of neuroscience-informed treatment approaches to
aberrant reward valuation, cognitive control, and rescue cognitive deficits and improve clinical out-
decision-making (Bickel et al., 2018; Everitt and Robbins, comes for people with addictions. These approaches
2016; Goldstein and Volkow, 2002; Verdejo-Garcia and include computerized cognitive training programs to
Bechara, 2009), overcoming old views about addictive retrain salience-related biases and build response
behavior been “self-destructive” or “morally weak” inhibition and working memory capacity, cognitive
(discussed in Hyman, 2007, Am J Bioeth). The advent of remediation therapies focused on executive functions,
automated computerized testing, neuroimaging, mindfulness interventions targeting cognitive control
and other biomedical techniques such as gene and monitoring, and pharmacological enhancement
sequencing and manipulation, and novel intervention and brain-stimulation techniques. Finally, Section (4)
approaches such as cognitive training and remediation, provides unique new vistas on research approaches
neuroscience-informed psychotherapies and neuro- that are pushing the boundaries of the cognition and
modulation have fueled the knowledge gain and addiction field. These exciting new avenues include
revamped the landscape of cognition and addiction population neuroscience, namely, the application of
research (Ekhtiari et al., 2019; Kwako et al., 2016; cutting-edge neuroscience tools to population-based
Mackey et al., 2016). This book attempts to provide a cohorts, neuroepidemiology, i.e., the leverage of
comprehensive view of this renewed landscape. epidemiology data to address neurocognitive ques-
The book is structured in four main sections: (1) tions, neuroethics, and longitudinal brain mapping. In
Cognitive Principles, (2) Cognitive Risk Factors and addition, it provides a pedagogic approach to the use
Consequences, (3) Cognitive Interventions, and (4) of new techniques for “big data” collection and
New Vistas. Section (1) covers updated neurocognitive analysis, and the application of genetic and neuro-
theories of addiction and its evidence base. These imaging techniques to understand the lifespan of
include views on addiction as a disorder that involves addiction pathophysiology, from preterm vulnerability
an aberrant transition from impulsivity to compulsivity, to adult abstinence-based neuroplasticity and recovery.
impaired response inhibition and salience attribution,
The book has been conceived with an inclusive and
decision-making dysfunctions, social cognition and
international perspective and includes contributors
interaction deficits, and personality comorbidities
from Europe, Africa, America, Australia, and the
underpinned by common alterations in executive
Middle East, which provide a truly global viewpoint.
functions. Section (2) reviews the cognitive alterations
The contributors are outstanding researchers and
that underlie vulnerability to substance use and
xxv
xxvi Introduction
clinicians, and the contents are geared towards a broad Biobehav. Rev. 104, 118e140. https://doi.org/10.1016/j.neubiorev.
audience including research students, researchers 2019.06.007. Epub 2019 Jul 2. Review. PubMed PMID: 31271802.
and academics, and frontline clinicians interested Everitt, B.J., Robbins, T.W., 2016. Drug addiction: updating actions to
habits to compulsions ten years on. Annu Rev Psychol 67, 23e50.
in learning and applying cognitive principles and
https://doi.org/10.1146/annurev-psych-122414-033457.
techniques in addiction research, prevention, assess-
Goldstein, R.Z., Volkow, N.D., 2002. Drug addiction and its underlying
ment, treatment, and recovery. We hope to succeed in neurobiological basis: neuroimaging evidence for the involvement of
our main goal, that readers share our enthusiasm about the frontal cortex. Am. J. Psychiatry 159 (10), 1642e1652.
this fascinating field. Hyman, S.E., 2007. The neurobiology of addiction: implications for
voluntary control of behavior. Am. J. Bioeth. 7 (1), 8e11.
Kardefelt-Winther, D., Heeren, A., Schimmenti, A., van Rooij, A.,
References Maurage, P., Carras, M., Edman, J., Blaszczynski, A., Khazaal, Y.,
Billieux, J., 2017. How can we conceptualize behavioural addiction
Bickel, W.K., Mellis, A.M., Snider, S.E., Athamneh, L.N., Stein, J.S.,
without pathologizing common behaviours? Addiction 112 (10),
Pope, D.A., 2018. 21st century neurobehavioral theories of decision
1709e1715. https://doi.org/10.1111/add.13763.
making in addiction: Review and evaluation. Pharmacol. Biochem.
Karila, L., Marillier, M., Chaumette, B., Billieux, J., Franchitto, N.,
Behav. 164, 4e21. https://doi.org/10.1016/j.pbb.2017.09.009.
Benyamina, A., 2018. New synthetic opioids: Part of a new addiction
Curran, H.V., Freeman, T.P., Mokrysz, C., Lewis, D.A., Morgan, C.J.,
landscape. Neurosci. Biobehav. Rev. https://doi.org/10.1016/j.neu-
Parsons, L.H., 2016. Keep off the grass? Cannabis, cognition and addiction.
biorev.2018.06.010 pii: S0149-7634(18)30114-3.
Nat. Rev. Neurosci. 17 (5), 293e306. https://doi.org/10.1038/nrn.2016.28.
Kwako, L.E., Momenan, R., Litten, R.Z., Koob, G.F., Goldman, D., 2016.
Ekhtiari, H., Tavakoli, H., Addolorato, G., Baeken, C., Bonci, A.,
Addictions neuroclinical assessment: a neuroscience-based framework
Campanella, S., Castelo-Branco, L., Challet-Bouju, G., Clark, V.P.,
for addictive disorders. Biol. Psychiatry 80 (3), 179e189. https://
Claus, E., Dannon, P.N., Del Felice, A., den Uyl, T., Diana, M., di
doi.org/10.1016/j.biopsych.2015.10.024.
Giannantonio, M., Fedota, J.R., Fitzgerald, P., Gallimberti, L., Grall-
Mackey, S., Kan, K.J., Chaarani, B., Alia-Klein, N., Batalla, A.,
Bronnec, M., Herremans, S.C., Herrmann, M.J., Jamil, A, Khedr, E.,
Brooks, S., Cousijn, J., Dagher, A., de Ruiter, M., Desrivieres, S.,
Kouimtsidis, C., Kozak, K., Krupitsky, E., Lamm, C., Lechner, W.V.,
Feldstein Ewing, S.W., Goldstein, R.Z., Goudriaan, A.E.,
Madeo, G., Malmir, N., Martinotti, G., McDonald, W.M.,
Heitzeg, M.M., Hutchison, K., Li, C.S., London, E.D., Lorenzetti, V.,
Montemitro, C., Nakamura-Palacios, E.M., Nasehi, M., Noël, X.,
Luijten, M., Martin-Santos, R., Morales, A.M., Paulus, M.P., Paus, T.,
Nosratabadi, M., Paulus, M., Pettorruso, M., Pradhan, B.,
Pearlson, G., Schluter, R., Momenan, R., Schmaal, L., Schumann, G.,
Praharaj, S.K., Rafferty, H., Sahlem, G., Salmeron, B.J., Sauvaget, A.,
Sinha, R., Sjoerds, Z., Stein, D.J., Stein, E.A., Solowij, N., Tapert, S.,
Schluter, R.S., Sergiou, C., Shahbabaie, A., Sheffer, C.,
Uhlmann, A., Veltman, D., van Holst, R., Walter, H., Wright, M.J.,
Spagnolo, P.A., Steele, V.R., Yuan, T.F., van Dongen, J.D.M., Van
Yucel, M., Yurgelun-Todd, D., Hibar, D.P., Jahanshad, N.,
Waes, V., Venkatasubramanian, G., Verdejo-García, A., Verveer, I.,
Thompson, P.M., Glahn, D.C., Garavan, H., Conrod, P., 2016. Genetic
Welsh, J.W., Wesley, M.J., Witkiewitz, K., Yavari, F.,
imaging consortium for addiction medicine: from neuroimaging to
Zarrindast, M.R., Zawertailo, L., Zhang, X., Cha, Y.H., George, T.P.,
genes. Prog. Brain Res. 224, 203e223. https://doi.org/10.1016/
Frohlich, F., Goudriaan, A.E., Fecteau, S., Daughters, S.B.,
bs.pbr.2015.07.026.
Stein, E.A., Fregni, F., Nitsche, M.A., Zangen, A., Bikson, M.,
Verdejo-García, A., Bechara, A., 2009. A somatic marker theory of
Hanlon, C.A., 2019 Sep. Transcranial electrical and magnetic stimu-
addiction. Neuropharmacology 56 (Suppl. 1), 48e62. https://doi.org/
lation (tES and TMS) for addiction medicine: A consensus paper on
10.1016/j.neuropharm.2008.07.035.
the present state of the science and the road ahead. Neurosci.
Chapter 1
Cognition: the interface between nature

and nurture in addiction
School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia
Introduction externalization among people with addiction (e.g., “I have a

disease, I can’t do anything about it”) (Hall et al., 2015b).
A key question in the field of addiction is whether some In this chapter, I will argue that a focus on cognitiond
people are hardwired to develop addictive disorders or if, encompassing thinking, emotion, and related behaviors,
conversely, drugs and “addictive products” or related as well as their neural underpinningsdcan provide a more
contexts generate addictions. Historically, the answers to comprehensive and integrative understanding of the nature
this question have fluctuated as a function of prevailing and the course of addiction. Cognition sits at the interface
theories. Old moral views and personality models saw of biological, psychological, and social drivers of addictive
inherent weaknesses in the individual (Eysenck, 1997; disorders, hinging on the interplay between nature and
Peele, 1987). Learning theories have focused on the ability nurture. Genetic and early environmental influences shape
of drugs and “addictive products” (e.g., electronic gaming the cognitive traits that make us vulnerable or resilient to
machines) to generate aberrant learning, which is then drug use/gambling and related social contexts (e.g., product
resistant to extinction relatively uniformly across availability, peer pressure) (Belcher et al., 2014). At the
individuals (Robinson and Berridge, 2003, 2008). Social same time, drugs and gambling modify learning and
theories have treated addiction as a manifestation of a cognitive control processes and change the way we interact
certain context and environment (e.g., the classic studies on with others and the environment (Everitt and Robbins,
Vietnam War veterans) (Moore, 1993; Zinberg, 1984). 2016; Goldstein and Volkow, 2011; Moeller and Goldstein,
Nowadays, there is agreement that none of these models, in 2014). By focusing on cognition, we can overcome
isolation, can satisfactorily explain the nature and the the reductionism of the “disease model,” i.e., it’s not in
course of addiction, but at the same time, there is a lack of the brain, it’s at the interface between the brain and the
comprehensive frameworks. Contemporary models have environment, and foster self-agency about recovery,
embraced a biopsychosocial approach, but there is a bias i.e., it’s not indelible, the same influences that originally
toward the bio-, at least in discovery science and thera- shaped cognition in a certain way can help restore or
peutic development, especially after the advent of neuro- compensate cognitive mechanisms to facilitate recovery
imaging tools and genetic manipulation techniques within (Garavan and Weierstall, 2012). To articulate this vision,
animal studies (Hall et al., 2015a). The current prevailing I will first discuss the role of cognition in contemporary
view is that addiction is a “brain disorder,” characterized by addiction theories and outline a cognition-centered
drug- or gambling-related neuroadaptations that ultimately integrative approach. Next, I will summarize cognitive
have an impact on psychological functioning (changes in neuroscience evidence showing that individual variations in
thinking, emotions, and behaviors) and social interaction core cognitive processes, particularly reward-related
(Volkow et al., 2011; Volkow et al., 2016). Critics of this processes and higher-order cognitive skills, plus
view argue that it mistakenly reproduces a physical disease disorder-specific impacts on such processes, can explain
model (inadequate for mental disorders or social both addiction vulnerability and disordered states and
constructs), lacks integration of social and environmental chronicity.
drivers, and fosters feelings of hopelessness and
Cognition and Addiction. https://doi.org/10.1016/B978-0-12-815298-0.00001-0 1

2 Cognition and Addiction
Cognition to bridge the gap between Translating the key notions of these models into a
cognitive framework can help to broaden their scope and
neurobiological models and social
impact. Essentially, contemporary neurobiological theories
accounts of addiction characterize the “backend” of addiction-related alterations.
Contemporary theories of addiction generally posit neuro- The “frontline” is the complex harmful behavior and the
biological alterations in three systems: the incentive negative social consequences that policy makers and
salience (or reward) system, the stress system, and the preventionists try to counteract and clinicians have to face
executive control system, which map into the striatum, (i.e., uncontrolled drug/gambling use, distress, deterioration
extended amygdala, and prefrontal cortex circuits, respec- of health and quality of life, lack of social support, personal
tively (Koob and Volkow, 2010). Incentive salience and social burden). In between these two, there is a range of
alterations are responsible for reward sensitization cognitive alterations involving reward valuation and
(increased motivation toward drugs/gambling resulting learning, emotion processing and affect regulation, and
from repeated administrationdi.e., instead of the expected executive control and decision-making affecting personal
habituation) and reward prediction errors (i.e., expecting and social domains (e.g., valuation of individual rewards
more reward than what is actually received). Heightened such as salary and career and social rewards such as
motivation toward drugs/gambling also occurs at the cost of friendships and relationships). And these alterations trace
reduced motivation toward natural reinforcers (Goldstein back to specific traits that interact with environmental and
and Volkow, 2002, 2011). Alterations in the stress system social factors before and during the emergence of addiction
account for persistently elevated negative affect, which can and can potentially cooperate with contextual factors in the
manifest as chronic stress and depression, as well as path to addiction recovery (Celma-Merola et al., 2018).
predominance of negative reinforcement mechanisms in the As addictions take time to develop, we can chronologically
control of behavior. That is, negative affective states map the unfolding of cognitive drivers and their interaction
become the norm, behaviors are mostly energized to try to with environmental and social factors. Cognitive-affective
get rid of unpleasant feelings, and this behavior results in traits, such as reward sensitivity, negative affectivity, and
short-term relief but long-term augmentation of the stress impulsivity/self-control, influence child and adolescent
response. Finally, executive alterations are responsible for learning and academic and social development. The inter-
the tendency to focus on immediate responses and short- action between these traits and environmental/social
term outcomes, neglecting goals and long-term conse- influences (socioeconomic disadvantage, trauma, poor
quences. Different theories emphasize two or more of these parenting, academic failure, peer pressure or social isola-
alterations and related brain systems. For example, “dual tion) predicts the onset of addictive behaviors. Once
models” focus on the imbalance between incentive salience initiated, drug use and gambling contribute to exacerbate
(ventral striatum) and executive control (dorsolateral preexisting traits, for example, they sensitize reward
prefrontal cortex [DLPFC] and anterior cingulate cortex) learning and stress responses and deteriorate cognitive
(McClure and Bickel, 2014). Stress models emphasize the control, fostering impulsive decisions and compulsive
link between negative affect (hypothalamicepituitarye behaviors. These changes contribute to worsen the
adrenal axis, amygdala, hippocampus) and poor control contextual milieu (i.e., loss of productivity, income, social
over stress-related responses (dorsal striatum, DLPFC), capital, and support) and foster a spiral of distress and
which has been ascribed to impulsivity (e.g., negative impoverishment of quality of life. Although this scenario
urgencydthe tendency to act impulsively under negative describes the “typical” developmental course of addictive
affect) or compulsivity (e.g., repetitive behaviors that “fly behaviors across adolescence and young adulthood, it can
under the radar” of top-down executive supervision) also apply to late-onset addiction, in which interpersonal
(Figee et al., 2016; Verdejo-García et al., 2007). Executive and social factors (e.g., trauma, relationship problems,
control and decision-making models highlight the unemployment) interact with cognitive characteristics
misalignment between goal-related systems (ventromedial (e.g., emotion regulation and resilience against negative
prefrontal cortex) and motivational, emotional, and affect, self-control, cognitive flexibility) as well as drug-
contextual drivers (striatum, insula, amygdala/hippocam- and gambling-related effects to generate protection against,
pus) (Bechara, 2005; Redish et al., 2008; Verdejo-García or escalation toward, addiction problems. Therefore,
and Bechara, 2009). Although the significance of these cognitive traits predict the onset of addictive behaviors via
models dwells in the way they characterize the drivers of direct and indirect pathways (e.g., interaction with
addictive behaviors, while acknowledging that these drivers academic and social factors and stressful life events). At the
are shaped by and operate in social contexts, they often same time, drug use and gambling deteriorate or exacerbate
come across as reductionist biological accounts of cognitive traits and their underlying neural processes,
behavior. giving rise to abnormal cognitive states or cognitive
Cognition: the interface between nature and nurture in addiction Chapter | 1 3
deficits, as well as contextual and social factors adolescence) and overlapping brain underpinnings
(i.e., disordered states), leading to the vicious cycle of involving lateral prefrontal cortex and anterior cingulate
addiction. regions (Vijayakumar et al., 2014a,b). Moreover, consci-
entiousness and cognitive control are strongly correlated
with intelligence quotient (IQ) and particularly fluid intel-
Evidence for the double role of ligence, probably reflecting meaningful interactions
cognition in addiction vulnerability and between trait characteristics and cognitive skills, as well as
consequences between these two and some of the social-contextual
determinants of IQ (e.g., social disadvantage correlates
The view that cognition may be the key to unlock the with low conscientiousness, poorer cognitive control and
nature and the course of addiction stands on evidence from low IQ) (Yücel et al., 2012). It could be argued that more
longitudinal studies, endophenotype-based approaches, and “affective” traits such as reward sensitivity or negative
“neurotoxicity-controlled designs” comparing people with emotionality do not fit in this pattern, but there are good
addiction versus nonaddicted recreational users and people reasons to think they do. For example, the trait of reward
with substance versus behavioral addictions. Longitudinal sensitivity overlaps with the ability to learn from reward
designs enable researchers to identify cognitive traits as feedback, which is critical for cognitive and social devel-
well as other factors that predate the onset of addictive opment as well as academic achievement (Telzer, 2016).
behaviors and to track the changes that result from drug/ In this context, longitudinal evidence has established
gambling use once initiated. It is worth noting that animal that lower general cognitive skills, lower conscientiousness
studies can also successfully address this transition (from (or higher disinhibition/impulsivity), and higher negative
trait characteristics to disorder-related states) but this affectivity predate and predict the onset of substance use/
approach will be covered in Chapter 2, and thus here I will gambling and the development of addictive disorders.
only focus on human research. Endophenotype studies rely In population-based cohorts within the general population,
on the assumption that cognition is an intermediate feature lower cognitive ability (IQ) measured in late adolescence
between the biological drivers and the complex behavioral predicts the risk of subsequent substance addiction during
manifestations of addictive disorders (Verdejo-García et al., adult life (Latvala et al., 2016). Although the association
2008). As such, the cognitive traits that predispose certain seems primarily due to genetic influences, these influences
people to addiction can be identified in their first-degree are indirectly inferred from behavioral genetic analyses,
relatives, and the cognitive differences between people which can slightly overestimate genetic versus environ-
with addiction and their unaffected relatives reflect drug mental effects (Joseph, 2002; Kendler et al., 2016). Inter-
use/gambling-related changes. Similarly, studies comparing estingly, the most predictive aspects of IQ in relation to
people with addiction and recreational users, or people with addiction are the inductive and verbal domains (strongly
substance versus behavioral addictions, can contribute to associated with cognitive control) versus the visuospatial
disentangling addiction-related traits and addiction- and technical domains. Within high-risk cohorts, which
resulting deficits. In the following sections, I summarize target individuals at greater risk of developing addiction
relevant evidence from each of these approaches. problems by virtue of family history or personality, studies
have consistently found that high levels of impulsivity/
disinhibition (or low levels of conscientiousness and
Longitudinal studies
cognitive control) measured in childhood predict the onset
A key assumption of the cognitive framework articulated in of addictive behaviors in adolescence and the development
this chapter is that certain cognitive traits and skills predate of addictive disorders (substance use disorders and
and influence onset of addictive behaviors. Before discus- gambling disorder) during young adulthood (Acheson
sing the evidence, it is important to note that although et al., 2011; Lovallo et al., 2013; Slutske et al., 2012; Tarter
“traits” and “skills” have been traditionally approached et al., 2004; Tarter et al., 2003). This association is direct
from different disciplines, i.e., personality versus cognitive and significant after controlling for other environmental and
sciences, respectively, now we know that they are mean- social factors (e.g., background, socioeconomic status,
ingfully intertwined and underpinned by common neural parenting), although it is possible that some of these factors
circuits and processes. As an example, the construct of conflate into impulsivity measures within the high-risk
“conscientiousness,” which has a long tradition in person- samples. Recently, longitudinal studies have focused on
ality science, is very similar to the concept of “cognitive adolescence as a natural model of risk within the general
control” or “disinhibition” within modern cognitive population and have incorporated multisite designs and
neuroscience (Nigg, 2017). In support of this view, these imaging measures as part of multimodal assessment
two constructs have similar developmental trajectories protocols including history (i.e., background characteris-
(peaking between 12 and 16 years during childhood and tics), personality, and cognitive/brain measures. One of
these studies, the IMAGEN consortium, found that a siblings. In the executive tests of working memory and
combination of background characteristics, the personality planning, stimulant users performed poorer than siblings
facets of conscientiousness and anxiety sensitivity, and and controls, and siblings poorer than controls. Conversely,
structural (GM:WM ratio; parenchymal volume) and inhibitory control measured with the Stop-Signal Task
cognitive-evoked functional brain features (right precentral (a motor impulsivity task) differed between the sibling pairs
gyrus activation during reward outcome and inhibition and controls but not between stimulant users and their
failure and bilateral superior frontal gyrus during reward siblings, suggesting that inhibitory control deficits are more
outcome) predict future binge drinking (a proxy of prob- of a vulnerability for and less of a consequence of addic-
lematic alcohol use and addictive behaviors) (Whelan et al., tion. Interestingly as well, there were no significant
2014). Conversely, ventromedial prefrontal cortex activa- differences between the groups on tests of memory or
tion during emotional reactivity and face recognition was a attention, suggesting that only certain cognitive functions,
better predictor of current binge drinking, probably i.e., those related to cognitive control/executive functions,
reflecting alcohol-related neuroadaptations. play a crucial role in the nature and course of addiction.
Altogether, longitudinal results support the dynamic Finally, structural neuroimaging measures revealed a set of
model sketched in the previous sections, whereby cognitive regions displaying overlapping abnormalities in both
traits and difficulties associated with cognitive control/ stimulant users and their siblings, compared with healthy
disinhibition and negative affectivity contribute to addic- controls: the putamen and the amygdala had both signifi-
tion vulnerability and are subsequently exacerbated by cantly larger volumes, while the posterior insula, the left
addictive behaviors. postcentral gyrus, and the superior temporal gyrus had
lower volumes (Ersche et al., 2012a).
Endophenotype studies Altogether, endophenotype studies support the notion
that specific trait characteristics, including heightened
In a series of studies including sibling pairs with the same impulsivity and negative affectivity and related neural
biological parents, one affected and one unaffected with systems, confer vulnerability to addiction and are subse-
stimulant use disorders, Ersche and colleagues identified quently exacerbated by drug use, leading to greater deficits
cognitive and brain features associated with addiction in executive functions and further behavioral dysregulation.
vulnerability (i.e., shared by affected and unaffected
siblings) and changes associated with stimulant use. With
Neurotoxicity-controlled studies
regard to trait impulsivity, indicated by self-reports
reflecting different aspects of impulsiveness and novelty This section summarizes the findings from two approaches:
seeking, stimulant users showed greater impulsivity than (i) comparing dependent versus recreational cocaine users
both sibling and controls, but there were also sizable and (ii) comparing substance users and gamblers. The first
differences between siblings and controls (Ersche et al., approach offers insights into which aspects of cognition
2010). Therefore, this approach shows that impulsivity is a deteriorate as a function of addiction progression (i.e., those
vulnerability factor for addiction, but crucially it is also observable in dependent vs. recreational users and
exacerbated by substance use. Interestingly, the main controls). The second approach offers insights into which
differences between siblings and controls were in the aspects of cognition are more sensitive to substance-
nonplanning aspect of impulsivity (theoretically associated induced neuroadaptations (i.e., those observable in
with the construct of conscientiousness) (Whiteside and substance users vs. gamblers) and which aspects are related
Lynam, 2001), whereas the main difference between to common vulnerability factors (overlapping between
stimulant users and siblings was in the disinhibition aspect substance users and gamblers and different from healthy
of novelty seeking, which reflects behavioral dysregulation, controls).
as manifested, for example, in uncontrolled drug use and/or
gambling. In a subsequent study that included trait Dependent versus recreational users
measures of impulsivity and compulsivity, emotional
sensitivity (negative affectivity and stress) and self- In a series of studies by Quednow and colleagues, people
evaluation (self-efficacy, locus of control, and social with cocaine addiction (meeting Diagnostic and Statistical
comparison), and cognitive measures of executive control Manual of Mental Disorders [DSM] criteria for depen-
and disinhibition, results showed that stimulant users, dence) and those with recreational cocaine use (but not
siblings, and controls differed in most of these measures dependence) underwent trait and neuropsychological
(Ersche et al., 2012b). Both sibling pairs differed from assessments. Both groups used cocaine as their primary
controls on impulsivityecompulsivity, negative affectivity, drug (>40 g per month) and were currently abstinent, but
and self-evaluation, suggesting that stimulant use exacer- critically cocaine exposure was eight times higher in the
bates the traits that are already elevated in nonaffected dependent versus the recreational group, as indicated by
hair toxicology analyses. With regard to trait and cognitive measures of cognitive flexibility (reversal learning perfor-
aspects of impulsivity, findings showed significant differ- mance and related brain activation) (Verdejo-Garcia et al.,
ences between the two cocaine groups and controls in 2015). The perseveration error rate (an index of cognitive
general impulsiveness and novelty seeking. However, only inflexibility) was higher in cocaine users versus gamblers
attentional-impulsive traits differed between dependent and and controls. In addition, cocaine users showed less
recreational usersdthey were higher in the dependent DLPFC activation during reversal shifting (i.e., the “flexi-
group. In addition, there were no differences between the bility” trials) versus gamblers and controls, whereas both
groups on cognitive measures of disinhibition, including cocaine users and gamblers showed reduced ventrolateral
attentional and motor impulsivity tasks (Rapid Visual prefrontal cortex (VLPFC) activation compared with
Processing or Stop-Signal Task) (Vonmoos et al., 2013b). controls and no differences between each other. The
When examining executive functions, findings showed DLPFC is strongly and generally implicated in executive
significant differences between dependent users, recrea- control and seems to be specifically affected by cocaine
tional users, and controls in tests of working memory and use, whereas the VLPFC is more specifically implicated in
recall consistency (an index of strategic retrieval). goal-related cognitive control and seems to be similarly
In addition, sustained attention was affected in recreational associated with cocaine and gambling use.
users and correlated with cumulative cocaine exposure Altogether, these studies suggest that positive urgency
(Vonmoos et al., 2013a). A subsequent study in this cohort and reduced response inhibition represent vulnerability
incorporated measures of decision-making, involving both factors for substance use and behavioral addictive disor-
individual rewards and social rewards. Both dependent and ders, whereas working memory and cognitive flexibility
recreational cocaine users exhibited social decision-making deficits are specific consequences of substance use.
deficits (more self-serving behavior in social economic
exchange games). However, only dependent users showed
deficits in tasks involving individual-based rewards, Cognition at the interface between
including the Iowa Gambling Task and Delay Discounting, nature and nurture
which also correlated with cocaine dose and duration
(Hulka et al., 2014). Here, I started by proposing that cognition sits at the
Altogether, these studies suggest that impulsivity and interface between the vulnerability for and the conse-
related cognitive constructs (sustained attention) represent quences of addiction and that it is pivotal to understand the
vulnerability factors or early signs of exposure to drug use, interplay between individual-based factors (genetics,
whereas working memory and executive-memory retrieval neuroadaptations) and environmental and social drivers.
deficits are specific consequences of substance use. The evidence reviewed suggests that an array of
cognitive traits and skills, which encompasses “personal-
ity” concepts of conscientiousness and negative affectivity
Stimulant users versus gamblers
(as manifested in emotional sensitivity or negative urgency)
These studies compared the trait characteristics and the and “cognitive” constructs associated with fluid intelli-
cognitive performance of people with cocaine addiction gence, attention, (dis)inhibition, and social decision-
versus those with gambling disorder and minimal exposure making, are part of the vulnerability to substance use and
to substance use, which was restricted to alcohol abuse behavioral addictive disorders, whereas traits associated
(as per DSM-IV-TR) and smoking. In an initial study with behavioral dysregulation and cognitive deficits in
examining trait impulsivity and executive functions, working memory, cognitive flexibility, and reward-based
findings showed that the negative urgency trait (acting decision-making are associated with the consequences of
impulsively under negative affect) was higher in cocaine substance and behavioral addictions. Of note, there is an
users versus gamblers and controls and higher in gamblers important overlap and continuity between premorbid traits
than controls. Conversely, positive urgency (acting impul- and “disordered states,” given conceptual similarities and
sively under negative affect) was elevated in cocaine users shared variance between, e.g., fluid intelligence, conscien-
and gamblers versus controls (showing no differences tiousness, and executive functions.
between each other) (Albein-Urios et al., 2012). The anal- The relevance of social cognition processes in the
ysis of executive function tests showed that cocaine users vulnerability to addiction (revealed by endophenotype and
had poorer working memory than both gamblers and neurotoxicity-controlled studies) also illustrates the inter-
controls, whereas response inhibition performance active nature of cognitionedrugs/addictive productse
(measured with an attentional inhibition task, the Stroop environment relationships, as faulty social decision-making
Test) was similar among cocaine users and gamblers and in processes can facilitate deviant social behavior (reduced
both cases poorer than in controls. A subsequent study social integration or heightened sensitivity to peer pressure)
examined the same cohort using the brain and behavioral and drug/gambling use, which can ultimately exacerbate
and broaden social-cognitive deficits, fostering a vicious Garavan, H., Weierstall, K., 2012. The neurobiology of reward and
cycle of social impoverishment. cognitive control systems and their role in incentivizing health
Cognition is central to addiction development and behavior. Prev. Med. 55, S17eS23.
Goldstein, R.Z., Volkow, N.D., 2002. Drug addiction and its underlying
maintenance. Higher-order cognitive traits and processes
neurobiological basis: neuroimaging evidence for the involvement of
such as conscientiousness and cognitive control over salient
the frontal cortex. Am. J. Psychiatry 159 (10), 1642e1652.
stimuli (attention) and emotions (negative affectivity) as Goldstein, R.Z., Volkow, N.D., 2011. Dysfunction of the prefrontal cortex
well as social-cognitive characteristics determine vulnera- in addiction: neuroimaging findings and clinical implications. Nat.
bility for addictive disorders. At the same time, substance Rev. Neurosci. 12 (11), 652.
use and behavioral addictions are associated with cognitive Hall, W., Carter, A., Forlini, C., 2015a. The brain disease model of
deficits in working memory, mental flexibility, and reward- addiction: is it supported by the evidence and has it delivered on its
based decision-making, which are essential for goal promises? Lancet Psychiatry 2 (1), 105e110.
achievement and successful social interactions. These Hall, W., Carter, A., Forlini, C., 2015b. Brain disease model of addiction:
cognitive alterations can then contribute to explaining the misplaced priorities? Lancet Psychiatry 2 (10), 867.
core manifestations of addiction (e.g., the persistence of Hulka, L., Eisenegger, C., Preller, K., Vonmoos, M., Jenni, D.,
Bendrick, K., et al., 2014. Altered social and non-social decision-
behavior despite negative consequences, recurrent cravings,
making in recreational and dependent cocaine users. Psychol. Med.
relapses) and compromise treatment and recovery goals.
44 (5), 1015e1028.
Joseph, J., 2002. Twin studies in psychiatry and psychology: science or
References pseudoscience? Psychiatr. Q. 73 (1), 71e82.
Kendler, K., Ohlsson, H., Edwards, A., Lichtenstein, P., Sundquist, K.,
Acheson, A., Vincent, A.S., Sorocco, K.H., Lovallo, W.R., 2011. Greater Sundquist, J., 2016. A novel sibling-based design to quantify genetic
discounting of delayed rewards in young adults with family histories and shared environmental effects: application to drug abuse, alcohol
of alcohol and drug use disorders: studies from the Oklahoma family use disorder and criminal behavior. Psychol. Med. 46 (8), 1639e1650.
health patterns project. Alcohol Clin. Exp. Res. 35 (9), 1607e1613. Koob, G.F., Volkow, N.D., 2010. Neurocircuitry of addiction. Neuro-
Albein-Urios, N., Martinez-González, J.M., Lozano, Ó., Clark, L., Verdejo- psychopharmacology 35 (1), 217.
García, A., 2012. Comparison of impulsivity and working memory Latvala, A., Kuja-Halkola, R., D’onofrio, B.M., Larsson, H.,
in cocaine addiction and pathological gambling: implications for Lichtenstein, P., 2016. Cognitive ability and risk for substance misuse
cocaine-induced neurotoxicity. Drug Alcohol Depend. 126 (1), 1e6. in men: genetic and environmental correlations in a longitudinal
Bechara, A., 2005. Decision making, impulse control and loss of will- nation-wide family study. Addiction 111 (10), 1814e1822.
power to resist drugs: a neurocognitive perspective. Nat. Neurosci. 8 Lovallo, W.R., Farag, N.H., Sorocco, K.H., Acheson, A., Cohoon, A.J.,
(11), 1458e1463. Vincent, A.S., 2013. Early life adversity contributes to impaired
Belcher, A.M., Volkow, N.D., Moeller, F.G., Ferré, S., 2014. Personality cognition and impulsive behavior: studies from the Oklahoma Family
traits and vulnerability or resilience to substance use disorders. Trends Health Patterns Project. Alcohol Clin. Exp. Res. 37 (4), 616e623.
Cognit. Sci. 18 (4), 211e217. McClure, S.M., Bickel, W.K., 2014. A dual-systems perspective on
Celma-Merola, J., Abella-Pons, F., Mata, F., Pedra-Pagés, G., Verdejo- addiction: contributions from neuroimaging and cognitive training.
Garcia, A., 2018. Self-changing behaviour in smoking cessation Ann. N.Y. Acad. Sci. 1327 (1), 62e78.
linked to trait and cognitive impulsivity. Addiction 113 (1), 107e112. Moeller, S.J., Goldstein, R.Z., 2014. Impaired self-awareness in human
https://doi.org/10.1111/add.13942. addiction: deficient attribution of personal relevance. Trends Cognit.
Ersche, K.D., Jones, P.S., Williams, G.B., Turton, A.J., Robbins, T.W., Sci. 18 (12), 635e641.
Bullmore, E.T., 2012a. Abnormal brain structure implicated in stim- Moore, D., 1993. Beyond Zinberg’s “social setting”: a processural view of
ulant drug addiction. Science 335 (6068), 601e604. illicit drug use. Drug Alcohol Rev. 12 (4), 413e421.
Ersche, K.D., Turton, A.J., Chamberlain, S.R., Müller, U., Bullmore, E.T., Nigg, J.T., 2017. Annual research review: on the relations among self-
Robbins, T.W., 2012b. Cognitive dysfunction and anxious-impulsive regulation, self-control, executive functioning, effortful control,
personality traits are endophenotypes for drug dependence. Am. J. cognitive control, impulsivity, risk-taking, and inhibition for devel-
Psychiatry 169 (9), 926e936. opmental psychopathology. J. Child Psychol. Psychiatry 58 (4),
Ersche, K.D., Turton, A.J., Pradhan, S., Bullmore, E.T., Robbins, T.W., 361e383.
2010. Drug addiction endophenotypes: impulsive versus sensation- Peele, S., 1987. A moral vision of addiction: how people’s values deter-
seeking personality traits. Biol. Psychiatry 68 (8), 770e773. mine whether they become and remain addicts. J. Drug Issues 17 (2),
Everitt, B.J., Robbins, T.W., 2016. Drug addiction: updating actions to 187e215.
habits to compulsions ten years on. Annu. Rev. Psychol. 67, 23e50. Redish, A.D., Jensen, S., Johnson, A., 2008. Addiction as vulnerabilities in
Eysenck, H., 1997. Addiction, personality and motivation. Hum. Psy- the decision process. Behav. Brain Sci. 31 (4), 461e487.
chopharmacol. Clin. Exp. 12 (2), S79. Robinson, T.E., Berridge, K.C., 2003. Addiction. Annu. Rev. Psychol. 54,
Figee, M., Pattij, T., Willuhn, I., Luigjes, J., van den Brink, W., 25e53. https://doi.org/10.1146/annurev.psych.54.101601.145237.
Goudriaan, A., et al., 2016. Compulsivity in obsessiveecompulsive Robinson, T.E., Berridge, K.C., 2008. The incentive sensitization theory of
disorder and addictions. Eur. Neuropsychopharmacol. 26 (5), addiction: some current issues. Phil. Trans. Biol. Sci. 363 (1507),
856e868. 3137e3146.
Slutske, W.S., Moffitt, T.E., Poulton, R., Caspi, A., 2012. Undercontrolled Vijayakumar, N., Whittle, S., Yücel, M., Dennison, M., Simmons, J.,
temperament at age 3 predicts disordered gambling at age 32: a longi- Allen, N.B., 2014b. Prefrontal structural correlates of cognitive con-
tudinal study of a complete birth cohort. Psychol. Sci. 23 (5), 510e516. trol during adolescent development: a 4-year longitudinal study.
Tarter, R.E., Kirisci, L., Habeych, M., Reynolds, M., Vanyukov, M., 2004. J. Cogn. Neurosci. 26 (5), 1118e1130.
Neurobehavior disinhibition in childhood predisposes boys to sub- Volkow, N.D., Baler, R.D., Goldstein, R.Z., 2011. Addiction: pulling at
stance use disorder by young adulthood: direct and mediated etiologic the neural threads of social behaviors. Neuron 69 (4), 599e602.
pathways. Drug Alcohol Depend. 73 (2), 121e132. Volkow, N.D., Koob, G.F., McLellan, A.T., 2016. Neurobiologic ad-
Tarter, R.E., Kirisci, L., Mezzich, A., Cornelius, J.R., Pajer, K., vances from the brain disease model of addiction. N. Engl. J. Med.
Vanyukov, M., et al., 2003. Neurobehavioral disinhibition in child- 374 (4), 363e371.
hood predicts early age at onset of substance use disorder. Am. J. Vonmoos, M., Hulka, L.M., Preller, K.H., Jenni, D., Baumgartner, M.R.,
Psychiatry 160 (6), 1078e1085. Stohler, R., et al., 2013a. Cognitive dysfunctions in recreational and
Telzer, E.H., 2016. Dopaminergic reward sensitivity can promote dependent cocaine users: role of attention-deficit hyperactivity disor-
adolescent health: a new perspective on the mechanism of ventral der, craving and early age at onset. Br. J. Psychiatry bjp. bp.
striatum activation. Dev. Cogn. Neurosci. 17, 57e67. 112.118091.
Verdejo-García, A., Bechara, A., 2009. A somatic marker theory of Vonmoos, M., Hulka, L.M., Preller, K.H., Jenni, D., Schulz, C.,
addiction. Neuropharmacology 56, 48e62. Baumgartner, M.R., Quednow, B.B., 2013b. Differences in self-
Verdejo-García, A., Bechara, A., Recknor, E.C., Pérez-García, M., 2007. reported and behavioral measures of impulsivity in recreational and
Negative emotion-driven impulsivity predicts substance dependence dependent cocaine users. Drug Alcohol Depend. 133 (1), 61e70.
problems. Drug Alcohol Depend. 91 (2), 213e219. https://doi.org/10.1016/j.drugalcdep.2013.05.032.
Verdejo-Garcia, A., Clark, L., Verdejo-Román, J., Albein-Urios, N., Whelan, R., Watts, R., Orr, C.A., Althoff, R.R., Artiges, E.,
Martinez-Gonzalez, J.M., Gutierrez, B., Soriano-Mas, C., 2015. Banaschewski, T., et al., 2014. Neuropsychosocial profiles of current
Neural substrates of cognitive flexibility in cocaine and gambling and future adolescent alcohol misusers. Nature 512 (7513), 185.
addictions. Br. J. Psychiatry 207 (2), 158e164. Whiteside, S.P., Lynam, D.R., 2001. The five factor model and impul-
Verdejo-García, A., Lawrence, A.J., Clark, L., 2008. Impulsivity as a sivity: using a structural model of personality to understand impul-
vulnerability marker for substance-use disorders: review of findings sivity. Pers. Indiv. Differ. 30 (4), 669e689.
from high-risk research, problem gamblers and genetic association Yücel, M., Fornito, A., Youssef, G., Dwyer, D., Whittle, S., Wood, S.J.,
studies. Neurosci. Biobehav. Rev. 32 (4), 777e810. et al., 2012. Inhibitory control in young adolescents: the role of sex,
Vijayakumar, N., Whittle, S., Dennison, M., Yücel, M., Simmons, J., intelligence, and temperament. Neuropsychology 26 (3), 347.
Allen, N.B., 2014a. Development of temperamental effortful control Zinberg, N.E., 1984. Drug, Set, and Setting: The Basis for Controlled
mediates the relationship between maturation of the prefrontal cortex Intoxicant Use. Yale University Press, New Haven, CT.
and psychopathology during adolescence: a 4-year longitudinal study.
Dev. Cogn. Neurosci. 9, 30e43.
Chapter 2
From impulses to compulsions

Kavya Raj1 and Antonio Verdejo-Garcia2
1
Brain, Mind and Society Research Hub, Monash University, Melbourne, VIC, Australia; 2School of Psychological Sciences and Turner Institute for
Brain and Mental Health, Monash University, Melbourne, VIC, Australia
Introduction outcomes of such behaviors are negative (Zapata et al.,

2010). Environmental stimuli associated with the effects of
Addiction can be conceptualized as a loss of control over drug self-administration gain incentive salience via
drug-seeking and -taking behavior, whereby drug use that Pavlovian conditioning, and drug-seeking responses are
was initially voluntary and recreational progresses to a automatically elicited by conditioned S-R loops (Everitt
habit, and ultimately a compulsion, continuing to persist and Robbins, 2005). Drug-seeking and -taking behavior
despite harmful consequences (Belin et al., 2013; Everitt controlled by this S-R process is severed from the value of
and Robbins, 2005, 2013, 2016). It is hypothesized that this the drug and can operate without full engagement of
behavioral transition from impulsive choices to compulsive cognitive control processes (Belin et al., 2013). Whether
drug seeking and taking is underpinned by a shift in the drug use is controlled by A-O or S-R mechanisms, at a
neural loci of control from the ventral to the dorsal striatum behavioral level, can be tested through outcome devalua-
(Belin and Everitt, 2008; Everitt and Robbins, 2013, 2016), tion procedures to observe whether instrumental respond-
as well as a progression from prefrontal cortical to ing for drug rewards changes as the outcome value changes
subcortical striatal control (Chen et al., 2013; Everitt and (Dickinson et al., 2002).
Robbins, 2016; Murray et al., 2012; Renteria et al., 2018). The shift from A-O to S-R mechanisms mediating drug
This chapter summarizes the animal and human evidence use is documented by a consistent body of animal research.
that sustains this notion, starting with preclinical studies, In a sophisticated series of experiments, Olmstead et al.
continuing with human neuroimaging and cognitive (2001) utilized a heterogenous chained schedule of intra-
studies, and concluding with ideas for future directions. venous cocaine self-administration in which rats performed
an initial drug-seeking response, which in turn provided
Animal models of drug-seeking habits access to a secondary drug-taking response that resulted in
delivery of cocaine. After briefly establishing cocaine self-
and compulsions administration, drug-seeking responses were shown to be
A key approach to understanding the transition from sensitive to devaluation when the taking link of the chained
voluntary to compulsive drug use is through the lens of schedule was extinguished, indicating that at an initial stage
Pavlovian and instrumental learning (Robbins and Everitt; of cocaine seeking, behavior is goal-directed and influenced
Everitt and Robbins, 2013). According to this perspective, by the value of the response outcome. To replicate and
initial drug use is goal-directed and controlled by action- extend this finding, Zapata et al. (2001) utilized a modified
outcome (A-O) mechanisms. In this context, drug-related chained schedule of intravenous cocaine self-administration
actions are sensitive to changes in outcome value, and and demonstrated that, following a moderate number of
thus drug seeking can stop if drug value decreases or is training sessions, initial cocaine seeking is goal directed
outweighed by alternative reinforcers (Everitt and Robbins, and sensitive to devaluation. However, as sessions
2005). However, as drug use escalates, a parallel instru- increased and the cocaine-seeking experience was
mental learning mechanism comes to dominate responding, extended, 43% of the sample continued to respond after the
and behavior shifts to a stimuluseresponse (S-R) habit outcome had been devalued, indicating that drug-seeking
process that is insensitive to outcome devaluation, i.e., behavior had become habitual for this subgroup and was
precludes stopping or changing behavior, even when the operating through an S-R mechanism. Similarly, while

instrumental responding for alcohol at early stages of (Letchworth et al., 2001; Porrino et al., 2004). In rats with
training is goal-directed, after 8 week of training, behav- well-established habitual cocaine-seeking behavior,
ioral control over alcohol seeking shifts to S-R habit presentation of drug-related cues during cocaine seeking
mechanisms and is no longer sensitive to devaluation results in marked increases of extracellular dopamine in the
(Corbit et al., 2012). These findings illustrate how escala- dorsal striatum but not in the nucleus accumbens core or
tion of drug use results in resistance of drug seeking to shell (Ito et al., 2002). Moreover, dopamine receptor
outcome devaluation, and thus habitual S-R behaviors. antagonist infusion into this region of the dorsal striatum in
While habitual drug-seeking and -taking behavior alone which elevated extracellular dopamine is detected signifi-
cannot provide a comprehensive explanation for addiction, cantly reduces S-R driven, cocaine-seeking behavior
it provides the foundation for compulsive drug use (Everitt (Belin and Everitt, 2008; Vanderschuren et al., 2005). The
and Robbins, 2016). Perseveration of habitual drug-seeking same infusion in the nucleus accumbens, however,
behavior despite drastically negative outcomes, such as produces no effect on habitual cocaine seeking (Vander-
deterioration of health and family bonds or loss of social schuren et al., 2005), indicating that once behavior has
support and employment, is a core aspect of addiction become S-R dominant, ventral striatal regions that are
(Ersche et al., 2011). Aversive conditioning studies in rats entwined with A-O mechanisms lose influence over actions
show that, after sufficient training and exposure, respond- that have become compulsive.
ing for oral cocaine (Miles et al., 2003) and alcohol In addition to the ventral striatum progressively losing
(Dickinson et al., 2002) perseveres even after devaluation control over drug-seeking behavior, the transition from
through nausea-inducing lithium chloride injections voluntary to compulsive drug use is further underpinned by
(Nachman, 1963). Recent evidence suggests that as few as a transition within competing regions of the dorsal striatum:
16 training sessions are sufficient to render alcohol-seeking from the posterior dorsomedial striatum (pDMS, early
behavior unresponsive to devaluation through aversive acquisition) to the anterior dorsolateral striatum (aDLS,
conditioning (López et al., 2016). Drug reinforcers are habitual drug seeking) (Balleine et al., 2009; Murray et al.,
significantly more resistant to aversive conditioning than 2012; Yin et al., 2004). Electrophysiological evidence from
natural foodebased reinforcers, for which responding is rodents performing motivational tasks shows that early
more readily reverted to an A-O process, perhaps due to acquisition correlates with DMS activity, but as training
evolutionary reasons (Dickinson et al., 2002; Miles et al., extends and behavior becomes S-R dominant, DLS activity
2003). This indicates that drug reinforcers induce an S-R increases (Thorn et al., 2010). At early stages of cocaine
habit process far more rapidly than natural rewards. self-administration, pharmacologically disabling the pDMS
Moreover, drug-induced difficulty to shift between S-R and by infusing that region with a D2 agonist infusion reduces
A-O processes suggests that a dominant habit system may initial cocaine seeking (Murray et al., 2012). At the same
become “compulsive” and trigger automatic drug-seeking time point, deactivating the aDLS with the same D2 agonist
behaviors under aversive conditions. infusion has no effect on cocaine seeking, indicating that
early A-Oedriven, drug seeking is dependent on the DMS
Neural circuits: transitioning from the and not the DLS. However, once self-administration is
well-established and S-R driven, cocaine-seeking behavior
ventral to dorsal striatum can only be reduced by disabling the aDLS, whereas
Converging evidence from animal research shows that the disabling the pDMS had no effect on behavior (Murray
transition from voluntary to habitual and eventually et al., 2012). A similar study utilizing microinjections of
compulsive use is neurally underpinned by a progression lidocaine to deactivate striatal regions has shown that
from the ventral to the dorsal striatum, via dopaminergic disabling the DLS in cocaine-seeking rats can successfully
circuits (Belin and Everitt, 2008; Everitt and Robbins, renew A-O control over compulsive cocaine-seeking
2005; Vanderschuren et al., 2005; Vanderschuren and behavior (Zapata et al., 2010), signifying that, within the
Everitt, 2005). This transition has been neatly revealed in dorsal striatum, the DMS relinquishes control to the DLS as
animal models of stimulant addiction. Early acquisition of drug use becomes S-R driven. Similar findings are reported
cocaine seeking depends on the nucleus accumbens core, a for alcohol seeking (Corbit et al., 2012). Deactivating the
region of the ventral striatum; lesions to this area disrupt DMS at early stages of alcohol exposure shifts control to
establishment of drug-seeking behavior (Ito et al., 2004). the habit system, preventing behavior from being sensitive
Yet, as cocaine exposure escalates and becomes chronic, to devaluation. However, after prolonged alcohol exposure,
drug-related neuroadaptationsdsuch as changes in meta- deactivation of the DLS (yet not DMS) is needed to reen-
bolic activity and density of dopamine transporter binding gage the goal-directed system. Moreover, this rich body of
sitesdincreasingly extend from the ventral striatum to research suggests that control over actions occurs through
encompass dorsal striatal regions, the caudate and putamen competing goal-directed (DMS) and habit (DLS) systems,
From impulses to compulsions Chapter | 2 11
and that while typically the DMS and DLS are simulta- cocaine despite electric foot shocks, extended cocaine
neously able to control the same behavior (Renteria et al., self-administration induced substantial hypoactivity in the
2018; Yin et al., 2006), this competition may be repeatedly prelimbic cortex. Furthermore, in vivo optogenetic stimu-
dominated by the DLS in substance use disorders, lation of the prelimbic cortex significantly diminished
ultimately resulting in compulsive drug use. cocaine-seeking responses. In contrast, in vivo optogenetic
It is important to note that while control of behavior inhibition of the prelimbic cortex during cocaine
may devolve to the DLS, ventral regions of the striatum self-administration significantly increased cocaine-seeking
may continue to influence and interact with the dorsal responses. More recent work by Limpens et al. (2014)
striatum. Belin and Everitt (2008) showed that combining a provides comparable findings and directly implicates the
unilateral lesion of the nucleus accumbens core with prelimbic cortex in loss of executive control. Inactivation of
contralateral dorsolateral striatum dopamine receptor the prelimbic cortex significantly reduces a previously
blockade reduces habitual cocaine intake, yet leaving newly conditioned suppression of cocaine seeking in rats, thereby
learned instrumental-seeking responses unaffected (Belin enabling the expression of compulsive drug-seeking
and Everitt, 2008; Everitt and Robbins, 2016). Therefore, behavior. Hypofunction of the prelimbic cortex has also
notwithstanding the progressive transition from ventral to been reported in opiate reward learning, wherein down-
dorsal striatal regions, ongoing interactions between the regulation of prefrontal-excitatory N-methyl D-aspartate
nucleus accumbens core and DLS will have a critical role in receptors substantially increases sensitivity to the
the formation and persistence of compulsive drug-seeking rewarding effects of opiate administration (Bishop et al.,
behavior. 2010). Together, these results not only indicate that
extended drug use induces marked neuroplastic changes in
Devolving from prefrontal to striatal prefrontal excitability but also that these changes are
critically involved in the expression of compulsive drug-
control seeking behavior. Moreover, when considered alongside
Along with the progressive strengthening of DLS-driven previous animal research (Belin and Everitt, 2008; Zapata
S-R habit processes, compulsive drug use is concurrently et al., 2010), these findings support the hypothesis that
mediated by weakened prefrontal control over striatal compulsive drug-seeking behavior may be driven by
regions (Koob and Volkow, 2010; Renteria et al., 2018). a combination of DLS hyperactivation and prelimbic/
Habitual behavior that occurs in the face of aversive con- frontal hypoactivation, whereby weakened prefrontal
ditions would typically promote the transition back to A-O activity enables the striatum and habit system to maintain
processes and encourage ventral striatal regions to regain control.
control of behavior (Everitt and Robbins, 2016; Murray In addition to the prelimbic cortex, hypoactivation of
et al., 2012); however, in substance use disorders, drug- the orbitofrontal cortex (OFC) (key region for decision-
seeking behavior perseveres despite harmful outcomes making in humans) has also been implicated in compul-
(Ersche et al., 2011). Dorsomedial and ventral striatal sive drug-seeking behavior (Renteria et al., 2018). Habitual
regions that are integral to the functioning of the ethanol use in mice induces marked reductions in OFC
goal-directed system receive prefrontal cortical projections, excitability (Renteria et al., 2018). The OFC directly
and prefrontal cortex (PFC) hypofunction has been reported projects onto the DMS and is critically involved in excit-
across substance use disorders (Goldstein and Volkow, atory circuits of the goal-directed system (Renteria et al.,
2011). Thus, a contributing factor to the development and 2018). Ethanol-induced suppression of OFC excitability
maintenance of compulsive drug seeking may be hypo- reduces glutamatergic transmission from the OFC to the
function of prefrontal regions and weakened cortical DMS via the direct output pathway and thus disrupts
projections to the striatum, which enables the DLS habit goal-directed control over ethanol-seeking behavior
system to remain dominant in controlling behavior (Renteria et al., 2018). Importantly, stimulating the OFC to
(Limpens et al., 2014). increase excitatory activity in the OFC-striatal circuit
Animal studies indicate that hypofunction of the notably reinstates goal-directed control over previous S-R
prelimbic cortexdwhich is homologous to the dorsolateral ethanol-seeking behavior (Renteria et al., 2018). Yet
prefrontal cortex (DLPFC) in humans (Bizon et al., 2012; again, these findings indicate that habit-driven drug seeking
Koob and Volkow, 2016)dmay be tightly linked to may stem from drug-induced OFC hypoactivation and
compulsive drug seeking (Chen et al., 2013; Bishop et al., subsequent disruption of communication to striatal regions
2010; Limpens et al., 2014). In fact, lesions to the prelimbic critical for goal-directed control. Collectively, animal
area enable the formation of inflexible S-R habits (Killcross research across models of various substance use disorders
and Coutureau, 2003). A seminal study by Chen et al. indicates that compulsive drug-seeking behavior may arise
(2013) demonstrated that, in rats that compulsively seek from a complex interaction between an intrastriatal shift
toward dorsolateral control and PFC hypoactivation, which which may suggest that greater dorsal striatal volume
together enable rigid S-R habit processes to continue con- increases risk for drug-related S-R conditioning and
trolling and perpetuating drug-seeking behavior under substance use disorders (Everitt and Robbins, 2016).
harmful or aversive conditions. Together, these findings suggest that dorsal striatal regions
(the putamen and caudate) are crucial to S-R driven
habitual craving responses in cocaine users, and that
Translating animal models to dopamine dysfunction within these regions may play a
understand compulsivity in people with fundamental role in the severity of drug use.
Similar findings have been reported in alcohol-
substance use disorders dependent individuals (Sjoerds et al., 2013, 2014;
Advancing from animal research, human studies also Vollstädt-Klein et al., 2010). Alcohol-related cues provoke
indicate that compulsive drug use may be underpinned by greater cue-induced activation in the left dorsal striatum in
an over reliance on S-R mechanisms as well as prefrontal- heavy drinkers (Schulte et al., 2012; Vollstädt-Klein et al.,
striatal adaptations (Ersche et al., 2011; Sjoerds et al., 2013; 2010). In addition, Vollstädt-Klein et al. (2010) found that
Vollstädt-Klein et al., 2010). In this section, we focus on while heavy drinkers show more cue-evoked activation in
cue-reactivity studies, in which drug-related cues are used the dorsal striatum, light drinkers show a stronger response
to provoke a conditioned craving response analogous to in the ventral striatum. Moreover, they showed a significant
habitual S-R behaviors (Koob and Volkow, 2010; Pickens positive relationship between activation of the dorsal
et al., 2011; Sinha and Li, 2007; Tricomi et al., 2009; Yoder striatum and scores on an obsessive-compulsive scale
et al., 2009). Craving (a compelling desire to use the drug) (a proxy of compulsivity), whereas ventral striatal activa-
is a paramount clinical phenomenon and a proxy of tion had a negative relationship with the same scale. This
compulsive drug use in clinical studies (Skinner and Aubin, study provides persuasive support for the notion of a
2010; Tiffany et al., 2012). The cue-reactivity procedure ventral to dorsal striatal control shift as alcohol use
enables researchers to observe behavioral and neural becomes more severe and compulsive (Vollstädt-Klein
responses to drug-related cues, providing an indirect et al., 2010). More recent work by Sjoerds et al. (2013,
measure of the severity of compulsive and automatic 2014) has shown that, during an instrumental learning task
responding in drug users (Carter and Tiffany, 1999; designed to explore potential imbalances between goal-
Tricomi et al., 2009). directed and habit learning processes, alcohol-dependent
A consistent finding that emerges in cue-reactivity individuals demonstrate a significant overreliance on S-R
studies across various substance use populations is the habit learning, resulting in poor task performance
importance of the dorsal striatum (caudate and putamen in outcomes. Additionally, poor task performance coincides
humans) in the transition from recreational to compulsive with decreased activation of brain regions implicated in
use (Ersche et al., 2011, 2012a,b; Sjoerds et al., 2013; goal-directed processes and increased activation in habit
Volkow et al., 2006; Wong et al., 2006; Zhou et al., 2018). learning brain regions, namely the posterior putamen
Early functional magnetic resonance imaging (MRI) and (analogous to the DLS in rodents). These results provide
positron emission tomography studies in cocaine users considerable evidence to indicate an overactive and
established that cue-induced craving is associated with inflexible habit system in alcohol-dependent individuals,
increased metabolic activity, dopamine release, and dopa- which appears to heavily depend on dorsal striatal regions
mine receptor occupancy in the dorsal striatum (Garavan (Sjoerds et al., 2013). Furthermore, duration of alcohol
et al., 2000; Volkow et al., 2006; Wong et al., 2006). dependence was strongly associated with greater
Interestingly, the caudate (which is the human homologue cue-induced activation of the posterior putamen (Sjoerds
of the DMS in rodents; Balleine and O’Doherty, 2009) et al., 2014), further supporting the hypothesized ventral to
response to sexually explicit stimuli is blunted in cocaine dorsal striatal shift as behavior advances toward addiction.
users, suggesting that S-R tendencies are sensitized to drug As the putamen is analogous to the DLS in rodents and the
cues and relatively insensitive to natural reinforcers caudate analogous to the DMS, this is a crucial detail for
(Garavan et al., 2000). Furthermore, increases in dopamine the S-R habit hypothesis first proposed by Everitt and
receptor occupancy (Wong et al., 2006) and dopamine Robbins (2005), which would predict greater putamen
release (Volkow et al., 2006) in the dorsal striatum are adaptations as seen in rodent studies (Everitt and Robbins,
proportionate to increases in cue-induced cocaine cravings 2016).
and also corresponded with addiction severity (Volkow Changes in neural activation and adaptations in the
et al., 2006). In addition to functional differences, structural dorsal striatum are also observed in nicotine- (McClernon
MRI studies indicate that, when compared with their et al., 2009) and cannabis-use disorder groups (Zhou et al.,
noncocaine using siblings, cocaine-dependent individuals 2018, 2019). Following a 24-h period of abstinence in adult
have enlarged putamen volumes (Ersche et al., 2011, 2013), tobacco smokers, smoking cues elicited greater activation
in the dorsal striatum, specifically the putamen, relative to hypoactivation may strongly contribute to the perpetuation
neutral cues (McClernon et al., 2009). Participants with of compulsive drug-seeking behavior, wherein multiple
cannabis dependence, compared with drug-naïve controls, prefrontal regions are critically involved in enabling dor-
show an aberrant pattern of functional connectivity sostriatal S-R control of behavior.
involving less efficient communication between both
ventral and dorsal striatum and the PFC (Zhou et al., 2018). Recommendations for future research
More specifically, when comparing dependent versus
nondependent cannabis users exposed to a cue-reactivity Animal experiments and cross-sectional human neuro-
paradigm, dependent users alone demonstrated heightened imaging studies strongly support the role of dorsal striatal
dorsal striatal activation during cue exposure (Zhou et al., control and weakened prefrontal regulation in compulsive
2019). drug use. However, human studies have not yet fully
Cumulatively, the results of human imaging cue- demonstrated the proposed dynamic shift between im-
reactivity studies support the consensus within animal pulses and compulsions or ventral to dorsal striatal control
literature and suggest that dorsostriatal adaptations are that putatively occurs in each individual over time. We
involved in compulsive drug use. In addition to evidence of propose two ways to trace this dynamic shift in the future.
dorsostriatal changes, human studies also implicate hypo- One is through longitudinal studies. Assessing PFC-
activation in multiple prefrontal regions across substance striatal function and related phenotypes (cue-conditioned
use disorders (Goldstein and Volkow, 2011; Zilverstand craving, impulsivity, and compulsivity) among children
et al., 2018; see Chapter 3 in this book), much the same as and adolescents before exposure to drugs and then
animal research. Individuals with alcohol use disorder throughout adolescence and young/mid adulthood would
exhibit decreased engagement of the ventromedial PFC compellingly tell us if neural and cognitive transitions
(encompassing the OFC), which directly projects to the similar to those observed in animals occur over the course
ventral striatum, indicating OFC-striatal dysfunction of human addiction. The advent of new ambitious and
(Sjoerds et al., 2013). Similarly, individuals with alcohol exciting longitudinal research initiatives, such as the
use disorder who relapse into compulsive use show hypo- Adolescent Brain Cognitive Development (ABCD) study
activation of the medial PFC during a goal-directed (https://abcdstudy.org/), has created a unique opportunity
decision-making task (Sebold et al., 2017), again suggest- to pursue this otherwise incredibly complex challenge.
ing disrupted prefrontal control of behavior. Structural The ABCD study will track the neurobiological and
imaging research by Ersche et al. (2013) demonstrates behavioral development of >11,000 children and includes
significant reductions in OFC gray matter volume in detailed measures of cognition, brain function, and drug
compulsive cocaine users, while recreational cocaine users use, providing a unique opportunity to address longitudi-
exhibit increased OFC volume. The increase in gray matter nal research questions. The study also has a remarkable
volume for recreational users may reflect a protective factor open data sharing policy, opening endless possibilities for
or potential resilience against progressing to compulsive early career researchers. Another potential approach is
drug use (Ersche et al., 2013). Lastly, more recent using rapidly evolving epigenetic tools. Discovering
preliminary research aiming to directly translate animal epigenetic markers of ventral and dorsal striatal nuclei
studies on hypoactivation of the prelimbic cortex (which is gene expression and conducting intraindividual analyses
the homolog of the human DLPFC) and optogenetic of changes in these markers over the course of substance
stimulation has utilized repetitive transcranial magnetic use and addiction, paralleled by detailed phenotyping,
stimulant (rTMS) to electrically stimulate the DLPFC in would be another persuasive (although currently futuris-
human cocaine users (Terraneo et al., 2016). rTMS of the tic) approach.
DLPFC significantly improved symptomology in
individuals with cocaine use disorder, as well as substan- References
tially reducing craving for cocaine, signifying that as with Balleine, B.W., O’Doherty, J.P., 2009. Human and rodent homologies in
in vivo optogenetic stimulation of the prelimbic cortex in action control: corticostriatal determinants of goal-directed and
animals reducing cocaine-seeking responses, electrical habitual action. Neuropsychopharmacology 35 (1), 48e69.
stimulation of the human homolog has similar potential to Balleine, B.W., Liljeholm, M., Ostlund, S.B., 2009. The integrative
reduce drug-seeking behaviors (Terraneo et al., 2016). function of the basal ganglia in instrumental conditioning. Behav.
For a more detailed discussion on brain stimulation Brain Res. 199 (1), 43e52. https://doi.org/10.1016/j.bbr.2008.10.034.
findings, see Chapter 22 of this book. Belin, D., Everitt, B.J., 2008. Cocaine seeking habits depend upon
Altogether, findings from structural MRI, functional dopamine-dependent serial connectivity linking the ventral with the
dorsal striatum. Neuron 57 (3), 432e441. https://doi.org/10.1016/j.
imaging using tasks of cue-reactivity (dorsal striatal
neuron.2007.12.019.
hyperactivity) and decision-making (PFC hyporeactivity),
and emerging brain stimulation studies indicate that PFC
Belin, D., Belin-Rauscent, A., Murray, J.E., Everitt, B.J., 2013. Addiction: for drug users and drug stimuli. Am. J. Psychiatry 157 (11),
failure of control over maladaptive incentive habits. Curr. Opin. Neu- 1789e1798. https://doi.org/10.1176/appi.ajp.157.11.1789.
robiol. 23 (4), 564e574. https://doi.org/10.1016/j.conb.2013.01.025. Goldstein, R.Z., Volkow, N.D., 2011. Dysfunction of the prefrontal cortex
Bishop, S.F., Lauzon, N.M., Bechard, M., Gholizadeh, S., Laviolette, S.R., in addiction: neuroimaging findings and clinical implications. Nat.
2010. NMDA receptor hypofunction in the prelimbic cortex increases Rev. Neurosci. 12, 652. https://doi.org/10.1038/nrn3119.
sensitivity to the rewarding properties of opiates via dopaminergic and Ito, R., Dalley, J.W., Robbins, T.W., Everitt, B.J., 2002. Dopamine release
amygdalar substrates. Cerebr. Cortex 21 (1), 68e80. https://doi.org/ in the dorsal striatum during cocaine-seeking behavior under the
10.1093/cercor/bhq060. control of a drug-associated cue. J. Neurosci. 22 (80), 1e7. https://doi.
Bizon, J., C Foster, T., E Alexander, G., Glisky, E., 2012. Characterizing org/10.1523/JNEUROSCI.22-14-06247.2002.
cognitive aging of working memory and executive function in animal Ito, R., Robbins, T.W., Everitt, B.J., 2004. Differential control over
models. Front. Aging Neurosci. 4, 19. https://doi.org/10.3389/fnagi. cocaine-seeking behavior by nucleus accumbens core and shell. Nat.
2012.00019. Neurosci. 7, 389e397. https://doi.org/10.1038/nn1217.
Carter, B.L., Tiffany, S.T., 1999. Meta-analysis of cue-reactivity in Killcross, S., Coutureau, E., 2003. Coordination of actions and habits in
addiction research. Addiction 94 (3), 327e340. https://doi.org/10. the medial prefrontal cortex of rats. Cerebr. Cortex 13 (4), 400e408.
1046/j.1360-0443.1999.9433273.x. https://doi.org/10.1093/cercor/13.4.400.
Chen, B.T., Yau, H.-J., Hatch, C., Kusumoto-Yoshida, I., Cho, S.L., Koob, G.F., Volkow, N.D., 2010. Neurocircuitry of addiction. Neuro-
Hopf, F.W., Bonci, A., 2013. Rescuing cocaine-induced prefrontal psychopharmacology 35, 217. https://doi.org/10.1038/npp.2009.
cortex hypoactivity prevents compulsive cocaine seeking. Nature 496, 110.
359. https://doi.org/10.1038/nature12024. Koob, G.F., Volkow, N.D., 2016. Neurobiology of addiction: A neuro-
Corbit, L.H., Nie, H., Janak, P.H., 2012. Habitual alcohol seeking: time circuitry analysis. The Lancet Psychiatry 3 (8), 760e773. https://doi.
course and the contribution of subregions of the dorsal striatum. Biol. org/10.1016/S2215-0366(16)00104-8.
Psychiatry 72 (5), 389e395. https://doi.org/10.1016/j.biopsych.2012. Letchworth, S.R., Porrino, L.J., Smith, H.R., Friedman, D.P., Nader, M.A.,
02.024. 2001. Progression of changes in dopamine transporter binding site
Dickinson, A., Wood, N., Smith, J.W., 2002. Alcohol seeking by rats: density as a result of cocaine self-administration in Rhesus monkeys.
action or habit? Q. J. Exp. Psychol. (3), 965e985. https://doi.org/10. J. Neurosci. 21 (8), 2799e2807. https://doi.org/10.1523/
1080/027249902440001. JNEUROSCI.21-08-02799.2001.
Ersche, K.D., Roiser, J.P., Abbott, S., Craig, K.J., Mller, U., Suckling, J., Limpens, H.W., Damsteegt, J., Broekhoven, R.H., Voorn, M.,
et al., 2011. Response perseveration in stimulant dependence is Vanderschuren, P.L., 2014. Pharmacological inactivation of the pre-
associated with striatal dysfunction and can be ameliorated by a D2/ limbic cortex emulates compulsive reward seeking in rats. Brain
3receptor agonist. Biol. Psychiatry 70 (8), 754e762. https://doi.org/ Research 1628. https://doi.org/10.1016/j.brainres.2014.10.045.
10.1016/j.biopsych.2011.06.033. López, M., Soto, A., Bura, S., 2016. Alcohol seeking by rats becomes
Ersche, K.D., Jones, P.S., Williams, G.B., Turton, A.J., Robbins, T.W., habitual after prolonged training. Psicothema 28 (4), 421e427. https://
Bullmore, E.T., 2012a. Abnormal brain structure implicated in stim- doi.org/10.7334/psicothema2016.114.
ulant drug addiction. Science 335 (6068), 601e604. https://doi.org/10. McClernon, F.J., Kozink, R.V., Lutz, A.M., Rose, J.E., 2009. 24-h
1126/science.1229223. smoking abstinence potentiates fMRI-BOLD activation to smoking
Ersche, K.D., Turton, A.J., Chamberlain, S.R., Müller, U., Bullmore, E.T., cues in cerebral cortex and dorsal striatum. Psychopharmacology 204
Robbins, T.W., 2012b. Cognitive dysfunction and anxious-impulsive (1), 25e35. https://doi.org/10.1007/s00213-008-1436-9.
personality traits are endophenotypes for drug dependence. Am. j. Miles, F.J., Everitt, B.J., Dickinson, A., 2003. Oral cocaine seeking by
psychiatry 169 (9), 926e936. https://doi.org/10.1176/ rats: action or habit? Behav. Neurosci. 117 (5), 927e938. https://doi.
appi.ajp.2012.11091421. org/10.1037/0735-7044.117.5.927.
Ersche, K.D., Jones, P.S., Williams, G.B., Smith, D.G., Bullmore, E.T., Murray, J.E., Belin, D., Everitt, B.J., 2012. Double dissociation of the
Robbins, T.W., 2013. Distinctive personality traits and neural corre- dorsomedial and dorsolateral striatal control over the acquisition and
lates associated with stimulant drug use versus familial risk of stim- performance of cocaine seeking. Neuropsychopharmacology 37 (11),
ulant dependence. Biol. Psychiatry 74 (2), 137e144. https://doi.org/ 2456e2466. https://doi.org/10.1038/npp.2012.104.
10.1016/j.biopsych.2012.11.016. Nachman, M., 1963. Learned aversion to the taste of lithium chloride and
Everitt, B.J., Robbins, T.W., 2005. Neural systems of reinforcement for generalization to other salts. J. Comp. Physiol. Psychol. 56 (2),
drug addiction: from actions to habits to compulsion. Nat. Neurosci. 8 343e349.
(11), 1481e1489. https://doi.org/10.1038/nn1579. Olmstead, M.C., Lafond, M.V., Everitt, B.J., Dickinson, A., 2001. Cocaine
Everitt, B.J., Robbins, T.W., 2013. From the ventral to the dorsal striatum: seeking by rats is a goal-directed action. Behav. Neurosci. 115 (2),
devolving views of their roles in drug addiction. Neurosci. Biobehav. 394e402.
Rev. 37 (9), 1946e1954. https://doi.org/10.1016/j.neubiorev.2013.02. Pickens, C.L., Airavaara, M., Theberge, F., Fanous, S., Hope, B.T.,
010. Shaham, Y., 2011. Neurobiology of the incubation of drug craving.
Everitt, B.J., Robbins, T.W., 2016. Drug addiction: updating actions to Trends Neurosci. 34 (8), 411e420. https://doi.org/https://doi.org/10.
habits to compulsions ten years on, vol. 67. Social Science Research 1016/j.tins.2011.06.001.
Network, pp. 23e50. https://doi.org/10.1146/annurev-psych-122414- Porrino, L.J., Daunais, J.B., Smith, H.R., Nader, M.A., 2004. The
033457. expanding effects of cocaine: studies in a nonhuman primate model of
Garavan, H., Pankiewicz, J., Bloom, A., Cho, J.K., Sperry, L., Ross, T.J., cocaine self-administration. Neurosci. Biobehav. Rev. 27 (8),
et al., 2000. Cue-induced cocaine craving: neuroanatomical specificity 813e820. https://doi.org/10.1016/j.neubiorev.2003.11.013.
Renteria, R., Baltz, E.T., Gremel, C.M., 2018. Chronic alcohol exposure Volkow, N.D., Wang, G.-J., Telang, F., Fowler, J.S., Logan, J.,
disrupts top-down control over basal ganglia action selection to pro- Childress, A.-R., et al., 2006. Cocaine cues and dopamine in dorsal
duce habits. Nat. Commun. 9 (1), 1e11. https://doi.org/10.1038/ striatum: mechanism of craving in cocaine addiction. J. Neurosci. 26
s41467-017-02615-9. (24), 6583e6588. https://doi.org/10.1523/JNEUROSCI.1544-06.
Robbins, T.W., Everitt, B.J., 1999. Drug addiction: bad habits add up. 2006.
Nature 398 (6728), 567e570. https://doi.org/10.1038/19208. Vollstädt-Klein, S., Wichert, S., Rabinstein, J., Bühler, M., Klein, O.,
Schulte, T., Oberlin, B.G., Kareken, D.A., Marinkovic, K., Müller- Ende, G., et al., 2010. Initial, habitual and compulsive alcohol use is
Oehring, E.M., Meyerhoff, D.J., Tapert, S., 2012. How acute and characterized by a shift of cue processing from ventral to dorsal
chronic alcohol consumption affects brain networks: insights from striatum. Addiction 105 (10), 1741e1749. https://doi.org/10.1111/j.
multimodal neuroimaging. Alcohol Clin. Exp. Res. 36 (12), 1360-0443.2010.03022.x.
2017e2027. Wong, D.F., Kuwabara, H., Schretlen, D.J., Bonson, K.R., Zhou, Y.,
Sebold, M., Nebe, S., Garbusow, M., Guggenmos, M., Schad, D.J., Nandi, A., et al., 2006. Increased occupancy of dopamine receptors in
Beck, A., et al., 2017. When habits are dangerous: alcohol expec- human striatum during cue-elicited cocaine craving. Neuro-
tancies and habitual decision making predict relapse in alcohol psychopharmacology 31 (12), 2716e2727. https://doi.org/10.1038/sj.
dependence. Biol. Psychiatry 82 (11), 847e856. https://doi.org/https:// npp.1301194.
doi.org/10.1016/j.biopsych.2017.04.019. Yin, H.H., Knowlton, B.J., Balleine, B.W., 2004. Lesions of dorsolateral
Sinha, R., Li, C.S., 2007. Imaging stress- and cue-induced drug and striatum preserve outcome expectancy but disrupt habit formation in
alcohol craving: association with relapse and clinical implications. instrumental learning. Eur. J. Neurosci. 19, 181e189. https://doi.org/
Drug Alcohol Rev. 26 (1), 25e31. https://doi.org/10.1080/ 10.1111/j.1460-9568.2004.03095.x.
09595230601036960. Yin, H.H., Knowlton, B.J., Balleine, B.W., 2006. Inactivation of dorso-
Sjoerds, Z., de Wit, S., van den Brink, W., Robbins, T.W., lateral striatum enhances sensitivity to changes in the actioneoutcome
Beekman, A.T.F., Penninx, B.W.J.H., Veltman, D.J., 2013. Behav- contingency in instrumental conditioning. Behav. Brain Res. 166 (2),
ioral and neuroimaging evidence for overreliance on habit learning in 189e196. https://doi.org/https://doi.org/10.1016/j.bbr.2005.07.012.
alcohol-dependent patients. Transl. Psychiatry 3, e337. https://doi.org/ Yoder, K.K., Morris, E.D., Constantinescu, C.C., Cheng, T.-E.,
10.1038/tp.2013.107. Normandin, M.D., O’Connor, S.J., Kareken, D.A., 2009. When what
Sjoerds, Z., van den Brink, W., Beekman, A.T.F., Penninx, B.W.J.H., you see isn’t what you get: alcohol cues, alcohol administration,
Veltman, D.J., 2014. Cue reactivity is associated with duration and prediction error, and human striatal dopamine. Alcohol Clin. Exp.
severity of alcohol dependence: an fMRI study. PLoS One 9 (1), 1e9. Res. 33 (1), 139e149. https://doi.org/10.1111/j.1530-0277.2008.
https://doi.org/10.1371/journal.pone.0084560. 00821.x.
Skinner, M.D., Aubin, H.J., 2010. Craving’s place in addiction theory: Zapata, A., Minney, V.L., Shippenberg, T.S., 2001. Shift from goal-
contributions of the major models. Neurosci. Biobehav. Rev. 34 (4), directed to habitual cocaine seeking after prolonged experience in
606e623. https://doi.org/10.1016/j.neubiorev.2009.11.024. rats. J. Neurosci. 30 (46), 15457e15463. https://doi.org/10.1523/
Terraneo, A., Leggio, L., Saladini, M., Ermani, M., Bonci, A., JNEUROSCI.4072-10.2010.
Gallimberti, L., 2016. Transcranial magnetic stimulation of dorsolat- Zapata, A., Minney, V.L., Shippenberg, T.S., 2010. Shift from goal-
eral prefrontal cortex reduces cocaine use: a pilot study. Eur. Neuro- directed to habitual cocaine seeking after prolonged experience in
psychopharmacol. 26 (1), 37e44. https://doi.org/https://doi.org/10. rats. J. Neurosci. 30 (46), 15457e15463. https://doi.org/10.1523/
1016/j.euroneuro.2015.11.011. JNEUROSCI.4072-10.2010.Shift.
Thorn, C.A., Atallah, H., Howe, M., Graybiel, A.M., 2010. Differential Zhou, F., Zimmermann, K., Xin, F., Scheele, D., Dau, W., Banger, M.,
dynamics of activity changes in dorsolateral and dorsomedial striatal et al., 2018. Shifted balance of dorsal versus ventral striatal commu-
loops during learning. Neuron 66, 781e795. https://doi.org/10.1016/j. nication with frontal reward and regulatory regions in cannabis-
neuron.2010.04.036. dependent males. Hum. Brain Mapp. 39 (12), 5062e5073. https://
Tiffany, S.T., Friedman, L., Greenfield, S.F., Hasin, D.S., Jackson, R., doi.org/10.1002/hbm.24345.
2012. Beyond drug use: a systematic consideration of other outcomes Zhou, X., Zimmermann, K., Xin, F., Derck, R., Sassmannshausen, A.,
in evaluations of treatments for substance use disorders. Addiction 107 Scheele, D., et al., 2019. Cue-reactivity in the ventral striatum char-
(4), 709e718. https://doi.org/10.1111/j.1360-0443.2011.03581.x. acterizes heavy cannabis use, whereas reactivity in the dorsal striatum
Tricomi, E., Balleine, B.W., O’Doherty, J.P., 2009. A specific role for pos- mediates dependent use. BioRxiv (Preprint). https://doi.org/10.1101/
terior dorsolateral striatum in human habit learning. Eur. J. Neurosci. 29 516385.
(11), 2225e2232. https://doi.org/10.1111/j.1460-9568.2009.06796.x. Zilverstand, A., Huang, A.S., Alia-Klein, N., Goldstein, R.Z., 2018.
Vanderschuren, L.J.M.J., Everitt, B.J., 2005. Behavioral and neural Neuroimaging impaired response inhibition and salience attribution in
mechanisms of compulsive drug seeking. Eur. J. Pharmacol. 526 human drug addiction: a systematic review. Neuron 98 (5), 886e903.
(1e3), 77e88. https://doi.org/10.1016/j.ejphar.2005.09.037. https://doi.org/10.1016/j.neuron.2018.03.048.
Vanderschuren, L.J.M.J., Di Ciano, P., Everitt, B.J., 2005. Involvement of
the dorsal striatum in cue-controlled cocaine seeking. J. Neurosci. 25
(38), 8665e8670. https://doi.org/10.1523/jneurosci.0925-05.2005.
Chapter 3
Dual models of drug addiction: the

impaired response inhibition and
salience attribution model
Anna Zilverstand1 and Rita Z. Goldstein2
1
Department of Psychiatry, University of Minnesota, Minneapolis, MN, United States; 2Departments of Psychiatry and Neuroscience, Icahn School of
Medicine at Mount Sinai, New York, NY, United States
Dual models of addiction that the impairments of two neuropsychological

functionsdimpaired response inhibition and salience
Addiction is a chronically relapsing disorder, characterized attributiondand their underlying neural substrates
by continued drug seeking despite reduced pleasure from contribute to the clinical symptomatology of addiction
drug-taking and substantial negative consequences to the encompassing craving, intoxication, bingeing, and with-
individual and their kin. Neurobiological models of drug drawal across a broad range of substance addictions,
addiction seek to explain this perplexing phenomenon by including nicotine, alcohol, and illicit drug addictions
understanding the changes in the brain driving this (Goldstein and Volkow, 2002, 2011; Zilverstand et al.,
behavior. Early neurobiological models focused on the role 2018). This model proposed for the first time that broad
of the reward system (also named “reinforcement,” higher-order cognitive functions involved in the “ability to
“approach,” “drive,” “motivational,” or “dopamine” sys- track, update, and modulate the salience of a reinforcer as a
tem), proposing that it was the repeated activation of the function of context and expectation” and the “ability to
positive reinforcement system that fueled repeated drug control and inhibit prepotent responses,” and their under-
taking (Wise and Bozarth, 1987). This theory was later lying neural networks, were impaired in human drug
refined as the “incentive-sensitization theory,” which pro- addiction (Goldstein and Volkow, 2002). Indeed, recent
posed that the attribution of incentive salience is the un- evidence suggests that impairments in iRISA in human
derlying function of the dopaminergic system, and that the drug addiction are linked to the altered function of six
increased attribution of salience to drugs or drug cues is large-scale brain networks: the limbic-orbitofrontal reward
associated with a “sensitization” or upregulation of this network, the fronto-insular-parietal salience network, the
system in drug addiction (Robinson and Berridge, 1993). prefrontal executive network, the fronto-parietal self-
However, while these early models explained how drug directed network, the subcortical habit, and memory net-
taking would propel the urge to seek drugs, they could not works (Fig. 3.1). The conclusions made and the evidence
explain the inability of addicted individuals to inhibit this reviewed in this chapter are, unless stated otherwise, a
urge (Jentsch and Taylor, 1999). Therefore, later dual summary of the evidence discussed in a systematic review
models of addiction proposed an interaction between a of 105 task-related neuroimaging studies published from
“drive” system (e.g., the reward system) and a “control” 2010 until 2018, which compared individuals with alcohol,
system located in the prefrontal cortex, which would need cannabis, heroin, stimulant, and other addictions to healthy
to be deployed to inhibit a sensitized reward system, but controls (Zilverstand et al., 2018). With very rare excep-
shows impairments with chronic drug use (Jentsch and tions, findings were consistent across different drug-
Taylor, 1999). A contemporary updated dual model, pri- addicted populations and are hence discussed under the
marily based on evidence from human neuroimaging assumption that the iRISA model provides a common
studies, is the impaired Response Inhibition and Salience model of addiction, independent of the primary drug of
Attribution (iRISA) model (Goldstein and Volkow, 2002, choice.
2011; Zilverstand et al., 2018). The iRISA model proposes

FIGURE 3.1 Evidence from more than 100 neuroimaging studies in drug-addicted individuals supports dual models of addiction, such as the impaired
response inhibition and salience attribution (iRISA) model. Findings demonstrate that abnormal levels in the reward and salience networks can be linked
to a shift in incentive salience, with decreased incentive salience of nondrug-related stimuli and increased salience of drug-related cues, whereas changed
function of the salience and executive networks underlies impaired response inhibition. Additionally, neuroimaging data suggest that altered function of
the habit, memory, and self-directed networks underlie altered learning processes linked to both impaired response inhibition and salience attribution.
Adapted from Zilverstand, A., Huang, A.S., Alia-Klein, N., Goldstein, R.Z., 2018. Neuroimaging impaired response inhibition and salience attribution in
human drug addiction. A systematic review. Neuron 98, 886e903.
Neuroimaging evidence for dual models model. Importantly, this shift in incentive value was
stronger in drug-addicted individuals who had used drugs
The reward network consists of the ventral striatum, sub- more frequently and for longer durations, in general man-
genual/rostral cingulate, and orbitofrontal and anterior ifesting more severe addiction, suggesting that these
prefrontal cortex, which together support the appraisal of changes may be a direct consequence of drug use (Zilver-
incentive value by estimating subjective value based on stand et al., 2018). Stronger abnormalities in the activation
expected reward outcomes. This network has been termed levels of the reward network were also linked to a greater
the “reward network,” as these brain regions show a likelihood of relapse in drug users seeking to remain
consistently strong response during rewarding events (in abstinent (Li et al., 2015; Seo et al., 2013), indicating that
contrast to the “salience network,” which reacts robustly to the incentive value shift toward drug-related stimuli con-
both pleasant and unpleasant events). In task neuroimaging tributes to the maintenance of drug seeking and taking in
studies, the reward network showed enhanced activation human drug addiction. Finally, treatment of individuals
levels when, compared to controls, addicted individuals with drug addiction led to a reduction of abnormalities in
were exposed to drug cues (Filbey et al., 2016; Hong et al., the reward network (Zilverstand et al., 2016), suggesting
2017; Kim et al., 2014; Kober et al., 2016; Li et al., 2012, such behavioral and neural normalizations may be a treat-
2015; Ray et al., 2015; Tabatabaei-Jafari et al., 2014), ment target, potentially reducing drug use and enhancing
providing evidence for an increased incentive value of drug abstinence.
cues to drug users. In contrast, studies that used gambling A second network shown to have abnormal brain
paradigms in drug users as compared with controls found function in drug addiction is the salience network, which
reduced activation levels of the reward network during gain encompasses the insula, dorsal anterior cingulate cortex,
anticipation (Luijten et al., 2017), as well as during loss and inferior parietal cortex. This network integrates inter-
anticipation and realization of monetary loss (Gowin et al., oceptive information with external inputs to detect salient
2017; Gradin et al., 2014; Worhunsky et al., 2017), sug- events, controlling the allocation of attentional control to-
gesting reduced incentive value of monetary rewards and ward them. Similar to the reward network, the salience
losses in drug addiction. Studies employing social- network was found to be hyperengaged when drug users
emotional stimuli to provoke an affective reaction simi- were confronted with drug-related stimuli (Kühn and Gal-
larly demonstrated a blunted reward network response in linat, 2011; Zilverstand et al., 2018) and hypoengaged
addicted individuals (Asensio et al., 2010; Caldwell et al., when drug users were anticipating monetary gains (Luijten
2015; Canterberry et al., 2016; Costumero et al., 2017; et al., 2017) or anticipating or realizing monetary loss in
Hong et al., 2017; Seo et al., 2013; Wesley et al., 2016), gambling tasks (Gowin et al., 2017; Gradin et al., 2014;
further indicating that the incentive value of nondrug- Stewart et al., 2014; Wesley et al., 2011) or when they were
related stimuli may be decreased in drug addiction. Taken confronted with social-emotional stimuli in emotion prov-
together, these findings suggest a shift of incentive value ocation task designs (Asensio et al., 2010; Costumero et al.,
away from nondrug rewards and toward drug-related cues 2017; Gilman et al., 2010; Hong et al., 2017; Landi et al.,
across addicted populations, as proposed by the iRISA 2011; Maurage et al., 2012; Seo et al., 2013). Beyond the
Dual models of drug addiction: the impaired response inhibition and salience attribution model Chapter | 3 19
evidence discussed above for the altered processing of motor area, and the superior parietal lobe. This network
incentive value (as indexed by the reward network), the plays a primary role in goal representation and response
observed changes in the salience network provide evidence selection during motivated behavior, and hence has a
for altered salience processing, with a shift in incentive crucial function in inhibitory control and self-regulation.
salience away from nondrug-related stimuli and toward However, similarly to the reward and salience networks,
drug-related cues, in concordance with the impaired the executive network also shows increased engagement
salience attribution hypothesis of the iRISA model. How- during exposure to drug-related cues (Albein-Urios et al.,
ever, in contrast to the reward network, the salience 2012; Harle et al., 2014; Hu et al., 2015; Kober et al., 2014;
network has also been implicated in impaired response in- Moeller et al., 2014a), suggesting recruitment of cognitive
hibition (Goldstein and Volkow, 2002, 2011; Zilverstand resources when cues with high incentive salience/valence
et al., 2018), the second aspect of the iRISA model. In are encountered by drug-addicted individuals. In contrast,
individuals with drug addiction, this network showed when individuals with addiction anticipated monetary gains
reduced activation levels during tasks that require either the (Luijten et al., 2017), or experienced or anticipated mone-
inhibition of a motor response or cognitive self-regulation tary losses during gambling tasks (Gowin et al., 2017;
(Albein-Urios et al., 2012; Czapla et al., 2017; Fryer Gradin et al., 2014), or when chronic drug users were
et al., 2013; Harle et al., 2014; Hu et al., 2015; Jan et al., confronted with potentially emotion provoking social-
2014; Kober et al., 2014; Luijten et al., 2013; Moeller et al., emotional stimuli (Caldwell et al., 2015; Costumero
2014a,b). Importantly, both the hyperengagement of the et al., 2017; Hong et al., 2017; Kim et al., 2014; Landi
salience network when confronted with drug-related stimuli et al., 2011; Maurage et al., 2012; Payer et al., 2012;
and the hypoactivation of this network during inhibitory Roberts and Garavan, 2013), the executive network showed
control tasks have been linked to clinical outcomes, such as reduced activation levels (as compared with control par-
the likelihood of relapse in individuals seeking abstinence ticipants). These hypoactivations are in line with reduced
(Kober et al., 2014; Luo et al., 2013; Moeller et al., 2016; deployment of executive functions during the processing of
Prisciandaro et al., 2013; Worhunsky et al., 2013). Again, nondrug stimuli, which have lowered valence and salience
therapeutic interventions could (partially) normalize in addicted populations. Beyond this shared role in altered
engagement of the salience network (Zilverstand et al., salience attribution, reduced activation levels in the exec-
2016). However, in contrast to the observed effects in the utive network have been observed during tasks requiring
reward network, alterations in salience network function the inhibition of a behavioral response or cognitive self-
did not show a linear relationship with lifetime duration of regulation in drug-addicted individuals as compared with
drug use or addiction severity (Zilverstand et al., 2018), healthy controls (Albein-Urios et al., 2012; Harle et al.,
which may be explained by different factors. First, the 2014; Hu et al., 2015; Kober et al., 2014; Moeller et al.,
relationship between drug use and engagement of the 2014a), supporting a functional role of this network in
salience network may be nonlinear over time, as has been response inhibition. A stronger disengagement of the ex-
suggested by a reversal in the incentive salience shift at 1- ecutive network has further been linked to higher addiction
month abstinence in cocaine-addicted individuals (Parvaz severity (Cousijn et al., 2012; Harle et al., 2014; Vollstädt-
et al., 2016). Second, altered processing in the salience Klein et al., 2011) and increased risk for relapse (Costu-
network may be linked to other factors, such as comorbid mero et al., 2017; Kober et al., 2014; Moeller et al., 2016;
pathologies. A previous systematic review across different Seo et al., 2013; Worhunsky et al., 2013), while abstinence
clinical populations (including addicted individuals) found and treatment have been shown to increase activation levels
a strong relationship between abnormal function of the in this network (Gradin et al., 2014; Kober et al., 2014;
salience network and increased anxiety levels (Zilverstand Tabatabaei-Jafari et al., 2014; Worhunsky et al., 2013;
et al., 2017). Third, altered salience processing may be a Zilverstand et al., 2016, 2018). Finally, disengagement of
precursor to drug use rather than a consequence. Indeed, the executive network during inhibitory control tasks has
abnormal activation levels in the salience network during also been associated with increased risk for addiction based
inhibitory control tasks have been shown in children (7e12 on family history (Hardee et al., 2014) and increased
years old) with a family history of addiction (Hardee et al., escalation of drug use in adolescence (Norman et al., 2011;
2014). Taken together, evidence from human neuroimaging Wetherill et al., 2013), suggesting that impairments in
studies suggests that abnormal function of the salience response inhibition may (in part) be a precursor of addic-
network is linked to alterations both in salience attribution tion. Of note is that, in contrast to the strong association
and response inhibition, while the factors contributing to between a hypoengagement of the executive network and
these alterations remain to be further studied. negative clinical outcomes, there is little evidence for a link
A third network of interest is the executive network, between the hyperengagement of the executive network
encompassing the ventral and dorsal prefrontal cortex in its during drug-cue exposure and clinical outcomes. Even in
core and extending into the premotor cortex, supplementary studies that did not use an explicit inhibitory control task
design (e.g., exposure to negative stimuli (Seo et al., 2013); modulated by the cues’ incentive salience suggests that
exposure to drug stimuli (Cousijn et al., 2012; Tabatabaei- learning is an important aspect of impaired salience attri-
Jafari et al., 2014; Vollstädt-Klein et al., 2011); exposure to bution in human drug addiction. And while the clinical
erotic stimuli (Costumero et al., 2017); monetary gambling relevance of these alterations remains to be fully explored,
task (Gradin et al., 2014)), negative clinical outcomes were partly because this question was rarely the main focus of
linked to lower and not higher executive network engage- the reviewed neuroimaging studies, at least one study re-
ment. In summary, the reduced ability to recruit the exec- ported that increased engagement of the habit network
utive network for response inhibition seems to be predictive during drug-cue exposure was linked to increased likeli-
of an individual’s trajectory in addiction, while its hood to relapse in initially abstinent-addicted individuals
involvement in approach behavior (when encountering (Prisciandaro et al., 2013). Beyond a potential role for
drug cues) has not been linked to clinical outcomes. altered learning processes in impaired salience attribution,
Finally, beyond these discussed fundamental changes in neuroimaging studies have also reported altered learning
the reward, salience, and executive networks, neuroimaging processes during tasks taxing the capacity for response
data also point to crucial changes in networks underlying inhibition in human drug addiction. In adults, the memory
habitual and flexible learning, which have been extensively networkdwhich supports more flexible learningdwas
studied using preclinical models (Everitt and Robbins, hypoengaged during inhibitory control tasks (Harle et al.,
2005, 2016), but have been less often a focus of investi- 2014; Hu et al., 2015; Kober et al., 2014; Luijten et al.,
gation in human neuroimaging studies (for a discussion, see 2013; Schulte et al., 2012), with therapeutic interventions
Zilverstand et al., 2018). The habit network, which in its generally increasing engagement of this network in addic-
core encompasses the dorsal caudate/putamen, supports ted individuals (Zilverstand et al., 2016). In contrast, youth
simple stimulus-response learning during automatization of at risk for addiction specifically demonstrated decreased
behavior or habit learning. In contrast, the memory network, involvement of the habit network during inhibitory control
consisting of the hippocampus, parahippocampus, rhinal, tasks (Hardee et al., 2014), and hypoengagement of this
and retrosplenial cortex, is a flexible, relational memory network was also linked to escalation of drug use in
system, which supports adaptive, voluntary, and flexible adolescence (Norman et al., 2011; Wetherill et al., 2013).
learning processes based on associative learning between Taken together, these findings suggest a role for altered
multiple cues (as compared with the simple associations learning processes in impaired salience attribution and
formed during habitual learning). Third, the self-directed response inhibition in human drug addiction, with alter-
network, in its core comprised of the dorsomedial pre- ations in habit, flexible, and self-directed learning
frontal cortex, the posterior cingulate, and the precuneus, is depending on the task context and age of the individual.
involved in self-focused learning processes, such as self-
awareness and self-reflection. As shown for the executive
network, all three of these learning networks have been
Conclusions
implicated in impaired salience processing, as they are In summary, a large body of evidence from more than a 100
hyperengaged by drug-related cues with high salience in task-based neuroimaging studies comparing drug-addicted
drug users (Arcurio et al., 2015; Filbey et al., 2016; Kober individuals with healthy controls and tracking their clin-
et al., 2016; Li et al., 2012, 2015; Ray et al., 2015; Wang ical outcomes supports the validity of dual addiction
et al., 2014), but hypoengaged when drug-addicted in- models, such as the iRISA model. Taken together, the
dividuals anticipate monetary gains (Luijten et al., 2017) or discussed evidence supports that alterations in the brain
anticipate or experience monetary loss during gambling networks underlying salience processing (reward and
tasks (Gowin et al., 2017; Gradin et al., 2014; Stewart et al., salience networks) and response inhibition (salience and
2014; Wesley et al., 2011) or when they are being con- executive networks) not only reliably differentiate drug
fronted with social-emotional stimuli (Caldwell et al., 2015; users from healthy control participants but also provide
Canterberry et al., 2016; Gilman et al., 2010; Hong et al., important biomarkers for tracking and predicting clinical
2017; Kim et al., 2014; Landi et al., 2011; Maurage et al., outcomes in addiction. Additionally, the reviewed evidence
2012; Seo et al., 2013; Wesley et al., 2016). More specif- revealed alterations in learning processes, which may be
ically, hyperengagement during drug-cue exposure gener- important subprocesses in changed salience processing and
ally involved all three learning networks, while response inhibition in drug addiction. Other subprocesses
disengagement during monetary tasks was primarily invoke stress reactivity, for example, due to its function in
observed in the habit learning and self-directed networks, detecting not only external but also internal salient events
and disengagement when confronted with social-emotional and its role in the allocation of attentional control, the
stimuli was mainly observed in the self-directed and salience network could be conceptualized as a stress reac-
memory networks (Zilverstand et al., 2018). This consistent tive system, as has been previously suggested in the
pattern of altered engagement of these learning networks as somatic-marker theory of addiction (Verdejo-García and
Bechara, 2009). This would be in line with other theories of Canterberry, M., Peltier, M.R., Brady, K.T., Hanlon, C.A., 2016. Atten-
addiction such as the “three functional domain model” on uated neural response to emotional cues in cocaine-dependence: a
incentive salience, executive function, and negative- preliminary analysis of gender differences. Am. J. Drug Alcohol
Abuse 42, 577e586.
emotional states (Koob and Volkow, 2016), which pro-
Costumero, V., Bustamante, J.C., Rosell-Negre, P., Fuentes, P.,
posed that a third brain system that is reactive to stress
Llopis, J.J., Ávila, C., Barrós-Loscertales, A., 2017. Reduced activity
interacts with appetitive (e.g., the reward network) and in functional networks during reward processing is modulated by
inhibitory processes (e.g., the executive network). This abstinence in cocaine addicts. Addict. Biol. 22, 479e489.
perspective would also converge with the “Competing Cousijn, J., Goudriaan, A.E., Ridderinkhof, K.R., van den Brink, W.,
Neurobehavioral Decision Systems (CNDS)” theory Veltman, D.J., Wiers, R.W., 2012. Approach-bias predicts develop-
(Bickel et al., 2018), which proposes that parts of the ment of cannabis problem severity in heavy cannabis users: results
salience network act as a moderating system between from a prospective FMRI study. PLoS One 7.
appetitive and inhibitory processes (Bickel et al., 2018). Czapla, M., Baeuchl, C., Simon, J.J., Richter, B., Kluge, M.,
The difference between the iRISA model and such triadic Friederich, H.C., Mann, K., Herpertz, S.C., Loeber, S., 2017. Do
theories would then be in the assignment of the core alcohol-dependent patients show different neural activation during
response inhibition than healthy controls in an alcohol-related fMRI
mechanisms of addiction to a dual (vs. a tripartite) process
go/no-go-task? Psychopharmacology (Berl.) 234, 1001e1015.
of imbalance between appetitive and inhibitory systems,
Everitt, B.J., Robbins, T.W., 2005. Neural systems of reinforcement for
with impairments in learning, stress reactivity, and attention drug addiction: from actions to habits to compulsion. Nat. Neurosci. 8,
allocation attributed to secondary processes modulating/ 1481e1489.
moderating the core two processes. As such, the iRISA Everitt, B.J., Robbins, T.W., 2016. Drug addiction: updating actions to
model provides a more parsimonious description of the habits to compulsions ten years on. Annu. Rev. Psychol. 67, 23e50.
reviewed evidence as remains to be empirically tested using Filbey, F.M., Dunlop, J., Ketcherside, A., Baine, J., Rhinehardt, T.,
computational/modeling approaches. Such approaches can, Kuhn, B., DeWitt, S., Alvi, T., 2016. fMRI study of neural sensiti-
for example, parse apart different processes underlying zation to hedonic stimuli in long-term, daily cannabis users. Hum.
inhibitory control (e.g., anticipation of conflict, learning Brain Mapp. 37, 3431e3443.
rate, response inhibition), hence allowing to separate Fryer, S.L., Jorgensen, K.W., Yetter, E.J., Daurignac, E.C., Watson, T.D.,
Shanbhag, H., Krystale, J.H., Mathalon, D.H., 2013. Differential brain
learning deficits from the execution of response inhibition
response to alcohol cue distractors across stages of alcohol depen-
itself. Initial studies using this approach indeed provide
dence. Biol. Psychol. 92, 282e291.
evidence for the involvement of learning deficits in Gilman, J.M., Davis, M.B., Hommer, D.W., 2010. Greater activation in
impaired inhibitory control in alcohol addiction (Hu et al., left hemisphere language-related regions during simple judgment tasks
2015) and those at risk for stimulant dependence (Harle among substance-dependent patients in treatment for alcoholism.
et al., 2014). A further, systematic investigation of how Alcohol. Clin. Exp. Res. 34, 331e341.
both impaired iRISA could be modulated by learning Goldstein, R.Z., Volkow, N.D., 2002. Drug addiction and its underlying
processes, or other factors such as stress reactivity, remains neurobiological Basis : neuroimaging evidence for the involvement of
an exciting future research endeavor in the addiction field. the frontal cortex. Am. J. Psychiatry 159, 1642e1652.
Goldstein, R.Z., Volkow, N.D., 2011. Dysfunction of the prefrontal cortex
in addiction: neuroimaging findings and clinical implications. Nat.
References
Rev. Neurosci. 12, 652e669.
Albein-Urios, N., Verdejo-Román, J., Asensio, S., Soriano-Mas, C., Gowin, J.L., May, A.C., Wittmann, M., Tapert, S.F., Paulus, M.P., 2017.
Martínez-González, J.M., Verdejo-García, A., 2012. Re-appraisal of Doubling down: increased risk-taking behavior following a loss by
negative emotions in cocaine dependence: dysfunctional corticolimbic individuals with cocaine use disorder is associated with striatal and
activation and connectivity. Addict. Biol. 19, 415e426. anterior cingulate dysfunction. Biol. Psychiatry Cogn. Neurosci.
Arcurio, L.R., Finn, P.R., James, T.W., 2015. Neural mechanisms of high- Neuroimaging 2, 94e103.
risk decisions-to-drink in alcohol-dependent women. Addict. Biol. 20, Gradin, V.B., Baldacchino, A., Balfour, D., Matthews, K., Steele, J.D.,
390e406. 2014. Abnormal brain activity during a reward and loss task in opiate
Asensio, S., Romero, M.J., Palau, C., Sanchez, A., Senabre, I., dependent patients receiving methadone maintenance therapy. Neu-
Morales, J.L., Carcelen, R., Romero, F.J., 2010. Altered neural ropsychopharmacology 39, 1e35.
response of the appetitive emotional system in cocaine addiction: an Hardee, J.E., Weiland, B.J., Nichols, T.E., Welsh, R.C., Soules, M.E.,
fMRI study. Addict. Biol. 15, 504e516. Steinberg, D.B., Zubieta, J.K., Zucker, R.A., Heitzeg, M.M., 2014.
Bickel, W.K., Mellis, A.M., Snider, S.E., Athamneh, L.N., Stein, S., Development of impulse control circuitry in children of alcoholics.
Pope, D.A., 2018. 21st century neurobehavioral theories of decision Biol. Psychiatry 76, 708e716.
making in addiction: review and evaluation. Pharmacol. Biochem. Harle, K.M., Shenoy, P., Stewart, J.L., Tapert, S.F., Yu, A.J., Paulus, M.P.,
Behav. 164, 4e21. 2014. Altered neural processing of the need to stop in young adults at
Caldwell, B.M., Harenski, C.L., Harenski, K.A., Fede, S.J., Steele, V.R., risk for stimulant dependence. J. Neurosci. 34, 4567e4580.
Koenigs, M.R., Kiehl, K.A., 2015. Abnormal frontostriatal activity in
recently abstinent cocaine users during implicit moral processing.
Front. Hum. Neurosci. 9, 565.
Hong, J.S., Kim, S.M., Jung, H.Y., Kang, K.D., Min, K.J., Han, D.H., Moeller, S.J., Konova, A.B., Parvaz, M.A., Tomasi, D., Lane, R.D., Fort, C.,
2017. Cognitive avoidance and aversive cues related to tobacco in Goldstein, R.Z., 2014a. Functional, structural, and emotional correlates
male smokers. Addict. Behav. 73, 158e164. of impaired insight in cocaine addiction. JAMA Psychiatry 71, 61.
Hu, S., Ide, J.S., Zhang, S., Sinha, R., Li, C.S.R., 2015. Conflict antici- Moeller, S.J., Froboese, M.I., Konova, A.B., Misyrlis, M., Parvaz, M.A.,
pation in alcohol dependence - a model-based fMRI study of stop Goldstein, R.Z., Alia-Klein, N., 2014b. Common and distinct neural
signal task. NeuroImage Clin. 8, 39e50. correlates of inhibitory dysregulation: stroop fMRI study of cocaine
Jan, R.K., Lin, J.C., McLaren, D.G., Kirk, I.J., Kydd, R.R., Russell, B.R., addiction and intermittent explosive disorder. J. Psychiatr. Res. 58,
2014. The effects of methylphenidate on cognitive control in active 55e62.
methamphetamine dependence using functional magnetic resonance Moeller, S.J., Bederson, L., Alia-Klein, N., Goldstein, R.Z., 2016.
imaging. Front. Psychiatry 5, 1e18. Neuroscience of Inhibition for Addiction Medicine: From Prediction
Jentsch, J.D., Taylor, J.R., 1999. Impulsivity resulting from frontostriatal of Initiation to Prediction of Relapse. Elsevier B.V.
dysfunction in drug abuse: implications for the control of behavior by Norman, A.L., Pulido, C., Squeglia, L.M., Spadoni, A.D., Paulus, M.P.,
reward-related stimuli. Psychopharmacology (Berl.) 146, 373e390. Tapert, S.F., 2011. Neural activation during inhibition predicts initi-
Kim, S.M., Han, D.H., Min, K.J., Kim, B.N., Cheong, J.H., 2014. Brain ation of substance use in adolescence. Drug Alcohol Depend. 119,
activation in response to craving- and aversion-inducing cues related 216e223.
to alcohol in patients with alcohol dependence. Drug Alcohol Depend. Parvaz, M.A., Moeller, S.J., Goldstein, R.Z., 2016. Incubation of cue-
141, 124e131. induced craving in adults addicted to cocaine measured by electro-
Kober, H., DeVito, E.E., Deleone, C.M., Carroll, K.M., Potenza, M.N., encephalography. JAMA Psychiatry 73, 1127.
2014. Cannabis abstinence during treatment and one-year follow-up: Payer, D.E., Nurmi, E.L., Wilson, S.A., McCracken, J.T., London, E.D.,
relationship to neural activity in men. Neuropsychopharmacology 39, 2012. Effects of methamphetamine abuse and serotonin transporter
1e11. gene variants on aggression and emotion-processing neurocircuitry.
Kober, H., Lacadie, C.M., Wexler, B.E., Malison, R.T., Sinha, R., Transl. Psychiatry 2, e80.
Potenza, M.N., 2016. Brain activity during cocaine craving and Prisciandaro, J.J., Myrick, H., Henderson, S., Mcrae-clark, A.L.,
gambling urges: an fMRI study. Neuropsychopharmacology 41, Brady, K.T., 2013. Prospective associations between brain activation
628e637. to cocaine and no-go cues and cocaine relapse. Drug Alcohol Depend.
Koob, G.F., Volkow, N.D., 2016. Neurobiology of addiction : a neuro- 131, 44e49.
circuitry analysis. Lancet Psychiatry 3, 760e773. Ray, S., Haney, M., Hanson, C., Biswal, B., Hanson, S.J., 2015. Modeling
Kühn, S., Gallinat, J., 2011. Common biology of craving across legal and causal relationship between brain regions within the drug-cue pro-
illegal drugs - a quantitative meta-analysis of cue-reactivity brain cessing network in chronic cocaine smokers. Neuro-
response. Eur. J. Neurosci. 33, 1318e1326. psychopharmacology 40, 2960e2968.
Landi, N., Montoya, J., Kober, H., Rutherford, H.J.V., Mencl, W.E., Roberts, G.M.P., Garavan, H., 2013. Neural mechanisms underlying
Worhunsky, P.D., Potenza, M.N., Mayes, L.C., 2011. Maternal neural ecstasy-related attentional bias. Psychiatry Res. Neuroimaging 213,
responses to infant cries and faces: relationships with substance use. 122e132.
Front. Psychiatry 2, 1e13. Robinson, T.E., Berridge, K.C., 1993. The neural basis of drug craving: an
Li, Q., Wang, Y., Zhang, Y., Li, W., Yang, W., Zhu, J., Wu, N., incentive-sensitization theory of addiction. Brain Res. Rev. 18,
Chang, H., Zheng, Y., Qin, W., et al., 2012. Craving correlates with 247e291.
mesolimbic responses to heroin-related cues in short-term abstinence Schulte, T., Mueller-Oehring, E.M., Sullivan, E.V., Pfefferbaum, A., 2012.
from heroin: an event-related fMRI study. Brain Res. 1469, 63e72. Synchrony of corticostriatal-midbrain activation enables normal
Li, Q., Li, W., Wang, H., Wang, Y., Zhang, Y., Zhu, J., Zheng, Y., inhibitory control and conflict processing in recovering alcoholic men.
Zhang, D., Wang, L., Li, Y., et al., 2015. Predicting subsequent Biol. Psychiatry 71, 269e278.
relapse by drug-related cue-induced brain activation in heroin addic- Seo, D., Lacadie, C.M., Tuit, K., Hong, K.-I., Constable, R.T., Sinha, R.,
tion: an event-related functional magnetic resonance imaging study. 2013. Disrupted ventromedial prefrontal function, alcohol craving,
Addict. Biol. 20, 968e978. and subsequent relapse risk. JAMA Psychiatry 70, 727e739.
Luijten, M., Veltman, D.J., Hester, R., Smits, M., Nijs, I.M.T., Stewart, J.L., May, A.C., Poppa, T., Davenport, P.W., Tapert, S.F.,
Pepplinkhuizen, L., Franken, I.H.A., 2013. The role of dopamine in Paulus, M.P., 2014. You are the danger: attenuated insula response in
inhibitory control in smokers and non-smokers: a pharmacological methamphetamine users during aversive interoceptive decision-
fMRI study. Eur. Neuropsychopharmacol. 23, 1247e1256. making. Drug Alcohol Depend. 142, 110e119.
Luijten, M., Schellekens, A.F., Kühn, S., Machielse, M.W.J., Tabatabaei-Jafari, H., Ekhtiari, H., Ganjgahi, H., Hassani-Abharian, P.,
Sescousse, G., 2017. Disruption of reward processing in addiction. Oghabian, M.-A., Moradi, A., Sadighi, N., Zarei, M., 2014. Patterns of
JAMA Psychiatry 74, 387. brain activation during craving in heroin dependents successfully
Luo, X., Zhang, S., Hu, S., Bednarski, S.R., Erdman, E., Farr, O.M., treated by methadone maintenance and abstinence-based treatments.
Hong, K., Sinha, R., Mazure, C.M., Li, C.R., 2013. Neural Predictors J. Addict. Med. 8, 123e129.
of Relapse in Cocaine Dependence. Verdejo-García, A., Bechara, A., 2009. A somatic marker theory of
Maurage, P., Joassin, F., Philippot, P., Heeren, A., Vermeulen, N., addiction. Neuropharmacology 56, 48e62.
Mahau, P., Delperdange, C., Corneille, O., Luminet, O., de Vollstädt-Klein, S., Kobiella, A., Bühler, M., Graf, C., Fehr, C., Mann, K.,
Timary, P., 2012. Disrupted regulation of social exclusion in alcohol- Smolka, M.N., 2011. Severity of dependence modulates smokers’
dependence: an fMRI study. Neuropsychopharmacology 37, neuronal cue reactivity and cigarette craving elicited by tobacco
2067e2075. advertisement. Addict. Biol. 16, 166e175.
Wang, Y., Wang, H., Li, W., Zhu, J., Gold, M.S., Zhang, D., Wang, L., Worhunsky, P.D., Stevens, M.C., Carroll, K.M., Rounsaville, B.J.,
Li, Y., Yan, X., Cheng, J., et al., 2014. Reduced responses to heroin- Calhoun, V.D., Pearlson, G.D., Potenza, M.N., 2013. Functional brain
cue-induced craving in the dorsal striatum: effects of long-term networks associated with cognitive control, cocaine dependence and
methadone maintenance treatment. Neurosci. Lett. 581, 120e124. treatment outcome. Psychol. Addict. Behav. 27, 477e488.
Wesley, M.J., Hanlon, C.A., Porrino, L.J., 2011. Poor decision-making by Worhunsky, P.D., Potenza, M.N., Rogers, R.D., 2017. Alterations in func-
chronic marijuana users is associated with decreased functional tional brain networks associated with loss-chasing in gambling disorder
responsiveness to negative consequences. Psychiatry Res. Neuro- and cocaine-use disorder. Drug Alcohol Depend. 178, 363e371.
imaging 191, 51e59. Zilverstand, A., Parvaz, M.A.M.A., Moeller, S.J.S.J., Goldstein, R.Z.R.Z.,
Wesley, M.J., Lile, J.A., Hanlon, C.A., Porrino, L.J., 2016. Abnormal 2016. Cognitive interventions for addiction medicine: understanding
medial prefrontal cortex activity in heavy cannabis users during the underlying neurobiological mechanisms. Prog. Brain Res. 224,
conscious emotional evaluation. Psychopharmacology (Berl.) 233, 285e304.
1035e1044. Zilverstand, A., Parvaz, M.A., Goldstein, R.Z., 2017. Neuroimaging
Wetherill, R.R., Castro, N., Squeglia, L.M., Tapert, S.F., 2013. Atypical cognitive reappraisal in clinical populations to define neural targets for
neural activity during inhibitory processing in substance-naïve youth enhancing emotion regulation. A systematic review. Neuroimage 151,
who later experience alcohol-induced blackouts. Drug Alcohol 105e116.
Depend. 128, 243e249. Zilverstand, A., Huang, A.S., Alia-Klein, N., Goldstein, R.Z., 2018.
Wise, R.A., Bozarth, M.A., 1987. A psychomotor stimulant theory of Neuroimaging impaired response inhibition and salience attribution in
addiction. Psychol. Rev. 94, 469e492. human drug addiction. A systematic review. Neuron 98, 886e903.
Chapter 4
Decision-making deficits in substance

use disorders: cognitive functions,
assessment paradigms, and levels of
evidence
Alireza Valyan1, Hamed Ekhtiari2, Ryan Smith2 and Martin P. Paulus2
1
Allameh Tabataba’i University, Tehran, Iran; 2Laureate Institute for Brain Research, Tulsa, United States
Introduction second dimension of the matrix of evidence, the main

assessment paradigms adopted in published studies are
As human beings, we make decisions frequently and in organized in four categories: (1) self-assessment, (2)
different situations that cover many aspects of our daily behavioral tasks, (3) computational models, and (4) neu-
personal and professional lives. Thus, it is not surprising roimaging with a focus on functional magnetic resonance
that a deficit in this highly important cognitive process imaging (fMRI). In the third dimension, available evidence
affects our well-being and causes different forms of phys- will be organized in five levels of quality: (1) systematic
ical and mental health disorders (Cáceda et al., 2014). reviews and metaanalyses, (2) randomized controlled trials
Among various mental health disorders, substance use (RCTs), (3) cohort studies, (4) case-control studies, and (5)
disorder (SUD) has a strong conceptual relationship with cross-sectional studies. We hope this three-dimensional
decision-making dysfunctions (DMDs) (Stoops and matrix will provide a structured framework allowing new-
Kearns, 2018). There is some empirical support that DMDs comers to the field to have an organized overview on DMD
contribute to several stages of SUD from initiation to in SUD. We also hope this three-dimensional matrix will
maintenance (Koffarnus and Kaplan, 2018). Furthermore, show the current gaps in available evidence, critical needs,
DMDs could be targets for the design and implementation and the emerging potential for production of new evidence.
of intervention strategies and treatment protocols in SUD We will conclude this chapter with a short discussion of the
(Verdejo-García et al., 2018). However, as shown previ- challenges and hopes in studying DMD in SUD and pro-
ously (Ekhtiari et al., 2017), empirical evidence in this field vide some suggestions for future studies.
is limited and inconsistent. Despite the previous attempts to
develop a framework that can address various aspects of
DMD in SUDs together (Kwako et al., 2017), methodo-
First dimension: cognitive functions of
logical deficits in assessment paradigms and lack of decision-making
empirical evidence make any rigorous scientific conclusion Decision-making is a complex cognitive process and can be
very hard and sometimes impossible. decomposed into four major functions as follows.
In this chapter, based on the most recent findings on 1. Temporality: This function reflects the role of
DMD in SUD, we will try to organize and review the temporal perspective and delay and their related processes
available evidence in a matrix that has three dimensions: (1) in decision-making. Deficits in temporal aspects of
cognitive functions, (2) assessment paradigms, and (3) decision-making may play a significant role in SUD
levels of evidence. In the first dimension, we will address (Ekhtiari et al., 2017). Among different temporal aspects of
four major cognitive functions of decision-making: (1) decision-making, impulsivity and higher delay discounting
temporal function, (2) value/reward function, (3) risk/ (i.e., preferring sooner smaller rewards over the larger but
probability function, and (4) learning function. In the delayed ones) are more frequently reported to be related to

SUD (Bickel et al., 2017b). The relationship between reward anticipation phase and higher activation during the
temporal functions and SUD has been investigated widely outcome delivery phase, in patients with SUD compared
in the SUD literature for alcohol (Bernhardt et al., 2017), with healthy controls (Costumero et al., 2017; Luijten et al.,
tobacco (Farris et al., 2017), marijuana (Gunn et al., 2017), 2017; Ostlund and Cui, 2018; Yanes et al., 2018).
nicotine (Kobiella et al., 2014), methamphetamine (Koga- Different labs have investigated the reward sensitivity
chi et al., 2017), cannabis (Lee et al., 2015), and cocaine aspect of DMD as a potential treatment target in SUD. For
(Ross et al., 2013). In addition to discriminating people example, it has been shown that a 25e30 min brief moti-
with SUDs from healthy controls, delay discounting is re- vational intervention followed by a 25e30 min substance-
ported to be associated with the severity of SUDs free activity session and a 25e30 min educative session
(e.g., Garrison et al., 2017). Several studies suggested that reduces the value of the substance in a sample of heavy
intervention strategies can be designed with the aim of drinking college students (Dennhardt et al., 2015a). In
improving temporal aspects of DMD, which ultimately addition, modulating the reward-related pathway in the
result in lower substance demand (Bulley and Gullo, 2017) brain (e.g., frontal-cingulate) appears to change druge
and consumption level (Chiou and Wu, 2017; Stein et al., nondrug reward processing in SUD patients (Baker et al.,
2016). 2017). Finally, reward sensitivity has been shown to be a
2. Risk/Probability: One of the other cognitive com- neurobiological predictor of successful intervention thera-
ponents of DMD in SUD is related to the extent to which pies in alcohol-dependent patients (Becker et al., 2018).
SUD patients get involved in risky behavior. In other 4. Learning: Finally, the fourth dimension of decision-
words, an individual’s risk perception, risk evaluation, and making deficits in SUD pertains to learning abilities. Here,
risk-taking or risk-averse mindset plays a pivotal role in we narrow our focus to deficits in learning in response to
DMDs (Orsini et al., 2015). The relationship between risk gains or losses, which can be viewed as forms of rein-
and SUD has been widely addressed in the SUD literature. forcement learning (RL) based on positive reinforcement
It is believed that, in general, SUD might play a role in (Wise and Koob, 2014) or negative punishment (Thompson
engaging in riskier behaviors, which itself results in more et al., 2012). For example, it has been shown that poor
substance consumption (Brand et al., 2006; Bechara, 2003; performance in learning can distinguish cocaine-dependent
Balogh et al., 2013; Thylstrup and Hesse, 2018). People patients from healthy controls (Patzelt et al., 2014). Other
with SUD engage more in other risky behaviors as well, findings suggest that acute and chronic use of cannabis is
such as risky sexual behaviors (Sanudo et al., 2018; Saw positively associated with impaired reward learning (Lawn
et al., 2018). Thus, in addition to the fact that poor risk et al., 2016). More recently, it was found that chronic
perception and high-risk behavior can characterize patients nicotine exposure can result in altered anterior cingulate
with SUD, it is also argued that the severity of SUD is cortex (ACC) function during RL (Wei et al., 2018).
associated with severity of risk-taking in decision-making
(Spear, 2018). Furthermore, recent findings showed that Second dimension: assessment paradigms for
impaired activation in brain areas involved in decision-
decision-making
making and risk estimation may predict future alcohol
consumption in adolescents (Morales et al., 2018). Thus, The accurate measurement of key constructs and processes
altering the mechanisms involved in risky decision-making often represents a significant challenge when exploring any
may be an important target for treatment (Claus et al., complex cognitive function like decision-making. In the
2018). A recent study showed that transcranial direct cur- following section, we focus on four major assessment
rent stimulation (tDCS) over the dorsolateral prefrontal paradigms for DMDs: self-reports, behavioral tasks,
cortex (dlPFC) can reduce risk-taking behavior in one- and computational modeling, and fMRI (Ekhtiari et al., 2017).
2-month follow-up visits after the intervention in a sample This will include a review of the most important tools in
of veterans (Gilmore et al., 2018). each paradigm, a brief background for each tool and its
3. Reward/Value: There is empirical evidence for structure, and some recent evidence using such tools in the
reward and/or value aspects of decision-making deficits in field of SUD.
SUD. For example, either overestimating the positive
consequences or underestimating the negative effects can
Self-reports
be important factors associated with various SUDs (Vol-
kow et al., 2010; Bruijnzeel, 2017; Zimmermann et al., As assessment tools, self-reports in the form of question-
2018). For example, it has been shown that abstinence from naires have a long history in the scientific world and
tobacco can result in decreased reward sensitivity (Hughes numerous studies have been designed and interpreted based
et al., 2017a). Several recent findings have shown that this on self-reports. Self-reports are rapid, inexpensive, and
decrease is related to lower activation in different areas of especially efficient when the objectives of a study require
the brain (e.g., frontoparietal and striatal), during the large samples to be briefly screened or assessed. That makes
Decision-making deficits in substance use disorders Chapter | 4 27
self-reports the first choice when an individual’s reportable construct addresses the nonplanning impulsiveness or lack
traits and tendencies are of interest. Self-reports have face of forethought. Participants are asked to rate statements like
validity and the meaning of the items and the idea behind “I get easily bored when solving thought problems”
them are to a large extent clear for both the researcher and (Stanford et al., 2009; Patton and Stanford, 2011).
the respondent. A brief version of the scale has also been developed
In the field of decision-making in SUD, self-reports (Steinberg et al., 2013), which includes eight items from the
have been used for a variety of constructs. Several as- original version. This version has better psychometric fea-
pects of decision-making deficits (i.e., temporal, probabil- tures compared with the original BIS-11 (Mathias et al.,
ity, value, and learning functions) have been assessed via 2018).
self-reports in substance-related disorder studies. This in- Evidence in SUD: While mostly known for addressing
cludes people with alcohol (Foster et al., 2015), nicotine impulsiveness, BIS-11 also has some items that target risk-
(Stein et al., 2016; Muench and Juliano, 2017), metham- taking behavior; thus, one can assume that this scale is
phetamine (Voon et al., 2015), and heroin (Walter et al., related to two dimensions of decision-making deficits:
2015) use disorders. In this regard, the temporal dimension temporal (impulsivity) and risk functions. Some case-
of decision-making, either measured with delay discounting control studies have utilized BIS-11 in conjunction with a
(Kirby, 2009) or impulsivity (e.g., Stevens et al., 2017) and delay discounting task (DDT) to highlight that heavier
value (reward) dimensions (Foster et al., 2015; Walter drinkers with lower scores in BIS-11 discount the value of
et al., 2015; Kulis et al., 2017), has been addressed more delay reward more steeply (Adams et al., 2017). Others
directly. However, assessing the other two aspects of have studied the relationship between SUD and impulsivity
decision-making (i.e., probability and learning) with self- in a cross-sectional setting and showed that personality
reports needs more scrutiny. traits related to impulsivity (along with sensation seeking)
In the following section, we describe some of the most can predict substance use in a sample of university students
utilized self-report measures to evaluate different aspects of (Hamdan-Mansour et al., 2018). Furthermore, BIS-11 has
decision-making (ordered by their number of citations in been used along with neuroimaging techniques to study
the literature) with an emphasis on their history and theo- structural deficits in alcohol dependents (Grodin et al.,
retical background. 2017) and brain morphometry in methamphetamine users
(Kogachi et al., 2017), showing that greater impulsivity has
Barratt Impulsivity Scale a positive relationship with structural abnormalities in
different regions of the brain.
Background: Among the various self-reports that target However, although showing sound internal consistency
any of the four dimensions of decision-making deficits, the and adequate power to differentiate SUD patients from
Barratt Impulsivity Scale (BIS) is one of the most healthy controls, additional psychometric evaluations
frequently used instruments (Patton et al., 1995). In its first revealed that in comparison with other scales (e.g., Eysenck
version, BIS-10 consisted of 25 impulsiveness and 35 filter I7 and Multidimensional Personality Questionnaire), BIS-
items (to determine the eligibility of the respondents) 11 did not show the adequate power in presenting the
(Barratt, 1959, 1965). Here, impulsiveness is defined as the subdomains of impulsivity as proposed by Barratt (Luengo
tendency to take chances or to seek adventure without et al., 1991). Thus, some scholars have recommended
consideration of future consequences. It is composed of switching to other impulsiveness scales to study a
four factors: (1) cognitive response speed, (2) lack of conceptually broad construct of impulsivity or alternatively
impulsive control, (3) adventure seeking, and (4) extra- adopting the BIS-Brief version (Reise et al., 2013; Stein-
version and risk-taking. berg et al., 2013).
Structure: The most used version of the BIS consists of
30 items, and participants are asked to rate their endorse-
Monetary choice questionnaire
ment on a 4-point Likert scale from rarely/never, occa-
sionally, often, to almost always/always. According to History and Background: Delay discounting, defined as
Patton et al. (1995), three second-order constructs cover the preferring a sooner smaller reward to a larger but delayed
main components of impulsiveness. The first construct is one, has been assumed to be an important personality
attentional impulsiveness or making quick decisions and characteristic influencing decision-making patterns
includes attention (five items) and cognitive instability (Rachlin, 1974; Ainslie, 1975; Mazur, 1987; Rachlin et al.,
(three items). A sample statement in this subscale is “I am 1991). The first version of a delay discounting self-report
restless at the theater or lectures.” Statements such as “I act scale, the Monetary Choice Questionnaire (MCQ), was
on the spur of the moment” or “I act on impulse” are developed to assess the relationship between discounting
addressing the motor impulsiveness or acting without rate and reward magnitude (Kirby and Marakovic, 1996).
thinking as the second construct in BIS-11. The third In 1999, MCQ was used for the first time in the field of
SUD, with results suggesting that delay discounting can might also have an influence on impulsive actions and, as a
quantify the DMDs in SUDs (Kirby et al., 1999). result, the fifth dimension of personality has been added to
Structure: In the first version of MCQ (Kirby and the scale forming the UPPS-P (Lynam et al., 2006; Cyders
Marakovic, 1996), rewards were divided into three classes: et al., 2007).
small (30$ to 35$), medium (55$ to 65$), and large rewards Structure: In its original version, the UPPS addressed
(70$ to 80$). The questionnaire consisted of 21 instructions four aspects of personality. The first dimension was Ur-
and choice trials and 5 additional questions about de- gency, reflecting the tendency to act rashly under extreme
mographic characteristics. In each choice trial, participants negative emotions (e.g., “I always keep my feelings under
were asked to choose between immediate smaller monetary control.”). The second dimension was lack of Premedita-
rewards and larger delayed ones (e.g., “Would you prefer tion, which means the tendency to act without thinking
$54 today or $55 in 117 days?”). For each indifference (e.g., “I am not one of those people who blurt out things
point (i.e., the point in which immediate and delayed offers without thinking.”). Lack of Perseverance was the third
are of the same value for the participant), a discounting rate dimension and addressed the inability to remain focused on
(k) is calculated either based on a hyperbolic or exponential a task (e.g., “Unfinished tasks really bother me.”). The
discounting function (Green and Myerson, 1996; Madden fourth dimension targeted Sensation Seeking, the tendency
et al., 1999). The first appearance of the scale in the field of to seek out novel and thrilling experiences (e.g., “I would
SUD was in a case-control study showing that heroin ad- enjoy parachute jumping.”). It consisted of 45 items and the
dicts discount the delayed rewards more steeply than the respondent was asked to rate the statements in a 4-point
controls (Kirby et al., 1999). Later, Kirby (2009) suggested Likert scale (1 ¼ strongly agree to 4 ¼ strongly disagree)
that so long as other test conditions are held constant, delay (Whiteside and Lynam, 2001). In the UPPS-P version, it
discounting is stable and can be treated as a personal trait. was assumed that there is room for impulsive behavior
Evidence in SUD: Addressing the temporal aspect of under extremely positive emotions (Positive Urgency)
decision-making deficits, MCQ has been used in a variety adding an additional 14 items (e.g., “Others would say I
of settings, from case-control and cross-sectional to moni- make bad choices when I am extremely happy about
toring longitudinal studies. For example, using MCQ, some something.”) to address this dimension (Cyders et al., 2007;
studies have shown that there is a positive relationship Lynam et al. 2006, 2007).
between substance demand intensity and delayed reward During the past decade, several versions of this scale
discounting (Amlung et al., 2017; Farris et al., 2017; have been developed targeting different groups and adapted
Hofmeyr et al., 2017). Along these lines, Schuster et al. for different national contexts. Cyders et al. (2014) have
(2019) have recently used MCQ to investigate the multi- developed a short version (S-UPPS-P) that has only four
variable correlates of cannabis use disorder, and Hobkirk items in each dimension. There is also a child version
et al. (2019) have used the scale to study reward circuitry in developed by Zapolski et al. (2010) that used one or two
cocaine users. Thus, the MCQ might be used along with syllable words targeting children at the age of 7e13 years.
other scales to assess the efficacy of intervention strategies Evidence in SUD: Designed to measure impulsivity,
in SUD patients, as more recently has been done using a UPPS-P addresses the temporal aspect of DMD. In the field
working memory training intervention in a sample of of SUD, several studies have utilized this scale. Rømer
alcohol dependents (Khemiri et al., 2019; Hendershot et al., Thomsen et al., 2018, used the scale in conjunction with
2018). standard questionnaires of problematic substance use to
show that different aspects of impulsivity have different
UPPS impulsive behavior scale relationships with addictive behaviors. According to their
findings, relationships were found between lack of perse-
History and Background: Among the different scales verance and sensation seeking, alcohol, and urgency with
measuring impulsivity, UPPS is the only one that empha- cannabis use. Furthermore, Tran et al., 2018, have used
sizes the multifaceted and multidimensional nature of this UPPS-P in a sample of young participants (aged 18e30) to
construct. Based on the five-factor model of personality highlight the pivotal role of both positive and negative
(FFM) (Costa and McCrae, 1990), it is argued that lower urgency in early problematic alcohol use in adults. Luba
levels of self-control are related to both impulsiveness (in et al. (2018) have used UPPS’s positive urgency to show
the neuroticism domain) and self-discipline (in the that stimulant expectancies might increase marijuana use
conscientiousness domain). Thus, Whiteside and Lynam behavior. Furthermore, with the idea that different sub-
(2001) tried to assess the relationship between common stances will cause different clinical characteristics, García-
scales of impulsiveness and FFM. This resulted in the in- Marchena et al. (2018) have used UPPS to show that severe
tegrated UPPS scale reflecting the four main attributes of cocaine use, compared with alcohol abuse, can cause
impulsivity. Later, it was argued that positive emotions increased impulsivity.
Eysenck impulsiveness scale (I7) Structure: The original scale in its final format, SSS-V,
consists of 40 items. In each item, participants are asked to
Background: The project of developing a unified scale of
consider two different situations or activities and select
personality began more than 70 years ago (Eysenck, 1947).
the one that they prefer. Later on, Arnett (1994) revised the
Then, with the idea of presenting such a scale in a hierar-
original version and developed a 20-item questionnaire, the
chical format (i.e., having first-order and second-order
Arnett Inventory of Sensation Seeking Scale (AISSS),
constructs), three aspects of Psychoticism, Extraversion,
which addressed two areas of sensation seeking: novelty
and Neuroticism were introduced in the Eysenck Person-
(odd items) and intensity (even items). In this regard, the
ality Questionnaire (EPQ) (Eysenck and Eysenck 1969,
novelty subscale of sensation seeking reflects the extent
1975, 1976). Impulsivity and sensation seeking/venture-
participants welcome new experiences (e.g., “I would like
someness were considered as the “primaries” for the so-
to travel to places that are strange and far away”). The
called higher-order constructs. However, in nascence,
intensity subscale, on the other hand, targets how intense
impulsivity was further divided into risk-taking, non-
the new experiences are for the participant (e.g., “In gen-
planning, liveliness, and (narrow) impulsivity (Eysenck and
eral I work better when I’m under pressure”). Arnett also
Eysenck, 1978). As a result, a 63-item self-report scale was
changed the responding pattern to a 4-point Likert scale
created with an additional 21 items to address empathy.
(A ¼ describes me very well to D ¼ does not describe me
Structure: The first version of this scale (I5) consisted
at all). Furthermore, in search for a brief version of the SSS,
of 63 items in accordance with the EPQ. This scale dif-
Hoyle et al. (2002) developed an eight-item version of the
ferentiates impulsiveness (doing things without thinking)
scale (Brief Sensation Seeking Scale) and further studies
and venturesomeness (sensation seeking and risk-taking).
have revealed that this version has the same validity and
The I6 version of the scale aimed at children and had 23
reliability scores as the original one (Sousa et al., 2018;
Yes/No questions which measured impulsiveness (Eysenck
Stephenson et al., 2007).
et al., 1984). The final version of the Eysenck impulsive-
Evidence in SUD: SSSs address the risk functions in
ness scale (I7) is composed of 54 items and measures three
decision-making deficits in SUD. For example, Hamdan-
subscales: impulsiveness (19 items), venturesomeness (16
Mansour et al. (2018) have utilized the AISSS in
items), and empathy (19 items) (Eysenck et al., 1985b).
conjunction with the BIS-11 to reveal that there is a posi-
Participants are asked to answer either YES or NO to a
tive relationship between sensation seeking and SUD
number of questions. In the impulsivity subscale, some
among a group of university students. In a case-control
sample questions include “Do you often buy things on
setting, Mahoney et al. (2015) used the impulsive sensa-
impulse?“, “Do you mostly speak before thinking things
tion seeking scale, which is a 19-item questionnaire based
out?”, and “Do you prefer to ‘sleep on it’ before making
on the work of Zuckerman and Kuhlman (2000), to
decisions?” There are several adaptations of the scale
differentiate among healthy controls and participants with
tested in several countries (Amini et al., 2016; Francis et al.,
either cocaine or methamphetamine use disorders.
2006; Heaven, 1991; Eysenck et al., 1985a; Tiwari et al.,
Furthermore, in a cross-sectional setting, Hefner and Gor-
2009).
dijn (2018) investigated whether severity of marijuana use
Evidence in SUD: While some addictive behaviors,
disorder was positively correlated with the disinhibition
e.g., pathologic gambling (Harries et al., 2018), have
subscale of the SSS.
received empirical diagnostic and predictive supports from
the I7 impulsivity sale, there is a limited amount of pub-
Temporal experience of pleasure scale
lished evidence in the field of SUDs. Ekhtiari et al. (2008),
for example, have used the Eysenck I7 questionnaire along Background: The theoretical foundations of the temporal
with other self-report measures of impulsivity in a group of experience of pleasure scale (TEPS) are rooted in the
patients with opioid use disorder and found that, compared concepts of anticipatory and consummatory joy in the
with other scales, I7 had better distinguished between the anhedonia literature (Depue and Collins, 1999; Berridge
patients and healthy controls. and Robinson, 1998). Here, anticipatory joy reflects the fact
that expected pleasure acts as a positive trigger for the
Sensation seeking scales decision, while consummatory joy reflects the online
pleasure in response to real-time stimuli. In an attempt to
Background: Sensation seeking, as a trait, is defined as the measure people’s dispositions in these two dimensions,
tendency toward new and intense experiences. Zuckerman Gard et al. (2006) developed and tested the TEPS and
et al. (1964) developed the sensation seeking scale (SSS) found that these two dimensions measure different con-
with the aim of assessing various aspects of sensation structs. Anticipatory pleasure was positively associated
seeking in different psychopathologies like neuroticism, with reward responsiveness and imagery, while consum-
antisocial behavior, and psychopathy. matory pleasure reflected openness to different experiences
and appreciation of positive stimuli. In this regard, one can et al., 1985). In addition to alcohol, Schafer and Brown
consider the TEPS as one of the scales targeting brain (1991) have analyzed the content of 794 self-reports and
reward processing systems. identified six major expectancies for marijuana use and five
Structure: In its original form, the TEPS consisted of for cocaine. Their attempt resulted in two questionnaires for
95 items. Participants were asked to rate each statement marijuana and cocaine use effect expectancies.
(e.g., “I enjoy taking a deep breath of fresh air when I walk Afterward, and based on the cognitive mediators of
outside”) in a 6-point Likert scale (one ¼ very true for me behavior approach, Leigh and Stacy (1993) have developed
to six ¼ very false for me). His score is then included a similar scale to assess alcohol outcome expectancies. They
within the anticipatory subscale (e.g., “When something have argued that other scales of expectancy assessment are
exciting is coming up in my life, I really look forward to focused only on the positive consequences, while from a
it”), consummatory subscale (“The sound of crackling learning theory point of view both positive and negative
wood in the fireplace is very relaxing”), and the overall reinforcements can have an influence on the behavior.
score (TEPS-Total). In its final format, the scale has 18 Structure: The primitive version of the scale (Alcohol
statements (10 items reflecting anticipatory and 9 items Expectancy Questionnaire) consisted of 30 statements in
reflecting consummatory pleasure) (Gard et al., 2006). The five groups of expectancies and participants were asked to
psychometric characteristics of both trait version and a state express their opinion in an agree/disagree format. The first
version of the TEPS have been evaluated in different dis- subscale was an enhancement in social and physical plea-
orders from SUD (Garfield et al., 2016) to schizophrenia sure (e.g., “Having a few drinks is a nice way to celebrate
(Horan et al., 2005) and Parkinson’s disease (Leentjens special occasions.”). Enhancing sexual performance and
et al., 2008). experience was the second subscale (e.g., “After a few
Evidence in SUD: In the field of SUD, TEPS is drinks, I am more sexually responsive.”) and increasing
assumed to address the reward aspect of decision-making. power and aggression was the third one (e.g., “If I’m feeling
Cassidy et al. (2012) found that lower hedonic responses restricted in any way, a few drinks make me feel better.”).
might have a positive relationship with heavy cannabis use Respectively, the fourth subscale was increasing social
in patients with psychotic disorders. In a similar attempt assertiveness (“If I have a couple of drinks it is easier to
within a population of cigarette smokers, Leventhal et al. express my feelings.”), and reducing tension was the last
(2014) have shown that smokers have an imbalance in one (e.g.,“ Alcohol enables me to fall asleep more easily.”)
valuating substance-related reinforcers over substance-free (Brown et al., 1980).
ones. Although the distinguishing power of the scale (i.e., In the marijuana and cocaine version of the effect ex-
between anticipatory and consummatory pleasure) was low pectancies measures (i.e., MEEQ and CEEQ), one example
(Garfield et al., 2017), the relationship between reward question is “what effects do you expect from a moderate
sensitivity and tobacco abstinence (Hughes et al., 2017a) as and normal use of marijuana/cocaine?” This resulted in
well as opioid use (Lubman et al., 2018) is generally different expectancies for marijuana and cocaine use dis-
empirically supported. orders (Schafer and Brown, 1991).
In a similar questionnaire, the alcohol outcome expec-
tancies questionnaire, participants are asked to say how
Effect expectancy questionnaire
likely the items happen to them when they drink alcohol. In
Background: Expectancies from substance use, as a part of this self-report, expectancies are assessed in six subscales
social learning theory, is assumed to influence the pattern of as social facilitation, sexual enhancement, tension reduc-
substance consumption in individuals. First, Marlatt et al. tion, emotional, physical, and social effects (Leigh and
(1973) attempted to show, using a taste-rating task, that the Stacy, 1993).
alcohol expectancy can determine drinking patterns in Evidence in SUD: Effect expectancies questionnaires
nonalcoholics. As some behavioral effects of alcohol have the potentials to deepen our understanding of the
drinking have been linked to alcohol expectancy, Brown learning aspects of decision-making deficits in SUD.
et al. (1980) developed a self-report scale based on 125 However, one can assume the reward/value aspects of
interviews and found six different groups of alcohol ex- DMD have also some traces in these questionnaires. In the
pectancies. This includes alcohol as (1) a positive trans- field of SUD with the use of the cognitive impairment
forming agent, (2) an enhancer of social and physical subscale of the Marijuana Effect Expectancy Questionnaire,
pleasure, (3) a sexual experience facilitator, (4) a promoter Gunn et al. (2017) have shown that the expectancy of
for power and aggression, (5) an enhancer of social asser- behavioral impairment due to use of marijuana were
tiveness, and (6) a mediator for relaxation and tension negatively correlated with the behavioral measures of
reduction. In another study, they extended the utility of the impulsivity and risk-taking. Furthermore, Patton et al.
scale to adult alcoholics and showed that these expectancies (2018) have divided alcohol-related expectancies into
affect different patterns of alcohol consumption (Brown positive (reflecting the alcohol consumption as a rewarding
outcome) and negative (acting as relieving the undesirable Evidence in SUD: Reward inventories have been
feelings). However, some studies argued that negative and mainly used in case-control and cross-sectional studies in
positive expectancies do not have the same prediction the field of SUD, focusing on the reward aspect of decision-
validity, as negative expectancies were not found related to making deficits. Roozen et al. (2008), for example, found
alcohol consumption (Mezquita et al., 2018). On the other that SUD is positively associated with less engagement in
side, in a randomized trial with a cognitive behavioral pleasant activities, both in frequency and level of joyfulness
therapy, Coates et al. (2018) argued that little improve- dimensions. Being less sensitive to rewards (anhedonia) is
ments have been made in positive expectancies of alcohol also seen as an important construct in SUD studies. In a
consumption without significant change in craving and systematic review, Hughes et al. (2018) found that despite
impulsivity. Nevertheless, one key point that should not be all differences in the sample size and targeting groups, one
overlooked in the inconsistencies in results from the effect can argue that early abstinence from nicotine can lead to
expectancies questionnaires is the significant effect of age less sensitivity to nondrug-related rewards (e.g., music,
and sex in how people expect to be affected by drugs. money, etc.). This reward sensitivity phenomenon should
be explored in more details among other groups of SUDs
Rewarding events inventory with different duration of abstinence.
Background: Initially, Baron et al. (1981) extracted 16

Reinforcement survey schedule
items to assess reinforcement preference as a function of
substance use and sexual behavior. In a similar study, Background: The estimated value of reward/punishment
MacPhillamy and Lewinsohn (1982) have introduced the (positive/negative reinforcers) is a significant part of the
Pleasure Events Schedule (PES) as a behavioral self-report decision-making process. In this line, Cautela and Kas-
inventory to find the potentially reinforcing events in peo- tenbaum (1967) developed a Reinforcement Survey
ple’s life. Other examples include the Leisure Interest Schedule (RSS) to assess how participants value different
Checklist (LIC) that was developed to find the activities activities. They had asked participant how joyful or plea-
with subjective positive value in coping with stress in a surable an activity or a specific event is for them. As the
population of college students (Rosenthal et al., 1989), and original version was limited to adult participants, Cautela
the Pleasant Activities List (PAL) that measures how much (1977) developed an adolescent reinforcement survey
people are engaged with joyful activities (Roozen et al., schedule (ARSS). 16 years later, on 1983, Cautela and
2008). The last member of this family, Rewarding Events Lynch with a thorough review have identified 14 versions
Inventory (REI), is a newly developed scale to assess the of the instrument with different target groups including
frequency and joyfulness of the activities based on aged persons, children, juvenile offenders, and males
assessing 21 former reward inventories, anhedonia scales, versus females (Cautela and Lynch, 1983b). ARSS has
and apathy scales (Hughes et al., 2017b). further been analyzed by Holmes and colleagues (Holmes
Structure: The main structure of all different versions of et al. 1987, 1991) and later on Murphy et al. (2005) used
reward inventories is the same. A list of activities is pre- this modified version to develop a substance use version of
sented to the participants and they are asked to rate each the measure (ARSS-SUV).
activity in two dimensions: frequency of engagement and Structure: In its original form, RSS consisted of 139
level of enjoyment. However, primary scales (e.g., PES, reinforcers in four categories. The first category comprises
PAL, and LIC) had a long list (about 150 items) and the reinforcers that are palpable like eating or drinking. The
included some outdated activities and events. Furthermore, second category reflects reinforcers that are presented just
most of these scales are future-oriented and address hypo- in facsimile form like watching sports or reading a book.
thetical enjoyment from rewards and have low quality in The third category is about reinforcers that are presented
psychometric measures. REI was developed to fill these just in an imaginary scenario such as a job situation or
gaps. REI consisted of 58 up-to-date items and participants being in a party. The fourth category consists of contextual
are asked to express their level of wanting (e.g., how much situations reflecting daily-life reinforcing activities like the
would they be willing to spend time, money, or effort to be things that participant thinks about or do frequently (Cau-
able to experience it?) and frequency (e.g., how often the tela and Kastenbaum, 1967; Cautela and Lynch, 1983a,
event has occurred to them in the last week). There are four 1983b). The substance use version of the instrument
subscales addressed in this scale as socializing (e.g., “Meet (ARSS-SUV) assesses the frequency of engagement and
someone new”); active hobbies (e.g., “Do gardening or yard the joyfulness of 45 activities, both with and without drug
work”); passive hobbies (e.g., “Surf the Internet”); and sex/ use. Participants are asked for the frequency and pleasure of
drug use (e.g., “Drink alcohol”). Hughes et al. (2017b) each activity twice and on a 5-point Likert scale. The total
showed that REI has an acceptable level of validity and reinforcement ratio is calculated for each participant as a
reliability. value between zero and one while the higher values reflect
related joyfulness of the activities with drug use (Murphy predict different aspects of temporality in decision-making:
et al., 2005). CFC-Immediate and CFC-Future. Here, items in CFC-
Evidence in SUD: Targeting the reward dimension of Immediate subscale (e.g., “My behavior is only influenced
the decision-making deficits, ARSS-SUV is used to identify by the immediate outcomes of my actions.”) reflect how
the individualized variations in patients with SUDs and much the participant is concerned with the immediate
thus provides valuable clinically relevant information for consequences of her decisions. On the other side, items in
treatment strategies. Dennhardt et al. (2015b) showed that a the CFC-Future subscale (e.g., “I am willing to sacrifice my
brief intervention could reduce the reward value of the immediate happiness or well-being in order to achieve
drug-related reinforcers and subsequently reduce drug future outcomes.”) reflect the consideration of later future
consumption. Hallgren et al. (2016) analyzed the psycho- consequences.
metric properties of ARSS-SUV-alcohol use among college Evidence in SUD: While both temporality and reward
student drinkers and showed that “with whom?” is more aspects of decision-making deficits might be addressed by
important than the reinforcer itself. They have identified CFCS, the evidence in the field of SUD is inconsistent. For
activities grouped by peer interaction, sexual activity, example, while some scholars found that interventions
school, and family interaction. Here, identifying the drug- targeting improvement in FTP has a positive relation with
free activities and contextual situations in which the rela- the decrease in alcohol consumption in students (Beenstock
tive value of drug-free activates increases may inform et al., 2010), others showed that although having some
interventional strategies in a range from motivational in- relations with the alcohol-related problems, there is no
terventions to contingency management. significant relationship between consideration of future
consequences and alcohol consumption (Acuff et al.,
Consideration of future consequences scale 2017). With regard to CFCS subscales, Adams (2012)
showed that CFC-Immediate has a positive relationship
Background: Considering future events or the so-called with health-related behaviors (smoking status and Body
future time perspective (FTP) has long been assumed to Mass Index) while she could not find such a relation with
play an important role in decision-making (Wallace, 1956; CFCS-Future and these variables. This puts forward the
Kastenbaum, 1961). In a systematic review and meta- idea that the time interval between baseline measurement
analysis, Kooij et al. (2018) have identified 212 studies and the follow-up seems to play a significant role in the
addressing different aspects of FTP, of which consideration interpretation of the results.
of future consequences scale (CFCS) is one of the most
used ones. Reviewing the most common scales to date,
Sensitivity to reinforcement of addictive and
Strathman et al. (1994) introduced a scale to measure to
what extent individuals consider immediate or delayed
other primary rewards
consequences of their decisions. They prepared a primary Background: The subjective value of substance-related
24-item self-report questionnaire and after reliability rewards versus primary substance-free rewards is an influ-
assessment and factor analysis, they reached a 12-item encing factor in SUDs. In other words, the key question
version of the instrument. The scale was further validated here is how the valuation of these two types of rewards
and a short version of CFCS consisting of eight items is shifts in individuals due to substance use. Based on some
also developed (Petrocelli, 2003). experiences with animals, Goldstein et al. (2010) developed
Structure: The original version of CFCS consisted of the Sensitivity to Reinforcement of Addictive and other
12 items, in which participants were asked to indicate Primary Rewards (STRAP-R) to distinguish between liking
whether or not the statement is among their characteristics and wanting of expected substance-related rewards versus
in a 5-point Likert scale from 1 (¼extremely uncharacter- food and sex. The idea of liking versus wanting is the core
istic) to 5 (¼extremely characteristic). Sample statements concepts in the inventive sensitization theory of SUD
are like “Often I engage in a particular behavior in order to which assumes SUD as a disorder caused primarily by a
achieve outcomes that may not result for many years” and shift in the saliency of the substance-related stimuli (Ber-
“I think it is more important to perform a behavior with ridge and Robinson, 2016; Robinson and Berridge, 2008).
important distant consequences than a behavior with less- Structure: In the original form, participants were asked
important immediate consequences.” The higher score to think about their most favorite food, sexual activity, and
participants gain, the more it is likely that they consider the drug or alcohol. Then, for each of these categories, they
potential consequences of their decisions (Strathman et al., respond the extent they like (i.e., how pleasant it is) and
1994). they want (i.e., if they want that) in three different hypo-
Petrocelli (2003) proposed omitting four items from the thetical situations: currently, in general, and under drug
original work to make the scale more stable. He also influence (Goldstein et al., 2010). In another attempt and
identified two underlying factors acting as subscales to based on the original scale, Arulkadacham et al. (2017)
have used items related to the alcohol and coffee to find if with the control group, patients with alcohol use disorder
they can distinguish between liking and wanting in have lower risk-seeking behavior in losses and higher risk
different groups of patients. To assess subjective wanting, aversion in gains. In another study, Pearson et al. (2018)
participants were asked “How much do you want to drink have used SURP scale and found that marijuana-related
it?” and in the linking part “How pleasant would it be to perceptions (i.e., descriptive norms, injunctive norms, and
drink it?” For each reward, a Likert scale from one internalization of marijuana use culture) play a mediating
(¼somewhat) to five (extremely) shows the participants’ role in the relationship between personality traits and
opinion. marijuana consumption.
Evidence in SUD: As a recently developed instrument,
there are not many pieces of evidence with SUDs using Concluding remarks for self-reports
STRAP-R, and thus, it is unlikely that one can form a
sound judgment about the psychometric and clinical quality A number of different self-report measures have been
of the scale. Goldstein et al. (2010) have found that the developed to measure various cognitive components of the
relative value of the rewards changed in the patients with DMDs, as shown in Table 4.1. The subscales addressed by
SUD and this change was greater in lower ages. They have each self-report and a sample question for each subscale are
concluded that these patients attribute salience to the re- provided. Reviewing the body of evidence yielded from
wards related to the substance of their choice as well as a decision-making self-reports in the field of SUD reveals
reduction in the nonsubstance-related rewards. This has that different dimensions of impulsivity with focus to
also been extended to alcohol and caffeine, and Arulka- temporal function of decision-making are covered more
dacham et al. (2017) showed that in patients with high risk, extensively. The reward/value function of decision-making
compared to the liking, wanting has the key role leading to is standing in the second rank in the literature. Here, vari-
more alcohol consumption and there is a significant dif- ables like pleasure, liking, and wanting are addressed with
ference between caffeine and alcohol at the neural level. the self-report measures. The risk/probability dimension of
However, the difference between liking and wanting effect the decision-making deficits in SUD is generally not
vanishes in higher levels of consumption. addressed independently within self-report measures.
However, real-life risk-taking and experience seeking is
well covered with self-reports mainly along with impul-
Substance use risk profile scale
sivity constructs. There are dimensions in risk preferences
Background: Based on the personality risk model, the that could be addressed better with behavioral tasks. A
Substance Use Risk Profile Scale (SURPS) is developed to similar situation exists for the learning function of decision-
link different patterns of substance use to four dimensions making. Learning function can be addressed indirectly in
of personality as happiness, anxiety sensitivity, impulsivity, self-reports but behavioral tasks especially with computa-
and sensation seeking (Woicik et al., 2009). Based on this, tional modeling can provide a more detailed picture.
SURPS assesses personality traits and positive and negative Despite the effectiveness and ease of use, there are some
reinforcement processing associated with SUD. weaknesses that should be considered when using self-
Structure: In the original form, the scale consists of 28 reports. First, due to the face validity feature, there is al-
items and participants were asked to rate the statements in a ways the risk that respondents do not show their real
Likert scale from one (¼strongly disagree) to four opinions. Second, many self-reports measure general be-
(¼strongly agree). In this version, seven items (e.g., “I feel haviors and although it is shown that self-reports have
that I’m a failure.”) measure happiness. Anxiety sensitivity better internal validity, it is argued that their predictive
is addressed with five items (e.g., “It frightens me when I power is low especially when used as the only assessment
feel my heart beat change”). In addition to that, impulsivity paradigm (Cyders and Coskunpinar, 2011), although some
is the target of five items (e.g., “I usually act without of the most recent findings show that they can predict real-
stopping to think.”) and six items are assigned to the world outcomes moderately well, especially when these
sensation seeking aspect of substance use risk (e.g., “I am real-world outcomes are self-reported as well (Eisenberg
interested in experience for its own sake even if it is et al., 2018). In addition to that, as mentioned in our pre-
illegal.”). Besides, a shorter, 23-item version of the scale vious work, as an assessment tool, questionnaires alone
has been developed and showed acceptable reliability and might not have a sufficient necessary power to “tease apart”
validity (Woicik et al., 2009). different neural and cognitive aspects of DMDs in SUD
Evidence in SUD: In the field of SUD, Bernhardt et al. (Ekhtiari et al., 2017). This can be a major deficit when we
(2017) have used SURPS to assess the relation between want to target these neural and cognitive aspects in certain
impulsivity and the personality traits related to SUD in a interventions.
group of young patients. They have shown that compared
TABLE 4.1 Summary of self-reports for assessing decision-making deficits (DMD) in SUD.
Self- Format of Aspects

report Original work answers Subscales Sample item/Statement of DMD
BIS Barratt (1985) 4-point Attentional impulsiveness I am restless at the theater or lectures. Temporal
likert scale Motor impulsiveness I act on the spur of the moment.
Nonplanning I get easily bored when solving thought
impulsiveness problems.
MCQ Kirby and Option - Would you prefer $54 today or $55 in Temporal
Marakovic selection 117 days?
(1996)
UPPS-P Whiteside and 4-point Negative urgency I always keep my feelings under control. Temporal
Lynam (2001) likert scale Lack of I am not one of those people who blurt Temporal
Lynam et al. ppremeditation out things without thinking. Temporal
(2006) Lack of perseverance Unfinished tasks really bother me.
Risk
Sensation seeking I would enjoy parachute jumping.
Positive urgency Others would say I make bad choices Temporal
when I am extremely happy about
something.
I7 Eysenck et al. Yes/No Impulsiveness Do you often buy things on impulse? Temporal
(1985b) Venturesomeness Do you think hitchhiking is too
Risk
Empathy dangerous a way to travel?
-
Do you find it silly for people to cry out
of happiness?
AISSS (Zuckerman, Item Novelty I would like to travel to places that are Temporal
1984) (Arnett, selection Intensity strange and far away.
1994) In general, I work better when I’m under
pressure.
TEPS Gard et al. 6-pointli- Anticipatory pleasure When something exciting is coming up in Reward
(2006) kert scale Consummatory pleasure my life, I really look forward to it.
The sound of crackling wood in the
fireplace is very relaxing.
EEQ (Brown et al., Agree/ Enhances in social and Having a few drinks is a nice way to Reward
1980) (Leigh disagree physical pleasure celebrate special occasions.
and Stacy, 1993) Enhancing sexual After a few drinks, I am more sexually
performance and responsive.
experience If I am feeling restricted in any way, a
Increasing power and few drinks make me feel better.
aggression If I have a couple of drinks, it is easier to
Increasing social express my feelings.
assertiveness Alcohol enables me to fall asleep more
Reducing tension easily.
REI Hughes et al. 4-pointli- Wanting How much would you be willing to Reward
(2017b) kert scale Frequency spend time, money, or effort to be able to
experience (the event)?
How often (the event) has occurred to
you in the last week?
RSS-SUV Cautela (1977) 5-likert Frequency (past month) How often (the activity) has occurred to Reward
Murphy et al. scale Joyfulness you in the past month (with and without
(2005) drug)?
How much would you enjoy doing (the
activity) (with and without drug)?
CFCS (Strathman 5-likert CFCF-immediate My behavior is only influenced by the Temporal
et al., 1994) scale CFCS-future immediate (i.e., a matter of days or
(Petrocelli, weeks) outcomes of my actions.
2003) I am willing to sacrifice my immediate
happiness or well-being to achieve future
outcomes.
Continued
TABLE 4.1 Summary of self-reports for assessing decision-making deficits (DMD) in SUD.dcont’d
Self- Format of Aspects

report Original work answers Subscales Sample item/Statement of DMD
STRAP-R Goldstein et al. 5-likert Wanting How much do you want to drink it? Reward
(2010) scale Liking (Now, in general, under drug influence.)
How pleasant would it be to drink it?
(Now, in general, under drug influence.)
SURPS Woicik et al. 4-likert (Lack of) happiness I feel that I am a failure. -
(2009) scale Anxiety sensitivity It frightens me when I feel my heart beat
-
Temporal change.
Impulsivity I usually act without stopping to think. Temporal
Sensation seeking I am interested in experience for its own
sake even if it is illegal Risk
I7, Eysenck Impulsiveness Scale; - AISSS, Arnett Inventory of Sensation Seeking Scale; BIS, Barrat Impulsiveness Scale; - CFCS, Consideration of Future
Consequences Scale; - EEQ, Effect Expectancy Questionnaire; - MCQ, Monetary Choice Questionnaire; - REI, Rewarding Events Inventory; - RSS-SUV,
Reinforcement Survey Schedule-Substance Use Version; - STRAP-R, Sensitivity to Reinforcement of Addictive and other Primary Rewards; - SURPS, Sub-
stance Use Risk Profile Scale; - TEPS, Temporal Experience of Pleasure; UPPS-P, Negative Urgency, Lack of Lack of Premeditation, Lack of Perseverance,
Sensation Seeking and Positive Urgency.
Behavioral task aspects of impulsivity have a positive correlation with delay

discounting (Fecteau et al., 2014).
Despite the advantages of self-reports in studying DMDs, Structure: It is possible to use self-reports, behavioral
not all aspects of the construct under investigation can tasks, or both to find out participants’ delay discounting
easily be addressed by self-reports. Behavioral tasks, on the rate (van Gelder et al., 2013). In different forms of DDTs,
other hand, are translatable (i.e., applicable for animal and and despite all detailed considerations, the idea behind
human), enable process models, stimulate “real-life” these tasks is almost the same. Two options are presented to
decision-making situations, and go beyond verbal behavior the participants: a smaller but immediate reward and a
of the participants. Therefore, behavioral tasks are utilized larger but delayed one. After choosing either of the im-
to quantify objective decision-making tendencies, which mediate/delayed rewards, the amount of the reward (in the
may not be experimentally accessible via self-report (Cy- adjusting amount approach) or the delay intervals (in the
ders and Coskunpinar, 2011). adjusting delays approach) will be adjusted. Thus, there
In this section, we review the most commonly used would be an indifference point for each participant, at
behavioral tasks addressing the four dimensions of DMDs which, the direction of the decision changes. Based on
in SUD. For each task, we supply a short history and either a hyperbolic or exponential model fitness, a dis-
background to clarify the aims and directions of the task. counting rate is assigned to each participant, showing the
Then, a short description of the task structure and its var- extent to which s/he discounts the delayed rewards and
iations and some of the recent evidence in the field of SUD prefers the immediate ones (Matta et al., 2012).
are provided. The original format was with two decks of actual cards
(Green et al. 1996, 1999); while nowadays, the computer-
Delay discounting task ized versions are mostly used (Myerson et al., 2003) in
different versions, e.g., random adjustment version
Background: Delay discounting is defined as “the phe-
(Richards et al., 1999), short version (Cherek et al., 1997)
nomenon in which the value of a reward decreases as the
and 5-trial adjusting DDT (Koffarnus and Bickel, 2014).
time delays until its receipt increases” (Goldstein and
However, despite having a similar conceptual founda-
Naglieri, 2011). During the past two decades, delay dis-
tion, there are some methodological considerations in
counting and its synonyms (delayed gratification, time
measuring delay discounting with behavioral tasks and
preference, time delay discounting, intertemporal choice,
several studies have shown that these parameters can
discounting of delayed rewards, etc.) have been increas-
significantly influence the findings and their interpretation
ingly investigated in a number of behavioral disorders form
(Matta et al., 2012; Robles and Vargas, 2008). These pa-
SUD to obesity, gambling, and sexual behaviors (Bickel
rameters include but are not limited to adjusting approach
et al. 2012, 2014). As a personal state or trait (Odum,
(time adjusting vs. reward adjusting), type of reward
2011), some scholars consider delay discounting as a
(monetary or nonmonetary) (Estle et al., 2007), magnitude
dimension of impulsivity (Barkley et al., 2001; Green et al.,
of the reward (Green et al., 1997), framing effect (Radu
1994). However, recent findings show that at least not all
et al., 2011), delayed gain or loss (Weatherly et al., 2010), BART. In many of them, BART demonstrated acceptable
and the intertrial interval (Smethells and Reilly, 2015). In psychometric characteristics and reasonable shared vari-
addition to these items, the discounting calculation method ance with other measures of risk-taking behavior (Aklin
(hyperbolic, exponential and the area under the curve) is et al., 2005; Crowley et al., 2006; Fernie et al., 2010;
another methodological parameter to be considered (Green Lejuez et al., 2002; MacPherson et al. 2010a, 2010b; White
and Myerson, 1996; Madden et al., 1999). et al., 2008). However, there are some methodological
Evidence in SUD: In the field of SUD, DDTs has been parameters to decide among in using this task, i.e., the
used extensively in recent years in several settings from optimum number and type of balloons and reward magni-
case-control to cross-sectional studies (Amlung et al., 2017; tude/type (Wallsten et al., 2005a; Dahne et al., 2013).
Owens et al., 2017; Gowin et al., 2018; Koffarnus and Evidence in SUD: In a case-control study, Claus et al.
Kaplan, 2018). In addition, several studies attempted to (2018) have used BART with fMRI to show that neural
modulate delay discounting with interventions (Bickel mechanisms of risky decision-making are different among
et al., 2015; Gray and MacKillop, 2015; Koffarnus et al., adolescents reporting alcohol and/or marihuana use. In a
2013; Ryan, 2013). Among interventions designed to cross-sectional setting, Gunn et al. (2017) have used BART
modulate delay discounting rate, episodic future thinking to show how the expectancy impairments reduce
(EFT) seems more promising in the field of SUD (Daniel marijuana-induced risk-taking. BART has also been used to
et al., 2013; Kaplan et al., 2016). Chiou and Wu (2017) test the effectiveness of different intervention strategies for
have shown that EFT not only modulates discounting rate SUD treatment such as community-based services (Forster
but also decreases cigarette consumption. This evidence is et al., 2017), contingency-based management (Beckham
replicated in e-cigarette (Stein et al., 2018) and alcohol et al., 2018), tDCS (Guo et al., 2018; Kaplan et al., 2016),
(Bulley and Gullo, 2017). and computerized therapy strategies (Zhu et al., 2018).
Balloon analogue risk task Iowa gambling task

Background: Lejuez et al. (2002) developed the Balloon Background: In general, in gambling tasks, participants
Analogue Risk Task (BART), inspired by Slovic’s devil should bet on two different options: one with greater gains
task (Slovic, 1966), as a laboratory measure to assess real- (and losses) but less success likelihood and the other with a
world risk-taking behavior. In the BART, participants are higher probability of success but fewer gains (and losses).
asked to pump a balloon to gain as much reward as possible Among different gambling tasks, Iowa gambling task (IGT)
with the caution that the balloon may explode in any time; is perhaps the most commonly used. With the aim of
and the more they pump, the more will be the risk that assessing the role of the ventromedial prefrontal cortex
balloon bursts. Here, like the real-world situations, being (vmPFC), Bechara et al. (1994) developed a task to simu-
riskier will bring more reward to a turning point after which late the real-world decision-making under ambiguity in the
increasing in risk-taking might result in a loss. Later, Ple- laboratory. The idea here was to let the participants select
skac et al. (2008) developed another version of the task in one card from four decks of cards with different probabil-
which participants are asked about the number of pumps ities of gain and loss, with the aim of maximizing their
they desire and the balloon would be pumped automatically monetary gain. The most important point here is that the
up to that number with the possibility of a burst in every number of trials and the reward/punishment rules is hidden
pump. A youth version of the task, in which monetary from the participants. In this regard, the IGT is addressing
balance is replaced with a point meter has also been the nonconscious biasing step in decision-making (Bechara
developed. Here, participants are told that their final points et al., 1997).
will determine the final reward (Lejuez et al., 2007). Structure: Originally, the IGT was comprised four
Structure: In its original form, pictures of balloons are decks of cards with different monetary gains and losses (A
presented to the participants asking which balloon they and B with $100 and C and D with $50 gain/loss). Due to
want to pump. Each pump brings a reward (a 5-cent gain the gambling nature of the task, cards with more rewards
per pump) and the participant may press a “stop” button to would have higher punishment probability. Participants are
send the gained money to the depository. However, the told that they can select one card in each trial to maximize
cash balance is not shown to the participant. Each trial their initial balance of $2000 (Bechara et al., 1994). It has
consists of three different colors of balloons, 30 balloons been shown that the task has three stages: (1) prehunch
each, with different probabilities of burst and the task is stage (with an anticipatory skin conductance response), (2)
done for 90 trials. The dependent variable here is the hunch stage (that participants recognize the advantageous
number of pumps, which represents the amount of risk that cards while being unable to explain the logic), and (3)
each participant takes (Lejuez et al., 2002). Numerous conceptual stage (in which 70% of the participants find the
studies have investigated the reliability and validity of
logic behind the task and it happens around the card developed the game of dice task (GDT) to investigate
number 80 on average) (Garon et al., 2006). decision-making under risk. In the GDT, participants are
Evidence in SUD: IGT has been widely used in a va- asked to guess a dice and receive gains/losses relative to the
riety of SUDs to depict DMDs (Biernacki et al., 2016; success probability of their guess (larger rewards/losses are
Brevers et al., 2013; Bickel et al., 2017a; Kovács et al., assigned to the less probable options).
2017). However, not everyone supports the IGT as an op- Structure: In its original format, each participant re-
timum behavioral task to differentiate SUDs from healthy ceives an initial balance of 1000 V with the aim of maxi-
controls on DMDs or as a reasonable tool to predict or mizing this initial balance. In each trial, a dice is thrown
monitor treatment outcome (Buelow and Suhr, 2009; and participants must guess the number. The answer could
Gansler et al., 2011; Lin et al., 2013). be a single number (1e6) or any combination of two, three,
or four numbers. The amount of gain/loss to bet would also
Cambridge gambling task/risk task be decreased as the likelihood of the correct answer in-
creases. Thus, the wining chance would be 16% for the first
Background: The first version of Cambridge gambling set (single number guess) and 33%, 50%, and 67% for the
task (CGT) (or risk task) was developed to assess orbito- combination sets, respectively. In this regard, one- and two-
frontal cortex activity while choosing between different number guesses are the risky and disadvantageous option,
options associated with rewards (Rogers et al., 1999b). The the three-number sets are neutral, and the four-number
idea was to show an array of boxes (in two colors) to the guesses are advantageous options (Brand et al., 2005).
participants and ask them to guess the box with a hidden Before the task starts, the rules of rewards and punishments
yellow coin (token). But before showing the result, they are are presented explicitly to the participants. An interesting
requested to bet on their choice. The probability of success study has shown that these changes, compared to the con-
will be reflected in the ratio of the colored boxes (Rogers ventional gambling tasks (e.g., IGT), would lead to
et al., 1999a). different results as only the final trial of IGT is correlated
Structure: The main outcomes of the CGT are the with GDT performance (Brand et al., 2007). This might
decision-making time (i.e., how much it takes for the confirm that decision-making under risk and decision-
participant to find the targeting box), risk aversion/risk- making under ambiguity should be distinguished in
taking (i.e., the number of alternatives chosen with less/ studying DMDs.
more probability), and risk adjustment (i.e., the rate by Evidence in SUD: Brand et al. (2008) have shown that
which individuals change their choices after receiving re- patients with opioid use disorder have poor performance in
wards). In the CGT, the gambling amount could be either the GDT, and this is positively correlated with their exec-
ascending or descending and the participants can stop the utive functioning. In a cross-sectional study to find the
increase/decrease process by pressing a button and fixing effect of family history on the risk for alcoholism, Kumar
the desired amount to bet. The ratio of the colored boxes et al. (2018) used both IGT and GDT. Although authors
varies in each trial and could be 5:1, 4:2, and 3:3 while have not found any correlation between measures of these
reward to loss balance changes from 10:90 to 50:50 two tasks, they found that alcohol naive offspring at high
(Rogers et al., 1999b). risk for alcoholism show significantly lower performance in
Evidence in SUD: Initially, Rogers et al. (1999a) have both tasks.
shown that chronic amphetamine abusers have more sub-
optimal decisions in CGT and this was positively associ-
Effort expenditure to reward task
ated with the years of use. This finding is being replicated
in recent years among different SUDs (Aharonovich et al., Background: Effort expenditure for reward task (EEfRT)
2018; Grant and Chamberlain, 2018; Rochat et al., 2018). was introduced as a measure of motivation, effort-based
tDCS over DLPFC is shown to modulate a risk-taking decision-making and reward learning under the coste
measure in a version of CGT among cigarette smokers in benefit decision-making paradigm (Floresco and Whelan,
association to their nicotine-taking behavior (Fecteau et al. 2009; Treadway et al., 2009). In this multitrial task, par-
2007, 2014). ticipants have the chance to choose between two alterna-
tives in each trial to gain the reward (Treadway et al.,
Game of dice task 2012).
Structure: During the EEfRT, participants are asked to
Background: In most of gambling tasks, the rules of choose between two options. One with low effort and less
reward and punishment and their probabilities are not clear gain, and the other which is more effortful but brings more
to the participants. These tasks, including IGT, are basically gains. Doing the task, a virtual bar shows the points or
addressing the decision-making under ambiguity and not monetary reward that has been gained. The easy task option
under risk. With these assumptions, Brand et al. (2005) is to press a button with the pointer finger of the dominant
hand and the effortful task is doing the same but with the they need more information or not and then they guess the
lower finger of the nondominant hand. The easy task must jar (Garety et al., 1991). Dudley et al. (1997) have replaced
be done 30 times in 7 seconds and the hard one must be the beads with students (boys and girls) or words (positive
done 100 times in 21 s (Treadway et al. 2009, 2012). and negative) and schools instead of jars. In the box version
In another version, Lawn et al. (2016) have imple- of the task, a series of gray boxes are shown to the par-
mented EEfRT with a probabilistic reward task. In this ticipants with two different underlying patterns. Partici-
version, the rewards of the task are probabilistic in a way pants can uncover the gray boxes to see the pattern by
that one-third of the trials have 12% (low), one-third have clicking on them. They should guess which pattern is the
50% (medium), and the remaining trials have 88% (high) dominant one. Again, the more boxes they uncover, the
probability of success. Thus, even completion of the task more likely they will find the answer but it will reduce their
(either the easy or the hard one) does not necessarily lead to gain (Balzan et al., 2017).
the reward. If a participant fails to complete the task, her Despite the conceptual similarity between BTs, there
record would be excluded from the analysis. Here, the are some parameters to select among such as the number of
outcome variables are the winning chance in each trial (in trials, the number of beads, and the form of the feedback.
case of completion), the amount of reward (money) gained Furthermore, it must be noted that participants have asked
through effortful option, and the expected value (i.e., less information in the beads task compared with the box
adjusting the probability and magnitude of the reward) task. Decision-making error (whether the participant
(Lawn et al., 2016). guessed correctly) and time to the decision (how much it
Evidence in SUD: To show DMDs in SUD, EEfRT has takes to find the correct answer) are of interest.
limited and inconsistent evidence. Wardle et al. (2012) Evidence in SUD: Although BTs are originally devel-
have shown that caffeine can increase probability of taking oped in the context of paranoid and delusional patients’
more effortful options in EEfRT. Lawn et al. (2016) have population, it could be used to address the temporal aspect
used EEfRT to demonstrate how chronic effects of of DMDs in SUD. It has been shown that the construct of
cannabis use can impair effort-related decision-making and impulsivity in decision-making can be further divided into
reward learning. Furthermore, Hughes et al. (2017a) have two subscales: waiting impulsivity and reflective impul-
reported that while abstinence from tobacco increased sivity (Voon, 2014). Waiting impulsivity shows premature
reward sensitivity in self-reports, EEfRT performance did decision-making before receiving the cues to reward (Voon
not show any change. Despite conflicting evidence, EEfRT et al., 2016). Reflective impulsivity, on the other hand,
still provides important potentials to investigate the reward shows to what extent the individual gathers information
and learning aspects of DMDs in close relationship with before making a decision (Kagan, 1966) and is related to
motivation in SUDs in future (Pacheco-Colon et al., 2018). the JTC bias. Beads Task has been utilized to measure
reflective impulsivity in pathologic gambling (Djamshidian
Beads task, box task et al., 2012). In the field of SUDs, Clark et al. (2006) have
shown that smoking has a negative effect on the in-
Background: As a probabilistic inference task, beads/box dividual’s performance in Beads Task. Banca et al. (2016)
task (BT) assesses the level of effort to gather information have also used Beads Task in conjunction with several
before making a probabilistic decision (Phillips and other behavioral tasks and with the help of computational
Edwards, 1966). BT measures tendency to gather less in- modeling showed that binge drinkers accumulate less evi-
formation to make decisions (Jumping to Conclusion (JTC) dence before making decisions. Similar results have been
bias) based on the optimal stopping paradigm (Moutoussis replicated after acute administration of Methylphenidate
et al., 2011). (Voon et al., 2016). However, the field of SUD has few
Structure: In its original form, two bags (jars) with pieces of evidence addressing reflection and waiting
equal number of beads are presented to the participants. impulsivity and future studies with the help of different
Beads are in two colors (blue and red) and each bag has a variations of Beads Task may deepen our understanding in
dominant color with the predetermined ratio (80:20). A this area.
single bead from an array of (predetermined) beads is
shown to the participants and s/he is asked to guess the bag
Risk gains task
from which it has been taken. Participants can guess
immediately or ask for another bead to be shown. The more Background: Although originally designed to address the
draws they make, the more likely they guess correctly but risk and reward learning aspects of DMDs, risk gains task
with smaller gains (Phillips and Edwards, 1966; Mou- (RGT) has the potential to be utilized the temporal aspects
toussis et al., 2011). In another version, four jars are shown of DMD. Although originally designed to address the risk
in two pairs of colors (i.e., yellow and black/pink and and reward learning aspects of DMDs, RGT has the po-
green) and participants are first asked to express whether tential to be utilized the temporal aspects of DMD. The task
has been used in patients with HIV (Connolly et al. 2014), occasional stimulant users and it was reported that while
and depression (Engelmann et al. 2013) apart from SUD. having no behavioral difference with controls, stimulant
Structure: In the RGT, three numbers are presented to users presented less differentiated neural processing of
participants in an ascending order (e.g., 20, 40, and 80) for risky and safe options (Reske et al., 2015). Another study
the duration of one second each, and they can earn the replicated this evidence in a group of problem stimulant
value of each number by selecting one of them. Thus, users compared with those who desisted from stimulant use
participants are requested to either select a number right (Blair et al., 2018). Same results are also reported by Gowin
after seeing it on the screen or wait for the next larger value. et al. (2017) in a group of participants with cocaine use
However, they are informed that in waiting for the two disorder who preferred risky options more often following
larger values (i.e., 40 and 80), there is a risk of having the a loss. Furthermore, Gowin et al. (2014) used RGT and
numbers in red which means they have lost 40 or 80 points, showed that methamphetamine dependence can result in
respectively (Paulus et al., 2003). The RGT consist of three different behavioral neural processing patterns in making
trial types in a randomized manner: 40 nonpunished trials risky decision. This result has also been strengthened when
and 90 punished trials. Here, the outcome measures are the Bischoff-Grethe et al. (2017) have shown in response to
degree of risk-taking (i.e., the relative frequency of nonrisk anticipated gain or loss, there is an attenuated neural
option vs. risky options or the magnitude of outcomes) and response in chronic methamphetamine users.
the response to punishment as a function of previous trial
outcome (punished vs. nonpunished or the direction of the Concluding remarks on behavioral tasks
outcome) that shows sensitivity to punishment (Kruschwitz
et al., 2012). The area of behavioral tasks in studying decision-making is
Evidence in SUD: The RGT has been used in several not limited to what we have mentioned here, and there are
studies in the field of SUD. First, and in a case-control several other tasks developed in this field that are not
study, Leland and Paulus (2005) used the RGT in a addressed above. However, to make this chapter as relevant
group of undergraduate students and showed that in com- and concise as possible, we have focused on the behavioral
parison with never users, stimulant users made more risky tasks that are used more frequently in the field of SUD and
decisions. This evidence was further clarified with the help are assumed to be involved in our framework. Table 4.2
of neuroimaging techniques (fMRI) in a sample of presents a list of the most commonly used behavioral tasks.
TABLE 4.2 Summary of behavioral tasks for assessing decision-making deficits(DMD) in SUD.
Aspects
Self- Original of DM
report work deficits Outcome variables Snapshot
DDT Green Temporal Discounting rate Which do you prefer to receive?
et al.
(1996)
$19 in 10 days $17 in 2 days
Choose Choose
BART Lejuez Risk The number of pumps A B C D
et al.
$1.00
$0.75
(2002) $0.25
$0.50 E
pump pump pump Cash-out
F
pump
Continued
TABLE 4.2 Summary of behavioral tasks for assessing decision-making deficits(DMD) in SUD.dcont’d
Aspects
Self- Original of DM
report work deficits Outcome variables Snapshot
IGT Bechara Risk The final balance, the number of ad- Winnings:
et al. vantageous and disadvantageous cards Cash

0 1000 2000 3000 4000 5000 6000 7000 8000
Borrowed
(1994)
You have won $100!
A B C D
CGT/ Rogers Risk The final balance, time to find the hid-
RT et al. den coin
(1999a)
POINTS: 100 75
RED BLUE
GDT Brand et al. Risk The final balance, number of correct Dice Money Balance
Parcipant: # 1
(2005) and incorrect guesses Gain/Loss
Sex: Female
Age: 35
Years of Educaon: 12
Round: 1 of 18
+ 1000 €
Possible Combinaons Gains/Losses
1000€
8 500€
200€
100€
EEfRT Treadway Reward The final balance, the number of easy Choose Your Task
et al. tasks chosen, the number of effortful
Probability of wins: 50%
(2009) tasks chosen
Easy Task Easy Task
$ 1.00 $ 1.00
Press E Press I
<SPASCEBAR> to Complete Failure to complete You have completed the task
BT Phillips and Temporal The number of draws before guessing, 85% green beads 15% green beads
15% yellow beads 85% yellow beads
Edwards the final balance
Jar A Jar B
(1966)
Part 1
20 beads
Part 2
38 beads
RGT Paulus Risk/ The relative frequency of safe versus A 1 seconds 2 seconds 3 seconds B 1 seconds 2 seconds 3 seconds
et al. learning risky options overall and as a function You Lose You Win
(2003) of previous trial outcome 20 40 -80 20
C 1 seconds 2 seconds 3 seconds D 1 seconds 2 seconds 3 seconds

You Win You Lose
20 40 20 -40
BART, Balloon Analogue Risk Task; BT, Beads Task; CGT, Cambridge Gambling Task; - DDT, Delay Discounting Task; EEfRT, Effort Expenditure to
Reward Task; IGT, Iowa Gambling Task; RGT, Risk Gains Task; RT, Risk Task.
The table shows the targeted aspects of decision-making in individual differences. Moreover, having more personally
addition to the variable(s) being assessed and a snapshot of characterized information about the different aspects of
how the task looks like. As in the case of self-report decision-making deficits, there may be a greater chance to
measures, behavioral tasks have also been utilized to design and implement customized and mechanistically
address different functions of decision-making. However, targeted intervention strategies (Ahn et al., 2016). The
contrary to self-reports, here the risk/probability function is goals for computational models are to optimally fit the
the most prominently featured. In this regard, parameters behavioral data and to determine how these models differ
targeting the risk seeking or risk aversion behavior in for individuals with SUD.
combination with reward function are of interest in the Subsequently, latent variables can be obtained to
gambling/bandit tasks. Besides, there are tasks that assess address the targeting underlying cognitive processes
the temporal function, either in the form of delay dis- involved in decision-making and its deficits (Ahn and
counting rate or impulsivity. On the other hand, although Busemeyer, 2016). In addition to teasing apart the funda-
there are some tasks that address the learning functions in mental cognitive processes contributing to an individual’s
SUD, similar to self-reports, the learning from reward and behavior, hidden variables (i.e., parameters) estimated by
punishment is not adequately investigated through the these computational models can also highlight individual
behavioral tasks. We will discuss in the next section how characteristics and differentiate participants where con-
computational models can compensate this gap. ventional behavioral analyses paradigms might fail to do so
Furthermore, behavioral tasks are useful when there is or do so with less quantitative precision (Ekhtiari et al.,
some doubt about having a common insight about a phe- 2017).
nomenon between the researcher and the participants. Here, Computational models can be categorized into two ap-
a behavioral task can be designed to measure a specific proaches: data-driven and theory-driven (Huys et al., 2016).
cognitive process of the phenomenon while controlling for In data-driven approaches, machine-learning techniques are
other processes in a simulation of the real-world situations utilized in a number of different settings in SUD. This in-
in the laboratory. This places behavioral tasks in a position cludes case-control studies to differentiate substance users
that can help us reach a better understanding of the from healthy controls (e.g., Sun, 2017; Mumtaz et al.,
cognitive processes contributing to the different aspects of 2018) and cross-sectional studies to determine the corre-
decision-making deficits in SUDs (Ekhtiari et al., 2017). lation between different aspects of substance use severity
However, behavioral tasks have their own weaknesses. and decision-making deficits (e.g., Squeglia et al., (2016);
Apart from the low construct validity and reliability, it Bae et al., (2017); Alghamdi et al., 2018). Furthermore,
should be noted that behavioral tasks take just a snapshot of data-driven computational models are also used to design
the behavior under investigation. Furthermore, they have a (Kahler et al., 2017) and predict the effectiveness of treat-
low nomothetic span regarding the integrity with other ment strategies (e.g., Acion et al., (2017); Larney et al.,
measures, e.g., self-reports (Coskunpinar et al., 2012) and 2018).
recent findings show that in comparison to self-reports, they In comparison, theory-driven or model-based ap-
have less power in reflecting real-world outcomes (Eisen- proaches to computational modeling provide a more
berg et al., 2018). mechanistic view of the phenomenon under investigation.
Here, the idea is to differentiate the underlying processes
that shape decision-making and behavior. The theory-
Computational modeling driven approaches can be further divided into three broad
Different behavioral assessment paradigms have been used levels of description: synthetic or neural process models
in the field of SUD, and these behavioral tasks are designed (e.g., biophysically detailed models), algorithmic models
to assess the underlying cognitive processes engaged dur- (i.e., models that describe tractable, step-by-step computa-
ing decision-making (e.g., learning from experiences or tional processes to implement a particular function), and
sensitivity to punishment and reward). Although behavioral optimal (i.e., Bayesian) computation-level models that
paradigms have helped to improve our understanding of the describe the mathematical problem that the brain is required
cognitive aspects of decision-making deficits, the heuristi- to solve (Huys et al., 2016).
cally proposed dysfunctions in SUD may not exactly match There are also different types of models that span these
what is being observed on these tasks (Busemeyer and levels of description. For example, one recently proposed
Stout, 2002). Computational models can help with the idea class of models are called active inference models. Ac-
of decomposing overall performance of the participants on cording to these models, agents simultaneously seek to
behavioral tasks into component processes that are quan- minimize uncertainty about their environment and choose
tified by computational parameters. Thus, computational actions expected to produce the observations they prefer
models can provide a more profound understanding of the under their model (Schwartenbeck et al., 2015). Over time,
cognitive substrates of decision-making deficits based on agents also acquire expectations about their own patterns of
actions, and decision-making can be influenced by these made prospectively, based on an internal learned model of
expectations. Aside from providing an optimal computa- the environment. Here, an expected future is simulated
tional and algorithmic level of description, active inference using the so-called model-based (MB) learning system and
also includes a neural process theory that associates evaluating potential outcomes fuels the decision-making
particular neural populations with (for example) repre- process. Habit-based algorithms depend on the history of
senting beliefs about the causes of observations, particular past experienced rewards, regardless of the changes in the
patterns of synaptic connections with encoding relation- immediate model of the environment. Here, the so-called
ships between causes and observations, and the role of model-free (MF) learning system calculates and uses a
various neuromodulators (e.g., the role of dopamine in reward prediction error signal (i.e., the difference between
encoding confidence in action selection). Theoretically, in what was expected and what was received) in the decision-
these models, SUD could involve underconfidence in the making process (Daw et al., 2005; Huys et al., 2016;
successful implementation of long-term action plans, strong Keramati et al., 2011; Maia, 2009; Voon et al., 2017).
expectations to engage in certain actions, and/or very strong Recent findings have suggested interactions between
and precise preferences for drug-related observations, reward prediction error, model-based, and model-free
among other possible mechanisms. However, limited work learning processes in the brain (Sambrook et al., 2018).
to date has investigated these possible mechanisms empir- However, it is argued that the amount of resources needed
ically (Friston et al., 2017). for the model-based/model-free (MB/MF) learning sys-
A more commonly used class of models with a history tems, and estimates of their relative reliability in a given
of use in empirical studies are based on reinforcement context, shapes their role in the decision-making process.
learning (RL). This is to some extent because they have That is while the MB system seems to be more flexible and
been around much longer and they represent the affective convenient in new situations; due to evaluating all possible
(i.e., rewarding and punishing outcomes) and motivational outcomes, it needs more resources and is thus more
(i.e., reward-seeking) aspects of decision-making in a expensive. MF systems, in contrast, need fewer resources
simple and straightforward manner. Specifically, RL and are more efficient in situations with resource scarcity
models describe trial and error value learning processes (Huys et al., 2016). Based on this classification, it is
during decision-making tasks in which the values of thought that SUDs can be understood as a result of shifting
different possible actions in different possible states are from MB- to more MF-guided behavior (Lucantonio et al.,
learned through repeated observations of the outcomes 2014; Sebold et al., 2014; Huys et al., 2014). There is also
produced by those actions. Quantifying these values in the evidence showing that not only can this transition initiate
way they are learned may provide a better understanding of SUDs (Galandra et al., 2017), but it also may lead to more
the cognitive basis of choice processes in the brain. This is relapses (Sebold et al., 2017).
done by comparing the model’s behavior under different
parameter values to the trial-by-trial behavior observed in Computational models of behavioral tasks
the experiment to find a parameter values that best repro-
duce of participants behavior, typically using statistical Several computational models have been developed to
techniques like maximum likelihood estimation and hier- explain SUD-related dysfunctions in MB learning systems.
archical Bayesian modeling (Daw, 2011; Lee, 2011). Here, we review the two main behavioral paradigms in
RL has three main components: states, actions, and assessing decision-making deficits: probabilistic risk-taking
outcomes. States are the current situations that the agent tasks (exemplified by the IGT) and sequential risk-taking
experiences, such as the present stimuli and the agent’s tasks (exemplified by the BART).
location. In each state, the agent selects an action which For the IGT, three initial computational models were
will bring her to a new state and also lead to receiving an introduced by Busemeyer and Stout 2002. The first is the
outcome that can be positive or negative to different de- strategy-switching heuristic choice model in which an
grees (positive or negative reward values). In this regard, initial tendency leads the participant to the “disadvanta-
reinforcement is the process by which, given a certain state, geous” decks. Nevertheless, after receiving several losses,
outcomes influence the probability of future actions. The the participant “switches” choice toward the “advanta-
goal of the agent is to choose the sequence of actions geous” decks. In this model, three parameters are of inter-
(policies) that leads to the highest amount of reward in the est: the initial tendency to choose the disadvantageous
long run (Maia, 2009). decks and two other parameters that determine the shape of
Furthermore, this learning to maximize approach can be a logistic function, representing the switching tendency
classified into two general classes of algorithms: goal- based on the losses received from the disadvantageous
directed or habitual. In the first approach, decisions are decks.
The second approach is the Bayesian-Expected Utility there is an option evaluation in addition to trial-by-trial
Model in which it is assumed that choices are made based learning. They have shown that in the BART, the best
on the premises of bounded rationality. In this model, explanation for the performance of the participants is that
participants use Bayesian inference to estimate the proba- they neglected the probabilistic nature of the trial outcome
bility of future gains or losses based on the experienced and used their judgment to guess the next trial’s probability
outcomes in each trial. The Bayesian-expected utility in a Bayesian updating process. Examining the correlation
model has three major elements: (1) probability of between the parameters of the computational model and
receiving a loss from a specific deck in each trial; (2) the substance use risk, it was also shown that the reinforcement
utility of a possible gain/loss in each trial; and (3) the choice specificity (monetary vs. sexual reinforcements) has no
rule, which is based on a comparison of the expected utility significant influence on predicting BART performance
for each deck and whether that deck is really chosen or not. (Prause and Lawyer, 2014).
Here, the parameters of interest are the probability of
guessing the maximum utility option and two other pa- Concluding remarks on computational models
rameters that shape the utility function for gains and losses
(Busemeyer and Stout, 2002). The role of computational models as an assessment para-
The third approach to explain how participants make digm for studying DMDs in SUD is largely related to the
decisions in the IGT is the Expectancy-Valence Learning behavioral paradigm utilized. Thus, as most of the
(EVL) model and its variations. The idea here is that after computational models are developed for the behavioral
receiving gains/losses in each trial, participants would risk-taking assessment tasks (e.g., IGT and BART),
experience a positive/negative emotional reaction computational models are mostly targeting the temporal,
(valence). The valence experienced in each trial shapes the risk, and reward aspects of decision-making deficits. For
participants’ choice through the process of expectancy example, Gullo and Stieger (2011) have shown that during
learning. Then, the probabilistic choice is made as a an IGT task, anticipatory stress in heavy drinkers increased
function of expectancies associated with each deck. Here, attention to losses and thus resulted in better task perfor-
the parameters of interest are the weight of attention to mance. Lane et al., 2006, have also used the EVL model to
losses, the learning rate, and the sensitivity switching. show that different substances have distinct effects on
In a newer version of the EVL model, Ahn et al., 2008, several aspects of reward/punishment sensitivity. They
have introduced Prospective Valence Learning (PVL) with have shown that alcohol increases attention to risky re-
some modifications in the utility learning and the choice wards while decreasing responding to risky losses. Mari-
probability functions. In this version, there are three pa- juana, on the other hand, increased the tendency to take
rameters of interest. This includes (1) a loss parameter that risky decisions due to influences on learning/memory and
means being insensitive to losses produces a poor IGT not on the motivational aspects. This finding has been
performance; (2) a recency parameter that shows how a confirmed by studies in which, even after punishments,
former experiences decay rate may result in poor perfor- people with alcohol use disorder did not change their
mance on the IGT; and (3) a sensitivity parameter, showing choices (Reiter et al., 2016). Furthermore, it is argued that
to what extent the participant is focused on the optimization computational models can help us quantify and trace the
of her former choices instead of choosing randomly. A two- changes in neurobiological and neurophysiological mech-
parameter version of the expectancy-valence model also anisms (e.g., Pavlovian and Instrumental learning) involved
exists in which the consistency parameter is assumed in relapse due to alcohol-related contextual parameters
constant. It is shown that this modified model has clearer (Heinz et al., 2017).
results (Humphries et al., 2015). It is also shown that PVL In summary, computational models can help us model
can better explain IGT performance in SUD patients some of the fundamental computations in the human brain,
compared with healthy controls (Ahn et al., 2016; Baitz, especially in reward learning processes (Hauser et al.,
2016; Dai et al., 2015). 2019). However, determining the exact cognitive processes
In a conceptually similar attempt, Wallsten et al., under investigation, designing new and to-the-point tasks
2005b, have introduced three models to explain overall suitable for modeling, and implementing test-re-test longi-
performance in the BART. They have assumed a baseline tudinal studies to show the reliability and validity of the
model in which no learning or sequential decision-making tasks and model parameters are among the main challenges
occurs. In addition to that, there is a target model in which in utilizing computational models (Ahn and Busemeyer,
no further evaluation is made by participants, although 2016). Fig. 4.1 presents a classification of the computa-
there is still a trial-by-trial learning function. Finally, the tional models used in the assessment of decision-making
learning and evaluation model assumes that in each trial deficits in the field of SUD.
Prospect
Learnign and
Valence
Evaluaon
Learnign
Model
Models
Predicon
Synthec Biophysical Bayesian Algorithmic Expectancy Valance Learnign
Error Signal
Models Models Models Models Models
Processing
Model-free
Learning Model-Based Learning System
System
Machine Computaional
Reinforcement Learning Learning fMRI
Approches Approaches
Data-Driven
Theory-Driven Models
Models
Computaonal Models for Decision-Making Deficits

FIGURE 4.1 Classification of computation models for studying decision-making deficits in substance use disorder.
Neuroimaging oxygenation/deoxygenation in that specific area (or

possibly in other parts). Thus, monitoring BOLD signal
Decision-making, as a multifaceted phenomenon, has might represent different levels of activities in the brain.
several representations of different levels, from attitudes Different imaging protocols could be implemented ac-
and behaviors to physiological processes and neural cir- cording to the aims of the investigations. Task-based fMRI
cuitry. Respectively, DMDs in SUD can be studied at is used in the studies in which the participant is asked to
different levels to characterize behavioral, cognitive, and perform a behavioral task while lying in the scanner to find
neural substrates of this phenomenon. Among these the correlations between behavioral tasks performance and
aspects, conscious attitudes and trait aspects of decision- the underlying brain circuitry.
making (measured by self-report), nonconscious dimensions In the area of SUD, fMRI is used to provide a better
and behaviors (targeted by behavioral assessment para- understanding of the biological underpinnings of substance
digms), and hidden cognitive processes (addressed by use, e.g., initiation, maintenance, consequences, and re-
computational models) have been reviewed in the pre- covery (Tarokh, 2012). In the field of DMDs, the neuro-
ceding sections. In this section, we move to another brain- cognitive components of decision-making can also be
based level of description in SUD, which reflect neural studied using functional neuroimaging. It is argued that
circuitry activations, and which is mainly addressed by there are four main systems involved in DMDs in SUD
neuroimaging methods. However, although different including the midbrain striatum system, amygdala-
neuroimaging techniques have been utilized, according to hippocampal system, insula ACC system, and PFC sys-
the aims of this chapter, we would limit this section to the tem (Ekhtiari et al., 2017; Zilverstand et al., 2018).
fMRI studies and the role that task-based fMRI techniques To illustrate how task-based fMRI protocols can help us
plays in studying DMDs in SUD. going through neural/physiological levels of decision-
Simply put, the ultimate goal of fMRI studies is to making deficits, in this section, we review some of the
examine the functional activity/connectivity of different latest evidence in addiction medicine. To keep the section
brain regions/networks, to find the relationship between adequately concise, we limit our focus to the four mostly
behaviors, cognition, and their neural substrates. This is utilized behavioral tasks in DMD studies: DDT; IGT;
attempted in fMRI mainly using the blood-oxygen-level- BART; and CGT.
dependent (BOLD) signal. The idea here is that activity
in different brain areas modulates the level of blood
Task-based fMRI evidence in SUD paradigm, it is assumed that one can assess the reward
dimension of decision-making with this behavioral task as
fMRI and delay discounting tasks well. In this regard, an exploratory study showed greater
SUD is proven to have a negative effect on delay dis- activity in the ACC and inferior frontal gyrus/anterior
counting rates, that is, substance users discount delayed insula in loss aversion status (i.e., deciding not to inflate
rewards more significantly, compared with healthy control more), as well as more activity in vmPFC when participants
groups. As a behavioral trait addressing the temporal aspect choose the more risky options (i.e., continuing to inflate)
of the decision-making deficits, delay discounting has (Fukunaga et al., 2012). Similar results are reported for
neural representations in the brain circuitry that can be used college-aged cannabis users, as cannabis users showed
to distinguish between different groups of patients and more activity in left inferior frontal gyrus, as well as the
healthy individuals (Claus et al., 2011; Peters and Büchel, finding that cannabis uses severity can influence the activity
2011). In this regard, Elton et al., 2017, have shown that in the precuneus (Paneto, 2017). However, recent findings
two large-scale brain networks are involved in DDTs: (1) a with a different gambling task showed the influence of the
temporal lobe network that has a positive relationship with expected value on the role of ACC and inferior frontal
DDT related impulsivity and (2) a frontoparietalestriatal gyrus during risky choices (Fukunaga et al., 2018).
network that has a negative relation with DDT related Kohno et al., 2014, have shown that neural correlates of
impulsivity. risky decision-making during BART are different in
Furthermore, in a recent study, Nestor et al., 2018, have methamphetamine-dependent patients and a healthy control
investigated the neural correlates of current smokers, ex- group. Based on this study, the activation in the ventral
smokers, and healthy control group and showed that both striatum (more in SUD) and right dlPFC (less in SUD) was
current smokers and ex-smokers have less activity in left positively associated with the number of pumps in the
amygdala during positive response outcomes and ACC BART task. The role of the reward-seeking medial frontal
during the positive and negative outcomes. They have also cortex (mPFC) in the excessive substance use was formerly
shown that activity in ACC and middle frontal gyrus was shown, as activation in mPFC during BART, could predict
negatively associated with nicotine dependency and con- alcohol consumption in a 1 week follow-up (Bogg et al.,
sumption level. It has also been shown that alcohol con- 2012). Claus et al. (2018) used BART with fMRI in the
sumption level was positively correlated with attenuated adolescents, who were using alcohol, marijuana, or both
frontal and parietal activity in a DDT (Herman et al., 2018). and found that all subjects had greater activation in the
This is consistent with former findings that alcohol con- dorsal ACC (dACC), anterior insula, ventral striatum, and
sumption severity has a positive correlation with activity in lateral PFC. Patients who used both substances showed
paracingulate gyrus and frontal lobe in delayed decisions decreased responses in dACC, insula, striatum, and supe-
compared to impulsive decisions (Lim et al., 2017). rior parietal lobe during risky decision-making.
Task-based fMRI could also be used to study the In addition to finding the neural substrates of risky
interventional strategies designed to improve delay dis- decision-making, task-based fMRI is used to investigate
counting performance. Schmaal et al., 2014, have shown interventional strategies. In a community-based substance
that receiving a 200 mg modafinil can improve delay dis- use treatment program, Forster et al. (2016) used fMRI
counting performance in alcohol-dependent patients. fMRI during BART and showed that an improvement in risk-
data showed that this improvement was due to increased informed outcome expectations was positively associated
activation in frontoparietal regions while reducing ventro- with more activation in the caudal ACC in high-risk re-
medial Prefrontal Cortex (vmPFC) activation. sponses and less activation in the caudal ACC and inferior
Lempert et al., 2017, have also shown that recalling frontal gyrus during negative responses. Besides, less
positive memories can improve delay discounting perfor- activation in the vmPFC (responding to higher rewards)
mance. This effect was also reported by other scholars could predict lower consumption levels in the follow-up
(Peters and Büchel, 2010; Daniel et al., 2013). However, (Forster et al., 2017).
positive memory recalling might be considered as a reward
as fMRI showed higher activity in the striatum and tem- fMRI and Iowa gambling task
poroparietal junction (which is related area in reward pro-
Among the gambling tasks that address the risk-taking and
cessing), while recalling positive memories.
reward learning aspects of the decision-making deficits, the
IGT is the one that relies on decision-making under am-
fMRI and balloon analogue risk task biguity. It is argued that IGT performance can distinguish
BART mainly addresses the risk aspect of the decision- between healthy participants and patients with medial
making deficits. However, as a sequential risk-taking frontal damages, including substance dependents (Tanabe
et al., 2007). Using IGT and fMRI, Lin et al. (2012) re- betting stage, frontal lobe and putamen, and in the outcome
ported that heroin dependents had greater activity in right (i.e., reward anticipation) stage, caudate nucleus and ventral
orbitofrontal cortex and medial PFC compared with the and dACC have shown greater activity. However, as there
control group. Similar results are shown in a study to find is not much evidence in the SUD with the CGT, future
the neural correlates of affective decision-making, where studies might show if CGT/risk task could be combined
binge drinkers showed worse performance in IGT. with fMRI protocols to provide a better understanding of
Furthermore, greater activation in insula compared with the the neural basis of real-world risk-taking behaviors.
orbitofrontal cortex was positively related to drinking
severity (Carbia et al., 2017; Xiao et al., 2013). Another Model-based fMRI approaches
study, using a modified version of IGT (Thompson et al.,
With the power of computational models in recognizing the
2012), showed more activation in frontostriatal and limbic
underlying processes of cognition and behaviors, there are
regions during IGT in the substance-dependent participants
some hopes that model-based fMRI might also fill the gap
(Yamamoto et al., 2014).
between physiological and behavioral levels of cognitive
In prospective settings, IGT-based fMRI was used to
phenomena. Similar to the computational models for
show that heavy cannabis users had more activity while
behavioral tasks, computational neuroimaging approaches
winning, in the regions involved in decision-making (i.e.,
are used to provide individual-specific analysis, which
right orbitofrontal cortex, right insula, and left superior
might lead to single-subject predictions and more person-
temporal gyrus). Furthermore, win-related activity and ac-
alized treatment strategies (Stephan et al., 2017). For
tivity related to the anticipating loss outcomes in the areas
example, in an attempt to find if a failure in neural mech-
related to executive functions (i.e., right insula, right
anisms of prediction error (a physiological signal that leads
caudate, and right ventrolateral PFC) could predict
the feedback-based decision-making) could play a role in
cannabis use in a 6-month follow-up (Cousijn et al., 2013).
substance-dependent patients’ performance in IGT. Tanabe
In addition to that, Fukunaga et al. (2013) modified the IGT
et al. (2013) used the computational neuroimaging
and added positively framed, negatively framed, and con-
approach. They found that compared with the healthy
trol messages about the long-term deck payoffs and showed
controls, in substance dependents, ventral striatum and
that substance-dependent participants have had lower neu-
medial orbitofrontal cortex did not track the prediction error
ral sensitivity in the ACC and anterior insula, showing
during the IGT. It is also argued that substance use might
worse performance after receiving negatively framed mes-
attenuate prediction error signal due to higher levels of
sages that reflects lower levels of risk aversion. However,
activity in mesolimbic areas (García-García et al., 2017).
recent findings reveal that because neural substrates of real-
Beylergil et al. (2017) have also used parametric modele
world risk-taking behavior are not localized in a single
based fMRI analysis to examine the neural mechanisms of
region, studies with an overall data driven from the whole
prediction errors during a reward-guided task (Deserno
brain activity might inform interventional strategies more
et al., 2015). They revealed that alcohol dependency and
substantially (Sherman et al., 2018).
the level of consumption made the left dlPFC less engaged
fMRI and cambridge gambling task in the processing of the negative prediction error signals. In
this regard, Cservenka et al. (2017) have developed and
CGT and risk task address the risk-taking and reward tested an alcohol-specific prediction error task using fMRI
processing aspects of the decision-making deficits. Using and found that compared to social drinkers, alcohol de-
fMRI with the CGT, it has been shown that compared with pendents showed greater prediction error-related activity in
controls, patients with SUD had higher levels of risk-taking the left superior parietal lobule, lateral occipital cortex, and
that was correlated with lower activity in ventral striatum postcentral gyrus, which were not normally addressed in
especially during the reward anticipation phase (Schneider prior studies. In another recent study, cocaine users
et al., 2012). Later on, a longitudinal study of adolescents completed a loss-learning task while being scanned and the
showed that lower activities in the ventral striatal and results showed that cocaine deprivation increased positive
midbrain and dlPFC during the reward anticipation phase in learning and positive prediction error responses (Wang
the CGT can predict SUD in a 2-year follow-up (Büchel et al., 2019).
et al., 2017).
In a most recent attempt to find the neurobiological
Concluding remarks on the task-based fMRI
processes during the CGT, Yazdi et al. (2019) found
different neural circuits activation during different phases As shown in the preceding sections, task-based fMRI might
of the task. Specifically, they have shown that during the be used in different settings and with different protocols to
make a link between decision-making deficits at the regard, as we have narrowed our review to human studies,
behavioral level and their neurobiological representations. we start this section with cross-sectional studies from the
Oldham et al. (2018) investigated several fMRI studies bottom of the pyramid. Then, going upward, we have case-
using the Monetary Incentive Delay Task and found that control studies, cohort studies, randomized controlled
during the anticipation phase several areas including the studies, and finally metaanalyses and systematic reviews.
striatum, amygdala, and thalamus are involved. Another Now we review each level briefly to form the third
systematic review showed that impairment in six large- dimension of our framework.
scale brain networks is involved in different substance- Cross-sectional studies: These studies are mostly
related behaviors apart from the substance type (reward, designed to investigate a correlation between a targeting
habit, salience, executive, memory, and self-directed). variable (i.e., outcome) and the variables having the po-
Based on this, while the executive and salience networks tential effect (i.e., independent variables). In these studies,
are most involved in the initiation phase of substance use, the outcome behavior can be explained based on the pa-
reward network deficiencies might play a more prominent rameters involved (unlike case-control studies). In the
role in the next phases (Zilverstand et al., 2018). decision-making deficits studies in SUD, the cross-
It is, however, argued that there are some inconsistent sectional setting is used to investigate if there is a corre-
findings with regard to the role of specific areas in decision- lation between a variable of interest in decision-making and
making deficits, for example, the role of the striatum in outcomes related to SUDs, e.g., substance consumption
reward processing (hyperactive or hypoactive) in substance severity, demand, time to replace, risky behaviors, and etc.
dependents is inconsistent between studies. Luijten et al. For instance, Adams et al. (2017) showed that acute alcohol
(2017) suggested that different levels of activities in striatal consumption does not have a meaningful relationship with
regions during different stages of reward-based decision- delay discounting, although it is argued that delay dis-
making tasks might be interpreted with different theories counting has a positive relationship with the intention to
(i.e., reward deficiency for the striatal hyperactivation quit smoking (Athamneh et al., 2017). In another cross-
during the anticipatory phase and the learning deficit theory sectional setting, Courtney et al. (2018) showed that
for the striatal hyperactivation during the outcome phase). reward system activation has a positive relationship with
This could highlight the multidimensional aspect of drinking. As an advantage, by utilizing data collection and
decision-making deficits and the need to consider several analysis tools that are easy to implement, cross-sectional
theories to get the most out of experimental findings. studies seem to be able to recruit larger sample sizes.
Furthermore, one possible suggestion is to have a global However, these studies cannot be considered as causee
view of the brain communications, based on the functional effect models. In other words, cross-sectional studies only
connectivity of different brain networks and using other show that there is a correlation between the target and in-
brain mapping techniques (e.g., Positron Emission To- dependent variable(s) but this does not mean that there is a
mography) to tease apart the substance-related neural ac- causal relationship between the two. There are potentials
tivities (Sharma, 2017; Suckling and Nestor, 2017). In this toward more causal interpretation from cross-sectional data
regard, in a multimodal imaging study, Vuletic et al. (2018) with quasiexperimental data analysis methods, but, at the
have shown that frontal, striatal, and limbic regions are end of the day, even these advanced statistical methods
involved in methamphetamine use disorder. However, cannot claim causality with cross-sectional data (Marinescu
decision-making deficits studies can more benefit from et al., 2018; Pearce and Lawlor, 2016).
these methodological innovations. Case-control studies: The main objective of a case-
control study is to investigate a variable in different
Third dimension: levels of evidence in groups of participants. Thus, case-control studies are
mostly limited to the group of interest and are not going to
decision-making studies cover the whole population. In the field of decision-making
The body of evidence in decision-making studies in SUD deficits in SUD, case-control designs are used to show how
can be understood based on the well-known quality of a variable can characterize a specific decision-making
evidence pyramid under the evidence-based practice para- deficit among patients. In addition to that, in case-control
digm (McGovern and Carroll, 2003). As a guiding tool to studies for DMDs in SUDs, we are looking for differ-
understand the different levels of evidence and despite ences in DM between healthy controls and people with
different versions, the general rule is that as one goes down SUD or within the groups with SUD matched or controlled
the pyramid, the number of publications in the field infor other variables such as age and education. However,
creases while the quality of evidence decreases. In this there is a difference between case-control studies and
historical cohort studies in which we consider DMD as a processing view, can predict the effectiveness of a
risk for SUD. Among the recent evidence in case-control community-based treatment in a sample of individuals with
studies, Costumero et al. (2017) have shown that reduced SUD (Forster et al., 2017). In another study, Sebold et al.
activity in functional networks during the processing of (2017) showed that alcohol expectancies can predict future
nondrug-related rewards can characterize the cocaine- alcohol dependence in 48 weeks follow-up. In another
dependent patients from healthy controls as they have setting in this level, the status of a specific variable is
showed diminished modulation in the left frontoparietal monitored during a period of time and in a longitudinal
network in response to unpredicted erotic pictures. In setting. Stewart et al. (2017) showed that transition from
another case-control study, delay discounting was shown to stimulant use to stimulant use disorder within a 3-year
have the power to distinguish between different groups of period in a group of occasionally stimulant users was
smokers (Hofmeyr et al., 2017). Case-control studies related to the gradual alteration in the neural substrates of
(compared to prospective ones) are faster to complete, do reward processing (i.e., anterior cingulate and insula
not face major dropout, and as a result, will be accom- cortices).
plished with a lower cost. However, there is always the risk Randomized controlled studies: In these studies,
of having bias both in sample selection and in interpreting normally there are two groups of participants: control group
the results. For anyone in the SUD research business, it is and intervention/treatment group. The main idea here is that
clear that finding a control group matched even for de- participants are divided in these two groups randomly
mographics is not easy. We know that even controlling for (unlike cohort studies). This will decrease different biases
confounding variables with statistical methods in case- in the study and may lead to discover the effects of inter-
control studies does not completely solve the problem. vention/treatment based on the comparison of the results of
Considering these limitations, running case-control studies the two groups. In the field of decision-making deficits in
for DMDs in SUDs can be an important initial step to show SUD, a number of RCTs have been implemented especially
if our variable of interest is basically able to differentiate with the aim of evaluation of treatment strategies. For
between groups. However, finding relationship between example, in a double blind placebo-controlled study, within
variables of interests and measures of disease severity will a 2 years period, it is shown that chronic nicotine depen-
increase the quality of evidence. But, eventually, prospec- dence has some effects on the behavioral and neural aspects
tive studies will provide a more causal insight to the of cognitive flexibility in smokers with regard to reward
importance of DMDs in the pathogenesis of SUDs. The aim sensitivity (Lesage et al., 2017). In another attempt, Kulis
of prospective studies, which are usually implemented in a et al. (2017) utilized a random controlled setting to test and
longitudinal setting, is either to predict a future variable based compare the effectiveness of two substance use prevention
on the current state or to monitor a specific decision-making programs that were designed and implemented to improve
variable in a sample. Here, maintaining a high retention rate decision-making and drug resistance skills in urban
in different follow-up phases is a big challenge. American Indian youth community.
Cohort studies: These studies are designed in a natu- Systematic Review and Metaanalyses: Finally, in the
ralistic longitudinal settings and aimed to find the status of peak of the pyramid, we have the systematic reviews and
the desired outcomes in a period of time. In these studies, metaanalyses. These settings are used when a significant
participants that already have the attributes under investi- body of evidence in the lower levels is available. Thus,
gation are included. Due to the time-consuming nature of systematic reviews and metaanalyses are designed to find
these studies, the cost would be high and there is always the an answer to the key questions and debating topics in the
risk of participant withdrawal or change in the research field. In the field of decision-making deficits in SUD, for
methodology due to the unpredicted conditions. In the field example, Barlow et al. (2017) have reviewed the relation-
of decision-making deficits in SUD, in a longitudinal ship between time-discounting and tobacco smoking. They
observational cohort study, it is shown that lower impul- have examined 69 studies and found that time-discounting
sivity can predict the poorer quality of life in the period of is considered to play as a risk in tobacco smoking. In
6e9 weeks after treatment in a population of another attempt, Hughes et al. (2018) tried to find if nico-
methamphetamine-dependent individuals (Rubenis et al., tine deprivation can result in less sensitivity to rewards in
2018). Furthermore, sometimes, the objective is to find if abstinent smokers. They have found that despite different
any variable in a sample population can predict a specific findings in the field, one cannot assert that abstinence in-
behavioral index in the future. In the field of decision- creases consummatory anhedonia (i.e., learning from the
making deficits in SUD, for example, it is shown that rewards). However, abstinence is considered to play a role
neural responses to negative outcomes, from a reward in anticipatory anhedonia.
Levels of evidence
Self-reports
Computaonal Models
Neuroimaging
FIGURE 4.2 A three-dimension framework to organize available literature from decision-making deficits studies in substance use disorder.
Lack of replicated longitudinal and interventional evi- utilized in investigating the DMDs in SUD. Here, we have
dence for DMDs in SUDs is the one of the main reasons for reviewed self-reports, behavioral tasks, computational
the current large gap between DM studies and daily clinical models, and fMRI techniques. The last dimension of the
practice in addiction medicine. space is the quality of the evidence which includes cross-
sectional, case-control, cohort, randomized controlled,
metaanalyses, and systematic reviews. In this dimension,
Three-dimensional matrix of evidence: we also have narrowed our work to the experimental human
cognitive functions, assessment studies and thus two bottom levels of the pyramid (i.e.,
paradigm, and levels of evidence reports and opinions and animal trials) are not included in
Fig. 4.2. We hope having a research matrix based on the
As we discussed through this chapter and summarized in
available evidence in the proposed three-dimensional space
Fig. 4.2, each piece of evidence provided through publi-
will help researchers to fill the gaps with quality evidence
cations addressing DMDs in SUD can be positioned in a
in the future.
three-dimensional matrix. This heuristic framework is
helpful to conceptually organize aberrant evidence in the
field for newcomers and also provide a map that shows
Summary and concluding remarks
serious gaps in the field. In a summary, the first dimension DMDs are assumed to have a significant role in the initi-
consists of the cognitive functions of decision-making ation, maintenance, and recovery of SUDs. That is why
deficits. Here, we have the value, probability, temporal, many scholars have attempted to investigate theses deficits
and learning functions as described in the initial section. In from different perspectives and with several research set-
the next dimension, the assessment paradigms that could be tings. This has resulted in a large body evidence for DMDs
in the field of SUD addiction medicine with many contra- needed to validate these potential biomarkers toward their
dictions and gaps. However, it seems that having a simple clinical application.
heuristic framework may help researchers to better position Finally, we assert that for the variables related to DMD
their research projects to fill the gaps in studies of DMDs in to play a biomarker role, a number of criteria must be met.
SUDs. With this objective, in this chapter, we have intro- First, they must be quantifiable as researchers can use
duced a three-dimensional matrix in which recent findings quantitative measures to assess those variables. Second,
in the field can be positioned and interpreted. they have to be replicable. Unless several studies can
As the first dimension of the framework, we have simulate the same assessment conditions and replicate the
investigated the cognitive functions of the decision-making experiments, we cannot name our findings as a biomarker.
deficits as temporal functions, value/reward functions, risk/ Reliability is another major challenge in all assessment
probability functions, and learning functions. Here, paradigms. Unless a marker could have a reasonable level
reviewing the recent findings in the field reveals that not all of reliability in multiple assessments, it is hard to be able to
aspects of the decision-making deficits are investigated use it as a biomarker to inform clinical decisions. Not only
equally and adequately. The second dimension is address- reliability is necessary for the interpretation of the results in
ing the assessment paradigms being used in the studies of longitudinal studies but it is also a must-have feature if we
the decision-making deficits in SUD. Here, we have are looking forward to having effective interventions tar-
reviewed self-reports, behavioral tasks, computational gets. Fourth, we like to have a clear mechanistic relation-
modeling, and fMRI paradigms. Fig. 4.2 shows a unified ship between the targeting decision-making variable and
form of the assessment paradigms with regard to units of the pathological characteristics of SUDs. Finally, decision-
analysis, levels of assessment, and levels of targeting making variables must be clinically meaningful to be
constructs. As shown in this figure, self-reports are most labeled as a biomarker. This means that they must have the
used for the higher-level constructs (i.e., personal states, power to (1) distinguish between different groups of pa-
attitudes, and traits) and moving to the right end of the tients and healthy control groups, (2) show a relationship
continuum, studying the lower level units of analysis (i.e., with SUD severity and drug consumption, (3) have the
behaviors, cognitive processes, and neural circuits) will power to predict future states within a causal relationship,
bring the need for other assessment paradigms such as and (4) could be utilized in the assessment of the effec-
behavioral tasks, computational models, and neuroimaging tiveness of interventional strategies. Unfortunately, there is
methods. Furthermore, a combination of different para- no single biomarker available yet not only in DMDs in
digms also can be utilized to perform second-level assess- SUD but also for all other neural and cognitive functions in
ments where task-based fMRI, model-based fMRI, more the entire field of psychiatry. However, there is a significant
theory-driven computational models, and multimodal neu- hope for future breakthroughs, and we hope the heuristic
roimaging methodologies are relevant. Currently, finding framework introduced in this chapter could contribute a
links between different levels of assessment is a big chal- small role to harmonize research in the field to move
lenge in the field. Recent findings show that there is not a forward.
significant overlap between variances in each two pairs We conclude this chapter pointing out that there is still
from self-reports, behavioral tasks, neuroimaging data, and no consensus among scholars about the most promising
actual behavior in daily life (Eisenberg et al., 2018; DMDs and their assessment tools to serve as biomarkers in
Thompson et al., 2017). addiction medicine. In this regard, there are two main areas
The third dimension of the framework is addressing the in which further investigations are needed for filling the
levels of evidence in studying DMDs in the field of SUD. gaps. First, we need more quality evidence for the current
This includes a range of studies from cross-sectional set- DMD measures. Design and implementation of more pro-
tings and case-control studies to cohort longitudinal studies, spective studies are necessary to find the longer-term
RCTs and systematic reviews, and metaanalyses. Here, we behavior of the variables related to DMDs. Furthermore,
argue that to achieve a better understandings of the neu- using more combined methodologies (e.g., multimodal
rocognitive substrates of the DMDs in SUD, there is a need neuroimaging and computational modeling) could also be
for more prospective studies especially in the form of used for this objective. Second, we need to design and
prediction, monitoring, and interventional settings. This is develop new assessment tools to cover all areas of decision-
because we need to monitor the status of the targeting making deficits to shape a better and holistic more
variables and design and implement more effective inter- comprehensive view of the phenomenon. Here, again
ventional strategies, in particular for treatment and reha- multidimensional studies (i.e., addressing more than one
bilitation purposes. As such, while more case-control and aspect of decision-making deficits) might help scholars
cross-sectional studies are needed to find new potential finding the internal mechanistic interactions of the lower
biomarkers of decision-making deficits, causal studies are level variables (Fig. 4.3).
Decision-making deficits in substance use disorders Chapter | 4
FIGURE 4.3 Units of analysis and levels of assessment paradigms in decision-making deficits studies in substance use disorder.
51
References Baitz, H.A., 2016. Component processes of decision making in persons

with substance use disorders. Doctoral dissertation, Arts & Soc. Sci.:
Acion, L., Kelmansky, D., van der Laan, M., Sahker, E., Jones, D.S., Dep. Psychol.
Arndt, S., 2017. Use of a machine learning framework to predict Baker, T.E., Lesperance, P., Tucholka, A., Potvin, S., Larcher, K.,
substance use disorder treatment success. PLoS One 12 (4), e0175383. Zhang, Y., et al., 2017. Reversing the atypical valuation of drug and
https://doi.org/10.1371/journal.pone.0175383. nondrug rewards in smokers using multimodal neuroimaging. Biol.
Acuff, S.F., Soltis, K.E., Dennhardt, A.A., Borsari, B., Martens, M.P., Psychiatry 82 (11), 819e827. https://doi.org/10.1016/j.biopsych.
Murphy, J.G., 2017. Future so bright? Delay discounting and 2017.01.015.
consideration of future consequences predict academic performance Balogh, K.N., Mayes, L.C., Potenza, M.N., 2013. Risk-taking and
among college drinkers. Exp. Clin. Psychopharmacol. vol. 25 (5), decision-making in youth. Relationships to addiction vulnerability.
412e421. https://doi.org/10.1037/pha0000143. J. Behav. Addict. 2 (1), 1e9.
Adams, J., 2012. Consideration of immediate and future consequences, Balzan, R.P., Ephraums, R., Delfabbro, P., Andreou, C., 2017. Beads task
smoking status, and body mass index. Health Psychol. 31 (2), 260. vs. box task: the specificity of the jumping to conclusions bias.
Adams, S., Attwood, A.S., Munafo, M.R., 2017. Drinking status but not J. Behav. Ther. Exp. Psychiatry 56, 42e50.
acute alcohol consumption influences delay discounting. Hum. Psy- Banca, P., Lange, I., Worbe, Y., Howell, N.A., Irvine, M., Harrison, N.A.,
chopharmacol. 32 (5) https://doi.org/10.1002/hup.2617. et al., 2016. Reflection impulsivity in binge drinking. Behavioural and
Aharonovich, E., Campbell, A.N.C., Shulman, M., Hu, M.-C., Kyle, T., volumetric correlates. Addict. Biol. 21 (2), 504e515.
Winhusen, T., Nunes, E.V., 2018. Neurocognitive profiling of adult Barkley, R.A., Edwards, G., Laneri, M., Fletcher, K., Metevia, L., 2001.
treatment seekers enrolled in a clinical trial of a web-delivered inter- Executive functioning, temporal discounting, and sense of time in
vention for substance use disorders. J. Addict. Med. 12 (2), 99e106. adolescents with attention deficit hyperactivity disorder (ADHD) and
Ahn, W.-Y., Busemeyer, J.R., 2016. Challenges and promises for trans- oppositional defiant disorder (ODD). J. Abnorm. Child Psychol. 29
lating computational tools into clinical practice. Curr. Opin. Behav. (6), 541e556.
Sci. 11, 1e7. Barlow, P., McKee, M., Reeves, A., Galea, G., Stuckler, D., 2017. Time-
Ahn, W.-Y., Busemeyer, J.R., Wagenmakers, E.-J., Stout, J.C., 2008. discounting and tobacco smoking: a systematic review and network
Comparison of decision learning models using the generalization analysis. Int. J. Epidemiol. 46 (3), 860e869. https://doi.org/10.1093/
criterion method. Cogn. Sci. 32 (8), 1376e1402. ije/dyw233.
Ahn, W.Y., Dai, J., Vassileva, J., Busemeyer, J.R., Stout, J.C., 2016. Baron, A., DeWaard, R.J., Galizio, M., 1981. Factor-analytically derived
Computational modeling for addiction medicine: from cognitive subscales for the Reinforcement Survey Schedule: reinforcer prefer-
models to clinical applications. Prog Brain Res. 224, 53e65. Elsevier. ences as a function of drug use and sex. Behav. Modif. 5 (2), 203e220.
Ainslie, G., 1975. Specious reward: a behavioral theory of impulsiveness Barratt, E.S., 1959. Anxiety and impulsiveness related to psychomotor
and impulse control. Psychol. Bull. 82 (4), 463. efficiency. Percept. Mot. Skills 9 (3), 191e198.
Aklin, W.M., Lejuez, C.W., Zvolensky, M.J., Kahler, C.W., Gwadz, M., Barratt, E.S., 1965. Factor analysis of some psychometric measures of
2005. Evaluation of behavioral measures of risk taking propensity impulsiveness and anxiety. Psychol. Rep. 16 (2), 547e554.
with inner city adolescents. Behav. Res. Therapy 43 (2), 215e228. Barratt, E.S., 1985. Impulsiveness subtraits: arousal and information pro-
Alghamdi, W., Stamate, D., Stahl, D., Zamyatin, A., Murray, R., Di Forti, cessing. Motivation, Emotion, and Personality 5, 137e146.
Marta, 2018. A new machine learning framework for understanding Bechara, A., 2003. Risky business. Emotion, decision-making, and
the link between cannabis use and first-episode psychosis. Stud. addiction. J. Gambl. Stud. 19 (1), 23e51.
Health Technol. Inform. 248, 9e16. Bechara, A., Damasio, A.R., Damasio, H., Anderson, S.W., 1994. Insen-
Amini, M., Namdari, K., Shirani, M., 2016. Validity and reliability of sitivity to future consequences following damage to human prefrontal
eysenck and murray impulsivity scale and divided attention ques- cortex. Cognition 50 (1e3), 7e15.
tionnaire (DAQ) in students of university of Isfahan, Iran. Bechara, A., Damasio, H., Tranel, D., Damasio, A.R., 1997. Deciding
J. Fundamentals .Mental Health 18 (3), 125e129. advantageously before knowing the advantageous strategy. Science
Amlung, M., Vedelago, L., Acker, J., Balodis, I., MacKillop, J., 2017. 275 (5304), 1293e1295.
Steep delay discounting and addictive behavior: a meta-analysis of Becker, A., Gerchen, M.F., Kirsch, M., Hoffmann, S., Kiefer, F.,
continuous associations. Addiction 112 (1), 51e62. https://doi.org/ Kirsch, P., 2018. Striatal reward sensitivity predicts therapy-related
10.1111/add.13535. neural changes in alcohol addiction. Eur. Arch. Psychiatry Clin.
Arnett, J., 1994. Sensation seeking: a new conceptualization and a new Neurosci. 268 (3), 231e242.
scale. Personal. Individ. Differ. 16, 289. Beckham, J.C., Adkisson, K.A., Hertzberg, J., Kimbrel, N.A.,
Arulkadacham, L.J., Richardson, B., Staiger, P.K., Kambouropoulos, N., Budney, A.J., Stephens, R.S., et al., 2018. Mobile contingency man-
O’Donnell, Renee, L., Ling, M., 2017. Dissociation between wanting agement as an adjunctive treatment for co-morbid cannabis use dis-
and liking for alcohol and caffeine: a test of the Incentive Sensitisation order and cigarette smoking. Addict. Behav. 79, 86e92.
Theory. J. psychopharmacol. 31 (7), 927e933. https://doi.org/ Beenstock, J., Adams, J., White, M., 2010. The association between time
10.1177/0269881117711711. perspective and alcohol consumption in university students: cross-
Athamneh, L.N., Stein, J.S., Bickel, W.K., 2017. Will delay discounting sectional study. Eur. J. Public Health 21 (4), 438e443.
predict intention to quit smoking? Exp. Clin. Psychopharmacol 25 (4), Bernhardt, N., Nebe, S., Pooseh, S., Sebold, M., Sommer, C.,
273e280. https://doi.org/10.1037/pha0000129. Birkenstock, J., et al., 2017. Impulsive decision making in young adult
Bae, Y., Yoo, B.W., Lee, J.C., Kim, H.C., 2017. Automated network social drinkers and detoxified alcohol-dependent patients: a cross-
analysis to measure brain effective connectivity estimated from EEG sectional and longitudinal study. Alcohol Clin. Exp. Res. 41 (10),
data of patients with alcoholism. Physiol. Meas. 38 (5), 759. 1794e1807. https://doi.org/10.1111/acer.13481.
Berridge, K.C., Robinson, T.E., 1998. What is the role of dopamine in Brand, M., Roth-Bauer, M., Driessen, M., Markowitsch, H.J., 2008. Ex-
reward: hedonic impact, reward learning, or incentive salience? Brain ecutive functions and risky decision-making in patients with opiate
Res. Rev. 28 (3), 309e369. dependence. Drug Alcohol Depend. 97 (1e2), 64e72.
Berridge, K.C., Robinson, T.E., 2016. Liking, wanting, and the incentive- Brevers, D., Bechara, A., Cleeremans, A., Noël, X., 2013. Iowa Gambling
sensitization theory of addiction. Am. Psychol. 71 (8), 670. Task (IGT): twenty years afteregambling disorder and IGT. Front.
Beylergil, S.B., Beck, A., Deserno, L., Lorenz, R.C., Rapp, M.A., Psychol. 4, 665.
Schlagenhauf, F., et al., 2017. Dorsolateral prefrontal cortex contrib- Brown, S.A., Goldman, M.S., Inn, A., Anderson, L.R., 1980. Expectations
utes to the impaired behavioral adaptation in alcohol dependence. of reinforcement from alcohol: their domain and relation to drinking
NeuroImage. Clin. 15, 80e94. patterns. J. Consult. Clin. Psychol. 48 (4), 419.
Bickel, W.K., Jarmolowicz, D.P., Mueller, E.T., Koffarnus, M.N., Brown, S.A., Goldman, M.S., Christiansen, B.A., 1985. Do alcohol ex-
Gatchalian, K.M., 2012. Excessive discounting of delayed reinforcers pectancies mediate drinking patterns of adults? J. Consult. Clin.
as a trans-disease process contributing to addiction and other disease- Psychol. 53 (4), 512.
related vulnerabilities: emerging evidence. Pharmacol. Therapeut. 134 Bruijnzeel, A.W., 2017. Reward processing and smoking. Nicotine Tob.
(3), 287e297. Res. 19 (6), 661e662.
Bickel, W.K., Koffarnus, M.N., Moody, L., Wilson, A.G., 2014. The Büchel, C., Peters, J., Banaschewski, T., Bokde, A.L.W., Bromberg, U.,
behavioral-and neuro-economic process of temporal discounting: a Conrod, P.J., et al., 2017. Blunted ventral striatal responses to antic-
candidate behavioral marker of addiction. Neuropharmacology 76, ipated rewards foreshadow problematic drug use in novelty-seeking
518e527. adolescents. Nat. Commun. 8, 14140.
Bickel, W.K., MacKillop, J., Madden, G.J., Odum, A.L., Yi, R., 2015. Buelow, M.T., Suhr, J.A., 2009. Construct validity of the Iowa gambling
Experimental manipulations of delay discounting & related processes: task. Neuropsychol. Rev. 19 (1), 102e114.
an introduction to the special issue. J. Exp. Anal. Behav. 103 (1), 1e9. Bulley, A., Gullo, M.J., 2017. The influence of episodic foresight on delay
https://doi.org/10.1002/jeab.133. discounting and demand for alcohol. Addict. Behav. 66, 1e6. https://
Bickel, W.K., Moody, L.N., Eddy, C.R., Franck, C.T., 2017a. Neuro- doi.org/10.1016/j.addbeh.2016.11.003.
cognitive dysfunction in addiction: testing hypotheses of diffuse Busemeyer, J.R., Stout, J.C., 2002. A contribution of cognitive decision
versus selective phenotypic dysfunction with a classification-based models to clinical assessment: decomposing performance on the
approach. Exp. Clin. Psychopharmacol 25 (4), 322. Bechara gambling task. Psychol. Assess. 14 (3), 253.
Bickel, W.K., Moody, L.N., Eddy, C.R., Franck, C.T., 2017b. Neuro- Cáceda, R., Nemeroff, C.B., Harvey, P.D., 2014. Toward an understanding
cognitive dysfunction in addiction: testing hypotheses of diffuse of decision making in severe mental illness. J. Neuropsychiat. Clin.
versus selective phenotypic dysfunction with a classification-based Neurosc. 26 (3), 196e213.
approach. Exp. Clin. Psychopharmacol 25 (4), 322e332. https:// Carbia, C., Cadaveira, F., Caamaño-Isorna, F., Holguín, R., Socorro,
doi.org/10.1037/pha0000115. Corral, M., 2017. Binge drinking trajectory and decision-making
Biernacki, K., McLennan, S.N., Terrett, G., Labuschagne, I., during late adolescence. Gender and developmental differences.
Rendell, P.G., 2016. Decision-making ability in current and past users Front. Psychol. 8, 783.
of opiates: a meta-analysis. Neurosci. Biobehav. Rev. 71, 342e351. Cassidy, C.M., Lepage, M., Harvey, P.-O., Malla, A., 2012. Cannabis use
Bischoff-Grethe, A., Connolly, C.G., Jordan, S.J., Brown, G.G., and anticipatory pleasure as reported by subjects with early psychosis
Paulus, M.P., Tapert, S.F., et al., 2017. Altered reward expectancy in and community controls. Schizophr. Res. 137 (1e3), 39e44.
individuals with recent methamphetamine dependence. Cautela, J.R., 1977. Behavior Analysis Forms for Clinical Intervention.
J. Psychopharmacol. 31 (1), 17e30. Research Press. [1](1983).
Blair, M.A., Stewart, J.L., May, A.C., Reske, M., Tapert, S.F., Cautela, J.R., Kastenbaum, R., 1967. A reinforcement survey schedule for
Paulus, M.P., 2018. Blunted frontostriatal blood oxygen levele use in therapy, training, and research. Psychol. Rep. 20, 1115e1130
dependent signals predict stimulant and marijuana use. Biol. Psychi- (3_suppl).
atry Cogn. Neurosci. Neuroimaging 3 (11), 947e958. Cautela, J., Lynch, E., 1983. Reinforcement survey schedules: scoring,
Bogg, T., Fukunaga, R., Finn, P.R., Brown, J.W., 2012. Cognitive control administration, and completed research. Psychol. Rep. 53 (2),
links alcohol use, trait disinhibition, and reduced cognitive capacity. 447e465.
Evidence for medial prefrontal cortex dysregulation during reward- Cherek, D.R., Moeller, F.G., Dougherty, D.M., Rhoades, H., 1997. Studies
seeking behavior. Drug Alcohol Depend. 122 (1e2), 112e118. of violent and nonviolent male parolees: II. Laboratory and psycho-
Brand, M., Fujiwara, E., Borsutzky, S., Kalbe, E., Kessler, J., metric measurements of impulsivity. Biol. Psychiat. 41 (5), 523e529.
Markowitsch, H.J., 2005. Decision-making deficits of korsakoff pa- Chiou, W.-B., Wu, W.-H., 2017. Episodic future thinking involving the
tients in a new gambling task with explicit rules: associations with nonsmoking self can induce lower discounting and cigarette con-
executive functions. Neuropsychology 19 (3), 267. sumption. J. Stud. Alcohol Drugs 78 (1), 106e112.
Brand, M., Labudda, K., Markowitsch, H.J., 2006. Neuropsychological Clark, L., Robbins, T.W., Ersche, K.D., Sahakian, B.J., 2006. Reflection
correlates of decision-making in ambiguous and risky situations. impulsivity in current and former substance users. Biol. Psychiat. 60
Neural Netw. 19 (8), 1266e1276. (5), 515e522.
Brand, M., Recknor, E.C., Grabenhorst, F., Bechara, A., 2007. Decisions Claus, E.D., Kiehl, K.A., Hutchison, K.E., 2011. Neural and behavioral
under ambiguity and decisions under risk: correlations with executive mechanisms of impulsive choice in alcohol use disorder. Alcohol Clin.
functions and comparisons of two different gambling tasks with im- Exp. Res. 35 (7), 1209e1219.
plicit and explicit rules. J. Clin. Exp. Neuropsychol. 29 (1), 86e99.
Claus, E.D., Ewing, S.W.F., Magnan, R.E., Montanaro, E., Daniel, T.O., Stanton, C.M., Epstein, L.H., 2013. The future is now.
Hutchison, K.E., Bryan, A.D., 2018. Neural mechanisms of risky Reducing impulsivity and energy intake using episodic future
decision making in adolescents reporting frequent alcohol and/or thinking. Psychological science 24 (11), 2339e2342.
marijuana use. Brain Imaging Behav. 12 (2), 564e576. Daw, N.D., 2011. Trial-by-trial data analysis using computational models.
Coates, J.M., Gullo, M.J., Feeney, G.F.X., Young, R.M., Connor, J.P., In: Decision making, affect, and learning: Attention and performance
2018. A randomized trial of personalized cognitive-behavior therapy XXIII, 23, pp. 3e38.
for alcohol use disorder in a public health clinic. Front. Psychiatry 9. Daw, N.D., Niv, Y., Dayan, P., 2005. Uncertainty-based competition be-
Connolly, C.G., Bischoff-Grethe, A., Jordan, S.J., Woods, S.P., Ellis, R.J., tween prefrontal and dorsolateral striatal systems for behavioral con-
Paulus, M.P., et al., 2014. Altered functional response to risky choice trol. Nat. Neurosci. 8 (12), 1704.
in HIV infection. PloS One 9 (10), e111583. Dennhardt, A.A., Yurasek, A.M., Murphy, J.G., 2015a. Change in delay
Coskunpinar, A., Dir, A.L., Cyders, M.A., 2012. Measurement of con- discounting and substance reward value following a brief alcohol and
structs using self-report and behavioral lab tasks. is there overlap in drug use intervention. J. Exp. Anal. Behav. 103 (1), 125e140. https://
nomothetic span and construct representation for impulsivity? Clin doi.org/10.1002/jeab.121.
Psychol Rev. Dennhardt, A.A., Yurasek, A.M., Murphy, J.G., 2015b. Change in delay
Costa, P.T., McCrae, R.R., 1990. Personality in Adulthood. Guilford discounting and substance reward value following a brief alcohol and
Press, New York. drug use intervention. J. Exp. Anal. Behav. 103 (1), 125e140.
Costumero, V., Bustamante, J.C., Rosell-Negre, P., Fuentes, P., Depue, R.A., Collins, P.F., 1999. Neurobiology of the structure of per-
Llopis, J.J., Ávila, C., Barrós-Loscertales, A., 2017. Reduced activity sonality: dopamine, facilitation of incentive motivation, and extra-
in functional networks during reward processing is modulated by version. Behav. Brain Sci. 22 (3), 491e517.
abstinence in cocaine addicts. Addict. Biol. 22 (2), 479e489. https:// Deserno, L., Beck, A., Huys, Q.J.M., Lorenz, R.C., Buchert, R.,
doi.org/10.1111/adb.12329. Buchholz, H.-G., et al., 2015. Chronic alcohol intake abolishes the
Courtney, A.L., Rapuano, K.M., Sargent, J.D., Heatherton, T.F., relationship between dopamine synthesis capacity and learning signals
Kelley, W.M., 2018. Reward system Activation in response to alcohol in the ventral striatum. Eur. J. Neurosci. 41 (4), 477e486.
advertisements predicts college drinking. J. Stud. Alcohol Drugs 79 Djamshidian, A., O’Sullivan, Sean, S., Sanotsky, Y., Sharman, S.,
(1), 29e38. Matviyenko, Y., Foltynie, T., et al., 2012. Decision making, impul-
Cousijn, J., Wiers, R.W., Ridderinkhof, K.R., van den Brink, W., sivity, and addictions. Do Parkinson’s disease patients jump to con-
Veltman, D.J., Porrino, L.J., Goudriaan, A.E., 2013. Individual dif- clusions? Mov. Disord. 27 (9), 1137e1145.
ferences in decision making and reward processing predict changes in Dudley, R.E.J., John, C.H., Young, A.W., Over, D.E., 1997. The effect of
cannabis use. A prospective functional magnetic resonance imaging self-referent material on the reasoning of people with delusions. Br. J.
study. Addict. Biol. 18 (6), 1013e1023. Clin. Psychol. 36 (4), 575e584.
Crowley, T.J., Raymond, K.M., Mikulich-Gilbertson, S.K., Eisenberg, I.W., Bissett, P., Enkavi, A.Z., Li, J., MacKinnon, D.,
Thompson, L.L., Lejuez, C.W., 2006. A risk-taking “set” in a novel Marsch, L., Poldrack, R., 2018. Uncovering Mental Structure through
task among adolescents with serious conduct and substance problems. Data-Driven Ontology Discovery.
J. Am. Acad. Child Adolesc. Psychiatry 45 (2), 175e183. Ekhtiari, H., Safaei, H., Djavid, E., Gholamreza, Atefvahid, M.K.,
Cservenka, A., Courtney, K.E., Ghahremani, D.G., Hutchison, K.E., Edalati, H., Mokri, A., 2008. Reliability and validity of Persian ver-
Ray, L.A., 2017. Development, initial testing and challenges of an sions of eysenck, barratt, dickman and zuckerman questionnaires in
ecologically valid reward prediction error fMRI task for alcoholism. assessing risky and impulsive behaviors. Iran. J. Psychiatry Clin.
Alcohol Alcohol 52 (5), 617e624. Psychol. 14 (3), 326e336.
Cyders, M.A., Coskunpinar, A., 2011. Measurement of constructs using Ekhtiari, H., Victor, T.A., Paulus, M.P., 2017. Aberrant decision-making
self-report and behavioral lab tasks: is there overlap in nomothetic and drug addictiondhow strong is the evidence? Curr. Opin.
span and construct representation for impulsivity? Clin. Psychol. Rev. Behav. Sci. 13, 25e33.
31 (6), 965e982. Elton, A., Smith, C.T., Parrish, M.H., Boettiger, C.A., 2017. Neural sys-
Cyders, M.A., Smith, G.T., Spillane, N.S., Fischer, S., Annus, A.M., tems underlying individual differences in intertemporal decision-
Peterson, C., 2007. Integration of impulsivity and positive mood to making. J. Cogn. Neurosci. 29 (3), 467e479. https://doi.org/
predict risky behavior: development and validation of a measure of 10.1162/jocn_a_01069.
positive urgency. Psychol. Assess. 19 (1), 107. Engelmann, J.B., Maciuba, B., Vaughan, C., Paulus, M.P., Dunlop, B.W.,
Cyders, M.A., Littlefield, A.K., Coffey, S., Karyadi, K.A., 2014. Exami- 2013. Posttraumatic stress disorder increases sensitivity to long term
nation of a short English version of the UPPS-P impulsive behavior losses among patients with major depressive disorder. PloS One 8
scale. Addict. Behav. 39 (9), 1372e1376. (10), e78292.
Dahne, J., Richards, J.M., Ernst, M., MacPherson, L., Lejuez, C.W., 2013. Estle, S.J., Green, L., Myerson, J., Holt, D.D., 2007. Discounting of
Assessment of risk taking in addiction research. In: The Wiley- monetary and directly consumable rewards. Psychol. Sci. 18 (1),
Blackwell Handbook of Addiction Psychopharmacology, 58e63. https://doi.org/10.1111/j.1467-9280.2007.01849.x.
pp. 209e231. Eysenck, H.J., 1947. Student selection by means of psychological testsda
Dai, J., Kerestes, R., Upton, D.J., Busemeyer, J.R., Stout, J.C., 2015. An critical survey. Br. J. Educ. Psychol. 17 (1), 20e39.
improved cognitive model of the Iowa and Soochow Gambling Tasks Eysenck, S.B.G., Eysenck, H.J., 1969. Scores on three personality vari-
with regard to model fitting performance and tests of parameter con- ables as a function of age, sex and social class. Br. J. Soc. Clin.
sistency. Front. Psychol. 6, 229. Psychol. 8 (1), 69e76.
Eysenck, H.J., Eysenck, S.B., Giuletta, 1975. Manual of the Eysenck Fukunaga, R., Purcell, J.R., Brown, J.W., 2018. Discriminating formal
Personality Questionnaire (Junior and Adult): Hodder and Stoughton. representations of risk in anterior cingulate cortex and inferior frontal
Eysenck, H.J., Eysenck, S.B.G., 1976. Eysenck Personality Questionnaire: gyrus. Front. Neurosci. 12.
Educational and Industrial Testing Service. Galandra, C., Basso, G., Cappa, S., Canessa, N., 2017. The alcoholic brain:
Eysenck, S.B.G., Eysenck, H.J., 1978. Impulsiveness and venturesome- neural bases of impaired reward-based decision-making in alcohol use
ness. Their position in a dimensional system of personality descrip- disorders. Neurol. Sci. 1e13.
tion. Psychol. Rep. 43 (3_Suppl. l), 1247e1255. Gansler, D.A., Jerram, M.W., Vannorsdall, T.D., Schretlen, D.J., 2011.
Eysenck, S.B.G., Easting, G., Pearson, P.R., 1984. Age norms for Does the Iowa Gambling Task measure executive function? Arch.
impulsiveness, venturesomeness and empathy in children. Personal. Clin. Neuropsychol. 26 (8), 706e717.
Individ. Differ. 5 (3), 315e321. García-García, I., Zeighami, Y., Dagher, A., 2017. Reward prediction er-
Eysenck, H.J., Barrett, P., Eysenck, S.B.G., 1985a. Indices of factor rors in drug addiction and Parkinson’s disease. From neurophysiology
comparison for homologous and non-homologous personality scales to neuroimaging. Curr. Neurol. Neurosci. Rep. 17 (6), 46.
in 24 different countries. Personal. Individ. Differ. 6 (4), 503e504. García-Marchena, N., Ladrón de Guevara-Miranda, D., Pedraz, M.,
Eysenck, S.B.G., Pearson, P.R., Easting, G., Allsopp, J.F., 1985b. Age Araos, P.F., Rubio, G., Ruiz, J.J., et al., 2018. Higher impulsivity as a
norms for impulsiveness, venturesomeness and empathy in adults. Distinctive Trait of severe cocaine addiction among individuals
Personal. Individ. Differ. 6 (5), 613e619. Treated for cocaine or alcohol Use Disorders. Front. Psychiatry 9, 26.
Farris, S.G., Aston, E.R., Abrantes, A.M., Zvolensky, M.J., 2017. Tobacco Gard, D.E., Gard, M.G., Kring, A.M., John, O.P., 2006. Anticipatory and
demand, delay discounting, and smoking topography among smokers consummatory components of the experience of pleasure: a scale
with and without psychopathology. Drug Alcohol Depend. 179, development study. J. Res. Personal. 40 (6), 1086e1102.
247e253. https://doi.org/10.1016/j.drugalcdep.2017.06.042. Garety, P.A., Hemsley, Wessely, S.M.R.C., 1991. Reasoning in deluded
Fecteau, S., Knoch, D., Fregni, F., Sultani, N., Boggio, P., Pascual- schizophrenic and paranoid patients: biases in performance on a
Leone, A., 2007. Diminishing risk-taking behavior by modulating probabilistic inference task. J. Nerv. Ment. Dis. 179 (4), 194e201.
activity in the prefrontal cortex: a direct current stimulation study. Garfield, J.B.B., Cotton, S.M., Lubman, D.I., 2016. Psychometric prop-
J. Neurosci. 27 (46), 12500e12505. erties, validity, and reliability of the Temporal Experience of Pleasure
Fecteau, S., Agosta, S., Hone-Blanchet, A., Fregni, F., Boggio, P., Scale state version in an opioid-dependent sample. Drug Alcohol
Ciraulo, D., Pascual-Leone, A., 2014. Modulation of smoking and Depend. 161, 238e246.
decision-making behaviors with transcranial direct current stimulation Garfield, J.B.B., Cotton, S.M., Allen, N.B., Cheetham, A., Kras, M.,
in tobacco smokers: a preliminary study. Drug Alcohol Depend. 140, Yücel, M., Lubman, D.I., 2017. Evidence that anhedonia is a symptom
78e84. https://doi.org/10.1016/j.drugalcdep.2014.03.036. of opioid dependence associated with recent use. Drug Alcohol
Fernie, G., Cole, J.C., Goudie, A.J., Field, M., 2010. Risk-taking but not Depend. 177, 29e38.
response inhibition or delay discounting predict alcohol consumption Garon, N., Moore, C., Waschbusch, D.A., 2006. Decision making in
in social drinkers. Drug Alcohol Depend. 112 (1e2), 54e61. children with ADHD only, ADHD-anxious/depressed, and control
Floresco, S.B., Whelan, J.M., 2009. Perturbations in different forms of children using a child version of the Iowa Gambling Task. J. Atten.
cost/benefit decision making induced by repeated amphetamine Disord. 9 (4), 607e619.
exposure. Psychopharmacology 205 (2), 189e201. Garrison, K.A., Yip, S.W., Balodis, I.M., Carroll, K.M., Potenza, M.N.,
Forster, S.E., Finn, P.R., Brown, J.W., 2016. A preliminary study of Krishnan-Sarin, Suchitra, 2017. Reward-related frontostriatal activity
longitudinal neuroadaptation associated with recovery from addiction. and smoking behavior among adolescents in treatment for smoking
Drug Alcohol Depend. 168, 52e60. cessation. Drug Alcohol Depend. 177, 268e276. https://doi.org/
Forster, S.E., Finn, P.R., Brown, J.W., 2017. Neural responses to negative 10.1016/j.drugalcdep.2017.03.035.
outcomes predict success in community-based substance use treat- Gilmore, C.S., Dickmann, P.J., Nelson, B.G., Lamberty, G.J., Lim, K.O.,
ment. Addiction 112 (5), 884e896. https://doi.org/10.1111/add. 2018. Transcranial Direct Current Stimulation (tDCS) paired with a
13734. decision-making task reduces risk-taking in a clinically impulsive
Foster, D.W., Neighbors, C., Pai, A., 2015. Decisional balance: alcohol sample. Brain stimul. 11 (2), 302e309.
decisional balance intervention for heavy drinking undergraduates. Goldstein, S., Naglieri, J.A., 2011. Encyclopedia of Child Behavior and
Subst. Use Misuse 50 (13), 1717e1727. https://doi.org/10.3109/ Development. Springer ScienceþBusiness Media (Springer reference,
10826084.2015.1036883. New York.
Francis, L.J., Lewis, C.A., Ziebertz, H., 2006. The Short-form Revised Goldstein, R.Z., Woicik, P.A., Moeller, S.J., Telang, F., Jayne, M.,
Eysenck Personality Questionnaire (EPQ-S). A German edition. Wong, C., et al., 2010. Liking and wanting of drug and non-drug
Friston, K., FitzGerald, T., Rigoli, F., Schwartenbeck, P., Pezzulo, G., rewards in active cocaine users: the STRAP-R questionnaire.
2017. Active inference: a process theory. Neural Computation 29 (1), J. Psychopharmacol. 24 (2), 257e266.
1e49. Gowin, J.L., Stewart, J.L., May, A.C., Ball, T.M., Wittmann, M.,
Fukunaga, R., Brown, J.W., Bogg, T., 2012. Decision making in the Tapert, S.F., Paulus, M.P., 2014. Altered cingulate and insular cortex
Balloon Analogue Risk Task (BART). Anterior cingulate cortex sig- activation during risk-taking in methamphetamine dependence: losses
nals loss aversion but not the infrequency of risky choices. Cognit. lose impact. Addiction 109 (2), 237e247.
Affect Behav. Neurosci. 12 (3), 479e490. Gowin, J.L., May, A.C., Wittmann, M., Tapert, S.F., Paulus, M.P., 2017.
Fukunaga, R., Bogg, T., Finn, P.R., Brown, J.W., 2013. Decisions during Doubling down: increased risk-taking behavior following a loss by
negatively-framed messages yield smaller risk-aversion-related brain individuals with cocaine use disorder is associated with striatal and
activation in substance-dependent individuals. Psychol. Addict. anterior cingulate dysfunction. Biol. Psychiatry Cogn. Neurosci.
Behav. 27 (4), 1141. Neuroimaging 2 (1), 94e103.
Gowin, J.L., Sloan, M.E., Ramchandani, V.A., Paulus, M.P., Lane, S.D., Heinz, A., Deserno, L., Zimmermann, U.S., Smolka, M.N., Beck, A.,
2018. Differences in decision-making as a function of drug of choice. Schlagenhauf, F., 2017. Targeted intervention: computational ap-
Pharmacol., Biochem., Behav. 164, 118e124. https://doi.org/10.1016/ proaches to elucidate and predict relapse in alcoholism. Neuroimage
j.pbb.2017.09.007. 151, 33e44. https://doi.org/10.1016/j.neuroimage.2016.07.055.
Grant, J.E., Chamberlain, S.R., 2018. Caffeine’s influence on gambling Hendershot, C.S., Wardell, J.D., Vandervoort, J., McPhee, M.D.,
behavior and other types of impulsivity. Addict. Behav. 76, 156e160. Keough, M.T., Quilty, L.C., 2018. Randomized trial of working
https://doi.org/10.1016/j.addbeh.2017.08.007. memory training as an adjunct to inpatient substance use disorder
Gray, J.C., MacKillop, J., 2015. Impulsive delayed reward discounting as a treatment. Psychol. Addict. Behav. 32 (8), 861.
genetically-influenced target for drug abuse prevention: a critical Herman, A.M., Critchley, H.D., Duka, T., 2018. Binge drinking is asso-
evaluation. Front. Psychol. 6, 1104. https://doi.org/10.3389/fpsyg.2015. ciated with attenuated frontal and parietal activation during successful
01104. response inhibition in fearful context. Eur. J. Neurosci. 1e14.
Green, L., Myerson, J., 1996. Exponential versus hyperbolic discounting Hobkirk, A.L., Bell, R.P., Utevsky, A.V., Huettel, S., Meade, C.S., 2019.
of delayed outcomes: risk and waiting time. Am. Zool. 36 (4), Reward and executive control network resting-state functional con-
496e505. nectivity is associated with impulsivity during reward-based decision
Green, L., Fry, A.F., Myerson, J., 1994. Discounting of delayed rewards: a making for cocaine users. Drug Alcohol Depend. 194, 32e39.
life-span comparison. Psychol. Sci. 5 (1), 33e36. Hofmeyr, A., Monterosso, J., Dean, A.C., Morales, A.M., Bilder, R.M.,
Green, L., Myerson, J., Lichtman, D., Rosen, S., Fry, A., 1996. Temporal Sabb, F.W., London, E.D., 2017. Mixture models of delay discounting
discounting in choice between delayed rewards: the role of age and and smoking behavior. Am. J. Drug Alcohol Abuse 43 (3), 271e280.
income. Psychol. Aging 11 (1), 79. https://doi.org/10.1080/00952990.2016.1198797.
Green, L., Myerson, J., McFadden, E., 1997. Rate of temporal discounting Holmes, G.R., Heckel, R.V., Chestnut, E., Harris, N., Cautela, J., 1987.
decreases with amount of reward. Mem. Cogn. 25 (5), 715e723. Factor analysis of the adolescent reinforcement survey schedule
Green, L., Myerson, J., Ostaszewski, P., 1999. Amount of reward has (ARSS) with college freshmen. J. Clin. Psychol. 43 (4), 386e390.
opposite effects on the discounting of delayed and probabilistic out- Holmes, G.R., Sakano, Y., Cautela, J., Holmes, G.L., 1991. Comparison of
comes. J. Exp. Psychol. Learn. Mem. Cogn. 25 (2), 418. factor-analyzed adolescent reinforcement survey schedule (ARSS)
Grodin, E.N., Cortes, C.R., Spagnolo, P.A., Momenan, R., 2017. Struc- responses from Japanese and American adolescents. J. Clin. Psychol.
tural deficits in salience network regions are associated with increased 47 (6), 749e755.
impulsivity and compulsivity in alcohol dependence. Drug Alcohol Horan, W.P., Kring, A.M., Blanchard, J.J., 2005. Anhedonia in schizo-
Depend. 179, 100e108. https://doi.org/10.1016/j.drugalcdep. phrenia: a review of assessment strategies. Schizophr. Bull. 32 (2),
2017.06.014. 259e273.
Gullo, M.J., Stieger, A.A., 2011. Anticipatory stress restores decision- Hoyle, R.H., Stephenson, M.T., Palmgreen, P., Lorch, E.P.,
making deficits in heavy drinkers by increasing sensitivity to losses. Donohew, R.L., 2002. Reliability and validity of a brief measure of
Drug Alcohol Depend. 117 (2e3), 204e210. sensation seeking. Personal. Individ. Differ. 32 (3), 401e414.
Gunn, R.L., Skalski, L., Metrik, J., 2017. Expectancy of impairment at- Hughes, J.R., Budney, A.J., Muellers, S.R., Lee, D.C., Callas, P.W.,
tenuates marijuana-induced risk taking. Drug Alcohol Depend. 178, Sigmon, S.C., et al., 2017a. Does tobacco abstinence decrease reward
39e42. https://doi.org/10.1016/j.drugalcdep.2017.04.027. sensitivity? A human laboratory test. Nicotine Tob. Res. 19 (6),
Guo, H., Zhang, Z., Da, S., Sheng, X., Zhang, X., 2018. High-definition 677e685. https://doi.org/10.1093/ntr/ntw204.
transcranial direct current stimulation (HD-tDCS) of left dorsolateral Hughes, J.R., Callas, P.W., Priest, J.S., Etter, J.-F., Budney, A.J.,
prefrontal cortex affects performance in Balloon Analogue Risk Task Sigmon, S.C., 2017b. Development of a self-report measure of reward
(BART). Brain Behav. 8 (2), e00884. sensitivity: a test in current and former smokers. Nicotine Tob. Res. 19
Hallgren, K.A., Greenfield, B.L., Ladd, B.O., 2016. Psychometric prop- (6), 723e728.
erties of the adolescent reinforcement survey schedule-alcohol use Hughes, J.R., Klemperer, E.M., Peasley-Miklus, Catherine, 2018. Possible
version with college student drinkers. Subst. Use Misuse 51 (7), new symptoms of tobacco withdrawal II. Anhedoniada systematic
812e822. review. Nicotine Tob. Res. nty171.
Hamdan-Mansour, Ayman, M., Mahmoud, K.F., Al, S., Ahmad, N., Humphries, M.A., Bruno, R., Karpievitch, Y., Wotherspoon, S., 2015. The
Arabiat, D.H., 2018. Impulsivity and sensation-seeking personality expectancy valence model of the Iowa Gambling Task: can it produce
traits as predictors of substance use among university students. reliable estimates for individuals? J. Math. Psychol. 64, 17e34.
J. Psychosoc. Nurs. Ment. Health Serv. 56 (1), 57e63. https://doi.org/ Huys, Q.J.M., Tobler, P.N., Hasler, G., Flagel, S.B., 2014. The role of
10.3928/02793695-20170905-04. learning-related dopamine signals in addiction vulnerability. Prog.
Harries, M.D., Redden, S.A., Grant, J.E., 2018. An analysis of treatment- Brain Res. 211, 31e77. Elsevier.
seeking behavior in individuals with gambling disorder. J. Gambl. Huys, Q.J.M., Maia, T.V., Frank, M.J., 2016. Computational psychiatry as
Stud. 34 (3), 999e1012. a bridge from neuroscience to clinical applications. Nat. Neurosci. 19
Hauser, T.U., Will, G.-J., Dubois, M., Dolan, R.J., 2019. Annual research (3), 404.
review: developmental computational psychiatry. J. Child Psychol. Kagan, J., 1966. Reflection-impulsivity. The generality and dynamics of
Psychiatry 60 (4), 412e426. conceptual tempo. J. Abnorm. Psychol. 71 (1), 17.
Heaven, P.C.L., 1991. Venturesomeness, impulsiveness, and Eysenck’s Kahler, C.W., Lechner, W.J., MacGlashan, J., Wray, T.B., Littman, M.L.,
personality dimensions. A study among Australian adolescents. 2017. Initial progress toward development of a voice-based computer-
J. Genet. Psychol. 152 (1), 91e99. delivered motivational intervention for heavy drinking college stu-
Hefner, A.D., Gordijn, C.M., 2018. Personality Traits Differences Among dents: an experimental study. JMIR Mental Health 4 (2).
Marijuana, Alcohol, and Other Substance Users. Brenau University.
Kaplan, B.A., Amlung, M., Reed, D.D., Jarmolowicz, D.P., Kumar, R., Kumar, K.J., Benegal, V., 2018. Cognitive and behavioural
McKerchar, T.L., Lemley, S.M., 2016. Automating scoring of delay dispositions in offspring at high risk for alcoholism. Asian J. Psychiat.
discounting for the 21-and 27-item monetary choice questionnaires. 35, 38e44.
Behav. Analyst 39 (2), 293e304. Kwako, L.E., Momenan, R., Grodin, E.N., Litten, R.Z., Koob, G.F.,
Kastenbaum, R., 1961. The dimensions of future time perspective, an Goldman, D., 2017. Addictions Neuroclinical Assessment: a reverse
experimental analysis. J. Gen. Psychol. 65 (2), 203e218. translational approach. Neuropharmacology 122, 254e264. https://
Keramati, M., Dezfouli, A., Piray, P., 2011. Speed/accuracy trade-off doi.org/10.1016/j.neuropharm.2017.03.006.
between the habitual and the goal-directed processes. PLoS Comput. Lane, S.D., Yechiam, E., Busemeyer, J.R., 2006. Application of a
Biol. 7 (5), e1002055. computational decision model to examine acute drug effects on human
Khemiri, L., Brynte, C., Stunkel, A., Klingberg, T., Jayaram- risk taking. Exp. Clin. Psychopharmacol 14 (2), 254.
Lindström, N., 2019. Working memory training in alcohol use dis- Larney, S., Hickman, M., Fiellin, D.A., Dobbins, T., Nielsen, S.,
order. A randomized controlled trial. Alcohol Clin. Exp. Res. 43 (1), Jones, N.R., et al., 2018. Using routinely collected data to understand
135e146. and predict adverse outcomes in opioid agonist treatment: protocol for
Kirby, K.N., 2009. One-year temporal stability of delay-discount rates. the Opioid Agonist Treatment Safety (OATS) Study. BMJ open 8 (8),
Psychon. Bull Rev. 16 (3), 457e462. e025204.
Kirby, K.N., Marakovic, N.N., 1996. Delay-discounting probabilistic re- Lawn, W., Freeman, T.P., Pope, R.A., Joye, A., Harvey, L., Hindocha, C.,
wards: rates decrease as amounts increase. Psychon. Bull Rev. 3 (1), et al., 2016. Acute and chronic effects of cannabinoids on effort-
100e104. related decision-making and reward learning: an evaluation of the
Kirby, K.N., Petry, N.M., Bickel, W.K., 1999. Heroin addicts have higher cannabis ’amotivational’ hypotheses. Psychopharmacology 233
discount rates for delayed rewards than non-drug-using controls. (19e20), 3537e3552. https://doi.org/10.1007/s00213-016-4383-x.
J. Exp. Psychol. Gen. 128 (1), 78. Lee, M.D., 2011. How cognitive modeling can benefit from hierarchical
Kobiella, A., Ripke, S., Kroemer, N.B., Vollmert, C., Vollstadt-Klein, S., Bayesian models. J. Math. Psychol. 55 (1), 1e7.
Ulshofer, D.E., Smolka, M.N., 2014. Acute and chronic nicotine ef- Lee, D.C., Stanger, C., Budney, A.J., 2015. A comparison of delay dis-
fects on behaviour and brain activation during intertemporal decision counting in adolescents and adults in treatment for cannabis use dis-
making. Addict. Biol. 19 (5), 918e930. https://doi.org/10.1111/ orders. Exp. Clin. Psychopharmacol 23 (2), 130e137. https://doi.org/
adb.12057. 10.1037/a0038792.
Koffarnus, M.N., Bickel, W.K., 2014. A 5-trial adjusting delay discount- Leentjens, A.F.G., Dujardin, K., Marsh, L., Martinez-Martin, P.,
ing task: accurate discount rates in less than one minute. Exp. Clin. Richard, I.H., Starkstein, S.E., et al., 2008. Apathy and anhedonia
Psychopharmacol. 22 (3), 222. rating scales in Parkinson’s disease: critique and recommendations.
Koffarnus, M.N., Kaplan, B.A., 2018. Clinical models of decision making Mov. Disord. 23 (14), 2004e2014.
in addiction. Pharmacol., Biochem., Behav. 164, 71e83. https:// Leigh, B.C., Stacy, A.W., 1993. Alcohol outcome expectancies: scale
doi.org/10.1016/j.pbb.2017.08.010. construction and predictive utility in higher order confirmatory
Koffarnus, M.N., Jarmolowicz, D.P., Mueller, E.T., Bickel, W.K., 2013. models. Psychol. Assess. 5 (2), 216.
Changing delay discounting in the light of the competing neuro- Lejuez, C.W., Read, J.P., Kahler, C.W., Richards, J.B., Ramsey, S.E.,
behavioral decision systems theory: a review. J. Exp. Anal Behav. 99 Stuart, G.L., et al., 2002. Evaluation of a behavioral measure of risk
(1), 32e57. https://doi.org/10.1002/jeab.2. taking: the balloon analogue risk task (BART). J. Exp. Psychol. Appl.
Kogachi, S., Chang, L., Alicata, D., Cunningham, E., Ernst, T., 2017. Sex 8 (2), 75.
differences in impulsivity and brain morphometry in methamphet- Lejuez, C.W., Aklin, W., Daughters, S., Zvolensky, M., Kahler, C.,
amine users. Brain Struct. Funct. 222 (1), 215e227. https://doi.org/ Gwadz, M., 2007. Reliability and validity of the youth version of the
10.1007/s00429-016-1212-2. balloon analogue risk task (BARTeY) in the assessment of risk-
Kohno, M., Morales, A.M., Ghahremani, D.G., Hellemann, G., taking behavior among inner-city adolescents. J. Clin. Child Ado-
London, E.D., 2014. Risky decision making, prefrontal cortex, and lesc. Psychol. 36 (1), 106e111.
mesocorticolimbic functional connectivity in methamphetamine Leland, D.S., Paulus, M.P., 2005. Increased risk-taking decision-making
dependence. JAMA psychiatry 71 (7), 812e820. but not altered response to punishment in stimulant-using young
Kooij, Dorien, T.A.M., Kanfer, R., Betts, M., Rudolph, C.W., 2018. adults. Drug Alcohol Depend. 78 (1), 83e90.
Future time perspective: a systematic review and meta-analysis. Lempert, K.M., Speer, M.E., Delgado, M.R., Phelps, E.A., 2017. Positive
J. Appl. Psychol. 103 (8), 867. autobiographical memory retrieval reduces temporal discounting. Soc.
Kovács, I., Richman, M., Janka, Z., Maraz, A., Andó, B., 2017. Decision Cogn. Affect. Neurosci. 12 (10), 1584e1593. https://doi.org/10.1093/
making measured by the Iowa Gambling Task in alcohol use disorder scan/nsx086.
and gambling disorder: a systematic review and meta-analysis. Drug Lesage, E., Aronson, S.E., Sutherland, M.T., Ross, T.J., Salmeron, B.J.,
Alcohol Depend. 181, 152e161. Stein, E.A., 2017. Neural Signatures of cognitive flexibility and
Kruschwitz, J.D., Simmons, A.N., Flagan, T., Paulus, M.P., 2012. Nothing reward sensitivity following nicotinic Receptor stimulation in depen-
to lose: processing blindness to potential losses drives thrill and dent smokers: a randomized trial. JAMA psychiatry 74 (6), 632e640.
adventure seekers. Neuroimage 59 (3), 2850e2859. https://doi.org/10.1001/jamapsychiatry.2017.0400.
Kulis, S.S., Ayers, S.L., Harthun, M.L., 2017. Substance use prevention Leventhal, A.M., Trujillo, M., Ameringer, K.J., Tidey, J.W., Sussman, S.,
for urban American Indian youth: a efficacy trial of the culturally Kahler, C.W., 2014. Anhedonia and the relative reward value of drug
adapted living in 2 worlds program. J. Prim. Prevent. 38 (1e2), and nondrug reinforcers in cigarette smokers. J. Abnorm. Psychol. 123
137e158. https://doi.org/10.1007/s10935-016-0461-4. (2), 375.
Lim, A.C., Cservenka, A., Ray, L.A., 2017. Effects of alcohol dependence Maia, T.V., 2009. Reinforcement learning, conditioning, and the brain:
severity on neural correlates of delay discounting. Alcohol Alcohol 52 successes and challenges. Cognit. Affect Behav. Neurosci. 9 (4),
(4), 506e515. https://doi.org/10.1093/alcalc/agx015. 343e364.
Lin, B., Qian, R.B., Fu, X.M., Ji, X.B., Wei, X.P., Niu, C.S., Wang, Y.H., Marinescu, I.E., Lawlor, P.N., Kording, K.P., 2018. Quasi-experimental
2012. Impulsive decision-making behaviors in heroin addicts. A study causality in neuroscience and behavioural research. Nat. Human
of functional magnetic resonance imaging. Zhonghua Yi Xue Za Zhi Behav. 1.
92 (15), 1033e1036. Marlatt, G.A., Demming, B., Reid, J.B., 1973. Loss of control drinking in
Lin, C.-H., Song, T.-J., Chen, Y.-Y., Lee, W.-K., Chiu, Y., 2013. Reex- alcoholics: an experimental analogue. J. Abnorm. Psychol. 81 (3),
amining the validity and reliability of the clinical version of the Iowa 233.
gambling task: evidence from a normal subject group. Front. Psychol. Mathias, C.W., Stanford, M.S., Liang, Y., Goros, M., Charles, N.E.,
4, 220. Sheftall, A.H., et al., 2018. A test of the psychometric characteristics
Luba, R., Earleywine, M., Farmer, S., Slavin, M., Mian, M., Altman, B., of the BIS-Brief among three groups of youth. Psychol. Assess. 30 (7),
2018. The role of impulsivity and expectancies in predicting marijuana 847.
Use: an application of the acquired Preparedness model. J. Psychoact. Matta, A.da, Gonçalves, F.L., Bizarro, L., 2012. Delay discounting: con-
Drugs 1e9. cepts and measures. Psychol. Neurosci. 5 (2), 135e146.
Lubman, D.I., Garfield, J.B.B., Gwini, S.M., Cheetham, A., Cotton, S.M., Mazur, J.E., 1987. An adjusting procedure for studying delayed rein-
Yücel, M., Allen, N.B., 2018. Dynamic associations between opioid forcement. In: Commons, M.L., Mazur, J.E. (Eds.). Nevin, JA,
use and anhedonia: a longitudinal study in opioid dependence. pp. 55e73.
J. Psychopharmacol. 32 (9), 957e964. McGovern, M.P., Carroll, K.M., 2003. Evidence-based practices for sub-
Lucantonio, F., Caprioli, D., Schoenbaum, G., 2014. Transition from stance use disorders. Psychiatr. Clin. N. Am. 26 (4), 991.
‘model-based’to ‘model-free’behavioral control in addiction: Mezquita, L., Camacho, L., Suso-Ribera, C., Ortet, G., Ibáñez, M.I., 2018.
involvement of the orbitofrontal cortex and dorsolateral striatum. Development and validation of the alcohol expectancy questionnaire
Neuropharmacology 76, 407e415. short form (EQ-SF). Adicciones 920.
Luengo, M.A., Carrillo-De-La-Pena, M.T., Otero, J.M., 1991. The com- Morales, A.M., Jones, S.A., Ehlers, A., Lavine, J.B., Nagel, B.J., 2018.
ponents of impulsiveness. A comparison of the I. 7 impulsiveness Ventral striatal response during decision making involving risk and
questionnaire and the barratt impulsiveness scale. Personal. Individ. reward is associated with future binge drinking in adolescents. Neu-
Differ. 12 (7), 657e667. ropsychopharmacology 1.
Luijten, M., Schellekens, A.F., Kühn, S., Machielse, M.W.J., Moutoussis, M., Bentall, R.P., El-Deredy, W., Dayan, P., 2011. Bayesian
Sescousse, G., 2017. Disruption of reward processing in addiction. An modelling of Jumping-to-Conclusions bias in delusional patients.
image-based meta-analysis of functional magnetic resonance imaging Cogn. Neuropsychiatry 16 (5), 422e447.
studies. JAMA Psychiatry 74 (4), 387e398. Muench, C., Juliano, L.M., 2017. Predictors of smoking lapse during a 48-
Lynam, D.R., Smith, G.T., Whiteside, S.P., Cyders, M.A., 2006. The hour laboratory analogue smoking cessation attempt. Psychol. Addict.
UPPS-P: assessing five personality pathways to impulsive behavior. Behav. 31 (4), 415e422. https://doi.org/10.1037/adb0000246.
In: West Lafayette. Purdue University. Mumtaz, W., Kamel, N., Ali, S.S.A., Malik, A.S., 2018. An EEG-based
Lynam, D., Smith, G.T., Cyders, M.A., Fischer, S., Whiteside, S.A., 2007. functional connectivity measure for automatic detection of alcohol
The UPPS-P: A Multidimensional Measure of Risk for Impulsive use disorder. Artif. Intell. Med. 84, 79e89.
Behavior (Unpublished technical report). Murphy, J.G., Correia, C.J., Colby, S.M., Vuchinich, R.E., 2005. Using
MacPherson, L., Magidson, J.F., Reynolds, E.K., Kahler, C.W., behavioral theories of choice to predict drinking outcomes following a
Lejuez, C.W., 2010a. Changes in sensation seeking and risk-taking brief intervention. Exp. Clin. Psychopharmacol 13 (2), 93.
propensity predict increases in alcohol use among early adolescents. Myerson, J., Green, L., Hanson, J.S., Holt, D.D., Estle, S.J., 2003. Dis-
Alcohol Clin. Exp. Res. 34 (8), 1400e1408. counting delayed and probabilistic rewards: processes and traits.
MacPherson, L., Reynolds, E.K., Daughters, S.B., Wang, F., Cassidy, J., J. Econ. Psychol. 24 (5), 619e635.
Mayes, L.C., Lejuez, C.W., 2010b. Positive and negative reinforce- Nestor, L.J., McCabe, E., Jones, J., Clancy, L., Garavan, H., 2018. Shared
ment underlying risk behavior in early adolescents. Prev. Sci. 11 (3), and divergent neural reactivity to non-drug operant response outcomes
331e342. in current smokers and ex-smokers. Brain Res. 1680, 54e61.
MacPhillamy, D.J., Lewinsohn, P.M., 1982. The pleasant events schedule: Odum, A.L., 2011. Delay discounting: I’m ak, you’re ak. J. Exp. Anal.
studies on reliability, validity, and scale intercorrelation. J. Consult. Behav. 96 (3), 427e439.
Clin. Psychol. 50 (3), 363. Oldham, S., Murawski, C., Fornito, A., Youssef, G., Yücel, M.,
Madden, G.J., Bickel, W.K., Jacobs, E.A., 1999. Discounting of delayed Lorenzetti, V., 2018. The anticipation and outcome phases of reward
rewards in opioid-dependent outpatients: exponential or hyperbolic and loss processing. A neuroimaging meta-analysis of the monetary
discounting functions? Exp. Clin. Psychopharmacol 7 (3), 284. incentive delay task. Hum. Brain Mapp. 39 (8), 3398e3418.
Mahoney 3rd, J.J., Thompson-Lake, Daisy, G.Y., Cooper, K., Orsini, C.A., Moorman, D.E., Young, J.W., Setlow, B., Floresco, S.B.,
Verrico, C.D., Newton, T.F., La Garza, R.2nd de, 2015. A comparison 2015. Neural mechanisms regulating different forms of risk-related
of impulsivity, depressive symptoms, lifetime stress and sensation decision-making. Insights from animal models. Neurosci. Biobehav.
seeking in healthy controls versus participants with cocaine or meth- Rev. 58, 147e167.
amphetamine use disorders. J. Psychopharmacol. 29 (1), 50e56. Ostlund, S.B., Cui, Y., 2018. Not worth the wait. Cocaine alters reward
https://doi.org/10.1177/0269881114560182. processing in the nucleus accumbens. Neuropsychopharmacology 1.
Owens, M.M., Amlung, M.T., Beach, S.R.H., Sweet, L.H., MacKillop, J., Reise, S.P., Moore, T.M., Sabb, F.W., Brown, A.K., London, E.D., 2013.
2017. Delay discounting differences in brain activation, connectiv- The barratt impulsiveness scalee11: reassessment of its structure in a
ity, and structure in individuals with addiction: a systematic review community sample. Psychol. Assess. 25 (2), 631.
protocol. Syst. Rev. 6 (1), 138. https://doi.org/10.1186/s13643-017- Reiter, A.M.F., Deserno, L., Kallert, T., Heinze, H.-J., Heinz, A.,
0537-0. Schlagenhauf, F., 2016. Behavioral and neural signatures of reduced
Pacheco-Colon, I., Limia, J.M., Gonzalez, R., 2018. Nonacute effects of updating of alternative options in alcohol-dependent patients during
cannabis use on motivation and reward sensitivity in humans: a sys- flexible decision-making. J. Neurosci. 36 (43), 10935e10948. https://
tematic review. Psychol. Addict. Behav. 32 (5), 497e507. https:// doi.org/10.1523/JNEUROSCI.4322-15.2016.
doi.org/10.1037/adb0000380. Reske, M., Stewart, J.L., Flagan, T.M., Paulus, M.P., 2015. Attenuated
Paneto, A., 2017. Risky Decision-Making in College-Aged Cannabis neural processing of risk in young adults at risk for stimulant
Users. A Preliminary fMRI Analysis. Indiana University. dependence. PLoS One 10 (6), e0127010.
Patton, J.H., Stanford, M.S., 2011. Psychology of impulsivity. In: The Richards, J.B., Zhang, L., Mitchell, S.H., Wit, H.de, 1999. Delay or
Oxford Handbook of Impulse Control Disorders, pp. 262e275. probability discounting in a model of impulsive behavior: effect of
Patton, J.H., Stanford, M.S., Barratt, E.S., 1995. Factor structure of the alcohol. J. Exp. Anal. Behav. 71 (2), 121e143.
Barratt impulsiveness scale. J. Clin. Psychol. 51 (6), 768e774. Robinson, T.E., Berridge, K.C., 2008. The incentive sensitization theory of
Patton, K.A., Connor, J.P., Rundle-Thiele, S., Dietrich, T., addiction. Some current issues. Philos. Trans. R. Soc. Lond. B Biol.
Young, R.M.D., Gullo, M.J., 2018. Validation of the adolescent Sci. 363 (1507), 3137e3146.
drinking expectancy questionnaire and development of a short form. Robles, E., Vargas, P.A., 2008. Parameters of delay discounting assess-
Drug Alcohol Rev. 37 (3), 396e405. ment: number of trials, effort, and sequential effects. Behav. Process.
Patzelt, E.H., Kurth-Nelson, Z., Lim, K.O., MacDonald 3rd, A.W., 2014. 78 (2), 285e290.
Excessive state switching underlies reversal learning deficits in Rochat, L., Maurage, P., Heeren, A., Billieux, J., 2018. Let’s open the
cocaine users. Drug Alcohol Depend. 134, 211e217. https://doi.org/ decision-making umbrella: a framework for conceptualizing and
10.1016/j.drugalcdep.2013.09.029. assessing features of impaired decision making in addiction. Neuro-
Paulus, M.P., Rogalsky, C., Simmons, A., Feinstein, J.S., Stein, M.B., psychol. Rev. 1e25.
2003. Increased activation in the right insula during risk-taking de- Rogers, R.D., Everitt, B.J., Baldacchino, A., Blackshaw, A.J.,
cision making is related to harm avoidance and neuroticism. Neuro- Swainson, R., Wynne, K., et al., 1999a. Dissociable deficits in the
image 19 (4), 1439e1448. decision-making cognition of chronic amphetamine abusers, opiate
Pearce, N., Lawlor, D.A., 2016. Causal inference-so much more than abusers, patients with focal damage to prefrontal cortex, and
statistics. Int. J. Epidemiol. 45 (6), 1895e1903. https://doi.org/ tryptophan-depleted normal volunteers: evidence for monoaminergic
10.1093/ije/dyw328. mechanisms. Neuropsychopharmacology 20 (4), 322e339.
Pearson, M.R., Hustad, J.T.P., Neighbors, C., Conner, B.T., Bravo, A.J., Rogers, R.D., Owen, A.M., Middleton, H.C., Williams, E.J., Pickard, J.D.,
2018. Personality, marijuana norms, and marijuana outcomes among Sahakian, B.J., Robbins, T.W., 1999b. Choosing between small, likely
college students. Addict. Behav. 76, 291e297. https://doi.org/ rewards and large, unlikely rewards activates inferior and orbital
10.1016/j.addbeh.2017.08.012. prefrontal cortex. J. Neurosci. 19 (20), 9029e9038.
Peters, J., Büchel, C., 2010. Episodic future thinking reduces reward delay Roozen, H.G., Wiersema, H., Strietman, M., Feij, J.A., Lewinsohn, P.M.,
discounting through an enhancement of prefrontal-mediotemporal Meyers, R.J., et al., 2008. Development and psychometric evaluation
interactions. Neuron 66 (1), 138e148. of the pleasant activities list. Am. J. Addict. 17 (5), 422e435.
Peters, J., Büchel, C., 2011. The neural mechanisms of inter-temporal Rosenthal, T.L., Montgomery, L.M., Shadish Jr., W.R., Lichstein, K.L.,
decision-making. Understanding variability. Trends Cogn. Sci. 15 1989. Leisure interest patterns and subjective stress in college stu-
(5), 227e239. dents. Behav. Res. Ther. 27 (1), 59e64.
Petrocelli, J.V., 2003. Factor validation of the consideration of future Ross, E.L., Yoon, J.H., Mahoney 3rd, J.J., Omar, Y., Newton, T.F.,
consequences scale: evidence for a short version. J. Soc. Psychol. 143 Garza, La, Richard, 2nd de, 2013. The impact of self-reported life
(4), 405e413. stress on current impulsivity in cocaine dependent adults. Prog.
Phillips, L.D., Edwards, W., 1966. Conservatism in a simple probability Neuropsychopharmacol. Biol. Psychiatry. 46, 113e119. https://
inference task. J. Exp. Psychol. 72 (3), 346. doi.org/10.1016/j.pnpbp.2013.06.002.
Pleskac, T.J., Wallsten, T.S., Wang, P., Lejuez, C.W., 2008. Development Rubenis, A.J., Fitzpatrick, R.E., Lubman, D.I., Verdejo-Garcia, A., 2018.
of an automatic response mode to improve the clinical utility of Impulsivity predicts poorer improvement in quality of life during early
sequential risk-taking tasks. Exp. Clin. Psychopharmacol 16 (6), 555. treatment for people with methamphetamine dependence. Addiction
Prause, N., Lawyer, S., 2014. Specificity of reinforcement for risk be- 113 (4), 668e676. https://doi.org/10.1111/add.14058.
haviors of the Balloon Analog Risk Task using math models of per- Ryan, F., 2013. Cognitive Therapy for Addiction. Motivation and Change.
formance. J. Risk Res. 17 (3), 317e335. John Wiley & Sons, Chichester, West Sussex, Malden, MA.
Rachlin, H., 1974. Self-control. Behaviorism 2 (1), 94e107. Sambrook, T.D., Hardwick, B., Wills, A.J., Goslin, J., 2018. Model-free
Rachlin, H., Raineri, A., Cross, D., 1991. Subjective probability and delay. and model-based reward prediction errors in EEG. Neuroimage 178,
J. Exp. Anal. Behav. 55 (2), 233e244. 162e171.
Radu, P.T., Yi, R., Bickel, W.K., Gross, J.J., McClure, S.M., 2011. Sanudo, A., Andreoni, S., Sanchez, Z.M., 2018. Alcohol-induced risk
A mechanism for reducing delay discounting by altering temporal behaviors among Brazilian nightclub patrons: a latent class analysis.
attention. J. Exp. Anal. Behav. 96 (3), 363e385. https://doi.org/ Public health 155, 99e106. https://doi.org/10.1016/j.puhe.2017.
10.1901/jeab.2011.96-363. 11.019.
Saw, Y.M., Saw, T.N., Chan, N., Cho, S.M., Jimba, M., 2018. Gender- Stein, J.S., Tegge, A.N., Turner, J.K., Bickel, W.K., 2018. Episodic future
specific differences in high-risk sexual behaviors among metham- thinking reduces delay discounting and cigarette demand: an investi-
phetamine users in Myanmar-China border city, Muse, Myanmar: who gation of the good-subject effect. J. Behav. Med. 41 (2), 269e276.
is at risk? BMC Public Health 18 (1), 209. https://doi.org/10.1186/ https://doi.org/10.1007/s10865-017-9908-1.
s12889-018-5113-6. Steinberg, L., Sharp, C., Stanford, M.S., Tharp, A.T., 2013. New tricks for
Schafer, J., Brown, S.A., 1991. Marijuana and cocaine effect expectancies an old measure: the development of the barratt impulsiveness
and drug use patterns. J. Consult. Clin. Psychol. 59 (4), 558. scaleebrief (BIS-brief). Psychol. Assess. 25 (1), 216.
Schmaal, L., Goudriaan, A.E., Joos, L., Dom, G., Pattij, T., van den Stephan, K.E., Schlagenhauf, F., Huys, Q.J.M., Raman, S., Aponte, E.A.,
Brink, W., Veltman, D.J., 2014. Neural substrates of impulsive de- Brodersen, K.H., et al., 2017. Computational neuroimaging strategies
cision making modulated by modafinil in alcohol-dependent patients. for single patient predictions. Neuroimage 145, 180e199.
Psychol. Med. 44 (13), 2787e2798. https://doi.org/10.1017/S00332 Stephenson, M.T., Velez, L.F., Chalela, P., Ramirez, A., Hoyle, R.H.,
91714000312. 2007. The reliability and validity of the Brief Sensation Seeking Scale
Schneider, S., Peters, J., Bromberg, U., Brassen, S., Miedl, S.F., (BSSS-8) with young adult Latino workers: implications for tobacco
Banaschewski, T., et al., 2012. Risk taking and the adolescent reward and alcohol disparity research. Addiction 102, 79e91.
system. A potential common link to substance abuse. Am. J. Psy- Stevens, A.K., Littlefield, A.K., Talley, A.E., Brown, J.L., 2017. Do in-
chiatry 169 (1), 39e46. dividuals higher in impulsivity drink more impulsively? A pilot study
Schuster, R.M., Hareli, M., Moser, A.D., Lowman, K., Gilman, J., within a high risk sample of young adults. Addict. Behav. 65,
Ulysse, C., et al., 2019. Cross-domain correlates of cannabis use 147e153. https://doi.org/10.1016/j.addbeh.2016.10.026.
disorder severity among young adults. Addict. Behav. 93, 212e218. Stewart, J.L., Butt, M., May, A.C., Tapert, S.F., Paulus, M.P., 2017.
Schwartenbeck, P., FitzGerald, T.H.B., Mathys, C., Dolan, R., Wurst, F., Insular and cingulate attenuation during decision making is associated
Kronbichler, M., Friston, K., 2015. Optimal inference with suboptimal with future transition to stimulant use disorder. Addiction 112 (9),
models: addiction and active Bayesian inference. Med. Hypotheses 84 1567e1577. https://doi.org/10.1111/add.13839.
(2), 109e117. Stoops, W.W., Kearns, D.N., 2018. Decision-making in Addiction. Cur-
Sebold, M., Deserno, L., Nebe, S., Schad, D.J., Garbusow, M., Hägele, C., rent Knowledge, Clinical Implications and Future Directions. Elsevier.
et al., 2014. Model-based and model-free decisions in alcohol Strathman, A., Gleicher, F., Boninger, D.S., Edwards, C.S., 1994. The
dependence. Neuropsychobiology 70 (2), 122e131. consideration of future consequences: weighing immediate and distant
Sebold, M., Nebe, S., Garbusow, M., Guggenmos, M., Schad, D.J., outcomes of behavior. J. Personal. Soc. Psychol. 66 (4), 742.
Beck, A., et al., 2017. When habits are dangerous: alcohol expec- Suckling, J., Nestor, L.J., 2017. The neurobiology of addiction: the
tancies and habitual decision making predict relapse in alcohol perspective from magnetic resonance imaging present and future.
dependence. Biol. Psychiatry 82 (11), 847e856. https://doi.org/ Addiction 112 (2), 360e369. https://doi.org/10.1111/add.13474.
10.1016/j.biopsych.2017.04.019. Sun, D., 2017. Development of new diagnostic techniquesemachine
Sharma, S., 2017. Translational multimodality neuroimaging. Curr. Drug learning. In: Substance and Non-substance Addiction. Springer,
Targets 18 (9), 1039e1050. pp. 203e215.
Sherman, L., Steinberg, L., Chein, J., 2018. Connecting brain responsivity Tanabe, J., Thompson, L., Claus, E., Dalwani, M., Hutchison, K.,
and real-world risk taking. Strengths and limitations of current Banich, M.T., 2007. Prefrontal cortex activity is reduced in gambling
methodological approaches. Dev. Cogn. Neuros-Neth. 33, 27e41. and nongambling substance users during decision-making. Hum.
Slovic, P., 1966. Risk-taking in children: age and sex differences. Child Brain Mapp. 28 (12), 1276e1286.
Dev. 169e176. Tanabe, J., Reynolds, J., Krmpotich, T., Claus, E., Thompson, L.L.,
Smethells, J.R., Reilly, M.P., 2015. Intertrial interval duration and Du, Y.P., Banich, M.T., 2013. Reduced neural tracking of prediction
impulsive choice. J. Exp. Anal. Behav. 103 (1), 153e165. https:// error in substance-dependent individuals. Am. J. Psychiatry 170 (11),
doi.org/10.1002/jeab.131. 1356e1363.
Sousa, C., Gonçalves, G., Sousa, A., Pinto, E., 2018. An assessment of the Tarokh, L., 2012. Neuroimaging in addiction. Acta Psychiatrica Scandi-
psychometric properties of the Brief Sensation Seeking Scale and its navica 126 (3), 230.
prediction in safety performance in a Portuguese adult sample. Curr. Thompson, L.L., Claus, E.D., Mikulich-Gilbertson, S.K., Banich, M.T.,
Psychol. 1e13. Crowley, T., Krmpotich, T., et al., 2012. Negative reinforcement
Spear, L.P., 2018. Effects of adolescent alcohol consumption on the brain learning is affected in substance dependence. Drug Alcohol Depend.
and behaviour. Nat. Rev. Neurosci. 19 (4), 197. 123 (1e3), 84e90.
Squeglia, L.M., Ball, T.M., Jacobus, J., Brumback, T., McKenna, B.S., Thompson, P.M., Andreassen, O.A., Arias-Vasquez, A., Bearden, C.E.,
Nguyen-Louie, Tam, T., et al., 2016. Neural predictors of initiating Boedhoe, P.S., Brouwer, R.M., et al., 2017. ENIGMA and the indi-
alcohol use during adolescence. Am. J. Psychiatry 174 (2), 172e185. vidual. Predicting factors that affect the brain in 35 countries world-
Stanford, M.S., Mathias, C.W., Dougherty, D.M., Lake, S.L., wide. Neuroimage 145, 389e408.
Anderson, N.E., Patton, J.H., 2009. Fifty years of the barratt impul- Thomsen, R., Kristine, Callesen, M.B., Hesse, M., Kvamme, T.L.,
siveness scale. An update and review. Personal. Individ. Differ. 47 (5), Pedersen, M.M., Pedersen, M.U., Voon, V., 2018. Impulsivity traits
385e395. and addiction-related behaviors in youth. J. Behav. Addict. 1e14.
Stein, J.S., Wilson, A.G., Koffarnus, M.N., Daniel, T.O., Epstein, L.H., Thylstrup, B., Hesse, M., 2018. Why run the risk? Motivation for offences
Bickel, W.K., 2016. Unstuck in time: episodic future thinking reduces by patients with substance use and antisocial personality disorders
delay discounting and cigarette smoking. Psychopharmacology 233 which they rated as most risky to their own well-being. Crim. Behav.
(21e22), 3771e3778. https://doi.org/10.1007/s00213-016-4410-y. Ment. Health 28 (2), 187e201. https://doi.org/10.1002/cbm.2059.
Tiwari, T., Singh, A.L., Singh, I.L., 2009. The short-form revised Eysenck Pharmacol. Biochem. Behag. 102 (4), 526e531. https://doi.org/
personality questionnaire. A Hindi edition (EPQRS-H). Ind. Psychi- 10.1016/j.pbb.2012.06.016.
atry J. 18 (1), 27. Weatherly, J.N., Derenne, A., Terrell, H.K., 2010. College students dis-
Tran, J., Teese, R., Gill, P.R., 2018. UPPS-P facets of impulsivity and count money “won” more than money “owed”. Psychol. Rec. 60 (3),
alcohol use patterns in college and noncollege emerging adults. Am. J. 463e471. https://doi.org/10.1007/BF03395721.
Drug Alcohol Abuse 44 (6), 695e704. Wei, Z., Han, L., Zhong, X., Liu, Y., Zha, R., Wang, Y., et al., 2018.
Treadway, M.T., Buckholtz, J.W., Schwartzman, A.N., Lambert, W.E., Chronic nicotine exposure impairs uncertainty modulation on rein-
Zald, D.H., 2009. Worth the ‘EEfRT’? The effort expenditure for forcement learning in anterior cingulate cortex and serotonin system.
rewards task as an objective measure of motivation and anhedonia. Neuroimage 169, 323e333.
PLoS One 4 (8), e6598. White, T.L., Lejuez, C.W., Wit, H.de, 2008. Test-retest characteristics of
Treadway, M.T., Bossaller, N.A., Shelton, R.C., Zald, D.H., 2012. Effort- the balloon analogue risk task (BART). Exp. Clin. Psychopharmacol
based decision-making in major depressive disorder: a translational 16 (6), 565.
model of motivational anhedonia. J. Abnorm. Psychol. 121 (3), 553. Whiteside, S.P., Lynam, D.R., 2001. The five factor model and impul-
van Gelder, Jean-Louis, Hershfield, H.E., Nordgren, L.F., 2013. Vividness sivity: using a structural model of personality to understand impul-
of the future self predicts delinquency. Psychol. Sci. 24 (6), 974e980. sivity. Personal. Individ. Differ. 30 (4), 669e689.
Verdejo-García, A., Alcázar-Córcoles, Miguel, A., Albein-Urios, Natalia, Wise, R.A., Koob, G.F., 2014. The development and maintenance of drug
2018. Neuropsychological interventions for decision-making in addiction. Neuropsychopharmacology 39 (2), 254.
addiction. A systematic review. Neuropsychol. Rev. 1e14. Woicik, P.A., Stewart, S.H., Pihl, R.O., Conrod, P.J., 2009. The substance
Volkow, N.D., Wang, G.-J., Fowler, J.S., Tomasi, D., Telang, F., use risk profile scale: a scale measuring traits linked to reinforcement-
Baler, R., 2010. Addiction. Decreased reward sensitivity and increased specific substance use profiles. Addict. Behav. 34 (12), 1042e1055.
expectation sensitivity conspire to overwhelm the brain’s control Xiao, L., Bechara, A., Gong, Q., Huang, X., Li, X., Xue, G., et al., 2013.
circuit. Bioessays 32 (9), 748e755. Abnormal affective decision making revealed in adolescent binge
Voon, V., 2014. Models of impulsivity with a focus on waiting impul- drinkers using a functional magnetic resonance imaging study. Psy-
sivity. Translational potential for neuropsychiatric disorders. Curr. chol. Addict. Behav. 27 (2), 443.
Addict. Rep. 1 (4), 281e288. Yamamoto, D.J., Reynolds, J., Krmpotich, T., Banich, M.T.,
Voon, V., Chang-Webb, Y.C., Morris, L.S., Cooper, E., Sethi, A., Thompson, L., Tanabe, J., 2014. Temporal profile of fronto-striatal-
Baek, K., et al., 2015. Waiting impulsivity: the influence of acute limbic activity during implicit decisions in drug dependence. Drug
methylphenidate and feedback. Intl. J. Neuropsychopharmacol. 19 (1) Alcohol Depend. 136, 108e114.
https://doi.org/10.1093/ijnp/pyv074. Yanes, J.A., Riedel, M.C., Ray, K.L., Kirkland, A.E., Bird, R.T.,
Voon, V., Chang-Webb, Y.C., Morris, L.S., Cooper, E., Sethi, A., Boeving, E.R., et al., 2018. Neuroimaging meta-analysis of cannabis
Baek, K., et al., 2016. Waiting impulsivity: the influence of acute use studies reveals convergent functional alterations in brain regions
methylphenidate and feedback. Int. J. Neuropsychopharmacol. 19 (1). supporting cognitive control and reward processing.
Voon, V., Reiter, A., Sebold, M., Groman, S., 2017. Model-based control J. Psychopharmacol. 32 (3), 283e295.
in dimensional psychiatry. Biol. Psychiatry 82 (6), 391e400. Yazdi, K., Rumetshofer, T., Gnauer, M., Csillag, D., Rosenleitner, J.,
Vuletic, D., Dupont, P., Robertson, F., Warwick, J., Zeevaart, J.R., Kleiser, R., 2019. Neurobiological processes during the Cambridge
Stein, D.J., 2018. Methamphetamine dependence with and without gambling task. Behav. Brain Res. 356, 295e304.
psychotic symptoms. A multi-modal brain imaging study. Neuro- Zapolski, T.C.B., Stairs, A.M., Settles, R.F., Combs, J.L., Smith, G.T.,
Image. Clin. 20, 1157e1162. 2010. The measurement of dispositions to rash action in children.
Wallace, M., 1956. Future time perspective in schizophrenia. J. Abnorm. Assessment 17 (1), 116e125.
Soc. Psychol. 52 (2), 240. Zhu, Y., Jiang, H., Su, H., Zhong, N., Li, R., Li, X., et al., 2018. A newly
Wallsten, T.S., Pleskac, T.J., Lejuez, C.W., 2005a. Modeling behavior in a designed mobile-based computerized cognitive addiction therapy app
clinically diagnostic sequential risk-taking task. Psychol. Rev. 112 (4), for the improvement of cognition impairments and risk decision
862. making in methamphetamine use disorder. Randomized controlled
Wallsten, T.S., Pleskac, T.J., Lejuez, C.W., 2005b. Modeling behavior in a trial. JMIR mHealth and uHealth 6 (6), e10292.
clinically diagnostic sequential risk-taking task. Psychol. Rev. 112 (4), Zilverstand, A., Huang, A.S., Alia-Klein, N., Goldstein, R.Z., 2018.
862. Neuroimaging impaired response inhibition and salience attribution in
Walter, M., Denier, N., Gerber, H., Schmid, O., Lanz, C., Brenneisen, R., human drug addiction. A systematic review. Neuron 98 (5), 886e903.
et al., 2015. Orbitofrontal response to drug-related stimuli after heroin Zimmermann, K., Kendrick, K., Scheele, D., Dau, W., Banger, M.,
administration. Addict. Biol. 20 (3), 570e579. https://doi.org/ Maier, W., et al., 2018. Altered reward processing in abstinent
10.1111/adb.12145. dependent cannabis users. Social context matters. In bioRxiv 278044.
Wang, J.M., Zhu, L., Brown, V.M., La Garza II, Richard de, Newton, T., Zuckerman, M., 1984. Experience and desire: a new format for sensation
King-Casas, B., Chiu, P.H., 2019. In cocaine dependence, neural seeking scales. J. Behav. Assess. 6 (2), 101e114.
prediction errors during loss avoidance are increased with cocaine Zuckerman, M., Kuhlman, D.M., 2000. Personality and risk-taking.
deprivation and predict drug use. Biol. Psychiatry Cogn. Neurosci. Common bisocial factors. J. Personal. 68 (6), 999e1029.
Neuroimagin 4 (3), 291e299. Zuckerman, M., Kolin, E.A., Price, L., Zoob, I., 1964. Development of a
Wardle, M.C., Treadway, M.T., Wit, H.de, 2012. Caffeine increases sensation-seeking scale. J. Consult. Psychol. 28 (6), 477.
psychomotor performance on the effort expenditure for rewards task.
Chapter 5
Social cognition in addiction

Boris B. Quednow1, 2
1
Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of
Zurich, Zurich, Switzerland; 2Neuroscience Centre Zurich, University of Zurich and Swiss Federal Institute of Technology (ETH) Zurich, Zurich,
Switzerland
Introduction decrease in social contacts and social support, leading to an

increase in social isolation, aggression, and depressive
Humans have developed specific cognitive functions to symptoms (Quednow, 2017; Homer et al., 2013). This
understand themselves and others, to predict and affect the coincides with a further reduction in social reward re-
behavior of others, and to dynamically interact with their sources, ongoing social withdrawal, and the establishment
social environment (Amodio and Frith, 2006; Fiske and of the drug as the main source of reward, resulting in
Taylor, 2013; Lieberman, 2007). These higher cognitive maintained substance use and recurrent relapses (Quednow,
functions have been congregated under the umbrella term 2017) (see Fig. 5.1). Taken together, drug-related changes
social cognition. This broad array of functions includes in social reward and social cognition likely contribute to the
more perceptive abilities, such as emotion perception and social problems and the decay of social relationships in
recognition, self-awareness and self-perception, emotional individuals with SUD. Therefore, it is also likely that dis-
empathy, and mental and emotional perspective-taking also turbances in social perception and behavior strongly
called Theory of Mind (ToM), as well as interactive social compromise therapeutic relationships and, thus, hamper the
functions, such as social gaze contact, social decision- success of any addiction treatment. Consequently, inter-
making, and the ability to perceive reward from social personal problems related to social cognition deficits likely
contacts, and, finally, social attitudes and values, such as contribute to high relapse rates found across a range of
altruism, fairness, trust, morale, stereotypes, and prejudices SUD. Importantly, social cognitive deficits can recover
(Amodio and Frith, 2006; Fiske and Taylor, 2013; Lie- partially simply through drug abstinence, e.g., as shown for
berman, 2007; Rilling and Sanfey, 2011). Unsurprisingly, cocaine users (Vonmoos et al., 2019) and alcohol depen-
given that social functioning in daily life depends on intact dence (AD) (Erol et al., 2017), and several treatment ap-
social cognition, disturbances in these functions have been proaches have been demonstrated to have a normalizing
shown to be crucial factors in the development, progress, effect on social cognitive abilities, e.g., in major depression
and prognosis of psychiatric conditions such as schizo- (Weightman et al., 2019), which encourages the inclusion
phrenia (Couture et al., 2006; Green, 2016) and depression of available social training techniques and development of
(Weightman et al., 2019). Analogously, it has been prosocial competences and social reward in psychotherapy of
posed that dysfunctional social cognition and interaction SUD. However, specific treatment modules focusing on the
likewise play a key role in the origin and course of sub- rehabilitation of social cognition and reward are so far
stance use disorders (SUDs) (Homer et al., 2008; Volkow lacking for SUD, even though they might have a positive
et al., 2011; Quednow, 2017). It has also been suggested impact on the overall treatment success.
that chronic drug use, e.g., of stimulants, impacts the At the beginning of this chapter, brief definitions of the
frontal-striatal reward system by enhancing the value of most important socio-cognitive functions will be given.
the substance, while simultaneously reducing sensitivity to Thereafter, investigations characterizing, quantifying, and
the rewards obtained via social activities (Tobler et al., explaining disturbances of different socially related mental
2016; Preller et al., 2014a). Accordingly, drug-induced functions will be reviewed with respect to specific SUD.
changes in brain regions and neurotransmitter systems Overall, only performance measures and measures of
involved in social cognition, social interaction, and social behavior will be discussed in this chapter, while
reward processing are assumed to contribute to a further

FIGURE 5.1 The proposed role of social cognition and interaction in maintenance and relapse of substance use disorders. Quednow, B.B., 2017. Social
cognition and interaction in stimulant use disorders. Curr. Opin. Behav. Sci. 13, 55e62.
questionnaire-based research will be omitted to keep emotional load of faces and voices (Schaffer et al., 2009).
the focus on cognitive processes. Moreover, although The Multifaceted Empathy Task (MET) also deserves
empathogens such as 3,4-methylenedioxymethamphetamine mention as an example of the assessment of cognitive
(MDMA) have a very low addictive potential, they (i) play a empathy using complex, emotionally laden scenes (Dzio-
role in addiction medicine primarily as a frequently co-used bek et al., 2008).
substance class and (ii) havedper definitionda strong effect Emotional empathy, also called affective empathy, is
on social cognition and thus they will be discussed below, defined as a person’s emotional response to another per-
alongside addiction-related substances. son’s emotional state, i.e., the ability to feel what another
person feels (Mehrabian and Epstein, 1972). Beyond basic
Definitions of socio-cognitive functions cognitive empathy, emotional empathy can also be
measured, e.g., with the MET (Dziobek et al., 2008) or
and their measurement Empathy-for-Pain tasks (e.g., Lamm et al., 2011).
Emotion recognition, also called cognitive empathy, affect Mental and emotional perspective-taking, also called
recognition, or emotion perception, is the capability to mentalizing or ToM, reflects the ability “to propositionally
recognize and understand the emotions of others from reason from one’s theory of how minds operate and how
faces, voices, gestures, and situational contexts (Banziger social situations affect mental states in general, in order to
et al., 2009). Numerous studies with drug users have represent the mental state of a particular individual given a
employed emotional facial expression tasks, primarily particular situation” (3, p. 263). A famous emotion
based on the famous picture set of Ekman and Friesen recognition taskdalthough perhaps more commonly
(1976). Beyond simple static face stimuli with different interpreted as a ToM-taskdthe Reading the Mind in the
intensities of emotion expression, presentations of dynamic Eyes Task (RMET), in which emotional states have to be
emotion expressions using short movies or morphed Ekman inferred only from eye pairs, has been applied frequently in
faces have also been developed (e.g., Harris et al., 2014; drug-using populations (Baron-Cohen et al., 2001). In
Holland et al., 2018). The Comprehensive Affect Test Sys- addition, tests measuring the ability to detect social faux
tem (CATS-A) includes emotion recognition from Ekman pas’ (Baron-Cohen et al., 1999) and to understand humor
faces and from voices, as well as the ability to align the (Uekermann et al., 2006, 2007) have been used to measure
Social cognition in addiction Chapter | 5 65
aspects of perspective-taking and ToM. A final D’Hondt et al., 2015; Maurage et al., 2008; Philippot et al.,
exampledand one with high ecological validitydis the 1999; Foisy et al., 2005, 2007; Kornreich et al., 2001, 2002,
video-based Movie for the Assessment of Social Cognition 2013a, 2016). However, there are also several studies that
(MASC), which assesses the understanding of emotions, were not able to identify impaired performance in facial
thoughts, and intentions and concepts such as false belief, emotion recognition tasks in similar patient groups (Korn-
faux pas, metaphor, and sarcasm in everyday-life situations reich et al., 2016; Sprah and Novak, 2008; Oscar-Berman
(Dziobek et al., 2006). et al., 1990; Uekermann et al., 2005; Cermak et al.,
Social decision-making describes the ability to process 1989). Moreover, there are contradicting results regarding
multiple alternatives and to choose an optimal course of the impact of abstinence: while the first longitudinal study
action in a social environment, which is usually oper- showed no improvement of impaired emotional face
ationalized using socially interactive tasks derived from recognition after 3 months of abstinence (Foisy et al.,
game theory (Sanfey, 2007). A variety of such social 2007), a recent study showed almost complete recovery of
decision-making games is discussed elsewhere (Houser and such deficits in the same time period (Erol et al., 2017).
McCabe, 2009; Sanfey and Dorris, 2009). Two cross-sectional studies reported sustained emotion
Moral decision-making or moral judgment is a com- recognition impairments in midterm abstinent (>2 months)
plex cognitive process enabling individuals to judge actions AD individuals (Foisy et al., 2005; Kornreich et al., 2001),
of other individuals on the basis of habits, values, and whereas another cross-sectional study did not detect accu-
norms orienting the conduct in a certain social group (Moll racy changes in a face recognition task in patients with very
et al., 2005). This kind of behavior is usually operational- long abstinence periods (>12 months, mean 75 months)
ized by presenting hypothetical moral dilemmasdoften (Fein et al., 2010). However, the latter study showed slower
with varying levels of personal involvementdand asking early processing of emotional facial stimuli in long-term
for preferred choices (Christensen and Gomila, 2012). abstinent AD patients using an electrophysiological event-
A great variety of text- and picture-based vignettes with related potentials paradigm (Fein et al., 2010). Finally, a
hypothetical dilemmas have been developed, such as the recent meta-analysis including only 12 of the previous
well-known examples of Greene et al. (2001) and Koenigs studies confirmed global face recognition deficits of mod-
et al. (2007), but also newer stimulus sets (Clifford et al., erate effect size (total score Cohen’s d ¼ 0.65), while also
2015). Moreover, vignettes specifically related to addiction demonstrating that the strongest deficits are for the recog-
have also been used (Fisher, 2011). Recently, a normative nition of disgust (d ¼ 0.62) and anger (d ¼ 0.47) and the
moral video databasedthe Moral and Affective Film weakest for happiness (d ¼ 0.19) (Bora and Zorlu, 2017).
Setdhas also been proposed (McCurrie et al., 2018). In addition to face recognition deficits, worse emotion
Social reward can be defined as perceiving pleasure recognition from voices (prosody) has been shown repeat-
during social interactions or social commitment. Of note, edly in AD patients (Uekermann et al., 2005; Monnot et al.,
reward by non-social objects, such as money, gifts, and 2001; Maurage et al., 2009). Given that deficits in emotion
drugs of abuse, as well as social reward, all activate the recognition from body postures and music have also been
same reward-related networks in the brain (Lin et al., 2012; reported, it has therefore been suggested that AD in-
Izuma et al., 2008). So far, experimental tasks usually dividuals suffer from a generalized emotional decoding
applied in social neuroscience contexts have been devel- impairment (Kornreich et al., 2013a; Maurage et al., 2009).
oped to measure facets of social reward such as positive In line with findings showing face and prosody recognition
social feedback (Campbell-Meiklejohn et al., 2010), initi- deficits in AD patients, emotion recognition (cognitive
ated joint attention (Schilbach et al., 2010), or charitable empathy) from complex emotionally laden scenes, as pre-
decision-making (Hare et al., 2010). sented in the MET, was also recently demonstrated to be
diminished (Grynberg et al., 2017). Furthermore, a number
Studies on social cognition and of studies have indicated that the integrated processing of
interaction in substance use disorders face and voice recognition in cross-modal conditions is
specifically affected in AD patients (Valmas et al., 2014;
Alcohol Kornreich et al., 2016; Maurage et al., 2007). Patients with
AD not only fail in the categorization of emotions from
Emotion recognition and cognitive empathy
faces or voices but also generally overestimate the intensity
Since the end of the 1980s, emotion recognition from faces of emotional expressions (Philippot et al., 1999), have a
has been investigated in individuals with AD across dozens globally increased identification threshold for emotions
of studies. Most of these identified either emotion-specific (D’Hondt et al., 2015), or misidentify emotions (Freeman
or global impairments, or both, in the decoding of emo- et al., 2018). It has been shown that episodic memory and
tions from faces (Erol et al., 2017; Valmas et al., 2014; cognitive flexibility are strongly associated with emotional
Townshend and Duka, 2003; Quaglino et al., 2015; face recognition, suggesting that socio-cognitive deficits
might be partially explained by more basic cognitive im- for negative. In addition, the mimicry of angry faces, as
pairments (Quaglino et al., 2015). However, another study assessed by filming the participants while they were
demonstrated that visuomotor impairment cannot watching the stimuli (Dethier and Blairy, 2012), was more
completely explain face recognition deficits in AD (Maur- pronounced in Type-II AD patients (according to Cloninger
age et al., 2008). In addition, face recognition abilities in (1987) subtypes of alcoholism) than Type-I patients and
AD patients have been shown to be modulated by gender controls (Dethier and Blairy, 2012). In contrast, emotional
(Valmas et al., 2014) and are related to self-reported empathy was not altered in AD individuals in a study
interpersonal problems (Kornreich et al., 2002). As applying the MET, although their cognitive empathy was
several studies have found that emotion recognition per- impaired (Grynberg et al., 2017).
formance is correlated with severity markers of chronic
alcohol use, such as binge drinking, early onset of use, Perspective-taking and ToM
drinks consumed in the last 3 months, and number of de-
The most commonly used ToM taskdthe RMETdhas
toxifications, it has been suggested that such deficits may
been applied in seven published studies, of which four
be acquired more than they are signs of a predisposition
found a significant deficiency in “mind reading” in in-
(Valmas et al., 2014; Townshend and Duka, 2003; Monnot
dividuals with AD (Gizewski et al., 2013; Maurage et al.,
et al., 2001; Freeman et al., 2018; Lannoy et al., 2018).
2011; Thoma et al., 2013; Nandrino et al., 2014), while
A structural imaging study found that AD individuals
displayed reduced gray matter volume in the inferior frontal three did not report any group differences (Kornreich et al.,
2011; Matyassy et al., 2006; Kopera et al., 2018). A recent
cortex (IFC) and insula. IFC gray matter volume was
meta-analysis that included all of these studiesdwith the
correlated with number of detoxifications and with the
exception of the newest one (Kopera et al., 2018)dplus an
recognition of fearful faces (Trick et al., 2014). A combined
unpublished doctoral thesis came to the conclusion of a
structural and functional imaging (fMRI) study revealed
significant deficit in RMET performance with a moderate
that patients with AD displayed decreased activation in
effect size (Cohen’s d ¼ 0.46) existing in patients with AD
response to aversive faces in bilateral fusiform gyrus, right
(Bora and Zorlu, 2017).
middle frontal gyrus, right inferior parietal lobule, and left
cerebellum, which were largely explained by gray matter An fMRI study additionally reported that a diagnosis of
AD was associated with decreased activity of the right
differences. Moreover, because an increased activation of
anterior insular cortex while performing the RMET
the anterior cingulate cortex (ACC) was correlated with less
(Gizewski et al., 2013). The second most commonly used
previous lifetime alcohol intake, longer abstinence periods,
ToM task is the Faux pas test: two studies have found
and less subsequent binge drinking, the authors concluded
impaired performance on this task in AD (Thoma et al.,
that chronic alcohol use appears to impair treatment
2013; Cox et al., 2018), while one has not (Amenta et al.,
outcome via exerting neurotoxic effects on the ACC
2013). Deficits in the understanding of irony and humor
(Charlet et al., 2014). Schuckit et al. (2016) showed that
baseline fMRI activation patterns, specifically in insular have also been reported for AD individuals in three inde-
pendent studies (Uekermann et al., 2007; Cermak et al.,
and frontal regions, predicted heavy drinking and alcohol
1989; Amenta et al., 2013), although one further study did
problems in AD 5 years later. Importantly, only poorer
not detect changes in the Strange Stories test assessing the
emotion recognition performance (but not emotional
comprehension of metaphors and irony (Bosco et al.,
perspective-taking and affective responsiveness) at baseline
2014). Furthermore, two video-based paradigms for the
was able to predict treatment outcomes of AD, such as
assessment of ToM and mental perspective-taking have
relapse or dropout (Rupp et al., 2017).
revealed a deficit in the affective component of ToM, while
Taken together, these findings suggest that patients with
AD display difficulties in the recognition and integration of its cognitive component was preserved (Nandrino et al.,
2014; Maurage et al., 2016). AD individuals were also
emotions from faces, voices, and other sources. These
shown to display deficits in False Belief tasks (specifically
deficits might be partially induced by neurotoxic effects of
in the tracking of others beliefs) (Maurage et al., 2015) and
chronic alcohol intake, but they may also be useful for the
in social problem solving, both of which depend on the
prediction of treatment success.
ability to infer mental states of others (Schmidt et al.,
2016). Two meta-analyses so far have assessed the effect
Emotional empathy sizes across several ToM paradigms and both concluded
In an emotional contagion task using emotional facial ex- that ToM abilities are impaired in AD individuals: the first
pressions, AD patients reported fewer positive and more of these included 8 studies with 187 patients and 187
negative emotions when confronted with, respectively, controls and found a very strong effect size (Hedges’
valent face stimuli than controls, indicating emotional g ¼ 1.62) (Onuoha et al., 2016). The second one included
empathy to be lower for positive emotions, but increased
12 studies with 317 patients and 298 controls and reported changes in moral judgment and, specifically, it may be that
a moderate effect size (d ¼ 0.58) (Bora and Zorlu, 2017). alcohol-induced damage to the ventromedial prefrontal
Importantly, ToM deficits in AD have been shown to be cortex (VMPFC) causes emotional dysfunction, leading to
correlated with executive and memory functions as well as a more utilitarian approach to moral judgment (Khemiri
with depressive symptoms (Uekermann et al., 2007; Thoma et al., 2012).
et al., 2013; Nandrino et al., 2014), and to increase with the
duration of AD (Gizewski et al., 2013; Cox et al., 2018). Cannabis
Taken together, a number of studies have shown impair-
ments in ToM and perspective-taking abilities that might be
induced or at least partially caused by chronic alcohol Several studies have investigated emotion recognition from
intake. Moreover, these disturbed abilities might be linked faces in moderate, heavy, and dependent cannabis users and
to other cognitive or emotional impairments and may not be all reported a generalized deficit in this kind of emotion
changes specific to mentalizing. processing (Platt et al., 2010; Hindocha et al., 2014;
Bayrakci et al., 2015; Huijbregts et al., 2014). This effect
Social decision-making was found in current (Platt et al., 2010; Hindocha et al.,
2014; Huijbregts et al., 2014) and medium-term abstinent
AD individuals have been consistently reported to reject
users (mean 3.2 months) (Bayrakci et al., 2015), thus the
unfair offers in the ultimatum game more often than healthy deficits are likely not fully explained by acute and postacute
controls (Tsukue et al., 2015; Brevers et al., 2013, 2015).
detrimental effects of D-9-tetrahydrocannabinol (THC) on
The proportion of rejected unfair offers has been shown to
emotion recognition (Hindocha et al., 2015). Importantly,
be correlated with elevated physiological arousal as
higher levels of schizotypy in cannabis users also failed to
assessed by the skin conductance response (Brevers et al.,
explain the results in one of the studies (Hindocha et al.,
2015) as well as with reward impulsivity measured using a
2014) and deficits might be more pronounced in the
delay discounting task (Tsukue et al., 2015). These findings
recognition of negative emotions (Bayrakci et al., 2015).
indicate that AD individuals have a higher sensitivity to
Interestingly, in a well-powered fMRI investigation, it was
unfairness, or that they have more problems with control- demonstrated that adolescent cannabis users showed a
ling their emotions in unfair situations, resulting in more
stronger activation of the bilateral amygdala in response to
aggressive or retributive responses (Tsukue et al., 2015;
angry faces, while their cortical areas did not discriminate
Brevers et al., 2013, 2015).
angry versus neutral faces, unlike in controls (Spechler
et al., 2015). The authors concluded that early cannabis use
Moral decision-making might be associated with hypersensitivity to signals of
Two studies have demonstrated that patients with AD threat, perhaps placing users at risk for mood disorders in
endorse utilitarian choices significantly more than controls adulthood. Moreover, enhanced recognition of angry faces
(Khemiri et al., 2012; Carmona-Perera et al., 2014). (Ernst et al., 2010), as well as misattribution of sad faces
Another study also observeddalthough below the margin (Fishbein et al., 2016), has been shown to predict later
to be reported as statistically significantdelevated utili- initiation of cannabis use in adolescents. In sum, these
tarian choices in individuals with AD (Kornreich et al., findings all point to emotion recognition problems in
2013b). Moreover, in a group of polysubstance users, cannabis users that might be partially present before onset
severity of alcohol use specifically predicted the proportion of use and worsened further by acute, postacute, and
of utilitarian judgments (Carmona-Perera et al., 2012). chronic cannabis effects.
Notably, moral judgment was changed in spite of in-
Emotional empathy
dividuals having sufficient knowledge of explicit social and
moral norms and normal responses to non-moral or Unpublished pilot data from our lab suggest that at least
impersonal moral dilemmas (Khemiri et al., 2012). More- moderate use of cannabis (mean 2.8 g/week) was not
over, neither non-social decision-making, measured with associated with changes in cognitive and emotional
the Iowa Gambling Task, nor trait impulsivity and mood empathy in the MET in a low-powered sample of 21 users
predicted moral judgments (Carmona-Perera et al., 2014; versus 21 healthy controls (Diener, 2014). Published data
Kornreich et al., 2013b). However, poorer decoding of fear on emotional empathy measured with a behavioral task in
and disgust from faces was correlated with more utilitarian cannabis users are not available yet. However, an early
choices (Carmona-Perera et al., 2014) and AD individuals interview-based study showed that smoking cannabis
did not show aversive psychophysiological responses (heart acutely decreased affective resonance between the
rate) to personal moral violations (Carmona-Perera et al., cannabis-intoxicated individuals and their non-intoxicated
2013). To summarize, AD seems to be associated with interaction partners (Janowsky et al., 1979).
Perspective-taking and ToM fear and anger recognition performance was negatively
correlated with cocaine use intensity (Fernandez-Serrano
Perspective-taking abilities seem to be largely intact in
et al., 2010), while another study did not show an effect
chronic cannabis users when measured with the RMET
of stimulant polysubstance use on facets of cognitive
(Platt et al., 2010; Diener, 2014), a cartoon-based fMRI
empathy when assessed with complex stimuli (Kroll et al.,
task (Roser et al., 2012), and the MASC (Diener, 2014).
2018a). Using a facial affect matching task, an fMRI study
Moreover, when assessed using the Eyes and Hinting Test,
in methamphetamine users also did not detect task-related
cannabis use was not related to ToM performance in
changes, but rather different cortical activation patterns in
schizophrenia patients (Helle et al., 2017). However, a
regions relevant for social cognition (Payer et al., 2008).
small fMRI study found some differences in brain activa-
Non-medical users of methylphenidate without attention-
tions (but no performance differences) between chronic
deficit/hyperactivity disorder (ADHD), who have taken
cannabis users (n ¼ 15) and controls (n ¼ 14) while
the drug for neuroenhancement purposes, exhibited prob-
watching cartoon stories in which the characters show
lems with cognitive empathy for complex emotional scenes
various facets of cooperative behavior (Roser et al., 2012).
measured with the MET (Maier et al., 2015). Interestingly,
cocaine users with a comorbid ADHD diagnosis also
Social decision-making showed impaired cognitive empathy in the MET (Wunderli
Studies investigating social behavior with game-theoretical et al., 2016). One investigation has shown that chronic
approaches in cannabis users have not yet been published. cocaine users displayed problems in emotion recognition
In our small pilot study in the context of a master thesis, we from voices (prosody) as well as in the detection of matches
found no significant differences in prosocial behavior be- and mismatches between emotional faces and voices when
tween modest chronic cannabis users and matched controls both were presented together (Hulka et al., 2013). Differ-
in three neuroeconomic gamesdthe Promise Task, the ences in study sample characteristics may account for some
Distribution Game, and the Dictator Game. Nevertheless, of the discrepant results discussed above, given that most of
there was a statistical trend (P ¼ 0.052) for cannabis users the studies had relatively small sample sizes and often
to share more money than controls did with the opposite included stimulant-preferring polysubstance users with
player in the Dictator Game, indicating rather prosocial further psychiatric comorbidities. Accordingly, Ersche et al.
fairness preferences (Diener, 2014). (2015) demonstrated that fear and anger recognition deficits
in cocaine users were mainly explained by lower IQ and
concurrent opioid dependence, respectively, while an
Social reward
additional impact of ADHD on cognitive empathy has
Employing a novel interpersonal pleasant touch fMRI recently been shown (Wunderli et al., 2016). Of note, well-
paradigm to dependent, but recently abstinent, male powered studies did not find alterations in visual emotional
cannabis users and healthy controls, Zimmermann et al. processing, but rather deficient prosodic emotion recogni-
(2019) found that, relative to the controls, cannabis users tion, in relatively pure recreational and dependent cocaine
reported lower reward responsiveness to female touch, as users with a low burden of psychiatric comorbidities
well as decoupling of striatal activations and subjectively (Hulka et al., 2013; Preller et al., 2014b).
reported reward experiences. However, neural processing
of pleasant touch in general was seemingly unchanged in Emotional empathy
dependent cannabis users (Zimmermann et al., 2019).
In the Zurich Cocaine Cognition Study (ZuCo2St), recrea-
tional and dependent cocaine users (Preller et al., 2014b) as
Stimulants well as stimulant polysubstance users (Kroll et al., 2018a)
reported lower emotional empathy ratings to the photo-
realistic affective stimuli in the MET. In cocaine users,
Most studies with cocaine and methamphetamine users implicit emotional empathy was correlated specifically with
have revealed that their ability to identify basic facial affect weekly and lifetime cocaine dose, and emotional empathy
expressions is largely unimpaired (Hulka et al., 2013; deficits were generally most pronounced in early age-of-
Woicik et al., 2009; Verdejo-Garcia et al., 2010, 2017; Fox onset users (Preller et al., 2014b). Interestingly, comorbid
et al., 2011; Romero-Ayuso et al., 2016; Payer et al., 2008). ADHD had an additional impact on emotional empathy but
However, a few studies have found specific alterations in did not explain the empathy impairment in general
fear (Ersche et al., 2015; Kemmis et al., 2007; Morgan and (Preller et al., 2014b). In a longitudinal analysis of the
Marshall, 2013; Kim et al., 2011) and anger processing ZuCo2St sample, it was shown that emotional empathy
(Ersche et al., 2015) from faces in regular users of cocaine can recover when cocaine use is reduced or ceased
or methamphetamine. Moreover, in polysubstance users, (Vonmoos et al., 2019).
An fMRI study has shown that methamphetamine users The acceptance rate for fair and unfair offers was not
showed reduced emotional empathy in a cartoon-based affected in cocaine users. However, compared with con-
task, which was accompanied by lower activation of the trols, cocaine users displayed reduced activation in the
orbitofrontal cortex (OFC), both temporal poles, and the dorsolateral prefrontal cortex during evaluation of unfair
right hippocampus, relative to healthy controls (Kim et al., offers and reduced activation in the subgenual ACC and the
2010). Finally, neuroenhancement methylphenidate users midbrain during rejection of these offers. Additionally,
taking relatively low doses did not exhibit abnormalities in cocaine users showed increased activation in superior
emotional empathy (Maier et al., 2015). frontal and lateral OFC regions during the evaluation of
unfair offers, which was correlated with deficient facial
Perspective-taking and ToM affect recognition (Verdejo-Garcia et al., 2017).
Dependent, but not recreational, cocaine users committed
Moral decision-making
more errors in the video-based MASC, suggesting that
worse mental perspective-taking is associated with cocaine An fMRI study did not find differences in the behavioral
addiction, yet not recreational use, or related premorbid responses to moral dilemmas between cocaine-dependent
characteristics (Preller et al., 2014b). Additionally, moder- patients and healthy controls, although the patients dis-
ate correlations between task performance and several played decreased activation of the ACC, left insula, and
subjective and objective cocaine intake indices have been brain stem as well as reduced functional connectivity be-
found (Preller et al., 2014b). Importantly, a concurrent tween ACC, thalamus, insula, and brain stem (Verdejo-
ADHD diagnosis had a modulating impact on perspective- Garcia et al., 2014). Recently, it was additionally shown
taking, i.e., only severe users with a comorbid ADHD that cocaine-using incarcerated individuals displayed
symptomatology showed significant impairments (Wun- impaired picture discrimination in the ventral ACC,
derli et al., 2016; Preller et al., 2014b). Studies using the VMPFC, lateral OFC, and left ventral striatum compared
RMET demonstrated that methamphetamine (Kim et al., with non-cocaine-using incarcerated individuals when
2011; Henry et al., 2009) but not cocaine users (Kemmis identifying pictures that did or did not depict immoral ac-
et al., 2007; Preller et al., 2014b) displayed alterations of tions (Caldwell et al., 2015).
“mind reading” from eye pairs. A single study in meth-
amphetamine users, investigating perspective-taking with a Social reward
story-based task, found only a trend for impaired ToM
In an interactive social gaze paradigm, cocaine users
abilities in the drug users (Kim et al., 2011). A trend for
showed blunted emotional responses and less activation of
weaker perspective-taking abilities has also been reported
the VMPFC during social gaze interaction, supporting the
for non-medical methylphenidate users (Maier et al., 2015).
assumption that social eye-contact might be less rewarding
for them (Preller et al., 2014a). Importantly, the activation
Social decision-making of the VMPFC was correlated with the size of the social
In the ZuCo2St, recreational and dependent cocaine users network of the cocaine users, indicating that a blunted
showed reduced prosocial decisions in comparison with a ability to perceive this implicit form of social reward is
control group in two social interaction tasks, given that reflected in diminished real-life social functioning (Preller
cocaine users preferred higher monetary payoffs for them- et al., 2014a). In another complex fMRI experiment,
selves and cared primarily about efficiency and less about cocaine users also displayed a reduced reward signal in the
fairness (Hulka et al., 2014). As no correlation between VMPFC in the context of positive social feedback. The
fairness preferences and cocaine use intensity was found, social rewarderelated activation in the VMPFC overlapped
the authors proposed that self-serving behavior might with a reduced response to object reward, which was
represent a predisposition for stimulant use (Hulka et al., additionally correlated with years of cocaine use (Tobler
2014); however, in a longitudinal analysis of these data, the et al., 2016). As the VMPFC has been proposed to be
reduction in cocaine use was weakly associated with critically involved in the encoding and maintenance of
improved social decision-making, indicating that these reward value (Peters and Buchel, 2010), it was proposed
deficits might be at least partially drug-induced (Vonmoos that chronic cocaine users suffer from a generalized
et al., 2019). Interestingly, it was also reported that meth- impairment in value processing, likely generalizing to their
ylphenidate neuroenhancement users display altered social social lives (Tobler et al., 2016). However, a recent study
decision-making (Maier et al., 2015). investigating aging cocaine users with a Social Incentive
Verdejo-Garcia et al. (2017) investigated social Delay Task, in which the positive feedback is simply given
decision-making during fMRI in cocaine-dependent in- by happy faces and short positive statements, did not find
dividuals with and without a comorbid personality disorder. an effect of chronic cocaine exposure on this facet of social
reward processing (Bedi et al., 2018). Finally, Hyatt et al. superior mental and emotional perspective-taking in the
(2012) applied an interactive competitive domino game MDMA users (Wunderli et al., 2018).
during fMRI, to investigate social reward in current and
former cocaine users. Remarkably, only former but not Social decision-making
current cocaine users showed altered activation of the
Stewart et al. (2014) investigated the acute effects of
dorsal caudate nucleus compared with controls, indicating
MDMA on the Ultimatum Game in chronic MDMA users,
changes in the reward processing related to social compe-
compared with non-intoxicated controls, and found
tition. Notably, the VMPFC was included in this region-of-
increased cooperative behavior on the dictator and ultima-
interest-based analysis, thus, these results are difficult to
compare with subsequent studies on social reward dis- tum games under the influence of the drug. However, on
the second measurement, 3 days after the MDMA intake,
cussed above.
the groups did not differ in any of the social decision-
making parameters. In contrast, in the study of Wunderli
Entactogenes et al. (2018), chronic MDMA users (off drug) displayed
Emotion recognition and cognitive empathy more prosocial decisions in Distribution and Dictator
Games compared with controls.
Acute MDMA intake has repeatedly been shown to reduce
the identification of negative emotions (Bedi et al., 2010;
Opioids
Hysek et al., 2012, 2014a,b; Kirkpatrick et al., 2014), while
one study additionally found increased recognition of Emotion recognition and cognitive empathy
positive emotions (Hysek et al., 2012). The valence-
Deficits in emotion perception were initially found in
dependent acute effects of MDMA were found in an
detoxified heroin users as well as methadone-maintained
emotional face recognition task (Bedi et al., 2010; Hysek
heroin users using the picture-based Emotional Facial
et al., 2014a) and the RMET (Hysek et al., 2012), whereas
Expression Decoding Test (Kornreich et al., 2003). In
cognitive empathy performance measured with the MET
was not affected by acute MDMA intake (Hysek et al., contrast, in a well-powered study, McDonald et al. (2013)
reported that only methadone- and buprenorphine-
2014a; Kuypers et al., 2017; Schmid et al., 2014). In
maintained heroin-dependent individuals, but not absti-
contrast to the acute effects, two studies have recently
nent heroin users without opioid-maintenance therapy,
shown that chronic users of MDMA exhibit superior
showed generally impaired emotion recognition in the
cognitive empathy compared with controls when assessed
video-based Awareness of Social Inference Test (TASIT).
with complex emotionally laden scenes from the MET
Importantly, these group differences disappeared if a gen-
(Carlyle et al., 2019; Wunderli et al., 2018). However, as
eral cognitive performance measure was introduced as a
lower cognitive empathy was clearly correlated with higher
MDMA concentrations in hair; it was concluded that the covariate in the model, suggesting that deficits in emotion
recognition are part of a more general cognitive impairment
differences at the group level were likely explained by
(McDonald et al., 2013). Using the CATS-A and the MET,
higher social affiliation motivations of the users, while at
Kroll et al. (2018b) recently demonstrated emotion recog-
higher chronic doses MDMA might nevertheless impair
nition/cognitive empathy deficits for faces, voices, and
cognitive empathy (Wunderli et al., 2018). Moreover, the
complex affective scenes in a group of nonemedical pre-
subjective response to a social exclusion paradigm
scription opioid users (NMPOU) without a history of her-
(cyberball game) was not altered in MDMA users (Carlyle
oin use, in which recreational or addicted users were
et al., 2019; Batschelet et al., 2015), although unpublished
MRI data from our group have suggested increased acti- included. Interestingly, a global cognitive empathy score
was correlated with morphine equivalent opioid concen-
vation of pain-related circuits such as the ACC during
trations in hair, indicating a dose-response relationship
exclusion in MDMA users (Batschelet et al., 2015).
regarding these deficits. Moreover, in this study, perfor-
mance in executive function tasks was also correlated with
Emotional empathy cognitive empathy measures in NMPOU; however, ac-
Wunderli et al. (2018) and Carlyle et al. (2019) both counting for executive function in the statistical model did
showed that chronic MDMA use was not associated with not change the group differences in cognitive empathy
changes of the emotional empathy domain of the MET. (Kroll et al., 2018b). The same study population of
NMPOU were also tested for their physiological stress
response to social exclusion, with an interesting finding: on
Perspective-taking and ToM
the one hand, NMPOU showed hyperreactivity of the
In the MASC, chronic MDMA users displayed better per- endocrinological stress axis and poorer regulation of the
formance than well-matched control individuals, indicating parasympathetic nervous system in response to social
exclusion, while on the other hand their self-ratings sug- Across both of these studies, the effects on fear recognition
gested that these users were aware but less emotionally were largest compared with other emotions. In contrast, a
affected by the rejection (Kroll et al., 2019). Taken group of mainly recreational polysubstance users did not
together, these results suggest thatdat least recent or show any deficits in cognitive empathy (MET) and emotion
currentdopioid use is associated with emotion recognition recognition measures (CATS-A) (Kroll et al., 2018a).
and cognitive empathy impairments, which cooccurs
withdbut may not be completely explained bydbroader Emotional empathy
cognitive deficits.
Recreational polysubstance users showed lower emotional
Emotional empathy empathy when assessed with the MET, and these problems
clearly increased with the number of substances used (Kroll
Studies in heroin users are thus far lacking, but NMPOU et al., 2018a). In contrast, only the number of substances,
were not impaired in emotional empathy measured with the but not single substance classes, such as stimulants, pre-
MET (Kroll et al., 2018b). Nonetheless, preliminary results dicted this deficit when introduced in multiple regression
suggest that heroin users showed lower emotional empathy models.
in an Empathy-for-Pain task (Sara L. Kroll, Linköping
University, Sweden, personal communication).
Perspective-taking and ToM
Perspective-taking and ToM In a single study, primarily recreational polysubstance users
Again, methadone- and buprenorphine-maintained heroin- did not show any abnormalities in the MASC, which
dependent individuals, but not abstinent heroin users measures mental and emotional perspective-taking (Kroll
without opioid-maintenance therapy, showed worse social et al., 2018a).
inference performance in the TASIT, specifically regarding
their ability to detect sarcasm. Social inference problems in Moral decision-making
these patients were also largely explained by their global
Two studies have shown that polysubstance-dependent in-
cognitive impairments (McDonald et al., 2013).
dividuals displayed more utilitarian choices when
responding to moral dilemmas (Kornreich et al., 2013b;
Social decision-making
Carmona-Perera et al., 2012).
Hou et al. (2016) investigated a small sample of heroin-
dependent individuals with regard to their decisions in the
Ultimatum Game and found that, in contrast to healthy Discussion
controls, heroin users displayed higher rejection rates of Although the importance of impairments in social cognition
most unfair offers under low-offer conditions, while most and interaction for the development, maintenance, and
unfair offers were more likely to be accepted in high-offer treatment of SUD is self-evident (Yacubian and Buchel,
conditions. Furthermore, rejection rates of most unfair of- 2009), only few studies have yet objectified socio-cognitive
fers under low-offer conditions were correlated with trait dysfunctions in substance users by means of psychological
impulsivity measured using the Barratt impulsiveness scale. test paradigms. The only exception to this is emotion
The authors concluded that heroin users acted more recognition in chronic alcohol use, as it has been researched
impulsively under low-offer conditions but became more for almost 30 years in a large number of studies, which
tolerant of inequity specifically in the high-offer condition have provided comprehensive evidence for a generalized
(Hou et al., 2016). emotion recognition deficit in AD that seem to bedat least
in partdinduced by chronic alcohol exposure. While dis-
Polysubstance use cussing most of the yet available studies above, it was
demonstrated that each substance class is associated with a
Emotion recognition and cognitive empathy range of specific impairments in social cognitive functions
Using a computer-based Ekman Faces Test, deficits in (see Table 5.1 for an overview). However, it was also
recognition of facial emotion expressions have been reported shown above that there are a number of blank spots on the
for substance-dependent individuals with polysubstance use social cognition and interaction map of substance use that
(Fernandez-Serrano et al., 2010; Verdejo-Garcia et al., 2007). have to be filled in by future studies.
TABLE 5.1 Changes in performance and behavioral measures of social cognition and interaction in addiction
and chronic drug use.
Social Moral
Emotion recognition Emotional Perspective-taking decision- decision- Social
Substance and cognitive empathy empathy and Theory of Mind making making reward
Alcohol Y [, Y, / Y Y Y ?
Cannabis Y ?(/) / ?(/) ? Y
Stimulants Y, / Y Y, / Y Y Y, /
Opioids Y, / / Y, / Y ? ?
Entactogens [ / / [, / ? ?
Polysubstance Y, / Y / ? Y ?
use
Y, finding(s) suggest(s) decrease or impairment; /, finding(s) suggest(s) no change; [, finding(s) suggest(s) increase or superiority; ?, not published yet;
brackets represent data from so far unpublished pilot studies.
Open questions socio-cognitive impairments coincide with changes, specif-

ically reductions, in other cognitive functions (Uekermann
It must be noted that, for most of the substances and
et al., 2007; Quaglino et al., 2015; Thoma et al., 2013;
functions, the number of available studies is low and,
Nandrino et al., 2014).1 Nevertheless, it is important to better
furthermore, most of the studies that have been reported
understand the origin and specificity of socio-cognitive dis-
have had rather small sample sizes. Therefore, more studies
turbances, especially if targeted socio-cognitive training
with larger samples are needed to better characterize the
schemes are to be developed for the improvement of treatment
true, specific, socio-cognitive profile of each substance.
outcomes (see below). Remarkably, it is also not yet fully clear
Although most substance users consume more than only
how lifestyle differences, intellectual abilities, and psychiatric
one psychoactive compound, we also currently have only
comorbidities might influence socio-cognitive deficits in
little information about how different substances might
substance users: for example, thus far it has been shown that
interact with each other regarding social cognition. As an
facial affect recognition deficits of cocaine users might be
example, we have shown detrimental effects of increasing
explained by their opioid co-consumption and lower IQ
polydrug use on emotional empathy (Kroll et al., 2018a),
(Ersche et al., 2015), while perspective-taking and cognitive
although this study was too small to directly assess specific
empathy deficits may only appear if a comorbid ADHD
drug combinations. It must also be noted that protective
diagnosis is present (Wunderli et al., 2016; Preller et al.,
drug effects are possible, e.g., when considering that
2014b). Finally, the question also of if (and which) socio-
MDMA use has been associated with superior socio-
cognitive dysfunctions are predisposed or drug-induced is
cognitive abilities (Wunderli et al., 2016). Thus, in samples
important for the implementation of new treatments, as ac-
with mixed stimulant and MDMA use, potential negative
quired impairments are likely to be easier to rehabilitate than
effects of stimulants might be compensated by higher
predisposed impairments and perhaps “hardwired” dysfunc-
socio-cognitive competences of people using MDMA.
tions. To date, some studies have shown that socio-cognitive
Moreover, most of the studies discussed have used rela-
problems predict initiation and onset of drug use (Ernst et al.,
tively passive “first-person” paradigms, such as emotion
2010; Fishbein et al., 2016), while others clearly showed re-
recognition or ToM tasks, which probably provide only
covery of such functions with prolonged abstinence (Von-
insufficient information about the real daily-life social prob-
moos et al., 2019; Erol et al., 2017). It has also been proposed
lems users experience in their interactions with other people.
that mentalizing deficits in SUD share similarities with such
Thus, more “second-person” approaches assessing behavioral
impairments in developmental disorders, such as autism and
and neuronal changes in real-life social interactions should be
borderline personality disorder, which argues that such defi-
employed, as they are likely more ecologically valid (Schil-
cits may be rather predisposed (Savov and Atanassov, 2013).
bach, 2016). In addition, the relationship between several
facets of social cognition (e.g., between emotional empathy
and perspective-taking abilities), as well as between social 1. Of note, no coherent theory of social cognition or its assumed sub-
cognition and non-social cognition, needs to be addressed components, such as “cognitive empathy” and ToM, has been developed
in further studies, as several studies have indicated that so far, such that different definitions exist and their concepts sometimes
overlap (e.g., emotion perception, cognitive empathy, and ToM).
The notion that drugs might be instrumentalized by some users specific (if not patient-specific) therapy modules have to be
to self-medicate social cognitive deficits has also been sug- developed (Rolland et al., 2019).
gested (Fein, 2015). However, predispositions to, as well as
chronic drug effects on, social cognition deficits might be
substance- as well as function-specific and future longitudinal Conclusion
studies are needed to delineate and characterize these different
When taken together, the research into SUD shows
factors for each substance-using population.
substance-specific profiles of impairments in a variety of
socio-cognitive functions and indicates that predisposed or
Relevance for treatment drug-related changes in social reward and social cognition
may contribute to the social problems and the decay of
It has been shown that specific impairments in social
social relationships in people with SUD. Beyond that,
cognitive functions of substance users are related to real-
although not investigated yet, it is likely that disturbances
life social functioning (Preller et al., 2014a,b; Kornreich
in social perception and behavior compromise any social
et al., 2002; Kopera et al., 2018; Janowsky et al., 1979;
interactions, including therapeutic relationships, thus hin-
Bedi et al., 2018) and that they can be used to predict
dering the success of each addiction treatment approach.
treatment outcomes (Charlet et al., 2014; Schuckit et al.,
2016; Rupp et al., 2017). Although not yet investigated, it Accordingly, interpersonal problems related to social
cognition deficits might partially account for high relapse
is also conceivable that these disturbances of social
rates for those enrolled in any kind of psychological or
perception, valuation, and behavior may directly affect the
psychopharmacological treatment developed so far. Addi-
therapeutic relationship between substance users and their
tionally, specific social reward deficits might also explain
psychiatrist or psychologist and, thus, hamper the success
why the social consequences of drug use
of their addiction treatment. Thus, interpersonal problems
(e.g., imprisonment or familial problems) do not discourage
affecting all social relationships, including relationships
substance-dependent individuals enough to cease using the
with therapists, might partially explain the high relapse
rates after treatment in most SUD (Milivojevic and Sinha, drug (Preller et al., 2014a). Therefore, a new focus on
psychosocial treatments of stimulant addiction might be
2018). Moreover, as social cognition and prosocial
needed to address these social dysfunctions to improve the
behavior can covary with alterations in substance use
therapeutic relationship and treatment success (Quednow,
across time, indicating their potential for plasticity (Von-
2016). Specifically, the rehabilitation of social reward
moos et al., 2019; Erol et al., 2017), new treatments of SUD
might be a promising avenue for providing an alternative to
might address these specific social problems more distinc-
bypass the accrual of drug-related reward system malad-
tively to improve the therapeutic relationship and their
aptations in SUD (Quednow, 2017; Preller et al., 2014a;
overall social functional level and, consequently, the
treatment success. Promising results in this regard are Verdejo-Garcia, 2014).
emerging from other neuropsychiatric disorders, such as
traumatic brain injury (Milders, 2018; Vallat-Azouvi et al., Acknowledgments
2018), schizophrenia (Kurtz et al., 2016; Fiszdon and
The author is grateful to Dr David Cole for critical comments and
Reddy, 2012; Wolwer and Frommann, 2011; Vaskinn suggestions regarding the first draft of this chapter.
et al., 2019), autism (Berggren et al., 2018; Happe and
Conway, 2016; Bishop-Fitzpatrick et al., 2013), and
depression (Weightman et al., 2019) suggesting that socio- References
cognitive abilities are trainable per se and that this can also
Amenta, S., Noel, X., Verbanck, P., Campanella, S., 2013. Decoding of
have a positive impact on treatment outcome. However,
emotional components in complex communicative situations (irony)
social cognitive training schemes specialized for SUD are and its relation to empathic abilities in male chronic alcoholics: an
not available thus far, although recently some encouraging issue for treatment. Alcohol Clin. Exp. Res. 37 (2), 339e347.
results emerged from very small studies with SUD patients Amodio, D.M., Frith, C.D., 2006. Meeting of minds: the medial frontal
applying mentalization-based interventionsda psychody- cortex and social cognition. Nat. Rev. Neurosci. 7 (4), 268e277.
namic approach shown to be effective in borderline per- Banziger, T., Grandjean, D., Scherer, K.R., 2009. Emotion recognition
sonality disorder that targets reflective functions such as from expressions in face, voice, and body: the Multimodal Emotion
perspective-taking (Philips et al., 2018; Suchman et al., Recognition Test (MERT). Emotion 9 (5), 691e704.
2017). Nevertheless, as is visible in the summary provided Baron-Cohen, S., O’Riordan, M., Stone, V., Jones, R., Plaisted, K., 1999.
in Table 5.1, a single treatment or training approach for all Recognition of faux pas by normally developing children and children
with Asperger syndrome or high-functioning autism. J. Autism Dev.
kinds of SUD will not be feasible, as the substance user
Disord. 29 (5), 407e418.
populations differ in their deficits and, therefore, substance-
Baron-Cohen, S., Wheelwright, S., Hill, J., Raste, Y., Plumb, I., 2001. The Cermak, L.S., Verfaellie, M., Letourneau, L., Blackford, S., Weiss, S.,
“Reading the Mind in the Eyes” Test revised version: a study with Numan, B., 1989. Verbal and nonverbal right hemisphere processing
normal adults, and adults with Asperger syndrome or high-functioning by chronic alcoholics. Alcohol Clin. Exp. Res. 13 (5), 611e616.
autism. J. Child Psychol. Psychiatry 42 (2), 241e251. Charlet, K., Schlagenhauf, F., Richter, A., Naundorf, K., Dornhof, L.,
Batschelet, H., Siegle, C., Quednow, B.B., Preller, K.H., 2015. Increased Weinfurtner, C.E., et al., 2014. Neural activation during processing of
Neural Response to Social Exclusion in Chronic MDMA (“Ecstasy”) aversive faces predicts treatment outcome in alcoholism. Addict. Biol.
Users. DGPPN, Berlin. 19 (3), 439e451.
Bayrakci, A., Sert, E., Zorlu, N., Erol, A., Saricicek, A., Mete, L., 2015. Christensen, J.F., Gomila, A., 2012. Moral dilemmas in cognitive neuro-
Facial emotion recognition deficits in abstinent cannabis dependent science of moral decision-making: a principled review. Neurosci.
patients. Compr. Psychiatry 58, 160e164. Biobehav. Rev. 36 (4), 1249e1264.
Bedi, G., Hyman, D., de Wit, H., 2010. Is ecstasy an “empathogen”? Clifford, S., Iyengar, V., Cabeza, R., Sinnott-Armstrong, W., 2015. Moral
Effects of þ/3,4-methylenedioxymethamphetamine on prosocial foundations vignettes: a standardized stimulus database of scenarios
feelings and identification of emotional states in others. Biol. Psy- based on moral foundations theory. Behav. Res. Methods 47 (4),
chiatry 68 (12), 1134e1140. 1178e1198.
Bedi, G., Hao, X., Van Dam, N.T., Cooper, Z.D., Rubin, E., Vadhan, N.P., Cloninger, C.R., 1987. Neurogenetic adaptive mechanisms in alcoholism.
et al., 2018. Social motivational processing and interpersonal function Science 236 (4800), 410e416.
in aging cocaine smokers. Addict. Biol. Available online: http://doi. Couture, S.M., Penn, D.L., Roberts, D.L., 2006. The functional signifi-
org/10.1111/adb.12669. cance of social cognition in schizophrenia: a review. Schizophr. Bull.
Berggren, S., Fletcher-Watson, S., Milenkovic, N., Marschik, P.B., 32 (Suppl. 1), S44eS63.
Bolte, S., Jonsson, U., 2018. Emotion recognition training in autism Cox, S., Bertoux, M., Turner, J.J.D., Moss, A., Locker, K., Riggs, K.,
spectrum disorder: a systematic review of challenges related to 2018. Aspects of alcohol use disorder affecting social cognition as
generalizability. Dev. Neurorehabil. 21 (3), 141e154. assessed using the Mini Social and Emotional Assessment (mini-
Bishop-Fitzpatrick, L., Minshew, N.J., Eack, S.M., 2013. A systematic SEA). Drug Alcohol Depend. 187, 165e170.
review of psychosocial interventions for adults with autism spectrum Dethier, M., Blairy, S., 2012. Capacity for cognitive and emotional
disorders. J. Autism Dev. Disord. 43 (3), 687e694. empathy in alcohol-dependent patients. Psychol. Addict. Behav. 26
Bora, E., Zorlu, N., 2017. Social cognition in alcohol use disorder: a meta- (3), 371e383.
analysis. Addiction 112 (1), 40e48. D’Hondt, F., de Timary, P., Bruneau, Y., Maurage, P., 2015. Categorical
Bosco, F.M., Capozzi, F., Colle, L., Marostica, P., Tirassa, M., 2014. perception of emotional facial expressions in alcohol-dependence.
Theory of mind deficit in subjects with alcohol use disorder: an Drug Alcohol Depend. 156, 267e274.
analysis of mindreading processes. Alcohol Alcohol 49 (3), 299e307. Diener, P., 2014. Soziale Kognition bei Cannabiskonsumenten (Master
Brevers, D., Noel, X., Ermer, E., Dabiri, D., Verbanck, P., Kornreich, C., thesis). University of Zurich, Zurich.
2013. Unfairness sensitivity and social decision-making in individuals Dziobek, I., Fleck, S., Kalbe, E., Rogers, K., Hassenstab, J., Brand, M.,
with alcohol dependence: a preliminary study. Drug Alcohol Depend. et al., 2006. Introducing MASC: a movie for the assessment of social
133 (2), 772e775. cognition. J. Autism Dev. Disord. 36 (5), 623e636.
Brevers, D., Noel, X., Hanak, C., Verbanck, P., Kornreich, C., 2015. On Dziobek, I., Rogers, K., Fleck, S., Bahnemann, M., Heekeren, H.R.,
the relationship between emotional state and abnormal unfairness Wolf, O.T., et al., 2008. Dissociation of cognitive and emotional
sensitivity in alcohol dependence. Front. Psychol. 6, 983. empathy in adults with Asperger syndrome using the Multifaceted
Caldwell, B.M., Harenski, C.L., Harenski, K.A., Fede, S.J., Steele, V.R., Empathy Test (MET). J. Autism Dev. Disord. 38 (3), 464e473.
Koenigs, M.R., et al., 2015. Abnormal frontostriatal activity in Ekman, P., Friesen, W.V., 1976. Pictures of Facial Affect. Consulting
recently abstinent cocaine users during implicit moral processing. Psychologists Press, Palo Alto.
Front. Hum. Neurosci. 9, 565. Ernst, M., Luckenbaugh, D.A., Moolchan, E.T., Temple, V.A., Jenness, J.,
Campbell-Meiklejohn, D.K., Bach, D.R., Roepstorff, A., Dolan, R.J., Korelitz, K.E., et al., 2010. Decision-making and facial emotion
Frith, C.D., 2010. How the opinion of others affects our valuation of recognition as predictors of substance-use initiation among adoles-
objects. Curr. Biol. 20 (13), 1165e1170. cents. Addict. Behav. 35 (3), 286e289.
Carlyle, M., Stevens, T., Fawaz, L., Marsh, B., Kosmider, S., Erol, A., Akyalcin Kirdok, A., Zorlu, N., Polat, S., Mete, L., 2017.
Morgan, C.J., 2019. Greater empathy in MDMA users. Empathy, and its relationship with cognitive and emotional functions
J. Psychopharmacol. 33 (3), 295e304. in alcohol dependency. Nord. J. Psychiatry 71 (3), 205e209.
Carmona-Perera, M., Verdejo-Garcia, A., Young, L., Molina- Ersche, K.D., Hagan, C.C., Smith, D.G., Jones, P.S., Calder, A.J.,
Fernandez, A., Perez-Garcia, M., 2012. Moral decision-making in Williams, G.B., 2015. In the face of threat: neural and endocrine
polysubstance dependent individuals. Drug Alcohol Depend. 126 (3), correlates of impaired facial emotion recognition in cocaine depen-
389e392. dence. Transl. Psychiatry 5, e570.
Carmona-Perera, M., Reyes Del Paso, G.A., Perez-Garcia, M., Verdejo- Fein, G., Key, K., Szymanski, M.D., 2010. ERP and RT delays in long-
Garcia, A., 2013. Heart rate correlates of utilitarian moral decision- term abstinent alcoholics in processing of emotional facial expres-
making in alcoholism. Drug Alcohol Depend. 133 (2), 413e419. sions during gender and emotion categorization tasks. Alcohol Clin.
Carmona-Perera, M., Clark, L., Young, L., Perez-Garcia, M., Verdejo- Exp. Res. 34 (7), 1127e1139.
Garcia, A., 2014. Impaired decoding of fear and disgust predicts Fein, G., 2015. Commentary on Maurage et al.: theory of Mind Difficulties
utilitarian moral judgment in alcohol-dependent individuals. Alcohol in Patients with Alcohol Dependence. Alcohol Clin. Exp. Res. 39 (7),
Clin. Exp. Res. 38 (1), 179e185. 1118e1119.
Fernandez-Serrano, M.J., Lozano, O., Perez-Garcia, M., Verdejo- Henry, J.D., Mazur, M., Rendell, P.G., 2009. Social-cognitive difficulties
Garcia, A., 2010. Impact of severity of drug use on discrete emo- in former users of methamphetamine. Br. J. Clin. Psychol. 48 (Pt 3),
tions recognition in polysubstance abusers. Drug Alcohol Depend. 323e327.
109 (1e3), 57e64. Hindocha, C., Wollenberg, O., Carter Leno, V., Alvarez, B.O.,
Fishbein, D.H., Novak, S.P., Ridenour, T.A., Thornburg, V., Curran, H.V., Freeman, T.P., 2014. Emotional processing deficits in
Hammond, J., Brown, J., 2016. Neurocognitive characteristics of early chronic cannabis use: a replication and extension.
marijuana use initiation in adolescents: a signature mapping analysis. J. Psychopharmacol. 28 (5), 466e471.
J. Stud. Alcohol Drugs 77 (3), 431e440. Hindocha, C., Freeman, T.P., Schafer, G., Gardener, C., Das, R.K.,
Fisher, C.B., 2011. Addiction research ethics and the Belmont principles: Morgan, C.J., et al., 2015. Acute effects of delta-9-
do drug users have a different moral voice? Subst. Use Misuse 46 (6), tetrahydrocannabinol, cannabidiol and their combination on facial
728e741. emotion recognition: a randomised, double-blind, placebo-controlled
Fiske, S.T., Taylor, S.E., 2013. In: Carmichael, M. (Ed.), Social Cognition: study in cannabis users. Eur. Neuropsychopharmacol. 25 (3),
From Brains to Culture. SAGE, London. 325e334.
Fiszdon, J.M., Reddy, L.F., 2012. Review of social cognitive treatments Holland, C.A.C., Ebner, N.C., Lin, T., Samanez-Larkin, G.R., 2018.
for psychosis. Clin. Psychol. Rev. 32 (8), 724e740. Emotion identification across adulthood using the Dynamic FACES
Foisy, M.L., Philippot, P., Verbanck, P., Pelc, I., van der Straten, G., database of emotional expressions in younger, middle aged, and older
Kornreich, C., 2005. Emotional facial expression decoding impair- adults. Cognit. Emot. 1e13.
ment in persons dependent on multiple substances: impact of a history Homer, B.D., Solomon, T.M., Moeller, R.W., Mascia, A., DeRaleau, L.,
of alcohol dependence. J. Stud. Alcohol 66 (5), 673e681. Halkitis, P.N., 2008. Methamphetamine abuse and impairment of
Foisy, M.L., Kornreich, C., Fobe, A., D’Hondt, L., Pelc, I., Hanak, C., social functioning: a review of the underlying neurophysiological
et al., 2007. Impaired emotional facial expression recognition in causes and behavioral implications. Psychol. Bull. 134 (2), 301e310.
alcohol dependence: do these deficits persist with midterm abstinence? Homer, B.D., Halkitis, P.N., Moeller, R.W., Solomon, T.M., 2013.
Alcohol Clin. Exp. Res. 31 (3), 404e410. Methamphetamine use and HIV in relation to social cognition.
Fox, H.C., Bergquist, K.L., Casey, J., Hong, K.A., Sinha, R., 2011. J. Health Psychol. 18 (7), 900e910.
Selective cocaine-related difficulties in emotional intelligence: rela- Hou, Y., Zhao, L., Yao, Q., Ding, L., 2016. Altered economic decision-
tionship to stress and impulse control. Am. J. Addict. 20 (2), making in abstinent heroin addicts: evidence from the ultimatum
151e160. game. Neurosci. Lett. 627, 148e154.
Freeman, C.R., Wiers, C.E., Sloan, M.E., Zehra, A., Ramirez, V., Houser, D., McCabe, K., 2009. Chapter 5 - Experimental neuroeconomics
Wang, G.J., et al., 2018. Emotion recognition biases in alcohol use and non-cooperative games. In: Glimcher, P.W., Camerer, C.F.,
disorder. Alcohol Clin. Exp. Res. Available online: http://doi.org/10. Fehr, E., Poldrack, R.A. (Eds.), Neuroeconomics. Academic Press,
1111/acer.13802. London, pp. 47e62.
Gizewski, E.R., Muller, B.W., Scherbaum, N., Lieb, B., Forsting, M., Huijbregts, S.C., Griffith-Lendering, M.F., Vollebergh, W.A., Swaab, H.,
Wiltfang, J., et al., 2013. The impact of alcohol dependence on social 2014. Neurocognitive moderation of associations between cannabis
brain function. Addict. Biol. 18 (1), 109e120. use and psychoneuroticism. J. Clin. Exp. Neuropsychol. 36 (8),
Green, M.F., 2016. Impact of cognitive and social cognitive impairment on 794e805.
functional outcomes in patients with schizophrenia. J. Clin. Psychiatry Hulka, L.M., Preller, K.H., Vonmoos, M., Broicher, S.D., Quednow, B.B.,
77 (Suppl. 2), 8e11. 2013. Cocaine users manifest impaired prosodic and cross-modal
Greene, J.D., Sommerville, R.B., Nystrom, L.E., Darley, J.M., emotion processing. Front. Psychiatry 4, 98.
Cohen, J.D., 2001. An fMRI investigation of emotional engagement in Hulka, L.M., Eisenegger, C., Preller, K.H., Vonmoos, M., Jenni, D.,
moral judgment. Science 293 (5537), 2105e2108. Bendrick, K., et al., 2014. Altered social and non-social decision-
Grynberg, D., Maurage, P., Nandrino, J.L., 2017. Preserved affective making in recreational and dependent cocaine users. Psychol. Med.
sharing but impaired decoding of contextual complex emotions in 44 (5), 1015e1028.
alcohol dependence. Alcohol Clin. Exp. Res. 41 (4), 779e785. Hyatt, C.J., Assaf, M., Muska, C.E., Rosen, R.I., Thomas, A.D.,
Happe, F., Conway, J.R., 2016. Recent progress in understanding skills Johnson, M.R., et al., 2012. Reward-related dorsal striatal activity
and impairments in social cognition. Curr. Opin. Pediatr. 28 (6), differences between former and current cocaine dependent individuals
736e742. during an interactive competitive game. PLoS One 7 (5), e34917.
Hare, T.A., Camerer, C.F., Knoepfle, D.T., Rangel, A., 2010. Value Hysek, C.M., Domes, G., Liechti, M.E., 2012. MDMA enhances “mind
computations in ventral medial prefrontal cortex during charitable reading” of positive emotions and impairs “mind reading” of negative
decision making incorporate input from regions involved in social emotions. Psychopharmacology (Berl.) 222 (2), 293e302.
cognition. J. Neurosci. 30 (2), 583e590. Hysek, C.M., Schmid, Y., Simmler, L.D., Domes, G., Heinrichs, M.,
Harris, R.J., Young, A.W., Andrews, T.J., 2014. Dynamic stimuli Eisenegger, C., et al., 2014a. MDMA enhances emotional empathy
demonstrate a categorical representation of facial expression in the and prosocial behavior. Soc. Cognit. Affect Neurosci. 9 (11),
amygdala. Neuropsychologia 56, 47e52. 1645e1652.
Helle, S., Loberg, E.M., Gjestad, R., Schnakenberg Martin, A.M., Hysek, C.M., Simmler, L.D., Schillinger, N., Meyer, N., Schmid, Y.,
Lysaker, P.H., 2017. The positive link between executive function and Donzelli, M., et al., 2014b. Pharmacokinetic and pharmacodynamic
lifetime cannabis use in schizophrenia is not explained by current effects of methylphenidate and MDMA administered alone or in
levels of superior social cognition. Psychiatry Res. 250, 92e98. combination. Int. J. Neuropsychopharmacol. 17 (3), 371e381.
Izuma, K., Saito, D.N., Sadato, N., 2008. Processing of social and mon- Kroll, S.L., Wunderli, M.D., Vonmoos, M., Hulka, L.M., Preller, K.H.,
etary rewards in the human striatum. Neuron 58 (2), 284e294. Bosch, O.G., et al., 2018a. Socio-cognitive functioning in stimulant
Janowsky, D.S., Clopton, P.L., Leichner, P.P., Abrams, A.A., Judd, L.L., polysubstance users. Drug Alcohol Depend. 190, 94e103.
Pechnick, R., 1979. Interpersonal effects of marijuana. A model for Kroll, S.L., Nikolic, E., Bieri, F., Soyka, M., Baumgartner, M.R.,
the study of interpersonal psychopharmacology. Arch. Gen. Psychia- Quednow, B.B., 2018b. Cognitive and socio-cognitive functioning of
try 36 (7), 781e785. chronic non-medical prescription opioid users. Psychopharmacology
Kemmis, L., Hall, J.K., Kingston, R., Morgan, M.J., 2007. Impaired fear (Berl.) 235 (12), 3451e3464.
recognition in regular recreational cocaine users. Psychopharmacol- Kroll, S.L., Williams, D.P., Thoma, M., Staib, M., Binz, T.M.,
ogy (Berl.) 194 (2), 151e159. Baumgartner, M.R., et al., 2019. Non-medical prescription opioid
Khemiri, L., Guterstam, J., Franck, J., Jayaram-Lindstrom, N., 2012. users exhibit dysfunctional physiological stress responses to social
Alcohol dependence associated with increased utilitarian moral rejection. Psychoneuroendocrinology 100, 264e275.
judgment: a case control study. PLoS One 7 (6), e39882. Kurtz, M.M., Gagen, E., Rocha, N.B., Machado, S., Penn, D.L., 2016.
Kim, Y.T., Lee, J.J., Song, H.J., Kim, J.H., Kwon, D.H., Kim, M.N., et al., Comprehensive treatments for social cognitive deficits in schizo-
2010. Alterations in cortical activity of male methamphetamine phrenia: a critical review and effect-size analysis of controlled studies.
abusers performing an empathy task: fMRI study. Hum. Psycho- Clin. Psychol. Rev. 43, 80e89.
pharmacol. 25 (1), 63e70. Kuypers, K.P., Dolder, P.C., Ramaekers, J.G., Liechti, M.E., 2017.
Kim, Y.T., Kwon, D.H., Chang, Y., 2011. Impairments of facial emotion Multifaceted empathy of healthy volunteers after single doses of
recognition and theory of mind in methamphetamine abusers. Psy- MDMA: a pooled sample of placebo-controlled studies.
chiatry Res. 186 (1), 80e84. J. Psychopharmacol. https://doi.org/10.1177/0269881117699617.
Kirkpatrick, M.G., Lee, R., Wardle, M.C., Jacob, S., de Wit, H., 2014. Lamm, C., Decety, J., Singer, T., 2011. Meta-analytic evidence for com-
Effects of MDMA and Intranasal oxytocin on social and emotional mon and distinct neural networks associated with directly experienced
processing. Neuropsychopharmacology 39 (7), 1654e1663. pain and empathy for pain. Neuroimage 54 (3), 2492e2502. https://
Koenigs, M., Young, L., Adolphs, R., Tranel, D., Cushman, F., doi.org/10.1016/j.neuroimage.2010.10.014.
Hauser, M., et al., 2007. Damage to the prefrontal cortex increases Lannoy, S., Dormal, V., Brion, M., Gaudelus, B., Billieux, J., Maurage, P.,
utilitarian moral judgements. Nature 446 (7138), 908e911. 2018. Affective impairments in binge drinking: investigation through
Kopera, M., Trucco, E.M., Jakubczyk, A., Suszek, H., Michalska, A., emotional facial expression decoding. Compr. Psychiatry 83,
Majewska, A., et al., 2018. Interpersonal and intrapersonal emotional 59e63.
processes in individuals treated for alcohol use disorder and non- Lieberman, M.D., 2007. Social cognitive neuroscience: a review of core
addicted healthy individuals. Addict. Behav. 79, 8e13. processes. Annu. Rev. Psychol. 58, 259e289.
Kornreich, C., Blairy, S., Philippot, P., Hess, U., Noel, X., Streel, E., et al., Lin, A., Adolphs, R., Rangel, A., 2012. Social and monetary reward
2001. Deficits in recognition of emotional facial expression are still learning engage overlapping neural substrates. Soc. Cognit. Affect
present in alcoholics after mid- to long-term abstinence. J. Stud. Neurosci. 7 (3), 274e281.
Alcohol 62 (4), 533e542. Maier, L.J., Wunderli, M.D., Vonmoos, M., Rommelt, A.T.,
Kornreich, C., Philippot, P., Foisy, M.L., Blairy, S., Raynaud, E., Dan, B., Baumgartner, M.R., Seifritz, E., et al., 2015. Pharmacological
et al., 2002. Impaired emotional facial expression recognition is cognitive enhancement in healthy individuals: a compensation for
associated with interpersonal problems in alcoholism. Alcohol cognitive deficits or a question of personality? PLoS One 10 (6),
Alcohol 37 (4), 394e400. e0129805.
Kornreich, C., Foisy, M.L., Philippot, P., Dan, B., Tecco, J., Noel, X., Matyassy, A., Kelemen, O., Sarkozi, Z., Janka, Z., Keri, S., 2006.
et al., 2003. Impaired emotional facial expression recognition in al- Recognition of complex mental states in patients with alcoholism after
coholics, opiate dependence subjects, methadone maintained subjects long-term abstinence. Alcohol Alcohol 41 (5), 512e514.
and mixed alcohol-opiate antecedents subjects compared with normal Maurage, P., Campanella, S., Philippot, P., Pham, T.H., Joassin, F., 2007.
controls. Psychiatry Res. 119 (3), 251e260. The crossmodal facilitation effect is disrupted in alcoholism: a study
Kornreich, C., Delle-Vigne, D., Knittel, J., Nerincx, A., Campanella, S., with emotional stimuli. Alcohol Alcohol 42 (6), 552e559.
Noel, X., et al., 2011. Impaired conditional reasoning in alcoholics: a Maurage, P., Campanella, S., Philippot, P., Martin, S., de Timary, P.,
negative impact on social interactions and risky behaviors? Addiction 2008. Face processing in chronic alcoholism: a specific deficit for
106 (5), 951e959. emotional features. Alcohol Clin. Exp. Res. 32 (4), 600e606.
Kornreich, C., Brevers, D., Canivet, D., Ermer, E., Naranjo, C., Maurage, P., Campanella, S., Philippot, P., Charest, I., Martin, S., de
Constant, E., et al., 2013a. Impaired processing of emotion in music, Timary, P., 2009. Impaired emotional facial expression decoding in
faces and voices supports a generalized emotional decoding deficit in alcoholism is also present for emotional prosody and body postures.
alcoholism. Addiction 108 (1), 80e88. Alcohol Alcohol 44 (5), 476e485.
Kornreich, C., Brevers, D., Ermer, E., Hanak, C., Verbanck, P., Maurage, P., Grynberg, D., Noel, X., Joassin, F., Hanak, C., Verbanck, P.,
Campanella, S., et al., 2013b. Polysubstance dependent patients et al., 2011. The “Reading the Mind in the Eyes” test as a new way to
display a more utilitarian profile in moral decision-making than explore complex emotions decoding in alcohol dependence. Psychi-
alcohol-dependent patients, depressive patients and controls. Drug atry Res. 190 (2e3), 375e378.
Alcohol Depend. 132 (3), 434e440. Maurage, F., de Timary, P., Tecco, J.M., Lechantre, S., Samson, D., 2015.
Kornreich, C., Petit, G., Rolin, H., Ermer, E., Campanella, S., Verbanck, P., Theory of mind difficulties in patients with alcohol dependence:
et al., 2016. Decoding of nonverbal language in alcoholism: a percep- beyond the prefrontal cortex dysfunction hypothesis. Alcohol Clin.
tion or a labeling problem? Psychol. Addict. Behav. 30 (2), 175e183. Exp. Res. 39 (6), 980e988.
Maurage, P., D’Hondt, F., de Timary, P., Mary, C., Franck, N., Preller, K.H., Hulka, L.M., Vonmoos, M., Jenni, D., Baumgartner, M.R.,
Peyroux, E., 2016. Dissociating affective and cognitive theory of mind Seifritz, E., et al., 2014b. Impaired emotional empathy and related social
in recently detoxified alcohol-dependent individuals. Alcohol Clin. network deficits in cocaine users. Addict. Biol. 19 (3), 452e466.
Exp. Res. 40 (9), 1926e1934. Quaglino, V., De Wever, E., Maurage, P., 2015. Relations between
McCurrie, C.H., Crone, D.L., Bigelow, F., Laham, S.M., 2018. Moral and cognitive abilities, drinking characteristics, and emotional recognition
Affective Film Set (MAAFS): a normed moral video database. PLoS in alcohol dependence: a preliminary exploration. Alcohol Clin. Exp.
One 13 (11), e0206604. Res. 39 (10), 2032e2038.
McDonald, S., Darke, S., Kaye, S., Torok, M., 2013. Deficits in social Quednow, B.B., 2016. The rise of the ego: social cognition and interaction
perception in opioid maintenance patients, abstinent opioid users and in cocaine users. In: Preedy, V.R. (Ed.), Neuropathology of Drug
non-opioid users. Addiction 108 (3), 566e574. Addictions and Substance Misuse, vol. 2. Academic Press, London.
Mehrabian, A., Epstein, N., 1972. A measure of emotional empathy. Quednow, B.B., 2017. Social cognition and interaction in stimulant use
J. Pers. 40 (4), 525e543. disorders. Curr. Opin. Behav. Sci. 13, 55e62.
Milders, M., 2018. Relationship between social cognition and social Rilling, J.K., Sanfey, A.G., 2011. The neuroscience of social decision-
behaviour following traumatic brain injury. Brain Inj. 1e7. making. Annu. Rev. Psychol. 62, 23e48.
Milivojevic, V., Sinha, R., 2018. Central and peripheral biomarkers of Rolland, B., D’Hondt, F., Montegue, S., Brion, M., Peyron, E., D’Aviau
stress response for addiction risk and relapse vulnerability. Trends de Ternay, J., et al., 2019. A patient-tailored evidence-based approach
Mol. Med. 24 (2), 173e186. for developing early neuropsychological training programs in addic-
Moll, J., Zahn, R., de Oliveira-Souza, R., Krueger, F., Grafman, J., 2005. tion settings. Neuropsychol. Rev. 29 (1), 103e115. https://doi.org/
Opinion: the neural basis of human moral cognition. Nat. Rev. Neu- 10.1007/s11065-018-9395-3.
rosci. 6 (10), 799e809. Romero-Ayuso, D., Mayoral-Gontan, Y., Trivino-Juarez, J.M., 2016.
Monnot, M., Nixon, S., Lovallo, W., Ross, E., 2001. Altered emotional Emotional intelligence, risk perception in abstinent cocaine dependent
perception in alcoholics: deficits in affective prosody comprehension. individuals. Actas Esp. Psiquiatr. 44 (2), 72e78.
Alcohol Clin. Exp. Res. 25 (3), 362e369. Roser, P., Lissek, S., Tegenthoff, M., Nicolas, V., Juckel, G., Brune, M.,
Morgan, M.J., Marshall, J.P., 2013. Deficient fear recognition in regular 2012. Alterations of theory of mind network activation in chronic
cocaine users is not attributable to elevated impulsivity or cannabis users. Schizophr. Res. 139 (1e3), 19e26.
conduct disorder prior to cocaine use. J. Psychopharmacol. 27 (6), Rupp, C.I., Derntl, B., Osthaus, F., Kemmler, G., Fleischhacker, W.W.,
526e532. 2017. Impact of social cognition on alcohol dependence treatment
Nandrino, J.L., Gandolphe, M.C., Alexandre, C., Kmiecik, E., Yguel, J., outcome: poorer facial emotion recognition predicts relapse/dropout.
Urso, L., 2014. Cognitive and affective theory of mind abilities in Alcohol Clin. Exp. Res. 41 (12), 2197e2206.
alcohol-dependent patients: the role of autobiographical memory. Sanfey, A., Dorris, M., 2009. Chapter 6 - Games in humans and non-
Drug Alcohol Depend. 143, 65e73. human primates: scanners to single units. In: Glimcher, P.W.,
Onuoha, R.C., Quintana, D.S., Lyvers, M., Guastella, A.J., 2016. A meta- Camerer, C.F., Fehr, E., Poldrack, R.A. (Eds.), Neuroeconomics.
analysis of theory of mind in alcohol use disorders. Alcohol Alcohol Academic Press, London, pp. 63e80.
51 (4), 410e415. Sanfey, A.G., 2007. Social decision-making: insights from game theory
Oscar-Berman, M., Hancock, M., Mildworf, B., Hutner, N., Weber, D.A., and neuroscience. Science 318 (5850), 598e602.
1990. Emotional perception and memory in alcoholism and aging. Savov, S., Atanassov, N., 2013. Deficits of affect mentalization in patients
Alcohol Clin. Exp. Res. 14 (3), 383e393. with drug addiction: theoretical and clinical aspects. ISRN Addict.
Payer, D.E., Lieberman, M.D., Monterosso, J.R., Xu, J., Fong, T.W., 2013, 250751.
London, E.D., 2008. Differences in cortical activity between Schaffer, S.G., Wisniewski, A., Dahdah, M., Froming, K.B., 2009. The
methamphetamine-dependent and healthy individuals performing a comprehensive affect testing system-abbreviated: effects of age on
facial affect matching task. Drug Alcohol Depend. 93 (1e2), 93e102. performance. Arch. Clin. Neuropsychol. 24 (1), 89e104.
Peters, J., Buchel, C., 2010. Neural representations of subjective reward Schilbach, L., Wilms, M., Eickhoff, S.B., Romanzetti, S., Tepest, R.,
value. Behav. Brain Res. 213 (2), 135e141. Bente, G., et al., 2010. Minds made for sharing: initiating joint
Philippot, P., Kornreich, C., Blairy, S., Baert, I., Den Dulk, A., Le Bon, O., attention recruits reward-related neurocircuitry. J. Cogn. Neurosci. 22
et al., 1999. Alcoholics’ deficits in the decoding of emotional facial (12), 2702e2715.
expression. Alcohol Clin. Exp. Res. 23 (6), 1031e1038. Schilbach, L., 2016. Towards a second-person neuropsychiatry. Philos.
Philips, B., Wennberg, P., Konradsson, P., Franck, J., 2018. Mentalization- Trans. R. Soc. Lond. B Biol. Sci. 371 (1686), 20150081.
based treatment for concurrent borderline personality disorder and Schmid, Y., Hysek, C.M., Simmler, L.D., Crockett, M.J., Quednow, B.B.,
substance use disorder: a randomized controlled feasibility study. Eur. Liechti, M.E., 2014. Differential effects of MDMA and methylphe-
Addict. Res. 24 (1), 1e8. nidate on social cognition. J. Psychopharmacol. 28 (9), 847e856.
Platt, B., Kamboj, S., Morgan, C.J., Curran, H.V., 2010. Processing dy- Schmidt, T., Roser, P., Juckel, G., Brune, M., Suchan, B., Thoma, P.,
namic facial affect in frequent cannabis-users: evidence of deficits in 2016. Social cognition and social problem solving abilities in in-
the speed of identifying emotional expressions. Drug Alcohol Depend. dividuals with alcohol use disorder. J. Clin. Exp. Neuropsychol. 38
112 (1e2), 27e32. (9), 974e990.
Preller, K.H., Herdener, M., Schilbach, L., Stampfli, P., Hulka, L.M., Schuckit, M.A., Smith, T.L., Paulus, M.P., Tapert, S.F., Simmons, A.N.,
Vonmoos, M., et al., 2014a. Functional changes of the reward system Tolentino, N.J., et al., 2016. The ability of functional magnetic reso-
underlie blunted response to social gaze in cocaine users. Proc. Natl. nance imaging to predict heavy drinking and alcohol problems 5
Acad. Sci. U.S.A. 111 (7), 2842e2847. Years later. Alcohol Clin. Exp. Res. 40 (1), 206e213.
Spechler, P.A., Orr, C.A., Chaarani, B., Kan, K.J., Mackey, S., effects for theory of mind. Eur. Arch. Psychiatry Clin. Neurosci. 269
Morton, A., et al., 2015. Cannabis use in early adolescence: evidence (5), 611e620. https://doi.org/10.1007/s00406-019-00997-z.
of amygdala hypersensitivity to signals of threat. Dev. Cogn. Neuro- Verdejo-Garcia, A., Rivas-Perez, C., Vilar-Lopez, R., Perez-Garcia, M.,
sci. 16, 63e70. 2007. Strategic self-regulation, decision-making and emotion pro-
Sprah, L., Novak, T., 2008. Behavioural inhibition system (BIS) and behav- cessing in poly-substance abusers in their first year of abstinence.
ioural activation system (BAS) as predictors of emotional and cognitive Drug Alcohol Depend. 86 (2e3), 139e146.
deficits observed in alcohol abstainers. Psychiatr. Danub. 20 (2), Verdejo-Garcia, A., Del Mar Sanchez-Fernandez, M., Alonso-
184e193. Maroto, L.M., Fernandez-Calderon, F., Perales, J.C., Lozano, O.,
Stewart, L.H., Ferguson, B., Morgan, C.J., Swaboda, N., Jones, L., et al., 2010. Impulsivity and executive functions in polysubstance-
Fenton, R., et al., 2014. Effects of ecstasy on cooperative behaviour using rave attenders. Psychopharmacology (Berl.) 210 (3), 377e392.
and perception of trustworthiness: a naturalistic study. Verdejo-Garcia, A., Contreras-Rodriguez, O., Fonseca, F., Cuenca, A.,
J. Psychopharmacol. 28 (11), 1001e1008. Soriano-Mas, C., Rodriguez, J., et al., 2014. Functional alteration in
Suchman, N.E., DeCoste, C.L., McMahon, T.J., Dalton, R., Mayes, L.C., frontolimbic systems relevant to moral judgment in cocaine-dependent
Borelli, J., 2017. Mothering from the inside out: results of a second subjects. Addict. Biol. 19 (2), 272e281.
randomized clinical trial testing a mentalization-based intervention for Verdejo-Garcia, A., Verdejo-Roman, J., Albein-Urios, N., Martinez-
mothers in addiction treatment. Dev. Psychopathol. 29 (2), 617e636. Gonzalez, J.M., Soriano-Mas, C., 2017. Brain substrates of social
Thoma, P., Winter, N., Juckel, G., Roser, P., 2013. Mental state decoding decision-making in dual diagnosis: cocaine dependence and person-
and mental state reasoning in recently detoxified alcohol-dependent ality disorders. Addict. Biol. 22 (2), 457e467.
individuals. Psychiatry Res. 205 (3), 232e240. Verdejo-Garcia, A., 2014. Social cognition in cocaine addiction. Proc.
Tobler, P.N., Preller, K.H., Campbell-Meiklejohn, D.K., Kirschner, M., Natl. Acad. Sci. U.S.A. 111 (7), 2406e2407.
Kraehenmann, R., Stampfli, P., et al., 2016. Shared neural basis of Volkow, N.D., Baler, R.D., Goldstein, R.Z., 2011. Addiction: pulling at
social and non-social reward deficits in chronic cocaine users. Soc. the neural threads of social behaviors. Neuron 69 (4), 599e602.
Cognit. Affect Neurosci. 11 (6), 1017e1025. Vonmoos, M., Eisenegger, C., Bosch, O.G., Preller, K.H., Hulka, L.M.,
Townshend, J.M., Duka, T., 2003. Mixed emotions: alcoholics’ impair- Baumgartner, M., et al., 2019. Improvement of emotional empathy
ments in the recognition of specific emotional facial expressions. and cluster B personality disorder symptoms associated with
Neuropsychologia 41 (7), 773e782. decreased cocaine use severity. Front. Psychiatry 10, 213. https://
Trick, L., Kempton, M.J., Williams, S.C., Duka, T., 2014. Impaired fear doi.org/10.3389/fpsyt.2019.00213.
recognition and attentional set-shifting is associated with brain Weightman, M.J., Knight, M.J., Baune, B.T., 2019. A systematic review of
structural changes in alcoholic patients. Addict. Biol. 19 (6), the impact of social cognitive deficits on psychosocial functioning in
1041e1054. major depressive disorder and opportunities for therapeutic interven-
Tsukue, R., Okamoto, Y., Yoshino, A., Kunisato, Y., Takagaki, K., tion. Psychiatry Res. 274, 195e212.
Takebayashi, Y., et al., 2015. Do individuals with alcohol dependence Woicik, P.A., Moeller, S.J., Alia-Klein, N., Maloney, T., Lukasik, T.M.,
show higher unfairness sensitivity? The relationship between impul- Yeliosof, O., et al., 2009. The neuropsychology of cocaine addiction:
sivity and unfairness sensitivity in alcohol-dependent adults. Alcohol recent cocaine use masks impairment. Neuropsychopharmacology 34 (5),
Clin. Exp. Res. 39 (10), 2016e2021. 1112e1122.
Uekermann, J., Daum, I., Schlebusch, P., Trenckmann, U., 2005. Pro- Wolwer, W., Frommann, N., 2011. Social-cognitive remediation in
cessing of affective stimuli in alcoholism. Cortex 41 (2), 189e194. schizophrenia: generalization of effects of the training of affect
Uekermann, J., Channon, S., Daum, I., 2006. Humor processing, mental- recognition (TAR). Schizophr. Bull. 37 (Suppl. 2), S63eS70.
izing, and executive function in normal aging. J. Int. Neuropsychol. Wunderli, M.D., Vonmoos, M., Niedecker, S.M., Hulka, L.M.,
Soc. 12 (2), 184e191. Preller, K.H., Baumgartner, M.R., et al., 2016. Cognitive and
Uekermann, J., Channon, S., Winkel, K., Schlebusch, P., Daum, I., 2007. emotional impairments in adults with attention-deficit/hyperactivity
Theory of mind, humour processing and executive functioning in disorder and cocaine use. Drug Alcohol Depend. 163, 92e99.
alcoholism. Addiction 102 (2), 232e240. Wunderli, M.D., Vonmoos, M., Treichler, L., Zeller, C., Dziobek, I.,
Vallat-Azouvi, C., Azouvi, P., Le-Bornec, G., Brunet-Gouet, E., 2018. Kraemer, T., et al., 2018. Social cognition and interaction in chronic
Treatment of social cognition impairments in patients with traumatic users of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”).
brain injury : a critical review. Brain Inj. 1e7. Int. J. Neuropsychopharmacol. 21 (4), 333e344.
Valmas, M.M., Mosher Ruiz, S., Gansler, D.A., Sawyer, K.S., Oscar- Yacubian, J., Buchel, C., 2009. The genetic basis of individual differences
Berman, M., 2014. Social cognition deficits and associations with in reward processing and the link to addictive behavior and social
drinking history in alcoholic men and women. Alcohol Clin. Exp. Res. cognition. Neuroscience 164 (1), 55e71.
38 (12), 2998e3007. Zimmermann, K., Kendrick, K.M., Scheele, D., Dau, W., Banger, M.,
Vaskinn, A., Lovgren, A., Egeland, M.K., Feyer, F.K., Ostefjells, T., Maier, W., et al., 2019. Altered striatal reward processing in abstinent
Andreassen, O.A., et al., 2019. A randomized controlled trial of dependent cannabis users: social context matters. Eur. Neuro-
training of affect recognition (TAR) in schizophrenia shows lasting psychopharmacol. 29 (3), 356e364.
Chapter 6
A neurocognitive model of the

comorbidity of substance use and
personality disorders
Jacob W. Koudys and Anthony C. Ruocco
University of Toronto, Toronto ON, Canada
The question of why addiction is so highly comorbid with Cluster B PDs, especially ASPD and BPD (Dolan-Sewell
other psychiatric disorders has been the topic of scientific et al., 2001; Fenton et al., 2012; McGlashan et al., 2000;
research for decades. The clinical significance of this co- Trull et al., 2010). Why addictiondand SUDs in
morbidity is reflected in the terms “dual diagnosis” and particulardis so markedly comorbid with PDs has been
“concurrent disorders,” which have variously been applied investigated from many different perspectives, including
to individuals who have both an addictive disorder and their shared symptom dimensions, personality traits, and
another psychiatric disorder, such as a depressive, anxiety, genetics. Surprisingly, little attention has been paid to
or psychotic disorder (Kessler, 2004; Khan, 2017). Co- neurocognitive functioning despite the preponderance of
morbidity research in addiction has ranged from studies cognitive deficits in both classes of disorders.
focused on treatment-related outcomes to those investi- In this chapter, we draw together theory and empirical
gating the etiology of these disorders (Kendler et al., 2003; findings to populate the gaps linking SUDs and PDs ac-
Krueger et al., 2002; Newton-Howes et al., 2017; van den cording to a neurocognitive framework. Neurocognitive
Bosch and Verheul, 2007). Although this research has often functions refer to a set of cognitive abilities, such as
centered on depressive and anxiety disorders (e.g., Lai attention, memory, and “executive functions” (EFs;
et al., 2015), a growing body of research has also examined e.g., working memory, cognitive flexibility, and response
personality disorders (PDs). inhibition), which have their basis in brain function. SUDs
As defined in the Fifth Edition of the Diagnostic and and PDs share disturbances in neurocognitive functioning
Statistical Manual of Mental Disorders (DSM-5; American that may help to explain their high comorbidity. Before
Psychiatric Association, 2013), PDs represent a pervasive reviewing the neurocognitive evidence, we begin by sum-
and inflexible pattern of inner experience and behavior as marizing research that supports both cross-sectional and
represented by a disturbance in at least two of four symp- longitudinal associations between SUDs and PDs. Next, we
tom areas: affect regulation, impulse control, identity, and describe broad symptom dimensions and impulsive per-
interpersonal functioning. PDs are separated into three sonality traits that cut across SUDs and PDs, which we
“clusters” denoted by the predominant symptoms that suggest are conceptually relevant to understanding the
characterize the individual diagnoses contained within neurocognitive deficits shared across the disorders. We
them: Cluster A is the odd or eccentric cluster (paranoid, subsequently review empirical research on neurocognitive
schizoid, and schizotypal PDs); Cluster B is the dramatic, functioning in Cluster B PDs and SUDs, focusing mainly
emotional, or erratic cluster (antisocial [ASPD], borderline on EFs because they represent key cognitive abilities that
[BPD], histrionic, and narcissistic PDs); and Cluster C is facilitate effective self-regulation and could be impacted by
the anxious or fearful cluster (avoidant, dependent, and problematic substance use. Finally, we present a pre-
obsessive-compulsive PDs). Much of the research on the liminary heuristic model that describes the neurocognitive
comorbidity of addiction and PDs has focused on substance dysfunctions that potentially underlie the comorbidity of
use disorders (SUDs), revealing a high comorbidity with SUDs and Cluster B PDs.
Cognition and Addiction. https://doi.org/10.1016/B978-0-12-815298-0.00006-X 79

Cross-sectional and longitudinal (Walter et al., 2009). A longitudinal study based on data
contained in the Taiwan National Health Insurance
evidence
Research Database found that a PD diagnosis conferred the
Cluster B PDs have been the main topic of study for most highest risk for a subsequent diagnosis of a SUD, above
cross-sectional studies investigating the relationship be- that associated with affective psychoses, neurotic disorders,
tween SUDs and PDs. In the National Epidemiologic schizophrenia, and adjustment reaction (Chiu et al., 2018).
Survey on Alcohol and Related Conditions, ASPD and In summary, these findings underscore the high diag-
BPD were found to be comorbid with SUDs at an odds nostic comorbidity between SUDs and PDs. Not only are
ratio higher than all other psychiatric disorders investigated Cluster B PDs especially comorbid with SUDs but also the
(Grant et al., 2016). Compared to schizotypal, avoidant, presence of these diagnoses appears to connote a vulnera-
and obsessive-compulsive PDs, BPD was more frequently bility to later developing a SUD. Both the cross-sectional
comorbid with SUDs in the Collaborative Longitudinal and longitudinal associations between Cluster B PDs and
Personality Disorders Study (McGlashan et al., 2000). In SUDs suggest that common individual difference factors
partial explanation of these differences in the comorbidity (e.g., symptom dimensions, personality traits, and neuro-
of PDs with SUDs, a twin study on cannabis use disorder cognitive variables) cutting across the diagnoses could ac-
found that the genetic risk associated with ASPD and BPD count for their strong associations.
traits explained 32%e60% of the variance, while avoidant
and dependent PD traits explained 16% and 11%, respec- Broad symptoms dimensions and
tively (Gillespie et al., 2018). From a symptom perspective,
Cluster B PD symptoms are uniquely associated with impulsive personality traits
alcohol use disorder (AUD) beyond what is accounted for The DSM-5 classification system employs a categorical
by major personality traits (Trull et al., 2004). SUDs also approach that conceptualizes psychiatric disorders as
appear to run in families affected with BPD (Ruocco et al., discrete diagnostic entities. In contrast, other frameworks of
2018). Importantly, the high level of comorbidity between psychopathology, such as the Hierarchical Taxonomy of
SUDs and BPD does not appear to be due to overlapping Psychopathology (HiTOP; Kotov et al., 2017), adopt a
symptoms (i.e., problematic substance use as an indicator dimensional conceptualization of psychiatric illness. The-
of impulsivity in BPD; Trull et al., 2018). ory drives the construction of the HiTOP model through
Cross-sectional studies, however, are limited in the in- factor analyses of dimensions, defined as “psychopatho-
ferences that can be drawn about the causal link between logic continua that reflect individual differences in mal-
SUDs and PDs. There is good reason to suspect that PDs adaptive characteristics across the entire population” (p.
could precede the development of SUDs: PDs have an early 456). This definition emphasizes the universality and
onset (i.e., at least by early adulthood) and are pervasive, richness of information provided by a dimensional frame-
inflexible, enduring, and distressing and/or impairing work for psychopathology. In the HiTOP model, over-
(American Psychiatric Association, 2013). Given its arching super spectra sit atop the hierarchy and govern the
intransigent quality, it is reasonable to surmise that the spectra (internalizing, thought disorder, disinhibited exter-
pathological personality traits underlying PDs may predis- nalizing, antagonistic externalizing, and detachment) below
pose people for addiction. Only a small number of studies them. From here, these spectra break into subfactors
have investigated longitudinal relationships between the (e.g., internalizing splits into sexual problems, eating pa-
onset of SUDs and PDs, but in those that have, a nuanced thology, fear, and distress). Finally, within these subfactors,
relationship between SUDs and PDs is evident. Most there are homogeneous componentsd“groups of related
research findings suggest that the presence of PDs increases symptoms” (p. 456)dand maladaptive traitsd“specific
the likelihood of SUD onset and contributes to its mainte- pathology personality characteristics” (p. 456). Factors at
nance. In a multiyear longitudinal study, specific PDs (i.e., every level represent constellations of lower-level factors,
BPD, ASPD, and schizotypal PD) were positively related to but there are some interstitial relationships among the
SUD persistence, while mood and anxiety disorders were immediately adjacent factor levels.
not (Fenton et al., 2012). Another study found that PDs are Although HiTOP is at the early stages of providing a
the comorbid disorders most related to the transition from framework of the broader structure of psychopathology, it
substance use initiation to dependence, although the con- presents a conceptual basis for understanding why certain
fidence intervals overlapped with that of mood disorders diagnoses are more likely to be comorbid. An explicit aim of
(Lopez-Quintero et al., 2011). Compared to obsessive- the HiTOP initiative is to incorporate comorbidities by
compulsive PD, BPD has been shown to be more related assigning syndromes to spectra. Metaanalysis of quantitative
to increased vulnerability for the onset of substance models fitted to comorbidity data corroborates the existence
dependence, a finding that is particularly interesting given of latent liability factors that affect the manifestation of
that this was true irrespective of its remission status frequently comorbid diagnoses (Krueger and Markon, 2006).
Neurocognitive model of addiction comorbidity Chapter | 6 81
Traditionally, SUDs and PDs have often been conceptu- (Berg et al., 2015), within which BPD holds the strongest
alized as distinct diagnostic entities. While they may be relationship. Indeed, negative affectivity operates indirectly
classified as separate diagnoses in conventional nosologies through negative urgency to affect alcohol-related prob-
like the DSM-5, their frequent comorbidity and shared lems, and negative urgency is directly related to risk
“impulsigenic” phenotypic identity (Lacey and Evans, behavior (Wray et al., 2012). Wray et al. further note that
1986) suggest that higher-order factors (and presumably these findings suggest that control deficits may contribute
associated neurocognitive functions, as we will review to the mechanism of addiction rather than attempts to self-
below) influence their joint manifestation. In application medicate to alleviate negative affect. In a similar vein,
to the specific comorbidity of Cluster B PDs and SUDs, mediation models demonstrate that the relationship be-
the spectra of greatest relevance are disinhibited exter- tween negative urgency and problematic drinking operates
nalizing and antagonistic externalizing. The former breaks through distinct pathways (i.e., is uniquely mediated by
into substance abuse and antisocial subfactors, with the drinking motives and affective instability) compared with
latter shared interstitially with antagonistic externalizing sensation seeking and lack of premeditation (Adams et al.,
(Kotov et al., 2017). Based on the emerging HiTOP 2012; Chugani et al., 2018; Coskunpinar and Cyders,
model, SUDs, ASPD, and BPD are speculated to share a 2012). With these mediation models in mind, attention to
broader externalizing symptom dimension, which helps to the interaction between affect and impulsivity in the study
explain their substantial comorbidity. This implies that of SUD has been gaining traction (Smith and Cyders, 2016;
impulsive personality traits may also be important to Verdejo-García et al., 2007). Sensation seeking appears to
consider as cross-cutting individual difference variables share the weakest relationship with general psychopathol-
that might partially explain the comorbidity of these ogy, but lack of perseverance and lack of premeditation are
diagnoses. especially related to BPD and SUDs (Berg et al., 2015).
Impulsivity has long been recognized as a trait linking Given this evidence, SUDs and PDs may be linked
the comorbidity of SUDs and PDs (Moeller et al., 2001). through externalizing symptoms and impulsive personality
For decades, researchers have sought to elucidate the traits, especially negative urgency. Negative urgency is
different components of impulsivity (e.g., Twain, 1957), highly related to externalizing behavior (Settles et al., 2012)
which is now recognized as a multidimensional construct. and increases risk for SUD onset, further highlighting the
Of the most prominent developments to emerge from importance of considering these findings within broader
research on the multidimensional nature of impulsivity, a symptom and personality domains related to disinhibition
personality-based structural model of impulsivity was and negative affectivity. These symptoms and traits could
produced based on factor analysis of self-report measures partially explain the strong cross-sectional and longitudinal
(Whiteside and Lynam, 2001). Operationalized in the associations between SUDs and PDs and are critical for
UPPS-P Impulsive Behavior Scale (Lynam et al., 2006), the implicating the role of negative affect in their comorbidity.
model comprises five impulsive personality traits: negative
urgency, the tendency toward rash actions during negative
affect; (lack of) premeditation, the tendency toward Neurocognitive functioning
delaying action in favor of planning ahead and careful
consideration; (lack of) perseverance, the tendency to Until this point, we have discussed major conceptual links
persist in completing a task and avoiding boredom; between SUDs and PDs based on broad symptom
sensation seeking, the tendency to pursue adventure or dimensions and specific personality traits that cut across
excitement; and most recently, positive urgency, the ten- traditional diagnostic categories. These findings converge
dency toward rash actions during positive affect (Cyders on externalizing symptoms and impulsive personality traits
et al., 2007). A lack of premeditation is most congruent as central to the comorbidity of SUDs and PDs, and more
with traditional understandings of impulsivity (Whiteside specifically, Cluster B PDs. The comorbidity of these dis-
and Lynam, 2001), but the other facets capture additional orders can also be scrutinized at a neurocognitive level,
elements purportedly related to impulsivity. Indeed, it has where deficits in certain cognitive abilities may underlie
been suggested that general impulsivity, specifically some forms of psychopathology and personality traits.
excluding sensation seeking, may be an endophenotype for While the cognitive underpinnings of externalizing symp-
substance dependence (Ersche et al., 2010). toms and impulsive personality traits are yet to be fully
The UPPS-P model of impulsive personality traits helps elucidated, it is reasonable to speculate that EFs are espe-
to clarify which specific traits are unique to PDs versus cially relevant to these dimensions because the cognitive
SUDs and it advances the body of knowledge that explains functions comprising EFs are crucial for effective self-
the overlap between them. In general, metaanalytic findings regulation (Hofmann et al., 2012). Indeed, EF deficits are
on the relationship between UPPS-P traits and psychopa- commonly found in association with externalizing symp-
thology reveal that negative urgency is the trait most toms and disorders and impulsive personality traits
strongly correlated with all forms of psychopathology (e.g., Cyders and Coskunpinar, 2012; Young et al., 2009).
Accordingly, we begin the next section by summarizing more specifically. Working memory and attentional aspects
research on EFs in Cluster B PDs because neurocognitive of EFs are the cognitive abilities most strongly associated
research on PDs has concentrated mainly on ASPD and with antisocial behavior groups, although the precise sub-
BPD. Next, we discuss research on EFs in SUDs, including components of these cognitive functions as they relate to
studies investigating their longitudinal associations and the EFs (e.g., updating, shifting, and inhibition) are not
interaction of EFs with emotion and reward. We end this consistently delineated. A metaanalysis of individuals with
section with a brief summary of theoretical models that ASPD and a history of violent, aggressive, or criminal
postulate a role for EFs and other factors in the comorbidity behavior revealed a small-to-medium effect size difference
of SUDs and PDs. in EF performance compared with healthy, nonviolent
controls (Sedgwick et al., 2017). Additionally, a more
nuanced relationship has been uncovered between EFs and
Personality disorder and executive specific facets of psychopathy: impulsive and antisocial
functioning behaviors appear to be more consistently related to EF
A range of neurocognitive functions have been investigated deficits (Baskin-Sommers et al., 2015), converging with
in Cluster B PDs. EFs are of particular relevance to the metaanalytic findings (Morgan and Lilienfeld, 2000; Ogil-
comorbidity of SUDs and Cluster B PDs, defined as “a set vie et al., 2011). While it is not yet clear whether decision-
of cognitive control processes.which regulate lower level making is disrupted in ASPD, it is suggested that comorbid
processes (e.g., perception, motor responses) and thereby addiction may increase the likelihood of greater delay
enable self-regulation and self-directed behavior toward a discounting in people with ASPD (Turner et al., 2017).
goal, allowing us to break out of habits, make decisions and BPD is associated with a range of neurocognitive def-
evaluate risks, plan for the future, prioritize and sequence icits, and EFs are among the most prominent (Koudys et al.,
our actions, and cope with novel situations” (Snyder et al., 2018). Metaanalyses show large decrements in EFs
2015, “Introduction,” para. 1). Models conceptualizing (Ruocco, 2005; Unoka and Richman, 2016), more specif-
various components of EFs have been put forward ically on tests of attention, cognitive flexibility, and plan-
(e.g., Hasher et al., 2007; Miyake and Friedman, 2012), ning. There is preliminary evidence that a deficit in
delineating specific cognitive functions, such as working planning (i.e., lower deliberation time before solving a
memory (including updating, or accessing and deleting, its problem) aggregates in the relatives of individuals with
contents), shifting (or flexibility moving between different BPD (Gvirts et al., 2012). Interestingly, the comorbidity of
tasks or set ways of thinking or responding), and restraining BPD with another Cluster B PD is associated with greater
or inhibiting a dominant or prepotent response. Other EFs, EF deficits (Unoka and Richman, 2016). A recent study
such as decision-making and planning, are likely to involve also found deficits in sustained visual attention and verbal
several of these cognitive functions (Miyake and Friedman, and visuospatial working memory in BPD compared to
2012). Decision-making is typically studied in PDs and healthy controls (Thomsen et al., 2017), further supporting
SUDs using tests of delay discounting and gambling tasks a prominent disturbance of cognitive abilities that rely on
(Bickel et al., 2014; de Wit, 2009; Dom et al., 2018; Paret EFs in BPD. The disorder is also characterized by higher
et al., 2017), that require participants to choose among delay discounting and more disadvantageous decisions on a
stimuli of varying quality, assessing individual differences gambling task (Paret et al., 2017). Only a small number of
in aspects of reward processing. In delay discounting par- studies have examined interactions between EFs and
adigms, impulsive choice is often exhibited as a dispro- emotions in BPD, yielding some evidence for a unique
portionate preference for immediate rewards of lower value impact of negative emotional stimuli on the performance of
over later rewards of higher value (Hamilton et al., 2015). tests of working memory and inhibitory control (Winter,
In gambling tasks, such as the Iowa Gambling Task (IGT; 2016).
Bechara et al., 1997), impulsive choice is often exhibited as
a greater preference for higher rewards despite unfavorable Substance use disorder and executive
odds or more severe punishers.
As mentioned, most neurocognitive investigations of
functioning
PDs have focused on ASPD and BPD. In studies related to A large body of research has investigated the neuro-
ASPD, psychopathy and antisocial behaviors have been the cognitive features of SUDs, revealing different patterns of
primary focuses. For example, early metaanalyses reveal an cognitive deficits depending on the substance in question,
overall deficit in EFs ranging in magnitude from medium the number of different substances used, acute versus long-
(Ogilvie et al., 2011) to medium-to-large (Morgan and term toxicological effects of the substance, and the time-
Lilienfeld, 2000) in various antisocial behavior groups, frame within which the cognitive functions are assessed. It
with small but statistically significant decrements for ASPD is beyond the scope of this chapter to discuss the findings
for each substance in detail, as they are presented in frequently studied in isolation in SUDs (Dom et al., 2018),
Chapters 7 through 13. To contextualize the findings that accompanying test batteries with decision-making tasks
follow, an overview of decision-making models in addic- like the IGT permits a more comprehensive assessment of
tion is warranted. One model outlines three imbalanced EF. For instance, a machine-learning approach revealed
systems in addiction: stimulus appraisal related to motiva- that cocaine-dependent individuals can be discriminated
tion, motivational state triggering, and motivational state from healthy controls based on their profiles of self-
execution (Noël et al., 2013). This model implies an reported impulsivity and performance on the Immediate
element of control (i.e., execution) over motivation influ- Memory Task (IMT), Stop Signal Task, Delay Discounting
enced by the environment while allowing for the separate Task, Delay Discounting questionnaire, IGT, and Proba-
influence of dysfunctional cognitive bias or physiological bilistic Reversal Learning task (Ahn et al., 2016). As part of
triggering. Akin to this model, but further refined to focus this classification, the Stop Signal Task and Probabilistic
on decision-making and cognitive tasks pertinent to Reversal Learning task did not meaningfully contribute to
assessment in addiction, decision-making can be concep- the prediction of cocaine dependence, but lower IGT
tualized in three stages: preference formation, choice scores, higher commission errors on the IMT, lower IMT
implementation, and feedback processing (Verdejo-García discriminability (i.e., lower ability to discriminate targets
et al., 2018). Within each of these stages, there are distinct from catch stimuli), and steeper delay discounting were
constituent components that sharply clarify the relevance of significant predictors.
various performance-based decision-making tests. For The relationship of emotion and affective states with EF
instance, the IGT maps onto uncertainty valuation within has also gained increased traction in research on SUDs. There
preference formation and to reward/punishment learning, is growing recognition that emotion is particularly important
memory, and consistency within feedback processing. for understanding the etiologic role of impulsivity in SUDs
Together, these models highlight the importance of and PDs (Trull et al., 2018). Although neurocognitive deficits
considering how decision-making concords with traditional generally predict SUD onset and differentiate patterns of use
EFs in research on SUDs. (Martinez-Loredo et al., 2018), prospective research of SUD
In a comprehensive review, Fernández-Serrano et al. onset from a family study suggests potential for an increased
(2011) concluded that EF deficits were present across studies level of specificity (Groenman et al., 2015). The researchers
of users of alcohol, cannabis, methamphetamines, cocaine, suggested that so-called “cold” EFs (i.e., those that do not
heroin, and 3,4-methylenedioxymethamphetamine. Some EF explicitly manipulate emotion or reward) do not predict SUDs
deficits appear to persist, albeit at an attenuated level of and nicotine dependence, but the investigation of “hot” EFs
severity, in users who achieve long-term abstinence. These (i.e., in this case, EFs that minimally involves reward-related
deficits were most severe in polysubstance usedespecially processes) could yield precise predictive information.
when involving methamphetamine or cocainedand the ef- Although there are numerous ways that emotional stimuli or
fects were often less severe when considering alcohol in contexts could be introduced to cognitive testing, relatively
isolation. Metaanalyses focusing on specific substances little research has been conducted on the interaction between
indicate somewhat differing neurocognitive features: chronic emotion and EFs in SUDs. This is important given evidence
heroin use is associated with impulsivity and cognitive that the performance of healthy individuals on a response in-
flexibility deficits (Baldacchino et al., 2012); inhibition is the hibition task may be affected by emotion, especially when
most impaired cognitive function in individuals remitted highly arousing images are presented (Verbruggen and De
from AUD for at least 12 weeks (Stavro et al., 2013); pol- Houwer, 2007).
ydrug use that includes ecstasy is associated with updating Beyond the various aspects of EFs and potential in-
and switching deficits, but not inhibition deficits (Roberts teractions with contexts involving emotion or reward, it is
et al., 2016); nonacute effects of cannabis do not include important to consider the potential reciprocal relationships
cognitive deficits related to EF (Grant et al., 2003; Schreiner between neurocognitive deficits, substance use, and SUDs.
and Dunn, 2012); and a comprehensive measure of EFs is EF deficits could place individuals at risk for later devel-
the cognitive index most associated with chronic metham- oping SUDs, and problematic substance use could exacer-
phetamine use, next to indices of memory and learning bate existing neurocognitive weaknesses (Moeller et al.,
(Scott et al., 2007). 2016). This is essentially a question of whether neuro-
SUDs have also been studied from the perspective of cognitive deficits are the cause of SUDs, a consequence of
decision-making, an aspect of neurocognitive functioning SUDs, or both. Verdejo-García et al. (2008) identified
that partially overlaps with EFs (Del Missier et al., 2012). impulsivity as a vulnerability marker for SUD onsetd
The IGT evaluates one’s ability to make advantageous through multiple channelsdbut the authors assert that the
choices among decks that offer variable levels of reward extant evidence supporting neurocognitive functions un-
and punishment (Bechara et al., 1997). Although the IGT is derlying impulsivity as both a cause and consequence of
SUDs requires alternate models of explanation. A recent dimensional psychopathology constructs, such as those
review dissected impulsivity into impulsive action (i.e., conceptualized in HiTOP; moreover, it proposes cognitive
deficient response inhibition) and impulsive choice (i.e., tasks to more comprehensively investigate addiction and its
deficient ability to defer gratification), indicating that both links well to potential neurobiological underpinnings
may be vulnerability markers for SUD onset (Grant and related to dopaminergic function and reward learning.
Chamberlain, 2014). Indeed, metaanalytic results reveal
that substance dependence is related to impaired response
inhibition after controlling for other psychopathology
A preliminary neurocognitive model
(Lipszyc and Schachar, 2010), and addictive behaviors are Several heuristic models have been proposed to describe
related to impulsive choice (MacKillop et al., 2011). the comorbidity between PDs and other psychiatric disor-
While multiple discrete EFs appear to be affected in ders (for a detailed review, see Lyons et al., 1997). The
SUDs, some research favors the importance of considering models are based on etiology (genetic, environmental),
impulsive choice in SUD onset. Impulsive choice on the pathophysiology (biological, psychological), and symp-
IGT, but not impulsive action on the Stop Signal Inhibition toms (or phenotypes). Based on the evidence that we have
task, was prospectively related to heavy, maladaptive reviewed on the longitudinal association between PDs and
alcohol use (Goudriaan et al., 2011). Similarly, a compre- SUDs, we propose that the substantial comorbidity of
hensive metaanalysis of neurocognitive functioning in BPD Cluster B PDs and SUD can be partially explained by a
and associations with comorbid psychiatric disorders “risk factor” model (Lyons et al., 1997), wherein the
revealed that the comorbidity of BPD with a history of presence of a PD increases the likelihood of substance use
substance use is associated with greater decision-making and the later development of SUD. However, as presented
dysfunction and gross EF deficits (Unoka and Richman, in Lyons et al. (1997), the model presumes that the two
2016). This should be considered in light of moderate syndromes have distinct etiologies. We suggest that the
correlations among decision-making tasks in addiction comorbidity of SUD and Cluster B PDs reflects both shared
(Monterosso et al., 2001), and that decision-making deficits and distinct etiologies and pathophysiologies. Therefore,
do not greatly differ as a function of substance type (Gowin the base of the model is built on an undifferentiated pool of
et al., 2018). The specific models of addiction described at etiology that proceeds through pathophysiology and
the beginning of this section elaborate on how decision- emerges as PD symptoms, SUD symptoms, and external-
making processes may go awry, although the stages of izing symptoms/impulsive personality traits. This illustrates
these models require more extensive empirical validation. the concept of pleiotropy, wherein comorbidity of the two
In any case, these models deconstruct decision-making syndromes results from a shared etiology and pathophysi-
processes in a way that promotes recognition of how ology (Lyons et al., 1997), while allowing for future
impulsivity may influence various stages of decision- research to parse out potentially heterogeneous or unique
making, whether in relation to emotion or otherwise. etiological elements with distinct pathways linked to
pathophysiology and symptoms. We theorize that a set of
shared etiology factors (whether genetic, environmental,
Comorbidity and executive functioning and/or an interaction between the two) predisposes in-
Linking models of addiction to personality psychopathol- dividuals to EF disruptions, including in working memory,
ogy, addiction researchers have specifically proffered ex- cognitive flexibility, and inhibitory control, consequently
planations for the frequent comorbidity of SUDs and PDs impacting decision-making and the ability to control one’s
centered around EF deficits and emotional impulsivity. The behavior in the face of negative emotions. In the model
necessity of such proposals is apparent in the face of at- depicted in Fig. 6.1, we highlight EF deficits because they
tempts to parse the attribution of cognitive deficits in co- are the focus of this chapter and they likely reflect in-
morbid PDs and SUDs (Berenson et al., 2016; Coffey et al., teractions between biological and psychological systems
2011). One model describes a genetically evidenced dual involved in behavioral and emotional control. Disruptions
system of personality with a competing bottom-up of these systems are theorized to underlie the externalizing
emotion-based drive and a top-down control system symptoms and impulsive personality traits that are shared
(Ellingson et al., 2013). This model is built around the between PDs and SUDs, with the former more likely to
interaction between these two systems and allows for a emerge as a syndrome earlier than the latter. A final level of
broad conceptualization of what bottom-up drive might complexity is added to the model for substances that are
entail. In similar recognition of the need to integrate likely to directly influence the pathophysiology of SUD by
disparate constructs into addiction research, another way of their toxicological influences on biological (and
framework outlines the importance of concurrently inves- corresponding psychological) systems that subserve
tigating incentive salience, EFs, and negative emotionality behavioral and emotional control. In these situations,
(Kwako et al., 2016). This model nods to the importance of problematic substance use can exacerbate existing EF
by the current diagnostic nosology. As the nosology of

personality psychopathology is clarified, personality phe-
notypes related to EF deficits may exist independently of
polythetic DSM-5 diagnostic criteria because bounded
symptom constellations may not communicate valuable
information in and of themselves. Given that PD diagnoses
require pervasive and persistent symptoms, the sequencing
of PDs to SUDs may be a diagnostic artifact by which
addiction nearly always follows PDs. However, there is a
current dearth of evidence for PD symptoms (vs. diagnoses)
relating to later SUD, aside from impulsive personality
traits and externalizing symptoms that are relevant to
Cluster B PDs. This warrants caution in relying solely on
evidence from categorical PD diagnoses and their longitu-
dinal associations with SUD initiation. Therefore, the
model should be considered preliminary given the limits of
the research studies to date and should be updated, as
research adopting a dimensional conceptualization of per-
sonality psychopathology is generated.
Future directions
In summary, there is consistent evidence from cross-
sectional and longitudinal studies that links PDs and
SUDs. The bridge between the diagnoses is likely to be
FIGURE 6.1 Heuristic model illustrating the role of executive functions
formed by externalizing psychopathology and impulsive
in the comorbidity of personality disorders and substance use disorders. personality traits, especially when considering the comor-
Syndromes are represented in rectangles. The coloring of the arrow bidity of SUDs with the dramatic, emotional, or erratic
connecting substance use disorder and executive function deficits com- Cluster B PDs. At a neurocognitive level, these symptoms
municates the uncertainty in the extent to which toxicology effects are and traits are undergirded in part by EFs, which facilitate
cyclical. PD, personality disorder; SUD, substance use disorder.
adaptive goal-directed behaviors and contribute to effective
decision-making. When these cognitive functions are dis-
weaknesses and lead to greater problems in behavioral rupted, as is often the case in ASPD and BPD, the likeli-
control that become manifest at the level of symptoms and hood of substance use initiation may increase and
phenotypes (e.g., externalizing symptoms, impulsive per- consequent substance use could in turn have deleterious
sonality traits). Whether some individuals are more effects on cognition. Our model attempts to synthesize
vulnerable to these effects (i.e., people with greater these findings using a neurocognitive frame of reference,
impulsive personality traits, more severe EF deficits, and/or although there are many places where the model can be
specific genetic predispositions) requires further investiga- clarified and updated based on future research advances.
tion. It also remains a point of future inquiry whether these First, more longitudinal research is needed to under-
toxicological effects could consequently increase the like- stand how EFs contribute to substance use initiation and
lihood of PD onset (or worsen the severity of PD symp- subsequent problematic use in the context of dimensional
toms) in individuals with SUD alone. personality psychopathology constructs, such as those
Our neurocognitive model overlaps in many respects described in HiTOP (e.g., disinhibited externalizing) and
with the previously described models (e.g., Ellingson et al., relevant personality trait domain qualifiers in the 11th
2013; Kwako et al., 2016; Trull et al., 2018), although we revision of the International Classification of Diseases
focus more specifically on EFs as a central manifestation of (e.g., disinhibition) (Tyrer et al., 2019). Relatedly, it will be
the pathophysiology that arises from the genetic and/or important to clarify whether substance use problems
environmental etiologies of SUDs and PDs. Our model also emerge concurrently with personality psychopathology or
applies more directly to PDs characterized by externalizing whether the former occurs (or perhaps worsens) after the
symptoms and impulsive personality traits (i.e., Cluster B latter has developed. Second, research in this area would
PDs) and could help to explain why less impulsive PDs are benefit from a more consistent and comprehensive oper-
not as likely to be comorbid with SUDs. It should also be ationalization of EFs and other cognitive constructs rele-
noted that the risk factor component of this model is limited vant to PDs and SUDs. Such efforts have already begun,
but it is apparent that congruously mapping factor analytic Berenson, K.R., Gregory, W.E., Glaser, E., Romirowsky, A., Rafaeli, E.,
results and novel dimensional conceptualizations of Yang, X., Downey, G., 2016. Impulsivity, rejection sensitivity, and
cognition to previous research has been challenging reactions to stressors in borderline personality disorder. Cogn. Ther.
Res. 40 (4), 510e521. https://doi.org/10.1007/s10608-015-9752-y.
(MacKillop et al., 2016; Morris and Voon, 2016; Stahl
Berg, J.M., Latzman, R.D., Bliwise, N.G., Lilienfeld, S.O., 2015. Parsing
et al., 2014). Third, there is little research on SUDs that
the heterogeneity of impulsivity: a meta-analytic review of the
links emotion and reward to cognition, let alone the co- behavioral implications of the UPPS for psychopathology. Psychol.
morbidity of SUDs and PDs. This is surprising given the Assess. 27 (4), 1129e1146. https://doi.org/10.1037/pas0000111.
relevance of emotion- and reward-cognition interactions to Bickel, W.K., Koffarnus, M.N., Moody, L., Wilson, A.G., 2014. The
both forms of psychopathology and the potential to illu- behavioral- and neuro-economic process of temporal discounting: a
minate how emotion could impact EFs to produce PDs and candidate behavioral marker of addiction. Neuropharmacology 76,
SUDs. Fourth, we focused our discussion primarily on 518e527. https://doi.org/10.1016/j.neuropharm.2013.06.013.
ASPD and BPD because these diagnoses are the most Chiu, M.L., Cheng, C.F., Liang, W.M., Lin, P.T., Wu, T.N., Chen, C.Y.,
frequently studied PDs in neurocognitive research. 2018. The temporal relationship between selected mental disorders
Accordingly, our model is most relevant to these PD di- and substance-related disorders: a nationwide population-based cohort
study. Psychiatry J. 12. https://doi.org/10.1155/2018/5697103.
agnoses, and more research on other forms of personality
Chugani, C.D., Byrd, A.L., Pedersen, S.L., Chung, T., Hipwell, A.E.,
psychopathology is needed to clarify the broader applica-
Stepp, S.D., 2018. Affective and sensation-seeking pathways linking
bility of the model. Similarly, we based our neurocognitive borderline personality disorder symptoms and alcohol-related prob-
model on SUDs without considering other addictive dis- lems in young women. J. Personal. Disord. Advance online publica-
orders (e.g., gambling disorder), which could broaden un- tion https://doi.org/10.1521/pedi_2018_32_389.
derstanding of the role of neurocognitive function in the Coffey, S.F., Schumacher, J.A., Baschnagel, J.S., Hawk, L.W.,
comorbidity of PDs and addiction. Taken together, signif- Holloman, G., 2011. Impulsivity and risk-taking in borderline per-
icant advancements in these areas will elucidate key sonality disorder with and without substance use disorders. Personal.
transdiagnostic factors that account for the comorbidity of Disord. 2 (2), 128e141. https://doi.org/10.1037/a0020574.
PDs and SUDs, which could accelerate treatment research Coskunpinar, A., Cyders, M.A., 2012. Mediationemoderation analysis of
for individuals with these concurrent disorders. problematic alcohol use: the roles of urgency, drinking motives, and
risk/benefit perception. Addict. Behav. 37 (7), 880e883. https://doi.
org/10.1016/j.addbeh.2012.03.014.
References Cyders, M.A., Coskunpinar, A., 2012. The relationship between self-report
Adams, Z.W., Kaiser, A.J., Lynam, D.R., Charnigo, R.J., Milich, R., 2012. and lab task conceptualizations of impulsivity. J. Res. Personal. 46 (1),
Drinking motives as mediators of the impulsivity-substance use rela- 121e124. https://doi.org/10.1016/j.jrp.2011.11.005.
tion: pathways for negative urgency, lack of premeditation, and Cyders, M.A., Smith, G.T., Spillane, N.S., Fischer, S., Annus, A.M.,
sensation seeking. Addict. Behav. 37 (7), 848e855. https://doi.org/10. Peterson, C., 2007. Integration of impulsivity and positive mood to
1016/j.addbeh.2012.03.016. predict risky behavior: development and validation of a measure of
Ahn, W.Y., Ramesh, D., Moeller, F.G., Vassileva, J., 2016. Utility of positive urgency. Psychol. Assess. 19 (1), 107e118. https://doi.org/
machine-learning approaches to identify behavioral markers for sub- 10.1037/1040-3590.19.1.107.
stance use disorders: impulsivity dimensions as predictors of current de Wit, H., 2009. Impulsivity as a determinant and consequence of drug
cocaine dependence. Front. Psychiatry 7. https://doi.org/10.3389/ use: a review of underlying processes. Addict. Biol. 14 (1), 22e31.
fpsyt.2016.00034. https://doi.org/10.1111/j.1369-1600.2008.00129.x.
American Psychiatric Association, 2013. Diagnostic and Statistical Manual Del Missier, F., Mäntylä, T., de Bruin, W.B., 2012. Decision-making
of Mental Disorders (DSM-5Ò). American Psychiatric Association competence, executive functioning, and general cognitive abilities.
Publishing. J. Behav. Decis. Mak. 25 (4), 331e351. https://doi.org/doi:10.1002/
Baldacchino, A., Balfour, D.J.K., Passetti, F., Humphris, G., bdm.731.
Matthews, K., 2012. Neuropsychological consequences of chronic Dolan-Sewell, R.T., Krueger, R.F., Shea, M.T., 2001. Co-occurrence with
opioid use: a quantitative review and meta-analysis. Neurosci. Bio- syndrome disorders. In: Livesley, J.W. (Ed.), Handbook of Personality
behav. Rev. 36 (9), 2056e2068. https://doi.org/10.1016/j.neubiorev. Disorders: Theory, Research, and Treatment. Guilford, New York,
2012.06.006. NY, pp. 84e104.
Baskin-Sommers, A.R., Brazil, I.A., Ryan, J., Kohlenberg, N.J., Dom, G., Sabbe, B., Hulstijn, W., van Den Brink, W., 2018. Substance use
Neumann, C.S., Newman, J.P., 2015. Mapping the association of disorders and the orbitofrontal cortex: systematic review of behav-
global executive functioning onto diverse measures of psychopathic ioural decision-making and neuroimaging studies. Br. J. Psychiatry
traits. Personal. Disord. 6 (4), 336e346. https://doi.org/10.1037/ 187 (3), 209e220. https://doi.org/10.1192/bjp.187.3.209.
per0000125. Ellingson, J.M., Verges, A., Littlefield, A.K., Martin, N.G., Slutske, W.S.,
Bechara, A., Damasio, H., Tranel, D., Damasio, A.R., 1997. Deciding ad- 2013. Are bottom-up and top-down traits in dual-systems models of
vantageously before knowing the advantageous strategy. Science 275 risky behavior genetically distinct? Behav. Genet. 43 (6), 480e490.
(5304), 1293e1295. https://doi.org/10.1126/science.275.5304.1293. https://doi.org/10.1007/s10519-013-9615-9.
Ersche, K.D., Turton, A.J., Pradhan, S., Bullmore, E.T., Robbins, T.W., Hofmann, W., Schmeichel, B.J., Baddeley, A.D., 2012. Executive func-
2010. Drug addiction endophenotypes: impulsive versus sensation- tions and self-regulation. Trends Cognit. Sci. 16 (3), 174e180. https://
seeking personality traits. Biol. Psychiatry 68 (8), 770e773. https:// doi.org/10.1016/j.tics.2012.01.006.
doi.org/10.1016/j.biopsych.2010.06.015. Kendler, K.S., Prescott, C.A., Myers, J., Neale, M.C., 2003. The structure
Fenton, M.C., Keyes, K., Geier, T., Greenstein, E., Skodol, A., of genetic and environmental risk factors for common psychiatric and
Krueger, B., et al., 2012. Psychiatric comorbidity and the persistence substance use disorders in men and women. Arch. Gen. Psychiatry 60
of drug use disorders in the United States. Addiction 107 (3), (9), 929e937. https://doi.org/10.1001/archpsyc.60.9.929.
599e609. https://doi.org/10.1111/j.1360-0443.2011.03638.x. Kessler, R.C., 2004. The epidemiology of dual diagnosis. Biol. Psychiatry
Fernández-Serrano, M.J., Pérez-García, M., Verdejo-García, A., 2011. 56 (10), 730e737. https://doi.org/10.1016/j.biopsych.2004.06.034.
What are the specific vs. generalized effects of drugs of abuse on Khan, S., 2017. Concurrent mental and substance use disorders in Canada.
neuropsychological performance? Neurosci. Biobehav. Rev. 35 (3), Health Rep. 28 (8), 3e8. Retrieved from: https://www150.statcan.gc.
377e406. https://doi.org/10.1016/j.neubiorev.2010.04.008. ca/n1/pub/82-003-x/2017008/article/54853-eng.htm.
Gillespie, N.A., Aggen, S.H., Neale, M.C., Knudsen, G.P., Krueger, R.F., Kotov, R., Krueger, R.F., Watson, D., Achenbach, T.M., Althoff, R.R.,
South, S.C., et al., 2018. Associations between personality disorders Bagby, R.M., et al., 2017. The hierarchical taxonomy of psychopa-
and cannabis use and cannabis use disorder: a population-based twin thology (HiTOP): a dimensional alternative to traditional nosologies.
study. Addiction 113 (8), 1488e1498. https://doi.org/10.1111/add. J. Abnorm. Psychol. 126 (4), 454e477. https://doi.org/10.1037/
14209. abn0000258.
Goudriaan, A.E., Grekin, E.R., Sher, K.J., 2011. Decision making and Koudys, J.W., Gulamani, T., Ruocco, A.C., 2018. Borderline personality
response inhibition as predictors of heavy alcohol use: a prospective disorder: refinements in phenotypic and cognitive profiling. Curr.
study. Alcohol Clin. Exp. Res. 35 (6), 1050e1057. https://doi.org/10. Behav. Neurosci. Rep. 5 (1), 102e112. https://doi.org/10.1007/
1111/j.1530-0277.2011.01437.x. s40473-018-0145-x.
Gowin, J.L., Sloan, M.E., Ramchandani, V.A., Paulus, M.P., Lane, S.D., Krueger, R.F., Hicks, B.M., Patrick, C.J., Carlson, S.R., Iacono, W.G.,
2018. Differences in decision-making as a function of drug of choice. McGue, M., 2002. Etiologic connections among substance depen-
Pharmacol. Biochem. Behav. 164, 118e124. https://doi.org/10.1016/j. dence, antisocial behavior and personality: modeling the externalizing
pbb.2017.09.007. spectrum. J. Abnorm. Psychol. 111 (3), 411e424. https://doi.org/10.
Grant, B.F., Saha, T.D., Ruan, W.J., Goldstein, R.B., Chou, S.P., Jung, J., 1037/0021-843X.111.3.411.
et al., 2016. Epidemiology of DSM-5 drug use disorder: results from Krueger, R.F., Markon, K.E., 2006. Reinterpreting comorbidity: a model-
the National Epidemiologic Survey on Alcohol and Related based approach to understanding and classifying psychopathology.
Conditions-III. JAMA Psychiatry 73 (1), 39e47. https://doi.org/10. Annu. Rev. Clin. Psychol. 2, 111e133. https://doi.org/10.1146/
1001/jamapsychiatry.2015.2132. annurev.clinpsy.2.022305.095213.
Grant, I., Gonzalez, R., Carey, C.L., Natarajan, L., Wolfson, T., 2003. Kwako, L.E., Momenan, R., Litten, R.Z., Koob, G.F., Goldman, D., 2016.
Non-acute (residual) neurocognitive effects of cannabis use: a meta- Addictions neuroclinical assessment: a neuroscience-based framework
analytic study. J. Int. Neuropsychol. Soc. 9 (5), 679e689. https:// for addictive disorders. Biol. Psychiatry 80 (3), 179e189. https://doi.
doi.org/10.1017/S1355617703950016. org/10.1016/j.biopsych.2015.10.024.
Grant, J.E., Chamberlain, S.R., 2014. Impulsive action and impulsive Lacey, J.H., Evans, C.D.H., 1986. The impulsivist: a multi-impulsive
choice across substance and behavioral addictions: cause or conse- personality disorder. Br. J. Addict. 81 (5), 641e649. https://doi.org/
quence? Addict. Behav. 39 (11), 1632e1639. https://doi.org/10.1016/ 10.1111/j.1360-0443.1986.tb00382.x.
j.addbeh.2014.04.022. Lai, H.M., Cleary, M., Sitharthan, T., Hunt, G.E., 2015. Prevalence of
Groenman, A.P., Oosterlaan, J.G., Corina, U., Vuijk, P.J., Rommelse, N., comorbid substance use, anxiety and mood disorders in epidemio-
Franke, B., et al., 2015. Neurocognitive predictors of substance use logical surveys, 1990e2014: a systematic review and meta-analysis.
disorders and nicotine dependence in ADHD probands, their unaf- Drug Alcohol Depend. 154, 1e13. https://doi.org/10.1016/j.
fected siblings, and controls: a 4-year prospective follow-up. J. Child drugalcdep.2015.05.031.
Psychol. Psychiatry 56 (5), 521e529. https://doi.org/10.1111/jcpp. Lipszyc, J., Schachar, R., 2010. Inhibitory control and psychopathology: a
12315. meta-analysis of studies using the stop signal task. J. Int. Neuro-
Gvirts, H.Z., Harari, H., Braw, Y., Shefet, D., Shamay-Tsoory, S.G., psychol. Soc. 16 (6), 1064e1076. https://doi.org/10.1017/
Levkovitz, Y., 2012. Executive functioning among patients with S1355617710000895.
borderline personality disorder (BPD) and their relatives. J. Affect. Lopez-Quintero, C., Pérez de los Cobos, J., Hasin, D.S., Okuda, M.,
Disord. 143 (1), 261e264. https://doi.org/10.1016/j.jad.2012.05.007. Wang, S., Grant, B.F., Blanco, C., 2011. Probability and predictors of
Hamilton, K.R., Mitchell, M.R., Wing, V.C., Balodis, I.M., Bickel, W.K., transition from first use to dependence on nicotine, alcohol, cannabis,
Fillmore, M., et al., 2015. Choice impulsivity: definitions, measure- and cocaine: results of the National Epidemiologic Survey on Alcohol
ment issues, and clinical implications. Personal. Disord. 6 (2), and Related Conditions (NESARC). Drug Alcohol Depend. 115 (1),
182e198. https://doi.org/10.1037/per0000099. 120e130. https://doi.org/10.1016/j.drugalcdep.2010.11.004.
Hasher, L., Lustig, C., Zacks, R.T., 2007. Inhibitory mechanisms and the Lynam, D.R., Smith, G.T., Whiteside, S.P., Cyders, M.A., 2006. The
control of attention. In: Conway, A., Jarrold, C., Kane, M., UPPS-P: Assessing Five Personality Pathways to Impulsive Behavior.
Miyake, A., Towse, J. (Eds.), Variation in Working Memory. Oxford Technical Report. Purdue University, West Lafayette, IN.
University Press, New York, NY, pp. 227e249.
Lyons, M.J., Tyrer, P., Gunderson, J., Tohen, M., 1997. Special feature: Roberts, C.A., Jones, A., Montgomery, C., 2016. Meta-analysis of exec-
heuristic models of comorbidity of Axis I and Axis II disorders. utive functioning in ecstasy/polydrug users. Psychol. Med. 46 (8),
J. Personal. Disord. 11 (3), 260e269. https://doi.org/10.1521/pedi. 1581e1596. https://doi.org/10.1017/S0033291716000258.
1997.11.3.260. Ruocco, A.C., 2005. The neuropsychology of borderline personality dis-
MacKillop, J., Amlung, M.T., Few, L.R., Ray, L.A., Sweet, L.H., order: a meta-analysis and review. Psychiatry Res. 137 (3), 191e202.
Munafò, M.R., 2011. Delayed reward discounting and addictive https://doi.org/10.1016/j.psychres.2005.07.004.
behavior: a meta-analysis. Psychopharmacology 216 (3), 305e321. Ruocco, A.C., Daros, A.R., Chang, J., Rodrigo, A.H., Lam, J.,
https://doi.org/10.1007/s00213-011-2229-0. Ledochowski, J., McMain, S.F., 2018. Clinical, personality, and
MacKillop, J., Weafer, J., Gray, J.C., Oshri, A., Palmer, A., de Wit, H., neurodevelopmental phenotypes in borderline personality disorder: a
2016. The latent structure of impulsivity: impulsive choice, impulsive family study. Psychol. Med. 1e12. https://doi.org/10.1017/
action, and impulsive personality traits. Psychopharmacology 233 S0033291718002908.
(18), 3361e3370. https://doi.org/10.1007/s00213-016-4372-0. Schreiner, A.M., Dunn, M.E., 2012. Residual effects of cannabis use on
Martinez-Loredo, V., Fernandez-Hermida, J.R., La Torre-Luque, A., neurocognitive performance after prolonged abstinence: a meta-
Fernandez-Artamendi, S., 2018. Polydrug use trajectories and differ- analysis. Exp. Clin. Psychopharmacol. 20 (5), 420e429. https://doi.
ences in impulsivity among adolescents. Int. J. Clin. Health Psychol. org/10.1037/a0029117.
18 (3), 235e244. https://doi.org/10.1016/j.ijchp.2018.07.003. Scott, J.C., Woods, S.P., Matt, G.E., Meyer, R.A., Heaton, R.K.,
McGlashan, T.H., Grilo, C.M., Skodol, A.E., Gunderson, J.G., Shea, M.T., Atkinson, J.H., Grant, I., 2007. Neurocognitive effects of metham-
Morey, L.C., et al., 2000. The collaborative longitudinal personality phetamine: a critical review and meta-analysis. Neuropsychol. Rev. 17
disorders study: baseline Axis I/II and II/II diagnostic co-occurrence. (3), 275e297. https://doi.org/10.1007/s11065-007-9031-0.
Acta Psychiatr. Scand. 102 (4), 256e264. https://doi.org/10.1034/j. Sedgwick, O., Young, S., Baumeister, D., Greer, B., Das, M., Kumari, V.,
1600-0447.2000.102004256.x. 2017. Neuropsychology and emotion processing in violent individuals
Miyake, A., Friedman, N.P., 2012. The nature and organization of indi- with antisocial personality disorder or schizophrenia: the same or
vidual differences in executive functions: four general conclusions. different? A systematic review and meta-analysis. Aust. N.Z. J. Psy-
Curr. Dir. Psychol. Sci. 21 (1), 8e14. https://doi.org/10.1177/ chiatry 51 (12), 1178e1197. https://doi.org/10.1177/000486741
0963721411429458. 7731525.
Moeller, F.G., Barratt, E.S., Dougherty, D.M., Schmitz, J.M., Swann, A.C., Settles, R.E., Fischer, S., Cyders, M.A., Combs, J.L., Gunn, R.L.,
2001. Psychiatric aspects of impulsivity. Am. J. Psychiatry 158 (11), Smith, G.T., 2012. Negative urgency: a personality predictor of
1783e1793. https://doi.org/10.1176/appi.ajp.158.11.1783. externalizing behavior characterized by neuroticism, low conscien-
Moeller, S.J., Bederson, L., Alia-Klein, N., Goldstein, R.Z., 2016. tiousness, and disagreeableness. J. Abnorm. Psychol. 121 (1),
Neuroscience of inhibition for addiction medicine: from prediction of 160e172. https://doi.org/10.1037/a0024948.
initiation to prediction of relapse. Prog. Brain Res. 223, 165e188. Smith, G.T., Cyders, M.A., 2016. Integrating affect and impulsivity: the
https://doi.org/10.1016/bs.pbr.2015.07.007. role of positive and negative urgency in substance use risk. Drug
Monterosso, J., Ehrman, R., Napier, K.L., O’Brien, C.P., Childress, A.R., Alcohol Depend. 163, S3eS12. https://doi.org/10.1016/j.drugalcdep.
2001. Three decision-making tasks in cocaine-dependent patients: do 2015.08.038.
they measure the same construct? Addiction 96 (12), 1825e1837. Snyder, H.R., Miyake, A., Hankin, B.L., 2015. Advancing understanding
https://doi.org/10.1046/j.1360-0443.2001.9612182512.x. of executive function impairments and psychopathology: bridging the
Morgan, A.B., Lilienfeld, S.O., 2000. A meta-analytic review of the gap between clinical and cognitive approaches. Front. Psychol. 6.
relation between antisocial behavior and neuropsychological measures https://doi.org/10.3389/fpsyg.2015.00328.
of executive function. Clin. Psychol. Rev. 20 (1), 113e136. https:// Stahl, C., Voss, A., Schmitz, F., Nuszbaum, M., Tüscher, O., Lieb, K.,
doi.org/10.1016/S0272-7358(98)00096-8. Klauer, K.C., 2014. Behavioral components of impulsivity. J. Exp.
Morris, L.S., Voon, V., 2016. Dimensionality of cognitions in behavioral Psychol. Gen. 143 (2), 850e886. https://doi.org/10.1037/a0033981.
addiction. Curr. Behav. Neurosci. Rep. 3 (1), 49e57. https://doi.org/ Stavro, K., Pelletier, J., Potvin, S., 2013. Widespread and sustained
10.1007/s40473-016-0068-3. cognitive deficits in alcoholism: a meta-analysis. Addict. Biol. 18 (2),
Newton-Howes, G.M., Foulds, J.A., Guy, N.H., Boden, J.M., 203e213. https://doi.org/10.1111/j.1369-1600.2011.00418.x.
Mulder, R.T., 2017. Personality disorder and alcohol treatment Thomsen, M.S., Ruocco, A.C., Carcone, D., Mathiesen, B.B.,
outcome: systematic review and meta-analysis. Br. J. Psychiatry 211 Simonsen, E., 2017. Neurocognitive deficits in borderline personality
(1), 22e30. https://doi.org/10.1192/bjp.bp.116.194720. disorder: associations with childhood trauma and dimensions of per-
Noël, X., Brevers, D., Bechara, A., 2013. A neurocognitive approach to sonality psychopathology. J. Personal. Disord. 31 (4), 503e521.
understanding the neurobiology of addiction. Curr. Opin. Neurobiol. https://doi.org/10.1521/pedi_2016_30_265.
23 (4), 632e638. https://doi.org/10.1016/j.conb.2013.01.018. Trull, T.J., Freeman, L.K., Vebares, T.J., Choate, A.M., Helle, A.C.,
Ogilvie, J.M., Stewart, A.L., Chan, R.C.K., Shum, D.H.K., 2011. Neu- Wycoff, A.M., 2018. Borderline personality disorder and substance
ropsychological measures of executive function and antisocial use disorders: an updated review. Borderline Personal. Disord. Emot.
behavior: a meta-analysis. Criminology 49 (4), 1063e1107. https:// Dysregul. 5 (1), 15. https://doi.org/10.1186/s40479-018-0093-9.
doi.org/10.1111/j.1745-9125.2011.00252.x. Trull, T.J., Jahng, S., Tomko, R.L., Wood, P.K., Sher, K.J., 2010. Revised
Paret, C., Jennen-Steinmetz, C., Schmahl, C., 2017. Disadvantageous NESARC personality disorder diagnoses: gender, prevalence, and
decision-making in borderline personality disorder: partial support comorbidity with substance dependence disorders. J. Personal. Disord.
from a meta-analytic review. Neurosci. Biobehav. Rev. 72, 301e309. 24 (4), 412e426. https://doi.org/10.1521/pedi.2010.24.4.412.
https://doi.org/10.1016/j.neubiorev.2016.11.019.
Trull, T.J., Waudby, C.J., Sher, K.J., 2004. Alcohol, tobacco, and drug use Pharmacol. Biochem. Behav. 164, 99e105. https://doi.org/10.1016/j.
disorders and personality disorder symptoms. Exp. Clin. Psycho- pbb.2017.02.003.
pharmacol 12 (1), 65e75. https://doi.org/10.1037/1064-1297.12.1.65. Verdejo-García, A., Lawrence, A.J., Clark, L., 2008. Impulsivity as a
Turner, D., Sebastian, A., Tüscher, O., 2017. Impulsivity and Cluster B vulnerability marker for substance-use disorders: review of findings
personality disorders. Curr. Psychiatry Rep. 19 (3), 15. https://doi.org/ from high-risk research, problem gamblers and genetic association
10.1007/s11920-017-0768-8. studies. Neurosci. Biobehav. Rev. 32 (4), 777e810. https://doi.org/10.
Twain, D.C., 1957. Factor analysis of a particular aspect of behavioral 1016/j.neubiorev.2007.11.003.
control: impulsivity. J. Clin. Psychol. 13 (2), 133e136. https://doi.org/ Walter, M., Gunderson, J.G., Zanarini, M.C., Sanislow, C.A., Grilo, C.M.,
10.1002/1097-4679(195704)13:2<133::AID- McGlashan, T.H., et al., 2009. New onsets of substance use disorders
JCLP2270130206>3.0.CO;2-X. in borderline personality disorder over 7 years of follow-ups: findings
Tyrer, P., Mulder, R., Kim, Y.R., Crawford, M.J., 2019. The Development from the Collaborative Longitudinal Personality Disorders Study.
of the ICD-11 Classification of Personality Disorders: an Amalgam of Addiction 104 (1), 97e103. https://doi.org/10.1111/j.1360-0443.
Science, Pragmatism, and Politics. Annual Review of Clinical Psy- 2008.02413.x.
chology. https://doi.org/10.1146/annurev-clinpsy-050718-095736. Whiteside, S.P., Lynam, D.R., 2001. The Five Factor Model and impul-
Unoka, Z., Richman, M.J., 2016. Neuropsychological deficits in BPD sivity: using a structural model of personality to understand impul-
patients and the moderator effects of co-occurring mental disorders: a sivity. Pers. Indiv. Differ. 30 (4), 669e689. https://doi.org/10.1016/
meta-analysis. Clin. Psychol. Rev. 44, 1e12. https://doi.org/10.1016/j. S0191-8869(00)00064-7.
cpr.2015.11.009. Winter, D., 2016. Attention to emotional stimuli in borderline personality
van den Bosch, L.M., Verheul, R., 2007. Patients with addiction and disorder e a review of the influence of dissociation, self-reference, and
personality disorder: treatment outcomes and clinical implications. psychotherapeutic interventions. Borderline Personal. Disord. Emot.
Curr. Opin. Psychiatry 20 (1), 67e71. https://doi.org/10.1097/YCO. Dysregul. 3 (1), 11. https://doi.org/10.1186/s40479-016-0047-z.
0b013e328011740c. Wray, T.B., Simons, J.S., Dvorak, R.D., Gaher, R.M., 2012. Trait-based
Verbruggen, F., De Houwer, J., 2007. Do emotional stimuli interfere with affective processes in alcohol-involved “risk behaviors”. Addict.
response inhibition? Evidence from the stop signal paradigm. Cognit. Behav. 37 (11), 1230e1239. https://doi.org/10.1016/j.addbeh.2012.
Emot. 21 (2), 391e403. https://doi.org/10.1080/02699930600625081. 06.004.
Verdejo-García, A., Bechara, A., Recknor, E.C., Pérez-García, M., 2007. Young, S.E., Friedman, N.P., Miyake, A., Willcutt, E.G., Corley, R.P.,
Negative emotion-driven impulsivity predicts substance dependence Haberstick, B.C., Hewitt, J.K., 2009. Behavioral disinhibition: liabil-
problems. Drug Alcohol Depend. 91 (2e3), 213e219. https://doi.org/ ity for externalizing spectrum disorders and its genetic and environ-
10.1016/j.drugalcdep.2007.05.025. mental relation to response inhibition across adolescence. J. Abnorm.
Verdejo-García, A., Chong, T.T.J., Stout, J.C., Yücel, M., London, E.D., Psychol. 118 (1), 117e130. https://doi.org/10.1037/a0014657.
2018. Stages of dysfunctional decision-making in addiction.
Chapter 7
Cognitive risk factors for alcohol and

substance addictions
Natalie Castellanos-Ryan and Patricia Conrod
Universite de Montreal, CHU Ste Justine, Montreal, QC, Canada
Substance misuse and addictions are highly prevalent Several studies show that heavy, long-term cannabis use
worldwide and represent a major health, social, and eco- is associated concurrently with impaired neurocognitive
nomic burden to societies (United Nations, 2018; Degen- function in animals and human adults (e.g, Fried et al.,
hardt and Hall, 2012). Adolescence is an important 2005; Lubman et al., 2015; Rubino and Parolaro, 2016;
developmental period for the onset of substance use and Verrico et al., 2014). Similarly, studies comparing adoles-
misuse (see Conrod and Nikolaou, 2016), with some cents using cannabis on a regular basis (i.e., weekly) with
epidemiologic studies in the United States showing that up controls reported that they perform worse on tasks assess-
to 36% of high school students attending grade 12 report ing attention (Hanson et al., 2010; Mathias et al., 2011;
being drunk over the last 12 months and around 50% report Medina et al., 2007), verbal memory (Hanson et al., 2010;
having ever tried any illicit substance (Johnston et al., 2016). Medina et al., 2007), intelligence (Harvey et al., 2007), and
Similarly, Canadian statistics show that 42% of adolescents executive function (EF) (Mathias et al., 2011; Medina et al.,
attending grades 9 through 11 (or 3e5 of high school) have 2007; Harvey et al., 2007; Grant et al., 2012; Lisdahl and
used cannabis in the last year, and by grade 11%, 86% of Price, 2012) and have reduced processing speed on
them were drinking alcohol (Dubé et al., 2009). Youth different tasks (Medina et al., 2007; Lisdahl and Price,
substance use is also prevalent in Europe, with 37% of youth 2012; Gruber et al., 2012). Some of the same cognitive
in the United Kingdom trying an illegal drug by the age of factors have been identified as important correlates of
15 years, and around 23% of 15 year olds reporting having alcohol use and other drug misuse (Jacobus and Tapert,
been drunk in the last 4 weeks (Statistics Team NHS Digital, 2013, 2014; Squeglia et al., 2009), with alcohol use dis-
2017). Short-term correlates of early onset drinking and drug order being particularly related to wide-ranging deficits in
use include psychosocial immaturity, poor grades, school response inhibition, cognitive flexibility, and working
dropout, higher risk for assault, teenage pregnancy and memory (WM) (Giancola and Mezzich, 2000; Giancola and
sexually transmitted diseases, suicide, homicide, and acci- Moss, 1998; Moss et al., 1994).
dental injuries, including death from alcohol poisoning, with However, most studies examining the association
long-term consequences including higher risk of developing between cognition and substance use are cross-sectional
substance use disorders (SUDs) and a range of behavioral caseecontrol or retrospective studies. While such designs
and mental health problems (Chassin et al., 2010; Grant and are able to identify concurrent cognitive correlates of sub-
Dawson, 1998; King et al., 2006; Odgers et al., 2008; Single stance use or investigate the differences between clinical
et al., 2000; Rioux et al., 2017; Scholes-Balog et al., 2016). samples of substance users versus nonusers or normative
Given these serious co-occurring difficulties and the samples, they cannot inform on the directionality of effects,
increased risk for adult SUDs observed as the age of sub- i.e., whether strengths or deficits in cognitive function pre-
stance use onset decreases (Grant and Dawson, 1998; Rioux date and confer risk for or protect against later substance use
et al., 2017), identifying risk and protective factors in problems or whether they are consequences of substance
childhood and adolescence related to substance use initiation use. That is, most human studies do not include a proper
and frequency is essential for developing evidence-based assessment of cognitive function before substance use onset.
targeted prevention and clinical practice guidelines.

This is an important limitation, as presubstance use perfor- Finally, a more general or global cognitive factor,
mance on certain cognitive tasks has been shown to be namely intelligence, has also been implicated in faulty
associated with later substance use onset and increased decision-making and substance misuse (Moss et al., 1994).
alcohol and cannabis use frequency (Castellanos-Ryan et al., Intelligence is considered a more global measure of
2013a; Squeglia et al., 2014; White and Batty, 2012; Meier cognitive function, as it is believed to be a combination
et al., 2018) or be associated with change in cannabis use of cognitive or intellectual abilities required to obtain
frequency and severity (Cousijn et al., 2014). Thus, to be knowledge and to use that knowledge to solve problems
able to identify and differentiate between cognitive risk and (Resing and Drenth, 2007). Thus, in theory, faulty problem-
protective factors from the cognitive consequences of sub- solving could result from low intelligence, which could be
stance use, it is important to give weight to the studies that involved in all phases of the problem-solving model.
allow us to make this distinction, e.g., those with prospective In this chapter, we attempt to integrate several models
longitudinal designs. of EF and decision-making and highlight the dissociable
deficits and mechanisms that have been implicated in
substance use initiation and substance use problems by
Structure of cognitive function reviewing the evidence focusing on the following cognitive
Substance misuse is often viewed as the result of faulty function domains: (1) basic EF processes implicated at all
decision-making or problem-solving. Optimal decision- stages of problem-solving, such as poor selective attention
making is defined as the process of choosing a particular or WM; (2) response inhibition; (3) delay discounting;
action among a number of alternative options, which is ex- (4) reward-based decision-making; and (5) intelligence.
pected to result in the most beneficial outcome. Based on
Luria’s problem-solving model (Luria, 1966), decision-
making is thought to involve four different phases: (1) an
Selective attention, working memory,
input or problem representation phase in which a problem is and general executive function
perceived and an attempt is made to understand it; (2) a EFs normally refer to the ability to monitor, direct, and
planning or a processing phase in which alternative options are regulate cognition and behavior in relation to goals rather
evaluated; (3) an output or execution of the plan phase, during than immediate stimuli (Nigg et al., 2004; Finn et al., 1999)
which the solution is executed; and (4) a monitoring or a or more generally to the cognitive processes that allow one
review phase during which the solution is evaluated and to behave in a contextually appropriate manner (Spreen and
errors detected and corrected. Faulty problem-solving or Strauss, 1998). Although commonly equated to functions
decision-making can result from deficits at different points pertaining to the prefrontal cortex, EFs comprise many
or phases of the decision-making process. For example, component processes, which are supported differentially by
substance misusing individuals could make poor choices a series of parallel neural loops that connect regions of the
because (a) they value immediate outcomes or rewards and prefrontal cortex, basal ganglia, and thalamus (Middleton
discount the value of delayed rewards (often referred to as and Strick, 2001). Selective attention, WM, set shifting,
temporal/delay discountingda deficit associated with interference control, inhibition, decision-making, and
phase two of Luria’s problem-solving model) (Green and planning are commonly studied as component processes of
Myerson, 2004; Kirby et al., 1999); (b) they have a strong executive functioning (Nigg et al., 2004; Pennington and
tendency to produce habitual/default actions prematurely or Ozonoff, 1996).
are incapable to override or stop habitual/default actions Recognizing the heritable nature of problematic alcohol
(i.e., deficits in response/motor inhibition; related to the and drug use, many studies have investigated differences in
third phase of the problem-solving model) (Aron et al., executive functioning between drug-naïve children with
2014; Chambers et al., 2009; Verbruggen and Logan, low and high genetic risk for alcoholism and have found
2009); (c) failure to reflect on the consequences of their mixed results with respect to performance on tests of
choices (i.e., broadly defined as a deficit in affective planning, conceptual shifting, and psychomotor functioning
“decision-making” (Bechara, 2005); related to phase four of (Nigg et al., 2004; Bauer and Hesselbrock, 1999; Corral
the problem-solving model); and/or (d) either incapacity to et al., 2003; Leonard and Das Eiden, 2002; Poon et al.,
perceive or attend to important information in their envi- 2000). The P300 amplitudes, which are an event-related
ronment that may help them make better decisions, that is, potential that can be recorded by electroencephalography
deficits in selective attention or interference control and are often used as a measure of cognitive function in
(Friedman and Miyake, 2004) or deficits in WM (Hofmann decision-making processes, have also been shown to
et al., 2012), both considered core processes necessary for differentiate children with a family history of alcoholism
EF (see Miyake et al., 2000; Stuss, 2011; Zelazo et al., from controls (Carlson et al., 2007; Hill et al., 1999).
2004), which are involved in all phases of the problem- Deckel et al. (1995), who assessed different neurocognitive
solving model.
Cognitive risk factors for alcohol and substance addictions Chapter | 7 93
measures in relation to alcohol use in sons of fathers with example, differences in WM have been found in several
alcohol use disorder, found that performance in neuro- studies comparing children of parents with alcohol use dis-
cognitive tests measuring frontal and/temporal neocortical order versus those whose parents had no alcohol use disorder
functioning was predictive of age of first drink and fre- (Ozkaragoz et al., 1997; Whipple et al., 1988) but, inter-
quency of heavy drinking (drinking to get intoxicated). estingly, not when comparing adults with and without family
These findings suggest that disturbances in the prefrontal or history of alcohol use disorder (Gillen and Hesselbrock,
anterior neocortex, potentially implicated in EFs, may be a 1992; Sher et al., 1991). Gillen and Hesselbrock (Gillen and
risk factor in the development of substance misuse. Indeed, a Hesselbrock, 1992) suggest that the deficits in WM found in
number of longitudinal studies suggest that executive func- childhood may reflect a lag in development, and that with
tioning in adolescents may be predictive of future alcohol age, these become less evident or even disappear. This
and drug use, above and beyond basic attentional deficits theory is supported in a more recent study comparing
(Aytaclar et al., 1999; Tapert et al., 2002a,b). Although more children from families with different densities of alcoholism,
research is needed to establish the mechanisms that underlie i.e., no family history of alcoholism, low density (children of
the link between EF and substance misuse, some researchers father, but no other relatives, with alcohol use disorder), and
suggest that deficits in EF lead to alcohol or substance high density (children of father and at least two other rela-
misuse because they result in poor self-regulation (Giancola tives with alcohol use disorder), in which scores on tasks of
and Mezzich, 2000; Tarter et al., 1989). WM and intelligence quotient (IQ), but not scores on more
In terms of specific core components of EF, WM is complex EF tasks (Mazes and Wisconsin card sorting task),
thought to play a central role in self-regulation (Barkley, differentiated the children of father and at least two other
1997; Finn, 2002) and is considered to be a limited capacity relatives with alcohol use disorder from those with no family
process that keeps stimuli activated in mind so that they history of alcohol use disorder (Corral et al., 1999). How-
may be retained and effectively used to guide behavior ever, a follow-up study carried out on some of this sample
(Finn, 2002). WM allows to hold and manipulate infor- three and half years later (when participants were aged
mation temporarily (Aronen ET Vuontela et al., 2005; 11e17 years) showed that the differences on WM and IQ
Rypma et al., 2002) and to integrate it into long-term scores previously found were no longer detectable (Corral
memory, which is fundamental for processes such as et al., 2003).
learning, reading, and reasoning (Aronen et al., 2005). Other researchers have proposed that WM is associated
Components of the WM system include attention capacity with other risk factors for substance use, such as delay dis-
and selective attention, also referred to as attentional con- counting, response inhibition, and impulsivity (Bobova
trol and shifting (Finn, 2002), and thus, findings related to et al., 2009; Ellingson et al., 2014). For example, it is posited
selective attention will also be reviewed here. that WM may influence other cognitive processes related to
Several studies show that deficits in WM capacity and response inhibition and addictive behavior, such as delay
selective attention have been associated with substance discounting (Bobova et al., 2009), and place an individual at
misuse (Finn and Hall, 2004), with, for example, longitu- increased risk for later substance use problems because the
dinal studies showing that poor WM capacity in early inability to recall past events and/or future consequences
adolescent nondrinkers was associated with increased (e.g., previous or potential instances of problematic
alcohol use by mid adolescence (Khurana et al., 2013), and substance use) reduces the value placed on future events.
poor performance on tests of attention in mid adolescence Others propose that WM interacts with other cognitive
(14e16 years) predicted more frequent substance use in processes involved in drug and alcohol attitudes and norms
early adulthood (22e24 years) (Tapert et al., 2002b). to confer risk for substance misuse (e.g, Finn and Hall,
Similarly, a recent study showed that poor short-term 2004). For example, proponents of the dual-process model
memory and WM capacity, as assessed by the paired asso- of substance use posit that substance use and problems are
ciative learning and self-ordered pointing tasks, respectively, influenced by the interaction between two types of cognitive
in noncannabis user at 13e14 years was associated with processes: (1) a set of processes that is reflective, controlled,
earlier onset of cannabis use (Castellanos-Ryan et al., 2017). deliberate, and executive in nature, in which WM figures
Poor WM has also been associated with other externalizing highly, and (2) cognitive processes that are more automatic,
problems, including aggression and attentional deficit and implicit, or associative in nature (Wiers et al., 2007; Barrett
hyperactivity disorder (ADHD) (Barkley, 1997; Peeters et al., 2004; Kane and Engle, 2002). In this model, it is
et al., 2014; Séguin et al., 1995, 2004; Young et al., 2009), suggested that the ability to control attentional resources (by
and thus could also be considered an important liability way of WM capacity) can moderate the effects that auto-
factor in an externalizing pathway to substance use. matic cognitive processes (drug-related associations in
That said the association between WM and substance use memory, which can be activated by environmental or
may be complex and nuanced, with developmental and other internal stimuli without the need for deliberate recollection)
cognitive factors potentially moderating the association. For have on substance use behavior. It is posited that activated
mental representations about substances of abuse are more which is a characteristic in many substance misusers, can
likely to influence behavior among individuals with lower result from a general inability to regulate or inhibit impulses
WM capacity because they are less likely to engage higher (or “prepotent” responses). However, two recent machine
cognitive processes to produce logical counterarguments to learning studies investigating multivariate predictors of early
drug cues/norms that are often implicitly presented to youth onset binge drinking and cannabis use failed to identify
through traditional and social media and peer influences. At response inhibition on a go/no-go task as a unique classifying
least one study has supported the role of WM capacity in this feature when other self-report measures of impulsivity were
dual-process model by showing that drug-related associations also included in the model (Whelan et al., 2014; Afzali et al.,
in memory predicted drug use more strongly in adolescents 2019). Therefore, while poor response inhibition might be
with lower levels of WM capacity (Grenard et al., 2008). related to future substance use and misuse, it appears to be
In summary, there is substantial evidence showing that implicated in a broader personality or temperament that
poor WM capacity plays an important role in the devel- overlaps with impulsivity and, therefore, might not be a spe-
opment of substance use, but further longitudinal studies cific risk factor for SUDs.
are needed to clarify its potential indirect influence through Problems in self-regulation and deficits in response
other cognitive processes, or its additive or interactive inhibition appear more generally implicated in externalizing
effects with independent processes, in the prediction of problems, with studies showing that deficits in response
substance use and misuse. inhibition are associated with ADHD (Lijffijt et al., 2005) and
conduct disorder (CD) (Hobson et al., 2011). Go/no-go and
stop signal reaction studies show that aggressive adolescent
Response inhibition males and children with ADHD and CD have reduced
Response inhibition is another key component of executive response inhibition (more commission errors) (Lijffijt et al.,
functioning and is the capacity to override or stop habitual, 2005; Oosterlaan and Sergeant, 1998). Children with ADHD
default, or learned responses or actions. In the last 20 years, are also slow to inhibit their responses on an stop signal
there has been much interest in studying the role of response reaction time (SSRT) (Castellanos et al., 2006). Furthermore,
inhibition in the development of different psychopathologies other studies have shown that response inhibition predicts
in youth, with a number of studies showing that response common variance shared across externalizing symptoms,
inhibition is an important correlate or contributing factor for rather than substance use behaviors specifically
substance use, and impulsive behavior, more generally (Castellanos-Ryan et al., 2014, 2016), and that the association
(Castellanos-Ryan et al., 2011, 2014; Uekermann et al., 2003; between deficits in response inhibition and substance use does
Courtney et al., 2012; Kamarajan et al., 2005; Lawrence et al., not survive control for other externalizing problems
2009). Indeed, substance use, including both alcohol and (Castellanos-Ryan et al., 2011, 2014). Taken together, these
cannabis use, has often been associated with poor response or findings suggest that although deficits in response inhibition
behavioral inhibition (Hester and Garavan, 2004; Kaufman are clearly associated with later substance use initiation and
et al., 2003; Nigg et al., 2006; Wiers et al., 1998; Li et al., 2006; misuse, they represent a more general liability to externalizing
Smith et al., 2014), with a growing body of research problems and may represent an important determining factor
suggesting that deficits in response inhibition predate sub- in what is often referred to as the externalizing pathway to
stance use initiation (Castellanos-Ryan et al., 2014; Norman substance use. These findings suggest that substance use is
et al., 2011; Morin et al., 2019; Wetherill et al., 2013). For only indirectly related to response inhibition through conduct
example, boys with positive family history of alcohol use problems.
disorder, who are considered at risk for future substance use
and addiction, perform worse on response inhibition tasks than
controls who do not have a family history (Nigg et al., 2004).
Delay discounting
Moreover, a number of longitudinal studies show that poor Optimal decision-making is defined as the process of
response inhibition during early adolescence is associated choosing a particular action, among a number of alternative
with greater substance use and related problems later in options, which is expected to result in the most beneficial
adolescence (Nigg et al., 2006; Tarter et al., 2004). A recent outcome. Most agree that basic/core EF processes such as
study by Squeglia et al. (2014) showed that poorer baseline (at selective attention, response inhibition, and WM, reviewed
12e14 years) performance on tests of cognitive inhibition- above, are key in optimal decision-making and problem-
interference, as assessed by a stroop inhibition task, solving (Carlson et al., 2013), regardless of context.
predicted higher drinking quantity and frequency, as well as These EF processes can affect decision-making and
cannabis use frequency by ages 17e18, above and beyond problem-solving in emotionally neutral context or condi-
important covariates, including family history of substance tions and thus are often referred to as “cool” EF processes.
use, pubertal development, and psychopathology symptoms. However, decision-making often occurs in emotional or
All these studies suggest that problems in self-regulation, rewarding contexts and is sensitive to motivational cues.
Consequently, faulty decision-making observed among abstinent marijuana and cocaine users (Bolla et al., 2003,
substance-using individuals could make poor choices 2005), MDMA (methylenedioxymethamphetamine or
because they overvalue immediate outcomes or rewards ecstasy) users (Morgan et al., 2006), and heavy binge drinking
and discount the value of delayed rewards (often referred to college students (Goudriaan et al., 2007). Longitudinal and
as temporal or delay discounting) (Green and Myerson, prospective studies provide some evidence that affective
2004; Kirby et al., 1999). While EF deficits have been decision-making may also be associated with future substance
associated with externalizing behaviors, including sub- use. Using a rewarded go/no-go task, the present authors
stance misuse, many posit that substance use problems showed that reward sensitivity specifically predicted higher
result more specifically from failures in optimally incor- binge drinking in adolescents and did not predict risk for other
porating temporal factors in decision-making (Bickel et al., externalizing problems (Castellanos-Ryan et al., 2011).
2014; Rachlin, 1997). Another longitudinal study showed that male college-aged
This conclusion is partly supported by a literature drinkers who displayed a disadvantageous pattern of affec-
reporting that while response inhibition and WM are asso- tive decision-making, as assessed by the Iowa Gambling Task,
ciated with externalizing problems in general, executive and exhibited significantly increased heavy drinking episodes and
other cognitive functions under rewarding or affective con- frequency and quantity of alcohol consumption over a 2 year
texts and cognitive measures that assess reward and temporal follow-up (Goudriaan et al., 2007). Similarly, poor decision-
processing such as delay discounting seem to be uniquely making has been shown to predict ecstacy use 18 months
associated with substance use (Castellanos-Ryan et al., 2014, later in adult females (Schilt et al., 2009).
2016; Bickel et al., 2012). High delay discounting has been As suggested by these behavioral results, there is emerging
consistently associated with cigarette smoking (Baker et al., evidence from neuroimaging studies of performance tasks that
2003), SUDs (Bickel et al., 2012, 2014; Bickel and Marsch, individuals who are prone to substance use problems can be
2001), and early onset alcoholism (Dom et al., 2005). It has distinguished from other clinically disinhibited/impulsive
also been shown to predict the increases in number of drugs groups based on motivational or reward sensitivity, rather than
used and drug use quantity (Johnson et al., 2007; Vuchinich on general deficits in response inhibition or other EF pro-
and Simpson, 1998; Ohmura et al., 2005; Takahashi et al., cesses. For example, high-functioning drug users (Yechiam
2009). Longitudinal and prospective studies have also shown et al., 2005) and adolescents with pure substance-using
that steeper delay discounting in adolescence predicts the profiles (Castellanos-Ryan et al., 2011) show impulsivity
onset of smoking (Audrain-McGovern et al., 2009) and later specifically in reward conditions as opposed to a general
alcohol and drug use (Castellanos-Ryan et al., 2014, 2016), tendency toward errors in response inhibition. These findings
even when controlling for important covariates, such as other were replicated with additional functional magnetic resonance
externalizing psychopathology and other cognitive factors. imaging measures, showing that adolescents at risk for early
Nevertheless, the literature is also mixed, with some studies onset substance misuse that did not cooccur with other forms
showing that conduct problems, antisocial personality of externalizing problems were specifically predicted by a
disorder (ASPD), and ADHD are associated with steep delay unique brain activity pattern during reward anticipation, while
discounting (e.g., Bobova et al., 2009; Acheson et al., 2011), externalizing symptoms were predicted by prefrontal cortical
while other studies suggest that individuals with ADHD, and activity on a go/no-go task (Castellanos-Ryan et al., 2014).
potentially other non-substance-related externalizing prob- According to this large neuroimaging study of 2200
lems, may be more sensitive to delay aversion than to adolescents, early onset substance use that is uncomplicated
discounting of rewards per se (Sonuga-Barke et al., 2003). by ADHD or CD is associated with greater left medial and
lateral orbital frontal cortex responding and reduced inferior
frontal gyrus responding when anticipating reward
Reward-based decision-making (Castellanos-Ryan et al., 2014). As these two structures are,
As complex cognitive processes involve the recruitment of respectively, implicated in reward valuation and stopping
multiple cognitive functions, advantageous long-term behavior, these findings potentially indicated a critical role of
decision-making around delayed rewards also requires an overvaluation of rewards in adolescent substance misuse and
intact reward valuation system (Bechara, 2005; Vassileva decision-making.
and Conrod, 2018) and can be impacted by heightened
reward sensitivity (Castellanos-Ryan et al., 2011). Studies
show that adults with SUDs (Bechara, 2005) perform poorly
Intelligence quotient
on reward-based or affective decision-making tasks, such as Results from studies examining the association between
the Iowa Gambling Task or Cambridge Gambling Task, intelligence (IQ) and substance use and misuse have been
which involve making decisions about potential rewards. mixed. While some studies have shown null findings for the
Impairments have been reported in alcohol-dependent adults association between IQ and later substance use (Ensminger
(Rogers et al., 1999; Petry, 2001; Bechara et al., 2002), et al., 2002; Fergusson et al., 2005), others show that low
IQ is associated with SUDs among adolescents (Moss et al., Discussion

1994) and adults (Osler et al., 2006; Mortensen et al.,
2005), and other studies indicate that substance use may be The literature reviewed suggests that neurocognitive defi-
associated with higher IQ in adolescence and adulthood cits, particularly related to delay discounting and reward-
(White and Batty, 2012; Castellanos-Ryan et al., 2013b, based decision-making, may directly predispose to
2017; Hanson et al., 2011; Johnson et al., 2009). Discrep- adolescent cannabis and alcohol use and later substance use
ancies in results may result from the confounding effects problems. Findings also suggest deficits in WM and
that comorbid psychopathology may have on these asso- response inhibition confer risk for substance use initiation
ciations, as some studies have shown that once psychopa- and problems, but more indirectly, through a predisposition
thology symptoms, such as antisocial and anxiety to other externalizing psychopathology. Furthermore,
symptoms, are taken into account, the positive associations emerging evidence suggests that these cognitive risk factors
between IQ and later substance use become clearer or confer risk by impacting on how young people evaluate
stronger. For example, a study by White et al. (2012) found drug-related messages and cues (WM), how youth form
that global IQ (including both verbal and spatial IQ) decisions around rules and conformity generally (EFs), how
assessed at 11 years in a very large population British well they are able to tolerate delayed reward and feedback
cohort was associated with increased risk of illegal drug use (temporal discounting), how well they are able to inhibit an
at 42 years of age, associations that became stronger when urge or reinforced behavior/habit (response inhibition), and
controlling for antisocial behavior and anxiety in the model. how susceptible they are to reward cues (reward sensi-
This was the case for all substances, except for ecstasy and tivity). Fig. 7.1 summarizes how these cognitive functions
anxiolytic drug use, with all associations being stronger for might be related to dimensions of psychopathology related
women than men (White et al., 2012). Similarly, a pro- to SUDs.
spective study of European adolescents where a bifactor This review also suggests that each of these domains
structure of psychopathology was modeled, separating can explain some of the mechanisms through which
variance that is common or shared across psychopathology cognitive variables confer risk, thus providing insights into
symptoms (often referred to as the P factor) from variances how drug prevention interventions targeting neurocognitive
unique to substance use and other psychopathologies, risk factors might be developed. WM training interventions
showed a complex pattern of relationships between IQ and are not necessarily proving to be effective treatments for
substance use (Castellanos-Ryan et al., 2016). Lower verbal SUD (see Chapter 18), but if used in combination with drug
and performance IQ, assessed at 14 years, were associated cue reactivity or implicit cognition paradigms, it is
with the common variance across psychopathology (P conceivable that more specific effects will occur on drug-
factor) at 16 years, but higher verbal IQ, but not perfor- related outcomes. Similarly, brief cognitive behavioral
mance IQ, was specifically associated with substance use interventions designed to help young people to better
2 years later. Thus, once other psychopathology symptoms manage their reward sensitivity or poor response inhibition
are accounted for, it seems that it is higher verbal IQ that is have been shown to be helpful in reducing risk for early
associated with adolescent substance misuse. There are onset substance misuse (Conrod et al., 2010, 2013). An
several hypotheses about why this is the case, with some important test of the causal effect of these cognitive vari-
suggesting that good cognitive abilities are necessary for ables on substance use behaviors would necessarily involve
early access to substances, which can be seen as a valuable intervening on these risk factors and demonstrating that
resource (Hyman et al., 2006). Another hypothesis is that their modification leads to reductions in risk. Studies
verbal IQ is also related to parent education and socioeco- investigating such treatment mechanisms are very rare in
nomic status, which has a positive relationship with alcohol this field and definitely warrant further attention.
and cannabis use (Patrick et al., 2012), despite having a Other important methodological considerations further
negative relationship with smoking (Patrick et al., 2012) and limit the interpretation of the reviewed findings, such as an
substance-related harms (Grant and Dawson, 1998). Although overreliance on cross-sectional/concurrent associations,
the mechanisms behind these links are still unclear, there is small samples, and not considering important covariates
some evidence suggesting that the positive relationship and correlates in the models, particularly other psychopa-
between social economic status (SES) and higher alcohol and thology. While high risk and longitudinal studies are
cannabis use is due to the fact that high SES youth have access providing more clarity on the nature of the relationship
to certain contexts that are especially supportive of excessive between cognitive risk factors and substance use outcomes,
alcohol and marijuana use, e.g., colleges and universities they have also illuminated some limitations in being able to
(Schulenberg and Maggs, 2002), or that these youth, espe- capture the evolving nature of the relationship between
cially those living in high SES neighborhoods, are less cognitive functions and substance use outcomes. One
supervised by parents and are exposed to more substance- possible explanation for variable findings on the relation-
using peers (Trim and Chassin, 2008). ship between cognitive functioning and substance use
NeurocogniƟve FuncƟons Psychopathology Dimension Observed Symptoms
ADHD
SelecƟve aƩenƟon and working Conduct Disorder

memory
OpposiƟonal
- Externalizing Defiant Disorder
- problems (…)
SƟmulant
Response InhibiƟon - Substance Abuse
Binge Drinking
General
Delay DiscounƟng
- Psychopathology
Drinking problems
(P) factor
Cannabis Abuse
Other Drug Abuse

Reward-based decision making
(…)
- Substance
Depression
Misuse
+
General Anxiety
General IQ
Phobias
Obsessive Compulsive
Disorder
(…)
FIGURE 7.1 Schemata of the associations between cognitive factors and patterns of substance use and comorbid psychopathology reviewed; a negative
sign (“”) denotes a negative association (i.e., poor performance on cognitive task associated with increased substance use and/or psychopathology) and a
positive sign (“þ”) denotes a positive association (i.e., good performance on cognitive task associated with increased substance use). Adapted from
Castellanos-Ryan, N., Briére, F.N., O’Leary-Barrett, M., et al., 2016. The structure of psychopathology in adolescence and its common personality and
cognitive correlates. J. Abnorm. Psychol. 125, 1039e1052 and Conrod, P.J., Nikolaou, K., 2016. Annual research review: on the developmental
neuropsychology of substance use disorders. J. Child Psychol. Psychiatry 57 (3), 371e394.
might be explained by age-related variability across studies tendency toward higher levels of substance use and
and the developmental stage at which cognitive processes cognitive functioning in substance naïve adolescents. This
are assessed. Cognitive functions and substance use can study showed that lower perceptual reasoning, recall
both be modeled at between- and within-person levels, memory, WM, and response inhibition all predicted greater
meaning that individuals might score stably high or low on likelihood of becoming a more frequent alcohol and
these variables (between-person effects), but biologic and cannabis consumer throughout middle and high school.
contextual factors can also cause them to vary over time Both common and specific cognitive risk profiles were
(within-person variability). Finally, these models can also revealed: accounting for the fact that alcohol and cannabis
be used to examine temporal precedence in the relationship co-occur and co-evolve, risk for alcohol misuse appeared
between two variables (e.g., change in one precedes specifically related to low levels of perceptual reasoning
changes in the other). This type of data modeling requires (performance IQ) throughout adolescence, and risk for
more than two observations per variable and large data sets. cannabis misuse was specifically related to poor response
Therefore, only a few studies have been published exam- inhibition. The longitudinal design of this study permitted
ining the relationship between cognition and substance use the estimation of within-person relationships between
in this way. One recent study used data from a large lon- cognitive and substance use variables, allowing for an
gitudinal cohort of students as they entered the seventh examination of hypotheses on the causal influence of sub-
grade and were followed annually on cognitive and stance use on cognitive development. This study showed
substance use outcomes until the 11th grade. Measures of that over and above general common vulnerability between
performance IQ (perceptual reasoning), delayed memory low cognitive functioning and substance misuse in
recall, WM and response inhibition were assessed using a adolescence, if a child showed an increase in cannabis use
computerized battery from the school computer laboratory in a given year over and above their mean level of use over
during a supervised group testing session. Multilevel the course of adolescence, they reliably showed a decrease
modeling first evaluated the relationship between overall in functioning across all four domains of cognition
assessed. Furthermore, two cognitive domains (response Aron, A.R., Robbins, T.W., Poldrack, R.A., 2014. Inhibition and the right
inhibition and WM) were shown to be impacted over the inferior frontal cortex: one decade on. Trends Cognit. Sci. 18 (4),
longer term, even if substance use returned to baseline 177e185.
Aronen, E.T., Vuontela, V., Steenari, M.R., Salmi, J., Carlson, S., 2005.
levels of use. This study also highlighted the additive
Working memory, psychiatric symptoms, and academic performance
effects of these multilevel relationships, showing that the
at school. Neurobiol. Learn. Mem. 83 (1), 33e42.
combination of premorbid cognitive risk factors with Audrain-McGovern, J., Rodriguez, D., Epstein, L.H., Cuevas, J.,
the more subtle concurrent and lagged effects of adolescent Rodgers, K., Wileyto, E.P., 2009. Does delay discounting play an
substance use on cognitive functioning resulted in signifi- etiological role in smoking or is it a consequence of smoking? Drug
cant cognitive lag (3 years) for adolescent cannabis users Alcohol Depend. 103 (3), 99e106.
compared with their nonusing peers on some cognitive Aytaclar, S., Tarter, R.E., Kirisci, L., Lu, S., 1999. Association between
outcomes. hyperactivity and executive cognitive functioning in childhood and
Another longitudinal study using a similar multilevel substance use in early adolescence. J. Am. Acad. Child Adolesc.
analytic strategy further delved into potential mediators of Psychiatry 38 (2), 172e178.
these long-term effects of substance use on cognitive out- Baker, F., Johnson, M.W., Bickel, W.K., 2003. Delay discounting in
current and never-before cigarette smokers: similarities and differ-
comes and found that some of the effects of cannabis use on
ences across commodity, sign, and magnitude. J. Abnorm. Psychol.
global cognition (verbal IQ) were mediated or accounted for
112, 382e392.
by academic achievement (i.e., high school graduation) Barkley, R.A., 1997. Behavioral inhibition, sustained attention, and ex-
(Castellanos-Ryan et al., 2017), suggesting that some effects ecutive functions: constructing a unifying theory of ADHD. Psychol.
of cannabis on global cognitive outcomes might be charac- Bull. 121 (1), 65e94.
terized by a cascading series of cognitive and academic Barrett, L.F., Tugade, M.M., Engle, R.W., 2004. Individual differences in
failures, with severe social consequences for the individual. working memory capacity and dual-process theories of the mind.
The findings from this new wave of studies that capitalize on Psychol. Bull. 130 (4), 553e573.
the availability of large longitudinal data sets and new Bauer, L.O., Hesselbrock, V.M., 1999. Subtypes of family history and
computational opportunities suggest that the relationship conduct disorder: effects on P300 during the stroop test. Neuro-
between cognition and substance use risk is bidirectional or psychopharmacology 21 (1), 51e62.
Bechara, A., 2005. Decision making, impulse control and loss of will-
reciprocal, which might explain the rapid escalation of
power to resist drugs: a neurocognitive perspective. Nat. Neurosci. 8
substance-related problems and academic and cognitive
(11), 1458e1463.
decline in young substance users (Grant and Dawson, 1998; Bechara, A., Dolan, S., Hindes, A., 2002. Decision-making and addiction
Rioux et al., 2017; Castellanos-Ryan et al., 2017). (part II): myopia for the future or hypersensitivity to reward? Neu-
In recent years, there has been much attention placed on ropsychologia 40, 1690e1705.
the consequences of substance use, particularly during Bickel, W.K., Marsch, L.A., 2001. Toward a behavioral economic un-
adolescence, and the findings reviewed above suggest that derstanding of drug dependence: delay discounting processes.
some of the focus and concern about the neurocognitive Addiction 96 (1), 73e86.
consequences of adolescent cannabis and other substance Bickel, W.K., Jarmolowicz, D.P., Mueller, E.T., Koffarnus, M.N.,
use exposure should be directed toward identifying and Gatchalian, K.M., 2012. Excessive discounting of delayed reinforcers
intervening with adolescents who display neurocognitive as a trans-disease process contributing to addiction and other disease-
related vulnerabilities: emerging evidence. Pharmacol. Ther. 134 (3),
impairment before the initiation of cannabis or other
287e297.
substance use and reducing their risk for early onset
Bickel, W.K., Koffarnus, M.N., Moody, L., Wilson, A.G., 2014. The
substance misuse. Understanding the neuropsychological behavioral- and neuro-economic process of temporal discounting: a
functions that predate substance use initiation is crucial to candidate behavioral marker of addiction. Neuropharmacology 76 Pt
preventing further neurocognitive impairments resulting B, 518e527.
from substance use. Bobova, L., Finn, P.R., Rickert, M.E., Lucas, J., 2009. Disinhibitory psy-
chopathology and delay discounting in alcohol dependence: personality
and cognitive correlates. Exp. Clin. Psychopharmacol. 17 (1), 51e61.
References Bolla, K.I., Eldreth, D.A., London, E.D., et al., 2003. Orbitofrontal cortex
Acheson, A., Vincent, A.S., Sorocco, K.H., Lovallo, W.R., 2011. Greater dysfunction in abstinent cocaine abusers performing a decision-
discounting of delayed rewards in young adults with family making task. NeuroImage 19 (3), 1085e1094.
histories of alcohol and drug use disorders: studies from the Bolla, K.I., Eldreth, D.A., Matochik, J.A., Cadet, J.L., 2005. Neural sub-
Oklahoma family health patterns project. Alcohol Clin. Exp. Res. 35 strates of faulty decision-making in abstinent marijuana users. Neu-
(9), 1607e1613. roImage 26 (2), 480e492.
Afzali, M.H., Sunderland, M., Stewart, S., et al., 2019. Machine-learning Carlson, S.R., McLarnon, M.E., Iacono, W.G., 2007. P300 amplitude,
prediction of adolescent alcohol use: a cross-study, cross-cultural externalizing psychopathology, and earlier- versus later-onset
validation. Addiction 114 (4), 662e671. substance-use disorder. J. Abnorm. Psychol. 116, 565e577.
Carlson, S.M., Zelazo, P.D., Faja, S., 2013. Executive function. In: Courtney, K.E., Arellano, R., Barkley-Levenson, E., et al., 2012. The
Zelazo, P.D. (Ed.), The Oxford Handbook of Developmental relationship between measures of impulsivity and alcohol misuse: an
Psychology. Vol 1: Body and Mind. Oxford University Press, New integrative structural equation modeling approach. Alcohol Clin. Exp.
York, pp. 706e743. Res. 36 (6), 923e931.
Castellanos, F.X., Sonuga-Barke, E.J.S., Milham, M.P., Tannock, R., Cousijn, J., Vingerhoets, W.A., Koenders, L., et al., 2014. Relationship
2006. Characterizing cognition in ADHD: beyond executive between working-memory network function and substance use: a 3-
dysfunction. Trends Cognit. Sci. 10, 117e123. year longitudinal fMRI study in heavy cannabis users and controls.
Castellanos-Ryan, N., Rubia, K., Conrod, P.J., 2011. Response inhibition Addict. Biol. 19 (2), 282e293.
and reward response bias mediate the predictive relationships between Deckel, A.W., Bauer, L., Hesselbrock, V., 1995. Anterior brain dysfunc-
impulsivity and sensation seeking and common and unique variance in tioning as a risk factor in alcoholic behaviors. Addiction 90 (10),
conduct disorder and substance misuse. Alcohol Clin. Exp. Res. 35 1323e1334.
(1), 140e155. Degenhardt, L., Hall, W., 2012. Extent of illicit drug use and dependence,
Castellanos-Ryan, N., Seguin, J.R., Vitaro, F., Parent, S., Tremblay, R.E., and their contribution to the global burden of disease. Lancet 379,
2013a. Impact of a 2-year multimodal intervention for disruptive 55e70.
6-year-olds on substance use in adolescence: randomised controlled Dom, G., Sabbe, B., Hulstijn, W., van den Brink, W., 2005. Substance use
trial. Br. J. Psychiatry 203 (3), 188e195. disorders and the orbitofrontal cortex: systematic review of behav-
Castellanos-Ryan, N., Séguin, J.R., Vitaro, F., Parent, S., Tremblay, R.E., ioural decision-making and neuroimaging studies. Br. J. Psychiatry
2013b. A multimodal intervention for disruptive kindergarten children 187, 209e220.
reduces substance-use across adolescence: a randomized control trial. Dubé, G., Bordeleau, M., Cazale, L., et al., 2009. Enquête québécoise sur
Br. J. Psychiatry 203, 188e195. le tabac, l’alcool, la drogue et le jeu chez les élèves du secondaire,
Castellanos-Ryan, N., Struve, M., Whelan, R., et al., 2014. Neural and 2008. Québec.
cognitive correlates of the common and specific variance across Ellingson, J.M., Fleming, K.A., Verges, A., Bartholow, B.D., Sher, K.J.,
externalizing problems in young adolescence. Am. J. Psychiatry 171 2014. Working memory as a moderator of impulsivity and alcohol
(12), 1310e1319. involvement: testing the cognitive-motivational theory of alcohol use
Castellanos-Ryan, N., Briére, F.N., O’Leary-Barrett, M., et al., 2016. The with prospective and working memory updating data. Addict. Behav.
structure of psychopathology in adolescence and its common per- 39 (11), 1622e1631.
sonality and cognitive correlates. J. Abnorm. Psychol. 125, Ensminger, M.E., Juon, H.S., Fothergill, K.E., 2002. Childhood and
1039e1052. adolescent antecedents of substance use in adulthood. Addiction 97
Castellanos-Ryan, N., Pingault, J.B., Parent, S., Vitaro, F., Tremblay, R.E., (7), 833e844.
Seguin, J.R., 2017. Adolescent cannabis use, change in neurocognitive Fergusson, D.M., Horwood, L.J., Ridder, E.M., 2005. Show me the child
function, and high-school graduation: a longitudinal study from early at seven II: childhood intelligence and later outcomes in adolescence
adolescence to young adulthood. Dev. Psychopathol. 29 (4), and young adulthood. J. Child Psychol. Psychiatry 46 (8), 850e858.
1253e1266. Finn, P.R., 2002. Motivation, working memory, and decision making: a
Chambers, C.D., Garavan, H., Bellgrove, M.A., 2009. Insights into the cognitive-motivational theory of personality vulnerability to
neural basis of response inhibition from cognitive and clinical alcoholism. Behav. Cognit. Neurosci. Rev. 1, 183e205.
neuroscience. Neurosci. Biobehav. Rev. 33 (5), 631e646. Finn, P.R., Hall, J., 2004. Cognitive ability and risk for alcoholism: short-
Chassin, L., Dmitrieva, J., Modecki, K., et al., 2010. Does adolescent term memory capacity and intelligence moderate personality risk for
alcohol and marijuana use predict suppressed growth in psychosocial alcohol problems. J. Abnorm. Psychol. 113, 569e581.
maturity among male juvenile offenders? Psychol. Addict. Behav. 24 Finn, P.R., Justus, a, Mazas, C., Steinmetz, J.E., 1999. Working memory,
(1), 48e60. executive processes and the effects of alcohol on Go/No-Go learning:
Conrod, P.J., Nikolaou, K., 2016. Annual research review: on the devel- testing a model of behavioral regulation and impulsivity. Psycho-
opmental neuropsychology of substance use disorders. J. Child pharmacology (Berl.) 146, 465e472.
Psychol. Psychiatry 57 (3), 371e394. Fried, P.A., Watkinson, B., Gray, R., 2005. Neurocognitive consequences
Conrod, P.J., Castellanos-Ryan, N., Strang, J., 2010. Brief, personality- of marihuana–a comparison with pre-drug performance. Neurotoxicol.
targeted coping skills interventions and survival as a non-drug user Teratol. 27 (2), 231e239.
over a 2-year period during adolescence. Arch. Gen. Psychiatry 67 (1), Friedman, N.P., Miyake, A., 2004. The relations among inhibition and
85e93. interference control functions: a latent-variable analysis. J. Exp.
Conrod, P.J., O’Leary-Barrett, M., Newton, N., et al., 2013. Effectiveness Psychol. Gen. 133 (1), 101e135.
of a selective, personality-targeted prevention program for adolescent Giancola, P.R., Mezzich, A.C., 2000. Neuropsychological deficits in
alcohol use and misuse: a cluster randomized controlled trial. JAMA female adolescents with a substance use disorder: better accounted for
Psychiatry 70 (3), 334e342. by conduct disorder? J. Stud. Alcohol 61 (6), 809e817.
Corral, M.M., Holguín, S.R., Cadaveira, F., 1999. Neuropsychological Giancola, P.R., Moss, H.B., 1998. Executive cognitive functioning in
characteristics in children of alcoholics: familial density. J. Stud. alcohol use disorders. Recent Dev. Alcohol 14, 227e251.
Alcohol 60, 509e513. Gillen, R., Hesselbrock, V., 1992. Cognitive functioning, ASP, and family
Corral, M., Holguín, S.R., Cadaveira, F., 2003. Neuropsychological history of alcoholism in young men at risk for alcoholism. Alcohol
characteristics of young children from high-density alcoholism fam- Clin. Exp. Res. 16 (2), 206e214.
ilies: a three-year follow-up. J. Stud. Alcohol 64, 195e199.
Goudriaan, A.E., Grekin, E.R., Sher, K.J., 2007. Decision making and Adolescent Drug Use. Institute for Social Research, The University of
binge drinking: a longitudinal study. Alcohol Clin. Exp. Res. 31 (6), Michigan., Ann Arbor.
928e938. Kamarajan, C., Porjesz, B., Jones, K.A., et al., 2005. Alcoholism is a
Grant, B.F., Dawson, D.A., 1998. Age of onset of drug use and its asso- disinhibitory disorder: neurophysiological evidence from a Go/No-Go
ciation with DSM-IV drug abuse and dependence: results from the task. Biol. Psychol. 69 (3), 353e373.
national longitudinal alcohol epidemiologic survey. J. Subst. Abus. 10 Kane, M.J., Engle, R.W., 2002. The role of prefrontal cortex in working-
(2), 163e173. memory capacity, executive attention, and general fluid intelligence:
Grant, J.E., Chamberlain, S.R., Schreiber, L., Odlaug, B.L., 2012. an individual-differences perspective. Psychonomic Bull. Rev. 9 (4),
Neuropsychological deficits associated with cannabis use in young 637e671.
adults. Drug Alcohol Depend. 121 (1e2), 159e162. Kaufman, J.N., Ross, T.J., Stein, E.A., Garavan, H., 2003. Cingulate
Green, L., Myerson, J., 2004. A discounting framework for choice with hypoactivity in cocaine users during a GO-NOGO task as revealed by
delayed and probabilistic rewards. Psychol. Bull. 130, 769e792. event-related functional magnetic resonance imaging. J. Neurosci. 23
Grenard, J.L., Ames, S.L., Wiers, R.W., Thush, C., Sussman, S., (21), 7839e7843.
Stacy, A.W., 2008. Working memory capacity moderates the predic- Khurana, A., Romer, D., Betancourt, L.M., Brodsky, N.L.,
tive effects of drug-related associations on substance use. Psychol. Giannetta, J.M., Hurt, H., 2013. Working memory ability predicts
Addict. Behav. 22 (3), 426e432. trajectories of early alcohol use in adolescents: the mediational role of
Gruber, S.A., Sagar, K.A., Dahlgren, M.K., Racine, M., Lukas, S.E., 2012. impulsivity. Addiction 108 (3), 506e515.
Age of onset of marijuana use and executive function. Psychol. King, K.M., Meehan, B.T., Trim, R.S., Chassin, L., 2006. Substance use
Addict. Behav. 26 (3), 496e506. and academic outcomes: synthesizing findings and future directions.
Hanson, K.L., Winward, J.L., Schweinsburg, A.D., Medina, K.L., Addiction 101 (12), 1688e1689.
Brown, S.A., Tapert, S.F., 2010. Longitudinal study of cognition Kirby, K.N., Petry, N.M., Bickel, W.K., 1999. Heroin addicts have higher
among adolescent marijuana users over three weeks of abstinence. discount rates for delayed rewards than non-drug-using controls.
Addict. Behav. 35 (11), 970e976. J. Exp. Psychol. Gen. 128, 78e87.
Hanson, K.L., Medina, K.L., Padula, C.B., Tapert, S.F., Brown, S.A., Lawrence, A.J., Luty, J., Bogdan, N.A., Sahakian, B.J., Clark, L., 2009.
2011. Impact of adolescent alcohol and drug use on neuropsycho- Impulsivity and response inhibition in alcohol dependence and prob-
logical functioning in young adulthood: 10-year outcomes. J. Child lem gambling. Psychopharmacology (Berl.) 207 (1), 163e172.
Adolesc. Subst. Abus. 20 (2), 135e154. Leonard, K.E., Das Eiden, R., 2002. Cognitive functioning among infants
Harvey, M.A., Sellman, J.D., Porter, R.J., Frampton, C.M., 2007. The of alcoholic fathers. Drug Alcohol Depend. 67, 139e147.
relationship between non-acute adolescent cannabis use and cognition. Li, C.-S.R., Milivojevic, V., Kemp, K., Hong, K., Sinha, R., 2006.
Drug Alcohol Rev. 26 (3), 309e319. Performance monitoring and stop signal inhibition in abstinent patients
Hester, R., Garavan, H., 2004. Executive dysfunction in cocaine addiction: with cocaine dependence. Drug Alcohol Depend. 85, 205e212.
evidence for discordant frontal, cingulate, and cerebellar activity. Lijffijt, M., Kenemans, J.L., Verbaten, M.N., van Engeland, H., 2005.
J. Neurosci. 24 (49), 11017e11022. A meta-analytic review of stopping performance in attention-deficit/
Hill, S.Y., Yuan, H., Locke, J., 1999. Path analysis of P300 amplitude of hyperactivity disorder: deficient inhibitory motor control? J. Abnorm.
individuals from families at high and low risk for developing Psychol. 114 (2), 216e222.
alcoholism. Biol. Psychiatry 45 (3), 346e359. Lisdahl, K.M., Price, J.S., 2012. Increased marijuana use and gender
Hobson, C.W., Scott, S., Rubia, K., 2011. Investigation of cool and hot predict poorer cognitive functioning in adolescents and emerging
executive function in ODD/CD independently of ADHD. J. Child adults. J. Int. Neuropsychol. Soc. 18 (4), 678e688.
Psychol. Psychiatry 52 (10), 1035e1043. Lubman, D.I., Cheetham, A., Yucel, M., 2015. Cannabis and adolescent
Hofmann, W., Schmeichel, B.J., Baddeley, A.D., 2012. Executive brain development. Pharmacol. Ther. 148, 1e16.
functions and self-regulation. Trends Cognit. Sci. 16 (3), 174e180. Luria, A.R., 1966. Higher Cortical Functions in Man, second ed. Basic
Hyman, S.E., Malenka, R.C., Nestler, E.J., 2006. Neural mechanisms of Books, New York.
addiction: the role of reward-related learning and memory. Annu. Rev. Mathias, C.W., Blumenthal, T.D., Dawes, M.A., et al., 2011. Failure to
Neurosci. 29, 565e598. sustain prepulse inhibition in adolescent marijuana users. Drug
Jacobus, J., Tapert, S.F., 2014. Effects of cannabis on the adolescent brain. Alcohol Depend. 116 (1e3), 110e116.
Curr. Pharm. Des. 20 (13), 2186e2193. Medina, K.L., Hanson, K.L., Schweinsburg, A.D., Cohen-Zion, M.,
Jacobus, J., Tapert, S.F., 2013. Neurotoxic effects of alcohol in adoles- Nagel, B.J., Tapert, S.F., 2007. Neuropsychological functioning in
cence. In: NolenHoeksema, S. (Ed.), Annual Review of Clinical adolescent marijuana users: subtle deficits detectable after a month of
Psychology, vol. 9, pp. 703e721. abstinence. J. Int. Neuropsychol. Soc. 13 (5), 807e820.
Johnson, M.W., Bickel, W.K., Baker, F., 2007. Moderate drug use and Meier, M.H., Caspi, A., Danese, A., et al., 2018. Associations between
delay discounting: a comparison of heavy, light, and never smokers. adolescent cannabis use and neuropsychological decline: a longitu-
Exp. Clin. Psychopharmacol. 15 (2), 187e194. dinal co-twin control study. Addiction 113 (2), 257e265.
Johnson, W., Hicks, B.M., McGue, M., Iacono, W.G., 2009. How intel- Middleton, F.A., Strick, P.L., 2001. Cerebellar projections to the prefrontal
ligence and education contribute to substance use: hints from the cortex of the primate. J. Neurosci. 21 (2), 700e712.
Minnesota twin family study. Intelligence 37 (6), 613e624. Miyake, A., Friedman, N.P., Emerson, M.J., Witzki, A.H., Howerter, A.,
Johnston, L.D., O’Malley, P.M., Miech, R.A., Bachman, J.G., Wager, T.D., 2000. The unity and diversity of executive functions and
Schulenberg, J.E., 2016. Monitoring the Future National Survey their contributions to complex “frontal lobe” tasks: a latent variable
Results on Drug Use, 1975e2015: Overview, Key Findings on analysis. Cognit. Psychol. 41 (1), 49e100.
Morgan, M.J., Impallomeni, L.C., Pirona, A., Rogers, R.D., 2006. Resing, W., Drenth, P., 2007. Intelligence: Knowing and Measuring.
Elevated impulsivity and impaired decision-making in abstinent Ec- Publisher Nieuwezijds, Amsterdam.
stasy (MDMA) users compared to polydrug and drug-naive controls. Rioux, C., Castellanos-Ryan, N., Parent, S., Vitaro, F., Tremblay, R.E.,
Neuropsychopharmacology 31 (7), 1562e1573. Séguin, J.R., 2017. Age of cannabis use onset and adult drug abuse
Morin, J.G., Afzali, M.H., Bourque, J., et al., 2019. A population-based symptoms: a prospective study of common risk factors and indirect
analysis of the relationship between substance use and adolescent effects. Can. J. Psychiatry 63 (7), 457e464.
cognitive development. Am. J. Psychiatry. https://doi.org/10.1176/ Rogers, R.D., Everitt, B.J., Baldacchino, A., et al., 1999. Dissociable
appi.ajp.2018.18020202. deficits in the decision-making cognition of chronic amphetamine
Mortensen, L.H., Sorensen, T.I., Gronbaek, M., 2005. Intelligence in abusers, opiate abusers, patients with focal damage to prefrontal
relation to later beverage preference and alcohol intake. Addiction 100 cortex, and tryptophan-depleted normal volunteers: evidence for
(10), 1445e1452. monoaminergic mechanisms. Neuropsychopharmacology 20 (4),
Moss, H.B., Kirisci, L., Gordon, H.W., Tarter, R.E., 1994. 322e339.
A neuropsychologic profile of adolescent alcoholics. Alcohol Clin. Rubino, T., Parolaro, D., 2016. The impact of exposure to cannabinoids in
Exp. Res. 18 (1), 159e163. adolescence: insights from animal models. Biol. Psychiatry 79 (7),
Nigg, J.T., Glass, J.M., Wong, M.M., et al., 2004. Neuropsychological 578e585.
executive functioning in children at elevated risk for alcoholism: Rypma, B., Berger, J.S., D’Esposito, M., 2002. The influence of working-
findings in early adolescence. J. Abnorm. Psychol. 113, 302e314. memory demand and subject performance on prefrontal cortical ac-
Nigg, J.T., Wong, M.M., Martel, M.M., et al., 2006. Poor response inhi- tivity. J. Cognit. Neurosci. 14 (5), 721e731.
bition as a predictor of problem drinking and illicit drug use in ado- Schilt, T., Goudriaan, A.E., Koeter, M.W., van den Brink, W.,
lescents at risk for alcoholism and other substance use disorders. Schmand, B., 2009. Decision making as a predictor of first ecstasy
J. Am. Acad. Child Adolesc. Psychiatry 45, 468e475. use: a prospective study. Psychopharmacology (Berl.) 203 (3),
Norman, A.L., Pulido, C., Squeglia, L.M., Spadoni, A.D., Paulus, M.P., 519e527.
Tapert, S.F., 2011. Neural activation during inhibition predicts initi- Scholes-Balog, K.E., Hemphill, S.A., Evans-Whipp, T.J.,
ation of substance use in adolescence. Drug Alcohol Depend. 119 (3), Toumbourou, J.W., Patton, G.C., 2016. Developmental trajectories of
216e223. adolescent cannabis use and their relationship to young adult social
Odgers, C.L., Caspi, A., Nagin, D.S., et al., 2008. Is it important to prevent and behavioural adjustment: a longitudinal study of Australian youth.
early exposure to drugs and alcohol among adolescents? Psychol. Sci. Addict. Behav. 53, 11e18.
19 (10), 1037e1044. Schulenberg, J.E., Maggs, J.L., 2002. A developmental perspective on
Ohmura, Y., Takahashi, T., Kitamura, N., 2005. Discounting delayed and alcohol use and heavy drinking during adolescence and the transition
probabilistic monetary gains and losses by smokers of cigarettes. to young adulthood. J. Stud. Alcohol Suppl. (14), 54e70.
Psychopharmacology (Berl.) 182 (4), 508e515. Séguin, J.R., Pihl, R.O., Harden, P.W., Tremblay, R.E., Boulerice, B.,
Oosterlaan, J., Sergeant, J.A., 1998. Response inhibition and response re- 1995. Cognitive and neuropsychological characteristics of physically
engagement in attention-deficit/hyperactivity disorder, disruptive, aggressive boys. J. Abnorm. Psychol. 104 (4), 614e624.
anxious and normal children. Behav. Brain Res. 94 (1), 33e43. Séguin, J.R., Nagin, D., Assaad, J.M., Tremblay, R.E., 2004. Cognitive-
Osler, M., Nordentoft, M., Andersen, A.M., 2006. Childhood social neuropsychological function in chronic physical aggression and hy-
environment and risk of drug and alcohol abuse in a cohort of Danish peractivity. J. Abnorm. Psychol. 113 (4), 603e613.
men born in 1953. Am. J. Epidemiol. 163 (7), 654e661. Sher, K., Walitzer, K., Wood, P., Brent, E., 1991. Characteristics of
Ozkaragoz, T., Satz, P., Noble, E.P., 1997. Neuropsychological func- children of alcoholics: putative risk factors, substance use and abuse,
tioning in sons of active alcoholic, recovering alcoholic, and social and psychopathology. J. Abnorm. Psychol. 100 (4), 427e448.
drinking fathers. Alcohol 14 (1), 31e37. Single, E., Rehm, J., Robson, L., Truong, M.V., 2000. The relative risks
Patrick, M.E., Wightman, P., Schoeni, R.F., Schulenberg, J.E., 2012. and etiologic fractions of different causes of death and disease
Socioeconomic status and substance use among young adults: a attributable to alcohol, tobacco and illicit drug use in Canada. CMAJ
comparison across constructs and drugs. J. Stud. Alcohol Drugs 73 162 (12), 1669e1675.
(5), 772e782. Smith, J.L., Mattick, R.P., Jamadar, S.D., Iredale, J.M., 2014. Deficits in
Peeters, M., Monshouwer, K., Janssen, T., Wiers, R.W., behavioural inhibition in substance abuse and addiction: a meta-
Vollebergh, W.A., 2014. Working memory and alcohol use in at-risk analysis. Drug Alcohol Depend. 145, 1e33.
adolescents: a 2-year follow-up. Alcohol Clin. Exp. Res. 38 (4), Sonuga-Barke, E.J., Dalen, L., Remington, B., 2003. Do executive deficits
1176e1183. and delay aversion make independent contributions to preschool
Pennington, B.F., Ozonoff, S., 1996. Executive functions and develop- attention-deficit/hyperactivity disorder symptoms? J. Am. Acad. Child
mental psychopathology. J. Child Psychol. Psychiatry 37, 51e88. Adolesc. Psychiatry 42 (11), 1335e1342.
Petry, N.M., 2001. Substance abuse, pathological gambling, and impul- Spreen, O., Strauss, E., 1998. A Compendium of Neuropsychological
siveness. Drug Alcohol Depend. 63 (1), 29e38. Tests: Administration, Norms, and Commentary, second ed. Oxford
Poon, E., Ellis, D.A., Fitzgerald, H.E., Zucker, R.A., 2000. Intellectual, University Press, New York, NY, US.
cognitive, and academic performance among sons of alcoholics, dur- Squeglia, L.M., Spadoni, A.D., Infante, M.A., Myers, M.G., Tapert, S.F.,
ing the early school years: differences related to subtypes of familial 2009. Initiating moderate to heavy alcohol use predicts changes in
alcoholism. Addiction 24, 1020e1027. neuropsychological functioning for adolescent girls and boys. Psy-
Rachlin, H., 1997. Self and self-control. Ann. N.Y. Acad. Sci. 818, 84e97. chol. Addict. Behav. 23 (4), 715e722.
Squeglia, L.M., Jacobus, J., Nguyen-Louie, T.T., Tapert, S.F., 2014. In- persistent effects selective for spatial working memory. Am. J. Psy-
hibition during early adolescence predicts alcohol and marijuana use chiatry 171 (4), 416e425.
by late adolescence. Neuropsychology 28 (5), 782e790. Vuchinich, R., Simpson, C., 1998. Hyperbolic temporal discounting in
Statistics Team NHS Digital, 2017. Statistics on Drugs Misuse: England, social drinkers and problem drinkers. Exp. Clin. Psychopharmacol. 6,
2017. https://digital.nhs.uk/data-and-information/publications/statisti- 292e305.
cal/statistics-on-drug-misuse/2017. Wetherill, R.R., Squeglia, L.M., Yang, T.T., Tapert, S.F., 2013.
Stuss, D.T., 2011. Functions of the frontal lobes: relation to executive A longitudinal examination of adolescent response inhibition: neural
functions. J. Int. Neuropsychol. Soc. 17 (5), 759e765. differences before and after the initiation of heavy drinking. Psycho-
Takahashi, T., Ohmura, Y., Oono, H., Radford, M., 2009. Alcohol use and pharmacology (Berl.) 230 (4), 663e671.
discounting of delayed and probabilistic gain and loss. Neuro- Whelan, R., Watts, R., Orr, C.A., et al., 2014. Neuropsychosocial profiles
endocrinol. Lett. 30 (6), 749e752. of current and future adolescent alcohol misusers. Nature 512 (7513),
Tapert, S.F., Baratta, M.V., Abrantes, A.M., Brown, S.A., 2002a. Atten- 185e189.
tion dysfunction predicts substance involvement in community Whipple, S.C., Parker, E.S., Noble, E.P., 1988. An atypical neurocognitive
youths. J. Am. Acad. Child Adolesc. Psychiatry 41 (6). profile in alcoholic fathers and their sons. J. Stud. Alcohol 49 (3),
Tapert, S.F., Granholm, E., Leedy, N.G., Brown, S.A., 2002b. Substance 240e244.
use and withdrawal: neuropsychological functioning over 8 years in White, J., Batty, G.D., 2012. Intelligence across childhood in relation to
youth. J. Int. Neuropsychol. Soc. 8 (7), 873e883. illegal drug use in adulthood: 1970 British Cohort Study.
Tarter, R.E., Jacob, T., Bremer, D.L., 1989. Specific cognitive impairment in J. Epidemiol. Community Health 66 (9), 767e774.
sons of early onset alcoholics. Alcohol Clin. Exp. Res. 13 (6), 786e789. White, J.W., Gale, C.R., Batty, G.D., 2012. Intelligence quotient in
Tarter, R., Kirisci, L., Habeych, M., Reynolds, M., 2004. Neurobehavior childhood and the risk of illegal drug use in middle-age: the 1958
disinhibition in childhood predisposes boys to substance use disorder National Child Development Survey. Ann. Epidemiol. 22 (9),
by young adulthood: direct and mediated etiologic pathways. Drug 654e657.
Alcohol 73, 121e132. Wiers, R.W., Gunning, B.W., Sergeant, J.A., 1998. Is a mild deficit in exec-
Trim, R.S., Chassin, L., 2008. Neighborhood socioeconomic status effects utive functions in boys related to childhood ADHD or to parental multi-
on adolescent alcohol outcomes using growth models: exploring the generational alcoholism. J. Abnorm. Child Psychol. 26, 415e430.
role of parental alcoholism. J. Stud. Alcohol Drugs 69 (5), 639e648. Wiers, R.W., Bartholow, B.D., van den Wildenberg, E., et al., 2007.
Uekermann, J., Daum, I., Schlebusch, P., Wiebel, B., Trenckmann, U., Automatic and controlled processes and the development of addictive
2003. Depression and cognitive functioning in alcoholism. Addiction behaviors in adolescents: a review and a model. Pharmacol. Biochem.
98 (11), 1521e1529. Behav. 86 (2), 263e283.
United Nations, 2018. World Drug Report 2018. Geneva. Yechiam, E., Stout, J.C., Busemeyer, J.R., Rock, S.L., Finn, P.R., 2005. In-
Vassileva, J., Conrod, P.J., 2018. Impulsivities and addictions: a multidi- dividual differences in the response to forgone payoffs: an examination of
mensional integrative framework informing assessment and novel high functioning drug abusers. J. Behav. Decis. Mak. 18 (2), 97e110.
interventions for substance use disorders. Phil. Trans. R. Soc. B 374 Young, S.E., Friedman, N.P., Miyake, A., et al., 2009. Behavioral disin-
(1766). https://doi.org/10.1098/rstb.2018.0137. hibition: liability for externalizing spectrum disorders and its genetic
Verbruggen, F., Logan, G.D., 2009. Models of response inhibition in the and environmental relation to response inhibition across adolescence.
stop-signal and stop-change paradigms. Neurosci. Biobehav. Rev. 33 J. Abnorm. Psychol. 118 (1), 117e130.
(5), 647e661. Zelazo, P.D., Craik, F.I., Booth, L., 2004. Executive function across the
Verrico, C.D., Gu, H., Peterson, M.L., Sampson, A.R., Lewis, D.A., 2014. life span. Acta Psychol. 115 (2e3), 167e183.
Repeated D9-tetrahydrocannabinol exposure in adolescent monkeys:
Chapter 8
Neuropsychological deficits in alcohol

use disorder: impact on treatment
Angéline Maillard, Nicolas Cabé, Fausto Viader and Anne Lise Pitel
Normandie Univ, UNICAEN, PSL Université de Paris, EPHE, INSERM, U1077, CHU de Caen, GIP Cyceron, Neuropsychologie et Imagerie de la
Mémoire Humaine, Caen, France
Introduction balance) but also with a variety of cognitive disorders.

After alcohol withdrawal, 50%e80% of the recently
Alcohol use disorder (AUD) is defined as a chronic, detoxified patients exhibit neuropsychological impairments
relapsing disease of the brain, which is characterized by a (Ihara et al., 2000; Oscar-Berman et al., 2014 for review).
high rate of relapse (Koob and Volkow, 2016). Acute The DSM-5 classification introduced a diagnosis of
alcohol-induced intoxication transiently alters the brain “alcohol-induced neurocognitive disorders” to describe
functioning while ethanol is still present in the blood, these neuropsychological deficits observed in AUD patients
whereas the effects of chronic alcohol misuse affect the even in absence of any neurological complications.
brain in enduring ways even after withdrawals. In 2013, the Alcohol-induced neurocognitive impairments are also
fifth edition of the Diagnostic and Statistical Manual of considered along a continuum of severity from mild to
Mental Disorders (DSM-5, American Psychiatric Associ- major deficits, comparable with those observed in patients
ation, 2013) has proposed to consider excessive alcohol with Korsakoff’s syndrome (KS), depending on how they
drinking no more as a categorical phenotype (dependence interfere with independence in everyday activities. Despite
vs. abuse, DSM-IV, American Psychiatric Association, their prevalence and their potential harmful effects on
2000) but as an AUD lying along a continuum of severity, social and occupational integration, as well as rehabilita-
from mild to moderate to severe according to the number of tion, these cognitive impairments remain frequently
criteria (out of 11) presented by the patient. undiagnosed because neuropsychological abilities are not
AUD is characterized by a 12-month prevalence of systematically assessed in AUD patients.
13.9% in the worldwide population, whereas lifetime In this chapter, we will describe the cognitive impair-
prevalence is 29.1% (Grant et al., 2015). Every year, 3.3 ments and brain abnormalities in AUD patients and the
million deaths are partially attributable to excessive alcohol reversibility of these deficits with abstinence. We will then
consumption. Life expectancy is reduced by 20 years for an focus on the clinical implications of the cognitive deficits.
alcohol-dependent person (John et al., 2013). Indeed, And finally, we will provide some recommendations for
alcohol is the direct cause of more than 60 diseases from clinicians and researchers who work in the field of alcohol
fetal alcohol syndrome to hepatic cirrhosis and psychotic addiction.
manifestations. In addition, alcohol contributes to the
development and the course of more than 200 diseases such
as cancers, neuropsychiatric conditions, cardiovascular or Altered brain structure and function in
neurological diseases, infectious diseases, etc. (World
alcohol use disorder
Health Organisation, 2014). For example, Schwarzinger
et al. (2018) indicated that AUD is a major risk factor for During the last decades, many studies have shown that
early onset of all types of dementia. Even in absence of chronic alcohol consumption results in brain damage and
ostensible alcohol-related disease, chronic alcohol associated heterogeneous cognitive deficits (Pitel et al.,
consumption can result in an invisible disability: AUD is 2011), including impairments of executive functions,
not only associated with motor dysfunctions (gait and memory, visuospatial abilities, difficulties in emotional

processing, and theory of mind (ToM) abilities (Le Berre frontal cortex. The cerebellum seems essential to the neural
et al., 2017 for review). circuitry subserving cognition, particularly executive
Alcohol-related brain damage is characterized by a function and working memory. The cerebellum and the
reduction of brain volume, an enlargement of the ventricles frontal cortex are connected through the pons (feedforward
and sulci, and an increased cerebrospinal fluid quantity. loop) and thalamus (feedback loop) within the FCC
Several brain regions, including the cerebellum, corpus (Ritz et al., 2016b). The different nodes of the FCC are
callosum, hippocampus, thalamus, amygdala, and frontal affected by heavy and chronic alcohol consumption
cortices, are especially vulnerable (Oscar-Berman and (Fig. 8.1). MRI studies have shown atrophy in AUD
Marinkovic, 2003; Sullivan, 2003). Thus, two brain patients compared with controls in the cerebellum (Antunez
networks seem particularly affected in AUD patients: the et al., 1998; Sullivan, 2003), pons (Chanraud et al., 2009b;
circuit of Papez (PC) and the frontocerebellar circuit (FCC), Sullivan, 2003) and thalamus (Le Berre et al., 2014; Pitel
which share the thalamus as a key node (Fig. 8.1) et al., 2012). These regional volumes have been related to
(Pitel et al., 2015). executive abilities in AUD patients (Chanraud et al., 2007;
Sullivan, 2003; Zahr et al., 2010). Regarding white matter
Attention, working memory, and executive volume, brain abnormalities have been found in AUD
patients in the cerebellum and midbrain (Mechtcheriakov
functions
et al., 2007; Pitel et al., 2012; Sullivan, 2003). An alteration
It is now well-known that attention, working memory, and of the white matter tracts within the midbrain and pons,
executive functions rely notably on the prefrontal cortex. characterized by 18% fewer fibers in AUD than in healthy
Indeed, patients with a frontal lobe lesion frequently have controls, indicates a disconnection within the FCC (Chan-
difficulties in behavioral control and regulation, potentially raud et al., 2009b). The authors also found a correlation
with harmful consequences in their daily life. Postmortem between these altered white matter fibers integrity and
analyses have revealed decreased neuronal density in the impaired results on a flexibility task (part B of Trail Making
frontal cortex of AUD patients (Harper and Matsumoto, Test). Brain alterations in nodes and connections of the
2005). Moreover, in vivo studies revealed alcohol-related FCC seem to be better predictors of executive dysfunction
gray matter volume deficits (Chanraud et al., 2007; Pitel than damage of the prefrontal regions solely (Chanraud
et al., 2012), functional abnormalities during a spatial et al., 2007; Sullivan, 2003).
working memory task (Tapert et al., 2001), decreased Attention is defined by Mesulam (1999) as “a prefer-
cerebral blood flow (Gansler et al., 2000), and lower ential allocation of limited processing resources to events
glucose metabolism (Dao-Castellana et al., 1998; Ritz et al., that have become behaviorally relevant.” Usually, three
2016b) in the frontal cortices. main higher order attentional processes are distinguished:
Not only is the frontal cortex implicated in executive (a) selective attention, the ability to focus cognitive set
functioning but also other brain regions connected to the on relevant information and inhibit distracting stimuli;
Fronto-cerebellar circuit Papez’s circuit
FRONTAL CINGULATE
CORTEX GYRUS
HIPPOCAMPAL
PONS THALAMUS
FORMATION
MAMMILLARY
CEREBELLUM
BODIES
FIGURE 8.1 The two brain circuits mainly affected in alcohol use disorder (AUD). From Pitel, A.L., Segobin, S.H., Ritz, L., Eustache, F., Beaunieux,
H., 2015. Thalamic abnormalities are a cardinal feature of alcohol-related brain dysfunction. Neurosci. Biobehav. Rev. 54, 38e45. https://doi.org/10.
1016/j.neubiorev.2014.07.023.
Neuropsychological deficits in alcohol use disorder: impact on treatment Chapter | 8 105
(b) sustained attention, the aptitude to maintain a consistent studies have shown that AUD patients perform worse than
response for a long time; and (c) divided attention, the healthy controls on part B of Trail Making Test, which
capacity to treat simultaneously two tasks. Selective and assesses set shifting and mental flexibility (Ihara et al.,
sustained attention seems to be preserved in AUD patients, 2000; Loeber et al., 2009; Moriyama et al., 2002; Noël
while divided attention abilities are impaired (Tedstone and et al., 2001). The Wisconsin Card Sorting Test is frequently
Coyle, 2004). Regarding processing speed, sometimes used to evaluate executive functions in AUD patients.
considered as reflecting low-level attention, results are It indicates that recently abstinent patients present an
more heterogeneous. Noël et al. (2001) reported that inability to conceptualize, be flexible, and consider
recently detoxified AUD patients had preserved perfor- feedback information from the experimenter (Chanraud
mance on parts A of the Trail Making Test and Hayling et al., 2007; Ratti et al., 2002; Salgado et al., 2009). The
Test, or color-naming part of the Stroop Task, and number of categories found and error rate are especially
presented normal latency time on the Tower of London test. sensitive to the effects of chronic alcohol consumption
On the contrary, Nowakowska-Domagała et al. (2017) (Stephan et al., 2017). AUD patients also present a deficit
found that AUD patients were slower than healthy controls of inhibition when evaluated with the Stroop Task (Konrad
on parts A of the Trail Making test. et al., 2012; Pitel et al., 2007a; Schulte et al., 2012;
Working memory is a short-term memory system that Tedstone and Coyle, 2004) and the part B of the Hayling
allows temporary storage and manipulation of the infor- Test (Noël et al., 2001). Stephan et al. (2017), in their
mation necessary for complex cognitive tasks such as lan- metaanalyses, indicated that the Hayling Test is very
guage comprehension, learning, and reasoning. Working sensitive to the effects of alcohol. AUD patients also
memory, which requires the simultaneous storage and presented organization difficulties and deficits in self-
processing of information, is composed of three slave generation of strategies as revealed by verbal fluency and
systems under the control of a central executive (Baddeley, Ruff Figural Fluency Tests (Oscar-Berman et al., 2009).
2000; Baddeley and Hitch, 1974). The slave systems are Updating abilities, assessed with n-back tasks, are impaired
short-term storage systems comprising the phonological in AUD patients (Pitel et al., 2007a, 2009). The use of the
loop, which processes verbal information, the visuospatial Tower of London test suggests that planning abilities are
sketchpad, which processes visuospatial information, and impaired as well (Goudriaan et al., 2006), but such finding
the episodic buffer, which links information across domains could also be related to the deficits of flexibility and inhi-
and maintains such multimodal information. The storage of bition. In impulsivity tests such as in a go/no-go task,
both verbal and nonverbal components can be impaired in AUD patients responded too quickly and did not inhibit
AUD patients (Beatty et al., 1996; Kopera et al., 2012; Pitel responses when a stop signal appeared (Pandey et al.,
et al., 2007b), although the nonverbal working memory 2012). Executive functions are also impaired when exam-
component is typically observed as more severely affected ined with the Behavioral Assessment of Dysexecutive
than the verbal one (Sullivan et al., 2000). The episodic Syndrome (BADS), a battery of executive tests designed to
buffer was also found to be impaired in AUD (Pitel et al., have an ecologic validity (Ihara et al., 2000). In this battery,
2007b). Finally, the central executive, which is regarded as the temporal judgment and the modified six elements
being similar to executive functions, is classically described subtests seemed particularly affected.
as compromised in AUD patients. All together, these data suggest that chronic and
Executive functions are cognitive abilities that control excessive alcohol consumption results in executive
and regulate the cognitive system to coordinate thoughts dysfunction. Despite the variety of executive deficits
and actions toward a goal. They enable us to face complex observed in AUD, several studies (Kamarajan et al., 2005;
and nonroutine situations (Alvarez and Emory, 2006). Noël et al., 2007) suggested that an impairment of inhibi-
These functions permit a behavioral adaptation to envi- tion could be a central feature in the neuropsychological
ronmental changes. Executive functions are not a unitary profile of the patients. In accordance, Brion et al. (2017)
construct, they are a multifactorial system composed of investigated whether the impurity and multidetermined
several components, presenting specific characteristics, nature of the executive tasks previously used could explain
which are interacting with each other (Hull et al., 2008; the variety of the deficits observed. They explored the three
Jurado and Rosselli, 2007). Executive functions include main executive components (shifting of mental sets,
mental flexibility, abstraction, planning, problem-solving, monitoring and updating of working memory representa-
shifting of mental states, monitoring and updating of tions, and inhibition of prepotent responses) described by
working memory representations, organization, rules Miyake et al. (2000) and conducted specific tasks to
deduction, and categorization. selectively evaluate these components in AUD patients. For
While two-thirds of AUD patients exhibit executive each task, they used accuracy and reaction time indexes as
function impairments (Ihara et al., 2000), there is hetero- dependent variables, and they found that reaction time was
geneity in the profile of executive dysfunction. Several relatively preserved, whereas AUD patients were
significantly less accurate than the healthy control partici- lower than healthy controls on the Free and Cued Selective
pants. They also found a moderate deficit of inhibition, Reminding Test (Pitel et al., 2007a), they seemed to
while shifting and updating were more severely impaired. improve their performance at the same rate. They can
The authors concluded that alcohol-related executive indeed show evidence of some learning over trials
deficits did not include only an inhibition deficit but also (Ryan and Butters, 1980). Pitel et al. (2007a) investigated
other executive alterations. episodic memory in accordance with the current and
comprehensive definition of this skill: encoding, storage,
Episodic memory and retrieval of factual information located in a precise
space-time context associated with autonoetic recollection.
Mnemonic functions and notably episodic memory mainly AUD patients showed impairment on a recognition task test
rely on PC. PC involves gray matter nodes of the limbic after a spontaneous encoding as well as on a free recall task
system including the hippocampus, thalamus, mammillary after a deep encoding. These results suggest an impairment
bodies, and cingulate cortex, interconnected by bundles of of both encoding and retrieval abilities in AUD. However,
white matter fibers (Fig. 8.1). The anterior thalamus authors did not find any storage impairment in AUD
receives inputs from the mammillary bodies via the patients, in accordance with a previous research (Sherer,
mammillothalamic tract and projects to the cingulate cortex 1992). Moreover, the spatiotemporal context of encoding
via the internal capsule. Then, the cingulum bundle was also altered, with a deficit in spatial and temporal
connects the cingulate cortex to the entorhinal cortex and contexts (Pitel et al., 2007a; Salmon et al., 1986). Patients
hippocampus, which projects to the mammillary bodies tended not to recall complete episodes, i.e., correct factual
through the fornix. Studies in AUD patients reported information associated with the correct spatiotemporal
volume loss in mammillary bodies (Pitel et al., 2012; context of encoding, suggesting incomplete episodic
Sheedy et al., 1999; Sullivan et al., 1999), hippocampus memories. AUD patients also present difficulties identi-
(Sullivan et al., 1995), thalamus (Cardenas et al., 2007; fying the source of remembered information (Schwartz
Chanraud et al., 2007), and cingulate cortex (Pitel et al., et al., 2002) and a deficit of autonoetic consciousness
2012) but failed to show any correlation between gray (Pitel et al., 2007a).
matter macrostructural abnormalities and episodic memory Noel et al. (2012) indicated that patients perform better
impairments. Rather, episodic memory disorder may be on cued-recall and recognition testing conditions, which are
associated with alteration of gray matter microstructure in less dependent on strategic retrieval operations. In AUD
the medial temporal lobes (Chanraud et al., 2009a) or patients, impaired learning abilities could be related to
damage of white matter bundles and tracts, in particular, the executive dysfunctions and notably impoverished genera-
cingulum and the fornix (Pfefferbaum et al., 2009; Schulte tion of spontaneous strategies. However, another study
et al., 2010; Trivedi et al., 2013), leading to a disruption of found very little relationship between episodic memory
the PC. Segobin et al. (2015) found lower episodic memory performance and executive results, and suggested rather a
performance in AUD patients with the most severe alter- genuine episodic memory impairment that could not be
ations of the microstructure within the cingulum and fornix. interpreted solely as the consequence of executive
Episodic memory is currently described as the memory dysfunctions (Pitel et al., 2007a).
system in charge of the encoding, storage, and retrieval of Another component of episodic memory is prospective
personally experienced events, associated with a precise memory, which is the ability of remembering to carry out
spatial and temporal context of encoding. Episodic memory an intended action at some future point in time (Brandi-
allows the conscious recollection of personal events from monte et al., 1996). The Prospective Memory Question-
one’s past and the mental projection of anticipated events naire, based on self-report measures, revealed prospective
into one’s subjective future (Wheeler et al., 1997). Recol- memory complaints in AUD (Heffernan et al., 2002; Ling
lection of episodic events requires autonoetic awareness, et al., 2003), suggesting that prospective memory may be
which is the impression of reexperiencing or reliving the impaired in AUD patients (Heffernan, 2008 for a review).
past and mentally traveling back in subjective time The severity of the complaints was associated with the total
(Tulving, 2001). Episodic memory is not only hierar- amount of alcohol consumption (Ling et al., 2003).
chically the most sophisticated memory system but also the Moreover, patients who reported prospective memory
most sensitive to pathology, trauma, and toxicity. difficulties also complained about impaired executive
Most studies investigated episodic memory in AUD functioning (Heffernan et al., 2005). They did not appear to
with classical learning tasks such as learning a list of words use sufficient internal or external memory strategies to
(Sherer, 1992), faceename associations (Beatty et al., compensate for prospective memory deficits (Heffernan
1995), or delayed recall of a complex figure (Sullivan et al., et al., 2002).
1992). Learning abilities were impaired for both verbal and Autobiographical memory (AM) refers to remote
nonverbal information. Although AUD patients performed memory, comprising the specific personal events (episodic
component) as well as general knowledge about one-self capable of recognizing the correct word while they actually
(semantic component) (Conway, 2001). Compared with failed to do so. An explanation of this metamemory deficit
healthy controls, AUD patients recalled specific memories is that AUD patients fail to update information about their
less frequently and general memories more frequently, level of memory and, as a consequence, assess their
which is a phenomenon of overgenerality (D’Argembeau memory skills regarding earlier functioning in life
et al., 2006). However, when a specific past event was (Le Berre and Sullivan, 2016). This metamemory impair-
provided, AUD patients subjectively experienced as many ment may be considered as a mild form of anosognosia, a
sensory and contextual details as controls. AUD patients lack of insight of the disease frequently observed in KS.
may encode and/or access fewer episodic memories than
controls, but when they do, the richness of the memories
Semantic memory
seems qualitatively equivalent to that of controls. Nandrino
et al. (2016) compared semantic and episodic dimensions of Semantic memory is sustained by relatively preserved
AM in AUD patients after a short-term (STA, nearly lateral temporal lobes in AUD. Semantic memory refers to
5 weeks) and long-term (LTA, at least 6 months) the memory of meaning, understanding, general knowledge
abstinence and healthy controls. On the overall, the two about the world, and other concept-based knowledge
groups of AUD patients were especially impaired for recall unrelated to specific experiences. The level of conscious-
of both episodic and semantic recent events and knowl- ness associated with semantic memory is noetic (giving rise
edge, corresponding to the drinking period. However, no to feelings of familiarity or knowing) because it is inde-
significant differences were observed between the AUD pendent of encoding context (Tulving, 1985, 2001). Fama
and control groups for childhood semantic events. et al. (2011) studied remote semantic memory processes in
Concerning episodic events from childhood, STA provided three clinical groups: AUD group, patients infected with the
fewer memories than healthy controls and LTA. First, these human immunodeficiency virus (HIV), and patients co-
results suggest encoding alteration during the drinking morbid for both conditions (AUD þ HIV group), compared
period. Second, the semantic component of AM may be with healthy controls. AUD and HIV groups exhibited
less affected by heavy chronic drinking than the episodic performance below healthy controls, but these differences
component. Third, the preservation of episodic memories were not statistically significant, whereas AUD þ HIV
from childhood may be preserved in LTA because of group appeared impaired compared with healthy controls.
cognitive and brain recovery with sobriety. Although remote semantic memory has been found
Although AUD patients are impaired on most of the preserved in AUD patients (Fama et al., 2011), recently
episodic memory components, they seem to present a detoxified patients may experience difficulties to acquire
limited awareness of those deficits. AUD patients may thus new semantic information. Pitel et al. (2007b) studied the
exhibit a deficit of metamemory, which refers to personal ability to acquire new semantic concepts including, for each
knowledge about one’s own memory abilities (Flavell, concept, a label, a superordinate category, and three
1971). Metamemory is related to monitoring and control features associated with a picture. The learning protocol
processes. Indeed, to improve performance during a comprised eight daily sessions. AUD patients were able to
memory task, it is necessary to adjust strategies according acquire the category and features of the semantic concepts,
to this one. Monitoring concerns the capacity to assess albeit slowly, but they presented impaired label learning.
future performance before a memory task and the skills to AUD patients invoked different and inefficient cognitive
evaluate performance retrospectively (Nelson and Narens, strategies to attempt to compensate for impaired episodic
1990). The most frequently used measure of metamemory and working memory. The use of errorless learning may be
is the feeling-of-knowing (FOK) (Hart, 1965), character- relevant for AUD patients with cognitive deficits to learn
ized by the ability to accurately predict the future perfor- new complex semantic knowledge, and more particularly,
mance on tasks requiring recognition of newly learned new labels (Pitel et al., 2010). Moreover, information
information. The FOK judgment is recorded on a Likert- acquired with errorless learning was flexible, i.e., it may be
type scale (from 0% “definitely will not recall” to 100% generalized and or transferred to other situations. This
“definitely will recall”). A FOK accuracy index is calcu- learning condition allows preventing that patients repeat
lated to evaluate the agreement between predictions of the their errors in the course of the acquisition, learning them
future recognition performance and real recognition instead of the correct answers, and leading to learning
performance (GoodmaneKruskal Gamma statistic; Nelson, impairments.
1984). Le Berre et al. (2010) found that AUD patients were
impaired in this task as they obtained a FOK index Procedural memory
significantly lower than that of the control group (not better
than chance level). Patients had a tendency to overestimate Hubert et al. (2007) highlighted a specific brain network
their memory skills: they predicted that they would be involved in procedural learning and memory. Procedural
learning is a dynamic process involving different phases of human memory because it is through perceptual memory
(cognitive, association, and autonomous) and resulting in that information is subsequently and progressively trans-
the automation of the procedure that underlie motor, ferred into the different representation memory systems.
visuospatial, or cognitive skills (Anderson, 1992). During This memory component depends on sensory modalities,
the cognitive phase, brain structures such as the prefrontal notably on sight. In this vein, perceptual memory is linked
cortex, anterior cingulate cortex, right angular cortex, and to three visuospatial abilities: visuoperceptual skills, which
posterior cerebellar regions are activated. The associative concern abilities to classify stimuli such as objects or faces;
phase is mainly underlined by caudate nucleus and occipital visuospatial skills, which include localization in space,
regions. The posterior brain is also found activated during navigation, and the conceptualization of the distance; and
the autonomous phase with the anterior cerebellum (Hubert visuoconstruction, which is the ability to organize elements
et al., 2007). into correct spatial relationships.
Although remote procedural memory seems to be In AUD, several structural brain abnormalities have
preserved, the acquisition of a new cognitive procedure been related to visuospatial deficits. A decreased volume in
may be affected by chronic alcohol consumption. Pitel et al. the parietal lobes has been observed (Chanraud et al., 2007;
(2007b) tested procedural learning with the Tower of Fein et al., 2002) and associated with poor performance in
Toronto task (TT task) during four daily sessions. AUD spatial processing (Fein et al., 2009). However, cerebellar
patients and healthy controls performed 10 trials in each hemispheric white matter may be a better predictor of
learning sessions (40 trials in total). The TT task consists of visuospatial abilities than parietal lobes volume (Sullivan,
a rectangular base with three pegs and four colored disks on 2003).
the leftmost peg. Participants are required to rebuild the Impairments in perceptual abilities have been reported
initial disk configuration on the rightmost peg, following in AUD patients by many studies using the embedded
some rules. Early in abstinence, AUD patients were slower figures test (Sullivan et al., 2002; Fama et al., 2004), mental
than controls and made more moves to achieve the task, but rotation test (Beatty et al., 1996), block design subtest from
they managed to reach the same level of performance as Weschler Adult Intelligence Scale (Beatty et al., 1996;
controls at the end of the 40 trials (Pitel et al., 2007b). The Oscar-Berman et al., 2009; Sullivan et al., 2002), and
between-group difference regarding the learning dynamics ReyeOsterrieth Complex Figure Test (Beatty et al., 1996;
may be related to the fact that cognitive procedural learning Sullivan et al., 2002). All these tasks are complex, they
requires episodic memory and working memory in the require different visuospatial components and the integrity
initial stage of learning (Beaunieux et al., 2006). Alcohol- of other cognitive functions. For example, poor perfor-
related episodic and working memory deficits may have mance in ReyeOsterrieth Complex Figure copy could be
prevented patients from completing the cognitive and explained by a deficit in visuoperceptual skills, visuocon-
associative stages at the same pace as controls, making it struction, or executive functioning. When using an implicit
difficult to automate the new cognitive procedure. An MRI perceptual learning paradigm (assessed with a picture
investigation reinforced this hypothesis as it indicated that fragment completion task, for example), AUD patients
procedural learning performance correlated with gray were impaired on the primary components of visuo-
matter volume of the angular gyrus and caudate nucleus, perception and explicit memory for visuospatial stimuli but
not only during the first learning trials but also after 40 obtained preserved results on the perceptual learning task
trials of the TT task (Ritz et al., 2014). Another explanation (Fama et al., 2004). These findings suggest that visuospatial
of these altered cognitive procedural learning abilities may perception is impaired in AUD but patients can take
be related to the visuospatial deficits frequently reported in advantage of prior exposure to enhance performance based
AUD (Beatty et al., 1996; Fama et al., 2004). on preserved implicit memory. Although AUD patients
performed at the same level as healthy controls on the
Perceptive memory and visuospatial abilities perceptual learning task, groups used different strategies:
visuoperceptual abilities predicted perceptual learning
There is no specific brain region involved in perceptive performance in the control group, whereas in the AUD
memory but several neural networks including sensory group, performance was predicted by executive abilities.
areas. Perceptive memory is in charge of the encoding and
the storage of perceptual features of physical objects. This
memory system includes both conscious and nonconscious Emotional processes and theory of mind
processing of sensoriperceptual information (Tulving and
Emotions
Schacter, 1990). Perceptual memory is assumed to be
involved in perceptual priming, which refers to the effect in The amygdala plays a key role in emotional regulation and
which exposure to the form of a stimulus influences a behavioral control (McBride, 2002 for review). Wrase et al.
response to a later stimulus. It can be considered as the root (2002) found a reduction of gray matter volume in the
limbic system of AUD patients, notably in amygdala. ToM is defined as the capacity to infer mental states
In addition, Marinkovic et al. (2009) identified abnormal from others’ social signals to predict their behaviors,
activation of the amygdala and hippocampus during a task desires, intentions, and beliefs. Several studies have
of facial emotions identification in AUD. reported ToM impairments in AUD patients (Bosco et al.,
Chronic and heavy alcohol consumption alters 2014; Maurage et al., 2015; Onuoha et al., 2016; Thoma
emotional processing. AUD patients present a tendency to et al., 2013). Maurage et al. (2015) specified that 50% of
alexithymia, i.e., they have difficulties to experiment, the AUD patients may present ToM impairments, and in
characterize, and express their own internal emotional state most cases, the deficit concerns the tracking of other
(Maurage et al., 2017; Uzun et al., 2003). They also exhibit people’s mental states. Maurage et al. (2016) highlighted a
deficits in detection and interpretation of others’ emotions dissociation between impaired affective ToM (i.e., the
(de Timary et al., 2010). Several studies have shown that ability to understand and experience others’ feelings and
AUD patients do not succeed in identifying emotions of emotions) and relatively preserved cognitive ToM (i.e., the
faces (Kornreich et al., 2002; Philippot et al., 1999), ability to identify others’ intentions and thoughts).
prosody (Brion et al., 2018; Maurage et al., 2009; Monnot Empathy is defined as the ability to understand and
et al., 2001), and body postures (Maurage et al., 2009). share others’ feelings and emotions. AUD patients may
Moreover, AUD patients do not seem aware of their present a dissociation between an impaired emotional
difficulties in interpreting facial emotions (Philippot et al., component of empathy (capacity to feel other people’s
1999). D’Hondt et al. (2015) indicates that AUD patients emotions) and a preserved cognitive empathy (capacity to
would need higher intensity in emotion expressing to make understand other people’s mental states such as though and
efficient identification. Comorbidity between AUD and opinions) (Maurage et al., 2011). Overall, deficits of social
mood disorders is well established. Moreover, most AUD cognition observed in AUD patients (Kornreich et al.,
patients exhibit heightened sensitivity to negative emotions 2002; Maurage et al., 2017) could disturb interpersonal
during early withdrawal, especially when they present relationships within the context of a vicious cycle with
anxious or depressed symptoms (Schuckit, 2006). alcohol consumption as a coping mechanism to overcome
Maurage et al. (2017) conducted a cluster analysis in social isolation.
AUD patients, taking into consideration two types of highly
prevalent socioemotional difficulties: alexithymia (three
Reversibility of cognitive deficits and
subscales’ scores of Toronto Alexithymia Scale-II) and
interpersonal problems (six subscales’ scores of the cerebral damage with abstinence
Inventory of Interpersonal Problem). They identified five Many studies provided evidence of the brain and cognitive
distinct subgroups of patients showing different specific recovery after drinking cessation (Mulhauser et al., 2018;
patterns of emotional and interpersonal difficulties. These Rosenbloom et al., 2004; van Eijk et al., 2013) even in the
findings are in line with the idea that cognitive deficits absence of any stimulation. Goldman (1990) refers to time-
observed in AUD are heterogeneous and suggest that dependent recovery to describe this phenomenon; the
classical group comparisons can be misleading and should phrase “spontaneous recovery” is also used. Recovery of
be completed by subgroup explorations. the brain structure and function has been reported in
cross-sectional investigations that compare groups of
Social cognition patients with different length of sobriety or in longitudinal
studies of a single AUD group to assess within-subject
Social cognition concerns the cognitive processes, such as changes in the course of abstinence.
emotion decoding, ToM, and empathy, that enable
individuals to take advantage of being part of a social group
(Frith, 2008). Several regions, including notably the pre- Brain recovery
frontal cortex, anterior cingulate cortex, the temporal pole, Improvement of brain structural integrity (Stavro et al.,
and the striatum, have been found to be involved in ToM. 2013) is related to the length of abstinence and varies
Abu-Akel and Shamay-Tsoory (2011) presented a model in according to the cerebral regions. After a long abstinence
which these cortical and subcortical regions are subdivided period (4 years of sobriety), the blood flow in the frontal
and functionally organized into networks that subserve the lobe seems to increase and even return to normal (Gansler
ability to represent cognitive and affective mental states to et al., 2000). One year of abstinence is also associated with
both self and others. A few studies have examined brain improved fractional anisotropy of the corpus callosum
dysfunction related to ToM. They report that in AUD, (Alhassoon et al., 2012). Cardenas et al. (2007) highlighted
social cognition deficits are related to prefrontal (Ueker- that recovery of temporal lobes, cerebellum, and anterior
mann and Daum, 2008) and temporoparietal dysfunction cingulate among others brain structures was more limited in
(Samson, 2009). relapser than in abstainer AUD patients at 8-month
follow-up. A short period of sobriety (1 month) has been Episodic memory

found to result in increased white matter volume and
Generally, episodic memory deficits are no longer observed
decreased cerebrospinal fluid (Agartz et al., 2003). Inter-
following prolonged abstinence (Fein et al., 2006; Reed
estingly, even a short-term period without alcohol induces
et al., 1992; Rourke and Grant, 1999). Episodic memory
noticeable changes in gray matter volume (20 days in
recovery may thus occur within a 6-month abstinence
Pfefferbaum et al., 1995; 2 weeks in van Eijk et al., 2013).
period (Bell et al., 2016) with a potential normalization of
More recently, Segobin et al. (2014) evaluated brain
memory performance (Pitel et al., 2009). There is also
recovery within 6 months with an original and novel
evidence of episodic memory improvements early in
method. In this longitudinal study, patients examined at
abstinence (3 weeks, Manning et al., 2008; 10 days,
follow-up were not classified into relapsers versus
Mulhauser et al., 2018) possibly through the reduction of
abstainers. The authors analyzed the relationship between
lateral ventricle volume (Rosenbloom et al., 2007).
regional brain changes and the total amount of alcohol
consumed over the 6-month follow-up. They found that
interim drinking correlated with the volume of different Executive functions
brain regions (cerebellum, striatum, and cingulate gyrus Fein et al. (2006) found that, after several years of sobriety,
notably): heavy interim drinking was related to lower inhibition, abstraction, flexibility, updating, and working
recovery. In addition, the degree of recovery was not the memory results were similar to those of healthy controls.
same for the entire brain, indicating that the dynamics of Six months of sobriety may be long enough to observe a
neural plasticity may be regionally specific. Interestingly, return to normal for inhibition, flexibility, and updating
the findings also revealed that very limited alcohol abilities (Loeber et al., 2010; Pitel et al., 2009). In the study
consumption (<10 g of pure alcohol per day) between conducted by Pitel et al. (2009), patients were considered as
baseline and follow-up did not prevent brain recovery. “relapsers” as soon as they had a single drink during the
6-month follow-up. “Relapsers” exhibited more severe
flexibility deficits at follow-up than early in abstinence,
Neuropsychological recovery
suggesting deterioration of executive abilities with even
Apparent discrepancies limited interim drinking. Regarding STA, there are
discrepancies in the findings. Several studies found
In accordance with the brain recovery observed with improvements of executive abilities during the first month
sobriety, neuropsychological deficits described early in of abstinence (Kish et al., 1980; Mann et al., 1999;
abstinence can also be reversible. According to Fein et al. Manning et al., 2008; Petit et al., 2017) except for inhibi-
(2006), AUD patients can even perform as well as healthy tion and for flexibility and planning. However, according to
controls after 7 years of sobriety, in agreement with Stavro Mulhauser et al. (2018), executive dysfunctions persist after
et al. (2013) who found that AUD patients sober for up to 2 weeks of sobriety. Taken together, these data suggest that
1 year exhibit cognitive performance in the normal range. inhibitory control remain impaired in AUD early in
On the contrary, others studies showed that cognitive abstinence.
dysfunctions are still observed after 1 year of abstinence
(Nowakowska-Domagała et al., 2017). There are also
Other functions
discrepancies in the findings regarding recovery after
6 months of sobriety. Several studies showed that perfor- Deficits of visuospatial processing may be particularly
mance returns to normal (Bell et al., 2016; Pitel et al., persistent even after long-term sobriety (Fein et al., 2006).
2009), whereas others indicated that impairments can still However, in a cross-sectional study, Munro et al. (2000)
be observed 6 months after alcohol withdrawal (Munro showed that low visuospatial performance observed after
et al., 2000). The same pattern of heterogeneous results is 6 months of sobriety on the ReyeOsterrieth Complex
found for short-term recovery. Wegner et al. (2001) and Figure may reflect impairments of executive functions
Stavro et al. (2013) reported that 1 month of abstinence is (such as organization and planning abilities) rather than
not enough to recover from alcohol-related cognitive visuospatial deficits per se. In effect, when visuospatial
deficits, whereas other authors showed that, after the first abilities were evaluated with other tests (e.g., Benton
weeks of sobriety, the recovery is sufficient for AUD Visual Form Discrimination Test) unrelated to executive
patients to fully benefit from therapeutic activities (Kish functions, AUD patients abstinent for 6 months had
et al., 1980; Mann et al., 1999; Petit et al., 2017). These preserved results, contrary to those early in abstinence.
apparent inconsistent results can notably be explained by These findings suggest an improvement of visuospatial
the fact that recovery of the different cognitive functions abilities with sobriety.
evaluated in these studies can require different length of Altered emotional processing and ToM abilities can still
sobriety (Petit et al., 2017). be observed 2 months after drinking cessation but in a less
severe form (Foisy et al., 2007; Kornreich et al., 2001). their behavior. It favors the development of internal
Although episodic memory and executive recovery has motivation to change drinking habits (Miller and Rollnick,
been relatively well studied, further studies are required to 1991). According to the Transtheoretical Model of moti-
explore changes in visuospatial processing and social vation (Prochaska and DiClemente, 1983), behavior
cognition over the course of abstinence. It is worthwhile changes involve an evolution of motivation along five
noting that the absence of recovery or very persistent stages (Precontemplation, Contemplation, Preparation,
neuropsychological alterations may reflect premorbid Action, Maintenance, and additionally Relapse). The
cognitive risk factor to develop AUD. motivation process to abandon maladjusted behavior in
favor of a healthier lifestyle requires becoming aware of
Factors influencing the recovery one’s own drinking problem, solving ambivalence,
deciding drinking cessation, and applying strategies to act
A critical factor possibly modulating recovery is the differently. Episodic memory impairments, executive
number of previous detoxifications (Loeber et al., 2010). dysfunction, and decision-making deficits have been linked
For example, AUD patients with fewer than two previous to readiness to change alcohol habits (Blume et al., 2005;
detoxifications had better set shifting and flexibility Le Berre et al., 2013, 2012). Patients with lower motivation
recovery than AUD patients with more than two level would present lower cognitive abilities and lower gray
detoxifications. The heterogeneity in the findings can also matter volume, whereas patients with preserved cognitive
be explained by the experimental designs of the studies: abilities and brain integrity would be at a more advanced
cross-sectional (e.g., Fein et al., 2006; Munro et al., 2000) motivational stage. A set of complementary cognitive
versus longitudinal (e.g., Mulhauser et al., 2018; Pitel et al., abilities is needed to achieve awareness and resolve
2009). Another factor that influences recovery is the age of ambivalence toward alcohol addiction, which is essential
the patients when they stop drinking (Rourke and Grant, for activating the desire to change problematic behavior.
1999; Pitel et al., 2009), with alcohol-related deficits being Some AUD patients may not be cognitively able to be
more persistent in elderly AUD patients (Munro et al., motivated (Le Berre et al., 2012).
2000). Finally, it is important to take account of the
smoking status of AUD patients as it seems to influence the
Decision-making
cognitive and brain recovery (Durazzo et al., 2015, 2014).
When AUD patients experience alcohol craving, i.e., an
irrepressible and unwanted desire to drink, they tend to
Clinical implication and relapse factors favor instant gratification of alcohol use and ignore the
While cognitive functions appear to be responsive to future negative consequences of their choice. This phe-
abstinence, they often remain severely impaired in recently nomenon, named “myopia” for the future (Le Berre et al.,
detoxified patients. The neuropsychological impairments 2014), is close to the psychopathological concept of denial
observed early in abstinence could have negative conse- (Verdejo-García and Pérez-García, 2008). Indeed, patients
quences on the patients’ capacity to benefit fully from continue drinking despite devastating consequences on
treatment (Fein et al., 1990; Tapert et al., 2004). Because of their social relations, work, health, and finances, suggesting
their cognitive deficits, they may be unmotivated or unable decision-making deficits in AUD. Using the Iowa
to maintain abstinence or decrease alcohol consumption. Gambling Task, several studies revealed impaired perfor-
Indeed, episodic memory deficits, executive dysfunctions, mance in AUD patients (Brevers et al., 2014; Fein et al.,
and impaired social cognition can alter motivation to 2004; Goudriaan et al., 2005) related to brain shrinkage in
change behavior, decision-making abilities, new complex regions involved in the emotional and cognitive compo-
learning, or interpersonal relationships. They can also nents of decision-making (Le Berre et al., 2014).
influence the treatment compliance and quality of life Galandra et al. (2018) described two theories developed
(Fig. 8.2). in the literature that could explain for a decision-making
disorder in addictions. The first theory, the control-related
Motivation deficit theory, hypothesizes that decision-making deficits
result from imbalance between two separate but interactive
Cognitive impairments can slow down the motivational brain networks: an impulsive system underlied by the
process to abandon excessive drinking behavior. Motiva- striatum and the amygdala considered as exciter, and a
tion to change drinking behavior is crucial for engagement reflective system underlied by the anterior cingulate and
in alcohol treatment (DiClemente et al., 1999). Motiva- prefrontal cortex, which play an inhibitory control role. The
tional interview can help to assess the degree of the hyperactive impulsive system (impulsive, automatic, and
patient’s readiness to change and to encourage patients emotional processes) would lead to overestimate the impact
exploring and resolving their ambivalence toward changing of the immediate outcomes. On the other hand, the
= =
Procedural
SemanƟc learning
learning
Episodic Denial?
memory Metamemory
MetacogniƟon
ALCOHOL
TREATMENT
ExecuƟve
InhibiƟon Flexibility funcƟons
MoƟvaƟon
Decision-
making Social
cogniƟon
?
FIGURE 8.2 Altered neuropsychological abilities limiting the benefit of alcohol treatment.
weakening of the reflective system (highly controlled) The overall hypothesis is that when patients know, under-
would lead to underestimate the future consequences of a stand, and learn what ethanol is, its action on the body and
decision. In response to an alcohol cue, this imbalance brain, and the consequences of chronic and heavy drinking,
accounts for rapid decision-making, prioritizing short-term they should be more motivated to change their behavior and
reward irrespective of the long-term consequences. This more active during treatment. Psychoeducational therapy
imbalance would result in a bias in decision-making abili- requires thus the acquisition of new and numerous complex
ties, which would increase the risk of relapse. Noël et al. general (semantic) pieces of information presented during
(2013) stated that the insula may play a regulatory role workshops. Moreover, cognitive behavioral therapy is
between these two systems, by translating bottom-up, based on modification of alcohol habits. Caregivers
interoceptive signals into subjective output, such as encourage patients to identify situations at risk of alcohol
craving. consumption. They propose new avoidance behavior or
The second theory is the reward deficit theory that refusal skills. Such therapies, classically proposed to AUD
highlights the key role played by the motivational brain patients during the first weeks of sobriety, require the
network. This network promotes behaviors that provide acquisition and implementation of new procedures, skills,
anticipated or experienced pleasure/reward versus stressing and habits without alcohol. As previously mentioned, Pitel
stimuli or events. AUD is characterized by a compulsion to et al. (2007b) reported that learning new complex semantic
seek and take alcohol, loss of control in limiting intake, and concepts and cognitive procedures are altered in AUD
the emergence of a negative emotional state when access to patients early in abstinence because of episodic memory
the drug (alcohol) is prevented. The theory argues that deficits and executive dysfunctions. Patients could acquire
AUD is a reward deficit disorder, and the emergence of a new semantic concepts or new procedures but more slowly
negative emotional state plays an important role in defining than healthy controls, suggesting that new complex
and perpetuating chronic heavy drinking. The development learning conducted early after detoxification would require
of AUD would reflect the evolution from impulsivity more repetitions and expositions to the new material.
(positive reinforcement) to compulsivity mainly driven by To benefit fully from treatment, high-level cognitive
negative reinforcement (i.e., by the need to avoid craving). abilities are crucial. Consequently, such therapies may not
Craving is considered as a result of a hypoactive reward be relevant, at least early in abstinence, in AUD patients
system desensitized by repetitive alcohol intake and a with impaired neuropsychological performance. They must
hyperactive stress system activated by acute excessive be personalized to the neuropsychological profile of
alcohol intake and sensitized during repeated withdrawal patients.
(Galandra et al., 2018; Koob, 2013).
Interpersonal relationships
New complex learning
Social integration constitutes a primary human need, but
Psychoeducational therapy aims at providing information AUD leads to social alterations and interpersonal impair-
and knowledge about alcohol and addictions to patients. ments such as ostracism, defined by the lack of awareness
and exclusion by others. Seventy percent of alcohol frequently used by AUD patients as a coping strategy to
relapses are consecutive to negative emotional and social overcome interpersonal difficulties, but leading to conflicts
exclusion feelings (Zywiak et al., 2003). Rupp et al. (2017) (Zeichner et al., 1994) and violence (Brismar and Bergman,
have confirmed previous results showing that emotion 1998). And in turn, emotional and social cognition abilities
recognition is still impaired after 3 months of abstinence in are even more severely affected by heavy drinking. As a
AUD patients (Foisy et al., 2007). They also indicated that consequence, ToM disabilities and emotion recognition
patients who had relapsed at follow-up presented lower deficits can be regarded as a risk factor of relapse in AUD
emotion recognition performance at baseline than healthy patients.
controls and patients who had maintained abstinent. Poor
performance on a facial emotion recognition task seems to Alcohol-related neurocognitive
be related to interpersonal difficulties in daily life (Korn-
reich et al., 2002) and could thus also be predictive of
complications
treatment outcome. In a longitudinal study, Moriyama et al. The assessment of cognitive function should not only target
(2002) showed that poor performance on two subtests of the harmful effects of severe and chronic alcohol use but
the BADS (temporal judgment and zoo map) was related to also look for associated nutritional deficiency or liver
lower social outcome (job status) in AUD patients. Efficient disease as these factors can result in exacerbated brain
executive function that involved, for example, being able to damage (Hayes et al., 2016; Ritz et al., 2016a).
use feedback may contribute to successful employment.
Functional MRI studies have provided novel insights on
Wernicke’s encephalopathy
the brain network associated with ostracism. During a
cyberball task that induces social exclusion feelings, Wernicke’s encephalopathy (WE) results from severe
activations in the dorsal anterior cingulate cortex and insula thiamine deficiency or depletion and is clinically charac-
have been linked to negative feelings and social distress in terized by the classical triad of confusion (particularly
healthy controls. In addition, the middle frontal gyrus and disorientation to time and place), ataxia, and oculomotor
inferior frontal gyrus have been involved in the regulation abnormalities, including nystagmus and ophthalmoplegia
and inhibition of this emotional response (Eisenberger (Wernicke, 1881). Mental status change is the most
et al., 2003; Gunther-Moor et al., 2010). Maurage et al. common symptom at WE presentation. The outcome of
(2012) revealed that AUD patients present a different WE is poor, around 80% of cases resulting in KS.
pattern of brain activations during a cyberball task, a virtual AUD patients are at special risk for thiamine deficiency
ball toss game where the participant is led to believe he is because of poor diet, compromised thiamine absorption
playing with two others partners. The cyberball task from the gastrointestinal tract, impaired thiamine storage,
includes “inclusion” phases during which the two other and reduced thiamine phosphorylation (Thomson, 2000).
partners play with the participant and “exclusion” phases Indeed, 30%e80% of AUD patients exhibit such deficiency
during which they throw the ball only to each other. (Thomson, 2000). Postmortem studies of large samples of
Activation of the cerebral network related to social exclu- AUD cases have indicated that WE is underdiagnosed
sion feelings was increased, whereas the ability to regulate in vivo (Harper, 2006). It is the reason why “operational
such feelings was reduced. Interestingly, these social criteria” for identifying WE have been proposed by Caine
exclusion feelings persisted even after reinclusion in the et al. (1997). They suggest that WE is associated to the
social context (Maurage et al., 2012) suggesting negative presence of, at least, two of the following four criteria:
ruminations (Zadro et al., 2006). Moreover, interpersonal (1) history of dietary deficiencies, (2) oculomotor abnor-
difficulties could be accentuated by alexithymia traits malities, (3) cerebellar dysfunction defined by instability of
(Maurage et al., 2017): it is especially difficult for AUD gait and static posture and contributed to cognitive
patients to identify others’ emotions and intentions as they impairment by FCC dysfunctions, and (4) either an altered
present reduced ability to describe and communicate their mental state or mild memory impairment. Preclinical signs
own emotions and feelings. of WE can thus be diagnosed in vivo, enabling the identi-
These emotional and social disabilities contribute to the fication of AUD patients who are at risk for neuropsycho-
vicious circle of AUD: difficulties in perceiving the logical complications. Retrospectively using these criteria
consequences of alcohol consumption, or conversely, in a sample of AUD patients not diagnosed with neuro-
difficulties in perceiving the benefit of abstinence, on logical complications, Pitel et al. (2011) found that there
others. AUD patients with cognitive deficits misinterpret were graded effects in cognitive and motor performance
their own emotional states as well as others’ emotions and between patients meeting zero criteria (27%) not differing
intentions (altered ToM), potentially resulting in inappro- from controls, those meeting one criterion (57%, at risk for
priate social behavior and interactions as well as social WE) presenting mild-to-moderate deficits, and those
stress (Maurage et al., 2011). Alcohol consumption is meeting two or more criteria (16%, with signs of WE),
having the most severe deficits on each of the domains that some AUD patients present as severe thalamus atrophy
examined. In addition, thiamine levels were selectively as KS patients, suggesting that these AUD patients may be
related to memory performance in the AUD patients. These at risk of developing KS. Similar results have been found in
findings suggest that the presence of signs of WE may a diffusion tensor imaging investigation. Segobin et al.
explain, at least partially, the heterogeneity of alcoholism- (2015) described graded effects of white matter micro-
related neuropsychological deficits. From a more clinical structural abnormalities in the fornix and cingulum. Taken
perspective, the use of these operational criteria may help together, these data suggest that the severity of the brain
identifying in vivo and clinically AUD patients at risk to abnormalities within the PC and the associated enduring
develop WE. Treatment of WE consists of thiamine amnesia can be considered as a specificity of KS. The
administration, preferably by intravenous route. While neurotoxicity of ethanol for the PC may be exacerbated by
there are no universally accepted guidelines, recommended the thiamine deficiency resulting in the pathophysiology of
doses range from 200 to 500 mg tds for 5e7 days, followed KS. It seems possible and clinically relevant to identify
by oral administration (Latt and Dore, 2014). AUD patients at risk of developing KS based on episodic
memory results and integrity of PC. As the amnesia in KS
Korsakoff’s syndrome is irreversible, prevention is the main therapeutic option.
The keys to prevent the occurrence of KS in AUD subjects
Although KS can result from different etiological causes, are the early identification of memory impairments through
it is most frequently observed in AUD patients. Alcohol- a cognitive follow-up and, when appropriate, the prompt
related KS results from the combination of chronic and diagnosis and thiamine supplementation in WE.
excessive alcohol consumption with thiamine (B1 vitamin)
deficiency. It usually occurs after the acute stage of WE but
can also develop insidiously.
MarchiafavaeBignami disease
In the early stage of the disease, KS includes anosog- MarchiafavaeBignami disease (MBD) is a rare complica-
nosia, confabulations, false recognition, and a profound tion of chronic alcohol consumption characterized by a
impairment of episodic memory, the latter persisting even demyelination and necrosis of the corpus callosum
at a chronic stage (Kopelman et al., 2009 for review). The (Fig. 8.3). Because the MBD mimicks other common
DSM-5 refers to “alcohol-induced major neurocognitive etiologies such as WE, corpus callosum glioma, demye-
disorder, amnestic-confabulatory type, persistent.” Indeed, lination, and vascular lesions (Parmanand, 2016), this
KS patients exhibit severe and persistent anterograde encephalopathy is difficult to diagnose. Hillbom et al.
amnesia associated to variable retrograde amnesia and (2014) reported the symptoms frequently presented by
mild-to-moderate working memory impairments and patients of studies cases among the literature, such as
executive dysfunction (Oscar-Berman, 2012 for review; altered mental state, confusion, delirium, impaired memory,
Van Oort and Kessels, 2009). A continuum of cognitive dysarthria, impaired walking, primitive reflexes, inconti-
impairments has been proposed between AUD and KS nence, and rigidity. Although no specific proven treatment
patients (Parsons, 1998; Ryback, 1971). AUD without is available for MBD, steroids and parental thiamine
neurological complication and KS patients mainly distin- treatment are often reported in case reports (Hillbom et al.,
guish themselves on the severity of episodic memory 2014; Nemlekar et al., 2016; Sehgal et al., 2013). Authors
deficits (Pitel et al., 2008) and more precisely by the also indicate that repeated neuropsychological assessment
disproportionate impairment of encoding abilities in KS could allow following the recovery, which appears to be
patients. In addition, contrary to what is reported in AUD, slow.
episodic memory deficits observed in KS do not recover
with abstinence, resulting in difficulties in daily life and
Hepatic encephalopathy
autonomy loss. Interestingly, analyses of individual
episodic memory results revealed an unexpected partial Hepatic encephalopathy (HE) covers an extensive spectrum
overlap between AUD patients with the worst performances of neuropsychiatric abnormalities induced by liver
and KS patients with the best ones. Those AUD with dysfunction (Ferro et al., 2016). HE may occur in the
equivocal episodic memory performances, similar to those setting of acute liver failure, mostly due to infectious or
of KS, may be regarded as AUD patients at risk of devel- toxic liver causes, or of chronic portosystemic shunting as a
oping KS and should receive particular attention and consequence of cirrhosis (Ferro et al., 2016). In rare cases,
preventive action. chronic liver dysfunction may result in a syndrome called
A gradient of brain volume deficits from AUD to KS acquired hepatocerebral degeneration (Fig. 8.3), which
patients has also been found notably in the hippocampus, manifests itself by cognitive changes together with motor
thalamus, and mammillary bodies (Sullivan and Pfeffer- symptoms such as tremor, rigidity, speech disorders, and
baum, 2009) (Fig. 8.3). Moreover, Pitel et al. (2012) found reflex modifications (Blei and Córdoba, 2001).
Central
Marchiafava Bignami
Wernicke-Korsakoff Liver Disease Pontine
Disease
Syndrome Myelinolysis
mammillary bodies
frontal lobes thalamus
corpus callosum pons caudate hypothalamus
cerebellum hippocampus putamen amygdala
FIGURE 8.3 Brain regions targeted by alcohol-related neurological complications. Alcohol’s effects on the brain: Neuroimaging results in humans and
animal models. Alcohol Research: Current Reviews 38:e1-24. Adapted from Zahr and Pfefferbaum (2017). Figure modification courtesy of Pfefferbaum,
A., Zahr, N.M., Sullivan, E.V., SRI International, CA and Stanford University School of Medicine, USA.
In cirrhotic portosystemic shunting, which is by far the liver disease associated with liver fibrosis may partially
most common mechanism of HE in AUD subjects, the explain executive dysfunction in AUD patients without
disease course may be either chronic, episodic, or recurrent clinically detectable HE. In agreement, Junghanns et al.
(Ferro et al., 2016). Most importantly, it is now known that (2004) showed that the GGT level was related to mental
in such cases, the cognitive impairment may be subtle, a flexibility abilities. These results indicate that associated
condition referred to as minimal hepatic encephalopathy liver function may predict the severity of executive
(MHE), which can go unnoticed in the absence of a thor- impairments in AUD patients.
ough neuropsychological assessment (Randolph et al.,
2009). It is thus of utmost importance to detect MHE, Central pontine myelinolysis
which can significantly impair daily activities and quality of
life (Arria et al., 1991). Patients at risk of MHE should be Central pontine myelinolysis (CPM) is an osmotic demy-
submitted to relevant tests (see Randolph et al., 2009 for elination syndrome, a condition in which the myelin sheath
review) to take the appropriate actions and prevent further of central nervous system neurons is damaged. The
worsening or complications. mechanism of demyelination is not inflammatory, like in
It is now well-known that an elevated level of gamma- multiple sclerosis, but is thought to be due to vasogenic and
glutamyltransferase (GGT), although nonspecific, can be intramyelinic edema, cerebral dehydration, and oligoden-
regarded as a biomarker of alcohol-related liver disease drocyte damage (Costin and Miles, 2014). CPM was first
(Mancinelli and Ceccanti, 2009). Twenty percent of AUD described by Adams et al. (1959). At first associated to
patients present liver steatosis, which may lead to hepatitis alcoholism, which remains a significant risk factor, CPM
and potentially ultimately cirrhosis. 30%e45% of AUD was later shown to be connected in most cases with overly
patients with cirrhosis develop HE (Vilstrup et al., 2014) rapid correction of hyponatremia, and other less frequent
characterized by cognitive impairments related to brain causes as well (Alleman, 2014).
abnormalities in frontal cortices (Lockwood et al., 2002) as Myelinolysis may extend well beyond the central pons
well as thalamus and cerebellum (Kril and Butterworth, (Fig. 8.3), to involve a number of other brain structures, of
1997). MHE has also been shown to induce changes in the which are, by decreasing order of frequency, the
structure and connectivity of the hippocampus (García- cerebellum, lateral geniculate body, external and extreme
García et al., 2018), which adds to the direct impact of capsules, hippocampus, putamen, cortex, thalamus, caudate
alcohol and thiamine deficiency on memory. nucleus, and others (Gocht and Colmant, 1987), always in a
Well before the development of a full-blown HE, symmetric pattern. CPM is isolated in 50% of cases, it is
altered liver function may affect brain structure and associated to extrapontine myelinolysis (EPM) in 30%,
function. Ritz et al.’s results (2016a) indicated that chronic and EPM occurs in isolation in the remaining 20%
(Martin, 2004). In all cases, the diagnosis is confirmed by abstinent, it is recommended to screen their cognitive
magnetic resonance imaging, showing diffusion restriction, functioning at treatment entry. Because of the limited
with decreased apparent diffusion coefficient. Microstruc- financial and human resources in addiction departments
tural changes of white matter, which can be reversible with that do not permit a systematic comprehensive evaluation,
abstinence (Alhassoon et al., 2012), have been demon- two screening tools can be used to detect alcohol-related
strated in AUD patients (Pfefferbaum et al., 2000). AUD cognitive deficits.
subjects may thus be particularly vulnerable to myelin The Montreal Cognitive Assessment (MoCA; Nas-
damage induced by electrolytic disturbances. Hypona- reddine et al., 2005) is constituted by subtests assessing
tremia is found as a causative factor in 80%, and AUD is visuospatial/executive abilities, memory, attention, lan-
the most common comorbidity (50% of cases). guage, abstraction, and orientation. Although the MoCA
The most common presentation of CPM is encepha- has initially been developed for the assessment of mild
lopathy, followed by paresis and epileptic seizures. In many cognitive impairment related to neurodegenerative diseases,
cases, the encephalopathy and seizures are associated to this screening tool has satisfactory psychometric properties
hyponatremia, and resolve as it is being corrected, before to distinguish KS and AUD patients from healthy controls
the appearance of the specific symptoms of myelinolysis, in (Alarcon et al., 2015; Copersino et al., 2009; Oudman et al.,
a characteristic biphasic clinical course. The neurological 2014). More precisely, the MoCA seems to have good
picture then depends on the anatomical location of demy- specificity and sensitivity to discriminate KS patients from
elination. In CPM, the corticospinal tract involvement healthy controls, whereas MoCA’s specificity to discrimi-
induces quadriparesis, dysarthria, dysphagia, and some- nate AUD patients from healthy controls is limited (Wester
times locked-in syndrome, while in EPM, many other et al., 2013b). That could be explained by the fact that the
symptoms may occur, including movement disorders, MOCA evaluates cognitive functions that are not impaired
behavioral disturbances, encephalopathy, and depression in AUD while other cognitive abilities altered in AUD are
(Alleman, 2014). In a metaanalysis of clinical studies from not evaluated.
1985 to 2013, Singh et al. found that one-fourth of subjects The Brief Evaluation of Alcohol-Related Neuropsy-
died, one-fourth were left with disability, and half recov- chological Impairment (BEARNI; Ritz et al., 2015) has
ered. Myelinolysis is also a complication of liver been specifically designed to assess the semiology of
transplantation, in which case the prognosis is much worse, alcohol-related cognitive and motor deficits in AUD. It is
with a rate of combined death and disability of 77% intended to be short and easy to score, making it useable by
(Singh et al., 2014). nonpsychologists. This screening tool is composed of five
CPM and EPM thus stand as another cause of neuro- subtests (verbal memory, working memory, executive
logical complications of AUD and should be considered functions, visuospatial abilities, and ataxia), with a total
whenever an AUD subject develops neurological symp- score and a “cognitive” subscore that allows interpreting
toms, particularly encephalopathy, and paresis or seizures, the results even when the patient cannot perform the ataxia
all the more in the presence of hyponatremia. subtest. BEARNI has a high sensitivity and gauges the
severity of cognitive impairments from mild to moderate to
severe cognitive deficits. The main limitation of the
Recommendations for researchers and BEARNI is its relative low specificity for the detection of
clinicians patients with mild impairments. Indeed, patients may be
It is now clear that chronic and excessive alcohol con- classified as having mild deficits on BEARNI, while an
sumption affects directly and indirectly brain and cognition. extensive neuropsychological battery does not reveal any
The nature and severity of these brain structure and func- cognitive deficits. BEARNI should be used especially for
tion alterations are very heterogeneous, but in some cases, the detection of moderate-to-severe impairments.
they can limit the benefit of treatment and be predictive of Recently, Pelletier et al. (2018) compared these two
poor treatment outcome. Cognitive assessment of AUD screening tools for the detection of cognitive impairments
patients is crucial for the detection of impaired and pre- in AUD patients. Although both tools exhibited a high
served neuropsychological functions and then the adaption sensitivity, BEARNI’s sensitivity was even higher than the
of treatment. Moreover, a neuropsychological assessment is MoCA’s one. Concerning specificity, the MoCA was much
crucial to make a differential diagnosis. Finally, the neu- better than BEARNI. Almost all AUD patients without
ropsychological profile is very informative to implement a cognitive deficits on a comprehensive neuropsychological
relevant rehabilitation program. battery had a BEARNI score below the normal cutoff
(< or ¼ to 16 for cognitive subscore or 19 for total score).
The proportion of well-classified patients was significantly
Modalities of screening and assessment
better with the MoCA than with the BEARNI test.
Given the potential impact of neuropsychological deficits In addition, a previous study found that the MoCA is
presented by AUD patients on patients’ ability to remain reliable tool for monitoring cognitive improvement during
hospitalization for rehabilitation (Pelletier et al., 2016). The impairments and the total amount of alcohol consumed
authors concluded that the MoCA appears to be more over a lifetime (Ryback, 1971) or duration of AUD
appropriate than BEARNI in clinical settings. (Sullivan et al., 2000), but these relationships are not
Whenever it is possible, and particularly when patients systematically found. The number of withdrawals (Duka
exhibit poor performance on screening tools, patients et al., 2003), length of sobriety (Zinn et al., 2004), asso-
should be referred to a neuropsychologist to conduct an ciated malnutrition (Pitel et al., 2011; Ritz et al., 2016a),
in-depth assessment based on gold standard tests. AUD and biological factors such as liver complications and
patients do not exhibit systematic deviation from the thiamine deficiencies (Fama et al., 2017; Ritz et al., 2016a)
normal range in the reference neuropsychological tests may also contribute to the presence and profile of cognitive
while they encounter problems in daily life. Indeed, day-to- impairments. The age at first drinking is significantly
day level of function is better determined by ecologically correlated with the decrease in gray matter volume in the
valid assessments than by laboratory-based neuropsycho- frontal cortex, the cerebellum, and the brainstem (Chanraud
logical tests. Several studies have reported executive and et al., 2007), structures previously described as supporting
memory dysfunctions, respectively, assessed with the impaired neuropsychological functions in AUD. In addi-
BADS (Ihara et al., 2000; Maharasingam et al., 2013; tion, it is well known that sleep participates in the brain and
Moriyama et al., 2002), and the Rivermead Behavioral cognitive integrity, particularly in memory consolidation,
Memory Test (RBMT) (Wester et al., 2013b). Moriyama and that sleep disturbances are frequently reported in AUD
et al. (2002) also found that executive dysfunction evalu- patients. Junghanns et al. (2009) showed that chronic and
ated by the BADS were associated to alcohol-unrelated excessive alcohol consumption is associated with impaired
outcomes (job performance) but not to alcohol-specific sleep-dependent memory consolidation, suggesting that
outcomes (control drinking). Using the RBMT allows sleep disorders may also contribute in the heterogeneity of
detecting more severe memory impairments in KS than in cognitive deficits.
AUD patients (Wester et al., 2013a). This pattern of This heterogeneity in the nature and the severity of the
difference was also found in executive performance deficits observed in AUD patients sometimes leads to
assessed with the BADS (Maharasingam et al., 2013) while difficulties in differential diagnostic. In effect, the differ-
laboratory-based measures mainly revealed a difference in ential diagnosis can be challenging especially with respect
memory. to KS, as described in the previous section, but also with
According to Stephan et al. (2017), some neuropsy- “normal” aging, Alzheimer’s disease (AD), and fronto-
chological tests are more sensitive to the effects of alcohol temporal lobar degeneration.
than others. According to these authors, it would be more
relevant to use the Wisconsin Card Sorting Test, Iowa Differential diagnosis
Gambling Task, and Hayling Test than a verbal fluency
task or a Stroop ColoreWord interference test. Ageealcohol use disorder interaction
Finally, it is important to specify that benzodiazepines
Cognitive deficits observed in AUD may be similar to those
impair memory functioning (Bacon et al., 1998) and affect
observed in healthy subjects as a result of normal aging
mood states (Curran, 1991). A neuropsychological assess-
(Oscar-Berman et al., 1997). The interaction between age
ment must be conducted when clinicians consider that the
and AUD may be explained by the premature aging
benzodiazepines commonly used during withdrawal no
hypothesis, suggesting that AUD patients exhibit neuro-
longer have an effect. It is also crucial to keep in mind that
psychological and brain changes typical of aging. Indeed, a
AUD patients frequently exhibit psychiatric, neurological,
longitudinal imaging study comparing AUD to healthy
and addictive comorbidities that can exacerbate neuropsy- subjects revealed that chronic alcohol consumption
chological impairments and hamper spontaneous recovery
increases volume of gray matter loss observed in frontal
after drinking cessation (Yang et al., 2018).
regions during aging (Pfefferbaum et al., 1998). Chronic
and excessive alcohol consumption leads to accelerated
Heterogeneity of the neuropsychological cortical aging, even when alcohol misuse develops later in
profile life (Sullivan et al., 2018).
Several factors that may contribute to the heterogeneity of
alcohol-related cognitive impairments have been identified
Alzheimer’s disease
(Fig. 8.4). The continuum hypothesis postulated that AD is a neurodegenerative disease that develops in elderly
alcohol-related cognitive deficits range from mild to subjects and is mainly characterized by episodic memory
moderate to severe, comparable to those observed in KS, impairments (McKhann et al., 2011). Although executive
depending on the severity of alcohol history. Some studies function and visuospatial abilities are similarly impaired in
confirmed a relationship between neuropsychological AUD and AD, AD patients exhibit more severe episodic
Signs of
Wernicke’s
encephalopathy
Thiamine Liver complicaƟons
deficiencies
Heterogeneity of the
neuropsychological Alcohol history
Sleep disorders profil And modaliƟes of
consumpƟon
FIGURE 8.4 Factors explaining the heterogeneity of the neuropsychological profile in alcohol use disorder (AUD) patients.
memory impairments than AUD patients (Liappas et al., treatment and would rather benefit from a recovery period
2007). AD patients are also impaired in a recognition task, (Fig. 8.5). For these patients, the hospitalization could last
which is usually relatively preserved in AUD patients. In longer to protect them from short-term relapse and favor
elderly subjects, the diagnosis between AUD and AD can spontaneous recovery. Ideally, treatment options (timing
thus be relatively easily and reliably made. and methods) could be adjusted for each and every patient
according to the neuropsychological profile. For example,
Frontotemporal lobar degeneration repetition of materials or procedures to be learned could be
a useful strategy for some AUD patients in educational
Frontotemporal lobar degeneration (FTLD) is a neurode- program, wherein they are expected to acquire new
generative disease that develops in middle age adults and complex information (Nixon et al., 1998). To increase even
initially consists notably of behavioral disturbances. more the efficiency of treatment, adjustments could also be
Among behavioral disturbances, abnormal alcohol based on the cognitive functions identified as preserved
consumption can be observed in 30%e41% of cases during the neuropsychological assessment. For example,
(Lebert and Pasquier, 2008). These consumptions are errorless learning (Pitel et al., 2010) allows compensating
characterized by specific features such as a recent onset of for the deficits of episodic memory and executive
alcohol abuse, an appetence for sugary alcoholic drinks that dysfunction.
may never have been consumed before, and quantities and
hours of consumptions becoming gradually ritualized.
Neuropsychological rehabilitation
Moreover, patients with FTLD do not exhibit withdrawal
syndrome as they do not experience genuine alcohol Another way to adjust treatment is to conduct neuropsy-
dependence. Neuropsychological disorders observed in chological rehabilitation programs. According to Sofuoglu
later stages of the FTLD are similar to those observed in et al. (2013), enhancement of executive control may
AUD: executive and emotional deficits as well as altered increase behavioral treatment efficacy in AUD. Neuropsy-
decision-making processes (Mendez et al., 2005). Because chological rehabilitation aims at facilitating cognitive
alcohol-related deficits recover with abstinence, whereas recovery or compensating for cognitive deficits. Roehrich
there is a global deterioration of performance in FTLD and Goldman (1993) found that AUD patients transferred
patients, a follow-up neuropsychological evaluation in what they had learned during experience-dependent
detoxified patients is very useful for an accurate diagnosis. recovery (i.e., cognitive remediation or rehabilitation) to a
In effect, cognitive recovery is expected in AUD after wide range of tasks that went well beyond the trained tasks.
drinking cessation, while the clinical diagnosis of FTLD is This transfer could thus occur to material that relates
supported by persistent and worsening cognitive and directly to AUD treatment as required in educational
behavioral deterioration even with sobriety. treatment, suggesting that such experience-dependent
recovery could be valuable for AUD treatment.
Other interventions have been developed to improve
Treatment modifications
cognitive functioning in AUD patients. For example,
As previously mentioned, severe deficits of episodic treatments validated in other diseases for the rehabilitation
memory, executive functions, and social cognition may of executive function, such as Goal Management Training
result in poor treatment outcome. A systematic screening (GMT) (Levine et al., 2011) and a combination of GMT
conducted early in abstinence would allow clinicians to with mindfulness-based meditation, improve working
identify patients who are not cognitively able to enter memory, inhibition, and decision-making abilities in AUD
HARMFUL ALCOHOL DRINKING CESSATION
Neuropsychological assessment
IdenƟficaƟon of risk factors for cogniƟve deficits
Preserved Mild-to-moderate Severe

neuropsychological neuropsychological neuropsychological
abiliƟes deficits deficits
Usual treatment :
- MoƟvaƟonal interviewing Mid-term care unit Nursing home
- Psycho-educaƟonal therapies To favor spontaneous Specialized unit (when
- CogniƟve behavioral treatment recovery available)
Neuropsycholoigcal
assessment
Persistent
Neuropsychological
neuropsychological
recovery
deficits
Neuropsychological
rehabilitaƟon
FIGURE 8.5 How to integrate the neuropsychological assessment as key information for relevant clinical decisions in AUD treatment? Early after the
cessation of alcohol drinking, a neuropsychological assessment enables clinicians to offer AUD patients the best treatment options according to their
neuropsychological profile. When neuropsychological abilities are preserved, patients can benefit from usual treatment. When patients exhibit mild-to-
moderate neuropsychological deficits, they can be referred to midterm care units to permit spontaneous cognitive recovery without drinking potentially
favored by neuropsychological rehabilitation. After several weeks, they can be reevaluated: a significant neuropsychological recovery would allow
attending usual treatment, while persisting neuropsychological deficits would require specialized care, just as patients with severe neuropsychological
deficits, including neuropsychological rehabilitation programs.
patients compared with treatment as usual (Alfonso et al., Wiers et al. (2011) focused on a bias observed in AUD
2011; Valls-Serrano et al., 2016). In the same vein, studies patients in the action tendency to approach alcohol-related
showed that patients in such rehabilitation group not only stimuli. They used a cognitive bias modification method,
improve cognitive functioning but also present decreased based on the alcohol approach/avoidance task (Wiers et al.,
craving, affective distress, and psychological symptoms 2010). This task aims at inhibiting alcohol habits that are
compared with patients who received usual treatment notably based on the attentional bias toward alcohol stimuli
(Marceau et al., 2017; Rupp et al., 2012). observed in AUD. During this task, AUD patients were
In 2011, Houben et al. examined the relationship instructed to respond to pictures of alcohol drink or soft
between neurocognitive functioning and alcohol outcomes. drink, with an approach movement (pulling a joystick) or
People presenting AUD were recruited via the Internet. an avoidance movement (pushing a joystick). The pulling
They performed working memory training or control tasks and pushing were accompanied by a zooming feature that
during 25 sessions. The authors found an improvement of made the picture increase in size consistent with approach
working memory, which persisted 1 month after the end of or decrease with avoidance. Patients performed four
the protocol, in the working memory training group. training sessions on four consecutive days. AUD patients
Moreover, alcohol consumption measured with the Time- trained to “avoid” alcohol stimuli during the task showed
line Followback questionnaire (Sobell and Sobell, 1992) better drinking outcomes than those in other conditions
decreased by approximately 10 drinks per week from when interviewed 1 year later.
pretest to posttest in the training group, and this reduction Regarding interpersonal difficulties, the development of
was still present 1 month after. The improvement of therapeutic programs that target social abilities to regulate
working memory could help restoring control over interpersonal relationships is required (Maurage et al.,
automatic impulses and thus reducing drinking. 2012) and could be inspired by what is currently proposed
in schizophrenia (Veltro et al., 2011). Self-esteem could Alhassoon, O.M., Sorg, S.F., Taylor, M.J., Stephan, R.A.,
also be a therapeutic target as low self-esteem is related to Schweinsburg, B.C., Stricker, N.H., et al., 2012. Callosal white matter
increased social difficulties (Trucco et al., 2007), interper- microstructural recovery in abstinent alcoholics: a longitudinal diffu-
sion tensor imaging study. Alcohol Clin. Exp. Res. 36 (11),
sonal deficits, and high risks of relapse (Maurage et al.,
1922e1931. https://doi.org/10.1111/j.1530-0277.2012.01808.x.
2012).
Alleman, A.M., 2014. Osmotic demyelination syndrome: central pontine
myelinolysis and extrapontine myelinolysis. Seminars Ultrasound CT
Conclusion MRI 35 (2), 153e159. https://doi.org/10.1053/j.sult.2013.09.009.
Alvarez, J.A., Emory, E., 2006. Executive function and the frontal lobes: a
AUD patients recently detoxified present altered brain meta-analytic review. Neuropsychol. Rev. 16 (1), 17e42. https://doi.
structure and function resulting in mild-to-moderate org/10.1007/s11065-006-9002-x.
cognitive impairments that are the most severe right at the American Psychiatric Association, 2000. DSM-IV. Diagnostic and Statisti-
time neuropsychological abilities are required for alcohol cal Manual of Mental Disorders, fourth ed. TR https://doi.org/10.1176.
treatment. Although cognitive impairments have the po- American Psychiatric Association, 2013. American Psychiatric Associa-
tential to limit the benefit of treatment, they remain tion, 2013. Diagnostic and statistical manual of mental disorders (fifth
ed.). Am. J. Psychiatry. https://doi.org/10.1176/appi.books.
underestimated in clinical practice. It is thus essential to
9780890425596.744053.
identify risks factors for cognitive dysfunction or to eval-
Anderson, J.R., 1992. Automaticity and the ACT theory. Am. J. Psychol.
uate alcohol-related cognitive deficits early after detoxifi- 105 (2), 165e180. https://doi.org/10.2307/1423026.
cation not only to adjust treatment options for impaired Antunez, E., Estruch, R., Cardenal, C., Nicolas, J.M., Fernandez-Sola, J.,
patients but also for early detection of patients at risk for Urbano-Marquez, A., 1998. Usefulness of CT and MR imaging in the
developing neurological complications. Further well- diagnosis of acute Wernicke’s encephalopathy. AJR Am. J. Roent-
designed studies are necessary to evaluate the benefit of genol. 171 (4), 1131e1137. https://doi.org/10.2214/ajr.171.4.
neuropsychological rehabilitation in accelerating cognitive 9763009.
recovery and favoring the benefit of alcohol treatment. Arria, A.M., Tarter, R.E., Kabene, M.A., Laird, S.B., Moss, H., Van
From a more fundamental perspective, the physiopathology Thiel, D.H., 1991. The role of cirrhosis in memory functioning of
of alcohol-related cognitive deficits and brain damage re- alcoholics. Alcohol Clin. Exp. Res. 15 (6), 932e937. https://doi.org/
10.1111/j.1530-0277.1991.tb05192.x.
mains unclear and requires further longitudinal and multi-
Ates, O., Cansever, A., Ozsahin, A., Uzun, O., 2003. Alexithymia in male
modal investigations including clinical, biological,
alcoholics: study in a Turkish sample. Compr. Psychiatry 44 (4),
neuropsychological, and neuroimaging examinations. The 349e352. https://doi.org/10.1016/S0010-440X(03)00009-9.
impact of the alcohol neurotoxicity per se and/or associated Bacon, E., Danion, J.-M., Kauffmann-Muller, F., Schelstraete, M.-A.,
liver disease, sleep disorders, or nutritional deficiency Bruant, A., Sellal, F., Grange, D., 1998. Confidence level and feeling
needs also to be clarified. of knowing for episodic and semantic memory: an investigation of
lorazepam effects on metamemory. Psychopharmacology 138 (3e4),
318e325. https://doi.org/10.1007/s002130050677.
References Baddeley, A.D., Hitch, G., 1974. Working memory. In: Psychology of
Abu-Akel, A., Shamay-Tsoory, S., 2011. Neuroanatomical and neuro- Learning and Motivation - Advances in Research and Theory, vol. 8.
chemical bases of theory of mind. Neuropsychologia 49 (11), Academic Press, pp. 47e89. https://doi.org/10.1016/S0079-7421(08)
2971e2984. https://doi.org/10.1016/j.neuropsychologia.2011.07.012. 60452-1.
Adams, R.D., Victor, M., Mancall, E.L., 1959. Central pontine myeli- Baddeley, A., 2000. The episodic buffer: a new component of working
nolysis: a hitherto undescribed disease occurring in alcoholic and memory? Trends Cognit. Sci. 4 (11), 417e423. https://doi.org/10.
malnourished patients. AMA Arch. Neurol. Psychiatry 81 (2), 1016/S1364-6613(00)01538-2.
154e172. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/ Beatty, W.W., Katzung, V.M., Moreland, V.J., Nixon, S.J., 1995. Neu-
13616772. ropsychological performance of recently abstinent alcoholics and
Agartz, I., Shoaf, S., Rawlings, R.R., Momenan, R., Hommer, D.W., 2003. cocaine abusers. Drug Alcohol Depend. 37 (3), 247e253. https://doi.
CSF monoamine metabolites and MRI brain volumes in alcohol org/10.1016/0376-8716(94)01072-S.
dependence. Psychiatry Res. Neuroimaging 122 (1), 21e35. https:// Beatty, W.W., Hames, K. a, Blanco, C.R., Nixon, S.J., Tivis, L.J., 1996.
doi.org/10.1016/S0925-4927(02)00084-7. Visuospatial perception, construction and memory in alcoholism. J. Stud.
Alarcon, R., Nalpas, B., Pelletier, S., Perney, P., 2015. MoCA as a Alcohol 57 (2), 136e143. https://doi.org/10.15288/jsa.1996.57.136.
screening tool of neuropsychological deficits in alcohol-dependent Beaunieux, H., Hubert, V., Witkowski, T., Pitel, A.L., Rossi, S.,
patients. Alcohol Clin. Exp. Res. 39 (6), 1042e1048. https://doi. Danion, J.M., et al., 2006. Which processes are involved in cognitive
org/10.1111/acer.12734. procedural learning? Memory 14 (5), 521e539. https://doi.org/10.
Alfonso, J.P., Caracuel, A., Delgado-Pastor, L.C., Verdejo-García, A., 1080/09658210500477766.
2011. Combined goal management training and mindfulness medita- Bell, M.D., Vissicchio, N.A., Weinstein, A.J., 2016. Cognitive training
tion improve executive functions and decision-making performance in and work therapy for the treatment of verbal learning and memory
abstinent polysubstance abusers. Drug Alcohol Depend. 117 (1), deficits in veterans with alcohol use disorders. J. Dual Diagn. 12 (1),
78e81. https://doi.org/10.1016/j.drugalcdep.2010.12.025. 83e89. https://doi.org/10.1080/15504263.2016.1145779.
Blei, A.T., Córdoba, J., 2001. Hepatic encephalopathy. Am. J. Gastro- Costin, B.N., Miles, M.F., 2014. Molecular and neurologic responses to
enterol. 96 (7), 1968e1976. https://doi.org/10.1111/j.1572-0241. chronic alcohol use. In: Handbook of Clinical Neurology,
2001.03964.x. pp. 157e171. https://doi.org/10.1016/B978-0-444-62619-6.00010-0.
Blume, A.W., Schmaling, K.B., Marlatt, G.A., 2005. Memory, executive Curran, H.V., 1991. Benzodiazepines, memory and mood: a review. Psy-
cognitive function, and readiness to change drinking behavior. Addict. chopharmacology 105, 1e8. https://doi.org/10.1007/BF0231
Behav. 30 (2), 301e314. https://doi.org/10.1016/j.addbeh.2004.05.019. 6856.
Bosco, F.M., Capozzi, F., Colle, L., Marostica, P., Tirassa, M., 2014. Dao-Castellana, M.H., Samson, Y., Legault, F., Martinot, J.L.,
Theory of mind deficit in subjects with alcohol use disorder: an Aubin, H.J., Crouzel, C., et al., 1998. Frontal dysfunction in neuro-
analysis of mindreading processes. Alcohol Alcohol. 49 (3), 299e307. logically normal chronic alcoholic subjects: metabolic and neuropsy-
https://doi.org/10.1093/alcalc/agt148. chological findings. Psychol. Med. 28 (5), 1039e1048. Retrieved
Brandimonte, M., Einstein, G.O., McDaniel, M.A. (Eds.), 1996. Pro- from: http://www.ncbi.nlm.nih.gov/pubmed/9794011.
spective memory: Theory and applications. Lawrence Erlbaum As- D’Argembeau, A., Van Der Linden, M., Verbanck, P., Noël, X., 2006.
sociates Publishers, Mahwah, NJ, US. Autobiographical memory in non-amnesic alcohol-dependent patients.
Brevers, D., Bechara, A., Cleeremans, A., Kornreich, C., Verbanck, P., Psychol. Med. 36 (12), 1707e1715. https://doi.org/10.1017/
Noël, X., 2014. Impaired decision-making under risk in individuals S0033291706008798.
with alcohol dependence. Alcohol Clin. Exp. Res. 38 (7), 1924e1931. de Timary, P., Luminet, O., Speth, A., Zorbas, A., Seron, X., 2010.
https://doi.org/10.1111/acer.12447. Working memory, executive functions and negative emotion-related
Brion, M., D’Hondt, F., Pitel, A.L., Lecomte, B., Ferauge, M., de variables among alcohol-dependent patients undergoing protracted
Timary, P., Maurage, P., 2017. Executive functions in alcohol- withdrawal. Alcohol Clin. Exp. Res. https://doi.org/10.1111/j.1530-
dependence: a theoretically grounded and integrative exploration. 0277.2010.01292-4.x.
Drug Alcohol Depend. 177, 39e47. https://doi.org/10.1016/j. D’Hondt, F., de Timary, P., Bruneau, Y., Maurage, P., 2015. Categorical
drugalcdep.2017.03.018. perception of emotional facial expressions in alcohol-dependence.
Brion, M., de Timary, P., Mertens de Wilmars, S., Maurage, P., 2018. Drug Alcohol Depend. 156, 267e274. https://doi.org/10.1016/j.
Impaired affective prosody decoding in severe alcohol use disorder drugalcdep.2015.09.017.
and Korsakoff syndrome. Psychiatry Res. 264, 404e406. https://doi. DiClemente, C.C., Bellino, L.E., Neavins, T.M., 1999. Motivation for
org/10.1016/j.psychres.2018.04.001. change and alcoholism treatment. Alcohol Res. Health 23 (2), 86e92.
Brismar, B., Bergman, B., 1998. The significance of alcohol for violence Duka, T., Townshend, J.M., Collier, K., Stephens, D.N., 2003. Impairment
and accidents. Alcohol Clin. Exp. Res. 22 (7), 299Se306S. in cognitive functions after multiple detoxifications in alcoholic in-
Caine, D., Halliday, G.M., Kril, J.J., Harper, C.G., 1997. Operational criteria patients. Alcohol Clin. Exp. Res. 27 (10), 1563e1572. https://doi.org/
for the classification of chronic alcoholics: identification of Wernicke’s 10.1097/01.ALC.0000090142.11260.D7.
encephalopathy. J. Neurol. Neurosurg. Psychiatry 62 (1), 51e60. Durazzo, T.C., Pennington, D.L., Schmidt, T.P., Meyerhoff, D.J., 2014.
Retrieved from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd¼ Effects of cigarette smoking history on neurocognitive recovery over
Retrieve&db¼PubMed&dopt¼Citation&list_uids¼9010400. 8 months of abstinence in alcohol-dependent individuals. Alcohol
Cardenas, V.A., Studholme, C., Gazdzinski, S., Durazzo, T.C., Clin. Exp. Res. 38 (11), 2816e2825. https://doi.org/10.1111/acer.
Meyerhoff, D.J., 2007. Deformation-based morphometry of brain 12552.
changes in alcohol dependence and abstinence. Neuroimage 34 (3), Durazzo, T.C., Mon, A., Gazdzinski, S., Yeh, P.-H., Meyerhoff, D.J.,
879e887. https://doi.org/10.1016/j.neuroimage.2006.10.015. 2015. Serial longitudinal magnetic resonance imaging data indicate
Chanraud, S., Martelli, C., Delain, F., Kostogianni, N., Douaud, G., non-linear regional gray matter volume recovery in abstinent alcohol-
Aubin, H.J., et al., 2007. Brain morphometry and cognitive perfor- dependent individuals. Addict. Biol. 20 (5), 956e967. https://doi.org/
mance in detoxified alcohol-dependents with preserved psychosocial 10.1111/adb.12180.
functioning. Neuropsychopharmacology 32 (2), 429e438. https://doi. Eisenberger, N.I., Lieberman, M., Williams, K., 2003. Does rejection hurt?
org/10.1038/sj.npp.1301219. An fMRI study of social exclusion. Science 302 (5643), 290e292.
Chanraud, S., Leroy, C., Martelli, C., Kostogianni, N., Delain, F., https://doi.org/10.1126/science.1089134.
Aubin, H.-J., et al., 2009a. Episodic memory in detoxified alcoholics: Fama, R., Pfefferbaum, A., Sullivan, E.V., 2004. Perceptual learning in
contribution of grey matter microstructure alteration. PLoS One 4 (8). detoxified alcoholic men: contributions from explicit memory, exec-
https://doi.org/10.1371/journal.pone.0006786. utive function, and age. Alcohol Clin. Exp. Res. 28 (11), 1657e1665.
Chanraud, S., Reynaud, M., Wessa, M., Penttilä, J., Kostogianni, N., https://doi.org/10.1097/01.ALC.0000145690.48510.DA.
Cachia, A., et al., 2009b. Diffusion tensor tractography in mesence- Fama, R., Rosenbloom, M.J., Sassoon, S.A., Thompson, M.A.,
phalic bundles: relation to mental flexibility in detoxified alcohol- Pfefferbaum, A., Sullivan, E.V., 2011. Remote semantic memory for
dependent subjects. Neuropsychopharmacology 34 (5), 1223e1232. public figures in HIV infection, alcoholism, and their comorbidity.
https://doi.org/10.1038/npp.2008.101. Alcohol Clin. Exp. Res. 35 (2), 265e276. https://doi.org/10.1111/j.
Conway, M.A., 2001. Sensory-perceptual episodic memory and its 1530-0277.2010.01342.x.
context: autobiographical memory. Philos. Trans. R. Soc. Lond. Ser. B Fama, R., Le Berre, A.-P., Hardcastle, C., Sassoon, S.A., Pfefferbaum, A.,
Biol. Sci. 356 (1413), 1375e1384. https://doi.org/10.1098/rstb.2001. Sullivan, E.V., Zahr, N.M., 2017. Neurological, nutritional and
0940. alcohol consumption factors underlie cognitive and motor deficits in
Copersino, M., Fals-stewart, W., Fitzmaurice, G., Schretlen, D., chronic alcoholism. Addict. Biol. https://doi.org/10.1111/adb.12584.
Sokoloff, J., Weiss, R., 2009. Rapid cognitive screening of patients Fein, G., Bachman, L., Fisher, S., Davenport, L., 1990. Cognitive im-
with substance use disorders. Exp. Clin. Psychopharmacol 17 (5), pairments in abstinent alcoholics. West. J. Med. 152 (5), 531e537.
337e344. https://doi.org/10.1037/a0017260.Rapid.
Fein, G., Sclafani, V., Cardenas, V.A., Goldmann, H., Tolou-Shams, M., Grant, B.F., Goldstein, R.B., Saha, T.D., Patricia Chou, S., Jung, J.,
Meyerhoff, D.J., 2002. Cortical gray matter loss in treatment-naive Zhang, H., et al., 2015. Epidemiology of DSM-5 alcohol use disorder
alcohol dependent individuals. Alcohol Clin. Exp. Res. 26 (4), results from the national epidemiologic survey on alcohol and related
558e564. https://doi.org/10.1111/j.1530-0277.2002.tb02574.x. conditions III. JAMA Psychiatry 72 (8), 757e766. https://doi.org/10.
Fein, G., Klein, L., Finn, P., 2004. Impairment on a simulated gambling task 1001/jamapsychiatry.2015.0584.
in long-term abstinent alcoholics. Alcohol Clin. Exp. Res. 28 (10), Gunther Moor, B., Crone, E.A., van der Molen, M.W., 2010. The heart-
1487e1491. https://doi.org/10.1097/01.ALC.0000141642.39065.9B. brake of social rejection. Psychol. Sci. 21 (9), 1326e1333. https://doi.
Fein, G., Torres, J., Price, L.J., Di Sclafani, V., 2006. Cognitive perfor- org/10.1177/0956797610379236.
mance in long-term abstinent alcoholics. Alcohol Clin. Exp. Res. 86 Harper, C., Matsumoto, I., 2005. Ethanol and brain damage. Curr. Opin.
(3), 573e579. https://doi.org/10.1109/TMI.2012.2196707.Separate. Pharmacol. 5 (1), 73e78. https://doi.org/10.1016/j.coph.2004.06.
Fein, G., Shimotsu, R., Chu, R., Barakos, J., 2009. Parietal gray matter 011.
volume loss is related to spatial processing deficits in long-term Harper, C., 2006. Thiamine (vitamin B1) deficiency and associated brain
abstinent alcoholic men. Alcohol Clin. Exp. Res. 33 (10), damage is still common throughout the world and prevention is simple
1806e1814. https://doi.org/10.1111/j.1530-0277.2009.01019.x. and safe! Eur. J. Neurol. 13 (10), 1078e1082. https://doi.org/10.1111/
Ferro, J.M., Viana, P., Santos, P., 2016. Management of neurologic j.1468-1331.2006.01530.x.
manifestations in patients with liver disease. Curr. Treat. Options Hart, J.T., 1965. Memory and the feeling-of-knowing experience. J. Educ.
Neurol. 18 (8), 37. https://doi.org/10.1007/s11940-016-0419-0. Psychol. 56 (4), 208e216. https://doi.org/10.1037/h0022263.
Flavell, J.H., 1971. First discussant’s comments: what is memory devel- Hayes, V., Demirkol, A., Ridley, N., Withall, A., Draper, B., 2016.
opment the development of? Hum. Dev. 14 (4), 272e278. https://doi. Alcohol-related cognitive impairment: current trends and future per-
org/10.1159/000271221. spectives. Neurodegener. Dis. Manag. 6 (6), 509e523. https://doi.org/
Foisy, M.-L., Kornreich, C., Fobe, A., D’Hondt, L., Pelc, I., Hanak, C., 10.2217/nmt-2016-0030.
et al., 2007. Impaired emotional facial expression recognition in Heffernan, T.M., Ling, J., Parrott, A.C., Buchanan, T., Scholey, A.B.,
alcohol dependence: do these deficits persist with midterm abstinence? Rodgers, J., 2005. Self-rated everyday and prospective memory
Alcohol Clin. Exp. Res. 31 (3), 404e410. https://doi.org/10.1111/j. abilities of cigarette smokers and non-smokers: a web-based study.
1530-0277.2006.00321.x. Drug Alcohol Depend. 78 (3), 235e241. https://doi.org/10.1016/j.
Frith, C.D., 2008. Social cognition. In: Philosophical Transactions of the drugalcdep.2004.11.008.
Royal Society of London. Series B, Biological Sciences, vol. 363, Heffernan, T.M., Moss, M., Ling, J., 2002. Subjective ratings of pro-
pp. 2033e2039, 1499. https://doi.org/10.1098/rstb.2008.0005. spective memory deficits in chronic heavy alcohol users. Alcohol
Galandra, C., Basso, G., Cappa, S., Canessa, N., 2018. The alcoholic brain: Alcohol. 37 (3), 269e271. https://doi.org/10.1093/alcalc/37.3.269.
neural bases of impaired reward-based decision-making in alcohol use Heffernan, T., 2008. The impact of excessive alcohol use on prospective
disorders. Neurol. Sci. 39 (3), 423e435. https://doi.org/10.1007/ memory: a brief review. Curr. Drug Abuse Rev. 1 (1), 36e41. https://
s10072-017-3205-1. doi.org/10.2174/1874473710801010036.
Gansler, D.A., Harris, G.J., Oscar-Berman, M., Streeter, C., Lewis, R.F., Hillbom, M., Saloheimo, P., Fujioka, S., Wszolek, Z.K., Juvela, S.,
Ahmed, I., Achong, D., 2000. Hypoperfusion of inferior frontal brain Leone, M.A., 2014. Diagnosis and management of Marchiafava-
regions in abstinent alcoholics: a pilot SPECT study. J. Stud. Alcohol Bignami disease: a review of CT/MRI confirmed cases. J. Neurol.
61 (1), 32e37. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/ Neurosurg. Psychiatry 85 (2), 168e173. https://doi.org/10.1136/jnnp-
10627094. 2013-305979.
García-García, R., Cruz-Gómez, Á.J., Urios, A., Mangas-Losada, A., Houben, K., Wiers, R.W., Jansen, A., 2011. Getting a grip on drinking
Forn, C., Escudero-García, D., et al., 2018. Learning and memory behavior: training working memory to reduce alcohol abuse. Psy-
impairments in patients with minimal hepatic encephalopathy are chol. Sci. 22 (7), 968e975. https://doi.org/10.1177/09567976114
associated with structural and functional connectivity alterations in 12392.
hippocampus. Sci. Rep. 8 (1), 9664. https://doi.org/10.1038/s41598- Hubert, V., Beaunieux, H., Chételat, G., Platel, H., Landeau, B.,
018-27978-x. Danion, J.-M., et al., 2007. The dynamic network subserving the three
Gocht, A., Colmant, H.J., 1987. Central pontine and extrapontine myeli- phases of cognitive procedural learning. Hum. Brain Mapp. 28 (12),
nolysis: a report of 58 cases. Clin. Neuropathol. 6 (6), 262e270. 1415e1429. https://doi.org/10.1002/hbm.20354.
Goldman, M.S., 1990. Experience-dependent neuropsychoiogical recovery Hull, R., Martin, R.C., Beier, M.E., Lane, D., Hamilton, A.C., 2008.
and the treatment of chronic alcoholism. Neuropsychol. Rev. 1 (1), Executive function in older adults: a structural equation modeling
75e101. approach. Neuropsychology 22 (4), 508e522. https://doi.org/10.1037/
Goudriaan, A.E., Oosterlaan, J., de Beurs, E., van den Brink, W., 2005. 0894-4105.22.4.508.
Decision making in pathological gambling: a comparison between Ihara, H., Berrios, G.E., London, M., 2000. Group and case study of the
pathological gamblers, alcohol dependents, persons with Tourette dysexecutive syndrome in alcoholism without amnesia. J. Neurol.
syndrome, and normal controls. Cogn. Brain Res. 23 (1), 137e151. Neurosurg. Psychiatry 68 (6), 731e737. https://doi.org/10.1136/jnnp.
https://doi.org/10.1016/j.cogbrainres.2005.01.017. 68.6.731.
Goudriaan, A.E., Oosterlaan, J., De Beurs, E., Van Den Brink, W., 2006. John, U., Rumpf, H.J., Bischof, G., Hapke, U., Hanke, M., Meyer, C.,
Neurocognitive functions in pathological gambling: a comparison 2013. Excess mortality of alcohol-dependent individuals after 14 years
with alcohol dependence, Tourette syndrome and normal controls. and mortality predictors based on treatment participation and severity
Addiction 101 (4), 534e547. https://doi.org/10.1111/j.1360-0443. of alcohol dependence. Alcohol Clin. Exp. Res. 37 (1), 156e163.
2006.01380.x. https://doi.org/10.1111/j.1530-0277.2012.01863.x.
Junghanns, K., Backhaus, J., Veltrup, C., Dageforde, J., Bruckmann, H., Le Berre, A.P., Pinon, K., Vabret, F., Pitel, A.L., Allain, P., Eustache, F.,
Wetterling, T., 2004. Mildly disturbed hepatic and pancreatic function Beaunieux, H., 2010. Study of metamemory in patients with chronic
during early abstention from alcohol is associated with brain atrophy alcoholism using a feeling-of-knowing episodic memory task. Alcohol
and with disturbed psychometric performance. Alcohol Alcohol. 39 Clin. Exp. Res. 34 (11), 1888e1898. https://doi.org/10.1111/j.1530-
(2), 113e118. https://doi.org/10.1093/alcalc/agh028. 0277.2010.01277.x.
Junghanns, K., Horbach, R., Ehrenthal, D., Blank, S., Backhaus, J., 2009. Le Berre, A.-P., Vabret, F., Cauvin, C., Pinon, K., Allain, P., Pitel, A.-L.,
Chronic and high alcohol consumption has a negative impact on sleep et al., 2012. Cognitive barriers to readiness to change in alcohol-
and sleep-associated consolidation of declarative memory. Alcohol dependent patients. Alcohol Clin. Exp. Res. 36 (9), 1542e1549.
Clin. Exp. Res. 33 (5), 893e897. https://doi.org/10.1111/j.1530-0277. https://doi.org/10.1111/j.1530-0277.2012.01760.x.
2009.00909.x. Le Berre, A.-P., Rauchs, G., La Joie, R., Segobin, S., Mézenge, F.,
Jurado, M.B., Rosselli, M., 2007. The elusive nature of executive func- Boudehent, C., et al., 2013. Readiness to change and brain damage in
tions: a review of our current understanding. Neuropsychol. Rev. 17 patients with chronic alcoholism. Psychiatry Res. Neuroimaging 213
(3), 213e233. https://doi.org/10.1007/s11065-007-9040-z. (3), 202e209. https://doi.org/10.1016/j.pscychresns.2013.03.009.
Kamarajan, C., Porjesz, B., Jones, K.A., Choi, K., Chorlian, D.B., Le Berre, A.P., Rauchs, G., La Joie, R., Mézenge, F., Boudehent, C.,
Padmanabhapillai, A., et al., 2005. NIH Public Access 69 (3), 353e373. Vabret, F., et al., 2014. Impaired decision-making and brain shrinkage
https://doi.org/10.1016/j.biopsycho.2004.08.004.Alcoholism. in alcoholism. Eur. Psychiatry 29 (3), 125e133. https://doi.org/10.
Kish, G.B., Hagen, J.M., Woody, M.M., Harvey, H.L., 1980. Alcoholics’ 1016/j.eurpsy.2012.10.002.
recovery from cerebral impairment as a function of duration of Le Berre, A.-P., Fama, R., Sullivan, E.V., 2017. Executive functions,
abstinence. J. Clin. Psychol. 36 (2), 584e589. https://doi.org/10.1002/ memory, and social cognitive deficits and recovery in chronic alco-
jclp.6120360234. holism: a critical review to inform future research. Alcohol Clin. Exp.
Konrad, A., Vucurevic, G., Lorscheider, M., Bernow, N., Thümmel, M., Res. 41 (8), 1432e1443. https://doi.org/10.1111/acer.13431.
Chai, C., et al., 2012. Broad disruption of brain white matter micro- Lebert, F., Pasquier, F., 2008. Démence frontotemporale : histoire com-
structure and relationship with neuropsychological performance in portementale d’une maladie neurologique, vol. 6, pp. 33e41. https://
male patients with severe alcohol dependence. Alcohol Alcohol. 47 doi.org/10.1684/pnv.2008.0113.
(2), 118e126. https://doi.org/10.1093/alcalc/agr157. Levine, B., Schweizer, T.A., O’Connor, C., Turner, G., Gillingham, S.,
Koob, G.F., Volkow, N.D., 2016. Neurobiology of addiction: a neuro- Stuss, D.T., et al., 2011. Rehabilitation of executive functioning in
circuitry analysis. Lancet Psychiatry. https://doi.org/10.1016/S2215- patients with frontal lobe brain damage with goal management training.
0366(16)00104-8. Front. Hum. Neurosci. 5. https://doi.org/10.3389/fnhum.2011.00009.
Koob, G.F., 2013. Negative reinforcement in drug addiction: the darkness Liappas, I., Theotoka, I., Kapaki, E., Ilias, I., Paraskevas, G.P.,
within. Curr. Opin. Neurobiol. 23 (4), 559e563. https://doi.org/10. Soldatos, C.R., 2007. Neuropsychological assessment of cognitive
1016/j.conb.2013.03.011. function in chronic alcohol-dependent patients and patients with
Kopelman, M.D., Thomson, A.D., Guerrini, I., Marshall, E.J., 2009. The Alzheimer’s disease. In Vivo (Athens Greece) 21 (6), 1115e1118.
Korsakoff syndrome: clinical aspects, psychology and treatment. Retrieved from: http://search.ebscohost.com/login.aspx?
Alcohol Alcohol. 44 (2), 148e154. https://doi.org/10.1093/alcalc/ direct¼true&db¼cmedm&AN¼18210766&site¼ehost-live.
agn118. Ling, J., Heffernan, T.M., Buchanan, T., Rodgers, J., Scholey, A.B.,
Kopera, M., Wojnar, M., Brower, K., Glass, J., Nowosad, I., Gmaj, B., Parrott, A.C., 2003. Effects of alcohol on subjective ratings of pro-
Szelenberger, W., 2012. Cognitive functions in abstinent alcohol- spective and everyday memory deficits. Alcohol Clin. Exp. Res. 27
dependent patients. Alcohol 46 (7), 665e671. https://doi.org/10. (6), 970e974. https://doi.org/10.1097/01.ALC.0000071741.63467.
1016/j.alcohol.2012.04.005. CB.
Kornreich, C., Blairy, S., Philippot, P., Hess, U., Noël, X., Streel, E., et al., Lockwood, A.H., Weissenborn, K., Bokemeyer, M., Tietge, U.,
2001. Deficits in recognition of emotional facial expression are still Burchert, W., 2002. Correlations between cerebral glucose meta-
present in alcoholics after mid- to long-term abstinence. J. Stud. bolism and neuropsychological test performance in nonalcoholic cir-
Alcohol 62 (4), 533e542. https://doi.org/https://doi.org/10.15288/jsa. rhotics. Metab. Brain Dis. 17 (1), 29e40. https://doi.org/10.1023/A:
2001.62.533. 1014000313824.
Kornreich, C., Philoppot, P., Foisy, M.-L., Blairy, S., Raynaud, E., Loeber, S., Duka, T., Welzel, H., Nakovics, H., Heinz, A., Flor, H.,
Dan, B., et al., 2002. Impaired emotional facial expression recognition Mann, K., 2009. Impairment of cognitive abilities and decision
is associated with interpersonal problems in alcoholism. Alcohol making after chronic use of alcohol: the impact of multiple de-
Alcohol. 37 (4), 394e400. https://doi.org/10.1093/alcalc/37.4.394. toxifications. Alcohol Alcohol. 44 (4), 372e381. https://doi.org/10.
Kril, J.J., Butterworth, R.F., 1997. Diencephalic and cerebellar pathology 1093/alcalc/agp030.
in alcoholic and nonalcoholic patients with end-stage liver disease. Loeber, S., Duka, T., Welzel Marquez, H., Nakovics, H., Heinz, A.,
Hepatology 26 (4), 837e841. https://doi.org/10.1002/hep.510260405. Mann, K., Flor, H., 2010. Effects of repeated withdrawal from alcohol
Latt, N., Dore, G., 2014. Thiamine in the treatment of Wernicke enceph- on recovery of cognitive impairment under abstinence and rate of
alopathy in patients with alcohol use disorders. Intern. Med. J. 44 (9), relapse. Alcohol Alcohol. 45 (6), 541e547. https://doi.org/10.1093/
911e915. https://doi.org/10.1111/imj.12522. alcalc/agq065.
Le Berre, A.P., Sullivan, E.V., 2016. Anosognosia for memory impairment Maharasingam, M., Macniven, J.A.B., Mason, O.J., 2013. Executive
in addiction: insights from neuroimaging and neuropsychological functioning in chronic alcoholism and Korsakoff syndrome. J. Clin.
assessment of metamemory. Neuropsychol. Rev. 26 (4), 420e431. Exp. Neuropsychol. 35 (5), 501e508. https://doi.org/10.1080/
https://doi.org/10.1007/s11065-016-9323-3. 13803395.2013.795527.
Mancinelli, R., Ceccanti, M., 2009. Biomarkers in alcohol misuse: their for Alzheimer’s disease. Alzheimer’s Dementia 7 (3), 263e269.
role in the prevention and detection of thiamine deficiency. Alcohol https://doi.org/10.1016/j.jalz.2011.03.005.
Alcohol. 44 (2), 177e182. https://doi.org/10.1093/alcalc/agn117. Mechtcheriakov, S., Brenneis, C., Egger, K., Koppelstaetter, F.,
Mann, K., Günther, A., Stetter, F., Ackermann, K., 1999. Rapid recovery Schocke, M., Marksteiner, J., 2007. A widespread distinct pattern of
from cognitive deficits in abstinent alcoholics: a controlled test-retest cerebral atrophy in patients with alcohol addiction revealed by voxel-
study. Alcohol Alcohol. 34 (4), 567e574. https://doi.org/10.1093/ based morphometry. J. Neurol. Neurosurg. Psychiatry 78 (6),
alcalc/34.4.567. 610e614. https://doi.org/10.1136/jnnp.2006.095869.
Manning, V., Wanigaratne, S., Best, D., Hill, R.G., Reed, L.J., Ball, D., Mendez, M.F., Chen, A.K., Shapira, J.S., Miller, B.L., 2005. Acquired
et al., 2008. Changes in neuropsychological functioning during sociopathy and frontotemporal dementia. Dement. Geriatr. Cognit.
alcohol detoxification. Eur. Addict. Res. 14 (4), 226e233. https://doi. Disord. 20 (2e3), 99e104. https://doi.org/10.1159/000086474.
org/10.1159/000156479. Mesulam, M.M., 1999. Spatial attention and neglect: parietal, frontal and
Marceau, E.M., Berry, J., Lunn, J., Kelly, P.J., Solowij, N., 2017. cingulate contributions to the mental representation and attentional
Cognitive remediation improves executive functions, self-regulation targeting of salient extrapersonal events. Phil. Trans. Biol. Sci. 354
and quality of life in residents of a substance use disorder therapeu- (1387), 1325e1346. https://doi.org/10.1098/rstb.1999.0482.
tic community. Drug Alcohol Depend. 178, 150e158. https://doi.org/ Miller, W., Rollnick, S., 1991. Motivational Interviewing: Preparing
10.1016/j.drugalcdep.2017.04.023. People to Change Addictive Behaviour. Guilford Press, New York,
Marinkovic, K., Oscar-Berman, M., Urban, T., O’Reilly, C.E., NY. https://doi.org/10.1002/casp.2450020410.
Howard, J.A., Sawyer, K., Harris, G.J., 2009. Alcoholism and Miyake, A., Friedman, N.P., Emerson, M.J., Witzki, A.H., Howerter, A.,
dampened temporal limbic activation to emotional faces. Alcohol Wager, T.D., 2000. The unity and diversity of executive functions and
Clin. Exp. Res. 33 (11), 1880e1892. https://doi.org/10.1111/j.1530- their contributions to complex “frontal lobe” tasks: a latent variable
0277.2009.01026.x. analysis. Cogn. Psychol. 41 (1), 49e100. https://doi.org/10.1006/
Martin, R.J., 2004. Central pontine and extrapontine myelinolysis: the cogp.1999.0734.
osmotic demyelination syndromes. J. Neurol. Neurosurg. Psychiatry Monnot, M., Nixon, S., Lovallo, W., Ross, E., 2001. Altered emotional
75 (Suppl. 3), iii22eiii28. https://doi.org/10.1136/jnnp.2004.045906. perception in alcoholics: deficits in affective prosody comprehension.
Maurage, P., Campanella, S., Philippot, P., Charest, I., Martin, S., De Alcohol Clin. Exp. Res. 25 (3), 362e369. https://doi.org/10.1111/j.
Timary, P., 2009. Impaired emotional facial expression decoding in 1530-0277.2001.tb02222.x.
alcoholism is also present for emotional prosody and body postures. Moriyama, Y., Mimura, M., Kato, M., Yoshino, A., Hara, T., Kashima, H.,
Alcohol Alcohol. 44 (5), 476e485. https://doi.org/10.1093/alcalc/ et al., 2002. Executive dysfunction and clinical outcome in chronic
agp037. alcoholics. Alcohol Clin. Exp. Res. 26 (8), 1239e1244. https://doi.
Maurage, P., Grynberg, D., Noël, X., Joassin, F., Philippot, P., Hanak, C., org/10.1111/j.1530-0277.2002.tb02662.x.
et al., 2011. Dissociation between affective and cognitive empathy in Mulhauser, K., Weinstock, J., Ruppert, P., Benware, J., 2018. Changes in
alcoholism: a specific deficit for the emotional dimension. Alcohol neuropsychological status during the initial phase of abstinence in
Clin. Exp. Res. 35 (9), 1662e1668. https://doi.org/10.1111/j.1530- alcohol use disorder: neurocognitive impairment and implications for
0277.2011.01512.x. clinical care. Subst. Use Misuse 53 (6), 881e890. https://doi.org/10.
Maurage, P., Joassin, F., Philippot, P., Heeren, A., Vermeulen, N., 1080/10826084.2017.1408328.
Mahau, P., et al., 2012. Disrupted regulation of social exclusion in Munro, C.A., Saxton, J., Butters, M.A., 2000. The neuropsychological
alcohol-dependence: an fmri study. Neuropsychopharmacology 37 consequences of abstinence among older alcoholics: a cross-sectional
(9), 2067e2075. https://doi.org/10.1038/npp.2012.54. study. Alcohol Clin. Exp. Res. 24 (10), 1510e1516. https://doi.org/
Maurage, F., de Timary, P., Tecco, J.M., Lechantre, S., Samson, D., 2015. 10.1097/00000374-200010000-00008.
Theory of mind difficulties in patients with alcohol dependence: Nandrino, J.-L., El Haj, M., Torre, J., Naye, D., Douchet, H., Danel, T.,
beyond the prefrontal cortex dysfunction hypothesis. Alcohol Clin. Cottençin, O., 2016. Autobiographical memory deficits in alcohol-
Exp. Res. 39 (6), 980e988. https://doi.org/10.1111/acer.12717. dependent patients with short- and long-term abstinence. Alcohol
Maurage, P., D’Hondt, F., de Timary, P., Mary, C., Franck, N., Clin. Exp. Res. 40 (4), 865e873. https://doi.org/10.1111/acer.
Peyroux, E., 2016. Dissociating affective and cognitive theory of mind 13001.
in recently detoxified alcohol-dependent individuals. Alcohol Clin. Nasreddine, Z.S., Phillips, N.A., Bédirian, V., Charbonneau, S.,
Exp. Res. 40 (9), 1926e1934. https://doi.org/10.1111/acer.13155. Whitehead, V., Collin, I., et al., 2005. The Montreal Cognitive
Maurage, P., de Timary, P., D’Hondt, F., 2017. Heterogeneity of Assessment, MoCA: a brief screening tool for mild cognitive
emotional and interpersonal difficulties in alcohol-dependence: a impairment. J. Am. Geriatr. Soc. 53 (4), 695e699. https://doi.org/10.
cluster analytic approach. J. Affect. Disord. 217, 163e173. https://doi. 1111/j.1532-5415.2005.53221.x.
org/10.1016/j.jad.2017.04.005. Nelson, T.O., Narens, L., 1990. Metamemory: a theoretical framwork and
McBride, W.J., 2002. Central nucleus of the amygdala and the effects of new findings. Psychol. Learn. Motiv. 26, 125e173.
alcohol and alcohol-drinking behavior in rodents. Pharmacol. Bio- Nelson, T.O., 1984. A comparison of current measures of the accuracy of
chem. Behav. 71 (3), 509e515. https://doi.org/10.1016/S0091- feeling-of-knowing predictions. Psychol. Bull. 95 (1), 109e133.
3057(01)00680-3. https://doi.org/10.1037/0033-2909.95.1.109.
McKhann, G.M., Knopman, D.S., Chertkow, H., Hyman, B.T., Jack, C.R., Nemlekar, S.S., Mehta, R.Y., Dave, K.R., Shah, N.D., 2016. Marchiafava:
Kawas, C.H., et al., 2011. The diagnosis of dementia due to Alz- bignami disease treated with parenteral thiamine. Indian J. Psychol.
heimer’s disease: recommendations from the National Institute on Med. 38 (2), 147e149. https://doi.org/10.4103/0253-7176.178810.
Aging-Alzheimer’s Association workgroups on diagnostic guidelines
Nixon, S.J., Tivis, R.D., Jenkins, M.R., Parsons, O.A., 1998. Effects of Parsons, O.A., 1998. Neurocognitive deficits in alcoholics and social
cues on memory in alcoholics and controls. Alcohol Clin. Exp. Res. drinkers: a continuum? Alcohol Clin. Exp. Res. 22 (4), 954e961.
22 (5), 1065e1069. https://doi.org/10.1111/j.1530-0277.1998. https://doi.org/10.1111/j.1530-0277.1998.tb03895.x.
tb03700.x. Pelletier, S., Nalpas, B., Alarcon, R., Rigole, H., Perney, P., 2016.
Noël, X., Van der Linden, M., Schmidt, N., Sferrazza, R., Hanak, C., Le Investigation of cognitive improvement in alcohol-dependent in-
Bon, O., et al., 2001. Supervisory attentional system in nonamnesic patients using the montreal cognitive assessment (MoCA) score.
alcoholic men. Arch. Gen. Psychiatry 58 (12), 1152. https://doi.org/ J. Addict. 2016, 1e7. https://doi.org/10.1155/2016/1539096.
10.1001/archpsyc.58.12.1152. Pelletier, S., Alarcon, R., Ewert, V., Forest, M., Nalpas, B., Perney, P.,
Noël, X., Van der Linden, M., D’Acremont, M., Bechara, A., Dan, B., 2018. Comparison of the MoCA and BEARNI tests for detection of
Hanak, C., Verbanck, P., 2007. Alcohol cues increase cognitive cognitive impairment in in-patients with alcohol use disorders. Drug
impulsivity in individuals with alcoholism. Psychopharmacology 192 Alcohol Depend. 187, 249e253. https://doi.org/10.1016/j.drugalcdep.
(2), 291e298. https://doi.org/10.1007/s00213-006-0695-6. 2018.02.026.
Noel, X., Van der Linden, M., Brevers, D., Campanella, S., Hanak, C., Petit, G., Luminet, O., Cordovil De Sousa Uva, M., Zorbas, A.,
Kornreich, C., Verbanck, P., 2012. The contribution of executive Maurage, P., De Timary, P., 2017. Differential spontaneous recovery
functions deficits to impaired episodic memory in individuals with across cognitive abilities during detoxification period in alcohol-
alcoholism. Psychiatry Res. 198 (1), 116e122. https://doi.org/10. dependence. PLoS One 12 (8), 1e18. https://doi.org/10.1371/
1016/j.psychres.2011.10.007. journal.pone.0176638.
Noël, X., Brevers, D., Bechara, A., 2013. A neurocognitive approach to Pfefferbaum, A., Sullivan, E.V., Mathalon, D.H., Shear, P.K.,
understanding the neurobiology of addiction. Curr. Opin. Neurobiol. Rosenbloom, M.J., Lim, K.O., 1995. Longitudinal changes in mag-
23 (4), 632e638. https://doi.org/10.1016/j.conb.2013.01.018. netic resonance imaging brain volumes in abstinent and relapsed al-
Nowakowska-Domagała, K., Jabłkowska-Górecka, K., Mokros, Ł., coholics. Alcohol Clin. Exp. Res. 19 (5), 1177e1191. https://doi.org/
Koprowicz, J., Pietras, T., 2017. Differences in the verbal fluency, 10.1111/j.1530-0277.1995.tb01598.x.
working memory and executive functions in alcoholics: short-term vs. Pfefferbaum, A., Sullivan, E.V., Rosenbloom, M.J., Mathalon, D.H.,
long-term abstainers. Psychiatry Res. 249, 1e8. https://doi.org/10. Lim, K.O., 1998. A controlled study of cortical gray matter and ven-
1016/j.psychres.2016.12.034. tricular changes in alcoholic men over a 5-year interval. Arch. Gen.
Onuoha, R.C., Quintana, D.S., Lyvers, M., Guastella, A.J., 2016. A meta- Psychiatry 55 (10), 905. https://doi.org/10.1001/archpsyc.55.10.905.
analysis of theory of mind in alcohol use disorders. Alcohol Alcohol. Pfefferbaum, A., Sullivan, E.V., Hedehus, M., Adalsteinsson, E.,
51 (4), 410e415. https://doi.org/10.1093/alcalc/agv137. Lim, K.O., Moseley, M., 2000. In vivo detection and functional cor-
Oscar-Berman, M., Marinkovic, K., 2003. Alcoholism and the brain: an relates of white matter microstructural disruption in chronic alco-
overview. Alcohol Res. Health 27 (2), 125e133. Retrieved from: holism. Alcohol Clin. Exp. Res. 24 (8), 1214e1221.
http://www.ncbi.nlm.nih.gov/pubmed/15303622. Pfefferbaum, A., Rosenbloom, M., Rohlfing, T., Sullivan, E.V., 2009.
Oscar-Berman, M., Shagrin, B., Evert, D.L., Epstein, C., 1997. Impair- Degradation of association and projection white matter systems in
ments of brain and behavior: the neurological effects of alcohol. alcoholism detected with quantitative fiber tracking. Biol. Psychiatry
Alcohol Health Res. World 21 (1), 65e75. Retrieved from: http:// 65 (8), 680e690. https://doi.org/10.1016/j.biopsych.2008.10.039.
www.ncbi.nlm.nih.gov/pubmed/15706764. Philippot, P., Kornreich, C., Blairy, S., Baert, I., Den Dulk, a, Le Bon, O.,
Oscar-Berman, M., Valmas, M.M., Sawyer, K.S., Kirkley, S.M., et al., 1999. Alcoholics’ deficits in the decoding of emotional facial
Gansler, D.A., Merritt, D., Couture, A., 2009. Frontal brain expression. Alcohol Clin. Exp. Res. 23 (6), 1031e1038 (pii). https://
dysfunction in alcoholism with and without antisocial personality doi.org/00000374-199906000-00010.
disorder. Neuropsychiatric Dis. Treat. 5 (1), 309e326. Pitel, A.L., Beaunieux, H., Witkowski, T., Vabret, F., Guillery-Girard, B.,
Oscar-Berman, M., Valmas, M.M., Sawyer, K.S., Ruiz, S.M., Luhar, R.B., Quinette, P., et al., 2007a. Genuine episodic memory deficits and
Gravitz, Z.R., 2014. Profiles of impaired, spared, and recovered executive dysfunctions in alcoholic subjects early in abstinence.
neuropsychologic processes in alcoholism. Handb. Clin. Neurol. 125. Alcohol Clin. Exp. Res. 31 (7), 1169e1178. https://doi.org/10.1111/j.
https://doi.org/10.1016/B978-0-444-62619-6.00012-4. 1530-0277.2007.00418.x.
Oscar-Berman, M., 2012. Function and dysfunction of prefrontal brain Pitel, A.L., Witkowski, T., Vabret, F., Guillery-Girard, B., Desgranges, B.,
circuitry in alcoholic Korsakoff’s syndrome. Neuropsychol. Rev. 22 Eustache, F., Beaunieux, H., 2007b. Effect of episodic and working
(2), 154e169. https://doi.org/10.1007/s11065-012-9198-x. memory impairments on semantic and cognitive procedural learning at
Oudman, E., Van der Stigchel, S., Postma, A., Wijnia, J.W., alcohol treatment entry. Alcohol Clin. Exp. Res. 31 (2), 238e248.
Nijboer, T.C.W., 2014. A case of chronic Wernicke’s encephalopathy: https://doi.org/10.1111/j.1530-0277.2006.00301.x.
a neuropsychological study. Front. Psychiatry 5 (59). https://doi.org/ Pitel, A.L., Beaunieux, H., Witkowski, T., Vabret, F., de la Sayette, V.,
10.3389/fpsyt.2014.00059. Viader, F., et al., 2008. Episodic and working memory deficits in
Pandey, A.K., Kamarajan, C., Tang, Y., Chorlian, D.B., Roopesh, B.N., alcoholic Korsakoff patients: the continuity theory revisited. Alcohol
Manz, N., et al., 2012. Neurocognitive deficits in male alcoholics: an Clin. Exp. Res. 32 (7), 1229e1241. https://doi.org/10.1111/j.1530-
ERP/sLORETA analysis of the N2 component in an equal probability 0277.2008.00677.x.
Go/NoGo task. Biol. Psychol. 89 (1), 170e182. https://doi.org/10. Pitel, A.L., Rivier, J., Beaunieux, H., Vabret, F., Desgranges, B.,
1016/j.biopsycho.2011.10.009. Eustache, F., 2009. Changes in the episodic memory and executive
Parmanand, H.T., 2016. MarchiafavaeBignami disease in chronic alco- functions of abstinent and relapsed alcoholics over a 6-month period.
holic patient. Radiol. Case Rep. 11 (3), 234e237. https://doi.org/10. Alcohol Clin. Exp. Res. 33 (3), 490e498. https://doi.org/10.1111/j.
1016/j.radcr.2016.05.015. 1530-0277.2008.00859.x.
Pitel, A.L., Perruchet, P., Vabret, F., Desgranges, B., Eustache, F., static balance with abstinence in alcoholic men and women: selective
Beaunieux, H., 2010. The advantage of errorless learning for the relations with change in brain structure. Psychiatry Res. Neuro-
acquisition of new concepts’ labels in alcoholics. Psychol. Med. 40 imaging 155 (2), 91e102. https://doi.org/10.1016/j.pscychresns.2006.
(3), 497e502. https://doi.org/10.1017/S0033291709990626. 12.019.
Pitel, A.L., Zahr, N.M., Jackson, K., Sassoon, S.A., Rosenbloom, M.J., Rourke, S.B., Grant, I., 1999. The interactive effects of age and length of
Pfefferbaum, A., Sullivan, E.V., 2011. Signs of preclinical wernicke’s abstinence on the recovery of neuropsychological functioning in
encephalopathy and thiamine levels as predictors of neuropsycho- chronic male alcoholics: a 2-year follow-up study. J. Int. Neuro-
logical deficits in alcoholism without Korsakoff’s syndrome. Neuro- psychol. Soc. 5 (3), 234e246. https://doi.org/10.1017/
psychopharmacology 36 (3), 580e588. https://doi.org/10.1038/npp. S1355617799533067.
2010.189. Rupp, C.I., Kemmler, G., Kurz, M., Hinterhuber, H., Fleischhacker, W.,
Pitel, A.L., Chételat, G., Le Berre, A.P., Desgranges, B., Eustache, F., 2012. Cognitive remediation therapy during treatment for alcohol
Beaunieux, H., 2012. Macrostructural abnormalities in Korsakoff dependence. J. Stud. Alcohol Drugs 73 (4), 625e634. https://doi.org/
syndrome compared with uncomplicated alcoholism. Neurology 78 10.15288/jsad.2012.73.625.
(17), 1330e1333. https://doi.org/10.1212/WNL.0b013e318251834e. Rupp, C.I., Derntl, B., Osthaus, F., Kemmler, G., Fleischhacker, W., 2017.
Pitel, A.L., Segobin, S.H., Ritz, L., Eustache, F., Beaunieux, H., 2015. Impact of social cognition on alcohol dependence treatment outcome:
Thalamic abnormalities are a cardinal feature of alcohol-related brain poorer facial emotion recognition predicts relapse/dropout. Alcohol
dysfunction. Neurosci. Biobehav. Rev. 54, 38e45. https://doi.org/10. Clin. Exp. Res. 41 (12), 2197e2206. Epub 2017 Nov 10. https://doi.
1016/j.neubiorev.2014.07.023. org/10.1111/acer.13522.
Prochaska, J.O., DiClemente, C.C., 1983. Stages and processes of self- Ryan, C., Butters, N., 1980. Learning and memory impairments in young
change of smoking: toward an integrative model of change. and old alcoholics: evidence for the premature aging hypothesis.
J. Consult. Clin. Psychol. https://doi.org/10.1037/0022-006X.51.3.390. Alcohol Clin. Exp. Res. 4 (3), 288e293. https://doi.org/10.1111/j.
Randolph, C., Hilsabeck, R., Kato, A., Kharbanda, P., Li, Y.-Y., 1530-0277.1980.tb04816.x.
Mapelli, D., et al., 2009. Neuropsychological assessment of hepatic Ryback, R.S., 1971. The continuum and specificity of the effects of
encephalopathy: ISHEN practice guidelines. Liver Int. 29 (5), alcohol on memory. A review. Q. J. Stud. Alcohol 32 (4), 995e1016.
629e635. https://doi.org/10.1111/j.1478-3231.2009.02009.x. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/4944697.
Ratti, M.T., Bo, P., Giardini, A., Soragna, D., 2002. Chronic alcoholism Salgado, J.V., Malloy-Diniz, L.F., Campos, V.R., Abrantes, S.S.C.,
and the frontal lobe: which executive functions are imparied? Acta Fuentes, D., Bechara, A., Correa, H., 2009. Neuropsychological
Neurol. Scand. 105 (4), 276e281. https://doi.org/10.1034/j.1600- assessment of impulsive behavior in abstinent alcohol-dependent
0404.2002.0o315.x. subjects. Rev. Bras. Psiquiatr. 31 (1), 4e9. https://doi.org/10.1590/
Reed, R.J., Grant, I., Rourke, S.B., 1992. Long-term abstinent alcoholics S1516-44462009000100003.
have normal memory. Alcohol Clin. Exp. Res. 16 (4), 677e683. Salmon, D.P., Butters, N., Schuckit, M., 1986. Memory for temporal order
https://doi.org/10.1111/j.1530-0277.1992.tb00660.x. and frequency of occurrence in detoxified alcoholics. Alcohol 3 (5),
Ritz, L., Segobin, S., Le Berre, A.P., Lannuzel, C., Boudehent, C., 323e329. https://doi.org/10.1016/0741-8329(86)90009-1.
Vabret, F., et al., 2014. Brain structural substrates of cognitive pro- Samson, D., 2009. Reading other people’s mind: insights from neuro-
cedural learning in alcoholic patients early in abstinence. Alcohol Clin. psychology. J. Neuropsychol. 3 (1), 3e16. https://doi.org/10.1348/
Exp. Res. 38 (8), 2208e2216. https://doi.org/10.1111/acer.12486. 174866408X377883.
Ritz, L., Lannuzel, C., Boudehent, C., Vabret, F., Bordas, N., Segobin, S., Schuckit, M.A., 2006. Comorbidity between substance use disorders and
et al., 2015. Validation of a brief screening tool for alcohol-related psychiatric conditions. Addiction 101 (Suppl. 1), 76e88. https://doi.
neuropsychological impairments. Alcohol Clin. Exp. Res. 39 (11), org/10.1111/j.1360-0443.2006.01592.x.
2249e2260. https://doi.org/10.1111/acer.12888. Schulte, T., M~uller-Oehring, E.M., Pfefferbaum, A., Sullivan, E.V., 2010.
Ritz, L., Coulbault, L., Lannuzel, C., Boudehent, C., Segobin, S., Neurocircuitry of emotion and cognition in alcoholism: contributions
Eustache, F., et al., 2016a. Clinical and biological risk factors for from white matter fiber tractography. Dialogues Clin. Neurosci. 12
neuropsychological impairment in alcohol use disorder. PLoS One 11 (4), 554e560. https://doi.org/10.1002/gepi.20430.
(9), 1e14. https://doi.org/10.1371/journal.pone.0159616. Schulte, T., Oberlin, B.G., Kareken, D.A., Marinkovic, K., Müller-
Ritz, L., Segobin, S., Lannuzel, C., Boudehent, C., Vabret, F., Oehring, E.M., Meyerhoff, D.J., Tapert, S., 2012. How acute and
Eustache, F., et al., 2016b. Direct voxel-based comparisons between chronic alcohol consumption affects brain networks: insights from
grey matter shrinkage and glucose hypometabolism in chronic alco- multimodal neuroimaging. Alcohol Clin. Exp. Res. 36 (12),
holism. J. Cereb. Blood Flow Metab. 36 (9), 1625e1640. https://doi. 2017e2027. https://doi.org/10.1111/j.1530-0277.2012.01831.x.
org/10.1177/0271678X15611136. Schwartz, B.L., Parker, E.S., Deutsch, S.I., Rosse, R.B., Kaushik, M.,
Roehrich, L., Goldman, M.S., 1993. Experience-dependent neuropsycho- Isaac, A., 2002. Source monitoring in alcoholism. J. Clin. Exp.
logical recovery and the treatment of alcoholism. J. Consult. Clin. Neuropsychol. 24 (6), 806e817. https://doi.org/10.1076/jcen.24.6.
Psychol. 61 (5), 812e821. https://doi.org/10.1037/0022-006X.61.5.812. 806.8406.
Rosenbloom, M.J., Pfefferbaum, A., Sullivan, E.V., 2004. Recovery of Schwarzinger, M., Pollock, B.G., Hasan, O.S.M., Dufouil, C., Rehm, J.,
short-term memory and psychomotor speed but not postural stability Baillot, S., et al., 2018. Contribution of alcohol use disorders to the
with long-term sobriety in alcoholic women. Neuropsychology 18 (3), burden of dementia in France 2008e13: a nationwide retrospective
589e597. https://doi.org/10.1037/0894-4105.18.3.589. cohort study. Lancet Public Health 3 (3), e124ee132. https://doi.org/
Rosenbloom, M.J., Rohlfing, T., O’Reilly, A.W., Sassoon, S.A., 10.1016/S2468-2667(18)30022-7.
Pfefferbaum, A., Sullivan, E.V., 2007. Improvement in memory and
Segobin, S.H., Chételat, G., Le Berre, A.-P., Lannuzel, C., Boudehent, C., Sullivan, E.V., Fama, R., Rosenbloom, M.J., Pfefferbaum, A., 2002.
Vabret, F., et al., 2014. Relationship between brain volumetric A profile of neuropsychological deficits in alcoholic women. Neuro-
changes and interim drinking at six months in alcohol-dependent psychology 16 (1), 74e83. https://doi.org/10.1037/0894-4105.16.1.74.
patients. Alcohol Clin. Exp. Res. 38 (3), 739e748. https://doi.org/ Sullivan, E.V., Zahr, N.M., Sassoon, S.A., Thompson, W.K., Kwon, D.,
10.1111/acer.12300. Pohl, K.M., Pfefferbaum, A., 2018. The role of aging, drug depen-
Segobin, S., Ritz, L., Lannuzel, C., Boudehent, C., Vabret, F., dence, and hepatitis C comorbidity in alcoholism cortical compromise.
Eustache, F., et al., 2015. Integrity of white matter microstructure in JAMA Psychiatry 75 (5), 474e483. https://doi.org/10.1001/
alcoholics with and without Korsakoff’s syndrome. Hum. Brain jamapsychiatry.2018.0021.
Mapp. 36 (7), 2795e2808. https://doi.org/10.1002/hbm.22808. Sullivan, E.V., 2003. Compromised pontocerebellar and cer-
Sehgal, V., Kesav, P., Modi, M., Ahuja, C.K., 2013. Acute Marchiafava- ebellothalamocortical systems: speculations on their contributions to
Bignami disease presenting as reversible dementia in a chronic alco- cognitive and motor impairment in nonamnesic alcoholism. Alcohol
holic. Case Rep. https://doi.org/10.1136/bcr-2012-008286. Clin. Exp. Res. 27 (9), 1409e1419. https://doi.org/10.1097/01.ALC.
Sheedy, D., Lara, A., Garrick, T., Harper, C., 1999. Size of mamillary 0000085586.91726.46.
bodies in health and disease: useful measurements in neuroradiolog- Tapert, S.F., Brown, G.G., Kindermann, S.S., Cheung, E.H., Frank, L.R.,
ical diagnosis of Wernicke’s encephalopathy. Alcohol Clin. Exp. Res. Brown, S.A., 2001. fMRI measurement of brain dysfunction in
23 (10), 1624e1628. Retrieved from: https://www.ncbi.nlm.nih.gov/ alcohol- dependent young women. Alcohol Clin. Exp. Res. 25 (2),
pmc/articles/PMC4519197/pdf/nihms385423.pdf. 236e245.
Sherer, M., 1992. Performance of alcoholic and brain-damaged subjects on Tapert, S.F., Ozyurt, S.S., Myers, M.G., Brown, S.A., 2004. Neuro-
the Luria memory words test. Arch. Clin. Neuropsychol. 7 (6), cognitive ability in adults coping with alcohol and drug relapse
499e504. https://doi.org/10.1016/0887-6177(92)90139-E. temptations. Am. J. Drug Alcohol Abuse 30 (2), 445e460. https://doi.
Singh, T.D., Fugate, J.E., Rabinstein, A.A., 2014. Central pontine and org/10.1081/ADA-120037387.
extrapontine myelinolysis: a systematic review. Eur. J. Neurol. 21 Tedstone, D., Coyle, K., 2004. Cognitive impairments in sober alcoholics:
(12), 1443e1450. https://doi.org/10.1111/ene.12571. performance on selective and divided attention tasks. Drug Alcohol
Sobell, L.C., Sobell, M.B., 1992. Timeline follow-back. Measuring Depend. 75 (3), 277e286. https://doi.org/10.1016/j.drugalcdep.2004.
Alcohol Consumption. Humana Press, Totowa, NJ, pp. 41e72. 03.005.
https://doi.org/10.1007/978-1-4612-0357-5_3. Thoma, P., Friedmann, C., Suchan, B., 2013. Empathy and social problem
Sofuoglu, M., DeVito, E.E., Waters, A.J., Carroll, K.M., 2013. Cognitive solving in alcohol dependence, mood disorders and selected person-
enhancement as a treatment for drug addictions. Neuropharmacology ality disorders. Neurosci. Biobehav. Rev. Pergamon https://doi.org/10.
64, 452e463. https://doi.org/10.1016/j.neuropharm.2012.06.021. 1016/j.neubiorev.2013.01.024.
Stavro, K., Pelletier, J., Potvin, S., 2013. Widespread and sustained Thomson, A.D., 2000. Mechanisms of vitamin deficiency in chronic
cognitive deficits in alcoholism: a meta-analysis. Addict. Biol. 18 (2), alcohol misusers and the development of the Wernicke-Korsakoff
203e213. https://doi.org/10.1111/j.1369-1600.2011.00418.x. syndrome. Alcohol Alcohol. 35 (Suppl. 1), 2e1. https://doi.org/10.
Stephan, R.A., Alhassoon, O.M., Allen, K.E., Wollman, S.C., Hall, M., 1093/alcalc/35.Supplement_1.2.
Thomas, W.J., et al., 2017. Meta-analyses of clinical neuropsycho- Trivedi, R., Bagga, D., Bhattacharya, D., Kaur, P., Kumar, P., Khushu, S.,
logical tests of executive dysfunction and impulsivity in alcohol use et al., 2013. White matter damage is associated with memory decline
disorder. Am. J. Drug Alcohol Abuse 43 (1), 24e43. https://doi.org/ in chronic alcoholics: a quantitative diffusion tensor tractography
10.1080/00952990.2016.1206113. study. Behav. Brain Res. 250, 192e198. https://doi.org/10.1016/j.bbr.
Sullivan, E.V., Pfefferbaum, A., 2009. Neuroimaging of the Wernicke- 2013.05.001.
Korsakoff syndrome. Alcohol Alcohol. 44 (2), 155e165. https://doi. Trucco, E.M., Connery, H.S., Griffin, M.L., Greenfield, S.F., 2007. The
org/10.1093/alcalc/agn103. relationship of self-esteem and self-efficacy to treatment outcomes of
Sullivan, E.V., Mathalon, D.H., Chung, N.H., Zipursky, R.B., alcohol-dependent men and women. Am. J. Addict. 16 (2), 85e92.
Pfefferbaum, A., 1992. The contribution of constructional accuracy https://doi.org/10.1080/10550490601184183.
and organizational strategy to nonverbal recall in Schizophrenia and Tulving, E., Schacter, D.L., 1990. Priming and human memory systems.
chronic alcoholism. Biol. Psychiatry 32 (4), 312e333. https://doi.org/ Science (New York N.Y.) 247, 301e306. https://doi.org/10.1126/
10.1016/0006-3223(92)90036-Y. science.2296719.
Sullivan, E.V., Marsh, L., Mathalon, D.H., Lim, K.O., Pfefferbaum, A., Tulving, E., 1985. Memory and consciousness. Can. Psychol. Psychol.
1995. Anterior hippocampal volume deficits in nonamnesic, aging Can. 26 (1), 1e12. https://doi.org/10.1037/h0080017.
chronic alcoholics. Alcohol Clin. Exp. Res. 19 (1), 110e122. https:// Tulving, E., 2001. Episodic memory and common sense: how far apart?
doi.org/10.1111/j.1530-0277.1995.tb01478.x. Phil. Trans. Biol. Sci. 356 (1413), 1505e1515. https://doi.org/10.
Sullivan, E.V., Lane, B., Deshmukh, A., Rosenbloom, M.J., 1098/rstb.2001.0937.
Desmond, J.E., Lim, K.O., Pfefferbaum, A., 1999. In vivo mammil- Uekermann, J., Daum, I., 2008. Social cognition in alcoholism: a link to
lary body volume deficits in amnesic and nonamnesic alcoholics. prefrontal cortex dysfunction? Addiction. https://doi.org/10.1111/j.
Alcohol Clin. Exp. Res. 23 (10), 1629e1636. https://doi.org/10.1111/ 1360-0443.2008.02157.x.
j.1530-0277.1999.tb04054.x. Valls-Serrano, C., Caracuel, A., Verdejo-Garcia, A., 2016. Goal manage-
Sullivan, E.V., Rosenbloom, M.J., Pfefferbaum, A., 2000. Pattern of motor ment training and mindfulness meditation improve executive functions
and cognitive deficits in detoxified alcoholic men. Alcohol Clin. Exp. and transfer to ecological tasks of daily life in polysubstance users
Res. 24 (5), 611e621. https://doi.org/10.1111/j.1530-0277.2000. enrolled in therapeutic community treatment. Drug Alcohol Depend.
tb02032.x. 165, 9e14. https://doi.org/10.1016/j.drugalcdep.2016.04.040.
van Eijk, J., Demirakca, T., Frischknecht, U., Hermann, D., Mann, K., hazardous drinkers. Addiction 105 (2), 279e287. https://doi.org/10.
Ende, G., 2013. Rapid partial regeneration of brain volume during the 1111/j.1360-0443.2009.02775.x.
first 14 days of abstinence from alcohol. Alcohol Clin. Exp. Res. 37 Wiers, R.W., Eberl, C., Rinck, M., Becker, E.S., Lindenmeyer, J., 2011.
(1), 67e74. https://doi.org/10.1111/j.1530-0277.2012.01853.x. Retraining automatic action tendencies changes alcoholic patients’
Van Oort, R., Kessels, R.P.C., 2009. Executive dysfunction in Korsakoff’s approach bias for alcohol and improves treatment outcome. Psychol.
syndrome: time to revise the DSM criteria for alcohol-induced per- Sci. 22 (4), 490e497. https://doi.org/10.1177/0956797611400615.
sisting amnestic disorder? Int. J. Psychiatry Clin. Pract. 13 (1), 78e81. World Health Organisation, 2014. Global Status Report on Alcohol and
https://doi.org/10.1080/13651500802308290. health 2014. Global Status Report on Alcohol, pp. 1e392. https://doi.
Veltro, F., Mazza, M., Vendittelli, N., Alberti, M., Casacchia, M., org//entity/substance_abuse/publications/global_alcohol_report/en/
Roncone, R., 2011. A comparison of the effectiveness of problem index.html.
solving training and of cognitive-emotional rehabilitation on neuro- Wrase, J., Grüsser, S.M., Klein, S., Diener, C., Hermann, D., Flor, H.,
cognition, social cognition and social functioning in people with et al., 2002. Development of alcohol-associated cues and cue-induced
schizophrenia. Clin. Pract. Epidemiol. Ment. Health 7 (1), 123e132. brain activation in alcoholics. Eur. Psychiatry 17 (5), 287e291.
https://doi.org/10.2174/1745017901107010123. https://doi.org/10.1016/S0924-9338(02)00676-4.
Verdejo-García, A., Pérez-García, M., 2008. Substance abusers’ self- Yang, P., Tao, R., He, C., Liu, S., Wang, Y., Zhang, X., 2018. The risk
awareness of the neurobehavioral consequences of addiction. Psy- factors of the alcohol use disordersdthrough review of its comor-
chiatry Res. 158 (2), 172e180. https://doi.org/10.1016/j.psychres. bidities. Front. Neurosci. 12, 1e7. https://doi.org/10.3389/fnins.2018.
2006.08.001. 00303.
Vilstrup, H., Amodio, P., Bajaj, J., Cordoba, J., Ferenci, P., Mullen, K.D., Zadro, L., Boland, C., Richardson, R., 2006. How long does it last? The
et al., 2014. Hepatic encephalopathy in chronic liver disease: 2014 persistence of the effects of ostracism in the socially anxious. J. Exp.
practice guideline by the American association for the study of liver Soc. Psychol. 42 (5), 692e697. https://doi.org/10.1016/j.jesp.2005.10.
diseases and the European Association for the study of the liver. 007.
Hepatology 60 (2), 715e735. https://doi.org/10.1002/hep.27210. Zahr, N.M., Pfefferbaum, A., 2017. Alcohol’s Effects on the Brain:
Wegner, A.J., Gunthner, A., Fahle, M., 2001. Visual performance and Neuroimaging Results in Humans and Animal Models. Alcohol
recovery in recently detoxified alcoholics. Alcohol Alcohol. 36 (2), Research: Current Reviews 38 (2), 183e206. Retrieved from: http://
171e179. https://doi.org/10.1093/alcalc/36.2.171. www.ncbi.nlm.nih.gov/pubmed/28988573.
Wernicke, C., 1881. Lehrbuch der Gehirnkheiten fur Artze und Studier- Zahr, N.M., Pitel, A.L., Chanraud, S., Sullivan, E.V., 2010. Contributions
ende. Fischer, Berlin. of studies on alcohol use disorders to understanding cerebellar func-
Wester, A.J., Van Herten, J., Egger, J., Kessels, R., 2013a. Applicability of tion. Neuropsychol. Rev. 20 (3), 280e289. https://doi.org/10.1007/
the rivermead behavioural memory test - third edition (RBMT-3) in s11065-010-9141-y.
Korsakoff’s syndrome and chronic alcoholics. Neuropsychiatric Dis. Zeichner, A., Alien, J.D., Giancola, P.R., Lating, J.M., 1994. Alcohol and
Treat. 9, 875e881. https://doi.org/10.2147/NDT.S44973. aggression: effects of personal threat on human aggression and af-
Wester, A.J., Westhoff, J., Kessels, R.P.C., Egger, J.I.M., 2013b. The fective arousal. Alcohol Clin. Exp. Res. 18 (3), 657e663. https://doi.
Montreal cognitive assessment (MoCA) as a measure of severity of org/10.1111/j.1530-0277.1994.tb00927.x.
amnesia in patients with alcohol-related cognitive impairments and Zinn, S., Stein, R., Swartzwelder, H.S., 2004. Executive functioning early
Korsakoff syndrome. Clin. Neuropsychiatry 10 (3e4), 134e141. in abstinence from alcohol. Alcohol Clin. Exp. Res. 28 (9),
Wheeler, M.A., Stuss, D.T., Tulving, E., 1997. Toward a theory of 1338e1346. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/
episodic memory: the frontal lobes and autonoetic consciousness. 15365304.
Psychol. Bull. 121 (3), 331e354. https://doi.org/10.1037/0033-2909. Zywiak, W.H., Westerberg, V.S., Connors, G.J., Maisto, S.A., 2003.
121.3.331. Exploratory findings from the reasons for drinking questionnaire.
Wiers, R.W., Rinck, M., Kordts, R., Houben, K., Strack, F., 2010. J. Subst. Abus. Treat. 25 (4), 287e292. https://doi.org/10.1016/
Retraining automatic action-tendencies to approach alcohol in S0740-5472(03)00118-1.
Chapter 9
Tobacco addiction: cognition,

reinforcement, and mood
Merideth A. Addicott
Department of Psychiatry, University of Arkansas for Medical Science, Little Rock, AR, United States
Introduction lesbian/gay/bisexual community, uninsured or covered by

Medicaid, and low ranking members of the military (Phil-
This chapter introduces current research topics in tobacco lips et al., 2017; Drope et al., 2018). These disparities may
addiction, beginning with a brief overview of the scope of have arisen from intentional tobacco industry targeting
the tobacco use problem and pharmacology of nicotine and (e.g., retail density is higher in low income neighborhoods),
tobacco. This chapter then focuses on three specific areas of reduced access to smoking cessation support, less support
research: nicotine and tobacco’s effects on cognition, and/or pressure to quit smoking, and perhaps an increased
reinforcement enhancement, and mood regulation. In each vulnerability for tobacco addiction. In particular, these
section, I review recent work in these areas. While relevant populations may experience high levels of social and/or
behavioral experiments in animals and human are dis- economic stress that feeds into the emotionesmoking
cussed, there is an emphasis on neuroimaging research. relationship (see The emotionesmoking relationship
section).
Scope of the problem Compared with the general population, smoking is also
much higher among individuals with serious psychological
Smoking prevalence distress and mental illness, including schizophrenia, bipolar
Tobacco is the second most used drug after caffeine, used disorder, attention-deficit hyperactivity disorder, major
by about 30% of men and 6% of women worldwide (Ng depression, anxiety/panic disorders, posttraumatic stress
et al., 2014). Currently in the United States, about 20% of disorder, alcohol or other drug use disorders, and gambling
adults use some form of tobacco, with cigarettes being the addiction (Grant and Potenza, 2005; Weinberger et al.,
most common followed by electronic cigarettes (e-cigs), 2016; Phillips et al., 2017; Drope et al., 2018).
cigars/cigarillos, smokeless tobacco (e.g., chewing tobacco
or snuff), and pipe (e.g., pipe, waterpipe/hookah) (Phillips
Smoking-related morbidity and mortality
et al., 2017). Given its prevalence, this review is focused on
cigarette smoking. Cigarette smoking continues to be the leading cause of
Among American adults, smoking rates have declined preventable morbidity and mortality. It is responsible for
from a peak of about 40% in the 1960s to about 15% in 12.7% of all deaths in high-income countries (Lopez et al.,
2017. However, between 35 and 40 million American 2006). It is well known that smoking causes cancer, and
adults currently smoke an average of 14 cigarettes per day there are at least 70 carcinogens in cigarette smoke (FDA,
(cigs/day) (Jamal et al., 2016; Drope et al., 2018). Despite 2012). Smoking also causes chronic obstructive pulmonary
the overall decline, some groups of people continue to have disease, type II diabetes, heart attacks, and strokes (Rostron
high smoking rates. Tobacco use, cigarette smoking in et al., 2014). There is no safe level of smoking, as in-
particular, tends to be higher among individuals with low dividuals who smoke only 1 cig/day have half the risk of
education level (no more than a high school education), low developing coronary heart disease as individuals who
socioeconomic status (earning <$35,000/year), physical smoke 20 cig/day (not 1/20th the risk as might be expected)
disabilities, and individuals who are American Indian/ (Hackshaw et al., 2018). Smoking is also associated with
Alaska Natives, living in the Midwest, members of the reproductive risks, such as infertility, spontaneous abortion,

low birth weight, and sudden infant death syndrome but the primary concern regarding e-cigs is their use among
(DHHS, 2016). Among HIV smokers receiving antiretro- adolescents and young adults. E-cig use increased 900%
viral therapy, more years of life are lost due to smoking between 2011 and 2015 among high school students, and e-
than to the HIV infection (Pacek and Cioe, 2015). In- cigs are now the most commonly used tobacco product
dividuals with chronic mental illness die prematurely pri- among youth (DHHS, 2016). Adolescents may become
marily due to cardiovascular disease and cancer (Colton addicted to nicotine in e-cigs, face long-term health con-
and Manderscheid, 2006), which can be caused or exac- sequences from inhaling e-cig vapor, and switch to con-
erbated by smoking. ventional cigarettes. Preventing adolescents from
experimenting with tobacco products is critical to
decreasing smoking rates across the life span.
Smoking cessation
Tobacco addiction is a chronic, relapsing disorder, and Tobacco policy in the United States and the
many smokers will make repeated quit attempts throughout
world
their lives. Quitting smoking at any age significantly re-
duces the associated health risks. By 2015, 59% of adults in The tobacco industry has played a major role in the prev-
the United States who had ever smoked had quit, 68% of alence of cigarette smoking in the United States via mass
current smokers reported that they wanted to quit, and 55% production and widespread advertising. Although the
reported making a past year quit attempt, of which about medical community had been aware of the link between
7% were successful (Babb et al., 2017). Smoking cessation smoking and disease before the 1960s, fierce opposition
support consists of pharmacotherapies and psychosocial from tobacco companies stymied policy and social change
therapies/support groups that can increase cessation success and even promoted the beneficial health effects of smoking
by 82%, although few smokers use proven cessation in cigarette advertisements (DHHS, 2014). In 1998, internal
treatments. Unfortunately, in 2017, only about two-thirds of documents from the tobacco industry became widely
smokers reported receiving advice from health pro- available as the result of the Master Settlement Agreement.
fessionals to quit in spite of the high morbidity and mor- These documents reveal the internal operations of the in-
tality burden (Babb et al., 2017). dustry regarding how they profited off the sale of tobacco
while preventing litigation, resisting regulation, and pro-
Electronic cigarettes tecting industry credibility. To accomplish these goals, they
actively deceived the public and policy makers about the
E-cigs and vaporizers are devices that use a battery- health risks of smoking, created controversy about these
powered heating element to aerosolize a cartridge of health risks, used lawyers extensively in the decision-
liquid nicotinedalong with flavorants and other making process, and used third parties to hide political
additivesdfor the user to inhale. The e-liquid usually lobbying, among other activities (Bero, 2003).
contains propylene glycol and/or glycerin as a solvent and Since the 1960s, there have been gradual changes in
flavorants, such as fruit or candy flavors. Nicotine con- tobacco control policies in the United States, including
centrations vary from 0 mg/mL up to 36 mg/mL (DHHS, warning labels on tobacco products, disclosure of tar and
2016), and the concentration of nicotine inhaled also de- nicotine content of cigarettes, antismoking public service
pends on the battery power and puff topography announcements, prohibition of tobacco advertisements in
(e.g., duration and volume of inhalation). some media, banning smoking in public places, taxes on
Given their recent rise in popularity, the long-term ef- cigarettes to deter sales, and prohibition of the sale of to-
fects of e-cig use is poorly understood, but e-cigs can bacco to minors (DHHS, 2014). In 2009, the Family
expose users to carbonyl compounds and volatile organic Smoking Prevention and Tobacco Control Act was signed
compounds, nitrosamines, formaldehyde, acetaldehyde, into law, giving the Food and Drug Administration (FDA)
and glycidol, which are thought to have adverse health the power to regulate tobacco, including the ability to set
effects (DHHS, 2016). Another health threat is the acci- national standards for the nicotine content, manufacture,
dental ingestion of liquid nicotine. The number of calls to labeling, advertising, and sale of all tobacco products
poison control centers regarding e-cig fluid exposure have (Gostin, 2009). As of 2017, the FDA is considering tobacco
risen dramatically since 2010 (Kim and Baum, 2015). product standards that would reduce nicotine in cigarettes
Although they are not marketed as smoking cessation to a minimal or nonaddictive level, considering regulating
aids, some smokers report using e-cigs to cut back or quit tobacco flavors, such as menthol, and considering actions to
smoking (Etter and Bullen, 2011; Siegel et al., 2011). But increase access to nicotine replacement therapies (FDA,
other evidence indicates the development of co-use among 2017).
conventional cigarette smokers (Pokhrel et al., 2015). For In 2005, the World Health Organization entered into
current smokers, e-cigs may be a means of harm reduction, force the Framework Convention on Tobacco Control
Tobacco addiction: cognition, reinforcement, and mood Chapter | 9 131
(FCTC), a global health treaty designed to stem the ionotropic nicotinic receptors (nAChRs), both of which are
epidemic of tobacco-related health problems. The FCTC located pre- and postsynaptically (Picciotto et al., 2012).
recommends a series of actions to achieve this goal, nAChRs are ligand-gated ion channels composed of five a
including measures to reduce both supply and demand of and b subunits. The a4b2* (*indicates possible presence of
tobacco products. For example, recommendations include other subunits) is one of the most abundant nAChR sub-
preventing tobacco industry interference with tobacco types in the human brain and is believed to mediate nicotine
control policies, banning tobacco advertisements and in- addiction (Benowitz, 2009).
dustry sponsorships, and increasing price and taxes to
reduce demand. By 2018, implementation of these recom- Neural effects of nicotine
mendations across countries varied from 13% to 88%
(WHO, 2018). The most successfully implemented actions Low doses of nicotine (equivalent to the absorption from 1
have been restricting smoking in public places, placing cigarette, 0.2e2.4 mg) improve mood, enhance arousal,
health warnings on tobacco packages, educating tobacco and can produce a brief, mild euphoric sensation (Kalman,
users, and restricting sales to minors (WHO, 2018). There 2002). Moderate doses of nicotine are anxiogenic and cause
remains a significant unmet need for cessation support, and vomiting, dizziness, abdominal pain, hypertension, and
Parties to the FCTC have been slow to implement tobacco tachycardia (Kim and Baum, 2015). High doses (>50 mg)
cessation measures, possibly due to the costs or uncertain cause hypotension, bradycardia, dyspnea, loss of con-
effectiveness of tobacco cessation treatment (Raw et al., sciousness, seizure, coma, and death (Mayer, 2014; Kim
2017). and Baum, 2015).
Nicotine acutely agonizes nAChRs on dopamine (DA)
neurons in the ventral tegmental area and nucleus accum-
Pharmacology bens, which stimulates DA release in the mesolimbic
Chemicals in tobacco smoke pathway. Nicotine also indirectly facilitates DA release by
enhancing glutamate release (Benowitz, 2009). Nicotine
Nicotine is an alkaloid found in the tobacco plant and acts administration releases other neurotransmitters, including
as a naturally occurring insecticide. Nicotine is considered ACh, norepinephrine, and gamma-aminobutyric acid
the primary psychoactive substance responsible for tobacco (GABA) (Wonnacott, 1997).
addiction. However, cigarette smoke contains >7000 At nicotine concentrations typical for daily smokers,
chemicals (Rodgman and Perfetti, 2009). Other chemicals a4b2* receptors are nearly saturated (Brody et al., 2006)
in cigarette smoke may be psychoactive and either have and are likely in a desensitized state (i.e., have a reduced
their own abuse potential or contribute to the abuse po- effect). nAChRs return to a sensitized state following
tential of nicotine (Hoffman and Evans, 2013). These overnight abstinence. Chronic daily smoking upregulates
chemicals include acetaldehyde (a major metabolite of nAChRs (Mukhin et al., 2008), thought to be due to the
alcohol), minor alkaloids (e.g., nornicotine, myosmine, prolonged desensitization, and also downregulates DA re-
cotinine, anabasine, anatabine), and b-carbolines ceptors in the striatum (Dagher et al., 2001). Nicotine has a
(e.g., harman and norharman) (Rupprecht et al., 2015). half-life of about 2 h (Benowitz et al., 1982), and with-
Furthermore, commercial tobacco products contain other drawal symptoms may begin as little as an hour after the
additives as preservatives, moisteners, and flavors that last cigarette. Symptoms include cigarette craving, irrita-
affect the burn rate, aroma, and rate of nicotine absorption bility, anxiety, difficulty concentrating, increased appetite,
(Goodman, 2005). restlessness, depressed mood, and insomnia (APA, 2013).
Withdrawal symptoms peak within the first week of absti-
Acetylcholine system nence and last 2e4 weeks (Hughes, 2007), although ciga-
rette cue-induced cravings can continue and even escalate
Nicotine agonizes nicotinic acetylcholine receptors over time (Bedi et al., 2011). Smoking cessation results in
(nAChRs). In the brain, acetylcholine (ACh) is a neuro- readaptations in nAChR; the density of b2 subunit nor-
modulator (i.e., a neurotransmitter that is not directly malizes to nonsmoker levels after 6e12 weeks of absti-
excitatory or inhibitory) that regulates cerebral blood flow, nence (Cosgrove et al., 2009).
cortical activity, sleep/wake cycle, cognitive function
(learning and memory in particular), and neural plasticity
Addiction liability
(Schliebs and Arendt, 2006). ACh neurons are found in the
pedunculopontine and laterodorsal tegmental areas, the Tobacco has a higher rate of dependence among users than
medial habenula, and the basal forebrain, and these neurons other drugs of abuse (Lopez-Quintero et al., 2011), which
project throughout the brain. There are two classes of ACh appears incongruent with the modest, acute effects of low
receptors (AChRs): metabotropic muscarinic receptors and nicotine doses. An important mediator between initial
smoking and addiction may be the age of acquisition. brain into networks, identified by their synchronous
Approximately 90% of adult daily smokers initiated use coupling of spontaneous activity fluctuations at rest and
before the age of 18, and nearly all began before the age of when engaged in a cognitive task. This is referred to as
25 (DHHS, 2014). Adolescence is a critical period for brain “functional connectivity” and represents the efficiency of
development and is marked by increased plasticity and neural communication within and between brain networks.
rapid growth of neural circuits that underlie social, Three major networks include the executive control
emotional, and motivational processes. Many of these network, which is active during cognitive task perfor-
processes are regulated by the prefrontal cortex, which mance, the default mode network, which is active during
continues developing into young adulthood, up to 25 years rest, and the salience network, which switches between
of age. The combination of immature prefrontal cognitive them (Seeley et al., 2007; Buckner et al., 2008; Goulden
control and increased reactivity of subcortical rewarde et al., 2014).
related processes may lead to a greater susceptibility to Nicotine and nAChR agonists may diminish default
addiction (DHHS, 2016). In fact, symptoms of nicotine mode network activity and/or enhance executive control
dependence can precede daily smoking among adolescents network activity, thus improving cognition by shifting
(Gervais et al., 2006). This, in combination with tobacco brain network activity from internally directed to externally
availability and popularity, may partly account for high directed processes (Sutherland et al. 2012, 2015). For
rates of tobacco addiction. example, in nonsmokers, nicotine suppressed activity in the
default mode network and increased activity in the visual
attention network (Tanabe et al., 2011).
Cognitive effects of nicotine and
tobacco
Long-term effects
Short-term effects
Long-term tobacco smoke exposure has been associated
Nicotine influences a range of cognitive processes, such as with cognitive deficits across the life span. Secondhand
reaction time, attention, learning, and memory. nAChRs smoke exposure in children and fetuses produces cognitive
have a role in encoding new memories; agonists enhance deficits later in life (Swan and Lessov-Schlaggar, 2007).
encoding of new information and antagonists produce For example, tobacco smoke extract (compared with
memory deficits (Felix and Levin, 1997; Prickaerts et al., nicotine alone) administered to pregnant rats in doses
2012). However, the effects on memory performance have equivalent to secondhand smoke produced hyperactivity,
been demonstrated in rodents more than in humans (Levin working memory deficits, and impaired emotional pro-
et al., 2006). In nonabstinent smokers and nonsmokers, cessing in their adolescent and adult offspring (Hall et al.,
nicotine has primarily been shown to reduce reaction times 2016). Smoking during adolescence produces both acute
on tests of attention and memory (Levin et al., 2006; Swan and long-term impairments in cognition and attention, and
and Lessov-Schlaggar, 2007; Heishman et al., 2010). nicotine exposure in adolescent rats produces long-lasting
It is possible that the broad array of nicotine effects on synaptic changes in prefrontal cortical regions that may
cognition are indirectly due to its effects on attentional underlie cognition and attention (DHHS, 2016). These
performance: nicotine could simply improve the ability to cognitive deficits may be partly due to smoking-related
focus attention and maintain task engagement and reduce smaller gray matter volume and lower gray matter den-
the influence of distracting irrelevant stimuli (Evans and sity, especially in the prefrontal cortex (Brody et al., 2004;
Drobes, 2009). In addition, nicotine’s effects on cognitive Gallinat et al., 2006; Vnukova et al., 2017). Smoking is also
performance may depend on the level of effort required by associated with cognitive deficits and decline in late life,
the task, the individual’s baseline level of performance, or and it may increase the risk of neurodegeneration in Alz-
their underlying cholinergic function. Nicotine improves heimer’s disease or other dementias possibly via oxidative
attention in people with poor baseline performance, such as stress, inflammation, or atherosclerosis (Swan and Lessov-
schizophrenia and attention deficit/hyperactivity disorder, Schlaggar, 2007).
which may explain why certain populations with poor
attentional performance are at higher risk of tobacco
Withdrawal effects
dependence (Evans and Drobes, 2009). Furthermore, ge-
netic variations in ACh and DA receptors could contribute Nicotine withdrawal impairs response inhibition, attention,
to individual differences in the attentional effects of nico- reaction time, and working memory (McClernon et al.,
tine (Ahrens et al., 2015). 2015). Although, the most consistent effects of overnight
Functional neuroimaging measures how nicotine and smoking abstinence are on subjective withdrawal symp-
tobacco withdrawal affect brain activity. Recent neuro- toms such as craving, negative mood, self-reported diffi-
imaging work focuses on the functional organization of the culty concentrating, and increased hunger. Abstinence
effects on cognitive performance are generally of a smaller of tobacco addiction. There are a couple different hypoth-
magnitude but reliably show deficits such as slower reac- eses about how this mechanism works:
tion times (Leventhal et al., 2010). Neuroimaging studies
(1) Nicotine may be enhancing the reinforcement strength
suggest that these cognitive deficits relate to dysfunction in
of other primary reinforcers or amplifying their incen-
frontal cortical areas (McClernon et al., 2015). One of the
tive salience (Chaudhri et al., 2006; Rupprecht et al.,
most consistent effects of withdrawal is on diminished
2015). Specifically, rats’ response rates to obtain both
sustained attention, which may indirectly contribute to
a nondrug reinforcer and nicotine are twice the response
other cognitive deficits (Evans and Drobes, 2009). Smok-
rate produced for either reinforcer alone (Donny et al.,
ing, or nicotine administration, can improve these deficits
2003). This couse of nicotine and other reinforcers ap-
in withdrawn smokers. For example, nicotine improved
pears to parallel some human behavior, such as non-
cued spatial attentional orienting among withdrawn
daily smokers using tobacco while socializing,
smokers who had slower reaction time (RT)s at baseline;
attending parties, and/or drinking alcohol (Nguyen
which supports the idea of baseline performance de-
and Zhu, 2009; Shiffman et al., 2009). Another example
pendency of nicotine’s attentional effects (Hammersley
is that taking a break from school/work to relax and so-
et al., 2016). In another study, individual differences in
cialize with friends/coworkers can elicit tobacco crav-
cognitive withdrawal symptom improvement during nico-
ings if frequently paired with smoking (i.e., a “smoke
tine replacement were associated with inverse coupling
break”). The repeated pairing of smoking with other re-
between the executive control network and the default
inforcers may be an important phase in the transition
mode network (Cole et al., 2010). This suggests that the
from initial use to tobacco addiction.
therapeutic effects of nicotine replacement are related to
(2) Neutral stimuli consistently paired with nicotine may
modulation of brain processes involved in cognitive
become conditioned stimuli that develop their own sec-
control.
ondary reinforcing properties (Palmatier et al., 2007).
Cognitive improvement may be a form of smoking
For example, when initially experienced, the sensori-
reinforcement, especially when it reverses the effects of
motor aspects of smoking (e.g., sight, smell, flavor,
withdrawal. Although there is some quantitative evidence
throat sensation, and hand to mouth motion) may be
for improvements in cognition, nicotine could indirectly
subjectively aversive, but over time, these aspects can
influence cognitive performance by improving mood and
become reinforcing on their own. In fact, replacing
the motivation to maintain attention and exert cognitive
smokers’ cigarettes with denicotinized cigarettes will
effort. This may be a small improvement above smokers’
maintain smoking behavior (Donny and Jones, 2009).
baseline function or a return to baseline during withdrawal
(Evans and Drobes, 2009). Outside the laboratory, the subjective effects of nicotine
may play a role in the initial use and acquisition of
smoking, but over time, tobacco use becomes associated
Nicotine reinforcement with contextual cues, such as one’s mood and surrounding
Reinforcement enhancement environment, in addition to the nonnicotine sensorimotor
aspects of smoking. Habitual cigarette smoking is main-
Nicotine is a weak primary reinforcer compared with other
tained by this conditioning, as many smokers reach for a
drugs of abuse. Rats that have been trained to self-
cigarette while driving their car, with a cup of coffee or
administer cocaine will work harder for the drug as the
glass of beer. Likewise, withdrawal symptoms such as ir-
schedule of reinforcement becomes more challenging
ritability and anxiety can be alleviated by smoking a
(Richardson and Roberts, 1996), but rats tend to not work
cigarette, thus smokers can become conditioned to regard
harder for nicotine (Rupprecht et al., 2015). Nicotine alone stress and frustration derived from any source as a cue for
does support modest levels of rat self-administration, but
smoking (Benowitz, 2009).
nicotine self-administration is facilitated by having a paired
sensory stimulus cue, such as a sound or light, even if the
stimulus itself has little to no reinforcing value on its own Neural mechanisms
(Sorge et al., 2009). Interestingly, pairing nicotine with
another weak, unconditioned reinforcer produces a syner- Although classical conditioning paradigms based on animal
gistic effect on motivation to obtain both (Donny et al., models may not be fully reproducible in humans because of
2003). This synergy is referred to as “reinforcement the amount of time involved, neuroimaging studies can
enhancement” (Caggiula et al., 2009), and this may be a provide insights into neural mechanisms of how nicotine
critical mechanism for understanding the discrepancy be- interacts with nondrug reinforcers (usually money) in the
tween the modest abuse liability of nicotine and the tenacity absence of behavioral effects.
An important concept in reinforcement learning is pre- an anticipatory money-reward cue phase, followed by a
diction errordthe difference between the cue-predicted feedback phase indicating whether any money was won on
outcome and the actual outcome (i.e., what was expected that trial based on the individual’s performance. This type
vs. what was received). Prediction errors may serve to alert of paradigm typically elicits activation in the striatum and
and orient the individual’s attention to the discrepancy. The prefrontal cortex as well as other regions (e.g., Knutson
orienting of attention can then drive additional learning and et al., 2001) and has been used in a number of studies to
memory about the cueeoutcome relationship, ultimately investigate the acute and chronic effects of nicotine and
helping the individual adapt its behavior to changes in the tobacco. This research tends to show that nicotine increases
environment. DA signaling in the mesolimbic pathway activation to anticipatory cues (Fedota et al., 2015; Moran
appears to code prediction errors. There is a phasic DA et al., 2018) and reward feedback (Addicott et al., 2019)
signal following unexpected natural rewards, and this (although one study reported acute nicotine reduced antic-
signal shifts to a predictive cue after classical conditioning ipatory activation in satiated smokers) (Rose et al., 2013),
(Schultz and Dickinson, 2000). Nicotine helps boost DA and smoking withdrawal reduces activation to reward
transmission and could potentially enhance DA signaling of feedback (Sweitzer et al., 2014; Addicott et al., 2019).
prediction errors, thereby amplifying the saliency of reward However, smokers’ anticipation-related activation for
cues or outcomes, or improve attention, learning, and cigarette reward is greater than for money reward during
memory for these events. Perhaps by strengthening the withdrawal (Sweitzer et al., 2014). This could account for
cueeoutcome relationship, nicotine enhances learning and the withdrawal-induced bias toward anticipation of smok-
memory for its own use. Conversely, if withdrawal ing rewards at the expense of other, nondrug rewards,
dampens prediction errors, perhaps this is related to anhe- which motivates smoking behavior and interferes with
donic effects of withdrawal (i.e., loss of interest in alter- cessation success.
native reinforcers). Alternatively, nicotine and tobacco
withdrawal may affect tonic DA tone or both tonic and
phasic signaling (Zhang et al., 2012). The emotionesmoking relationship
There have been a few neuroimaging studies on how Smoking as a maladaptive response to negative
nicotine/smoking affects prediction error signaling during
mood
classical conditioning, although results have been mixed.
Compared with nonsmokers, smokers had reduced predic- Tobacco addiction disproportionately affects individuals
tion error signaling in the striatum and medial prefrontal with mood disorders. Compared with never smokers,
cortex, which was related to the duration of smoking in smokers are 1.85 times more likely to have depression, 1.71
years (Rose et al., 2012). Although these smokers were not times more likely to have anxiety, and 1.69 times more
withdrawn, this may inform the anhedonic consequences of likely to experience psychological distress (Taylor et al.,
smoking cessation. In nonsmokers, both unexpected out- 2014a). Nicotine and other nAChR agonists have antide-
comes and acute nicotine increased activation in the ante- pressant effects (Gandelman et al., 2018), and smoking
rior insula, which is part of the salience network, and may could potentially mitigate symptoms of depression while
subserve how nicotine amplifies the salience of nondrug nicotine withdrawal exacerbates them. A smoker’s pro-
reinforcers (Addicott et al., 2017). Another study reported pensity to relieve stress and negative mood by smoking
that smoking withdrawal decreased the signal associated parsimoniously explains emotion-smoking comorbidity
with phasic DA signals across both expected and unex- (Leventhal and Zvolensky, 2015).
pected outcomes, suggesting that changes in phasic DA are Several important concepts related to the emotione
unlikely contributing to reward processing deficits (Oliver smoking relationship are anhedonia, anxiety sensitivity,
et al., 2016). An interesting twist in this line of research is and distress tolerance. Anhedonia is the loss of an ability to
the influence of drug expectations. Smokers who believed feel pleasure and may be a symptom of tobacco withdrawal
they were smoking nicotine-free cigarettes had less neural (Cook et al., 2017). High levels of anhedonia have been
responses in the striatum to reward prediction errors, negatively associated with smokers’ time to relapse (Cook
compared with when they were told they were smoking et al., 2010). Anxiety sensitivity is the belief that symptoms
nicotine cigarettes. These effects were not observed in other of anxiety are intolerable or have harmful consequences,
brain regions activated by the task. This suggests that be- and it is related to more severe nicotine withdrawal
liefs about the presence of a neuroactive substance such as symptoms (Zvolensky et al., 2004). During a quit attempt,
nicotine can override its physical presence. Evidently, drug smokers with high anxiety sensitivity had a greater risk of
expectation is an important cognitive mechanism in smoking on days when they experienced increased negative
addiction (Gu et al., 2015). affect (Langdon et al., 2016). Distress tolerance is the
A related type of neuroimaging paradigm used to un- ability to pursue a goal (e.g., smoking cessation) in spite of
derstand the function of the mesolimbic DA pathway uses physical or psychological distress (e.g., withdrawal
symptoms or cigarette craving). Laboratory-based behav- signaling in the interpeduncular nucleus, and overactivation
ioral measures of distress tolerance have been positively of neurons in the interpeduncular nucleus intermediate
associated with smokers’ time to lapse/relapse (Brown subregion may be responsible for anxiogenic effects of
et al., 2009; Kahler et al., 2013), and low distress tolerance withdrawal (Molas et al., 2017).
may be related to diminished top-down cognitive control of
behavior during stress (Daughters et al., 2016). The role of the insular cortex
Leventhal and Zvolensky wrote a comprehensive re-
view and analysis of research linking anhedonia, anxiety The insular cortex, folded deeply within the lateral sulcus,
sensitivity, and distress tolerance to smoking behaviors, plays a special role in the emotionesmoking relationship.
including the initiation of smoking, progression to regular The insula is integral to interoception (i.e., the conscious
smoking, tobacco addiction/dependence, cessation, and awareness of the internal state of one’s body) and its sub-
lapse/relapse. To summarize, smoking is particularly rein- jective emotional interpretation (Craig, 2009). The insula is
forcing for individuals with poor emotional regulation also connected to cognitive control brain regions that sub-
because smoking can enhance positive affect, relieve anx- serve goal-directed behavior (Nelson et al., 2010; Chang
iety, and terminate distress. Individuals with anhedonia, et al., 2013). This is highly relevant to addiction because
anxiety sensitivity, and low distress tolerance may be the insula may link the physical and emotional awareness
hypermotivated to react to emotional disturbance with of drug withdrawal and cravings to volitional drug-taking
smoking behavior. They may also be more sensitive to the behavior (e.g., smoking a cigarette in response to
effects of smoking on affective state. Likewise, these three craving) (Garavan, 2010; Naqvi et al., 2014).
emotional vulnerabilities amplify the effects of tobacco A landmark study reported that smokers with stroke-
withdrawal on loss of reward, anxiogenesis, and distress induced insula lesions were more likely to quit smoking
exacerbation (Leventhal and Zvolensky, 2015). easily, notably with a sudden loss of the urge to smoke or
“disruption of smoking addiction” (Naqvi et al., 2007).
Although this retrospective study was limited by potentially
Neural mechanisms
inaccurate recollection of smokers’ behavior, several pro-
Common to many mental illnesses, including addictions, is spective studies have reported similar results. One study
an increased sensitivity to stress or elevated stress levels found that smokers with insula lesions were more likely to
(Esch et al., 2002). Across different drug addictions, stress have quit smoking 1-year poststroke and had less difficulty
often provokes craving and relapse (Mantsch et al., 2016), quitting (Suner-Soler et al., 2012), although a follow-up
and chronic stress is an important trigger for relapse during investigation showed insula lesions no longer predicted
a smoking cessation attempt (McKee et al., 2003). In fact, abstinence at 6-years poststroke (Suner-Soler et al., 2018).
acute stress, which can reinstate extinguished drug-seeking Other prospective studies have shown that strokes affecting
behavior, is an animal model for relapse (Shaham et al., the basal ganglia, and the basal ganglia and the insula, were
2003). more likely to result in smoking cessation at 12-months
Several different neural mechanisms may underlie the poststroke (Gaznick et al., 2014), and smokers with
stressesmoking relationship. To begin with, cholinergic insula lesions had less withdrawal symptom severity during
signaling in the hippocampus, amygdala, prefrontal cortex, hospitalization (Abdolahi et al., 2015). With one exception
and striatum modulates behavioral responses to stressors (Bienkowski et al., 2010) these studies support the role of
(Higley and Picciotto, 2014). In addition, stress-related the insula in tobacco addiction.
drug-taking behaviors are associated with amygdala func- Neuroimaging studies of neurologically intact smokers
tion (Sharp, 2017), and noradrenergic and cholinergic also support a role for the insula. At rest, smokers have
signaling in the amygdala regulate anxiety- and depression- weaker functional connectivity between the insula and
related behaviors (Mineur et al., 2018). Another neural other brain regions than nonsmokers (Bi et al., 2017; Zhou
mechanism is the extrahypothalamic corticotropine et al., 2017). Weaker insula connectivity among smokers
releasing factor receptor system, which elicits anxiety- has also been associated with an increased likelihood of
related behaviors and is thought to be related to negative lapse and relapse (Janes et al., 2010; Addicott et al., 2015;
mood states associated with withdrawal from nicotine or Zelle et al., 2017). Alternatively, while viewing cigarette-
other drugs (George et al., 2007). This system is also related images, stronger insula connectivity was associ-
implicated in stress-induced reinstatement of nicotine- ated with the magnitude of smokers’ craving (Maria et al.,
seeking behavior (Zislis et al., 2007). Lastly, the medial 2015) and with increased pleasantness ratings for smoking
habenulaeinterpeduncular axis has a high density of images during withdrawal (Avery et al., 2017). Although
nAChRs, and accumulating evidence suggests that this axis an insula lesion may lessen the interoceptive awareness of
relates to fear/anxiety-related responses. Animal studies withdrawal or cravings, in an intact brain, the insula co-
have shown nicotine withdrawal increases glutamatergic ordinates with other brain regions to respond, or inhibit a
response, to cravings according to one’s goal to smoke or failed (Berlin et al., 2010). However, another study re-
remain abstinent. Thus, both stronger and weaker connec- ported that successful quitters did not show significant
tivity between the insula and other brain regions can sup- changes in depression or anxiety over a 1-month period,
port tobacco addiction or smoking cessation. nor did quitting contribute to adverse mental health out-
comes (Capron et al., 2014).
Cause, consequence, or shared underlying Ultimately, long-term cessation is associated with im-
provements in depression, anxiety, stress, and mood, both
mechanism
in the general population and clinical populations. This is
Is smoking a cause or consequence of mood disorders? The perhaps due to breaking the cycle of recurring withdrawal
“self-medication” hypothesis postulates that symptoms of symptoms. Effect sizes on the improvements in mood due
mood disorders precede smoking and smoking helps alle- to smoking cessation are equal or larger than those of an-
viate these symptoms, suggesting that tobacco addiction is tidepressant treatment for mood and anxiety disorders
a consequence of these disorders. Smoking may provide (Taylor et al., 2014b). Long-term cessation may even lead
temporary relief of negative mood symptoms and improve to a reduced incidence of depression (Shahab et al., 2014;
arousal and motivation, while nicotine withdrawal could Bakhshaie et al., 2015). Potentially, quitting smoking im-
exacerbate negative mood symptoms and interfere with proves mental health, or improving mental health assists
tobacco cessation efforts. As smokers learn to modulate cessation, or there is a common underlying factor. How-
their mood with tobacco, they may lose the ability to ever, existing studies cannot determine causality (Taylor
engage alternative coping mechanisms, thus becoming et al., 2014b).
more and more dependent on smoking to provide stress Smokers with mood disorders and other mental illnesses
relief. face additional barriers to smoking cessation. The most
Alternatively, smoking may increase the risk of commonly cited barriers are the management of mental
depression or anxiety. Chronic nicotine dysregulates the illness symptoms (i.e., smoking to improve attention/
hypothalamicepituitaryeadrenal axis, which leads to hy- cognition/motivation, reduce negative affect, cope with
persecretion of cortisol and changes in associated mono- stress) and social barriers (i.e., smoking is a way to fit in,
amine neurotransmitters (Markou et al., 1998). Ultimately, smoking with peers) (Trainor and Leavey, 2017). The ef-
this can change the response to stress and exacerbate ficacy of pharmacotherapy is similar between smokers with
symptoms of depression and anxiety over time, suggesting and without mental illness (West et al., 2018), but the high
that tobacco addiction can cause mood disorders. However, rates of smoking suggest that tobacco cessation programs
recent genetic research does not suggest a causal role for designed for the general population are poorly integrated,
smoking heaviness in the development of depression and less effective, or not addressing the additional barriers faced
anxiety (Taylor et al., 2014a; Skov-Ettrup et al., 2017). A by individuals with mental illness (Cook et al., 2014).
review of longitudinal studies reported that about 50% of Research is needed on the development and implementa-
studies provided evidence that smoking was a consequence tion of effective cessation interventions for this group
of depression or anxiety, and about 33% of studies pro- (Metse et al., 2017).
vided evidence that smoking caused depression and anxi-
ety. However, there was substantial heterogeneity across
studies in populations, design, and diagnostic measures Recommendations for clinicians and
(Fluharty et al., 2017). researchers
It is also possible that smoking and mood disorders
Given its broad range of negative health effects, clinicians
have a shared etiology or develop in conjunction with one
in all fields of medicine should discuss tobacco use with
another. There may be shared genetic vulnerability, or early
their patients, especially e-cig use with adolescent patients.
life stress may precipitate the onset and progression of both.
Unfortunately, many clinicians and health-care systems do
not treat tobacco use consistently and effectively (Fiore
Smoking cessation and mood et al., 2008b), possibly because clinicians lack training in
Despite the interaction between smoking and mood, tobacco intervention strategies, or health-care systems lack
smokers with mental illness desire to quit smoking similar policies for routine tobacco screening and intervention.
to smokers in the general population (Prochaska et al., However, many resources are available to help guide dis-
2017). However, their actual rates of smoking cessation are cussions about patients’ smoking (e.g., Fiore et al., 2008a).
lower (RCP, 2013). This could be due to an exacerbation of Additionally, the National Institutes of Health provides a
mood symptoms during withdrawal. Among smokers with free toolbox (nihtoolbox.org) of standardized measures of
mood disorders, anxiety and depression may initially smoking and tobacco use, such as emotional and health
worsen during a quit attempt, especially if the quit attempt expectations for smoking, motivations for smoking, and
nicotine dependence severity. These measures can help improves attention, especially in populations with poor
improve communication between clinicians and patients. baseline performance characteristic of some mental ill-
The research reviewed in this chapter brings together nesses. Neuroimaging studies suggest that these cognitive
the cognitive, affective, and reinforcing effects of nicotine effects may relate to enhancement of the executive control
and tobacco. There is an ongoing need for smoking network (engaged by externally driven processes, e.g., a
cessation therapies that target where and how these three cognitive task), suppression of the default mode network
areas overlap. In particular, we need cessation interventions (engaged by internally driven processes, e.g., while day-
tailored to specific populations, such as people with dreaming), or a combination of both. Likewise, tobacco
schizophrenia, depression, type II diabetes, or substance withdrawal may change the relationship between these two
use disorders. Each group has its own set of challenges and networks. If true, future research in this area ought to
standard of care. Smoking cessation interventions should be investigate how these networks can be manipulated to
custom fit for each population. As described in this chapter, support tobacco cessation, via pharmacological or non-
smoking has a high rate of comorbidity with other psy- pharmacological (e.g., neurofeedback, transcranial mag-
chiatric disorders, especially substance use disorders. If a netic stimulation) methods.
patient is undergoing treatment for a serious substance use It is difficult to understand why tobacco is so highly
disorder, his/her smoking may not be considered a priority. addictive, given its modest acute effects. The extent of
However, evidence suggests that smoking can act syner- classical conditioning (i.e., the number of times cigarette
gistically with other drugs of abuse, and treatment for to- smoking is paired with another stimulus or experience) and
bacco dependence does not interfere with treatment for the age of initiation play critical roles in the transition from
other substance use disorders (e.g., alcoholism) (Kalman occasional to daily smoking. Nicotine appears to enhance
et al., 2010). Clinicians should consider providing con- the motivation for other reinforcers as well, which is
current treatment for tobacco and other substance use dis- evident in the amount of effort expended to obtain other
orders. Importantly, research should investigate if quitting reinforcers when nicotine is physiologically present and in
smoking improves overall well-being and therapeutic out- DA-rich mesolimbic brain activation when anticipating or
comes for other physical and mental health problems. receiving other reinforcers. Research in this area is
important to understanding withdrawal-related anhedonia
and the loss of motivation for nondrug rewards.
Summary and conclusions As the smoking rates in the general population decline,
In summary, tobacco remains a widely used drug. Although there may be less concern or funding for tobacco addiction
cigarettes are the most commonly used form of tobacco, e- research. This may leave many vulnerable populations
cig use is on the rise. The popularity of e-cigs among ad- understudied and underserved. As tobacco addiction is a
olescents and young adults is especially troubling because pervasive disease that interacts with and exacerbates other
the risk of developing nicotine addiction and then tran- physical and mental illnesses, treatment for tobacco
sitioning to cigarette usage could undermine the decline in addiction should be an integral part of primary care
smoking rates. Now that the FDA has the power to regulate medicine.
tobacco, additional policies could be implemented to
reduce nicotine content and flavorants in tobacco and e-cigs References
to help prevent such a reversal. While smoking rates have
Abdolahi, A., Williams, G.C., Benesch, C.G., Wang, H.Z., Spitzer, E.M.,
generally been in decline, certain populations, such as those et al., 2015. Damage to the insula leads to decreased nicotine with-
with mental illness, have persistently high rates of smoking. drawal during abstinence. Addiction 110, 1994e2003.
One explanation for this is the relationship between Addicott, M.A., Oliver, J.A., Joseph McClernon, F., 2017. Nicotine in-
smoking and mood regulation. Many smokers, especially creases anterior insula activation to expected and unexpected out-
those experiencing anhedonia and anxiety, smoke to relieve comes among nonsmokers. Psychopharmacology (Berl.) 234,
negative mood and stress. Withdrawal symptoms can 1145e1154.
exacerbate negative moods and create an additional barrier Addicott, M.A., Sweitzer, M., McClernon, F.J., 2019. The effects of
to cessation. Evidence suggests that quitting smoking can nicotine and tobacco use on brain reward function: interaction with
improve mood in the long term, but additional research is nicotine dependence severity. Nicotine Tob. Res. 21, 764e771.
Addicott, M.A., Sweitzer, M.M., Froeliger, B., Rose, J.E.,
needed to improve the efficacy of smoking cessation
McClernon, F.J., 2015. Increased functional connectivity in an insula-
treatments for individuals with mental illness and affective based network is associated with improved smoking cessation out-
distress. comes. Neuropsychopharmacology 40, 2648e2656.
There may be some overlap in the effects of nicotine Ahrens, S., Markett, S., Breckel, T.P.K., Behler, O., Reuter, M., et al.,
and tobacco on mood and on cognitive performance. As 2015. Modulation of nicotine effects on selective attention by DRD2
mood is improved by smoking, there may be increased and CHRNA4 gene polymorphisms. Psychopharmacology 232,
motivation to concentrate and perform well. Nicotine 2323e2331.
APA, 2013. Diagnostic and Statistical Manual of Mental Disorders: DSM- Chaudhri, N., Caggiula, A.R., Donny, E.C., Palmatier, M.I., Liu, X., et al.,
5. American Psychiatric Association, Washington, DC. 2006. Complex interactions between nicotine and nonpharmacological
Avery, J.A., Burrows, K., Kerr, K.L., Bodurka, J., Khalsa, S.S., et al., stimuli reveal multiple roles for nicotine in reinforcement. Psycho-
2017. How the brain wants what the body needs: the neural basis of pharmacology 184, 353e366.
positive alliesthesia. Neuropsychopharmacology 42, 822e830. Cole, D.M., Beckmann, C.F., Long, C.J., Matthews, P.M., Durcan, M.J.,
Babb, S., Malarcher, A., Schauer, G., Asman, K., Jamal, A., 2017. Quit- et al., 2010. Nicotine replacement in abstinent smokers improves
ting smoking among adults - United States, 2000-2015. Morb. Mortal. cognitive withdrawal symptoms with modulation of resting brain
Wkly. Rep. 65, 1457e1464. network dynamics. Neuroimage 52, 590e599.
Bakhshaie, J., Zvolensky, M.J., Goodwin, R.D., 2015. Cigarette smoking Colton, C.W., Manderscheid, R.W., 2006. Congruencies in increased
and the onset and persistence of depression among adults in the United mortality rates, years of potential life lost, and causes of death among
States: 1994e2005. Compr. Psychiatry 60, 142e148. public mental health clients in eight states. Prev. Chronic Dis. 3, A42.
Bedi, G., Preston, K.L., Epstein, D.H., Heishman, S.J., Marrone, G.F., Cook, B.L., Wayne, G.F., Kafali, E.N., Liu, Z., Shu, C., et al., 2014.
et al., 2011. Incubation of cue-induced cigarette craving during Trends in smoking among adults with mental illness and association
abstinence in human smokers. Biol. Psychiatry 69, 708e711. between mental health treatment and smoking cessation. JAMA 311,
Benowitz, N.L., 2009. Pharmacology of nicotine: addiction, smoking- 172e182.
induced disease, and therapeutics. Annu. Rev. Pharmacol. Toxicol. Cook, J., Spring, B., McChargue, D., Doran, N., 2010. Effects of anhe-
49, 57e71. donia on days to relapse among smokers with a history of depression:
Benowitz, N.L., Jacob, P., Jones, R.T., Rosenberg, J., 1982. Interindi- a brief report. Nicotine Tob. Res. 12, 978e982.
vidual variability in the metabolism and cardiovascular effects of Cook, J.W., Lanza, S.T., Chu, W.H., Baker, T.B., Piper, M.E., 2017.
nicotine in man. J. Pharmacol. Exp. Ther. 221, 368e372. Anhedonia: its dynamic relations with craving, negative affect, and
Berlin, I., Chen, H.N., Covey, L.S., 2010. Depressive mood, suicide treatment during a quit smoking attempt. Nicotine Tob. Res. 19,
ideation and anxiety in smokers who do and smokers who do not 703e709.
manage to stop smoking after a target quit day. Addiction 105, Cosgrove, K.P., Batis, J., Bois, F., Maciejewski, P.K., Esterlis, I., et al.,
2209e2216. 2009. beta(2)-Nicotinic acetylcholine receptor availability during
Bero, L., 2003. Implications of the tobacco industry documents for public acute and prolonged abstinence from tobacco smoking. Arch. Gen.
health and policy. Annu. Rev. Public Health 24, 267e288. Psychiatry 66, 666e676.
Bi, Y.Z., Yuan, K., Guan, Y.Y., Cheng, J.D., Zhang, Y.J., et al., 2017. Craig, A.D., 2009. How do you feel - now? The anterior insula and human
Altered resting state functional connectivity of anterior insula in young awareness. Nat. Rev. Neurosci. 10, 59e70.
smokers. Brain Imaging Behav. 11, 155e165. Dagher, A., Bleicher, C., Aston, J.A., Gunn, R.N., Clarke, P.B., et al.,
Bienkowski, P., Zatorski, P., Baranowska, A., Ryglewicz, D., 2001. Reduced dopamine D1 receptor binding in the ventral striatum
Sienkiewicz-Jarosz, H., 2010. Insular lesions and smoking cessation of cigarette smokers. Synapse 42, 48e53.
after first-ever ischemic stroke: a 3-month follow-up. Neurosci. Lett. Daughters, S.B., Ross, T.J., Bell, R.P., Yi, J.Y., Ryan, J., et al., 2016.
478, 161e164. Distress tolerance among substance users is associated with functional
Brody, A.L., Mandelkern, M.A., Jarvik, M.E., Lee, G.S., Smith, E.C., connectivity between prefrontal regions during a distress tolerance
et al., 2004. Differences between smokers and nonsmokers in regional task. Addict. Biol. 22, 1378e1390.
gray matter volumes and densities. Biol. Psychiatry 55, 77e84. DHHS, 2014. The Health Consequences of Smoking - 50 Years of
Brody, A.L., Mandelkern, M.A., London, E.D., Olmstead, R.E., Farahi, J., Progress: A Report of the Surgeon General. Retrieved from: https://
et al., 2006. Cigarette smoking saturates brain alpha(4)beta(2) nico- www.surgeongeneral.gov/library/reports/50-years-of-progress/.
tinic acetylcholine receptors. Arch. Gen. Psychiatry 63, 907e915. DHHS, 2016. E-Cigarette Use Among Youth and Young Adults: A Report
Brown, R.A., Lejuez, C.W., Strong, D.R., Kahler, C.W., Zvolensky, M.J., of the Surgeon General. Retrieved from: https://e-cigarettes.surgeon-
et al., 2009. A prospective examination of distress tolerance and early general.gov/documents/2016_sgr_full_report_non-508.pdf.
smoking lapse in adult self-quitters. Nicotine Tob. Res. 11, Donny, E.C., Chaudhri, N., Caggiula, A.R., Evans-Martin, F.F., Booth, S.,
493e502. et al., 2003. Operant responding for a visual reinforcer in rats is
Buckner, R.L., Andrews-Hanna, J.R., Schacter, D.L., 2008. The brain’s enhanced by noncontingent nicotine: implications for nicotine self-
default network - anatomy, function, and relevance to disease. In: Year administration and reinforcement. Psychopharmacology 169, 68e76.
in Cognitive Neuroscience 2008, vol. 1124, pp. 1e38. Donny, E.C., Jones, M., 2009. Prolonged exposure to denicotinized cig-
Caggiula, A.R., Donny, E.C., Palmatier, M.I., Liu, X., Chaudhri, N., et al., arettes with or without transdermal nicotine. Drug Alcohol Depend.
2009. The role of nicotine in smoking: a dual-reinforcement model. 104, 23e33.
Nebr. Symp. Motiv. 55, 91e109. Drope, J., Liber, A.C., Cahn, Z., Stoklosa, M., Kennedy, R., et al., 2018.
Capron, D.W., Allan, N.P., Norr, A.M., Zvolensky, M.J., Schmidt, N.B., Who’s still smoking? Disparities in adult cigarette smoking prevalence
2014. The effect of successful and unsuccessful smoking cessation on in the United States. CA Cancer J. Clin. 68, 106e115.
short-term anxiety, depression, and suicidality. Addict. Behav. 39, Esch, T., Stefano, G.B., Fricchione, G.L., Benson, H., 2002. The role of
782e788. stress in neurodegenerative diseases and mental disorders. Neuro-
Chang, L.J., Yarkoni, T., Khaw, M.W., Sanfey, A.G., 2013. Decoding the endocrinol. Lett. 23, 199e208.
role of the insula in human cognition: functional parcellation and Etter, J.F., Bullen, C., 2011. Electronic cigarette: users profile, utilization,
large-scale reverse inference. Cerebr. Cortex 23, 739e749. satisfaction and perceived efficacy. Addiction 106, 2017e2028.
Evans, D.E., Drobes, D.J., 2009. Nicotine self-medication of cognitive- Gu, X.S., Lohrenz, T., Salas, R., Baldwin, P.R., Soltani, A., et al., 2015.
attentional processing. Addict. Biol. 14, 32e42. Belief about nicotine selectively modulates value and reward predic-
FDA, 2012. Harmful and Potentially Harmful Constituents in Tobacco tion error signals in smokers. Proc. Natl. Acad. Sci. U.S.A. 112,
Products and Tobacco Smoke: Established List. Retrieved from: 2539e2544.
www.fda.gov/TobaccoProducts/ Hackshaw, A., Morris, J.K., Boniface, S., Tang, J.L., Milenkovic, D.,
GuidanceComplianceRegulatoryInformation/ucm297786.htm. 2018. Low cigarette consumption and risk of coronary heart disease
FDA, 2017. FDA’s Plan for Tobacco and Nicotine Regulation. Retrieved and stroke: meta-analysis of 141 cohort studies in 55 study reports.
from: https://www.fda.gov/TobaccoProducts/NewsEvents/ BMJ Br. Med. J. 360, j5855, 361.
ucm568425.htm. Hall, B.J., Cauley, M., Burke, D.A., Kiany, A., Slotkin, T.A., et al., 2016.
Fedota, J.R., Sutherland, M.T., Salmeron, B.J., Ross, T.J., Hong, L.E., Cognitive and behavioral impairments evoked by low-level exposure
et al., 2015. Reward anticipation is differentially modulated by vare- to tobacco smoke components: comparison with nicotine alone.
nicline and nicotine in smokers. Neuropsychopharmacology 40, Toxicol. Sci. 151, 236e244.
2038e2046. Hammersley, J.J., Gilbert, D.G., Rzetelny, A., Rabinovich, N.E., 2016.
Felix, R., Levin, E.D., 1997. Nicotinic antagonist administration into the Moderation of nicotine effects on covert orienting of attention tasks by
ventral hippocampus and spatial working memory in rats. Neurosci- poor placebo performance and cue validity. Pharmacol. Biochem.
ence 81, 1009e1017. Behav. 149, 9e16.
Fiore, M.C., Jaen, C.R., Baker, T.B., Bailey, W.C., Bennett, G., et al., Heishman, S.J., Kleykamp, B.A., Singleton, E.G., 2010. Meta-analysis of
2008a. A clinical practice guideline for treating tobacco use and the acute effects of nicotine and smoking on human performance.
dependence: 2008 update - a US Public Health Service report. Am. J. Psychopharmacology 210, 453e469.
Prev. Med. 35, 158e176. Higley, M.J., Picciotto, M.R., 2014. Neuromodulation by acetylcholine:
Fiore, M.C., Jaen, C.R., Baker, T.B., Bailey, W.C., Benowitz, N.L., et al., examples from schizophrenia and depression. Curr. Opin. Neurobiol.
2008b. Treating Tobacco Use and Dependence: 2008 Update. 29, 88e95.
Department of Health and Human Services. Public Health Service, Hoffman, A.C., Evans, S.E., 2013. Abuse potential of non-nicotine to-
Rockville, MD, US. bacco smoke components: acetaldehyde, nornicotine, cotinine, and
Fluharty, M., Taylor, A.E., Grabski, M., Munafo, M.R., 2017. The asso- anabasine. Nicotine Tob. Res. 15, 622e632.
ciation of cigarette smoking with depression and anxiety: a systematic Hughes, J.R., 2007. Effects of abstinence from tobacco: valid symptoms
review. Nicotine Tob. Res. 19, 3e13. and time course. Nicotine Tob. Res. 9, 315e327.
Gallinat, J., Meisenzahl, E., Jacobsen, L.K., Kalus, P., Bierbrauer, J., et al., Jamal, A., King, B.A., Neff, L.J., Whitmill, J., Babb, S.D., et al., 2016.
2006. Smoking and structural brain deficits: a volumetric MR inves- Current cigarette smoking among adults - United States, 2005e2015.
tigation. Eur. J. Neurosci. 24, 1744e1750. Morb. Mortal. Wkly. Rep. 65, 1205e1211.
Gandelman, J.A., Newhouse, P., Taylor, W.D., 2018. Nicotine and net- Janes, A.C., Pizzagalli, D.A., Richardt, S., Frederick, B.D., Chuzi, S.,
works: potential for enhancement of mood and cognition in late-life et al., 2010. Brain reactivity to smoking cues prior to smoking
depression. Neurosci. Biobehav. Rev. 84, 289e298. cessation predicts ability to maintain tobacco abstinence. Biol. Psy-
Garavan, H., 2010. Insula and drug cravings. Brain Struct. Funct. 214, chiatry 67, 722e729.
593e601. Kahler, C.W., McHugh, R.K., Metrik, J., Spillane, N.S., Rohsenow, D.J.,
Gaznick, N., Tranel, D., McNutt, A., Bechara, A., 2014. Basal ganglia plus 2013. Breath holding duration and self-reported smoking abstinence
insula damage yields stronger disruption of smoking addiction than intolerance as predictors of smoking lapse behavior in a laboratory
basal ganglia damage alone. Nicotine Tob. Res. 16, 445e453. analog task. Nicotine Tob. Res. 15, 1151e1154.
George, O., Ghozland, S., Azar, M.R., Cottone, P., Zorrilla, E.P., et al., Kalman, D., 2002. The subjective effects of nicotine: methodological is-
2007. CRF-CRF1 system activation mediates withdrawal-induced sues, a review of experimental studies, and recommendations for
increases in nicotine self-administration in nicotine-dependent rats. future research. Nicotine Tob. Res. 4, 25e70.
Proc. Natl. Acad. Sci. U.S.A. 104, 17198e17203. Kalman, D., Kim, S., DiGirolamo, G., Smelson, D., Ziedonis, D., 2010.
Gervais, A., O’Loughlin, J., Meshefedjian, G., Bancej, C., Tremblay, M., Addressing tobacco use disorder in smokers in early remission from
2006. Milestones in the natural course of onset of cigarette use among alcohol dependence: the case for integrating smoking cessation ser-
adolescents. Can. Med. Assoc. J. 175, 255e261. vices in substance use disorder treatment programs. Clin. Psychol.
Goodman, J., 2005. Tobacco in History and Culture: An Encyclopedia. Rev. 30, 12e24.
Charles Scribner’s Sons, Thomson Gale, Farmington Hills, MI. Kim, J.W., Baum, C.R., 2015. Liquid nicotine toxicity. Pediatr. Emerg.
Gostin, L.O., 2009. FDA regulation of tobacco politics, law, and the Care 31, 517e521.
public’s health. JAMA 302, 1459e1460. Knutson, B., Adams, C.M., Fong, G.W., Hommer, D., 2001. Anticipation
Goulden, N., Khusnulina, A., Davis, N.J., Bracewell, R.M., Bokde, A.L., of increasing monetary reward selectively recruits nucleus accumbens.
et al., 2014. The salience network is responsible for switching between J. Neurosci. 21, RC159.
the default mode network and the central executive network: repli- Langdon, K.J., Farris, S.G., Overup, C.S., Zvolensky, M.J., 2016. Asso-
cation from DCM. Neuroimage 99, 180e190. ciations between anxiety sensitivity, negative affect, and smoking
Grant, J.E., Potenza, M.N., 2005. Tobacco use and pathological gambling. during a self-guided smoking cessation attempt. Nicotine Tob. Res.
Ann. Clin. Psychiatry 17, 237e241. 18, 1188e1195.
Leventhal, A.M., Waters, A.J., Moolchan, E.T., Heishman, S.J., Naqvi, N.H., Gaznick, N., Tranel, D., Bechara, A., 2014. The insula: a
Pickworth, W.B., 2010. A quantitative analysis of subjective, cogni- critical neural substrate for craving and drug seeking under conflict
tive, and physiological manifestations of the acute tobacco abstinence and risk. In: Year in Cognitive Neuroscience, vol. 1316, pp. 53e70.
syndrome. Addict. Behav. 35, 1120e1130. Naqvi, N.H., Rudrauf, D., Damasio, H., Bechara, A., 2007. Damage to the
Leventhal, A.M., Zvolensky, M.J., 2015. Anxiety, depression, and ciga- insula disrupts addiction to cigarette smoking. Science 315,
rette smoking: a transdiagnostic vulnerability framework to under- 531e534.
standing emotion-smoking comorbidity. Psychol. Bull. 141, 176e212. Nelson, S.M., Dosenbach, N.U.F., Cohen, A.L., Wheeler, M.E.,
Levin, E.D., McClernon, F.J., Rezvani, A.H., 2006. Nicotinic effects on Schlaggar, B.L., et al., 2010. Role of the anterior insula in task-level
cognitive function: behavioral characterization, pharmacological control and focal attention. Brain Struct. Funct. 214, 669e680.
specification, and anatomic localization. Psychopharmacology 184, Ng, M., Freeman, M.K., Fleming, T.D., Robinson, M., Dwyer-
523e539. Lindgren, L., et al., 2014. Smoking prevalence and cigarette con-
Lopez-Quintero, C., de los Cobos, J.P., Hasin, D.S., Okuda, M., Wang, S., sumption in 187 countries, 1980-2012. JAMA 311, 183e192.
et al., 2011. Probability and predictors of transition from first use to Nguyen, Q.B., Zhu, S.H., 2009. Intermittent smokers who used to smoke
dependence on nicotine, alcohol, cannabis, and cocaine: results of the daily: a preliminary study on smoking situations. Nicotine Tob. Res.
National Epidemiologic Survey on Alcohol and Related Conditions 11, 164e170.
(NESARC). Drug Alcohol Depend. 115, 120e130. Oliver, J.A., Evans, D.E., Addicott, M.A., Brandon, T.H., Drobes, D.J.,
Lopez, A.D., Mathers, C.D., Ezzati, M., Jamison, D.T., Murray, C.J.L., 2016. Nicotine Withdrawal Induces Neural and Behavioral Deficits in
2006. Global and regional burden of disease and risk factors, 2001: Reward Processing.
systematic analysis of population health data. Lancet 367, Pacek, L.R., Cioe, P.A., 2015. Tobacco use, use disorders, and smoking
1747e1757. cessation interventions in persons living with HIV. Curr. HIV AIDS
Mantsch, J.R., Baker, D.A., Funk, D., Le, A.D., Shaham, Y., 2016. Stress- Rep. 12, 413e420.
induced reinstatement of drug seeking: 20 years of progress. Neuro- Palmatier, M.I., Liu, X., Matteson, G.L., Donny, E.C., Caggiula, A.R.,
psychopharmacology 41, 335e356. et al., 2007. Conditioned reinforcement in rats established with self-
Maria, M.M.M.S., Hartwell, K.J., Hanlon, C.A., Canterberry, M., administered nicotine and enhanced by noncontingent nicotine. Psy-
Lematty, T., et al., 2015. Right anterior insula connectivity is chopharmacology 195, 235e243.
important for cue-induced craving in nicotine-dependent smokers. Phillips, E., Wang, T.W., Husten, C.G., Corey, C.G., Apelberg, B.J., et al.,
Addict. Biol. 20, 407e414. 2017. Tobacco product use among adults - United States, 2015. Morb.
Markou, A., Kosten, T.R., Koob, G.F., 1998. Neurobiological similarities Mortal. Wkly. Rep. 66, 1209e1215.
in depression and drug dependence: a self-medication hypothesis. Picciotto, M.R., Higley, M.J., Mineur, Y.S., 2012. Acetylcholine as a
Neuropsychopharmacology 18, 135e174. neuromodulator: cholinergic signaling shapes nervous system function
Mayer, B., 2014. How much nicotine kills a human? Tracing back the and behavior. Neuron 76, 116e129.
generally accepted lethal dose to dubious self-experiments in the Pokhrel, P., Herzog, T.A., Muranaka, N., Regmi, S., Fagan, P., 2015.
nineteenth century. Arch. Toxicol. 88, 5e7. Contexts of cigarette and e-cigarette use among dual users: a quali-
McClernon, F.J., Addicott, M.A., Sweitzer, M.M., 2015. Smoking absti- tative study. BMC Public Health 15.
nence and neurocognition: implications for cessation and relapse. Prickaerts, J., van Goethem, N.P., Chesworth, R., Shapiro, G., Boess, F.G.,
Curr. Top. Behav. Neurosci. 23, 193e227. et al., 2012. EVP-6124, a novel and selective alpha 7 nicotinic
McKee, S.A., Maciejewski, P.K., Falba, T., Mazure, C.M., 2003. Sex acetylcholine receptor partial agonist, improves memory performance
differences in the effects of stressful life events on changes in smoking by potentiating the acetylcholine response of alpha 7 nicotinic
status. Addiction 98, 847e855. acetylcholine receptors. Neuropharmacology 62, 1099e1110.
Metse, A.P., Wiggers, J.H., Wye, P.M., Wolfenden, L., Prochaska, J.J., Prochaska, J.J., Das, S., Young-Wolff, K.C., 2017. Smoking, mental
et al., 2017. Smoking and mental illness: a bibliometric analysis of illness, and public health. Annu. Rev. Public Health 38 38, 165e185.
research output over time. Nicotine Tob. Res. 19, 24e31. Raw, M., Ayo-Yusuf, O., Chaloupka, F., Fiore, M., Glynn, T., et al., 2017.
Mineur, Y.S., Cahuzac, E.L., Mose, T.N., Bentham, M.P., Recommendations for the implementation of WHO framework
Plantenga, M.E., et al., 2018. Interaction between noradrenergic and convention on tobacco control article 14 on tobacco cessation support.
cholinergic signaling in amygdala regulates anxiety- and depression- Addiction 112, 1703e1708.
related behaviors in mice. Neuropsychopharmacology 43, RCP, 2013. Smoking and Mental Health. Royal College of Physicians,
2118e2125. Royal College of Psychiatrists, London.
Molas, S., DeGroot, S.R., Zhao-Shea, R., Tapper, A.R., 2017. Anxiety and Richardson, N.R., Roberts, D.C., 1996. Progressive ratio schedules in drug
nicotine dependence: emerging role of the habenulo-interpeduncular self-administration studies in rats: a method to evaluate reinforcing
axis. Trends Pharmacol. Sci. 38, 169e180. efficacy. J. Neurosci. Methods 66, 1e11.
Moran, L.V., Stoeckel, L.E., Wang, K., Caine, C.E., Villafuerte, R., et al., Rodgman, A., Perfetti, T.A., 2009. The Chemical Components of Tobacco
2018. Nicotine increases activation to anticipatory valence cues in and Tobacco Smoke. CRC Press, Taylor & Francis Group, Boca
anterior insula and striatum. Nicotine Tob. Res. 20, 851e858. Raton, FL.
Mukhin, A.G., Kimes, A.S., Chefer, S.I., Matochikl, J.A., Rose, E.J., Ross, T.J., Salmeron, B.J., Lee, M., Shakleya, D.M., et al.,
Contoreggi, C.S., et al., 2008. Greater nicotinic acetylcholine receptor 2012. Chronic exposure to nicotine is associated with reduced reward-
density in smokers than in nonsmokers: a PET study with 2-F-18-FA- related activity in the striatum but not the midbrain. Biol. Psychiatry
85380. J. Nucl. Med. 49, 1628e1635. 71, 206e213.
Rose, E.J., Ross, T.J., Salmeron, B.J., Lee, M., Shakleya, D.M., et al., Sweitzer, M.M., Geier, C.F., Joel, D.L., McGurrin, P., Denlinger, R.L.,
2013. Acute nicotine differentially impacts anticipatory valence- and et al., 2014. Dissociated effects of anticipating smoking versus mon-
magnitude-related striatal activity. Biol. Psychiatry 73, 280e288. etary reward in the caudate as a function of smoking abstinence. Biol.
Rostron, B.L., Chang, C.M., Pechacek, T.F., 2014. Estimation of cigarette Psychiatry 76, 681e688.
smoking-attributable morbidity in the United States. JAMA Intern. Tanabe, J., Nyberg, E., Martin, L.F., Martin, J., Cordes, D., et al., 2011.
Med. 174, 1922e1928. Nicotine effects on default mode network during resting state. Psy-
Rupprecht, L.E., Smith, T.T., Schassburger, R.L., Buffalari, D.M., chopharmacology 216, 287e295.
Sved, A.F., et al., 2015. Behavioral mechanisms underlying nicotine Taylor, A.E., Fluharty, M.E., Munafo, M.R., 2014a. Investigating the
reinforcement. Curr. Top. Behav. Neurosci. 24, 19e53. possible causal association between smoking and depression and
Schliebs, R., Arendt, T., 2006. The significance of the cholinergic system anxiety using Mendelian randomisation meta-analysis: the carta con-
in the brain during aging and in Alzheimer’s disease. J. Neural sortium. J. Epidemiol. Community Health 68. A45-A45.
Transm. 113, 1625e1644. Taylor, G., McNeill, A., Girling, A., Farley, A., Lindson-Hawley, N.,
Schultz, W., Dickinson, A., 2000. Neuronal coding of prediction errors. et al., 2014b. Change in mental health after smoking cessation: sys-
Annu. Rev. Neurosci. 23, 473e500. tematic review and meta-analysis. Br. Med. J. 348.
Seeley, W.W., Menon, V., Schatzberg, A.F., Keller, J., Glover, G.H., et al., Trainor, K., Leavey, G., 2017. Barriers and facilitators to smoking
2007. Dissociable intrinsic connectivity networks for salience pro- cessation among people with severe mental illness: a critical appraisal
cessing and executive control. J. Neurosci. 27, 2349e2356. of qualitative studies. Nicotine Tob. Res. 19, 14e23.
Shahab, L., Andrew, S., West, R., 2014. Changes in prevalence of Vnukova, M., Ptacek, R., Raboch, J., Stefano, G., 2017. Central nervous
depression and anxiety following smoking cessation: results from an system grey matter decreases in volume in smokers impacting
international cohort study (ATTEMPT). Psychol. Med. 44, 127e141. cognitive abilities: a systematic review. Eur. Psychiatry 41. S883-
Shaham, Y., Shalev, U., Lu, L., de Wit, H., Stewart, J., 2003. The rein- S883.
statement model of drug relapse: history, methodology and major Weinberger, A.H., Funk, A.P., Goodwin, R.D., 2016. A review of
findings. Psychopharmacology 168, 3e20. epidemiologic research on smoking behavior among persons with
Sharp, B.M., 2017. Basolateral amygdala and stress-induced hyperexcit- alcohol and illicit substance use disorders. Prev. Med. 92,
ability affect motivated behaviors and addiction. Transl. Psychiatry 7. 148e159.
Shiffman, S., Kirchner, T.R., Ferguson, S.G., Scharf, D.M., 2009. Patterns West, R., Evins, A.E., Benowitz, N.L., Russ, C., McRae, T., et al., 2018.
of intermittent smoking: an analysis using ecological momentary Factors associated with the efficacy of smoking cessation treatments
assessment. Addict. Behav. 34, 514e519. and predictors of smoking abstinence in EAGLES. Addiction 113,
Siegel, M.B., Tanwar, K.L., Wood, K.S., 2011. Electronic cigarettes as a 1507e1516.
smoking-cessation: tool results from an online survey. Am. J. Prev. WHO, 2018. Global progress report on implementation of the WHO
Med. 40, 472e475. framework convention on tobacco control. Retrieved from: http://
Skov-Ettrup, L.S., Nordestgaard, B.G., Petersen, C.B., Tolstrup, J.S., www.who.int/fctc/reporting/WHO-FCTC-2018_global_progress_
2017. Does high tobacco consumption cause psychological distress? A report.pdf.
Mendelian randomization study. Nicotine Tob. Res. 19, 32e38. Wonnacott, S., 1997. Presynaptic nicotinic ACh receptors. Trends Neu-
Sorge, R.E., Pierre, V.J., Clarke, P.B.S., 2009. Facilitation of intravenous rosci. 20, 92e98.
nicotine self-administration in rats by a motivationally neutral sensory Zelle, S.L., Gates, K.M., Fiez, J.A., Sayette, M.A., Wilson, S.J., 2017. The
stimulus. Psychopharmacology 207, 191e200. first day is always the hardest: functional connectivity during cue
Suner-Soler, R., Grau-Martin, A., Terceno, M., Silva, Y., Davalos, A., exposure and the ability to resist smoking in the initial hours of a quit
et al., 2018. Biological and psychological factors associated with attempt. Neuroimage 151, 24e32.
smoking abstinence six years post-stroke. Nicotine Tob. Res. 20, Zhang, L.F., Dong, Y., Doyon, W.M., Dani, J.A., 2012. Withdrawal from
1182e1188. chronic nicotine exposure alters dopamine signaling dynamics in the
Suner-Soler, R., Grau, A., Gras, M.E., Font-Mayolas, S., Silva, Y., et al., nucleus accumbens. Biol. Psychiatry 71, 184e191.
2012. Smoking cessation 1 Year poststroke and damage to the insular Zhou, S., Xiao, D., Peng, P., Wang, S.K., Liu, Z., et al., 2017. Effect of
cortex. Stroke 43, 131e136. smoking on resting-state functional connectivity in smokers: an fMRI
Sutherland, M.T., McHugh, M.J., Pariyadath, V., Stein, E.A., 2012. study. Respirology 22, 1118e1124.
Resting state functional connectivity in addiction: lessons learned and Zislis, G., Desai, T.V., Prado, M., Shah, H.P., Bruijnzeel, A.W., 2007.
a road ahead. Neuroimage 62, 2281e2295. Effects of the CRF receptor antagonist D-Phe CRF(12-41) and the
Sutherland, M.T., Ray, K.L., Riedel, M.C., Yanes, J.A., Stein, E.A., et al., alpha 2-adrenergic receptor agonist clonidine on stress-induced rein-
2015. Neurobiological impact of nicotinic acetylcholine receptor ag- statement of nicotine-seeking behavior in rats. Neuropharmacology
onists: an activation likelihood estimation meta-analysis of pharma- 53, 958e966.
cologic neuroimaging studies. Biol. Psychiatry 78, 711e720. Zvolensky, M.J., Feldner, M.T., Leen-Feldner, E., Bonn-Miller, M.O.,
Swan, G.E., Lessov-Schlaggar, C.N., 2007. The effects of tobacco smoke McLeish, A.C., et al., 2004. Evaluating the role of anxiety sensitivity
and nicotine on cognition and the brain. Neuropsychol. Rev. 17, in smoking outcome expectancies among regular smokers. Cognit.
259e273. Ther. Res. 28, 473e486.
Chapter 10
Cognitive sequelae of cannabis use

Ileana Pacheco-Colón and Raul Gonzalez
Center for Children and Families, Department of Psychology, Florida International University, Miami, United States
Introduction functioning. First, we provide a brief overview of the

neuropharmacology of cannabis and its constituents. We
Cannabis use is prevalent. In 2016, approximately 44% of then synthesize available evidence from neurobehavioral
Americans over the age of 12 reported having tried cannabis studies on acute and nonacute effects of cannabis on
at least once (Center for Behavioral Health Statistics and cognition. An exhaustive review of all published studies
Quality, 2017). Additionally, 45% of 12th graders reported would be beyond the scope of this chapter; thus, we
having used cannabis, with 36% reporting use in the past highlight recent and/or notable studies. Finally, we discuss
year (Johnston et al., 2016). Although these figures represent the clinical significance and implications of these findings
an increase in the annual prevalence of use since 1991, they and make recommendations for future cannabis research.
remain significantly lower than estimates from 1977 to 1980,
which neared 50% (Johnston et al., 2016). At the same time,
public opinion toward cannabis legalization has become Neuropharmacology of cannabis
more favorable. While only 12% of Americans supported The cannabis plant contains 426 known active chemical
the legalization of cannabis in 1969, more recent surveys compounds, approximately 60 of which are cannabinoids.
indicate that 57% support legalization of cannabis (Pew Of these, the two most researched cannabinoids are delta-9-
Research Center, 2016). Consistent with these trends, 29 US tetrahydrocannabinol (THC) and cannabidiol (CBD). There
states and the District of Columbia have passed medical are also two main cannabis strains: Cannabis indica and
marijuana legislation, and 9 have legalized recreational use Cannabis sativa. Indica-dominant strains are primarily
for adults 21 and older. These trends can also be observed enjoyed for relaxation, pain relief, and sleep, whereas sativa-
internationally, with countries such as Uruguay legalizing dominant strains are preferred for euphoria and energy
recreational use and countries such as Germany, Canada, enhancement (Erkelens and Hazekamp, 2014; Pearce et al.,
Argentina, Czech Republic, Italy, and Mexico passing 2014). However, the extent to which these subjective reports
medical marijuana laws. correlate with pharmacological distinctions between these
A recent evidence-based consensus report from the strains is not yet clear (Erkelens and Hazekamp, 2014).
National Academies of Sciences concluded that there is THC has been identified as the primary psychoactive
moderate evidence for acute effects of cannabis on cogni- constituent in cannabis. Both animal and human research
tion, but limited evidence for cannabis-associated cognitive have demonstrated that THC exerts its effects on the central
sequelae after prolonged abstinence (National Academies nervous system primarily through activity at cannabinoid
of Sciences, 2017). Indeed, the majority of the extant receptor type 1 (CB1; Pertwee, 2006, 2008). CB1 receptors
literature on the nonacute cognitive sequelae of cannabis are located throughout the cortex, with dense concentrations
use consists of cross-sectional studies and modestly sized in brain regions relevant to cognitive and psychomotor
samples (e.g., N < 100) with varying levels of cannabis functioning, including the hippocampus, amygdala, basal
use. Several meta-analyses have helped to synthesize ganglia, and cerebellum (Burns et al., 2007; Glass et al.,
results from studies examining nonacute effects of cannabis 1997). They can also be found in peripheral nervous tissue,
use on cognition. However, an increasing number of lon- liver, thyroid, uterus, and testicles (Pertwee, 2006). CB1
gitudinal studies have allowed for causal inferences receptors mediate inhibitory action on the release of several
regarding the effects of cannabis use on cognitive func- neurotransmitters, including serotonin, acetylcholine, dopa-
tioning. This chapter aims to summarize the evidence for mine, and glutamate (Atakan, 2012). Thus, when cannabis is
acute and nonacute effects of cannabis on cognitive

used, THC functions as a partial agonist at CB1 receptors (Zuardi et al., 2012). A recent review article concluded
and inhibits the release of neurotransmitters normally that although exposure to high THC or low CBD cannabis
modulated by endocannabinoids, thereby influencing is associated with greater cognitive impairment, it is still
cognition. not clear whether increased CBD concentrations may
Although THC shows an affinity for CB1 receptors, it is offset detrimental cognitive effects of THC (Colizzi and
also a partial agonist at a second type of receptor, canna- Bhattacharyya, 2017). Therefore, more carefully charac-
binoid receptor type 2 (CB2; Pertwee, 2008). CB2 terizing the time between CBD and THC intake and/or the
receptors are mostly expressed in immune cells, spleen, and precise CBD to THC ratio would help elucidate the
the gastrointestinal tissue (Pertwee, 2006). Indeed, THC complex interactions between these cannabinoids (Zuardi
exerts its immunosuppressive effects through its activity at et al., 2012). This research will enable scientists to
CB2 receptors (Onaivi et al., 2012). Nonetheless, recent determine how to maximize potentially therapeutic effects
research has shown that CB2 receptors can also be found in of CBD while minimizing deleterious consequences
neuronal, glial, and endothelial cells in the brain (Onaivi associated with THC, which could make cannabis a more
et al., 2012). CB1 and CB2 receptors may work both viable treatment option for many.
independently and cooperatively across different cell pop- In addition to the cannabinoids, the cannabis plant
ulations to regulate important physiological activities contains many other types of compounds that may interact
(Onaivi et al., 2012). However, more research is needed to synergistically to produce therapeutic effects. This inter-
understand the effects of THC activity at CB2 receptors in active synergy between active and “inactive” components
the central nervous system and the nature of the complex is referred to as the cannabis entourage effect (Ben-Shabat
interactions between receptor types. et al., 1998). Terpenoids, for instance, are essential oil
Several other non-CB1 and non-CB2 receptors have components responsible for the aroma of cannabis. These
been suggested as potential members of the cannabinoid are “generally recognized as safe” by the US Food and
receptor family (Atakan, 2012). These include G proteine Drug Administration, but are considered “of pharmaco-
coupled receptor (GPR) 3, GPR6, GPR12, GPR19, and, logical interest” when present at high concentrations (Russo,
most notably, GPR18 and GPR55 (Morales and Reggio, 2011). It is plausible that terpenoids with pain-relieving,
2017). However, findings have been largely inconsistent, antianxiety, or sedative effects could supplement effects of
thus precluding complete characterization of these receptors cannabinoids such as THC and CBD on sleep, pain, anxiety,
and their relationships with the endocannabinoid system. and other clinical conditions, thereby enhancing the efficacy
Thus, the existence of a CB3 receptor has not yet been of cannabis as a therapeutic agent (Russo, 2011). However,
confirmed (Morales and Reggio, 2017). the lack of scientific rigor in existing studies and the dearth
Recently, there has been increased interest in CBD as a of randomized controlled trials make it difficult to draw
potentially therapeutic agent. CBD appears to exert its conclusions regarding the extent to which other cannabis
effects through activity on several different types of compounds are relevant to the cognitive and/or therapeutic
receptors. For instance, although CBD has low affinity for effects of cannabis (Russo, 2011).
both CB1 and CB2 receptors, it can antagonize CB1 and
CB2 receptor agonists or serve as an inverse agonist even at
low concentrations (Bergamaschi et al., 2011). Research
Cognitive deficits associated with
has also identified other potential mechanisms of action for cannabis
CBD, including GPR55 (Bergamaschi et al., 2011). Acute effects of cannabis intoxication on
Furthermore, findings from both animal and human studies
cognition
suggest that CBD is associated with a variety of therapeutic
effects, including anxiolytic, antipsychotic, antiepileptic, Reviews
sedative, antiinflammatory, and neuroprotective properties
A large body of work has examined the effects of acute
(Bergamaschi et al., 2011; Maroon and Bost, 2018).
cannabis intoxication on various aspects of cognitive
CBD and THC have similar effects in some domains
functioning. For instance, Gonzalez (2007) conducted a
and differing or opposite effects in others. For instance,
review of findings from studies published between the
both THC and CBD have antiemetic and immunomodu-
1970s and 2007 and concluded that acute cannabis intoxi-
latory effects (Atakan, 2012). However, unlike THC, CBD
cation is consistently linked to retrieval-based memory
is not associated with psychoactive effects or cognitive
problems. Specifically, when individuals are shown infor-
impairment (Russo and Guy, 2006). Some studies have
mation while they are intoxicated, they show deficits in
found that CBD potentiates the effects of THC through its
their ability to recall that information. However, intoxicated
activity at CB1 receptors (Hayakawa et al., 2008; Klein
participants can recall information that was presented
et al., 2011), whereas others have found that CBD can
before cannabis intoxication. Acute cannabis intoxication
antagonize THC effects via other receptors such as GPR55
Cognitive sequelae of cannabis use Chapter | 10 145
was also frequently linked to increased regional cerebral users than for light, infrequent users such that heavier users
blood flow and metabolism in frontal, limbic, and cere- show lesser impairments. There is preclinical evidence to
bellar regions (Gonzalez, 2007). support the development of tolerance among frequent
Crean et al. (2011) conducted an evidence-based review cannabis users, although evidence of tolerance in cognitive
of the acute effects of cannabis on executive functions in domains among humans is limited (Broyd et al., 2016).
adults. They concluded that while cannabis effects on
memory are well-established, evidence of effects of acute Notable cross-sectional studies
cannabis intoxication on other domains of executive func-
Several recent cannabis administration studies have made
tioning was mixed. Among studies focusing on attention
and information processing, some have found improved significant contributions to our understanding of the acute
effects of cannabis. In the first study to administer cannabis
performance among acutely intoxicated heavy cannabis
to users under the age of 18, Mokrysz et al. (2016) con-
users, whereas others have found poorer performance
ducted a double-blind placebo-controlled study to compare
among acutely intoxicated light users. This suggests that
the acute effects of cannabis use in adolescents with adult
the impairing effects of cannabis intoxication may be
males. Adolescents and adults were matched on premorbid
stronger among inexperienced than regular users because of
IQ, anxiety, depression, impulsivity, and schizotypy. After
tolerance and/or neuroadaptive effects associated with
receiving either active or placebo cannabis, participants
cannabis (Crean et al., 2011). Acute cannabis use was also
linked to impairments in decision-making, although studies completed a prose recall task measuring episodic memory,
a spatial N-back task measuring working memory, and a
varied as to whether they examined response speed,
stop signal task measuring response inhibition. When
latency, or accuracy. In general, higher doses of THC were
intoxicated with cannabis, adults showed greater impair-
associated with poorer cognitive performance than lower
ment in delayed recall of prose and had longer reaction
doses of THC (Crean et al., 2011).
times on the spatial N-back task than adolescents. Cannabis
More recently, a systematic review by Broyd et al.
intoxication also led to impaired response inhibition accu-
(2016) reported on findings from 38 studies examining acute
racy in adolescents but not adults. Importantly, although all
effects of cannabis on cognition. Consistent with other
reviews, acute cannabis effects were most often reported in participants in this study were “regular” users, adolescents
reported greater frequency of cannabis use per month than
the domain of verbal learning and memory, albeit less
adults. Thus, the reduced impairment seen in adolescents
consistently for working memory. Acute cannabis intoxica-
relative to adults may reflect tolerance effects. Alterna-
tion was also linked to impairments in focused, divided, and
tively, adolescents have a higher basal metabolism and a
sustained attention, psychomotor functioning, and inhibition.
lower percentage body fat than adults, which could lead
However, reported effects on executive functioning
adolescents to metabolize THC more quickly, potentially
domains, such as planning, reasoning, interference control,
resulting in reduced memory effects. Finally, adolescents
and decision-making, were mixed.
Inconsistencies across acute administration studies reported more frequent and heavier use of cigarettes than
adults, which may offset cannabis effects on working
could be explained by a variety of factors. First, these
memory (Schuster et al., 2015; Schuster et al., 2016b), as
studies differ in the route of administration of cannabis they
well as less frequent alcohol use. Therefore, it is possible
employed. Specifically, studies that used smoked, vapor-
that group differences in use of other substances may have
ized, or intravenous cannabis administration are likely to
influenced these findings.
see more immediate yet shorter-lasting effects than studies
Ramaekers et al. (2016a) examined acute effects of
using oral or sublingual cannabis administration. These
cannabis as a function of participants’ drug use history in a
differences in route of administration could also explain
why dose-dependent effects are not consistently reported. sample of 132 adult users of cannabis and cocaine. In this
double-blind placebo-controlled study, participants
Second, cannabis effects on cognition may vary across types
received a dose of cannabis, cocaine, or placebo. Cannabis
of cannabinoids. For instance, CBD may moderate the
use in this sample ranged from infrequent to daily.
effects of THC such that greater CBD content may protect
Participants completed a neurocognitive battery assessing
THC-induced impairments in verbal learning and memory
executive functioning (Tower of London task), impulse
(Englund et al., 2013; Morgan et al., 2010). Third, although
control (stop signal task), attention (divided attention task),
sex differences in cannabinoid metabolism and action are
and psychomotor performance (critical tracking task).
well-established, these differences are not sufficiently
accounted for in these studies (Crane et al., 2013). Finally, Results indicated a main effect of cannabis intoxication
across all measures such that the cannabis group showed
participants’ histories of use could result in differential
worse performance relative to those who received placebo.
cognitive effects of acute cannabis intoxication. Several
Although there was no main effect of cannabis use history,
studies have found that cannabis intoxication affects cogni-
there was an interaction between cannabis use history and
tive performance differently for heavy, regular cannabis
psychomotor performance such that cannabis-induced Nonacute or residual/long-term effects of

impairment decreased with increasing frequency of use, cannabis use on cognition
which would suggest tolerance effects. However, these
effects may have been driven by worsening psychomotor Reviews and meta-analyses
performance over time in the placebo group, rather than in Several recent reviews have examined the long-term effects
any of the drug conditions, for which psychomotor per- of cannabis use on cognition. Ganzer et al. (2016) conducted
formance remained stable. Together, these results suggest a systematic review of 38 studies between 2004 and 2015
that acute cannabis-induced neurocognitive impairment examining the residual neurocognitive effects of cannabis
may not depend on cannabis use history and that tolerance use in adolescents and adults after a prolonged period of
to these acute effects is generally absent in regular users. abstinence. Overall, the findings regarding neurocognition
Other studies have examined the effects of different were heterogeneous. Most studies reported some deficits in
cannabis compositions on cognition. Notably, Lawn et al. attention or concentration in abstinent cannabis users, as well
(2016) examined the acute effects of cannabis with and as in different aspects of memory. Findings in the domains
without CBD on effort-related decision-making in a sample of inhibition, impulsivity, visuospatial functioning, and
of 17 occasional cannabis users (3 times/week and 4 decision-making were mixed. Although not many studies
times in the past year). Using repeated measures, placebo- examined motor function, most of those that did found
controlled double-blind design, participants received worse performance in cannabis users relative to nonusing
vaporized cannabis with CBD, cannabis without CBD, and controls even after prolonged abstinence. Furthermore,
placebo. They completed an effort expenditure for rewards results suggested that neuropsychological functioning in
task, in which they decided between a low-effort choice, individuals who initiated cannabis use at an earlier age was
which yielded a small amount of money, and a high-effort not significantly different from that of individuals with a
choice, which could yield larger amounts of money. Results later age of onset (Ganzer et al., 2016).
indicated that administration of placebo predicted higher On the other hand, a review by Curran et al. (2016)
effort relative to cannabis without CBD, suggesting that identified episodic memory impairments as the most
acute cannabis intoxication is associated with lower effort. consistently reported long-term effects of cannabis use,
Because the difference between cannabis with and without while findings for working memory, attention, and impul-
CBD was not significant, there is no evidence to suggest sivity were mixed. Somewhat similarly, reviews by Broyd
that CBD can reduce the negative impact of THC on effort- et al. (2016) and Nader and Sanchez (2018) identified
related decision-making. verbal learning and memory and executive functions as the
Some studies have examined the moderating influence of domains most consistently impaired with long-term
genetic expression on the association between cannabis cannabis use. These reviews concluded that neuro-
intoxication and cognitive performance. Notably, Ramaekers cognitive impairments may persist for at least 1 week when
et al. (2016b) examined levels of the enzyme dopamine cannabis use is chronic, but are often resolved with long
b-hydroxylase (DbH), which transforms dopamine to periods of abstinence (e.g., 4 weeks; Broyd et al., 2016;
noradrenaline, and tonic dopamine levels in 122 regular Nader and Sanchez, 2018).
users of cannabis (i.e., used at least twice over 3 months) and Three meta-analyses have synthesized findings from
cocaine (i.e., used at least 5 times in past year). Individuals studies examining associations between cannabis use and
were identified as having either low-activity or high-activity various aspects of neuropsychological functioning, focusing
DbH genotypes. All participants received acute doses of on nonacute use (i.e., when participants are not acutely
cannabis, cocaine, or placebo and completed the Matching intoxicated). Grant et al. (2003) conducted a meta-analysis
Familiar Figures Test to assess cognitive impulse control. on 15 studies, with a total of 704 cannabis users and 484
Users with the low DbH genotype under acute intoxication nonusing controls. Results suggested a small but significant
of cannabis or cocaine showed increased cognitive impul- “residual cannabis effect” on cognition, suggesting that
sivity on the Matching Familiar Figures Test. These results cannabis users’ overall neuropsychological performance was
suggest that certain cannabis users who also use cocaine may worse than that of controls by approximately one-fifth of a
be at risk for experiencing hyperdopaminergic cognitive standard deviation. Specifically, cannabis users showed
states influencing substance-driven behaviors especially significantly worse performance than nonusers in the
among users with high-risk DbH genotypes. Although domains of learning and forgetting. Similarly, the meta-
participants in this study used both cocaine and cannabis, the analysis by Schreiner and Dunn (2012) included 33 studies,
results suggest that genetic differences may impact cannabis independent from those in the Grant et al. meta-analysis,
effects on cognition.
which yielded 1010 cannabis users and 839 controls. Results attenuated after controlling for confounding variables, such
indicated a modest negative association between cannabis as use of other substances.
use and global neuropsychological functioning. Significant Since this review was published, several longitudinal
negative effects were also observed in the domains of studies have continued to find links between cannabis use
learning, forgetting/retrieval, abstraction/executive function, and poorer neuropsychological functioning. For instance,
attention, motor skills, and verbal language. The magnitude Castellanos-Ryan et al. (2017) followed a sample of 294
of these effects approximated one-third of a standard male participants from ages 13 to 20. Substance use was
deviation. assessed annually until age 17, and again at age 20, and
More recently, Scott et al. (2018) conducted a meta- neurocognition was assessed twicedin early adolescence
analysis examining the nonacute effects of cannabis on and early adulthood. Results indicated that before initiation
cognition among adolescents and young adults. This anal- of cannabis use, poor short-term and working memory and
ysis included 69 studies for a total of 2152 cannabis users high verbal IQ were prospectively associated with earlier
and 6575 controls with minimal cannabis exposure. Results age of onset of cannabis use. Earlier age of onset and higher
indicated a small negative association between frequent or frequency of cannabis use throughout adolescence were, in
heavy cannabis use and overall cognitive functioning. Effect turn, associated with neurocognitive decline in verbal IQ
sizes were significant in the domains of learning, executive and worsening performance on executive functioning tasks
functioning (abstraction)/shifting, speed of information pro- assessing reward learning and processing in young adult-
cessing, delayed memory, executive functioning (inhibition, hood. Although the link between cannabis use frequency
updating)/working memory, and attention. Effect sizes were and verbal IQ was mediated by lower rates of high school
modest and did not vary by sample age or age of onset of graduation among cannabis users, the association between
cannabis use. Importantly, studies with eligibility criteria cannabis use and poorer executive functioning persisted
requiring abstinence longer than 72 h had a very small even after controlling for graduation, other substance use,
nonsignificant overall effect of cannabis use on cognition and externalizing symptoms. These findings suggest that
relative to studies requiring abstinence of 72 h or less. the link between cannabis use and cognition can be bidi-
Together, results from reviews and meta-analyses sug- rectional such that certain cognitive profiles can lead to
gest that frequent or heavy cannabis use is associated with earlier age of onset, which can, in turn, adversely impact
small negative effects on overall cognition, as well as cognitive functioning and later life outcomes.
specific domains, including learning and memory, execu- Becker et al. (2018) examined a sample of 26 heavy
tive functioning, and attention. However, these reductions cannabis users who initiated cannabis use before age 17 and
in cognitive functioning may reflect residual effects from 31 age- and sex-matched controls. Participants completed
acute use, as they significantly diminish with prolonged neuropsychological assessments at ages 19e20 and 21e22,
abstinence. Across most studies, age of onset of cannabis which included measures of psychomotor function,
use did not have a significant effect on the degree of speeded attention, verbal fluency, memory, planning, and
observed cognitive impairment. decision-making. After controlling for age, sex, and alcohol
use, cannabis users showed relative impairments in work-
ing memory, planning, and verbal memory at both baseline
Longitudinal studies
and follow-up; however, cannabis use was not associated
Although meta-analyses have been valuable in synthesizing with declines in cognitive performance, which remained
and advancing cannabis research, they preclude making stable over time. Rather, results suggest that these deficits
causal inferences regarding the links between cannabis use represent enduring vulnerabilities, especially among chronic
and cognitive functioning. Longitudinal designs which heavy users. Importantly, earlier age of onset of cannabis use
assess how changes in cannabis use prospectively influence was associated with poorer performance in the domains of
cognitive functioning are better equipped to address ques- verbal learning and memory and planning over time. This
tions of causality. Recently, Gonzalez et al. (2017) finding suggests that early onset cannabis use may have a
reviewed seven longitudinal studies published between neurotoxic effect on underlying brain circuitry, which results
2005 and 2016, which examined nonacute effects of in decreased retention of information over time.
cannabis use on neuropsychological functioning. Four of Similarly, Boccio and Beaver (2017) assessed a large
these studies compared neuropsychological data before and sample of adolescents at four different time points: ages
after initiation of cannabis use. Across studies, IQ and 12e21 (Wave I), 13e22 (Wave II), and 18e26 (Wave III).
episodic memory were most often reported to be impacted This study examined associations between cannabis use
by cannabis use, with the magnitude of effects ranging from and verbal intelligence after controlling for age, sex, race,
1/5 to 1/2 of a standard deviation. Importantly, cannabis use and socioeconomic status. Results revealed that having
was associated with neuropsychological decline only at the tried cannabis at Waves II or III was significantly associ-
highest levels of cannabis use, and this effect was often ated with declines in verbal IQ from Waves I to III, with
effect magnitude ranging from 1 to 2 IQ points. However, socioeconomic status), this difference remained significant
cumulative cannabis frequency was not associated with for the RFAB, but not the MTFS cohort. Changes in neu-
changes in IQ. In short, although initiation of cannabis use ropsychological performance did not vary as a function of
was associated with neuropsychological decline, effects of cannabis use frequency. Furthermore, co-twin control
cannabis were not dose-dependent, suggesting that the analyses indicated no significant differences in test perfor-
relationship between cannabis and cognition may be mance between mono- or dizygotic twin pairs discordant
explained by other factors. for cannabis use history.
Interestingly, findings from a small, preliminary longi- Another longitudinal co-twin study by Meier et al.
tudinal analysis by Gruber et al. (2016) suggest that medical (2018) found similar results. This study followed a sample
marijuana might have positive effects on cognition. This of 1989 twins from the Environmental Risk Longitudinal
study examined the impact of medical marijuana on execu- Twin Study. IQ was assessed at ages 5, 12, and 18, with
tive functioning in a sample of 11 adults who were either substance use and executive functions assessed at age 18.
cannabis-naïve or abstinent for at least 10 years before study Results revealed that cannabis-dependent adolescents had
entry. All participants had a valid certification for medical lower IQs at all ages than nondependent adolescents.
marijuana as prescribed for a variety of conditions, including Relative to nonusers, adolescent cannabis users had lower
anxiety, depression, sleep problems, and chronic pain. IQ at ages 12 and 18 and showed greater decline from ages
Participants completed executive functioning assessments at 12 to 18. However, there was little evidence that these
baseline and 3-month follow-up. Results indicated that, in differences were associated with cannabis use, as differ-
general, patients experienced significant improvement in ences in IQ were not significant between discordant twin
measures of executive functioning at the follow-up visit, pairs. Twins who used cannabis more frequently did,
namely the Stroop Color Word Test and the Trail Making however, perform more poorly on a working memory test
Test, such that they were faster but equally accurate. There than their co-twins.
were also trends suggesting slight improvements in tasks Together, results from longitudinal co-twin studies sug-
such as the Wisconsin Card Sorting Test or the Letter- gest cannabis use does not appear to cause decline in
Number Sequencing Task. Although the influence of neuropsychological functioning. Rather, family background
practice effects could not be ruled out, practice effects are factors may better explain why cannabis users perform
typically observed only with more frequent administration worse on measures of neuropsychological functioning.
and alternate versions of these tasks were used at follow-up.
Gruber et al. (2016) proposed that improvements may have Notable cross-sectional studies
been a result of participants experiencing amelioration of
Recent cross-sectional studies have examined the impact of
their clinical symptoms, differences in the active ingredients
age of cannabis use initiation on adult neurocognitive
in medical (e.g., high CBD, low THC) versus recreational
performance. For instance, Schuster et al. (2016a) exam-
marijuana (e.g., high THC, low CBD), or reduction in use of
other medications with known neurocognitive side effects ined the association between age of onset and learning
impairments in a sample of 48 young adults who reported
(e.g., benzodiazepines). Similar results have been reported
using cannabis at least once a week, as compared with 48
with a larger sample during an executive functioning fMRI
age- and gender-matched nonusers. Users were classified as
task (Gruber et al., 2018).
early onset (use at or before age 16) or late onset (use after
Of all longitudinal studies, co-twin designs with large
age 16). Cannabis users with early onset showed lower
samples, which can control for genetic and shared family
overall learning and worse delayed recall performance on
factors, are best positioned to make strong causal inferences
the California Verbal Learning Test-II than late-onset users
regarding the nonacute effects of cannabis on cognitive
functioning over time. One such study by Jackson et al. and controls. However, there were no significant between-
group differences in delayed recall after controlling for
(2016) used data from 3066 twins from two longitudinal
performance on the learning trials. Early onset users also
cohorts: the Risk Factors for Antisocial Behavior (RFAB)
evidenced significantly less semantic clustering than con-
study and the Minnesota Twin Family Study (MTFS).
trols, though this difference in learning strategy use did not
Participants in the RFAB study underwent IQ testing at
mediate the association between onset of cannabis use and
ages 9e10 and 19e20, and those in the MTFS underwent
delayed recall. Thus, these results suggest that the poor
IQ testing at ages 11e12 and ages 17e19. Participants
memory performance typically associated with cannabis
were classified as nonusers or users, with users further
divided into those who had ever used cannabis, those who use may be explained by factors such as age of onset and
learning inefficiencies.
had used cannabis 30 or more times, and those who were
Similarly, Dahlgren et al. (2016) assessed the impact of
ever daily users for a period greater than 6 months. Across
different patterns of cannabis use on executive functioning,
both cohorts, users showed a significant decline in
as measured by the Stroop Color Word Test and the
performance in the Vocabulary and Information subtests.
Wisconsin Card Sorting Task. Participants were 44 chronic
After controlling for covariates (i.e., age, sex, zygosity,
heavy adult cannabis users (used 5 times per week) and 32 clinical significance. Most of the reported effects range
nonusers. Users were subdivided into early onset (regular from approximately 1/5 to 1/2 of a standard deviation.
use before age 16) and late onset (regular use at or after age Therefore, these effects fall short of the criteria typically
16), with regular use broadly defined as cannabis use on a used by clinicians to determine whether observed impair-
routine, expected, and consistent basis. Cannabis users ment is significant (i.e., 1e1.5 standard deviations below
showed poorer performance on both tasks relative to non- average.) Thus, although effects of cannabis use on
users. These differences, however, were driven by the cognition are statistically significant, they may not be
performance of the early onset cannabis users; late onset clinically meaningful and may represent relative rather than
users’ performance was similar to that of nonusers. The absolute impairments. However, this is not to suggest that
association between early onset and poorer performance on cannabis use has no effect on neurocognitive functioning;
the Wisconsin Card Sorting Task was still present after rather, more detailed studies are needed to better under-
accounting for frequency and amount of weekly cannabis stand the functional impact of its documented adverse
use, suggesting that age of onset of regular cannabis use effects on neurocognition. Moreover, preexisting individual
uniquely contributed to executive functioning impairments. differences in cognition, family background factors, and
Together, findings from these cross-sectional studies suggest genetics may make some individuals more vulnerable than
that poor neurocognitive performance by cannabis users may others to cannabis-associated neurocognitive deficits.
be at least partially explained by age of onset.
Some studies have also examined the moderating
influence of genetic factors on the long-term cognitive
Recommendations for researchers/
effects of cannabis use, although most have done so in the clinicians interested in cognitive
context of psychosis. Verdejo-García et al. (2013) exam- profiling in the context of cannabis
ined whether two common genetic polymorphismsdthe
As can be seen in Table 10.1, it can be concluded that
catechol-O-methyltransferase (COMT) gene val 158met
heavy cannabis users (e.g., daily or almost daily) are likely
polymorphism and the SLC6A4 gene 5-HTTLPR
to exhibit lower neuropsychological performance than
polymorphismdmoderated the effects of cannabis on
nonusers across studies. These relative impairments are
executive functioning. Participants were 86 daily cannabis
most likely to be reported on measures of learning, mem-
users who met criteria for cannabis abuse or dependence
ory, and IQ. Impairments are also frequently reported in the
and 58 nonusers, with groups matched for genetic
domain of executive function, albeit less consistently.
makeup, sex, age, IQ, and education. Although there were
However, these deficits are likely to remit with prolonged
no significant between-group differences in performance
abstinence (4 weeks). Deficits that persist may represent
of any executive function task, a genotype X group
preexisting vulnerabilities. Furthermore, earlier cannabis
interaction revealed more nuanced results. Cannabis users
use onset seems to be associated with poorer outcomes,
with the val/val genotype showed lower accuracy of
although results across studies are not wholly consistent
sustained attention in the CANTAB Rapid Visual
with this finding, and the link between cannabis use and
Information Processing Test than nonusers with this geno-
cognitive function may not be dose-dependent. Thus, we
type. Cannabis users carrying the COMT val allele
recommend that researchers or clinicians interested in
committed more response monitoring and set shifting errors
cognitive profiling assess neurocognitive functioning in the
in the CANTAB intradimensional/extradimensional set
domains of IQ, learning and memory, and executive
shifting task than cannabis users with the met/met genotype.
functioning, as well as substance use characteristics
Also, cannabis users with the 5-HTTLPR s/s genotype per-
including level of cannabis use, length of abstinence, other
formed worse than s/s nonusers on the Iowa Gambling Task
substance use, and age of onset of cannabis use.
such that s/s cannabis users take longer to learn the task than
their nonuser counterparts. Thus, results from this study
suggest that genetic factors may make some cannabis users Conclusion
more vulnerable to negative long-term neurocognitive
Cannabis is a complex drug with numerous components, of
effects, particularly in the realm of executive functioning.
which THC and CBD are the most studied. THC is the
main psychoactive constituent in cannabis, and it exerts its
effects on the central nervous system primarily through its
Clinical significance of cognitive activity at CB1 receptors. Because these receptors are
deficits associated with cannabis densely distributed throughout brain regions including
hippocampal and limbic areas, exposure to cannabis results
Although most of the studies described have found statis-
in a variety of acute and nonacute effects on cognition.
tically significant effects of cannabis on cognition, it is
These findings are summarized in Table 10.1. Specifically,
important to consider the difference between statistical and
TABLE 10.1 Integrated and summarized key findings for each discussed study approach.
Studies on acute effects Key findings

Reviews l Cannabis intoxication is consistently linked to impairments in learning and
memory and less consistently linked to problems with attention and executive
functioning (e.g., decision-making)
Cross-sectional studies l Acute effects of cannabis on cognition may be moderated by factors such as
cannabis composition (e.g., THC:CBD ratio), genetics, and cannabis use history
Studies on nonacute effects Key findings

Reviews and meta-analyses l Frequent and/or heavy cannabis use leads to small negative effects on overall
cognition, as well as learning and memory, executive functioning, and attention
l These residual effects diminish with prolonged abstinence
l Age of onset may not impact degree of impairment
Longitudinal and co-twin studies l Small residual effects of cannabis use are most often observed in the domains of
episodic memory and IQ
l Observed cognitive decline among cannabis users may be better explained by
factors other than cannabis use, such as family background and other
substance use
l Earlier age of onset may negatively impact cognition
Cross-sectional studies l Residual effects of cannabis use on cognition may be moderated by factors such as
age of onset and genetics
acute intoxication with cannabis has been most consistently or times used. Some rely on lifetime use, while others focus
linked to impairments in learning, memory, and psycho- on past month or past week use. A more careful charac-
motor function, with some studies also reporting impair- terization of participants’ patterns and histories of cannabis
ments in attention and executive functioning. With regard use will facilitate reconciliation of results across studies.
to nonacute effects, evidence suggests that heavy or chronic Age of onset of cannabis use has also been inconsis-
cannabis use may be associated with declines in IQ, tently linked to cognitive function. Longitudinal and cross-
episodic memory, and executive functioning. However, sectional studies have found that earlier age of onset of
these effects are small in magnitude and likely to diminish cannabis use predicts poorer cognitive functioning in
with prolonged abstinence. Furthermore, longitudinal adulthood (Becker et al., 2018; Boccio and Beaver, 2017;
co-twin studies suggest that family background factors, not Castellanos-Ryan et al., 2017; Dahlgren et al., 2016;
cannabis, may explain poorer cognitive performance Schuster et al., 2016a). Some studies suggest a bidirectional
among cannabis users (Gonzalez et al., 2017). relationship between age of onset and cognition, such that
Several important factors may account for cross-study certain preexisting cognitive profiles may predict an earlier
variability in results. First, the level of cannabis use in age of onset, which, in turn, predicts greater impairment,
the sample may influence the extent or magnitude of perhaps because of cannabis adversely impacting neuro-
observed cognitive impairments. Studies suggest that acute development during adolescence (Becker et al., 2018;
cannabis intoxication may differentially impact cognition Castellanos-Ryan et al., 2017). However, other studies have
among heavy and light cannabis users such that heavy users found that observed cannabis-related cognitive impairments
are less impaired. This could reflect potential tolerance did not vary as a function of age of onset (Ganzer et al.,
effects or neuroadaptation to chronic exposure. On the 2016; Scott et al., 2018). To further complicate this issue,
other hand, results from studies examining nonacute effects there is also a great deal of variability in studies’ definitions
most often report impairments only for participants with the of “early” age of onset. Therefore, although it is neuro-
highest levels of cannabis use, although many studies have biologically plausible, more research is needed to
failed to find a dose-dependent effect (Boccio and Beaver, unequivocally determine whether earlier age of onset is
2017; Jackson et al., 2016). However, there is a great deal associated with poorer cognitive outcomes later in life.
of inconsistency across studies in the operationalization of Future studies should also continue to examine the
terms such as “regular” cannabis use, which has ranged cognitive effects of different cannabis compositions
from daily to monthly use, as well as in the quantification (e.g., different THC to CBD ratios). Studies examining
and assessment of prior cannabis use. For instance, some acute effects have yielded mixed results; high THC or low
studies measure cannabis use in grams, while others mea- CBD cannabis has been consistently linked to poorer
sure number of joints, and others measure number of days cognitive performance, but the effects of the interaction
between THC and CBD are still unclear. A more precise among variables, allow for subgroup analyses, and facilitate
characterization of the CBD to THC ratio and of the time the use of powerful data mining techniques. Because it is a
between CBD and THC intake would help advance nationally representative sample, it will also allow for
research in this area (Zuardi et al., 2012). Studies focusing generalizability of findings to the population at large.
on nonacute effects of cannabis have rarely examined Furthermore, the prospective longitudinal design that begins
effects of cannabis potency or composition. Research in at an age young enough to track effects of puberty, adoles-
this area will enable scientists to determine how to leverage cent development, and onset and course of cannabis use will
potentially therapeutic effects of CBD while minimizing better enable us to disentangle risk factors from conse-
the possibility of THC-related harm. Understanding the quences of cannabis use. Finally, the use of an “open
effects of different cannabis potencies or THC concentra- science” framework facilitates transparency, reproducibility,
tions is also increasingly urgent, as cannabis potency has and access to the broader scientific community.
continued to rise and use of more potent products In conclusion, findings from studies reviewed in this
(e.g., waxes) is becoming more prevalent (Smart et al., chapter have made significant contributions to our under-
2017). These challenges are compounded by growing standing of the neuropharmacology of cannabis, as well as
recognition that additional compounds found in the cannabis its acute and nonacute effects on cognition. Several
plant (e.g., terpenes) might have their own psychoactive questions remain unanswered, such as the acute and long-
effects or modify the effects of THC at cannabinoid term effects of different cannabis compositions, the cogni-
receptors (Russo, 2011). tive sequelae of lower levels of cannabis use, the impact of
The field requires transdisciplinary, translational, earlier age of onset, and long-term adverse consequences
observational, and experimental studies at varying levels of attributable specifically to cannabis. With the rapid
analysis to better understand for whom and under what commercialization and deregulation of cannabis, along with
conditions cannabis may be most harmful to the brain and heightened interest in its medical use, it is now more
cognition. Tightly controlled experimental studies with important than ever for science to inform the public on the
nonhuman subjects that administer and compare effects of potential benefits and risks of cannabis consumption.
specific cannabis preparations of known composition may
shed the most light in this area. Providing human research
participants with cannabis may be feasible for acute
References
administration studies, but too burdensome and problematic Atakan, Z., 2012. Cannabis, a complex plant: different compounds and
from a legal and ethical standpoint when considering different effects on individuals. Ther. Adv. Psychopharmacol. 2 (6),
longer-term use. In observational studies of human 241e254. https://doi.org/10.1177/2045125312457586.
cannabis users, questions on effects of cannabis constitu- Becker, M.P., Collins, P.F., Schultz, A., Urosevic, S., Schmaling, B.,
Luciana, M., 2018. Longitudinal changes in cognition in young
ents and potency may be addressed by having users bring in
adult cannabis users. J. Clin. Exp. Neuropsychol. 40 (6), 529e543.
samples of their cannabis for chemical analysis. Unfortu- https://doi.org/10.1080/13803395.2017.1385729.
nately, this approach bring its own challenges because of Ben-Shabat, S., Fride, E., Sheskin, T., Tamiri, T., Rhee, M.H., Vogel, Z.,
laws and regulations that may impede the collection and et al., 1998. An entourage effect: inactive endogenous fatty acid
processing of cannabis at universities, as well as the chal- glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity.
lenges of growing cannabis strains with the same chemical Eur. J. Pharmacol. 353 (1), 23e31.
composition (de Meijer et al., 1992; Jikomes and Zoorob, Bergamaschi, M.M., Queiroz, R.H.C., Zuardi, A.W., Crippa, J.A.S., 2011.
2018; Vandrey et al., 2015). Safety and side effects of cannabidiol, a Cannabis sativa constituent.
Other critical avenues for strengthening observational Curr. Drug Saf. 6 (4), 237e249.
studies on the effects of cannabis on cognition come from Boccio, C.M., Beaver, K.M., 2017. Examining the influence of adolescent
“big science” approaches that include very large sample marijuana use on adult intelligence: further evidence in the causation
versus spuriousness debate. Drug Alcohol Depend. 177, 199e206.
sizes, transdisciplinary protocols, and prospective longitu-
https://doi.org/10.1016/j.drugalcdep.2017.04.007.
dinal designs. An example of such an undertaking is the
Broyd, S.J., van Hell, H.H., Beale, C., Yücel, M., Solowij, N., 2016. Acute
Adolescent Brain and Cognitive Development (ABCD) and chronic effects of cannabinoids on human cognitionda system-
study (www.abcd-study.org) recently launched by the NIH, atic review. Biol. Psychiatry 79 (7), 557e567. https://doi.org/10.1016/
which follows a nationally representative sample of more j.biopsych.2015.12.002.
than 11,000 9- and 10-year-old substance-naïve children for Burns, H.D., Van Laere, K., Sanabria-Bohórquez, S., Hamill, T.G.,
a period of 10 years, assessing a variety of domains Bormans, G., Eng, W., et al., 2007. [18F]MK-9470, a positron
including cognition, brain structure and function, genetics, emission tomography (PET) tracer for in vivo human PET brain im-
substance use, mental health, family, and cultural environ- aging of the cannabinoid-1 receptor. Proc. Natl. Acad. Sci. U.S.A. 104
ment. The study’s large sample size will allow for sufficient (23), 9800e9805. https://doi.org/10.1073/pnas.0703472104.
power to detect small effects and complex interactions
Castellanos-Ryan, N., Pingault, J.-B., Parent, S., Vitaro, F., Grant, I., Gonzalez, R., Carey, C.L., Natarajan, L., Wolfson, T., 2003.
Tremblay, R.E., Séguin, J.R., 2017. Adolescent cannabis use, Non-acute (residual) neurocognitive effects of cannabis use: a
change in neurocognitive function, and high-school graduation: a meta-analytic study. J. Int. Neuropsychol. Soc. 9 (5), 679e689.
longitudinal study from early adolescence to young adulthood. Dev. https://doi.org/10.1017/S1355617703950016.
Psychopathol. 29 (4), 1253e1266. https://doi.org/10.1017/ Gruber, S.A., Sagar, K.A., Dahlgren, M.K., Gonenc, A., Smith, R.T.,
S0954579416001280. Lambros, A.M., et al., 2018. The grass might Be greener: medical
Center for Behavioral Health Statistics and Quality, 2017. 2016 National marijuana patients exhibit altered brain activity and improved exec-
Survey on Drug Use and Health: Detailed Tables. Substance Abuse utive function after 3 months of treatment. Front. Pharmacol. 8.
and Mental Health Services Administration. https://doi.org/10.3389/fphar.2017.00983.
Colizzi, M., Bhattacharyya, S., 2017. Does cannabis composition matter? Gruber, S.A., Sagar, K.A., Dahlgren, M.K., Racine, M.T., Smith, R.T.,
Differential effects of delta-9-tetrahydrocannabinol and cannabidiol on Lukas, S.E., 2016. Splendor in the grass? A pilot study assessing the
human cognition. Curr. Addict. Rep. 4 (2), 62e74. https://doi.org/10. impact of medical marijuana on executive function. Front. Pharmacol.
1007/s40429-017-0142-2. 7, 355. https://doi.org/10.3389/fphar.2016.00355.
Crane, N.A., Schuster, R.M., Fusar-Poli, P., Gonzalez, R., 2013. Effects of Hayakawa, K., Mishima, K., Hazekawa, M., Sano, K., Irie, K., Orito, K.,
cannabis on neurocognitive functioning: recent advances, neuro- et al., 2008. Cannabidiol potentiates pharmacological effects of D9-
developmental influences, and sex differences. Neuropsychol. Rev. 23 tetrahydrocannabinol via CB1 receptor-dependent mechanism. Brain
(2), 117e137. https://doi.org/10.1007/s11065-012-9222-1. Res. 1188, 157e164. https://doi.org/10.1016/j.brainres.2007.09.090.
Crean, R.D., Crane, N.A., Mason, B.J., 2011. An evidence based review of Jackson, N.J., Isen, J.D., Khoddam, R., Irons, D., Tuvblad, C.,
acute and long-term effects of cannabis use on executive cognitive Iacono, W.G., et al., 2016. Impact of adolescent marijuana use on
functions. J. Addict. Med. 5 (1), 1e8. https://doi.org/10.1097/ADM. intelligence: results from two longitudinal twin studies. Proc. Natl.
0b013e31820c23fa. Acad. Sci. U.S.A. 113 (5), E500eE508. https://doi.org/10.1073/pnas.
Curran, H.V., Freeman, T.P., Mokrysz, C., Lewis, D.A., Morgan, C.J.A., 1516648113.
Parsons, L.H., 2016. Keep off the grass? Cannabis, cognition and Jikomes, N., Zoorob, M., 2018. The cannabinoid content of legal cannabis
addiction. Nat. Rev. Neurosci. 17 (5), 293e306. https://doi.org/10. in Washington state varies systematically across testing facilities and
1038/nrn.2016.28. popular consumer products. Sci. Rep. 8 (1), 4519. https://doi.org/10.
Dahlgren, M.K., Sagar, K.A., Racine, M.T., Dreman, M.W., Gruber, S.A., 1038/s41598-018-22755-2.
2016. Marijuana use predicts cognitive performance on tasks of Johnston, L.D., Miech, R.A., O’Malley, P.M., Bachman, J.G.,
executive function. J. Stud. Alcohol Drugs. https://doi.org/10.15288/ Schulenberg, J.E., 2016. Teen Use of Any Illicit Drug Other than
jsad.2016.77.298. Marijuana at New Low, Same True for Alcohol.
de Meijer, E.P.M., van der Kamp, H.J., van Eeuwijk, F.A., 1992. Char- Klein, C., Karanges, E., Spiro, A., Wong, A., Spencer, J., Huynh, T., et al.,
acterisation of Cannabis accessions with regard to cannabinoid content 2011. Cannabidiol potentiates D9-tetrahydrocannabinol (THC)
in relation to other plant characters. Euphytica 62 (3), 187e200. behavioural effects and alters THC pharmacokinetics during acute and
https://doi.org/10.1007/BF00041753. chronic treatment in adolescent rats. Psychopharmacology 218 (2),
Englund, A., Morrison, P.D., Nottage, J., Hague, D., Kane, F., 443e457. https://doi.org/10.1007/s00213-011-2342-0.
Bonaccorso, S., et al., 2013. Cannabidiol inhibits THC-elicited Lawn, W., Freeman, T.P., Pope, R.A., Joye, A., Harvey, L., Hindocha, C.,
paranoid symptoms and hippocampal-dependent memory et al., 2016. Acute and chronic effects of cannabinoids on effort-
impairment. J. Psychopharmacol. (Oxford, Engl.) 27 (1), 19e27. related decision-making and reward learning: an evaluation of the
https://doi.org/10.1177/0269881112460109. cannabis “amotivational” hypotheses. Psychopharmacology 233
Erkelens, J.L., Hazekamp, A., 2014. That which we call Indica, by any (19e20), 3537e3552. https://doi.org/10.1007/s00213-016-4383-x.
other name would smell as sweet. Cannabinoids 9 (1), 9e15. Maroon, J., Bost, J., 2018. Review of the neurological benefits of phyto-
Ganzer, F., Bröning, S., Kraft, S., Sack, P.-M., Thomasius, R., 2016. cannabinoids. Surg. Neurol. Int. 9, 91. https://doi.org/10.4103/sni.sni_
Weighing the evidence: a systematic review on long-term neuro- 45_18.
cognitive effects of cannabis use in abstinent adolescents and adults. Meier, M.H., Caspi, A., Danese, A., Fisher, H.L., Houts, R.,
Neuropsychol. Rev. 26 (2), 186e222. https://doi.org/10.1007/s11065- Arseneault, L., Moffitt, T.E., 2018. Associations between adolescent
016-9316-2. cannabis use and neuropsychological decline: a longitudinal co-twin
Glass, M., Faull, R.L.M., Dragunow, M., 1997. Cannabinoid receptors in control study. Addiction 113 (2), 257e265. https://doi.org/10.1111/
the human brain: a detailed anatomical and quantitative autoradio- add.13946.
graphic study in the fetal, neonatal and adult human brain. Mokrysz, C., Freeman, T.P., Korkki, S., Griffiths, K., Curran, H.V., 2016.
Neuroscience 77 (2), 299e318. https://doi.org/10.1016/S0306- Are adolescents more vulnerable to the harmful effects of cannabis
4522(96)00428-9. than adults? A placebo-controlled study in human males. Transl.
Gonzalez, R., 2007. Acute and non-acute effects of cannabis on brain Psychiatry 6 (11), e961. https://doi.org/10.1038/tp.2016.225.
functioning and neuropsychological performance. Neuropsychol. Rev. Morales, P., Reggio, P.H., 2017. An update on non-CB1, non-CB2
17 (3), 347e361. https://doi.org/10.1007/s11065-007-9036-8. cannabinoid related G-protein-coupled receptors. Cannabis Cannabi-
Gonzalez, R., Pacheco-Colón, I., Duperrouzel, J.C., Hawes, S.W., 2017. noid Res. 2 (1), 265. https://doi.org/10.1089/can.2017.0036.
Does cannabis use cause declines in neuropsychological functioning?
A review of longitudinal studies. J. Int. Neuropsychol. Soc. 23
(9e10), 893e902. https://doi.org/10.1017/S1355617717000789.
Morgan, C.J.A., Schafer, G., Freeman, T.P., Curran, H.V., 2010. Impact of Hypotheses 66 (2), 234e246. https://doi.org/10.1016/j.mehy.2005.08.
cannabidiol on the acute memory and psychotomimetic effects of 026.
smoked cannabis: naturalistic study. Br. J. Psychiatry 197 (4), Schreiner, A.M., Dunn, M.E., 2012. Residual effects of cannabis use on
285e290. https://doi.org/10.1192/bjp.bp.110.077503. neurocognitive performance after prolonged abstinence: a meta-
Nader, D.A., Sanchez, Z.M., 2018. Effects of regular cannabis use on analysis. Exp. Clin. Psychopharmacol. 20 (5), 420e429. https://doi.
neurocognition, brain structure, and function: a systematic review of org/10.1037/a0029117.
findings in adults. Am. J. Drug Alcohol Abuse 44 (1), 4e18. https:// Schuster, R.M., Crane, N.A., Mermelstein, R., Gonzalez, R., 2015. To-
doi.org/10.1080/00952990.2017.1306746. bacco may mask poorer episodic memory among young adult
National Academies of Sciences, E., & Medicine, 2017. The Health Ef- cannabis users. Neuropsychology 29 (5), 759e766. https://doi.org/10.
fects of Cannabis and Cannabinoids: The Current State of Evidence 1037/neu0000173.
and Recommendations for Research. The National Academies Press, Schuster, R.M., Hoeppner, S.S., Evins, A.E., Gilman, J.M., 2016a. Early
Washington, DC. onset marijuana use is associated with learning inefficiencies.
Onaivi, E.S., Ishiguro, H., Gu, S., Liu, Q.-R., 2012. CNS effects of CB2 Neuropsychology 30 (4), 405e415. https://doi.org/10.1037/
cannabinoid receptors: beyond neuro-immuno-cannabinoid activity. neu0000281.
J. Psychopharmacol. 26 (1), 92e103. https://doi.org/10.1177/ Schuster, R.M., Mermelstein, R.J., Hedeker, D., 2016b. Ecological
0269881111400652. momentary assessment of working memory under conditions of
Pearce, D.D., Mitsouras, K., Irizarry, K.J., 2014. Discriminating the effects simultaneous marijuana and tobacco use. Addiction (Abingdon, Engl.)
of cannabis sativa and cannabis indica: a web survey of medical 111 (8), 1466e1476. https://doi.org/10.1111/add.13342.
cannabis users. J. Altern. Complement. Med. 20 (10), 787e791. Scott, J.C., Slomiak, S.T., Jones, J.D., Rosen, A.F.G., Moore, T.M.,
https://doi.org/10.1089/acm.2013.0190. Gur, R.C., 2018. Association of cannabis with cognitive functioning
Pertwee, R.G., 2006. Cannabinoid pharmacology: the first 66 years. Br. J. in adolescents and young adults: a systematic review and meta-
Pharmacol. 147 (S1), S163eS171. https://doi.org/10.1038/sj.bjp. analysis. JAMA Psychiatry. https://doi.org/10.1001/jamapsychiatry.
0706406. 2018.0335.
Pertwee, R.G., 2008. Ligands that target cannabinoid receptors in the Smart, R., Caulkins, J.P., Kilmer, B., Davenport, S., Midgette, G., 2017.
brain: from THC to anandamide and beyond. Addict. Biol. 13 (2), Variation in cannabis potency and prices in a newly legal market:
147e159. https://doi.org/10.1111/j.1369-1600.2008.00108.x. evidence from 30 million cannabis sales in Washington state.
Pew Research Center, 2016. Support for Marijuana Legalization Continues Addiction (Abingdon, Engl.) 112 (12), 2167e2177. https://doi.org/10.
to Rise. 1111/add.13886.
Ramaekers, J.G., van Wel, J.H., Spronk, D.B., Toennes, S.W., Vandrey, R., Raber, J.C., Raber, M.E., Douglass, B., Miller, C., Bonn-
Kuypers, K.P.C., Theunissen, E.L., Verkes, R.J., 2016a. Cannabis and Miller, M.O., 2015. Cannabinoid dose and label accuracy in edible
tolerance: acute drug impairment as a function of cannabis use history. medical cannabis products. JAMA 313 (24), 2491e2493. https://doi.
Sci. Rep. 6. https://doi.org/10.1038/srep26843. org/10.1001/jama.2015.6613.
Ramaekers, J.G., van Wel, J.H., Spronk, D., Franke, B., Kenis, G., Verdejo-García, A., Fagundo, A.B., Cuenca, A., Rodriguez, J., Cuyás, E.,
Toennes, S.W., et al., 2016b. Cannabis and cocaine decrease cognitive Langohr, K., et al., 2013. COMT val158met and 5-HTTLPR genetic
impulse control and functional corticostriatal connectivity in drug polymorphisms moderate executive control in cannabis users. Neu-
users with low activity DBH genotypes. Brain Imaging Behav. 10 (4), ropsychopharmacology 38 (8), 1598. https://doi.org/10.1038/npp.
1254e1263. https://doi.org/10.1007/s11682-015-9488-z. 2013.59.
Russo, E.B., 2011. Taming THC: potential cannabis synergy and Zuardi, A.W., Hallak, J.E.C., Crippa, J.A.S., 2012. Interaction between
phytocannabinoid-terpenoid entourage effects. Br. J. Pharmacol. 163 cannabidiol (CBD) and D(9)-tetrahydrocannabinol (THC): influence
(7), 1344e1364. https://doi.org/10.1111/j.1476-5381.2011.01238.x. of administration interval and dose ratio between the cannabinoids.
Russo, E., Guy, G.W., 2006. A tale of two cannabinoids: the therapeutic Psychopharmacology 219 (1), 247e249. https://doi.org/10.1007/
rationale for combining tetrahydrocannabinol and cannabidiol. Med. s00213-011-2495-x.
Chapter 11
Cognitive deficits in people with

stimulant use disorders
Antonio Verdejo-Garcia1 and Adam J. Rubenis2
1
School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia; 2Turning Point
Alcohol and Drug Centre, Melbourne, VIC, Australia
State of the problem disability (Rubenis et al., 2018; Tiffany et al., 2012). This
chapter reviews the cognitive deficits associated with
Amphetamines and cocaine are the most used illicit stim- cocaine and methamphetamine addiction, starting with an
ulants globally. Amphetamines are the second most used overview of neuropharmacological and neuroadaptive
illicit drug after cannabis, and cocaine ranks number four effects of these drugs and then moving on to their acute and
after opioids (Peacock et al., 2018). The mean annual long-term cognitive effects and related clinical
prevalence of use is 0.77 for amphetamines and 0.35 for implications.
cocaine (Peacock et al., 2018). However, there is substan-
tial variation as a function of geographical location and age.
For example, the mean rate of amphetamines use is up to
Neuroadaptive effects of stimulants
4.9% in Australia, while mean rates of cocaine use are up to Cocaine produces its psychoactive effects primarily by
4% in the United Kingdom and 3% in the United States blocking the reuptake of dopamine into presynaptic neu-
(Mounteney et al., 2016; Peacock et al., 2018). Moreover rons, thus increasing dopamine availability in the frontal-
“last year” and “lifetime” use prevalence rates are striatal circuits (i.e., ventral tegmental area, striatum,
substantially higher among people aged 15e34 years amygdala, prefrontal cortex). Repeated cocaine use results
(Mounteney et al., 2016; Peacock et al., 2018). Repeated in long-term neurophysiological changes, or neuroadaptive
use of cocaine and amphetamines (particularly the stron- effects, which are often opposite to the acute effects of the
gest, most harmful form “methamphetamine”) can result in drug. To illustrate these changes, we draw on evidence
stimulant use disorder, or stimulant addiction, as well as from animal models designed to mimic the long-term
other physical and mental health conditions. The burden of effects of cocaine use in humans (e.g., extended cocaine
disease associated with the use of illicit stimulants is mainly self-administration). Based on these models, the long-term
linked to substance use disorders and other psychiatric neuroadaptive effects of cocaine include (1) reduction of
comorbidities (e.g., mood disorders, borderline personality dopamine and glutamate receptors in frontostriatal circuits,
disorder), as well as cirrhosis, liver cancer, and HIV in which these neurotransmitters are densely expressed
(mostly in relation to injecting methamphetamine) (Luscher, 2016; Spencer et al., 2016); (2) changes in gene
(Grant et al., 2016; Peacock et al., 2018). This burden of expression via transcriptional factors (e.g., deltaFOSB,
disease has been estimated at 37.6 disability-adjusted life CREB, BDNF) or epigenetic mechanisms (Li and Wolf,
years (DALYs) per 100,000 population for amphetamine 2015; Nestler, 2014; Robison and Nestler, 2011); (3) sup-
addiction and 15.9 DALYs per 100,000 population for pression of adult neurogenesis (Noonan et al., 2010; Sudai
cocaine addiction (Degenhardt et al., 2014). et al., 2011); and (4) persistent upregulation of the stress
Chronic use of cocaine and (meth)amphetamine is neuroendocrine systems (Koob and Kreek, 2007; McRey-
associated with long-term harmful effects in the brain and nolds et al., 2014). Animal models have shown that
cognition, which in turn contribute to the development repeated cocaine use produces long-term depletion in
and maintenance of addiction (Koob and Volkow, 2010) metabotropic glutamate receptors and dopamine D2
and have a significant impact on quality of life and related receptors in the medial prefrontal and orbitofrontal cortices

(Ben-Shahar et al., 2012, 2013; Briand et al., 2008; drug-related motivation (i.e., conditioned place preference)
Kasanetz et al., 2013). Further neuroadaptations in gluta- (Shibasaki et al., 2011), while histone H4 hypoacetylation
mate and dopamine systems encompass upregulation of is associated with decreased glutamate receptor expression
AMPA-type glutamate receptors, changes in intrinsic in the striatum (Cadet and Jayanthi, 2013; Jayanthi et al.,
membrane excitability, and decreased extracellular neuro- 2014), which impacts frontal-striatal circuits and executive
transmitter levels, all having a profound impact on synaptic functions (McClure and Bickel, 2014).
connections between the striatum, the limbic system, and
the prefrontal cortex (Bonci et al., 2003; Wolf, 2010).
Another well-established neuroadaptive mechanism Cognitive profiles
involves cocaine-induced mobilization of gene transcrip- Acute effects
tion factors; for example, cocaine-induced overexpression
of the deltaFOSB is associated with orbitofrontal In this section, we rely on evidence from placebo-
dysfunction and poor impulse control in cocaine-treated controlled acute administration studies in humans.
rats (Winstanley et al., 2009). There is also evidence for Cocaine and amphetamines have cognitive enhancing
more stable cocaine-induced epigenetic changes in DNA effects on processing speed, attention, and response inhi-
methylation and histone modification causing global brain bition in psychomotor tasks after acute administration
and hippocampal attrition and deficits in cognitive tests of (reviewed in Spronk et al., 2013). Interestingly, these
attention and working memory (He et al., 2006; Novikova effects are associated with drug-induced activations in brain
et al., 2008; Zhao et al., 2015). Cocaine can also block cell regions implicated in cognitive control and performance
proliferation and neurogenesis in the dentate gyrus of the monitoring, including the dorsolateral prefrontal cortex, the
hippocampus, negatively affecting working memory (Sudai inferior frontal gyrus, and the insula (Garavan et al., 2008).
et al., 2011), and persistently elevate cortisol and Acute administration of methamphetamine is also associ-
corticotropin-releasing hormone levels (Smith et al., 2004) ated with better episodic memory encoding, particularly for
contributing to memory and executive dysfunctions positive affective material, in adequate sleep conditions (the
(Fox et al., 2009). drug has the opposite effect for poor sleepers) (Ballard
Methamphetamine exerts its psychoactive effects via et al., 2015). There are no studies on the acute effects of
release of large quantities of monoamine neurotransmitters, stimulant drugs on executive functions such as working
especially dopamine, and by preventing their reuptake, memory, cognitive flexibility, and decision-making.
resulting in an abnormally high concentration of these
neurotransmitters at the receiving synapse (Panenka et al., Long-term effects
2013). Over time, neuroadaptive processes include
(1) reduced neurotransmitter availability and (2) transcrip- In this section, we rely mostly on meta-analytic studies on
tional and epigenetic alterations. Methamphetamine cognitive differences between people with stimulant use
primarily appears to result in neuroadaptation of dopamine- disorders versus healthy controls. People with cocaine use
related function. Indeed, dopamine availability and function disorder and intermediate abstinence (3 months),
in the striatum is reduced (Chang et al., 2007; Panenka compared with controls, have moderate cognitive deficits
et al., 2013) and appears to be underpinned by down- (Cohen’s d 0.5) in attention, verbal learning and mem-
regulation of D2-type receptors and dopamine transporter ory, working memory, and impulsivity (Potvin et al., 2014;
availability (Ashok et al., 2017). Concentrations of Jovanovski et al., 2005). Impulsivity deficits include
monoamines are also diminished in other regions of the attention and motor inhibition problems (Czermainski et al.,
brain associated with higher-order cognitive processes and 2017; Smith et al., 2014). After 6e12 months of absti-
emotion regulation. For example, low levels of norepi- nence, general cognitive function recovers and deficits
nephrine in prefrontal cortex regions can result in memory become largely negligible, although the few studies avail-
and executive function problems and increased levels of able do not allow reliable conclusions about the recovery of
anxiety (Freye, 2009; Wang et al., 2000) as well as low specific cognitive domains (Potvin et al., 2014). For
levels of serotonin in the orbitofrontal and occipital cortices example, a comprehensive review of cocaine-related
(Kish et al., 2009; Scott et al., 2007). Methamphetamine cognitive deficits observed strong, consistent deficits in
use is similarly associated with reduced frontal cortex reward-based decision-making (Spronk et al., 2013), and
volumes and diminished connectivity between the these particular deficits seem to persist during long-term
prefrontal cortex and the parietal cortex (Oh et al., 2005; abstinence in cocaine users (Verdejo-Garcia et al.,
Thompson et al., 2004; Tobias et al., 2010) and may 2007b). People with cocaine use disorder also show social
underpin executive dysfunctions among users (Dean et al., cognition problems, including poorer emotion recognition
2013). Additionally, methamphetamine use can result in (Castellano et al., 2015) and blunted social-affective
increased acetylated histone H3, contributing to enhance valuation (Preller et al., 2014), and these deficits are still
Cognitive deficits in people with stimulant use disorders Chapter | 11 157
observable in participants with long-term abstinence 2013). Although there is limited evidence on which specific
(Fernandez-Serrano et al., 2011). domains are most affected by early use, initial evidence
People with methamphetamine use disorder, compared suggests that episodic memory and working memory can be
with controls, have moderate cognitive deficits in verbal particularly impacted (Lopes et al., 2017; Vonmoos et al.,
learning/memory, working memory, impulsivity/executive 2014). This finding is consistent with the notion of
functions, and social cognition (Dean et al., 2013; Potvin stimulant-induced disruption of the maturation of dorso-
et al., 2018). These deficits were observed during lateral prefrontal cortex regions, which are responsible for
abstinence, although there is not sufficient evidence to memory encoding and working memory processes
analyze the specific impact of short-term versus long-term (Tendilla-Beltran et al., 2016).
abstinence. The strongest and most clinically significant
deficits (Cohen’s d 0.9) are related to impulsivity and Cumulative exposure
social cognition (Potvin et al., 2018), although the social
Higher levels of stimulant use (greater exposure to their
cognition findings are based on a limited number of studies.
neuroadaptive effects) should be associated with poorer
A comparison between the cognitive deficits of people
cognitive performance. However, there are important
with cocaine versus methamphetamine use disorders
limitations in the measurement of cumulative drug expo-
indicates that cocaine use is distinctively associated with
sure. Self-report measures are limited by memory biases
deficits in working memory, whereas methamphetamine
use is distinctively associated with delayed episodic and demand characteristics, whereas biological assays have
inherent limitations in the time window that they can cover
memory (Hall et al., 2017).
(e.g., urine analyses can only cover hours to a few days
after last use) and/or their sensitivity and specificity
Recovery (e.g., hair analyses can be potentially confounded by hair
Recent longitudinal evidence in cocaine users suggests that color and external exposure) (Donovan et al., 2012).
attention and episodic memory deficits recover to normal Notwithstanding these limitations, several studies have
levels after long-term abstinence (12 months) (Vonmoos shown significant correlations between amount of cocaine
et al., 2014). Conversely, working memory and executive use and response inhibition and decision-making deficits
functions (including tests of fluency and cognitive (Bolla et al., 2004; Fernandez-Serrano et al., 2010;
flexibility) seem to be more stable across intermediate and Verdejo-Garcia et al., 2007a; Verdejo-Garcıa et al., 2005).
long-term abstinence (Almeida et al., 2017; Vonmoos et al., Moreover, research comparing chronic and recreational
2014). Cross-sectional studies including participants with cocaine users has shown that long-term cocaine exposure,
large ranges of abstinence have also supported the notion indicated by hair analyses, significantly increases the risk of
that executive deficits, and specifically response inhibition, cognitive deficits in attention, memory, working memory,
cognitive flexibility, and affective-based decision-making and executive functions (Vonmoos et al., 2013). With
deficits, are less sensitive to individual variation in absti- regard to methamphetamine use, the findings on the impact
nence duration (Crocker et al., 2017; Fernandez-Serrano of cumulative exposure are still inconclusive (Dean et al.,
et al., 2011). 2013). Self-report of drug use can be especially problematic
The limited longitudinal evidence in methamphetamine in methamphetamine users, as they have particularly strong
users suggests that long-term abstinence is associated with episodic memory deficits (Hall et al., 2017), and there is a
general cognitive recovery, but not with significant recov- lack of cognitive research using biological assays. There-
ery of specific cognitive domains, including attention, fore, future studies should incorporate reliable biological
impulsivity, and executive functions (Iudicello et al., 2010; assays. According to emerging evidence, amount/frequency
Schulte et al., 2014). of methamphetamine use and recent use (vs. duration/
chronicity) seem to be more closely related with cognitive
deficits, particularly memory and executive functions
Moderators (Dean et al., 2013).
Age of onset
Route of administration
Stimulant use during adolescence can generate dispropor-
tionate cognitive deficits because of interference with Smoking and injecting routes of administration bring more
maturational processes (Paus et al., 2008). Accordingly, drug to the brain more quickly (Stahl, 2013), and hence
cognitive studies have shown that people with cocaine use these patterns should be theoretically associated with
disorder who started stimulant use during adolescence greater cognitive impairment. However, no studies have
(18 years old) have significantly greater general cognitive specifically and systematically examined the impact of
deficits than those with later age of onset (Vonmoos et al., route of administration on cognitive performance among
stimulant users. Moreover, post hoc analyses of subgroups studies did not find any support for the role of verbal
of methamphetamine users with and without cognitive learning and memory in either treatment abstinence and
impairment have not shown significant differences as retention (Aharonovich et al., 2003; Turner et al., 2009) or
a function of route of administration (Cherner et al., 2010). adherence defined as appointment attendance and/or
There is a need for more research in this area, as there is compliance with medication (Fagan et al., 2015). However,
a clear neurobiological basis to expect differences in the role of learning and memory might have been masked
cognition, and differences in route of administration are by small sample sizes and low power. In summary, there is
clinically meaningful, e.g., cocaine smokers versus suggestive evidence of a meaningful link between learning
snorters have poorer addiction treatment prognosis (Kiluk and memory and treatment outcomes in stimulant users.
et al., 2013).
Attention
Clinical significance of cognitive There is strong support for the role of attentional function
deficits associated with stimulants use in predicting treatment outcomes. Five studies have found
significant support for this link (Aharonovich et al., 2003,
The cognitive deficits identified in the previous section 2006; Fagan et al., 2015; Harris et al., 2014; Streeter et al.,
(i.e., attention, memory, impulsivity, and executive 2008), while two found partial support (Carroll et al., 2011;
functions) can hinder the ability to benefit from addiction Chen et al., 2015). Sustained or selective attention
treatment (Dominguez-Salas et al., 2016). Attention and predicted attendance or number of sessions completed in
memory problems can compromise understanding of the psychologically based treatments (e.g., cognitive behav-
contents of “talking therapies” (Shoptaw, 2014). Height- ioral therapy; CBT) in several studies (Aharonovich et al.,
ened impulsivity and reduced executive functions may also 2003, 2006; Carroll et al., 2011; Fagan et al., 2015; Harris
affect the ability to engage with treatment activities (Carroll et al., 2014; Streeter et al., 2008). One study found that
et al., 2011) and to remain in treatment long enough to attention was predictive of relapse but not dropout in a
achieve beneficial effects (Vergara-Moragues et al., 2017; sample of individuals with methamphetamine addiction
Washio et al., 2011). The importance of understanding (Chen et al., 2015), while another study found that
these links is reinforced by high vulnerability to relapse sustained attention predicted the number of psychological
among individuals with stimulant use disorders (Brecht and treatment modules completed and days in treatment, but not
Herbeck, 2014). This section examines the longitudinal abstinence (Carroll et al., 2011).
predictive link between cognitive function in early treat- Although these findings primarily relate to cocaine
ment and subsequent treatment outcomes. In these studies, (Aharonovich et al., 2003, 2006; Carroll et al., 2011; Fagan
participants are tested in early treatment and then followed et al., 2015; Streeter et al., 2008), all available research
up to confirm abstinence/completion of a treatment provides either complete or partial support for a link
program or their level of engagement. Because people with between attentional function and psychological treatment
cocaine and methamphetamine use disorders have outcomes and suggests a consistent link between these
overlapping deficits in memory, attention, impulsivity, and variables. The association between attentional function and
executive functions and enroll in similar treatment modal- drug use/relapse is less conclusive, with one study finding a
ities, we organize the section by cognitive domains and significant relationship (Chen et al., 2015) and another
discuss together findings in users of both stimulants. finding no relationship (Carroll et al., 2011), and suggests
that further well-controlled research is required.
Memory
Working memory and executive functions
Although there are no studies on people with metham-
phetamine use disorders, five studies have examined the Two studies have directly examined the predictive value of
link between learning/memory and cocaine addiction working memory on stimulant addiction treatment
treatment outcomes (Aharonovich et al., 2003; outcomes (Dean et al., 2009; Patterson et al., 2010).
Aharonovich et al., 2006; Fagan et al., 2015; Fox et al., In participants with methamphetamine use disorder,
2009; Turner et al., 2009). Deficits in visual and verbal working memory performance significantly predicted
memory were significantly greater in those who dropped completion of a 12-week treatment program, although this
out of treatment when compared with individuals relationship was no longer significant after adjusting for
completing the program (Aharonovich et al., 2006), while baseline methamphetamine use (Dean et al., 2009). Poorer
verbal and auditory declarative memory have been signif- working memory performance (slower reaction time under
icantly associated with higher levels of cocaine use after highest working memory load) was also significantly
inpatient treatment (Fox et al., 2009). However, three negatively associated with days to nicotine (an alkaloid
stimulant) relapse (Patterson et al., 2010). Other measures predict days in treatment (Carroll et al., 2011) or relapse
of cognitive control have significantly predicted stimulant (Adinoff et al., 2016; Chen et al., 2015).
treatment outcomes in eight studies, including relapse Overall, these findings are mixed and suggest that while
(Adinoff et al., 2016; Carroll et al., 2011; Powell et al., there is evidence that impulsive action and delay
2010), treatment retention/completion (Aharonovich et al., discounting frequently predict relapse, it is unclear what
2003, 2006; Streeter et al., 2008; Turner et al., 2009), and role these constructs play in predicting retention and
adherence to a treatment program (Fagan et al., 2015). adherence to treatment. Furthermore, decision-making
However, three of these studies found only partial support shows a relationship with treatment outcomes broadly but
for the relationship, where not all measures of executive does not show a consistent pattern (i.e., there is conflicting
functions were significantly predictive (Aharonovich et al., evidence for relapse and treatment retention, while one
2006), abstinence was predicted at only one of three time study supports a link with treatment engagement).
points (Powell et al., 2010), or executive functions did not
predict other treatment-related outcomes (treatment ses- Summary
sions completed; Carroll et al., 2011). Furthermore, two
studies found no significant relationship between executive There is evidence of specific domains of cognition
functions and treatment outcomes (Chen et al., 2015; Harris predicting treatment outcomes in individuals with stimulant
et al., 2014). However, relationships may have been use disorders. While evidence for the role of memory is
masked by liberal inclusion criteria (i.e., participants who inconclusive, there is strong evidence linking attentional
met DSM-IV criteria for methamphetamine abuse rather function with outcomes in psychological treatments
than dependence; Chen et al., 2015) or a small sample size (e.g., CBT), but not relapse or drug use. Findings relating to
(Harris et al., 2014). working memory and executive functions suggest an
Overall, the available evidence supports a relationship association with lower treatment retention and relapse, and
between working memory/executive functions and a range impulsivity and decision-making deficits predict relapse.
of treatment outcomes (relapse, treatment completion, and These findings collectively suggest that higher-order
adherence). cognitive skills are predictive of treatment outcomes in a
range of domains. However, it appears that these relation-
ships are complex, where different cognitive domains
Impulsivity and decision-making
influence different treatment outcomes and interact with
Several forms of impulsivity have been examined in the each other in outcome prediction (Rubenis et al., 2017),
context of stimulant addiction treatment outcomes. Two which highlights the importance of a nuanced approach to
studies have supported a link between motor response cognitive prediction of outcomes.
inhibition and treatment outcomes, predicting nicotine
abstinence at 1 week, 1 month, and 3 months (Powell et al.,
2010), and relapse in participants with cocaine addiction, Recommendations for researchers and
but not days in treatment or sessions completed (Carroll clinicians interested in cognitive
et al., 2011). assessment in the context of stimulants
Delay discounting significantly predicted treatment
retention (Stevens et al., 2014) and abstinence in primarily
use
stimulant-addicted individuals (Sheffer et al., 2012; Washio The cognitive assessment of people with cocaine and
et al., 2011). However, Harris et al. (2014) found that delay methamphetamine use disorders should focus on the
discounting was not a significant predictor of reduction in domains of attention, verbal memory, working memory and
nicotine use, but may be partly explained by the young age executive functions, and impulsivity/decision-making.
of the sample (adolescents) and the tendency for delay Assessment of attention, verbal memory, working memory,
discounting to be higher and less variable in younger and executive functions can be particularly useful to char-
individuals and therefore less useful as a predictor. acterize long-term cognitive deficits (Vonmoos et al.,
Decision-making has been examined in stimulant- 2013), whereas assessment of working memory/executive
dependent individuals in five studies and has predicted functions and impulsivity/decision-making is especially
relapse at 3 months (Verdejo-Garcia et al., 2014), propor- relevant when predicting treatment outcomes and relapse
tion of positive drug tests up to 20 weeks (Nejtek et al., (Dominguez-Salas et al., 2016; Stevens et al., 2014).
2013), dropout from methamphetamine treatment Cognitive assessment in stimulant users should carefully
(Chen et al., 2015), and psychological sessions/modules control for potential moderators and confounders, including
completed and days of abstinence (Carroll et al., 2011). background characteristics (i.e., education, IQ, trait
However, other studies found that decision-making did not features, and clinical diagnoses such as ADHD and
personality disorders) and drug use patterns, particularly Bolla, K., Ernst, M., Kiehl, K., Mouratidis, M., Eldreth, D.,
age of onset and cumulative amount of drug use indicated Contoreggi, C., et al., 2004. Prefrontal cortical dysfunction in absti-
with reliable assessments (cue-guided self-report or nent cocaine abusers. J. Neuropsychiatry Clin. Neurosci. 16 (4),
456e464.
adequate biological assays).
Bonci, A., Bernardi, G., Grillner, P., Mercuri, N.B., 2003. The dopamine-
Although there is a solid body of evidence on the
containing neuron: maestro or simple musician in the orchestra of
cognitive domains that we should assess in the context of addiction? Trends Pharmacol. Sci. 24 (4), 172e177.
stimulant use disorders, there are no common, harmonized, or Brecht, M., Herbeck, D., 2014. Time to relapse following treatment for
standardized tools to perform these assessments, and this is a methamphetamine use: a long-term perspective on patterns and pre-
question for future research. The development of a harmo- dictors. Drug Alcohol Depend. 139, 18e25.
nized cognitive assessment tool/battery should be guided by Briand, L.A., Flagel, S.B., Garcia-Fuster, M.J., Watson, S.J., Akil, H.,
the purpose of the assessment (e.g., characterization of Sarter, M., Robinson, T.E., 2008. Persistent alterations in cognitive
deficits vs. prediction of outcomes), the evidence base function and prefrontal dopamine D2 receptors following extended,
(i.e., the assessment should focus on the most relevant but not limited, access to self-administered cocaine. Neuro-
domains identified in this chapter), and evidences of reli- psychopharmacology 33 (12), 2969e2980.
Cadet, J.L., Jayanthi, S., 2013. Epigenetics of methamphetamine-induced
ability, especially testeretest reliability to enable multiple
changes in glutamate function. Neuropsychopharmacology 38 (1),
assessments during abstinence and/or monitoring of
248e249.
treatment-related recovery and construct ecological and Carroll, K.M., Kiluk, B.D., Nich, C., Babuscio, T.A., Brewer, J.A.,
predictive validity including positive and negative predictive Potenza, M.N., et al., 2011. Cognitive function and treatment response
values (Verdejo-Garcia, 2017). in a randomized clinical trial of computer-based training in cognitive-
behavioral therapy. Subst. Use Misuse 46 (1), 23e34.
Castellano, F., Bartoli, F., Crocamo, C., Gamba, G., Tremolada, M.,
References Santambrogio, J., et al., 2015. Facial emotion recognition in alcohol
Ben-Shahar, O.M., Szumlinski, K.K., Lominac, K.D., Cohen, A., and substance use disorders: a meta-analysis. Neurosci. Biobehav.
Gordon, E., Ploense, K.L., et al., 2012. Extended access to cocaine Rev. 59, 147e154.
self-administration results in reduced glutamate function within the Chang, L., Alicata, D., Ernst, T., Volkow, N., 2007. Structural and
medial prefrontal cortex. Addict. Biol. 17 (4), 746e757. metabolic brain changes in the striatum associated with metham-
Adinoff, B., Carmody, T.J., Walker, R., Donovan, D.M., Brigham, G.S., phetamine abuse. Addiction 102 (s1), 16e32.
Winhusen, T.M., 2016. Decision-making processes as predictors of Chen, Y.C., Chen, C.K., Wang, L.J., 2015. Predictors of relapse and
relapse and subsequent use in stimulant-dependent patients. Am. J. dropout during a 12-week relapse prevention program for metham-
Drug Alcohol Abuse 42 (1), 88e97. phetamine users. J. Psychoact. Drugs 47 (4), 317e324.
Aharonovich, E., Nunes, E., Hasin, D., 2003. Cognitive impairment, Cherner, M., Suarez, P., Casey, C., Deiss, R., Letendre, S., Marcotte, T.,
retention and abstinence among cocaine abusers in cognitive- et al., 2010. Methamphetamine use parameters do not predict neuro-
behavioral treatment. Drug Alcohol Depend. 71 (2), 207e211. psychological impairment in currently abstinent dependent adults.
Aharonovich, E., Hasin, D.S., Brooks, A.C., Liu, X., Bisaga, A., Drug Alcohol Depend. 106 (2), 154e163.
Nunes, E.V., 2006. Cognitive deficits predict low treatment retention Crocker, C.E., Purdon, S.E., Hanstock, C.C., Lakusta, B., Seres, P.,
in cocaine dependent patients. Drug Alcohol Depend. 81 (3), Tibbo, P.G., 2017. Enduring changes in brain metabolites and exec-
313e322. utive functioning in abstinent cocaine users. Drug Alcohol Depend.
Almeida, P.P., de Araujo Filho, G.M., Malta, S.M., Laranjeira, R.R., 178, 435e442.
Marques, A.C.R., Bressan, R.A., Lacerda, A.L., 2017. Attention and Czermainski, F.R., Willhelm, A.R., Santos, Á.Z., Pachado, M.P., de
memory deficits in crack-cocaine users persist over four weeks of Almeida, R.M.M., 2017. Assessment of inhibitory control in crack
abstinence. J. Subst. Abus. Treat. 81, 73e78. and/or cocaine users: a systematic review. Trends Psychiatry Psy-
Ashok, A.H., Mizuno, Y., Volkow, N.D., Howes, O.D., 2017. Association chother. 39 (3), 216e225.
of stimulant use with dopaminergic alterations in users of cocaine, Dean, A.C., London, E.D., Sugar, C.A., Kitchen, C.M.R., Swanson, A.-N.,
amphetamine, or methamphetamine: a systematic review and meta- Heinzerling, K.G., et al., 2009. Predicting adherence to treatment for
analysis. JAMA Psychiatry 74 (5), 511e519. methamphetamine dependence from neuropsychological and drug use
Ballard, M.E., Weafer, J., Gallo, D.A., de Wit, H., 2015. Effects of acute variables. Drug Alcohol Depend. 105 (1e2), 48e55.
methamphetamine on emotional memory formation in humans: Dean, A.C., Groman, S.M., Morales, A.M., London, E.D., 2013. An
encoding vs consolidation. PLoS One 10 (2), e0117062. evaluation of the evidence that methamphetamine abuse causes
Ben-Shahar, O., Sacramento, A.D., Miller, B.W., Webb, S.M., cognitive decline in humans. Neuropsychopharmacology 38 (2),
Wroten, M.G., Silva, H.E., et al., 2013. Deficits in ventromedial 259e274.
prefrontal cortex group 1 metabotropic glutamate receptor function Degenhardt, L., Baxter, A.J., Lee, Y.Y., Hall, W., Sara, G.E., Johns, N.,
mediate resistance to extinction during protracted withdrawal from an et al., 2014. The global epidemiology and burden of psychostimulant
extensive history of cocaine self-administration. J. Neurosci. 33 (2), dependence: findings from the Global Burden of Disease Study 2010.
495e506a. Drug Alcohol Depend. 137 (1), 36e47.
Domínguez-Salas, S., Díaz-Batanero, C., Lozano-Rojas, O.M., Verdejo- Jovanovski, D., Erb, S., Zakzanis, K.K., 2005. Neurocognitive deficits in
García, A., 2016. Impact of general cognition and executive func- cocaine users: a quantitative review of the evidence. J. Clin. Exp.
tion deficits on addiction treatment outcomes: systematic review and Neuropsychol. 27 (2), 189e204.
discussion of neurocognitive pathways. Neurosci. Biobehav. Rev. 71, Kasanetz, F., Lafourcade, M., Deroche-Gamonet, V., Revest, J.M.,
772e801. Berson, N., Balado, E., et al., 2013. Prefrontal synaptic markers of
Donovan, D.M., Bigelow, G.E., Brigham, G.S., Carroll, K.M., cocaine addiction-like behavior in rats. Mol. Psychiatry 18 (6),
Cohen, A.J., Gardin, J.G., et al., 2012. Primary outcome indices in 729e737.
illicit drug dependence treatment research: systematic approach to Kiluk, B.D., Babuscio, T.A., Nich, C., Carroll, K.M., 2013. Smokers
selection and measurement of drug use end-points in clinical trials. versus snorters: do treatment outcomes differ according to route of
Addiction 107 (4), 694e708. cocaine administration? Exp. Clin. Psychopharmacol 21 (6),
Fagan, C.S., Carmody, T.J., McClintock, S.M., Suris, A., Nakamura, A., 490e498.
Jeon-Slaughter, H., et al., 2015. The effect of cognitive functioning on Kish, S.J., Fitzmaurice, P.S., Boileau, I., Schmunk, G.A., Ang, L.C.,
treatment attendance and adherence in comorbid bipolar disorder and Furukawa, Y., et al., 2009. Brain serotonin transporter in human
cocaine dependence. J. Subst. Abus. Treat. 49, 15e20. methamphetamine users. Psychopharmacology 202 (4), 649e661.
Fernandez-Serrano, M.J., Pérez-García, M., Schmidt Río-Valle, J., Koob, G., Kreek, M.J., 2007. Stress, dysregulation of drug reward path-
Verdejo-Garcia, A., 2010. Neuropsychological consequences of ways, and the transition to drug dependence. Am. J. Psychiatry 164
alcohol and drug abuse on different components of executive func- (8), 1149e1159.
tions. J. Psychopharmacol. 24 (9), 1317e1332. Koob, G.F., Volkow, N.D., 2010. Neurocircuitry of addiction. Neuro-
Fernández-Serrano, M.J., Pérez-García, M., Verdejo-García, A., 2011. psychopharmacology 35 (1), 217e238.
What are the specific vs. generalized effects of drugs of abuse on Li, X., Wolf, M.E., 2015. Multiple faces of BDNF in cocaine addiction.
neuropsychological performance? Neurosci. Biobehav. Rev. 35 (3), Behav. Brain Res. 279, 240e254.
377e406. Lopes, B.M., Gonçalves, P.D., Ometto, M., dos Santos, B., Cavallet, M.,
Fox, H.C., Jackson, E.D., Sinha, R., 2009. Elevated cortisol and learning Chaim-Avancini, T.M., et al., 2017. Distinct cognitive performance
and memory deficits in cocaine-dependent individuals: relationship and patterns of drug use among early and late onset cocaine users.
to relapse outcomes. Psychoneuroendocrinology 34 (8), Addict. Behav. 73, 41e47.
1198e1207. Luscher, C., 2016. The emergence of a circuit model for addiction. Annu.
Freye, E., 2009. Pharmacology and Abuse of Cocaine, Amphetamines, Rev. Neurosci. 39, 257e276.
Ecstasy and Related Designer Drugs. Springer Netherlands, Dor- McClure, S.M., Bickel, W.K., 2014. A dual-systems perspective on
drecht, Netherlands. addiction: contributions from neuroimaging and cognitive training.
Garavan, H., Kaufman, J.N., Hester, R., 2008. Acute effects of cocaine on Ann. N. Y. Acad. Sci. 1327 (1), 62e78.
the neurobiology of cognitive control. Phil. Trans. Biol. Sci. 363 McReynolds, J.R., Vranjkovic, O., Thao, M., Baker, D.A., Makky, K.,
(1507), 3267e3276. Lim, Y., Mantsch, J.R., 2014. Beta-2 adrenergic receptors mediate
Grant, B.F., Saha, T.D., Ruan, W.J., Goldstein, R.B., Chou, S.P., Jung, J., stress-evoked reinstatement of cocaine-induced conditioned place
et al., 2016. Epidemiology of DSM-5 drug use disorder: results from preference and increases in CRF mRNA in the bed nucleus of the stria
the national epidemiologic survey on alcohol and related terminalis in mice. Psychopharmacology 231 (20), 3953e3963.
conditionseIII. JAMA Psychiatry 73 (1), 39e47. Mounteney, J., Griffiths, P., Sedefov, R., Noor, A., Vicente, J., Simon, R.,
Hall, M.G., Hauson, A.O., Wollman, S.C., Allen, K.E., Connors, E.J., 2016. The drug situation in Europe: an overview of data available on
Stern, M.J., et al., 2017. Neuropsychological comparisons of cocaine illicit drugs and new psychoactive substances from European moni-
versus methamphetamine users: a research synthesis and meta- toring in 2015. Addiction 111 (1), 34e48.
analysis. Am. J. Drug Alcohol Abuse 44 (3), 1e17. Nejtek, V.A., Kaiser, K.A., Zhang, B., Djokovic, M., 2013. Iowa
Harris, M., Penfold, R.B., Hawkins, A., Maccombs, J., Wallace, B., Gambling Task scores predict future drug use in bipolar disorder
Reynolds, B., 2014. Dimensions of impulsive behavior and treatment outpatients with stimulant dependence. Psychiatr. Res. 210 (3),
outcomes for adolescent smokers. Exp. Clin. Psychopharmacol 22 (1), 871e879.
57e64. Nestler, E.J., 2014. Epigenetic mechanisms of drug addiction. Neuro-
He, F., Lidow, I.A., Lidow, M.S., 2006. Consequences of paternal cocaine pharmacology 76 (Part B), 259e268.
exposure in mice. Neurotoxicol. Teratol. 28 (2), 198e209. Noonan, M.A., Bulin, S.E., Fuller, D.C., Eisch, A.J., 2010. Reduction of
Iudicello, J.E., Woods, S.P., Vigil, O., Cobb Scott, J., Cherner, M., adult hippocampal neurogenesis confers vulnerability in an animal
Heaton, R.K., et al., 2010. Longer term improvement in neuro- model of cocaine addiction. J. Neurosci. 30 (1), 304e315.
cognitive functioning and affective distress among methamphetamine Novikova, S.I., He, F., Bai, J., Cutrufello, N.J., Lidow, M.S., Undieh, A.S.,
users who achieve stable abstinence. J. Clin. Exp. Neuropsychol. 32 2008. Maternal cocaine administration in mice alters DNA methyl-
(7), 704e718. ation and gene expression in hippocampal neurons of neonatal and
Jayanthi, S., McCoy, M.T., Chen, B., Britt, J.P., Kourrich, S., Yau, H.J., prepubertal offspring. PLoS One 3 (4), e1919.
et al., 2014. Methamphetamine downregulates striatal glutamate re- Oh, J.S., Lyoo, I.K., Sung, Y.H., Hwang, J., Kim, J., Chung, A., et al.,
ceptors via diverse epigenetic mechanisms. Biol. Psychiatry 76 (1), 2005. Shape changes of the corpus callosum in abstinent metham-
47e56. phetamine users. Neurosci. Lett. 384 (1), 76e81.
Panenka, W.J., Procyshyn, R.M., Lecomte, T., MacEwan, G.W., Smith, S.M., Vaughan, J.M., Donaldson, C.J., Rivier, J., Li, C., Chen, A.,
Flynn, S.W., Honer, W.G., Barr, A.M., 2013. Methamphetamine use: Vale, W.W., 2004. Cocaine-and amphetamine-regulated transcript
a comprehensive review of molecular, preclinical and clinical findings. activates the hypothalamic-pituitary-adrenal axis through a
Drug Alcohol Depend. 129 (3), 167e179. corticotropin-releasing factor receptor-dependent mechanism. Endo-
Patterson, F., Jepson, C., Loughead, J., Perkins, K., Strasser, A.A., crinology 145 (11), 5202e5209.
Siegel, S., et al., 2010. Working memory deficits predict short-term Smith, J.L., Mattick, R.P., Jamadar, S.D., Iredale, J.M., 2014. Deficits in
smoking resumption following brief abstinence. Drug Alcohol behavioural inhibition in substance abuse and addiction: a meta-
Depend. 106 (1), 61e64. analysis. Drug Alcohol Depend. 145, 1e33.
Paus, T., Keshavan, M., Giedd, J.N., 2008. Why do many psychiatric Spencer, S., Scofield, M., Kalivas, P.W., 2016. The good and bad news
disorders emerge during adolescence? Nat. Rev. Neurosci. 9 (12), about glutamate in drug addiction. J. Psychopharmacol. 30 (11),
947e957. 1095e1098.
Peacock, A., Leung, J., Larney, S., Colledge, S., Hickman, M., Rehm, J., Spronk, D.B., van Wel, J.H., Ramaekers, J.G., Verkes, R.J., 2013. Char-
et al., 2018. Global statistics on alcohol, tobacco and illicit drug use: acterizing the cognitive effects of cocaine: a comprehensive review.
2017 status report. Addiction. https://doi.org/10.1111/add.14234. Neurosci. Biobehav. Rev. 37 (8), 1838e1859.
Potvin, S., Stavro, K., Rizkallah, É., Pelletier, J., 2014. Cocaine and Stahl, S.M., 2013. Stahl’s Essential Psychopharmacology: Neuroscientific
cognition: a systematic quantitative review. J. Addict. Med. 8 (5), Basis and Practical Applications, fourth ed. Cambridge University
368e376. Press, Cambridge, UK.
Potvin, S., Pelletier, J., Grot, S., Hébert, C., Barr, A., Lecomte, T., 2018. Stevens, L., Verdejo-García, A., Goudriaan, A.E., Roeyers, H., Dom, G.,
Cognitive deficits in individuals with methamphetamine use disorder: Vanderplasschen, W., 2014. Impulsivity as a vulnerability factor for
a meta-analysis. Addict. Behav. 80, 154e160. poor addiction treatment outcomes: a review of neurocognitive find-
Powell, J., Dawkins, L., West, R., Powell, J., Pickering, A., 2010. Relapse ings among individuals with substance use disorders. J. Subst. Abus.
to smoking during unaided cessation: clinical, cognitive and motiva- Treat. 47 (1), 58e72.
tional predictors. Psychopharmacology 212 (4), 537e549. Streeter, C.C., Terhune, D.B., Whitfield, T.H., Gruber, S., Sarid-Segal, O.,
Preller, K.H., Herdener, M., Schilbach, L., Stämpfli, P., Hulka, L.M., Silveri, M.M., et al., 2008. Performance on the Stroop predicts treat-
Vonmoos, M., et al., 2014. Functional changes of the reward system ment compliance in cocaine-dependent individuals. Neuro-
underlie blunted response to social gaze in cocaine users. Proc. Natl. psychopharmacology 33 (4), 827e836.
Acad. Sci. U.S.A. 111 (7), 2842e2847. Sudai, E., Croitoru, O., Shaldubina, A., Abraham, L., Gispan, I.,
Robison, A.J., Nestler, E.J., 2011. Transcriptional and epigenetic mecha- Flaumenhaft, Y., et al., 2011. High cocaine dosage decreases neuro-
nisms of addiction. Nat. Rev. Neurosci. 12 (11), 623e637. genesis in the hippocampus and impairs working memory. Addict.
Rubenis, A.J., Fitzpatrick, R.E., Lubman, D.I., Verdejo-Garcia, A., 2017. Biol. 16 (2), 251e260.
Working memory predicts methamphetamine hair concentration over Tendilla-Beltrán, H., Arroyo-García, L.E., Diaz, A., Camacho-Abrego, I.,
the course of treatment: moderating effect of impulsivity and impli- de la Cruz, F., Rodríguez-Moreno, A., Flores, G., 2016. The effects of
cations for dual-systems model. Addict. Biol. https://doi.org/10.1111/ amphetamine exposure on juvenile rats on the neuronal morphology
adb.12575. of the limbic system at prepubertal, pubertal and postpubertal ages.
Rubenis, A.J., Fitzpatrick, R.E., Lubman, D.I., Verdejo-Garcia, A., 2018. J. Chem. Neuroanat. 77, 68e77.
Impulsivity predicts poorer improvement in quality of life during early Thompson, P.M., Hayashi, K.M., Simon, S.L., Geaga, J.A., Hong, M.S.,
treatment for people with methamphetamine dependence. Addiction Sui, Y., et al., 2004. Structural abnormalities in the brains of human
113 (4), 668e676. subjects who use methamphetamine. J. Neurosci. 24 (26),
Schulte, M.H., Cousijn, J., den Uyl, T.E., Goudriaan, A.E., van den 6028e6036.
Brink, W., Veltman, D.J., et al., 2014. Recovery of neurocognitive Tiffany, S.T., Friedman, L., Greenfield, S.F., Hasin, D.S., Jackson, R.,
functions following sustained abstinence after substance dependence 2012. Beyond drug use: a systematic consideration of other outcomes
and implications for treatment. Clin. Psychol. Rev. 34 (7), 531e550. in evaluations of treatments for substance use disorders. Addiction 107
Scott, J.C., Woods, S.P., Matt, G.E., Meyer, R.A., Heaton, R.K., (4), 709e718.
Atkinson, J.H., Grant, I., 2007. Neurocognitive effects of metham- Tobias, M.C., O’Neill, J., Hudkins, M., Bartzokis, G., Dean, A.C.,
phetamine: a critical review and meta-analysis. Neuropsychol. Rev. 17 London, E.D., 2010. White-matter abnormalities in brain during early
(3), 275e297. abstinence from methamphetamine abuse. Psychopharmacology 209
Sheffer, C., MacKillop, J., McGeary, J., Landes, R., Carter, L., Yi, R., (1), 13e24.
et al., 2012. Delay discounting, locus of control, and cognitive Turner, T.H., LaRowe, S., Horner, M.D., Herron, J., Malcolm, R., 2009.
impulsiveness independently predict tobacco dependence treatment Measures of cognitive functioning as predictors of treatment outcome
outcomes in a highly dependent, lower socioeconomic group of for cocaine dependence. J. Subst. Abus. Treat. 37 (4), 328e334.
smokers. Am. J. Addict. 21 (3), 221e232. Verdejo-Garcıa, A.J., López-Torrecillas, F., de Arcos, F.A., Pérez-
Shibasaki, M., Mizuno, K., Kurokawa, K., Ohkuma, S., 2011. L-type Garcıa, M., 2005. Differential effects of MDMA, cocaine, and
voltage-dependent calcium channels facilitate acetylation of histone cannabis use severity on distinctive components of the executive
H3 through PKCg phosphorylation in mice with methamphetamine- functions in polysubstance users: a multiple regression analysis.
induced place preference. J. Neurochem. 118 (6), 1056e1066. Addict. Behav. 30 (1), 89e101.
Shoptaw, S., 2014. Commentary on Gowin et al. (2014): brain is Verdejo-Garcia, A., 2017. Neuroclinical assessment of addiction needs to
behaviordmethamphetamine dependence and recovery. Addiction incorporate decision-making measures and ecological validity. Biol.
109 (2), 248e249. Psychiatry 81 (7), e53ee54.
Verdejo-Garcia, A., Benbrook, A., Funderburk, F., David, P., Cadet, J.L., induced but partially reversible: evidence from a longitudinal study.
Bolla, K.I., 2007a. The differential relationship between cocaine use Neuropsychopharmacology 39 (9), 2200e2210.
and marijuana use on decision-making performance over repeat testing Wang, Y., Chou, J., Jeng, C.H., Morales, M., Wang, J.Y., 2000. Chronic
with the Iowa Gambling Task. Drug Alcohol Depend. 90 (1), 2e11. methamphetamine exposure decreases high affinity uptake function in
Verdejo-García, A., Rivas-Pérez, C., Vilar-López, R., Pérez-García, M., norepinephrine afferents in the cerebellar cortex: an electrophysio-
2007b. Strategic self-regulation, decision-making and emotion pro- logical and electrochemical study. Neuropharmacology 39 (11),
cessing in poly-substance abusers in their first year of abstinence. 2112e2123.
Drug Alcohol Depend. 86 (2e3), 139e146. Washio, Y., Higgins, S.T., Heil, S.H., McKerchar, T.L., Badger, G.J.,
Verdejo-Garcia, A., Albein-Urios, N., Martinez-Gonzalez, J.M., Civit, E., Skelly, J.M., Dantona, R.L., 2011. Delay discounting is associated
De la Torre, R., Lozano, O., 2014. Decision-making impairment with treatment response among cocaine-dependent outpatients. Exp.
predicts 3-month hair-indexed cocaine relapse. Psychopharmacology Clin. Psychopharmacol 19 (3), 243e248.
231 (21), 4179e4187. Winstanley, C.A., Green, T.A., Theobald, D.E., Renthal, W., LaPlant, Q.,
Vergara-Moragues, E., Verdejo-García, A., Lozano, O.M., Santiago- DiLeone, R.J., et al., 2009. DFosB induction in orbitofrontal cortex
Ramajo, S., González-Saiz, F., Espinosa, P.B., García, M.P., 2017. potentiates locomotor sensitization despite attenuating the cognitive
Association between executive function and outcome measure of dysfunction caused by cocaine. Pharmacol. Biochem. Behav. 93 (3),
treatment in therapeutic community among cocaine dependent in- 278e284.
dividuals. J. Subst. Abus. Treat. 78, 48e55. Wolf, M.E., 2010. The Bermuda Triangle of cocaine-induced neuro-
Vonmoos, M., Hulka, L.M., Preller, K.H., Jenni, D., Schulz, C., adaptations. Trends Neurosci. 33 (9), 391e398.
Baumgartner, M.R., Quednow, B.B., 2013. Differences in self- Zhao, Q., Hou, J., Chen, B., Shao, X., Zhu, R., Bu, Q., et al., 2015.
reported and behavioral measures of impulsivity in recreational and Prenatal cocaine exposure impairs cognitive function of progeny via
dependent cocaine users. Drug Alcohol Depend. 133 (1), 61e70. insulin growth factor II epigenetic regulation. Neurobiol. Dis. 82,
Vonmoos, M., Hulka, L.M., Preller, K.H., Minder, F., Baumgartner, M.R., 54e65.
Quednow, B.B., 2014. Cognitive impairment in cocaine users is drug-
Chapter 12
Cognitive consequences of
3,4-methylenedioxymethamphetamine
use
Catharine Montgomery1 and Carl A. Roberts2
1
School of Natural Sciences and Psychology, Liverpool John Moores University, Liverpool, United Kingdom; 2Institute of Psychology, Health and
Society, University of Liverpool, Liverpool, United Kingdom
Introductiondepidemiology of highest estimated use (0.69%), followed by the Americas

(0.51%), Asia (0.43%), and Africa (0.22%). Household pop-
3,4-methylenedioxymethamphetamine ulation estimate surveys in various countries indicate that use
use is highest in the 16e25 age group (e.g., Broadfield, 2017).
3,4-Methylenedioxymethamphetamine commonly referred The global market for substances containing MDMA is
to as MDMA or ecstasy is a ring-substituted phenethyl- smaller than that of other amphetamine-type drugs such as
amine with empathogenic properties (Dumont and Verkes, methamphetamine, but it is becoming more complex, with
2006). While MDMA was originally patented by the various forms and types of substances available. The WDR
German pharmaceutical company Merck in 1914, it did not (UNODC, 2017) highlights that there are currently three
really come to prominence until it was resynthesized by main types of MDMA available: (i) ecstasy in tablet form,
Alexander Shulgin in 1965 (Shulgin and Shulgin, 1991). which contains little or no MDMA; (ii) ecstasy in tablet
After this time, MDMA was used as an aid to psychological form with very high MDMA content; and (iii) ecstasy
therapy in the United States (Beck and Rosenbaum, 1994), which is sold in powder or crystal form of varying purities
showing promising effects for increasing openness in and under a range of names, e.g., Molly, Mandy, Magic.
marriage and relationship problems (Greer and Tolbert, After the increases in use in the 1980s and 1990s, use
1986). It went on to become popular as a club drug during peaked around early 2000s (Parrott, 2013) at about the
the 1980s, particularly at raves and dance music events same time purity of tablets was also at its peak. In the late
(Parrott, 2001), and increases in use continued for the next 2000s, purity dropped significantly. At this time, there was
20 years (Schuster et al., 1998). MDMA use was made a subsequent rise in the use of Novel Psychoactive Sub-
illegal in the United Kingdom in 1977 under a modification stances (NPS) and a drop in MDMA use. One purported
of the Misuse of Drugs Act (1977), making it a Class A reason for this is a decrease in MDMA supply driven by a
drug and placing it under schedule I, which contains drugs number of seizures of MDMA precursors such as Safrole
that are believed to have no therapeutic value and are thus oil (Mounteney et al., 2018). During this low purity period,
illegal to possess, supply, or prescribe (White et al., 1997). many tablets contained NPS and other adulterants such as
Similarly, it was banned in the United States in 1985 and paramethoxymethamphetamine, which lead to increases in
placed on the schedule I list of prohibited substances risk of harm from using MDMA (Nicol et al., 2015;
(Kraner et al., 2001) and in Australia in 1986, where it was EMCDDA, 2003). Anecdotally, reports suggest that users
placed in schedule 9. Despite prohibition of MDMA, believe that powdered MDMA is of higher quality and thus
according to the World Drug Report (WDR) (United safer than tablets, leading to increased popularity of
Nations Office on Drugs and Crime, UNODC, 2017), powdered MDMA in recent years, particularly in the
globally in 2017, it was estimated that there were United States (Palamar, 2017). Recently, the ecstasy market
21,650,000 MDMA users, representing 0.45% of adults has recovered, with a decrease in adulterants reported in
aged 16e54. After Oceania (2.42%), Europe has the

drug seizures over the 2010e16 period and fewer NPS and In the brain, MDMA is a monoamine reuptake inhibitor,
stimulant adulterants (UNODC, 2017). causing the release of serotonin, dopamine, and norepineph-
Use of MDMA is generally recreational, and while rine, in addition to blocking their reuptake (Berger et al., 1992;
individuals can become habituated to use as with any Nichols et al., 1982). Increased levels of serotonin in the
substance, addictive potential is low (O’Brien, 1996). It is synapse are responsible for the majority of the primary
thus not clear what might predispose one to use MDMA as subjective effects, with MDMA administration purported to
opposed to another recreational drug, although the desired release up to 80% of stored serotonin (Green et al., 2003). It
empathogenic effects are the most likely cause of use. has been suggested that use of MDMA can damage the
Some studies have proposed a role for self-medication serotonin system, and the remainder of this section discusses
(Khantzian, 1997) with depression predating MDMA. research investigating MDMA-related changes in brain
One Dutch cohort study found that abnormal scores on function.
anxiety and depression at age 10 could predict future
ecstasy use at age 25 (Huizink et al., 2006), with two Animal research
further studies implicating a role for preexisting phobias,
somatoform disorders and syndromes, dysthymia, and There are a number of factors that might contribute to
panic disorders in future ecstasy use (Falck et al., 2006; MDMA-related serotonergic damage in the brains of both
Lieb et al., 2002). In addition to these psychiatric abnor- animals and humans. One of the most prominent theories of
malities, a range of sociodemographic variables including axonal damage is The Integrated Hypothesis proposed by
education, employment status, relationship status, and Sprague et al. (1998), in which the authors propose a clear
social class were all correlated with future use of ecstasy role for dopamine in the damage sustained to serotonin
suggesting that use is multifaceted. In retrospective studies, axons. This hypothesis is based on animal studies which
such mood differences have been observed in MDMA have observed that manipulating levels of dopamine causes
users, with some studies reporting higher rates of depression, changes in levels of neurotoxicity following MDMA
especially in the short-term after use (e.g., McGuire et al., administration (see, for example, Aguirre et al. (1998);
1994; MacInnes et al., 2001; Parrott and Lasky, 1998), Nash and Nichols, 1991; Stone et al. (1988)). However, the
although polysubstance abuse is believed to contribute to exact mechanism of MDMA-related neurotoxicity in
these effects (Roiser and Sahakian, 2004). MDMA users animal models is not fully understood. Studies in both
have also exhibited differences on personality scales, which animals and humans have implicated external factors which
could contribute to drug initiation and continuation of drug may play a role, for example, increased ambient tempera-
use, as seen in other substance users. For example, MDMA ture leading to hyperthermia can increase the level of
users report higher levels of extraversion on the Big Five axonal loss (Capela et al., 2006; Green et al., 2003).
personality scale (Ter Bogt et al., 2006), a trait which has Furthermore, when housed at higher temperatures to induce
been linked to reward sensitivity and frequency of intoxica- hyperthermia, rats do still sustain serotonergic damage even
tion (Depue and Collins, 1999). Users of MDMA also exhibit if administered a-methyl-p-tyrosine to inhibit dopamine
higher scores on measures of novelty seeking (Dughiero synthesis (Yuan et al., 2002). Thus the mechanism of
et al., 2001) and impulsivity (Morgan, 1998; Morgan et al., neurotoxicity must be more complex than previously
2006), although the latter is not a consistent finding thought. One likely explanation is that a neurotoxic
(Gouzoulis-Mayfrank et al., 2003). metabolite of MDMA itself causes axonal loss. For
example, methylenedioxyethylamphetamine (MDA), which
is both a metabolite of MDMA (de la Torre et al., 2004) and
Neuropharmacological/neuroadaptive an adulterant in MDMA tablets/powder (ecstasydata.org,
effects of 3,4- 2018), has been shown to cause similar axonal loss in
methylenedioxymethamphetamine rodent studies (Battaglia et al., 1987; Stone et al., 1986).
Moreover, metabolites of both MDMA and MDA have also
Pharmacokinetics and pharmacodynamics been found to cause degeneration of serotonin axons in
Recreationally, MDMA is usually administered orally and rodents, particularly under higher ambient temperatures
enters circulation via the liver. Peak plasma concentrations (Capela et al., 2006). Thus it is likely that metabolites of
are seen 1.5e3.0 h after oral administration (de la Torre MDMA and related compounds, potentially in conjunction
et al., 2000), with a 100 mg dose producing an elimination with dopamine, are the cause of MDMA-related seroto-
half-life of around 9 h (de la Torre et al., 2000b). For a nergic axon loss in animals.
discussion of pharmacokinetic time course and related Animal research has been useful for elucidating a potential
effects, see de la Torre et al. (2000). mechanism of neurotoxicity and testing this theory in a range
of paradigms. Early studies in rodents, using various dosing
Cognitive consequences of 3,4-methylenedioxymethamphetamine use Chapter | 12 167
regimens, showed loss of serotonergic uptake sites following substances (alcohol, hallucinogens, sedatives, cannabis)
MDMA administration (Broening et al., 1994b, 1995; was inversely related to this measure.
Schmidt et al., 1994), in addition to reductions in brain sero- MDMA-related decreases in cerebral blood flow (CBF)
tonin (Schmidt et al., 1986; Stone et al., 1987). It is unclear in response to pharmacological challenge have also been
why MDMA-related damage appears to be restricted to axon observed using MRI. Schouw et al. (2012) found that such
terminals in rodent studies, but this could be related to dose. differences were most pronounced in the left thalamus,
Studies in nonhuman primates have similarly provided although significant decreases were also observed in the
evidence of the neurotoxicity of MDMA. Rhesus monkeys right occipital cortex and the right frontal cortex. However,
have shown significant reductions in levels of brain 5-HT and increases in CBF were observed in the left globus pallidus
5-HIAA 14 weeks following administration, coupled with a and left frontal cortex.
significant loss of cortical serotonin, but not dopamine uptake Using diffusion tensor imaging (DTI) in MRI, which
sites (Insel et al., 1989). Rhesus monkeys have also shown allows imaging of tissue at a microscopic level, de Win
significant decreases in hippocampal 5-HT 30 days after et al. (2007) found that significant differences in white
MDMA administration (Ali et al., 1993). For reviews of matter following MDMA use were reduced to below
animal literature, see Battaglia et al. (1998) and Ricaurte et al. statistical significance following control for multiple com-
(2000). parisons. However, it is worthy of note that the reductions
While studies in rodents and nonhuman primates have in the apparent diffusion coefficient (ADC) observed in
shown that MDMA has the potential to be a neurotoxin and MDMA users in the thalamus remained significant. The
have suggested a mechanism for this neurotoxicity, it is authors suggest that this could reflect sustained vasocon-
sometimes difficult to extrapolate these findings from striction of cerebral blood vessels following even moderate
animal studies to humans. However, it is believed that use of MDMA. Furthermore, at follow-up (de Win et al.,
interspecies scaling paradigms are relatively robust (Nair 2008), MDMA users still exhibited significant decreases in
and Jacob, 2016). For a discussion of the comparable doses fractional anisotropy (FA) in the thalamus and white matter
in humans and rodents, see Baumann et al. (2009). in frontoparietal areas. These changes were again coupled
with changes in ADC in the thalamus, which the authors
propose reflect axonal damage related to MDMA use.
Human imaging
Furthermore, changes in ADC proposed to reflect axon loss
Various paradigms and techniques of neuroimaging have have also been reported by Reneman and co-workers
been used to retrospectively investigate changes to brain (Reneman et al., 2001) in the globus pallidus. However,
structure and function in human MDMA users. For brevity, these decreases in FA in the thalamus have not been
this section focuses primarily on studies using magnetic consistently shown in other studies, with Liu et al. (2011)
resonance imaging (MRI) and positron emission tomogra- showing significant increases in FA in the bilateral thalami.
phy (PET). For functional imaging during cognitive MDMA users did, however, show similar changes in
performance, see Section 3.2. ADCs, with decreases observed in the thalamus bilaterally
MRI has been used extensively in human MDMA users and increases in the bilateral anterior internal capsule, the
to assess changes of the neural correlates that might bilateral superior longitudinal fasciculus, and the splenium
underlie changes in behavior and cognition. Using func- and genu of the corpus callosum. Moeller et al. (2007) also
tional MRI (fMRI), Cowan et al. (2003) observed reduced observed reduced diffusivities in MDMA users relative to
gray matter density in ecstasy polydrug users in areas of the controls in the corpus callosum, although no differences
neocortex that have been linked to executive functions were observed in FA as in previous studies. Taken together,
(Miyake et al., 2000), namely Brodmann’s areas 18, 21, the findings in DTI suggest that human users of MDMA
and 45 (secondary visual cortex, middle temporal gyrus, sustain damage to serotonergic axons, with some studies
and inferior frontal gyrus, respectively). Decreases in gray suggesting recovery with abstinence and a role of the use of
matter density were also observed in the bilateral cere- other drugs.
bellum and the midline brainstem. In a later study, Cowan PET studies have also variably been used to investigate
and co-workers (Cowan et al., 2006) investigated the blood MDMA-related changes in CBF and to measure changes in
oxygen leveledependent (BOLD) response to visual cortex serotonin transporter (SERT) density when using radio-
activation in ecstasy users; however, no between-group ligands that label the SERT during the scan. An early study
differences were observed in visual cortex activation. by McCann et al. (1998) used the latter technique and
Subsequent within-group analyses revealed that MDMA observed a significant global decrease in the distribution
exposure was correlated with number of activated pixels for volume ratios (DVRs) of SERT in MDMA users relative to
photic stimulation. However, MDMA exposure was not controls. These differences were also related to extent of
correlated with BOLD signal change; lifetime use of other previous MDMA exposure, suggesting a doseeresponse
relationship. These results were supported by Buchert et al.
(2003), who found ecstasy-related reductions in DVRs of prolonged abstinence, a role for the concomitant use of
SERT in the mesencephalon, caudate, and thalamus. The other drugs and a role for level of previous ecstasy use. In
effects were not present in former users, suggesting addition, the use of some radioligands in PET studies has
possible recovery of function with extending abstinence. been criticized in relation to their selectivity for SERT.
Another study replicated this, showing significantly However, a recent metaanalysis of imaging studies has
reduced DVRs in the mesencephalon, with typical number provided a good discussion of the specificity of ligands
of ecstasy exposures predicting DVRs in the thalamus and used in such studies and provides evidence that these
caudate nucleus and lifetime dose (tablets) predicting DVRs techniques can be useful for reducing polydrug effects in
in the mesencephalon (Thomasius et al., 2003). A longitu- subsequent analyses (see Roberts et al., 2016a).
dinal study has also shown that there may be some recovery
of function with decreases in level of use (Thomasius et al., Potential adverse effects and
2006). Ecstasy-related differences in DVRs of SERT were
pharmacologically confounding factors
observed at baseline in the mesencephalon, although these
effects were nonsignificant at follow-up, where the current Cognitive consequences of use are discussed in the Section
MDMA users indicated that they were using at lower levels Cognitive deficits associated with MDMA, while negative
compared with baseline. Interestingly, in a study comparing physiological consequences and potential confounding
only former users with polydrug users and nondrug users, no factors are discussed here. The acute effects of MDMA
differences were observed between any group in DVRs range from mild empathogen and entactogen qualities to
(Sudhakar et al., 2009). potential systemic toxicity (Rietjens et al., 2012). The most
In addition, a follow-up of original participants by frequently reported adverse effects following administra-
Buchert et al. (2003) (Buchert et al., 2004) observed sig- tion are hypertension (Harris et al., 2002), hyperthermia
nificant reductions in DVRs in current users in the posterior (Ridpath et al., 2014), arrhythmia (Badon et al., 2002), lack
cingulate gyrus, left caudate, thalamus, occipital cortex, of appetite (Gamma et al., 2000), nausea (Liechti et al.,
medial temporal lobes, and the mesencephalon. Moreover, 2000), and, in more severe cases, loss of consciousness (Le
abstinence was positively correlated with DVRs, further Roux et al., 2015). For prevalence of adverse effects, see
supporting the notion that SERT damage can be reversed Green et al. (2003) or Devlin & Henry (2008). There are a
after cessation of use. However, the reduced binding was number of factors, both physiological and environmental,
more pronounced in female users than in male users. This which could exacerbate the toxic effects of MDMA,
was explored further in a study looking solely at female through their interaction with individual differences in
MDMA users, where increases in 5-HT2a binding were pharmacokinetics (Capela et al., 2009). For example,
observed in occipital-parietal, temporal, occipito-temporal- gender differences have been observed, with females more
parietal, frontal, and frontoparietal regions (Di lorio et al., likely to experience adverse effects, possibly because of the
2012). The effects appear to be attributable to previous effects of hormones on pharmacokinetics (Liechti et al., 2001;
ecstasy use within the sample, with lifetime dose corre- Simmler et al., 2011). Genetic differences in the levels of
lating with 5-HT2a binding in frontoparietal, occipito- enzymes used in the metabolism of MDMA might also play a
temporal, frontolimbic, and frontal regions. Urban et al. role. Poor metabolizers (PM) with low activity of the main
(2012) observed similar upregulation of 5-HT2a receptor enzyme used to metabolize MDMAdCYP2D6dhave been
binding, with decreased regional SERT availability in shown to experience heightened subjective effects acutely
various cortical, but not subcortical, regions. because of higher plasma levels of the drug (Tucker et al.,
McCann and co-workers have also shown significantly 1994). Sustained higher plasma levels could also increase the
reduced SERT binding in multiple brain regions (occipital adverse effects as rodent studies have shown that CYP2D6
cortex, parietal cortex, temporal cortex, anterior cingulate status determines hyperthermia-related toxicity (Colado et al.,
cortex, posterior cingulate cortex, dorsolateral prefrontal 1995), although this has been difficult to replicate in humans
cortex [DLPFC], and hippocampus) (McCann et al., 2008), (Farré et al., 2007). Nonetheless, poorer CYP2D6 function has
with DVRs of SERT correlating with duration of absti- been shown to result in a longer plasma half-life in humans,
nence and typical monthly dose of MDMA (McCann et al., which results in sustained acute effects and thus possible
2005). This is supported by Kish et al. (2010), reporting toxicity (Hysek et al., 2012). The effects of CYP2D6 status are
region-specific decreases in SERT binding in ecstasy users further confounded by MDMA-related inhibition of enzyme
in the entire cerebral cortex, with the occipital cortex activity (see Rietjens et al., 2012 for review). Other enzymes
reductions being most pronounced. implicated in the breakdown of monoamines have also been
In summary, both MRI and PET have been useful in implicated in heightened MDMA toxicity. For example,
providing evidence for changes to the structure of the brain decreases in catechol-O-methyl-transferase (COMT) have
in human MDMA users. However, it should be noted that been shown to increase systemic (Capela et al., 2009) and
many studies suggest recovery, at least in part, after hepatotoxicity (Antolino-Lobo et al., 2010). SERT
polymorphisms, such as the SERT genotype 5-HTTLPR, 2001; Thomasius et al., 2003) and prose (Bhattachary and
which indicates decreased SERT and therefore results in lower Powell, 2001; Krystal et al., 1992; Morgan, 1999; Morgan
levels of 5-HT uptake, have been implicated in a number of et al., 2002) recall tasks. Further to this, individual reports
studies of MDMA users. MDMA users with this genotype suggest that poor recall is associated with increased
have been shown to have a higher susceptibility to mood monthly (Bolla et al., 1998), past year (Price et al., 2014),
disorders (Martín-Santos et al., 2010), although there is and lifetime dose of ecstasy (Gouzoulis-Mayfrank et al.,
limited evidence for increased severity of cognitive deficits in 2000; Downey et al., 2015). Schilt et al. (2007) suggest that
human users with this polymorphism (Reneman et al., 2006). novice users with low ecstasy exposure show significant
Polydrug use increases the risk associated with MDMA immediate and delayed recall deficits compared with
use because of interactions between drugs and their controls and that verbal recall is particularly sensitive to
metabolites. Different drug combinations can increase or ecstasy effects. However, Thomasius et al. (2003) suggest
decrease toxicity; for example, co-use of an Selective that deficits in prose recall do not improve with abstinence.
Serotonin Reuptake Inhibitor (SSRI) at the same time as Prospective memory (PRM) is a “real-world” memory
MDMA, either as medically recommended or recreation- process which involves remembering to carry out a future
ally, can affect the metabolism of any drugs taken at the intended action, e.g., remembering to post a birthday card.
same time via induction of enzymes in the liver (Farré et al., Ecstasy users appear to be poor at this type of memory.
2007; Segura et al., 2005). Polydrug use is very common This has been shown by Heffernan et al. (2001a; 2001b),
among recreational ecstasy users, with relatively few who report ecstasy-related impairment on short-term
studies utilizing samples of ecstasy-only users habitual memory subscales of the Prospective Memory
(e.g., Halpern et al., 2004). Thus it is likely that any Questionnaire (PMQ). Rendell et al. (2007) observe ecstasy
observed neurotoxic effects in human users are related to users to be significantly impaired relative to nonusers on
combined drug effects. This is problematic as some drugs prospective memory measures in an ecologically valid
have been suggested to increase the neurotoxic potential of “virtual week” paradigm, a pattern which remained
MDMA; for example, the co-use of ecstasy with cocaine unchanged after controlling for cannabis use. Furthermore,
could increase circulating levels of dopamine, and thus Rendell et al. (2007) suggest that greater PRM deficits are
increase neurotoxicity, while co-use of ecstasy and apparent in more frequent ecstasy users. Gallagher et al.
cannabis could reduce ecstasy-related hyperthermia and (2014) also suggest that ecstasy users have generalized
thus reduce any adverse effects (Sarne and Keren, 2004). PRM problems which may interfere with everyday func-
For a review of polydrug use and effects of MDMA, see tioning, with ecstasy users displaying PRM problems that
Carvalho et al., 2012). are associated with increased average session dose (i.e.,
higher nightly doses), rather than cumulative lifetime dose.
Cognitive deficits associated with Executive functioning in the broader context of working
3,4-methylenedioxymethamphetamine memory has been examined extensively in ecstasy polydrug
users. This is due to the executive functions relying on
Research on cognitive deficits in ecstasy polydrug users is recruitment of the prefrontal cortex (PFC) for adequate
borne out of preclinical psychopharmacology work performance. The PFC contains a large number of 5-HT2A
showing dense innervation of serotonin receptors in pre- receptors, as such it is thought that executive performance
frontal brain regions necessary for performing many deficits may be the result of serotonergic neurodegeneration.
higher-order cognitive tasks. Unfortunately data on long- Miyake et al. (2000) suggested that the central executive of
term abstinence from use are generally lacking (>5 years working memory was not a unified construct and that the
abstinence). However, there are many studies investigating executive functions comprise 3 separable subfunctions,
short/medium-term cognitive effects. The initial paragraphs including mental set switching, inhibitory control, and
in this section are a brief overview of the most robust memory updating. Fisk and Sharp (2004) added access to
effects observed with recreational MDMA polydrug users, long-term memory as a further component. Findings have
which are in explicit memory domains. Following this, we been mixed in terms of ecstasy users’ performance on
discuss higher-order “executive” functions which are a set of executive tasks. For example, many studies examining
general-purpose control processes (Miyake and Friedman, switching (the ability to switch attention between tasks)
2012) which underpin and contribute more broadly to our suggest there are limited performance differences between
overall cognitive functioning. ecstasy users and controls (see, for example, Back-Madruga
Ecstasy users show consistent deficits relative to con- et al., 2003; Dafters et al., 2004; Fox et al., 2001; Hoshi
trols in the declarative memory, i.e., conscious memory et al., 2007; McCardle et al., 2004; Montgomery et al., 2005;
recall. This appears to be true for immediate, as well as Reneman et al., 2006; Zakzanis and Young, 2001), yet using
delayed word (Bolla et al. 1998; Downey et al., 2015; pooled data in a metaanalysis, Roberts et al. (2016b) observe
Parrott et al. 1998; Parrott and Lasky, 1998; Reneman et al.,
ecstasy users to be significantly impaired relative to nonuser investigated differences in activation between heavy
control groups. MDMA users, moderate MDMA users, and nonuser con-
Inhibitory control, the ability to withhold or inhibit a trols during n-back performance. Deficits were seen in
dominant response when it is not necessary, seems gener- heavy users and BOLD responses were observed in the left
ally unaffected in ecstasy users compared with controls frontal and temporal regions relative to moderate users and
whether it is assessed using the Stroop task (Back-Madruga controls. In another study, to attempt to control for the
et al., 2003; Croft et al., 2001; Gouzoulis-Mayfrank et al., effects of concomitant use of other drugs in the ecstasy-
2000; Halpern et al., 2011; Morgan et al., 2002; Wagner using group, Daumann et al. (2003b) compared pure ec-
et al., 2012), Random Letter Generation (Fisk et al., 2004; stasy users, polyvalent ecstasy users (concomitant use of
Fisk and Montgomery, 2009; Montgomery et al., 2005; ecstasy and amphetamines and cannabis), and nonuser
Murphy et al., 2011), or Go/No Go (Gouzoulis-Mayfrank controls on the n-back task. Only pure MDMA users
et al., 2003; Hanson and Luciana, 2010; Roberts and showed reduced BOLD signaling in the temporal and
Garavan, 2010). However, memory updating (involving angular gyri during the 1-back condition. A similar pattern
continuous monitoring and filtering of information to was seen in the 2-back condition, where pure MDMA users
update the contents of working memory) shows more exhibited lower BOLD activation in the angular gyrus. In
consistent impairment following ecstasy use. Ecstasy users another fMRI study, Daumann et al. (2005) report hippo-
perform consistently worse than controls at letter updating campal dysfunction in ecstasy/polydrug users relative to
(Montgomery and Fisk, 2008; Montgomery et al., 2005), cannabis-only users. While there were no performance
whereby increased MDMA use leads to poorer perfor- deficits on a paired associate learning task, ecstasy users
mance. Conversely, studies using the backward digit span exhibited less activity in the left hippocampus compared
measure of memory updating frequently report no observ- with the control group.
able deficits in ecstasy users (Bedi and Redman, 2008; Ecstasy users have also displayed greater BOLD
Bhattachary and Powell, 2001; Croft et al., 2001; activation during delayed, but not immediate, recall tasks in
Gouzoulis-Mayfrank et al., 2003; Nulsen et al., 2011; Reay three discreet brain areas (Moeller et al., 2004): the left medial
et al., 2006; Thomasius et al., 2006). and superior frontal gyri; the left thalamus, caudate, and pu-
Spatial working memory deficits are associated with tamen; the right hippocampal formation. However, after
MDMA dose intensity (Hanson and Luciana, 2010) and controlling for cannabis use in the sample, the effects in the
frequency of use (Montgomery and Fisk, 2008). Spatial frontal cortex were no longer significant, suggesting that
working memory effects may also persist after prolonged concomitant use of cannabis is a confounding factor. In line
abstinence (>6 months) and remain after controlling for with the preceding findings of hippocampal dysfunction,
cannabis use (Montgomery and Fisk, 2008). Similarly users Jacobsen et al. (2004) found that adolescent MDMA users
are poorer at computation span than controls, and this also displayed significantly lower hippocampal activity relative to
persists after cessation of use (Wareing et al., 2004, 2005). controls during a working memory task. Further analyses
However, low-level difficulty n-back tasks rarely yield revealed that abstinence period was significantly negatively
ecstasy-related cognitive deficits (Daumann et al., 2003a,b; correlated with left hippocampal activity, but that this may
Daumann et al., 2004; Gouzoulis-Mayfrank et al., 2003) recover after prolonged abstinence. Raj et al. (2010) used
probably because of the low-level cognitive demand. fMRI during a semantic recognition task and observed
Finally, access to semantic/long-term memory (retrieval reduced BOLD signal in MDMA polydrug users. In addition,
of words and ability to access long-term memory) is usually there were a number of significant correlations between
assessed using word fluency tasks such as the Chicago MDMA use and BOLD signal change in left BA 9 (DLPFC),
Word Fluency Task (CWFT) and Controlled Oral Word 18 (secondary visual cortex), and 21/22 (inferior/middle
Association Task (COWAT). Ability to perform this temporal gyrus), but not BA 45 (inferior frontal gyrus). Indices
function accurately relies on areas of the DLPFC (Stuss of MDMA use (lifetime episodes and lifetime dose) were
et al., 1998). Ecstasy-related deficits are apparent in written correlated inversely with %BOLD signal change at BA 9, in
word fluency using the CWFT (Fisk and Montgomery, the DLPFC. While there were also a number of significant
2009; Montgomery et al., 2005, 2007), yet this seems to be correlations between activation and indices of cannabis and
less problematic in its oral format (FAS task or COWAT), cocaine use, after controlling for these, the relationship
perhaps because of the oral version being much shorter and between MDMA use and activation in BA9 remained signif-
not placing sustained load on the DLPFC (e.g., Semple icant. Roberts and Garavan (2010) observed MDMA-related
et al., 1999). changes in activity during a response inhibition task, with
users displaying greater activity in right middle and inferior
Functional imaging frontal gyri, right middle frontal gyrus, and right inferior
parietal lobule, compared with controls. There were also
A number of fMRI studies from Daumann and co-workers significant differences in the right middle and inferior tem-
have investigated brain activity during cognitive perfor- poral gyri, with MDMA users displaying greater activation
mance in MDMA users. Daumann et al. (2003a) after errors. Conversely, nonusers displayed greater
deactivation after errors in the left medial frontal gyrus and left Recommendations for researchers/
posterior cingulate.
clinicians interested in cognitive
Taken together, the differences in brain activation,
despite the nonsignificant behavioral differences, show that profiling in the context of 3,4-
MDMA users are working harder to obtain the same methylenedioxymethamphetamine
behavioral output. Such findings are supported in func- It is clear that users of ecstasy exhibit cognitive deficits
tional near-infrared spectroscopy studies, where changes in and/or changes in indices of brain activity. Retrospective
oxygenated and deoxygenated hemoglobin have been cognitive profiling of ecstasy users in the domains of
observed in MDMA users in areas of the DLPFC in the executive functioning and working memory would allow
absence of any behavioral differences on a range of
researchers to characterize cognitive deficits and tailor
cognitive tasks (Montgomery et al., 2017; Roberts and
harm reduction advice using salient strategies for
Montgomery, 2015a,b; Roberts et al., 2015). fMRI has not
individuals who may exhibit impaired decision-making
always elucidated dysfunction during working memory
(Panagopoulos and Ricciardelli, 2005). While recrea-
tasks. Jager et al. (2008) found no significant differences in tional ecstasy use is not classically associated with
activation between MDMA users and nonusers on the dependency in the same way that alcohol, cannabis,
Sternberg task or an attention task. However, in an asso- cocaine, methamphetamine, and opioids are, there is
ciative learning task, ecstasy use was related to lower left evidence that a minority of users are concerned about their
DLPFC activity relative to controls, in addition to higher
use and seek treatment. As with other studies of halluci-
activation of the right middle occipital gyrus.
nogenic drugs, Degenhardt et al. (2010) have suggested
problematic MDMA use is best defined by, and described
Clinical significance of cognitive using, the terms “compulsive use” and “escalating use.”
deficits associated with 3,4- Future research could investigate cognitive phenotyping,
functional connectome phenotyping, or identification of
methylenedioxymethamphetamine neurobiomarkers which predict susceptibility to escalating
It is difficult to estimate the clinical significance of deficits MDMA use. This would require experimental and brain
associated with MDMA use. It is clear from the preceding imaging methods for neurocognitive profiling before
sections that MDMA users do exhibit some differences in initiation of drug use to observe (neuro)cognitive pre-
cognition relative to nonusers, but relatively few studies assess dictors of initiation of use, as well as tracking changes
how this will impact everyday function. A systematic review over time. There are already large neurocognitive and
of cognitive studies in 2009 suggested that while MDMA brain imaging consortium projects (e.g., IMAGEN and
users are impaired in various facets of cognitive function ENIGMA) which are conducting research in this area.
(particularly immediate and delayed recall), the clinical im- However, such research must seek to carefully control the
plications of such deficits are likely to be small (Rogers et al., many confounding variables in the drug research field
2009). More recently, a pooled data analysis looking at light (indices and patterns of drug use, drug purity, personality,
MDMA polydrug users investigated the clinical relevance of IQ, socioeconomic factors, state and trait psychological
verbal memory deficits by computing a clinical memory factors), as mentioned earlier in the chapter.
impairment quotient (Kuypers et al., 2016). The analysis Most of the knowledge of MDMA-associated cognitive
concluded that there were clinically relevant verbal memory deficits comes from retrospective studies of recreational
impairments present during intoxication, but not during polydrug users. However, there has been recent interest in
abstinence. Thus it seems that deficits in verbal memory in the therapeutic potential of MDMA as an adjunct to talking
MDMA users, while well-documented in the literature, may therapy in treatment-resistant psychological disorders. The
not be of clinical relevance. However, a recent metaanalysis Multidisciplinary Association for Psychedelic Studies
looking at executive functioning only, and not verbal (MAPS) has recently began recruitment for the first phase
memory, found robust evidence for MDMA-related deficits III clinical trial of MDMA-assisted psychotherapy for the
in three executive functions (updating, attention switching, treatment of Post Traumatic Stress Disorder (PTSD). It may
and access to semantic memory) (Roberts et al., 2016b). be necessary to better understand the cognitive effects of a
While a number of studies have also reported mood controlled use of clinical-grade MDMA. Isolation of
differences between users and nonusers subacutely (Curran MDMA from extrapsychopharmacological factors, poly-
and Travill, 1997; Parrott and Lasky, 1998; Verheyden drug use, and drug purity issues may be an avenue for
et al., 2002) and long-term (MacInnes et al., 2001; cognitive profiling, which may result in better informed
Thomasius et al., 2003), a metaanalysis of available studies harm reduction strategies for recreational use.
suggests that these differences are unlikely to be of clinical Pharmacological cognitive profiling of recreational
significance (Sumnall and Cole, 2005). MDMA is problematic, not least because of the vast
differences in drug purity. While some administration cardiotoxicity elicited during binge administration of Ecstasy.
studies investigating adverse effects have shown changes J. Pharmacol. Exp. Ther. 302 (3), 898e907.
indicative of neurotoxicity in human users (e.g., Gamma Back-Madruga, C., Boone, K.B., Chang, L., Grob, C.S., Lee, A.,
Nations, H., Poland, R.E., 2003. Neuropsychological effects of 3,4-
et al., 2000), recent controlled trials using clinical-grade
methylenedioxymethamphetamine (MDMA or ecstasy) in recrea-
MDMA have investigated acute changes in brain activity
tional users. Clin. Neuropsychol. 17 (4), 446e459.
that could indicate utility of MDMA in treatment-resistant Battaglia, G., Yeh, S.Y., O’Hearn, E., Molliver, M.E., Kuhar, M.J., De
psychological conditions (e.g., Carhart-Harris et al., Souza, E.B., 1987. 3,4-Methylenedioxymethamphetamine and 3,4-
2015). More research is needed to elucidate the acute methylenedioxyamphetamine destroy serotonin terminals in rat
potential benefits of MDMA on psychological function, brain: quantification of neurodegeneration by measurement of [3H]
and distinctions should be made in the literature between paroxetine-labeled serotonin uptake sites. J. Pharmacol. Exp. Ther.
recreational ecstasy use and controlled medical MDMA 242, 911e916.
administration. Battaglia, G., Yeh, S.Y., De Souza, E.B., 1988. MDMA-induced neuro-
toxicity: parameters of degeneration and recovery of brain serotonin
neurons. Pharmacol. Biochem. Behav. 29 (2), 269e274.
Key points and conclusion Baumann, M.H., Zolkowska, D., Kim, I., Scheidweiler, K.B., Rothman, R.B.,
Huestis, M.A., 2009. Effects of dose and route of administration on
The recreational use of MDMA/ecstasy is prevalent
pharmacokinetics of (þ or -)-3,4-methylenedioxymethamphetamine in
throughout the world. While there have been year-by-year the rat. Drug Metab. Dispos. 37, 2163e2170.
changes in levels of use associated with various factors Beck, J., Rosenbaum, M., 1994. The Pursuit of Ecstasy: The MDMA
(e.g., availability, purity, current trends in use), ecstasy Experience. State University of New York Press, Albany, NY.
remains a popular drug of choice for many individuals, Bedi, G., Redman, J., 2008. Ecstasy use and higher-level cognitive func-
particularly those between the ages of 16e24. Given the tions: weak effects of ecstasy after control for potential confounds.
research summarized herewith regarding the potential to Psychol. Med. 38 (9), 1319e1330.
affect both the structure and function of the central nervous Berger, U.V., Gu, X.F., Azmitia, E.C., 1992. The substituted amphet-
system, health information targeted at users of the drug amines 3,4-methylenedioxymethamphetamine, methamphetamine, p-
should focus on harm reduction techniques. Such tech- chloroamphetamine and fenfluramine induce 5-hydroxytryptamine
release via a common mechanism blocked by fluoxetine and
niques could be related to reducing acute effects that users
cocaine. Eur. J. Pharmacol. 215, 153e160.
may exacerbate with environmental factors (e.g., increased
Bhattachary, S., Powell, J.H., 2001. Recreational use of 3,4- methyl-
temperature), and also approaching drug testing services at enedioxymethamphetamine (MDMA) or “ecstasy”: evidence for
events and festivals to confirm the presence of the intended cognitive impairment. Psychol. Med. 31 (4), 647e658.
chemicals in the substance they are using. Prohibition of Bolla, K.I., McCann, U.D., Ricaurte, G.A., 1998. Memory impairment in
MDMA use has been in force for over 30 years, yet use abstinent MDMA (“ecstasy”) users. Neurology 51, 1532e1537.
continues at a steady rate, so it is unlikely that continued Broadfield, D. (Ed.), 2017. Statistical Bulletin 07/17: Drug Misuse:
prohibition will change this. Drug policymakers should Findings from the 2016/17 Crime Survey for England and Wales.
consider how best to protect substance users from risks of Home Office, London. Available at: https://www.gov.uk/government/
harm when reforming drug policies and consider that pro- uploads/system/uploads/attachment_data/file/633349/drug-misuse-
hibition and criminalization of use may not be the most 2017-hosb1117.pdf.
Broening, H.W., Bowyer, J.F., Slikker Jr., W., 1995. Age-dependent
appropriate response.
sensitivity of rats to the long-term effects of the serotonergic neuro-
toxicant (þ/-)-3,4-methylenedioxymethamphetamine (MDMA) cor-
References relates with the magnitude of the MDMA-induced thermal response.
J. Pharmacol. Exp. Ther. 275, 325e333.
Aguirre, N., Barrionuevo, M., Lasheras, B., DelRio, J., 1998. The role of Broening, H.W., Bacon, L., Slikker, W., 1994. Age modulates the long-
dopaminergic systems in the perinatal sensitivity to 3,4- term but not the acute effects of the serotonergic neurotoxicant 3,4-
methylenedioxymethamphetamine-induced neurotoxicity in rats. methylenedioxymethamphetamine. J. Pharmacol. Exp. Ther. 271 (1),
J. Pharmacol. Exp. Ther. 286, 1159e1165. 285e293.
Ali, S.F., Newport, G.D., Scallet, A.C., Biniedna, Z., Ferguston, S.A., Buchert, R., Thomasius, R., Nebeling, B., Petersen, K., Obrocki, J.,
BailyJR, Paul, M.G., Slikker Jr., W., 1993. Oral administration of 3,4- Jenicke, L., Wilke, F., Wartberg, L., Zapletalova, P., Clausen, M.,
methylenedioxymethamphetamine (MDMA) produces selectiveser- 2003. Long-term effects of “ecstasy” use on serotonin transporters of
otonergic depletion in the nonhuman primate. Neurotoxicol.Teratol. the brain investigated by PET. J. Nucl. Med. 44 (3), 375e384.
15, 91e96. Buchert, R., Thomasius, R., Wilke, F., Petersen, K., Nebeling, B.,
Antolino-Lobo, I., Meulenbelt, J., Nijmeijer, S.M., Scherpenisse, P., van Obrocki, J., Clausen, M., 2004. A voxel-based PET investigation of
den Berg, M., van Duursen, M.B., 2010. Differential roles of phase I the long-term effects of “ecstasy” consumption on brain serotonin
and phase II enzymes in 3,4-methylendioxymethamphetamineinduced transporters. Am. J. Psychiatry 161 (7), 1181e1189.
cytotoxicity. Drug Metab. Dispos. 38, 1105e1112.
Badon, L.A., Hicks, A., Lord, K., Ogden, B.A., Meleg-Smith, S.,
Varner, K.J., 2002. Changes in cardiovascular responsiveness and
Capela, J.P., Meisel, A., Abreu, A.R., Branco, P.S., Ferreira, L.M., de la Torre, R., Farré, M., Roset, P.N., Hernández López, C., Mas, M.,
Lobo, A.M., et al., 2006. Neurotoxicity of ecstasy metabolites in rat Ortuño, J., et al., 2000. Pharmacology of MDMA in humans. Ann. N.
cortical neurons, and influence of hyperthermia. J. Pharmacol. Exp. Y. Acad. Sci. 914 (1), 225e237.
Ther. 316 (1), 53e61. de La Torre, R., Farré, M., Ortuño, J., Mas, M., Brenneisen, R.,
Capela, J.P., Carmo, H., Remião, F., Bastos, M.L., Meisel, A., Roset, P.N., et al., 2000b. Non-linear pharmacokinetics of MDMA
Carvalho, F., 2009. Molecular and cellular mechanisms of ecstasy- (“ecstasy”) in humans. Ann. N. Y. Acad. Sci. 49 (2), 104e109.
induced neurotoxicity: an overview. Mol. Neurobiol. 39, 210e271. de la Torre, R., Farre, M., Roset, P.N., Pizzaro, N., Abanades, S.,
Carhart-Harris, R.L., Murphy, K., Leech, R., Erritzoe, D., Wall, M.B., Segura, M., Camí, J., 2004. Human pharmacology of MDMA: phar-
Ferguson, B., et al., 2015. The effects of acutely administered 3, 4- macokinetics, metabolism, and disposition. Ther. Drug Monit. 26,
methylenedioxymethamphetamine on spontaneous brain function in 137e144.
healthy volunteers measured with arterial spin labeling and blood de Win, M.M., Reneman, L., Jager, G., Vlieger, E.J., Olabarriaga, S.D.,
oxygen leveledependent resting state functional connectivity. Biol. Lavini, C., et al., 2007. A prospective cohort study on sustained ef-
Psychiatry 78, 554e562. fects of low-dose ecstasy use on the brain in new ecstasy users.
Carvalho, M., Carmo, H., Costa, V.M., Capela, J.P., Pontes, H., Neuropsychopharmacology 32, 458e470.
Remião, F., Carvalho, F., Bastos Mde, L., 2012. Toxicity of am- de Win, M.M., Jager, G., Booij, J., Reneman, L., Schilt, T., Lavini, C.,
phetamines: an update. Arch. Toxicol. 86, 1167e1231. Olabarriaga, S.D., Ramsey, N.F., den Heeten, G.J., van den Brink, W.,
Colado, M.I., Williams, J.L., Green, A.R., 1995. The hyperthermic and 2008. Neurotoxic effects of ecstasy on the thalamus. Br. J. Psychiatry
neurotoxic effects of “Ecstasy” (MDMA) and 3,4 methylenediox- 193, 289e296.
yamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the Depue, R.A., Collins, P.F., 1999. Neurobiology of the structure of
CYP2D6 poor metabolizer phenotype. Br. J. Pharmacol. 115, personality: dopamine, facilitation of incentive motivation, and
1281e1289. extraversion. Behav. Brain Sci. 22 (3), 491e517.
Cowan, R.L., Haga, E., Frederick, B.B., Dietrich, M.S., Vimal, R.L.P., Devlin, R.J., Henry, J.A., 2008. Clinical review: major consequences of
Lukas, S.E., Renshaw, P.F., 2006. MDMA use is associated with illicit drug consumption. Crit. Care 12, 202.
increased spatial BOLD fMRI visual cortex activation in human Di lorio, C.R., Watkins, T.J., Dietrich, M.S., Cao, A., Blackford, J.U.,
MDMA users. Psychopharmacol. Biochem. Behav. 84, 219e228. Rogers, B., Ansari, M.S., Baldwin, R.M., Li, R., Kessler, R.M.,
Cowan, R.L., Lyoo, I.K., Sung, S.M., Ahn, K.H., Kim, M.J., Hwang, J., Salomon, R.M., Benningfield, M., Cowan, R.L., 2012. Evidence for
Haga, E., Vimal, R.L.P., Lukas, S.E., Renshaw, P.F., 2003. Reduced chronically altered cortical serotonin function in human female rec-
cortical gray matter density in human MDMA (Ecstasy) users: a reational ecstasy (MDMA) polydrug users. Arch. Gen. Psychiatr. 69
voxel-based morphometry study. Drug Alcohol Depend. 72 (3), (4), 399e409.
225e235. Downey, L.A., Sands, H., Jones, L., Clow, A., Evans, P., Stalder, T.,
Croft, R.J., Mackay, A.J., Mills, A.T.D., Gruzelier, J.G.H., 2001. The Parrott, A.C., 2015. Reduced memory skills and increased hair cortisol
relative contributions of ecstasy and cannabis to cognitive impairment. levels in recent Ecstasy/MDMA users: significant but independent
Psychopharmacology 153, 373e379. neurocognitive and neurohormonal deficits. Hum. Psychopharmacol.
Curran, H.V., Travill, R.A., 1997. Mood and cognitive effects of 3,4- Clin. Exp. 30 (3), 199e207.
methylenedioxymethamphetamine (MDMA, “Ecstasy”): weekend Dughiero, G., Schifano, F., Forza, G., 2001. Personality dimensions and
“high” followed by mid-week “low”. Addiction 92 (7), 821e831. psychopathological profiles of Ecstasy users. Hum. Psychopharmacol.
Dafters, R.I., Hoshi, R., Talbot, A.C., 2004. Contribution of cannabis and 16, 635e639.
MDMA (“ecstasy”) to cognitive changes in long-term polydrug users. Dumont, G.J., Verkes, R.J., 2006. A review of acute effects of 3,4-
Psychopharmacology 173, 405e410. methylenedioxymethamphetamine in healthy volunteers.
Daumann, J., Fimm, B., Willmes, K., Thron, A., Gouzoulis-Mayfrank, E., J. Psychopharmacol. 20, 176e187.
2003a. Cerebral activation in abstinent ecstasy (MDMA) users during EcstasyData.org, 2018. EcstasyData.org: Test Result Statistics: Substances
a working memory task: a functional magnetic resonance imaging by Year. www.ecstasydata.org.
(fMRI) study. Cogn. Brain Res. 16 (3), 479e487. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA),
Daumann, J., Schnitker, R., Weidemann, J., Schnell, K., Thron, A., 2003. Report on the Risk Assessment of PMMA in the Framework of
Gouzoulis-Mayfrank, 2003b. Neural correlates of working memory in the Joint Action on New Synthetic Drugs. EMCDDA Risk Assess-
pure and polyvalent ecstasy (MDMA) users. Neuroreport 14 (15), ments Series, vol. 5. Lisbon, March 2003.
1983e1987. Falck, R.S., Wang, J., Carlson, R.G., Siegal, H.A., 2006. Prevalence and
Daumann, J., Fischermann, T., Heekeren, K., Thron, A., Gouzoulis- correlates of current depressive symptomatology among a community
Mayfrank, E., 2004. Neural mechanisms of working memory in ec- sample of MDMA users in Ohio. Addict. Behav. 31, 90e101.
stasy (MDMA) users who continue or discontinue ecstasy and Farré, M., Abanades, S., Roset, P.N., Peiró, A.M., Torrens, M.,
amphetamine use: evidence from an 18-month longitudinal functional O’Mathúna, B., Segura, M., de la Torre, R., 2007. Pharmacological
magnetic resonance imaging study. Biol. Psychiatry 56 (5), 349e355. interaction between 3,4-methylenedioxymethamphetamine (ecstasy)
Daumann, J., Fischermann, T., Heekeren, K., Henke, K., Thron, A., and paroxetine: pharmacological effects and pharmacokinetics.
Gouzoulis-Mayfrank, E., 2005. Memory-related hippocampal dysfunc- J. Pharmacol. Exp. Ther. 323, 954e962.
tion in poly-drug ecstasy (3,4-methylenedioxymethamphetamine) users. Fisk, J.E., Montgomery, C., Murphy, P., Wareing, M., 2004. Evidence for
Psychopharmacology 180, 607e611. executive deficits among users of MDMA (Ecstasy). B. J. Psychol. 95
Degenhardt, K., Bruno, R., Topp, L., 2010. Is ecstasy a drug of (4), 457e466.
dependence? Drug Alcohol Depend. 107 (1), 1e10.
Fisk, J.E., Montgomery, C., 2009. Evidence for selective executive comparison to both matched polydrug-using controls and drug-naive
function deficits in ecstasy/polydrug users. J. Psychopharmacol. 23 controls. Psychopharmacology 194, 371e379.
(1), 40e50. Huizink, A.C., Ferdinand, R.F., van der Ende, J., Verhulst, F.C., 2006.
Fisk, J.E., Sharp, C.A., 2004. Age-related impairment in executive Symptoms of anxiety and depression in childhood and use of MDMA:
functioning: updating, inhibition, shifting and access. J. Clin. Exp. prospective, population-based study. Br. Med. J. 332, 825e827.
Neuropsychol. 26 (7), 874e890. Hysek, C.M., Simmler, L.D., Nicola, V.G., Vischer, N., Donzelli, M.,
Fox, H.C., Parrott, A.C., Turner, J.J.D., 2001. Ecstasy use: cognitive Krähenbühl, S., Grouzmann, E., Huwyler, J., Hoener, M.C.,
deficits related to doseage rather than self reported problematic use of Liechti, M.E., 2012. Duloxetine inhibits effects of MDMA (“ecstasy”)
the drug. J. Psychopharmacol. 15 (4), 273e281. in vitro and in humans in a randomized placebo-controlled laboratory
Gallagher, D.T., Hadjiefthyvoulou, F., Fisk, J.E., Montgomery, C., study. PLoS One 7, e36476.
Robinson, S., Judge, J., 2014. Prospective memory deficits in in illicit Insel, T.R., Battaglia, G., Johannessen, J.N., Marra, S., De Souza, E.B.,
polydrug users are associated with the average long-term typical dose 1989. 4-Methylenedioxymethamphetamine (“ecstasy”) selectively
of ecstasy typically consumed in a single session. Neuropsychology destroys brain serotonin terminals in rhesus monkeys. J. Pharmacol.
28 (1), 43e54. Exp. Ther. 249 (3), 713e720.
Gamma, A., Buck, A., Berthold, T., Liechti, M.E., Vollenweider, F.X., Jacobsen, L.K., Mencl, W.E., Pugh, K.R., Skudlarski, P., Krystal, J.H.,
Hell, D., 2000. 3,4-Methylenedioxymethamphetamine (MDMA) 2004. Preliminary evidence of hippocampal dysfunction in adolescent
modulates cortical and limbic brain activity as measured by [H(2)(15) MDMA (“ecstasy”) users: possible relationship to neurotoxic effects.
O]-PET in healthy humans. Neuropsychopharmacology 23 (4), Psychopharmacology 173, 383e390.
388e395. Jager, G., de Win, M.M.L., van der Tweel, I., Schilt, T., Kahn, R.S., van
Gouzoulis-Mayfrank, E., Daumann, J., Tuchtenhagen, F., Pelz, S., den Brink, W., van Ree, J.M., Ramsey, N.F., 2008. Assessment of
Becker, S., Kunert, H.-J., Fimm, B., Sass, H., 2000. Impaired cogni- cognitive brain function in ecstasy users and contributions of other
tive performance in drug free users of recreational ecstasy (MDMA). drugs of abuse: results from an fMRI study. Neuro-
J. Neurol. Neurosurg. Psychiatry 68 (6), 719e725. psychopharmacology 33, 247e258.
Gouzoulis-Mayfrank, E., Thimm, B., Rezk, M., Hensen, G., Daumann, J., Khantzian, E.J., 1997. The self-medication hypothesis of substance use
2003. Memory impairment suggests hippocampal dysfunction in disorders: a reconsideration and recent applications. Harv. Rev.
abstinent ecstasy users. Prog. Neuropsychopharmacol. Biol. Psychia- Psychiatry 4 (5), 231e244.
try 27, 819e827. Kish, S.J., Lerch, J., Furukawa, Y., Tong, J., McCluskey, T., Wilkins, D.,
Green, A.R., Mechan, A.O., Elliott, J.M., O’Shea, E., Colado, M.I., 2003. Houle, S., Meyer, J., Mundo, E., Wilson, A.A., Rusjan, P.M., Saint-
The pharmacology and clinical pharmacology of 3,4- Cyr, J.A., Guttman, M., Collins, D.L., Shapiro, C., Warsh, J.J.,
methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol. Boileau, I., 2010. Decreased cerebral cortical serotonin transporter
Rev. 55, 463e508. binding in ecstasy users: a positron emission tomography/[11C]DASB
Greer, G., Tolbert, R., 1986. Subjective reports of the effects of MDMA in and structural brain imaging study. Brain J. Neurol. 133, 1779e1797.
a clinical setting. J. Psychoact. Drugs 18, 319e327. Kraner, J.C., McCoy, D.J., Evans, M.A., Evans, L.E., Sweeney, B.J.,
Hanson, K., Luciana, M., 2010. Neurocognitive impairments in MDMA 2001. Fatalities caused by the MDMA-related drug para-
and other drug users: MDMA alone may not be a cognitive risk factor. methoxyamphetamine (PMA). J. Anal. Toxicol. 25, 645e648.
J. Clin. Exp. Neuropsychopharmacol. 32 (4), 337e349. Krystal, J.H., Price, L.H., Opsahl, C., Ricaurte, G.A., Heninger, G.R.,
Halpern, J.H., Pope, H.r., Sherwood, A.R., Barry, S., Hudson, J.I., 1992. Chronic 3,4-Methylenedioxymethamphetamine (MDMA) use:
Yurgelun-Todd, D., 2004. Residual neuropsychological effects of effects of mood and neurophysiological function. Am. J. Drug
illicit 3,4-methylenedioxymethamphetamine (MDMA) in individuals Alcohol Abuse 18 (3), 331e341.
with minimal exposure to other drugs. Drug Alcohol Depend. 75 (2), Kuypers, K.P.C., Theunissen, E.L., van Wel, J.H.P., de Sousa Fernandes
135e147. Perna, E.B., Linssen, A., Sambeth, A., et al., 2016. Verbal memory
Halpern, J.H., Sherwood, A.R., Hudson, J.I., Gruber, S., Kozin, D., impairment in polydrug ecstasy users: a clinical perspective. PLoS
Pope Jr., H.G., 2011. Residual neurocognitive features of long-term One 11 (2), e0149438.
ecstasy users with minimal exposure to other drugs. Addiction 106 Le Roux, G., Bruneau, C., Lelièvre, B., Bretaudeau-Deguigne, M.,
(4), 777e786. Turcant, A., Harry, P., Boels, D., 2015. Recreational phenethylamine
Harris, D.S., Baggott, M., Mendelson, J.H., Mendelson, J.E., Jones, R.T., poisonings reported to a French poison control center. Drug Alcohol
2002. Subjective and hormonal effects of 3,4- Depend. 154, 46e53.
methylenedioxymethamphetamine (MDMA) in humans. Psycho- Lieb, R., Schuetz, C.G., Pfister, H., Sydow, K., von Wittchen, H.U., 2002.
pharmacology 162 (4), 396e405. Mental disorders in ecstasy users: a prospective longitudinal investi-
Heffernan, T.M., Jarvis, H., Rodgers, J., Scholey, A.B., Ling, J., 2001a. gation. Drug Alcohol Depend. 68, 195e207.
Prospective memory, everyday cognitive failure and central executive Liechti, M.E., Gamma, A., Vollenweider, F.X., 2001. Gender differences
function in recreational users of ecstasy. Hum. Psychopharmacol. in the subjective effects of MDMA. Psychopharmacology 154 (2),
Clin. Exp. 16, 607e612. 161e168.
Heffernan, T.M., Ling, J., Scholey, A.B., 2001b. Subjective ratings of Liechti, M.E., Baumann, C., Gamma, A., Vollenweider, F.X., 2000. Acute
prospective memory deficits in MDMA (“ecstasy”) users. Hum. psychological effects of 3,4-methylenedioxymethamphetamine
Psychopharmacol. Clin. Exp. 16, 339e344. (MDMA, ecstasy) are attenuated by the serotonin uptake inhibitor
Hoshi, R., Mullins, K., Boundy, C., Brignell, C., Piccini, P., Curran, H.V., citalopram. Neuropsychopharmacology 22, 513e521.
2007. Neurocognitive function in current and ex-users of ecstasy in
Liu, H.S., Chou, M.C., Chung, H.W., Cho, N.Y., Chiang, S.W., Morgan, M.J., Impallomeni, L.C., Pirona, A., Rogers, R.D., 2006.
Wang, C.Y., Kao, H.W., Huang, G.S., Chen, C.Y., 2011. Potential Elevated impulsivity and impaired decision-making in abstinent
long-term effects of MDMA on the basalganglia-thalamocortical cir- ecstasy (MDMA) users compared to polydrug and drug naïve controls.
cuit: a proton MR spectroscopy and diffusion-tensorimaging study. Neuropsychopharmacology 31, 1562e1573.
Radiology 260, 531e540. Montgomery, C., Fisk, J.E., 2008. Ecstasy-related deficits in the updating
MacInnes, N., Handley, S.L., Harding, G.F.A., 2001. Former chronic component of executive processes. Hum. Psychopharmacol. 23,
methylenedioxymethamphetamine (MDMA or ecstasy) users report 495e511.
mild depressive symptoms. J. Psychopharmacol. 15 (3), 181e186. Montgomery, C., Fisk, J.E., Newcombe, R., Murphy, P.N., 2005. The
Martín-Santos, R., Torrens, M., Poudevida, S., Langohr, K., Cuyás, E., differential effects of ecstasy/polydrug use on executive components:
Pacifici, R., Farré, M., Pichini, S., de la Torre, R., 2010. 5-HTTLPR shifting, inhibition, updating and access to semantic memory.
polymorphism, mood disorders and MDMA use in a 3-year follow- Psychopharmacology 182, 262e276.
up study. Addict. Biol. 15, 15e22. Montgomery, C., Fisk, J.E., Wareing, M., Murphy, P., 2007. Self-reported
McCann, U.D., Szabo, Z., Scheffel, U., Dannals, R.F., Ricaurte, G.A., sleep quality and cognitive performance in ecstasy users. Hum. Psy-
1998. Positron emission tomogpaphic evidence of toxic effect of chopharmacol. 22, 537e548.
MDMA on brain serotonin neurons in human beings. Lancet 352, Montgomery, C., Fisk, J.E., Roberts, C.A., 2017. Updating of working
1433e1437. memory in ecstasy polydrug users: findings from fNIRS. Hum. Psy-
McCann, U., Szabo, Z., Seckin, E., Rosenblatt, P., Mathews, W.B., chopharmacol. Clin. Exp. 32, e32609.
Ravert, H.T., Dannals, R.F., Ricaurte, G.A., 2005. Quantitative PET Mounteney, J., Griffiths, P., Bo, A., Cunningham, A., Matias, J.,
studies of the serotonin transporter in MDMA users and controls using Pirona, A., 2018. Nine reasons why ecstasy is not quite what it used to
[11C]McN5652 and [11C]DASB. Neuropsychopharmacology 30, be. Int. J. Drug Policy 51, 36e41.
1741e1750. Murphy, P.N., Erwin, P.G., Maciver, L., Fisk, J.E., Larkin, D.,
McCann, U.D., Szabo, Z., Vranesic, M., Palermo, M., Mathews, W.B., Wareing, M., Montgomery, C., Hilton, J., Tames, F.J., Bradley, B.,
Ravert, H.T., Dannals, R.F., Ricaurte, G.A., 2008. Positron emission Yanulevitch, K., Ralley, R., 2011. The relationships of “ecstasy”
tomographic studies of brain dopamine and serotonin transporters in (MDMA) and cannabis use to impaired executive inhibition and ac-
abstinent () 3,4-methylenedioxymethamphetamine (“ecstasy”) users: cess to semantic long-term memory. Hum. Psychopharmacol. 26,
relationship to cognitive performance. Psychopharmacology 200 (3), 460e469.
439e450. Nair, A.B., Jacob, S., 2016. A simple practice guide for dose conversion
McCardle, K., Luebbers, S., Carter, J.D., Croft, R.J., Stough, C., 2004. between animals and human. J. Basic Clin. Pharm. 7 (2), 27e31.
Chronic MDMA (ecstasy) use, cognition and mood. Psychopharma- Nash, J.F., Nichols, D.E., 1991. Microdialysis studies on 3,4-
cology 173, 434e439. methylenedioxy-amphetamine and structurally related analogues.
McGuire, P.K., Cope, H., Fahy, T.A., 1994. Diversity of psychopathology Eur. J. Pharmacol. 200, 53e58.
associated with use of 3,4-methylenedioxymethamphetamine Nicol, J.J.E., Yarema, M.C., Jones, G.R., Martz, W., Purssell, R.A.,
(Ecstasy). Br. J. Psychiatry 165, 391e395. MacDonald, J.C., Wishart, I., Durigon, M., Tzemis, D., Buxton, J.A.,
Miyake, A., Friedman, N.P., 2012. The nature and organization of 2015. Deaths from exposure to paramethoxymethamphetamine in
individual differences in executive functions: four general conclu- Alberta and British Columbia, Canada: a case series. CMAJ Open 3
sions. Curr. Dir. Psychol. Sci. 21 (1), 8e14. (1), E83eE90.
Miyake, A., Friedman, N.P., Emerson, M.J., Witzki Howerter, A., Nichols, D., Lloyd, D.H., Hoffman, A.J., Nichols, M.B., Yim, G.K.W.,
Wager, T.D., 2000. The unity and diversity of executive functions and 1982. Effects of certain hallucinogenic amphetamine analogues on the
their contributions to complex “frontal lobe” tasks: a latent variable release of 3H-serotonin from the rat whole brain synaptosomes.
analysis. Cogn. Psychol. 41, 49e100. J. Med. Chem. 25, 530e535.
Moeller, F.G., Steinberg, J.L., Dougherty, D.M., Narayana, P.A., Nulsen, C., Fox, A., Hammond, G., 2011. Electrophysiological indices of
Kramer, L.A., Renshaw, P.F., 2004. Functional MRI study of working altered working memory processes in long-term ecstasy users. Hum.
memory in MDMA users. Psychopharmacology (Berl.) 177, Psychopharmacol. 26, 488e497.
185e194. O’Brien, 1996. Drug addiction and drug abuse. In: Hardman, J.G.,
Moeller, F.G., Steinberg, J.L., Lane, S.D., Buzby, M., Swann, A.C., Goodman Gilman, A., Limbird, L.E. (Eds.), Goodman and Gilman’s:
Hasan, K.M., Kramer, L.A., Narayana, P.A., 2007. Diffusion tensor The Pharmacological Basis of Therapeutics, ninth ed. McGraw-Hill,
imaging in MDMA users and controls: association with decision New York, pp. 557e577.
making. Am. J. Drug Alcohol Abuse 33, 777e789. Palamar, J.J., 2017. There’s something about Molly: the underresearched
Morgan, M.J., 1998. Recreational use of “ecstasy” (MDMA) is associated yet popular powder form of ecstasy in the United States. Subst. Abuse
with elevated impulsivity. Neuropsychopharmacology 19 (4), 38 (1), 15e17.
252e264. Panagopoulos, I., Ricciardelli, L.A., 2005. Harm reduction and decision
Morgan, M.J., 1999. Memory deficits associated with recreational use of making among recreational ecstasy users. Int. J. Drug Policy 16 (1),
“ecstasy” (MDMA). Psychopharmacology 141, 30e36. 54e64.
Morgan, M.J., McFie, L., Fleetwood, L.H., Robinson, J.A., 2002. Ecstasy Parrott, A.C., 2001. Human psychopharmacology of Ecstasy (MDMA): a
(MDMA): are the psychological problems associated with its use review of 15 years of empirical research. Hum. Psychopharmacol.
reversed by prolonged abstinence? Psychopharmacology 159, Clin. Exp. 16, 557e577.
294e303.
Parrott, A.C., 2013. Human psychobiology of MDMA or “Ecstasy”: an Roberts, C.A., Montgomery, C., 2015b. fNIRS suggests increased effort
overview of 25 years of empirical research. Hum. Psychopharmacol. during executive access in ecstasy polydrug users. Psychopharma-
Clin. Exp. 28, 289e307. cology (Berl.) 232, 1571e1582.
Parrott, A.C., Lees, A., Garnham, N.J., Jones, M., Wesnes, K., 1998. Roberts, C.A., Jones, A., Montgomery, C., 2016b. Meta-analysis of
Cognitive performance in recreational users of MDMA or “ecstasy”: executive functioning in ecstasy/polydrug users. Psychol. Med. 46 (8),
evidence for memory deficits. J. Psychopharmacol. 12, 79e83. 1581e1596.
Parrott, A.C., Lasky, J., 1998. Ecstasy (MDMA) effects upon mood and Roberts, C.A., Jones, A., Montgomery, C., 2016a. Meta-analysis of mo-
cognition: before, during and after a Saturday night dance. Psycho- lecular imaging of serotonin transporters in ecstasy/polydrug users.
pharmacology 139 (3), 261e268. Neurosci. Biobehav. Rev. 63, 158e167.
Price, J.S., Shear, P., Lisdahl, K.M., 2014. Ecstasy exposure and gender: Rogers, G., Elston, J., Garside, R., Roome, C., Taylor, R., Younger, P.,
examining components of verbal memory functioning. PLoS One 9 et al., 2009. The harmful health effects of recreational ecstasy: a
(12), e115645. systematic review of observational evidence. Health Technol. Assess.
Raj, V., Liang, H.C., Woodward, N.D., Bauernfeind, A.L., Lee, J., 13 (6), 354.
Dietrich, M.S., Park, S., Cowan, R.L., 2010. MDMA (ecstasy) use is Sarne, Y., Keren, O., 2004. Are cannabinoid drugs neurotoxic or neuro-
associated with reduced BOLD signal change during semantic protective? Med. Hypotheses 63, 187e192.
recognition in abstinent human polydrug users: a preliminary fMRI Schilt T, de Win, T.M.M.L., Koeter, M., Jager, G., Korf, D.J., van den
study. J. Psychopharmacol. 24 (2), 187e201. Brink, W., Schmand, B., 2007. Cognition in novice ecstasy users with
Reay, J.L., Hamilton, C., Kennedy, D.O., Scholey, A.B., 2006. MDMA minimal exposure to other drugs e a prospective cohort study. JAMA
polydrug users show process-specific central executive impairments Psychiatr. 64 (6), 728e736.
coupled with impaired social and emotional judgement processes. Schmidt, C.J., Sullivan, C.K., Fadayel, G.N., 1994. Blockade of striatal 5-
J. Psychopharmacol. 20 (3), 385e388. hydroxytryptamine2 receptors reduced the increase in extracellular
Rendell, P.G., Gray, T.J., Henry, J.D., Tolan, A., 2007. Prospective concentrations of dopamine produced by the amphetamine analogue
memory impairment in ecstasy (MDMA) users. Psychopharmacology 3,4-methylenedioxymethamphetamine. J. Neurochem. 62,
194, 497e504. 1382e1389.
Reneman, L., Lavalaye, J., Schmand, B., de Wolff, F.A., van den Schmidt, C.J., Wu, L., Lovenberg, W., 1986. Methylenedioxy metham-
Brink, W., den Heeten, G.J., Booij, J., 2001. Cortical serotonin phetamine: a potentially neurotoxic amphetamine analogue. Eur. J.
transporter density and verbal memory in individuals who stopped Pharmacol. 124, 175e178.
using 3,4-Methylenedioxymethamphetamine (MDMA or “Ecstasy”). Schouw, M.L.J., Gevers, S., Caan, M.W.A., Majoie, C.B.L.M., Booij, J.,
Arch. Gen. Psychiatr. 58 (10), 901e906. Nederveen, A.J., Reneman, L., 2012. Mapping serotonergic
Reneman, L., Schilt, T., de Win, M.M., Booij, J., Schmand, B., van den dysfunction in MDMA (ecstasy) users using pharmacological MRI.
Brink, W., Bakker, O., 2006. Memory function and serotonin trans- Eur. Neuropsychopharmacol. 22 (8), 537e545.
porter promoter gene polymorphism in ecstasy (MDMA) users. Schuster, P., Lieb, R., Lamertz, C., Wittchen, H.U., 1998. Is the use of
J. Psychopharmacol. 20, 389e399. ecstasy and hallucinogens increasing? Eur. Addict. Res. 4, 75e82.
Ricaurte, G.A., Jie, Y., McCann, U.D., 2000. (þ/-)3,4- Segura, M., Farré, M., Pichini, S., Peiró, A.M., Roset, P.N., Ramírez, A.,
methylenedioxymethamphetamine (“ecstasy”)-induced serotonin Ortuño, J., Pacifici, R., Zuccaro, P., Segura, J., de la Torre, R., 2005.
neurotoxicity: studies in animals. Neuropsychobiology 42 (1), 5e10. Contribution of cytochrome P450 2D6 to 3,4-
Rietjens, S.K., Hondebrink, L., Westerink, R.H.S., Meulenbelt, J., 2012. methylenedioxymethamphetamine disposition in humans: use of par-
Pharmacokinetics and pharmacodynamics of 3,4- oxetine as a metabolic inhibitor probe. Clin. Pharmacokinet. 44,
methylenedioxymethamphetamine (MDMA): interindividual differ- 649e660.
ences due to polymorphisms and drugedrug interactions. Crit. Rev. Semple, D.M., Ebmeier, K.P., Glabus, M.F., O’Carroll, R.E.,
Toxicol. 42 (10), 854e876. Johnstone, E.C., 1999. Reduced in vivo binding to the serotonin
Ridpath, A., Driver, C.R., Nolan, M.L., et al., 2014. Illnesses and deaths transporter in the cerebral cortex of MDMA (‘ecstasy’) users. Br. J.
among persons attending an electronic dance-music festival e New Psychiatr. 175, 63e69.
York City, 2013. MMWR Morb. Mortal. Wkly. Rep. 63 (50), Shulgin, A.T., Shulgin, 1991. PHIKAL. Transform Press, Berkeley, CA.
1195e1198. Simmler, L.D., Hysek, C.M., Liechti, M.E., 2011. Sex differences in the
Roiser, J.P., Sahakian, B.J., 2004. Relationship between ecstasy use and effects of MDMA (ecstasy) on plasma copeptin in healthy subjects.
depression: a study controlling for poly-drug use. Psychopharmacol- J. Clin. Endocrinol. Metab. 96, 2844e2850.
ogy 173, 411e417. Sprague, J., Everman, S., Nichols, D., 1998. An integrated hypothesis for
Roberts, G.M., Garavan, H., 2010. Evidence of increased activation the serotonergic axonal loss induced by 3,4-
underlying cognitive control in ecstasy and cannabis users. Neuro- methylenedioxymethamphetamine. Neurotoxicology 19, 427e441.
image 52 (2), 429e435. Stone, D.M., Stahl, D.C., Hanson, G.R., Gibb, J.W., 1986. The effects of
Roberts, C.A., Wetherell, M.A., Fisk, J.E., Montgomery, C., 2015. Dif- 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-
ferences in prefrontal blood oxygenation during an acute multitasking methylenedioxyamphetamine (MDA) on monoaminergic systems in
stressor in ecstasy polydrug users. Psychol. Med. 45, 395e406. the rat brain. Eur. J. Pharmacol. 128, 41e48.
Roberts, C.A., Montgomery, C., 2015a. Cortical oxygenation suggests Stone, D.M., Merchant, K.M., Hanson, G.R., Gibb, J.W., 1987. Immediate
increased effort during cognitive inhibition in ecstasy polydrug users. and long-term effects of 3,4-methylenedioxymethamphetamine on
J. Psychopharmacol. 29, 1170e1181. serotonin pathways in brain of rat. Neuropharmacology 26 (12),
1677e1683.
Stone, D.M., Johnson, M., Hanson, G.R., 1988. Role of endogenous Wareing, M., Fisk, J.E., Murphy, P., Montgomery, C., 2005. Visuo-spatial
dopamine in the central serotonergic deficits induced by 3,4- working memory deficits in current and former users of MDMA
methylenedioxymethamphetainine. J. Pharmacol. Exp. Ther. 247, (“ecstasy”). Hum. Psychopharmacol. 20, 115e123.
79e87. White, J.M., Bochner, F., Irvine, R.J., 1997. The agony of ecstasy. Med. J.
Stuss, D.T., Alexander, M.P., Hamer, L., Palumbo, C., Dempster, R., Aust. 166, 117.
Binns, M., Levine, B., Izukawa, D., 1998. The effects of focal anterior Yuan, J., Cord, B.J., McCann, U.D., Callahan, B.T., Ricaurte, G.A., 2002.
and posterior brain lesions on verbal fluency. J. Int. Neuropsychol. Effect of depleting vesicular and cytoplasmic dopamine on methyl-
Soc. 4, 265e278. enedioxymethamphetamine neurotoxicity. J. Neurochem. 80 (6),
Sudhakar, S., Hoshi, R., Bhagwagar, Z., Murthy, N.V., Hinz, R., 960e969.
Cowen, P., Curran, H.V., Grasby, P., 2009. Brain serotonin trans- Zakzanis, K.K., Young, D.A., 2001. Memory impairment in abstinent
porter binding in former users of MDMA (“ecstasy”). Br. J. Psychiatry MDMA (“ecstasy”) users: a longitudinal investigation. Neurology 56,
194, 355e359. 966e969.
Sumnall, H.R., Cole, J.C., 2005. Self-reported depressive symptomatology
in community samples of polysubstance misusers who report Ecstasy
use: a meta-analysis. J. Psychopharmacol. 19 (1), 84e92. Further reading
Ter Bogt, T.F.M., Engels, R.C.M.E., Dubas, J.S., 2006. Party people: Benzenhöfer, U., Passie, T., 2010. Rediscovering MDMA (ecstasy): the
personality and MDMA use of house party visitors. Addict. Behav. role of the American chemist Alexander T. Shulgin. Addiction 105,
31, 1240e1244. 1355e1361.
Thomasius, R., Petersen, K., Buchert, R., Andersen, B., Zapletalova, P., Broening, H.W., 1994a. Developmental Age Modulates Sensitivity to the
Wartberg, L., Nebeling, B., Schmoldt, A., 2003. Mood, cognition and Serotonergic Neurotoxicant 3,4-Methylenedioxymethamphetamine.
serotonin transporter availability in current and former ecstasy Dissertation. University of Arkansas for Medical Sciences.
(MDMA) users. Psychopharmacology 167, 85e96. Chang, L., Grob, C., Ernst, T., Itti, L., Mishkin, F.S., Jose-Melchor, R.,
Thomasius, R., Zapletalova, P., Petersen, K., Buchert, R., Andersend, B., Poland, R.E., 2000. Effect of ecstasy [3,4-
Wartberg, L., Nebeling, B., Schmoldt, A., 2006. Mood, cognition and methylenedioxymethamphetamine (MDMA)] on cerebral blood
serotonin transporter availability in current and former ecstasy flow: a co-registered SPECT and MRI study. Psychiatr. Res. Neuro-
(MDMA) users: the longitudinal perspective. J. Psychopharmacol. 20 imaging Section 98, 15e28.
(2), 211e225. Commins, D.L., Vosmer, G., Virus, R., Woolverton, W., Schuster, C.,
Tucker, G.T., Lennard, M.S., Ellis, S.W., Woods, H.F., Cho, A.K., Seiden, L., 1987. Biochemical and histological evidence that meth-
Lin, L.Y., Hiratsuka, A., Schmitz, D.A., Chu, T.Y., 1994. The ylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat
demethylenation of methylenedioxymethamphetamine (“ecstasy”) by brain. J. Pharmacol. Exp. Ther. 241, 338e345.
debrisoquine hydroxylase (CYP2D6). Biochem. Pharmacol. 47, Hatzidimitriou, G., McCann, U.D., Ricaurte, G.A., 1999. Altered serotonin
1151e1156. innervation patterns in the forebrain of monkeys treated with (þ/-)3,4-
United Nations Office on Drugs and Crime, UNODC, 2017. World Drug methylenedioxymethamphetamine seven years previously: factors
Report 2017. Available at. https://www.unodc.org/wdr2017/index. influencing abnormal recovery. J. Neurosci. 19, 5096e5107.
html. O’Hearn, E., Battaglia, G., De Souza, E.B., Kuhar, M.J., Molliver, M.E.,
Urban, N.B.L., Girgis, R.R., Talbot, P.S., Kegeles, L.S., Xu, X., 1988. Methylenedioxyamphetamine (MDA) and methylenediox-
Frankle, W.G., Hart, C.L., Slifstein, M., Abi-Dargham, A., ymethamphetamine (MDMA) cause selective ablation of serotonergic
Laruelle, M., 2012. Sustained recreational use of ecstasy is associated axon terminals in forebrain: immunocytochemical evidence for
with altered pre and postsynaptic markers of serotonin transmission in neurotoxicity. J. Neurosci. 8 (8), 2788e2803.
neocortical areas: a PET study with [11C]DASB and [11C]MDL Parrott, A.C., 2011. Residual neurocognitive features of ecstasy use: a
100907. Neuropsychopharmacology 37, 1465e1473. reinterpretation of Halpern et al. (2011) consistent with serotonergic
Verheyden, S.L., Hadfield, J., Calin, T., Curran, H.V., 2002. Sub-acute neurotoxicity. Addiction 106, 1365e1372.
effects of MDMA (3,4-methylenedioxymethamphetamine, Salzmann, J., Marie-Claire, C., Noble, F., 2004. Acute and long-term ef-
“ecstasy”) on mood: evidence of gender differences. Psychopharma- fects of ecstasy. Presse Med. 33 (18 Suppl), 24e32.
cology 161, 23e31. Schmidt, C.J., Black, C.K., Taylor, V.L., 1990. Antagonism of the
Wagner, D., Becker, B., Koester, P., Gouzoulis-Mayfrank, E., neurotoxicity due to a single administration of methylenediox-
Daumann, J., 2012. A prospective study of learning, memory, and ymethamphetamine. Eur. J. Pharmacol. 181, 59e70.
executive function in new MDMA users. Addiction 108, 136e145.
Wareing, M., Fisk, J.E., Murphy, P., Montgomery, C., 2004. Verbal
working memory deficits in current and previous users of MDMA.
Hum. Psychopharmacol. 19, 225e234.
Chapter 13
Cognitive consequences of opioid use

Alex Baldacchino1, Douglas Steele2, Fleur Davey3 and Serenella Tolomeo1
1
Division of Populations and Health Science, St Andrews Medical School, University of St Andrews, St Andrews, Fife, United Kingdom; 2Institute of
Neuroscience, Ninewells Hospital Medical School, University of Dundee, Dundee, Tayside, United Kingdom; 3Research and Development
Department, NHS Fife, Dunfermline, Fife, United Kingdom
Introduction individuals misusing prescribed opioids were using larger

amounts than directed, 14.6% used them more frequently, and
Opioids are widely administered in many countries because of 13.1% used them for longer than recommended (Han et al.,
their ability to treat mild to severe pain, suppress coughs, treat 2017). Furthermore, a study by Shei et al. (2015), considering
diarrhea, and alleviate the physical withdrawal symptoms prescription opioid abuse in European countries, estimated a
associated with opioid dependency. According to data from prevalence per 10,000 of about 13.7 in France, 11.0 in Ger-
the 2015 North American National Survey on Drug Use and many, and 10.7 in the United Kingdom but less than 1 per
Health, 91.8 million (37.8%) of the US adults over the age of 10,000 in Spain and Italy. This is not just a consideration in the
18 had been prescribed opioids in the previous year (Han et al., adult population; a survey of American 10e18 year olds from
2017). This accounts for approximately one third of all US 2008 to 11 (Osborne et al., 2017) reported that 4.8% had used
adults at that time. To further consider the duration of the prescription opiates in the previous 30 days (two-thirds of
prescription, a study by Hudson et al. (2008) using the whom had abused prescription opioids and one-third had been
2000e01 Healthcare for Communities survey showed 2% of prescribed them). This is a particular cohort of concern due to
the 7909 respondents reported regular medicinal opioid use (at the risk of opioid use continuing into adulthood and the un-
least 5 days opioid consumption per week for at least 4 weeks). clear potential detrimental effects of opioids on the developing
Kelly et al. (2008) who surveyed 19,150 US adults between nervous system of these younger individuals.
1998 and 2006 also found 2% of responders (equating to 4.3 In addition to this legitimate medical source of opiates,
million nationwide) reported regular opioid use, nearly half of which may be further misused by the recipient, or diverted
whom had been taking opioids for two or more years, and to the illegal market, the prevalence of the illicit opiate
nearly 20% for over 5 years. Studies in Finland from 1998 to heroin is also widespread in many countries. This avail-
99 (Pitkala et al., 2002) and Denmark in 2000 (Eriksen et al., ability of opioids from potentially multiple sources
2006) showed a similar prevalence of 2.8% and 3% regular contributes to a widespread global, regional, and local
opioid use, respectively. Other studies considering general US pattern of opioid use. According to the 2017 European
population surveys have reported a range of opioid prescrip- Drug Report, published by the European Monitoring Center
tion prevalence from 3% of the population up to 6.3% for Drugs and Drug Addiction, heroin is the most
depending on the particular study population or the specific commonly used illicit opiate in Europe although other licit
measurement/definition of opioid use (Paulose-Ram et al., synthetic opioids are being increasingly misused
2003; Olsen et al., 2006). In 2012, a large population-based (EMCDDA, 2017). In 2015, 0.4% or 1.3 million European
Canadian study suggested a level of opioid abuse of about adults (15e64 years of age) were estimated to be high-risk
5% of the population (Shield et al., 2013). The US National opioid users. Germany, Spain, France, Italy, and the United
Surveys on Drug Use and Health (NSDUH) estimated that Kingdom accounted for 76% of these users. In the United
almost 12.5 million Americans over the age of 12 abused States, it has been estimated that between 2007 and 2011,
prescription opioids in 2012 (SAMH, 2013). In 2014, 11.5 the number of US citizens having used heroin rose from
million adults abused prescription opioids, with almost two 373,000 to 620,000 (SAMH, 2013).
million individuals with a prescription opioid use disorder It is difficult to accurately calculate the overall level of
defined according to DSM-IV diagnostic criteria (Han et al., opioid consumption due to the multiple legal and illicit
2017). Additionally, the 2015 NSDUH found 22.2% of sources of these substances. This calculation is further

complicated by the illegal nature of prescription misuse, studies may help to examine whether there is a neuropsy-
prescription diversion, and illicit drug use, hindering accu- chological profile characteristic of this population.
rate self-reporting for epidemiological monitoring to An early example of this type of research was conducted
authorities due to fear of adverse repercussions following by Rounsaville et al. (1982), who assessed a group of 72
disclosure. To further understand the prevalence of opioid opioid addicts on entering treatment, using a brief neuro-
dependence globally, Degenhardt et al. (2014) undertook a psychological battery. This group consisted of individuals
systematic review of epidemiology of opioid dependence as who were still using illicit heroin, those who had recently
part of the 2010 global burden of disease project publica- commenced on a prescribed methadone dose, and those who
tions. Between 1990 and 2010, the estimation of opioid- had recently been detoxified from all opioids. Many of these
dependent individuals aged over 15 increased from 10.4 individuals could be classified as poly drug users, reporting
million to 15.5 million with the United Kingdom and regular use of other substances including amphetamines,
Australia having the highest estimated prevalence (0.48% cocaine, sedatives, cannabis, and alcohol. The group varied
and 0.46%, respectively) followed by western Europe and widely in terms of the length and nature of their drug abuse.
North America. In 2010, 9.2 million disability-adjusted life The authors found that although the opioid group’s intel-
years, a summary measure of overall disease burden, were lectual functioning scores were in the normal range, their
attributable to opioid dependence, a figure that has increased performance in a number of areas of neuropsychological
over time. This increase in disease burden has been driven functioning was at the mildly impaired range. These
by an increased prevalence of dependence, rather than included tasks of attention, cognitive flexibility, and motor
changes in global age profiles or population size. impulsivity. When the opioid group was compared with a
control group of nonsubstance using participants matched
for sociodemographic variables, the former did not perform
Long-term cognitive deficits associated significantly below the latter group on any of the measures
with opioids included. Six months after the initial assessment, the authors
In the following sections, we will review the cognitive noted that the improvements observed could not be attrib-
literature on several different groups of opioid users uted to the effects of detoxification from opioids as more
including those (1) taking illicit heroin and prescribed than half of the sample had positive urine samples for
methadone and buprenorphine for the treatment of opioid opioids. Instead it was suggested that these improvements
dependence, (2) other opioids for treatment of chronic pain, were associated to an overall change in clinical status of this
and (3) abstinent populations with a history of opioid group compared with their initial presentation. Although this
dependence or abuse. study failed to find any significant differences between
A large number of studies reported the effects of opioid users and nonsubstance using controls, it did show
chronic opioid use on a variety of neuropsychological that following a period of relative stability in treatment,
skills. The population studied was either from the opioid- improvements were seen in some areas of functioning. This
dependent or chronic pain clinical settings. Most studies suggested that on entering treatment, opioid-dependent
have attempted to target one opioid such as prescribed individuals were performing at a level below their actual
methadone or illicit heroin use. In addition to the literature optimal ability on several indices of neuropsychological
on the chronic effects of heroin and methadone, some functioning.
studies have examined neuropsychological functioning in Ersche et al. (2006a and 2005) compared a group
the more general group of “opioid addicts” by combining of opioid-dependent individuals with a group of
participants with current methadone, heroin, and/or other amphetamine-dependent individuals across a number of
opioid use. The progress in each of these areas will be neuropsychological domains. The opioid-dependent group
examined in turn. consisted largely of methadone maintenance patients and
current illicit heroin users, as well as participants receiving
prescribed buprenorphine, dihydrocodeine, diamorphine,
Neuropsychological functioning in mixed and morphine sulfate. Urine analysis showed recent use of
opioid using and dependent populations other substances in around half of the opioid group. Control
The results of such studies are difficult to interpret as these groups included drug-free controls, drug-free (abstinent)
groups often contain individuals who abuse various previously opioid users, and drug-free (abstinent) ex-
different opioids, and it is therefore not possible to attribute amphetamine users. All participants were assessed using
observed deficits to the effects of any specific type of three measures of executive functioning (impulsivity,
opioid. However as many individuals in this population planning, and cognitive flexibility tests) and two measures
will use a variety of different opioids in their lifetime, these of visual memory. On the planning task, both the current
Cognitive consequences of opioid use Chapter | 13 181
and former poly drug users performed significantly worse impairment in heroin-dependent individuals who were still
than the nonsubstance use healthy controls. Amphetamine using heroin.
users’ performance was poorer than opioid users, and there Overall chronic opioid effects in cognition were sum-
was no difference between current and former substance users. marized in a metaanalysis by Baldacchino et al. (2012),
Performance on cognitive flexibility (attentional set-shifting which suggested that chronic opioid exposure is associated
task) was comparable for all groups. On both visual memory with impairments across a range of different neuropsy-
tests, current and former substance users performed at a level chological domains. However, the only domains that the
that was significantly poorer than controls. analysis suggests robust impairments with medium effect
These results contradicted previous and subsequent sizes according to Cohen were those of verbal memory,
studies as they failed to find any difference between current cognitive impulsivity, and flexibility (Table 13.1).
and former heroin users. Instead, these results supported the
notion that the neuropsychological deficits observed in Neuropsychological functioning in illicit heroin
chronic opioid users were not a direct result of the opioid
using and dependent populations
itself but rather were a consequence of the factors associ-
ated with long-term drug abuse (Darke et al., 2000). This is Heroin (diamorphine) is a semisynthetic opioid that is
in contrast with more recent studies which had provided derived from morphine. It is most often used medically as
evidence for impairments in current opioid users above and an analgesic or illicitly for recreation. Illicit heroin users
beyond those observed in abstinent ex-opioid addicts often start by “smoking” this substance (burning the heroin
(e.g., Mintzer et al., 2005; Verdejo-Garcia et al., 2005a,b). and inhaling the fumes), but many will quickly progress to
However, there were a number of limitations to the study intravenous use. Injecting heroin allows it to pass quickly
by Ersche et al. (2006a and 2005), the most obvious of through the bloodebrain barrier where it is broken down
these being the heterogeneous nature of the opioid group in into monoacetylmorphine and morphine. These bind to mu-
terms of the type of opioid used, whether opioid use was opioid receptors and result in intense analgesic, euphoric,
illicit or prescribed opioid, and whether other illicit drugs and anxiolytic effects (Jaffe, 1990).
were used concurrently. In addition, the former amphet- A review by Lundqvist (2005) discussed the research
amine and opioid users were combined into one group for evidence for neuropsychological impairments as a result of
comparison, with some reporting a history of previous different types of substance use. This paper concluded that
amphetamine use or previous opioid use and others “there is a consensus that all drugs cause a disharmony in the
reporting a history of both amphetamine and opioid use. neuropsychological network, causing a decrease in activity
Given these limitations, the results of this study should be in areas responsible for short term memory, attention and
treated with caution. executive functioning, with the possible exception of hero-
Ornstein et al. (2000) conducted a study that aimed to in.” However, the literature described in this section paints a
clarify the notion that there exists a distinct profile of different picture. Although some studies have failed to find
neuropsychological impairment that is common to heroin- any evidence for significant neuropsychological decline
dependent individuals. In this study, a group of partici- associated with heroin abuse, others have shown that
pants whose primary drug of abuse was heroin and most individuals with current heroin use displayed impairments in
also treated with methadone was compared with a group a variety of neuropsychological domains. However, the
who primarily used amphetamine. A third group of evidence did not support a link between the amount of
substance-free participants was matched to the other two heroin used and/or duration of heroin use and level of
groups for age and premorbid intellectual functioning. The impairment (Prosser et al., 2006).
assessment consisted of a number of subtests chosen from In a test by Stevens et al. (2007) for assessing various
the Cambridge Neuropsychological Test Automated Bat- executive functions, memory and learning were adminis-
tery (CANTAB)ecomputerized test battery (Sahakian tered to 25 male heroin-dependent individuals and
et al., 1988), as well as a test of verbal fluency. CANTAB compared with 26 poly drug abusers abstinent for more
tests included measures of visual and visuospatial recog- than 3 months and another 26 nonsubstance-using healthy
nition memory, spatial working memory, attentional rule male controls. There was significant impairment in cogni-
shifting, and spatial planning. This study found that, relative to tive flexibility, working memory, and sustained attention in
controls, the heroin group generated fewer words (but not the heroin group (Stevens et al., 2007).
significantly) on the verbal fluency task and showed no The heroin-dependent group attending a chronic pain
improvement following practice trials on the test of visuo- clinic in McNairy et al. (1984) was significantly impaired in
spatial strategy. In addition, significant impairments were verbal learning but not in memory, cognitive flexibility, and
found in visual and visuospatial recognition memory, atten- sustained attention. The study suggested that the neuro-
tional set-shifting, and spatial planning. These results pointed psychological impairment could have been caused by the
to the existence of a diverse pattern of neuropsychological chronic use of opioids and compounded by the “slowed,
TABLE 13.1 Summary of the evidence presented in this review for an association between chronic and
dependent opioid use and neuropsychological impairment.
Neuropsychological domain Chronic opioid dependence studies* Standardized Effect size d

Cognitive impulsivity Clark et al. (2006)Y 0.78 (IGT)
Rogers et al. (1999)Y 0.68 (BIS)
Ersche et al. (2005)4 0.46 (CGT)
0.31 (CGT)
Motor impulsivity n/a n/a
Nonplanning impulsivity Ersche et al. (2006a)Y 0.95 (TOL)
Ornstein et al. (2000)Y 1.18 (TOL)
Clark et al. (2006)Y 0.78 (IGT)

Cognitive flexibility Ersche et al. (2006a)4 0.18 (IED)
Ornstein et al. (2000)Y 0.55 (IED)
Short-term memory Ersche et al. (2006a)Y 0.89 (PAL) and 0.64 (PRM)
Ornstein et al. (2000)Y 0.87 (SRM) and 0.53 (SWM)
Long-term memory Ersche et al. (2006a)Y 0.98 (PRM)
Ornstein et al. (2000)Y 0.80 (PRM)
*, P < .05; 4, no significant difference in neuropsychological performance; Y, significant neuropsychological deficits present; [, significant improve-
ment in neuropsychological performance when compared with healthy controls; d, Cohen’s effect size defined as the difference between two means
divided by a standard deviation for the data. Standardized effect sizes are reported regardless of the statistical significance (P-value) of the results
reported in the original studies. n/a, data not available. BIS, Barratt Impulsivity Scale; CANTAB, Cambridge Neuropsychological Test Automated Battery;
CGT, Cambridge Gambling Task; DMS, Delayed Matching to Sample Test; IED, Intra/Extra Dimensional Set-Shifting Task; IGT, Iowa Gambling Task;
PAL, Paired Associate Learning Task; PRM, Pattern Recognition Memory; SRM, Spatial Recognition Memory; SWM, Spatial Working Memory; TOL,
Tower of London; VFT, Verbal Fluency Test.
disorganized or inappropriate responses to environmental abstinent polysubstance users whose primary addiction was
demands for adaptive and stressful behavior such as heroin and in those whose primary addiction was cocaine.
chronic pain and the iatrogenic prescription of opioids.” A third group of healthy, substance-free controls was also
Finally in an empirical study by Tolomeo et al. (2016), included in the study. All participants in the heroin and
illicit heroin use (n ¼ 24) presented with significant cocaine groups had been abstinent for a minimum of
impairments in cognitive and motor impulsivity and strategic 2 weeks with no history of mood disorder, head injury, or
planning when compared with stable methadone (n ¼ 29) neurological disorder. The results showed that the heroin
users and healthy controls (n ¼ 28). polysubstance users displayed significant impairment in
motor impulsivity, cognitive impulsivity, and cognitive
flexibility relative to controls.
Neuropsychological functioning in abstinent Fishbein et al. (2007) contrasted the cognitive perfor-
former heroin-dependent populations mance of four groups of participants, pure users of heroin,
co-users of heroin and alcohol, pure alcohol users, and non-
A number of the studies of methadone use and neuropsy-
users, on measures of visual memory and different com-
chological functioning included a control group of absti-
ponents of executive functions including, nonplanning
nent ex-heroin users (Mintzer et al., 2005; Prosser et al.,
2006; Clark et al., 2006), and these have generally indi- impulsivity, cognitive flexibility, and cognitive impulsivity.
Substance users were evaluated after 3 weeks of abstinence.
cated that this group may be impaired in some areas relative
The data suggested that heroin users had significantly
to controls with no history of opioid use but may be less
impaired performance on cognitive impulsivity and cogni-
impaired than current methadone users. Several further
tive flexibility, taking more risk even though they had more
studies that focused on abstinent ex-heroin users contrib-
time to make a decision. However, performance on visual
uted to the research in this area.
memory and problem-solving tasks (nonplanning impul-
Two studies by Verdejo-Garcia et al. (2007a); Verdejo-
sivity) by heroin users did better than the other two cohorts,
García and Pérez-García (2007b) focused on the effects of
substance misuse on executive functions. Specifically, suggesting that these tasks were more closely linked to
chronic alcohol rather than heroin use.
these studies set out to examine executive function in
The results of this study added further support to the study examined a number of areas of neuropsychological
idea that long-term heroin use cause deficits in at least some functioning, including information processing, attention,
areas of executive functioning. short- and long-term verbal and nonverbal memory and
A similar study by the same author (Fishbein et al., 2005) cognitive flexibility. The authors reported that despite being
observed similar impairments in decision-making with a matched to the control group in terms of their premorbid
group of heroin users who have been abstinent for more than level of intellectual functioning, the methadone maintenance
12 weeks. This heroin group selected significantly more groups’ performance was significantly poorer than the con-
risky choices, particularly riskiest scenarios despite repeated trol group in all domains tested. There was no significant
penalties incurred (i.e., they were less likely to employ a effect of methadone dose on performance in any of the
more cautious strategy in response to improbable options). domains. However, the authors pointed out that the
The group’s choice did not appear to be due to motor methadone-maintained group reported a significantly higher
impulsivity as they had ample time to think about their next incidence of alcohol dependence and nonfatal overdose, both
move and could have a willingness to accept the likelihood of which were found to be independent predictors of poorer
of negative consequences even in unfavorable circum- performance in each neuropsychological domain.
stances. Such significant increase in cognitive (risk-taking) The methadone maintenance group also had a signifi-
impulsivity in heroin-dependent individuals was suggested cantly higher prevalence of head injury than the control
as a cognitive marker of substance dependence that does not group, another common cause of neuropsychological
recover with prolonged abstinence (Clark et al., 2006). impairment. This study demonstrated the potential diffi-
In Brand et al. (2008), 18 inpatients from an addiction culties in identifying neuropsychological impairment that
unit were tested after a 2 week opioid detoxification period can unequivocally be attributed to opioid abuse rather than
from heroin. These opioid-dependent individuals signifi- to the range of conditions that are frequently comorbid with
cantly chose the risky alternatives more frequently but opioid dependency. In addition, the results of this study are
performing no different in nonplanning impulsivity and limited by the fact that the methadone maintenance group
problem-solving from the healthy nonsubstance user reported a high incidence of other substance use, and recent
control group. illicit substance use was not objectively verified using urine
Although the research in this area was limited, it seemed analysis. The authors suggested that the neuropsychological
to point to a general improvement in at least some areas of impairments seen in opioid users are likely to be a conse-
neuropsychological functioning after at least 2 weeks quence of factors associated with substance abuse lifestyle,
of abstinence from heroin use. This suggested that some of rather than the direct effects of the opioids or other
the deficits observed in the active opioid users were either substance.
transient effects from the acute intoxication of the drug In the same year, a study by Specka et al. (2000) also
itself. It is therefore important to test if there is an effect in compared methadone-maintained participants with matched
neuropsychological performance with the same individuals substance-free controls on a number of measures of neu-
prospectively at different stages of duration of abstinence. ropsychological functions relevant specifically to driving
In two observational studies by Baldacchino et al., ability. The methadone maintained group in this study
(2016) and Tolomeo et al. (2018), abstinent, previously demonstrated significant impairments in attention and
opioid-dependent individuals showed significantly tachistoscopic perception, they were faster but less accurate
impaired cognitive and nonplanning impulsivity and flexi- on a response time task (motor impulsivity deficits), and
bility when compared with healthy controls (Table 13.2). they were more accurate than controls but slower on a
visual tracking test (reduced reaction time). Although this
Neuropsychological functioning in study had implications in further understanding the asso-
ciation between methadone and neuropsychological skills
methadone users
relative to driving, it was limited by the fact that partici-
Early studies (conducted between 1970 and 1982) failed to pants who tested positive for other substances in their urine
detect any difference in neuropsychological functioning. were not excluded.
However, systematic reviews of these early studies Rotheram-Fuller et al. (2004) compared methadone-
concluded several methodological limitations (Lombardo maintained patients with substance-free controls matched
et al. (1976), Gordon (1970), Gordon and Appel (1995), for premorbid intellectual functioning on cognitive impul-
Appel (1982), Rothenberg et al. (1977), Mintzer and Stitzer sivity (risk-taking) and cognitive flexibility (perseveration).
(2002), Zacny (1995). In addition, the authors divided both groups into smokers
Starting a new generation of better-controlled studies, and nonsmokers to determine whether smoking had any
Darke et al. (2000) compared neuropsychological perfor- impact on performance of these tasks. This study showed
mance in methadone-maintained individuals with opioid- that the methadone-maintained group who smoked dis-
free controls matched for age, gender, and education. This played significant impairments in cognitive impulsivity
TABLE 13.2 Summary of the evidence presented in this review for an association between illicit and dependent heroin use
and neuropsychological impairment at two stages of opioid receptor occupancy (use and abstinent).
Neuropsychological Illicit chronic Standardized effect size Abstinent ex- Standardized effect size
domain heroin use* d (neuropsychological test) heroin use* d (neuropsychological test)
Cognitive impulsivity Baldacchino et al. (2014)Y 0.84 (CGT) Mintzer et al. 0.30 (IGT)
(reflection impulsivity) Ersche et al. (2005)4 0.31 (CGT) (2005)Y
Verdejo-Garcia 0.54 (IGT)
et al. (2007a)Y
Fishbein et al. 0.38 (RDMT)
(2007)Y
Fishbein et al. 1.00 (RDMT)
(2005)Y
Clark et al. 0.68 (BIS)
(2006)Y
Tolomeo et al. 0.70 (CGT)
(2016)Y
Motor impulsivity Baldacchino et al. (2014)Y 1.00(AGN) Verdejo-Garcia 0.66 (go/no-go)

et al. (2007a)4
Verdejo-Garcia 0.87 (go/no-go)
et al. (2007b)Y
Nonplanning Baldacchino et al. 0.80 (SOC) Fishbein et al. 1.05 (SOC)
impulsivity (2014) Y (2007)4
Brand et al. 0.19 (TOH)
(2008)4
Tolomeo et al. (SOC)
(2016)
Cognitive flexibility Hill andand Mikhael 0.44 (CT) Verdejo-Garcia 0.67 (ST) andand 0.29 (WCST)
(1979)Y et al. (2007a)Y
Stevens et al. (2007)Y 0.40 (TMT) Fishbein et al. 0.27 (ST)
(2007)Y
Brand et al. 1.42 (MCST)
(2008)Y
McNairy et al. (1984)4 0.18 (TMT) Tolomeo et al. 3.30 (IED)
(2018)Y
Prosser et al. 0.33(COWAT)
(2006)4
Tolomeo et al. (2018)Y 0.70 (IED)
Sustained attention McNairy et al. (1984)4 0.20 (WAIS II) Verdejo-Garcia 0.34 (5DT)
et al. (2007a)Y
Stevens et al. (2007)Y 0.32 (SRTT) Mintzer et al. 0.52 (DSST)
(2005)Y
Short-term memory McNairy et al. (1984)4 0.21 (AVLT) Verdejo-Garcia 0.81 (CBT)
et al. (2007a)Y
Stevens et al. (2007)4 0.39 (DMS) Fishbein et al. 0.59 (PAL)
(2007)4
Long-term memory Stevens et al. (2007)4 0.22 (WMSR)
Overall, the literature suggested limited but significant deficits in attention and cognitive flexibility in the heroin-dependent population and significant deficits in atten-
tion, impulsivity, and cognitive flexibility in the abstinent heroin cohorts (Fernández-Serrano et al., 2010a,b). *, P < 0.05; 4, no difference in neuropsychological perfor-
mance; Y, neuropsychological deficits present; [, improvement in neuropsychological performance when compared with healthy controls; d, Cohen’s effect size defined
as the difference between two means divided by a standard deviation for the data. Standardized effect sizes are reported regardless of the statistical significance (P-value)
of the results reported in the original studies. n/c, controls not healthy controls or not enough information to calculate effect size. AGN, Affective go/no-go; AVLT, Audi-
tory Verbal Learning Test; BIS, Barratt Impulsivity Scale; CANTAB, Cambridge Neuropsychological Test Automated Battery; CBT, Cognitive Bias Test; CGT/RDMT, Cam-
bridge Gambling Task/Roger’s Decision-Making Test, Halstead Reitan Neuropsychological Test Battery; COWAT/FAS, Controlled Oral Word Association Test/
Phonological Fluency Test; CT, Category Test; 5DT, Five Digit Test; DMS, Delayed Matching to Sample Test; DSST, Digital Symbol Substitution Test; Go/no-go, Go/no-go
test; IED, Intra/Extra Dimensional Shift; IGT, Iowa Gambling Task; MCST, Maudsley Card Sorting Test; PAL, Paired Associate Learning Task; RFFT, Ruff Figural Fluency
Test; SRTT, Serial Reaction Time Task; ST, Stroop Test; TOH, Tower of Hanoi; TMT, Trail Making Test; TOL/SOC, Tower of London/Stockings of Cambridge; WAIS II,
Wechsler Adult Intelligence Scale Second Edition; WCST, Wisconsin Card Sorting Test; WMSR, Wechsler Memory Scale Revised.
relative to controls and the nonsmoking methadone- groups was on a test of visuospatial memory, with the
maintained group. There were no differences between abstinent heroin group performing more poorly. No effect of
groups in cognitive flexibility. These results suggest that in length or level of prior heroin use on neuropsychological
addition to the numerous other risk factors for neuropsy- functioning was found. Although this study is useful as it
chological impairment associated with substance use, compared the effects of current methadone use with the
smoking may be related to impairment in cognitive possible residual effects of long-term opioid use, caution
impulsivity and possibly in other neuropsychological should be used in comparing the results of the two heroin-
domains. dependent groups with the nonsubstance using healthy
Research conducted by Mintzer and Stitzer (2002) control group. This is because both the former groups had
provided evidence for the presence of impaired neuropsy- fewer years of formal education than controls, and their
chological functioning as a result of methadone-maintenance scores on a test of verbal functioning were lower than those
therapy. Their study compared the performance of a group of of the controls. As the authors explained, this measure is
methadone-maintained participants with matched drug-free often used as an estimate of an individual’s premorbid level
controls across a range of neuropsychological domains. of intellectual functioning, suggesting that the two heroin
Urine testing before assessment provided objective evidence groups had lower levels of premorbid intellectual func-
of recent abstinence from other substances. The authors tioning than the control group. If this is the case, then it
suggested that the methadone maintenance group showed would be expected that their performance on other measures
significant impairments relative to controls in the areas of of neuropsychological functioning would also be lower,
psychomotor speed, short-term memory, and cognitive consistent with their estimated premorbid level of
flexibility. functioning.
In 2005, Mintzer et al. developed their earlier study by Passetti et al. (2008) tested 37 opioid-dependent heroin
comparing the results of a new group of opioid-free users 6 weeks after starting a community methadone treat-
ex-heroin users on the same battery of neuropsychologi- ment program and subsequently followed up 3 months after.
cal tests retrospectively with their initial two groups. The They were tested on measures of nonplanning impulsivity,
new group was matched to the earlier two groups demo- motor impulsivity, and cognitive impulsivity (risk-taking).
graphically and matched to the methadone maintenance Three months after initiation of methadone treatment, 10
group in terms of history of substance use. The authors individuals had become abstinent for heroin while another
found that in general, the new group’s scores fell between 24 were taking at least heroin on a weekly basis on top of
that of the methadone maintenance group and the controls their methadone medication. The study stated that perfor-
on most tests, although they only performed significantly mance on cognitive impulsivity (Cambridge Gambling Task
better than the methadone group on a test of cognitive [CGT] and Iowa Gambling Task) at baseline could predict
flexibility and significantly below the control group on the clinical outcome. There were no significant deficits observed
task of psychomotor speed. The results of this study in strategic planning and motor impulsivity.
supported to the notion that the significant impairments Finally Gradin et al. (2013) followed by Tolomeo et al.
seen in methadone-maintained patients may be related to (2016, 2018) and Baldacchino et al. (2014) from the same
the direct effects of opioids rather than factors other than research team presented a group of stable methadone users
those associated with substance abuse (e.g., history of head with significantly impaired impulsivity-related domains but
injury overdose etc.), as it suggested that some recovery of no impairments in compulsivity domains (Table 13.3).
function may occur with detoxification from all opioids. From the range of studies that have examined the
In a similar study, Prosser et al. (2006) compared impact of methadone on neuropsychological functioning,
methadone-maintained ex-heroinedependent group with a there seems to be an evidence base describing impairment
group of abstinent heroin-dependents who had been detox- in methadone users in a number of neuropsychological
ified from methadone. Both groups were matched for domains. There is conflicting evidence regarding the
substance using history. A group of healthy nonsubstance possible impact of the dose of methadone on level of
using controls was also included in this study. The authors impairment with some research pointing to no effect of
hypothesized that abstinent heroin-dependent individuals dose on performance, and some research reporting a dose-
should perform better than methadone-maintained partici- related impact on the specific domains of delayed verbal
pants on tests of various neuropsychological skills. memory and reaction time. Furthermore, other studies
However, the results of this study showed that both metha- suggested that some recovery of functioning takes places
done maintenance and abstinent heroin-dependent groups with time in methadone-maintained ex-heroin users.
performed significantly worse than controls but, at a similar Finally, those studies that have compared methadone users
level to one another, on attention and cognitive flexibility with abstinent ex-heroinedependent and substance-free
(perseveration). The only significant difference between healthy controls have indicated that the abstinent
methadone maintenance and abstinent heroin-dependent ex-heroinedependent group performed at a superior level
TABLE 13.3 Summary of the evidence presented in this review for an association between methadone use and
neuropsychological impairments.
Neuropsychological domain Methadone use* Cohen’s d test (Neuropsychological)

Cognitive impulsivity Pirastu et al. (2006)Y 3.02 (IGT)
Rotheram-Fuller et al. (2004)Y 0.89 (IGT)
Passetti et al. (2008)Y n/c
Tolomeo et al. (2016)Y 0.06 (CGT)

Ersche et al. (2006b)4 0.31 (CGT)
Mintzer et al. (2005)Y 0.30 (IGT)
Yin et al. (2012)Y 0.7 (WCST)
Baldacchino et al. (2014)4 0.99 (CGT)
Motor impulsivity Passetti et al. (2008)4 n/c
Prosser et al. (2006)4 0.78
Baldacchino et al. (2014)4 0.87 (AGN)
Clark et al. (2006)Y 0.68 (BIS)
Fadardi and Ziaee (2010) n/c
Liao et al. (2014)4 0.03 (SSRT)

Mintzer et al. (2005)Y 0.30 (IGT)
Wang et al. (2014)4 5.18 (MT)
Nonplanning impulsivity Passetti et al. (2008)4 0.98 (TOL)
Tolomeo et al. (2016) 0.12 (SOC)

Ornstein et al. (2000)Y 1.18 (TOL)
Cognitive flexibility Darke et al. (2000)Y 0.65 (WCST); 0.57 (COWAT)
Mintzer et al. (2005)Y 0.87 (TMT)
Rotheram-Fuller et al. (2004)4 0.61 (WCST)
Pirastu et al. (2006)Y 7.27 (WCST)
Prosser et al. (2006)Y 0.65 (ST)
Soyka et al. (2008)Y 0.81 (TMT); 0.54 (RWT)
Tolomeo et al. (2018)4 0.05 (IED)

Ersche et al. (2006b)Y 0.95 (TOL)
Gupta et al. (2014)Y 0.4 (ST)
Ornstein et al. (2000)Y 0.55 (IED)
Yates (2009) 0.49 (ST)
Sustained attention Darke et al. (2000)Y 0.76 (WAIS II)
Specka et al. (2000)Y 0.45 (DR2) and 0.64 (Q1)
Mintzer et al. (2005)Y 1.00 (DSST)
Soyka et al. (2008)Y 0.77 (DR2)
Continued
TABLE 13.3 Summary of the evidence presented in this review for an association between methadone use and
neuropsychological impairments.dcont’d
Neuropsychological domain Methadone use* Cohen’s d test (Neuropsychological)

Wang et al. (2014)4 8.79 (CPT)
Lin et al. (2012) 0.03 (PASAT)
Yates (2009) 0.6 (WCST)
Short-term memory Darke et al. (2000)Y 0.80 (WMSR) and 0.55 (RCFT)
Mintzer et al. (2005)Y 0.70 (2BT)
Prosser et al. (2006)Y 0.97 (BVRT)
Pirastu et al. (2006)Y 7.82 (BVRT)
Soyka et al. (2008)Y 0.83 (AVLT)
Ersche et al. (2006b)Y 7.82 (BVRT), 0.83 (AVLT) 0.89 (PAL) and 0.64 (PRM)
Gupta et al. (2014)4 0.01 (BVMT)
Ornstein et al. (2000)Y 0.87 (SRM) and 0.53 (SWM)
Wang et al. (2014)4 0.8 (WMSR)
Yates (2009)Y 0.7 (WMS)
Long-term memory Darke et al. (2000)Y; Gupta et al. (2014) 1.40 (WMSR)
Wang et al. (2014)4 0.3 (WMSR)
Yates (2009)Y 0.68 (WMS)
*P < 0.05; 4, no difference in neuropsychological performance; Y, neuropsychological deficits present; [, improvement in neuropsychological
performance when compared with healthy controls; d, Cohen’s effect size defined as the difference between two means divided by a standard
deviation for the data. Standardized effect sizes are reported regardless of the statistical significance (P-value) of the results reported in the original
studies. n/c, controls not healthy controls or not enough information to calculate effect size. AVLT, Auditory Verbal Learning Test; 2BT, Two Back Task;
BVRT, Benton Visual Retention Test; CANTAB, Cambridge Neuropsychological Test Automated Battery; COWAT/FAS, Controlled Oral Word Association
Test/Phonological Fluency Test; DR2, Simple Choice Reaction; DSST, Digital Symbol Substitution Test; IGT, Iowa Gambling Task; Q1, Attention under
Monotonous Circumstances; RCFT, Rey Osterreith Complex Figure Test; RWT, Regensburger Word Fluency Test; ST, Stroop Test; TMT, Trail Making Test,
Act React Test Systems (ART 90/2020); TOL, Tower of London, Halstead Reitan Neuropsychological Test Battery; WAIS II, Weschler Adult Intelligence
Scale Second Edition; WCST, Wisconsin Card Sorting Test; d, Weschler Memory Scale Revised.
to methadone users but below the level of substance-free Soyka et al. (2008) assessed the neuropsychological
and healthy controls. functioning after at least 2 weeks of stable substitution treat-
A metaanalysis of data from a total cohort of 1063 ment with buprenorphine or methadone and then followed up
methadone users, 412 abstinent (<1 year), and 879 healthy using a repeated cognitive assessment after 8e10 weeks of
nonsubstance using population from 23 independent stable substitution treatment. In their study, the neuropsy-
studies indicate global impairments in neurocognitive chological battery measured attention, reaction time, verbal
function in the methadone cohorts when compared with memory, and cognitive flexibility. Participants in both treat-
healthy controls. However, it was not possible to compare ment modalities performed equally well at baseline in every
methadone cohorts with the abstinent population due to neuropsychological domains compared with the healthy
several methodological issues notably small sample sizes, control group. At follow-up, however, there was significant
heterogeneity, and poor quality (Baldacchino et al., 2017). impairment in cognitive flexibility and memory in both
experimental groups compared with the healthy control group.
Neuropsychological functioning and use of Pirastu et al. (2006) compared a group of methadone-
maintained and another group of buprenorphine-treated
buprenorphine
opioid-dependent individuals after 12 months of treat-
Buprenorphine is a partial mu-receptor agonist and kappa ment, with a group of substance-free healthy controls. Each
receptor antagonist that has increasingly been used as an of the three groups included in this study was assessed
alternative to methadone in the treatment of opiate using tests of cognitive flexibility, cognitive impulsivity,
dependency (British National Formulary 75, 2008).
and verbal memory, with the aim of identifying any experimental groups making errors to complete the task
differences in the neuropsychological profiles of patients quicker, at the expense of accuracy. There were no sig-
receiving methadone versus patients receiving buprenor- nificant differences in nonplanning impulsivity, cognitive
phine. Participants were excluded if they had any other flexibility, and motor impulsivity in the two groups when
major risk factors for neuropsychological impairment, such compared with nonsubstance using healthy control group.
as DSM-IV diagnoses of psychiatric disorder(s) (other than Recently, a systematic review by Hill et al. (2018)
substance misuse disorder), serious head injury, neurolog- concluded that results indicate fewer impairments in
ical disease, psychosis, HIV, epilepsy, or primary neurocognitive impulsivity and flexibility domains when the
psychological deficit. Their results showed that the buprenorphine population was compared with methadone
buprenorphine group performed significantly better than users. However, again this should be interpreted cautiously
those participants maintained on methadone and the control due to the poor quality of the studies conducted
group in the cognitive impulsivity tasks. But both the (Table 13.4).
methadone and buprenorphine groups struggled markedly
on tasks measuring cognitive flexibility and memory when Combinations of opioids (morphine, tramadol,
compared with the control groups.
fentanyl, oxycodone buprenorphine, and/or
Schindler et al. (2004) assessed the influence of
methadone)
15 months of either methadone or buprenorphine mainte-
nance treatment on the driving abilities of opioid-dependent Sjogren et al. (2005) investigated the influence of pain,
individuals. Using the ART 2020 Standard Test (Bukasa sedation, pain medication, and sociodemographic charac-
et al., 1997), both experimental groups showed significant teristics on cognitive functioning of 19 participants with
impairment in the Attention under Monotonous Circum- chronic nonmalignant pain prescribed morphine, tramadol,
stances Test (ACT) when compared with healthy controls. buprenorphine, and/or methadone compared with 64 healthy
The authors postulated that this could be as a result of both controls. The opioid-medicated individuals identified
TABLE 13.4 Summary of the evidence presented in this review for an association between other opioid use and
neuropsychological functioning.
Neuropsychological domain Buprenorphine use * Standardized effect size d

Cognitive impulsivity Pirastu et al. (2006)[ 1.94 (IGT)
Motor impulsivity Schindler et al. (2004)4 n/c
Nonplanning impulsivity Schindler et al. (2004)4 n/c
Cognitive flexibility Pirastu et al. (2006)Y 5.10 (WCST)
Soyka et al. (2008)Y 0.78 (TMT); 0.52 (RWT)
Schindler et al. (2004)4 n/c
Messinis et al. (2009) VFT
Sustained attention Soyka et al. (2008)Y 0.93 (D2)
Schindler et al. (2004)Y 0.57 (D2) and 0.66 (Q1)
Messinis et al. (2009) RSAT
Shmygalev et al. (2011) COG
Short-term memory Pirastu et al. (2006)Y 6.16 (BVRT)

Messinis et al. (2009) RAVLT
Long-term memory n/a n/a
*, P < 0.05; 4, no difference in neuropsychological performance; Y, neuropsychological deficits present; [, improvement in neuropsychological perfor-
mance when compared with healthy controls; d, Cohen’s effect size defined as the difference between two means divided by a standard deviation for
the data. Standardized effect sizes are reported regardless of the statistical significance (P-value) of the results reported in the original studies. n/c, con-
trols not healthy controls or not enough information to calculate effect size. AVLT, Auditory Verbal Learning Test; BVRT, Benton Visual Retention Test;
COG, Cognitrone Test; DR2, Simple Choice Reaction; IGT, Iowa Gambling Task; PASAT, Paced Auditory Serial Addition Task; Q1, Attention under
Monotonous Circumstances; RAVLT, Rey Auditory Verbal Learning Test; RSAT, Ruff Selection Attention Test; RWT, Regensburger Word Fluency Test;
WCST, Wisconsin Card Sorting Test, Halstead Reitan Neuropsychological Test Battery; TMT, Trail Making Test, Act React Test Systems (ART 90/2020).
significant deficits in motor impulsivity but not in memory. In Baldacchino et al. (2014, 2018), participants with
The authors suggested that impaired sustained attention and histories of illicit heroin use (n ¼ 24), former heroin users
reduced psychomotor speed in this cohort could be a stabilized on prescribed methadone (n ¼ 29), licit opioid
consequence of high pain scores in the cohort group. prescriptions for chronic pain without history of abuse or
Jamison et al. (2003) investigated the psychomotor effects dependence (n ¼ 28), and healthy controls (n ¼ 28) were
of long-term opioid use in 144 patients with chronic nonma- recruited and tested on a task battery that included measures
lignant low back pain. All participants were administered the of cognitive impulsivity (CGT), motor impulsivity (affec-
Digit Symbol and Trail Making Test B before being pre- tive go/no-go), nonplanning impulsivity (Stockings of
scribed opioids for pain. Tests were readministered at 90-day Cambridge), and visuospatial memory (Paired Associate
and 180-day intervals. Test scores significantly improved Learning Task). The data support the hypothesis that
while participants were taking opioids for pain, which sug- different aspects of neuropsychological measures of
gested that long-term opioids do not significantly impair impulsivity and memory appear to be associated with
cognitive ability or psychomotor function. Between 16% and exposure to different opioids. However, specifically chronic
25% of these participants demonstrated declining perfor- opioideexposed pain participants did not differ from
mance on the individual neuropsychological tests while on healthy controls on any measures on any tasks (Table 13.5).
opioids. In general, those who were older and had lower pain
intensity scores at their first measurement were most predis-
posed to poor test scores. The impaired cognition in this study
Methodological issues related with the
group compared with published standardized neuropsycho- study of the neuropsychological
logical test results may be attributable to chronic pain correlates of chronic opioid use, abuse,
conditions and is consistent with other findings of neuropsy- and dependence and relevant to both
chological impairment in those with chronic pain (Lorenz
et al., 1997; Sjogren et al., 2000a,b; Vainio et al., 1995;
researchers and clinicians
Crombez et al., 1996). Given that high pain intensity at This extensive review exploring the neuropsychological
baseline was most predictive of improvement on neuropsy- impairments associated with the chronic use of opioids
chological tests, it can be inferred that improvement in per- highlights the need to ensure rigorous control over a number
formance in this population was attributable to the of methodological variables that may affect the reliability,
ameliorating effects of opioids on pain rather than properties validity, and clinical relevance of the results obtained.
of the opioids per se. This was supported by the overall The lack of sufficient methodological rigor could be
decrease in average pain intensity scores and SF-36 bodily partly responsible for the lack of consistency in the results
pain scores between baseline and follow-up. of different studies and the marked interindividual and
A number of limitations of this study deserve mention. temporal variability noted in the available literature in the
Firstly, testing was performed in multiple sites by field. Both the large number of variables that must be
researchers who were not licensed psychological examiners. controlled and the difficulties involved in their control in
Thus, despite the fact that each examiner was given specific this type of population present great obstacles that are
instruction on how to administer the tests and had to perform difficult to surmount in the context of clinical research. In
five practice test protocols, the reliability of the examiner spite of the difficulties, the detection of neuropsychological
technique was not established. Secondly, the practice effect impairments closely associated with substance abuse re-
of test taking for patients may account for some improve- quires extreme methodological rigor and the control of the
ment in scores. The literature suggests that a 5% improve- variables that have most often been associated with the
ment is possible after a 3-week interval (Lezak, 1995). discrepancies in result characteristic of research in this field
Although this effect cannot be ruled out, most participants, (Verdejo-Garcıa et al., 2004). Among the variables that
however, showed a better than 5% improvement on their must be considered would be
scores. Thirdly, this study did not include a control group of
l Context: e.g., operational definitions, diagnostic
patients who were not taking opioids. We do not know
categories;
whether such a group followed for 6 months would also
l Study population: e.g., treatment cultures, therapeutic
show improvement. Fourthly, approximately 30% of the
environments, variety of recruitment strategies and sam-
participants were not followed for the full 180 days.
pling techniques, sample size, comorbid physical and
Although no differences were found between those patients
psychological conditions;
who completed the study and those who did not, it is
l Substance misuse and dependence: e.g., polysubstance
possible that the dropouts may have biased the results.
(nicotine and cannabis) use and other dependencies,
Finally, the patients in this study were not opioid naive.
chronicity, severity of use, dosage of opioid replace-
They may have accommodated less to the opioids and
ment therapies, objective measurements of drug use;
shown more cognitive impairment had they been given
opioids for the first time.
TABLE 13.5 Summary of the evidence presented in this review for an association between other opioid use and
neuropsychological functioning.
Neuropsychological domain Other opioid use* Standardized effect size d

Cognitive impulsivity Pirastu et al. (2006)[ 1.94 (IGT)
Baldacchino et al. (2014)4 0.40 (CGT)
Motor impulsivity Sjogren et al. (2005)Y n/c
Vainio et al. (1995)4 n/c
Baldacchino et al. (2014)4 0,10 (AGN)
Nonplanning impulsivity Vainio et al. (1995)4 n/c
Baldacchino et al. (2014)4 0.10 (SOC)
Cognitive flexibility Pirastu et al. (2006)Y 5.10 (WCST)
Soyka et al. (2008)Y 0.78 (TMT)
Jamieson et al. (2003)[ n/c
Tassain et al. (2003)4 n/c
Sustained attention Soyka et al. (2008)Y 0.93 (D2)
Sjogren et al. (2005)Y 0.36 (PASAT)
Jamieson et al. (2003)4 n/c
Vainio et al. (1995)4 n/c
Schindler et al. (2004)Y 0.57 (D2) andand 0.66 (Q1)

Short-term memory Pirastu et al. (2006)Y 6.16 (BVRT)

Baldacchino et al. (2018) 0.11 (PAL)
Long-term memory Tassain et al. (2003)4 n/c
*P < 0.05; 4, no difference in neuropsychological performance; Y, neuropsychological deficits present; [, improvement in neuropsychological
performance when compared with healthy controls; d, Cohen’s effect size defined as the difference between two means divided by a standard deviation
for the data. Standardized effect sizes are reported regardless of the statistical significance (P-value) of the results reported in the original studies. n/c,
controls not healthy controls or not enough information to calculate effect size. AGN, Affective go/no-go; AVLT, Auditory Verbal Learning Test; BVRT,
Benton Visual Retention Test; CGT, Cambridge Gambling Task; DR2, Simple Choice Reaction; IGT, Iowa Gambling Task; PAL, Paired Associate
Learning; PASAT, Paced Auditory Serial Addition Task; Q1, Attention under Monotonous Circumstances; RWT, Regensburger Word Fluency Test; SOC,
Stockings of Cambridge; TMT, Trail Making Test, Act React Test Systems (ART 90/2020); WCST, Wisconsin Card Sorting Test, Halstead Reitan
Neuropsychological Test Battery.
l Moment of evaluation: e.g., acute, subacute and chronic Context

episodes, short- and long-term abstinence, reversible
Considerable confusion and misleading information has
versus irreversible cognitive domains;
arisen from many studies because of loose definitions of the
l Cotoxins: e.g., polypharmacy, adulterants;
terms chronicity, neuropsychology, and opioids. Confusion
l Neurocognitive tests: ecological and predictive validity,
has also arisen because many research groups, for example,
specificity, usage of battery assessments;
only vaguely describe specific diagnostic algorithms and
l Data handling and analysis: e.g., hypothesis driven,
the degree to which they consider diagnostic exclusion
bias, level, and complexity of statistics to be used (latent
rules. This is relevant whether none, some, or all of the
variable analysis and machine learning).
diagnostic exclusions and hierarchies have been consid- (Ornstein et al., 2000), or among the incarcerated population
ered. Complex sets of symptom, syndrome, and diagnostic (Selby and Azrin, 1998). Therefore, an opposite (Berkson)
exclusions (as employed by DSM-III-R, DSM-IV, ICD-9, bias emerges because most of the studies are unable to access
and ICD-10) might all affect the result as well as their those users who are not in treatment (Berkson, 1946).
interpretation (Wittchen, 1996). Furthermore, opioid treatment programs may include agonist
A further problem with defining the populations is that maintenance treatment with methadone and buprenorphine,
historically mental health, psychology, and substance introducing additional confounding factors in the detection
misuse services have evolved in their own way, using of possible long-term effects of opioid abuse.
different language and models to inform their service Therefore, different recruitment strategies would be
policies and objectives (Todd et al., 2004). advisable, with special emphasis on accessing the “hidden”
The method(s) of assessment and diagnosis may change population of abusers to help obtain a more representative
within a country or scientific community. The settings population.
where studies take place differ, and even if apparently
similar may not be so. Studies in one region or location Sample size
may not reflect the situation in another, especially in the
Another frequent methodological problem is that of sample
international context.
size. Participants need to be matched on a series of vari-
For studies looking at treatment-seeking opioid pop-
ulations, it is necessary to distinguish between general ables (duration of abstinence, chronicity and severity of
use, type of substances used), which are sometimes very
psychiatric, pain, and addiction services. For example, in
difficult to control if strict methodological rigor is not
general psychiatric services, alcohol and cannabis are more
observed (Del Boca and Darkes, 2007). Probably for these
likely to be encountered as the comorbid dimension,
reasons, the majority of the studies that attempted to relate
whereas in pain and addiction services, depression, anxiety,
chronic opioid use with significant neuropsychological
and personality disorders are going to be the additional
impairments have used small samples.
problems most commonly reported together with opioids
The main problem associated with using small sample
and cannabis being the main substance used.
sizes is the low representativity. Sample size is closely
interrelated with methodological problems as a result of
The population studied weak statistical power. The statistical power of a study
Recruitment depends on three variables: the level of significance
established for the alpha level (or P value), the sample size,
Recruitment related methodological problems depend largely and the size of the effect that must be detected (Zakzanis,
on the type of substance abused by the target population, and 2001). A reduced sample size can be appropriate for
an important challenge in sampling is that of tracking the detecting an average effect but inappropriate for capturing
so-called “hidden” population (Heckathorn, 2002). For small effects. Therefore, if the effects detected in the study
example, dihydrocodeine abuse has been traditionally of the neuropsychological correlates of chronic opioid use
restricted to private and erratic consumption patterns within a are of a medium size, small samples may be enough to
gainfully occupied population that rarely generate admission capture them. But if, on the other hand, what we are
to treatment centers (Shewan and Dalgarno, 2005). looking for are small effects, the sample sizes that have
Therefore, studies tend to use the “snowball tech- been used would be inappropriate for their verification.
nique,” originally described by Solowij et al. (1992), in Up until now, there have been very few studies in the
which volunteers agreeing to participate in the study field that have incorporated estimations of the size of the
contact other acquaintances who are asked to contact other effect. Among those that have, Brand et al. (2008) and
users (Fox et al., 2002). Fishbein et al. (2007) used Cohen’s arbitrary method of
However, some other strategies have been described to differentiating low, medium, and strong effect size (Cohen,
recruit this population, including advertisements over the 1977). The systematic review in this chapter calculated the
Internet, in local newspapers and music magazines effect sizes of most identified studies showing a broad
(Thomasius et al., 2003), flyers and posters in the areas sur- range of variation. Overall, there has been a medium effect
rounding schools and universities (Simon and Mattick, 2002), size (at least 0.45) in methadone and opioid studies but not
through word of mouth, or directly “in vivo” on the rave scene in the heroin studies, which had an overall low effect size
(Gouzoulis-Mayfrank et al., 2003). These tracking procedures (Fernandez-Serrano et al., 2011).
introduce a methodological bias because the subjects recruited However, Bezeau and Graves (2001) considered that
may not be representative of the whole population. this effect size is probably too small to be applied to
In contrast, opioid and cocaine users are often recruited as research in clinical neuropsychology. These authors
they join inpatient or outpatient treatment programs considered that, to assume the clinical usefulness of the
study, it would be necessary for both populations (in this Kandel, 1988) so that the data provided can skew possible
case, opioid users or dependent and controls) to be sepa- correlational analyses regarding the amount of neuropsy-
rated by at least 0.80 typical deviations in the variable chological impairment with the levels of chronicity and
measured (Fernandez-Serrano et al., 2011). severity of opioid use.
The option of carrying out toxicological urine analyses
Substance misuse and dependence is not conclusive either. In spite of the fact that these an-
alyses allow us to confirm the presence of a certain sub-
Effects of polysubstance use stance in the participants at a particular moment in time,
The majority of opioid-dependent participants are not users these measures may lack comprehensiveness. A large
quantity of information is lost about the frequency of use,
of only one substance, but rather a wide spectrum of them,
the amount consumed, how recent the use was, or the
so that the potentially detected neuropsychological
pattern the use has followed over a long period of time, and
impairments cannot really be attributed to the specific effect
the results of the analyses present low correlations with the
of the drug used. Instead, they are caused by the global
self-report measures (Easton and Bauer, 1996).
effect of the group of drugs consumed (Hay et al., 2007).
This could be minimized either through serial analyses
Neuropsychological research has shown that alcohol
of drug metabolites or utilizing newer technology such as a
consumption and smoking are important confounding
variable in the study of the neuropsychological conse- hair analysis, which have been shown to provide more
definitive information about patterns of use (Fraser et al.,
quences of chronic opioid use (Fishbein et al., 2007;
2002). However, these methods tend to be either not
Rotherham-Fuller et al., 2004). The interpretation of the
practical or prohibitively expensive.
neuropsychological impairments identified in chronic
opioid users also seem to be frequently complicated by the
high incidence of treatments with other opioids such as Time window (moment of evaluation)
methadone, buprenorphine, naloxone, naltrexone, and an- The moment in time of the neuropsychological evaluation
tidepressant, sedative, and sometimes antipsychotic medi- is of utmost importance for an adequate detection of the
cations (Ornstein et al., 2000). impairments. If the evaluation takes place between 24 and
In general, the studies that discriminate between the 72 h after the use, what we may be detecting are impair-
cognitive impairments attributable to the use of one isolated ments produced by the acute (Ersek et al., 2004) or with-
substance and those that are derived from effects of poly- drawal effects of the drug (Lyvers and Yakimoff, 2003). If
substance use have detected a greater number of impaired evaluation takes place during the first 3 months of absti-
functions and an increase in the magnitude of the damage nence, impairments might be related to the residual effects
among polysubstance (including nicotine dependence) user of the drug on the participant (Ersek et al., 2004). If eval-
participants as well as a reduced capacity to recover these uated from the third month of abstinence onwards, the
functions (Passetti et al., 2008, Fernandez-Serrano et al., neuropsychological impairments might be associated with
2011). However, studies are too few and far between to lasting alterations of the central nervous system that might
make any conclusive remarks. be more stable in time and that might not revert with
abstinence (Roselli and Ardila, 1996).
Chronicity and severity of use It was suggested that the neuropsychological impair-
ments resulting from substance use are partially reversible
The control of the chronicity and severity of the use of
(Davis et al., 2002) and that this reversibility depends on
diverse drugs is another methodological challenge faced
the duration of the abstinence period (Bauer, 2001). This
when studying the neuropsychological impairments asso-
ciated with chronic opioid use. Some studies directly systematic review shows that abstinent heroin users expe-
rience impairment in decision-making but it is not clear the
correlated both variables with the magnitude of the neu-
magnitude of the impairments or if it is related to the length
ropsychological deterioration in opioid users (Grant et al.,
of the abstinence period (i.e., the more prolonged the
1978; Hill and Mikhael, 1979; Ornstein et al., 2000) while
abstinence, the greater the level of recovery) (Pezawas
others have pointed out the lack of consistent relationships
et al., 1998; Selby et al., 1995).
between the severity and chronicity of the use and the
Although no cutoff point has been defined from which the
performance registered on the neuropsychological tests
extension of the abstinence is not relevant for the continuation
(Prosser et al., 2006).
This lack of consistency probably reflects the low reli- to recover, it has been suggested that most of the neuropsy-
chological recovery in substance misuse takes place during the
ability of the self-report measures that are usually used for
first month (Solowij, 1995), but that superior functions or
control and the lack of objective measurements of drug
abilities such as abstract reasoning or problem-solving take
taking in the opioid users. Opioid-dependent participants
much longer to recover, and in many cases, might never return
tend to underestimate their own levels of use (Mensch and
to their premorbid levels (Gottschalk et al., 2001). There is no when measuring performance in decision-making, memory,
literature to suggest that this is the same for opioid users. and attentional functions. By using these ecologically friendly
paradigms, studies showed that the neuropsychological pre-
Other relevant factors diction of everyday outcomes in substance users tend to
improve (Verdejo-Garcia and Pérez-García, 2007c; Verdejo-
Exposure to adulterants, prevalence of particular patterns of
Garcia et al., 2007d). In addition, one needs to be careful not
polysubstance abuse, and the impact of the route of
to assume that tests have the predictive validity to determine
administration (e.g., injecting behavior) all contribute to the
who will recover from impaired neuropsychological functions
uncertainties of attributing any observed impairment to
and/or enhance a successful recovery process, unless this type
chronic opioid use under consideration (Gruber et al., 2007; of validity is well established (Passetti et al., 2008).
Lyvers and Yakimoff, 2003).
Another aspect that impacts on test performance is
One possible solution to reduce these methodological
familiarity with tests stimuli. Beatty and Borrell (2000)
confounders is by planning an experimental design in which
showed that a group of drug users could perform better than
(a) Control groups of pure users (e.g., alcohol, nicotine) or a control group on a memory task in which the content of
poly drug users who do not use the target substance are the items was adapted to the circumstances that character-
included (Verdejo-García et al., 2007a) ized the lifestyle of the subjects. They suggested that some
(b) Using nonsubstance using populations such as those of the impairments detected by the “classical” neuropsy-
with a diagnosis of chronic nonmalignant pain and pre- chological tests and attributed to prolonged substance use
scribed opioids for analgesia (Tassain et al., 2003). could be explained by the limited opportunities for
knowledge acquisition imposed by their lifestyle.
Other potential methodological issues include the use of
Data gathering (diagnostic and screening
battery assessments instead of a succession of individual
instruments)
tests and deciding on the pros and cons of using comput-
Type of neuropsychological tests erized neuropsychological assessments instead of pen and
paper assessments (Levaux et al., 2007). Some of these
The selection of the neuropsychological tests used should issues arise as a result of unstandardized presentation of
take into consideration the type of functions that are of
stimuli and recording of responsesdinefficient, inaccurate,
interest in measuring, as well, as the sensitivity of these
lack of comparable collection of detailed data, and lack of
tests in detecting specific impairments in these same
ecological validity between the “classic” neuropsycholog-
functions (Lezak et al., 2004).
ical tests and computerized tests among others. Additional
While some studies focused on the evaluation of spe-
factors to consider include the time taken to complete the
cific functions, mainly sustained attention and memory
tests, the order of the test presentation, and the practice
(Mintzer et al., 2005; Soyka et al., 2008) and executive
effects if the same tests are repeated over time (Lowe and
functioning (Ornstein et al., 2000), others carried out a Rabbitt, 1998). All these factors, if not either standardized
more exhaustive neuropsychological evaluation (Ersche
or taken into account, will influence the results.
et al., 2006a,b; Fishbein et al., 2007; Verdejo-García et al.,
2007a). However, in this review, one finds that few studies
Defining the population
are using the same tests, therefore making it difficult to
compare the results, even when identical functions are The clinical assessment and diagnostic instruments used
being measured. For example, in executive functioning, can also affect interpretation of neuropsychological testing.
various authors (Bechara et al., 2000; Ornstein et al., 2000) For example, a comparison of ICD-10 and the Composite
have detected impairments in cognitive flexibility and International Diagnostic Interview (CIDI) suggests that two
decision-making in amphetamine and opiate users by using or three times as many psychiatric diagnoses as the clini-
three different instruments: IGT (Bechara and Martin, cian would assign in routine diagnostic assessment are
2004), the CANTAB Battery (Robbins et al., 1994), and the revealed by standardized instruments (Baldacchino and
Rogers Decision-Making Task (Rogers et al., 1999), Crome, 2010). This is particularly true for substance use
respectively. Further research should be conducted to disorders. Although it is not clear which of the diagnoses
determine the exact relationship and significance between are really valid, it can at least be assumed that the higher
such tests (Monterosso et al., 2001). comorbidity rates of the CIDI cannot be fully explained as
On the other hand, the ecological validity of these “clas- artifactual or invalid (Baldacchino and Crome, 2010).
sical” neuropsychological tests (their ability to detect im- There is some evidence that in the mid-1990s, clinicians
pairments in functions that are adaptively relevant for the focused more on the current circumstances of a patient
participant in their everyday endeavors) has been questioned rather than the prior history of minor mental disorders as it
by various authors (Verdejo-Garcia and Pérez-García, 2007c), was more likely to employ implicit hierarchies. As most
clinicians were trained at that time in traditional nosological opioid use. A growing line of evidence from human studies
concepts and ICD-9, they were therefore more likely to indicate that preexisting executive dysfunction especially in
include in their diagnosis features that might justify a cognitive impulsivity may predate the onset of drug use and
separate diagnosis (Wittchen, 1996). constitute vulnerability markers for liability to addiction.
Francis et al. (1990) suggest that semistructured diag- Previous literature has highlighted that illicit heroin use,
nostic instruments might be more susceptible to “halo methadone, and buprenorphine treatment but not chronic
effect” than standardized instruments. The “halo effect” is use of other opioids could determine neuropsychological
where one characteristic or quality of an individual over- impairment in all the cognitive domains when compared
shadows all other attributes (i.e., the extension of an overall with healthy nonsubstance using control groups. These
impression of one particular outstanding trait to influence impairments seem to improve following abstinence from
the total judgment and assessment of that person by an opioids for at least between 2 and 4 weeks or more.
observer). Kessler (1995) demonstrated that technical The previous literature has not only highlighted the
modifications can significantly impact symptom reports as current knowledge base on this subject but also identified
well as the accuracy of dating lifetime episodes of mental methodological limitations and subsequent difficulties in
disorders. Such modifications can include changes to the interpretating what is essentially a heterogeneous and
order in which disorders are assessed and the use of stem noncomparable set of data.
questions.
When conducting diagnostic interviews, reliable and
consistent information is crucial. The accuracy of data
References
provided by the patient and the stability of presenting Appel, P.W., 1982. Sustained attention in methadone patients. Int. J.
symptoms need to be taken into account. To distinguish Addict. 17 (8), 1313e1327.
between chronologically primary and secondary disorders, Baldacchino, A., Crome, I.B., 2010. Epidemiological issues in mental
age of onset, duration of symptoms as well as periods of health-substance use. A case for a life long approach to chronic dis-
ease epidemiology. In: Cooper, D.B. (Ed.), Developing Service in
remission and symptom offset are fundamental building
Mental Health-Substance Use. Radcliffe Publishing Ltd, Cornwall,
blocks into which further information can be added and a UK.
fuller picture constructed. It is imperative to obtain collat- Baldacchino, A., Balfour, D., Passetti, F., Humphris, G., Matthews, K.,
eral detailed information from the referring agencies, case 2012. The neuropsychological consequences of chronic opioid use: a
records, and significant others. This will lessen the distor- quantitative review and meta-analysis. Neurosci. Biobehav. Rev. 36,
tion caused by intoxication, insufficient periods of absti- 2056e2068.
nence on the part of participant, impaired memory, Baldacchino, A., Balfour, D.J., Matthews, K., 2014. Impulsivity and
inconsistent answers, or deliberately falsified information. opioid drugs: differential effects of heroin, methadone and prescribed
analgesic medication. Psychol. Med. 8, 1e13.
Baldacchino, A., Aramanyous, M., Balfour, D., Humphris, G.,
Data analysis Matthews, K., 2017. The neuropsychological consequences of chronic
Most studies have been concerned with minimizing Type 1 methadone use: a quantitative review and meta- analysis. Neurosci.
error by adjusting alpha level for multiple tests of signifi- Biobehav. Rev. 73, 23e38.
Baldacchino, A., Tolomeo, S., Balfour, D., Matthews, K., 2018. Profiles of
cance (e.g., Bonferroni adjustment) (Westfall et al., 1997).
visuospatial memory dysfunction in opioid dependent and opioid us-
Most studies reviewed are either underpowered with no
ing populations. Psychol. Med. 49 (7), 1174e1184 (in press).
adjustment for attrition present (Del Boca and Darkes, Bauer, L., 2001. Antisocial personality disorder and cocaine dependence:
2007). Others fail to take into consideration the level and their effects in behavioural and electroencephalographic measures of
significance of the P value when multiple comparisons, such time estimation. Drug Alcohol Depend. 63, 87e95.
as using a family of neuropsychological tests or when Beatty, W.W., Borrell, G.K., 2000. Forms of knowledge, cognitive
multiple outcomes, are analyzed (Ioannidis, 2005). This is impairment and drug abuse: a demonstration. Prog. Neuro-
further compounded by the lack of a clear hypothesis-driven Psychopharmacol. Biol. Psychiatry 24, 17e22.
cohort experimental design (Sterne and Smith; 2001). Bechara, A., Damasio, H., Damasio, A.R., 2000. Emotion, decision-
making and the orbitofrontal cortex. Cereb. Cortex 10, 295e307.
Bechara, A., Martin, E.M., 2004. Impaired decision making related to
Conclusion working memory deficits in individuals with substance addictions.
Neuropsychology 18, 152e162.
Most of the data reviewed are designed as cross-sectional
Berkson, J., 1946. Limitations of the application of the fourfold table
studies and therefore do not allow determination whether analysis to hospital data. Biometrics 2, 47e53.
neuropsychological impairment observed precede drug use Bezeau, S., Graves, R., 2001. Statistical power and effect sizes of clinical
or if they occur as a consequence of the effects of continued neuropsychology research. J. Clin. Exp. Psychol. 23, 399e406.
Brand, M., Roth-Bauer, M., Driessen, M., Markowitsch, H.J., 2008. Ex- Fadardi, J.S., Ziaee, S.S., 2010. A comparative study of drug-related
ecutive functions and risky decision-making in patients with opiate attentional bias: evidence from Iran. Exp. Clin. Psychopharmacol-
dependence. Drug Alcohol Depend. 7, 64e72. ogy 6, 539e545.
British National Formulary 75, 2018. British Medical Journal Publishing Fernández-Serrano, M.J., Pérez-García, M., Perales, J.C., Verdejo-
Group Ltd and Royal Pharmaceutical Society of Great Britain Joint García, A., 2010a. Prevalence of executive dysfunction in cocaine,
Publication. Leck: Clausen & Bosse. www.bnf.org. heroin and alcohol users enrolled in therapeutic communities. Eur. J.
Bukasa, B., Brandstätter, C., Wenninger, U., 1997. Entwicklung eines Pharmacol. 626, 104e112.
neuen Testinstrumentariums zur Durchführung verkehrs- Fernandez-Serrano, M.J., Perez-Garcia, M., Schmidt Rio-Valle, J.,
psychologischer Fahreignungsuntersuchungen. In: Baumgärtel, F., Verdejo-Garcia, A., 2010b. Neuropsychological consequences of
Wilker, F.W., Winterfeld, U. (Eds.), Innovation und Erfahrung. alcohol and drug abuse on different components of executive func-
Analysen. Planungen und Erfahrungsberichte zu psychologischen tions. J. Psychopharmacol. https://doi.org/10.1177/
Arbeitsfeldern. Deutscher Psychologenverlag, Bonn. 0269881109349841.
Clark, L., Robbins, T.W., Ersche, K.D., Sahakian, B.J., 2006. Reflection Fernandez-Serrano, M.J., Perez-Garcia, M., Verdejo-Garcia, A., 2011.
impulsivity in chronic and former substance users. Biol. Psychiatry What are the specific vs. generalised effects of drugs of abuse on
60, 512e522. neuropsychological performance? Neurosci. Biobehav. Rev. 35 (3),
Cohen, J., 1977. Statistical Power Analysis for the Behavioural Sciences. 377e406.
Revised. Academic Press, New York. Fishbein, D.H., Eldreth, D.L., Hyde, C., Matochik, J.A., London, E.D.,
Crombez, G., Ecceston, C., Baeyens, F., Eelen, P., 1996. The disruptive Contoreggic, C., Kurian, V., Kimes, A.S., Breeden, A., Grant, S.,
nature of pain: an experimental investigation. Behavioral Research 2005. Risky decision making and the anterior cingulate cortex in
and Therapy 34, 911e918. abstinent drug abusers and nonusers. Cogn. Brain Res. 23, 119e136.
Darke, S., Sims, J., McDonald, S., Wickes, W., 2000. Cognitive impair- Fishbein, D.H., Krupitsky, E., Flannery, B.A., Langevin, D.J.,
ment among methadone maintenance patients. Addiction 95 (5), Bobashev, J., Verbitskaya, E., Augustine, C.B., Bolla, K.I.,
687e695. Zvartau, E., Schech, B., Egorova, V., Bushara, N., Tsoy, M., 2007.
Davis, P.E., Liddiard, H., McMillan, T.M., 2002. Neuropsychological Neurocognitive characterizations of Russian heroin addicts without a
deficits and opiate abuse. Drug Alcohol Depend. 67, 105e108. significant history of other drug use. Drug and Alcohol Dependence
Degenhardt, L., Charlson, F., Mathers, B., Hall, W.D., Flaxman, A.D., 90, 25e38.
Johns, N., Vos, T., 2014. The global epidemiology and burden of Fox, H.C., McLean, A., Turner, J.J.D., Parrot, A.C., Rogers, R.,
opioid dependence: results from the global burden of disease 2010 Sahakian, B.J., 2002. Neuropsychological evidence of a relatively
study. Addiction 109, 1320e1333. selective profile of temporal dysfunction in drug-free MDMA (“ec-
Del Boca, F.K., Darkes, J., 2007. Enhancing the validity and utility of the stasy”) polydrug users. Psychopharmacology 162, 203e214.
randomised clinical trials in addictions treatment research: III. Data Francis, A., Widinger, T., Fyer, M.R., 1990. The influence of classification
processing and statistical analysis. Addiction 201, 1356e1364. methods on comorbidity. In: Maser, J.D., Cloninger, C.L. (Eds.),
Easton, C., Bauer, L.O., 1996. Neuropsychological correlates of urine Comorbidity of Mood and Anxiety Disorders. American Psychiatric
toxicology results. Neuropsychopharmacol. Biol. Psychiatry 20, Publishing, Arlington, D.C.
969e982. Fraser, A.D., Coffin, L., Worth, D., 2002. Drug and chemical metabolites
EMCDDA, 2017. European Monitoring Centre for Drugs and Drug in clinical toxicology investigations: the importance of ethylene gly-
Addiction European Drug Report 2017: Trends and Developments. col, methanol and cannabinoid metabolite analyses. ChemBioChem
EMCDDA, Lisbon. 35, 501e511.
Eriksen, J., Sjøgren, P., Bruera, E., Ekholm, O., Rasmussen, N.K., 2006. Gordon, N.B., 1970. Reaction times of methadone treated ex-heroin ad-
Critical issues on opioids in chronic non-cancer pain: an epidemio- dicts. Psychopharmacologia 16 (4), 337e344.
logical study. Pain 125, 172e179. Gordon, N.B., Appel, P.W., 1995. Functional potential of the methadone-
Ersche, K.D., Fletcher, P.C., Lewis, S.J.G., Clark, L., Stocks-Gee, G., maintained person. Alcohol Drugs Driv. 11 (1), 31e37.
London, M., Deakin, J.B., Robbins, T.W., Sahakian, B.J., 2005. Gottschalk, P.C., Beauvais, J., Hart, R., Kosten, T.R., 2001. Cognitive
Abnormal frontal activations related to decision-making in current and function and cerebral perfusion during cocaine abstinence. Am. J.
former amphetamine and opiate dependent individuals. Psychophar- Psychiatry 158, 540e545.
macology 180, 612e623. Gouzoulis-Mayfrank, E., Thimm, B., Rezk, M., Hensen, G., Daumann, J.,
Ersche, K.D., Clark, L., London, M., Robbins, T.W., Sahakian, B.J., 2003. Memory impairment suggests hippocampal dysfunction in
2006a. Profile of executive and memory function associated with abstinent ecstasy abusers. Prog. Neuro Psychopharmacol. Biol. Psy-
amphetamine and opiate dependence. Neuropsychopharmacology 31, chiatr. 27, 819e827.
1036e1047. Gradin, V., Baldacchino, A., Matthews, K., Balfour, D., Steele, D., 2013.
Ersche, K.D., Fletcher, P.C., Roiser, J.P., Fryer, T.D., London, M., Abnormal brain activity during a reward and aversive task in patients
Robbins, T.W., Sahakian, B.J., 2006b. Differences in orbitofrontal with opiate dependence receiving methadone maintenance therapy.
activation during decision-making between methadone-maintained Neuropsychopharmacology. https://doi.org/10.1038/npp.2013.289.
opiate users, heroin users and healthy volunteers. Psychopharmacol- Grant, I., Adams, K.M., Carlin, A.S., Rennick, P.M., Judd, L.L.,
ogy 188, 364e373. Schooff, K., 1978. The collaborative neuropsychological study of
Ersek, M., Cherrier, M.M., Overman, S.S., Irving, G.A., 2004. The polydrug users. Arch. Gen. Psychiatry 35, 1063e1074.
cognitive effects of opioids. Pain Manag. Nurs. 5 (2), 75e93.
Gruber, S.A., Silveri, M.M., Yurgelun-Todd, D.A., 2007. Neuropsycho- Lin, W.-C., Chou, K.-H., Chen, H.-L., Huang, C.-C., Lu, C.-H., Li, S.-H.,
logical consequences of opiate use. Neuropsychol. Rev. 17 (3), Wang, Y.-L., Cheng, Y.-F., Lin, C.-P., Chen, C.-C., 2012. Structural
299e315. deficits in the emotioncircuit and cerebellum are associated with
Gupta, S., Ludicello, J., Shi, C., Letendre, S., Knight, A., Li, J., depression, anxiety and cognitivedysfunction in methadone maintenance
Riggs, P.K., Franklin, J.,D.R., Duart, N., Jin, H., Hampton patients: a voxel-based morphometricstudy. Psych. Res. 201, 89e97.
Atkinson, J., Yu, X., Wu, Z., Grant, I., Heaton, R.K., HNRC China Lombardo, W.K., Lombardo, B., Goldstein, A., 1976. Cognitive func-
Collaboration Group, 2014. Absence of neurocognitive impairment in tioning under moderate and low dosage methadone maintenance. Int.
a large Chinese sample of HCV-infected injection drug users receiving J. Addict. 11 (3), 389e401.
methadone treatment. Drug Alcohol Depend. 137, 29e35. Lorenz, J., Beck, H., Bromm, B., 1997. Cognitive performance, mood and
Han, B., Compton, W.M., Blanco, C., Crane, E., Lee, J., Jones, C.M., experimental pain before and during morphine-induced analgesia in
2017. Prescription opioid use, misuse, and use disorders in U.S. patients with chronic nonmalignant pain. Pain 73, 369e375.
adults: 2015 national survey on drug use and health. Ann. Intern. Med. Lowe, C., Rabbitt, P., 1998. Test/retest reliability of the CANTAB and
167, 293e301. ISPOCD neuropsychological batteries: theoretical and practical issues.
Hay, G., Gannon, M., MacDougall, J., Millar, T., Eastwood, C., Neuropsychologia 36 (9), 915e923.
McKeganey, N., 2007. National and Regional Estimates for the Prev- Lundqvist, T., 2005. Cognitive consequences of cannabis use: comparison
alence of Opiate Use and/or Crack Cocaine Use 2005/06. Home Office, with abuse of stimulants and heroin with regard to attention, memory
London. http://www.homeoffice/gov.uk/rds/pdfs08/horr09.pdf. and executive functions. Pharmacol. Biochem. Behav. 81 (2), 319e330.
Heckathorn, D., 2002. Respondent driven sampling II: deriving valid Lyvers, M., Yakimoff, M., 2003. Neuropsychological correlates of opioid
population estimates from chain-referral samples of hidden pop- dependence and withdrawal. Addict. Behav. 28 (3), 605e611.
ulations. Soc. Probl. 49, 11e34. McNairy, S.L., Maruta, T., Ivnik, R.J., Swanson, D.W., Ilstrup, D.M.,
Hill, S.Y., Mikhael, M.A., 1979. Computerised transaxial tomographic and 1984. Prescription medication dependence and neuropsychological
neuropsychological evaluations in chronic alcoholics and heroin function. Pain 18 (2), 169e177.
abusers. Am. J. Psychiatry 136, 598e602. Mensch, B.S., Kandel, D.B., 1988. Underreporting of substanceuse in a
Hill, D., Garner, D., Baldacchino, A., 2018. Comparing neurocognitive national longitudinal youth cohort: individual and interviewer effects.
function in individuals receiving chronic methadone or buprenorphine Publ. Opin. Q. 52, 100e124.
for the treatment of opioid dependence: a systematic review. Heroin Messinis, L., Lyros, E., Andrian, V., Katsakiori, P., Panagis, G.,
Heroin Relat. Clin. Probl. 20 (5), 35e49. Georgiou, V., Papathanasopoulos, P., 2009. Neuropsychological
Hudson, T.J., Edlund, M.J., Steffick, D.E., Tripathi, S.P., Sullivan, M.D., functioning in buprenorphine maintained patients versus abstinent
2008. Epidemiology of regular prescribed opioid use: results from a heroin abusers on naltrexone hydrochloride therapy. Hum. Psycho-
national, population-based survey. J. Pain Symptom Manag. 36 (3), pharmacol. 24 (7), 524e531.
280e288. Mintzer, M.Z., Stitzer, M.L., 2002. Cognitive impairment in methadone
Ioannidis, J.P.A., 2005. Why most published research findings are false. maintenance patients. Addiction 95 (5), 687e695.
PLoS Med. 2 (8), e124. https://doi.org/10.1371/journal.pmed.0020124. Mintzer, M.Z., Copersino, M.L., Stitzer, M.L., 2005. Opioid abuse and
Jaffe, J.H., 1990. Drug addiction and drug abuse. In: Goodman, A.G., cognitive performance. Drug Alcohol Depend. 78, 225e230.
Rall, T.W., Niles, A.S., Taylor, P. (Eds.), The Pharmacological Basis Monterosso, J., Ehrman, R., Napier, K., O’Brien, C.P., Childress, A.R.,
of Therapeutics, eighth ed. Pergamon Press, New York. 2001. Three decision-making tasks in cocaine-dependent patients: do
Jamison, R.N., Schein, J.R., Vallow, S., Ascher, S., Vorsanger, G.J., they measure the same construct? Addiction 96, 1825e1837.
Katz, N.P., 2003. Neuropsychological effects of long-term opioid Olsen, Y., Daumit, G.L., Ford, D.E., 2006. Opioid prescriptions by US
use in chronic pain patients. J. Pain Symptom Manag. 284, primary care physicians from 1992 to 2001. J. Pain 7, 225e235.
240e247. Ornstein, T.J., Iddon, J.L., Baldacchino, A.M., Sahakian, B.J.,
Kelly, J.P., Cook, S.F., Kaufman, D.W., Anderson, T., Rosenberg, L., London, M., Everitt, B.J., Robbins, T.W., 2000. Profiles of cognitive
Mitchell, A.A., 2008. Prevalence and characteristics of opioid use in dysfunction in chronic amphetamine and heroin abusers. Neuro-
the US adult population. Pain 138, 507e513. psychopharmacology 23 (2), 113e126.
Kessler, R., 1995. The epidemiology of psychiatric comorbidity. In: Osborne, V., Serdarevic, M., Crooke, H., Striley, C., Cottler, L.B., 2017.
Tsuang, M.T., Tohen, M., Zahner, G.E.P. (Eds.), Textbook of Psy- Non-medical opioid use in youth: gender differences in risk factors
chiatric Epidemiology. John Wiley and Sons, New York. and prevalence. Addict. Behav. 72, 114e119.
Levaux, M.-N., Potvin, S., Sepehry, A.A., Sablier, J., Mendrek, A., Passetti, F., Clark, L., Mehta, M.A., Joyce, E., King, M., 2008. Neuro-
Stip, E., 2007. Computerised assessment of cognition in schizo- psychological predictors of clinical outcome in opiate addiction. Drug
phrenia. Promises and pitfalls of CANTAB. Eur. Psychiatry 22, Alcohol Depend. 94, 82e91.
104e115. Paulose-Ram, R., Hirsch, R., Dillon, C., Losonczy, K., Cooper, M.,
Lezak, M.D., 1995. Neuropsychological assessment, third ed. Oxford Ostchega, Y., 2003. Prescription and non-prescription analgesic use
University Press, New York. among the US adult population: results from the third National Health
Lezak, M.D., Howieson, D.B., Loring, D.W., 2004. Neuropsychological and Nutrition Examiation Survey (NHANES III). Pharmacoepidemiol.
Assessment, fourth ed. Oxford University Press, New York. Drug Saf. 12 (4), 315e326.
Liao, D.-L., Huang, C.-Y., Hu, S., Fang, S.-C., Wu, C.-S., Chen, W.-T., Pezawas, L.M., Fischer, G., Diamant, K., Schneider, C., Schindler, S.D.,
Lee, T.S., Chen, P.-C., Li, C.-S.R., 2014. Cognitive control in opioid Thurnher, M., Ploechl, W., Eder, H., Kasper, S., 1998. Cerebral CT
dependence and methadone maintenance treatment. PLoS One 9 (4), findings in male opioid-dependent patients: stereological, planimetric
1e7 e94589. and linear measurements. Psychiatr. Res. Neuroimaging 83, 139e147.
Pirastu, M., Fais, R., Messina, M., Bini, V., Spiga, S., Falconieri, D., Shield, K.D., Jones, W., Rehm, J., Fischer, B., 2013. Use and nonmedical
Diana, M., 2006. Impaired decision- making in opiate-dependent use of prescription opioid analgesics in the general population of
subjects: effect of pharmacological therapies. Drug Alcohol Depend. Canada and correlations with dispensing levels in 2009. Pain Res.
83, 163e168. Manag. 18, 69e74.
Pitkala, K.H., Strandberg, T.E., Tilvis, R.S., 2002. Management of Shmygalev, S., Damm, M., Weckbecker, K., Berghaus, G., Petzke, F.,
nonmalignant pain in home- dwelling older people: a population- Sabatowski, R., 2011. The impact of long-term maintenance treatment
based survey. J. Am. Geriatr. Soc. 50, 1861e1865. with buprenorphine on complex psychomotor and cognitive function.
Prosser, J., Cohen, L.J., Steinfeld, M., Eisenberg, D., London, E.D., Drug Alcohol Depend. 117 (2e3), 190e197.
Galynker, I.I., 2006. Neuropsychological functioning in opiate Simon, N.G., Mattick, R.P., 2002. The impact of regular ecstasy use on
dependent subjects receiving and following methadone maintenance memory function. Addiction 97, 1523e1529.
treatment. Drug Alcohol Depend. 84, 240e247. Sjogren, P., Thomsen, A.B., Olsen, M., 2000a. Impaired neuropsycho-
Robbins, T.W., James, M., Owen, A.M., Sahakian, B.J., McInnes, L., logical performance in chronic non-malignant pain patients receiving
Rabbitt, P., 1994. Cambridge Neuropsychological Test Automated long-term oral opioid therapy. Journal of Pain and Symptom Man-
Battery (CANTAB): a factor analytic study of a large sample of agement 19 (2), 100e108.
normal elderly volunteers. Dementia 5 (5), 266-281. Sjogren, P., Olsen, A.K., Thomsen, A.B., Dalberg, J.A., 2000b. Neuro-
Rogers, R.D., Everitt, B.J., Baldacchino, A., Blackshaw, A.J., psychological performance in cancer patients: the role of oral opioids,
Swainson, R., Wynne, K., Baker, N.B., Hunter, J., Carthy, T., pain and performance status. Pain 86, 237e245.
Booker, E., London, M., Deakin, J.F.W., Sahakian, B.J., Sjogren, P., Christup, L.L., Peterson, M.A., Hojsted, J., 2005. Neuropsy-
Robbins, T.W., 1999. Dissociable deficits in the decision-making chological assessment of chronic non-malignant pain patients treated
cognition of chronic amphetamine abusers, opiate abusers, patients in a multidisciplinary pain centre. European Journal of Pain 9,
with focal damage to prefrontal cortex, and tryptophan-depleted 453e462.
normal volunteers: evidence for monoaminergic mechanisms. Neu- Solowij, N., Hall, W., Lee, N., 1992. Recreational MDMA use in Sydney:
ropsychopharmacology 20 (4), 322e339. a profile of “ecstasy” users and their experiences with the drug. Br. J.
Roselli, M., Ardila, A., 1996. Cognitive effects of cocaine and polydrug Addict. 87, 1161e1172.
abuse. J. Clin. Exp. Neuropsychol. 18, 122e135. Solowij, N., 1995. Do cognitive impairments recover following cessation
Rothenberg, S., Schottenfeld, S., Mayer, R.E., Krauss, B., Gross, K., 1977. of cannabis use? Life Sci. 56, 2119e2126.
Performance differences between addicts and non-addicts. Psycho- Soyka, M., Lieb, M., Kagerer, S., Zingg, C., Koller, G., Lehnert, P.,
pharmacology 52, 299e306. Limmer, P., Kuefner, H., Henning-Fast, K., 2008. Cognitive func-
Rotherham-Fuller, E., Shoptaw, S., Berman, S.M., London, E.D., 2004. tioning during methadone and buprenorphine treatment. J. Clin.
Impaired performance in a test of decision-making by opiate- Psychopharmacol. 28 (6), 699e703.
dependent tobacco smokers. Drug Alcohol Depend. 73, 79e86. Specka, M., Finkbeiner, T., Lodemann, E., Leifert, K., Kluwig, J.,
Rounsaville, J.B., Jones, C., Novelly, R.A., Kleber, A., 1982. Neuropsy- Gastpar, M., 2000. Cognitive-motor performance of methadone
chological functioning in opiate addicts. J. Nerv. Ment. Dis. 170 (4), maintained patients. Eur. Addict. Res. 6, 8e19.
209e216. Sterne, J.A., Smith, G.D., 2001. Sifting through the evidence- what’s
Sahakian, B.J., Morris, R.G., Evenden, J.L., Heald, A., Levy, R., wrong with significance tests? Br. Med. J. 322, 226e231.
Philpot, M., Robbins, T.W., 1988. A comparative study of visuo- Stevens, A., Peschk, I., Schwarz, J., 2007. Implicit learning, executive
spatial memory and learning in Alzheimer-type dementia and Par- function and hedonic activity in chronic polydrugabusers,
kinson’s disease. Brain 111, 695e718. currently abstinent polydrug abusers and controls. Addiction 102,
SAMH, 2013. Results from the 2012 national survey on drug use and 937e946.
health: detailed tables. Retrieved from: http://www.samhsa.gov/data/ Tassain, N.V., Fletcher, A.D., Brasseur, L., Degieux, P., Chauvin, M.,
NSDUH/2012SummNatFindDetTables/DetTabs/NSDUH- Bouhassira, D., 2003. Long term effects of oral sustained release
DetTabsTOC2012.htm. morphine on neuropsychological performance in patients with chronic
Schindler, S.-D., Ortner, R., Peternell, A., Eder, H., Opgenoorth, E., non-cancer pain. Pain 104, 389e400.
Fischer, G., 2004. Maintenance therapy with synthetic opioids and Thomasius, R., Petersen, K., Buchert, R., Andresen, B., Zapletalova, P.,
driving aptitude. Eur. Addict. Res. 10, 80e87. Wartberg, L., Nebeling, B., Schmoldt, A., 2003. Mood,cognition and
Selby, P.J., Azrin, R.L., Ireland, S.J., Quiroga, M., Malow, R.M., 1995. serotonin transporter availability in current and former ecstasy
Differential recovery of neuropsychological functioning in alcohol, (MDMA) users. Psychopharmacology 167, 85e96.
cocaine, and polysubstance abusers. Arch. Clin. Neuropsychol. 10, 390. Todd, J., Green, G., Harrison, M., Ikuesan, B.A., Self, C., Baldacchino, A.,
Selby, M.J., Azrin, R.L., 1998. Neuropsychological functioning in drug Sherwood, S., 2004. Defining dual diagnosis of mental illness and
abusers. Drug Alcohol. Depend. 50, 39e45. substance misuse: some methodological issues. J. Psychiatr. Ment.
Shei, A., Hirst, M., Kirson, N.Y., Enloe, C.J., Birnbaum, H.G., Health Nurs. 11 (1), 48e54.
Dunlop, W.C.N., 2015. Estimating the health care burden of pre- Tolomeo, S., Gray, S., Matthews, K., Steele, D., Baldacchino, A., 2016.
scription opioid abuse in five European countries. Clin. Outcomes Multifaceted impairments in impulsivity and brain structural abnor-
Res. 7, 477e488. malities in opioid dependence and abstinence. Psychol. Med. 46 (13),
Shewan, D., Dalgarno, P., 2005. Evidence for controlled heroin use? Low 2841e2853.
levels of negative health and social outcomes among non-treatment Tolomeo, S., Matthews, K., Steele, D.J., Baldacchino, A., 2018.
heroin users in Glasgow (Scotland). Br. J. Health Psychol. 10 (1), Compulsivity and opioid dependence. Prog. Neuropharmacol. Biol.
33e48. Psychiatry 81, 333e339.
Vainio, A., Ollila, J., Matikainen, E., Rosenberg, P., Kalso, E., 1995. Verdejo Garcia, A.J., Bechera, A., Recknor, E., Pérez-García, M., 2007d.
Driving ability in cancer patients receiving long-term morphine Negative emotion-driven impulsivity predicts substance dependence
analgesia. Lancet 346, 667e670. problems. Drug Alcohol. Depend. 91 (2-3), 213e219.
Verdejo-Garcıa, A., López-Torrecillas, F., Gimenez, C.O., Pérez- Wang, G.Y., Wouldes, T.A., Kydd, R., Jensen, M., Russell, B., 2014.
García, M., 2004. Clinical implications and methodological chal- Neuropsychological performance of methadone-maintained opiate
lenges in the study of the neuropsychological correlates of cannabis, users. J. Psychopharmacol. 28 (8), 789e799.
stimulant, and opioid abuse. Neuropsychol. Rev. 14 (1), 1e41. Westfall, P.H., Johnson, W.O., Utts, J.M., 1997. A Bayesian perspective
Verdejo Garcia, A.J., Toribio, I., Orozco, C., Puente, K.L., Pérez- on the Bonferroni adjustment. Biometrika 84, 419e427.
García, M., 2005a. Neuropsychological functioning in methadone Wittchen, H.-U., 1996. Critical issues in the evaluation of comorbidity of
maintenance patients versus abstinent heroin abusers. Drug Alcohol psychiatric disorders. Br. J. Psychiatry 168 (Suppl. 30), 9e16.
Depend. 78, 283e288. Yates, S.T., 2009. An Evaluation of the Cognitive Functioning of In-
Verdejo Garcıa, A.J., López Torrecillas, F., Aguilar de Arcos, F., Pérez- dividuals on Methadone Maintenance Treatment And its Relation to
García, M., 2005b. Effects of executive impairments on maladaptive Treatment Adherence. A thesis submitted in partial fulfilment of the
explanatory styles in substance abusers: clinical implications. Arch. PhD. University of Waikato, New Zealand.
Clin. Neuropsychol. 20, 67e80. Yin, L.-S., Li, Z.-A., Pang, L.-J., Zhu, C.-Y., Wang, S.-M., Zhang, L.-X.,
Verdejo-García, A.J., Perales, J.C., Pérez-García, M., 2007a. Cognitive Tang, W.-C., Dai, J., 2012. The effects of methadone maintenance
impulsivity in cocaine and heroin polysubstance abusers. Addict. treatment on decision-making biases in male heroin dependent pa-
Behav. 32, 950e966. tients. Chin. J. Behav. Med. Brain Sci. 20 (4), 20e25.
Verdejo-García, A.J., Pérez-García, M., 2007b. Profile of executive deficits Zacny, J.P., 1995. A review of the effects of opioids on psychomotor and
in cocaine and heroin polysubstance users: common and differential cognitive functioning in humans. Exp. Clin. Psychopharmacol 3 (4),
effects on separate executive components. Psychopharmacology 432e466.
(Berl.) 190, 517e530. Zakzanis, K.K., 2001. Statistics to tell the truth, the whole truth, and
Verdejo-Garcia, A.J., Pérez-García, M., 2007c. Ecological assessment of nothing but the truth: formulae, illustrative numerical examples, and
executive functions in substance dependent individuals. Drug Alcohol heuristic interpretation of effect size analyses for neuropsychological
Depend. 90, 48e55. researchers. Arch. Clin. Neuropsychol. 16, 653e667.
Chapter 14
Predictors of problem gambling and

other addictive behaviors: from context
to genes
Anna E. Goudriaan1, 2, 3
1
Amsterdam UMC, Department of Psychiatry, University of Amsterdam, the Netherlands; 2Amsterdam Institute for Addiction Research; 3Arkin
Mental Health; Department of Quality of Care and Research and Jellinek, Amsterdam, The Netherlands
Introduction Twin Registry (Eisen et al., 2001) and from smaller genetic
studies that focus on the relation between problem
In the last 20 years, the extensive research on predictors of gambling and certain genetic polymorphisms
substance use disorders has inspired gambling research and (e.g., Comings et al., 1996). Of course, besides individual
studies in other addictive behaviors into the investigation of factors, psychosocial factors such as socioeconomic status,
predictors of these behavioral problems. The largest liter- popularity of activities such as gaming and gambling, in-
ature is present regarding gambling disorder, as it was come, and the distance to the closest gambling hall or ca-
recognized and acknowledged as a disorder starting in the sino can also influence the risk of developing problematic
1980s. As studies on problem gambling and its predictors gambling. In this chapter, an overview is given of these
have been of interest since the 70s of the 20th century, with different individual and social factors for gambling and
pathological gambling being recognized as a disorder by other behavioral addictive disorders such as gaming dis-
the World Health Organization and included in the ninth order. As gambling has a lower prevalence than common
version of the International Classification of Diseases (ICD) substance use disorders, such as alcohol use disorder,
in 1977, followed by the DSM-III in 1980, there is an detecting relations is sometimes limited in power for these
abundance of studies relating to predictors of disordered studies. Because gambling was frequently an additional
gambling. However, studies on other (potential) behavioral interest in a larger study on mental health predictors, and
addictions, such as problematic gaming (only included as because definitions for gambling disorder changed over
“gaming disorder” in the ICD-11 since 2018), problematic time, the relations that have been studied are diverse,
Internet use, including activities such as online gambling, ranging from engagement in gambling or a low level of
gaming, sex, and shopping, are scarce. To start with problems with gambling to a DSM-based classification of
gambling, gambling activity or short screening measures on pathological or disordered gambling. As there is evidence
problem gambling were sometimes included in large-scale that gambling disorder is not a dichotomous phenomenon,
birth cohort studies investigating psychosocial factors but can be seen as a dimensional problem behavior,
relating to mental health. This enabled the study of how the e.g., from findings from genetic studies discussed below,
development of problems relating to gambling was influ- this chapter covers the range of problem behaviors from
enced by these psychosocial factors. One of these large low-level problems to studies on gambling disorder. As
birth cohort studies is the well-known Dunedin study from only gaming disorder was recognized as the second
New Zealand, lead by researchers Caspi and Moffit. behavioral addictive disorder in 2018 by the World Health
Another large cohort study is present from the United Organization, for other “addictive behaviors,” current
States, the Collaborative Perinatal Project, from Boston and research relies majorly on dimensional self-report measures
other East coast cities and areas in the United States and not on studies in populations in (addiction) treatment.
(Broman, 1984). Studies on the genetic risk for problem In the sections below, research on individual factors, ge-
gambling derive from twin studies, such as the Vietnam Era netic, and social environmental influences on behavioral

addictive disorders is discussed. A summary of effects of Based on a large longitudinal birth cohort from New
these factors on behavioral addictions is presented in Zealand (the Dunedin cohort), Slutske and colleagues
Fig. 14.1. reported on the prediction of “disordered gambling” at
either age 21 or 32, based on temperamental behavior when
the participants from this study were only 3-year-old tod-
Individual risk factors for problem dlers (Slutske et al., 2012). Children were categorized into
gambling one of the five temperament groups based on an observa-
Personality tional 90-minute assessment at age 3 and could be cate-
gorized as behavioral emotionally (1) undercontrolled,
In the addictions literature, the relation between external- (2) inhibited, (3) confident, (4) reserved, and (5) well-
izing disorders and personality traits such as impulsivity adjusted. Only the undercontrolled temperament style
and initiation of substance use and risk for developing group was associated with later development of “disordered
substance use disorders has been well-established gambling” as adults. In this study, “disordered gambling”
(see Chapter 7 in this book). Impulsivity can be defined was defined as meeting at least one out of several of the 10
as not only the tendency to act on impulses without suffi- DSM-IV symptoms according to a disordered gambling
cient thinking but also includes tendencies like a preference screen (National Opinion Research Center DSM-IV Screen
for immediate rewards instead of delayed rewards. It is for Gambling problems; NODS) and one out of seven of
recognized that impulsivity is not a unitary construct but the Sydney Laval Universities Gambling Screen at the age
consists of and is influenced by several cognitive, of 32 or meeting at least one out of eight South Oaks
emotional, and neural processes (Broos et al., 2012; Gambling Screen (SOGS) items at age 21 in combination
Evenden, 1999). Externalizing psychopathologies such as with at least having bet $50 or more in during a single
attention deficit/hyperactivity disorder (AD/HD), behavior month in the past year. Even after controlling for sex, IQ,
dysregulation, and antisocial traits are risk factors for both and socioeconomic status, the undercontrolled children at
the (early) initiation of substance use and for the develop- age 3 had an odds ratio of 2.35 for developing disordered
ment of substance use disorders (e.g., Chang et al., 2012; gambling as an adult.
Holtmann et al., 2011; Kuperman et al., 2001). Because Around the same time, a study from the Collaborative
problem gambling has a lower prevalence compared with Perinatal Project cohort study from the United States was
substance use disorders like alcohol or cannabis use dis- published (Shenassa et al., 2012), in which childhood
orders, specific relations between early childhood behavior behavior and its links to problem gambling in adulthood were
and personality traits are more difficult to investigate. studied. In this study, 958 children were followed, and
Despite this, a few studies indicate that a similar relation impulsivity and other behavioral traits were assessed by a
exists between early childhood behavior, which can be psychologist at age 7, with follow-up data on gambling-
characterized as dysregulated, impulsive/disinhibited, or related problems as measured with the SOGS at a mean
externalizing, and later development of (problematic) age of 39. Impulsive behavior was associated with a signif-
gambling. icant odds ratio of 3.09 to develop gambling-related problems
Genetics/Neurobiology
Individual Executive
Factors functions
Cognitive Gambling/Gaming
Impulsivity
misperceptions /Behavioural
/Perceived control Addictions
Self-esteem Social
integration
Social – Environmental factors
FIGURE 14.1 Individual, social, and biological influences on behavioral addictions. Individual factors such as impulsivity and executive functions
influence the development and course of behavioral addictions, having its basis in genetic and neural processes. Social factors seem to influence gaming
and other behavioral addictions more than gambling disorder, including social integration, parental monitoring, and self-esteem. All three types of factors
can increase or decrease the development and course of behavioral addictions and can also influence each other, e.g., through the effect of impulsivity on
social interactions and thus on social integration and self-esteem.
Predictors of problem gambling and other addictive behaviors: from context to genes Chapter | 14 201
later in life, whereas shy-depressed behavior at age 7 did not In summary, for problem gambling, impulsivity has
predict the later development of gambling problems. Inter- been established as a strong predictor, whereas for Internet
estingly, this study thus implies a specific effect of impul- and gaming disorders, higher scores on related constructs
sivity for the risk of problem gambling and not so much an such as hyperactivity/inattention seem to be predictive. In
overall effect of unadjusted childhood temperamental addition, in gaming and Internet use disorders, social fac-
behavior on problem gambling. In a smaller longitudinal tors such as lower social competence and individual factors
cohort from the Johns Hopkins University (Second- such as low self-esteem seem to play a more prominent role
Generation Intervention Trial) in 678 first-grade students, compared with the factors associated with vulnerability for
teacher rated impulsivity in early adolescence (age 11e15) gambling disorder. In all disorders, there is far more evi-
predicted problem gambling by three times compared with dence for the role of impulsivity compared with other in-
social gambling and doubled the odds of at-risk gambling dividual factors such as depression or anxiety.
compared with problem gambling in males (Liu et al., 2013).
Regarding other behavioral addictive disorders, the first (Neuro)cognitive factors
longitudinal studies regarding Internet gaming disorder are
emerging. In a cross-lagged panel design study examining There are not a lot of studies exploring the relationships
adolescents and one of their parents from Germany, pre- between neurocognitive aspects of impulsivitydmeasuring
dictors of Internet gaming problems were assessed (Wart- impulsive behavior based on neurocognitive tasks, in
berg et al., 2018). In this study, questionnaire-based contrast to personality approaches where impulsive ten-
instruments were used. Male gender, hyperactivity/inat- dencies are measured using questionnairesdand the
tention symptoms (rated by the parent at baseline), and development of problem gambling at a later age. However,
lower self-esteem were predictors for Internet gaming the behavioral measures of impulsive behaviors of some of
problems, but these effects were smaller compared with the the longitudinal studies above can be seen as having a close
effect of having Internet gaming disorder at baseline. link to the behavioral neurocognitive measures which are
Parental depression or anxiety and other indicators of employed usually in adolescents and adults. One early
mental health in the adolescents (antisocial behavior, anger study in 154 low Socioeconomic status (SES) boys inves-
control problems, and emotional distress) were not pre- tigated the predictive value of impulsivity, including a
dictive of future gaming disorder. neurocognitive measure of card sorting perseveration for
The findings of lower self-esteem as a predictor of previously rewarded contingencies (controlling for
problematic Internet gaming are consistent with findings aggressiveness and anxiety) on problem gambling. In this
from an earlier study in 851 adolescents from the study, problem gambling at age 17 was predicted (18-fold
Netherlands, which reported that lower self-esteem, lone- increase) by a self-report measure on impulsivity and this
liness, and lower social competence predicted problematic card sorting task (Vitaro et al., 1999). Several other studies
gaming 6 months later. Measures of loneliness and lower on risk factors for problem gambling were published from
social competence had the strongest relation (remaining this and a larger cohort, but one of the most recent studies
significant after bootstrapping) to future Internet gaming including also a representative sample of 1001 kindergarten
disorder. In this study, life satisfaction was not predictive of boys, investigated the importance of several risk factors
future problematic gaming (Lemmens et al., 2011). In a ranging from behavioral disinhibition to deviant peers and
study from Singapore, in over 2500 primary and secondary low parental monitoring. When investigating the predictive
school children and adolescents, self-report measures on value at age 16 for problem gambling at age 23, behavioral
impulsivity and lower social competence were predictive of disinhibition was related to the stability of problem
pathological gaming 2 years later, and pathological gaming gambling (high stability for gambling problems in the high-
was associated with negative consequences on depression, disinhibition group and low stability in the low-
anxiety, and social phobia scores and resulted in lower disinhibition group) and to the stability of other problem
school grades (Gentile et al., 2011). behaviors (Wanner et al., 2009).
In another very recent study (Peeters et al., 2018), Gambling cognitions, such as distorted cognitions
young adolescents aged 14 were followed over 1 year, and relating to chance, erroneous beliefs regarding skills versus
attention problems, social vulnerability, and life satisfaction chance, have been related to problem gambling in cross-
were investigated as predictors of an increase in problem- sectional studies (Michalczuk et al., 2011). A recent
atic Internet gaming. Both attention problems and social study indicates that these cognitive distortions can also
vulnerability were predictive of Internet gaming disorder affect problem gambling longitudinally. In a young adult
symptoms, and specifically there was a stronger effect in sample of over 578 Australian adults, a bidirectional effect
those adolescents with attention problems who were more was found: faulty gambling cognitions led to problematic
socially vulnerable and less satisfied with life. gambling behavior 2e3 years later (and vice versa),
when these erroneous cognitions were taken as a total to gambling problems longitudinally, and for problematic
score. Specific beliefs about chance could, however, not be gaming, gaming-specific factors such as gaming perfec-
related to the later development of gambling problems after tionism and cognitive salience are related to development
adjusting for baseline group membership (no gambling/low of problematic gaming. Thus, behavioral impulsivity can be
risk vs. moderate to severe), restricting the potential for viewed as a transdiagnostic factor related to several
addressing these cognitive misperceptions in preventive behavioral addictions, whereas other disorder-specific fac-
interventions (Nicholson et al., 2016). tors (cognitive distortions, gaming perfectionism, and
On a related construct, cognitions regarding gaming salience) influence individual behavioral addictions.
have been investigated as a predictor for the development
of Internet gaming disorder in an Australian study among Genetic risk
adults with a mean age of 26 years (Forrest et al., 2017).
Higher perfectionism regarding gaming, higher cognitive Regarding genetic studies, twin studies enable the identi-
salience, and regret were related to development of prob- fication of the level of risk that can be explained by genetic,
lematic gaming 1 year after baseline. In another study from shared environmental, and unique environmental factors.
the Netherlands (Haagsma et al., 2013), in about 300 ad- For problematic gambling, the largest twin study results
olescents and young adults, positive attitudes toward available derive from the USA-based Vietnam Era Twin
gaming and the intention to play too much were associated Registry database, which includes over 3000 twin pairs.
with higher levels of problem gaming after 6 months, The first genetic publication on problematic gambling from
whereas perceived behavioral control as measured with the this database (Eisen et al., 1998) suggested that genetic
Revised Theory of Planned Behavior Questionnaire was factors explained increased variance in symptoms of path-
associated with a lower level of problematic gaming. Thus, ological gambling, with 48% of the variance explained if
cognitions regarding gaming may be a relevant factor for one symptom is present to 54% when two symptoms are
preventive interventions or in interventions for disordered present, 56% if three or more symptoms are present, and
gamers, as changing these cognitions may influence the 62% for four or more symptoms. These numbers indicate
development or course of Internet gaming disorder. that a dimensional approach to problem gambling is
Regarding the extent to which neurocognitive factors needed, as the genetic load increases for more severe forms
are associated with problem gambling, a more consistent of gambling-related problems, indicated by the number of
literature exists, which is discussed in Chapter 15. To diagnostic criteria (DSM-III criteria for pathological
summarize, with regard to the constructs that we also gambling). Subsequent papers using the same twin registry
discuss in this chapter, high levels of behavioral impulsivity indicate that although there is a shared genetic vulnerability
(as measured by disinhibition tasks, delay discounting between problematic gambling and antisocial personality
tasks, and decision-making tasks) have been associated disorder and alcohol use disorder, this shared genetic
with problem and pathological gambling (Goudriaan et al., vulnerability is only 16% and 12%, respectively (Slutske
2014), with more consistent evidence for disinhibition in et al., 2000; Slutske et al., 2001).
reward-related tasks (choice impulsivity and decision- A more recent twin study (King et al., 2017) in ado-
making). Besides impulsivity, compulsivity (a lack of lescents and young adults indicates that the genetic influ-
cognitive flexibility, attentional set switching, and atten- ence on gambling behavior and problem gambling
tional bias as, for example, in Stroop-like interference increases from age 18 to age 25 (from 21% to 57%,
tasks) is affected in pathological gambling as discussed in a respectively), whereas the influence of nonshared envi-
recent metaanalysis (van Timmeren et al., 2018). In these ronment remains equally important and the influence of
studies, the higher impulsivity and compulsivity could be shared environmental factors decreases over time, specif-
explained by a predating higher level of these factors, ically for males (from 0.29 to 0.09). A recent metaanalysis
rendering persons vulnerable to the development of by Xuan and colleagues corroborates these findings. In this
gambling problems, or it could be the consequence of the metaanalysis, heritability of both gambling behavior and
disordered gambling resulting in development of higher problematic gambling was investigated, and 18 studies
impulsivity and/or compulsivity. As studies provide evi- were included in the metaanalyses (Xuan et al., 2017). Here
dence for both, this “chicken or egg” problem is likely also, adult gambling was influenced by heritable factors to a
more a question of and/and: impulsivity and executive larger degree than in adolescents (53% vs. 42%, respec-
functions more broadly forming both a risk factor and a tively). Genetic factors explained a larger part of the vari-
consequence of disordered gambling. ability in problematic gambling (53%) compared with
In conclusion, the role of neurocognitive factors relating behavioral indicators of gambling (41%), which is in line
to behavioral impulsivity/disinhibition in problem with findings in substance use disorders, where higher
gambling seems to be firmly established, whereas, addi- heritability is found for tobacco dependence, compared
tionally, gambling-specific cognitive distortions are related with tobacco initiation for instance (Vink et al., 2005).
Interestingly, findings from this metaanalysis indicate that environmental effects compared with males. These last
in women, there is a sizable shared environmental effect findings have implications for preventive studies in female
(14%), whereas this effect is not present for males. Xuan populations, where the social environment could be
and colleagues conclude that an AE model (A ¼ additive investigated as a target to change vulnerability for behav-
genetic effects; E ¼ nonshared environmental effects) best ioral addictions.
fits the data for men, whereas for women, an ACE model
best fits the data (C ¼ shared environmental effects). Thus,
while in adolescents and women, the environment and Social and individual predictors of
peers may have a larger influence, in men and in older age problem gambling: from family to
groups (adults vs. adolescents), the influence of genetics is friends and from alcohol to academic
larger. This may have important implications for prevention
achievement
specifically for women because the influence of the social
environment is more important for targeting preventive Several large longitudinal studies have investigated the
interventions for women and for adolescents in general, impact of the combination of social and psychological risk
whereas at a later age, the genetic factors are a more factors. From a large longitudinal sample from the Inter-
difficult target and less amenable for interventions. national Youth Development Study (Australia and United
For the study of the more diverse “compulsive Internet States) including data on gambling and problem gambling,
use,” a genetic study from the Netherlands (Dutch Twin data were analyzed for prospective analyses, when cohort
Register) focused on scores on the compulsive Internet use members were on average 15 years old, and when they
scale (CIUS) and its heritability in girls and boys (Vink were on average 21 years old (Scholes-Balog et al., 2014).
et al., 2016). The CIUS focuses on diverse Internet activ- Although several individual factors predicted problem
ities such as gaming, as well as social media use and gambling, and these factors ranged from individual factors
chatting. In this study, similar CIUS scores were measured to family, community, and peer influences (e.g., family
in boys and girls, but as boys engaged in gaming more history of antisocial behavior, rebelliousness, academic
often, girls spent more time on social network sites and failure, interaction with antisocial peers, antisocial
chatting. Half of the individual differences in CIUS scores behavior, current alcohol, and drug use), when these single
could be explained by genetic factors, whereas the predictors were put in a multivariate model, only gender
remainder of the scores could be explained by nonshared (being female as a protective factor) and an interaction of
environmental factors. Another large twin study from the the factor “family rewards for prosocial involvement”
United Kingdom showed that there is a substantial genetic (involving a contingency system within the family for
influence on time spent online, across activities such as prosocial involvement) with alcohol use predicted problem
educational sites, entertainment, and gaming (34%e39%) gambling later on. That is, for those with low family re-
(Ayorech et al., 2017). wards for prosocial involvement and high alcohol use, there
In a study from the Brisbane Longitudinal Twin study, was a positive association with problem gambling, whereas
about 2000 twins were studied regarding Internet use pat- if family rewards were high for prosocial involvement, the
terns such as frequency and Internet use after 11 p.m. (Long level of alcohol use did not influence the future probability
et al., 2016). Forty one percent of the variance for family for problem gambling. Specifically, this study shows that
aggregation of Internet use frequency could be explained the predictors of problem gambling in a univariate model
by genetic factors, whereas additive genetic and shared (e.g., family history of antisocial behavior, rebelliousness,
environmental factors accounted for such factors as Internet academic failure, interaction with antisocial peers, antiso-
use after 11 p.m. and use of the Internet to contact peers or cial behavior, current alcohol, and drug use) are not specific
for social network sites. In this study, the associations with predictors of gambling, but of other problem behaviors as
psychopathology were small (social phobia) and variation well, such as substance use, and that the relation to
in Internet use was mostly unrelated to psychopathology. gambling disappears because there is a more proximal
In conclusion, there is a substantial body of evidence relation to another risk or problem behavior, such as
regarding genetic studies in gambling disorder, which im- alcohol or drug use.
plies similarities in genetic risk factors for gambling dis- In another study from this International Youth Devel-
order and substance use disorders. For problem gambling opment Study (Scholes-Balog et al., 2016), focusing on
as well as problematic gaming and Internet involvement, resistance, persistence, or desistence for PG over time (ages
substantial genetic influence is present, with higher genetic 21 at baseline to age 23 at follow-up), a protective factor
load for more severe gambling problems. For problem (resistance) was individual civic activism, whereas risk
gaming and other behavioral addictions, more genetic factors for persisting PG over time were frequent alcohol
research is needed, although the first studies show that in use and having antisocial peers. New incidence of PG was
females, a larger effect is present for (shared) associated with internalizing symptoms at the time of PG
occurrence. In another publication from this cohort problem gambling through their association with other risk
(Scholes-Balog et al., 2014), at the same age, the coexis- behaviors, such as higher substance use. Nonetheless,
tence of internalizing symptoms and problem gambling was antisocial behaviors/conduct problems, antisocial peers,
reported, but longitudinal protective factors for internal- and more frequent alcohol use have been associated with
izing disorders like a stable neighborhood, social cohesion higher problem gambling and problematic gaming. Social
and trust, family concord, and attachment to peers and factors such as higher parental monitoring and better social
interaction with prosocial peers were not related to problem integration can be protective for behavioral addictions,
gambling as protective factors. although larger longitudinal studies are needed. The role of
In a study focusing on the association of parental these predictive factors also seems to be higher in adoles-
monitoring throughout adolescence and the occurrence of cent samples compared with older adult samples, indicating
problem gambling in young adulthood (ages 16e22 years) the need for longitudinal research in more diverse age
from the Johns Hopkins University Second-Generation groups.
Intervention Trial (678 first-grade students), low and
declining parental monitoring from age 11e14 increased
the odds for problem gambling between age 16 and 22. In
Summary and discussion
contrast, stable high parental monitoring between ages 11 In summarizing the results of this chapter on factors that
and 14 did not predict problem gambling (Lee et al., 2014). predate behavioral addictive disorders, a distinction has to
Their analyses were corrected for intervention, parental be made regarding the number of studies available; most
monitoring at age 6, aggression at age 6, and deviant peer studies pertaining to risk factors are focused specifically on
affiliation at age 16. From this same study, impulsivity in problem gambling, and less studies are available for other
early adolescence (age 11e15) in interaction with depres- behavioral disorders such as problematic gaming or Internet
sive symptoms predicted problem gambling (for those with use because of the recent development of interest in these
high impulsivity, higher depressive scores were protective potentially addictive behaviors. Thus, in general, for
for developing gambling problems) (Lee et al., 2011). gaming disorder and other addictive behaviors, more lon-
Regarding longitudinal studies that focused on risk gitudinal research is needed.
factors and consequences of Internet gaming disorder, a For problem gambling, it is clear from large-scale (birth
recent review described the results of 13 longitudinal cohort) studies that higher impulsivity during childhood is a
studies in Internet gaming disorder (Mihara and Higuchi, risk factor for the development of problem gambling both
2017). Some of these studies were described above under in adolescence and in adulthood. Studies that point in this
2.1 (personality)de.g., Lemmens et al. (2011): loneliness direction include teacher- and parent-rated measures of
and self-esteem. In a study from Germany in children of 10 impulsivity in very young children and behavioral mea-
years, both risk and protective factors could be identified sures of impulsivity, whereas in somewhat older age
relating to school and family, whereas being from a single groups, self-report measures of impulsivity point in the
parent family was a risk factor, a higher social integration same direction (Lee et al., 2011; Liu et al., 2013; Shenassa
in the classroom and school-related well-being were pro- et al., 2012; Slutske et al., 2012; Vitaro et al., 1999;
tective factors for problematic gaming over time (Rehbein Wanner et al., 2009). In some of these studies, multiple
and Baier, 2013). In a study from Norway, adolescents vulnerability factors were studied, and in two studies, a
aged 13e17 (about 2000 of a total sample of above 8000; dissociation was found for the effect of impulsivity and
the study had a high attrition rate) were followed up at 2 depressive/internalizing symptoms: a lack of evidence was
years from baseline, and besides amount of gaming at present for depressive/shy behavior in a birth cohort study
baseline, conduct problems were a risk factor for devel- (Shenassa et al., 2012), and in a study in adolescents and
oping problematic gaming, whereas higher academic young adults, depressive scores even were a protective
achievement and surprisingly also higher episodic drinking factor in those with high impulsivity scores (Lee et al.,
were protective factors for gaming-related problems at 2011). Although the number of studies focusing on gender
follow-up, and depression was unrelated as a risk factor differences is small, it seems that impulsivity has a larger
(Brunborg et al., 2014). In an older age group of gamers effect in males/boys compared with females/girls; however,
(mean age 40; about 900 participants) in a German study this could also be related to the fact that problem gambling
with a follow-up of 2 years, no risk factors could be is less prevalent in females compared with males (Slutske
identified, and problematic gaming did not have negative et al., 2012) or to the fact that some studies only or pre-
consequences, e.g., on social support or similar factors dominantly include boys/males (Lee et al., 2011; Liu et al.,
(Scharkow et al., 2014). 2013; Vitaro et al., 1999; Wanner et al., 2009).
In short, for combined social and psychological risk Studies on problematic gaming or problematic Internet
factors for problem gambling, several risk factors are not use include partially distinct factors that are studied as
specifically related to problem gambling but are linked to predictors, such as loneliness, self-esteem, and social
competence. These factors are more easily measured in behavior compared to lower levels of problem gambling or
adolescents, and the fact that most problem gaming/Internet just gambling involvement and with a larger heritability in
use studies focus on adolescents is probably related to the adults compared with adolescents. Shared- and nonshared
inclusion of these factors in the gaming/Internet use liter- environmental factors seem to differ between men and
ature. Based on the personality and individual risk factors women, with shared environmental effects having an effect
studied, there currently is evidence for lower social func- in women, but not in men, based on metaanalyses of ge-
tioning and social problems being related to problem netic studies in gambling (Xuan et al., 2017). Compulsive
gaming (e.g., higher loneliness, lower social competence) Internet use scores can also be explained by genetic factors
as well as individual personality factors such as lower self- (half of the variance) and nonshared environmental factors
esteem and higher impulsivity (as measured by indicators (Vink et al., 2016), whereas for a measure which is more
such as hyperactivity/inattention rated by parents or self- loosely related to problem behavior, time spent online or
rated impulsivity or attention problems) related to the Internet use frequency in addition to a considerable genetic
development of gaming problems (Gentile et al., 2011; loading of 34%e41% is reported (Ayorech et al., 2017;
Lemmens et al., 2011; Peeters et al., 2018; Wartberg et al., Long et al., 2016). These studies implicate that although
2018). more variance can be explained when addictive behaviors
Compared to the longitudinal studies in gambling, are more problematic, subclinical aspects of potentially
which tend to span longer time periods, with a substantial addictive behaviors can also be explained by genetic fac-
number of studies spanning decades, the longitudinal tors. In future genetic studies, the shared genetic load of
studies on gaming focus on shorter time frames: most behavioral addictions with substance use or substance use
studies in problem gaming focus on adolescents or young disorders could give insight into whether shared genetics
adults, the question raises to what extent these risk factors underlie both behavioral and substance use disorders. The
are developmentally limited factors, with lower relevance specific finding of shared environmental effects for women
for problematic gaming later in life. The fact that in the suggests that in women the social environment is more
review of Mihara and Higuchi (2013) only 13 longitudinal important in the determination of problem gambling, and
studies were included indicates that more research is therefore preventive interventions for women could be
needed, as the number of factors investigated is limited. targeted at to this. Similarly, as genetic factors are less
Also, the time frame used in studies investigating Internet prominent and environmental factors are more important in
gaming disorder is rather limited, with short follow-ups explaining gambling behavior and gambling problems in
(e.g., 6 months or 1 year) used frequently. Longer time adolescents, preventive efforts may be more relevant for
frames could shed light on the question whether certain risk this group.
or protective factors could be targeted in prevention efforts, Social and educational factors that are related to prob-
as for instance evident from the longer time frames used in lem gambling are also related to other deviant behavior
gambling research. Obviously, this is a consequence of the such as substance use, and thus more general risk factors
recent development of Internet usedin older birth cohorts, for addictive disorders and substance use disorder can be
no questions on Internet use or gaming were included identified, such as antisocial behavior, interaction with
because popularity of Internet use only developed in the antisocial peers, current alcohol and drug use, low aca-
last two decades. demic achievement, and low or declining parental moni-
For gambling- and gaming-related studies, the effect of toring, and on the other hand, as a protective factor, civic
cognitive perceptions on gambling and gamingdfor activism (Lee et al., 2014; Scholes-Balog et al., 2014,
gambling more specifically the area related to cognitive 2016). For problematic gaming, higher social integration in
misperceptions; and for gaming cognitions such as the classroom, school-related well-being, and higher aca-
perceived behavioral control over gaming and perfec- demic achievement are protective factors, whereas sur-
tionism relating to gamingdhas been examined only in a prisingly also higher episodic drinking was a protective
few studies. The only two studies that were identified on factor (Brunborg et al., 2014; Rehbein and Baier, 2013).
this topic indicate a role for cognitive perceptions in the This evidence suggests that specifically for problematic
development of problem gambling and problem gaming gaming, social factors may play a larger role compared with
(Forrest et al., 2017; Nicholson et al., 2016), and thus this is individual risk factors. The fact that episodic drinking is a
a relevant area for future research, as cognitions can be protective factor may also relate to social functioning, as
amenable for change or could be used as a risk indicator for episodic alcohol use can be a sign of social adaptation to a
preventive interventions. subculture during adolescence in which episodic drinking is
Regarding the heritability of addictive disorders, the normative. The fact that the only study that did not find risk
evidence is clear that there is a substantial part of addictive factors for problem gaming in a group of adults aged about
behaviors that are due to genetic factors, with increasing 40, as well as did not report negative consequences of
load of genetics for more severe problem gambling gaming, raises the question as to whether problematic
gaming is more harmful in adolescents than in adults action: a cross-species translational study. PLoS One 7 (5), e36781.
(Scharkow et al., 2014). The low stability of problem https://doi.org/10.1371/journal.pone.0036781.
gaming over time in adults (mean age around 40 in the Brunborg, G.S., Mentzoni, R.A., Froyland, L.R., 2014. Is video gaming, or
video game addiction, associated with depression, academic
study by Scharkow et al. and mean age around 46 in the
achievement, heavy episodic drinking, or conduct problems? J. Behav.
study by Konkoly et al.) (Konkoly Thege et al., 2015) in-
Addict. 3 (1), 27e32. https://doi.org/10.1556/JBA.3.2014.002.
dicates that more research is needed into whether stability Chang, Z., Lichtenstein, P., Larsson, H., 2012. The effects of childhood
and criteria endorsed differ for adolescents/young adults ADHD symptoms on early-onset substance use: a Swedish twin study.
and older middle-aged adults, as differences in character- J. Abnorm. Child Psychol. 40 (3), 425e435. https://doi.org/10.1007/
istics of problem gaming could indicate that differential s10802-011-9575-6.
preventive and treatment responses are needed for these age Comings, D.E., Rosenthal, R.J., Lesieur, H.R., Rugle, L.J., Muhleman, D.,
groups. Chiu, C., et al., 1996. A study of the dopamine D2 receptor gene in
pathological gambling. Pharmacogenetics 6 (3), 223e234.
Eisen, S.A., Lin, N., Lyons, M.J., Scherrer, J.F., Griffith, K., True, W.R.,
Conclusion et al., 1998. Familial influences on gambling behavior: an analysis of
3359 twin pairs. Addiction 93 (9), 1375e1384.
From the current longitudinal research studies, it is evident
Eisen, S.A., Slutske, W.S., Lyons, M.J., Lassman, J., Xian, H.,
that both individual factors, in interaction with genetic
Toomey, R., et al., 2001. The genetics of pathological gambling.
factors, and social environmental factors influence the Semin. Clin. Neuropsychiatry 6 (3), 195e204.
development and persistence of behavioral addictive dis- Evenden, JL, 1999 Oct. Varieties of impulsivity. Psychopharmacology
orders (see Fig. 14.1). When examining factors predating Berl 146 (4), 348e361.
the development of addictive behavior, a substantive body Forrest, C.J., King, D.L., Delfabbro, P.H., 2017. Maladaptive cognitions
of literature on problematic gambling and gambling disor- predict changes in problematic gaming in highly-engaged adults: a 12-
der indicates that impulsivity is a predictive factor, as well month longitudinal study. Addict. Behav. 65, 125e130. https://
as other risk factors commonly associated with substance doi.org/10.1016/j.addbeh.2016.10.013.
use disorders such as involvement in alcohol and substance Gentile, D.A., Choo, H., Liau, A., Sim, T., Li, D., Fung, D., Khoo, A.,
use, antisocial traits, and/or deviant peers. In addition, there 2011. Pathological video game use among youths: a two-year longi-
tudinal study. Pediatrics 127 (2), e319ee329. https://doi.org/10.1542/
is substantial evidence for a genetic load for problem
peds.2010-1353.
gambling, which increases for higher severity levels of
Goudriaan, A.E., Yucel, M., van Holst, R.J., 2014. Getting a grip on
problem gambling. For gaming disorder or problematic problem gambling: what can neuroscience tell us? Front. Behav.
(Internet) gaming, the body of evidence is smaller, and Neurosci. 8, 141. https://doi.org/10.3389/fnbeh.2014.00141.
social factors such as social integration and parental Haagsma, M.C., King, D.L., Pieterse, M.E., Peters, O., 2013. Assessing
monitoring seem to play a larger role. Here, more research problematic video gaming using the theory of planned behavior: a
is needed into older age groups besides adolescents. For longitudinal study of Dutch young people. Int. J. Ment. Health Addict.
gaming and Internet involvement, a genetic load seems to 11 (2), 172e185. https://doi.org/10.1007/s11469-012-9407-0.
be present as well, ranging from frequency and time spent Holtmann, M., Buchmann, A.F., Esser, G., Schmidt, M.H.,
online to a genetic load for problematic Internet use scale Banaschewski, T., Laucht, M., 2011. The child behavior checklist-
scores. Clearly, more research is needed here into specific dysregulation profile predicts substance use, suicidality, and func-
tional impairment: a longitudinal analysis. J. Child Psychol. Psychi-
genetic and environmental influences, also given the fact
atry 52 (2), 139e147. https://doi.org/10.1111/j.1469-7610.
that some first studies indicate gender differences, with a
2010.02309.x.
larger shared environmental influence in female compared King, S.M., Keyes, M., Winters, K.C., McGue, M., Iacono, W.G., 2017.
with male samples. Genetic and environmental origins of gambling behaviors from ages
18 to 25: a longitudinal twin family study. Psychol. Addict. Behav. 31
(3), 367e374. https://doi.org/10.1037/adb0000266.
References
Konkoly Thege, B., Woodin, E.M., Hodgins, D.C., Williams, R.J., 2015.
Ayorech, Z., von Stumm, S., Haworth, C.M., Davis, O.S., Plomin, R., Natural course of behavioral addictions: a 5-year longitudinal study.
2017. Personalized media: a genetically informative investigation of BMC Psychiatry 15, 4. https://doi.org/10.1186/s12888-015-
individual differences in online media use. PLoS One 12 (1), 0383-3.
e0168895. https://doi.org/10.1371/journal.pone.0168895. Kuperman, S., Schlosser, S.S., Kramer, J.R., Bucholz, K., Hesselbrock, V.,
Broman, S.H., 1984. The collaborative perinatal project: an overview. In: Reich, T., Reich, W., 2001. Developmental sequence from disruptive
Mednick, S., Harway, M., Finello, K. (Eds.), Handbook of Longitu- behavior diagnosis to adolescent alcohol dependence. Am. J. Psy-
dinal Research. Praeger, New York, pp. 185e215. chiatry 158 (12), 2022e2026.
Broos, N., Schmaal, L., Wiskerke, J., Kostelijk, L., Lam, T., Stoop, N., Lee, G.P., Storr, C.L., Ialongo, N.S., Martins, S.S., 2011. Compounded
Weierink, L., Ham, J., de Geus, EJ., Schoffelmeer, AN., van den effect of early adolescence depressive symptoms and impulsivity on
Brink, W., Veltman, DJ., de Vries, TJ., Pattij, T., Goudriaan, AE., late adolescence gambling: a longitudinal study. J. Adolesc. Health 48
2012. The relationship between impulsive choice and impulsive (2), 164e169. https://doi.org/10.1016/j.jadohealth.2010.06.002.
Lee, G.P., Stuart, E.A., Ialongo, N.S., Martins, S.S., 2014. Parental adjustment. Addict. Behav. 55, 38e45. https://doi.org/10.1016/
monitoring trajectories and gambling among a longitudinal cohort of j.addbeh.2015.12.016.
urban youth. Addiction 109 (6), 977e985. https://doi.org/10.1111/ Shenassa, E.D., Paradis, A.D., Dolan, S.L., Wilhelm, C.S., Buka, S.L.,
add.12399. 2012. Childhood impulsive behavior and problem gambling by adult-
Lemmens, J.S., Valkenburg, P.M., Peter, J., 2011. Psychosocial causes and hood: a 30-year prospective community-based study. Addiction 107
consequences of pathological gaming. Comput. Hum. Behav. 27, (1), 160e168. https://doi.org/10.1111/j.1360-0443.2011.03571.x.
144e152. Slutske, W.S., Eisen, S., True, W.R., Lyons, M.J., Goldberg, J.,
Liu, W., Lee, G.P., Goldweber, A., Petras, H., Storr, C.L., Ialongo, N.S., Tsuang, M., 2000. Common genetic vulnerability for pathological
Martins, S.S., 2013. Impulsivity trajectories and gambling in adoles- gambling and alcohol dependence in men. Arch. Gen. Psychiatr. 57
cence among urban male youth. Addiction 108 (4), 780e788. https:// (7), 666e673.
doi.org/10.1111/add.12049. Slutske, W.S., Eisen, S., Xian, H., et al., 2001. A twin study of the as-
Long, E.C., Verhulst, B., Neale, M.C., Lind, P.A., Hickie, I.B., sociation between pathological gambling and antisocial personality
Martin, N.G., Gillespie, N.A., 2016. The genetic and environmental disorder. J. Abnorm. Psychol. 110, 297e308.
contributions to internet use and associations with psychopathology: a Slutske, W.S., Moffitt, T.E., Poulton, R., Caspi, A., 2012. Undercontrolled
twin study. Twin Res. Hum. Genet. 19 (1), 1e9. https://doi.org/ temperament at age 3 predicts disordered gambling at age 32: a lon-
10.1017/thg.2015.91. gitudinal study of a complete birth cohort. Psychol. Sci. 23 (5),
Michalczuk, R., Bowden-Jones, H., Verdejo-Garcia, A., Clark, L., 2011. 510e516. https://doi.org/10.1177/0956797611429708.
Impulsivity and cognitive distortions in pathological gamblers van Timmeren, T., Daams, J.G., van Holst, R.J., Goudriaan, A.E., 2018.
attending the UK National Problem Gambling Clinic: a preliminary Compulsivity-related neurocognitive performance deficits in gambling
report. Psychol. Med. 1e11. https://doi.org/10.1017/S003329 disorder: a systematic review and meta-analysis. Neurosci. Biobehav.
171100095X. Rev. 84, 204e217. https://doi.org/10.1016/j.neubiorev.2017.11.022.
Mihara, S., Higuchi, S., 2017. Cross-sectional and longitudinal epidemi- Vink, J.M., van Beijsterveldt, T.C., Huppertz, C., Bartels, M.,
ological studies of Internet gaming disorder: a systematic review of the Boomsma, D.I., 2016. Heritability of compulsive Internet use in ad-
literature. Psychiatr. Clin. Neurosci. 71 (7), 425e444. https://doi.org/ olescents. Addict. Biol. 21 (2), 460e468. https://doi.org/10.1111/
10.1111/pcn.12532. adb.12218.
Nicholson, R., Graves, C., Ellery, M., Afifi, T.O., 2016. The temporal Vink, J.M., Willemsen, G., Boomsma, D.I., 2005. Heritability of smoking
relationship between faulty gambling cognitions and gambling initiation and nicotine dependence. Behav. Genet. 35 (4), 397e406.
severity in young adults. J. Gambl. Stud. 32 (4), 1215e1229. https:// https://doi.org/10.1007/s10519-004-1327-8.
doi.org/10.1007/s10899-016-9605-y. Vitaro, F., Arseneault, L., Tremblay, R.E., 1999. Impulsivity predicts
Peeters, M., Koning, I., Van den Eijnden, R., 2018. Predicting Internet problem gambling in low SES adolescent males. Addiction 94 (4),
Gaming Disorder symptoms in young adolescents: a one-year follow- 565e575.
up study. Comput. Hum. Behav. 80, 255e261. Wanner, B., Vitaro, F., Carbonneau, R., Tremblay, R.E., 2009. Cross-
Rehbein, F., Baier, D., 2013. Family-, media-, and school-related risk lagged links among gambling, substance use, and delinquency from
factors of video game addiction. J. Media Psychol. 25, 118e128. midadolescence to young adulthood: additive and moderating effects
Scharkow, M., Festl, R., Quandt, T., 2014. Longitudinal patterns of of common risk factors. Psychol. Addict. Behav. 23 (1), 91e104.
problematic computer game use among adolescents and adultsda 2- https://doi.org/10.1037/a0013182.
year panel study. Addiction 109 (11), 1910e1917. https://doi.org/ Wartberg, L., Kriston, L., Zieglmeier, M., Lincoln, T., Kammerl, R., 2018.
10.1111/add.12662. A longitudinal study on psychosocial causes and consequences of
Scholes-Balog, K.E., Hemphill, S.A., Dowling, N.A., Toumbourou, J.W., Internet gaming disorder in adolescence. Psychol. Med. 1e8. https://
2014. A prospective study of adolescent risk and protective factors for doi.org/10.1017/S003329171800082X.
problem gambling among young adults. J. Adolesc. 37 (2), 215e224. Xuan, Y.H., Li, S., Tao, R., Chen, J., Rao, L.L., Wang, X.T., Zheng, R.,
https://doi.org/10.1016/j.adolescence.2013.12.006. 2017. Genetic and environmental influences on gambling: a meta-
Scholes-Balog, K.E., Hemphill, S.A., Toumbourou, J.W., Dowling, N.A., analysis of twin studies. Front. Psychol. 8, 2121. https://doi.org/
2016. Problem gambling patterns among Australian young adults: 10.3389/fpsyg.2017.02121.
associations with prospective risk and protective factors and adult
Chapter 15
Cognitive factors in gambling disorder, a

behavioral addiction
Gabriel Brooks, Mario Ferrari and Luke Clark
Centre for Gambling Research at UBC, Department of Psychology, University of British Columbia, Vancouver, BC, Canada
Introduction the academic research on gambling uses the term “problem

gambling” (or disordered gambling) to refer to this lower
Gambling and substance addictions have been linked in both threshold of severity. It is also acknowledged that the
public discourse and academic research for several decades. consequences of problem gambling extend beyond the
However, the medical conceptualization of gambling disorder affected individual to friends and family, with a recent
as a behavioral addiction is a recent development, formalized empirically derived estimate that each person with problem
in the DSM-5 (APA, 2013). Originally termed pathological gambling adversely affects an average of six others
gambling, this condition was first included in the DSM-III in (Goodwin et al., 2017).
1980, where it was grouped in the impulse control disorders Personal vulnerabilities render some individuals within
category. In the run-up to the DSM-5, reviews of the extant our societies at increasing risk of developing gambling
literature highlighted overlap between pathological gambling problems. These risk factors overlap with those identified
and substance use disorders in terms of neurobiological and for substance addictions, including personality traits such
neuropsychological features, heritability, and effective treat- as impulsivity (Verdejo-García et al., 2008), life experi-
ments (Petry, 2006; Potenza, 2006), and this culminated in a ences such as childhood adversity (Hodgins et al., 2010),
reclassification of gambling disorder into the section and neurobiological factors such as dopaminergic geno-
“Substance-Related and Addictive Disorders.” The ICD-11 types (Lobo, 2016) and brain structure (Clark et al., 2018;
has recently followed suit with the DSM-5, with the further Leeman and Potenza, 2012). Considered in isolation, the
addition of (video) gaming disorders as a second form of emphasis given to these vulnerabilities could be taken to
behavioral addiction (Grant and Chamberlain, 2016). imply that gambling products are relatively unimportant.
Similar to substance use disorders, the diagnostic fea- To the contrary, it is clearly shown that gambling problems
tures of gambling disorder comprise some symptoms vary substantially across different types of gambling (Binde
associated with withdrawal (e.g., irritability, nausea, heart et al., 2017; Dowling et al., 2005; Markham et al., 2016).
palpitations) (Wray and Dickerson, 1981) and some func- Weekly lotteries are often the most popular form of
tional negative consequences of excessive gambling that gambling in large epidemiological surveys but have few
typically arise from the incurred losses. At a behavioral associations with gambling problem severity (Short et al.,
level, loss chasing is a key phenotype for which the parallel 2015). At the opposite extreme, electronic gaming ma-
in substance use disorders is unclear, whereby the gambler chines (EGMs) are an umbrella term for computerized,
continues to gamble or returns to the venue at a later date, terminal-based games that includes modern slot machine,
still trying to recoup their prior losses. Loss chasing is often video poker, and various other games. Across many juris-
the single most endorsed feature from the DSM list of dictions, frequency of EGM use is predictive of financial
criteria (Gainsbury et al., 2013; Temcheff et al., 2016). losses and problem gambling symptoms (Binde et al.,
Prevalence estimates for the full diagnosis of gambling 2017; Markham et al., 2016), and EGMs are the modal
disorder are typically around 1% (Kessler et al., 2008), but game of choice among many people seeking treatment for
the binary nature of diagnosis downplays the reliable gambling problems (e.g., Urbanoski and Rush, 2006). This
observation that 3%e4% of the population experience chapter embraces a public healtheinspired approach to
objective negative consequences from gambling in the gambling disorder that asserts that gambling harms arise
“subclinical” range (Toce-Gerstein et al., 2003). Much of

through the “playereproduct” interaction of personal distribution of reds and blacks. This cognitive distortion of
vulnerability factors and the psychological impacts of self-correcting probability (or “negative recency”) is widely
gambling products and the wider gambling environment labeled “the gambler’s fallacy.” It is erroneous because it
(Korn and Shaffer, 1999; Murch and Clark, 2016). The ignores the independence of turns; clearly, the roulette wheel
product features may be analyzed as an array of “structural has no memory for its past outcomes. Representativeness
characteristics” (Griffiths, 1993): psychological ingredients may also explain the “hot hand fallacy,” in which a series of
that include the speed of the game, different payout prop- wins is believed to portend continued success (Ayton and
erties (e.g., jackpot size), the presence of sensory feedback, Fischer, 2004; Gilovich et al., 1985). This bias may emerge
and so on. when the information provided by a winning streak refutes a
random distribution, so that the gambler revises their
assumption that the game is a chance, instead concluding that
The cognitive model of gambling more wins will follow. Note that the hot hand fallacy typi-
Most gamblers are aware that gambling games are designed cally applies to individual, intentional performance, rather
to produce a net loss (the “house edge”). As such, there is a than the outcomes of a random agent, so that the hot hand
seeming discrepancy between this negative expected value effect is also related to perceptions of skill (Caruso et al.,
and the widespread prevalence of gambling. The cognitive 2010). Both the gamblers fallacy and hot hand fallacy have
mechanisms associated with gambling may help to explain been described in field studies, including lottery and roulette
the maintenance of this activity (Clark, 2010). Fundamental players (Croson and Sundali, 2005; Suetens et al., 2016).
processes described in the field of judgment and decision- The availability heuristic occurs when the estimated
making provide a foundation from which gambling- likelihood of an event is based on its salience, either within
related cognitive distortions emerge (Clark, 2016; memory or in the environment (Tversky and Kahneman,
Leonard et al., 2015). Humans regularly face situations that 1974). The emotional intensity of winning is a potent
have uncertain outcomes, and judgment refers to the source of such availability bias. Such experiences are
process through which we estimate the likelihoods of recalled with greater ease and vividness, such that these
different possibilities occurring. Decision-making entails outcomes are highly available during subsequent decisions
the integration of these estimates with the perceived costs whether to gamble again (Wagenaar, 1988). Research from
and benefits of each outcome, to select an option. Rather associative learning shows that the co-occurrence of suc-
than performing this integration using complex and time- cess with behavioral actions is more memorable than the
consuming mental calculations, we often rely on shortcuts absence of such pairings, leading to illusory correlations. In
known as heuristics, and there is a long-standing debate as this way, behavioral rituals can be reinforced even if they
to whether this reliance on heuristics is adaptive or fool- have only been associated with winning on a single occa-
hardy in the real world (Gigerenzer and Gaissmaier, 2011; sion (Orgaz et al., 2013; Ejova et al., 2015). Within a
Kahneman, 2011). Nonetheless, under certain casino, the sounds of machine payouts and cheering patrons
conditionsdwhich may well include gambling games as are substantially more salient than the feedback given to
games of chancedthe use of mental shortcuts can generate losing outcomes (Griffiths, 1994). Frequent encounters of
systematic errors (i.e., biases) and poor, costly choices. The “vicarious” wins (e.g., gamblers playing at adjacent slot
structural design of gambling products may perpetuate such machines or tables) heighten the availability of winning,
biases, leading to erroneous beliefs about these games. adding a social dimension to these effects (Rockloff and
Fortune and Goodie (2012) categorized several Dyer, 2007; Rockloff et al., 2011).
gambling-related cognitive distortions by their association Within the gambling field, much research has examined
with two of the most established heuristics, originally char- the relationships between these gambling-related cognitive
acterized by Tversky and Kahneman (1973, 1974). The distortions and problematic gambling. Gaboury and Ladou-
representativeness heuristic is enacted when a likelihood is ceur (1989) developed the “think-aloud” method to assess
estimated based on its similarity to a known likelihood. such beliefs: during a period of actual gambling, the
When applied to sequential events, such as a series of bets in participant is asked to verbalize constantly on their thoughts
roulette, individuals often mistakenly believe that short-term and experiences. In their initial study, Gaboury and Ladou-
deviations are “due” to correct. This may arise because such ceur found that approximately 70% of verbalizations were
correction would increase the representativeness of the erroneous. Often these statements reflected erroneous beliefs
observed sequence to the overall expected distribution. To about the degree of skill or control in the game. Problem
illustrate, a game of roulette that has produced four consec- gamblers make more of these inaccurate statements than
utive “red” outcomes may be thought to have increased odds nonproblematic gamblers (Hardoon et al., 2001). The think-
of “black” in the next round. Representativeness explains this aloud approach has received some criticism for whether the
prediction because a black outcome would shift the sequence requirement to verbalize alters the gambling experience it-
toward a closer representation of the assumed equal self, and from the early 2000s, measurement of gambling
Cognitive factors in gambling disorder, a behavioral addiction Chapter | 15 211
beliefs shifted toward the use of self-report questionnaires. by neuropsychological research using cognitive tests that
Problem gambling predicted higher scores on the Gambling- are sensitive to localized brain injury. Classic observations
Related Cognitions Scale (Raylu and Oei, 2004; Emond and that damage the ventromedial prefrontal cortex could
Marmurek, 2010; Michalczuk et al., 2011) and Gambling impair judgment and lead to risky decision-making that
Beliefs Questionnaire (Steenbergh et al., 2002), two of the prompted the design of neuropsychological tasks to capture
more widely used scales. While the evidence linking this syndrome, including the Iowa Gambling Task (Bechara
gambling-related cognitive distortions and problem et al., 2000) and Cambridge Gamble Task (Rogers et al.,
gambling behavior is robust, the association suffers from a 1999). People with gambling disorder show comparable
“chicken and egg” problem. It is unclear whether individual changes on these tests; for example, a recent metaanalysis
differences (such as personality) in these beliefs predispose of seven studies using the Iowa Gambling Task in groups
disordered gambling or whether these biases arise from of problem gamblers (n ¼ 292 cases) found a robust
extensive experience of gambling. An unusual longitudinal impairment of greater severity than that observed for
study by Yakovenko et al. (2016) compared these hypoth- alcohol dependence (Kovács et al., 2017). Neuropsycho-
eses: distortions predicted subsequent escalation of gambling logical changes are also described using tests of impul-
to a greater degree than the inverse. Trait-measured indus- sivity, both in terms of motor impulsivity (or response
triousness has also been seen to mediate the relationship inhibition) (Chowdhury et al., 2017) and tests of choice
between these cognitions and problem gambling (MacLaren impulsivity (delay discounting) (Amlung et al., 2017).
et al., 2015), indicating that broader personality traits un- These neuropsychological measures may have some value
derlie gambling-specific irrational beliefs. Also consistent in predicting treatment outcomes and relapse (Goudriaan
with a causal impact, psychological treatments that target et al., 2008; Stevens et al., 2014). Moreover, these changes
these erroneous beliefs have shown reasonable effectiveness in reward-based decision-making and impulse control are
in clinical trials of gambling disorder, a topic we will return typically greater than any differences seen for traditional
to later. tests of executive function such as cognitive flexibility and
Unfortunately, the widespread reliance on self-report working memory (Cavedini et al., 2002; Lawrence et al.,
questionnaires neglects an interesting temporal aspect to 2009), although such changes can likely exist in severe
these cognitions. Using the think-aloud technique, gam- cases (Blaszczynski and Nower, 2002).
blers often expressed more accurate beliefs about gambling
(e.g., that gambling is fundamentally a chance) when they
were not playing (Gaboury and Ladouceur, 1989). During
Specific cognitive distortions in
gambling, irrational statements took over. Sevigny and gambling
Ladouceur (2003) proposed the concept of “double Illusion of control
switching,” highlighting the activation of “state” cognitions
on a baseline of dispositional “trait” beliefs. During The “illusion of control” refers to the belief in a game of
gambling, rational knowledge about the game may “switch chance that personal involvement will increase the proba-
off” and “switch on” again after ceasing the activity. We bility of winning (Langer, 1975). In the original studies on
note that this has much in common with popular dual- this effect, Langer used a lottery experiment in which some
system accounts of decision-making (Kahneman, 2011). participants were able to choose their lottery ticket.
EGMs’ structural characteristics, such as stopper buttons Compared with participants who were simply given their
(see below), could directly activate these state beliefs. The ticket, the experimental group ascribed higher monetary
double switching concept implies that questionnaire mea- value to those tickets and was less willing to trade them for
sures, which inherently emphasize trait-related beliefs, other tickets, even for those with an objectively higher
could underestimate gambling-related cognitions in either a chance of winning. Subsequent research has shown that
quantitative or qualitative way. Double switching also has people with gambling problems display greater illusory
practical implications for both treatment and prevention of control, using both gambling (“domain-specific”) and
disordered gambling through education on gambling domain-general measures (Goodie, 2005; Orgaz et al.,
mathematics, risk, and common myths (see Ladouceur 2013). In a field study, Davis et al. (2000) examined betting
et al., 2013 for critique of such approaches). in craps players in a casino, showing that craps players who
threw the dice themselves bet with greater frequency and
amounts, and on riskier odds, compared with when other
Neurocognitive correlates of gambling players were “shooting” (see also Ladouceur and Mayrand,
disorder 1987).
Of course, the negative expected value of gambling
Research using measures from judgment and decision-
means that a gambler will often encounter more losses than
making in people with disordered gambling is augmented
wins. How is the illusion of control maintained in that
context? Despite the aforementioned availability of win-

ning memories, gamblers will also invest considerable
mental resources to explaining away their losses, in a way
that protects their self-identity as a skillful player (Gilovich,
1983). Using a coin toss game, Cowley et al. (2015) had
regular gamblers view the outcomes of six tosses before
placing a bet on the seventh. Participants then provided
ratings on their experiences during the gambling task, in
addition to a measure of illusion of control. The results
showed that among losing participants, strength of illusory
control beliefs interacted with the size of their largest win to
predict gambling experiences; when illusory control was
high, participants tended to use their largest win to deter-
mine the valence of their gambling experience. In other FIGURE 15.1 The effect of a “stopper device” on operant responding
words, gamblers with greater illusion of control selectively during slot machine play. The graph shows the proportion of stop button
presses in the five trials on either side of winning outcomes, on which the
attended to a specific part of their gambling session that participant either did, or did not, use the stopping device. The interaction
was most compatible with their belief that they could effect is statistically significant, and participants increase their use of the
control their wins. stopper device following stopper-paired wins. Error bars represent stan-
In the specific case of EGMs, there are several situa- dard error of the mean. Graph from Chu, S., Limbrick-Oldfield, E.H.,
tional and structural characteristics that might promote an Murch W.S., Clark L., 2018. Why do slot machine gamblers use stopping
devices? Findings from a ‘Casino Lab’ experiment. Int. Gambl. Stud.
illusion of control, beginning with the gambler’s choice of 18(2), 310e326. Copyright Taylor-Francis.
which EGM to play at. Players also have a choice in their
style of play, such that bet amounts can be varied and
different line combinations can be bet on. MacLaren (2015) games promote illusory control, the psychological mecha-
showed that experienced slots players could respond to nisms that underpin these effects, and their relevance to
instructions to “do your best” or “go broke” by configuring disordered gambling. The further relevance to policy was
their betting strategies to manipulate the rate of reinforce- highlighted recently by Lopez-Gonzalez et al. (2018), who
ment. Although these strategies do not affect the overall showed how gambling advertisements in the United
payout rate of the EGM, they may nonetheless maintain Kingdom often portrayed the use of betting platforms as
illusory control beliefs that the player does have some enhancing one’s control over outcomes. In a qualitative
influence over the game’s outcomes (MacLaren, 2015). In analysis of 102 television advertisements for online sports
many jurisdictions, slot machines may be equipped with a betting, Lopez-Gonzales et al. found that new features such
“stopping device,” a manual response that brakes the reels as betting exchanges or cash out options often conflated the
but has no actual impact on the symbols that are chosen. In genuine control afforded in the placing of the bet with the
a laboratory study of the influence of this device on illusory control over the bet outcomes. In addition to online
gambling beliefs and behavior, Ladouceur and Sévigny gambling, other forms of gambling include various
(2005) assigned groups of participants to either use or not elements of instrumentality (e.g., die throwing, choosing
use the stopper device on a slot machine. Stopper device numbers, etc.), and in the case of EGMs, the recent emer-
use promoted faulty beliefs and increased gambling gence of “skill-based” games that overlap with video
persistence. However, in a recent study where players could gaming raises natural concerns about amplification of
choose whether and when they used the stopper, a illusory control.
disconnect with cognitive beliefs was observed (Chu et al.,
2018). In both undergraduates (mostly novice gamblers)
Anthropomorphism of gambling games
and a community sample of regular slot machine players,
self-reported illusory control beliefs did not predict the Most people have experienced seeing a face or other real-
frequency of use. Rather, use of the stopper substantially world object in a cloud formation, and this “anthropo-
increased the speed of play and was also increased on trials morphism” can arise in the context of gambling, as the
following wins where the participant had deployed the tendency to treat (inanimate) gambling devices such as slot
stopper feature (see Fig. 15.1). Chu et al. (2018) interpreted machines as possessing human features, such as thoughts or
this pattern as more consistent with principles of operant intentions (Toneatto, 1999). This mode of thinking displays
(and superstitious) conditioning than with an explicit stable individual differences (Waytz et al., 2010) that may
cognitive bias. be relevant to gambling engagement and potentially
These results highlight the need for further research disordered gambling. A study by Ladouceur et al. (1988)
examining how the structural characteristics of gambling was the first to document this phenomenon in gambling
behavior, using the think-aloud procedure described above, interviews, Schull discusses gamblers’ reports of a desir-
with a simulated roulette game. Among the various forms able state of diminished awareness of time, money, body,
of irrational verbalization, frequent statements appeared to and physical space, while playing EGMs. Other versions of
“personify” the game (e.g., “This machine is making me this account are captured in constructs such as “immersion”
mad on purpose.” p. 412) (see also Delfabbro and Wine- (Murch et al., 2017) or “dark flow” (Dixon et al., 2014). At
field, 2000). a cognitive level, these descriptions share a strong degree of
Toneatto (1999) categorizes such anthropomorphism as attentional capture by the gambling game, at the expense of
an interpretive bias: the tendency to attribute meaning or the surrounding environment (Murch et al., 2017). This
patterns to ostensibly random outcomes. As discussed converges with other work demonstrating biases in sus-
earlier, this overlaps with the Gambler’s Fallacy. Anthro- tained attention and selective attention toward gambling
pomorphizing a gambling game as something with human stimuli as function of problematic gambling (Hudson et al.,
motives may also provide an explanation of why losses 2016; McGrath et al., 2018).
continue to occur, with the self-serving benefit that the From an empirical perspective, one of the main chal-
game’s disposition may soon change for the better (“This lenges with research on game immersion is its measure-
machine is starting to like me!”). Alternatively, anthropo- ment. Immersion is a fragile state that may only be reliably
morphism may foster an illusion of control over the game’s elicited using realistic gambling games and/or gambling
outcomes (Kim and McGill, 2011; Riva et al., 2015). Kim environments. In the first studies to address this, Diskin and
and McGill found that participants who were primed to feel Hodgins (1999, 2001) compared pathological and occa-
greater social power were more willing to play a slot sional gamblers who played an EGM for 10 min while also
machine with anthropomorphic features and rated it as less performing a second target detection task, to indicate
risky, whereas feelings of low power were associated with a changes in the illumination of four lights positioned at the
reduced willingness and increased perception of risk. corners of the EGM screen. The pathological gamblers
Few studies to date have specifically examined missed more targets and responded more slowly, which
anthropomorphism in relation to gambling pathology, but a was interpreted as a narrowing of attention toward the game
recent series of experiments by Riva et al. (2015) estab- itself. Pathological gamblers also reported a greater ten-
lished a connection to gambling persistence. Compared dency toward dissociative experiences and more frequently
with nonregular slot machine gamblers, regular slots endorsed having had a gambling experience wherein they
players reported higher levels of slot machine anthropo- lost track of time. Building on the Diskin and Hodgins
morphization, and this tendency was moderately correlated procedure, Murch et al. (2017) found that in regular
with self-reported gambling frequency. Furthermore, using gamblers, higher problem gambling risk scores predicted
online slot machine simulators and anthropomorphized subjective reports of “flow” and dissociation during modern
instructions that primed a belief that the game can choose EGM play and reduced target detection to peripheral visual
who wins, participants played more spins and sustained stimuli (see Fig. 15.2). Additional psychophysiological
greater slot machine losses compared with an unprimed changes in heart rate variability during EGM play were not
control condition. Interestingly, Riva et al. demonstrated predictive of these immersion measures.
that positive emotions associated with heightened arousal Other work by Dixon and colleagues has begun to
(e.g., confidence, excitement) mediated the link between triangulate the relationships between immersion, product
anthropomorphism and increased gambling. Further features, and disordered gambling. Using realistic slot
research will be necessary to determine the specific roles of machine simulations to assign regular gamblers to either
machine characteristics (e.g., human-like visual themes and single- or multi-line conditions, regular gamblers over-
sounds, which are common in modern EGMs) and indi- whelmingly preferred the multi-line format and reported
vidual differences in the tendency to humanize gambling higher positive affect in that condition (Dixon et al., 2017).
games, in predicting development and maintenance of Importantly, individuals with problematic gambling
gambling problems. reported greater immersion in the multi-line game
compared with the single-line game. A further link was
shown between depressive symptoms, whereby greater
Immersion in the game depressive symptomology predicted higher ratings of flow
The tendency to enter dissociative states was originally during gambling and greater expectations that gambling
described in problem gamblers by Jacobs (1988) and has would enhance one’s mood. Similarly, these positive
also been discussed as predicting problematic use of sub- gambling expectancies predicted ratings of flow. Thus,
stances. This idea has seen a recent resurgence with problem gamblers may enter an immersive state during
discussion of a trance-like “machine zone” that was argued gambling to improve their mood and potentially reinforce
to be a central motivating factor among slot machine their gambling involvement by doing so (Dixon et al.,
gamblers in particular (Schull, 2012). Using qualitative 2017).
FIGURE 15.2 Measures of slot machine immersion are correlated with symptoms of problem gambling (PGSI, Problem Gambling Severity Index). (A)
Self-reported immersion following 20 min of slot machine play, using a Dissociation Questionnaire; (B) Targets detected in the peripheral visual field, using
screens mounted on either side of the slot machine. Open circles are data from undergraduates (mostly novice gamblers), and filled circles are data from a
community sample of regular slot machine gamblers. Graphs redrawn from Murch, W.S., Chu, S.W.M., Clark, L., 2017. Measuring the slot machine zone with
attentional dual tasks and respiratory sinus arrhythmia. Psychol. Addict. Behav. 31(3), 375e384. Copyright American Psychological Association.
Treatment and intervention of chapters in many countries (Petry, 2005). GA follows the
“12-step” design, like Alcoholics Anonymous, with the goal
Interventions for people with gambling problems include of complete abstinence from gambling. This is a group
not only some strategies that have direct analogues in treatment, where individuals are provided with a nonjudg-
substance addictions but also some strategies that do not. mental venue to voice their struggles with gambling.
Voluntary self-exclusion programs are an example of the Members may share stories of success and relapse, allowing
latter, where the gambler enters a contract with the attendees to learn coping methods through others experi-
gambling operator that bans them from entering gambling ence. Oei and Gordon (2008) outlined several predictors of
venues for a set period of time. The specifics of self- abstinence for GA members. These include attendance and
exclusion programs vary widely across jurisdictions; for participation in meetings, available social support, religi-
example, in terms of the consequences for a gambler osity, and adherence to the 12 steps. Notably, gambling-
breaking self-exclusion (which is common), how many related cognitive distortions and gambling urges were sig-
venues are included in the ban (i.e., single-site or multisite), nificant predictors of poor outcome.
and what other forms of gambling remain available to the In terms of treatments delivered by a mental health
gambler, such as online platforms or lottery products professional, cognitive behavioral therapy (CBT) for
(McCormick et al., 2018; Pickering et al., 2018). Self- problem gambling has reasonable evidence for effective-
exclusion programs may direct individuals to treatment ness. Several variants of CBT exist for problem gambling,
resources, but self-exclusion by itself does not contain any with quite distinct emphases. The formulation by Ladou-
active treatment component. In a review of the effective- ceur et al. (1998) directly targets gambling-related cogni-
ness of self-exclusion programs across several countries, tive distortions, with training in the concept of randomness
Gainsbury (2014) concluded that such programs afford and the activation of erroneous beliefs during active
benefits in terms of reduced financial duress, decreased gambling. The gambler may practice identifying and cor-
gambling behavior, and improved psychological well- recting these beliefs during imaginal exposure. This
being. In a recent study that included a noneself-excluder approach has promising data on efficacy; for example,
control group, self-excluders demonstrated reduced prob- randomized controlled trials find that psychological thera-
lem gambling severity scores over 6-month follow-up pies that include cognitive restructuring significantly
(McCormick et al., 2018). Multisite exclusion, ease of improve treatment outcomes (Tolchard, 2017). From a
enrollment, and clear information about the program are more behavioral perspective, exposure therapy, where in-
considered by gamblers to be the most helpful features dividuals are introduced to increasingly potent gambling
(Pickering et al., 2018). It is widely noted, however, that stimuli, has also been demonstrated as effective. In a direct
the majority of problem gamblers do not make use of such comparison, no differences were detected between expo-
programs. sure therapy and cognitive restructuring, with both signif-
Gamblers Anonymous (GA) is the most widely available icantly reducing symptoms. Motivational interviewing is
form of treatment for problematic gambling, with thousands
increasingly combined with CBT and aims to target read- In terms of future directions, there is a clear knowledge
iness to change and resolve ambivalence relating to treat- gap in understanding how individual differences in
ment. Motivational interviewing was associated with gambling-related cognitive distortions arise and shape the
significant reductions in gambling frequency that persisted development of disordered gambling. We have seen that
at 1-year follow-up (Yakovenko et al., 2015). Compared impulsivity, as a personality dimension associated with the
with group settings, individual CBT appears to encourage a vulnerability to both behavioral and substance addictions, is
greater breadth of recovery, including reduced symptoms of correlated with gambling distortions in a clinical sample
depression and anxiety (Fortune and Goodie, 2012). Thus, (Michalczuk et al., 2011). The tendency to overestimate
research to date supports several promising treatments for control on a domain-general Contingency Judgment Task
problem gambling, including variants built on the cognitive (evaluating whether a medication was effective in treating a
behavioral framework (Petry, 2009). fictitious illness) was also increased in people with gambling
problems (Orgaz et al., 2013). It is notable that professional
and university-level sports athletes appear to be a vulnerable
Conclusion group for problem gambling, with hypothetical mediators
This chapter has sought to describe how gambling-related involving self-efficacy and illusory control when operating
cognitive distortions arise from cognitive psychological outside of their highly skilled environment (Grall-Bronnec
mechanisms that have been characterized in basic research et al., 2016). New techniques are also needed to capture
on judgment and decision-making. These distortions are the more temporary activation of gambling distortions dur-
familiar to many as the “gambling myths” that gamblers, ing play, as articulated in the “double switching” framework
gambling clinicians, and casino workers encounter on a (Sevigny and Ladouceur, 2003), and to separate the state and
daily basis. We have considered some of the broader types trait aspects of these phenomena.
of bias, including sequential (or predictive) biases such as Rapid changing in gambling technology underscores
the gambler’s fallacy and hot hand belief and the tendency the relevance of such research to gambling policy. Many
to infer illusory control in games of chance, as well as a games that were formerly confined to casinos or betting
more specific bias, anthropomorphization, which might be shops can now be accessed online, either in the home or via
subsumed under the broader effects. Indeed, an overarching mobile devices. As these forms of gambling increase in
taxonomy of gambling distortions is not available at the accessibility and popularity, it is challenging to gage to
current time. Nevertheless, compelling evidence exists to what extent these modes increase gambling harms (Gains-
show that these distortions are elevated in people with bury, 2015). Even within “offline” forms of gambling, the
disordered gambling, using both experiential (i.e., think- increasing sophistication of EGMs enables gambling to
aloud) and self-report measures. occur at a faster pace, with easier forms of payment and
Gambling distortions represent a natural point of amplified sensory feedback (Meyer et al., 2011). Increasing
connection between the personal risk factors that predis- convergence with the video game industry comprises both
pose some individuals to disordered gambling and the ef- the “gamblification” of modern video games, for example,
fects of gambling products. Neurocognitive data in via in-game monetization features such as loot boxes (King
gambling disorder indicate impairments in reward-based and Delfabbro, 2018), and “gamification” of gambling, for
decision-making and impulse control that are likely example, via slot machines with skill-based components.
linked to developmental pathophysiology in the ventro- We believe that theory and evidence from psychology and
medial aspects of prefrontal cortex. Research from medi- neuroscience regarding the interplay between personal
cine and neuroscience has tended to neglect the impact of dispositions, gambling products, and the wider gambling
product features, but gambling harms clearly vary across environment can support policy makers in evaluating the
different forms of gambling, in a manner that can be potential risks of these emerging technologies.
explained by the underlying structural characteristics. Op-
tions to vary one’s bet and the number of lines may Funding
enhance the illusion of control on modern EGMs. In rou-
This work is supported by the Centre for Gambling Research at UBC,
lette games, a common feature of displaying a “history
which is funded by the Province of British Columbia Government and
board” of recent outcomes may perpetuate the gambler’s
the British Columbia Lottery Corporation. Gabriel Brooks is sup-
fallacy. Recent evidence also indicates that in-game im- ported by a Four Year Doctoral Fellowship from UBC. Mario Ferrari
mersion may be an important net result of these products is supported a Natural Sciences and Engineering Research Council
and is linked to problematic gambling especially in the case (Canada) fellowship and by the Dr. William Arthur Paskins Memorial
of EGM play. Immersion may be understood in relation to Fellowship from the UBC Department of Psychology. LC receives
cognitive psychology mechanisms of attention rather than funding from the Natural Sciences and Engineering Research Council
decision-making. (Canada) (RGPIN-2017-04069).
Conflict of Interest statement Clark, L., Boileau, I., Zack, M., 2019. Neuroimaging of reward mecha-
nisms in Gambling disorder: an integrative review. Mol. Psychiatry
LC is the Director of the Centre for Gambling Research at UBC, 24, 674e693. http://doi.org/10.1038/s41380-018-0230-2.
which is supported by the Province of British Columbia Government Cowley, E., Briley, D.A., Farrell, C., 2015. How do gamblers maintain an
and the British Columbia Lottery Corporation (BCLC). The BCLC is illusion of control ? J. Bus. Res. http://doi.org/10.1016/j.jbusres.2015.
a Canadian Crown Corporation. The Province of British Columbia 03.018.
government and BCLC had no involvement in the research and Croson, R., Sundali, J., 2005. The gambler’s fallacy and the hot hand:
impose no constraints on publishing. LC has received speaker/travel empirical data from casinos. J. Risk Uncertain. 30 (3), 195e209.
reimbursements from Svenska Spel (Sweden), the National Center for http://doi.org/10.1007/s11166-005-1153-2.
Responsible Gaming (US), and the National Association of Gambling Davis, D., Sundahl, I., Lesbo, M., 2000. Illusory personal control as a
Studies (Australia). He has not received any further direct or indirect determinant of bet size and type in casino craps games. J. Appl. Soc.
payments from the gambling industry or groups substantially funded Psychol. 30, 1224e1242.
by gambling. He has received royalties from Cambridge Cognition Delfabbro, P., Winefield, A.H., 2000. Predictors of irrational thinking in
Ltd. relating to the licensing of a neurocognitive test. The other au- regular slot machine gamblers. J. Psychol. 134 (2), 117e128.
thors declare no conflicts of interest. Retrieved from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
cmd¼Retrieve&db¼PubMed&dopt¼Citation&list_uids¼10766103.
References Diskin, K.M., Hodgins, D.C., 1999. Narrowing of attention and dissoci-
ation in pathological video lottery gamblers. J. Gambl. Stud. 15,
Amlung, M., Vedelago, L., Acker, J., Balodis, I., Mackillop, J., 2017. Steep 17e28. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/
delay discounting and addictive behavior : a meta-analysis of contin- 12766452.
uous associations, 112, pp. 51e62. http://doi.org/10.1111/add.13535. Diskin, K.M., Hodgins, D.C., 2001. Narrowed focus and dissociative ex-
American Psychiatric Association, 2013. In: Diagnostic and statistical periences in a community sample of experienced video lottery gam-
manual of mental disorders, fifth edition. American Psychiatric Pub- blers. Can. J. Behav. Sci. 33, 58e64.
lishing, Washington, DC (DSM-5). Dixon, M.J., Graydon, C., Harrigan, K.A., Wojtowicz, L., Siu, V.,
Ayton, P., Fischer, I., 2004. The hot hand fallacy and the gambler’s fal- Fugelsang, J.A., 2014. The allure of multi-line games in modern slot
lacy: two faces of subjective randomness? Mem. Cogn. 32 (8), machines. Addiction 109, 1920e1928. http://doi.org/10.1111/add.
1369e1378. http://doi.org/10.3758/BF03206327. 12675.
Bechara, A., Tranel, D., Damasio, H., 2000. Characterization of the Dixon, M.J., Stange, M., Larche, C.J., Graydon, C., Fugelsang, J.A.,
decision-making deficit of patients with ventromedial prefrontal cortex Harrigan, K.A., 2017. Dark flow, depression and multiline slot ma-
lesions. Brain 123, 2189e2202. chine play. J. Gambl. Stud. http://doi.org/10.1007/s10899-017-9695-
Binde, P., Romild, U., Volberg, R.A., 2017. Forms of gambling, gambling 1.
involvement and problem gambling: evidence from a Swedish popu- Dowling, N., Smith, D., Thomas, T., 2005. Electronic gambling machines:
lation survey. Int. Gambl. Stud. 17 (3), 490e507. http://doi.org/10. are they the “crack cocaine” of gambling? Addiction 100, 33e45.
1080/14459795.2017.1360928. http://doi.org/10.1111/j.1360-0443.2004.00962.x.
Blaszczynski, A., Nower, L., 2002. A pathways model of problem and Ejova, A., Delfabbro, P.H., Navarro, D.J., 2015. Erroneous gambling-
pathological gambling. Addiction 97, 487e499. http://doi.org/10. related beliefs as illusions of primary and secondary control: a
1046/j.1360-0443.2002.00015.x. confirmatory factor analysis. J. Gambl. Stud. 31 (1), 133e160. http://
Caruso, E.M., Waytz, A., Epley, N., 2010. The intentional mind and the doi.org/10.1007/s10899-013-9402-9.
hot hand: perceiving intentions makes streaks seem likely to continue. Emond, M.S., Marmurek, H.H.C., 2010. Gambling related cognitions
Cognition 116 (1), 149e153. http://doi.org/10.1016/j.cognition.2010. mediate the association between thinking style and problem gambling
04.006. severity. J. Gambl. Stud. 26 (2), 257e267. http://doi.org/10.1007/
Cavedini, P., Riboldi, G., Keller, R., D’Annucci, A., Bellodi, L., 2002. Frontal s10899-009-9164-6.
lobe dysfunction in pathological gambling patients. Biol. Psychiatry 51 Fortune, E.E., Goodie, A.S., 2012. Cognitive distortions as a component
(4), 334e341. http://doi.org/10.1016/S0006-3223(01)01227-6. and treatment focus of pathological gambling: a review. Psychol.
Chowdhury, N.S., Livesey, E.J., Blaszczynski, A., Harris, J.A., 2017. Addict. Behav. 26, 298e310. http://doi.org/10.1037/a0026422.
Pathological gambling and motor impulsivity: a systematic review Gaboury, A., Ladouceur, R., 1989. Erroneous perceptions and gambling.
with meta-analysis. J. Gambl. Stud. 33 (4), 1213e1239. http://doi.org/ J. Soc. Behav. Personal. 4, 411e420.
10.1007/s10899-017-9683-5. Gainsbury, S.M., 2014. Review of self-exclusion from gambling venues as
Chu, S., Limbrick-Oldfield, E.H., Murch, W.S., Clark, L., 2018. Why do an intervention for problem gambling. J. Gambl. Stud. 30 (2),
slot machine gamblers use stopping devices? Findings from a ‘Casino 229e251. http://doi.org/10.1007/s10899-013-9362-0.
Lab’ experiment. Int. Gambl. Stud. 18 (2), 310e326. http://doi.org/10. Gainsbury, S.M., 2015. Online gambling addiction: the relationship be-
1080/14459795.2017.1413125. tween internet gambling and disordered gambling. Curr. Addict. Rep.
Clark, L., 2010. Decision-making during gambling: an integration of 185e193. http://doi.org/10.1007/s40429-015-0057-8.
cognitive and psychobiological approaches. Phil. Trans. Biol. Sci. 365 Gainsbury, S.M., Russell, A., Hing, N., Wood, R., Blaszczynski, A., 2013.
(1538), 319e330. http://doi.org/10.1098/rstb.2009.0147. The impact of internet gambling on gambling problems: a comparison
Clark, L., 2016. Decision-making in gambling disorder: understanding of moderate-risk and problem Internet and non-internet gamblers.
behavioural addictions. In: Dreher, J.-C., Tremblay, L.K. (Eds.), Deci- Psychol. Addict. Behav. 27 (4), 1092e1101. http://doi.org/10.1037/
sion Neuroscience. Elsevier. http://doi.org/10.1017/CBO97811074153 a0031475.
24.004.
Gigerenzer, G., Gaissmaier, W., 2011. Heuristic decision making. Annu. King, D.L., Delfabbro, P.H., 2018. Predatory monetization schemes in
Rev. Psychol. 62, 451e482. http://doi.org/10.1146/annurev-psych- video games (e.g. ‘loot boxes’) and internet gaming disorder.
120709-145346. Addiction 113, 1967e1969. http://doi.org/10.1111/add.14286.
Gilovich, T., 1983. Biased evaluation and persistence in gambling. Korn, D.A., Shaffer, H.J., 1999. Gambling and the health of the public:
J. Personal. Soc. Psychol. 44 (6), 1110e1126. Retrieved from: http:// adopting a public health perspective. J. Gambl. Stud. 15, 289e365.
www.ncbi.nlm.nih.gov/entrez/query.fcgi? http://doi.org/10.1023/A:1023005115932.
cmd¼Retrieve&db¼PubMed&dopt¼Citation&list_uids¼6875803. Kovács, I., Richman, M.J., Janka, Z., Maraz, A., Andó, B., 2017. Decision
Gilovich, T., Vallone, R., Tversky, A., 1985. The hot hand in basketball: making measured by the Iowa Gambling Task in alcohol use disorder
on the misperception of random sequences. Cogn. Psychol. 17 (3), and gambling disorder: a systematic review and meta-analysis. Drug
295e314. http://doi.org/10.1016/0010-0285(85)90010-6. Alcohol Depend. 181 (October), 152e161. http://doi.org/10.1016/j.
Goodie, A.S., 2005. The role of perceived control and overconfidence in drugalcdep.2017.09.023.
pathological gambling. J. Gambl. Stud. 21 (4), 481e502. http://doi. Ladouceur, R., Gaboury, A., Dumont, M., Rochette, P., 1988. Gambling:
org/10.1007/s10899-005-5559-1. relationship between the frequency of wins and irrational thinking.
Goodwin, B.C., Browne, M., Rockloff, M., Rose, J., 2017. A typical J. Psychol. 122 (4), 409e414. http://doi.org/10.1080/00223980.1988.
problem gambler affects six others. Int. Gambl. Stud. 17 (2), 9915527.
276e289. http://doi.org/10.1080/14459795.2017.1331252. Ladouceur, R., Goulet, A., Vitaro, F., 2013. Prevention programmes for
Goudriaan, A.E., Oosterlaan, J., De Beurs, E., Van Den Brink, W., 2008. youth gambling: a review of the empirical evidence. Int. Gambl. Stud.
The role of self-reported impulsivity and reward sensitivity versus 13 (2), 141e159. http://doi.org/10.1080/14459795.2012.740496.
neurocognitive measures of disinhibition and decision-making in the Ladouceur, R., Mayrand, R., 1987. The level of involvement and the
prediction of relapse in pathological gamblers. Psychol. Med. 38 (1), timing of betting in roulette. J. Psychol. 121 (2), 169e176.
41e50. http://doi.org/S0033291707000694 [pii]10.1017/ Ladouceur, R., Sevigny, S., 2005. Structural characteristics of video lot-
S0033291707000694. teries: effects of a stopping device on illusion of control and gambling
Grall-Bronnec, M., Caillon, J., Humeau, E., Perrot, B., Remaud, M., persistence. J. Gambl. Stud. 21 (2), 117e131. http://doi.org/10.1007/
Guilleux, A., et al., 2016. Gambling among European professional s10899-005-3028-5.
athletes. Prevalence and associated factors. J. Addict. Dis. 35 (4), Ladouceur, R., Sylvain, C., Letarte, H., Giroux, I., Jacques, C., 1998.
278e290. http://doi.org/10.1080/10550887.2016.1177807. Cognitive treatment of pathological gamblers. Behav. Res. Ther. 36
Grant, J.E., Chamberlain, S.R., 2016. Expanding the definition of addic- (12), 1111e1119. http://doi.org/10.1097/00005053-200111000-00007.
tion: DSM-5 vs. ICD-11. CNS Spectr. 21, 300e303 (in press). http:// Langer, E.J., 1975. The illusion of control. J. Personal. Soc. Psychol. 32
doi.org/10.1017/S1092852916000183. (2), 311.
Griffiths, M.D., 1993. Fruit machine gambling: the importance of struc- Lawrence, A.J., Luty, J., Bogdan, N.A., Sahakian, B.J., Clark, L., 2009.
tural characteristics. J. Gambl. Stud. 9, 101e121. Problem gamblers share deficits in impulsive decision-making with
Griffiths, M.D., 1994. The role of cognitive bias and skill in fruit machine alcohol-dependent individuals. Addiction 104 (6), 1006e1015. http://
gambling. Br. J. Psychol. 85, 1e19. doi.org/10.1111/j.1360-0443.2009.02533.x.
Hardoon, K.K.R., Baboushkin, H.R., Derevensky, J.L., Gupta, R., 2001. Leeman, R.F., Potenza, M.N., 2012. Similarities and differences between
Underlying cognitions in gambing behaviour among university stu- pathological gambling and substance use disorders: a focus on
dents. J. Appl. Soc. Psychol. 57 (6), 1409e1430 [pii]. http://doi.org/ impulsivity and compulsivity. Psychopharmacology 219 (2),
10.1002/jclp.1047. 469e490. http://doi.org/10.1007/s00213-011-2550-7.
Hodgins, D.C., Schopflocher, D.P., El-Guebaly, N., Casey, D.M., Leonard, C.A., Williams, R.J., Vokey, J., 2015. Gambling fallacies: what
Smith, G.J., Williams, R.J., Wood, R.T., 2010. The association be- are they and how are they best measured ? Addict. Res. Ther. 6 (4),
tween childhood maltreatment and gambling problems in a commu- 1e9. http://doi.org/10.4172/2155-6105.1000256.
nity sample of adult men and women. Psychol. Addict. Behav. 24, Lobo, D.S., 2016. Genetic aspects of gambling disorders: recent de-
548e554. http://doi.org/10.1037/a0019946. velopments and future directions. Curr. Behav. Neurosci. Rep. 3 (1),
Hudson, A., Olatunji, B.O., Gough, K., Yi, S., Stewart, S.H., 2016. Eye on 58e66. http://doi.org/10.1007/s40473-016-0064-7.
the prize: high-risk gamblers show sustained selective attention to Lopez-Gonzalez, H., Estévez, A., Griffiths, M.D., 2018. Controlling the
gambling cues. J. Gambl. Issues 34 (34), 100e119. http://doi.org/10. illusion of control: a grounded theory of sports betting advertising in
4309/jgi.2016.34.6. the UK. Int. Gambl. Stud. 18 (1), 39e55. http://doi.org/10.1080/
Jacobs, D.F., 1988. Evidence for a common dissociative-like reaction 14459795.2017.1377747.
among addicts. J. Gambl. Behav. 4 (1), 27e37. http://doi.org/10.1007/ MacLaren, V., Ellery, M., Knoll, T., 2015. Personality, gambling motives
BF01043526. and cognitive distortions in electronic gambling machine players. Pers.
Kahneman, D., 2011. Thinking, Fast and Slow. Penguin. Indiv. Differ. 73, 24e28. http://doi.org/10.1016/j.paid.2014.09.019.
Kessler, R.C., Hwang, I., LaBrie, R., Petukhova, M., Sampson, N.A., MacLaren, V.V., 2015. Experienced EGM players know how to control
Winters, K.C., Shaffer, H.J., 2008. DSM-IV pathological gambling in the reinforcement rate and time on device. J. Gambl. Stud. 31 (4),
the national comorbidity survey replication. Psychol. Med. 38, 1789e1798. http://doi.org/10.1007/s10899-014-9498-6.
1351e1360. http://doi.org/10.1017/S0033291708002900. Markham, F., Young, M., Doran, B., 2016. The relationship between
Kim, S., McGill, A.L., 2011. Gaming with Mr. Slot or gaming the slot player losses and gambling-related harm: evidence from nationally
machine? Power, anthropomorphism, and risk perception. J. Consum. representative cross-sectional surveys in four countries. Addiction
Res. 38 (1), 94e107. http://doi.org/10.1086/658148. 111, 320e330. http://doi.org/10.1111/add.13178.
McCormick, A.V., Cohen, I.M., Davies, G., 2018. Differential effects of Rogers, R.D., Everitt, B.J., Baldacchino, A., Blackshaw, A.J.,
formal and informal gambling on symptoms of problem gambling Swainson, R., Wynne, K., et al., 1999. Dissociable deficits in the
during voluntary self-exclusion. J. Gambl. Stud. http://doi.org/10. decision-making cognition of chronic amphetamine abusers, opiate
1007/s10899-018-9743-5. abusers, patients with focal damage to prefrontal cortex, and
McGrath, D.S., Meitner, A., Sears, C.R., 2018. The specificity of atten- tryptophan-depleted normal volunteers: evidence for monoaminergic
tional biases by type of gambling: an eye-tracking study. PLoS One 13 mechanisms. Neuropsychopharmacology 20 (4), 322e339.
(1), e0190614. http://doi.org/10.1371/journal.pone.0190614. Schull, N.D., 2012. Addiction by Design: Machine Gambling in Las
Meyer, G., Fiebig, M., Häfeli, J., Mörsen, C., 2011. Development of an Vegas. Princeton University Press, Princeton, NJ.
assessment tool to evaluate the risk potential of different gambling Sevigny, S., Ladouceur, R., 2003. Gamblers’ irrational thinking about
types. Int. Gambl. Stud. 11 (2), 221e236. http://doi.org/10.1080/ chance events: the ‘double switching’ concept. Int. Gambl. Stud. 3 (2),
14459795.2011.584890. 149e161. http://doi.org/10.1080/1356347032000142261.
Michalczuk, R., Bowden-Jones, H., Verdejo-Garcia, A., Clark, L., 2011. Short, M.M., Penney, A.M., Mazmanian, D., Jamieson, J., 2015. Lottery
Impulsivity and cognitive distortions in pathological gamblers ticket and instant win ticket gambling : exploring the distinctions.
attending the UK National Problem Gambling Clinic: a preliminary J. Gambl. Issues 30, 6e21.
report. Psychol. Med. 41, 2625e2635. http://doi.org/10.1017/ Steenbergh, T.A., Meyers, A.W., May, R.K., Whelan, J.P., 2002. Devel-
S003329171100095X. opment and validation of the gamblers’ beliefs questionnaire. Psychol.
Murch, W.S., Chu, S.W.M., Clark, L., 2017. Measuring the slot machine Addict. Behav. 16 (2), 143e149. http://doi.org/10.1037/0893-164X.
zone with attentional dual tasks and respiratory sinus arrhythmia. 16.2.143.
Psychol. Addict. Behav. 31 (3), 375e384. http://doi.org/10.1037/ Stevens, L., Verdejo-García, A., Goudriaan, A.E., Roeyers, H., Dom, G.,
adb0000251. Vanderplasschen, W., 2014. Impulsivity as a vulnerability factor for
Murch, W.S., Clark, L., 2016. Games in the brain: neural substrates of poor addiction treatment outcomes: a review of neurocognitive find-
gambling addiction. Neuroscientist 22, 534e545. http://doi.org/10. ings among individuals with substance use disorders. J. Subst. Abuse
1177/1073858415591474. Treat. http://doi.org/10.1016/j.jsat.2014.01.008.
Oei, T.P., Gordon, L.M., 2008. Psychosocial factors related to gambling Suetens, S., Galbo-Jørgensen, C.B., Tyran, J.R., 2016. Predicting lotto
abstinence and relapse in members of gamblers anonymous. J. Gambl. numbers: a natural experiment on the gambler’S fallacy and the hot-
Stud. 24 (1), 91e105. http://doi.org/10.1007/s10899-007-9071-7. hand fallacy. J. Eur. Econ. Assoc. 14 (3), 584e607. http://doi.org/
Orgaz, C., Estévez, A., Matute, H., 2013. Pathological gamblers are more 10.1111/jeea.12147.
vulnerable to the illusion of control in a standard associative learning Temcheff, C.E., Paskus, T.S., Potenza, M.N., Derevensky, J.L., 2016.
task. Front. Psychol. 4 (306), 1e7. http://doi.org/10.3389/fpsyg.2013. Which diagnostic criteria are most useful in discriminating between
00306. social gamblers and individuals with gambling problems? An exam-
Petry, N.M., 2005. Gamblers anonymous and cognitive-behavioral thera- ination of DSM-IV and DSM-5 criteria. J. Gambl. Stud. 32, 957e968.
pies for pathological gamblers. J. Gambl. Stud. 21 (1), 27e33. http:// http://doi.org/10.1007/s10899-015-9591-5.
doi.org/10.1007/s10899-004-1919-5. Toce-Gerstein, M., Gerstein, D.R., Volberg, R.A., 2003. A hierarchy of
Petry, N.M., 2006. Should the scope of addictive behaviors be broadened gambling disorders in the community. Addiction 98, 1661e1672.
to include pathological gambling? Addiction 101 (S1), 152e160. http://doi.org/10.1111/j.1360-0443.2003.00545.x.
http://doi.org/ADD1593 [pii]10.1111/j.1360-0443.2006.01593.x. Tolchard, B., 2017. Cognitive-behavior therapy for problem gambling: a
Petry, N.M., 2009. Disordered gambling and its treatment. Cogn. Behav. critique of current treatments and proposed new unified approach.
Pract. 16 (4), 457e467. http://doi.org/10.1016/j.cbpra.2009.02.005. J. Ment. Health 26 (3), 283e290. http://doi.org/10.1080/09638237.
Pickering, D., Blaszczynski, A., Gainsbury, S.M., 2018. Multi-venue self- 2016.1207235.
exclusion for gambling disorders: a retrospective process investiga- Toneatto, T., 1999. Cognitive psychopathology of problem gambling.
tion. J. Gambl. Issues 38, 127e151. http://doi.org/10.4309/jgi.2018. Subst. Use Misuse 34 (11), 1593e1604. http://doi.org/10.3109/
38.7. 10826089909039417.
Potenza, M.N., 2006. Should addictive disorders include non-substance- Tversky, A., Kahneman, D., 1973. Availability: a heuristic for judging
related conditions? Addiction 101 (Suppl. l), 142e151. http://doi.org/ frequency and probability. Cogn. Psychol. 5 (2), 207e232. http://doi.
ADD1591 [pii]10.1111/j.1360-0443.2006.01591.x. org/10.1016/0010-0285(73)90033-9.
Raylu, N., Oei, T.P.S., 2004. The Gambling Related Cognitions Scale Tversky, A., Kahneman, D., 1974. Judgment under uncertainty: heuristics
(GRCS): development, confirmatory factor validation and psycho- and biases. Science 185, 1124e1131. http://doi.org/10.1126/science.
metric properties. Addiction 99 (6), 757e769. http://doi.org/10.1111/ 185.4157.1124.
j.1360-0443.2004.00753.x. Urbanoski, K.A., Rush, B.R., 2006. Characteristics of people seeking
Riva, P., Sacchi, S., Brambilla, M., October 2015. Humanizing machines : treatment for problem gambling in Ontario: trends from 1998 to 2002.
anthropomorphization of slot machines increases gambling. J. Exp. J. Gambl. Issues 16. http://doi.org/10.4309/jgi.2006.16.18.
Psychol. Appl. Verdejo-García, A., Lawrence, A.J., Clark, L., 2008. Impulsivity as a
Rockloff, M.J., Dyer, V., 2007. An experiment on the social facilitation of vulnerability marker for substance-use disorders: review of findings
gambling behavior. J. Gambl. Stud. 23 (1), 1e12. http://doi.org/10. from high-risk research, problem gamblers and genetic association
1007/s10899-006-9042-4. studies. Neurosci. Biobehav. Rev. 32 (4), 777e810. http://doi.org/
Rockloff, M.J., Greer, N., Fay, C., 2011. The social contagion of S0149-7634(08)00006-7 [pii] 10.1016/j.neubiorev.2007.11.003.
gambling: how venue size contributes to player losses. J. Gambl. Stud. Wagenaar, W., 1988. Paradoxes of Gambling Behaviour. Lawrence Erl-
27 (3), 487e497. http://doi.org/10.1007/s10899-010-9220-2. baum Associates, London.
Waytz, A., Cacioppo, J., Epley, N., 2010. Who sees human?: the stability involvement. Int. Gambl. Stud. 16, 175e192. http://doi.org/10.1080/
and importance of individual differences in anthropomorphism. Per- 14459795.2016.1147592.
spect. Psychol. Sci. 5 (3), 219e232. http://doi.org/10.1177/ Yakovenko, I., Quigley, L., Hemmelgarn, B.R., Hodgins, D.C.,
1745691610369336. Ronksley, P., 2015. The efficacy of motivational interviewing
Wray, I., Dickerson, M.G., 1981. Cessation of high frequency gambling for disordered gambling: systematic review and meta-analysis.
and “withdrawal’’ symptoms. Br. J. Addict. 76 (4), 401e405. Addict. Behav. 43, 72e82. http://doi.org/10.1016/j.addbeh.2014.12.
Yakovenko, I., Hodgins, D.C., El-Guebaly, N., Casey, D.M., Currie, S.R., 011.
Smith, G.J., et al., 2016. Cognitive distortions predict future gambling
Chapter 16
Cognitive factors associated with gaming

disorder
Joël Billieux1, Marc N. Potenza2, 3, 4, Pierre Maurage5, Damien Brevers6, 7, Matthias Brand8, 9 and
Daniel L. King10, 11
1
Addictive and Compulsive Behaviours Laboratory, Institute for Health and Behaviours, University of Luxembourg, Esch-sur-Alzette, Luxembourg;
2
Departments of Psychiatry and Neuroscience and Child Study Center, Yale School of Medicine, New Haven, CT, United States; 3The Connecticut
Council on Problem Gambling, Wethersfield, CT, United States; 4The Connecticut Mental Health Center, New Haven, CT, United States;
5
Laboratory for Experimental Psychopathology, Psychological Science Research Institute, Université Catholique de Louvain, Louvain-la-Neuve,
Belgium; 6Laboratory of Psychological Medicine and Addictology, Faculty of Medicine, Brugmann-Campus, Université Libre de Bruxelles, Brussels,
Belgium; 7Research in Psychology Applied to Motor Learning, Faculty of Motor Sciences, Erasme Campus, Université Libre de Bruxelles, Brussels,
Belgium; 8General Psychology: Cognition and Center for Behavioral Addiction Research (CeBAR), University of Duisburg-Essen, Duisburg,
Germany; 9Erwin L. Hahn Institute for Magnetic Resonance Imaging, Essen, Germany; 10
School of Psychology, The University of Adelaide,
11
Adelaide, SA, Australia; College of Education, Psychology and Social Work, Flinders University, Adelaide, SA, Australia
From internet addiction to gaming addiction” has been criticized by multiple researchers since
its appearance in the scientific literature. A common criti-
disorder cism of the concept has been that the Internet should be
Over the last two decades, significant progress in digital considered the medium (or the delivery mechanism) for
technologies (e.g., development of online infrastructure and problematic behaviors, not the object of the addiction per se
portable hardware such as smartphones) has led to massive (Shaffer et al., 2000; Starcevic, 2013). This reasoning may
societal changes. The widespread uptake and continuous similarly apply to the notion of “smartphone addiction,”
improvement of Information and Communication Technolo- which has been recently proposed because these devices
gies (ICTs) has generated many positive outcomes and have become sufficiently powerful to enable a wide range
opportunities for health (e.g., telemedicine), social commu- of potentially excessive or addictive behaviors (Billieux
nication (e.g., social network sites), education (e.g., e-learning et al., 2015b). Many researchers in the field consider that
and online libraries), and leisure (e.g., video games, people do not become addicted to the Internet or a smart-
on-demand streaming services). However, there has also been phone (or other device) but to one or more types of online
an increase in evidences documenting associations between activities (e.g., gaming, gambling, cybersex, social
problematic (and/or addictive) use of ICTs and psychological networking, or TV series watching). This approach has
distress and/or health problems (Kuss et al., 2014; World been supported by Baggio et al. (2018) using network
Health Organization [WHO], 2015). analyses (a data-driven statistical approach considering
An initial mention of “Internet addiction” can be traced mental disorders as networks of symptoms; see Borsboom,
back to 1995, when psychiatrist Yvan Goldberg, in the 2017) that provide support for the view that Internet and
form of a hoax, adapted the DSM-IV criteria for substance smartphone addictions are not valid constructs.
use disorders (SUD) to Internet use to propose the condi- At the time of writing, gaming disorder is the only
tion of Internet addiction. However, many readers of online-specific behavior recognized as an acquired addic-
Goldberg’s work believe that, despite its comedic intention, tive disorder in clinical nomenclature (i.e., DSM and ICD
his brief paper described a genuine condition, and some systems). Recognition of gaming disorder as a psychiatric
scholars undertook research to investigate the phenomenon, condition was supported by a variety of scientific evidence
thereby paving the way for a new research field (Griffiths, (e.g., epidemiological, psychological, and neurobiological
1999; Young, 1998). However, the construct of “Internet data), including clinical studies documenting individuals

seeking treatment (Billieux et al., 2017a; King et al., 2018; treatment-seeking participants (Rumpf et al., 2018; Saunders
Rumpf et al., 2018). Although other online behaviors et al., 2017). In this chapter, we will refer systematically to
(e.g., cybersex and social media use) have been associated either problematic gamers (i.e., nonclinical community
with negative consequences and functional impairment, the gamers having some symptoms of gaming disorder) or
available evidence has been considered premature to patients with gaming disorder (i.e., clinical gamers treated
recognize problematic engagement in these behaviors as for their condition). Many major studies have been con-
psychiatric disorders. ducted in Asian regions (i.e., South Korea, China, and Japan;
In the ICD-11, gaming disorder is defined as a pattern of countries that have generally provided more funding in these
gaming that is characterized by (1) impaired control areas) and thus have been published in Mandarin and other
(e.g., onset, frequency, intensity, duration, termination, Asian languages. Such work has consequently been largely
context); (2) increasing priority given to gaming to the inaccessible to English readers. To overcome this language
extent that gaming takes precedence over other life interests barrier, this chapter cites a recent systematic review of
and daily activities; and (3) continuation or escalation of Chinese studies published in English (Long et al., 2018).
gaming despite the occurrence of negative consequences.
Furthermore, to be considered as a disorder, the gaming Cognitive deficits
pattern must be associated with distress or significant
impairment in personal, family, social, and/or other A cognitive deficit is considered an inclusive term that de-
important areas of functioning. scribes any characteristic that negatively impacts on the
Data suggest that multiple factors (e.g., cognitive, af- cognition process (Coren et al., 1999). This may include
fective, motivational, interpersonal) contribute to the onset, neuropsychological impairments (e.g., impairment in exec-
progression, and maintenance of gaming disorder (Billieux utive function, attention, memory, decision-making),
et al., 2015a; Brand et al., 2016). A growing body of learning disabilities (e.g., dyslexia), or drug-induced
research has examined various cognitive factors commonly impairment (e.g., psychoactive substances that reduce,
observed in addiction (e.g., executive deficits, decision- increase, or alter the functioning of the central nervous
makingerelated processes, cognitive biases) in gaming system). In the context of gaming disorder, studies have
disorder, consistent with its conceptualization as an addic- attempted to identify the specific neuropsychological
tive disorder (King et al., 2013). The following sections impairments related to gaming disorder, including those
review the cognitive factors associated with gaming proposed in recent models (Brand et al., 2016; Dong and
disorder and suggest directions for future research. Potenza, 2014). Most available data have focused on
executive functioning (especially inhibitory control) and
decision-making tendencies (and related processes, such as
Cognitive factors associated with delay discounting). Other types of cognitive deficits have
been related to gaming disorder (e.g., other executive deficits
gaming disorder such as updating or shifting or deficits affecting the cognitive
Multiple studies have linked problem video gaming and processes involved in time control). These deficits have only
gaming disorder to a wide range of cognitive factors, which been reported in a few studies and have not been replicated,
may be divided into two broad categories: (1) cognitive deficits and therefore they are not described in detail in this chapter.
(e.g., impaired executive functioning, reduced deliberative
processes, and disadvantageous decision-making) and Inhibitory control and other executive
(2) cognitive biases (e.g., attentional biases, cognitive distor- functions
tions, dysfunctional cognitions). Recent integrative models of
Impaired control is a core feature of addictive and impul-
gaming disorder, such as the I-PACE (Interaction of Person-
sive disorders (Groman et al., 2009). Many studies have
Affect-Cognition-Execution) model, have highlighted the
examined whether problematic gaming and gaming disor-
pivotal role of cognitive variables in the etiology of the con-
dition (Brand et al., 2016; Dong and Potenza, 2014). der, like other addictive disorders, may be characterized by
inhibitory control impairments. Studies have used neuro-
Research on cognitive factors associated with gaming
cognitive tasks, such as the “stop signal task” or the “go/no-
disorder has involved diverse samples and different meth-
go task,” which assess abilities to stop an initiated (stop
odologies. Some studies are based on data from surveys of
signal) or uninitiated (go/no-go) prepotent motor response
self-selected or convenience samples of online gamers
(Verbruggen and Logan, 2008).
reporting symptoms of excessive and addictive gaming
Most studies have investigated inhibitory control in
patterns (King et al., 2013), which have provided some
caseecontrol designs, comparing patients with gaming dis-
insight but also have various shortcomings. In the last
5 years, there has been an increase in the number of in- orders (or community gamers endorsing specific diagnostic
criteria) and nongaming or recreationally gaming healthy
vestigations using neuroimaging techniques and including
Cognitive factors associated with gaming disorder Chapter | 16 223
control participants. These studies report mixed findings; an action. A standard task to assess this process is the Iowa
however, the majority favor of the existence of inhibitory Gambling Task (IGT; Bechara et al., 1994), where the
control impairment in problematic gaming and gaming participant has to select a series of cards from different
disorder (e.g., Choi et al., 2014; Littel et al., 2012; Xing et al., decks, which appear similar at first sight but are actually
2014). One study in particular compared different types of associated with distinct reinforcement schedules. As the
mental conditions and reported that gaming disordererelated participant progresses in the task, the participant is
inhibitory control impairment was comparable with the expected to acquire knowledge about the reinforcement
impairment displayed by individuals with alcohol use disorder contingencies of each deck and progressively adapt his
(Choi et al., 2014). In a recent metaanalysis, Argyriou et al. choices. In the IGT, the act of perseverating on disadvan-
(2017) reported a medium overall effect size (d ¼ 0.56), tageous decks is considered to indicate decision-making
indicating that individuals with problematic gaming or impairment, which is typically displayed by individuals
gaming disorder (as compared with those without) are more with addictive disorders (Brevers et al., 2013; Dom et al.,
likely to display impaired prepotent response inhibition. Other 2005). However, deficits in learning from risk/reward out-
studies documented inhibitory impairment in individuals with comes may also contribute to IGT findings, and other tasks
problematic Internet use (Dong et al., 2010, 2011, 2012). may more accurately assess decision-making under ambi-
However, some studies found that individuals with problem- guity and dissect it from other types of decision-making
atic gaming did not differ on tasks measuring inhibitory (e.g., decision-making under risk, Levy et al., 2010).
control (e.g., Deleuze et al., 2017b; Ding et al., 2014). Deleuze Some studies have investigated decision-making using the
et al. (2017b) examined regularly gaming individuals from the IGT in problem video gaming, obtaining mixed results. Baily
community, divided into two distinct groups according to the et al. (2013) reported a positive relation between symptoms of
preliminary diagnostic criteria proposed in the conditions for excessive gaming and disadvantageous decisions on the IGT.
further study section of DSM-5 to define Internet Gaming A more recent study did not replicate this finding, instead
Disorder (IGD): those with healthy gaming (fewer than five reporting equivalent IGT scores among participants display-
IGD criteria) and problem gaming (five or more criteria). ing gaming disorder symptoms and those without (Yao et al.,
Contrary to the hypotheses, the two groups did not differ in a 2015b). A study employing the Balloon Analogue Risk Task
hybrid task mixing stop signal and go/no-go trials. To explain (BARTda task assessing risk-taking under uncertainty as
these non-significant results, the authors questioned the outcomes are not predictable; Lejuez et al., 2002) reported that
validity of IGD criteria, mostly with respect to screening individuals with gaming disorder symptoms demonstrated
individuals according to high (but healthy) engagement and greater risk-taking than did individuals without (Qi et al.,
problematic use. In another study combining behavioral and 2015). Despite these possibly converging findings, these
fMRI analyses in a sample of patients with gaming disorder, results should be interpreted with caution. For example, the
Ding et al. (2014) failed to identify an inhibition impairment construct validity of the IGT has been debated (Buelow and
(in a go/no-go task) at the behavioral level, although those with Suhr, 2009) and this task is considered to measure decision-
gaming disorder demonstrated greater brain activation to making in a decreasingly ambiguous context (i.e., reinforce-
inhibit responses during no-go trials, suggesting the presence ment schedules are learned after having completed enough
of brain compensation mechanisms. Taken together, available trials, Persaud et al., 2007). Furthermore, tasks such as the IGT
evidence supports the existence of at least mild deficits in or the BART are affected by a variety of cognitive, affective,
prepotent response inhibition in gaming disorder. and motivational factors (e.g., reinforcement sensitivity,
somatic markers, executive functions), which complicate their
interpretation (e.g., Dunn et al., 2006).
Decision-making and related processes
Decision-making under risk refers to decision-making
Impairments in decision-making and related processes have in a situation where the individual has explicit informa-
been implicated in the etiology of SUD and gambling tion about the potential positive and negative consequences
disorder (Bickel et al., 2018; van Holst et al., 2010). of an action. Decision-making under risk can be measured
Several recent studies have investigated decision-making by tasks that provide the odds of gain/loss associated with
related in problematic gaming and gaming disorder (see each choice, such as the Game of Dice Task (GDT; Brand
Schiebener and Brand, 2017, for a review). These findings et al., 2005). Studies to date have consistently shown that
largely concern three types of cognitive processes, namely individuals with problematic gaming or gaming disorder
(1) decision-making under ambiguity, (2) decision-making engage in riskier decisions according to scores on the GDT
under risk, and (3) and delay discounting. (Pawlikowski and Brand, 2011; Yao et al., 2014), and other
Decision-making under ambiguity refers to decision- tasks measuring decision-making under risk (Dong and
making in a situation where no information is available Potenza, 2016; Yao et al., 2015a,b), and in probability
about the potential positive and negative consequences of discounting tasks where participants must choose between
a “small but safe” versus a “large but less safe” bets (Wang processes may lead to addiction-related cues acquiring a
et al., 2016, 2017b). These converging data, with the strong incentive value that increases attentional priority to
exception of the study by Deleuze et al. (2017b), suggest these cues (for a review, see Anderson, 2016). Similarly,
that gaming disorder is associated to a preference for riskier recent models of gaming disorder posit that attentional
choices. biases may contribute importantly to its etiology (Brand
Delay discounting refers to the relative preference for et al., 2016; Dong and Potenza, 2014). Available research
smaller immediate rewards as compared with larger delayed evidence can be divided into studies that (1) directly
rewards (Vanderveldt et al., 2016). The rewarding value of a measure general attention biases and (2) incorporate
stimulus proportionally decreases with the time of delay gaming stimuli (e.g., screenshots, game-related words) into
associated with its receipt, generally following a hyperbolic neurocognitive tasks that measure inhibitory control or
curve (Ainslie, 2016). Delay discounting is relevant in decision-makingerelated processes.
addictive disorders because these conditions are typically Research studies on attentional biases in problematic
defined by a preference for immediate gratification (i.e., gaming and gaming disorder have consistently reached the
short-term rewards) without considering the long-term costs same conclusion that problematic gaming is associated with
of use and benefits of abstinence and/or reduced consump- attentional bias for gaming-related stimuli. First, laboratory-
tion. A metaanalysis by MacKillop et al. (2011) reported that based studies by Metcalf and Pammer (2011) and Jeromin
compromised reward discounting was common in a range of et al. (2016a) have employed adapted Stroop tasks and found
addictive disorders, with a larger effect size (d ¼ 0.61) in that participants with problematic gaming showed greater
studies comparing clinical samples of individuals with SUD Stroop interference for game-related words (i.e., ability to
as compared to those without. Several caseecontrol studies selectively attend to color rather verbal information), thereby
have investigated delay discounting in adolescent and adult indicating a specific gaming-related attentional bias. Inter-
individuals with gaming disorder symptoms and matched estingly, Metcalf and Pammer (2011) also reported that
comparison subjects (Tian et al., 2018; Wang et al., individuals who frequently game but at nonproblematic
2017a,b,c; Weinstein et al., 2016). These studies consistently levels did not demonstrate this attentional bias. However, it
report that the gaming disorder groups demonstrated greater bears noting that a recent study by Jeromin et al. (2016b)
preferences than comparison subjects in choosing smaller, failed to replicate the attentional bias toward gaming words
immediate rewards over larger, delayed ones. effect. It should be noted, however, that this study was
conducted online and therefore was less-controlled, which
may have affected measurement of reaction time.
Cognitive biases Other experimental studies have employed visual probe
tasks to detect the presence of attentional biases in problematic
A cognitive bias is reflected by a systematic error in thinking
gaming, but these studies have reported mixed results. A study
or an automatic processing of specific stimuli that influences
behavior, which may lead to maladaptive behaviors and the by Zhang (2008) identified an attentional bias in problem
gaming (indicated by reduced reaction time for video game
development of psychopathological symptoms (Anderson,
stimuli); however, this result was not replicated in a later study
2016; Mineka and Sutton, 1992). There are different types of
by Jeromin et al. (2016a). However, Jeromin et al. (2016a)
cognitive biases, including biases affecting attention
employed pictures of gaming hardware as stimuli (e.g., a
(e.g., specific stimuli or categories of stimuli are perceived
computer screen, a game console) rather than specific game-
preferentially), memory (e.g., certain memories are prefer-
related stimuli (e.g., screenshot of specific video game), and
entially stored and/or accessed), or judgment (e.g., distorted
therefore the target stimuli may have been less salient for
beliefs that promote irrational behavior). In the context of
gaming disorder, cognitive biases may be classified into two participants. Attentional biases in gaming disorder have also
been evaluated in Event-Related Potential (ERP) studies.
broad categories: those related to attentional biases
Higher late positive potential (a potential marker of emotion
(e.g., preferential perceptual treatment of gaming-related
dysregulation) and higher P300 (an event-related potential
stimuli) and dysfunctional cognitions about gaming
related to stimulus evaluation or categorization) were identi-
(e.g., maladaptive and inflexible rules that guide gaming
fied in patients with gaming disorder following the presenta-
behavior and maladaptive metacognitive cognitions such as
tion of gaming cues (Dai et al., 2011; Kim et al., 2018).
beliefs about the uncontrollability of gaming behavior).
Several studies have investigated how game-related
stimuli influence performance on neurocognitive tasks by
Attentional biases
measuring specific cognitive processes implicated in the
There is considerable interest in the measurement and etiology of addictive disorders. Researchers have tested
modification of attentional biases in addictive disorders individuals with gaming disorder symptoms using adapted
(Cox et al., 2014; Robbins and Ehrman, 2004). Several go/no-go tasks that combine neutral and gaming cues.
models of addictive disorders state that associative learning These studies have found that inhibitory control is
compromised for these individuals when gaming cues are Dysfunctional beliefs and metacognitions about the self
displayed (Li et al., 2014; van Holst et al., 2012; Yao et al., in relation to gaming have also received scholarly attention
2015b). Yao et al. (2015b) have found that compromised (King and Delfabbro, 2014; Marino and Spada, 2017). As
inhibitory control when presented with gaming-related an example, gaming expectancies refer to cognitions
stimuli is associated with disadvantageous decision-making regarding the positive reinforcement value
in the last set of trials of the IGT (which may be considered (e.g., excitement) or negative reinforcement value
as measuring decision-making under risk rather than (e.g., relief of negative mood or boredom) associated with
decision-making under ambiguity, see Dunn et al., 2006). A gaming behavior. Models such as the I-PACE (Brand et al.,
pilot study by Nuyens et al. (2016) reported a positive 2016) and the theory of compensatory Internet use
correlation between features of problematic gaming and a (Kardefelt-Winther, 2014) suggest that gaming expec-
difficulty to postpone rewards in a discounting task using tancies may play a pivotal role in the development and
stimuli from participants’ favorite game. maintenance of gaming disorder. Research has found that
negative reinforcementebased expectancies (akin to
Dysfunctional cognitions about gaming “gaming to escape” as described in the DSM-5 IGD
criteria) are related to excessive and addictive patterns of
Early research on psychological factors influencing
video gaming (Billieux et al., 2015d; Kuss et al., 2012;
gaming disorder included investigation of dysfunctional
Yee, 2007). Another type of cognition/belief about the self
cognitions, guided by influential models such as Davis’ in relation to gaming that may influence problematic games
(2001) cognitive-behavioral model of pathological
is avatar identification (e.g., “I feel a special connection to
Internet use and some attempts to apply cognitive phe-
my game character, as it is a part of who I am”), positive
nomena observed in gambling to video gaming. Research
metacognitions about gaming (e.g., “online gaming helps
on gaming cognitions is a growing area that includes a
me to control my disturbing thoughts”), or negative meta-
range of debates and conceptualizations; therefore, it is
cognitions about gaming (e.g., “I am not able of controlling
beyond the scope of this chapter to summarize all of these
my involvement in video gaming”). Research in this area is
developments (see King and Delfabbro, 2014; Marino and
currently at a nascent stage; however, measurement tools
Spada, 2017, for comprehensive reviews and classification have been recently developed that are likely to stimulate
of gaming-related cognitions). For this discussion,
further research in this area (e.g., Beard and Wickham,
gaming-related maladaptive cognitions and beliefs have
2016; Forrest et al., 2016; Spada and Caselli, 2017).
been divided into two categories: (1) gaming-related
cognitive distortions and (2) and beliefs about the self in
relation to gaming. Key points and conclusion
A wide range of gaming-related cognitive distortions have
been proposed and investigated, particularly as gaming This chapter has shown that problem gaming and gaming
activities have become more sophisticated in their creation of disorder may be characterized by a range of specific cognitive
online worlds and identities for the player. This category refers deficits (impairment in inhibitory control and decision-
to cognitions with content that is “distorted” or “irrational” and making) and cognitive biases (attentional biases, maladap-
may promote persistent, excessive, or dysfunctional gaming tive gaming-related cognitions). Given findings in SUD and
behaviors (Davis, 2001; King and Delfabbro, 2014; Marino gambling disorder, these findings support the classification of
and Spada, 2017). Typical examples include cognitive gaming disorder together with these disorders as a behavioral
distortions about the world (e.g., “The online world is the only addiction (Saunders et al., 2017). They also suggest that dual-
place where I am respected”), cognitive distortions about system approaches (e.g., Mukherjee, 2010; Stacy and Wiers,
gaming-related achievement (e.g., “I can achieve more in 2010), which are currently dominant in SUD, might be applied
online video games than in the real world”), or cognitive to gaming disorder, this disorder then being conceptualized as
distortions about gaming-related behavioral rules (e.g., “I resulting from the imbalance between two distinct but inter-
cannot stop playing for now because of time and energy already acting neural systems: an “impulsive” bottom-up system
invested in the game”). The idiosyncratic nature and hetero- related to amygdala/striatum activity and driven toward
geneity of these cognitions may be influenced by the demands immediate reinforcement (positive and/or negative), and a
and structural characteristics of video games (for a recent “reflective” top-down system related to prefrontal activity
review, see Griffiths and Nuyens, 2017). The variety of gaming (Brand et al., 2016; D’Hondt et al., 2015; Dong and Potenza,
experiences and their varying influences on player cognitions 2014; Wei et al., 2017). Accordingly, gaming disorder
may pose some challenges in adapting standard psychological symptoms may manifest when the former system is
interventions used in other addictive disorders (e.g., cognitive- overactivated (e.g., when attentional focus is attracted by
behavioral therapy) (Delfabbro and King, 2015).
gaming-related cues) and the latter system impaired expectancies). This approach should foster the translation of
(e.g., when inhibitory control is compromised). The dual- these models to diagnostic, treatment, and prevention of
system approach of gaming disorder should also benefit gaming disorder.
from research that attempts to integrate study-specific Despite these advancements in theory and research,
(e.g., craving/stress induction, gaming/reward availability, some scholars have cautioned against a reliance on the
personalized gaming cue) and individual-specific (symptom “confirmatory” approach that considers all excessive
severity, length/intensity of use, active user vs. trying to quit) appetitive behaviors as similar to addictive disorders
factors, which have been shown to modulate impulsive and (e.g., using the same screening items for all behaviors) and
reflective processes rooted in SUD (Jasinska et al., 2014) and ignoring exploration of potential alternative etiologies
behavioral addictions (e.g., Brevers et al., 2018). It is, how- (Billieux et al., 2015c, 2017b; Kardefelt-Winther, 2017).
ever, worth noting that this dual-process approach is currently While there is growing evidence to support the validity and
criticized as most processes related to addictive disorders have appropriateness of the addiction model as relating to
been shown to simultaneously involve both systems, leading gaming behaviors, it bears noting that alternative models
to new theoretical models proposing a unique functionally may be tenable from conceptual and practical clinical per-
integrated system (Hommel and Wiers, 2017; Melnikoff and spectives, and alternative views and hypotheses should be
Bargh, 2018). Conversely, other authors have proposed a considered in further research (e.g., gaming disorder as an
triadic model, encompassing a third system responsible for impulse-control disorder, an obsessive-compulsive disor-
interoceptive processes (Noël et al., 2013), which has recently der, or a maladaptive coping strategy displayed in the
been conceptualized as a “gate” system that responds to ho- context of adversity or psychopathological symptoms,
meostatic perturbations and, in turn, has the capacity to “hi- Kardefelt-Winther, 2017; Starcevic and Aboujaoude,
jack” reflective processes toward addiction-related cues at the 2017). As has been recognized in studies of gambling
expense of executive control resources (Naqvi et al., 2014; disorder, it is likely that gaming disorder is a heterogeneous
Noël et al., 2013). This triadic model approach is also in line condition that consists of different subtypes (Billieux et al.,
with theoretical accounts that propose to embrace the diversity 2015d; Blaszczynski and Nower, 2002).
of combination between impulsive and reflective processes, There are multiple important avenues for future research
that is, as a functionally integrated system (Hommel and on gaming disorder. First, further research is necessary to
Wiers, 2017; Melnikoff and Bargh, 2018; Monterosso and improve classification of gaming disorder
Luo, 2013). Future studies will thus have to explore whether (e.g., maladaptive coping vs. addiction) and tailor preven-
dual-process (and triadic-process) approaches can satisfacto- tion and treatment strategies. Future research should also
rily account for the processes involved in gaming disorder or systematically investigate video game genres
whether other theoretical models provide a better explanation (e.g., massively multiplayer online role-playing games,
of the processes involved. Centrally, the current challenge is to first-person shooters, or multiplayer online battle arena; see
clarify whether the SUD models (e.g., dual-process) can be Table 16.1 for a comparison of structural characteristics of
applied or adapted to gaming disorder to promote a trans- these game genres) as related to gaming disorder. Given
diagnostic perspective of addictive disorders or whether it their different structural characteristics, some game genres
would be more efficient to develop separate models for SUD might differentially influence players’ cognitive functions
and behavioral addictions (e.g., Brand et al., 2016; Dong and (e.g., Bediou et al., 2018; Deleuze et al., 2017a).
Potenza, 2014), in view of the distinct nature of the processes Eventually, it will be necessary to refine the criteria
involved (e.g., specific gaming-related cognitive distortions or used to define gaming disorder. It is often noted that
TABLE 16.1 Comparison of structural characteristics of the three main online video game genres.
Massively multiplayer online role-

playing game Multiplayer online battle arena Online first person shooter
Persistent virtual worlds Achievement (with rankings) Action, precision, reflexes
Advancement system Social aspects (cooperation and battles PvP) Competition and cooperation
Achievement (quests, battles, events) Short and intense play sessions Achievement (defeating the enemy, accom-
Exploration and immersion (virtual Necessity to play regularly (to maintain plishing missions, reaching objectives)
worlds, lore, stories) level/ranking) e-Sport (broadcast of interna- Rewards (better items and weapons)
Social aspects (competition, coopera- tional tournament, millions of viewers)
tion, creation of guilds, virtual life)
PvP, player versus player.

inconsistencies across studies may be due to individuals Bediou, B., Adams, D.M., Mayer, R.E., Tipton, E., Green, C.S.,
highly involved in gaming (but nonproblematically) being Bavelier, D., 2018. Meta-analysis of action video game impact on
misidentified as having gaming disorder (Charlton and perceptual, attentional, and cognitive skills. Psychol. Bull. 144 (1),
77e110. https://doi.org/10.1037/bul0000130.
Danforth, 2007; Deleuze et al., 2018). The recently released
Bickel, W.K., Mellis, A.M., Snider, S.E., Athamneh, L.N., Stein, J.S.,
ICD-11 description, with its emphasis on impaired control
Pope, D.A., 2018. 21st century neurobehavioral theories of decision
and functional impairment (Billieux et al., 2017a), should making in addiction: review and evaluation. Pharmacol. Biochem.
help to reduce pathologization of healthy gaming and help Behav. 164, 4e21. https://doi.org/10.1016/j.pbb.2017.09.009.
to distinguish between “passionate” and “addictive” pat- Billieux, J., Deleuze, J., Griffiths, M.D., Kuss, D.J., 2015a. Internet
terns of gaming. As the identification and understanding of gaming addiction: the case of massively multiplayer online role-
problematic gaming and gaming disorder improves, so too playing games. In: el-Guebaly, N., Carrà, G., Galanter, M. (Eds.),
will the study of gaming-related cognitions. Textbook of Addiction Treatment: International Perspectives. Springer
Milan, Milano, pp. 1515e1525. https://doi.org/10.1007/978-88-470-
5322-9_105.
Conflict of interest Billieux, J., King, D.L., Higuchi, S., Achab, S., Bowden-Jones, H.,
Joël Billieux, Pierre Maurage, Damien Brevers, Matthias Brand, and Hao, W., et al., 2017a. Functional impairment matters in the screening
Daniel Luke King declare no conflict of interest. Marc Potenza has and diagnosis of gaming disorder: commentary on: scholars’ open
consulted for Shire, INSYS, Rivermend Health, Opiant/Lightlake debate paper on the World Health Organization ICD-11 Gaming
Therapeutics, and Jazz Pharmaceuticals; has received research support Disorder proposal (Aarseth et al.). J. Behav. Addict. 6 (3), 285e289.
(to Yale) from Mohegan Sun Casino and the National Center for https://doi.org/10.1556/2006.6.2017.036.
Responsible Gaming; has participated in surveys, mailings, or tele- Billieux, J., Maurage, P., Lopez-Fernandez, O., Kuss, D.J., Griffiths, M.D.,
phone consultations related to drug addiction, impulse-control disor- 2015b. Can disordered mobile phone use be considered a behavioral
ders or other health topics; has consulted for and/or advised gambling addiction? An update on current evidence and a comprehensive model
and legal entities on issues related to impulse-control/addictive dis- for future research. Curr. Addict. Rep. 2 (2), 156e162. https://doi.org/
orders; has provided clinical care in a problem gambling services 10.1007/s40429-015-0054-y.
program; has performed grant reviews for research funding agencies; Billieux, J., Schimmenti, A., Khazaal, Y., Maurage, P., Heeren, A., 2015c.
has edited journals and journal sections; has given academic lectures Are we overpathologizing everyday life? A tenable blueprint for
in grand rounds, CME events, and other clinical or scientific venues; behavioral addiction research. J. Behav. Addict. 4 (3), 119e123.
and has generated books or book chapters for publishers of mental https://doi.org/10.1556/2006.4.2015.009.
health texts. Billieux, J., Thorens, G., Khazaal, Y., Zullino, D., Achab, S., Van der
Linden, M., 2015d. Problematic involvement in online games: a
cluster analytic approach. Comput. Hum. Behav. 43, 242e250.
References https://doi.org/10.1016/j.chb.2014.10.055.
Billieux, J., van Rooij, A.J., Heeren, A., Schimmenti, A., Maurage, P.,
Ainslie, G., 2016. The cardinal anomalies that led to behavioral
Edman, J., et al., 2017b. Behavioural addiction open definition 2.0-
economics: cognitive or motivational? Manag. Decis. Econ. 37 (4e5),
using the open science framework for collaborative and transparent
261e273. https://doi.org/10.1002/mde.2715.
theoretical development: commentaries. Addiction 112 (10),
Anderson, B.A., 2016. What is abnormal about addiction-related
1723e1724. https://doi.org/10.1111/add.13938.
attentional biases? Drug Alcohol Depend. 167, 8e14. https://doi.
Blaszczynski, A., Nower, L., 2002. A pathways model of problem and
org/10.1016/j.drugalcdep.2016.08.002.
pathological gambling. Addiction 97, 487e499. https://doi.org/10.
Argyriou, E., Davison, C.B., Lee, T.T.C., 2017. Response inhibition and
1046/j.1360-0443.2002.00015.x.
internet gaming disorder: a meta-analysis. Addict. Behav. 71, 54e60.
Borsboom, D., 2017. A network theory of mental disorders. World Psy-
https://doi.org/10.1016/j.addbeh.2017.02.026.
chiatry 16 (1), 5e13. https://doi.org/10.1002/wps.20375.
Baggio, S., Starcevic, V., Studer, J., Simon, O., Gainsbury, S.M.,
Brand, M., Fujiwara, E., Borsutzky, S., Kalbe, E., Kessler, J.,
Gmel, G., Billieux, J., 2018. Technology-mediated addictive behav-
Markowitsch, H.J., 2005. Decision-making deficits of Korsakoff
iors constitute a spectrum of related yet distinct conditions: a network
patients in a new gambling task with explicit rules: associations
perspective. Psychol. Addict. Behav. 32 (5), 564e572. https://doi.org/
with executive functions. Neuropsychology 19 (3), 267e277.
10.1037/adb0000379.
https://doi.org/10.1037/0894-4105.19.3.267.
Bailey, K., West, R., Kuffel, J., 2013. What would my avatar do?
Brand, M., Young, K.S., Laier, C., Wölfling, K., Potenza, M.N., 2016.
Gaming, pathology, and risky decision making. Front. Psychol. 4,
Integrating psychological and neurobiological considerations regarding
609. https://doi.org/10.3389/fpsyg.2013.00609.
the development and maintenance of specific Internet-use disorders: an
Beard, C.L., Wickham, R.E., 2016. Gaming-contingent self-worth, gaming
Interaction of Person-Affect-Cognition-Execution (I-PACE) model.
motivation, and internet gaming disorder. Comput. Hum. Behav. 61,
Neurosci. Biobehav. Rev. 71, 252e266. https://doi.org/10.1016/j.
507e515. https://doi.org/10.1016/j.chb.2016.03.046.
neubiorev.2016.08.033.
Bechara, A., Damasio, A.R., Damasio, H., Anderson, S.W., 1994. Insen-
sitivity to future consequences following damage to human prefrontal
cortex. Cognition 50 (1e3), 7e15. https://doi.org/10.1016/0010-
0277(94)90018-3.
Brevers, D., Bechara, A., Kilts, C.D., Antoniali, V., Bruylant, A., Dom, G., Sabbe, W., Hulstijn, W., 2005. Substance use disorders and the
Verbanck, P., et al., 2018. Competing motivations: proactive response orbitofrontal cortex: systematic review of behavioural decision-
inhibition toward addiction-related stimuli in quitting-motivated making and neuroimaging studies. Br. J. Psychiatry 187, 209e220.
individuals. J. Gambl. Stud. 34 (3), 785e806. https://doi.org/10. https://doi.org/10.1192/bjp.187.3.209.
1007/s10899-017-9722-2. Dong, G., DeVito, E.E., Du, X., Cui, Z., 2012. Impaired inhibitory control
Brevers, D., Bechara, A., Cleeremans, A., Noël, X., 2013. Iowa Gambling in ‘internet addiction disorder’: a functional magnetic resonance
Task (IGT): twenty years after e gambling disorder and IGT. Front. imaging study. Psychiatry Res. Neuroimaging 203 (2e3), 153e158.
Psychol. 4. https://doi.org/10.3389/fpsyg.2013.00665. https://doi.org/10.1016/j.pscychresns.2012.02.001.
Buelow, M.T., Suhr, J.A., 2009. Construct validity of the Iowa gambling Dong, G., Lu, Q., Zhou, H., Zhao, X., 2010. Impulse inhibition in people
task. Neuropsychol. Rev. 19 (1), 102e114. https://doi.org/10.1007/ with Internet addiction disorder: electrophysiological evidence from a
s11065-009-9083-4. Go/NoGo study. Neurosci. Lett. 485 (2), 138e142. https://doi.org/10.
Charlton, J.P., Danforth, I.D.W., 2007. Distinguishing addiction and 1016/j.neulet.2010.09.002.
high engagement in the context of online game playing. Comput. Dong, G., Potenza, M.N., 2014. A cognitive-behavioral model of Internet
Hum. Behav. 23 (3), 1531e1548. https://doi.org/10.1016/j.chb. gaming disorder: theoretical underpinnings and clinical implications.
2005.07.002. J. Psychiatry Res. 58, 7e11. https://doi.org/10.1016/j.jpsychires.2014.
Choi, S.-W., Kim, H., Kim, G.-Y., Jeon, Y., Park, S., Lee, J.-Y., et al., 07.005.
2014. Similarities and differences among internet gaming disorder, Dong, G., Potenza, M.N., 2016. Risk-taking and risky decision-making in
gambling disorder and alcohol use disorder: a focus on impulsivity internet gaming disorder: implications regarding online gaming in the
and compulsivity. J. Behav. Addict. 3 (4), 246e253. https://doi.org/ setting of negative consequences. J. Psychiatry Res. 73, 1e8. https://
10.1556/JBA.3.2014.4.6. doi.org/10.1016/j.jpsychires.2015.11.011.
Coren, S., Ward, L.M., Enns, J.T., 1999. Sensation and Perception, fifth Dong, G., Zhou, H., Zhao, X., 2011. Male Internet addicts show impaired
ed. Harcourt Brace College Publishers, Fort Worth. executive control ability: evidence from a color-word Stroop task.
Cox, W.M., Fadardi, J.S., Intriligator, J.M., Klinger, E., 2014. Attentional Neurosci. Lett. 499 (2), 114e118. https://doi.org/10.1016/j.neulet.
bias modification for addictive behaviors: clinical implications. CNS 2011.05.047.
Spectr. 19 (03), 215e224. https://doi.org/10.1017/ Dunn, B.D., Dalgleish, T., Lawrence, A.D., 2006. The somatic marker
S1092852914000091. hypothesis: a critical evaluation. Neurosci. Biobehav. Rev. 30 (2),
Dai, S.Y., Ma, Q.G., Wang, X.Y., 2011. Attentional bias to addiction- 239e271. https://doi.org/10.1016/j.neubiorev.2005.07.001.
related stimuli in internet addiction patients: an ERP study (article Forrest, C.J., King, D.L., Delfabbro, P.H., 2016. The measurement of
in Chinese). J. Psychol. Sci. 34 (6), 1302e1307. maladaptive cognitions underlying problematic video-game playing
Davis, R.A., 2001. A cognitive-behavioral model of pathological Internet among adults. Comput. Hum. Behav. 55, 399e405. https://doi.org/10.
use. Comput. Hum. Behav. 17 (2), 187e195. https://doi.org/10.1016/ 1016/j.chb.2015.09.017.
S0747-5632(00)00041-8. Griffiths, M.D., Nuyens, F., 2017. An overview of structural characteristics
Deleuze, J., Christiaens, M., Nuyens, F., Billieux, J., 2017a. Shoot at first in problematic video game playing. Curr. Addict. Rep. 4 (3),
sight! First person shooter players display reduced reaction time and 272e283. https://doi.org/10.1007/s40429-017-0162-y.
compromised inhibitory control in comparison to other video game Griffiths, M.D., 1999. Internet addiction: fact or fiction ? Psychologist 12
players. Comput. Hum. Behav. 72, 570e576. https://doi.org/10.1016/ (5), 246e250.
j.chb.2017.02.027. Groman, S.M., James, A.S., Jentsch, J.D., 2009. Poor response inhibition:
Deleuze, J., Long, J., Liu, T.-Q., Maurage, P., Billieux, J., 2018. Passion or at the nexus between substance abuse and attention deficit/hyperac-
addiction? Correlates of healthy versus problematic use of videogames tivity disorder. Neurosci. Biobehav. Rev. 33, 690e698. https://doi.
in a sample of French-speaking regular players. Addict. Behav. 82, org/10.1016/j.neubiorev.2008.08.008.
114e121. https://doi.org/10.1016/j.addbeh.2018.02.031. Hommel, B., Wiers, R.W., 2017. Towards a unitary approach to human
Deleuze, J., Nuyens, F., Rochat, L., Rothen, S., Maurage, P., Billieux, J., action control. Trends Cognit. Sci. 21, 940e949. https://doi.org/10.
2017b. Established risk factors for addiction fail to discriminate 1016/j.tics.2017.09.009.
between healthy gamers and gamers endorsing DSM-5 Internet Jasinska, A.J., Stein, E.A., Kaiser, J., Naumer, M.J., Yalachkov, Y., 2014.
gaming disorder. J. Behav. Addict. 6 (4), 516e524. https://doi.org/10. Factors modulating neural reactivity to drug cues in addiction: a
1556/2006.6.2017.074. survey of human neuroimaging studies. Neurosci. Biobehav. Rev. 38,
Delfabbro, P., King, D., 2015. On finding the C in CBT: the challenges of 1e16. https://doi.org/10.1016/j.neubiorev.2013.10.013.
applying gambling-related cognitive approaches to video-gaming. Jeromin, F., Nyenhuis, N., Barke, A., 2016a. Attentional bias in excessive
J. Gambl. Stud. 31 (1), 315e329. Internet gamers: experimental investigations using an addiction Stroop
D’Hondt, F., Billieux, J., Maurage, P., 2015. Electrophysiological and a visual probe. J. Behav. Addict. 5 (1), 32e40. https://doi.org/10.
correlates of problematic Internet use: critical review and perspectives 1556/2006.5.2016.012.
for future research. Neurosci. Biobehav. Rev. 59, 64e82. https://doi. Jeromin, F., Rief, W., Barke, A., 2016b. Using two web-based addiction
org/10.1016/j.neubiorev.2015.10.005. Stroops to measure the attentional bias in adults with Internet Gaming
Ding, W., Sun, J., Sun, Y., Chen, X., Zhou, Y., Zhuang, Z., et al., 2014. Disorder. J. Behav. Addict. 5 (4), 666e673. https://doi.org/10.1556/
Trait impulsivity and impaired prefrontal impulse inhibition function 2006.5.2016.075.
in adolescents with internet gaming addiction revealed by a Go/No-Go
fMRI study. Behav. Brain Funct. 10 (1), 20. https://doi.org/10.1186/
1744-9081-10-20.
Kardefelt-Winther, D., 2014. A conceptual and methodological critique of Marino, C., Spada, M.M., 2017. Dysfunctional cognitions in online
internet addiction research: towards a model of compensatory internet gaming and Internet Gaming Disorder: a narrative review and new
use. Comput. Hum. Behav. 31, 351e354. https://doi.org/10.1016/j. classification. Curr. Addict. Rep. 4 (3), 308e316. https://doi.org/10.
chb.2013.10.059. 1007/s40429-017-0160-0.
Kardefelt-Winther, D., 2017. Conceptualizing Internet use disorders: Melnikoff, D.E., Bargh, J.A., 2018. The mythical number two. Trends
addiction or coping process? Psychiatry Clin. Neurosci. 71 (7), Cognit. Sci. 22, 280e293. https://doi.org/10.1016/j.tics.2018.02.001.
459e466. https://doi.org/10.1111/pcn.12413. Metcalf, O., Pammer, K., 2011. Attentional bias in excessive massively
Kim, S.N., Kim, M., Lee, T.H., Lee, J.-Y., Park, S., Park, M., et al., 2018. multiplayer online role-playing gamers using a modified Stroop task.
Increased attentional bias toward visual cues in internet gaming dis- Comput. Hum. Behav. 27 (5), 1942e1947. https://doi.org/10.1016/j.
order and obsessive-compulsive disorder: an event-related potential chb.2011.05.001.
study. Front. Psychiatry 9, 315. https://doi.org/10.3389/fpsyt.2018. Mineka, S., Sutton, S.K., 1992. Cognitive biases and the emotional dis-
00315. orders. Psychol. Sci. 3 (1), 65e69. https://doi.org/10.1111/j.1467-
King, D.L., Delfabbro, P.H., 2014. The cognitive psychology of internet 9280.1992.tb00260.x.
gaming disorder. Clin. Psychol. Rev. 34 (4), 298e308. https://doi.org/ Mukherjee, K., 2010. A dual system model of preferences under risk.
10.1016/j.cpr.2014.03.006. Psychol. Rev. 117 (1), 243e255. https://doi.org/10.1037/a0017884.
King, D.L., Delfabbro, P.H., Potenza, M.N., Demetrovics, Z., Billieux, J., Monterosso, J., Luo, S., 2013. Willpower is not synonymous with “ex-
Brand, M., 2018. Internet gaming disorder should qualify as a mental ecutive function”. Behav. Brain Sci. 36 (6), 707e726. https://doi.org/
disorder. Aust. N.Z. J. Psychiatry 52 (7), 615e617. https://doi.org/10. 10.1017/S0140525X1300112X.
1177/0004867418771189. Naqvi, N.H., Gaznick, N., Tranel, D., Bechara, A., 2014. The insula: a
King, D.L., Haagsma, M.C., Delfabbro, P.H., Gradisar, M., critical neural substrate for craving and drug seeking under conflict
Griffiths, M.D., 2013. Toward a consensus definition of pathological and risk. Ann. N.Y. Acad. Sci. 1316, 53e70.
video-gaming: a systematic review of psychometric assessment tools. Noël, X., Brevers, D., Bechara, A., 2013. A neurocognitive approach to
Clin. Psychol. Rev. 33 (3), 331e342. https://doi.org/10.1016/j.cpr. understanding the neurobiology of addiction. Curr. Opin. Neurobiol.
2013.01.002. 23 (4), 632e638. https://doi.org/10.1016/j.conb.2013.01.018.
Kuss, D.J., Griffiths, M.D., Karila, L., Billieux, J., 2014. Internet addic- Nuyens, F., Deleuze, J., Maurage, P., Griffiths, M.D., Kuss, D.J.,
tion: a systematic review of epidemiological research for the Last Billieux, J., 2016. Impulsivity in multiplayer online battle arena
decade. Curr. Pharm. Des. 20, 4026e4052. https://doi.org/10.2174/ gamers: preliminary results on experimental and self-report measures.
13816128113199990617. J. Behav. Addict. 5 (2), 351e356. https://doi.org/10.1556/2006.5.
Kuss, D.J., Louws, J., Wiers, R.W., 2012. Online gaming addiction? 2016.028.
Motives predict addictive play behavior in massively multiplayer Pawlikowski, M., Brand, M., 2011. Excessive internet gaming and deci-
online role-playing games. Cyberpsychol. Behav. Soc. Netw. 15 (9), sion making: do excessive World of Warcraft players have problems
480e485. https://doi.org/10.1089/cyber.2012.0034. in decision making under risky conditions? Psychiatry Res. 188 (3),
Lejuez, C.W., Read, J.P., Kahler, C.W., Richards, J.B., Ramsey, S.E., 428e433. https://doi.org/10.1016/j.psychres.2011.05.017.
Stuart, G.L., et al., 2002. Evaluation of a behavioral measure of risk Persaud, N., McLeod, P., Cowey, A., 2007. Post-decision wagering
taking: the balloon analogue risk task (BART). J. Exp. Psychol. Appl. objectively measures awareness. Nat. Neurosci. 10 (2), 257e261.
8 (2), 75e84. https://doi.org/10.1037//1076-898X.8.2.75. https://doi.org/10.1038/nn1840.
Levy, I., Snell, J., Nelson, A.J., Rustichini, A., Glimcher, P.W., 2010. Qi, X., Du, X., Yang, Y., Du, G., Gao, P., Zhang, Y., et al., 2015.
Neural representation of subjective value under risk and ambiguity. Decreased modulation by the risk level on the brain activation during
J. Neurophysiol. 103 (2), 1036e1047. https://doi.org/10.1152/jn. decision making in adolescents with internet gaming disorder.
00853.2009. Front. Behav. Neurosci. 9, 296. https://doi.org/10.3389/fnbeh.2015.
Li, Z.J., Li, Y., Guo, W., 2014. Pre-potent response inhibition functions 00296.
under “cold” and “hot” representations in excessive internet use col- Robbins, S.J., Ehrman, R.N., 2004. The role of attentional bias in sub-
lege students (article in Chinese). Chin. Ment. Health J. 28 (5), stance abuse. Behav. Cogn. Neurosci. Rev. 3 (4), 243e260. https://
374e380. doi.org/10.1177/1534582305275423.
Littel, M., van den Berg, I., Luijten, M., van Rooij, A.J., Keemink, L., Rumpf, H.-J., Achab, S., Billieux, J., Bowden-Jones, H., Carragher, N.,
Franken, I.H.A., 2012. Error processing and response inhibition in Demetrovics, Z., et al., 2018. Including gaming disorder in the ICD-
excessive computer game players: an event-related potential study: 11: the need to do so from a clinical and public health perspective:
error processing in gamers. Addict. Biol. 17 (5), 934e947. https://doi. commentary on: a weak scientific basis for gaming disorder: let us err
org/10.1111/j.1369-1600.2012.00467.x. on the side of caution (van Rooij et al., 2018). J. Behav. Addict. 7,
Long, J., Liu, T., Liu, Y., Hao, W., Maurage, P., Billieux, J., 2018. 556e561. https://doi.org/10.1556/2006.7.2018.59.
Prevalence and correlates of problematic online gaming: a systematic Saunders, J.B., Hao, W., Long, J., King, D.L., Mann, K., Fauth-
review of the evidence published in Chinese. Curr. Addict. Rep. 5, Bühler, M., et al., 2017. Gaming disorder: its delineation as an
359e371. https://doi.org/10.1007/s40429-018-0219-6. important condition for diagnosis, management, and prevention.
MacKillop, J., Amlung, M.T., Few, L.R., Ray, L.A., Sweet, L.H., J. Behav. Addict. 6 (3), 271e279. https://doi.org/10.1556/2006.6.
Munafò, M.R., 2011. Delayed reward discounting and addictive 2017.039.
behavior: a meta-analysis. Psychopharmacology 216 (3), 305e321.
https://doi.org/10.1007/s00213-011-2229-0.
Schiebener, J., Brand, M., 2017. Decision-making and related processes in addicts: evidence from the comparison with recreational Internet game
Internet Gaming Disorder and other types of internet-use disorders. Curr. users: recreational game users. Addict. Biol. 22 (6), 1610e1621.
Addict. Rep. 4 (3), 262e271. https://doi.org/10.1007/s40429-017-0156-9. https://doi.org/10.1111/adb.12458.
Shaffer, H.J., Hall, M.N., Vander Bilt, J., 2000. “Computer addiction”: a Wang, Y., Wu, L., Zhou, H., Lin, X., Zhang, Y., Du, X., Dong, G., 2017c.
critical consideration. Am. J. Orthopsychiatry 70 (2), 162e168. Impaired executive control and reward circuit in Internet gaming ad-
https://doi.org/10.1037/h0087741. dicts under a delay discounting task: independent component analysis.
Spada, M.M., Caselli, G., 2017. The metacognitions about online gaming Eur. Arch. Psychiatry Clin. Neurosci. 267 (3), 245e255. https://doi.
scale: development and psychometric properties. Addict. Behav. 64, org/10.1007/s00406-016-0721-6.
281e286. https://doi.org/10.1016/j.addbeh.2015.07.007. Wei, L., Zhang, S., Turel, O., Bechara, A., He, Q., 2017. A Tripartite
Stacy, A.W., Wiers, R.W., 2010. Implicit cognition and addiction: a tool neurocognitive model of Internet gaming disorder. Front. Psychiatry 8.
for explaining paradoxical behavior. Annu. Rev. Clin. Psychol. 6, https://doi.org/10.3389/fpsyt.2017.00285.
551e575. https://doi.org/10.1146/annurev.clinpsy.121208.131444. Weinstein, A., Abu, H.B., Timor, A., Mama, Y., 2016. Delay discounting,
Starcevic, V., 2013. Is Internet addiction a useful concept? Aust. N.Z. J. risk-taking, and rejection sensitivity among individuals with Internet
Psychiatry 47 (1), 16e19. https://doi.org/10.1177/0004867412461693. and video gaming disorders. J. Behav. Addict. 5 (4), 674e682. https://
Starcevic, V., Aboujaoude, E., 2017. Internet gaming disorder, obsessive- doi.org/10.1556/2006.5.2016.081.
compulsive disorder, and addiction. Curr. Addict. Rep. 4 (3), World Health Organization [WHO], 2015. Public Health Implications of
317e322. https://doi.org/10.1007/s40429-017-0158-7. Excessive Use of the Internet, Computers, Smartphones and Similar
Tian, M., Tao, R., Zheng, Y., Zhang, H., Yang, G., Li, Q., Liu, X., 2018. Electronic Devices. Report. Main Meeting Hall, Foundation for Pro-
Internet gaming disorder in adolescents is linked to delay discounting motion of Cancer Research, National Cancer Research Center, Tokyo,
but not probability discounting. Comput. Hum. Behav. 80, 59e66. Japan. WHO, Geneva, Switzerland.
https://doi.org/10.1016/j.chb.2017.10.018. World Health Organization, 2019. ICD-11 for Mortality and Morbidity
van Holst, R.J., Lemmens, J.S., Valkenburg, P.M., Peter, J., Veltman, D.J., Statistics. Retrieved July 17, 2019, From: https://icd.who.int/
Goudriaan, A.E., 2012. Attentional bias and disinhibition toward browse11/l-m/en.
gaming cues are related to problem gaming in male adolescents. Xing, L., Yuan, K., Bi, Y., Yin, J., Cai, C., Feng, D., et al., 2014. Reduced
J. Adolesc. Health 50 (6), 541e546. https://doi.org/10.1016/j. fiber integrity and cognitive control in adolescents with internet
jadohealth.2011.07.006. gaming disorder. Brain Res. 1586, 109e117. https://doi.org/10.1016/j.
van Holst, R.J., van den Brink, W., Veltman, D.J., Goudriaan, A.E., 2010. brainres.2014.08.044.
Why gamblers fail to win: a review of cognitive and neuroimaging Yao, Y.-W., Chen, P.-R., Chen, C., Wang, L.-J., Zhang, J.-T., Xue, G.,
findings in pathological gambling. Neurosci. Biobehav. Rev. 34 (1), et al., 2014. Failure to utilize feedback causes decision-making deficits
87e107. https://doi.org/10.1016/j.neubiorev.2009.07.007. among excessive Internet gamers. Psychiatry Res. 219 (3), 583e588.
Vanderveldt, A., Oliveira, L., Green, L., 2016. Delay discounting: pigeon, https://doi.org/10.1016/j.psychres.2014.06.033.
rat, humanddoes it matter? J. Exp. Psychol. Anim. Learn. Cognit. 42 Yao, Y.-W., Chen, P.-R., Li, S., Wang, L.-J., Zhang, J.-T., Yip, S.W.,
(2), 141e162. https://doi.org/10.1037/xan0000097. et al., 2015a. Decision-making for risky gains and losses among
Verbruggen, F., Logan, G.D., 2008. Automatic and controlled response college students with Internet Gaming Disorder. PLoS One 10 (1),
inhibition: associative learning in the go/no-go and stop-signal para- e0116471. https://doi.org/10.1371/journal.pone.0116471.
digms. J. Exp. Psychol. Gen. 137, 649e672. https://doi.org/10.1037/ Yao, Y.-W., Wang, L.-J., Yip, S.W., Chen, P.-R., Li, S., Xu, J., et al.,
a0013170. 2015b. Impaired decision-making under risk is associated with
Wang, L., Wu, L., Lin, X., Zhang, Y., Zhou, H., Du, X., Dong, G., 2016. gaming-specific inhibition deficits among college students with
Dysfunctional default mode network and executive control network in Internet gaming disorder. Psychiatry Res. 229 (1e2), 302e309.
people with Internet gaming disorder: independent component anal- https://doi.org/10.1016/j.psychres.2015.07.004.
ysis under a probability discounting task. Eur. Psychiatry 34, 36e42. Yee, N., 2007. Motivations for play in online games. Cyberpsychol.
https://doi.org/10.1016/j.eurpsy.2016.01.2424. Behav. 9 (6), 772e775. https://doi.org/10.1089/cpb.2006.9.772.
Wang, Y., Hu, Y., Xu, J., Zhou, H., Lin, X., Du, X., Dong, G., 2017a. Young, K.S., 1998. Internet addiction: the emergence of a new clinical
Dysfunctional prefrontal function is associated with impulsivity in disorder. Cyberpsychol. Behav. 1 (3), 237e244. https://doi.org/10.
people with internet gaming disorder during a delay 1089/cpb.1998.1.237.
discounting task. Front. Psychiatry 8, 287. https://doi.org/10.3389/ Zhang, Z.J., 2008. Heavy online-game user’s attention bias and its ERP
fpsyt.2017.00287. patterns (article in Chinese). Chin. J. Appl. Psychol. 14 (4), 291e296.
Wang, Y., Wu, L., Wang, L., Zhang, Y., Du, X., Dong, G., 2017b.
Impaired decision-making and impulse control in Internet gaming
Chapter 17
Cognitive bias modification in the

treatment of addiction
Reinout W. Wiers1, Oulmann Zerhouni2, Tess den Uyl1 and Marilisa Boffo1, 3
1
Addiction Development and Psychopathology (ADAPT) Laboratory, Department of Psychology, University of Amsterdam, Amsterdam, The
Netherlands; 2UFR Sciences Psychologiques et Sciences de l’Éducation (SPSE), Université Paris Nanterre, Paris, France; 3Department of
Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, The Netherlands
Introduction studies (typically done in students not motivated to change)

and on the other hand, behavior change studies, typically
Conceptually, cognitive training interventions can be randomized controlled trials (RCTs), in clinical samples
divided into two broad classes: training of general abilities (Sheeran et al., 2017; Wiers et al., 2018a,b). Note that a
(e.g., working memory (WM), covered in Chapter 18) and recent metaanalysis cast doubt on the clinical usefulness of
training of automatically activated reactions (i.e., cognitive CBM for addiction, but it combined PoP studies in students
biases) to disorder-related stimuli, which fall under the with RCTs in clinical samples (Cristea et al., 2016). A
general heading of cognitive bias modification (CBM, recent review in which the “apples and oranges” were
Wiers, 2018; Wiers et al., 2013). In CBM, different sorted (Wiers et al., 2018a,b) demonstrated that CBM has
cognitive biases can be targeted, all in relation to motiva- an add-on effect to regular treatment in clinical samples,
tionally salient environmental and internal cues relating to a which was also suggested by a recent Bayesian meta-
substance or addictive activity: (a) selective attentional analysis of patient-level data including only clinical studies
processes toward (salient) substance-related cues (atten- (Boffo et al., 2019), although more evidence is needed to
tional bias, AtB), (b) behavioral approach tendencies irrefutably establish CBM therapeutic effects.
associated with the rewarding outcome of substance use The chapter is organized as follows: we first discuss the
(approach bias, ApB), and (c) memory associations research in two branches of CBM that have been used in
(memory bias; see for a review Wiers et al., 2013). CBM behavior change studies in clinical samples, AtB and ApB
interventions aim to modulate the relative strength of these modification (AtBM and ApBM, respectively). We then
biases, to allow for more adaptive behavior and emotion discuss research aimed at a memory bias, with an emphasis
regulation. For example, memory bias can be targeted on the role of awareness, which has so far mostly been used
through a computerized procedure in which addiction cues in preclinical experimental studies. We then discuss what is
are selectively inhibited, such as a modified go/no-go task, known of neurocognitive mechanisms underlying CBM. In
in which addiction cues are always coupled with a no-go the final section, we discuss ways forward, both regarding
response (Houben et al., 2011, 2012), making the affec- optimizing clinical applications, including combinations of
tive evaluation of those stimuli more negative. Note that CBM with neurostimulation, and by making training more
response inhibition can be trained both as a general ability motivating and personally relevant.
(without addiction cues, such as WM training, see Wiers,
2018) and in relation to addiction cues (i.e., cue-specific
response inhibition), which makes it is a form of CBM Attentional bias modification
(see, Wiers, 2018) as discussed in Chapter 19. CBM started with the seminal study of MacLeod et al.
Importantly, when synthesizing research in a clinically (2002), in the domain of anxiety, in which selective
relevant domain such as CBM, it is crucial to distinguish at attention toward threatening cues was manipulated (i.e.,
least between two types of qualitatively different studies: AtB). Before this study, many studies had found correla-
on the one hand, experimental proof-of-principle (PoP) tions between AtB and anxiety. However, cross-sectional

studies do not provide evidence for causal relationships, 2005), which was not done in a study with heavy drinking
which require the adoption of an experimental approach students (Schoenmakers et al., 2007), where continued
(Spencer et al., 2005). The primary purpose of early PoP assessment was used as a control condition. While these
CBM studies was then to systematically manipulate first studies found effects on the AtB for trained stimuli, no
disorder-relevant cognitive biases and test the effects on generalization was found to untrained stimuli (Field et al.,
disorder-related symptoms. These were typically done in 2007; Schoenmakers et al., 2007).
student volunteers without a disorder (e.g., students with Similar to the anxiety domain, the second step was to
medium levels of anxiety). Participants were randomly move out of the lab and evaluate the effects of CBM in
assigned to a condition in which their attention was trained studies with a clinical goal (abstinence or reduction of use)
toward or away from threatening stimuli. The latter group in individuals aware of the behavior change goal of the
showed less anxiety during a subsequent stressful task intervention. These studies have been summarized in recent
compared with the first group. Note that to establish cau- narrative reviews of all CBM studies in the alcohol (Wiers
sality, psychological constructs can be manipulated in both et al., 2018a) and tobacco use disorder (TUD) domains
directions: toward or away from disorder-relevant stimuli, (Mühlig et al., 2017), and in a (Bayesian) metaanalysis of
which is not done in clinical trials for obvious ethical individual participant data from exclusively clinical studies
reasons (Wiers et al., 2018a). After establishing the causal evaluating CBM as a treatment intervention for alcohol use
role of AtB in disorder-relevant symptoms (in this case, disorder (AUD) and TUD (Boffo et al., 2019).
sensitivity to stress), later studies also tested the effects of Three clinical studies used multiple sessions of AtBM in
AtBM as a treatment intervention in clinical samples AUD patients using training varieties of the visual probe
(e.g., Amir et al., 2009). Given these initial successes and task1 (as in MacLeod and colleagues). The first small RCT
the fact that AtBM, and more in general CBM, typically included 43 patients, who received five sessions of AtBM
employs computerized interventions, large online trials training or sham training in addition to regular treatment
were conducted. These largely resulted in nonsignificant (Schoenmakers et al., 2010). AtB for alcohol was reduced in
findings, related to the fact that in most cases, the targeted the experimental condition (with generalization to untrained
bias was not changed when AtBM was delivered online alcohol stimuli). Although there was no significant effect of
(see Macleod and Clarke, 2015). Metaanalyses focusing on AtBM on the primary outcome measures, there was an
clinical samples (Heeren et al., 2015; Linetzky et al., 2015) indication of clinical impact: patients in the experimental
concluded that there are reliable effects of AtBM on AtB condition were discharged from treatment earlier than pa-
and clinical symptoms in the anxiety domain. A recent tients in the control condition and relapsed later. A second
individual participant data metaanalysis (including patient- small RCT (86 participants randomized over four condi-
level data from 13 clinical studies), confirmed this (Price tions) combined eight sessions of experimental or placebo
et al., 2016), with training setting (clinical context or AtBM training for alcohol and threatening cues in AUD
online) as a significant moderator (smaller effects for patients with social anxiety (Clerkin et al., 2016). Alcohol
training online). Hence, from AtBM studies on anxiety, AtB was reduced, as well as AUD outcomes across all
where CBM started, we can learn that it is crucial to conditions (no Time by Condition interaction).
distinguish PoP studies from clinical RCTs; that within Cox et al. (2015) combined AtBM training and moti-
RCTs, it is important to distinguish online trials from vational enhancement, in 148 university- and community-
studies in a clinic; and that to establish effects on clinically recruited individuals who wanted to reduce their drinking.
relevant outcomes, it is important to first test whether the The training paradigm employed was the Alcohol Attention
targeted bias is successfully manipulated. Control Training Program (AACTP), which had shown
In the field of addiction, a similar development can be promise in an earlier uncontrolled study in which problem
observed. Many cross-sectional studies had demonstrated
that an AtB toward substance-related cues was related to
addictive behaviors (review and metaanalysis: Field and 1. In this task, participants have to respond to a probe presented at the
Cox, 2008; Rooke et al., 2008). First experimental studies location of one of the two stimuli on the computer screen, such as a
investigated the causal status of AtB, by testing whether picture of a bottle of wine and a picture of a bottle of water. When used to
assess AtB, the probe is presented equally often at the location previ-
changing AtB in students resulted in short-lived changes in ously occupied by both types of stimuli. Typically, participants respond
alcohol intake directly after the manipulation (Field et al., faster when the probe appears at the location on which their attention was
2007; Field and Eastwood, 2005; Schoenmakers et al., already focused (i.e., selective attention or AtB), e.g., in the case of
2007). Again, note that in some of these studies, one drinkers, on the picture depicting the bottle of wine. When used for
experimental group was trained toward alcohol to test training, the task includes a built-in stimuluseresponse contingency
systematically presenting the probe at the location of the neutral stimulus
whether this resulted in increased drinking in a bogus “taste (i.e., the picture of the bottle of water), thus training participants
test,” compared with a group that was trained away from to consistently shift attention away from substance-related cues and to
the alcohol stimuli (Field et al., 2007; Field and Eastwood, attend to neutral cues instead.
Cognitive bias modification in the treatment of addiction Chapter | 17 233
drinkers reduced drinking compared with baseline (Fadardi one AtBM session and 2 of sham training, or three sessions
and Cox, 2009). The AACTP uses training varieties of the of sham training. Participants did show a strong smoking
emotional Stroop Task and employs increasing levels of AtB bias at baseline, which significantly decreased in the
difficulty to motivate participants. In a study by Cox et al. short term (24 h and 1-month follow-up) in the group
(2015), AACTP and motivational enhancement could both receiving three sessions of AtBM. However, no group by
be present or absent (2 2 design). AACTP led to reduced time interaction effects was found on any of the behavioral
drinking in the short term (3 but not 6 months after the outcomes, which decreased across all groups. Note that the
intervention). Motivational enhancement reduced drinking 3 study suffered from 24% dropout after the 24 h posttest,
and 6 months after the intervention. The AACTP paradigm greatly decreasing power to detect interaction effects over
was also deployed in the first online CBM study in alcohol time (the groups had an n w 15 across the follow-ups).
addiction (Wiers et al., 2015c) comparing the effects of In contrast to the only online study of AtBM for AUD
AACTP with different varieties of ApBM (discussed below), (Wiers et al., 2015c), the first online study of AtBM for
including a sham control condition. A main effect of time smoking cessation (N ¼ 434 treatment-seeking smokers
was found, in the absence of an interaction with condition: recruited online; Elfeddali et al., 2016) did find an
hence, participants in all conditions reduced their drinking, increased abstinence rate only among heavy smokers (50%
which was also their goal (not abstinence). compared with 25% in the sham training control group).
A very recent large study (N ¼ 1405 AUD inpatients, However, the effect on AtB reduction was not significant
not yet included in the metaanlyses) examined two types of (probably again related to poor reliability of the visual
CBM as add-on to regular treatment: six sessions of AtBM probe task as an assessment instrument and to participants
or ApBM (discussed below) or the combination of the two not showing a strong smoking AtB at baseline). The more
(three sessions each; Rinck et al., 2018). A long-term effect positive finding in this online study could be related to the
was found for all three active CBM conditions, with 8.4% abstinence goal and motivation for treatment (before start-
less relapse 1 year after treatment discharge compared with ing the training, participants were checked to have actually
patients receiving sham training or no training. When made a quit attempt on the indicated quit day).
looking at the effects on AtB (with much incomplete data; The use of AtBM in other substance use disorders has
as the study was added to everyday practice, in the context been less explored, with one feasibility study examining the
of strict data privacy regulations prescribing that computers clinical effects of three sessions of AACTP in a sample of
are “cleaned” every night, data on biases are missing from 48 male opiate abusers on methadone replacement therapy
about half of the patients), the three active CBM groups (Ziaee et al., 2016) and one in heavy cannabis users (Wolf
showed no significant decrease in AtB, likely related to et al., 2016). Ziaee et al. found that the AACTP group
participants already showing an AtB away from alcohol at showed a greater reduction in AtB than the control group at
baseline. Further, changes in AtB did not mediate the posttest (but not at follow-up), temptations to use, and
clinical effect, which is likely related to the poor reliability number of relapses from baseline to 3- and 6-month follow-
of the visual probe task as an assessment instrument (Ataya up. Wolf et al. (2016), in contrast, did not find training
et al., 2012) and to the absence of a strong AtB toward effects in a small sample (N ¼ 17).
alcohol at baseline. Interestingly, although no effect was In summary, AtBM shows promise as adjunct treatment
found on alcohol AtB, AtBM alone and in combination intervention for AUD (Schoenmakers et al., 2010; Rinck
with ApBM showed a crossover effect on the other targeted et al., 2018), but a major limitation concerns the low reli-
bias, ApB for alcohol. ability of the most often used assessment instrument, the
In the TUD domain, the evidence on the effect of AtBM visual probe task, which makes it hard to show effects on
as a behavior change intervention is still very limited. To the bias and therefore to find mediation of the clinical
date, only two studies evaluated multiple sessions of AtBM effects by change in AtB. Although the evidence is
training on top of standard treatment (Begh et al., 2015; currently very limited, there is also some promise to use
Lopes et al., 2014). In Begh et al. (2015), 118 adult AtBM to help people quit smoking, even when done in an
smokers seeking help to quit completed five sessions of online format only (Elfeddali et al., 2016), which has
either AtBM or sham training on top of a smoking cessation generally found less strong effects compared with training
program. Training effects were neither found on smoking- in a more controlled setting.
related AtB nor on craving, abstinence rates, or other
clinical outcomes. Note that the sample showed on average
no AtB toward smoking cues before treatment, which may
Approach bias modification
have hindered the detection of effects for those with high Based on emotion theory, in which an appraisal and action
level of AtB at baseline. In contrast, in Lopes et al. (2014), tendency are distinguished (Frijda, 1986), one can distin-
67 adult smokers attending group CBT to quit smoking guish between an AtB for addiction-related stimuli and an
were randomized to receive either three sessions of AtBM, associated action tendency, in the case of addiction
typically approach (Wiers et al., 2009, 2013). Different postdischarge, the ApBM group showed a 21% lower
tasks have been developed to assess the approach bias, relapse rate than the sham training group (statistical trend
including varieties of the approach avoidance task (AAT, for intention-to-treat [ITT] analysis and significant for per-
Rinck and Becker, 2007), which was originally developed protocol analysis). Training task performance improved in
as a relevant-feature task (i.e., in one block, the instruction the ApBM group (i.e., increased accuracy in pushing away
was to pull the joystick in response to disorder-relevant alcohol) but did not predict relapse rate. Finally, in the
stimuli, whereas in another block, the instruction was to previously mentioned recent large study (N ¼ 1405; Rinck
push the joystick to disorder-relevant stimuli) but later used et al., 2018), all three active CBM conditions showed better
as an irrelevant-feature task, in which participants react to clinical outcomes (8.4% lower relapse rate) at 1-year
content-irrelevant feature of the stimulus, such as picture follow-up than sham training or no training. Similar to
format (Wiers et al., 2009) or orientation (Cousijn, 2011). the AtBM results, participants did not show an ApB toward
The disadvantage of using an irrelevant-feature version of a alcohol at baseline. However, ApBM and the combination
task is that the reliability is lower than for a relevant-feature of ApBM and AtBM significantly modified the ApB into an
task (Field et al., 2011), but the advantage is that the task avoidance bias. The effect was yet small and did not
can be changed from an assessment task to a modification mediate the training effect on relapse, most likely because
instrument without changing the instructions (Wiers et al., of measurement issues and loss of training data for half the
2010). In this first proof-of-concept study in moderately sample. Finally, the first online study testing both AtBM
drinking students, participants were randomly assigned to a and ApBM as a stand-alone intervention, already
condition in which they started pulling in response to most mentioned above (Wiers et al., 2015c), showed a significant
of the alcohol pictures and pushing in response to most of decrease in drinking over time irrespective of condition.
the nonalcohol pictures (“approach alcohol condition”) or In the smoking domain, the evidence for ApB is still
to a condition with reversed contingencies (“avoid alcohol very limited with only four clinical studies. Three studies
condition”). It was found that the bias changed in accor- examined the effects of four sessions of ApB against a
dance with training condition, with effects on untrained sham training condition, two on top of CBT-based treat-
stimuli (typically not found in AtBM), and on a relevant- ment for TUD (Kong et al., 2015; Machulska et al., 2016)
feature task of implicit memory associations, the Implicit and one as a stand-alone intervention (Baird et al., 2017). In
Association Test (IAT), in which alcohol and soft drink Kong et al. (2015) and Machulska et al. (2016), 60
words were combined with approach or avoid words in adolescent and 145 adult smokers, respectively, completed
different conditions (Ostafin and Palfai, 2006). In addition, four sessions of ApBM or sham training on top of smoking
an effect was found on alcohol consumption in a taste test, cessation treatment (e.g., CBT or psychiatric treatment). In
with heavier drinkers who had been successfully trained to both studies, no changes in smoking ApB as a result of the
avoid alcohol drinking less than heavier drinkers who had ApBM intervention were observed, with no significant
been successfully trained to approach alcohol. After this difference in smoking outcomes in Kong et al. (2015).
first successful proof-of-concept study, four studies tested However, in Machulska et al. (2016), the ApBM did result
ApBM as add-on to treatment for AUDs. in a continued, larger decrease in self-reported amount of
In the first study (N ¼ 214), four sessions of ApBM cigarettes at follow-up in the ApBM group, which was not
resulted in reduced alcohol ApB, with generalization to mediated by changes in smoking ApB. In Baird et al.
alcohol-approach implicit associations in the IAT and 13% (2017), 52 treatment-seeking smokers were randomized to
lower relapse rate a year after treatment discharge, either stand-alone ApBM or sham training before a self-
compared with controls (Wiers et al., 2011). Mediation of guided quit attempt and were assessed again a week later.
the clinical effect by change in ApB was not found, Although there was no group difference in amount of days
although a later analysis using a different mathematical abstinent after the quit attempt, the ApBM group showed a
method to estimate the change in bias did find support for significant reduction in smoking ApB. Further, a greater
mediation by the change in alcohol-approach associations decrease in ApBM (but not baseline level of ApB) was
in the IAT (Gladwin et al., 2015). In the second large study associated with a larger decrease in amount of days absti-
(N ¼ 509), 12 sessions of ApBM, compared with no nent (independently of condition).
training, resulted in 9% lower relapse rate at 1-year follow- The last study (N ¼ 257 adult smokers recruited online)
up, and this effect was mediated by the change in ApB explored the short-term effects of one session of ApBM
(Eberl et al., 2013). Moderation was also found, with a delivered online, compared with a waitlist control condition
stronger effect on the change in bias in patients with a (Wittekind et al., 2015). Despite almost 30% dropout rate,
relatively strong alcohol ApB before training. A third study both per-protocol and ITT analyses showed a significant
(N ¼ 83) in Australia investigated the effect of four ses- decrease in self-reported smoking, craving, and symptoms of
sions of ApBM versus sham training administered during tobacco dependence in the ApB group at 4-week follow-up.
alcohol detoxification (Manning et al., 2019). At 2-week
In summary, these findings indicate that ApBM shows a pioneering work using open-ended memory associations by
positive add-on effect in the treatment of AUD. This effect Szalay and Stacy and colleagues (Stacy, 1997; Stacy et al.,
is small but similar to the effect of medication (number 1994; Szalay et al., 1992), followed by first reaction time
needed to treat of 12,2 see Wiers et al., 2018b). When measures (Palfai and Wood, 2001; Wiers et al., 2002). Find-
looking at the clinical efficacy of ApBM in TUD, evidence ings can be summarized as follows (see for review and
for positive effects is still scarce and inconsistent. Note that metaanalysis: Roefs et al., 2011; Rooke et al., 2008; Stacy and
regarding other addictions, first PoP studies in cannabis Wiers, 2010): heavy drinkers tend to have stronger positive
users have been conducted (Jacobus et al., 2018; Sherman associations with alcohol than light drinkers, and stronger
et al., 2018) but no RCTs yet in clinical samples. These positive associations are related to heavier drinking. Similar
findings are in line with the results of a Bayesian meta- results have been observed for smoking (e.g., McCarthy and
analysis of patient-level data from 14 clinical CBM studies Thompsen, 2006), and implicit associations with smoking
(Boffo et al., 2019), which showed small effects of CBM in have also been associated with craving for tobacco (Waters
general on cognitive bias and relapse rate but not on et al., 2007), as well as dependence and difficulty quitting
reduction of substance use (note that only studies published smoking (Chassin et al., 2010). The relationship between as-
until May 2016 were included, hence not including the sociations and consumption is even stronger when individuals
evidence provided by the more recent studies by Rinck score low on executive functions, as now many studies have
et al., 2018; Baird et al., 2017; and Ziaee et al., 2016). demonstrated (Friese et al., 2015; Grenard et al., 2008;
Noteworthy, the effects of CBM on bias reduction were Hofmann et al., 2008; Houben and Wiers, 2009; Thush et al.,
found to be stronger for AUD than for TUD, most likely 2008). Substance associations are not necessarily formed
related to the greater amount of studies in the alcohol through direct experience with substances, as they are also
domain and to the inconsistency of results in the few influenced by the social environment. For example, associa-
clinical TUD studies. However, both effects on bias tions were found to predict alcohol consumption 1 year later in
reduction and relapse rate were associated with much adolescents (Thush and Wiers, 2007) and found to be influ-
uncertainty (i.e., extremely wide 95% Bayesian credible enced by the degree of parental approval toward alcohol
intervals), indicating the need for a larger body of evidence (Payne et al., 2016). Implicit associations have also been
to draw firm conclusions about the clinical effectiveness of shown to explain substance use beyond direct measures
CBM interventions. (Rooke et al., 2008) and to prospectively predict substance use
The latter result is of particular importance when sum- and problems (Lindgren et al., 2013, 2016; Stacy, 1997).
marizing the extant evidence of treatment effects: one of the From these findings, the question arises on how asso-
advantages of the Bayesian approach is in fact the possi- ciations can be modified to reduce substance use. As
bility of quantifying the likelihood that a hypothesis is mentioned above, one paradigm used to this end has been
truedotherwise not possible within the classical frequentist selective inhibition, discussed in Chapter 19. Another well-
approachdtherefore providing a realistic summary of the established paradigm to alter evaluative memory associa-
available evidence in favor or against a hypothesized effect. tions is evaluative conditioning (EC), which has been
To date, the use of CBM as a behavior change interventions defined as a change in the evaluation of the valence of a
for addiction disorders appears to be still in its infancy, and conditioned stimulus (CS, here a substance-related
a larger amount of clinical studies is necessary to fully stimulus) after it has been paired with a positive or nega-
establish the robustness and reproducibility of its clinical tive unconditioned stimulus (US, metaanalysis: Hofmann
effectiveness (Boffo et al., 2019). et al., 2010). Studies have shown that EC can change both
indirect and direct measures of smoking evaluations and
smoking (Magurean et al., 2016), as well as alcohol eval-
Memory bias modificationdevaluative uations and alcohol consumption (Houben et al., 2010a,b).
conditioning However, the processes by which EC affects memory
Another approach to CBM is to focus on memory associations associations, and consequently behaviors, remain unclear.
between substance-related concepts and (automatically acti- Traditionally, EC was thought to change associations by
vated) evaluations. Substance-related memory associations exerting its effect outside conscious awareness, in contrast
have now been studied for over 2 decades, starting with the to classical conditioning (De Houwer et al., 2001; Sweldens
et al., 2014). More recently, the idea gained support that
conscious detection of CS-US pairings may be necessary
2. This number indicates how many patients would have to be treated for EC. Methodological refinements in assessing contin-
(based on statistical outcomes) to make a difference in the outcome. Hence gency awareness revealed that EC effects were only
a strong effect is reflected in a low NNT, e.g., NNT ¼ 4 would indicate
that four patients are needed (on average) to make the difference in one.
observed in those participants with contingency awareness
For CBM as add-on (and medication) in alcohol use disorders, the NNT is (Pleyers et al., 2007, 2009). However, other evidence
around 12. suggests that, under certain conditions, EC may occur
independently of contingency awareness (Rydell and 2015b). After training, patients in the ApBM condition
McConnell, 2006; Walther and Nagengast, 2006). More showed reduced cue reactivity to alcohol in the amygdala,
recently, more sensitive methods have been proposed for which correlated with cue-induced craving, and reductions in
assessing contingency awareness, which are more sensitive neural cue reactivity correlated with reductions in craving in
to implicit encoding (Hütter et al., 2012; see for an appli- the ApBM group only. In a second study, effects of ApBM on
cation to alcohol, Zerhouni et al., 2018). The current weight neural correlates of the alcohol ApB were studied in 26 pa-
of the evidence suggests that awareness plays an important tients, who performed an fMRI-adapted version of the AAT
role in EC effects (review: Corneille and Stahl, 2018; but before and after ApBM (Wiers et al., 2015a,b,c). Before
see Greenwald and De Houwer, 2017 for recent evidence in training, both groups showed significant alcohol ApB-
favor of unconscious conditioning). When applied to related activation in the medial PFC. After training,
addiction, EC was also found to be more effective when it patients in the CBM group showed stronger reductions in
had features encouraging the implementation of proposi- medial PFC compared with the sham training group. These
tional rather than associative processes (Zerhouni et al., reductions in neural cue reactivity correlated with reductions
2018). Similarly, Magurean et al. (2016) highlighted con- in ApB scores in the CBM group only. These studies indicate
tingency awareness as a necessary condition for EC to have that ApBM reduces the activation in brain areas that represent
an effect on smoking-related measures. It has been pro- the motivational salience of alcohol cues.
posed that the formation of propositional beliefs between
the CS and the US (i.e., inferring a relation between stim-
uli) is critical in generating EC effects (De Houwer, 2018).
Toward optimized clinical applications
This logic can be used to improve CBM (Van Dessel et al., of cognitive bias modification in
2018) and better link it to CBT (Kopetz et al., 2017; Wiers addiction
et al., 2016), further discussed below.
Given these neural effects of CBM, one potential way to
improve effectiveness of CBM is by combining it with
Neurocognitive effects of cognitive bias neuromodulation techniques, such as transcranial direct
modification current stimulation (tDCS). There have only been a few
studies exploring this new approach. In recent years, brain
As CBM interventions modulate cognitive processes, it is stimulation protocols without concurrent training have also
also important to learn what underlying neural processes been used to treat addiction (covered in Chapter 22). There
are changed with CBM. These findings can help elucidate are two types of techniques most frequently used: repetitive
the underlying mechanisms of CBM and can be used to transcranial magnetic stimulation (rTMS) and tDCS. The
optimize interventions by targeted brain stimulation. Neural working mechanism and underlying neural effects of these
networks related to addiction, such as heightened cue techniques are different; however, the objective in this
reactivity and impulsivity, also play a role in cognitive research context is similar. Anodal tDCS or high-frequency
biases. An AtB toward smoking or alcohol cues is associ- rTMS is used to enhance cortical plasticity, and cathodal
ated with activation in limbic and reward-related areas tDCS or low-frequency rTMS is used to reduce cortical
(Janes et al., 2010; Luijten et al., 2011; Vollstädt-Klein plasticity in the targeted brain area. As cognitive biases of
et al., 2012). Dysfunctional prefrontal areas, such as AUD patients have developed over many years and
lateral prefrontal cortex and anterior cingulate cortex cognitive control processes are generally weak, improving
(ACC), are associated with numerous problems in inhibi- the efficiency of the cortical processes involved in the
tory and regulatory processes and also contribute to modification of the bias could make it easier to retrain these
cognitive biases (Goldstein and Volkow, 2011). This was cognitive biases. A first PoP study testing the combination
also shown with an AAT, where higher levels of dorso- of tDCS and CBM was done in the field of anxiety (Clarke
lateral prefrontal cortex (DLPFC) and ACC activation et al., 2014). In a study with 77 healthy participants, they
during approach predicted a decrease in problems with trained participants toward or away from threat in a single
cannabis use (Cousijn et al., 2012). AtBM session, while receiving anodal or sham tDCS
The neurocognitive effects of CBM have recently been stimulation over the left DLPFC. They found that bias
reviewed (Wiers and Wiers, 2017). Most studies have acquisition in the trained direction was enhanced by
focused on CBM for anxiety and depressive behavior and DLPFC stimulation. A first PoP study in healthy partici-
indicate that CBM can influence activation and connectivity pants (heavy drinkers) did not find effects on bias
in relevant subcortical signaling structures and executive enhancement after three sessions of ApBM combined with
lateral and medial prefrontal areas. Two studies have spe- anodal left DLPFC tDCS (den Uyl et al., 2016).
cifically investigated the role of ApBM in samples of people Two clinical studies focused on stimulation of the left
with AUD during inpatient treatment (Wiers et al., 2015a,b). DLPFC in combination with AtBM and ApBM in alcohol-
In the first study, effects of ApBM on neural cue reactivity dependent inpatients (den Uyl et al., 2017, 2019). In the
was studied in 32 abstinent AUD patients, randomly assigned study combining tDCS with ApBM (den Uyl et al., 2017),
to receive 6 sessions of ApBM or sham training (Wiers et al.,
all 91 patients received four sessions of active CBM (after also other ways can be explored to enhance CBM training
three positive trials now standard treatment), two groups effects, such as combining it with pharmacological en-
received anodal tDCS, either during the training or separate hancers, but we are not aware of studies yet, testing this.
from the training, and one group received sham tDCS. Second, one problem is that CBM is typically experi-
There was a small decrease in bias reduction in the second enced as rather boring and useless (Beard et al., 2012). This
ApBM training session in the group who received tDCS might be countered in different (not mutually exclusive)
concurrently, but no bias enhancing effects were found ways. First, CBM can be gamified, but this runs the risk of
postassessment. In the study combining AtBM and CBM, only leading to a temporary increase in motivation to do the
in a two-by-two design with active/placebo tDCS and training, without affecting the necessary motivation to
AtBM (den Uyl et al., 2019), no bias enhancing effects change the addictive behavior (see Boendermaker et al.,
were found after assessment. A small effectda larger 2015). However, when training is made more attractive in
avoidance bias in the active AtBM with anodal tDCS an unobtrusive way, for example, by contingent music
groupdwas found during training, but only when all four reward (Lazarov et al., 2017), this may be helpful. Another
training sessions were combined. Hence, these findings promising avenue for clinical research is to personalize
suggest that there could be small benefits of this specific treatment elements from “treatment as usual” (CBT and/or
form of tDCS when added to CBM, but they do not motivational interviewing), such as personal goals to
translate into relevant clinical improvements afterward. change (e.g., health, partner, live longer for grandchildren,
However, anodal tDCS over the DLPFC irrespective of etc.), and personally meaningful alternative means to deal
training did show indications of a beneficial effect on with stress (e.g., jogging rather than smoking, Wiers et al.,
relapse. 2016). These elements can be included into CBM, as a
Studies investigating optimization techniques would recent PoP study in smoking demonstrated (Kopetz et al.,
also benefit from better and more reliable assessment tasks, 2017). Note that this makes CBM less “implicit” and more
to be able to more confidently state whether enhancement related to explicit goals, which might in fact be helpful as
effects are present or not. Other future directions would recent experimental work suggests (Van Dessel et al.,
involve optimizing the combination of brain areas and 2018), and might lead to a more optimal mix of traditional
training type. Brain stimulation without concurrent training treatment and CBM approaches.
already shows potential in treating addiction (Chapter 22
here; Dunlop et al., 2017). However, modulation of neural
excitability is dependent of the current activation state (Hsu
References
et al., 2016), thus it may be more beneficial to activate the Amir, N., Beard, C., Burns, M., Bomyea, J., 2009. Attention modification
neural pathways before neurostimulation. Note that this program in individuals with generalized anxiety disorder. J. Abnorm.
strategy may also be beneficial for CBM in general, as a Psychol. 118 (1), 28e33. https://doi.org/10.1037/a0012589.
Ataya, A.F., Adams, S., Mullings, E., Cooper, R.M., Attwood, A.S.,
recent PoP study indicated (Das et al., 2015). In contrast
Munafò, M.R., 2012. Internal reliability of measures of substance-
with the current studies on AtBM and ApBM, it may be
related cognitive bias. Drug Alcohol Depend. 121 (1e2), 148e151.
that stimulation of the DLPFC may be more suitable to
https://doi.org/10.1016/j.drugalcdep.2011.08.023. Elsevier Ireland Ltd.
combine with cognitive control training (Chapter 18), as Baird, S.O., Rinck, M., Rosenfield, D., Davis, M.L., Fisher, J.R.,
several studies have aimed to use neurostimulation tech- Becker, E.S., Powers, M.B., et al., 2017. Reducing approach bias to
niques to improve training of general functions, such as achieve smoking cessation: a pilot randomized placebo-controlled
WM training, mostly in healthy participants in relation to trial. Cogn. Ther. Res. 41 (4), 662e670. https://doi.org/10.1007/
anxiety and depression (review: Elmasry et al., 2015). s10608-017-9835-z. Springer US.
Current studies on CBM and brain stimulation have only Beard, C., Weisberg, R.B., Primack, J., 2012. Socially anxious primary
focused on DLPFC stimulation, as this area is most care patients’ attitudes toward cognitive bias modification (CBM): a
frequently targeted in cognitive research and has shown qualitative study. Behav. Cognit. Psychother. 40 (5), 618e633.
beneficial effects on WM (Hill et al., 2016). However, other https://doi.org/10.1017/S1352465811000671.
Begh, R., Munafò, M.R., Shiffman, S., Ferguson, S.G., Nichols, L.,
brain areas could also be targeted. Following the initial
Mohammed, M.A., Holder, R.L., et al., 2015. Lack of attentional
findings on neural effects of CBM discussed above, it may
retraining effects in cigarette smokers attempting cessation: a proof of
be useful to modulate activation in the mPFC, which has concept double-blind randomised controlled trial. Drug Alcohol
shown promise in the domain of changing affective asso- Depend. 149, 158e165. https://doi.org/10.1016/j.dru-
ciations in prejudice (Sellaro et al., 2015). It would also be galcdep.2015.01.041. Elsevier Ireland Ltd.
relevant to first image the neural pathways that play a role Boendermaker, W.J., Prins, P.J.M., Wiers, R.W., 2015. Cognitive Bias
in these biases and personalize combinations of treatments Modification for adolescents with substance use problems - can
based on which areas show abnormal activation. An serious games help? J. Behav. Ther. Exp. Psychiatry 49. https://
optimal optimization strategy has not been found, but there doi.org/10.1016/j.jbtep.2015.03.008.
are many research directions still to be explored. Note that
Boffo, M., Zerhouni, O., van Beek, R.J.J., Gronaua, Q.F., Marsman, M., Dunlop, K., Hanlon, C.A., Downar, J., 2017. Noninvasive brain stimula-
Nikolaou, K., Wiers, R.W., 2019. Cognitive Bias Modification for tion treatments for addiction and major depression. Ann. N.Y. Acad.
behavior change in alcohol and smoking addiction: frequentist and Sci. 1394 (1), 31e54. https://doi.org/10.1111/nyas.12985.
Bayesian meta-analysis of individual participant data. Neuropsychol. Eberl, C., Wiers, R.W., Pawelczack, S., Rinck, M., Becker, E.S.,
Rev. https://doi.org/10.1007/s11065-018-9386-4. Online Fir. Lindenmeyer, J., 2013. Approach bias modification in alcohol
Chassin, L., Presson, C.C., Sherman, S.J., Seo, D.-C., Macy, J.T., 2010. Im- dependence: Do clinical effects replicate and for whom does it work
plicit and explicit attitudes predict smoking cessation: moderating effects best? Dev. Cogn. Neurosci. 4, 38e51.
of experienced failure to control smoking and plans to quit. Psychol. Elfeddali, I., de Vries, H., Bolman, C., Pronk, T., Wiers, R.W., 2016.
Addict. Behav. 24 (4), 670. American Psychological Association. A randomized controlled trial of web-based attentional bias modifi-
Clarke, P.J.F., Browning, M., Hammond, G., Notebaert, L., MacLeod, C., cation to help smokers quit. Health Psychol. 35 (8), 870e880. https://
2014. The causal role of the dorsolateral prefrontal cortex in the doi.org/10.1037/hea0000346.
modification of attentional bias: evidence from transcranial direct Elmasry, J., Loo, C., Martin, D., 2015. A systematic review of transcranial
current stimulation. Biol. Psychiatry 76 (12), 946e952. https:// electrical stimulation combined with cognitive training. Restor. Neu-
doi.org/10.1016/j.biopsych.2014.03.003. Elsevier. rol. Neurosci. 33 (3), 263e278. https://doi.org/10.3233/RNN-140473.
Clerkin, E.M., Magee, J.C., Wells, T.T., Beard, C., Barnett, N.P., 2016. Fadardi, J.S., Cox, W.M., 2009. Reversing the sequence: reducing alcohol
Randomized controlled trial of attention bias modification in a racially consumption by overcoming alcohol attentional bias. Drug Alcohol
diverse, socially anxious, alcohol dependent sample. Behav. Res. Ther. Depend. 101 (3), 137e145. https://doi.org/10.1016/j.drugalcdep.
87, 58e69. https://doi.org/10.1016/j.brat.2016.08.010. Elsevier Ltd. 2008.11.015.
Corneille, O., Stahl, C., 2018. Associative attitude learning: a closer look Field, M., Cox, W.M., 2008. Attentional bias in addictive behaviors: a review
at evidence and how it relates to attitude models. Pers. Soc. Psychol. of its development, causes, and consequences. Drug Alcohol Depend. 97
Rev. https://doi.org/10.1177/1088868318763261. (1e2), 1e20. https://doi.org/10.1016/j.drugalcdep.2008.03.030.
Cousijn, J., Goudriaan, A.E., Ridderinkhof, K.R., van den Brink, W., Field, M., Eastwood, B., 2005. Experimental manipulation of attentional
Veltman, D.J., Wiers, R.W., 2012. Approach-bias predicts develop- bias increases the motivation to drink alcohol. Psychopharmacology
ment of cannabis problem severity in heavy cannabis users: results 183 (3), 350e357. https://doi.org/10.1007/s00213-005-0202-5.
from a prospective FMRI study. PLoS One 7 (9), e42394. https:// Field, M., Duka, T., Eastwood, B., Child, R., Santarcangelo, M.,
doi.org/10.1371/journal.pone.0042394. Gayton, M., 2007. Experimental manipulation of attentional biases in
Cousijn, J., 2011. Reaching Out Towards Cannabis : Approach - Bias in heavy drinkers: do the effects generalise? Psychopharmacology 192
Heavy Cannabis Users Predicts Changes in Cannabis Use. https:// (4), 593e608. https://doi.org/10.1007/s00213-007-0760-9.
doi.org/10.1111/j.1360-0443.2011.03475.x. Field, M., Caren, R., Fernie, G., De Houwer, J., 2011. Alcohol approach
Cox, W.M., Fadardi, J.S., Hosier, S.G., Pothos, E.M., 2015. Differential tendencies in heavy drinkers: comparison of effects in a relevant
effects and temporal course of attentional and motivational training on stimulus-response compatibility task and an approach/avoidance
excessive drinking. Exp. Clin. Psychopharmacol. 23 (6), 445e454. Simon task. Psychol. Addict. Behav. 25 (4), 697e701. https://doi.org/
Cristea, I.A., Kok, R.N., Cuijpers, P., 2016. The efficiency of cognitive 10.1037/a0023285.
bias modification interventions for addictions: a meta-analysis. PLoS Friese, M., Gianotti, L.R.R., Knoch, D., 2015. The association between
One 11 (9), e0162226. https://doi.org/10.1371/journal.pone.0162226. implicit alcohol attitudes and drinking behavior is moderated by
Das, R.K., Lawn, W., Kamboj, S.K., 2015. Rewriting the valuation and baseline activation in the lateral prefrontal cortex. Health Psychol. 35
salience of alcohol-related stimuli via memory reconsolidation. Transl. (8), 837e841. https://doi.org/10.1037/hea0000179.
Psychiatry 5 (9), e645. Nature Publishing Group. Frijda, N.H., 1986. The Emotions. Cambridge University Press.
De Houwer, J., Thomas, S., Baeyens, F., 2001. Association learning of Gladwin, T.E., Rinck, M., Eberl, C., Becker, E.S., Lindenmeyer, J.,
likes and dislikes: a review of 25 years of research on human evalu- Wiers, R.W., 2015. Mediation of cognitive bias modification for alcohol
ative conditioning. Psychol. Bull. 127 (6), 853e869. American addiction via stimulus-specific alcohol avoidance association. Alcohol.
Psychological Association. Clin. Exp. Res. 39 (1), 101e107. https://doi.org/10.1111/acer.12602.
De Houwer, J., 2018. Propositional models of evaluative conditioning. Goldstein, R.Z., Volkow, N.D., November 2011. Dysfunction of the pre-
Soc. Psychol. Bull. frontal cortex in addiction : neuroimaging findings and clinical im-
den Uyl, T.E., Gladwin, T.E., Wiers, R.W., 2016. Electrophysiological and plications. Nat. Rev. Neurosci. 12 https://doi.org/10.1038/nrn3119.
behavioral effects of combined transcranial direct current stimulation Nature Publishing Group.
and alcohol approach bias retraining in hazardous drinkers. Alcohol. Greenwald, A.G., De Houwer, J., 2017. Unconscious conditioning:
Clin. Exp. Res. 40 (10) https://doi.org/10.1111/acer.13171. demonstration of existence and difference from conscious condition-
den Uyl, T.E., Gladwin, T.E., Rinck, M., Lindenmeyer, J., Wiers, R.W., ing. J. Exp. Psychol. Gen. 146 (12), 1705e1721. https://doi.org/
2017. A clinical trial with combined transcranial direct current stim- 10.1037/xge0000371.
ulation and alcohol approach bias retraining. Addict. Biol. 22 (6), Grenard, J.L., Ames, S.L., Wiers, R.W., Thush, C., Sussman, S.,
1632e1640. https://doi.org/10.1111/adb.12463. Stacy, A.W., 2008. Working memory capacity moderates the predic-
den Uyl, T.E., Gladwin, T.E., Lindenmeyer, J., Wiers, R.W., 2019. tive effects of drug-related associations on substance use. Psychol.
A clinical trial with combined transcranial direct current stimulation Addict. Behav. 22 (3), 426e432. https://doi.org/10.1037/0893-
and alcohol attentional retraining. Alcohol. Clin. Exp. Res. 42 (10), 164X.22.3.426.
1961e1969.
Heeren, A., Mogoase, C., Philippot, P., McNally, R.J., 2015. Attention Neuropsychopharmacology 35 (12), 2339e2345. https://doi.org/
bias modification for social anxiety: a systematic review and meta- 10.1038/npp.2010.103. Nature Publishing Group.
analysis. Clin. Psychol. Rev. 40, 76e90. https://doi.org/10.1016/ Kong, G., Larsen, H., Cavallo, D.A., Becker, D., Cousijn, J., Salemink, E.,
j.cpr.2015.06.001. Collot Descury-Koenigs, A.L., et al., 2015. Re-training automatic
Hill, A.T., Fitzgerald, P.B., Hoy, K.E., 2016. Effects of anodal transcranial action tendencies to approach cigarettes among adolescent smokers: a
direct current stimulation on working memory: a systematic review pilot study. Am. J. Drug Alcohol Abuse 41 (5). https://doi.org/
and meta-analysis of findings from healthy and neuropsychiatric 10.3109/00952990.2015.1049492.
populations. Brain Stimul. 9 (2), 197e208. https://doi.org/10.1016/ Kopetz, C., MacPherson, L., Mitchell, A.D., Houston-Ludlam, A.,
j.brs.2015.10.006. Elsevier Inc. Wiers, R.W., 2017. A novel training approach to activate alternative
Hofmann, W., Gschwendner, T., Friese, M., Wiers, R.W., Schmitt, M., behaviors for smoking as part of a quit attempt. Exp. Clin. Psycho-
2008. Working memory capacity and self-regulatory behavior: toward pharmacol. 25 (1), 50e60. https://doi.org/10.1037/pha0000108.
an individual differences perspective on behavior determination by Lazarov, A., Pine, D.S., Bar-Haim, Y., 2017. Gaze-contingent music
automatic versus controlled processes. J. Personal. Soc. Psychol. 95 reward therapy for social anxiety disorder: a randomized controlled
(4), 962e977. https://doi.org/10.1037/a0012705. trial. Am. J. Psychiatry 174 (7), 649e656. https://doi.org/10.1176/
Hofmann, W., De Houwer, J., Perugini, M., Baeyens, F., Crombez, G., appi.ajp.2016.16080894.
2010. Evaluative conditioning in humans: a meta-analysis. Psychol. Lindgren, K.P., Neighbors, C., Teachman, B.A., Wiers, R.W.,
Bull. 136 (3), 390. American Psychological Association. Westgate, E., Greenwald, A.G., 2013. I drink therefore I am: vali-
Houben, K., Wiers, R.W., 2009. Response inhibition moderates the rela- dating alcohol-related implicit association tests. Psychol. Addict.
tionship between implicit associations and drinking behavior. Alcohol. Behav. 27 (1), 1e13. https://doi.org/10.1037/a0027640.
Clin. Exp. Res. 33 (4), 626e633. https://doi.org/10.1111/j.1530- Lindgren, K.P., Neighbors, C., Teachman, B.A., Baldwin, S.A., Norris, J.,
0277.2008.00877.x. Kaysen, D., Gasser, M.L., et al., 2016. Implicit alcohol associations,
Houben, K., Havermans, R.C., Wiers, R.W., 2010a. Learning to dislike especially drinking identity, predict drinking over time. Health Psy-
alcohol: conditioning negative implicit attitudes toward alcohol and its chol. 35 (8) https://doi.org/10.1037/hea0000396.
effect on drinking behavior. Psychopharmacology 211 (1), 79e86. Linetzky, M., Pergamin-Hight, L., Pine, D.S., Bar-Haim, Y., 2015.
https://doi.org/10.1007/s00213-010-1872-1. Quantitative evaluation of the clinical efficacy of attention bias
Houben, K., Schoenmakers, T.M., Wiers, R.W., 2010b. I didn’t feel like modification treatment for anxiety disorders. Depress. Anxiety 32 (6),
drinking but I don’t know why: the effects of evaluative conditioning 383e391. https://doi.org/10.1002/da.22344.
on alcohol-related attitudes, craving and behavior. Addict. Behav. 35 Lopes, F.M., Pires, A.V., Bizarro, L., 2014. Attentional bias modification
(12), 1161e1163. https://doi.org/10.1016/j.addbeh.2010.08.012. in smokers trying to quit: a longitudinal study about the effects of
Elsevier Ltd. number of sessions. J. Subst. Abus. Treat. 47 (1), 50e57. https://
Houben, K., Nederkoorn, C., Wiers, R.W., Jansen, A., 2011. Resisting doi.org/10.1016/j.jsat.2014.03.002. Elsevier Inc.
temptation: decreasing alcohol-related affect and drinking behavior by Luijten, M., Veltman, D.J., van den Brink, W., Hester, R., Field, M.,
training response inhibition. Drug Alcohol Depend. 116 (1e3), Smits, M., Franken, I.H.A., 2011. Neurobiological substrate of
132e136. https://doi.org/10.1016/j.drugalcdep.2010.12.011. Elsevier smoking-related attentional bias. NeuroImage 54 (3), 2374e2381.
Ireland Ltd. https://doi.org/10.1016/j.neuroimage.2010.09.064. Elsevier Inc.
Houben, K., Havermans, R.C., Nederkoorn, C., Jansen, A., 2012. Beer à Machulska, A., Zlomuzica, A., Rinck, M., Assion, H.J., Margraf, J., 2016.
no-go: learning to stop responding to alcohol cues reduces alcohol Approach bias modification in inpatient psychiatric smokers.
intake via reduced affective associations rather than increased J. Psychiatry Res. 76, 44e51. https://doi.org/10.1016/
response inhibition. Addiction 107 (7), 1280e1287. https://doi.org/ j.jpsychires.2015.11.015.
10.1111/j.1360-0443.2012.03827.x. Macleod, C., Clarke, P.J.F., 2015. The attentional bias modification
Hsu, T.-Y., Juan, C.-H., Tseng, P., December 2016. Individual differences approach to anxiety intervention. Clin. Psychol. Sci. 3 (1), 58e78.
and state-dependent responses in transcranial direct current stimula- https://doi.org/10.1177/2167702614560749.
tion. Front. Hum. Neurosci. 10, 1e12. https://doi.org/10.3389/ MacLeod, C., Rutherford, E., Campbell, L., Ebsworthy, G., Holker, L.,
fnhum.2016.00643. 2002. Selective attention and emotional vulnerability: assessing the
Hütter, M., Sweldens, S., Stahl, C., Unkelbach, C., Klauer, K.C., 2012. causal basis of their association through the experimental manipula-
Dissociating contingency awareness and conditioned attitudes: evi- tion of attentional bias. J. Abnorm. Psychol. 111 (1), 107e123. https://
dence of contingency-unaware evaluative conditioning. J. Exp. Psy- doi.org/10.1037/0021-843X.111.1.107.
chol. Gen. 141 (3), 539. American Psychological Association. Magurean, S., Constantin, T., Sava, F.A., 2016. The indirect effect of
Jacobus, J., Taylor, C.T., Gray, K.M., Meredith, L.R., Porter, A.M., Li, I., evaluative conditioning on smoking. J. Subst. Use 21 (2), 198e203.
Castro, N., et al., 2018. A multi-site proof-of-concept investigation of Taylor & Francis.
computerized approach-avoidance training in adolescent cannabis Manning, V., Staiger, P., Hall, K., Garfield, J., Flaks, G., Leung, D.,
users. Drug Alcohol Depend. https://doi.org/10.1016/j.dru- Hughes, L., et al., 2019. Cognitive bias modification training during
galcdep.2018.03.007. Elsevier Ireland Ltd. inpatient alcohol detoxification reduces early relapse: a randomized
Janes, A.C., Pizzagalli, D.A., Richardt, S., Frederick, B.D.B., controlled trial. Alcohol. Clin. Exp. Res. 40 (9), 2011e2019. https://
Holmes, A.J., Sousa, J., Fava, M., et al., 2010. Neural substrates of doi.org/10.1111/acer.13163.
attentional bias for smoking-related cues: an fMRI study.
McCarthy, D.M., Thompsen, D.M., 2006. Implicit and explicit measures Sellaro, R., Derks, B., Nitsche, M.A., Hommel, B., van den
of alcohol and smoking cognitions. Psychol. Addict. Behav. 20 (4), Wildenberg, W.P.M., van Dam, K., Colzato, L.S., 2015. Reducing prej-
436e444. https://doi.org/10.1037/0893-164X.20.4.436. udice through brain stimulation. Brain Stimul. 8 (5), 891e897. Elsevier.
Mühlig, S., Paulick, J., Lindenmeyer, J., Rinck, M., Cina, R., Wiers, R.W., Sheeran, P., Klein, W.M.P., Rothman, A.J., 2017. Health behavior change:
2017. Applying the ‘Cognitive Bias Modification’ Concept to moving from observation to intervention. Annu. Rev. Psychol. 68,
Smoking CessationeA Systematic Review. SUCHT, Hogrefe, AG. 573e600. Annual Reviews.
Ostafin, B.D., Palfai, T.P., 2006. Compelled to consume: the implicit as- Sherman, B.J., Baker, N.L., Squeglia, L.M., McRae-Clark, A.L., 2018.
sociation test and automatic alcohol motivation. Psychol. Addict. Approach bias modification for cannabis use disorder: a proof-of-prin-
Behav. 20 (3), 322e327. https://doi.org/10.1037/0893-164X.20.3.322. ciple study. J. Subst. Abus. Treat. 87, 16e22. https://doi.org/10.1016/
Palfai, T.P., Wood, M.D., 2001. Positive alcohol expectancies and j.jsat.2018.01.012. Elsevier Inc.
drinking behavior: the influence of expectancy strength and memory Spencer, S.J., Zanna, M.P., Fong, G.T., 2005. Establishing a causal chain:
accessibility. Psychol. Addict. Behav. 15, 60e67. why experiments are often more effective than mediational analyses in
Payne, B.K., Lee, K.M., Giletta, M., Prinstein, M.J., 2016. Implicit atti- examining psychological processes. J. Personal. Soc. Psychol. 89 (6),
tudes predict drinking onset in adolescents: shaping by social norms. 845e851. https://doi.org/10.1037/0022-3514.89.6.845.
Health Psychol. 35 (8), 829e836. https://doi.org/10.1037/ Stacy, A.W., Wiers, R.W., 2010. Implicit cognition and addiction: a tool
hea0000353. for explaining paradoxical behavior. Annu. Rev. Clin. Psychol. 6,
Pleyers, G., Corneille, O., Luminet, O., Yzerbyt, V., 2007. Aware and (dis) 551e575. https://doi.org/10.1146/annurev.clinpsy.121208.131444.
liking: item-based analyses reveal that valence acquisition via evalu- Stacy, A.W., Leigh, B.C., Weingardt, K.R., 1994. Memory Accessibility
ative conditioning emerges only when there is contingency awareness. and Association of Alcohol Use and its Positive Outcomes. Experi-
J. Exp. Psychol. Learn. Mem. Cogn. 33 (1), 130. American Psycho- mental and Clinical Psychopharmacology.
logical Association. Stacy, A.W., 1997. Memory activation and expectancy as prospective
Pleyers, G., Corneille, O., Yzerbyt, V., Luminet, O., 2009. Evaluative predictors of alcohol and marijuana use. J. Abnorm. Psychol. 106 (1),
conditioning may incur attentional costs. J. Exp. Psychol. 61e73. https://doi.org/10.1037/0021-843X.106.1.61.
Anim. Behav. Process. 35 (2), 279. American Psychological Sweldens, S., Corneille, O., Yzerbyt, V., 2014. The role of awareness in
Association. attitude formation through evaluative conditioning. Pers. Soc. Psychol.
Price, R.B., Wallace, M., Kuckertz, J.M., Amir, N., Graur, S., Rev. 18 (2), 187e209. https://doi.org/10.1177/1088868314527832.
Cummings, L., Popa, P., et al., 2016. Pooled patient-level meta- Szalay, L., Bovasso, G., Vilov, S., Williams, R.E., 1992. Assessing
analysis of children and adults completing a computer-based anxiety treatment effects through changes in perceptions and cognitive orga-
intervention targeting attentional bias. Clin. Psychol. Rev. 50, 37e49. nization. Am. J. Drug Alcohol Abuse 18 (4), 407e428. Taylor &
https://doi.org/10.1016/j.cpr.2016.09.009. Elsevier Ltd. Francis.
Rinck, M., Becker, E.S., 2007. Approach and avoidance in fear of spiders. Thush, C., Wiers, R.W., 2007. Explicit and implicit alcohol-related cognitions
J. Behav. Ther. Exp. Psychiatry 38 (2), 105e120. https://doi.org/ and the prediction of future drinking in adolescents. Addict. Behav. 32 (7),
10.1016/j.jbtep.2006.10.001. 1367e1383. https://doi.org/10.1016/j.addbeh.2006.09.011.
Rinck, M., Wiers, R.W., Becker, E.S., Lindenmeyer, J., 2018. Relapse Thush, C., Wiers, R.W., Ames, S.L., Grenard, J.L., Sussman, S.,
prevention in abstinent alcoholics by cognitive bias modification: Stacy, A.W., 2008. Interactions between implicit and explicit cogni-
clinical effects of combining approach bias modification and attention tion and working memory capacity in the prediction of alcohol use in
bias modification. J. Consult. Clin. Psychol. 86 (12), 1005e1016. at-risk adolescents. Drug Alcohol Depend. 94 (1e3), 116e124.
Roefs, A., Huijding, J., Smulders, F.T.Y., MacLeod, C.M., de Jong, P.J., https://doi.org/10.1016/j.drugalcdep.2007.10.019.
Wiers, R.W., Jansen, A.T.M., 2011. Implicit measures of association Van Dessel, P., Hughes, S.J., De Houwer, J., 2018. Consequence-based
in psychopathology research. Psychol. Bull. 137 (1), 149e193. https:// approach-avoidance training: a new and improved method for
doi.org/10.1037/a0021729. changing behavior. Psychol. Sci. 29 (12), 1899e1910.
Rooke, S.E., Hine, D.W., Thorsteinsson, E.B., 2008. Implicit cognition Vollstädt-Klein, S., Loeber, S., Richter, A., Kirsch, M., Bach, P., Von Der
and substance use: a meta-analysis. Addict. Behav. 33 (10), Goltz, C., Hermann, D., et al., 2012. Validating incentive salience
1314e1328. https://doi.org/10.1016/j.addbeh.2008.06.009. with functional magnetic resonance imaging: association between
Rydell, R.J., McConnell, A.R., 2006. Understanding implicit and explicit mesolimbic cue reactivity and attentional bias in alcohol-dependent
attitude change: a systems of reasoning analysis. J. Personal. Soc. patients. Addict. Biol. 17 (4), 807e816. https://doi.org/10.1111/
Psychol. 91 (6), 995. American Psychological Association. j.1369-1600.2011.00352.x.
Schoenmakers, T.M., Wiers, R.W., Jones, B.T., Bruce, G., Jansen, A.T.M., Walther, E., Nagengast, B., 2006. Evaluative conditioning and the
2007. Attentional re-training decreases attentional bias in heavy drinkers awareness issue: assessing contingency awareness with the four-
without generalization. Addiction (Abingdon Engl.) 102 (3), 399e405. picture recognition test. J. Exp. Psychol. Anim. Behav. Process. 32
https://doi.org/10.1111/j.1360-0443.2006.01718.x. (4), 454. American Psychological Association.
Schoenmakers, T.M., de Bruin, M., Lux, I.F.M., Goertz, A.G., Van Waters, A.J., Carter, B.L., Robinson, J.D., Wetter, D.W., Lam, C.Y.,
Kerkhof, D.H.A.T., Wiers, R.W., 2010. Clinical effectiveness of Cinciripini, P.M., 2007. Implicit attitudes to smoking are associated
attentional bias modification training in abstinent alcoholic patients. with craving and dependence. Drug Alcohol Depend. 91 (2e3),
Drug Alcohol Depend. 109 (1e3), 30e36. https://doi.org/10.1016/ 178e186. Elsevier.
j.drugalcdep.2009.11.022.
Wiers, C.E., Wiers, R.W., 2017. Imaging the neural effects of cognitive problem drinkers over the web. Addict. Behav. 40 https://doi.org/
bias modification training. NeuroImage 151. https://doi.org/10.1016/ 10.1016/j.addbeh.2014.08.010.
j.neuroimage.2016.07.041. Wiers, R.W., Becker, D., Holland, R., Moggi, F., Lejuez, C.W., Yield, A.,
Wiers, R.W., Eberl, C., Rinck, M., Becker, E., Lindenmeyer, J., 2011. Re- 2016. Cognitive motivational processes underlying addiction treat-
training automatic action tendencies changes alcoholic patients’ ment. In: Kopetz, C.E., Lejuez, C.W. (Eds.), Addiction. Psychology
approach bias for alcohol and improves treatment outcome. Psycho- Press, pp. 201e236.
logical Science 22 (4), 490e497. Wiers, R.W., Boffo, M., Field, M., 2018a. What’s in a trial? On the
Wiers, R.W., Van Woerden, N., Smulders, F.T.Y., De Jong, P.J., 2002. importance of distinguishing between experimental lab studies and
Implicit and explicit alcohol-related cognitions in heavy and light randomized controlled trials: the case of cognitive bias modification
drinkers. J. Abnorm. Psychol. 111 (4), 648e658. https://doi.org/ and alcohol use disorders. J. Stud. Alcohol Drugs 79 (3), 333e343.
10.1037//0021-843X.111.4.648. https://doi.org/10.15288/jsad.2018.79.333.
Wiers, R.W., Rinck, M., Dictus, M., van den Wildenberg, E., 2009. Wiers, R.W., Boffo, M., Field, M., 2018b. Persistent mixing of apples and
Relatively strong automatic appetitive action-tendencies in male car- oranges, or carefully synthesizing and designing the next steps
riers of the OPRM1 G-allele. Genes Brain Behav. 8 (1), 101e106. in research on cognitive bias modifi cation in addiction. J. Stud.
https://doi.org/10.1111/j.1601-183X.2008.00454.x. Alcohol Drugs 79 (3), 348e349. https://doi.org/10.15288/
Wiers, R.W., Rinck, M., Kordts, R., Houben, K., Strack, F., 2010. jsad.2018.79.348.
Retraining automatic action-tendencies to approach alcohol in haz- Wiers, R.W., 2018. Cognitive training in addiction: does it have clinical
ardous drinkers. Addiction (Abingdon Engl.) 105 (2), 279e287. potential? Biol. Psychiatry 3 (2). https://doi.org/10.1016/
https://doi.org/10.1111/j.1360-0443.2009.02775.x. j.bpsc.2017.12.008.
Wiers, R.W., Gladwin, T.E., Hofmann, W., Salemink, E., Wittekind, C.E., Feist, A., Schneider, B.C., Moritz, S., Fritzsche, A., 2015.
Ridderinkhof, K.R., 2013. Cognitive bias modification and cognitive The approach-avoidance task as an online intervention in cigarette
control training in addiction and related psychopathology: mecha- smoking: a pilot study. J. Behav. Ther. Exp. Psychiatry 46, 115e120.
nisms, clinical perspectives, and ways forward. Clin. Psychol. Sci. 1 https://doi.org/10.1016/j.jbtep.2014.08.006. Elsevier Ltd.
(2), 192e212. https://doi.org/10.1177/2167702612466547. Wolf, P.A., Salemink, E., Wiers, R.W., 2016. Attentional retraining and
Wiers, C.E., Ludwig, V.U., Gladwin, T.E., Park, S.Q., Heinz, A., cognitive biases in a regular cannabis smoking student population.
Wiers, R.W., Rinck, M., et al., 2015a. Effects of cognitive bias SUCHT 62 (6), 355e365. https://doi.org/10.1024/0939-5911/
modification training on neural signatures of alcohol approach ten- a000455.
dencies in male alcohol-dependent patients. Addict. Biol. 20 (5), Zerhouni, O., Bègue, L., Comiran, F., Wiers, R.W., 2018. Controlled and
990e999. https://doi.org/10.1111/adb.12221. implicit processes in evaluative conditioning on implicit and explicit
Wiers, C.E., Stelzel, C., Gladwin, T.E., Park, S.Q., Pawelczack, S., attitudes toward alcohol and intentions to drink. Addict. Behav. 76
Gawron, C.K., Stuke, H., et al., 2015b. Effects of cognitive bias https://doi.org/10.1016/j.addbeh.2017.08.026.
modification training on neural alcohol cue reactivity in alcohol Ziaee, S.S., Fadardi, J.S., Cox, W.M., Yazdi, S.A.A., 2016. Effects of
dependence. Am. J. Psychiatry 172 (4), 335e343. https://doi.org/ attention control training on drug abusers’ attentional bias and treat-
10.1176/appi.ajp.2014.13111495. ment outcome. J. Consult. Clin. Psychol. 84 (10), 861. American
Wiers, R.W., Houben, K., Fadardi, J.S., van Beek, P., Rhemtulla, M., Psychological Association.
Cox, W.M., 2015c. Alcohol cognitive bias modification training for
Chapter 18
Peer-reviewed working memory training:

is it an effective intervention for
addiction?
S.J. Brooks1, 2, S. Funk3, C. Rabier3 and H.B. Schiöth2
1
School of Natural Sciences and Psychology, Liverpool John Moores University, Liverpool, United Kingdom; 2Department of Neuroscience, Uppsala
University, Uppsala, Sweden; 3Department of Psychology, University of Cape Town, Cape Town, South Africa
Introduction and attentional resources (Morrison and Chein, 2011;

Spencer-Smith and Klingberg, 2015). The ability of WMT
Working memory (WM) is associated with frontostriatal to evoke improvements in other (sometimes unrelated)
and parietal cortex function and is a hallmark for deficits in cognitive domains is known as “far transfer,” whereas the
people with addiction (Ramey and Regier, 2018). In ability of WMT to demonstrate long-term improvements
particular, deficits in top-down regulation of bottom-up (e.g., 1 month) in WM or related cognitions is referred to
midbrain affective processes that are appetitive (reward, as “longevity of skills transfer.” Indeed, by comparison
incentive salience) or aversive (stress, negative affect) are with other types of cognitive training (e.g., cognitive bias
important targets for intervention. For example, those with modification, cognitive remediation, contingency manage-
substance use disorder have greater preference for risky ment, memory recall, response inhibition, visuospatial
choices; they tend to favor choices that are immediately detection), WMT seems an effective tool for the improve-
appetitive or rewarding over future, delayed benefits ment of attention and impulse control in line with fron-
(temporal/delay discounting), and are more likely to expe- tostriatal brain changes, particularly in people with
rience reinforcement learning from reward than from pun- addictions such as stimulant (cocaine, methamphetamine)
ishment (Verdejo-Garcia et al., 2018). To date, however, no and alcohol use disorder (AUD) (Bickel et al., 2011;
intervention for addiction has led to significant long-term Spencer-Smith and Klingberg, 2015; Brooks et al., 2016,
prevention of relapse, which could be improved with a 2017a,b; Khemiri et al., 2019). The relevance of WM for
focus on the frontostriatal circuitry associated with WM. self-regulation is supported by research in a range of sci-
Improved WM capacity is linked to an ability to hold entific fields, such as animal models (Swank and Sweatt,
alternative cognitive strategies in mind for longer 2001; Levenson et al., 2004; Bock et al., 2014; Cassanelli
(e.g., learned during cognitive therapy), better top-down et al., 2015; Anderson et al., 2016), theoretical physics
self-regulation of affect, and greater impulse control in (Parr and Friston, 2017), and human neurocognitive studies
those with addiction (Bickel et al., 2011; Brooks et al., (Constantinidis and Klingberg, 2016).
2016, 2017a,b; Khemiri et al., 2019). WM therefore pro- Nevertheless, skepticism continues regarding the
vides a pertinent cognitive marker that may be useful for potency of WMT to improve far transfer for attention and
novel intervention development for addiction. fluid intelligence (e.g., Morra and Borella, 2015) and its
Working memory training (WMT) that aims to improve application potential as a treatment tool in general. How-
WM capacity has attracted attention within the scientific ever, the potency of WMT for improving brain processes
community (Constantinidis and Klingberg, 2016), which underlying other constructs, such as self-regulation and
may be of benefit to the treatment of addiction. WMT is impulse control (as opposed to attention and fluid intelli-
associated with improved executive functioning and greater gence), in those with addiction (Brooks et al., 2016,
ability for holding a larger number of strategies/decisions in 2017a,b) should not be overlooked, at least not in peer-
mind for longer, which may also improve fluid intelligence reviewed WMT products. Peer-reviewed WMT has been

developed and is available to the public, yet paradigms

Records identified through database
differ in various ways, such as their administration (via searching
apps, websites, or desktop computers, as well as the dura- (n = 207)
tion/frequency of training required), the population or ser-
vice user: clinical (e.g., attention deficit hyperactivity
disorder [ADHD], anxiety disorders, cognitive decline/de-
Records after inaccessible articles removed
mentia, depression, eating disorders, neurological patients, (n = 203)
schizophrenia, substance use disorders) and nonclinical
(e.g., children, adolescents, adults, elderly, or across the life
span). Moreover, the differences in the constructs measured
during WMT, the method of measurement, and the lack of Records screened Records excluded for
peer-reviewed empirical evidence in many WMT apps (n = 203) criteria violation
(n = 127)
available add to the burden of proof when attempting to
determine the efficacy of WMT to improve treatment for
addiction. Currently, based on the number of peer-reviewed Full-text articles assessed
publications, media attention, and global outreach, for eligibility
(n = 75)
CogMed is the most researched WMT available to date
(Constantinidis and Klingberg, 2016) and has had a sig-
nificant impact in the field. CogMed is a multitasked,
Studies included in
computerized, counselor-supported WMT package that systematic review
appears to evoke significant attentional improvements in (n = 75)
children, adolescents, and adults with ADHD, as well as
FIGURE 18.1 PRISMA flowchart illustrating the search strategy and
nondisordered individuals (Spencer-Smith and Klingberg,
results.
2015). However, CogMed researchers, by measuring
attention and intelligence, have not yet demonstrated
convincing far transfer effects. That said that the signifi- searched for relevant articles: Google, Google Scholar,
cance of effects may be strengthened with different mea- Pubmed, Medline, and ScienceDirect, with a search using
sures, such as self-regulation and impulsivity. the phrase “working memory training.” From this initial
With the differences between WMT paradigms search, various popular WMT programs were found, and
considered, as well as the efficacy to evoke far transfer the name of these programs were subsequently used in
improvement effects to other cognitive domains, and/or additional searches. Inclusion criteria for the review were
longevity of skills transfer (e.g., 1 month), it is currently (a) articles written in English; (b) WMT programs sup-
uncertain as to whether there is validity in pursuing WMT ported by published peer-reviewed literature; (c) original
as a research adjunct to treatment for addiction, particularly articles and not reviews or metaanalyses (although these are
in terms of improvements in self-regulation and impulse referred to in the discussion); (d) publications that report a
control. Against this background, and according to the protocol for a future WMT study; (e) articles published in
authors’ knowledge, this is the first systematic addiction- the last 5 years; and (f) only WMT and no other forms of
focused review of peer-reviewed WMT paradigms. The cognitive training.
focus here is to evaluate WMT as opposed to other
cognitive training paradigms, to form conclusions as to its Results
utility for those with addictions. The aims of this review,
therefore, are to determine (a) which WMT paradigms are From n ¼ 75 studies, a total of eight peer-reviewed WMT
peer-reviewed in scientific journals, (b) the significance of programs were found to meet the inclusion criteria and are
far transfer and longevity of skills transfer effects of these described below, namely (i) n-back; (ii) PSSCogRehab;
WMT paradigms, (c) in which human populations (clinical (iii) Jungle Memory (JM); (iv) CogMed (v) Lumosity, (vi)
and/or nonclinical) WMT effects are observed, (d) the na- Neuroracer/Project:EVO; (vii) Neuronation, and (viii) Curb
ture of difference between tasks in WMT paradigms, Your Addiction (C-Ya).
(f) existing limitations of WMT, and (g) applying these While the n-back WM task was the most utilized
findings to the treatment of addiction. paradigm in many variations of WMT with n ¼ 32 studies
adopting it, CogMed was the WMT program with the most
peer-reviewed publications as a single paradigm, with
Methods n ¼ 31 articles that met our criteria. Of note, some of the
See Fig. 18.1 for a CONSORT diagram describing the most popular WMT paradigms (e.g., by Internet ‘likes,’
search criteria. The following online platforms were user reviews, and social media sharing) included Simon
Peer-reviewed working memory training: is it an effective intervention for addiction? Chapter | 18 245
Says, Brain Age, Activate, MyHAPPYneuron, Flashcards, temporary storage and continuous updating of information
Cognifit, and Brain Fitness Pro, and yet none of these have as well as inference resolution and interference regulation,
been peer-reviewed in scientific publications at the time of in line with the classic WM model (Au et al., 2014). The
writing. The description of these popular, nonepeer- number of trials (e.g., N ¼ number of items “back” to be
reviewed WMT Apps is outside the scope of this review. remembered) can be adjusted according to the ability of the
Next follows a summary of the peer-reviewed WMT participant, with the aim of keeping the participant at their
programs in chronological order according to their date of WM limit (Jaeggi et al., 2008). It is the ongoing mental
creation/publication. If the date is not easily identified by challenge or “cognitive load” that is suggested to result in
the creator’s website, the first peer-reviewed publication is neurocognitive changes (e.g., “neuroplasticity”) in fron-
taken. WMT programs are listed chronologically to tostriatal and parietal cortex circuitry underlying a greater
comment on the general progression of research into WMT. capacity for WM storage and improved functioningd
Of note, many of the WMT paradigms were developed and particularly increased temporary storage of items in mind
published as a website before formal peer-reviewed (Jaeggi et al., 2008).
publications. A summary is provided on the practical de- Adaptive dual n-back training appears to be the
livery of each paradigm as well as a review of some recent preferred method of n-back WMT for published studies.
publications and the main findings and limitations. See This consists of paying attention to two sets of unrelated
Fig. 18.2 for a timeline of the included peer-reviewed stimuli at once (dual) with the difficulty of the game being
WMT programs. continuously updated according to the skill of the user
See Table 18.1 for details of the peer-reviewed working (adaptive) (Lilienthal et al., 2013). Lilienthal and col-
memory training programs and their supporting studies. leagues claim it to be the most effective of all n-back
training types after conducting a study on 52 healthy un-
N-back (n [ 32); Kirchner (1958) dergraduate students. In this study, 13 students underwent
eight 30-minute adaptive training sessions and demon-
Thirty-two publications were found to use various versions strated significant improvements (especially regarding
of the n-back task for WMT training, none of which (bar C- attention), compared with nonadaptive training sessions of
Ya, described below) have been conducted in people with the same magnitude. In a more recent study, Sari et al.
addictive disorders. However, currently, there are hundreds (2016) found positive effects of adaptive dual n-back
of apps and online games available, which purport to use training on attentional control in high trait anxious in-
the n-back task or a variation, most likely because this is the dividuals after 3 weeks of training (N ¼ 33; mean age ¼ 25
most widely known neuroscientific WM paradigm and years). Other studies using adaptive WMT have shown
demonstrates the most consistent brain activation (incor- improvements in cognitive inhibition (Owens et al., 2013)
porating the dorsolateral prefrontal cortex, parietal cortex, and cognitive control (Schweizer et al., 2013). However, it
striatum, and insular cortex) in imaging studies (Rottschy must be noted that these positive results have not always
et al., 2012). N-back training typically involves gauging been consistently shown (see Chooi and Thompson, 2012;
whether stimuli (visual or auditory, such as letters, objects, Thompson, et al., 2013). Conversely, Jaeggi et al.’s (2014)
or sounds) match a stimulus presented a certain number of study on 78 healthy students (mean age ¼ 25.21 years) who
trials before (Jaeggi, et al., 2008). N-back thus requires underwent training once a day, five times per week for a
N-Back PSSCogRehab Cogmed Lumosity Jungle Memory Neuronation C-Ya

(1958) (1982) (2016)
(2001) (2005) (2008) (2011)
Neuro-Racer
(2008)
FIGURE 18.2 Timeline of working memory training (WMT) peer-reviewed paradigms explored in this systematic review (from 1958 to present).
TABLE 18.1 Details of peer-reviewed working memory training programs and their supporting studies.
N-back (n [ 32)
Author Title Length of working Study Population Main Findings
memory (WM)
training
Anguera The effects of working 5 weeks 69 students (mean age: Training WM using dual
et al., 2013 memory resource 21.0 years), 35 males n-back did not result in
depletion and training improved rates of visiomotor
on sensorimotor adaptation. The results thus
adaptation. suggest that WM capacity may
not be the factor limiting
maximal rate of visiomotor
adaptation in young adults.
Salminen On the impacts of 14 daily training ses- 24 students (age 24.4 Participants showed improve-
et al., 2012 working memory sions of visual and years) ments in the trained task as
training on executive auditory task for well as in the transfer WM
functioning. 3 weeks updating task. Participants also
demonstrated improvements in
a task switching situation and
in attentional processing (exec-
utive functioning), showing
generalized gains to other, non-
trained tasks.
Schneiders The impact of auditory 8 50 min auditory 16 healthy students, Transfer effects were found for
et al., 2012 working memory training sessions over mean age: 21.13 years the auditory but not for the
training on the fronto- 2 weeks (17 females) visual transfer task. Decreased
parietal working mem- activation after training was
ory network. found in the right inferior
frontal gyrus, which may indi-
cate increased neural effi-
ciency in auditory WM
processes. The study also
found decreases in the right
inferior parietal lobule reflect-
ing less demand on general
attentional control processes.
Rudebeck A potential spatial 20 days of visuospatial 28 experiment partici- Results revealed increase in
et al., 2012 working memory dual n-back pants and 28 controls fluid intelligence and episodic
training task to improve memory arising from training.
both episodic memory
and fluid intelligence.
Redick, No evidence of intelli- 20 sessions of adaptive 75 students (18e30 Despite improvements on both
2013 gence improvement after dual n-back or an adap- years) the dual n-back and visual
working memory tive visual search pro- search tasks with practice, and
training: a randomized, gram (active placebo- despite a high level of statisti-
placebo-controlled control group) as well as cal power, there was no posi-
study. a no-contact control tive transfer to any of the
group that received no cognitive ability tests.
practice.
Lilienthal Dual n-back training in- 8 30-min training 52 undergraduates were Adaptive dual n-back results in
et al., 2013 creases the capacity of sessions randomly assigned to one improvements in focus of
the focus of attention. of the three groups: adap- attention.
tive training (n ¼ 13),
nonadaptive training
(n ¼ 13), and no-contact
control (n ¼ 26)
Owens Improving attention control 8 days, 6 h in total (adap- 11 dysphoric participants Participants had WM gains and
et al., 2013 in dysphoria through cognitive dual n-back vs. filtering efficiency gains.
tive training: transfer effects nonadaptive dual 1-back Results indicate that greater
on working memory capac- task) attentional control can improve
ity and filtering efficiency. behavioral performance and
neural function in dysphoria.
Continued
TABLE 18.1 Details of peer-reviewed working memory training programs and their supporting studies.dcont’d
N-back (n [ 32)
Thompson Failure of working 20 sessions of an adap- 58 participants (aged be- Improvements were found for
et al., 2013 memory training to tive dual n-back work- tween 18 and 45 years); 20 the task trained 6 months after
enhance cognition or ing memory training participants in WM task; 21 training, but there were no
intelligence. (WMT) participants in active con- transfer effects found for non-
trol group; 19 participants trained tasks such as fluid
in passive control group intelligence.
Martin et al., Can transcranial direct 10 daily sessions 54 participants were Participants in the active
2014 current stimulation randomly assigned to a tDCSþCT condition performed
enhance outcomes from group that would receive more accurately on the CT task
cognitive training? A either an active or sham than participants who received
randomized controlled transcranial direct current the sham tDCSþCT.
trial in healthy stimulation (tDCS) along
participants. with a dual n-back task
or tDCS alone
Oelhafen Increased parietal activ- 3 weeks, with a high or 43 participants (mean N-back training with high inter-
et al., 2013 ity after training of low interference age: 25.2 years). Both ference led to some improve-
interference control. training variant of the training groups consisted ments in the Attention Network
dual n-back task or a of 14 participants (6 fe- Test but not to measures of
passive control group male), and 15 people WM and fluid intelligence. The
were assigned to the study also observed higher
control group (8 female) electrophysiological activity in
the parietal cortex, which the
authors suggest may be demon-
strative of the observed im-
provements in processing
speed, attentional control, or
both.
Heinzel Working memory 4 weeks: 12 sessions of Training groups: 15 For younger participants, trans-
et al., 2014 training improvements adaptive n-back younger participants (6 fer to Verbal Fluency and Digit
and gains in non- training men, 9 women; mean Symbol Substitution test was
trained cognitive tasks age: 25.9 years) and 15 found. In older participants,
in young and older older participants (5 transfer to Digit Span Forward,
adults. men, 10 women; mean CERAD Delayed Recall, and
age: 66.07 years) Digit Symbol Substitution test
Controls: A group of 15 was found. The authors suggest
younger participants (6 that these results indicate that
men, 9 women; mean WM training may be a benefi-
age: 25.6 years) and a cial intervention for maintain-
group of 15 older partici- ing and improving cognitive
pants (4 men, 11 functioning in old age.
women; mean age: 65.6
years)
Stepankova The malleability of Verbal n-back task over 65 participants (65e74 Both training groups outper-
et al., 2014 working memory and the course of a month years) (19 males) formed control group on mea-
visuospatial skills: a for either 10 or 20 sures of WM and visuospatial
randomized controlled sessions skills. The study also found that
study in older adults. more training resulted in greater
improvements in visuospatial
skills. This study provides
further evidence for plasticity of
cognitive functions in old age.
Heinzel Working memory load- 12 session of different 19 older participants (6 At low difficulty levels,
et al., 2014 dependent brain n-back loads females; mean age: 66.0 decreases in BOLD FMRI
response predicts years) and 18 younger responses were found after
behavioral training adults (8 females; mean WMT. WM may improve neu-
gains in older adults. 24.1 years) ral efficiency in older adults
Continued
N-back (n [ 32)
Buschkuehl Neural effects of short- 20 min a day over 55 participants (20 Results revealed that training
et al., 2014 term training on work- 7 days women; mean age: 21.8 on an n-back task led to
ing memory. years improved performance on the
Experimental group: 27 trained task. The experimental
participants (10 women; group also demonstrated cross-
mean age: 22.3 years) modal transfer, compared with
Control group: 28 partic- an active control group.
ipants (10 women; mean Increased perfusion during task
age: 21.2 years) performance was observed in
selected brain regions, reflect-
ing a neural response to cope
with high task demand.
Increased blood flow at rest in
regions where training effects
occurred was also found.
Heinzel Catechol-O- Adaptive training in n- 14 younger participants The study found that both
et al., 2014 methyltransferase back over 12 sessions, (aged 24e30 years) and younger and older adults
(COMT) genotype af- with increasing diffi- 25 older participants exhibited plasticity through
fects age-related culty conditions (aged 60e75 years) training. These results were
changes in plasticity in larger for the younger adults.
working memory: a pi- The findings indicate that age-
lot study. related changes in plasticity in
WM are critically affected by
genetic variation in prefrontal
dopamine metabolism.
Katz et al., Differential effect of 3 days 107 students (average This study looked at how moti-
2014 motivational features on age ¼ 10.65 years, 44% vational features of WM n-back
training improvements girls) training influence improve-
in school-based cogni- ments on the task. Five motiva-
tive training. tional features were looked at,
a real-time scoring system,
theme changes, prizes, end-of-
session certificates, and scaf-
folding, to explain the lives
and leveling system included
in the game. The study found
that the inclusion of real-time
scoring during play was found
to negatively impact training.
Scaffolding to explain lives and
levels also negatively impacted
training gains. The other game
adjustments did not signifi-
cantly impact training improve-
ment compared with the
original version of the game
with all features included. The
findings suggest that certain
motivational elements may
distract from the core cognitive
training task, reducing task
improvement, especially at the
initial stage of learning.
Continued
N-back (n [ 32)
Martin et al., Use of transcranial 2 days, 30 min of 20 participants Results showed that “online”
2014 direct current stimula- anodal tDCS to the left tDCS was associated with
tion (tDCS) to enhance dorsolateral prefrontal better-within session skill
cognitive training: effect cortex immediately acquisition on the WM task,
of timing of stimulation. before (“offline” tDCS) with a significant difference
and during performance found between conditions the
(“online” tDCS) on a following day. These results
dual n-back WM task, suggest that “online” tDCS is
in an intraindividual superior to “offline” tDCS for
crossover design. enhancing skill acquisition
when combining anodal tDCS
with WMT.
Sun et al., Topological changes of Neuroimaging of func- 2 participants The neuroimaging revealed sig-
2014 the effective connectiv- tional connectivity of nificant decreased clustering
ity during the working 3 days of spatial n-back coefficient and normalized
memory training. training shortest path length, suggesting
a reduced local efficiency with
an increased global efficiency
after WMT.
Pugin et al., Working memory Visuospatial n-back task Experimental group: 14 Significant differences in an
2014 training shows over 3 weeks (30 min male subjects (10e16 auditory n-back task were
immediate and long- daily) years) observed after the 3 weeks of
term effects on cogni- Control group: 15 males training and also after 2
tive performance in of the same age range e6 months. The improvement
children. was more pronounced in sub-
jects who improved their per-
formance during the training.
Other cognitive functions
(matrices test and Stroop Task)
did not change significantly.
Beatty and Transfer of training from 3 20-min training ses- Control group of 22 Results suggest that although n-
Vartanian, one working memory sions on separate days participants back training is more likely to
2015 task to another: behav- improve performance in easier
ioural and neural blocks, it is improvement in
evidence. more difficult blocks that is
predictive of performance on a
target task drawing on WM. In
addition, the extent to which
training on a task can transfer
to another task is likely due to
the engagement of shared
cognitive capacities and under-
lying neural substrates in this
case of WM.
Chan et al., Visuospatial working 1 h daily over a 10-day Younger adults (n ¼ 26, The experimental group
2015 memory training facili- period 21.1 1.37years) and increased their accuracy in the
tates visually-aided older adults (n ¼ 22, spatial n-back tasks; they also
explicit sequence 70.6 4.01years) showed improvements in their
learning. retention of sequences. The
findings support the hypothesis
that computerized visuospatial
WMT improves sequence
learning (for young and old
adults).
Continued
N-back (n [ 32)
Schwarb Working memory 8 1 hour sessions 53 participants (aged 18 Results revealed training-
et al., 2016 training improves visual over approximately 2 e30 years; 23 women) related improvement of global
short-term memory e4 weeks with normal to measures of visual short-term
capacity. corrected-to-normal memory and of measures of
vision the independent subprocesses
that contribute to capacity.
These results suggest that the
ability to inhibit irrelevant in-
formation within and between
trials is enhanced via n-back
training allowing for selective
improvement on untrained
tasks.
Salminen Age-specific differences 14 training sessions 26 participants (11 male; Although the training effect in
et al., 2016 of dual n-back training. over 3e6 weeks age range 57e73 years; older adults was smaller than
(approximately 2e5 mean age 65.0 years) the training effect in young
training sessions per adults, the older adults still
week) showed a notable improvement
so that after training they per-
formed on the same level as
young adults without training.
Present study provides encour-
aging evidence toward the pos-
sibilities to compensate for
age-related decline in
executive functions by a WM
training intervention.
Waris et al., Transfer after Working 3 45 min training ses- 31 healthy young adults The WMT group showed stron-
2015 Memory Updating sion per week for randomized into either gest transfer to an n-back task,
Training. 5 weeks WMT group or an active followed by WM updating, in
control group (27 turn followed by active WM
females) capacity. The results support
the view that WMT produces
near transfer effects (degree of
transfer depends on the cogni-
tive overlap between the
training and transfer measure).
Sari et al., Training working mem- 3 week daily training Training group n ¼ 17. Training related gains were
2016 ory to improve atten- intervention individuals preselected associated with lower levels of
tional control in on the basis of their trait anxiety at post (vs. pre)
anxiety: A proof-of- elevated trait anxiety intervention. Results demon-
principle study using scores (State-Trait Anxiety strated that adaptive WM
behavioral and electro- Inventory with STAI- training in anxiety can have
physiological measures. TA 50) and low scores beneficial effects on attentional
on the Derryberry and control and cognitive perfor-
Reed’s attentional control mance (which may protect
scale with ACS 60 against emotional vulnerability
in individuals at risk of devel-
oping clinical anxiety).
Pelegrina Normative data on the 3 sessions (each 3722 school children There are age-related changes;
et al., 2015 n-back task for children session ¼ 1 h aged 7e13 years old gender differences (girl>boys)
and young adolescents. approximatively) in performance but girls took
longer to respond than boys.
Continued
N-back (n [ 32)
Thompson Intensive Working 20 sessions of adaptive 39 participants in active Training resulted in task-
et al. (2016) Memory Training Pro- training training group; between specific expansion of dual
duces Functional 18 and 45-year-old n-back abilities. Training differ-
Changes in Large-scale adults, R handed, good entially affected activations in
Frontoparietal health, and not taking two large-scale frontoparietal
Networks. psychoactive medication networks thought to underlie
WM: the executive control
network and the dorsal atten-
tion network. Activations in
both networks linearly scaled
with WM load before training,
but training dissociated the
role of the two networks and
eliminated this relationship in
the executive control network.
Load-dependent functional
connectivity both within and
between these two networks
increased following training,
and the magnitudes of
increased connectivity were
positively correlated with im-
provements in task perfor-
mance. These results provide
insight into the adaptive neural
systems that underlie large
gains in WM capacity through
training.
Lindeløv Training and transfer ef- 20 sessions 17 patients and 18 Neither group demonstrated
et al., 2016 fects of N-back training healthy subjects transfer to untrained tasks;
for brain-injured and computerized training facili-
healthy subjects. tates improvement of specific
skills rather than high-level
cognition in healthy and ABI
subjects. The acquisition of
these specific skills seems to
be impaired by brain injury.
Lawlor- Dual N-Back Working 20e30 min training ses- 57 healthy adults aged Findings suggest that dual
Savage and Memory Training in sion in 1 sitting, 5 days 30e60 years n-back WM training may not
Goghari, Healthy Adults: A Ran- a week, for 5 weeks at benefit WM or fluid intelli-
2016 domized Comparison to a location of their con- gence in healthy adults. Further
Processing Speed venience. Participants investigation is necessary to
Training. completed a log indi- clarify if other forms of WMT
cating dates and times may be beneficial and what
trained across the 5- factors impact training-related
week period benefits, should they occur, in
this population.
Heinzel Neural correlates of 12 sessions (45 min 32 healthy older partici- WM performance improved
et al., 2016 training and transfer ef- each) pants (60e75 years) with training and behavioral
fects in working mem- transfer to tests measuring ex-
ory in older adults. ecutive functions, processing
speed, and fluid intelligence
was found. MRI findings indi-
cate a training-related increase
in processing efficiency of WM
networks, potentially related to
the process of WM updating.
Performance gains in untrained
tasks suggest that transfer to
other cognitive tasks remains
possible in aging.
Continued
N-back (n [ 32)
Minear A simultaneous exami- 4 weeks of training 31 undergraduates Evidence for near transfer from
et al., 2016 nation of two forms of the spatial n-back training to
working memory new forms of n-back.
training: Evidence for
near transfer only.
Heinzel Transfer Effects to a 4 weeks of 12 training 18 participants (11 fe- The results indicate that 12 ses-
et al., 2017 Multimodal Dual-Task sessions of an adaptive males; mean SD sions of numerical n-back
after Working Memory n-back training (approx- age ¼ 65.78 3.04) in training can improve the per-
Training and Associated imately 45 min each) the training group formance in the trained task.
Neural Correlates in Moreover, a transfer to the per-
Older Adults e A Pilot formance in a dual-task was
Study. found.
Jungle Memory (n [ 2)
Author Title Length of working Study population Main findings
memory training
Nelwan and Limited Near and Far Three different groups: 64 school-aged children Some possible short-term effects
Kroesbergen Transfer Effects of Jungle (1) the experimental between 9 and 12 years on near transfer measures of ver-
(2016) Memory Working Mem- group (first Jungle old with difficulties in bal WM. Improvements in math-
ory Training on Learning Memory (JM) for mathematics, attention, ematics but unknown if
Mathematics in Children 8 weeks then MT (math and WM mediated by gains in WM.
with Attentional and training) for 8 weeks); Furthermore, it remains unclear
Mathematical (2) the first control whether the effects found on
Difficulties. group (MT first then improving mathematics were
JM); (3) a second con- actually mediated by gains in
trol (usual education WM. It is argued that JM does
first, then MT). Assess- not train the components of WM
ment occurred three involved in maths enough, and
times: before training, this can be because of the train-
after 8 weeks, and ing’s lack of adaptivity, failing to
posttraining. provide children with tailored
instruction, and feedback.
Alloway Computerized working Active control: com- 94 students classified as Evidence that children with JM
et al. (2013) memory training: Can it plete the training pro- having learning diffi- first performed better after MT
lead to gains in cogni- gram once a week over culties, allocated to 3 than children who did not
tive skills in students? an 8-week period. They different groups (nonac- follow JM first or did not train
completed 24 sessions tive control, active con- with JM at all.
on average for all three trol, and training group)
memory games (eight
sessions per game).-
Training group used the
program 4 times a
week and completed
84 sessions on average
for all three memory
games (28 sessions per
game) over an 8-week
period.
PssCogRehab (n [ 1)
Author Title Length of working Study population Main findings
memory training
Bickel et al. Remember the future: All participants 27 adults in treatment for Discount rates were positively
(2011) working memory completed 1 pretraining stimulant use were correlated with memory
training decreases delay session, 4 to 15 training randomly assigned to training performance measures.
discounting among sessions, and 1 post- receive either WM These results offer further evi-
stimulant addicts training session. The training or control dence of a functional relation-
range of time lapsed training ship between delay discounting
between pre- and post- and working memory.
training sessions was 9
Continued
N-back (n [ 32)
e44 days, with a mean
of 25 days.
Cogmed (n [ 30)
Author Title Length of working Study Population Main Findings
memory training
Aasvik et al., Effectiveness of Work- 1 training session Patients currently on sick Working memory training
2016 ing Memory Training (30e45 min) every day leave due to symptoms (WMT) does not improve gen-
among Subjects for 5 weeks. of pain, insomnia, fa- eral WM capacity per se in
Currently on Sick Leave tigue, depression, and addition to no added effects in
Due to Complex anxiety targeting and improving self-
Symptoms. perceived memory functioning.
But evidence suggests that
inhibitory control is accessible
and susceptible to modification
by adaptive WMT.
Sadeghi Feasibility of computer- The patients underwent 9 early stage patients Improvement on Cogmed tasks;
et al., 2017 ized working memory 25 sessions of Cogmed with Huntington’s (26 patients found training helpful
training in individuals in total (5 day/week for e62 years) and reported memory
with Huntington 5 weeks). improvement.
disease
Fuentes and Maintenance effects of The WM intervention 28 children with epilepsy WMT possibly improves
Kerr, 2016 working memory inter- was the Cogmed “Robo- (between 6.5 and 15.5 related skills and these effects
vention (Cogmed) in Memo” program and years) are maintained for 3 months.
children with symptom- consisted of five 30e45- No transfer to fluid reasoning.
atic epilepsy min sessions per week
over a 5e7-week
period. Participants
were exposed to 12
WM exercises (7 visual
espatial, 2 visual
everbal, and 3 auditory
with visual responses) in
all over the duration of
training, with each ses-
sion consisting of 8
exercises.
Hitchcock & A cluster-randomised, 45min/every school day Primary school children CWMT did not improve
Westwell controlled trial of the for 5 weeks. control of attention in the
(2017) impact of Cogmed classroom or regulation of so-
Working Memory cial, emotional, and behavioral
Training on both aca- difficulties.
demic performance and
regulation of social,
emotional and behaviou-
ral challenges.
Lee et al. Effects of working 15 min a day, 5 days a Preterm children aged Results revealed that significant
(2016) memory training on week for 5 weeks. between 4 and 6 years improvements in verbal WM
children born preterm. was emerging in preterm chil-
dren at 5-week follow-up,
while significant gains in visuo-
spatial working memory was
found posttraining and at 5-
week follow-up in age-
matched term-born children.
These results indicated that
WMT has benefits for preterm
children.
Continued
N-back (n [ 32)
Hardy et al. Feasibility of Home- 5 days each week for Youth with SCD Children who completed
(2016) Based Computerized 5 weeks (25 training between the age of 7 Cogmed exhibited improve-
Working Memory sessions). and 16 years ments in verbal WM, visuospa-
Training With Children tial STM, and visuospatial WM.
and Adolescents With Suggestive that Cogmed is
Sickle Cell Disease. associated with WM improve-
ment in youth with SCD.
Phillips Computerized Working 27 children with moder- Study provides evidence of near
et al. (2016) Memory Training for ate to severe TBI and far transfer of training to
Children with Moderate WM and academic skills for
to Severe Traumatic children with TBI.
Brain Injury: A Double-
Blind, Randomized,
Placebo-Controlled Trial.
Wayne et al. Working Memory 25 sessions (30me1h/ 5 26 healthy subjects (13 Scores on the adaptive WMT
(2016) Training and Speech in sessions per week) of male, 13 female) be- tasks improved as a result of
Noise Comprehension adaptive working mem- tween 59 and 73 years training. However, training did
in Older Adults. ory training and pla- not transfer to other WM tasks,
cebo training over nor to tasks recruiting other
10 weeks in crossover cognitive domains. No
design. training-related improvement
in speech-in-noise perfor-
mance. The Reading Span Test
significantly correlated only
with a test of visual episodic
memory, suggesting that the
Reading Span Test is not a pure
test of working memory, as is
commonly assumed.
Roberts Academic Outcomes 20e25 training sessions First graders from 44 WM screening of children 6e7
et al. (2016) 2 Years After Working of 45 min duration at schools in Melbourne, years of age is feasible, and an
Memory Training for school. Australia adaptive working memory
Children With Low training program may tempo-
Working Memory: A rarily improve
Randomized Clinical visuospatial short-term
Trial. memory.
van der Predictors and Modera- 25 sessions (standard) A total of 98 children Cognitive training can be bene-
Donk et al. tors of Treatment (aged 8e12 years) with ficial for certain subgroups of
(2016) Outcome in Cognitive ADHD and comorbid children with ADHD; individ-
Training for Children LDs and/or ODD and on ual differences should be taken
With ADHD. medication into account in future trials.
Bigorra et al. Long-term far transfer 25 sessions of 66 children with CWMT had a significant
(2016) effects of working 30e35 min: 5 sessions combined-type ADHD (7 impact on ADHD deficits by
memory training in per week over 5 weeks. e12 years) from child achieving long-term far transfer
children with ADHD: a and adolescent psychiat- effects. Based on the
randomized controlled ric unit results obtained in the present
trial. study, CWMT may be a
recommended intervention.
Grunewaldt Computerized working The children in the 20 VLBW (very low birth Computerized working mem-
et al. (2016) memory training has intervention group weight) preschool chil- ory training seems to have pos-
positive long-term effect trained dren (5e6 years) itive and persisting effects on
in very low birth weight 10e15 min per day, working memory, and
preschool children. 5 days a week for visual and verbal learning, at
5 weeks (25 sessions). 7-month follow-up in VLBW
preschool children.
Continued
N-back (n [ 32)
Steeger et al. Combined cognitive Over 5w, completed a 91 adolescents (ages 11 Individual intervention effects
(2016) and parent training in- high- or low-dose e15 years) showed that treatment CWMT
terventions for adoles- version of Cogmed-RM significantly improved WM
cents with ADHD and (25 sessions). spans.
their mothers: A ran-
domized controlled
trial.
Cox et al. Feasibility and accept- 25 WMT sessions over Survivors of childhood Cogmed is a feasible and
(2015) ability of a remotely 5e9 weeks at home cancers between 8 and acceptable intervention for
administered computer- with weekly phone- 16 years of age, spoke childhood cancer survivors.
ized intervention to based coaching. English as a primary lan-
address cognitive late guage, and had been off
effects among childhood treatment for at least
cancer survivors. 1 year with no evidence
of recurrent disease.
Mawjee Working Memory 5 training sessions per 97 postsecondary stu- This study failed to find robust
et al. (2015) Training in Post- week for 5 weeks (1 dents 18e35 years old evidence of benefits of
Secondary Students with session/day of specified with ADHD (59.8% standard-length CWMT for
ADHD: A Randomized length: standard length females). improving WM in college stu-
Controlled Study. vs. shortened length dents with ADHD, and the
training group). overall pattern of findings raise
questions about the specificity
of training effects.
Söderqvist Working Memory The CMWT group un- All 20 students in a The results suggest that WM
and Berg- Training is Associated derwent training as part grade 4 classroom (9e10 training can help optimize the
man Nutley with Long Term Attain- of their curriculum for years) academic potential of high
(2015) ments in Math and 5 weeks. performers.
Reading.
Kerr and Near transfer effects 5 sessions per week for 77 children with symp- This is the first study to evaluate
Blackwell following working 5e7 weeks. tomatic epilepsy (ages the effectiveness of intervention
(2015) memory intervention 6.5e15.5 years; 100% to ameliorate WM deficits
(Cogmed) in children taking medication) commonly experienced by chil-
with symptomatic epi- dren with symptomatic epilepsy.
lepsy: An open random- Results support group improve-
ized clinical trial. ment on some untrained tasks
immediately postintervention,
demonstrating preliminary use-
fulness of Cogmed as a treat-
ment option.
Van der Cognitive training for Children followed the 102 children with ADHD Results showed an effect of
Donk et al., children with ADHD: a standard CWMT proto- between 8 and 12 years time on verbal WM, attention,
2015 randomized controlled col, which means both medicated and inhibition, planning, parent,
trial of cogmed working following the computer medication naı̈ve and teacher ratings of execu-
memory training and training program for tive functioning and ADHD-
’paying attention in 5 weeks, 5 times a related behavior.
class’. week, w45 min a day.
Holmes Improving working 20 sessions of Cogmed 19 children aged 8e10 Preliminary evidence that inten-
et al. (2015) memory in children Working Memory years with LLA (low lan- sive working memory training
with low language Training (45min). guage abilities) (n ¼ 12, may be effective for enhancing
abilities. after dropout and others) the weakest aspects of STM in
children with low verbal abili-
ties and may also be of value in
developing compensatory
strategies.
Continued
N-back (n [ 32)
Mawjee Working Memory Participants randomized 38 postsecondary stu- There was no significant differ-
et al., 2014 Training in ADHD: Con- into 25 sessions of stan- dents with ADHD ence in completion rate or
trolling for Engagement, dard (45 min) or short- training index score between
Motivation, and Expec- ened (15 min) sessions. the standard- and shortened-
tancy of Improvement length groups, indicating that
(Pilot Study). both groups showed improve-
ment and put forth good effort
during training.
Au et al. A feasibility trial of 1 session a day, 5 days 8 participants with Frag- Cogmed Jungle Memory is a
(2014) Cogmed working mem- a week for 5 weeks ile X Syndrome feasible intervention in FXS,
ory training in fragile X (session: 15e30 min). though a certain baseline level
syndrome. of ability is required.
Chacko A randomized clinical 30e45 min increments 85 school children with CWMT demonstrates effects on
et al. (2014) trial of Cogmed Work- over 5 days per week ADHD (7e11 years) ran- certain aspects of working mem-
ing Memory Training in (25 training days total). domized to either stan- ory in children with ADHD;
school-age children dard CWMT or CWMT however, CWMT does not
with ADHD: a replica- placebo condition appear to foster treatment gener-
tion in a diverse sample alization to other domains of
using a control functioning. As such, CWMT
condition. should not be considered a
viable treatment for children
with ADHD.
Dongen- Working memory 25 sessions of 15 min, 47 children (5e7 years) This study failed to find robust
Boomsma training in young chil- 5 days a week. with ADHD (w/o psy- evidence for benefits of CWMT
et al. (2014) dren with ADHD: a chotropic medication) over the placebo training on
randomized placebo- RA to active (adaptive) or behavioral symptoms, neuro-
controlled trial. placebo (nonadaptive). cognitive, daily executive, and
global clinical functioning in
young children with ADHD.
Björkdahl A randomized study of 30e45 min per session, 20 outpatients with WM The WM training seems to
et al., 2013 computerized working 5 days a week for deficits (22-63yoa) were have a generalized effect on
memory training and 5 weeks (25 sessions). randomized into inter- functional activity and lessens
effects on functioning vention group. fatigue; the intervention group
in everyday life for pa- improved on digit span, FIS
tients with brain injury. (Fatigue Impact Scale) and WM
questionnaire. Improved in mo-
tor skills and process skills
(AMPS).
Akerlund Can computerized 30e45 min, 5 days/ Randomized study Results indicated that comput-
et al. (2013) working memory week for 5 weeks. (n ¼ 47) with an inter- erized WM training can
training improve vention group and a con- improve working memory,
impaired working mem- trol group (mean cognition, and psychological
ory, cognition and psy- age ¼ 47.7y) health.
chological health?
Grunewaldt Working memory 10e15 min a day, 20 VLBW preschoolers This study shows that VLBW
et al. (2013) training improves 5 days a week over a 5- aged 5e6 years. preschoolers benefit from a
cognitive function in week period. computerized working memory
VLBW preschoolers. training program. It is specu-
lated that such training before
starting school may prevent or
reduce cognitive problems that
impact educational
achievement.
Continued
N-back (n [ 32)
Gibson et al. Exploration of an adap- 25 days of WM training 20 undergraduates The main findings suggested
(2013) tive training regimen within 5 weeks. randomly assigned to that the SM component could
that can target the sec- standard exercise be enhanced by span-based ex-
ondary memory (n ¼ 10) or modified exercises when a more lenient
component of working ercise (n ¼ 10) condition. recall accuracy threshold was
memory capacity. used; manipulation of exercise
type (complex span vs. simple
span) showed little effect on
the SM component of WM
capacity.
Gibson Component Analysis of 25 days of CWMT 74 adolescents (9e16 The main findings showed that
et al. (2012) Simple Span vs. Com- within 5 weeks; but years) randomly assigned SM capacity did not improve,
plex Span Adaptive required to complete at to either the standard ex- even in the modified training
Working Memory Exer- least 20 days to be ercise (N ¼ 36) or the condition. Hence, the potency
cises: A Randomized, included. modified exercise of span-based WM interven-
Controlled Trial. (N ¼ 38) training tions cannot be increased sim-
condition. ply by converting simple span
exercises into complex span
exercises.
Gray et al. Effects of a computer- 12 different WMT exer- 60 teenagers with LD/ Adolescents in the WM
(2012) ized working memory cises with an average ADHD (12e17 years) training group showed greater
training program on training time per day of improvements in a subset of
working memory, atten- 45 min approximately WM criterion measures
tion, and academics in (excluding breaks). compared with those in the
adolescents with severe math training group, but no
LD and comorbid training effects were observed
ADHD: a randomized on the near or far measures.
controlled trial. Results suggest that WM
training may enhance some as-
pects of WM in youths with
LD/ADHD.
Johansson Working memory Training for 30e45 min, 18 patients, aged 17e64, The computerized training
and Torn- training for patients three times a week dur- who had difficulties in showed a significant improve-
malm, 2012 with acquired brain ing a period of 7 daily life pertaining to ment on trained working mem-
injury: effects in daily e8 weeks. working memory deficits ory tasks. Patients starting at a
life. To this, 30 min per low training level improved the
training day was sched- most. Self-rating measurements
uled to exchange expe- and interviews indicated that
riences of WM deficits, patients experienced fewer
training experiences, cognitive problems in daily life
and strategies. after training. The effect was
maintained at the 6 month
follow-up.
Lumosity (n [ 4)
Author Title Length of working Study Population Main findings
memory training
Toril et al. Video Game Training 15 1-h video game Participants were 19 Suggests that video game
(2016) Enhances Visuospatial training sessions with a volunteer older adults training might be an effective
Working Memory and series of video games intervention tool to improve
Episodic Memory in selected from a com- WM and other cognitive func-
Older Adults. mercial package tions in older adults.
(Lumosity).
Continued
N-back (n [ 32)
Wentink The effects of an 8- The training consisted 107 participants between The effects found in the study
et al. (2016) week computer-based of gaming at home dur- 45 and 75 years, diag- on the WM tests were smaller
brain training pro- ing a period of 8 weeks, nosed with stroke 12 than other studies using CBCR
gramme on cognitive at least 5 days per e36 months ago, having training primarily focused on
functioning, QoL and week, approximately self-perceived cognitive one cognitive function among
self-efficacy after stroke. 15e20 min per day, impairments stroke patient indicating that
resulting in a requested this was attempting to test too
play time of 600 min. many components rather than
The control group targeted WM training. There
received general infor- was also no evidence of far
mation about the brain transfer effects.
weekly. The total dura-
tion of the control inter-
vention was on average
70 min per person.
Ballesteros Brain training with non- 20 1 h nonaction 40 healthy older volun- Visuospatial WM and executive
et al., 2014 action video games en- video game training teers (age range 57e80 control (shifting strategy) did
hances aspects of sessions selected from years) not improve.
cognition in older the Lumosity package.
adults: a randomized
controlled trial.
Thompson Optimizing memory Memory training was 70 people with TLE, Lumosity use was not associ-
et al. (2016) function in temporal provided on an individ- complaining of memory ated with changes in the mem-
lobe epilepsy. ual basis in up to 2 ses- difficulties. Aged from 19 ory outcome measures versus
sions and totaled a to 67 years. 40 with left conventional memory tests. So,
maximum of 4 h. TLE the study indicates traditional
memory rehabilitation tech-
niques can help reduce the
burden of memory impairment
in TLE and so no evidence that
Lumosity has specific
advantages.
Neuroracer (n [ 1); Project Evo (n [ 2)
Authors Title Length of working Study population Main findings
memory training
Anguera Video game training en- 1 h a day, three times a 46 participants (60e85 Working memory and sus-
et al. (2013) hances cognitive con- week, for 4 weeks years) tained attention improved and
trol in older adults. persisted for 6 months.
Anguera Improving late life 20 min five times a 12 participants, 60 years Mood, self-reported func-
et al., 2017 depression and cogni- week, for 4 weeks and over tioning, working memory. and
tive control through the attention improved.
use of therapeutic video
game technology: A
proof-of-concept ran-
domized trial.
Arean et al., The Use and Effective- Participants were 626 participants with The study found that both the
2016 ness of Mobile Apps for randomly assigned to mild to moderate depres- Project:EVO and iPST groups
Depression: Results one of the three groups: sion as determined by a had greater improvements in
From a Fully Remote (1) Project:EVO (experi- 9-item Patient Health mood than the control group.
Clinical Trial. mental group) (2) iPST Questionnaire This was particularly true for
(active control), and (3) participants with moderate
Health Tips (passive levels of depression.
control).
Neuronation (n [ 1)
Author Title Length of training Study Population Main Findings
Continued
N-back (n [ 32)
Niedeggen A computer-based 25 min, 4 weeks Experimental group: Although both groups demon-
et al. cognitive training based n ¼ 13 (8 women; 55 strated improvements in the
on NeuroNation e80 years) nontrained visuospatial working
Control group: n ¼ 11 (8 memory (WM) task, it was
women; 55e78 years) higher for the experimental
group. Both groups also showed
improvements in unrelated tasks
measuring mental flexibility,
with improvements greatest for
the experimental group. Neither
group demonstrated a general-
ized transfer effect (memory; se-
lective and divided attention;
processing speed) and neither
group showed a change in sub-
jective well-being or the estima-
tion of their own cognitive
capacities.
C-ya (n [ 2)
Author Title Length of WM training Study population Main findings
Brooks et al. The impact of cognitive 4 weeks, 5 days per Methamphetamine use Feelings of self-control and
(2017a) training in substance week, half an hour per disorder male inpatients mood were significantly higher
use disorder: the effect day, 5 5 min sessions in Cape Town South Af- in the MUD group who had
of working memory with 1 min break in rica versus healthy WMT compared with those who
training on impulse between matched controls had only standard treatment.
control in methamphet- Also, total impulsivity scores and
amine users. lack of planning significantly
improved in the WMT group
compared with the treatment
only group. Finally, self-
regulation questionnaire scores
were also significantly improved
in patients who engaged in
WMT versus those who did not.
Brooks et al. Psychological interven- 4 weeks, 5 days per Methamphetamine use Treatment as usual was associ-
(2016) tion with working week, half an hour per disorder male inpatients ated with increased bilateral
memory training in- day, 5 5 min sessions in Cape Town South Af- striatal volume, whereas those
creases basal ganglia with 1 min break in rica versus healthy who engaged in WMT had
volume: A VBM study between matched controls more widespread bilateral
of inpatient treatment basal ganglia volume increase,
for methamphetamine extending to the amygdala and
use hippocampus. Reduced bilat-
eral cerebellar volume was
associated with reduced impul-
sivity scores.
total of 17 half-hour sessions, found that single n-back was Shah, 2011). However, more recent studies have not found
as effective as dual n-back in terms of temporary near these effects, often commenting that a major problem with
transfer to measures of general intelligence. They also n-back training is its limit of effect solely to the task
found that n-back training appears domain free in that trained (Thompson et al., 2013; Lindeløv et al., 2016).
verbal n-back training had near transfer improvements to Although far transfer effects on attention and intelligence,
visuospatial reasoning (Jaeggi et al., 2014). In line with as well as skills transfer to demonstrate long-term
this, earlier studies have shown near transfer of effects of improvement over months are not usually demonstrated
n-back training on measures of general intelligence and with n-back, earlier tests have demonstrated longevity of
matrix reasoning (see Jaeggi, Buschkuehl, Jonides and skills transfer illustrated by n-back training effects for over
3 months (see Jaeggi et al., 2011). However, a later study potential far transfer benefits of WMT on mathematical
(Jaeggi et al., 2014) did not replicate this finding after a skills, as WM may be an essential component for mathe-
3-month follow-up. Thus, while there is some indication matical reasoning, although its exact role and mechanisms
that n-back WMT improves far transfer effects on other underlying mathematical abilities remain unclear. The
cognitive modalities such as attention and intelligence in study compared three groups of Dutch children between the
the short term, there is not yet convincing evidence that ages of 9 and 12, with mathematical and attentional diffi-
the improvement effects are long-lasting. However, it is culties after they received JM and maths training (Math
not yet known whether far transfer effects of n-back WMT Garden). The overall findings provided a limited contri-
will be observed for measures other than attention and bution to WMT literature and its near and far transfer ef-
intelligence, such as self-regulation and impulse control, fects. The study found that the computerized mathematics
which may be more relevant to the treatment of cognitive training had beneficial effects on children’s mathematical
deficits in addiction. abilities, whereas JM WMT training did not exhibit a
positive or added effect. However, it is mentioned that
Jungle memory (n [ 2); Alloway (2009) perhaps increasing the amount of effort during WMT could
improve the outcomes on JM and therefore mathematics.
JM is a WMT program designed for children (aged from 7 Unfortunately, the study presented with limitations such as
to 16 years old) and uses games that are colorful and lack of students’ investment and effort and therefore claims
stimulating to motivate children to engage. Given that the that more research is needed before attempting to link
focus of JM is on children’s cognitive performance, this improved cognitive performance to WMT, at least in
could explain why it has not been used for people with children.
addictive disorders. JM involves three training pro-
grammes: quicksand, codebreaker, and river crossing.
PSSCogRehab (n [ 1) Bracy (1994)
Quicksand involves remembering the location of a letter or
a string of letters. Codebreaker involves spatial awareness PSSCogRehab is a Cognitive Rehabilitation Therapy
and recognition of letters in different positions. River System packaged as a computerized program that runs on
crossing involves a WM task that encourages children to computers. The WMT element consists of 8 modules that
complete increasingly difficult mathematical problems. include 67 computerized tasks. WMT is completed in
Typically, children complete all of these tasks over 6e12 months depending on the level of impairment or
8 weeks, and the authors report sustained improvement to commitment, and the program aims to retrain cognitive
WM after the completion of the program. skills that are deficient due to brain degeneration or brain
In a study by Alloway et al. (2013), participants with damage, caused by substance use for example. The
learning difficulties were sorted into three groups: the training mostly focuses on attention, problem-solving,
controls who received no training and continued with memory recall, and visuospatial exercises. The memory
regular classroom activities, a low-frequency WMT group training includes using sequenced recall (e.g., words,
that performed training once a week (total of 24 sessions digits, and graphics, involving auditory and visual tasks)
over 8 weeks), and a third high-frequency WMT group that and nonsequenced recall. The problem-solving skills
performed training four times a week (total of 84 sessions development includes tasks such as completing additions
over 8 weeks). Findings indicated that there were and subtractions, creating pyramids by placing smaller disks
improvements in verbal and nonverbal, as well as visuo- on larger ones using as little movements as possible, or
spatial, WM tasks for the high-frequency WMT group arranging marbles in specific color patterns. Finally, visuo-
compared with the low frequency group, and significant spatial training includes exercises such as line and angle
improvements in spelling were also noted in the high- discrimination tasks, design completions, block counting, or
frequency group. Additionally, with high-frequency deciding which pattern is different to the others.
training, it was evidenced that JM led to longevity far In addition to these exercises, participants are advised to
transfer of skills transfer, with students exhibiting im- complete the PSSCogRehab exercises at home in their own
provements that were still evident up to 8 months post- time, but must also attend face-to-face sessions with a
training. Specifically, the data indicated a longevity of skills clinician to track progress and adjust the therapy exercises
effect in both verbal and visuospatial WM, verbal ability, accordingly. The exercises are challenging but not impos-
and spelling, but no convincing far transfer effects of sible, and accordingly, participants are expected to perform
improvement in other cognitive domains. the right amount of exercise daily, which matches their
Another study using JM, conducted by Nelwan and level of ability. The participant completes these exercises
Kroesbergen (2016), found no evidence of far transfer daily, between the weekly face-to-face sessions at the
effects, at least in mathematical skills (which is all that was center. This “homework” concept allows the participant to
tested in this study). Indeed, the study explored the incorporate and practice compensation skills discussed
during the face-to-face session. However, it is important to It is, however, the CogMed research conducted on
note that the computer program by itself is not used as a children and adolescents that has yielded the most signifi-
monotherapy and has been shown in the publication to be cant results, with evidence of verbal, visuospatial WM, and
most effective when used in parallel with other processes. short-term memory (STM) improvements in children with
For example, during teaching and using compensatory SCD and those born preterm (Lee et al., 2016; Hardy et al.,
skills developed in face-to-face sessions, psychological 2016). In neurotypical first graders, there was evidence of
counseling, and environment restructuring and following improvements in visuospatial STM, although these were
outpatients when they have reintegrated back into their temporary (Roberts et al., 2016). Additionally, there was
work, school, or home environment. Additionally, the evidence of a significant impact on WM deficits and a long-
PSSCogRehab program has demonstrated statistically sig- term far transfer effect in children with ADHD, and as such,
nificant improvements in cognitive functioning in patients CogMed was a recommended intervention by Bigorra et al.
on completion. (2016). Another study by Grunewaldt et al. (2016) found
Only one study to date has published research using CogMed to have long-lasting effects on WM in VLBW
PSSCogRehab, to the authors’ knowledge, in patients with preschool children (e.g., over many months). Similarly,
substance use disorder. Bickel et al. (2011) examined 27 Gray et al. (2012) found that adolescents with ADHD and
participants with stimulant use disorder (mainly cocaine, LDs showed great improvements in WM (specifically
some with methamphetamine use disorder), who were mathematical reasoning), although with no evidence of long-
randomly assigned to either PSSCogRehab training or to an term skill transfer. On the other hand, Hitchock and West-
active control condition. Participants completed 1 pre- well (2017) found that CogMed had no impact on neuro-
training session, 4e15 training sessions, and 1 posttraining logically intact children, and Chacko et al. (2014) deemed
session. The training sessions involved completing the four CogMed to be an incomplete and inefficient treatment by
memory training programs twice. The number of sessions itself; however, limited findings could be due to variations in
completed was due to each participant’s progress. For the number of sessions provided across studies. Klingberg
example, three consecutive sessions without improved and colleagues suggest that sessions of CogMed should
performance on any two programs resulted in the conclu- typically last between 30 and 45 min, with training extend-
sion of training, with a minimum of 4 and a maximum of 15 ing to between 5 weeks (minimum) and 8 weeks. Moreover,
training sessions. By comparison, the active control session Klingberg and colleagues suggest that these training sessions
was almost identical but for the fact that participants were should occur at least three times a week to ensure and
given the answers during the session, so they did not maintain gradual increase in performance, which may
engage WM. Bickel and colleagues reported that the strengthen the effects on WM performance and also far
stimulant users who engaged in WMT had a significant transfer effects to other cognitive domains.
decrease in delay discounting (a measure of decision In line with these suggestions, a recent pilot study
impulsivity, based on whether immediate or future rewards conducted by Sadegh et al. (2017) explored the effects of
are chosen), and so they suggest that WM plays a vital role CogMed on nine early stage patients with Huntington’s
in the control of impulsivity. However, follow-up studies to disease (26e62 years of age). The patients underwent 25
test far transfer effects have yet to be conducted with sessions of CogMed in total (5 days/week for 5 weeks).
PSSCogRehab. The patients who successfully adhered to the training
showed both improvements on CogMed tasks and noted
CogMed (n [ 31) Klingberg et al., (2002) that they found the training helpful. These findings serve to
highlight the feasibility of CogMed in this population.
CogMed is a computerized WM training program first However, because of the small sample size, a wider and
developed to improve WM in children with ADHD. more controlled intervention is necessary to understand the
CogMed has showed promising results in this and other efficacy of CogMed and the reliability of findings (Sadegh
populations, such as autism spectrum disorders, Hunting- et al., 2017). In terms of far transfer effects of CogMed,
ton’s disease, epilepsy, and also AUD. However, the ma- Fuentes and Kerr (2016) studied the effects on 28 epileptic
jority of the research is still conducted in children, mostly children and were interested in the maintenance effects of
with conditions characterized by poor WM, such as the training (3-month follow-up). The children underwent
learning disabilities (LDs), ADHD, dyslexia, children with the training five times a week over 5e7 weeks (each ses-
genetic conditions like sickle cell disease (SCD), and sion lasting between 30 and 45 min). The children showed
children born preterm, in other words, with very low birth improvements in auditory and visual attention as well as
weight (VLBW). The other clinical populations include WM immediately after the training, and these improve-
adults with clinical conditions (e.g., symptoms of pain, ments were sustained at a 3 month follow-up. However, no
insomnia, fatigue, depression, and anxiety), who are HIV transfer to other WM areas (e.g., visual/verbal WM, fluid
positive or with recognized WM deficits. reasoning) was noted. This study, albeit with a small
sample size, indicates that there is evidence of WM WMT, but no overall effects of training on other measures
improvement, particularly in attention measures that can of cognition, food intake, HbA1c, cholesterol, food crav-
sustain after the training (Fuentes and Kerr, 2016). ings, and dietary self-efficacy and self-care. In post hoc
In terms of those with addictive disorders, CogMed has analyses, the authors reported that participants who scored
been used to examine the effect of WMT in those with highly on dietary restraint in the active training group
AUDs. For example, Houben and colleagues, in 2011, showed a more significant reduction in fat intake pre- to
examined 48 problem drinkers who performed a visuo- posttest compared with controls.
spatial WM task, a backward digit span task, and a letter The most recent study using CogMed was by Khemiri
span task that was adapted from the CogMed training and colleagues in 2019, and it examined participants with
paradigm. Participants also took part in control tasks, dur- AUD with 5 weeks of either active WMT or a control
ing 25 sessions over at least 25 days. Before and after training (Khemiri et al., 2019). The authors report that the
training, the authors measured WM and levels of drinking AUD group demonstrated significantly greater verbal WM
behavior. It was reported that WMT improved WM per- compared with the control group after 5 weeks. Addition-
formance and also reduced alcohol intake for more than ally, there was a trend for WMT to reduce the number of
1 month after the training (e.g., longevity of skills transfer drinks consumed per drinking occasion, but had no signifi-
and far transfer effects). Interestingly, the authors reported cant influence on any other neuropsychological measure.
that increased WM ability following the WMT reduced This studydwith measures of executive function and
alcohol consumption, but particularly in participants with impulse control (number of drinks consumed), as opposed to
relatively strong automatic preferences for alcohol (Houben the common measures of attention and global
et al., 2011). intelligencedgoes some way to support the hypothesis that
In another study by Houben and colleagues in 2016, WMT improves processes of executive function and self-
improvement in overeating (which is considered by some to regulation/impulse control (in this case, for drinking per
be a form of food addiction, with deficits in self-regulation) occasion).
was examined using CogMed-inspired WMT. In the study,
50 overweight participants performed 20e25 sessions of Lumosity (n [ 4) Lumos Labs (2005)
WMT or control/sham training (Houben et al., 2016). The
authors reported that relative to the control condition, Lumosity is an online cognitive training program with
CogMed reduced psychopathological eating-related games claiming to improve memory, attention, speed of
thoughts and emotional eating (but not external eating). processing, and problem-solving. However, in 2016,
At 1 month later, the effects were still present, suggesting a Lumosity became an example for the need to engage in the
longevity of skills transfer effect. Food intake and body robust peer-review process, as it was fined $2K by the
weight was not significantly influenced by WMT, although Federal State Commission, for its claims that the training
it did reduce food intake among highly restrained partici- helps users perform better at work and in school, reducing
pants. In a similar study by the same group, but this time or delaying cognitive impairment associated with age and
with a gamified (e.g., computer gameelike) version of the other serious health conditions (Federal Trade Commission,
CogMed-inspired WMT intervention, the authors examined 2016). Studies using Lumosity as a WMT have demon-
weight, food intake, executive functioning, self-control, strated mixed results. A study conducted by Toril et al.
eating style, eating psychopathology, and healthy eating in (2016) on neurologically intact older adults found signifi-
a group of 91 overweight individuals with a desire to lose cant WM enhancements in the trained group when assessed
weight (Dassen et al., 2018b). The authors found that WM on visuospatial WM tasks (Corsi blocks and Jigsaw puzzle
span was higher than control from pretest to posttest. task), compared with the control group who demonstrated
Furthermore, there was some evidence of longevity of skills no changes. Improvements in episodic and STM were also
transfer (e.g., WM span increase) at 1, but not 6, month. noted, and these were maintained for 3 months. This led
However, no far transfer effects to other executive func- Toril et al. (2016) to conclude that video game training
tioning measures were found. could be an effective intervention tool to improve WM and
In a study by the Higgs group using a CogMed-inspired other cognitive functions in older adults. On the other hand,
WMT paradigm, dietary self-care in people with Type 2 Wentink et al. (2016) who examined stroke patients found
diabetes was examined for its effects on cognition, food Lumosity to have limited effects on WM and speed of
intake, glycemic control (HbA1c), cholesterol, and also processing. Thompson et al. (2016), in a study on WM in
self-reports of the experience of the training (Whitelock individuals with temporal lobe epilepsy, also failed to find
et al., 2018). The authors used a double-blind, parallel significant links between the use of Lumosity and WM
group, randomized control trial to examine 45 participants improvements. Furthermore, although Ballesteros et al.
in the active WMT group versus 36 in the control WMT (2014) (who examined neurologically intact older adults)
group. They found improved WM updating ability after found significant improvements in the Lumosity-trained
groups in processing speed, attention, and immediate and attention and WM, which were not observed in the PST
delayed visual recognition memory, it was also found that participants. Furthermore, in another study of 209 adults
visuospatial WM did not improve. Thus, concluding that (18 years and older) with mild to moderate depression,
video game training can enhance some cognitive abilities symptoms of depression were lessened after Project:EVO
but perhaps not WM in a neurotypical sample. Unfortu- training compared with controls (Arean et al., 2016).
nately, neither the duration of Lumosity training sessions, Neuroracer is not available commercially, but Project:EVO
nor the frequency of training, was noted. As such, given the will be available on mobile phones and the iPad in the near
lack of research using Lumosity in addiction populations at future. Given that the authors report significant findings in
present, it is not yet clear whether this intervention would adultsdparticularly those with affect regulation
be useful for those with various addictive behaviors. (e.g., higher levels of anxiety/depression) and cognitive
difficulties, which are often comorbidities in those with
Neuroracer (n [ 1); Project:EVO (n [ 2); both addictiondthere appears to be support for the notion that
WM training may be useful in reducing cognitive-affective
versions of the same product founded by
difficulties in those being treated for addiction.
Gazzaley and Akili Interactive
Neuroracer is an adaptive video game (Project:EVO is the NeuroNation (n [ 1); Ahmadi and Futorjanski
newer version of the game) challenging players on two (2011)
tasks, navigating and responding to signs while steering a
car. One peer-reviewed publication was found, which tests NeuroNation is an online brain-training platform attesting
this version of the training. The task engages multiple to improve cognitive skills such as numeracy, language
skills, particularly aspects of attention, task switching, (verbal fluency), reasoning, memory (WM specifically),
focusing, and WM. Anguera and colleagues comment that and perception (behavioral control required for flexible
even though Neuroracer is not designed specifically to thinking, concentration, multitasking, and willpower). One
improve WM, the multitasking nature of it may put strain peer-reviewed publication demonstrates the effects of
on the cognitive system, improving all of its sub- NeuroNation on processing speed, set-shifting, inhibition,
components, including aspects of attention and WM reasoning, and self-reported cognitive failures, as well as
(Anguera et al., 2013). A study by Anguera et al. (2013) on improvements in the WMT itself. Training was completely
46 participants (60e85 years) found that those who administered at home in 176 healthy control participants
completed the multitasking training condition (n ¼ 16) for (mean age 50%, 62% female) with 82 participants in the
1 hour a day, three times a week, for 4 weeks, found training group and 94 participants in the control group
improvement in WM and sustained attention. These results (Strobach and Huestegge, 2017). The authors found that in
indicate achievement “beyond that of untrained 20 year contrast to the active control training group, NeuroNation
olds” (Anguera et al., 2013) and persisted for 6 months improved processing speed and set-shifting tasks (i.e., far
after the training concluded. transfer effects), but these improvements were not as
The newly branded form of the game (Project:EVO) is conclusive as the improvements found for WM near
currently being tested as a diagnostic tool for Alzheimer’s transfer effects. Moreover, performance improvements us-
disease as well as a treatment for depression, autism, ing NeuroNation were more pronounced for high-
traumatic brain injury, cerebrovascular dementia, and performing participants (i.e., magnification effects), sug-
ADHD (http://www.akiliinteractive.com/). Two peer- gesting an added effect of participant motivation. Neuro-
reviewed publications were found for Project:EVO, which Nation is an adaptive program, adjusting to the user’s
involves guiding a character through a virtual environment abilities. Progress is charted and can be compared with
while engaging with certain targets (Anguera et al., 2017). others also playing. It claims that only 15 min of brain
It is adaptive to the ability of the user while remaining training is required per day and is available on the Internet
challenging, which helps to encourage cognitive improve- or as an App for phones and tablets/iPads. In 2013, Neu-
ment in the user. Project:EVO aims to improve the symp- roNation received recognition from the German Federal
toms of WM, inattention, and executive function deficits as Ministry of Health, and their website claims collaborations
well as mood. In a pilot trial by Anguera et al. (2017), of 22 with numerous hospitals, universities, and outpatient reha-
participants (60 years and over) with late-life depression, bilitative programs. The collaborations address areas such
12 participants were assigned to play Project:EVO for as improving symptomatology of schizophrenia, anorexia
20 min, five times a week, for 4 weeks, while the other nervosa, stroke, cognitive decline, Parkinson’s, Hunting-
participants receiving problem-solving therapy (PST) ton’s, and chemotherapy’s aversive effects, depression as
(n ¼ 10). Both groups showed improvements in mood and well as contributing to cognitive and athletic enhancement.
self-reported cognitive functions. However, the Project:- These studies and programs appear to be ongoing, and no
EVO participants also demonstrated gains in areas of information regarding their published material is given on
NeuroNation’s website, barring the one study described application of WMT interventions for addiction treatment
above (Strobach and Huestegge, 2017). will be further discussed below.
Curb Your Addiction (n [ 2); Brooks (2016). Discussion

C-Ya is the newest peer-reviewed WMT App at time of The aim of this systematic review of WMT paradigms was
writing, according to the authors’ knowledge, and was first to examine the effects of currently peer-reviewed WMT
published in 2016 to examine the effects on inpatients be- interventions on various populations, in terms of the mea-
ing treated for methamphetamine use disorder (Brooks sures used and the near versus far transfer effects reported.
et al., 2016). The background research to the App is based Primarily, this was to critically consider whether there is
on neuroimaging data (structural and functional) in patients utility in pursuing WMT as an intervention option for the
with chronic anorexia nervosa (for review see Brooks et al., treatment of addiction. Additionally, the review sought to
2017a,b), who appear to have maladaptive WM processes determine a) WMT Apps that have been peer-reviewed in
underlying cognitions and ruminations pertaining to scientific journals, b) near and far transfer effects, c) the
excessive appetite control. The authors suggest that type of human populations (clinical and/or nonclinical)
improved (e.g., broadened, strengthened) appetite/impulse studied, d) the nature of the differences between WMT
control may be achieved by harnessing WM processes paradigms, f) existing limitations of the delivery of WMT,
using the C-Ya App. The C-Ya App is based on the and g) whether there is utility in using WMT for the
traditional n-back WM task (see 3.1), but it differs in that it treatment of addiction. By addressing these aims, it might
includes stimulation up to 8-back with peripheral and be easier to evaluate the claims laid by the most robust
supraliminal distraction with images of food and drugs for (e.g., scientific peer-reviewed and published) WMT apps
example. The first published study of C-Ya demonstrated available, which will better support the choices made by
that 4 weeks (20 sessions) of half-hour standard (without researchers and clinicians when considering the use of these
subliminal stimulation) C-Ya sessions appeared to increase interventions for addiction. The findings of this review are
brain volume in a brain region associated with appetite and explained in relation to these aims below.
impulsivity (bilateral basal ganglia). A second publication
followed, demonstrating that the level of C-Ya engagement
Peer-reviewed working memory training
in the first publication appeared to improve self-reported
impulse control, mood, and anxiety in these patients
paradigms
(Brooks et al., 2017a,b). C-Ya training follows the classic Eight peer-reviewed WMT paradigms were found, namely
n-back task, where single letters are presented consecu- (in chronological order of creation) (i) Classic n-back tasks;
tively on the screen of the smartphone, and the screen is (ii) PSSCogRehab; (iii) Jungle Memory; (iv) CogMed (v)
pressed when a target letter appears. The target is deter- Lumosity, (vi) Neuroracer/Project:EVO; (vii) Neuronation,
mined by the “n-back” level, for example, 0-back repre- and (viii) Curb Your Addiction (C-Ya). The most popular
sents the target letter “X”; 1-back is when the targetdthe WMT paradigm is n-back, whereas the most published/
current letter on the screendis the same as one shown peer-reviewed App/intervention, including extensive
previously; 2-backdtwo previously; 3-backdthree previ- reviews, is CogMed
ously, and so on, up to 8-back. The rationale for the su- All of the WMT paradigms reviewed here purport to
praliminal distraction categories is that they stimulate the alter neurocognitive processes, which are likely associated
mesolimbic salience/arousal regions of the brain, placing with changes in top-down prefrontal cortex and bottom-up
additional attentional processing demands on the user basal ganglia function. For example, recent studies of
during the completion of the WMT. As such, if players can WMT paradigms, such as CogMed, C-Ya, n-back, have
improve their competency during the supraliminal cate- demonstrated neural effects in children, adults with AUD,
gories, in line with a specific stimulus that is particularly overeating, Type 2 diabetes, and methamphetamine addic-
relevant to the user, the author suggests that players will tion, and older adults (Klingberg, 2010; Brooks et al., 2016;
strengthen neural pathways that enable an ecologically Pergher et al., 2018), in line with neurocognitive perfor-
valid application of the training to exert cognitive control in mance benefits to various domains, such as attention, in-
real life (e.g., peripheral distractions are constant in telligence, and most recently, self-regulation and impulse
everyday life). control (e.g., reduced drinking of alcohol and improved
To date, according to the authors’ knowledge, C-Ya, self-report measures of impulse control). It is suggested that
PSSCogRehab, and most recently CogMed are the only with adaptive WMT (e.g., updating the difficulty based on
WMT interventions that have examined their effects in the participant’s fluctuating performance), by multitasking
people with addiction (methamphetamine use, cocaine use (paradigms such as CogMed), or via progression through
disorder and AUD, and overeating as a food addiction). The increasingly difficult levels (paradigms such as C-Ya for
impulse control training using supraliminal distractions), et al., 2013; Jaeggi et al., 2014; Arean et al., 2016). Most
synaptic plasticity in the prefrontal cortex and basal ganglia recently, improved verbal WM in line with a trend for less
can lead to far transfer and longevity of skills transfer alcoholic drinks consumed per drinking occasion was re-
effects. And as the field currently reports inconsistent ported after 5 weeks of CogMed training (Khemiri et al.,
findings, the skepticism for WMT may be fueled by 2019). There is an understanding that these WMT para-
measures that do not adequately assess the underlying digms influence other cognitive abilities (besides simply
neural mechanisms associated with the neurocognitive allowing for improved ability in the paradigm practiced) as
process that is actually being altered (e.g., attention versus they activate common neural networks shared by other
self-regulation). cognitive areas, such as those prefrontal cortex networks
To test whether neurocognitive processes are altered, involved in future planning and reward evaluation (Jaeggi
WMT studies to date have focused their measures on et al., 2014; Beatty and Vartanian, 2015; Brooks et al.,
attention, global intelligence, mathematical ability, and the 2016). Furthermore, pushing participants to their limits was
transfer to other cognitive skills such as visuospatial acuity; seen to have the most influence on positive outcomes,
only a few studies have measured self-regulation/impulse particularly if participants were required to do two or more
control and control of eating or alcohol drinking activities at once (Jaeggi et al., 2008). The frequency of
(e.g., Bickel et al., 2011; Houben et al., 2011; Brooks et al., practice was also stressed as imperative to the success of
2016; Houben et al., 2016; Khemiri et al., 2019). Related the training, with more practice producing better and more
studies of overeating suggest a small improvement over lasting results (Alloway et al., 2013). WMT, like other
control of eating following WMT (Houben et al., 2016; forms of (e.g., physical) training, appears to require
Dassen et al., 2018a; Whitelock et al., 2018). Most studies continuous practice to produce positive cognitive and
of WMT have been conducted in children and adolescents, behavioral change in the individual, and this may be
with the forerunner in this research being CogMed, something that is not currently adhered to in practice or in
demonstrating improvements to inattention, visual, and studies of WMT. Yet, it should be noted that even a min-
verbal WM (Spencer-Smith and Klingberg, 2015). At the imum training period of 3e4 weeks was found to produce
end of 2018, an update in the field of WMT for children lasting benefits 6e12 months later by some studies
and adolescents has been provided, with a review of WMT reviewed. In line with this, the motivation and investment
paradigms and their neural (e.g., neuroplasticity) and of the participant was also frequently mentioned by studies
cognitive (e.g., near versus far transfer) effects was pub- as an integral part of the success of any cognitive training
lished (Rossignoli-Palomeque et al., 2018). This review program (Nelwan and Kroesbergen; 2016). However,
concluded that only 14% (n ¼ 10) of the WMT studies somewhat more optimistically, the latest review of WMT
included scientific data to support the theory that WMT is by Rossignoli-Palomeque and colleagues in 2018
useful to alter neuroplasticity. This is due to the fact that concluded that 51% of studies (n ¼ 36) demonstrated far
many studies make claims without conducting brain im- transfer effects (e.g., to other cognitive domains besides
aging studies, while those studies that do report some im- WM during the experiments) in child and adolescent pop-
aging data demonstrate changes in frontostriatal circuitry ulations, although only 16% (n ¼ 11) reported that these
(Klingberg, 2010; Brooks et al., 2016; Pergher et al., 2018). effects remained at follow-up (e.g., at least 1 month after
Unfortunately, of the peer-reviewed WMT studies to date, testing).
68% (n ¼ 40) were not randomized or controlled, and of
those that were randomized, only 13% (n ¼ 9) of studies Previous research into working memory
were double-blinded. Finally, only 19% (n ¼ 13) WMT
training and implications for addiction
studies included an active control group. As such, it can be
clearly established that skepticism and inconsistency in the The first systematic review of WMT was by Takeuchi
findings of WMT studies to date may be due not only to (2010), which explored the effects of WMT on cognitive
insignificant data and/or false positive data but also to lack function and neural systems in adults, providing a good
of robust testing and false negative data. theoretical background on the history of WMT. The review
explored facets of WMT that were beyond the scope of this
systematic review, such as (i) the combination of WMT with
Near and far transfer effects of peer-reviewed
other cognitive training (which might be difficult for those
working memory training paradigms
with addiction who have compromised executive func-
Visuospatial and verbal WM, processing speed, attention, tioning), (ii) how other cognitive functions, such as crea-
memory, fluid intelligence, and mood were the neuro- tivity (which is difficult to assess), are influenced by WMT,
cognitive areas where researchers reported the most (iii) the neural networks involved in WMT, and (iv) the
improvement after a period of WMT (Bickel et al., 2011; genetic mechanisms of WMT. Furthermore, the paper also
Alloway et al., 2013; Lilienthal et al., 2013; Schweizer expanded on the mechanisms of action in various clinical
populations that this systematic review did not cover between these regions. The review documents how a
(e.g., an emphasis on stroke [very briefly covered in wealth of modern neuroimaging data, both from primates
Lumosity] and multiple sclerosis patients). Similarly, the and humans, as well as computer-modeling techniques, has
current systematic review took the approach of summarizing been able to pinpoint more precisely the brain regions that
the different components of the training process: in terms of may be influenced by WMT. Constantinidis and Klingberg
training content (the tasks to be performed), the type of WM summarize in the review that improved neural connectivity
that was assessed (e.g., visuospatial), the duration of the (e.g., via a process of neuroplasticity) occurs following a
training session (in minutes), the intensity of the training course of WMT, between prefrontal cortex neuronal clus-
regime (how often to train a week and for how many weeks), ters specifically within the dorsolateral prefrontal cortex
and the mode of WM training delivery (e.g., on a smart- and the parietal cortex. Moreover, the role of dopamine as a
phone or a website via a PC). Factors found to affect the facilitator within the corticolimbic and parietal networks
training process were also looked at including adaptive during WMT is largely implied by the various reviews to
WMT and participant motivation. As the previous review date (e.g., Constantinidis and Klingberg, 2016; Brooks
found, the current review discovered that many WMT paret al., 2017a,b; Parr and Friston, 2017).
adigms provide feedback on completion of the task/game, The findings of the current and previous reviews of
with an option for a more detailed feedback and the op- WMT, particularly those that examine neural processes, are
portunity to rely on a coach or clinician. These aspects pertinent for those with addiction, as the frontostriatal
appear to demonstrate that feedback is an integral part of the dopaminergic system is largely implicated in maladaptive
WMT motivation process. C-Ya made use of immediate decision-making (valuation), lack of control over drug
feedback during the task by providing alerts when correct or taking, and addictive behaviors (Guttman et al., 2018). For
incorrect. Additionally, making use of colorful and stimu- example, those with substance use disorder have greater
lating games also nurtured motivation in participants preference for risky choices, favoring appetitive choices for
(Brooks et al., 2016). However, in general, it is noted that immediate versus future rewards (temporal/delay dis-
some clinical populations struggle with remaining attentive counting), and are more likely to experience reinforcement
or motivated to perform the tasks (notably ADHD children learning from reward than from punishment (Verdejo-
and children with LDs). Some of these factors may also be Garcia et al., 2018). It is suggested that adaptive, progres-
pertinent to those with addiction; for example, participant sively difficult ecologically valid WMT (e.g., that moti-
motivation is a factor, particularly given that most substance vates the participant and includes peripheral distractors
use disorders tend to damage the prefrontal cortex function mimicking real life), which measures self-regulation and
that is involved in goal-oriented skills. Given that few WMT impulse control as opposed to attention and intelligence,
studies to date have been conducted in those with addiction, may be most beneficial, not only to improve treatment for
including stimulant use, alcohol use, and food addiction/ addiction but also to improve randomized controlled
overeating (Bickel et al., 2011; Houben et al., 2011, 2016; double-blind studies on the effects of WMT.
Dassen et al., 2018a; Brooks et al., 2016, 2017; Whitelock
et al., 2018), it is not yet possible to comment on the factors Limitations
that may help to improve symptoms for addiction, and more
exploration of WMT in addiction is needed. Various limitations of WMT research need to be considered
A second review by the founder of the WMT program for this field to be evaluated as a viable avenue for addic-
CogMed Klingberg (2010) focuses on neuroplasticity tion research. The most problematic issue is the concern
occurring during WMT. The results yielded by Klingberg’s over how far the benefits of using the WMT paradigms
research were supported by the findings of the current re- extend. In other words, there were mixed results as to
view, in that there is likely an increase in WM capacity whether participants just became better at using the WMT
after training, which may be sustained in line with fron- paradigms (e.g., “near transfer effects” or longevity of skills
tostriatal structural and functional changes (e.g., Brooks transfer ¼ />1 month) or whether this benefit extended to
et al., 2016, 2017). There is some evidence of transfer ef- real-life applications of WM and other cognitive areas such
fects, such as improvements in attention and verbal WM as fluid intelligence (e.g., “far transfer effects”) (Alloway
and in inhibition and reasoning. Klingberg’s review also et al., 2013; Thompson et al., 2013; Anguera et al., 2017;
focused on aspects such as the underlying neural correlates Lindeløv et al., 2016; Nelwan and Kroesbergen, 2016).
of WMT, which have been more recently reviewed again There were also mixed results regarding how long the ef-
(Constantinidis and Klingberg, 2016). It is suggested that fects of the training lasted posttraining, ranging from 3 to
the neural machinery of WM is limited in function to the 8 months (Jaeggi et al., 2011; Alloway et al., 2013;
frontoparietal and insular cortex circuitry (see Rottschy Anguera et al., 2013; Toril et al., 2016). Another limitation
et al., 2012) but can be expanded with WMT, which may was the reliance on participants’ effort, investment, and
mean better global versus local neurocircuitry synchrony motivation for the paradigms to work (Nelwan and
Kroesbergen, 2016). Participant dropout, boredom, and Supplementary table of nonepeer-reviewed paradigms.
fatigue are the major concerns, and thus there is pressure on
Name Source
these paradigms to provide services that will entice their
users to use the WMT paradigms on a continuous basis, as Study Blue https://www.studyblue.com/
this is seen to bring about the best results (Alloway et al., Vismory http://mermoz.net/portfolio/vismory
2013). Finally, it could be argued that lack of far transfer Memory! https://www.neurodevelop.com/Memory
and longevity of skills transfer directly after training and Monster Hunt https://www.neurodevelop.com/
during follow-up may be due to testing/measurement bias Monster_Hunt
and also that WMTdlike physical exercisedneeds to be Brain HQ https://www.brainhq.com/
continued for beneficial effects to be observed long term, Activate http://www.c8home.com/
and most studies of WMT rely on measures of attention and Elevate https://www.elevateapp.com/
intelligence. These measures that may not be sufficient to
MyHAPPYNeuron http://www.happy-neuron.com/
identify ecologically valid improvements in addiction
Brain Fitness Pro http://www.mindsparke.com/brain_
populations following WMT, and other measures might be
fitness_training.php
better at teasing out effects, such as those using decision-
Brain Trainer https://play.google.com/store/apps/
making, self-regulation, or impulse control. Special details?id¼com.fit.brain.trainer.
special&hl¼en
Conclusions Cognifit https://www.cognifit.com/
Peak Brain http://www.peak.net/
Peer-reviewed computerized WMT programs are few Training
(n ¼ 8), by comparison to the number of programs avail-
Fit Brains Trainer https://www.neurodevelop.com/Fit_
able on the Internet to date. Lack of peer review invites Brain_Trainer
higher levels of skepticism, diminishing the impact of
legitimate, rigorous research conducted by researchers in
the WMT field. A gold standard for WMT research spec-
ifying how training should be administered to people with References
addiction and how best to measure potential effects would
Aasvik, J.K., Woodhouse, A., Stiles, T.C., Jacobsen, H.B., Landmark, T.,
reduce the inconsistencies in the field and aid identification Glette, M., et al., 2016. Effectiveness of working memory training
of the existence of far transfer and longevity of skills ef- among subjects currently on sick leave due to complex symptoms.
fects. Currently, it appears that progressively difficult, Front. Psychol. 7.
adaptive WMT that requires users to reach their current Ahmadi, Futorjanski, 2011. https://www.neuronation.de/.
limit of WM capacity is most beneficial, but maintaining Åkerlund, E., Esbjörnsson, E., Sunnerhagen, K.S., Björkdahl, A., 2013.
user motivation to engage can be difficult. From the peer- Can computerized working memory training improve impaired working
reviewed publications to date, which comprise mostly of memory, cognition and psychological health? Brain Inj. 27 (13e14),
studies using the multitasked CogMed and the n-back WM 1649e1657.
task, it seems that those with learning difficulties and Alloway, T.P., Alloway, R., 2009. The efficacy of working memory
training in improving crystallized intelligence. Nat. Proced.
attention deficit disorders, especially children and adoles-
Alloway, T.P., Bibile, V., Lau, G., 2013. Computerized working memory
cents, benefit the most over the long term from WMT.
training: can it lead to gains in cognitive skills in students? Comput.
However, there is currently a paucity of WMT research Hum. Behav. 29 (3), 632e638.
examining the potential beneficial effects in people with Anderson, M.C., Bunce, J.G., Barbas, H., 2016. Prefrontal-hippocampal
addiction (Bickel et al., 2011; Houben et al., 2011, 2016; pathways underlying inhibitory control over memory. Neurobiol.
Brooks et al., 2016, 2017a,b; Dassen et al., 2018b; Learn. Mem. 134, 145e161.
Whitelock et al., 2018). This is striking, given that common Anguera, J.A., Boccanfuso, J., Rintoul, J.L., Al-Hashimi, O., Faraji, F.,
pre- and comorbid traits of those with addictions are linked Janowich, J., Kong, E., Larraburo, Y., Rolle, C., Johnston, E.,
to WM deficits, including risky decision-making, reward Gazzaley, A., 2013. Video game training enhances cognitive control
reinforcement learning, and impulse control disorders in older adults. Nature 501 (7465), 97e101.
(Verdejo-Garcia et al., 2018). Furthermore, WMT studies Anguera, J.A., Gunning, F.M., Arean, P.A., 2017. Improving late life
depression and cognitive control through the use of therapeutic video
of the benefits in those with addiction should ensure to
game technology: a proof-of-concept randomized trial. Depress.
measure, not only attention and global intelligence, as is
Anxiety 34 (6), 508e517.
common in current studies, but also cognitions underlying Arean, P.A., Hallgren, K.A., Jordan, J.T., Gazzaley, A., Atkins, D.C.,
addiction-related deficits. Finally, WMT studies of addic- Heagerty, P.J., et al., 2016. The use and effectiveness of mobile apps
tion should be randomized controlled, double-blind studies, for depression: results from a fully remote clinical trial. J. Med.
if the field is to understand the link between the neural Internet Res. 18 (12), e330.
processes of WM and training.
Au, J., Berkowitz-Sutherland, L., Schneider, A., Schweitzer, J.B., Chan, J.S., Wu, Q., Liang, D., Yan, J.H., 2015. Visuospatial working
Hessl, D., Hagerman, R., 2014. A feasibility trial of CogMedÔ memory training facilitates visually-aided explicit sequence learning.
working memory training in fragile X syndrome. J. Pediatr. Genet. 3 Acta Psychol. 161, 145e153.
(03), 147e156. Chooi, W.-T., Thompson, L.A., 2012. Working memory training does not
Ballesteros, S., Prieto, A., Mayas, J., Toril, P., Pita, C., de León, L.P., improve intelligence in healthy young adults. Intelligence 40,
et al., 2014. Brain training with non-action video games enhances 531e542.
aspects of cognition in older adults: a randomized controlled trial. Constantinidis, C., Klingberg, T., 2016. The neuroscience of working
Front. Aging Neurosci. 6. memory capacity and training. Nat. Rev. Neurosci. 17 (7),
Beatty, E.L., Vartanian, O., 2015. The prospects of working memory 438e449.
training for improving deductive reasoning. Front. Hum. Neurosci. 9. Cox, L.E., Ashford, J.M., Clark, K.N., Martin-Elbahesh, K., Hardy, K.K.,
Bickel, W.K., Yi, R., Landes, R.D., Hill, P.F., Baxter, C., 2011. Merchant, T.E., Zhang, H., 2015. Feasibility and acceptability of a
Remember the future: WM training decreases delay discounting remotely administered computerized intervention to address cognitive
among stimulant addicts. Biol. Psychiatry 69 (3), 260e265. late effects among childhood cancer survivors. Neuro oncol. Prac. 2
Bigorra, A., Garolera, M., Guijarro, S., Hervás, A., 2016. Long-term far (2), 78e87.
transfer effects of working memory training in children with ADHD: a Dassen, F.C.M., Houben, K., Allom, V., Jansen, A., 2018a. Self-regulation
randomized controlled trial. Eur. Child Adolesc. Psychiatry 25 (8), and obesity: the role of executive function and delay discounting in
853e867. the prediction of weight loss. J Behav Med. 41 (6), 806e818.
Bjorkdahl, A., Akerlund, E., Svensson, S., Esbjornsson, E., 2013. A ran- Dassen, F.C.M., Houben, K., Van Breukelen, G.J.P., Jansen, A., 2018b.
domized study of computerized working memory training and effects Gamified working memory training in overweight individuals reduces
on functioning in everyday life for patients with brain injury. Brain food intake but not body weight. Appetite 124, 89e98.
Inj. 27 (13e14), 1658e1665. Dongen-Boomsma, M., Vollebregt, M.A., Buitelaar, J.K., Slaats-
Bock, J., Poeggel, G., Gruss, M., Wingenfeld, K., Braun, K., 2014. Infant Willemse, D., 2014. Working memory training in young children with
cognitive training preshapes learning- relevant prefrontal circuits for ADHD: a randomized placebo-controlled trial. J. Child Psychol.
adult learning: learning-induced tagging of dendritic spines. Cerebr. Psychiatry 55 (8), 886e896.
Cortex 24, 2920e2930. Federal Trade Commission, 2016. Lumosity to Pay $2 Million to Settle
Bracy, O.L., 1994. Psychological software services cognitive rehabilita- FTC Deceptive Advertising Charges for its “Brain Training” Program
tion: technical manual Indianapolis. In: PSSCogReHab. Company Claimed Program Would Sharpen Performance in Everyday
Brooks, S.J., Burch, K.H., Maiorana, S.A., Cocolas, E., Schioth, H.B., Life and Protect Against Cognitive Decline. https://www.ftc.gov/
Nilsson, E.K., Kamaloodien, K., Stein, D.J., 2016. Psychological news-events/press-releases/2016/01/lumosity-pay-2-million-settle-ftc-
intervention with working memory training increases basal ganglia deceptive-advertising-charges.
volume: a VBM study of inpatient treatment for methamphetamine Fuentes, A., Kerr, E.N., 2016. Maintenance effects of working memory
use. Neuroimage Clinic 12, 478e491. intervention (Cogmed) in children with symptomatic epilepsy. Epi-
Brooks, S.J., Funk, S.G., Young, S.Y., Schiöth, H.B., 2017b. The role of lepsy Behav. 67, 51e59.
working memory for cognitive control in anorexia nervosa versus Gibson, B.S., Gondoli, D.M., Kronenberger, W.G., Johnson, A.C.,
substance use disorder. Front. Psychol. 8, 1651. Steeger, C.M., Morrissey, R.A., 2013. Exploration of an adaptive
Brooks, S.J., January 16, 2016. A debate on working memory and training regimen that can target the secondary memory component of
cognitive control: can we learn about the treatment of substance use working memory capacity. Mem. Cogn. 41 (5), 726e737.
disorders from the neural correlates of anorexia nervosa? BMC Psy- Gibson, B.S., Kronenberger, W.G., Gondoli, D.M., Johnson, A.C.,
chiatry 16, 10. Morrissey, R.A., Steeger, C.M., 2012. Component analysis of simple
Brooks, S.J., Wiemerslage, L., Burch, K.H., Maiorana, S.A., Cocolas, E., span vs. complex span adaptive working memory exercises: a ran-
Schiöth, H.B., Kamaloodien, K., Stein, D.J., 2017a. The impact of domized, controlled trial. J. Appl. Res. Memory Cogn. 1 (3), 179e184.
cognitive training in substance use disorder: the effect of working Gray, S.A., Chaban, P., Martinussen, R., Goldberg, R., Gotlieb, H.,
memory training on impulse control in methamphetamine users. Kronitz, R., Tannock, R., 2012. Effects of a computerized working
Psychopharmacology 234 (12), 1911e1921. memory training program on working memory, attention, and aca-
Buschkuehl, M., Hernandez-Garcia, L., Jaeggi, S.M., Bernard, J.A., demics in adolescents with severe LD and comorbid ADHD: a ran-
Jonides, J., 2014. Neural effects of short-term training on working domized controlled trial. J. Child Psychol. Psychiatry 53 (12),
memory. Cogn. Affect. Behav. Neurosci. 14 (1), 147e160. 1277e1284.
Cassanelli, P.M., Cladouchos, M.L., Fernández Macedo, G., Sifonios, L., Grunewaldt, K.H., Løhaugen, G.C.C., Austeng, D., Brubakk, A.M.,
Giaccardi, L.I., Gutiérrez, M.L., et al., 2015. Working memory Skranes, J., 2013. Working memory training improves cognitive
training triggers delayed chromatin remodeling in the mouse corti- function in VLBW preschoolers. Pediatrics 131 (3), e747ee754.
costriatothalamic circuit. Prog. Neuropsychopharmacol. Biol. Psy- Grunewaldt, K.H., Skranes, J., Brubakk, A.M., Lähaugen, G.C., 2016.
chiatry 60, 93e103. Computerized working memory training has positive long-term effect
Chacko, A., Bedard, A.C., Marks, D.J., Feirsen, N., Uderman, J.Z., in very low birthweight preschool children. Dev. Med. Child Neurol.
Chimiklis, A., et al., 2014. A randomized clinical trial of CogMedÔ 58 (2), 195e201.
CogMedÔ Ô working memory training in school-age children with Guttman, Z., Moeller, S.J., London, E.D., 2018. Neural underpinnings of
ADHD: a replication in a diverse sample using a control condition. maladaptive decision-making in addictions. Pharmacol. Biochem.
J. Child Psychol. Psychiatry 55 (3), 247e255. Behav. 164, 84e98.
Hardy, S.J., Hardy, K.K., Schatz, J.C., Thompson, A.L., Meier, E.R., Labs, 2005. https://www.lumosity.com/en/.
2016. Feasibility of home-based computerized working memory Lawlor-Savage, L., Goghari, V.M., 2016. Dual N-back working memory
training with children and adolescents with Sickle Cell disease. training in healthy adults: a randomized Comparison to Processing
Pediatr. Blood Canc. 63 (9), 1578e1585. Speed Training. PLoS One 11 (4), e0151817.
Heinzel, S., Lorenz, R.C., Pelz, P., Heinz, A., Walter, H., Kathmann, N., Lee, C.S., Pei, J., Andrew, G., A Kerns, K., Rasmussen, C., 2016. Effects
et al., 2016. Neural correlates of training and transfer effects in of working memory training on children born preterm. Appl. Neuro-
working memory in older adults. Neuroimage 134, 236e249. psychol.: Child 1e16.
Heinzel, S., Rimpel, J., Stelzel, C., Rapp, M.A., 2017. Transfer effects to a Levenson, J.M., O’Riordan, K.J., Brown, K.D., Trinh, M.A.,
multimodal dual-task after working memory training and associated Molfese, D.L., Sweatt, J.D., 2004. Regulation of histone acetylation
neural correlates in older adults e a pilot study. Front. Hum. Neurosci. during memory formation in the hippocampus. J. Biol. Chem. 279,
11, 85. 405450e405459.
Heinzel, S., Schulte, S., Onken, J., Duong, Q.L., Riemer, T.G., Heinz, A., Lilienthal, L., Tamez, E., Shelton, J.T., Myerson, J., Hale, S., 2013. Dual
et al., 2014. Working memory training improvements and gains in n-back training increases the capacity of the focus of attention. Psy-
non-trained cognitive tasks in young and older adults. Neuropsychol. chon. Bull. Rev. 20 (1), 135e141.
Dev. Cogn. B Aging Neuropsychol. Cogn. 21 (2), 146e173. Lindelov, J.K., Dall, J.O., Kristensen, C.D., Aagesen, M.H., Olsen, S.A.,
Hitchcock, C., Westwell, M.S., 2017. A cluster-randomised, controlled Snuggerud, T.R., et al., 2016. Training and transfer effects of N-back
trial of the impact of CogMedÔ Working Memory Training on both training for brain-injured and healthy subjects. Neuropsychol. Rehabil.
academic performance and regulation of social, emotional and 26 (5e6), 895e909.
behavioural challenges. J. Child Psychol. Psychiatry 58 (2), 140e150. Martin, D.M., Liu, R., Alonzo, A., Green, M., Player, M.J., Sachdev, P.,
Holmes, J., Butterfield, S., Cormack, F., van Loenhoud, A., Ruggero, L., et al., 2014. Can transcranial direct current stimulation enhance out-
Kashikar, L., Gathercole, S., 2015. Improving working memory in comes from cognitive training? A randomized controlled trial in healthy
children with low language abilities. Front. Psychol. 6. participants. Int. J. Neuropsychopharmacol. 16 (9), 1927e1936.
Houben, K., Dassen, F.C., Jansen, A., 2016. Taking control: working Mawjee, K., Woltering, S., Lai, N., Gotlieb, H., Kronitz, R., Tannock, R.,
memory training in overweight individuals increases self-regulation of 2017. Working Memory Training in ADHD: Controlling for
food intake. Appetite 105, 567e574. Engagement, Motivation, and Expectancy of Improvement (pilot
Houben, K., Wiers, R.W., Jansen, A., 2011. Getting a grip on drinking study). J. Atten. Disord. 21 (11), 956e968.
behavior: training working memory to reduce alcohol abuse. Psychol. Mawjee, K., Woltering, S., Tannock, R., 2015. Working memory training
Sci. 22 (7), 968e975. in post secondary students with ADHD: a randomized controlled
Jaeggi, S.M., Buschkuehl, M., Jonides, J., Perrig, W.J., 2008. Improving study. PLoS One 10 (9), e0137173.
fluid intelligence with training on working memory. Proc. Natl. Acad. Minear, M., Brasher, F., Guerrero, C.B., Brasher, M., Moore, A.,
Sci. U. S. A. 105 (19), 6829e6833. Sukeena, J., 2016. A simultaneous examination of two forms of
Jaeggi, S.M., Buschkuehl, M., Jonides, J., Shah, P., 2011. Short- and long- working memory training: evidence for near transfer only. Mem
term benefits of cognitive training. Proc. Natl. Acad. Sci. U. S. A. 108 Cognit 44 (7), 1014e1037.
(25), 10081e10086. Morra, S., Borella, E., 2015. Working memory training: from metaphors to
Jaeggi, S.M., Buschkuehl, M., Shah, P., Jonides, J., 2014. The role of models. Front. Psychol. 6, 1097.
individual differences in cognitive training and transfer. Mem. Cognit. Morrison, A.B., Chein, J.M., 2011. Does working memory training work?
42 (3), 464e480. The promise and challenges of enhancing cognition by training
Johansson, B., Tornmalm, M., 2012. Working memory training for pa- working memory. Psychon. Bull. Rev. 18 (1), 46e60.
tients with acquired brain injury: effects in daily life. Scand. J. Occup. Nelwan, M., Kroesbergen, E.H., 2016. Limited near and far transfer effects
Ther. 19 (2), 176e183. of Jungle Memory working memory training on learning mathematics
Katz, B., Jaeggi, S., Buschkuehl, M., Stegman, A., Shah, P., 2014. Dif- in children with attentional and mathematical difficulties. Front.
ferential effect of motivational features on training improvements in Psychol. 7.
school-based cognitive training. Front. Hum. Neurosci. 8, 242. Oelhafen, S., Nikolaidis, A., Padovani, T., Blaser, D., Koenig, T.,
Kerr, E.N., Blackwell, M.C., 2015. Near-transfer effects following work- Perrig, W.J., 2013. Increased parietal activity after training of inter-
ing memory intervention (CogMedÔ CogMedÔ Ô ) in children with ference control. Neuropsychologia 51 (13), 2781e2790.
symptomatic epilepsy: an open randomized clinical trial. Epilepsia 56 Owens, M., Koster, E.H., Derakshan, N., 2013. Improving attention con-
(11), 1784e1792. trol in dysphoria through cognitive training: transfer effects on
Khemiri, L., Brynte, C., Stunkel, A., Klingberg, T., Jayaram-Lindström, N., working memory capacity and filtering efficiency. Psychophysiology
2019. Working memory training in alcohol use disorder: a randomized 50 (3), 297e307.
controlled trial. Alcohol Clin. Exp. Res. 43 (1), 135e146. Parr, T., Friston, K.J., 2017. Working memory, attention, and salience in
Kirchner, W.K., 1958. Age differences in short-term retention of rapidly active inference. Sci. Rep. 7 (1), 14678.
changing information. J. Exp. Psychol. 55, 352e358. Pelegrina, S., Lechuga, M.T., Garcia-Madruga, J.A., Elosua, M.R.,
Klingberg, T., 2010. Training and plasticity of working memory. Trends Macizo, P., Carreiras, M., et al., 2015. Normative data on the n-back
Cognit. Sci. 14 (7), 317e324. task for children and young adolescents. Front. Psychol. 6, 1544.
Klingberg, T., Forssberg, H., Westerberg, H., 2002. Training of working Pergher, V., Wittevrongel, B., Tournoy, J., Schoenmakers, B., Van
memory in children with ADHD. J. Clin. Exp. Neuropsychol. 24 (6), Hulle, M.M., 2018. N-back training and transfer effects revealed by
781e791. behavioral responses and EEG. Brain Behav. 8 (11), e01136.
Phillips, N.L., Mandalis, A., Benson, S., Parry, L., Epps, A., Morrow, A., with ADHD and their mothers: a randomized controlled trial. Child
Lah, S., 2016. Computerized working memory training for children with Neuropsychol. 22 (4), 394e419.
moderate to severe traumatic brain injury: a double-blind, randomized, Stepankova, H., Lukavsky, J., Buschkuehl, M., Kopecek, M., Ripova, D.,
placebo-controlled trial. J. Neurotrauma 33 (23), 2097e2104. Jaeggi, S.M., 2014. The malleability of working memory and visuo-
Pugin, F., Metz, A.J., Stauffer, M., Wolf, M., Jenni, O.G., Huber, R., 2014. spatial skills: a randomized controlled study in older adults. Dev.
Working memory training shows immediate and long-term effects on Psychol. 50 (4), 1049e1059.
cognitive performance in children. F1000Res 3, 82. Strobach, T., Huestegge, L., 2017. Evaluating the effectiveness of com-
Ramey, T., Regier, P.S., 2018. Cognitive impairment in substance use mercial brain game training with working memory tasks. J. Cogn.
disorders. CNS Spectr. 2018, 1e12. Enhance. 1 (4), 539e558.
Redick, T.S., Shipstead, Z., Harrison, T.L., Hicks, K.L., Fried, D.E., Sun, Y., Taya, F., Chen, Y., Delgado Martinez, I., Thakor, N.,
Hambrick, D.Z., et al., 2013. No evidence of intelligence improve- Bezerianos, A., 2014. Topological changes of the effective connec-
ment after working memory training: a randomized, placebo- tivity during the working memory training. Conf. Proc. IEEE Eng.
controlled study. J. Exp. Psychol. Gen. 142 (2), 359e379. Med. Biol. Soc. 2014, 6242e6245.
Roberts, G., Quach, J., Spencer-Smith, M., Anderson, P.J., Gathercole, S., Swank, M.W., Sweatt, J.D., 2001. Increased histone acetyltransferase and
Gold, L., et al., 2016. Academic outcomes 2 years after working lysine acetyltransferase activity and biphasic activation of the ERK/
memory training for children with low working memory: a random- RSK cascasde in insular cortex during novel taste learning.
ized clinical trial. JAMA Pediatr. 170 (5), e154568. J. Neurosci. 21, 3383e3391.
Rossignoli-Palomeque, T., Perez-Hernandez, E., González-Marqués, J., Takeuchi, H., Taki, Y., Kawashima, R., 2010. Effects of working memory
2018. Brain training in children and adolescents: is it scientifically training on cognitive functions and neural systems. Rev. Neurosci. 21
valid? Front. Psychol. 9, 565. (6), 427e449.
Rottschy, C., Langner, R., Dogan, I., Reetz, K., Laird, A.R., Schulz, J.B., Thompson, P.J., Conn, H., Baxendale, S.A., Donnachie, E., McGrath, K.,
Fox, P.T., Eickhoff, S.B., 2012. Modelling neural correlates of Geraldi, C., Duncan, J.S., 2016. Optimizing memory function in
working memory: a coordinate-based meta-analysis. Neuroimage 60 temporal lobe epilepsy. Seizure 38, 68e74.
(1), 830e846. Thompson, T.W., Waskom, M.L., Garel, K.L., Cardenas-Iniguez, C.,
Rudebeck, S.R., Bor, D., Ormond, A., O’Reilly, J.X., Lee, A.C., 2012. A Reynolds, G.O., Winter, R., et al., 2013. Failure of working memory
potential spatial working memory training task to improve both training to enhance cognition or intelligence. PLoS One 8 (5),
episodic memory and fluid intelligence. PLoS One 7 (11), e50431. e63614.
Sadeghi, M., Barlow-Krelina, E., Gibbons, C., Shaikh, K.T., Toril, P., Reales, J.M., Mayas, J., Ballesteros, S., 2016. Video game
Fung, W.L.A., Meschino, W.S., et al., 2017. Feasibility of comput- training enhances visuospatial working memory and episodic memory
erized working memory training in individuals with Huntington disin older adults. Front. Hum. Neurosci. 10.
ease. PLoS One 12 (4), e0176429. van der Donk, M., Hiemstra-Beernink, A.C., Tjeenk-Kalff, A., van der
Salminen, T., Frensch, P., Strobach, T., Schubert, T., 2016. Age-specific Leij, A., Lindauer, R., 2015. Cognitive training for children
differences of dual n-back training. Neuropsychol. Dev. Cogn. B with ADHD: a randomized controlled trial of Cogmed working
Aging Neuropsychol. Cogn. 23 (1), 18e39. memory training and ‘paying attention in class’. Front. Psychol. 6,
Salminen, T., Strobach, T., Schubert, T., 2012. On the impacts of working 1081.
memory training on executive functioning. Front. Hum. Neurosci. 6, 166. Van der Donk, M.L., Hiemstra-Beernink, A.C., Tjeenk-Kalff, A.C., van
Sari, B.A., Koster, E.H., Pourtois, G., Derakshan, N., 2016. Training der Leij, A., Lindauer, R.J., 2016. Predictors and moderators of
working memory to improve attentional control in anxiety: a proof-of- treatment outcome in cognitive training for children with ADHD.
principle study using behavioral and electrophysiological measures. J. Atten. Disord. 1087054716632876.
Biol. Psychol. 121 (Pt B), 203e212. Verdejo-Garcia, A., Chong, T.T., Stout, J.C., Yücel, M., London, E.D.,
Schneiders, J.A., Opitz, B., Tang, H., Deng, Y., Xie, C., Li, H., et al., 2018. Stages of dysfunctional decision-making in addiction. Phar-
2012. The impact of auditory working memory training on the fronto- macol. Biochem. Behav. 164, 99e105.
parietal working memory network. Front. Hum. Neurosci. 6, 173. Waris, O., Soveri, A., Laine, M., 2015. Transfer after Working Memory
Schwarb, H., Nail, J., Schumacher, E.H., 2016. Working memory training Updating Training. PLoS One 10 (9), e0138734.
improves visual short-term memory capacity. Psychol. Res. 80 (1), Wayne, R.V., Hamilton, C., Huyck, J.J., Johnsrude, I.S., 2016. Working
128e148. memory training and speech in noise comprehension in older adults.
Schweizer, S., Grahn, J., Hampshire, A., Mobbs, D., Dalgleish, T., 2013. Front. Aging Neurosci. 8.
Training the emotional brain: improving affective control through Wentink, M.M., Berger, M.A.M., de Kloet, A.J., Meesters, J.,
emotional working memory training. J. Neurosci. 33 (12), Band, G.P.H., Wolterbeek, R., Vliet Vlieland, T.P.M., 2016. The ef-
5301e5311. fects of an 8-week computer-based brain training programme on
Söderqvist, S., Nutley, S.B., 2015. Working memory training is associated cognitive functioning, QoL and self-efficacy after stroke. Neuro-
with long term attainments in math and reading. Front. Psychol. 6. psychol. Rehabil. 26 (5e6), 847e865.
Spencer-Smith, M., Klingberg, T., 2015. Benefits of a working memory Whitelock, V., Nouwen, A., Houben, K., van den Akker, O.,
training program for inattention in daily life: a systematic review and Rosenthal, M., Higgs, S., 2018. Does working memory training
meta-analysis. PLoS One 10 (3), e0119522. improve dietary self-care in type 2 diabetes mellitus? Results of a
Steeger, C.M., Gondoli, D.M., Gibson, B.S., Morrissey, R.A., 2016. double blind randomised controlled trial. Diabetes Res. Clin. Pract.
Combined cognitive and parent training interventions for adolescents 143, 204e214.
Chapter 19
Inhibitory control training

Andrew Jones1 and Matt Field2
1
Department of Psychological Sciences, University of Liverpool, Liverpool, Merseyside, United Kingdom; 2Department of Psychology, University of
Sheffield, Sheffield, South Yorkshire, United Kingdom
Introduction: alignment between the may confer increased risk of relapse to substance use after
treatment (Petit et al., 2014; Rupp et al., 2016).
training and cognitive changes that Substance users’ deficits in inhibitory control are
characterize addiction exacerbated when they are in the presence of substance-
Inhibitory control refers to the ability to stop, change, or delay related cues. This has been demonstrated for alcohol-,
a response that is no longer appropriate in the circumstances tobacco-, and cocaine-related cues (Luijten et al., 2011;
(Logan et al., 1984). A prototypical example is when one is Pike et al., 2013), and this is a very general feature of
driving toward an intersection and a traffic signal changes motivation because food-related cues also lead to impair-
from red to green: the red light serves as a cue to inhibit the act ments in inhibitory control (Jones et al., 2018). These
of pressing the accelerator, and failure to do so can have transient state fluctuations in inhibitory control during
negative consequences. Inhibitory control can be measured in exposure to substance-related cues may partially account
the laboratory using computerized tasks such as the Stop for the influence of those cues on subjective craving and
Signal and Go/No-Go tasks (Diamond, 2013). These tasks relapse to substance use after a period of abstinence (De
require participants to respond to environmental stimuli as Wit, 2009; Jones et al., 2013a). Indeed, a recent study
quickly and accurately as possible, unless a different stimulus demonstrated that the effects of alcohol cues on alcohol
(the “Stop Signal” or “No-Go cue”) is presented, in which case consumption in the laboratory were partially mediated by
the participant should refrain from responding. Difficulty the influence of those cues on inhibitory control (Field and
exercising inhibitory control can be inferred from the number Jones, 2017).
of inhibition errors or by modeling the latency to execute a
stopping response based on reaction times and inhibition Description of the training and
errors (Band et al., 2003).
Individual differences in inhibitory control contribute to
proposed mechanisms
broader constructs including executive functions and impul- Two forms of inhibitory control training (ICT) can be
sivity (Bickel et al., 2012), and inhibitory control may also distinguished: “general” and “cue-specific.” The goal of
underlie more fuzzy constructs such as “self-control” general ICT is to improve global inhibitory control capacity
(Baumeister, 2014); see (Fujita, 2011). Deficits in inhibitory or the motivation to engage inhibitory control, whereas cue-
control (and executive functions, impulsivity, and self-control specific ICT works on associative learning principles with
more broadly) are theorized to play an important causal role in the goal to train participants to engage inhibitory control
the onset and persistence of substance use disorders (SUDs) whenever specific types of environmental cues are
(De Wit, 2009; Dick et al., 2010; Goldstein and Volkow, encountered in the future.
2011). These claims are founded on observations that a variety During general ICT, participants might practice
of SUDs and behavioral addictions (such as problem inhibitory control tasks (such as the Stop Signal task)
gambling) are characterized by impaired inhibitory control several times over several days, weeks, or months (Spierer
(Smith et al., 2014), that inhibitory deficits may occur pre- et al., 2013). To facilitate robust improvements in inhib-
morbid to substance involvement (Fernie et al., 2013; Tarter itory control, the inhibitory control task could escalate in
et al., 2004), and that severe inhibitory control impairments

difficulty over time. For example, Berkman et al. (2014) The two forms of ICT are thought to have distinct
demonstrated progressive improvements in inhibitory mechanisms of action. General ICT rests on the assumption
control in participants who completed multiple sessions of that practice or training of a specific task will result in
a modified Stop Signal task that became progressively improvements in the target construct, which generalize or
more difficult in line with participants’ performance. transfer to other tasks that measure the same or similar
During cue-specific ICT, participants repeatedly perform constructs. Although it is possible to train participants to
a modified inhibitory control task (such as the Go/No-Go or improve their performance on a specific task through
Stop Signal task) that has substance-related cues embedded practice, the existence of transfer effects is a matter of some
into it. The contingency between substance-related cues and debate (Diamond and Ling, 2016; Enge et al., 2014; Owen
inhibition signals can be manipulated so that participants et al., 2010). Regarding cue-specific ICT, there is evidence
who receive active ICT form an association between that the training changes associations between substance-
substance-related cues and inhibition of behavior. See related cues and engagement of inhibitory control: after
Fig. 19.1 for an example. On each trial, participants would training, participants make fewer inhibition errors during
be instructed to press one of the two keys to indicate whether exposure to substance-related cues, and they are slower to
the picture that is presented depicts an alcohol-related or a respond to substance-related cues when required to do so
soda-related object. On some trials, the signal to inhibit (the (Jones and Field, 2012), with similar findings after ICT
“No-Go” or “Stop Signal”) would be presented alongside the with food-related cues reported by Lawrence et al. (2015).
picture. Over a number of trials, if the contingency between There is also some evidence that these effects may be
the alcohol-related pictures and the occurrence of inhibitory underpinned by changes in evaluation of substance-related
signals is high (typically 80%e100%), and the contingency cues because repeated exercise of inhibitory control during
between the soda-related pictures and the occurrence of exposure to substance-related cues results in devaluation of
inhibitory signals is low (typically 0%e20%), then partici- those cues, which in turn blunts the influence of those cues
pants should form an association between alcohol-related on motivated behavior (Houben et al., 2011). However, as
cues and engagement of inhibitory control. discussed in Section 4, the mechanisms of action of
cue-specific ICT are still under investigation.
Evidence for the efficacy of inhibitory

control training
To date, the majority of studies that have investigated the
influence of ICT on substance use can be characterized as
translational, proof-of-concept laboratory studies with healthy
participants. As with other forms of cognitive bias modifica-
tion, these types of studies should be distinguished from ran-
domized controlled trials (RCTs) of interventions with clinical
populations (Wiers et al., 2018). Most of these laboratory
studies administered a single brief session of ICT in the
laboratory before measuring how much alcohol participants
would voluntarily consume in the context of a bogus “taste
test” or similar. The rationale for these proof-of-concept
studies is to investigate if direct manipulation of a target
construct (inhibitory control, in this case) has a causal influ-
ence on a target behavior (alcohol consumption, in this case).
Regarding general ICT, several studies manipulated task
instructions before participants completed a Stop Signal task,
with the intention to manipulate participants’ motivation to
exercise inhibitory control (rather than their inhibitory con-
trol capacity per se). For example, Jones et al. (2011a,b) gave
FIGURE 19.1 Panels represent the sequence of events during a single participants a Stop Signal task with instructions to either
trial of alcohol-related cue-specific inhibitory control training. Participants
focus on inhibiting to stop signals or to respond as quickly as
are instructed to categorize pictures according to their content (alcohol- or
stationery-related, in this example), unless a “Stop Signal” (“¼” in this they could. In both studies, participants who were prompted
example) is presented. If Stop Signals are consistently presented on alcohol to focus on inhibition made fewer inhibition errors during the
picture trials, participants should form associations between alcohol and task and, crucially, they consumed less alcohol during a
engagement of inhibitory control.
Inhibitory control training Chapter | 19 273
bogus taste test immediately afterward, compared to control Efficacy in people with substance use disorder
groups of participants who were instructed to prioritize rapid
In a recent RCT, we randomized heavy drinkers to complete
responding (however, see “null” findings in Jones et al.,
multiple sessions of different forms of ICT over the Internet
2013b; Smith et al., 2017). Although these findings provide
(Jones et al., 2018). Although not formally diagnosed with
important support for the general principle that short-term
alcohol use disorder, participants were recruited on the basis of
changes in inhibitory control might have a causal influence
their heavy drinking and a desire to “cut down,” and therefore
on alcohol consumption, they do not establish that inhibitory
they would likely have met diagnostic criteria for (at least)
control capacity can be improved through training and that
mild alcohol use disorder (American Psychiatric Association,
this could have beneficial effects on alcohol consumption or
2013). After receiving a brief intervention, participants
other substance use. Indeed, a study that administered mul-
completed online general or alcohol cue-specific ICT sessions
tiple sessions of general ICT to healthy volunteers detected
(or an active control intervention, in which participants
no improvement in inhibitory control capacity after training
responded quickly to alcohol and neutral images but were
and no reduction in self-reported alcohol consumption
never required to inhibit their behavior) every other day for
(Bartsch et al., 2016). Similarly, after initially promising
4 weeks (up to 14 ICT sessions in total). Participants
demonstrations of general ICT effects on gambling behaviors
self-reported their alcohol consumption every day during this
in the laboratory (Verbruggen et al., 2012), multiple ICT
4-week intervention period and again at 6-week follow-up.
sessions delivered over an extended period of time failed to
Results indicated that all participants reported substantial
influence gambling behaviors (Verbruggen et al., 2013).
reductions in alcohol consumption over the course of the
Turning to cue-specific ICT, numerous studies have
intervention period (approximately 13 UK units, or 104 g of
demonstrated that, compared to a control intervention, a
alcohol, per week, on average). However, there were no
single brief session of alcohol cue-specific ICT results in a
between-group differences, i.e., no beneficial effects of gen-
robust reduction in alcohol consumption in the laboratory
eral or cue-specific ICT relative to each other or relative to an
(Jones et al., 2016b). Some studies reported that these
active control. These findings raise questions about the
beneficial effects of cue-specific ICT also influenced self-
efficacy of other related interventions such as the Alcohol
reported alcohol consumption for up to 1 week after
Attention Control Training Program (AACTP), the reported
receiving cue-specific ICT (Houben et al., 2011), although
beneficial effects of which (Fadardi and Cox, 2009) tend to
this finding has not always been replicated (Bowley et al.,
disappear when it is compared with an active rather than a
2013; Jones and Field, 2012; Smith et al., 2017). One recent
passive control condition (Wiers et al., 2015).
study applied a similar cue-specific ICT paradigm to tobacco
These disappointing findings suggest that despite prom-
smokers and reported suggestive evidence that cue-specific
ising findings from proof-of-concept laboratory studies, when
ICT may increase the resistance to smoke a cigarette in the
administered to people with SUDs symptoms in real-world
laboratory after overnight abstinence, although this effect
settings, any beneficial effects of either general or cue-
was not statistically significant (Adams et al., 2017). The
specific ICT may be obscured by nonspecific factors such as
literature on food cue-specific ICT is also relevant here:
regular self-monitoring of alcohol consumption and receipt of
compared to a control intervention, a single session of food
a brief intervention (Jenkins et al., 2009). This echoes a recent
cue-specific ICT leads to reductions in food consumption and
observation from a metaanalysis of “self-control training”
changes in food choice in laboratory settings (Allom et al.,
(such as repeatedly squeezing a handgrip over several weeks),
2015; Jones et al., 2016b), and multiple sessions of food cue-
which demonstrated that the effects of self-control training are
specific ICT result in weight loss in people who are trying to
typically fairly small compared with the effects of commonly
lose weight (Lawrence et al., 2015; Stice et al., 2016; Van
used interventions on symptoms of psychological disorders
Koningsbruggen et al., 2014).
(Friese et al., 2017). As ICT is investigated for other pop-
Despite this overall optimistic picture, it is noteworthy
ulations (e.g., Alcorn et al., 2017), it is important to ensure that
that a number of recent studies have failed to replicate the
nonspecific treatment effects are adequately controlled for
effects of a single session of cue-specific ICT on alcohol or
when evaluating effects on substance use. We await findings
food consumption in the laboratory (Adams et al., 2017;
from additional RCTs in participants with SUDs or behavioral
Bongers et al., 2018; Smith et al., 2017). Furthermore, it is
addictions.
important not to overinterpret findings from laboratory
studies, given that such studies are typically conducted with
healthy volunteers (rather than people with SUDs) using Mechanisms of action of inhibitory
proxy measures of alcohol or food consumption that may control training
bear little resemblance to alcohol or food consumption, or
other substance use, outside of the laboratory (Field et al., As previously noted, it is a matter of some debate whether
2018; Jones et al., 2016a). general ICT (and other “cognitive training” interventions)
can yield generalizable and transferable improvements in some studies have demonstrated that alcohol cue-specific ICT
the target psychological construct (Diamond and Ling, results in changes in implicit evaluations of alcohol-related
2016; Owen et al., 2010). Both studies that investigated the cues (Houben et al., 2012). However, this has not been
effects of general ICT in substance using populations found consistently replicated (Bowley et al., 2013; Di Lemma and
no improvement in inhibitory control capacity after multi- Field, 2017), and metaanalysis of the alcohol- and food cue-
ple sessions of training (Bartsch et al., 2016; Jones et al., specific ICT literature suggests that these devaluation effects
2018), which is consistent with the broader literature on may not be robust (Jones et al., 2016b).
transfer effects after cognitive training. Finally, we note that we comprehensively tested the
The mechanisms of action of cue-specific ICT have been mechanisms of action of general and cue-specific ICT in
more intensively studied. The importance of associative our recent RCT (Jones et al., 2018), and we found no
learning to inhibitory control is well known (Verbruggen evidence of changes in inhibitory control capacity, inhibi-
et al., 2014; Verbruggen and Logan, 2008), and the rationale tory control in response to alcohol cues, or devaluation of
behind cue-specific ICT is to exploit associative learning alcohol cues after multiple sessions of ICT delivered via the
principles to train participants to form associations between Internet. Similarly, no support for these mechanisms was
substance-related cues and inhibition of behavior such that found after multiple sessions of food cue-specific ICT,
inhibitory control is automatically evoked whenever compared with a control group who received health infor-
substance-related cues are encountered in the future. mation, over the course of 1 week (Poppelaars et al., 2018).
Findings from laboratory studies demonstrate that such This complicates interpretation of the null effects of ICT on
learning does indeed take place. For example, Jones and self-reported alcohol consumption and calorie intake
Field (2012) demonstrated that over the course of alcohol because one should not expect ICT to lead to changes in
cue-specific ICT, participants made fewer inhibition errors to substance use if it does not cause robust changes in its
alcohol-related cues and they were slower to respond to candidate mechanisms of action (see Wiers et al., 2018).
alcohol-related cues when required to respond to them, While there are considerable benefits to online delivery of
although this was not replicated in a more recent study interventions (Griffiths et al., 2006), limitations such as
(Di Lemma and Field, 2017). However, in a metaanalysis, poor participant retention (White et al., 2010) and lack of
we demonstrated that the extent to which participants contact with health care professionals (Riper et al., 2011)
formed associations between appetitive cues and inhibitory may partially account for these disappointing findings
control (as inferred from the number of inhibitory failures (Table 19.1).
during exposure to those cues after ICT) was correlated with
the effect of ICT on appetitive behavior in the laboratory
(Jones et al., 2016b). This implicates changes in cue inhi-
Conclusions and recommendations
bition associations as an important mechanism of action of The available evidence provides important “proof-of-
ICT on behavior. concept” support for ICT because it demonstrates that brief
A second potential mechanism of action of cue-specific sessions of ICT can prompt reductions in alcohol con-
ICT is a reduction in the value of cues that are paired with sumption in the laboratory. Furthermore, a comparable
inhibition. According to Behavior Stimulus Interaction (BSI) literature on food-specific ICT and food consumption in the
theory (Veling et al., 2008), the act of inhibiting behavior to laboratory suggests that ICT operates through fairly general
appetitive cues creates a response conflict. During cue-specific motivational mechanisms that are not unique to addiction.
ICT, this conflict is resolved by devaluing those cues such that However, based on the (very limited) evidence conducted
they no longer elicit appetitive approach behaviors. Indeed, outside of laboratory settings, our strong recommendation
TABLE 19.1 Summary of the evidence for effectiveness of inhibitory control training (ICT) on key outcomes in
different types of studies.
Outcome Translational lab studies Studies performed in real-world settings

Change in inhibitory control or other candidate mechanisms
General ICT Generally positive findings Generally null findings
Cue-specific ICT Mixed findings Generally null findings
Change in drinking behavior
General ICT Mixed findings Generally null findings
Cue-specific ICT Mixed findings Generally null findings
Inhibitory control training Chapter | 19 275
is that ICT is not ready to implement as a standalone or Diamond, A., Ling, D.S., 2016. Conclusions about interventions, pro-
adjunct treatment for SUDs or behavioral addictions. grams, and approaches for improving executive functions that appear
Further research is required to clarify the psychological justified and those that, despite much hype, do not. Dev. Cogn.
Neurosci. 18, 34e48. https://doi.org/10.1016/j.dcn.2015.11.005.
mechanisms of action of ICT and to confirm that the
Dick, D.M., Smith, G., Olausson, P., Mitchell, S.H., Leeman, R.F.,
parameters and contexts in which ICT is likely to be
O’Malley, S.S., Sher, K., 2010. Understanding the construct of
delivered in clinical, naturalistic, or online settings are impulsivity and its relationship to alcohol use disorders. Addict. Biol.
likely to yield robust changes in these psychological 15 (2), 217e226.
mechanisms of action. At this point, but not before, it Di Lemma, L.C.G., Field, M., 2017. Cue avoidance training and inhibitory
would be appropriate to evaluate the effectiveness of ICT as control training for the reduction of alcohol consumption: a compar-
a standalone or adjunct intervention for SUDs. ison of effectiveness and investigation of their mechanisms of action.
Psychopharm 234, 2489e2498.
Enge, S., Behnke, A., Fleischhauer, M., Küttler, L., Kliegel, M.,
References Strobel, A., 2014. No evidence for true training and transfer effects
Adams, R.C., Lawrence, N.S., Verbruggen, F., Chambers, C.D., 2017. after inhibitory control training in young healthy adults. J. Exp. Psy-
Training response inhibition to reduce food consumption: mecha- chol. Learn. Mem. Cogn. 40 (4), 987e1001.
nisms, stimulus specificity and appropriate training protocols. Appetite Fadardi, J.S., Cox, W.M., 2009. Reversing the sequence: reducing alcohol
109, 11e23. https://doi.org/10.1016/j.appet.2016.11.014. consumption by overcoming alcohol attentional bias. Drug Alcohol
Adams, S., Mokrysz, C., Attwood, A.S., Munafò, M.R., 2017. Resisting Depend. 101, 137e145. https://doi.org/10.1016/
the urge to smoke: inhibitory control training in cigarette smokers. j.drugalcdep.2008.11.015.
R. Soc. Open Sci. 4 (8). Fernie, G., Peeters, P., Gullo, M.J., Christiansen, P., Cole, J., Sumnall, H.,
Alcorn 3rd, J.L., Pike, E., Stoops, W.S., Lile, J.A., Rush, C.R., 2017. Field, M., 2013. Multiple components of impulsivity predict pro-
A pilot investigation of acute inhibitory control training in cocaine spective alcohol involvement in adolescents. Addiction 108,
users. Drug Alcohol Depend. 174, 145e149. https://doi.org/10.1016/ 1916e1923.
j.drugalcdep.2017.01.014. Field, M., Jones, A., 2017. Elevated alcohol consumption following
Allom, V., Mullan, B., Hagger, M.S., 2015. Does inhibitory control alcohol cue exposure is partially mediated by reduced inhibitory
training improve health behaviour? A meta-analysis. Health Psychol. control and increased craving. Psychopharm 234, 2979e2988.
Rev. 10, 168e186. Field, M., Jones, A., Kersbergen, I., Robinson, E., 2018. Experimental
American Psychiatric Association, 2013. Diagnostic and statistical manual research requires valid and sensitive measures of alcohol intake, and
of mental disorders, fifth ed. Washington, DC. this is a step in the right direction: commentary on Leeman and col-
Band, G.P.H., van der Molen, M.W., Logan, G.D., 2003. Horse-race leagues (2018). Alcohol Clin. Exp. Res. 42 (6), 1019e1021. https://
model simulations of the stop-signal procedure. Acta Psychol. 112 doi.org/10.1111/acer.13641.
(2), 105e142. Friese, M., Frankenbach, J., Job, V., Loschelder, D.D., 2017. Does self-
Bartsch, A.L., Kothe, E., Allom, V., Mullan, B., Houben, K., 2016. The control training improve self-control? A meta-analysis. Perspect.
effect of non-specific response inhibition training on alcohol con- Psychol. Sci. 12 (6), 1077e1099. https://doi.org/10.1177/
sumption: an intervention. J. Addict. Res. Ther. 7 (1), 260. 1745691617697076.
Baumeister, R.F., 2014. Self-regulation, ego depletion, and inhibition. Fujita, K., 2011. On conceptualizing self-control as more than the effortful
Neuropsychologia 65, 313e319. https://doi.org/10.1016/ inhibition of impulses. Pers. Soc. Psychol. Rev. 15 (4), 352e366.
j.neuropsychologia.2014.08.012. Goldstein, R.Z., Volkow, N., 2011. Dysfunction of the prefrontal cortex in
Berkman, E.T., Kahn, L.E., Merchant, J.S., 2014. Training-induced addiction: neuroimaging findings and clinical implications. Nat. Rev.
changes in inhibitory control network activity. J. Neurosci. 34 (1), Neurosci. 12, 652e669.
149e157. Griffiths, F., Lindenmeyer, A., Powell, J., Lowe, P., Thorogood, M., 2006.
Bickel, W.K., Jarmolowicz, D.P., Mueller, E.T., Gatchalian, K.M., Why are health care interventions delivered over the internet? A
McClure, S.M., 2012. Are executive function and impulsivity anti- systematic review of the published literature. J. Med. Internet Res. 8
podes? A conceptual reconstruction with special reference to addic- (2), e10. https://doi.org/10.2196/jmir.8.2.e10.
tion. Psychopharmacology 221 (3), 361e387. Houben, K., Havermans, R.C., Nederkoorn, C., Jansen, A., 2012. Beer à
Bongers, P., Houben, K., Jansen, A., 2018. Double up! Examining the no-go: learning to stop responding to alcohol cues reduces alcohol
effects of adding inhibition training to food cue exposure in chocolate- intake via reduced affective associations rather than increased
loving female students. Appetite 121, 154e162. https://doi.org/10. response inhibition. Addiction 107 (7), 1280e1287.
1016/j.appet.2017.11.096. Houben, K., Nederkoorn, C., Wiers, R.W., Jansen, A., 2011. Resisting
Bowley, C., Faricy, C., Hegarty, B., Johnstone, S.J., Smith, J., Kelly, P., temptation: decreasing alcohol-related affect and drinking behavior by
Rushby, J., 2013. The effects of inhibitory control training on alcohol training response inhibition. Drug Alcohol Depend. 116, 132e136.
consumption, implicit alcohol-related cognitions and brain electrical https://doi.org/10.1016/j.drugalcdep.2010.12.011.
activity. Int. J. Psychophysiol. 89, 342e348. Jenkins, R.J., McAlaney, J., McCambridge, J., 2009. Change over time
De Wit, H., 2009. Impulsivity as a determinant and consequence of drug in alcohol consumption in control groups in brief intervention
use: a review of underlying processes. Addict. Biol. 14 (1), 22e31. studies: systematic review and meta-regression study. Drug
Diamond, A., 2013. Executive functions. Annu. Rev. Psychol. 64, Alcohol Depend. 100 (1e2), 107e114. https://doi.org/10.1016/
135e168. j.drugalcdep.2008.09.016.
Jones, A., Button, E., Rose, A.K., Robinson, E., Christiansen, P., Di curbing adult problem drinking: a meta-analysis. J. Med. Internet
Lemma, L., Field, M., 2016a. The ad-libitum alcohol “taste test”: Res. 13 (2).
secondary analyses of potential confounds and construct validity. Rupp, C.I., Beck, J.K., Heinz, A., Kemmler, G., Manz, S., Tempel, K.,
Psychopharmacology 233 (5), 917e924. https://doi.org/10.1007/ Fleischhacker, W.W., 2016. Impulsivity and alcohol dependence
s00213-015-4171-z. treatment completion: is there a neurocognitive risk factor at treatment
Jones, A., McGrath, E., Robinson, E., Houben, K., Nederkoorn, C., entry? Alcohol Clin. Exp. Res. 40 (1), 152e160. https://doi.org/
Field, M., 2018. A randomized controlled trial of inhibitory control 10.1111/acer.12924.
training for the reduction of alcohol consumption in problem drinkers. Smith, J., Mattick, R., Jamadar, S., Iredale, J., 2014. Deficits in behav-
J Consult Clin Psychol 86, 991e1004. ioural inhibition in substance abuse and addiction: a meta-analysis.
Jones, A., Christiansen, P., Nederkoorn, C., Houben, K., Field, M., 2013a. Drug Alcohol Depend. 145, 1e33.
Fluctuating disinhibition: implications for the understanding and Smith, J.L., Dash, N.J., Johnstone, S.J., Houben, K., Field, M., 2017.
treatment of alcohol and other substance use disorders. Front. Current forms of inhibitory training produce no greater reduction in
Psychiatry 22 (4). drinking than simple assessment: a preliminary study. Drug Alcohol
Jones, A., Cole, J., Goudie, A., Field, M., 2011a. Priming a restrained Depend. 173, 47e58. https://doi.org/10.1016/j.drugalcdep.2016.
mental set reduces alcohol-seeking independently of mood. Psycho- 12.018.
pharmacology 218 (3), 557e565. Spierer, L., Chavan, C.F., Manuel, A.L., 2013. Training-induced behavioral
Jones, A., Di Lemma, L.C.G., Robinson, E., Christiansen, P., Nolan, S., and brain plasticity in inhibitory control. Front. Hum. Neurosci. 7, 427.
Tudur-Smith, C., Field, M., 2016b. Inhibitory control training for Stice, E., Lawrence, N.S., Kemps, E., Veling, H., 2016. Training motor
appetitive behaviour change: a meta-analytic investigation of mecha- responses to food: a novel treatment for obesity targeting implicit
nisms of action and moderators of effectiveness. Appetite 97, 16e28. processes. Clin. Psychol. Rev. 49, 16e27. https://doi.org/10.1016/
https://doi.org/10.1016/j.appet.2015.11.013. j.cpr.2016.06.005.
Jones, A., Field, M., 2012. The effects of cue-specific inhibition training Tarter, R.E., Kirisci, L., Habeych, M., Reynolds, M., Vanyukov, M., 2004.
on alcohol consumption in heavy social drinkers. Exp. Clin. Neurobehavior disinhibition in childhood predisposes boys to sub-
Psychopharmacol 21, 8e16. https://doi.org/10.1037/a0030683. stance use disorder by young adulthood: direct and mediated etiologic
Jones, A., Field, M., Christiansen, P., Stancak, A., 2013b. P300 during pathways. Drug Alcohol Depend. 73 (2), 121e132.
response inhibition is associated with ad-lib alcohol consumption in Van Koningsbruggen, G.M., Veling, H., Stroebe, W., Aarts, H., 2014.
social drinkers. J. Psychopharmacol. 27 (6), 507e514. https://doi.org/ Comparing two psychological interventions in reducing impulsive
10.1177/0269881113485142. processes of eating behaviour: effects on self-selected portion size. Br.
Jones, A., Guerrieri, R., Fernie, G., Cole, J., Goudie, A., Field, M., 2011b. J. Health Psychol. 19 (4), 767e782.
The effects of priming restrained versus disinhibited behaviour on Veling, H., Holland, R.W., van Knippenberg, A., 2008. When approach
alcohol-seeking in social drinkers. Drug Alcohol Depend. 113 (1), motivation and behavioral inhibition collide: behavior regulation
55e61. through stimulus devaluation. J. Exp. Soc. Psychol. 44 (4),
Lawrence, N.S., Verbruggen, F., Morrison, S., Adams, R.C., 1013e1019.
Chambers, C.D., 2015. Stopping to food can reduce intake. Effects of Verbruggen, F., Adams, R., Chambers, C.D., 2012. Proactive motor
stimulus-specificity and individual differences in dietary restraint. control reduces monetary risk taking in gambling. Psychol. Sci. 23 (7),
Appetite 85, 91e103. 805e815.
Logan, G.D., Cowan, W.B., Davis, K.A., 1984. On the ability to inhibit Verbruggen, F., Adams, R.C., van ’t Wout, F., Stevens, T.,
simple and choice reaction time responses: a model and a method. McLaren, I.P.L., Chambers, C.D., 2013. Are the effects of response
J. Exp. Psychol. Hum. Percept. Perform. 10 (2), 276e291. inhibition on gambling long-lasting? PLoS One 8 (7).
Luijten, M., Littel, M., Franken, I.H.A., 2011. Deficits in inhibitory control Verbruggen, F., Best, M., Bowditch, W.A., Stevens, T., McLaren, I.P.L.,
in smokers during a Go/Nogo task: an investigation using event- 2014. The inhibitory control reflex. Neuropsychologia 65, 263e278.
related brain potentials. PLoS One 6 (4). https://doi.org/10.1016/j.neuropsychologia.2014.08.014.
Owen, A.M., Hampshire, A., Grahn, J.A., Stenton, R., Dajani, S., Verbruggen, F., Logan, G.D., 2008. Automatic and controlled response
Burns, A.S., et al., 2010. Putting brain training to the test. Nature 465 inhibition: associative learning in the go/No-go and stop-signal para-
(7299), 775e778. https://doi.org/10.1038/nature09042. digms. J. Exp. Psychol. Gen. 137 (4), 649e672.
Petit, G., Cimochowska, A., Kornreich, C., Hanak, C., Verbanck, P., White, A., Kavanagh, D., Stallman, H., Klein, B., Kay-Lambkin, F.,
Campanella, S., 2014. Neurophysiological correlates of response Proudfoot, J., et al., 2010. Online alcohol interventions: a systematic
inhibition predict relapse in detoxified alcoholic patients: some review. J. Med. Internet Res. 12 (5), e62. https://doi.org/10.2196/
preliminary evidence from event-related potentials. Neuropsychiatric jmir.1479.
Dis. Treat. 10, 1025e1037. https://doi.org/10.2147/NDT.S61475. Wiers, R.W., Boffo, M., Field, M., 2018. What’s in a trial? On the
Pike, E., Stoops, W.W., Fillmore, M.T., Rush, C.R., 2013. Drug-related importance of distinguishing between experimental lab studies
stimuli impair inhibitory control in cocaine abusers. Drug Alcohol and randomized controlled trials: the case of cognitive bias modifi-
Depend. 133 (2), 768e771. cation and alcohol use disorders. J. Stud. Alcohol Drugs 79 (3),
Poppelaars, A., Scholten, H., Granic, I., Veling, H., Johnson- 333e343.
Glenberg, M.C., Luijten, M., 2018. When winning is losing: a Wiers, R.W., Houben, K., Fadardi, J.S., van Beek, P., Rhemtulla, M.,
randomized controlled trial testing a video game to train food-specific Cox, W.M., 2015. Alcohol cognitive bias modification training for
inhibitory control. Appetite 129, 143e154. https://doi.org/10.1016/j. problem drinkers over the web. Addict. Behav. 40, 21e26. https://
appet.2018.06.039. doi.org/10.1016/j.addbeh.2014.08.010.
Riper, H., Spek, V., Boon, B., Conijn, B., Kramer, J., Martin-Abello, K.,
Smit, F., 2011. Effectiveness of E-Self-help interventions for
Chapter 20
Goal-based interventions for executive

dysfunction in addiction treatment
School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia
Goal-based interventions for cognitive other hand, goal-based interventions use interactive exer-
cises and personal projects to practice, apply, and correct
deficits associated with addiction goal-directed actions and decisions, and hence they foster
People with substance use disorders often have deficits in engagement, rehearsal in a controlled environment, and
executive functions, including working memory, response transfer to real-life goals. Supervised practice and feedback
inhibition, cognitive flexibility, and decision-making skills contributes to overcoming one of the main challenges of
(Fernández-Serrano et al., 2010; Fernández-Serrano et al., addiction treatment, which is the generalization of self-
2011; Verdejo-García et al., 2018). Crucially, executive regulation skills to exert control over drug use in real-life
deficits are strong predictors of clinical outcomes in the scenarios.
context of addiction treatment. Reduced performance in The best-validated goal-based intervention, which has
tests of response inhibition/impulsivity and cognitive flex- been applied in people with substance use disorders, is
ibility is associated with lower treatment retention (Stevens called Goal Management Training (GMT) (Levine et al.,
et al., 2015; Streeter et al., 2008; Turner et al., 2009) and 2007, 2011) (first applied in substance users by Alfonso
poor performance in tests of working memory and et al., 2011). Originally designed for patients with brain
decision-making linked to greater risk of drug relapse injuries causing self-regulation deficits, GMT is a man-
(Domínguez-Salas et al., 2016; Rubenis et al., 2018; ualized group intervention that involves instruction and
Stevens et al., 2014; Verdejo-García et al., 2014). Goal- practice on response inhibition, mindfulness, goal setting,
based interventions were originally designed to address strategy application, and decision-making, as well as an
self-regulation deficits in people with brain injuries that overarching strategy to link these trainings (Levine et al.,
damaged executive functions, but spared more basic 2011). GMT practice is applied to real-life examples from
cognitive skills, such as language and memory (Hart and participants, which facilitates transfer to tangible treatment
Evans, 2006; Levine et al., 2000). They utilize interactive goals such as drug abstinence (Verdejo-García, 2016).
training tasks, strategy learning, and real-life examples to In addition to GMT, there are at least two other experi-
enable participants to control prepotent responses and align mental interventions that utilize goal-directed approaches
behavior with goals (Hart and Evans, 2006; Levine et al., and have been applied in the context of addiction treatment.
2011). Although the executive and self-regulation deficits One is based on a combination of GMT and other programs
of people with substance use disorders are subtler than for rehabilitation of executive functions and training on
those found in the brain injury presentations described implementation of intentions (Gollwitzer and Sheeran,
above (Caracuel et al., 2008), the rationale of goal-based 2006; Prestwich et al., 2006), which was created “ad hoc”
interventions and the “hands-on” approach they utilize for Cognitive Remediation (CR) in people with substance
seem optimal for addiction treatment (Verdejo-García, use disorders (Marceau et al., 2017). The other one is an
2016). On the one hand, they are designed to train the ecological intervention based on chess, i.e., it uses the game
executive skills needed to achieve complex goals as a platform to train goal-related strategies, including
(e.g., abstinence, return to work). Standard addiction response inhibition and planning (“stop and think”) and
treatments are also based on these goals, but they may not strategic decision-making (“analysis of short- and long-
explicitly train participants on how to achieve them. On the term consequences”) during the preparation of chess

movements (Gonçalves et al., 2014). Chess training was with substance use disorders (Alfonso et al., 2011;
supplemented with a motivational intervention to facilitate Casaletto et al., 2016; Valls-Serrano et al., 2016). Alfonso
treatment engagement. In the following sections, the et al. (2011) applied the standard version of GMT (Levine
rationale and the contents of these interventions are dis- et al., 2011) combined with mindfulness meditation
cussed, as well as their main findings and proposed (Kabat-Zinn, 2003) in alcohol and stimulant polysubstance
mechanisms, with special emphasis on GMT and specific users enrolled in community-based outpatient treatment.
mentions to CR and chess when relevant. Participants chose to enroll in GMT as an adjunctive to
treatment as usual (i.e., counseling and relapse prevention)
or standard treatment alone. Although participants were not
Intervention approaches and randomized, the two groups did not significantly differ on
mechanisms clinical characteristics. Seven GMT modules were applied
GMT uses therapist-guided instruction, practice, and strat- across 14 weeks, together with 14 values-based mindful-
egy learning. It contains seven to nine modules that follow ness meditation sessions. The value-based mindfulness
a progressive structure; that is, more basic abilities are component was added to GMT, which already contains
trained first, and more complex abilities and strategies rest mindfulness practice, to facilitate the switch between
on initial trainings. The executive function exercises prepotent responses (i.e., impulsive and habitual actions)
include training of response inhibition (“stop”), mindful- and goal setting (via mindfulness training on goal-related
ness (“focus on the goal”), working memory (“goal values such as “willpower” and “endurance”) in the
setting”), and decision-making (“alignment between goals context of the “StopeStateeCheck” strategy. The training,
and subsequent action selection”). These exercises/trained compared to treatment as usual, was associated with
skills are progressively combined in the strategy “Stope significant improvements in working memory indicated by
State goaleCheck” that is applied to multitasking exercises the Letter Number Sequencing test (Wechsler, 1997),
and everyday projects. The strategy enables participants to response inhibition indicated by the Stroop test (Delis et al.,
overcome action slips (e.g., impulsive responses, habits), 2001), and decision-making measured with the Iowa
navigate complex decisions, and ultimately achieve long- Gambling Task (Bechara et al., 2000). In a subsequent
term goals. randomized trial, Valls-Serrano et al. (2016) applied a
The GMT program applied in the context of substance similar GMT plus mindfulness protocol in polysubstance
use disorders contains seven to eight modules of 90 min users enrolled in residential treatment. Eight GMT modules
each, plus w3 h per week homework in the form of projects and eight mindfulness sessions, applied weekly, were
(Alfonso et al., 2011; Valls-Serrano et al., 2016). In modules compared to treatment as usual (therapeutic community).
1e2, participants are trained on mindfulness and response Findings showed that GMT, compared to treatment as
inhibition skills. Response inhibition training is applied to usual, was associated with significant improvements in
control impulsive and habitual responses and mindfulness working memory measured via Letter Number Sequencing,
exercises to train present-mindedness and attentional control reflection impulsivity (a tendency to gather less information
(or goal focus). In modules 3e4, participants are trained to before making a decision) measured with the Information
use working memory (“the mental blackboard”) to maintain Sampling Task (Clark et al., 2006), and strategy application
their goals “on line” and make them resistant to distraction in a real-life planning task (the Multiple Errands Test)
and habits. Working memory and goal setting exercises are (Burgess et al., 2006). GMT was also associated with a
followed by association strategies that teach them how to significant reduction of subjective stress levels. Casaletto
link the “Stop” and mindfulness techniques with goal setting et al. (2016) tested an abbreviated version of GMT, i.e., a
in the mental blackboard (“State goal”). In modules 5e8, single session focused on learning of the strategy: “Stope
participants are trained on decision-making skills, including StateeCheck” in a three-group randomized design
managing competing goals, goal-based prioritization of comparing (1) GMT, (2) GMT plus metacognitive strate-
action selection, and monitoring of decision-making out- gies (i.e., additional instruction on the link between GMT
comes (“Check”). They are also trained on the overarching training and executive dysfunction), and (3) no-treatment
strategy, i.e., “StopeState goaleCheck,” and instructed to control in a sample of polysubstance users with HIV.
apply this strategy in real-life activities and personal Findings showed that the two GMT interventions,
projects. compared with no-treatment, resulted in significant
improvement on an Everyday Multitasking Test (Scott
et al., 2011) (similar to the Multiple Errands Test used in
Evidence of the efficacy of the training Valls-Serrano et al. (2016)). There were no differences
Three studies have examined the effects of GMT on between the two versions of GMT. The analysis of
executive functions and self-regulation deficits in people moderators showed that the participants with poorer
Goal-based interventions for executive dysfunction in addiction treatment Chapter | 20 279
baseline executive functions, methamphetamine use reduction and improvement of affective-based decision-
(vs. other substance use) disorders, and depression were the making are consistent with the findings of mindfulness
ones who got more benefit from GMT. interventions in the context of addiction treatment (Garland
With regard to other goal-based interventions, two et al., 2014), and GMT also teaches strategies to manage
studies have applied goal-oriented cognitive rehabilitation conflictive goals and stress during decision-making
in the context of substance use disorders (Gonçalves et al., (Verdejo-García, 2016). The results from other goal-
2014; Marceau et al., 2017). Marceau et al. (2017) applied a related interventions support the notion that goal-based
miscellaneous CR program incorporating aspects of GMT trainings can significantly improve executive functions,
and other goal interventions among a mixed sample of although their active ingredients and specific outcomes are
primarily methamphetamine and alcohol users following still unclear, as different approaches have shown benefits
residential treatment. They applied 12 2-h sessions across on different executive components (i.e., CR on response
4 weeks and compared the goal intervention with treatment inhibition vs. chess on working memory).
as usual (therapeutic community). Findings showed that the
CR program, compared to treatment as usual, was associ- Discussion of the neurocognitive
ated with significant improvements in response inhibition
indicated by the Stroop inhibition index (Delis et al., 2001),
mechanisms in light of evidence
as well as behavioral indices of executive functions and GMT is the best-examined goal-based intervention both in
self-regulation, measured with well-validated question- the general context of executive function/self-regulation
naires. The CR program did not achieve significant effects deficits and in the specific context of substance use disor-
on working memory indicated by the working memory ders (Stamenova and Levine, 2018; Verdejo-García, 2016).
index of the Wechsler Adult Intelligence Scale (Wechsler, The overarching “StopeState goaleCheck” strategy
2008) or flexibility indicated by the Stroop shifting index trained by GMT improves response inhibition and atten-
(Delis et al., 2001) and the Trail Making Test (Strauss et al., tional control (i.e., goal focus) and promotes a more
2006). Moving beyond traditional approaches, Gonçalves cautious approach to action selection (Levine et al., 2011).
et al. (2014) applied an innovative goal-oriented training Through consolidation of this strategy, GMT places
via chess exercises to strengthen goal-based planning and specific emphasis on goal-based strategies that can override
action selection in cocaine-dependent inpatients following a automatic responses including reward-driven impulsive
4-week inpatient treatment. This training consisted of 10 behaviors and automatic habits (Verdejo-García et al.,
90 min therapist-assisted group sessions that instructed 2019). The strategy can also strengthen representations of
participants on chess rules (to train goal-directed behavior) action-outcome relationships during decision-making
and chess strategy (to train “stop and think” and decision- (Verdejo-García, 2016). In addition to specific mecha-
making strategies, i.e., adequate consideration of the nisms, Hart and Evans (2006) defined more general
consequences of different moves/decisions). In addition, advantages of structured goal-based interventions,
they incorporated motivational enhancement techniques to including fostering of self-direction, energization,
pair chess exercises with real-life goals and strategies. The (goal-related) persistence, and knowledge of novel strate-
chess training approach is theoretically relevant to address gies via rehearsal and practice. These aspects are particu-
real-life self-regulation deficits, as it has been proposed that larly relevant for people with substance use disorders, who
goal-based training is more effective in the context of often have problems with directing attention to goals,
meaningful everyday activities (Diamond and Ling, 2015). apathy, and lack of perseverance symptoms and rigid sets
The training was associated with improvement of working of habits and routines (Caracuel et al., 2008; Verdejo-
memory span, but no significant improvements were found García et al., 2007). Also noteworthy, GMT uses the
in other executive tasks or an impulsivity questionnaire basic principles of associative learning to train therapeutic
(i.e., the Barratt Impulsivity Scale (Patton et al., 1995)). strategies, which is one of the cognitive abilities that is
In summary, preliminary studies of GMT in the context preserved and even enhanced in people with substance use
of addiction treatment have shown beneficial effects of the disorders (Leland et al., 2008), making them more suitable
training on executive functions, including working mem- to benefit from it.
ory, response inhibition/impulsivity, and strategy applica- CR for substance users and chess-based training are less
tion in planning and multitasking tests. These benefits are structured interventions, still in need of further evidence,
theoretically consistent with the active ingredients of GMT, but they have shown relatively consistent findings in terms
i.e., the “StopeStateeCheck” strategy (Levine et al., of improvement of executive functions (although the
2011), and similar to the cognitive gains observed in executive gains vary across the two interventions) and
clinical trials using GMT in brain injury patients with self- behavioral self-regulation. They also offer interesting
regulation deficits (Novakovic-Agopian et al., 2011; additions to standard goal-based interventions. The chess
Stubberud et al., 2013; Tornås et al., 2016). Stress intervention is an example of how executive functions can
be trained within the context of real-life meaningful activ- outcomes, and if these clinical outcomes are mediated by
ities, provided that they have executive demands, such as the proposed neurocognitive and neurobiological mecha-
ambiguity and complexity. The miscellaneous CR program nisms. Neurocognitive assessment tools and relevant bio-
applied by Marceau et al. (2017) combines classic markers such as functional neuroimaging should assist in
goal-based approaches based on neuropsychological this line of research. Another common limitation in all
principles with implementation of intentions, which is a studies is that goal-based trainings are typically tested
goal-oriented intervention stemming from a different within the context of treatment as usual, and thus it is not
tradition of cognitive psychology. Implementation of clear if the observed effects are because of the training itself
intentions acts through formation of intentions (detailed or to synergistic effects of the standard treatment and the
plans about when and how to act) and associations between training. Three-group designs including training, sham
opportunities and planned responses, in the form of an “if, control, and treatment as usual are required to upgrade the
then” structure (Forcano, Mata, de la Torre and Verdejo- quality of cognitive training research in substance use
García, 2019; Webb et al., 2010). It adds new aspects to disorders (Wykes and Spaulding, 2011). In addition, goal-
the active ingredients of GMT, such as the strengthening of based intervention studies are in need of more thorough
future-based representations (intentions) and the “if, then” investigation of mediation and moderation mechanisms,
strategy, similar to a selective cueing for goals, also used in similar to what has been done in other cognitive trainings
earlier versions of GMT (Levine et al., 2000). (Eberl et al., 2013; Gladwin et al., 2015; Houben et al.,
The neurobiological mechanisms that underpin goal- 2012). More research is needed to determine if improve-
based intervention effects in substance use disorders ment in goal-based self-regulation is the mechanism
remain untested. In patients with brain injuries that have relevant to GMT and if such mechanism is relevant to
overlapping neurobiology with substance use disorders prevent relapse. More research is also needed to determine
(frontal-striatal deficits), Chen et al. (2011) examined the the differential contribution of goal management
impact of GMT on brain activity in a goal-based selective “cognitive” exercises versus mindfulness meditation
attention task. Findings showed that GMT, compared to “affective” exercises into GMT therapeutic and neurobio-
control, enhanced goal-oriented neural activation in the logical pathways (Garland et al., 2014; McConnell and
dorsolateral prefrontal cortex (DLPFC) and the extrastriate Froeliger, 2015).
cortex during this task. Importantly, individual differences Therefore, to circumvent the limitations of the existing
in DLPFC activation were associated with treatment literature, future studies could benefit from applying the
response. Most of the studies that have applied goal-based following recommendations: (1) align with current SPIRIT
interventions in substance users have also incorporated guidelines for the design of randomized controlled trials;
aspects of mindfulness and motivational interventions (2) apply goal-based interventions with specific active in-
(Alfonso et al., 2011; Gonçalves et al., 2014; Valls-Serrano gredients (i.e., mechanisms) and analogous “sham” condi-
et al., 2016). Hypothetically, mindfulness and motivational tions that control for nonspecific effects of the cognitive
trainings aim to improve the integration of goal represen- training, along with treatment as usual as a third arm;
tations, coded in the DLPFC, with feedback representa- (3) apply treatment fidelity strategies to ensure standardized
tions, coded in the medial prefrontal cortex, the anterior delivery of goal-based trainings; (4) conduct intention to
cingulate cortex, and the insula (Verdejo-Garcia et al., treat analyses of the targeted cognitive outcomes plus
2015). That is, mindfulness and motivational strategies meaningful clinical outcomes, such as alcohol and/or drug
would speculatively boost GMT effects on cortical use during and after the intervention, craving, and quality
networks relevant to attentional control and decision- of life; and (5) allow power to conduct mediation and
making (McConnell and Froeliger, 2015). moderation analyses to establish the pathways of thera-
peutic effects. Goal-based interventions seem to be theo-
retically relevant and practically useful for populations with
Recommendations for researchers and substance use disorders, but clinically oriented research is
needed to determine its efficacy and efficiency in the
clinicians interested in using goal-based context of addiction treatment.
interventions
Goal-oriented trainings have been successfully tested in References
“proof-of-concept” studies and in randomized observa-
tional studies with small samples, but they are in need of Alfonso, J.P., Caracuel, A., Delgado-Pastor, L.C., Verdejo-García, A.,
2011. Combined goal management training and mindfulness medita-
randomized controlled studies. Future studies would benefit
tion improve executive functions and decision-making performance in
from more rigorous clinical trial designs that are adequately
abstinent polysubstance abusers. Drug Alcohol Depend. 117 (1),
powered and aligned with the current SPIRIT recommen- 78e81.
dations (Chan et al., 2013). Ideally, these trials should Bechara, A., Tranel, D., Damasio, H., 2000. Characterization of the
incorporate mechanistic accounts and determine if the decision-making deficit of patients with ventromedial prefrontal cortex
trainings have significant effects on alcohol and drug use lesions. Brain 123 (11), 2189e2202.
Goal-based interventions for executive dysfunction in addiction treatment Chapter | 20 281
Burgess, P.W., Alderman, N., Forbes, C., Costello, A., Coates, L.M.-A., Gladwin, T.E., Rinck, M., Eberl, C., Becker, E.S., Lindenmeyer, J.,
Dawson, D.R., et al., 2006. The case for the development and use of Wiers, R.W., 2015. Mediation of cognitive bias modification for
“ecologically valid” measures of executive function in experimental alcohol addiction via stimulus-specific alcohol avoidance association.
and clinical neuropsychology. J. Int. Neuropsychol. Soc. 12 (2), Alcohol Clin. Exp. Res. 39 (1), 101e107.
194e209. Gollwitzer, P.M., Sheeran, P., 2006. Implementation intentions and goal
Caracuel, A., Verdejo-García, A., Vilar-Lopez, R., Perez-Garcia, M., achievement: a meta-analysis of effects and processes. Adv. Exp. Soc.
Salinas, I., Cuberos, G., et al., 2008. Frontal behavioral and emotional Psychol. 38, 69e119.
symptoms in Spanish individuals with acquired brain injury and Gonçalves, P.D., Ometto, M., Bechara, A., Malbergier, A., Amaral, R.,
substance use disorders. Arch. Clin. Neuropsychol. 23 (4), 447e454. Nicastri, S., et al., 2014. Motivational interviewing combined with
Casaletto, K.B., Moore, D.J., Woods, S.P., Umlauf, A., Scott, J., chess accelerates improvement in executive functions in cocaine
Heaton, R.K., 2016. Abbreviated goal management training shows dependent patients: a one-month prospective study. Drug Alcohol
preliminary evidence as a neurorehabilitation tool for HIV-associated Depend. 141, 79e84.
neurocognitive disorders among substance users. Clin. Neuropsychol. Hart, T., Evans, J., 2006. Self-regulation and goal theories in brain injury
30 (1), 107e130. rehabilitation. J. Head Trauma Rehabil. 21 (2), 142e155.
Chan, A.-W., Tetzlaff, J.M., Altman, D.G., Dickersin, K., Moher, D., Houben, K., Havermans, R.C., Nederkoorn, C., Jansen, A., 2012. Beer à
2013. SPIRIT 2013: new guidance for content of clinical trial pro- No-Go: learning to stop responding to alcohol cues reduces alcohol
tocols. Lancet 381 (9861), 91e92. intake via reduced affective associations rather than increased
Chen, A.J.-W., Novakovic-Agopian, T., Nycum, T.J., Song, S., response inhibition. Addiction 107 (7), 1280e1287.
Turner, G.R., Hills, N.K., et al., 2011. Training of goal-directed Kabat-Zinn, J., 2003. Mindfulness-based interventions in context: past,
attention regulation enhances control over neural processing for in- present, and future. Clin. Psychol. Sci. Pract. 10 (2), 144e156.
dividuals with brain injury. Brain 134 (5), 1541e1554. Leland, D.S., Arce, E., Miller, D.A., Paulus, M.P., 2008. Anterior cingu-
Clark, L., Robbins, T.W., Ersche, K.D., Sahakian, B.J., 2006. Reflection late cortex and benefit of predictive cueing on response inhibition in
impulsivity in current and former substance users. Biol. Psychiatry 60 stimulant dependent individuals. Biol. Psychiatry 63 (2), 184e190.
(5), 515e522. Levine, B., Robertson, I.H., Clare, L., Carter, G., Hong, J., Wilson, B.A.,
Delis, D.C., Kaplan, E., Kramer, J.H., 2001. Delis-Kaplan Executive et al., 2000. Rehabilitation of executive functioning: an
Function SystemÒ(D-KEFSÒ): Examiner’s Manual: Flexibility of experimentaleclinical validation of goal management training. J. Int.
Thinking, Concept Formation, Problem Solving, Planning, Creativity, Neuropsychol. Soc. 6 (3), 299e312.
Impluse Control, Inhibition. Pearson. Levine, B., Schweizer, T.A., O’Connor, C., Turner, G., Gillingham, S.,
Diamond, A., Ling, D.S., 2015. Conclusions about interventions, pro- Stuss, D.T., et al., 2011. Rehabilitation of executive functioning in
grams, and approaches for improving executive functions that appear patients with frontal lobe brain damage with goal management
justified and those that, despite much hype, do not. Dev. Cogn. training. Front. Hum. Neurosci. 5.
Neurosci. https://doi.org/10.1016/j.dcn.2015.11.005. Levine, B., Stuss, D.T., Winocur, G., Binns, M.A., Fahy, L., Mandic, M.,
Domínguez-Salas, S., Díaz-Batanero, C., Lozano-Rojas, O.M., Verdejo- et al., 2007. Cognitive rehabilitation in the elderly: effects on strategic
García, A., 2016. Impact of general cognition and executive func- behavior in relation to goal management. J. Int. Neuropsychol. Soc. 13
tion deficits on addiction treatment outcomes: systematic review and (1), 143e152.
discussion of neurocognitive pathways. Neurosci. Biobehav. Rev. 71, Marceau, E.M., Berry, J., Lunn, J., Kelly, P.J., Solowij, N., 2017.
772e801. Cognitive remediation improves executive functions, self-regulation
Eberl, C., Wiers, R.W., Pawelczack, S., Rinck, M., Becker, E.S., and quality of life in residents of a substance use disorder therapeu-
Lindenmeyer, J., 2013. Approach bias modification in alcohol tic community. Drug Alcohol Depend. 178, 150e158.
dependence: do clinical effects replicate and for whom does it work McConnell, P.A., Froeliger, B., 2015. Mindfulness, mechanisms and
best? Dev. Cogn. Neurosci. 4, 38e51. meaning: perspectives from the cognitive neuroscience of addiction.
Fernández-Serrano, M.J., Pérez-García, M., Perales, J.C., Verdejo- Psychol. Inq. 26 (4), 349e357.
García, A., 2010. Prevalence of executive dysfunction in cocaine, Novakovic-Agopian, T., Chen, A.J.-W., Rome, S., Abrams, G.,
heroin and alcohol users enrolled in therapeutic communities. Eur. J. Castelli, H., Rossi, A., et al., 2011. Rehabilitation of executive func-
Pharmacol. 626 (1), 104e112. tioning with training in attention regulation applied to individually
Fernández-Serrano, M.J., Pérez-García, M., Verdejo-García, A., 2011. defined goals: a pilot study bridging theory, assessment, and treat-
What are the specific vs. generalized effects of drugs of abuse on ment. J. Head Trauma Rehabil. 26 (5), 325e338.
neuropsychological performance? Neurosci. Biobehav. Rev. 35 (3), Patton, J.H., Stanford, M.S., Barratt, E.S., 1995. Factor structure of the
377e406. Barratt impulsiveness scale. J. Clin. Psychol. 51 (6), 768e774.
Forcano, L., Mata, F., de la Torre, R., Verdejo-García, A., 2018. Cognitive Prestwich, A., Conner, M., Lawton, R.J., 2006. Implementation intentions:
and neuromodulation strategies for unhealthy eating and obesity: can they be used to prevent and treat addiction. In: Wiers, R.W.,
systematic review and discussion of neurocognitive mechanisms. Stacy, A.W. (Eds.), Handbook of Implicit Cognition and Addiction.
Neurosci. Biobehav. Rev. 87, 161e191. https://doi.org/10.1016/ Sage Publications, pp. 455e469.
j.neubiorev.2018.02.003. Rubenis, A.J., Fitzpatrick, R.E., Lubman, D.I., Verdejo-García, A., 2018.
Garland, E., Froeliger, B., Howard, M., 2014. Mindfulness training targets Impulsivity predicts poorer improvement in quality of life during early
neurocognitive mechanisms of addiction at the attention-appraisal- treatment for people with methamphetamine dependence. Addiction
emotion interface. Front. Psychiatry 4, 173. 113 (4), 668e676.
Scott, J.C., Woods, S.P., Vigil, O., Heaton, R.K., Schweinsburg, B.C., Valls-Serrano, C., Caracuel, A., Verdejo-García, A., 2016. Goal manage-
Ellis, R.J., et al., 2011. A neuropsychological investigation of multi- ment training and mindfulness meditation improve executive func-
tasking in HIV infection: implications for everyday functioning. tions and transfer to ecological tasks of daily life in polysubstance
Neuropsychology 25 (4), 511. users enrolled in therapeutic community treatment. Drug Alcohol
Stamenova, V., Levine, B., 2018. Effectiveness of goal management Depend. 165, 9e14.
trainingÒ in improving executive functions: a meta-analysis. Neuro- Verdejo-García, A., 2016. Cognitive training for substance use disorders:
psychol. Rehabil. 1e31. neuroscientific mechanisms. Neurosci. Biobehav. Rev. 68, 270e281.
Stevens, L., Goudriaan, A., Verdejo-García, A., Dom, G., Roeyers, H., https://doi.org/10.1016/j.neubiorev.2016.05.018.
Vanderplasschen, W., 2015. Impulsive choice predicts short-term Verdejo-García, A., Albein-Urios, N., Martinez-Gonzalez, J.M., Civit, E.,
relapse in substance-dependent individuals attending an in-patient De la Torre, R., Lozano, O., 2014. Decision-making impairment
detoxification programme. Psychol. Med. 45 (10), 2083e2093. predicts 3-month hair-indexed cocaine relapse. Psychopharmacology
Stevens, L., Verdejo-García, A., Goudriaan, A.E., Roeyers, H., Dom, G., 231 (21), 4179e4187.
Vanderplasschen, W., 2014. Impulsivity as a vulnerability factor for Verdejo-García, A., Alcázar-Córcoles, M.A., Albein-Urios, N., 2019.
poor addiction treatment outcomes: a review of neurocognitive find- Neuropsychological Interventions for Decision-Making in Addiction:
ings among individuals with substance use disorders. J. Subst. Abus. a Systematic Review. Neuropsychol Rev. 29 (1), 79e92. https://
Treat. 47 (1), 58e72. doi.org/10.1007/s11065-018-9384-6.
Strauss, E., Sherman, E.M., Spreen, O., 2006. A Compendium of Neu- Verdejo-García, A., Bechara, A., Recknor, E.C., Pérez-García, M., 2007.
ropsychological Tests: Administration, Norms, and Commentary. Negative emotion-driven impulsivity predicts substance dependence
American Chemical Society. problems. Drug Alcohol Depend. 91 (2), 213e219.
Streeter, C.C., Terhune, D.B., Whitfield, T.H., Gruber, S., Sarid-Segal, O., Verdejo-García, A., Chong, T.T.-J., Stout, J.C., Yücel, M., London, E.D.,
Silveri, M.M., et al., 2008. Performance on the Stroop predicts treat- 2018. Stages of dysfunctional decision-making in addiction. Phar-
ment compliance in cocaine-dependent individuals. Neuro- macol. Biochem. Behav. 164, 99e105.
psychopharmacology 33 (4), 827. Verdejo-Garcia, A., Clark, L., Verdejo-Román, J., Albein-Urios, N.,
Stubberud, J., Langenbahn, D., Levine, B., Stanghelle, J., Schanke, A.-K., Martinez-Gonzalez, J.M., Gutierrez, B., Soriano-Mas, C., 2015.
2013. Goal management training of executive functions in patients Neural substrates of cognitive flexibility in cocaine and gambling
with spina bifida: a randomized controlled trial. J. Int. Neuropsychol. addictions. Br. J. Psychiatry 207 (2), 158e164.
Soc. 19 (6), 672e685. Webb, T.L., Sniehotta, F.F., Michie, S., 2010. Using theories of behaviour
Tornås, S., Løvstad, M., Solbakk, A.-K., Evans, J., Endestad, T., change to inform interventions for addictive behaviours. Addiction
Hol, P.K., et al., 2016. Rehabilitation of executive functions in pa- 105 (11), 1879e1892.
tients with chronic acquired brain injury with goal management Wechsler, D., 1997. Wechsler Memory Scale (WMS-III), vol. 14. Psy-
training, external cuing, and emotional regulation: a randomized chological corporation San Antonio, TX.
controlled trial. J. Int. Neuropsychol. Soc. 22 (4), 436e452. Wechsler, D., 2008. Wechsler Adult Intelligence ScaleeFourth Edition
Turner, T.H., LaRowe, S., Horner, M.D., Herron, J., Malcolm, R., 2009. (WAISeIV). Psychological Corporation, San Antonio, Texas.
Measures of cognitive functioning as predictors of treatment Wykes, T., Spaulding, W.D., 2011. Thinking about the future cognitive
outcome for cocaine dependence. J. Subst. Abus. Treat. 37 (4), remediation therapydwhat works and could we do better? Schizophr.
328e334. Bull. 37 (Suppl. l_2), S80eS90.
Chapter 21
Neurocognitive mechanisms of
mindfulness-based interventions for
addiction
Eric L. Garland1, M. Aryana Bryan1, Adam W. Hanley1 and Matthew O. Howard2
1
Center on Mindfulness and Integrative Health Intervention Development, University of Utah, Salt Lake City, UT, United States; 2University of North
Carolina at Chapel Hill, NC, United States
Introduction revival of mindfulness meditation in treating stress-related

conditions, including addiction, concurrent with advances
In recent decades, the cross-fertilization of cognitive in neuroscience. Early mindfulness-based interventions
science and neuroscience has deepened insights into (MBIs) such as Mindfulness-Based Stress Reduction
mechanisms underlying addiction. Prevailing models depict (MBSR) (Kabat-Zinn, 1990) and Mindfulness-Based
addiction as a disease process of reward dysregulation Cognitive Therapy (MBCT) (Segal et al., 2002) have
caused by exaggerated incentive salience and habit for- demonstrated efficacy in treating myriad psychological
mation coupled with natural reward deficits and excessive disorders (Goldberg et al., 2018). More recently, MBIs
stressdmaladaptive processes exacerbated by impairments have been developed as extensions of these earlier programs,
in executive function (Koob and Volkow, 2016). These adapted to specifically target biobehavioral mechanisms
processes are thought to result in the canonical, core underlying addictions. These treatments include
behavioral feature of addiction: a pattern of compulsive, Mindfulness-Based Relapse Prevention (MBRP) (Bowen
maladaptive drug seeking and use despite negative conse- et al., 2010) and Mindfulness-Oriented Recovery Enhance-
quences (Robinson and Berridge, 1993). ment (MORE) (Garland, 2013). MBRP and MORE are
Although neurobiological research elucidated new similar in their shared 8-week group structure, modeled after
treatment targets for pharmacotherapeutic interventions, the first-generation MBIs. Each group treatment session includes
development of novel behavioral treatments has lagged clinician-guided mindfulness exercises, such as body scans
behind these discoveries. Contemporary behavioral treat- and mindful breathing, followed by a debriefing group
ments are mostly limited to psychotherapeutic methods process and psychoeducational information. However,
developed decades before current neuroscientific models of MORE and MBRP differ significantly with respect to (1) the
addiction, such as motivational interviewing, cognitive techniques and psychoeducational topics addressed and
behavioral therapy, and dialectical behavioral therapy. While (2) the way in which mindfulness practices are debriefed and
breakthroughs at the time of their inception, the efficacy of processed. First, while both interventions target addictive
these first- and second-wave behavioral approaches in behaviors, craving, and automaticity with mindfulness,
treating many facets of addictive disorders is limited to MORE specifically leverages mindfulness training to foster
modest effect sizes overall (Lundahl et al., 2010; Magill and negative emotion regulation via cognitive reappraisal and
Ray, 2009), and many patients remain nonresponsive to amplify natural reward processing via savoring. Thus,
treatmentdparticularly those with neurocognitive deficits MORE is an integrative treatment, integrating traditional
(Stevens et al., 2014). Yet, a third wave of behavioral mindfulness practices with techniques drawn from cognitive
interventions may hold promise for specifically targeting behavioral therapy and positive psychology. Comparatively,
dysregulated neurocognitive processes underlying addiction. MBRP is more exclusively oriented around traditional
Mindfulness meditation is one promising third-wave mindfulness skill training and does not teach participants
treatment. In the past two decades, there has been a to engage in reappraisal or savoring techniques.

Second, MORE uses a structured, directive form of pro- cognitive neuroscience perspective, this field might be
cessing in which therapists are explicitly taught to elicit considered the entirety of the adaptive global workspace of
phenomenological descriptions of practice experiences, consciousness (Raffone and Srinivasan, 2009). Open
positively reinforce therapeutic practice outcomes while monitoring is a metacognitive state of awareness in the
reframing practice challenges, and explore how in-session sense that it involves observing the content of conscious
practice experiences could be translated into daily life. In experience while simultaneously appraising the process or
that regard, MORE draws upon behavioral change theory quality of consciousness itself.
principles of selective reinforcement and successive Such mindfulness practices are thought to reduce
approximation to shape participant responses to maximize cognitive, emotional, and behavioral reactivity through
therapeutic experiences and reduce addictive behavior. revealing the relative impermanence and insubstantiality of
Comparatively, MBRP engages participants through a any particular thought or feeling (Hanh, 2002). Neuro-
more nondirective, Rogerian, client-centered approach to imaging studies have found that mindfulness practice is
processing mindfulness experiences that strongly empha- associated with enhanced activity and connectivity among
sizes qualities of acceptance and nonjudgment. the prefrontal cortex (PFC) and anterior cingulate cortex
A wealth of controlled research studies have supported (ACC) with the striatum (Tang et al., 2015). Importantly,
these MBIs as having significant clinical benefits to these circuits, which become dysregulated in addiction,
individuals struggling with use of reinforcing substances modulate attention, automaticity, and reward, suggesting
such as alcohol, cocaine, nicotine, and opioids (Li et al., that mindfulness practice drives enduring changes in how
2017). This chapter operationalizes mindfulness in the the brain encodes motivational salience, habit behavior, and
treatment process as a means of training neurocognitive self-control. Neurocognitive models have linked mindful-
processes and then details evidence for neurocognitive ness practice to persistent changes in neural networks
mechanisms underlying the effectiveness of MBIs. involved in executive monitoring of working memory,
response inhibition, and emotion regulation (Vago and
Silbersweig, 2012). These models propose that mindfulness
Mindfulness as a means of targeting practice involves a cyclic series of mental operations in
which one (1) orients and sustains attention on an object,
mechanisms of addiction (2) monitors working memory for instances of mind wan-
Mindfulness as a construct is derived from ancient Indo- dering, (3) engages inhibitory control when habitual
Sino-Tibetan contemplative practices and philosophies emotional associations and behavioral impulses arise, and
focused on liberation from suffering via training the mind (4) reorients attention back to the initial meditative object.
to gain insight into the nature of reality. Contemporary These and other key neural alterations are discussed below.
scientific literature, however, has examined and oper- Importantly, structural and functional neural changes
ationalized mindfulness as a discrete state, trait, and prac- following mindfulness practice appear to be lasting (Tang,
tice. As behavioral treatments, MBIs train practitioners to 2015). Durable neuroplastic changes induced via mindful-
cultivate a metacognitive state of awareness known as state ness practice may support dispositional or trait
mindfulness. This state is characterized by present moment mindfulnessdthe proclivity to exhibit mindful attitudes and
attention and nonreactive, nonjudgmental observation of behavioral tendencies in everyday life and outside the
thoughts, feelings, physical sensations, and perceptions context of meditation sessions (Baer and Krietemeyer,
(Kabat-Zinn, 2003). 2006). Data indicate that the development of trait
The practice of mindfulness is comprised of two core mindfulness is a linear function of the trajectory of state
elements: focused attention and open monitoring (Lutz mindfulness induced over repeated mindfulness practice
et al., 2008; Vago and Silbersweig, 2012). Focused atten- sessions (Kiken et al., 2015). The accrual of state mindful-
tion involves concentration on a sensory object while ness into dispositional mindfulness is of note, as increases in
gently acknowledging and then disengaging from sustained dispositional mindfulness appear to mediate many
emotional or cognitive elaboration. The focus of attention of the therapeutic outcomes of MBIs in clinical settings (Gu
may be on interoceptive and proprioceptive body sensa- et al., 2015).
tions such as the sensation of one’s breathing or contact of Importantly, core attributes of dispositional or trait
one’s legs with a chair; however, external visual foci can mindfulness are the ability to remain nonreactive to and
also be used. Typically, focused attention transitions into observant of interoceptive and exteroceptive stimuli, with
the practice of open monitoring. This practice continues to nonjudgmental acceptance and self-awareness of automatic
include observation and disengagement from emerging thoughts and behavioral tendencies (Baer et al., 2006).
thoughts and feelings while also reflexively turning atten- These capacities are associated with increased cognitive
tion back on itself to attend to the field of awareness in emotion regulation (Anicha et al., 2012; Hanley and
which mental contents arise (Lutz et al., 2008). From a Garland, 2014). Dispositional mindfulness is antithetical to
Neurocognitive mechanisms of mindfulness-based interventions for addiction Chapter | 21 285
impulsivity and compulsivity, traits that characterize and psychoeducation. Additionally, participants are instructed
drive addictive behaviors; thus, it is logical that developing to complete at-home therapeutic exercises of formal and
trait mindfulness could mitigate compulsive drug-seeking informal mindfulness practices along with assignments to
and drug-taking behaviors. In fact, addiction could be self-monitor symptoms associated with addiction, such as
described as mindlessness (Langer, 1992) in that addictive craving and negative affect.
behaviors are facilitated by an “autopilot”-like drive, Metaanalyses support the efficacy of MBIs. Random-
compromising the inhibitory power that would typically be ized control trials (RCTs) consistently demonstrate signif-
exerted by conscious volition in the context of negative icant reductions in severity and frequency of substance
consequences that await the individual. misuse (d ¼ 0.33, 95% CI [0.88, 0.14]) and craving
The acquisition of dispositional mindfulness may buffer (d ¼ 0.68, 95% CI [1.11, 0.025]) following MBI (Li
against the compulsive, automatized behaviors hallmarking et al., 2017). Moreover, RCTs show that MBIs can
addiction. In that regard, trait mindfulness is significantly significantly alleviate affective and physical symptoms
inversely correlated with substance use (Karyadi et al., frequently co-occurring with addiction, including stress,
2014), substance misuse (Priddy et al., 2018), and craving negative affect, and pain (Goyal et al., 2014). In a collective
(Garland et al., 2014). Additionally, trait mindfulness assessment of the effects of MBIs across a host of psy-
practice is positively associated with the ability to atten- chiatric disorders (including substance use disorders),
tionally disengage and recover autonomic functioning after MBIs were found to be superior to minimal treatment and
exposure to substance-related cues (Baker and Garland, nonspecific active control conditions, while showing com-
2018; Garland, 2011; Garland et al., 2011). Given that parable effects to other bona fide evidence-based treatments
attentional and autonomic cue reactivity predicts relapse to (Goldberg et al., 2018).
substance use (Garland et al., 2012; Sinha et al., 2003),
dispositional mindfulness may serve an important protec-
tive effect in individuals with substance use disorders.
Neurocognitive mechanisms of
While drug seeking does frequently require novel and mindfulness as a treatment for
flexible behaviors in the seeking, acquisition, and use of addiction
drugs (Singer et al., 2017), automaticity plays a large role in
Here we review findings concerning neurocognitive
appetitive and consummatory actions present in substance
mechanisms through which MBIs support recovery from
use disorders (Tiffany, 1990). Thus, mindfulness of one’s
addiction. A neurocognitive model of mindfulness-
automatized behavioral and emotional reactions may allow
centered regulation of addictive behavior by Garland
for greater self-regulation of habitual addictive behavior.
et al. (2014b) (see Fig. 21.1) hypothesizes that MBIs exert
From this perspective, mindfulness practice may evoke the
their effects by (1) strengthening functional connectivity
state of mindfulness, which accrues into a durable
within a top-down metacognitive control network integral
propensity to exhibit the trait of mindfulness in everyday
to attention and inhibitory control and (2) strengthening
life, thereby acting as a buffer against addictive behaviors.
functional connectivity between the metacognitive control
network and bottom-up brain regions implicated in
Clinical format and efficacy of reward, habit behavior, and emotional experience.
mindfulness-based interventions for According to this model, MBIs are mental training pro-
grams designed to exercise and strengthen prefrontally
addiction mediated cognitive control networks that have become
MBIs for addiction provide instruction in standard focused weak during the process of addiction. Remediation of
attention and open monitoring meditation practices found functional and structural atrophy in brain circuits instanti-
in other MBIs (e.g., MBSR, MBCT) in addition to training ating cognitive control allows for regulation of impulses
in tailored mindfulness techniques designed to target neu- originating in subcortical brain networks, providing the
rocognitive mechanisms underpinning craving, attentional neural substrate through which mindfulness training can
bias, and addictive automaticity. MBIs for addiction also lead to deautomatization of addictive habits and restruc-
teach mindfulness skills to mitigate relapse risk factors, turing of valuation processes to motivate adaptive, goal-
including maladaptive beliefs and negative affective states. directed behavior. We now discuss evidence derived from
These intervention models (e.g., MBRP, MORE) typically early-stage studies (e.g., proof of principle / stage II
follow an 8e10-week group therapy format led by trained RCTs) demonstrating mindfulness’ efficacy in regulating
clinicians (Bowen et al., 2010; Garland, 2013). In each these neurocognitive processes in both naïve/advanced
session, participants are led through formal mindfulness meditators and healthy/subclinical/clinical populations.
meditation practices, followed by structured debriefing and
FIGURE 21.1 Neurocognitive model of mindfulness-centered regulation of addictive behavior. This adaptation of Garland et al., (2014) model of
mindfulness-centered regulation posits that mindfulness-based interventions ameliorate the craving, negative affective states, and automatic habit be-
haviors underpinning addiction by enhancing functional connectivity (1) within a “top-down” metacognitive brain network integral to attentional and
inhibitory control (DLPFC, dACC, parietal cortex) and (2) between this metacognitive attentional/inhibitory control network and “bottom-up” brain
regions implicated in reward, habit behavior, and emotional experience. Enhanced functional connectivity within and between these neural circuits may
facilitate deautomatization of addictive habits and restructuring of valuation processes to motivate adaptive, goal-directed behavior. DLPFC, dorsolateral
prefrontal cortex; dACC, dorsal anterior cingulate cortex; PCC, posterior cingulate cortex; DS, dorsal striatum; VS, ventral striatum; Thal, thalamus;
Hipp, hippocampus; Amy, amygdala; OFC, orbitofrontal cortex; MFC, medial prefrontal cortex.
Effects of mindfulness on “top-down” interoceptive sensations and integration of interoceptive

mechanisms of cognitive control and exteroceptive inputs (Farb et al., 2013). Taken together,
these findings suggest that overall improvements in atten-
Attentional control tional control via mindfulness are mediated by enhance-
Mindfulness meditation practices and MBIs that emphasize ments in various subcomponents of attentional processing
focused attention have been shown to improve various and changes in neural resource allocation.
indices of attentional control. Intensive mindfulness medi- Mindfulness-based improvements in attentional control
tation training produces durable increases in sustained may result in decreases in addiction attentional bias (Field
attention capacity (Zanesco et al., 2018). Brief mindfulness and Cox, 2008). In that regard, mindfulness training
practice also has positive effects on sustained attention through MORE was associated with significant effects on
(Wenk-Sormaz, 2005; Zeidan et al., 2010). Examination of both alcohol (Garland et al., 2010) and opioid attentional
attentional subsystems found that intensive mindfulness bias (Garland et al., 2017), the latter of which predicted
practice enhanced alerting and attentional orienting, as well decreases in opioid misuse by follow-up.
as selective attention/conflict monitoring (Jha et al.,
2007)dan attentional capacity that is stronger among Regulation of automaticity
regular mindfulness meditators than among meditation- Mindfulness also appears to facilitate deautomatization of
naïve individuals (Hodgins and Adair, 2010). Similarly, habitual behaviors through practices of both open
mindfulness training attenuates the attentional blink, and monitoring and focused attention. Reviews suggest that
concurrent EEG data suggest this phenomenon is mediated mindfulness-induced metaawareness of one’s internal and
by flexible reallocation of attentional resources (Slagter external experiences and improvements in cognitive flexi-
et al., 2007). Neuroimaging studies have demonstrated that bility lead to enhanced regulation of automatic habits
mindfulness training is associated with increased activity in (Kang et al., 2013; Lao et al., 2016).
various PFC subregions underlying attentional control Deautomatization appears to occur through the process
(Chan and Woollacott, 2007; Tomasino and Fabbro, 2016). of decentering (i.e., shifting from immersion in internal
Furthermore, mindfulness training changes activation and eventsdsuch as thought, emotions, and physical
connectivity in brain regions governing attention to
sensationsdto a third-person perspective in which internal (Friese et al., 2012). These behavioral improvements have
events are viewed from a psychological distance), which in been paralleled by effects of mindfulness training on event-
turn creates opportunity for conscious responding in place of related potentials during Go/No-Go task performance
automatic reaction (Segal et al., 2002). This metacognitive among individuals with attention deficit/hyperactivity dis-
insight promotes reallocation of attention from the automatic order (Schoenberg et al., 2014) and addictive behaviors
fixation to the intended stimuli (Teasdale, 1999). Such (Andreu et al., 2018). In addition, in a sample of opioid users,
regulation of automaticity is evident in multiple studies 8 weeks of MORE improved inhibitory control during
demonstrating effects of mindfulness meditation on reducing negative affective interference on an emotional Go/No-Go
automatic cognitive interference during the Stroop task (Fan task (Garland et al., 2019). Similar effects of mindfulness
et al., 2014; Moore and Malinowski, 2009; Wenk-Sormaz, have been observed using functional magnetic resonance
2005). Mindfulness training appears to promote cognitive imaging (fMRI). MBI participants exhibited reduced errors
flexibility on semantic tasks requiring switching from over- on a response inhibition task coupled with concurrent in-
learned habitual associations (Wenk-Sormaz, 2005; creases in dorsolateral PFC responses (Allen et al., 2012).
Whitmarsh et al., 2013). Heeren et al. (2009) also assessed MBIs have also been shown to increase functional connec-
cognitive flexibility via the Verbal Fluency Task and found tivity in circuits mediating intentional inhibition (Sevinc
that mindfulness supported reduced rigidity in responses. et al., 2018). Participation in an MBI was associated with
Similarly, a study employing the Water Jug Task showed that increased white matter integrity and functional connectivity
mindfulness contributed to increased problem solving, in brain regions implicated in inhibitory control networks,
which requires cognitive flexibility, allowing for specifically the ACC and striatum (Tang et al., 2012; Tang
interruptions in automatic cognition and responding et al., 2010; Xue et al., 2011).
(Greenberg et al., 2012).
Mindfulness is also associated with enhanced behav- Effects of mindfulness on enhancing cognitive
ioral flexibility, indicating a reduced reliance on scripted,
regulation of reward, negative emotion, and
habitual responses. Focused attention practice (i.e., mindful
cue reactivity
eating) among novices facilitated reversal learning, an
indicator of behavioral flexibility (Janssen et al., 2018). Amplifying reward and positive affect
Similarly, mindfulness training decreased classically
Mindfulness training can amplify positive affective expe-
conditioned behavior by delaying onset of first conditioned
rience in clinical and healthy populations (Garland et al.,
response and decreasing conditioned response frequency
2015). The positive emotion regulatory effects of mind-
during an eyeblink conditioning task (Hanley and Garland,
fulness are explicated in the Mindfulness-to-Meaning
2019). Among advanced meditators, open monitoring
Theory (MMT), which proposes that mindfulness training
meditation improved metrics of behavioral flexibility on the
propels an upward spiral of positive cognitioneemotion
flanker task (Tsai and Chou, 2016). Neuroimaging research
complements these findings by demonstrating effects of interactions involving broadening of attention to positive
information that informs subsequent positive reappraisals,
mindfulness training on functional connectivity among
resulting in positive emotions even in the face of adversity
frontoparietal regions integral to top-down control of
(Garland et al., 2015). Outside the context of addiction, the
bottom-up reactions (Taren et al., 2017).
MMT is supported by longitudinal empirical research
(Garland et al., 2017c).
Inhibitory control
Attention to positive information may also be a key
A growing body of evidence demonstrates that mindfulness means by which mindfulness ameliorates addiction. The
training strengthens inhibitory control capacity, likely restructuring reward hypothesis (Garland, 2016; Garland
through overlapping mechanisms as those involved in et al., 2014b) proposes that mindfulness training may
modulating automaticity. MBIs reduce self-reported facilitate a shift in the relative salience of drug and natural
impulsivity and improve inhibitory control performance rewards, thereby reducing addictive behavior. Specifically,
on the Go/No-Go task and two choice impulsivity paradigm this shift occurs through mindfulness techniques aimed at
(Soler et al., 2016). Similarly, intensive mindfulness downregulating the heightened or sensitized valuation of
meditation training improves response inhibition with drug-related reward while simultaneously upregulating the
consequent effects on self-regulatory capacity (Sahdra perceived value of natural rewardsdi.e., natural reinforcers
et al., 2011); these effects were partially maintained several and socially constructed rewards that were pleasurable and
years later (Sahdra et al., 2011). Such inhibitory control reinforcing before the development of addiction (Garland,
benefits do not necessarily require long-term training. Brief 2016). Simply put, MBIs may increase the pleasure and
mindfulness meditation has been shown to restore inhibi- meaning derived from natural rewards and thereby decrease
tory control capacity following self-control depletion wanting for drugs, restoring function in key hedonic
systems of the brain that have become dysregulated during These mechanisms are likely interconnected and reciprocally
addiction. MBIs may facilitate this restructuring of reward energizing (cf., the MMT). Independently or interactively,
through savoring, a technique that involves sustained these mechanisms may be implicated in the significant
attention on the pleasurable sensory features of a naturally decreases in negative affect (Goyal et al., 2014) and stress (Li
rewarding stimulus coupled with metacognitive awareness et al., 2017) observed in metaanalyses of MBIs.
of pleasant somatic and affective responses to that stimulus. The effects of MBIs on negative affect and stress are
Oscillating between these exteroceptive and interoceptive evident in autonomic responses. In that regard, heart rate
forms of attention to positive information is thought to variability (HRV) has been widely used in mindfulness
overcome the “hedonic treadmill effect” to magnify and studies as a parasympathetically mediated indicator of self-
sustain the pleasure derived from the rewarding object or regulation of stress and negative emotions (Holzman and
event (Garland, 2016). Bridgett, 2017; Thayer and Lane, 2000). In that regard,
A wealth of evidence supports the restructuring reward participation in MBRP was associated with greater in-
hypothesis. Practicing mindfulness has been shown to increases in HRV during stress exposure compared to
crease the hedonic experience of food consumption (Arch treatment-as usual and control conditions for individuals
et al., 2016; Hong et al., 2014; Hong et al., 2011), and diagnosed with substance use disorders (Carroll and
participation in MBCT facilitated increases in subjective Lustyk, 2017). Similarly, in a sample of nicotine-deprived
reward valuation of daily living activities (Geschwind et al., smokers, mindfulness training was associated with signifi-
2011). An RCT of MORE as a treatment for prescription cant increases in HRV during stress exposure (Paz et al.,
opioid misuse demonstrated significant increases in auto- 2017). In a pilot RCT of MORE as a treatment for alcohol
nomic and electrocortical responses to natural rewards that use disorder, participants demonstrated significantly greater
were associated with decreases in opioid craving (Garland HRV recovery from stress-primed alcohol cues following
et al., 2014a, 2014c). In direct support of the restructuring the MORE intervention (Garland et al., 2010). Finally, in a
reward hypothesis, MORE increased autonomic responses Stage 2 RCT of MORE treatment for prescription opioid
to naturally rewarding stimuli relative to opioid-related misuse, participants receiving MORE exhibited significant
stimuli, and increases in this measure of relative cardiac increases in HRV during attention to negative emotional
responsiveness predicted reduced opioid misuse at 3-month stimuli presented in dot probe (Garland et al., 2014a) and
follow-up (Garland et al., 2017d). Ecological momentary affective picture viewing tasks (Garland et al., 2017d).
assessment data collected during this trial bolstered these A growing body of neuroimaging studies further eluci-
autonomic results by demonstrating that participation in dates mechanisms underlying mindfulness practice in
MORE led to increases in momentary positive affect that improving negative emotion regulation. In that regard, MBIs
predicted decreases in opioid misuse (Garland et al., attenuate amygdala and insula activation in response to
2017b). Finally, in a small sample of nicotine-dependent stressful stimuli (Kober et al., 2017; Taren et al., 2015).
smokers participating in a pilot fMRI study of MORE, Similarly, mindfulness training increased functional con-
increased activation in brain regions encoding reward nectivity and white matter changes in cognitive control net-
(ventral striatum and rostral anterior cingulate cortex works (e.g., the mPFC-ACC circuit) that were associated
[rACC]) was observed during savoring practice. These with significant improvements in self-reported emotion
neural reward-based activations significantly predicted re- regulation capacity (Tang et al., 2016). These findings are of
ductions in cigarette smoking over the course of treatment particular importance as functional connectivity between
(Froeliger et al., 2017). Positive-affect-enhancing effects of these two regions has been hypothesized to drive symptoms
MBIs have been demonstrated across multiple studies in of addiction and propensity to relapse (Droutman et al., 2015;
myriad contexts. The generalizability of the effects of Xie et al., 2011).
mindfulness on positive affect makes such interventions
valuable methods for treating the reward-related pathology Regulating craving and cue reactivity
and anhedonia undergirding addiction.
Although MBIs appear to enhance pleasure derived from
naturally rewarding experiences, pleasure or “liking” alone
Dampening negative affect and stress
has been shown insufficient to drive addiction (Robinson
In addition to enhancing reward processing and positive and Berridge, 2008). Similarly, while anhedonia and
affect, MBIs appear to facilitate the regulation of stress and negative affect support relapse to drug use, motivation to
negative affect. Some candidate cognitive emotion regula- carry out drug-seeking behavior is necessary (Koob and
tory mechanisms include acceptance (Lindsay and Moal, 2008; Robinson and Berridge, 1993). Thus, to be
Creswell, 2017), attentional control (Malinowski, 2013), efficacious in treating addiction, MBIs must disrupt nega-
decentering (Bernstein et al., 2015), disruption of rumina- tive affect and amplify liking responses to natural rewards
tion (Gu et al., 2015), and reappraisal (Garland et al., 2015). and also attenuate the wanting of drug rewards, preventing
them from supplanting natural and prosocial reinforcers. initially emphasize the focused attention element, designed
Craving, manifested by a subjective wanting for addictive to encourage “top-down” mechanisms of cognitive control,
substances and heightened incentive salience of substance- before introducing the more advanced practice of open
related cues, is an important driver in escalating compulsive monitoring. The rationale behind this graduated approach is
drug seeking and drug use, as well as relapse to substance use that attentional stability developed through focused
after periods of abstinence (Robinson and Berridge, 1993). attention practice will promote the capacity to engage
As previously discussed, metaanalysis indicates that metacognitive awareness during open monitoring practice,
MBIs result in moderate effect size decreases in craving (Li which in turn will facilitate regulation of maladaptive
et al., 2017). These reductions in craving might be behaviors and destructive emotions while promoting well-
explained by the effects of MBIs on attentional and phys- being. Furthermore, stabilizing subjective experience
iological reactivity to substance cues. As previously dis- through focused attention is likely to allow one to gain
cussed, MORE has been shown to significantly modify insight into the transitory and nonveridical nature of
addiction attentional bias in samples of alcohol-dependent experience (e.g., “thoughts and cravings are unsubstantial
individuals (Garland et al., 2010) and opioid misusers mental experiences that continually come and go, so I do
(Garland et al., 2017). In the same vein, MORE signifi- not have to react to them”), an insight that can be more
cantly modulates autonomic markers of drug cue reactivity directly explored with open monitoring practice. Thus, the
(Garland et al., 2014; Garland et al., 2017d). The effects of synergy of these two elements provide (1) the self-
MBIs on attentional and autonomic indices of cue reactivity monitoring skills to more quickly notice when attention is
have been paralleled by changes in neural markers of captured by a maladaptive object (e.g., craving) and to gain
incentive salience. In a lab-based brief mindfulness induc- awareness of automaticity; (2) the cognitive capacity to
tion, mindful attention to nicotine cues decreased activity in shift attention from maladaptive objects onto an intended
the subgenual ACC that was associated with attenuated object (e.g., the breath) while inhibiting behavioral
craving (Westbrook et al., 2011). Similarly, smokers impulses to disrupt automatic appetitive habits; (3) the ability
viewing cigarette images during a cue reactivity task to expand awareness to include naturally rewarding aspects
showed significant posttreatment reductions in ventral of the social and natural environment (e.g., the feel of the sun
striatal activity following treatment with MORE (Froeliger on the skin, spending time with a loved one); and (4) a means
et al., 2017). Collectively, these findings suggest that MBIs of sustaining attention on salutary objects and events to
are capable of decreasing subjective, attentional, and augment (i.e., savor) the healthy sense of pleasure and
physiological markers of drug-related wanting. Insofar as meaning that can be derived from them, thereby diminishing
sensitized physiological and behavioral responding to drug- the need for substance use to obtain hedonic equilibrium.
related cues drives the cycle of addiction, the ability of Over time, these elements of mindfulness may work in
MBIs to modulate and perhaps even reverse this phenom- combination to reshape subjective experience and adaptively
enon appears highly clinically significant. reorganize neural pathways integral to addiction recovery.
Returning to the restructuring reward hypothesis,
because liking or pleasure is embedded within the larger
neural network subserving wanting or motivation (Olney
Future directions for mindfulness-based
et al., 2018), it is possible that the effects of MBIs on interventions and addiction
enhancing responsivity to natural reward might attenuate Although a substantial body of evidence has accumulated
the wanting or craving of drug reward governed by supporting the efficacy of MBIs for addiction treatment
dysregulation in this broader reward system. Ultimately, the (Black, 2014; Brewer et al., 2014; Garland, 2016;
ability of MBIs to restore responding to natural rewards McConnell and Froeliger, 2015), Stage III and IV clinical
while dampening maladaptive appetitive motivations may trials with larger samples and longer follow-up periods are
have robust therapeutic value. needed to determine the durability of therapeutic effects. In
addition, there is a need for additional mechanistic studies
Hypothesized roles of core mindfulness among individuals with substance use disorders at various
elements in addiction treatment stages of recovery. Well-controlled, longitudinal functional,
and structural neuroimaging (e.g., fMRI) studies can
While accumulating evidence suggests MBIs are effica- elucidate effects of MBIs on top-down cognitive regulation
cious addiction treatment options that target a variety of of bottom-up limbic and striatal responses integral to
therapeutic mechanisms, optimally tailoring MBIs for addictive behavior. Imaging techniques with fine-grained
addiction treatment will require a better understanding of temporal resolution (e.g., EEG, MEG) may determine at
how the core mindfulness elements (focused attention and which stage of neurocognitive processing MBIs exert their
open monitoring) individually and synergistically exert effects. For instance, MBIs might target initial attentional
therapeutic effects. Many mindfulness training programs
orienting and automatic behavioral processes arising within tractable to therapeutic strategies like mindfulness that
the first few hundred milliseconds after the presentation of a appear to enhance top-down cognitive regulation over
substance-related cue. Conversely, MBIs might modify bottom-up appetitive habits. To the extent that MBIs
later cognitive and emotional elaboration occurring around effectively target maladaptive neurocognitive processes
1000 ms or later after onset of a substance cue or poten- underlying addiction, they hold promise as key elements in
tially foster physiological recovery from cue exposure. the armamentarium of addictions treatment.
Molecular neuroimaging (e.g., PET) studies may also
provide important insights into the effects of MBIs on a
synaptic level to explore the key neurotransmitters under-
Funding
lying mindfulness efficacy. In light of the apparent effects E.L.G. was supported by NIDA grant R01DA042033 (PI: Garland)
of MBIs on neurocognition, and given the important role of and NCCIH grant R61AT009296 (PI: Garland) during the preparation
acetylcholine in modulating prefrontal cortical activity of this manuscript.
(Klinkenberg et al., 2011), investigation of this neuro-
transmitter has valuable exploratory potential. Furthermore, References
in view of the role of dopamine in attention, learning, and
Allen, M., Dietz, M., Blair, K.S., van Beek, M., Rees, G., Vestergaard-
reward, MBIs might produce dopaminergic effects, and
Poulsen, P., et al., 2012. Cognitive-affective neural plasticity
indeed, data from early meditation research suggest this
following active-controlled mindfulness intervention. J. Neurosci.
may be the case (Kjaer et al., 2002). Finally, MBIs such as 32 (44), 15601e15610. https://doi.org/10.1523/JNEUROSCI.2957-
MORE enhance hedonic function, suggesting a role for 12.2012.
endogenous opioids or endocannabinoids in mediating Andreu, C.I., Cosmelli, D., Slagter, H.A., Franken, I.H.A., 2018. Effects of
these effects. Cognitive and affective neuroscience can test a brief mindfulness-meditation intervention on neural measures of
these hypotheses and elucidate malleable mechanisms of response inhibition in cigarette smokers. PLoS One 13 (1), e0191661.
mindfulness to inform future iterations of MBI treatment https://doi.org/10.1371/journal.pone.0191661.
optimization. Anicha, C.L., Ode, S., Moeller, S.K., Robinson, M.D., 2012. Toward a
Addiction neuroscience suggests that escalation to cognitive view of trait mindfulness: distinct cognitive skills predict its
compulsive drug use develops via usurpation of reward observing and nonreactivity Facets. J. Personal. 80 (2), 255e285.
https://doi.org/10.1111/j.1467-6494.2011.00722.x.
learning circuitry by increasing the salience of drug-related
Arch, J.J., Brown, K.W., Goodman, R.J., Della Porta, M.D., Kiken, L.G.,
cues, driving the overlearned, maladaptive drug-seeking
Tillman, S., 2016. Enjoying food without caloric cost: the impact of
behaviors that characterize addiction (Hyman et al., brief mindfulness on laboratory eating outcomes. Behav. Res. Ther.
2006). Recent data show that despite multiple treatment 79, 23e34. https://doi.org/10.1016/j.brat.2016.02.002.
episodes, approximately half of those with substance use Baer, R.A., Krietemeyer, J., 2006. Overview of mindfulness- and
disorders do not achieve sustained remission (Fleury et al., acceptance-based treatment approaches. In: Mindfulness-Based
2016). Yet, extant addiction treatments have often been Treatment Approaches: Clinician’s Guide to Evidence Base and
delivered within an acute care model, resulting in remission Applications. Elsevier, Boston, MA, pp. 1e27.
of symptoms during the course of treatment, followed by Baer, R.A., Smith, G.T., Hopkins, J., Krietemeyer, J., Toney, L., 2006.
successive relapses after a series of acute care episodes Using self-report assessment methods to explore facets of mindful-
(McLellan, 2002). Given that the chronically relapsing ness. Assessment 13, 27e45.
Bernstein, A., Hadash, Y., Lichtash, Y., Tanay, G., Shepherd, K.,
condition of addiction involves a process of overlearning
Fresco, D.M., 2015. Decentering and related constructs: a critical re-
(Hyman et al., 2006), it is highly plausible that mindfulness
view and metacognitive processes model. Perspect. Psychol. Sci. 10
itself must be overlearned to sustainably treat symptoms of (5), 599e617. https://doi.org/10.1177/1745691615594577.
this recalcitrant malady. Because most studies have focused Black, D.S., 2014. Mindfulness-based interventions: an antidote to
on MBIs approximately 8 weeks in duration, it is unknown suffering in the context of substance use, misuse, and addiction. Subst.
whether mindfulness is most effective when practiced Use Misuse 49 (5), 487e491. https://doi.org/10.3109/10826084.2014.
regularly over one’s lifetime to support long-term recovery 860749.
from addiction. Plausibly, long-term practice of MBIs may Bowen, S., Chawla, N., Marlatt, G.A., 2010. Mindfulness-Based Relapse
be required to produce enduring neural plasticity capable of Prevention for Addictive Behaviors. Guilford Press, New York.
counteracting neurocognitive deficits underlying addiction, Brewer, J., Judson, A., Elwafi, H., Davis, J., 2014. Craving to quit: psy-
but to answer this question doseeresponse studies are chological models and neurobiological mechanisms of mindfulness
training as treatment for addictions. Transl. Issues Psychol. Sci. 1,
needed. Future studies could also examine to what extent
70e90. S. https://doi.org/10.1037/2332-2136.1.S.70.
mindful regulatory strategies must be activated consciously
Carroll, H., Lustyk, M.K.B., 2017. Mindfulness-based relapse prevention
versus through a process of automatic self-regulation (c.f., for substance use disorders: effects on cardiac vagal control and
Mauss et al., 2007). craving under stress. Mindfulness 1e12. https://doi.org/10.1007/
Altogether, contemporary models regard addiction as s12671-017-0791-1.
largely mediated by loss of cognitive control over auto- Chan, D., Woollacott, M., 2007. T. J. Altern. Complement. Med. 13,
maticity and driven by dysregulation of hedonic brain cir- 651e657.
cuitry. This form of behavioral escalation may be especially
Droutman, V., Read, S.J., Bechara, A., 2015. Revisiting the role of the Garland, E.L., Farb, N.A., Goldin, P.R., Fredrickson, B.L., 2015. Mind-
insula in addiction. Trends Cognit. Sci. 19 (7), 414e420. https://doi. fulness broadens awareness and builds eudaimonic meaning: a process
org/10.1016/j.tics.2015.05.005. model of mindful positive emotion regulation. Psychol. Inq. 26 (4),
Fan, Y., Tang, Y.-Y., Tang, R., Posner, M.I., 2014. Short term integrative 293e314. https://doi.org/10.1080/1047840X.2015.1064294.
meditation improves resting alpha activity and stroop performance. Garland, E.L., Franken, I.H., Howard, M.O., 2012. Cue-elicited heart rate
Appl. Psychophysiol. Biofeedback 39 (3e4), 213e217. https://doi. variability and attentional bias predict alcohol relapse following
org/10.1007/s10484-014-9258-5. treatment. Psychopharmacology 222 (1), 17e26.
Farb, N.A., Segal, Z.V., Anderson, A.K., 2013. Mindfulness meditation Garland, E.L., Froeliger, B., Howard, M.O., 2014a. Effects of
training alters cortical representations of interoceptive attention. Soc. mindfulness-oriented recovery enhancement on reward responsiveness
Cognit. Affect Neurosci. 8 (1), 15e26. and opioid cue-reactivity. Psychopharmacology 231 (16),
Field, M., Cox, W.M., 2008. Attentional bias in addictive behaviors: a 3229e3238. https://doi.org/10.1007/s00213-014-3504-7.
review of its development, causes, and consequences. Drug Alcohol Garland, E.L., Froeliger, B., Howard, M.O., 2014b. Mindfulness training
Depend. 97, 1e20. targets neurocognitive mechanisms of addiction at the attention-
Fleury, M.-J., Djouini, A., Huỳnh, C., Tremblay, J., Ferland, F., Ménard, J.- appraisal-emotion interface. Front. Psychiatry 4. https://doi.org/10.
M., Belleville, G., 2016. Remission from substance use disorders: a 3389/fpsyt.2013.00173.
systematic review and meta-analysis. Drug Alcohol Depend. 168, Garland, E.L., Froeliger, B., Howard, M.O., 2014c. Neurophysiological
293e306. https://doi.org/10.1016/j.drugalcdep.2016.08.625. evidence for remediation of reward processing deficits in chronic pain
Friese, M., Messner, C., Schaffner, Y., 2012. Mindfulness meditation and opioid misuse following treatment with mindfulness-oriented
counteracts self-control depletion. Conscious. Cognit. 21 (2), recovery enhancement: exploratory ERP findings from a pilot RCT.
1016e1022. https://doi.org/10.1016/j.concog.2012.01.008. J. Behav. Med. 38 (2), 327e336. https://doi.org/10.1007/s10865-014-
Froeliger, B., Mathew, A.R., Mcconnell, P.A., Eichberg, C., Saladin, M.E., 9607-0.
Carpenter, M.J., Garland, E.L., 2017. Restructuring reward Garland, E.L., Hanley, A.W., Goldin, P.R., Gross, J.J., 2017c. Testing the
mechanisms in nicotine addiction: a pilot fMRI study of mindfulness- mindfulness-to-meaning theory: evidence for mindful positive
oriented recovery enhancement for cigarette smokers. Evid. Based emotion regulation from a reanalysis of longitudinal data. PLoS One
Complement Altern. Med. 2017. https://doi.org/10.1155/2017/ 12 (12), e0187727. https://doi.org/10.1371/journal.pone.0187727.
7018014. Garland, E.L., Howard, M.O., Zubieta, J.-K., Froeliger, B., 2017d.
Garland, E.L., 2013. Mindfulness-Oriented Recovery Enhancement for Restructuring hedonic dysregulation in chronic pain and prescription
Addiction, Stress, and Pain. NASW Press, Washington, D.C. opioid misuse: effects of mindfulness-oriented recovery enhancement
Garland, E.L., Gaylord, S.A., Boettiger, C.A., Howard, M.O., 2010. on responsiveness to drug cues and natural rewards. Psychother.
Mindfulness training modifies cognitive, affective, and physiological Psychosom. 86 (2), 111e112.
mechanisms implicated in alcohol dependence: results of a random- Garland, E.L., Roberts-Lewis, A., Kelley, K., Tronnier, C., Hanley, A.,
ized controlled pilot trial. J. Psychoact. Drugs 42 (2), 177e192. 2014. Cognitive and affective mechanisms linking trait mindfulness to
Garland, E.L., 2011. Trait mindfulness predicts attentional and autonomic craving among individuals in addiction recovery. Subst. Use Misuse
regulation of alcohol cue-reactivity. J. Psychophysiol. 25 (4), 49 (5), 525e535. https://doi.org/10.3109/10826084.2014.850309.
180e189. https://doi.org/10.1027/0269-8803/a000060. Geschwind, N., Peeters, F., Drukker, M., van Os, J., Wichers, M., 2011.
Garland, E.L., 2016. Restructuring reward processing with mindfulness- Mindfulness training increases momentary positive emotions and
oriented recovery enhancement: novel therapeutic mechanisms to reward experience in adults vulnerable to depression: a randomized
remediate hedonic dysregulation in addiction, stress, and pain. Ann. controlled trial. J. Consult. Clin. Psychol. 79 (5), 618.
N. Y. Acad. Sci. 1373 (1), 25e37. Goldberg, S.B., Tucker, R.P., Greene, P.A., Davidson, R.J.,
Garland, E.L., Baker, A.K., Howard, M.O., 2017. Mindfulness-oriented Wampold, B.E., Kearney, D.J., Simpson, T.L., 2018. Mindfulness-
recovery enhancement reduces opioid attentional bias among based interventions for psychiatric disorders: a systematic review
prescription opioid-treated chronic pain patients. J. Soc. Soc. Work. and meta-analysis. Clin. Psychol. Rev. 59, 52e60. https://doi.org/10.
Res. 8 (4), 493e509. https://doi.org/10.1086/694324. 1016/j.cpr.2017.10.011.
Garland, E.L., Boettiger, C.A., Howard, M.O., 2011. Targeting cognitive- Goyal, M., Singh, S., Sibinga, E.M., Gould, N.F., Rowland-Seymour, A.,
affective risk mechanisms in stress-precipitated alcohol dependence: Sharma, R., 2014. Meditation programs for psychological stress and
an integrated, biopsychosocial model of automaticity, allostasis, and well-being: a systematic review and meta-analysis. others JAMA
addiction. Med. Hypotheses 76 (5), 745e754. Intern. Med. 174 (3), 357e368.
Garland, E.L., Bryan, C.J., Finan, P.H., Thomas, E.A., Priddy, S.E., Greenberg, J., Reiner, K., Meiran, N., 2012. “Mind the trap”: mindfulness
Riquino, M.R., Howard, M.O., 2017b. Pain, hedonic regulation, and practice reduces cognitive rigidity. PLoS One 7 (5), e36206.
opioid misuse: modulation of momentary experience by mindfulness- Gu, J., Strauss, C., Bond, R., Cavanagh, K., 2015. How do mindfulness-
oriented recovery enhancement in opioid-treated chronic pain patients. based cognitive therapy and mindfulness-based stress reduction
Drug Alcohol Depend. 173, S65eS72. improve mental health and wellbeing? A systematic review and meta-
Garland, E.L., Bryan, M.A., Priddy, S.E., Riquino, M.R., Froeliger, B., analysis of mediation studies. Clin. Psychol. Rev. 37, 1e12. https://
Howard, M.O., 2019. Effects of mindfulness-oriented recovery doi.org/10.1016/j.cpr.2015.01.006.
enhancement versus social support on negative affective interference Hanh, T.N., 2002. Transformation and Healing: Sutra on the Four Es-
during inhibitory control among opioid-treated chronic pain patients: a tablishments of Mindfulness, second ed. Parallax Press.
pilot mechanistic study. Ann. Behav. Med.
Hanley, A., Garland, E.L., 2019. Mindfulness training disrupts Pavlovian Langer, E.J., 1992. Matters of mind: mindfulness/mindlessness in
conditioning. Physiol. Behav. 204, 151e154. https://doi.org/10.1016/ perspective. Conscious. Cognit. 1 (3), 289e305. https://doi.org/10.
j.physbeh.2019.02.028. 1016/1053-8100(92)90066-J.
Hanley, A.W., Garland, E.L., 2014. Dispositional mindfulness co-varies Lao, S.-A., Kissane, D., Meadows, G., 2016. Cognitive effects of MBSR/
with self-reported positive reappraisal. Pers. Indiv. Differ. 66, MBCT: a systematic review of neuropsychological outcomes.
146e152. Conscious. Cognit. 45, 109e123. https://doi.org/10.1016/j.concog.
Heeren, A., Van Broeck, N., Philippot, P., 2009. The effects of mindful- 2016.08.017.
ness on executive processes and autobiographical memory specificity. Li, W., Howard, M.O., Garland, E.L., McGovern, P., Lazar, M., 2017.
Behav. Res. Ther. 47 (5), 403e409. Mindfulness treatment for substance misuse: a systematic review and
Hodgins, H.S., Adair, K.C., 2010. Attentional processes and meditation. meta-analysis. J. Subst. Abus. Treat. 75, 62e96. https://doi.org/10.
Conscious. Cognit. 19 (4), 872e878. https://doi.org/10.1016/j.concog. 1016/j.jsat.2017.01.008.
2010.04.002. Lindsay, E.K., Creswell, J.D., 2017. Mechanisms of mindfulness training:
Holzman, J.B., Bridgett, D.J., 2017. Heart rate variability indices as bio- monitor and acceptance theory (MAT). Clin. Psychol. Rev. 51,
markers of top-down self-regulatory mechanisms: a meta-analytic 48e59.
review. Neurosci. Biobehav. Rev. 74, 233e255. Lundahl, B.W., Kunz, C., Brownell, C., Tollefson, D., Burke, B.L., 2010.
Hong, P.Y., Lishner, D.A., Han, K.H., 2014. Mindfulness and eating: an A meta-analysis of motivational interviewing: twenty-five years of
experiment examining the effect of mindful raisin eating on the empirical studies. Res. Soc. Work. Pract. 20 (2), 137e160. https://doi.
enjoyment of sampled food. Mindfulness 5 (1), 80e87. org/10.1177/1049731509347850.
Hong, P.Y., Lishner, D.A., Han, K.H., Huss, E.A., 2011. The positive Lutz, A., Slagter, H.A., Dunne, J.D., Davidson, R.J., 2008. Attention
impact of mindful eating on expectations of food liking. Mindfulness regulation and monitoring in meditation. Trends Cognit. Sci. 12,
2 (2), 103e113. 163e169.
Hyman, S.E., Malenka, R.C., Nestler, E.J., 2006. Neural mechanisms of Magill, M., Ray, L.A., 2009. Cognitive-behavioral treatment with adult
addiction: the role of reward-related learning and memory. Annu. Rev. alcohol and illicit drug users: a meta-analysis of randomized
Neurosci. 29 (1), 565e598. https://doi.org/10.1146/annurev.neuro.29. controlled trials. J. Stud. Alcohol Drugs 70 (4), 516e527. https://doi.
051605.113009. org/10.15288/jsad.2009.70.516.
Janssen, L.K., Duif, I., van Loon, I., de Vries, J.H.M., Speckens, A.E.M., Malinowski, P., 2013. Neural mechanisms of attentional control in
Cools, R., Aarts, E., 2018. Greater mindful eating practice is associ- mindfulness meditation. Front. Neurosci. 7. https://doi.org/10.3389/
ated with better reversal learning. Sci. Rep. 8 (1), 5702. https://doi.org/ fnins.2013.00008.
10.1038/s41598-018-24001-1. Mauss, I.B., Bunge, S.A., Gross, J.J., 2007. Automatic emotion regulation.
Jha, A.P., Krompinger, J., Baime, M.J., 2007. Mindfulness training Soc. Personal. Psychol. Compass 1 (1), 146e167.
modifies subsystems of attention. Cognit. Affect Behav. Neurosci. 7 McConnell, P.A., Froeliger, B., 2015. Mindfulness, mechanisms and
(2), 109e119. https://doi.org/10.3758/CABN.7.2.109. meaning: perspectives from the cognitive neuroscience of addiction.
Kabat-Zinn, J., 2003. Mindfulness-based interventions in context: past, Psychol. Inq. 26 (4), 349e357.
present, and future. Clin. Psychol. Sci. Pract. 10, 144e156. McLellan, A.T., 2002. Have we evaluated addiction treatment correctly?
Kabat-Zinn, J., 1990. Full Catastrophe Living. Delacorte Press, NY. Implications from a chronic care perspective. Addiction 97 (3),
Kang, Y., Gruber, J., Gray, J.R., 2013. Mindfulness and de-automatization. 249e252. https://doi.org/10.1046/j.1360-0443.2002.00127.x.
Emotion Rev. 5 (2), 192e201. https://doi.org/10.1177/ Moore, A., Malinowski, P., 2009. Meditation, mindfulness and cognitive
1754073912451629. flexibility. Conscious. Cognit. 18, 176e186.
Karyadi, K.A., VanderVeen, J.D., Cyders, M.A., 2014. A meta-analysis of Olney, J.J., Warlow, S.M., Naffziger, E.E., Berridge, K.C., 2018. Current
the relationship between trait mindfulness and substance use behav- perspectives on incentive salience and applications to clinical disor-
iors. Drug Alcohol Depend. 143 (Suppl. C), 1e10. https://doi.org/10. ders. Curr. Opin. Behav. Sci. 22, 59e69. https://doi.org/10.1016/j.
1016/j.drugalcdep.2014.07.014. cobeha.2018.01.007.
Kiken, L.G., Garland, E.L., Bluth, K., Palsson, O.S., Gaylord, S.A., 2015. Paz, R., Zvielli, A., Goldstein, P., Bernstein, A., 2017. Brief mindfulness
From a state to a trait: trajectories of state mindfulness in meditation training de-couples the anxiogenic effects of distress intolerance on
during intervention predict changes in trait mindfulness. Pers. Indiv. reactivity to and recovery from stress among deprived smokers.
Differ. 81, 41e46. https://doi.org/10.1016/j.paid.2014.12.044. Behav. Res. Ther. 95 (Suppl. C), 117e127. https://doi.org/10.1016/j.
Kjaer, T.W., Bertelsen, C., Piccini, P., Brooks, D., Alving, J., Lou, H.C., brat.2017.05.017.
2002. Increased dopamine tone during meditation-induced change of Priddy, S.E., Hanley, A.W., Riquino, M.R., Platt, K.A., Baker, A.K.,
consciousness. Cogn. Brain Res. 13 (2), 255e259. Garland, E.L., 2018. Dispositional mindfulness and prescription
Klinkenberg, I., Sambeth, A., Blokland, A., 2011. Acetylcholine and opioid misuse among chronic pain patients: craving and attention to
attention. Behav. Brain Res. 221 (2), 430e442. positive information as mediating mechanisms. Drug Alcohol Depend.
Kober, H., Brewer, J.A., Height, K.L., Sinha, R., 2017. Neural stress 188, 86e93. https://doi.org/10.1016/j.drugalcdep.2018.03.040.
reactivity relates to smoking outcomes and differentiates between Raffone, A., Srinivasan, N., 2009. An adaptive workspace hypothesis
mindfulness and cognitive-behavioral treatments. Neuroimage 1 about the neural correlates of consciousness: insights from neurosci-
(151(Suppl. C)), 4e13. ence and meditation studies. In: Srinivasan, N. (Ed.), Progress in Brain
Koob, G.F., Moal, M.L., 2008. Addiction and the brain antireward system. Research, vol. 176. Elsevier, pp. 161e180. https://doi.org/10.1016/
Annu. Rev. Psychol. 59 (1), 29e53. https://doi.org/10.1146/annurev. S0079-6123(09)17620-3.
psych.59.103006.093548. Robinson, T.E., Berridge, K.C., 1993. The neural basis of drug craving: an
Koob, G.F., Volkow, N.D., 2016. Neurobiology of addiction: a neuro- incentive-sensitization theory of addiction. Brain Res. Brain Res. Rev.
circuitry analysis. Lancet Psychiatry 3 (8), 760e773. https://doi.org/ 18 (3), 247e291.
10.1016/S2215-0366(16)00104-8.
Robinson, T.E., Berridge, K.C., 2008. Review. The incentive sensitization Taren, A.A., Gianaros, P.J., Greco, C.M., Lindsay, E.K., Fairgrieve, A.,
theory of addiction: some current issues. Philos. Trans. R. Soc. Lond. Brown, K.W., et al., 2015. Mindfulness meditation training alters
B Biol. Sci. 363, 3137e3146. stress-related amygdala resting state functional connectivity: a ran-
Sahdra, B., Maclean, K., Ferrer, E., Shaver, P., Rosenberg, E., Jacobs, T., domized controlled trial. Soc. Cognit. Affect Neurosci. 10 (12),
et al., 2011. Enhanced response inhibition during intensive meditation 1758e1768. https://doi.org/10.1093/scan/nsv066.
training predicts improvements in self-reported adaptive socioemo- Taren, A.A., Gianaros, P.J., Greco, C.M., Lindsay, E.K., Fairgrieve, A.,
tional functioning. Emotion (Washington, D.C.) 11, 299e312. https:// Brown, K.W., et al., 2017. Mindfulness meditation training and ex-
doi.org/10.1037/a0022764. ecutive control network resting state functional connectivity: a ran-
Schoenberg, P.L.A., Hepark, S., Kan, C.C., Barendregt, H.P., domized controlled trial. Psychosom. Med. 79 (6), 674e683. https://
Buitelaar, J.K., Speckens, A.E.M., 2014. Effects of mindfulness-based doi.org/10.1097/PSY.0000000000000466.
cognitive therapy on neurophysiological correlates of performance Teasdale, J.D., 1999. Metacognition, mindfulness, and the modification of
monitoring in adult attention-deficit/hyperactivity disorder. Clin. mood disorders. Clin. Psychol. Psychother. 6, 146e155.
Neurophysiol. 125 (7), 1407e1416. https://doi.org/10.1016/j.clinph. Thayer, J.F., Lane, R.D., 2000. A model of neurovisceral integration in
2013.11.031. emotion regulation and dysregulation. J. Affect. Disord. 61, 201e216.
Segal, Z., Williams, J.M., Teasdale, J.D., 2002. Mindfulness-Based Tiffany, S.T., 1990. A cognitive model of drug urges and drug-use
Cognitive Therapy for Depression. The Guilford Press, New York. behavior: role of automatic and nonautomatic processes. Psychol.
Sevinc, G., Holzel, B., Hashmi, J., Greenberg, J., McCallister, A., Rev. 97, 147e168.
Treadway, M., et al., 2018. Common and dissociable neural activity Tomasino, B., Fabbro, F., 2016. Increases in the right dorsolateral pre-
following mindfulness-based stress reduction and relaxation response frontal cortex and decreases the rostral prefrontal cortex activation
programs. Psychosom. Med. 1. https://doi.org/10.1097/PSY. after-8 weeks of focused attention based mindfulness meditation.
0000000000000590. Brain Cogn. 102, 46e54. https://doi.org/10.1016/j.bandc.2015.12.
Singer, B.F., Fadanelli, M., Kawa, A.B., Robinson, T.E., 2018. Are 004.
cocaine-seeking “habits” necessary for the development of addiction- Tsai, M.-H., Chou, W.-L., 2016. Attentional orienting and executive
like behavior in rats? J. Neurosci. 38 (1), 60e73, 2458e17. https:// control are affected by different types of meditation practice.
doi.org/10.1523/JNEUROSCI.2458-17.2017. Conscious. Cognit. 46, 110e126. https://doi.org/10.1016/j.concog.
Sinha, R., Talih, M., Malison, R., Cooney, N., Anderson, G., Jeanne 2016.09.020.
Kreek, M., 2003. Hypothalamic-pituitary-adrenal axis and sympatho- Vago, D.R., Silbersweig, D.A., 2012. Self-awareness, self-regulation, and
adreno-medullary responses during stress-induced and drug cue- self-transcendence (S-ART): a framework for understanding the
induced cocaine craving states. Psychopharmacology 170, 62e72. neurobiological mechanisms of mindfulness. Front. Hum. Neurosci. 6.
https://doi.org/10.1007/s00213-003-1525-8. Retrieved from. https://www.ncbi.nlm.nih.gov/pmc/articles/
Slagter, H.A., Lutz, A., Greischar, L.L., Francis, A.D., Nieuwenhuis, S., PMC3480633/.
Davis, J.M., Davidson, R.J., 2007. Mental training affects distribution Wenk-Sormaz, H., 2005. Meditation can reduce habitual responding.
of limited brain resources. PLoS Biol. 5, e138. Altern. Ther. Health Med. 11, 42e58.
Soler, J., Elices, M., Pascual, J.C., Martin-Blanco, A., Feliu-Soler, A., Westbrook, C., Creswell, J.D., Tabibnia, G., Julson, E., Kober, H.,
Carmona, C., Portella, M.J., 2016. Effects of Mindfulness Training on Tindle, H.A., 2011. Mindful attention reduces neural and self-reported
Different Components of Impulsivity in Borderline Personality Dis- cue-induced craving in smokers. Soc. Cognit. Affect Neurosci. 8 (1),
order: Results from a Pilot Randomized Study. Borderline Personality 73e84.
Disorder and Emotion Dysregulation; London, vol. 3. Retrieved from. Whitmarsh, S., Uddén, J., Barendregt, H., Petersson, K.M., 2013. Mind-
http://search.proquest.com/docview/1767700696/abstract/ fulness reduces habitual responding based on implicit knowledge:
DEAE59DCE9224444PQ/1. evidence from artificial grammar learning. Conscious. Cognit. 22 (3),
Stevens, L., Verdejo-García, A., Goudriaan, A.E., Roeyers, H., Dom, G., 833e845. https://doi.org/10.1016/j.concog.2013.05.007.
Vanderplasschen, W., 2014. Impulsivity as a vulnerability factor for Xie, C., Li, S.-J., Shao, Y., Fu, L., Goveas, J., Ye, E., et al., 2011. Iden-
poor addiction treatment outcomes: a review of neurocognitive find- tification of hyperactive intrinsic amygdala network connectivity
ings among individuals with substance use disorders. J. Subst. Abus. associated with impulsivity in abstinent heroin addicts. Behav. Brain
Treat. 47 (1), 58e72. https://doi.org/10.1016/j.jsat.2014.01.008. Res. 216 (2), 639e646. https://doi.org/10.1016/j.bbr.2010.09.004.
Tang, Y.-Y., Hölzel, B.K., Posner, M.I., 2015. The neuroscience of Xue, S., Tang, Y.-Y., Posner, M.I., 2011. Short-term meditation increases
mindfulness meditation. Nat. Rev. Neurosci. 16 (4), 213e225. network efficiency of the anterior cingulate cortex. Neuroreport 22
Tang, Y.-Y., Lu, Q., Fan, M., Yang, Y., Posner, M.I., 2012. Mechanisms (12), 570. https://doi.org/10.1097/WNR.0b013e328348c750.
of white matter changes induced by meditation. Proc. Natl. Acad. Sci. Zanesco, A.P., King, B.G., MacLean, K.A., Saron, C.D., 2018. Cognitive
U.S.A. 109 (26), 10570e10574. aging and long-term maintenance of attentional improvements
Tang, Y.-Y., Lu, Q., Geng, X., Stein, E.A., Yang, Y., Posner, M.I., 2010. following meditation training. J. Cognit. Enhanc. 1e17. https://doi.
Short-term meditation induces white matter changes in the anterior org/10.1007/s41465-018-0068-1.
cingulate. Proc. Natl. Acad. Sci. U.S.A. 107 (35), 15649e15652. Zeidan, F., Johnson, S.K., Diamond, B.J., David, Z., Goolkasian, P., 2010.
Tang, Y.-Y., Tang, R., Posner, M.I., 2016. Mindfulness meditation im- Mindfulness meditation improves cognition: evidence of brief mental
proves emotion regulation and reduces drug abuse. Drug Alcohol training. Conscious. Cognit. 19 (2), 597e605.
Depend. 163, S13eS18. https://doi.org/10.1016/j.drugalcdep.2015.11.
041.
Chapter 22
Brain stimulation as an emerging

treatment for addiction
Colleen A. Hanlon, Logan T. Dowdle, Daniel H. Lench and Tonisha Kearney Ramos
Department of Psychiatry and Behavioral Sciences, College of Medicine, Medical University of South Carolina. Charleston, SC, United States of
America
Noninvasive modulation of neural that optogenetics or designer receptors allow in preclinical

research.
circuitry in humans
Through decades of preclinical research, it is now well- Moving to the clinic
understood that drug-taking behavior can be modulated by
altering activity in frontal-striatal circuits. Additionally, The earliest treatments for addiction were behavioral
altered functional and structural integrity in these circuits has interventions, many of which are still used frequently
been related to substance abuse chronicity and resilience to including contingency management and cognitive behav-
relapse. The challenge now is to translate these basic science ioral therapy (CBT). Many of these interventions are
discoveries into a safe and effective treatment for our discussed in other chapters of this book. To date, there are no
patients. This chapter will introduce transcranial magnetic FDA-approved pharmacological treatments for either
stimulation (TMS) as a noninvasive brain stimulation tool cocaine or methamphetamine; however, some studies have
that is currently being used to advance therapeutic options shown modest reductions in substance use. In this section,
for patients with various substance use disorders. we will discuss a growing new domain of research in
addiction, which is utilizing TMS as a tool to decrease drug
use and associated behaviors (e.g., craving) through long-
Preclinical foundation
term potentiation (LTP) and/or depression of the frontal-
Through direct cortical stimulation and optogenetic stimu- striatal circuits, which have been discussed in the previous
lation, it is possible to change drug self-administration in a sections. Although this line of research is still in its infancy,
causal manner (Bass et al., 2013; Cassataro et al., 2014). the development of innovative, biologically based brain
The prefrontal cortex in rodents is typically divided into an stimulation therapies for substance dependence is among the
infralimbic and a prelimbic domain. The infralimbic cortex best examples of translating decades of functional neuro-
is functionally and anatomically similar to the ventral imaging research into a clinically meaningful treatment.
medial prefrontal cortex (PFC) (also referred to as the
orbitomedial prefrontal cortex) in primates (Barbas, 1995; What is transcranial magnetic stimulation?
Barbas, 2000; Groenewegen and Uylings, 2000), whereas
the prelimbic cortex is functionally similar to more dorsal The majority of our knowledge regarding the basic elec-
and lateral aspects of the human prefrontal cortex (Vertes, trophysiological effects of TMS on the brain is from
2004). Optogenetic stimulation of these areas can alter studies in the motor system. When applied over the hand
cocaine seeking in a direction-specific manner (Chen et al., areas of the primary motor cortex, a single pulse of TMS
2013; Stefanik et al., 2013). These data provide a founda- induces a contraction of the contralateral hand. The
tion for developing a brain stimulation intervention in strength of this contraction (e.g., motor evoked potential
clinical populations. Until recently, however, we have not [MEP]) is dose-dependently related to the strength of the
had the ability to selectively modulate limbic or executive induced electrical field (Barker et al., 1986). The MEP can
control circuits in human clinical research in the manner be manipulated by pharmaceutical agents that effect

glutamate and voltage-gated sodium channels (DiLazzarro circuit, repetitive pulses of TMS can be used to induce LTP
et al., 2008; Ziemann and Rothwell, 2000). Nearly 70% of or long-term depression (LTD) in a given neural region as
the variance in motor threshold (defined as the minimum well as its monosynaptic afferents (Denslow et al., 2005;
TMS intensity required to generate an MEP on 50% of the Bestmann et al., 2004; Nahas et al., 2001; Bohning et al.,
trials) is accounted for by variability in scalp to cortex 2000). An LTD-like effect can be achieved through TMS
distance. The effects of a single TMS pulse decay expo- by either using a low-frequency stimulation (typically
nentially with distance and are spatially restricted to 1 Hz) or through a bursting frequency, such as continuous
cortical areas directly exposed to the TMS-induced field theta burst (Huang et al., 2005). In preclinical literature,
(typically 2e4 cm from the center of the coil). When the theta burst stimulation is a well-known form of electrical
depolarizing current from TMS is strong enough, how- stimulation which can induce LTP or LTD of synaptic
ever, it leads to a cascade of neurotransmitter release, activity in a given brain region (Malenka and Bear, 2004;
excitatory postsynaptic synaptic potentials, and eventually Bear and Malenka, 1994). Human theta burst stimulation
action potentials in neurons receiving monosynaptic protocols use repetitive transcranial magnetic stimulation
inputs from the neurons depolarized by the TMS pulse. (rTMS) to induce similar forms of LTP and LTD by using
This polysynaptic modulation via TMS underscores its intermittent or continuous bursts, respectively (Huang
utility as a tool to modulate frontal-striatal circuits in sub- et al., 2005; Di Lazzaro et al., 2005). With continuous theta
stance use disorder patients. This has been documented burst stimulation (cTBS), bursts of three pulses at 50 Hz are
using interleaved TMS/BOLD imaging, wherein a single applied at a frequency of 5 Hz at amplitude that is typically
pulse of TMS induces an elevation in the blood oxygen determined by the active motor threshold. When performed
leveledependent (BOLD) signal in the vicinity of the TMS over the primary motor cortex, a lower amplitude of cTBS
coil and in monosynaptic target regions (Bohning et al., for 40 s leads to an attenuation of motor-evoked potentials
1998). The amplitude of the BOLD signal induced by a that is comparable to a higher amplitude to 1Hz single-
single pulse of TMS to the primary motor cortex is similar frequency stimulation for 20 min. Stagg and colleagues
to the amplitude of the BOLD signal induced by an have demonstrated that this attenuating effect of cTBS is
intentional contraction (Denslow et al., 2005). likely due to an increase in g-aminobutyric acid (GABA) at
From the perspective of addiction, it is possible to the area of stimulation (Stagg et al., 2009) rather than a
differentially activate frontostriatal circuits involved in change in glutamate.
limbic control from those involved in executive control The use of rTMS to modulate neural circuits will be the
through stimulating the MPFC and dorsolateral prefrontal topic of the remainder of this article, as that it is the tech-
cortex (DLPFC), respectively (Hanlon et al., 2013). nique most likely to induce a sustainable change in neural
Cocaine users, for example, have a lower ventral striatal circuitry of substance-dependent individuals.
BOLD response to MPFC stimulation than healthy controls
(Hanlon et al., 2016). In this study, TMS was applied to the
MPFC (Brodmann area [BA] 10) and the DLPFC (lateral
Applications to substance use disorders
BA 9) of 36 individualsd18 cocaine-dependent individuals The potential of rTMS as a new tool for modulating craving
with a history of failed quit attempts and 18 age-matched among substance-dependent populations has garnered sig-
controls. Cocaine users had a lower ventral striatal BOLD nificant attention in the literature (see reviews: Bellamoli
response to MPFC stimulation but no difference in dorsal et al., 2014, Gorelick et al., 2014, Wing et al., 2013, Barr
striatal response to DLPFC stimulation. Among controls, et al., 2011). As this field develops, the primary questions
DLPFC stimulation led to a reciprocal attenuation of MPFC will likely be as follows: (1) what cortical location should
activity (BA 10), but this pattern did not exist in cocaine we target to maximally affect the circuitry we are interested
users. No relationship was found between regional diffu- in changing? and (2) what stimulation frequency should we
sion metrics and functional activity. Considered together, choose? There will likely not be a single “optimal” protocol
these data suggest that, when engaged, cocaine users can for all individuals or all classes of drugs. For example,
mobilize their executive control system similar to controls some individuals may benefit the most of a treatment
but that the “set point” for mobilizing their limbic arousal strategy that amplifies their executive control circuitry
system has been elevated; an interpretation consistent with (e.g., 10 Hz DLPFC stimulation), while others may benefit
opponent process theories of addiction. the most from a strategy that attenuates limbic circuitry
involved in drug craving (e.g., 1 Hz medial prefrontal/
Using repetitive transcranial magnetic frontal pole stimulation). Before moving forward with
expensive and slow multisite clinical trials investigating the
stimulation to modulate cortical-striatal
efficacy of rTMS as a viable treatment tool for addiction,
connectivity
however, it is useful to explore these combinations of fre-
While single pulses of TMS coupled with neuroimaging quencies and cortical targets to maximize our potential
provide a controlled method to probe function in a neural impact on the patients.
Brain stimulation as an emerging treatment for addiction Chapter | 22 297
To date, nearly all of the rTMS studies in addiction have largest TMS addiction clinical trial to date, delivering 13
targeted the same neural regiondthe DLPFC (Eichhammer sessions to 115 subjects. They found that high-frequency
et al., 2003; Li et al., 2013a,b; Pripfl et al., 2014; Herremans stimulation, delivered the lateral prefrontal cortex and
et al., 2012; Hoppner et al., 2011; Mishra et al., 2010; insula, was effective at reducing the number of cigarettes
Camprodon et al., 2007; Politi et al., 2008). While many of smoked. Additionally, this effect was larger in the group
these studies demonstrated that high-frequency (LTP-like) randomized to have cue exposure before stimulation ses-
rTMS stimulation to the DLPFC can result in a significant sions (Dinur-Klein et al., 2014). This cue exposure repre-
reduction of craving, the neurobiological mechanism through sents one method of context- or state-dependent
which this might happen is not clear. In a comprehensive modification of treatment effectiveness. Put simply, it may
review of the literature on the efficacy of rTMS as a treatment be easier to modify an active or engaged circuit. While
tool for smoking, Wing and colleagues (Wing et al., 2013) Dinur-Klein used cue exposure, this idea can easily be
present a model in which the beneficial effects of LTP-like extended into many other paradigms. One alternative
TMS on the DLPFC are associated with a release of dopa- possibility to be discussed in further detail in Applications
mine in the nucleus accumbens. This model is supported by to substance use disorders section is the engagement of
important work from Strafella and colleagues which used executive control circuitry. Briefly, Sheffer and colleagues
positron emission tomography to demonstrate that DLPFC combined eight sessions of self-help therapy with active or
stimulation was associated with an increase in dopamine sham rTMS, finding that the combination of active rTMS
binding in the caudate (Strafella et al., 2001). and therapy was better than therapy alone, leading to
The primary cortical inputs to the nucleus accumbens, greater smoking abstinence (Sheffer et al., 2018).
however, are the medial and orbital prefrontal cortices, not
the DLPFC. Given that the nucleus accumbens is one of the Application to alcohol
primary brain regions involved in craving, it seems that
targeting the MPFC would be a more direct method to The number of completed studies in the field of alcohol
modulate nucleus accumbens activity among substance- addiction is similar to that of nicotine, with 10 studies currently
dependent populations. Given that craving for cocaine is published. Seven of these studies have used high-frequency
associated with an increase in dopamine in the striatum, it is stimulation at the DLPFC, though most have targeted the
reasonable to pursue an LTD-like rTMS protocol over the right side, rather than the left. This is likely based on an early
MPFC to attenuate activity in this neural circuit. Prior data and promising study which found reductions in craving
from our laboratory demonstrates that a single pulse of compared to sham, after 10 sessions of active 10 Hz stimu-
TMS to the MPFC in healthy individuals leads to an lation (Mishra et al., 2010). Unlike early nicotine work,
increase in BOLD signal in the ventral striatum (Hanlon reductions in craving were not found after a single session
et al., 2013). Recent extension of that work to cocaine- (Herremans et al., 2012), though this does not invalidate the
dependent population demonstrated that the cocaine users use of rTMS in alcohol. For example, despite Class I evidence
have a hyperactive BOLD response in the dorsal and for the treatment of depression, a single session of rTMS likely
ventral striatum relative to controls (Hanlon et al., 2016). has no effect on mood (Remue et al., 2016). For the left
This elevated ventral striatal sensitivity following MPFC DLPFC, an additional study failed to find an effect of 10
stimulation, a frontostriatal circuit involved in the limbic sessions of 20 Hz stimulation on craving (Hoppner et al.,
aspects of craving, may be a prime circuit to attenuate these 2011). The diversity of these studies brings to the forefront the
individuals vulnerability to drug-related cues. number of choices that are available to a TMS researcher.
While we will discuss alternative TMS targets at a later point,
the investigator must also decide on the specific frequency or
Applications to smoking
pattern of stimulation, the number of sessions, simultaneous
Since 2003, 12 studies have investigated rTMS and ciga- task (if any), and specific outcome of interest, just to name a
rette smoking. All but one of these studies exclusively used few. The importance of this last component is shown by a
high-frequency stimulation (10e20 Hz), with most recent study which found that changes in cue reactivity depend
choosing the conventional left hemisphere as the target for on the level of cue reactivity before the delivery of rTMS, that
stimulation. Early results were somewhat mixed, finding is, there were rate-dependent effects (Herremans et al., 2016).
that a single session of high-frequency left DLPFC stimu- The alcohol literature supports the need of delivering multiple
lation reduced smoking, but not craving (Eichhammer rTMS sessions for larger, measurable effects.
et al., 2003), while another study found that it was effective
in reducing craving (Li et al., 2013a). Following the pub- Application to cocaine
lication of a study that suggested that 10 sessions were
sufficient to alter both craving and consumption (Amiaz There have been eight reports of the effectiveness of rTMS
et al., 2009), Dinur-Klein and colleagues reported the for cocaine use disorder; of these, half targeted the DLPFC
with high-frequency stimulation. The earliest report found bulimia nervosa. Many case reports, some occurring inci-
that right but not left high-frequency stimulation of the dentally during rTMS for depression, were encouraging,
DLPFC was able to transiently reduce craving (Camprodon finding that rTMS reduced bingeing and purging (Hausmann
et al., 2007). Latter work exploring more sessions matched et al., 2004; Downar et al., 2012; McClelland et al., 2013).
common depression protocols and targeted the left DLPFC. There were also pilot studies that found reduced food craving
The most recent example of this, from 2016, found that after a single session (Van den Eynde et al., 2010), although
eight sessions of rTMS were more effective that treatment well-matched sham stimulation had similar effects (Barth
as usual (pharmacotherapy), with the rTMS group having a et al., 2011). Recent larger randomized trials have also failed to
higher number of cocaine-free urine drug screens (Terraneo find these positive effects (McClelland et al., 2016; Gay et al.,
et al., 2016). This finding builds on earlier work, which 2016).
reported that cocaine craving reduced over 10 sessions of The development of rTMS for pathological gambling
rTMS (Politi et al., 2008). While these two studies support has followed a similar trajectory. Early studies found that
the use of high-frequency left DLPFC stimulation as a the DLPFC may be a reasonable target, with 1Hz stimu-
promising target, there is still a need for larger sham- lation, often thought of as decreasing circuit activity,
controlled studies to confirm these preliminary findings. increasing risk-taking behavior (Knoch et al., 2006). One
sham-controlled crossover study found that 10 Hz stimu-
Application to other substance using lation at the left DLPFC was able to reduce gambling cue-
induced craving (Gay et al., 2017). This is in contrast to
populations
more recent work using 1 Hz stimulation at the right
For other substances of abuse, such as opiates (including DLPFC, which found reductions in craving from both
heroin), methamphetamine, and marijuana, there has been active and sham stimulation (Sauvaget et al., 2018).
limited research on the effectiveness of rTMS. Opiates may As with other conditions, it is important to consider that
be the most promising target, as there is growing evidence these behavioral addictions are heterogenous, and in many
that DLPFC stimulation is able to reduce pain (Taylor et al., of these studies, the sample sizes remain relatively small.
2013; Brighina et al., 2011; Borckardt et al., 2007; As is the case in substance use disorders, there is a need for
Borckardt et al., 2008), which can lead to the initiation or further research to determine the optimal target and stim-
maintenance of opiate use disorders. Currently, there is ulation frequency.
only one published research study examining rTMS for
heroin use, finding that a single session of high-frequency
stimulation was able to reduce cue-induced craving in
Integration of neuromodulation with
heroin users Shen and Cao (Shen et al., 2016). It is cognitive and pharmacotherapies
important to note that is likely to change rapidly, as there
Repetitive transcranial magnetic stimulation
are a number of ongoing trials in the United States based on
with cognitive therapy
the studies registered in clinicaltrials.gov.
For marijuana, there is evidence that rTMS can be safely In the first applications of rTMS for neuropsychiatric dis-
delivered to this population, but in the sample studied there orders, treatment was performed at rest and in the absence
were no significant changes in craving, relative to sham of other forms of intervention (Tsagaris et al., 2016; George
(Sahlem et al., 2018). Among those with methamphetamine et al., 2010). Today, an increasing interest in how to
use disorder, there is currently no consensus on the most improve the therapeutic effects of rTMS is being explored.
effective treatment. Early work found that 1 Hz stimulation of The principle that a neural circuit is more “plastic” or
the DLPFC increased cue-induced craving (Li et al., 2013b), primed when it is engaged during stimulation has offered
though another group found that both 10 and 1 Hz reduced the field of rTMS a potential solution to increase treatment
craving (Liu et al., 2017). Of these, 10 Hz stimulation, as in efficacy and even durability (Vedeniapin et al., 2010). In
other substance use disorders, appears to be the most prom- clinical depression and posttraumatic stress disorder
ising. Recently, five sessions of 10 Hz DLPFC stimulation studies, combining modified CBT protocols with high-
reduced methamphetamine cue-induced craving relative to frequency DLPFC stimulation has shown both feasibility
sham (Su et al., 2017). and promise (Donse et al., 2018; Vedeniapin et al., 2010;
Kozel et al., 2018). Combined rTMS and behavioral ther-
Application to compulsive eating and gambling apy is now in the early stages of being evaluated in
addiction and substance abuse disorders (Sheffer et al.,
In parallel with the increasing application of rTMS to sub- 2018). Independently, CBT has developed as a therapeutic
stance use disorders, other groups have explored rTMS as a approach to prevent relapse in drug abuse and addiction by
tool to treat other disorders. Among eating disorders, having patients identify and correct problematic behaviors.
researchers have sought to use rTMS for both anorexia and This form of therapy has been shown to be effective for
alcohol use disorder, marijuana-dependent, and cocaine- has been shown to enhance PAS-LTP, as has acute nicotine
dependent individuals (Carroll and Onken, 2005). Cogni- (Thirugnanasambandam et al., 2011).
tive therapies such as CBT engage executive and inhibitory While the preceding paragraph related possible bene-
control circuitry, which includes brain regions like the fits, there is also a note of caution. Commonly used
DLPFC and anterior cingulate cortex (Beauregard, 2014). medications that antagonize NMDA receptors, such as
Although several other behavioral interventions have been dextromethorphan (Liebetanz et al., 2002; Nitsche et al.,
explored for substance use disorders, cognitive therapies 2003), or have GABAergic effects such as diazepam
are unique in their ability to enhance the engagement of (Heidegger et al., 2010) and baclofen (McDonnell et al.,
these networks, which are also being explored as rTMS tar- 2007) may block LTP- or LTD-like effects. Still other
gets (Hanlon et al., 2015). In a study of smoking relapse drugs, such as D-cycloserine, may reverse the direction of
prevention, participants were given eight FF (Forever Free) plasticity in an rTMS protocol (Teo et al., 2007).
relapse prevention booklets to read during and between Thus far, no studies have combined standard rTMS
sessions of 20Hz DLPFC stimulation (Sheffer et al., 2018). protocols, such as 10 Hz stimulation, with an unrelated
Results showed that this combined evidence-based self-help pharmacological agent to affect behavioral changes in a
and rTMS treatment can significantly increase abstinence clinical population. It is clear, however, that the effects of
rates and reduce relapse. One question that remains to be rTMS protocols can also be altered by concurrent drug
answered in studies combining cognitive therapies with administration. For example, both lorazepam, a GABA
rTMS treatment is the impact of their temporal relationship. facilitator, and dextromethorphan can attenuate the effects
The timing of the therapies can be delivered concurrently, of 1 Hz stimulation (Fitzgerald et al., 2005). Findings such
sequentially, or interleaved, although a consensus on the as this highlight both the promise of combinatorial thera-
best ordering is yet to be determined (Huerta and Volpe, pies and the importance of considering the pharmacological
2009). history of patients-seeking treatment. It is critical that the
fields extend these results beyond the motor system and
Repetitive transcranial magnetic stimulation seek out treatments that combine the systemic and powerful
and pharmacotherapy effects of pharmacological agents with the specificity of
TMS in a beneficial way.
A full discussion of this can be found in a recent manuscript
in Pharmacological Reviews (Hanlon et al., 2018), but we
will highlight a few components of the idea here. Much of Summary
the promise of rTMS stems from characterization as a Selective modulation of frontal-striatal circuits involved in
circuit-based tool, in contrast to the effective but systemic limbic and executive control may be an innovative and
nature of pharmacological agents. Furthermore, rTMS is useful treatment strategy to prevent cue-associated relapse
being developed as a treatment specifically for disorders in substance-dependent individuals. rTMS is an FDA-
with no FDA-approved medications. Despite this posture, approved treatment for depression and is growing in clin-
there may be untapped potential in the combination of these ical use and acceptance, with >700 machines in the United
tools. Blending the circuit-specific effects of TMS with the States and emerging insurance reimbursement. As the field
historical knowledge of pharmacological agents may lead of addiction moves forward with pursuing rTMS as a new
to larger or more durable effects on plasticity in the circuit tool to modulate craving and the frontal-striatal circuits that
of interest. contribute to chronic use and relapse, it will be important to
While much of this chapter focused on standard rTMS consider the optimal site, frequency, and patient population
protocols, in the study of pharmacological TMS, the bulk of to target. The data presented in this chapter demonstrate
the findings have been derived from other methods. A that while most of the efforts for rTMS in addiction have
common technique used in pharmacological TMS studies been focused on increasing activity in the DLPFC,
to induce plasticity changes involves pairing a peripheral decreasing activity in the MPFC and ventral striatum may
stimulation (a paired associative stimulus [PAS]) at the also be a feasible and fruitful target to consider. It seems
median nerve of the arm with a TMS pulse to the contra- plausible that either increasing neural firing in the executive
lateral M1 region. If the median nerve stimulus is paired control circuit (perhaps via high-frequency TMS in the
with a 10-ms delay, subsequent TMS-induced MEPs are DLPFC) or decreasing firing in the limbic circuit in
reduced. This effect is known as PAS-LTD (Wolters et al., the presence of cues (perhaps via low-frequency TMS in
2003). In contrast, a 25-ms delay leads to larger MEPs, a the MPFC) may be valuable strategies for decreasing
method known as PAS-LTP (Stefan et al., 2000). These vulnerability to drug-related cues among our patients.
techniques can be used to measure plasticity changes and Before moving forward with slow and expensive clinical
provide insight into the mechanisms that underlie rTMS trials, however, it is important to have a comprehensive
outcomes. For example, amphetamine (Nitsche et al., 2004) understanding of limbic and executive circuit functioning
in a diverse cross section of substance-dependent in- Bestmann, S., et al., 2004. Functional MRI of the immediate impact of
dividuals. With this knowledge we will be able to develop transcranial magnetic stimulation on cortical and subcortical motor
circuit-specific treatment strategies for these populations. circuits. Eur. J. Neurosci. 19 (7), 1950e1962.
Bellamoli, E., Manganotti, P., Schwartz, R.P., Rimondo, C., Gomma, M.,
Before pursuing large expensive clinical trials of DLPFC
Serpelloni, G., 2014. rTMS in the treatment of drug addiction: an
stimulation or MPFC stimulation as a potential treatment
update about human studies. BehavNeurol 2014, 815215. https://
adjuvant to CBT among substance-dependent individuals, doi.org/10.1155/2014/815215. Epub 2014 Jan 23. Review.PubMed
however, it is critical to determine whether it is tolerable, is PMID: 24803733; PubMed Central PMCID: PMC4006612.
feasible, effects craving, and improves outcomes to Bohning, D.E., et al., 1998. Echoplanar BOLD fMRI of brain activation
treatment-engaged individuals. induced by concurrent transcranial magnetic stimulation. Investig.
In summary, this chapter hopes to have planted several Radiol. 33 (6), 336e340.
seeds in the reader’s mind regarding the utility of dopa- Bohning, D.E., et al., 2000. BOLD-f MRI response to single-pulse
minergic frontal-striatal systems as useful targets for TMS transcranial magnetic stimulation (TMS). J. Magn. Reson. Imaging
treatment development. Many of the challenges facing 11 (6), 569e574.
development of efficacious pharmacotherapies for sub- Borckardt, J.J., et al., 2007. Fifteen minutes of left prefrontal repetitive
transcranial magnetic stimulation acutely increases thermal pain
stance dependence could be ameliorated by delivering the
thresholds in healthy adults. Pain Res. Manag. 12 (4), 287e290.
drugs to specific neural circuits in a functionally relevant
Borckardt, J.J., et al., 2008. Significant analgesic effects of one session of
manner. Through the continued refinement of noninvasive postoperative left prefrontal cortex repetitive transcranial magnetic
brain stimulation as a tool to modulate neural circuits, in the stimulation: a replication study. Brain Stimul. 1 (2), 122e127.
next decade, we will be rigorously evaluating these tools to Brighina, F., et al., 2011. Modulation of pain perception by transcranial
enhance and refine pharmacotherapeutic development for magnetic stimulation of left prefrontal cortex. J. Headache Pain 12 (2),
neurologic and psychiatric disorders, including substance 185e191.
use disorder. Camprodon, J.A., et al., 2007. One session of high frequency repetitive
transcranial magnetic stimulation (rTMS) to the right prefrontal cortex
transiently reduces cocaine craving. Drug Alcohol Depend. 86 (1),
References 91e94.
Amiaz, R., et al., 2009. Repeated high-frequency transcranial magnetic Carroll, K.M., Onken, L.S., 2005. Behavioral therapies for drug abuse.
stimulation over the dorsolateral prefrontal cortex reduces cigarette Am. J. Psychiatry 162 (8), 1452e1460.
craving and consumption. Addiction 104 (4), 653e660. Cassataro, D., Bergfeldt, D., Malekian, C., Van Snellenberg, J.X.,
Barbas, H., 1995 Mar-Apr. Pattern in the cortical distribution of prefrontally Thanos, P.K., FishellG, Sjulson, L., 2014 Jan. Reverse pharmacoge-
directedneurons with divergent axons in the rhesus monkey. Cereb netic modulation of the nucleus accumbens reducesethanol con-
Cortex 5 (2), 158e165. PubMed PMID: 7620292. sumption in a limited access paradigm. Neuropsychopharmacology 39
Barbas, H., 2000. Complementary roles of prefrontal cortical regions in (2), 283e290. https://doi.org/10.1038/npp.2013.184. Epub 2013 Aug
cognition,memory, and emotion in primates. Adv Neurol 84, 87e110. 1. PubMed PMID:23903031; PubMed Central PMCID:
Review. PubMed PMID:11091860. PMC3870771.
Barker, A.T., et al., 1986. Clinical evaluation of conduction time mea- Chen, B.T., Yau, H.J., Hatch, C., Kusumoto-Yoshida, I., Cho, S.L.,
surements in central motor pathways using magnetic stimulation of Hopf, F.W., Bonci, A., 2013 Apr 18. Rescuing cocaine-induced pre-
human brain. Lancet 1 (8493), 1325e1326. frontal cortex hypoactivity prevents compulsivecocaine seeking.
Barr, M.S., Farzan, F., Wing, V.C., George, T.P., Fitzgerald, P.B., Nature 496 (7445), 359e362. https://doi.org/10.1038/nature12024.
Daskalakis, Z.J., 2011 Oct. Repetitive transcranial magnetic stimulation Epub 2013 Apr 3. PubMed PMID: 23552889.
and drug addiction. Int RevPsychiatry 23 (5), 454e466. https://doi.org/ Denslow, S., et al., 2005. Cortical and subcortical brain effects of trans-
10.3109/09540261.2011.618827. Review. PubMed PMID: 22200135. cranial magnetic stimulation (TMS)-induced movement: an inter-
Barth, K.S., et al., 2011. Food cravings and the effects of left prefrontal leaved TMS/functional magnetic resonance imaging study. Biol.
repetitive transcranial magnetic stimulation using an improved sham Psychiatry 57 (7), 752e760.
condition. Front. Psychiatry 2, 9. Di Lazzaro, V., et al., 2005. Theta-burst repetitive transcranial magnetic
Bass, C.E., Grinevich, V.P., Gioia, D., Day-Brown, J.D., Bonin, K.D., stimulation suppresses specific excitatory circuits in the human motor
Stuber, G.D., Weiner, J.L., Budygin, E.A., 2013 Nov 26. Optogenetic cortex. J. Physiol. 565 (Pt 3), 945e950.
stimulation of VTA dopamine neurons reveals that tonicbut not phasic Di Lazzaro, V., Ziemann, U., Lemon, R.N., 2008 Oct. State of the art:
patterns of dopamine transmission reduce ethanolself-administration. Physiology oftranscranial motor cortex stimulation. Brain Stimul 1
Front Behav Neurosci 7, 173. https://doi.org/10.3389/ (4), 345e362. https://doi.org/10.1016/j.brs.2008.07.004. Epub 2008
fnbeh.2013.00173 eCollection 2013. PubMed PMID: 24324415; Oct 7. Review PubMed PMID: 20633393.
PubMed CentralPMCID: PMC3840465. Dinur-Klein, L., et al., 2014. Smoking cessation induced by deep repetitive
Bear, M.F., Malenka, R.C., 1994. Synaptic plasticity: LTP and LTD. Curr. transcranial magnetic stimulation of the prefrontal and insular cortices:
Opin. Neurobiol. 4 (3), 389e399. a prospective, randomized controlled trial. Biol. Psychiatry 76 (9),
Beauregard, M., 2014. Functional neuroimaging studies of the effects of 742e749.
psychotherapy. Dialogues Clin. Neurosci. 16 (1), 75e81.
Donse, L., et al., 2018. Simultaneous rTMS and psychotherapy in major dependent patients: results of a naturalistic study. Drug Alcohol
depressive disorder: clinical outcomes and predictors from a large Depend. 120 (1e3), 209e213.
naturalistic study. Brain Stimulation 11 (2), 337e345. Herremans, S.C., et al., 2016. Accelerated HF-rTMS protocol has a rate-
Downar, J., et al., 2012. Unanticipated rapid remission of refractory dependent effect on dACC activation in alcohol-dependent patients:
bulimia nervosa, during high-dose repetitive transcranial magnetic an open-label feasibility study. Alcohol Clin. Exp. Res. 40 (1),
stimulation of the dorsomedial prefrontal cortex: a case report. Front. 196e205.
Psychiatry 3, 30. Hoppner, J., et al., 2011. Repetitive transcranial magnetic stimulation
Eichhammer, P., et al., 2003. High-frequency repetitive transcranial mag- (rTMS) for treatment of alcohol dependence. World J. Biol. Psychiatr.
netic stimulation decreases cigarette smoking. J. Clin. Psychiatry 64 (8), 12 (Suppl. 1), 57e62.
951e953. Huang, Y.Z., et al., 2005. Theta burst stimulation of the human motor
Fitzgerald, P.B., et al., 2005. A study of the effects of lorazepam and cortex. Neuron 45 (2), 201e206.
dextromethorphan on the response to cortical 1 Hz repetitive trans- Huerta, P.T., Volpe, B.T., 2009. Transcranial magnetic stimulation, synaptic
cranial magnetic stimulation. Neuroreport 16 (13), 1525e1528. plasticity and network oscillations. J. NeuroEng. Rehabil. 6, 7.
Gay, A., et al., 2016. A lack of clinical effect of high-frequency rTMS to Knoch, D., et al., 2006. Disruption of right prefrontal cortex by
dorsolateral prefrontal cortex on bulimic symptoms: a randomised, low-frequency repetitive transcranial magnetic stimulation induces
double-blind trial. Eur. Eat. Disord. Rev. 24 (6), 474e481. risk-taking behavior. J. Neurosci. 26 (24), 6469e6472.
Gay, A., et al., 2017. A single session of repetitive transcranial magnetic Kozel, F.A., et al., 2018. Repetitive TMS to augment cognitive processing
stimulation of the prefrontal cortex reduces cue-induced craving in therapy in combat veterans of recent conflicts with PTSD: a
patients with gambling disorder. Eur. Psychiatry 41, 68e74. randomized clinical trial. J. Affect. Disord. 229, 506e514.
George, M.S., et al., 2010. Daily left prefrontal transcranial magnetic Li, X., et al., 2013a. Repetitive transcranial magnetic stimulation of the
stimulation therapy for major depressive disorder: a sham-controlled dorsolateral prefrontal cortex reduces nicotine cue craving. Biol.
randomized trial. Arch. Gen. Psychiatry 67 (5), 507e516. Psychiatry 73 (8), 714e720.
Gorelick, D.A., Zangen, A., George, M.S., 2014 Oct. Transcranial mag- Li, X., et al., 2013b. Low frequency repetitive transcranial magnetic
netic stimulation in thetreatment of substance addiction. Ann N Y stimulation of the left dorsolateral prefrontal cortex transiently in-
Acad Sci 1327, 79e93. https://doi.org/10.1111/nyas.12479. Epub creases cue-induced craving for methamphetamine: a preliminary
2014 Jul 28. Review. PubMed PMID: 25069523; PubMedCentral study. Drug Alcohol Depend. 133 (2), 641e646.
PMCID: PMC4206564. Liebetanz, D., et al., 2002. Pharmacological approach to the mechanisms
Groenewegen, H.J., Uylings, H.B., 2000. The prefrontal cortex and the of transcranial DC-stimulation-induced after-effects of human motor
integration ofsensory, limbic and autonomic information. Prog Brain cortex excitability. Brain 125 (10), 2238e2247.
Res 126, 3e28. Review.PubMed PMID: 11105636. Liu, Q., et al., 2017. Either at left or right, both high and low frequency
Hanlon, C.A., et al., 2013. Probing the frontostriatal loops involved in ex- rTMS of dorsolateral prefrontal cortex decreases cue induced craving
ecutive and limbic processing via interleaved TMS and functional MRI for methamphetamine. Am. J. Addict. 26 (8), 776e779.
at two prefrontal locations: a pilot study. PLoS One 8 (7), e67917. Malenka, R.C., Bear, M.F., 2004. LTP and LTD: an embarrassment of
Hanlon, C.A., et al., 2015. What goes up, can come down: novel brain riches. Neuron 44 (1), 5e21.
stimulation paradigms may attenuate craving and craving-related McClelland, J., et al., 2013. Improvements in symptoms following neu-
neural circuitry in substance dependent individuals. Brain Res. 1628 ronavigated repetitive transcranial magnetic stimulation (rTMS) in
(Pt A), 199e209. severe and enduring anorexia nervosa: findings from two case studies.
Hanlon, C.A., Dowdle, L.T., Henderson, J.S., 2018 Jul. Modulating Eur. Eat. Disord. Rev. 21 (6), 500e506.
Neural Circuits withTranscranial Magnetic Stimulation: Implications McClelland, J., et al., 2016. A randomised controlled trial of neuro-
for Addiction TreatmentDevelopment. Pharmacol Rev 70 (3), navigated repetitive transcranial magnetic stimulation (rTMS) in
661e683. https://doi.org/10.1124/pr.116.013649. Review. PubMed anorexia nervosa. PLoS One 11 (3), e0148606.
PMID: 29945899; PubMed Central PMCID: PMC6020107. McDonnell, M.N., Orekhov, Y., Ziemann, U., 2007. Suppression of LTP-
Hausmann, A., et al., 2004. Repetitive transcranial magnetic stimulation like plasticity in human motor cortex by the GABAB receptor agonist
(rTMS) in the double-blind treatment of a depressed patient suffering baclofen. Exp. Brain Res. 180 (1), 181e186.
from bulimia nervosa: a case report. Int. J. Neuropsychopharmacol. 7 Mishra, B.R., et al., 2010. Efficacy of repetitive transcranial magnetic
(3), 371e373. stimulation in alcohol dependence: a sham-controlled study. Addiction
Hanlon, C.A., Dowdle, L.T., Moss, H., Canterberry, M., George, M.S., 105 (1), 49e55.
2016 Dec. Mobilization ofMedial and Lateral Frontal-Striatal Circuits Nahas, Z., et al., 2001. Unilateral left prefrontal transcranial magnetic
in Cocaine Users and Controls: AnInterleaved TMS/BOLD Functional stimulation (TMS) produces intensity-dependent bilateral effects as
Connectivity Study. Neuropsychopharmacology 41 (13), 3032e3041. measured by interleaved BOLD fMRI. Biol. Psychiatry 50 (9),
https://doi.org/10.1038/npp.2016.114. Epub 2016 Jul 4. PubMed 712e720.
PMID:27374278; PubMed Central PMCID: PMC5101551. Nitsche, M.A., et al., 2003. Pharmacological modulation of cortical
Heidegger, T., Krakow, K., Ziemann, U., 2010. Effects of antiepileptic excitability shifts induced by transcranial direct current stimulation in
drugs on associative LTP-like plasticity in human motor cortex. Eur. J. humans. J. Physiol. 553 (Pt 1), 293e301.
Neurosci. 32 (7), 1215e1222. Nitsche, M.A., et al., 2004. Catecholaminergic consolidation of motor
Herremans, S.C., et al., 2012. No influence of one right-sided prefrontal cortical neuroplasticity in humans. Cerebr. Cortex 14 (11),
HF-rTMS session on alcohol craving in recently detoxified alcohol- 1240e1245.
Politi, E., et al., 2008. Daily sessions of transcranial magnetic stimulation Su, H., et al., 2017. High frequency repetitive transcranial magnetic
to the left prefrontal cortex gradually reduce cocaine craving. Am. J. stimulation of the left dorsolateral prefrontal cortex for methamphet-
Addict. 17 (4), 345e346. amine use disorders: a randomised clinical trial. Drug Alcohol
Pripfl, J., et al., 2014. Transcranial magnetic stimulation of the left Depend. 175, 84e91.
dorsolateral prefrontal cortex decreases cue-induced nicotine craving Taylor, J.J., et al., 2013. Naloxone-reversible modulation of pain circuitry
and EEG delta power. Brain Stimul. 7 (2), 226e233. by left prefrontal rTMS. Neuropsychopharmacology 38 (7),
Remue, J., Baeken, C., De Raedt, R., 2016. Does a single neurostimulation 1189e1197.
session really affect mood in healthy individuals? A systematic re- Teo, J.T., Swayne, O.B., Rothwell, J.C., 2007. Further evidence for
view. Neuropsychologia 85, 184e198. NMDA-dependence of the after-effects of human theta burst stimu-
Sahlem, G.L., et al., 2018. Repetitive transcranial magnetic stimulation lation. Clin. Neurophysiol. 118 (7), 1649e1651.
(rTMS) administration to heavy cannabis users. Am. J. Drug Alcohol Terraneo, A., et al., 2016. Transcranial magnetic stimulation of dorsolat-
Abuse 44 (1), 47e55. eral prefrontal cortex reduces cocaine use: a pilot study. Eur. Neuro-
Sauvaget, A., et al., 2018. Both active and sham low-frequency rTMS psychopharmacol. 26 (1), 37e44.
single sessions over the right DLPFC decrease cue-induced cravings Thirugnanasambandam, N., et al., 2011. Nicotinergic impact on focal and
among pathological gamblers seeking treatment: a randomized, non-focal neuroplasticity induced by non-invasive brain stimulation in
double-blind, sham-controlled crossover trial. J. Behav. Addict. 7 (1), non-smoking humans. Neuropsychopharmacology 36 (4), 879e886.
126e136. Tsagaris, K.Z., Labar, D.R., Edwards, D.J., 2016. A framework for
Sheffer, C.E., et al., 2018. Preventing relapse to smoking with transcranial combining rTMS with behavioral therapy. Front. Syst. Neurosci. 10,
magnetic stimulation: feasibility and potential efficacy. Drug Alcohol 82.
Depend. 182, 8e18. Van den Eynde, F., et al., 2010. Repetitive transcranial magnetic stimu-
Shen, Y., et al., 2016. 10-Hz repetitive transcranial magnetic stimulation of lation reduces cue-induced food craving in bulimic disorders. Biol.
the left dorsolateral prefrontal cortex reduces heroin cue craving in Psychiatry 67 (8), 793e795.
long-term addicts. Biol. Psychiatry 80 (3), e13ee14. Vedeniapin, A., Cheng, L., George, M.S., 2010a. Feasibility of simulta-
Stagg, C.J., et al., 2009. Neurochemical effects of theta burst stimulation as neous cognitive behavioral therapy and left prefrontal rTMS for
assessed by magnetic resonance spectroscopy. J. Neurophysiol. 101 treatment resistant depression. Brain Stimul. 3 (4), 207e210.
(6), 2872e2877. Vertes, R.P., 2004 Jan. Differential projections of the infralimbic and
Stefan, K., et al., 2000. Induction of plasticity in the human motor cortex prelimbic cortex inthe rat. Synapse 51 (1), 32e58. PubMed PMID:
by paired associative stimulation. Brain 123 (3), 572e584. 14579424.
Stefanik, M.T., Kupchik, Y.M., Brown, R.M., Kalivas, P.W., 2013 Aug21. Wing, V.C., et al., 2013. Brain stimulation methods to treat tobacco
Optogenetic evidence thatpallidal projections, not nigral projections, addiction. Brain Stimul. 6 (3), 221e230.
from the nucleus accumbens core arenecessary for reinstating cocaine Wolters, A., et al., 2003. A temporally asymmetric Hebbian rule governing
seeking. J Neurosci 33 (34), 13654e13662. https://doi.org/10.1523/ plasticity in the human motor cortex. J. Neurophysiol. 89 (5),
JNEUROSCI.1570-13.2013. PubMed PMID: 23966687;PubMed 2339e2345.
Central PMCID: PMC3755713. Ziemann, U., Rothwell, J.C., 2000 Jul. I-waves in motor cortex. J Clin
Strafella, A.P., et al., 2001. Repetitive transcranial magnetic stimulation of Neurophysiol 17 (4), 397e405. PubMed PMID: 11012042.
the human prefrontal cortex induces dopamine release in the caudate
nucleus. J. Neurosci. 21 (15), RC157.
Chapter 23
Pharmacological cognitive enhancers

MacKenzie R. Peltier1, 2 and Mehmet Sofuoglu1, 2
1
Yale School of Medicine, Department of Psychiatry, New Haven, United States; 2VA Connecticut Healthcare System, West Haven, United States
Introduction Executive functioning

Substance use disorders (SUDs) remain a significant public Executive control is related to the dorsolateral/medial, supe-
health problem with over 250 million current illicit drug rior frontal, and orbitofrontal networks of the prefrontal cortex
users worldwide (United Nations Office on Drug and Crime, (Abernathy et al., 2010; McGuire and Botvinick, 2010). These
2017). Despite recent developments in pharmacological networks regulate the majority of an individual’s goal-directed
interventions, no medications are available for the treatment behavior and conflict resolution, as well as determine the
of methamphetamine, cocaine, or cannabis use disorders importance of environmental information. Disruptions in
(Sofuoglu and Kosten, 2005; Hill and Sofuoglu, 2007; executive control have been postulated to play a role
Sofuoglu et al., 2010). Additionally, while there are several in compulsive drug use (Everitt et al., 2008; Goldstein and
effective pharmacological treatments available for nicotine, Volkow, 2011; Robbins and Arnsten, 2009; Sofuoglu et al.,
alcohol, and opioid use disorders, relapse rates remain high. 2013). Monoamines, including dopamine, serotonin, and
This highlights the imperative need for the development of norepinephrine, as well as orexin and acetylcholine, impact
new pharmacological interventions to treat SUDs. these functions (Robbins and Arnsten, 2009). Executive
This chapter will first provide a brief overview of functioning consists of numerous cognitive functions
cognitive functioning as it relates to SUD and the rationale including working memory, sustained attention, problem
for targeting cognitive enhancement in the treatment of solving, decision-making, response inhibition, and cognitive
SUDs. It will present a summary of potential target flexibility (Friedman et al., 2008). Of note, working memory,
mechanisms to address cognitive deficits related to drug sustained attention, and response inhibition have been
use. This will be followed by discussion of candidate previously identified as potential target mechanisms for the
medications for cognitive enhancement for substance use. treatment of SUDs and will be further described below
(Sofuoglu et al., 2013; de Wit, 2009; Eagle et al., 2008a,b;
Grégoire et al., 2012).
Cognitive function within the context of Response inhibition is described as an individual’s
substance use disorder capacity to voluntarily inhibit an automatic process. Response
inhibition is often probed through tasks including the
Cognitive function is broadly defined as one’s mental
processing and includes domains of learning, memory, Stop-Signal Task (SST) and Go/No-Go. These tests are timed
choice response tasks, which assess inhibition of a response
emotions, executive function, language, and sensory motor
that has already begun (Eagle et al., 2008a,b; Littman and
processing (Sachdev et al., 2014). A cognitive model of
Takács, 2017). The SST requires individuals to respond as
SUD is proposed in the dual-process theory. Accordingly,
quickly as possible to a series of choices (e.g., press corre-
SUD can be viewed as a conflict between automatic or
sponding button for the presented direction of the arrow), with
implicit cognitions, which generally enhance the risk of
a stop signal presented after the choice in some instances,
drug taking and relapses, and executive or explicit cogni-
which requires the individual to withhold the response (Band
tions, which generally inhibit the automatic cognitions as
well as the risk of drug use or relapse (Sava et al., 2009; and van Boxtel, 1999). Similarly, during the Go/No-Go, the
individual responds to the “go” or “no-go” choice as quickly
Sofuoglu et al., 2013). These processes are also relevant
as possible; however, a stop signal is presented with the initial
when discussing drug use and subsequent treatment.
Cognition and Addiction. https://doi.org/10.1016/B978-0-12-815298-0.00023-X 303

signal, requiring the individual to withhold the choice including methamphetamine, cocaine, cannabis, and nicotine
response (Eagle et al., 2008a,b). use, which have been associated with poor sustained attention
Impaired response inhibition function, as measured by (de Wit, 2009; Jovanovski et al., 2005; Scott et al., 2007;
either task, has been associated with substance use. Specif- Sofuoglu et al., 2012; Bolla et al., 2002; Simon et al., 2010;
ically, individuals with cocaine and methamphetamine Durazzo et al., 2012). These processes are modulated by
dependence have shown worse response inhibition perfor- acetylcholine, as well as dopamine, norepinephrine, gluta-
mance than healthy controls, and poor response inhibition mate, and gamma-aminobutyric acid (GABA) (Levin et al.,
performance has been a predictor of substance use among 2011). It is thought that acetylcholine release in the prefrontal
at-risk adolescents (Li et al., 2006; Fernández-Serrano et al., cortex mediates such processes, and enhancement of dopa-
2012; Monterosso et al., 2005; Nigg et al., 2006). The brain’s mine, norepinephrine, and acetylcholine may prove to be
norepinephrine system contributes to the response inhibition pharmacological targets to improve sustained attention (Levin
function, with research indicating that the dorsomedial pre- et al., 2011; Sofuoglu et al., 2013).
frontal cortical areas are important for inhibiting the initiated
response (Aston-Jones and Gold, 2009; Friedman et al., Automatic cognitive processes
2008a,b; Bari et al., 2011). Using pharmacological probes,
increases in synaptic norepinephrine levels have been asso- Automatic or implicit cognitive processes have been asso-
ciated with improved response inhibition performance ciated with craving, as well as substance use and subse-
(Aston-Jones and Gold, 2009). For instance, atomoxetine, a quent relapse (Carpenter et al., 2006; Cox et al., 2006; Field
norepinephrine transporter inhibitor, improves response et al., 2009; Rooke et al., 2008). These processes are rapid
inhibition, likely through increases of synaptic dopamine and and often bypass conscious awareness. Incentive sensiti-
norepinephrine levels in the prefrontal cortex (Aston-Jones zation theory within the context of SUDs asserts that
and Gold, 2009; Bari et al., 2011). This finding may trans- chronic drug use “rewires” the brain to pathologically
late to improved ability to resist drug craving and urges by incentivize motivation for drugs (Robinson and Berridge,
atomoxetine treatment (Bari et al., 2011). 2008; Waters et al., 2009). Attentional bias describes the
Working memory is defined as remembering an event or implicit attention to or on specific stimuli (e.g., to drug-
retrieving an event from long-term storage, to regulate related stimuli), reflecting the incentive value of drug
behavior, including drug seeking and use (Arnsten et al., cues (Cox et al., 2014; Colzato et al., 2007; Dougherty
2015). Laboratory measures of working memory have et al., 2008; Wagner et al., 2013).
historically consisted of auditory or visuospatial span tasks, Measures of attentional bias include modified Stroop
during which individuals are asked to change the provided tasks, during which individuals are presented with words
information, by updating or manipulating it while the written in a colored ink and then asked to name that ink
information is being held (Sofuoglu et al., 2013). Given color, and dot probe tasks, which measure the speed one
that dopamine and norepinephrine are the primary visually attends to neutral stimuli when it is with other
neuromodulators associated with working memory function, drug-related cues (Wiers and Stacy, 2006; Sofuoglu et al.,
monoamine transport inhibitors (e.g., atomoxetine, modafinil, 2013). Attentional bias is related to addiction as it refers to
and methylphenidate) and alpha2-adrenergic agonists the effect of decreased or slowed performance for drug-
(e.g., guanfacine) have been used in studies to probe and related cues (e.g., visual cues) and thus has been related
enhance working memory function (Marquand et al., 2011; to increased drug cue exposure, provocation of craving, and
Minzenberg and Carter, 2007; Swartz et al., 2008). Impaired subsequent use (Sofuoglu et al., 2013). It is important to
working memory function has been associated with chronic note that attentional bias is a dynamic process that is not
cocaine and methamphetamine use, as it may be related to necessarily pathological; it is not always a consequence of
deficits in response inhibition, which have been suggested to substance use, as it can also be impacted by such use. In
facilitate substance use craving or relapse (Jovanovski et al., fact, healthy individuals are also able to quickly learn
2005; Scott et al., 2007; Chambers et al., 2009). Thus, working associations between arbitrary stimuli and reward outcomes
memory may be a target for novel SUD interventions. (Anderson, 2016).
Sustained attention refers to a controlled process rooted in In light of this learned relationship between stimuli and
external stimuli, as well as executive attention. Laboratory rewards, several reviews have asserted that attentional bias
studies often probe sustained attention through continuous is an important cognitive mechanism in the treatment of
performance tasks (e.g., Rapid Visual Information Processing SUDs (Field and Cox, 2008; Franken, 2003). It has been
Task; RVIP). The RVIP instructs individuals to engage with suggested that addiction-related attentional bias describes
visual stimuli, which are presented rapidly, and respond to the learning in which reward is paired with drug cues and
infrequently presented stimuli (Turner et al., 2005). Lapses in those drug-associated stimuli become salient (Anderson,
attention, often measured by this task, have been proposed as a 2016; Leeman et al., 2014). Targeting the underlying
precursor to drug-seeking behavior and substance use, mechanisms of this learned relationship in SUD treatment
Pharmacological cognitive enhancers Chapter | 23 305
may improve treatment outcomes and decrease cravings performance on tests of working memory (Vonmoos et al.,
(Anderson, 2016; Leeman et al., 2014). It has been 2014). Similarly, previously naive 3,4-methylenediox-
proposed that attentional bias is attenuated by several ymethamphetamine (MDMA) users were followed over
pharmacological interventions including dopamine 1 year and those using more than 10 MDMA pills had
antagonists (e.g., haloperidol), glutamatergic medications poorer performance on a test of learning, as compared to
(e.g., n-acetylcysteine), and monoamine transporters controls, despite no previous cognitive differences between
(e.g., atomoxetine) (Levi Bolin et al., 2017; Passamonti the groups (Wagner et al., 2012).
et al., 2017; Franken et al., 2004). Additionally, psycho- Furthermore, many psychiatric disorders are also associ-
logical interventions such as attentional bias modification ated with cognitive impairments and thus may make an
(ABM) have been associated with decreased attentional individual more vulnerable to abuse substances (Sofuoglu
bias among alcohol and cigarette users, and cognitive et al., 2013; Bakhshaie et al., 2015; Carrà et al., 2017). For
behavioral therapy (CBT) has also shown promise in atten- instance, in a study of cocaine-dependent adults, those with
uating attentional bias in cocaine users (Leeman et al., 2014; attention-deficit/hyperactivity disorder (ADHD) demon-
DeVito et al., 2018). Given the relevance to addictive dis- strated greater cognitive impairments than those without an
orders, these mechanisms may serve as potential treatment ADHD comorbidity (Cunha et al., 2013). This demonstrates
targets for cognitive enhancement approaches. that preexisting psychiatric symptoms may impact underlying
cognitive functions, thus increasing an individual’s vulnera-
Cognitive deficits in substance use bility for drug use.
Cognitive impairments have also been generally linked to
disorders poorer treatment retention for SUDs; studies of individuals
A large body of literature has established that chronic using alcohol, cocaine, cannabis, and methamphetamines
substance use is associated with significant cognitive demonstrate that those who do not complete SUD treatment
deficits, with impairments spanning decision-making, have significantly worse performance on measures assessing a
attentional functioning, working memory, response inhibi- range of cognitive functions and domains (e.g., attention,
tion, and other executive functions (for review, see memory, abstract reasoning) compared with individuals
Sofuoglu et al. (2013)). This relationship has often been completing SUD treatment (Carroll et al., 2014; Dean et al.,
postulated to be dose-related with greater use associated 2009; Verdejo-García et al., 2007; Copersino et al., 2012;
with greater deficits (Bolla et al., 2002; Colzato et al., 2007; Bates et al., 2013). Furthermore, it has been consistently
Dougherty et al., 2008). However, it is important to note established that cognitive impairments, including executive
that cognitive deficits and drug use may not be causally function and inhibitory control, are associated with increased
linked; this association is also complicated by other treatment attrition (Verdejo-García et al., 2007; Copersino
moderating factors (Sofuoglu et al., 2013). et al., 2012; Brewer et al., 2008; Streeter et al., 2007; Turner
Cognitive deficits may be a preexisting feature, which et al., 2009). Thus, it is postulated that cognitive impairments
may place individuals at increased risk for initiating and observed in executive and implicit mechanisms may be pre-
escalating drug use (Wagner et al., 2013; Grant et al., 2012; dictors of SUD treatment engagement and positive treatment
Squeglia et al., 2014; Aharonovich et al., 2017). For outcomes.
instance, one study demonstrated that tobacco smokers These deficits also hinder the ability of individuals in
were more likely to have poor performance on tests of SUD treatment to learn new coping skills as part of their
visual attention and impulsivity than nonsmokers; these recovery. Many psychological interventions, including
differences were not related to lifetime cigarette exposure CBT, strive to improve cognitive control and enhance
(Wagner et al., 2013). This indicates that the cognitive executive functioning through cognitively demanding
impairment observed may have been present before onset treatment tasks (DeVito et al., 2018; Sofuoglu et al., 2016).
of cigarette use (Wagner et al., 2013). Furthermore, when Cognitive deficits are often associated with decreased
comparing cognitive function and personality traits asso- ability to maintain daily living activities (e.g., working and
ciated with drug use, in stimulant-dependent individuals independent living) and impaired social capacity, among
and their siblings without a drug use history, cognitive individuals with schizophrenia (Eack et al., 2007; Thaker
deficits were found in both siblings using substances and and Carpenter Jr, 2001; Tripathi et al., 2018).
those who were not drug-dependent (Ersche et al., 2012). Evidence within the context of SUDs supports this
Conversely, there is also evidence for drug-related cogni- hypothesis, as it has been shown that the cognitive deficits
tive deficits. A recent longitudinal study demonstrated that may interfere with the ability of the individual to appropriately
moderate cocaine use was related to cognitive impairment engage in the intervention’s tasks, thus potentially mediating
among 57 cocaine users. After 12 months, participants poorer treatment outcomes (Bates et al., 2013). Given this
who reduced cocaine use improved on cognitive tasks, information, further investigation of these cognitive deficits as
while those increase their cocaine use exhibited poorer targets for pharmacological intervention is warranted to
improve treatment retention and outcomes. To date, cholin- demonstrated that among detoxified individuals with alcohol
ergic medications, monoamine transporters, dopamine use disorder, they consumed less alcohol per day than those
antagonists (e.g., antipsychotics), glutamatergic medications, receiving placebo, although there was no effect on time until
GABAergic medications, and sex steroids have been explored first severe relapse (Mann et al., 2006). Thus, galantamine has
as underlying mechanisms and possible interventions. The demonstrated promising results in these studies for the treat-
recent relevant findings are discussed below. ment of SUDs, including alcohol, cocaine, and nicotine use.
Target mechanisms Rivastigmine

Table 23.1 summarizes the most recent evidence of Rivastigmine is an acetylcholinesterase inhibitor, which has
cognitive functioning enhancement in each of the following demonstrated efficacy for many of the cognitive and func-
targets within the context of SUDs. tional problems related to Alzheimer’s disease (Corey-Bloom
et al., 1998; Winblad et al., 2007). In a recent study of occa-
sional cannabis users, 3 mg/day pretreatment of
Cholinergic medications
rivastigmine attenuated effects of delayed recalls and there
Pharmacological interventions targeting the cholinergic was a trend of improvement on immediate recall
system have been well-established to improve cognitive (Theunissen et al., 2015). Additionally in another study,
functions. Cholinesterase inhibitors have been shown to cocaine-dependent, nonetreatment-seeking participants
increase concentration of acetylcholine at the synapse and demonstrated improved working memory span following
thus increase acetylcholine transmission. Acetylcholine has administration of rivastigmine (3 mg or 6 mg/day)
been associated with improved attention, working memory, (Mahoney et al., 2014). In terms of substance use outcomes,
motivation, and reward (Mooney et al., 2009; Sarter et al., rivastigmine demonstrated reductions in tobacco cravings and
2014; Mark et al., 2011). Accordingly, cholinesterase consumption (30% decrease in cigarettes per day over
inhibitors have been approved for the treatment of 12-week study) in alcohol-dependent daily smokers who were
Alzheimer’s disease and are currently being explored as randomized to receive either 6 mg/day of rivastigmine or
novel treatments for schizophrenia or traumatic brain injury placebo (Diehl et al., 2009). Evidence suggests that further
(Sofuoglu et al., 2016; Pae, 2013; Bengtsson and Godbolt, investigation of acetylcholinesterase inhibitors is warranted.
2016). Recent interest in their utility to improve cognitive
function in the treatment of SUDs is explored below. Donepezil
Galantamine Donepezil is another acetylcholinesterase inhibitor utilized to
increase cortical acetylcholine for the treatment of
Galantamine is not only an acetylcholinesterase inhibitor but it Alzheimer’s disease (Repantis et al., 2010). Following 3 days
is also an allosteric potentiator of the nicotinic acetylcholine of daily administration of 5 mg of donepezil in cocaine-
receptor, notably in the a7 and a4b2 subtypes (Schilström dependent participants, donepezil increased subjective rat-
et al., 2006). Several studies have demonstrated the potential ings, including “any” and “good” drug effects, following
use of galantamine as a treatment for SUDs. For example, the low-dose intravenous cocaine administration (Grasing et al.,
use of galantamine (8 mg/day) in a double-blinded study of 2010). Looking across intravenous cocaine doses, donepezil
methadone-maintained cocaine-dependent participants resul- decreased dysphoric and somatic symptoms, but did not affect
ted in a reduction in frequency of cocaine use over time. the number of cocaine injections participants self-
However, it did not demonstrate improvement in cognitive administered within the laboratory paradigm (Grasing et al.,
functioning, including in sustained attention (Carroll et al., 2010). Additionally, daily doses of donepezil (10 mg) for
2018). Another placebo-controlled study of galantamine 10 weeks were associated with decreases in cocaine severity
(8 mg/day) improved sustained attention and response inhi- scores (as measured by self- and study physician-rated
bition among abstinent cigarette smokers. It was also found to Clinical Global Impression scales) and self-reported cocaine
attenuate the positive subjective effects of intravenous use (Winhusen et al., 2005). However, to date, no study has
nicotine (Sofuoglu et al., 2012). Similar results were reported explored donepezil’s effect on cognitive functioning within
by Ashare et al. (2016), demonstrating its potential utility for the context of substance use. Given the limited data, it is
smoking cessation. Following 2 weeks of daily galantamine unclear if donepezil is a potential pharmacological interven-
administration (8 mg/day week one; 16 mg/day week two), tion for SUDs.
decreased cigarettes smoked per day, as well as positive
subjective effects of smoking as compared to placebo, were Varenicline
observed (Ashare et al., 2016). In addition to the treatment of
cocaine and tobacco use disorders, galantamine has shown Varenicline is a partial agonist of the a4b2, as well as a full
promise in the treatment of alcohol use disorder. One study agonist of a7, which has demonstrated efficacy for
TABLE 23.1 Studies of pharmacological enhancers in the context of substance use.
Enhanced Cognitive Cognitive
Target Medication Authors Dose/Design Domain Measure Participants Results
0
Acetylcholine Galantamine Carroll 8 mg/day for Memory and sus- RVP A ; intra/extra- 120 methadone- Reduction in frequency
et al., 2018 12 weeks; tained attention dimensional set maintained, cocaine- of cocaine use over
between-subjects shifting dependent participants time; no improvement
(28 galantami- in cognitive
ne þ CBT4CBT; 27 galan- functioning
tamine þ TAU; 38
placebo þ CBT4CBT; 27
placebo þTAU)
Sofuoglu Two 4-day treat- Sustained attention SART 12 nonetreatment-seeking Attenuated
et al., 2012 ments of 8 mg/day; and response smokers subjective response to
within-subject inhibition nicotine; showed
improved performance
on No-Go trials
Rivastigmine Theunissen 20 mg pretreat- Memory, perceptual Visual verbal 15 occasional cannabis Attenuated effects on
et al., 2015 ment; within- motor control, atten- learning task; pro- users delayed recall; trended
subject tion, and motor spective memory toward improvement
impulsivity test; Sternberg on immediate recall
memory test; crit-
ical tracking task;
divided attention
task; Stop-Signal
Task
Pharmacological cognitive enhancers Chapter | 23

Mahoney 3 or 6 mg for Attention, verbal/ CPT-II; HVLT-R; 41 cocaine-dependent, Improved working
et al., 2014 7 days; between- episodic memory, and Dual N-Back task nonetreatment-seeking memory span; no sub-
subjects working memory participants stance use outcome
measures included
Varenicline Roberts and 1 or 2 mg/day; Working memory, Digit span back- 55 heavy drinkers, Reduced alcohol use;
McKee, between-subjects sustained attention, ward; CPT meeting criteria for AUD dose-dependent in-
2018 and response crease in working
inhibition memory; faster reaction
time; no improvement
of inhibitory control or
sustained attention
Verplaetse 1 or 2 mg/day; Sustained attention, CPT; DSST; N- 44 participants meeting Attenuated increases in
et al., 2016 between-subjects response inhibition, Back; Pursuit Rotor criteria for AUD subjective intoxication,
working memory, pro- task perceptual motor
cessing speed, and response; attenuated
perceptional motor alcohol-related execu-
performance tive functioning
decreases
307
Continued
TABLE 23.1 Studies of pharmacological enhancers in the context of substance use.dcont’d

Monoamine Modafinil Schmaal 200 mg/study ses- Cognitive control and Stroop task; within- 31 participants (15 AUD; Improved cognitive
transporters et al., 2013 sion; within-subject cognitive network and 16 control) control; induced
performance between-network changes in between-
functional connec- network functional
tivity (fMRI) connectivity in AUD
indicating enhanced
cognitive performance
Kalechstein 200 mg/daily; Attention/information CPT-II; HVLT-R; 61 cocaine-dependent in- Improved working
et al., 2010 between-subjects processing, episodic Dual n-back task dividuals (16 modafinil; memory span; trend-
memory, and working 16 escitalopram; 15 mod- level improvements in
memory afinil þ escitalopram; 14 visual working mem-
placebo) ory, and sustained
attention; no effect on
processing speed or
episodic memory
Methylphenidate Li et al., 0.5 mg/kg of body Inhibitory control Stop-Signal Task 10 nonetreatment- Improved inhibitory
2010 weight, IV injec- (fMRI) seeking, cocaine- control; evoked
tion; within- dependent participants changes in prefrontal
subjects brain activation
Methamphetamine/ Reed and 10 or 20 mg/study Impulsivity and risk- IMT/DMT, GoStop 34 cocaine users (13 Did not attenuate
D-amphetamine Evans, 2016 session; within- taking task, DDT, Balloon intranasal; 21 smoked) impulsive responding
subject Analogue Risk Task
Atomoxetine Passamonti 50 mg/single dose; Attentional bias Line-counting task; 28 cocaine-dependent Reduced attentional
et al., 2017 between subject Go/No-Go task participants; 28 healthy bias to drug-related
controls cues
Anti- Haloperidol Franken 2 mg/ single dose; Attentional bias Emotional Stroop 18 heroin dependent Improved performance
psychotic et al., 2004 within-subject Task males on task
Alpha2- Guanfacine McKee 3 mg/day for Self-control fMRI Stroop Color 33 nicotine-deprived Increased ability to
adrenergic et al., 2015 21 days before Word Interference smokers resist smoking in labo-
study sessions; Task ratory; increased
between-subject ventromedial prefrontal
activity during task; did
not affect Stroop results
Glutamate Memantine Jackson 40 mg; between- Sustained attention Word recall, RVIP, 60 heavy regulareheavy No effect on smoking
et al., 2009 subjects DSST PAL, SRM, smokers (smoked at least behavior; failed to
PAL, AGNG 10 CPD) show any cognitive
effects
Krupitsky 20 mg or 40 mg on Verbal fluency and Verbal Fluency 38 male inpatients Attenuated alcohol
et al., 2007 study day; immediate/delayed Test; HVLT meeting criteria for craving in dose-related
between-subjects recall alcohol dependence trend; no significant ef-
fects on cognitive
functioning
D-Cycloserine Kalechstein 50 mg on each Attention/information CPT-II; HVLT-R; 27 concurrent cocaine- Did not modulate neu-
et al., 2012 study day; processing speed, Dual N-back task; and nicotine-dependent rocognitive functioning
between-subjects episodic memory, and participants (15 D-cyclo-
executive/frontal lobe serine; 12 placebo)
functioning
Kamboj 125 mg; between- Attentional basis Dot probe task 36 heavy social drinkers Reduction in atten-
et al., 2011 subjects (19 D-cycloserine; 17 tional bias to alcohol
placebo) cues over time; did not
enhance habituation of
alcohol cue reactivity
Minocycline Sofuoglu 200 mg/day for Sustained attention SART 10 healthy participants Attenuated DAMP-
et al., 2011 5 days and then induced subjective
assigned to either reward; increased reac-
20 mg/70 DAMP or tion times on Go/No-
placebo/DAMP; Go task
Pharmacological cognitive enhancers Chapter | 23

within-subject
Sofuoglu 200 mg/day for 5- Sustained attention SART 12 nonetreatment-seeking No effect on smoking
et al., 2009 day treatment pe- smokers SA, withdrawal or
riods; within- cognitive performance
subject
N-acetylcysteine Levi Bolin 2400 mg/day for Attentional bias Visual probe task 14 individuals meeting Attenuated attentional
et al., 2017 four practice days criteria for cocaine abuse bias
and then seven or dependence (DSM-TR-
maintenance days; IV)
within-subject
Continued
309
TABLE 23.1 Studies of pharmacological enhancers in the context of substance use.dcont’d

GABA Tiagabine Morgan and 12 mg on two Motor learning and CPT-AX; Motor 6 nonetreatment-seeking, Did not differ from pla-
Malison, study days over 12- impulsivity Sequence Task cocaine-dependent cebo in cue responses
2008 day experiment; subjects and false alarm rates;
between-subjects positive correlation be-
tween motor learning
and total sleep time
Sofuoglu 4 or 8 mg single Response inhibition Stroop test 12 nonetreatment-seeking Attenuated cigarette
et al., 2005 dose; within- smokers craving and enhanced
subjects performances on
Stroop test
Sex steroids Progesterone Fox et al., 400 mg/day for Inhibitory control Stroop Color Word 42 abstinent, treatment- Attenuated drug
2013 7 days; between- Task seeking cocaine- craving; cognitive per-
subjects dependent individuals formance improved
across conditions
Sofuoglu 200 or 400 mg/ Sustained attention, DSST; Stroop test 64 male and female absti- Improved cognitive
et al., 2011 study day; within- response speed, nent smokers performance and
subjects visuomotor coordina- reduced urge to smoke
tion, and response
inhibition
AGNG, Affective Go/No-Go; AUD, alcohol use disorder; BID, twice a day; CPD, cigarettes per day; CPT, continuous performance task; DAMP, dextroamphetamine; DDT, Delay-Discounting Task; DSST, Digit
Symbol Substitution Task; HVLT-R, Hopkins Verbal Learning Test-Revised; IMT/DMT, Immediate Memory Task/Delayed Memory Task; PAL, Paired Associates Learning; RVIP, Rapid Visual Information Processing
Task; RVP A’, Rapid Visual Information Processing task; SA, self-administration; SART, Sustained Attention to Response Test; SRM, spatial recognition memory.
smoking cessation. Recent studies have suggested that observed in self-reported state impulsivity, and among
varenicline may improve drinking outcomes through the those with poor baseline response inhibition, modafinil
enhancement of cognitive functioning (Roberts and increased the percentage of abstinent days and increased the
McKee, 2018; Verplaetse et al., 2016). Roberts and time to relapse. Of note, in individuals with better baseline
McKee (2018) randomized adult heavy drinkers to receive response inhibition, modafinil increased drinking behavior
varenicline (1 mg/day; 2 mg/day) or placebo. Among (Joos et al., 2013). Results warrant further exploration of
those participants receiving 2 mg/day, improvements in the role of response inhibition to substance use and the
working memory were associated with decreased drinking utility of modafinil to augment this cognitive function.
during an ad-lib drinking task (Roberts and McKee, 2018).
Comparable results were observed in a similar study, in Methylphenidate
which varenicline attenuated increases in subjective
Methylphenidate is also an inhibitor of dopamine and
intoxication, as well as perceptual motor responses
norepinephrine transporters and has been shown to be an
(Verplaetse et al., 2016). In addition to effects on drinking
effective intervention for improving response inhibition in
outcomes, varenicline has also shown improvements in
ADHD (DeVito et al., 2009). There was initial promise in
reaction time to both visual and auditory stimuli among
methylphenidate’s ability to reduce cocaine use. One study of
methamphetamine-dependent participants, receiving oral
a single 20 mg dose of methylphenidate increased responses
varenicline (titrated up to 1 mg), as well as improvements in
working memory and attention during nicotine withdrawal to rewarded drug cue reactivity task, which in turn was asso-
ciated with reduced behavioral measure of impulsivity
(Kalechstein et al., 2014; Patterson et al., 2009). These
(Goldstein et al., 2010). Consistent with these findings, other
promising results are indicative of the potential utility of
studies have demonstrated improvements in response inhibi-
varenicline to improve cognitive functioning and subse-
tion, as well as decreased cocaine use (Levin et al., 2007; Li
quently positively impact substance use outcomes.
et al., 2010). However, a recent review (see Dürsteler et al.
(2015)) describes overall inconsistent findings, highlighting
Monoamine transporter inhibitors several negative clinical trials. Considering this, the clinical
Modafinil utility of methylphenidate remains to be uncertain.
Modafinil is a weak inhibitor of dopamine and norepi- Oral methamphetamine/D-amphetamine

nephrine transporters and it has been shown to also affect
GABA, glutamate, and orexin (Minzenberg and Carter, Oral methamphetamine and D-amphetamine (the latter is an
2007; Sofuoglu et al., 2016). To date, modafinil has been enantiomer of amphetamine) are utilized to treat ADHD
used as a wakefulness promoter and its cognitive-enhancing through indirectly increasing dopaminergic functioning
effects have been used to treat various neuropsychiatric (Mooney et al., 2009; Reed and Evans, 2016). Previous
disorders, including several SUDs (Minzenberg and Carter, limited evidence showed that oral D-amphetamine increases
2007). With regard to methamphetamine use disorder, impulsivity, as measured by inhibitory responding, among
7 days of 200 mg/day modafinil was associated with smoked cocaine users (Fillmore et al., 2002, 2003). However,
improved immediate verbal function among individuals a recent study demonstrated that those receiving the 10 mg
following detoxification from methamphetamine (Hester oral D-amphetamine demonstrated a blunted response to the
et al., 2010). Higher doses of modafinil (400 mg/day for positive subjective drug effects, while those in the 20 mg
3 days) have also been associated with improved working group endorsed higher ratings of cocaine craving. Across dose
memory in this population (Kalechstein et al., 2010). groups, there was little effect on measures of impulsivity
Consistent with these findings, modafinil has also been (Reed and Evans, 2016).
shown to attenuate positive subjective ratings of intravenous Conversely, cocaine users receiving sustained release
cocaine (Verrico et al., 2014; Hart et al., 2007). oral methamphetamine (30 mg) exhibited a decreased pro-
Additionally, among individuals meeting criteria for portion of cocaine-positive urine drug screens and reported
alcohol dependence, those receiving a single dose of less cocaine cravings (Mooney et al., 2009). In a random-
modafinil (200 mg) demonstrated improved response inhi- ized control trial of D-amphetamine, among individuals
bition among those participants who had poor baseline with methamphetamine use disorder, 110 mg/day of sus-
levels of response inhibition. This finding was likely tained release D-amphetamine for 12 weeks was associated
mediated through the greater observed activation in the with increased length in treatment stay, general reduction in
thalamus and supplementary motor area (Schmaal et al., self-reported and biologically confirmed methamphetamine
2013). Furthermore, another study administrating modafinil use, as well as decreased severity in addiction measures
300 mg/day for 10 weeks to individuals with alcohol use (Longo et al., 2010). These findings indicate that these
disorder demonstrated similar results; improvements were substances may have promise in the treatment of SUD and
there is continued need to evaluate them in clinical trials for study of abstinent individuals with opioid use disorder, a
stimulant addiction. single dose of haloperidol was found to improve performance
on measures of attentional bias, thus indicating that dopa-
Atomoxetine minergic mechanisms may mediate cognitive functioning in
substance-using populations (Franken et al., 2004). Further
Atomoxetine is an inhibitor of norepinephrine transporters
research is needed to elucidate the role of haloperidol in
and has also been shown to increase norepinephrine and
improving attentional biases in SUD populations.
dopamine levels in the prefrontal cortex (Bymaster et al.,
2002; Swanson et al., 2006). Among healthy volunteers,
atomoxetine (40 mg) improved inhibitory control, likely Alpha2-adrenergic agonist
through the modulation of increased activation in the right
Guanfacine
inferior frontal gyrus (Chamberlain et al., 2009). Further-
more, the same research group studying a 60 mg dose of Guanfacine is an alpha2-adrenergic agonist that reduces
atomoxetine demonstrated similar improvements in inhib- norepinephrine activity via stimulation of presynaptic
itory control among individuals diagnosed with ADHD alpha2-adrenergic agonist receptors. It has been utilized in
(Chamberlain et al., 2007). the treatment of hypertension and ADHD (Sofuoglu et al.,
To date, only two studies have explored the utility of 2013). One study of nicotine-deprived smokers receiving
atomoxetine for the treatment of SUDs. Passamonti et al. guanfacine (3 mg/day) demonstrated altered prefrontal
(2017) administered a single 40 mg oral dose of atomoxetine activity during the Stroop cognitive control task and reduced
to 28 cocaine-dependent individuals and 28 healthy controls cigarette use (McKee et al., 2015). It has also been shown to
(Passamonti et al., 2017). Atomoxetine, when compared to improve working memory among healthy individuals, as
placebo, attenuated attentional bias, as measured by line- well as those with ADHD or schizophrenia (Swartz et al.,
counting task with cocaine-related and neutral pictures, in 2008; Friedman et al., 2001; Scahill et al., 2001). Further
the cocaine-dependent individuals (Passamonti et al., 2017). study of guanfacine among participants with SUDs is needed
Additionally, daily administration of 80 mg of atomoxetine to determine its utility to assist in cessation treatments.
among individuals with opioid/amphetamine dependence,
who were maintained on buprenorphine/naloxone, was shown Glutamatergic medications
to decrease depressive symptoms and also the use of
amphetamine-based stimulants (e.g., combinations of meth- Memantine
amphetamine and amphetamine), as measured by urine toxi-
Memantine is a noncompetitive NMDA antagonist that is
cology (Schottenfeld et al., 2018). Thus, illustrating
used to enhance cognitive functioning in Alzheimer’s
atomoxetine’s promise to improve inhibitory control in this
disease (Hashimoto, 2009; Sofuoglu et al., 2013).
population and potentially augment established SUD Regarding the utility of memantine in the treatment of
treatments.
addictions, Krishnan-Sarin et al. (2015) reported that
among individuals with higher baseline levels of impul-
Antipsychotic sivity, those receiving 20 mg/day (titrated for 8 days) of
memantine reported not only reduced alcohol craving, as
Haloperidol
previously observed (Krupitsky et al., 2007), but also
It has been hypothesized, primarily based on preclinical increased alcohol drinking (Krishnan-Sarin et al., 2015).
studies, that increases in dopaminergic activity in the corti- These findings are similar to previously negative clinical
costriatal reward circuit following drug-related cues may trials, in which memantine did not improve alcohol, nico-
contribute to enhanced attentional bias toward these salient tine, or cocaine dependence (Bisaga et al., 2011; Evans
drug-related cues, thus leading to continued drug use et al., 2007; Jackson et al., 2008). Conversely, in a study of
(Franken et al., 2004; Robinson and Berridge, 1993). Halo- opioid-dependent young adults, 30 mg memantine, in
peridol is a first-generation antipsychotic, traditionally used combination with buprenorphine/naloxone, showed prom-
in the treatment of schizophrenia spectrum disorders, by ise in the short-term treatment opioid use disorder, reducing
blocking dopaminergic D2 receptors throughout the central relapse and subsequent opioid use after individuals stopped
nervous system (Risch, 1996; Richelson, 1999; Jibson, taking buprenorphine/naloxone (Gonzalez et al., 2015),
2018). To date, few studies have explored the utility of thus warranting further exploration of memantine’s utility
haloperidol for the treatment of SUDs (Franken et al., 2004; to augment opioid use disorder treatments.
Berger et al., 1996). It has been demonstrated that an oral
4 mg dose of haloperidol decreased cue-elicited cocaine D-Cycloserine
cravings in individuals meeting criteria for cocaine depen-
D-Cycloserine (DCS) is a partial agonist of the NMDA-type
dence (Berger et al., 1996); however, an oral 2 mg dose did
glutamate receptor, at the glycine site (Sofuoglu et al.,
not attenuate opioid cravings among detoxified individuals
2013). It has demonstrated utility as an augmentation for
with opioid use disorder (Franken et al., 2004). In the same
behavioral interventions for anxiety disorders (McNally, recent clinical trial has established that treatment-seeking
2007; Ressler et al., 2004; Wilhelm et al., 2008). Furthermore, adolescents with cannabis use disorder receiving 1200 mg
among healthy individuals, it is has been shown to improve twice per day had 2.4 times the odds of having negative
declarative memory (Onur et al., 2010). While a recent study urine test for cannabis during treatment (Gray et al., 2012).
of a 50 mg dose of DCS did not attenuate cocaine cue NAC has also demonstrated utility in the treatment of
reactivity, as measured through subjective craving and phys- cocaine use disorder. A recent study administering
iological reactivity, it has been shown to reduce smoking urges 2400 mg/day over four practice days and seven mainte-
and physiological reactivity in response to smoking cues nance days demonstrated that NAC attenuated salience of
among nicotine-dependent participants (Santa Ana et al., cocaine-related cues (Levi Bolin et al., 2017). Furthermore,
2015; Santa Ana et al., 2009). Additionally, evidence suggests secondary analysis demonstrated that among more impul-
that 50 mg of DCS enhanced reductions in alcohol cravings sive patients who were medication adherent, NAC had
during an extinction therapy session, an effect that was increased abstinence rates (Bentzley et al., 2016).
observed throughout all subsequent extinction sessions In terms of smoking abstinence, NAC has also shown
(MacKillop et al., 2015). However, enhancement of neuro- promise. One study of frontal striatal resting-state func-
cognitive function among substance users remains mixed tional connectivity demonstrated that participants receiving
(Kalechstein et al., 2014; Kamboj et al., 2011). This indicates 1200 mg twice per day reported less nicotine craving and
that DCS may have promise as a treatment for specific increased positive affect; additionally, they exhibited strong
substances of abuse, but further research is needed. frontal striatal resting-state functional connectivity and
continued abstinence (Froeliger et al., 2015). This evidence
Minocycline suggests that NAC has potential utility as an intervention
for SUDs via its modulation of glutamatergic pathways.
Minocycline, an antibiotic that treats acne, has been explored
for its potential cognitive-enhancing effects in the treatment of
neurodegenerative and neuropsychiatric disorders. For GABAergic medications
instance, there is preliminary evidence that minocycline im-
Tiagabine
proves the negative symptoms of schizophrenia and attention
(as measured by the continuous performance test, identical Several studies have demonstrated that tiagabine treatment
pairs), when added to an atypical antipsychotic treatment attenuates the subjective ratings of stimulant administration
protocol (Liu et al., 2014). There is additional evidence that (cocaine and nicotine). One study showed that following two
minocycline improves performance on measures of working oral doses of 4 mg of tiagabine participants reported attenuated
memory, as well as avolition and anxiety/depressive symp- subjective ratings of “stimulated” and “cocaine craving,” after
tomology in treatment refractory patients with schizophrenia intravenous cocaine administration (Sofuoglu and Kosten,
or schizoaffective disorder (Kelly et al., 2015). 2005). Another study of cocaine-dependent participants
Regarding its use for treatment of SUDs, research has demonstrated decreased levels of the inactive cocaine metab-
shown that, among healthy controls, 4e5 days of 200 mg/day olite, benzoylecgonine, following daily doses of tiagabine
minocycline improved response inhibition and attenuates (20 mg/day) and weekly CBT for 10 weeks (Winhusen et al.,
subjective reward effects in response to dextroamphetamine 2005). Additionally, among overnight abstinent smokers in a
(Sofuoglu et al., 2011a). Additionally, minocycline demon- double-blind, placebo-controlled cross-over study, 8 mg of
strated a greater reduction in craving for cigarettes within an tiagabine demonstrated that it attenuated positive subject rat-
IV nicotine paradigm, among smokers receiving 4 days of ings and craving in response to intravenous nicotine, as well as
200 mg/day minocycline treatment (Sofuoglu et al., 2009a). improved performance in the Stroop test (Sofuoglu et al.,
This illustrates its potential use in the treatment of nicotine and 2005). Of note, one study demonstrated that tiagabine did not
exploration of its use in the treatment of other stimulant use differ from placebo responding on a vigilance task (Morgan
disorders. and Malison, 2008). Accordingly, tiagabine shows promising
results for reducing drug craving and positive drug effects
N-Acetylcysteine through improvement of cognitive functioning.
N-acetylcysteine (NAC) is an agent that modulates gluta-
matergic pathways, which has begun to be studied in Exogenous sex steroids
psychiatric disorders (for review, see Dean et al. (2011)).
Estradiol
Of note, it has also been shown to normalize glutamate
levels among cocaine-dependent patients, and thus, it is Accumulating evidence suggests that estradiol modulates
currently being explored as an intervention for SUDs cognitive functioning, with higher levels of estradiol associ-
(Schmaal et al., 2012). It has begun to be studied specif- ated with improvement on performances on tests of verbal
ically as a treatment for adolescent cannabis use disorder. A fluency, fine motor skills, verbal memory, spatial abilities, and
perceptual speed (Luine, 2014). Despite these cognitive Attenuating these impairments may prove to be a novel
improvements, high levels of estradiol are generally associ- area for the development of pharmacological interventions
ated with increased drug craving and response, likely through to improve treatment of SUDs. Review of the current
increasing levels of dopamine in the brain (Becker and Hu, literature indicates that many cognitive-enhancing phar-
2008). In the preclinical literature, administration of estradiol macological therapeutics are available; however, only
has been associated with enhanced positive drug effects, limited studies to date have explored their utility in the
motivation for drug use, and enhanced behavioral response to treatment of SUDs.
drugs (for review, see Becker and Hu (2008); Moran-Santa Among these limited studies, preliminary evidence
Maria et al. (2014)). Additionally, among clinical pop- suggests that minocycline may be one promising candidate
ulations, increased levels of endogenous estradiol have been for the future treatment of SUDs. Minocycline has gener-
associated with heightened reinforcing drug effects and ally decreased craving and other drug-related positive
enhanced subjective, positive drug responses, most notably subjective effects across several stimulants in preliminary
nicotine and cocaine (for review, see Moran-Santa Maria et al. studies (Sofuoglu et al., 2009a, 2011a). Given the evidence
(2014)). Thus, despite estradiol being associated with that minocycline also improves cognitive functions such as
improved cognitive functioning, it is unclear if it has utility in attention, response inhibition, and working memory, as
the treatment of SUDs. well as targets negative symptoms associated with schizo-
phrenia, exploration of the treatment utility of minocycline
Progesterone across substances use of abuse is promising (Liu et al.,
2014; Kelly et al., 2015; Sofuoglu et al., 2011a). Use of
Evidence has emerged that exogenous progesterone may be
progesterone in the treatment of SUDs also warrants further
utilized as a pharmacological treatment for SUDs, as it has a
investigation, as current research demonstrates that it im-
wide range of effect of the brain including modulating
proves cognitive functions important in SUD treatment,
cognitive functioning. Administering micronized, exogenous
such as response inhibition and information processing,
progesterone, which interacts with multiple neurotransmitter
while also decreasing urges/cravings for substances and
receptors (e.g., sigma, glutamate, GABAA, and nicotinic), has
positive subjective effects (Lynch and Sofuoglu, 2010; Fox
been shown to have positive effects on cognitive inhibition in et al., 2013; Evans, 2007; Sofuoglu et al., 2009b).
individuals abusing nicotine and cocaine (Baulieu, 1998;
Additionally, oral methamphetamine and dextroamphet-
Turkmen et al., 2011; Lynch and Sofuoglu, 2010; Milivojevic
amine, as well as derivatives of these substances, have
et al., 2016; Fox et al., 2013; Sofuoglu et al., 2011a). Men and
shown promise in generally lowering drug cravings and
women abstaining from cocaine demonstrated enhanced per-
reducing use of some stimulants (Mooney et al., 2009;
formance on the Stroop Color Word Task following 7 days of
Reed and Evans, 2016; Longo et al., 2010); however, future
administration of 400 mg/day progesterone (Fox et al., 2013).
research is needed to investigate the abuse potential of these
Similarly, a dose of 200 mg progesterone improved inhibitory
substances and determine novel directions for their devel-
control performance (measured by the Stroop Test) in women opment in SUDs treatment.
tobacco smokers (Sofuoglu et al., 2011b). Compared with
Based on the current literature, it is difficult to draw
placebo, progesterone has also been shown to enhance
overarching conclusions regarding the utility of these treat-
cognitive performance on the Digit Symbol Substitution Test
ments to modulate underlying cognitive mechanisms to treat
in abstinent tobacco smokers and improve scores on the
SUDs. There is a clear need for standardized measurements
Thought Facilitation Task scale on the Mayer-Salovey-Caruso
to assess the modulation of cognitive functioning in sub-
Emotional Intelligence Test among cocaine users who also
stance use treatment outcomes, as well as identify what
abuse alcohol (Sofuoglu et al., 2011b; Milivojevic et al.,
clinical populations are most likely to benefit from these
2014). In addition to enhancing cognitive effects, exogenous interventions. Kwako et al. (2016) have proposed a frame-
progesterone has been shown to also reduce drug craving/
work for assessing key cognitive domains in substance use,
urges and attenuate subjective positive effects of substances,
the Addictions Neuroclinical Assessment (ANA), which
including nicotine and cocaine (for review, see Lynch and
may address this limitation (Kwako et al., 2016). The ANA
Sofuoglu (2010); Evans (2007)). This promising evidence
includes focused assessment of three functional domains
suggests that progesterone may modulate effects of drugs of
relevant to SUDs, executive functioning, incentive salience,
abuse, at least in part, through cognitive enhancement.
and negative emotionality, paired with assessment of biolog-
ical (e.g., neuroimaging) and psychosocial (e.g., substance use
history) variables (Kwako et al., 2016). It has been postulated
Conclusions that the ANA will assist in the important integration of
There is a large body of literature that associates long-term research with clinical practice, as it directly compliments the
drug use with significant cognitive impairments, which efforts of the Research Domain Criteria (RDoC) to provide a
negatively impact SUDs treatment retention and outcomes. systematic framework to assess/treat SUDs as an
endophenotype (Kwako et al., 2016; DeVito et al., 2016). It Arnsten, A.F.T., Wang, M., Paspalas, C.D., 2015. Dopamine’s actions in
should also be noted that ANA has been criticized for not primate prefrontal cortex: challenges for treating cognitive disorders.
including a decision-making measures, a relevant cognitive Pharmacol. Rev. 67 (3), 681e696.
Ashare, R.L., Kimmey, B.A., Rupprecht, L.E., Bowers, M.E.,
domain for the assessment and treatment addiction, as well as
Hayes, M.R., Schmidt, H.D., 2016. Repeated administration of an
not including neurocognitive measures with established
acetylcholinesterase inhibitor attenuates nicotine taking in rats and
ecological validity, to improve translation between research smoking behavior in human smokers. Transl. Psychiatry 6 (1), e713.
and clinical practices (Verdejo-Garcia, 2017). Despite these Aston-Jones, G., Gold, J.I., 2009. How we say no: norepinephrine, inferior
potential limitations, ANA is one possible tool to elucidate the frontal gyrus, and response inhibition. Biol. Psychiatry 65 (7),
role of cognitive functioning in the etiology and development 548e549.
of SUDs and how modulation of addiction-relevant domains Bakhshaie, J., Zvolensky, M.J., Goodwin, R.D., 2015. Cigarette smoking
of cognitive functioning can be utilized in SUDs treatment, and the onset and persistence of depression among adults in the United
thus advancing clinical care (DeVito et al., 2016). States: 1994e2005. Compr. Psychiatry 60, 142e148.
Future research efforts should also focus on delineating the Band, G.P.H., van Boxtel, G.J.M., 1999. Inhibitory motor control in stop
individual differences regarding response to pharmacological paradigms: review and reinterpretation of neural mechanisms. Acta
Psychol. 101 (2), 179e211.
cognitive enhancers, which may affect what clinical
Bari, A., Mar, A.C., Theobald, D.E., et al., 2011. Prefrontal and
populations would most benefit from these treatments. For
monoaminergic contributions to stop-signal task performance in rats.
instance, it is unclear based on the current evidence if J. Neurosci. 31 (25), 9254e9263.
individuals with mild versus more severe cognitive impair- Bates, M.E., Buckman, J.F., Nguyen, T.T., 2013. A role for cognitive
ments, or those with comorbid psychiatric disorders, would be rehabilitation in increasing the effectiveness of treatment for alcohol
more likely to benefit from these pharmacological approaches. use disorders. Neuropsychol. Rev. 23 (1), 27e47.
Additionally, it is currently unclear at what point during SUDs Baulieu, E.E., 1998. Neurosteroids: a novel function of the brain.
treatment these medications should be implemented Psychoneuroendocrinology 23 (8), 963e987.
(e.g., following abstinence) or if they may be utilized to Becker, J.B., Hu, M., 2008. Sex differences in drug abuse. Front.
augment current psychological interventions, such as CBT. Neuroendocrinol. 29 (1), 36e47.
The implementation of a standardized measurement, such as Bengtsson, M., Godbolt, A.K., 2016. Effects of acetylcholinesterase
inhibitors on cognitive function in patients with chronic traumatic
the ANA, would allow for important clarification regarding
brain injury: a systematic review. J. Rehabil. Med. 48 (1), 1e5.
who would most likely benefit from these interventions and
Bentzley, J.P., Tomko, R.L., Gray, K.M., 2016. Low pretreatment
the way they should be implemented in an individual’s treat- impulsivity and high medication adherence increase the odds of
ment plan. abstinence in a trial of N-acetylcysteine in adolescents with cannabis
Overall, the present review indicates that pharmaco- use disorder. J. Subst. Abus. Treat. 63, 72e77.
logical cognitive enhancement is a promising treatment for Berger, S.P., Reid, M.S., Delucchi, K., et al., 1996. Haloperidol antago-
SUDs; however, significant future research is needed to nism of cue-elicited cocaine craving. Lancet 347 (9000), 504e508.
elucidate the utility of such treatments across different Bisaga, A., Sullivan, M.A., Cheng, W.Y., et al., 2011. A placebo
substances and populations. controlled trial of memantine as an adjunct to oral naltrexone for
opioid dependence. Drug Alcohol Depend. 119 (1e2), e23ee29.
Bolla, K.I., Brown, K., Eldreth, D., Tate, K., Cadet, J.L., 2002. Dose-
Acknowledgments related neurocognitive effects of marijuana use. Neurology 59 (9),
This work was supported by the Veterans Administration Mental 1337.
Illness Research, Education and Clinical Center (MIRECC), and Brewer, J.A., Worhunsky, P.D., Carroll, K.M., Rounsaville, B.J.,
National Institute of Drug Abuse (NIDA training grant T32- Potenza, M.N., 2008. Pre-treatment brain activation during Stroop task
DA007238). is associated with outcomes in cocaine dependent patients. Biol.
Psychiatry 64 (11), 998e1004.
Bymaster, F.P., Katner, J.S., Nelson, D.L., et al., 2002. Atomoxetine
References increases extracellular levels of norepinephrine and dopamine in
prefrontal cortex of rat: a potential mechanism for efficacy in attention
Abernathy, K., Chandler, L.J., Woodward, J.J., 2010. Alcohol and the
deficit/hyperactivity disorder. Neuropsychopharmacology 27, 699.
prefrontal cortex. Int. Rev. Neurobiol. 91, 289e320.
Carpenter, K.M., Schreiber, E., Church, S., McDowell, D., 2006. Drug
Aharonovich, E., Shmulewitz, D., Wall Melanie, M., Grant Bridget, F.,
Stroop performance: relationships with primary substance of use and
Hasin Deborah, S., 2017. Self-reported cognitive scales in a US
treatment outcome in a drug-dependent outpatient sample. Addict.
National Survey: reliability, validity, and preliminary evidence for
Behav. 31 (1), 174e181.
associations with alcohol and drug use. Addiction 112 (12),
Carrà, G., Nicolini, G., Crocamo, C., et al., 2017. Executive control in
2132e2143.
schizophrenia: a preliminary study on the moderating role of COMT
Anderson, B.A., 2016. What is abnormal about addiction-related atten-
Val158Met for comorbid alcohol and substance use disorders. Nord. J.
tional biases? Drug Alcohol Depend. 167, 8e14.
Psychiatr. 71 (5), 332e339.
Carroll, K.M., Kiluk, B.D., Nich, C., et al., 2014. Computer-assisted behavioral therapy for cocaine dependence in a randomized clinical
delivery of cognitive-behavioral therapy: efficacy and durability of trial. Drug Alcohol Depend. 183, 162e168.
CBT4CBT among cocaine-dependent individuals maintained on Diehl, A., Nakovics, H., Mutschler, J., Hermann, D., Kiefer, F., 2009.
methadone. Am. J. Psychiatry 171 (4), 436e444. Rivastigmine reduces tobacco craving in alcohol-dependent smokers.
Carroll, K.M., Charla, N., DeVito, E.E., Shi, J.M., Sofuoglu, M., 2018. Pharmacopsychiatry 42 (03), 89e94.
Galantamine and computerized cognitive behavioral therapy for Dougherty, D.M., Marsh-Richard, D.M., Hatzis, E.S., Nouvion, S.O.,
cocaine dependence: a randomized clinical trial. J. Clin. Psychiatry 79 Mathias, C.W., 2008. A test of alcohol dose effects on multiple
(1), 17m11669. behavioral measures of impulsivity. Drug Alcohol Depend. 96 (1e2),
Chamberlain, S.R., del Campo, N., Dowson, J., et al., 2007. Atomoxetine 111e120.
improved response inhibition in adults with attention deficit/hyper- Durazzo, T.C., Meyerhoff, D.J., Nixon, S.J., 2012. A comprehensive
activity disorder. Biol. Psychiatry 62 (9), 977e984. assessment of neurocognition in middle-aged chronic cigarette
Chamberlain, S.R., Hampshire, A., Müller, U., et al., 2009. Atomoxetine smokers. Drug Alcohol Depend. 122 (1e2), 105e111.
modulates right inferior frontal activation during inhibitory control: a Dürsteler, K.M., Berger, E.-M., Strasser, J., et al., 2015. Clinical potential
pharmacological functional magnetic resonance imaging study. Biol. of methylphenidate in the treatment of cocaine addiction: a review of
Psychiatry 65 (7), 550e555. the current evidence. Subst. Abuse Rehabil. 6, 61e74.
Chambers, C.D., Garavan, H., Bellgrove, M.A., 2009. Insights into the Eack, S.M., Hogarty, G.E., Greenwald, D.P., Hogarty, S.S.,
neural basis of response inhibition from cognitive and clinical Keshavan, M.S., 2007. Cognitive enhancement therapy improves
neuroscience. Neurosci. Biobehav. Rev. 33 (5), 631e646. emotional intelligence in early course schizophrenia: preliminary ef-
Colzato, L.S., van den Wildenberg, W.P.M., Hommel, B., 2007. Impaired fects. Schizophr. Res. 89 (1e3), 308e311.
inhibitory control in recreational cocaine users. PLoS One 2 (11), e1143. Eagle, D.M., Bari, A., Robbins, T.W., 2008a. The neuro-
Copersino, M.L., Schretlen, D.J., Fitzmaurice, G.M., et al., 2012. Effects psychopharmacology of action inhibition: cross-species translation of
of cognitive impairment on substance abuse treatment attendance: the stop-signal and go/no-go tasks. Psychopharmacology 199 (3),
predictive validation of a brief cognitive screening measure. Am. J. 439e456.
Drug Alcohol Abuse 38 (3), 246e250. Eagle, D.M., Baunez, C., Hutcheson, D.M., Lehmann, O., Shah, A.P.,
Corey-Bloom, J.R., Anand, J.V., Veach, J., et al., 1998. A randomized trial Robbins, T.W., 2008b. Stop-signal reaction-time task performance:
evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), role of prefrontal cortex and subthalamic nucleus. Cerebr. Cortex 18
a new acetylcholinesterase inhibitor, in patients with mild to moder- (1), 178e188.
ately severe Alzheimer’s disease. Int. J. Geriatr. Psychopharmacol. 1, Ersche, K.D., Turton, A.J., Chamberlain, S.R., Müller, U., Bullmore, E.T.,
55e65. Robbins, T.W., 2012. Cognitive dysfunction and anxious-impulsive
Cox, W., Fadardi, J., Pothos, E., 2006. The addiction-Stroop test: theo- personality traits are endophenotypes for drug dependence. Am. J.
retical considerations and procedural recommendations. Psychol. Bull. Psychiatry 169 (9), 926e936.
132 (3), 443e476. Evans, S.M., 2007. The role of estradiol and progesterone in modulating
Cox, W.M., Fadardi, J.S., Intriligator, J.M., Klinger, E., 2014. Attentional the subjective effects of stimulants in humans. Exp. Clin. Psycho-
bias modification for addictive behaviors: clinical implications. CNS pharmacol 15 (5), 418e426.
Spectr. 19 (3), 215e224. Evans, S.M., Levin, F.R., Brooks, D.J., Garawi, F., 2007. A pilot double-
Cunha, P.J., Gonçalves, P.D., Ometto, M., et al., 2013. Executive cogni- blind treatment trial of memantine for alcohol dependence. Alcohol
tive dysfunction and ADHD in cocaine dependence: searching for a Clin. Exp. Res. 31 (5), 775e782.
common cognitive endophenotype for addictive disorders. Front. Everitt, B.J., Belin, D., Economidou, D., Pelloux, Y., Dalley, J.W.,
Psychiatry 4, 126. Robbins, T.W., 2008. Neural mechanisms underlying the vulnerability
de Wit, H., 2009. Impulsivity as a determinant and consequence of drug to develop compulsive drug-seeking habits and addiction. Phil. Trans.
use: a review of underlying processes. Addict. Biol. 14 (1), 22e31. Biol. Sci. 363 (1507), 3125e3135.
Dean, A.C., London, E.D., Sugar, C.A., et al., 2009. Predicting adherence Fernández-Serrano, M.J., Perales, J.C., Moreno-López, L., Pérez-
to treatment for methamphetamine dependence from neuropsycho- García, M., Verdejo-García, A., 2012. Neuropsychological profiling
logical and drug use variables. Drug Alcohol Depend. 105 (1e2), of impulsivity and compulsivity in cocaine dependent individuals.
48e55. Psychopharmacology 219 (2), 673e683.
Dean, O., Giorlando, F., Berk, M., 2011. N-acetylcysteine in psychiatry: Field, M., Cox, W.M., 2008. Attentional bias in addictive behaviors: a
current therapeutic evidence and potential mechanisms of action. review of its development, causes, and consequences. Drug Alcohol
J. Psychiatry Neurosci. 36 (2), 78e86. Depend. 97 (1), 1e20.
DeVito, E.E., Blackwell, A.D., Clark, L., et al., 2009. Methylphenidate Field, M., Munafò, M.R., Franken, I.H.A., 2009. A meta-analytic inves-
improves response inhibition but not reflectioneimpulsivity in chil- tigation of the relationship between attentional bias and subjective
dren with attention deficit hyperactivity disorder (ADHD). craving in substance abuse. Psychol. Bull. 135 (4), 589e607.
Psychopharmacology 202 (1e3), 531e539. Fillmore, M.T., Rush, C.R., Hays, L., 2002. Acute effects of oral cocaine
DeVito, E.E., Carroll, K.M., Sofuoglu, M., 2016. Toward refinement of on inhibitory control of behavior in humans. Drug Alcohol Depend.
our understanding of the fundamental nature of addiction. Biol. Psy- 67 (2), 157e167.
chiatry 80 (3), 172e173. Fillmore, M.T., Rush, C.R., Marczinski, C.A., 2003. Effects of d-
DeVito, E.E., Kiluk, B.D., Nich, C., Mouratidis, M., Carroll, K.M., 2018. amphetamine on behavioral control in stimulant abusers: the role of
Drug Stroop: mechanisms of response to computerized cognitive prepotent response tendencies. Drug Alcohol Depend. 71 (2), 143e152.
Fox, H.C., Sofuoglu, M., Morgan, P.T., Tuit, K.L., Sinha, R., 2013. The Jackson, A., Nesic, J., Groombridge, C., Clowry, O., Rusted, J., Duka, T.,
effects of exogenous progesterone on drug craving and stress arousal 2009. Differential involvement of glutamatergic mechanisms in the
in cocaine dependence: impact of gender and cue type. Psychoneur- cognitive and subjective effects of smoking. Neuro-
oendocrinology 38 (9), 1532e1544. psychopharmacology 34, 257e265.
Franken, I.H.A., 2003. Drug craving and addiction: integrating psycho- Jibson, MD., 2018. First-generation antipsychotic medications: Pharma-
logical and neuropsychopharmacological approaches. Prog. Neuro cology, administration, and comparative side effects. UptoDate.
Psychopharmacol. Biol. Psychiatry 27 (4), 563e579. https://www.uptodate.com/contents/first-generation-antipsychotic-
Franken, I.H.A., Hendriks, V.M., Stam, C.J., Van den Brink, W., 2004. medications-pharmacology-administration-and-comparative-side-
A role for dopamine in the processing of drug cues in heroin depen- effects.
dent patients. Eur. Neuropsychopharmacol. 14 (6), 503e508. Joos, L., Goudriaan, A.E., Schmaal, L., et al., 2013. Effect of modafinil on
Friedman, J.I., Adler, D.N., Temporini, H.D., et al., 2001. Guanfacine impulsivity and relapse in alcohol dependent patients: a randomized,
treatment of cognitive impairment in schizophrenia. Neuro- placebo-controlled trial. Eur. Neuropsychopharmacol. 23 (8),
psychopharmacology 25 (3), 402e409. 948e955.
Friedman, N.P., Miyake, A., Young, S.E., DeFries, J.C., Corley, R.P., Jovanovski, D., Erb, S., Zakzanis, K.K., 2005. Neurocognitive deficits in
Hewitt, J.K., 2008. Individual differences in executive functions are cocaine users: a quantitative review of the evidence. J. Clin. Exp.
almost entirely genetic in origin. J. Exp. Psychol. Gen. 137 (2), Neuropsychol. 27 (2), 189e204.
201e225. Kalechstein, A.D., De La Garza, R., Newton, T.F., 2010. Modafinil
Froeliger, B., McConnell, P.A., Stankeviciute, N., McClure, E.A., administration improves working memory in methamphetamine-
Kalivas, P.W., Gray, K.M., 2015. The effects of N-Acetylcysteine on dependent individuals who demonstrate baseline impairment. Am. J.
frontostriatal resting-state functional connectivity, withdrawal symp- Addict. 19 (4), 340e344.
toms and smoking abstinence: a double-blind, placebo-controlled Kalechstein, AD., Yoon, JH., Mahoney 3rd, JJ., Newton, TF., Chang, L.,
fMRI pilot study. Drug Alcohol Depend. 156, 234e242. De La Garza 2nd, R., 2012. d-Cycloserine administration does not
Goldstein, R.Z., Volkow, N.D., 2011. Dysfunction of the prefrontal cortex affect neurocognition in concurrent cocaine- and nicotine-dependent
in addiction: neuroimaging findings and clinical implications. Nat. volunteers. Pharmacol Biochem Behav 103 (2), 403e407.
Rev. Neurosci. 12 (11), 652e669. Kalechstein, A.D., Mahoney, J.J., Verrico, C.D., De La Garza, R., 2014.
Goldstein, R.Z., Woicik, P.A., Maloney, T., et al., 2010. Oral methyl- Short-term, low-dose varenicline administration enhances information
phenidate normalizes cingulate activity in cocaine addiction during a processing speed in methamphetamine-dependent users. Neurophar-
salient cognitive task. Proc. Natl. Acad. Sci. U.S.A. 107 (38), macology 85, 493e498.
16667e16672. Kamboj, S.K., Massey-Chase, R., Rodney, L., et al., 2011. Changes in cue
Gonzalez, G., DiGirolamo, G., Romero-Gonzalez, M., Smelson, D., reactivity and attentional bias following experimental cue exposure
Ziedonis, D., Kolodziej, M., 2015. Memantine improves buprenor- and response prevention: a laboratory study of the effects of d-
phine/naloxone treatment for opioid dependent young adults. Drug cycloserine in heavy drinkers. Psychopharmacology 217 (1), 25e37.
Alcohol Depend. 156, 243e253. Kelly, D.L., Sullivan, K.M., McEvoy, J.P., et al., 2015. Adjunctive min-
Grant, J.E., Chamberlain, S.R., Schreiber, L., Odlaug, B.L., 2012. Neu- ocycline in clozapine treated schizophrenia patients with persistent
ropsychological deficits associated with cannabis use in young adults. symptoms. J. Clin. Psychopharmacol. 35 (4), 374e381.
Drug Alcohol Depend. 121 (1e2), 159e162. Krishnan-Sarin, S., O’Malley, S.S., Franco, N., et al., 2015. NMDA
Grasing, K., Mathur, D., Newton, T.F., DeSouza, C., 2010. Donepezil receptor antagonism has differential effects on alcohol craving and
treatment and the subjective effects of intravenous cocaine in depen- drinking in heavy drinkers. Alcohol Clin. Exp. Res. 39 (2), 300e307.
dent individuals. Drug Alcohol Depend. 107 (1), 69e75. Krupitsky, E.M., Neznanova, O., Masalov, D., et al., 2007. Effect of
Gray, K.M., Carpenter, M.J., Baker, N.L., et al., 2012. A double-blind memantine on cue-induced alcohol craving in recovering alcohol-
randomized controlled trial of N-acetylcysteine in cannabis- dependent patients. Am. J. Psychiatry 164 (3), 519e523.
dependent adolescents. Am. J. Psychiatry 169 (8), 805e812. Kwako, L.E., Momenan, R., Litten, R.Z., Koob, G.F., Goldman, D., 2016.
Grégoire, S., Rivalan, M., Le Moine, C., Dellu-Hagedorn, F., 2012. The Addictions neuroclinical assessment: a neuroscience-based framework
synergy of working memory and inhibitory control: behavioral, for addictive disorders. Biol. Psychiatry 80 (3), 179e189.
pharmacological and neural functional evidences. Neurobiol. Learn. Leeman, R.F., Robinson, C.D., Waters, A.J., Sofuoglu, M., 2014.
Mem. 97 (2), 202e212. A critical review of the literature on attentional bias in cocaine use
Hart, C.L., Haney, M., Vosburg, S.K., Rubin, E., Foltin, R.W., 2007. disorder and suggestions for future research. Exp. Clin. Psycho-
Smoked cocaine self-administration is decreased by modafinil. pharmacol 22 (6), 469e483.
Neuropsychopharmacology 33, 761. Levi Bolin, B., Alcorn III, J.L., Lile, J.A., et al., 2017. N-Acetylcysteine
Hashimoto, K., 2009. Emerging role of glutamate in the pathophysiology reduces cocaine-cue attentional bias and differentially alters cocaine
of major depressive disorder. Brain Res. Rev. 61 (2), 105e123. self-administration based on dosing order. Drug Alcohol Depend. 178,
Hester, R., Lee, N., Pennay, A., Nielsen, S., Ferris, J., 2010. The effects of 452e460.
modafinil treatment on neuropsychological and attentional bias per- Levin, F.R., Evans, S.M., Brooks, D.J., Garawi, F., 2007. Treatment of
formance during 7-day inpatient withdrawal from methamphetamine cocaine dependent treatment seekers with adult ADHD: double-blind
dependence. Exp. Clin. Psychopharmacol 18 (6), 489e497. comparison of methylphenidate and placebo. Drug Alcohol Depend.
Hill, K.P., Sofuoglu, M., 2007. Biological treatments for amphetamine 87 (1), 20e29.
dependence: recent progress. CNS Drugs 21 (10), 851.
Levin, E.D., Bushnell, P.J., Rezvani, A.H., 2011. Attention-modulating Minzenberg, M.J., Carter, C.S., 2007. Modafinil: a review of neuro-
effects of cognitive enhancers. Pharmacol. Biochem. Behav. 99 (2), chemical actions and effects on cognition. Neuropsychopharmacology
146e154. 33, 1477.
Li, C.-S.R., Morgan, P.T., Matuskey, D., et al., 2010. Biological markers Monterosso, J.R., Aron, A.R., Cordova, X., Xu, J., London, E.D., 2005.
of the effects of intravenous methylphenidate on improving inhibitory Deficits in response inhibition associated with chronic methamphet-
control in cocaine-dependent patients. Proc. Natl. Acad. Sci. U.S.A. amine abuse. Drug Alcohol Depend. 79 (2), 273e277.
107 (32), 14455e14459. Mooney, M.E., Herin, D.V., Schmitz, J.M., Moukaddam, N., Green, C.,
Littman, R., Takács, Á., 2017. Do all inhibitions act alike? A study of go/ Grabowski, J., 2009. Effects of oral methamphetamine on cocaine use:
no-go and stop-signal paradigms. PLoS One 12 (10), e0186774. a randomized, double-blind, placebo-controlled trial. Drug Alcohol
Liu, F., Guo, X., Wu, R., et al., 2014. Minocycline supplementation for Depend. 101 (1e2), 34e41.
treatment of negative symptoms in early-phase schizophrenia: a double Moran-Santa Maria, M.M., Flanagan, J., Brady, K., 2014. Ovarian hor-
blind, randomized, controlled trial. Schizophr. Res. 153 (1), 169e176. mones and drug abuse. Curr. Psychiatr. Rep. 16 (11), 511e511.
Longo, M., Wickes, W., Smout, M., Harrison, S., Cahill, S., White, J.M., Morgan, P.T., Malison, R.T., 2008. Pilot study of Lorazepam and tiaga-
2010. Randomized controlled trial of dexamphetamine maintenance bine effects on sleep, motor learning, and impulsivity in cocaine
for the treatment of methamphetamine dependence. Addiction 105 (1), abstinence. Am. J. Drug Alcohol Abuse 34 (6), 692e702.
146e154. Nigg, J.T., Wong, M.M., Martel, M.M., et al., 2006. Poor response
Luine, V.N., 2014. Estradiol and cognitive function: past, present and inhibition as a predictor of problem drinking and illicit drug use in
future. Horm. Behav. 66 (4), 602e618. adolescents at risk for alcoholism and other substance use disorders.
Lynch, W.J., Sofuoglu, M., 2010. Role of progesterone in nicotine J. Am. Acad. Child Adolesc. Psychiatry 45 (4), 468e475.
addiction: evidence from initiation to relapse. Exp. Clin. Psycho- Onur, O.A., Schlaepfer, T.E., Kukolja, J., et al., 2010. The N-Methyl-D-
pharmacol 18 (6), 451e461. Aspartate receptor Co-agonist D-cycloserine facilitates declarative
MacKillop, J., Few, L.R., Stojek, M.K., et al., 2015. D-cycloserine to learning and hippocampal activity in humans. Biol. Psychiatry 67
enhance extinction of cue-elicited craving for alcohol: a translational (12), 1205e1211.
approach. Transl. Psychiatry 5, e544. Pae, C.-U., 2013. Role of the cholinesterase inhibitors in the treatment of
Mahoney, J.J., Kalechstein, A.D., Verrico, C.D., Arnoudse, N.M., schizophrenia. Expert Opin. Investig. Drugs 22 (3), 293e298.
Shapiro, B.A., De La Garza, R., 2014. Preliminary findings of the Passamonti, L., Luijten, M., Ziauddeen, H., et al., 2017. Atomoxetine
effects of rivastigmine, an acetylcholinesterase inhibitor, on working effects on attentional bias to drug-related cues in cocaine dependent
memory in cocaine-dependent volunteers. Progress Neuro- individuals. Psychopharmacology 234 (15), 2289e2297.
Psychopharmacol. Biol. Psychiatry 50, 137e142. Patterson, F., Jepson, C., Strasser, A.A., et al., 2009. Varenicline improves
Mann, K., Ackermann, K., Diehl, A., et al., 2006. Galantamine: a mood and cognition during smoking abstinence. Biol. Psychiatry 65
cholinergic patch in the treatment of alcoholism: a randomized, (2), 144e149.
placebo-controlled trial. Psychopharmacology 184 (1), 115e121. Ray Li, C.-S., Huang, C., Constable, R.T., Sinha, R., 2006. Imaging
Mark, G.P., Shabani, S., Dobbs, L.K., Hansen, S.T., 2011. Cholinergic response inhibition in a stop-signal task: neural correlates independent
modulation of mesolimbic dopamine function and reward. Physiol. of signal monitoring and post-response processing. J. Neurosci. 26 (1),
Behav. 104 (1), 76e81. 186e192.
Marquand, A.F., De Simoni, S., O’Daly, O.G., Williams, S.C.R., Mourão- Reed, S.C., Evans, S.M., 2016. The effects of oral d-amphetamine on
Miranda, J., Mehta, M.A., 2011. Pattern classification of working impulsivity in smoked and intranasal cocaine users. Drug Alcohol
memory networks reveals differential effects of methylphenidate, Depend. 163, 141e152.
atomoxetine, and placebo in healthy volunteers. Neuro- Repantis, D., Laisney, O., Heuser, I., 2010. Acetylcholinesterase inhibitors
psychopharmacology 36, 1237. and memantine for neuroenhancement in healthy individuals: a sys-
McGuire, J.T., Botvinick, M.M., 2010. Prefrontal cortex, cognitive con- tematic review. Pharmacol. Res. 61 (6), 473e481.
trol, and the registration of decision costs. Proc. Natl. Acad. Sci. Ressler, K.J., Rothbaum, B.O., Tannenbaum, L., et al., 2004. Cognitive
U.S.A. 107 (17), 7922e7926. enhancers as adjuncts to psychotherapy: use of d-cycloserine in phobic
McKee, S.A., Potenza, M.N., Kober, H., et al., 2015. A translational individuals to facilitate extinctionof fear. Arch. Gen. Psychiatry 61
investigation targeting stress-reactivity and pre-frontal cognitive con- (11), 1136e1144.
trol with guanfacine for smoking cessation. J. Psychopharmacol. Richelson, E., 1999. Receptor pharmacology of neuroleptics: relation to
(Oxford, England) 29 (3), 300e311. clinical effects. J. Clin. Psychiatry 60 (Suppl. 10), 5e14.
McNally, R.J., 2007. Mechanisms of exposure therapy: how neuroscience Risch, C.S., 1996. Pathophysiology of schizophrenia and the role of newer
can improve psychological treatments for anxiety disorders. Clin. antipsychotics. Pharmacotherapy 16 (1), 11e14.
Psychol. Rev. 27 (6), 750e759. Robbins, T.W., Amnsten, A.F.T., 2009. The neuropsychopharmacology of
Milivojevic, V., Sinha, R., Morgan, P.T., Sofuoglu, M., Fox, H.C., 2014. fronto-executive function: monoaminergic modulation. Annu. Rev.
Effects of endogenous and exogenous progesterone on emotional in- Neurosci. 32, 267e287.
telligence in cocaine dependent men and women who also abuse Roberts, W., McKee, S., 2018. Effects of varenicline on cognitive per-
alcohol. Hum. Psychopharmacol. 29 (6), 589e598. formance in heavy drinkers: dose-response effects and associations
Milivojevic, V., Fox, H.C., Sofuoglu, M., Covault, J., Sinha, R., 2016. with drinking outcomes. Exp. Clin. Psychopharmacol 26 (1), 49e57.
Effects of progesterone stimulated allopregnanolone on craving and Robinson, T.E., Berridge, K.C., 1993. The neural basis of drug craving: an
stress response in cocaine dependent men and women. Psychoneur- incentive-sensitization theory of addiction. Brain Res. Rev. 18 (3),
oendocrinology 65, 44e53. 247e291.
Robinson, T.E., Berridge, K.C., 2008. The incentive sensitization theory of intravenous nicotine responses in humans. Pharmacol.
addiction: some current issues. Phil. Trans. Biol. Sci. 363 (1507), Biochem.Behav. 92 (1), 135e140.
3137e3146. Sofuoglu, M., Mitchell, E., Mooney, M., 2009b. Progesterone effects on
Rooke, S.E., Hine, D.W., Thorsteinsson, E.B., 2008. Implicit cognition subjective and physiological responses to intravenous nicotine in male
and substance use: a meta-analysis. Addict. Behav. 33 (10), and female smokers. Hum. Psychopharmacol. 24 (7), 559e564.
1314e1328. Sofuoglu, M., Sugarman, D.E., Carroll, K.M., 2010. Cognitive function as
Sachdev, P.S., Blacker, D., Blazer, D.G., et al., 2014. Classifying neuro- an emerging treatment target for marijuana addiction. Exp. Clin.
cognitive disorders: the DSM-5 approach. Nat. Rev. Neurol. 10, 634. Psychopharmacol 18 (2), 109e119.
Santa Ana, E.J., Prisciandaro, J.J., Saladin, M.E., et al., 2015. D-cyclo- Sofuoglu, M., Mooney, M., Kosten, T., Waters, A., Hashimoto, K., 2011a.
serine combined with cue exposure therapy fails to attenuate subjec- Minocycline attenuates subjective-rewarding effects of dextroam-
tive and physiological craving in cocaine dependence. Am. J. Addict. phetamine in humans. Psychopharmacology 213 (1), 61e68.
24 (3), 217e224. Sofuoglu, M., Mouratidis, M., Mooney, M., 2011b. Progesterone improves
Santa Ana, E.J., Rounsaville, B.J., Frankforter, T.L., et al., 2009. D- cognitive performance and attenuates smoking urges in abstinent
Cycloserine attenuates reactivity to smoking cues in nicotine depen- smokers. Psychoneuroendocrinology 36 (1), 123e132.
dent smokers: a pilot investigation. Drug Alcohol Depend. 104 (3), Sofuoglu, M., Herman, A.I., Li, Y., Waters, A.J., 2012. Galantamine at-
220e227. tenuates some of the subjective effects of intravenous nicotine and
Sarter, M., Lustig, C., Howe, W.M., Gritton, H., Berry, A.S., 2014. improves performance on a Go No-Go task in abstinent cigarette
Deterministic functions of cortical acetylcholine. Eur. J. Neurosci. 39 smokers: a preliminary report. Psychopharmacology 224 (3),
(11), 1912e1920. 413e420.
Sava, S., McCaffrey, A., Yurgelun-Todd, Deborah, A., 2009. Gender, Sofuoglu, M., DeVito, E.E., Waters, A.J., Carroll, K.M., 2013. Cognitive
cognition, and addiction. In: Brady Kathleen, T., Back Sudie, E., enhancement as a treatment for drug addictions. Neuropharmacology
Greenfield, S.F. (Eds.), Women & Addiction A Comprehensive 64 (1), 452e463.
Handbook. The Guilford Press, New York, NY, pp. 133e146. Sofuoglu, M., DeVito, E.E., Waters, A.J., Carroll, K.M., 2016. Cognitive
Scahill, L., Chappell, P.B., Kim, Y.S., et al., 2001. A placebo-controlled function as a trans-diagnostic treatment target in stimulant use disor-
study of guanfacine in the treatment of children with tic disorders ders. J. Dual Diagnosis 12 (1), 90e106.
and attention deficit hyperactivity disorder. Am. J. Psychiatry 158 (7), Squeglia, L.M., Jacobus, J., Nguyen-Louie, T.T., Tapert, S.F., 2014.
1067e1074. Inhibition during early adolescence predicts alcohol and marijuana use
Schilström, B., Ivanov, V.B., Wiker, C., Svensson, T.H., 2006. Galant- by late adolescence. Neuropsychology 28 (5), 782e790.
amine enhances dopaminergic neurotransmission in vivo via allosteric Streeter, C.C., Terhune, D.B., Whitfield, T.H., et al., 2007. Performance on
potentiation of nicotinic acetylcholine receptors. Neuro- the Stroop predicts treatment compliance in cocaine-dependent
psychopharmacology 32, 43e53. individuals. Neuropsychopharmacology 33, 827.
Schmaal, L., Veltman, D.J., Nederveen, A., van den Brink, W., Swanson, C.J., Perry, K.W., Koch-Krueger, S., Katner, J., Svensson, K.A.,
Goudriaan, A.E., 2012. N-acetylcysteine normalizes glutamate levels Bymaster, F.P., 2006. Effect of the attention deficit/hyperactivity
in cocaine-dependent patients: a randomized crossover magnetic disorder drug atomoxetine on extracellular concentrations of norepi-
resonance spectroscopy study. Neuropsychopharmacology 37 (9), nephrine and dopamine in several brain regions of the rat. Neuro-
2143e2152. pharmacology 50 (6), 755e760.
Schmaal, L., Joos, L., Koeleman, M., Veltman, D.J., van den Brink, W., Swartz, B.E., McDonald, C.R., Patel, A., Torgersen, D., 2008. The effects
Goudriaan, A.E., 2013. Effects of modafinil on neural correlates of of guanfacine on working memory performance in patients with
response inhibition in alcohol-dependent patients. Biol. Psychiatry 73 localization-related epilepsy and healthy controls. Clin. Neuro-
(3), 211e218. pharmacol. 31 (5), 251e260.
Schottenfeld, R.S., Chawarski, M.C., Sofuoglu, M., et al., 2018. Atom- Thaker, G.K., Carpenter Jr., W.T., 2001. Advances in schizophrenia. Nat.
oxetine for amphetamine-type stimulant dependence during bupre- Med. 7, 667.
norphine treatment: a randomized controlled trial. Drug Alcohol Theunissen, E., Heckman, P., Sousa Fernandes Perna, E., et al., 2015.
Depend. 186, 130e137. Rivastigmine but not vardenafil reverses cannabis-induced impairment
Scott, J.C., Woods, S.P., Matt, G.E., et al., 2007. Neurocognitive effects of of verbal memory in healthy humans. Psychopharmacology 232 (2),
methamphetamine: a critical review and meta-analysis. Neuropsychol. 343e353.
Rev. 17 (3), 275e297. Tripathi, A., Kar, S.K., Shukla, R., 2018. Cognitive deficits in schizo-
Simon, S.L., Dean, A.C., Cordova, X., Monterosso, J.R., London, E.D., phrenia: understanding the biological correlates and remediation
2010. Methamphetamine dependence and neuropsychological func- strategies. Clin. Psychopharmacol. Neurosci. 16 (1), 7e17.
tioning: evaluating change during early abstinence. J. Stud. Alcohol Turkmen, S., Backstrom, T., Wahlstrom, G., Andreen, L., Johansson, I.-
Drugs 71 (3), 335e344. M., 2011. Tolerance to allopregnanolone with focus on the GABA-A
Sofuoglu, M., Kosten, T.R., 2005. Novel approaches to the treatment of receptor. Br. J. Pharmacol. 162 (2), 311e327.
cocaine addiction. CNS Drugs 19 (1), 13e25. Turner, D.C., Blackwell, A.D., Dowson, J.H., McLean, A., Sahakian, B.J.,
Sofuoglu, M., Mouratidis, M., Yoo, S., Culligan, K., Kosten, T., 2005. 2005. Neurocognitive effects of methylphenidate in adult attention-
Effects of tiagabine in combination with intravenous nicotine in deficit/hyperactivity disorder. Psychopharmacology 178 (2),
overnight abstinent smokers. Psychopharmacology 181 (3), 504e510. 286e295.
Sofuoglu, M., Waters, A.J., Mooney, M., O’Malley, S.S., 2009a. Mino-
cycline reduced craving for cigarettes but did not affect smoking or
Turner, T.H., LaRowe, S., Horner, M.D., Herron, J., Malcolm, R., 2009. Wagner, D., Becker, B., Koester, P., Gouzoulis-Mayfrank, E.,
Measures of cognitive functioning as predictors of treatment outcome Daumann, J., 2012. A prospective study of learning, memory,
for cocaine dependence. J. Subst. Abus. Treat. 37 (4), 328e334. and executive function in new MDMA users. Addiction 108 (1),
United Nations Office on Drug & Crime, 2017. Fact Sheet on Statistics and 136e145.
Trends in Illicit Drugs. Wagner, M., Schulze-Rauschenbach, S., Petrovsky, N., et al., 2013.
Verdejo-Garcia, A., 2017. Neuroclinical assessment of addiction needs to Neurocognitive impairments in non-deprived smokersdresults from a
incorporate decision-making measures and ecological validity. Biol. population-based multi-center study on smoking-related behavior.
Psychiatry 81 (7), e53ee54. Addict. Biol. 18 (4), 752e761.
Verdejo-García, A.J., Perales, J.C., Pérez-García, M., 2007. Cognitive Waters, A.J., Carter, B.L., Robinson, J.D., et al., 2009. Attentional bias is
impulsivity in cocaine and heroin polysubstance abusers. Addict. associated with incentive-related physiological and subjective mea-
Behav. 32 (5), 950e966. sures. Exp. Clin. Psychopharmacol 17 (4), 247e257.
Verplaetse, T.L., Pittman, B.P., Shi, J.M., Tetrault, J.M., Coppola, S., Wiers, R.W., Stacy, A.W., 2006. Handbook of Implicit Cognition and
McKee, S.A., 2016. Effect of varenicline combined with high-dose Addiction. Sage Publications, Thousand Oaks.
alcohol on craving, subjective intoxication, perceptual motor response, Wilhelm, S., Buhlmann, U., Tolin, D.F., et al., 2008. Augmentation of
and executive cognitive function in adults with alcohol use disorders: behavior therapy with d -cycloserine for obsessive-compulsive
preliminary findings. Alcohol Clin. Exp. Res. 40 (7), 1567e1576. disorder. Am. J. Psychiatry 165 (3), 335e341.
Verrico, C.D., Haile, C.N., Mahoney, J.J., Thompson-Lake, D.G.Y., Winblad, B., Cummings, J., Andreasen, N., et al., 2007. A six-month
Newton, T.F., De La Garza, R., 2014. Treatment with modafinil and double-blind, randomized, placebo-controlled study of a transdermal
escitalopram, alone and in combination, on cocaine-induced effects: a patch in Alzheimer’s diseaseee rivastigmine patch versus capsule.
randomized, double blind, placebo-controlled human laboratory study. Int. J. Geriatr. Psychiatry 22 (5), 456e467.
Drug Alcohol Depend. 141, 72e78. Winhusen, T.M., Somoza, E.C., Harrer, J.M., et al., 2005. A placebo-
Vonmoos, M., Hulka, L.M., Preller, K.H., Minder, F., Baumgartner, M.R., controlled screening trial of tiagabine, sertraline and donepezil as
Quednow, B.B., 2014. Cognitive impairment in cocaine users is drug- cocaine dependence treatments. Addiction 100, 68e77.
induced but partially reversible: evidence from a longitudinal study.
Neuropsychopharmacology 39 (9), 2200e2210.
Chapter 24
Cognitive research on addiction in a

changing policy landscape
Andrew Dawson1, Wayne Hall2, 3, 4 and Adrian Carter1, 2
1
School of Psychological Sciences, Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia; 2UQ
Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia; 3Centre for Youth Substance Abuse Research, University of
Queensland, Brisbane, QLD, Australia; 4National Addiction Centre, Kings College London, London, WC2R 2LS, United Kingdom
Introduction all policy changes have been in a more liberal direction.

Some governments, such as those in Australia, Brazil, and
Since the 1970s, cognitive research on addiction1 has Singapore, have banned the sale and criminalized the use of
advanced at an impressive rate. Pioneering developments in less hazardous ways of consuming some drugs, such as
precise and robust cognitive assessment (e.g., the Cam- electronic cigarettes. Some low- and middle-income coun-
bridge Neuropsychological Test Automated Battery; Rob- tries, such as the Philippines, have instituted widespread
bins et al., 1994) and task-based imaging technologies have extrajudicial murder as national drug control policy.
fueled this advance. There is now a growing literature on In this chapter we address the following questions: How
the cognitive processes that are perturbed in people much have advances in cognitive research on addiction
addicted to various substances, both licit (e.g., alcohol and influenced policies toward drugs, mental health, and crim-
nicotine) and illicit (e.g., opioids, stimulants, and psyche- inal justice in high-income countries? And how might they
delics), and some forms of addictive behaviors exert greater influence in the future? In contrast, how much
(e.g., gambling, gaming). have shifts in drug policy affected the sort of cognitive
During this period of scientific growth, the policy research that is being conducted around the globe? Are
landscape around the use of addictive substances and be- there looming shifts on the policy landscape for which
haviors has undergone major changes. For example, we cognitive researchers of addiction should prepare?
have witnessed a tentative and often contested embrace of We begin by briefly summarizing research insights into
harm reduction measures, such as supervised injecting addicted individuals’ cognitive functioning. We then
centers in some cities (e.g., Vancouver, Barcelona, Sydney, discuss cognitive research’s limited impact on policy to-
Melbourne) and trials of prescribed injectable opioids ward addictive drugs, mental health, and criminal justice
(e.g., United Kingdom, Switzerland, Canada, Spain) policy to date, before describing how cognitive science
(March et al., 2006). Recreational cannabis use has been research may influence policy in the future. We then argue
legalized in a growing number of jurisdictions (e.g., several that top-down changes to the policy landscape can sud-
US states, Canada, and Uruguay) and there is a growing denly and dramatically influence cognitive research on
skepticism about the justification and utility of the “war on addictions. To illustrate this, we discuss the plausible
drugs” (e.g., British Broadcasting Corporation, 2015). Not downstream effects on cognitive research of policies that
loosen restrictions on the use of psychedelic drugs in
1. We define “cognitive research on addiction” as peer-reviewed quanti- clinical research and the legalization of recreational
tative research that has employed neuropsychological or cognitive cannabis use.
(“decision-making”) paradigms (with or without neuroimaging) in casee
control studies of addicted individuals (both substance and gambling
addiction) and healthy controls. We do not include findings from Cognitive research on addiction
attention-based paradigms (e.g., cue reactivity and attentional bias modi-
fication) in this chapter, mostly for theoretical reasons (unconscious desires Addiction is commonly understood as an impaired ability
or “wants” are distinct from cognitive desires; Berridge et al., 2009) and to control one’s use of an addictive substance or one’s
also for brevity.

engagement in addictive forms of behavior. This impaired Subdomains of compulsivity are far from established,
decision-making is often described somewhat loosely as a but there is some agreement that cognitive inflexibility,
compulsion or loss of control. Cognitive research on attentional inflexibility, and habit learning (see above) are
addiction attempts to uncover in detail the specific decision- crucial processes in persons with compulsive tendencies
making processes that are affected when someone becomes (Fineberg et al., 2014). Relevant human evidence is sparse,
addicted to using a drug or engaging in a specific behavior however, as there are few available cognitive paradigms
in a way that adversely affects their life. capable of adequately capturing these processes. There is
also some uncertainty about how to demarcate “habits”
Aberrant learning from “compulsions” (Sjoerds et al., 2014). Sjoerds et al.
(2014) point out that while negative motivational habits, or
Addiction is often referred to as a "disorder of learning" “compulsions,” are distinct from motor habits, both are
(Hyman et al., 2006; Lewis, 2015). Addictive behaviors, on likely to play a role in addiction. A thorough attempt to
this view, are overlearned habits; people who have devel- map the compulsivity elements involved in gambling
oped addictions are initially goal-directed (or "model- addiction was a recent systematic review and metaanalysis
based") in their use of drugs or engagement in behavior from Van Timmeren et al. (2018). They found individuals
(i.e., they aim to experience hedonic or motivational effects with gambling addiction demonstrate performance deficits
from using the substance or behavior). Over time, however, on behavioral tasks requiring (1) cognitive flexibility, (2)
their need to use drugs or engage in the behavior comes to cognitive control of intuitive, but incorrect, responses, and
be habitual or "model-free" (Everitt and Robbins, 2016). (3) the ability to shift one’s prior response pattern or
Most of the empirical support for this account stems from attention.
work in rodents, although supportive evidence has emerged
from cross-sectional research on people with poly-
substance-, stimulant-, or alcohol-dependent use (Ersche Impaired impulse inhibition
et al., 2016; McKim et al., 2016; Sebold et al., 2014; A third line of cognitive research on addiction emphasizes
Sebold et al., 2017; Sjoerds et al., 2013; Voon et al., 2015; the importance of loss of top-down control as much as
cf. Hogarth et al., 2018). Longitudinal studies with human bottom-up habit domination or compulsion (Goldstein and
subjects are still required to track this potential transition Volkow, 2011). The “brake failure” perspective empha-
from goal-directed to habitual drug-related behaviors in sized in this line of research suggests that people with ad-
addicted individuals. dictions have difficulties on tasks that tap into response
inhibition (see “motor impulsivity” above) and executive
Impulsivity to compulsivity function. Establishing the dimensions of “executive func-
tion” has proven challenging, but cognitive control, plan-
Another conceptually overlapping cognitive account of
ning, task-and-rule shifting, and working memory often
addiction focuses on a transition from “impulsivity” to
feature in these models (Snyder et al., 2015). There is ev-
“compulsivity” (Fineberg et al., 2014). In humans, impul-
idence of deficits in these domains in individuals who are
sivity and compulsivity are multidimensional constructs.
alcohol-, cannabis-, cocaine-, methamphetamine-, and
Two dimensions of impulsivity are choice and motor
opioid-dependent (Baldacchino et al., 2012; Broyd et al.,
impulsivity (Hamilton et al., 2015a,b). Choice impulsivity 2016; Le Berre et al., 2017; Potvin et al., 2018; Potvin
(also referred to as excessive delay or temporal discount-
et al., 2014; Stephan et al., 2017; cf. Frazer et al., 2018;
ing) refers to a consistent tendency in most people to prefer
Hart et al., 2012).
to receive smaller rewards sooner rather than larger rewards
In sum, there are various competing and overlapping
later. Choice impulsivity is a potential behavioral marker,
theories of cognition in addictive behavior. However, there
or cognitive endophenotype, of addiction (Bickel et al.,
is no overarching consensus as to which model captures all
2014; MacKillop, 2013). Although not generally consid-
crucial features of cognition in addiction for all individuals.
ered to be a dimension of impulsivity (cf. Fineberg et al.,
Next, we look at the implications of this research for policy.
2014), risky decision-making under uncertainty seems to be
common in addicted individuals (Verdejo-Garcia et al.,
2018), along with the heightened discounting of later, Cognitive research on addiction and its
larger rewards. Motor impulsivity, or impaired response
(so far) limited impact on policy
inhibition, is an impaired ability to refrain from initiating a
response or difficulty in stopping an on-going response. It Cognitive research on addiction and chronic drug use has
also appears to be a defining cognitive feature of addicted been used to argue that addicted individuals have signifi-
individuals (Morein-Zamir and Robbins, 2015). cant impairments in decision-making capacity. These
Cognitive research on addiction in a changing policy landscape Chapter | 24 323
findings are supported by human neuroimaging and animal et al., 2016). It would also be ethically unjustifiable to
studies that identify neurobiological changes in brain punish people for behavior that they lack the cognitive
structure and function, which suggest that addicted incapacity to control. These two cognitive models imply a
dividuals have cognitive impairments. In the United States, strong domain-general degree of automaticity in the
this research has been used to argue that addiction is a behavior of people with addictions. It suggests that people
chronic and relapsing brain disease (Leshner, 1997; Vol- who are addicted would also be resistant to positive treat-
kow et al., 2016). This view has been heavily promoted by ment incentives (e.g., contingency management) and
the National Institute on Drug Addiction (NIDA), the body environment improvements (e.g., reduced gambling
responsible for 85% of the world’s addiction research (Hall advertising, secure accommodation, alcohol price increases,
et al., 2015). It is also a view that has been adopted by and so on). We know, however, that positive treatment
prominent addiction agencies such as the American Society incentives and environment improvements can both reduce
of Addiction Medicine (2011). drug consumption and enable people with addictions to
An explicit promise of the “brain disease model of move out of drug use.
addiction” (BDMA) is that it will improve addiction The impaired impulse inhibition account is potentially
treatment by providing more effective treatments, reducing more optimistic about addicted individuals’ agency and
the use of coercive and punitive responses to addictive prospects for recovery than habit- and compulsivity-
behavior, and reducing the stigma and discrimination focused accounts. It implies that much of the suffering
experienced by people with addictions (Volkow et al., that characterizes addiction could be reduced through
2016). There has been significant criticism of both the effective executive function training (e.g., tablet-based
evidence supporting a BDMA and its assumed positive working memory training or therapist-based goal manage-
impact on society (e.g., Heather, 2017; Lewis, 2015; Satel ment rehabilitation; Verdejo-Garcia, 2016), targeted envi-
and Lilienfeld, 2017). For a detailed review of the evidence, ronmental approaches to reduce the likelihood of drug use
see Hall et al. (2015). or harm (e.g., syringe dispensing machines that alleviate the
The view that addiction is a chronic brain disease that need to plan ahead and make it easier for people to make
“hijacks” users’ ability to control their drug use is incon- better decisions about drug consumption), or being
sistent with observational evidence that the majority of encouraged to “outsource” their higher-order thinking
people who meet lifetime diagnostic criteria for addiction in through “implementation intentions” or precommitment
epidemiological surveys have matured out of addiction, strategies (e.g., deciding to avoid people or places associ-
usually in the absence of treatment (Heyman, 2009). The ated with drug use) (Brandstätter et al., 2001; Gollwitzer,
fact that even severely dependent individuals are able to 1999). A potent example is the attempt to introduce
titrate or stop using drugs in response to small financial mandatory or voluntary precommitment cards that enable
rewards or punitive responses is also difficult to reconcile people with gambling addictions to set a maximum amount
with the chronic relapsing brain disease view of addiction of money they can lose before beginning gambling, before
(see Hall et al., 2015). cognitive distortions caused by gambling drastically impair
There is also very little evidence that the BDMA has their ability to stop gambling (Ladouceur et al., 2012).
produced the benefits that Leshner and colleagues prom- Unfortunately, many attempts to introduce precommitment
ised. While it is plausible that ascribing addiction to neu- approaches have been met with significant political and
rocognitive changes outside a person’s control may reduce commercial resistance, despite strong cognitive evidence to
the stigma of addiction, there has been no evidence that this support their trialling or introduction.
has proved to be the case. Longitudinal studies suggest that Keith Humphreys et al. (2017) recently argued that
neurobiological explanations of mental disorders may have “research on the brain and its interactions with the envi-
in fact increased stigma (Pescosolido, 2010). Advances in ronment . has only occasionally been applied in public
neuroscience have also failed to increase treatment seeking policy [emphasis added]” (p. 1237). This should come as
or treatment access, with 85% of people with addictions not no surprise to those who recognize that, unfortunately,
accessing any treatment, let alone more effective forms of scientific evidence is seldom the determining, or even a
treatment (Hall et al., 2015). major, factor in actual policy decisions (Australian Acad-
emy of Science, 2017; Humphreys and Piot, 2012). This
Potential policy impacts of cognitive accounts also holds true for cognitive research on addiction.
of addiction
Drug policy
One policy implication of work on aberrant learning and
compulsivity is that severe penalties (e.g., imprisonment) Cognitive research on addiction has had negligible impact
imposed after long delays (as typically happens in the on drug policy in large part because most policies and
criminal justice system) will fail to reduce drug use (Ersche regulations governing the sale and production of addictive
drugs emerged at the beginning of the 20th century, well (Freyer, 2018). The BDMA has similarly been employed to
before various types of addiction became the subject of support the continued prohibition of and “war” on drugs
systematic scientific investigation (Nutt and McLellan, (Courtwright, 2010; Vrecko, 2010).
2014). The major national agreements (such as the 1914
Harrison Act in the United States) that formed the basis of
Addiction treatment policy
modern drug control policies were in response to the
growing consumption of drugs, such as opium, laudanum, It is difficult to find evidence that cognitive research on
and cocaine and the social harms and nuisance that they addiction has had a positive effect on mental health policy.
caused (Courtwright, 2001). The changing attitudes toward Nora Volkow has claimed that advances in addiction
different types of drug use over the past century and reg- cognitive neuroscience paved the way for substance
ulations governing what we can drink or consume have addiction treatment to be covered under medical insurance
been driven by complex social and cultural concerns, such (“Obamacare”) in the Mental Health Parity and Addiction
as gender, class, commercial trade, and race (Berridge, Equity Act 2008 (Volkow and Koob, 2015). We were un-
2013). The “war on drugs” that emerged in the 1970s under able to find any convincing support for this claim, even in
President Nixon was in response to the cultural upheavals the document Volkow cites (Busch et al., 2014) or in other
of the late 1960s and a perceived epidemic of heroin use by relevant documents (e.g., Botticelli, 2014). It is possible
US soldiers in Vietnam. that this policy change may have come from subtle shifts in
The drivers of subsequent shifts in more liberal di- public opinion encouraged by the public embrace of some
rections (e.g., medicinal cannabis in the United States) are neurocognitive findings on addiction. Yet evidence for any
similarly difficult to disentangle. Public support for me- uptake of addiction science is absent and it is difficult to
dicinal and legalized cannabis probably grew in response to reconcile with longitudinal survey data showing that public
repeated exposure to claimed medical benefits of cannabis attitudes toward addicted individuals remain steadfastly
use, which have often gone beyond what the evidence negative (Pescosolido et al., 2010).
supports (Grant et al., 2003; Sznitman and Bretteville- Nor has the BDMA increased the use of effective harm
Jensen, 2015). Other political, social, and cultural factors reduction policies in the United States (e.g., needle and
have also played a role that remains to be elucidated (Cruz syringe programs [NSPs]; supervised injection centers;
et al., 2016, 2018). opioid substitution treatment [OST] programs; Mattick
Cognitive evidence has had little impact on the classi- et al., 2014). If addiction was widely accepted to be a brain
fication of substances as legal or illegal (Kalant, 2010; Nutt disease that hijacked people’s brains, as the BMDA claims,
et al., 2010). Cognitive factors have not played a major role then one might expect to see more public support for in-
in attempts to construct more “rational” scales of the harms terventions that reduce the harm caused by these disorders.
caused by different drugs of abuse (Nutt et al., 2007). Nutt However, access to harm reduction programs (e.g., NSPs,
and colleagues’ more “rational” classification of drugs was OST, injecting centers) in the United States is minimal, and
based primarily on the estimated individual and societal where they are provided, they are usually done in a punitive
harm that each drug produces. Concepts such as “intensity way, such as expelling patients from programs for failing to
of pleasure” and “psychological dependence” were the only recover, as indicated by a positive urine test (Nadelmann
parameters of relevance to the neurocognitive changes and LaSalle, 2017).
described above. The general point is illustrated by the very
minor role played by neurocognitive evidence in the de- Criminal justice policy
bates around legalization of recreational cannabis use in the
United States (Cressey, 2015). The loosening of regulations Volkow et al. (2016) have also claimed that addiction
of cannabis, whether as medicalized, decriminalized, or neuroscience has facilitated the passage of US legislation to
legalized recreational use, has arguably been the most reduce prison sentences for nonviolent drug-related
significant shift in drug policy in the United States in recent offending. Again, we cannot find support for this claim in
years. We take no particular stance on whether and how the documents cited for the claim. Increased treatment for
this evidence should have influenced cannabis policy de- addicted offenders is more likely to be the result of politi-
bates. It seems that public attitudes have become more cians, police, and judges realizing that mass incarceration
supportive of legalization primarily on the basis of growing of drug offenders is economically unsustainable (Williams,
familiarity with the alleged benefits of medicinal uses of 2015). For example, in California, the reduced imprison-
cannabis and political preferences, rather than on the neu- ment of nonviolent criminal offenders was driven by the
rocognitive literature (Cressey, 2015; Cruz et al., 2018). economic unsustainability of the state prison system.
These policy changes occurred despite the NIDA Director, Lobbying by the pharmaceutical industry and politicians’
Nora Volkow, using neuroscientific evidence to vigorously searching for ways to reduce the economic burden of
advocate against cannabis legalization in the United States prisons have encouraged courts’ to use legal coercion and
compulsory treatment to divert offenders from prisons Cognitive science also provides support for the use of
(Carter and Hall, 2018; Hall and Carter, 2013). financial incentives (e.g., vouchers or money) to encourage
individuals to refrain from using drugs (Higgins and Petry,
An avenue for a greater impact on mental 1999). There is good evidence that paying small amounts of
money to people with addictions to refrain from using
health and criminal justice policy
drugs can significantly reduce their drug use (cf. Washio
Cognitive science does offer some support for more et al., 2011). A Scottish study of pregnant smokers, for
effective criminal justice responses to addictive drug use, example, found that small financial rewards that accumu-
such as Sobriety 24/7 (Kleiman, 2009). These approaches lated over time reduced the number of women who smoked
aim to provide “swift, certain, and fair” punishment (SCFP) during pregnancy, increasing the length of their pregnancy
by ensuring quick delivery of less severe penalties for in- and their baby’s birth weight (Higgins et al., 2012).
fringements that are well-defined and articulated Cognitive science could be used to inform the design of
(e.g., testing positive for alcohol or drugs) (Curtis et al., reward schedules in financial incentive programs. These
2018). SCFP programs were introduced in Hawaii (Klei- programs are particularly effective for initiatives that only
man, 2009) and showed that addicted offenders reduced require adherence for short, defined periods of time
their drug use and offending in response to modest in- (e.g., during pregnancy, receiving Hepatitis vaccinations,
centives delivered swiftly and surely (e.g., avoiding short blood-borne virus treatment). Unfortunately, programs that
periods in jail) after testing positive for drugs. Kleiman reward or pay people with substance use disorders for not
reported observational evidence on the effectiveness of using drugs are often unpopular with the public and poli-
what he describes as “coerced abstinence” in a court in cymakers who believe that refraining from using drugs is
Hawaii in which drug use and recidivism in something that they should be doing without any reward.
methamphetamine-using offenders was substantially As we saw with the BDMA, moral attitudes toward people
reduced by requiring them to undergo random weekly with addictions are difficult to shift by providing mecha-
urinalyses and punishing positive urine tests with 24 h of nistic explanations of people’s behavior.
immediate and certain imprisonment. Kleiman argued that
court-supervised addiction treatment should be reserved for
offenders who fail to respond to this type of coerced Public policy can powerfully affect
abstinence program. Similar programs for repeat drink- cognitive research
driving offenders, such as Sobriety 24/7, have been
The changing regulation of substances can affect the type
shown to significantly reduce alcohol use and drink driving
of cognitive research that can be conducted. Regulatory
(Midgette, 2016).
barriers may be removed that make the use of a drug in
The use of incentives to assist people with addictions to
research difficult. Changes in drug policy may also create
control their drug use is consistent with neuroeconomic
new social environments that allow researchers to better
theories of addiction (e.g., Ainslie, 2001). These predict
study the cognitive effects of a drug. We briefly outline
that addicted individuals will be insensitive to large disin-
below two examples of how potential and recent changes in
centives that uncertainly occur in the distant future (e.g., a
long prison sentence following a protracted trial process) drug policy are affecting the type of cognitive research that
is now possible.
because they heavily discount future punishment against
the immediate benefits of drug use. While many of these
programs were developed without the direct influence of Loosening of restrictions on use of psychedelics
cognitive research, SCFP programs are consistent with in clinical research
what we know about the impact of addictive drug use on
cognition. Cognitive neuroscience could be used to support There is growing momentum to reduce restrictions on
their introduction (Curtis et al., 2018; Hall and Carter, studies of the therapeutic use of psychedelics (i.e., lysergic
2013) and optimize the design of the schedules of rein- acid diethylamide (LSD), psilocybin/psilocin, dipropyl-
forcement. While these programs are not couched explicitly tryptamine, ibogaine, ayahuasca, mescaline, and ketamine)
in the language of cognitive science, their features over- in the treatment of addiction and other clinical disorders
come the cognitive limitations of people with addictions in (Belouin and Henningfield, 2018). Concerns that people
that penalties are delivered quickly and with certainty and with addictions will abuse these substances are beginning
predictability and that the programs are simple to under- to decrease as evidence confirms that psychedelics have a
stand and require no elaborate planning or prospective low abuse potential and toxicity and have potential thera-
memory to complete (Curtis et al., 2018). Research on peutic benefits in conditions that are not responsive to
SCFP programs is preliminary but promising (Curtis et al., treatment (Morgan et al., 2017).
2018). Future evaluations are warranted.
The history of research on psychedelics as addiction They will permit researchers to study larger samples of
treatments provides a nice illustration of how drug policy people who are regularly using highly potent forms of
can affect research. During the 1950s and 60s, research on cannabis, thereby increasing the statistical power and sci-
LSD as a treatment for alcohol addiction flourished. The entific quality of studies on the cognitive effects of
findings from this early research were promising, if limited cannabis use. To date, most work in cannabis and cognition
by small samples and short follow-up periods. The state of has been cross-sectional and therefore unable to distinguish
the research was equivalent to phase 1 or 2 clinical studies between causation and correlation. It has also not been able
in current terminology (Belouin and Henningfield, 2018; to quantify the amount of cannabis used or the amounts of
Bogenschutz and Johnson, 2016). A metaanalysis of six cannabinoids administered.
randomized controlled trials concluded that LSD reduced Cannabis is often described as a single substance or at
drinking after 6 months (Krebs and Johansen, 2012). This best two: tetrahydrocannabinol (THC) and cannabidiol
research was abruptly halted in the 1970s because of fears (CBD). It is in fact made up of over 200 ingredients that
that LSD would be misused by young people and produce may have a yet-unknown impact on an individual’s
dramatic cultural changes. The recent loosening of recognition and behavior (Atakan, 2012). Most laboratory
strictions on clinical research is enabling a new wave of research relies on pharmaceutically controlled cannabinoid
trials of LSD treatment for alcohol and other addictions, products that contain a very limited number of the psy-
such as heroin (Savage and McCabe, 1973). Growing choactive cannabinoids. Recent research suggests that the
disenchantment and frustration with current treatments for psychotogenic effects of cannabis may be due to the high
addictive disorders, together with their enormous human concentrations of THC and low concentrations of CBD in
and economic burden, has prompted this willingness to modern hybridized plants (Murray et al., 2016). High
reexplore psychedelics’ therapeutic potential (Bogenschutz concentrations of CBD may have a neuroprotective effect,
and Johnson, 2016). Cultural practices (e.g., ayahuasca and and CBD may also be useful in treating epilepsy and
ibogaine use at addiction retreats in Latin America, Canada, psychoses (Englund et al., 2013; Perucca, 2017). It is not
and New Zealand) and the potential benefits of ketamine in clear what the relative effects of THC and CBD concen-
managing depression (DeWilde et al., 2015) may also have trations may be on cognition and mental health in humans.
been influential. Very preliminary evidence suggests that coadministration
Randomized controlled trials of psychedelics could of THC and CBD can reduce THC-induced time perception
include measures to assess whether the cognitive deficits errors, emotional blunting, and immediate and delayed
seen in alcohol-dependent individuals improve with LSD recall deficits (Englund et al., 2017), although much more
and psilocybin (Bogenschutz et al., 2015; Perry et al., work in humans is needed. The legalization of cannabis
2007). Deficits in executive function in alcohol-dependent may thus provide an opportunity to better understand
individuals (e.g., cognitive control, planning) may be whether CBD can offset the adverse effects of THC (Hall
amendable to recovery if psychedelic drugs’ can increase and Lynskey, 2016). Studies showing that CBD can reduce
“self-efficacy” and “self-reflection” and reduce cravings some THC-induced cognitive impairments require inde-
and negative affect (Bogenschutz et al., 2015; Jones et al., pendent replication (Colizzi and Bhattacharyya, 2017). If
2018). replicated, any policy change (e.g., requiring minimum
CBD levels in legal cannabis products) will also need to be
Legalization of recreational cannabis rigorously evaluated.
At the time of writing, recreational cannabis is legal in nine

states in the United States (Alaska, California, Colorado, Conclusion
Massachusetts, Maine, Nevada, Oregon, Vermont, and Cognitive research on the addictions has grown at an
Washington) and Uruguay. It will become legal in Canada impressive rate and is providing a comprehensive account
in October 2018. Legalization of recreational cannabis in of different types of compromised cognition in people who
these jurisdictions will make cannabis more readily acces- are addicted. There is increasing potential for cognitive
sible at a lower price and allow it to be used in the absence research to influence addiction treatment and criminal jus-
of criminal penalties. These changes are likely to increase tice policy if moralistic resistance to innovative approaches
the frequency of use among current cannabis users, among the public and policymakers can be reduced. Its
possibly increase their duration of use, and, in the longer tools will also prove extremely useful in assessing the
term, probably increase the number of cannabis users (Hall therapeutic effects of currently illicit drugs if policymakers
and Lynskey, 2016). open up new opportunities for cognitive researchers
These policy changes provide a number of natural ex- (e.g., by reducing barriers to research on psychedelics).
periments that will allow researchers to compare the effects These opportunities might, in turn, provide cognitive re-
of increased cannabis use on cognition (Cressey, 2015). searchers armed with new data a novel way to advocate for
drug policy reform, although history would suggest that Colizzi, M., Bhattacharyya, S., 2017. Does cannabis composition matter?
optimism about the impact of evidence should be tempered. Differential effects of delta-9-tetrahydrocannabinol and cannabidiol on
human cognition. Curr. Addict. Rep. 4 (2), 62e74.
Courtwright, D.T., 2001. Forces of Habit: Drugs and the Making of the
References Modern World. Harvard University Press, Cambridge, MA.
Courtwright, D., 2010. The NIDA brain-disease paradigm: history, resis-
Ainslie, G., 2001. Breakdown of Will. Cambridge University Press,
tance, and spinoffs. BioSocieties 5 (1), 137e147.
Cambridge.
Cressey, D., 2015. The cannabis experiment. Nature 524 (7565),
American Society of Addiction Medicine, 2011. Public Policy Statement:
280e283.
Definition of Addiction (Long Version). American Society of
Cruz, J.M., Boidi, M.F., Queirolo, R., 2018. Saying no to weed: public
Addiction Medicine, Chevy Chase, MD.
opinion towards cannabis legalisation in Uruguay. Drugs Educ. Prev.
Atakan, Z., 2012. Cannabis, a complex plant: different compounds and
Policy 25 (1), 67e76.
different effects on individuals. Ther. Adv. Psychopharmacol. 2 (6),
Cruz, J.M., Queirolo, R., Boidi, M.F., 2016. Determinants of public sup-
241e254.
port for marijuana legalisation in Uruguay, the United States, and El
Australian Academy of Science, 2017. An Interdisciplinary Approach to
Salvador. J. Drug Issues 46 (4), 308e325.
Living in a Risky World. Australian Academy of Science, Canberra.
Curtis, A., Youssef, G., Guadagno, B., Manning, V., Enticott, P.G., et al.,
Baldacchino, A., Balfour, D.J.K., Passetti, F., Humphris, G.,
2018. Swift, certain and fair justice: insights from behavioural learning
Matthews, K., 2012. Neuropsychological consequences of chronic
and neurocognitive research. Drug Alcohol Rev. 37 (Suppl. 1),
opioid use: a quantitative review and meta-analysis. Neurosci. Bio-
s240es245.
behav. Rev. 36, 2056e2068.
DeWilde, K.E., Levitch, C.F., Murrough, J.W., Mathew, S.J.,
Belouin, S.J., Henningfield, J.E., February 21, 2018. Psychedelics: where
Iosifescu, D.V., 2015. The promise of ketamine for treatment-resistant
we are now, why we got here, what we must do. Neuropharmacology
depression: current evidence and future directions. Ann. N. Y. Acad.
[Epub ahead of print].
Sci. 1345 (1), 47e58.
Berridge, K.C., Robinson, T.E., Aldridge, J.W., 2009. Dissecting com-
Englund, A., Freeman, T.P., Murray, R.M., McGuire, P., 2017. Can we
ponents of reward: ‘Liking’, ‘wanting’, and learning. Curr. Opin.
make cannabis safer? Lancet Psychiatry 4, 643e648.
Pharmacol. 9 (1), 65e73.
Englund, A., Morrison, P.D., Nottage, J., Hague, D., Kane, F., Kapur, S.,
Berridge, V., 2013. Demons: Our Changing Attitudes to Alcohol, Tobacco
2013. Cannabidiol inhibits THC-elicited paranoid symptoms and
and Drugs. Oxford University Press, Oxford.
hippocampal-dependent memory impairment. J. Psychopharmacol. 27
Bickel, W.K., Koffarnus, M.N., Moody, L., Wilson, A.G., 2014. The
(1), 19e27.
behavioural- and neuro-economic process of temporal discounting:
Ersche, K.D., Gillan, C.M., Jones, P.S., Williams, G.B., Ward, L.H.,
a candidate behavioral marker of addiction. Neuropharmacology
Robbins, T.W., 2016. Carrots and sticks fail to change behaviour in
76 (Pt B), 518e527.
cocaine addiction. Science 352 (6292), 1468e1471.
British Broadcasting Corporation, 2015. Has the War on Drugs Been Lost?
Everitt, B.J., Robbins, T.W., 2016. Drug addiction: updating actions to
http://www.bbc.com/news/health-31922609.
habits to compulsions ten years on. Annu. Rev. Psychol. 67, 23e50.
Bogenschutz, M.P., Johnson, M.W., 2016. Classic hallucinogens in the
Fineberg, N.A., Chamberlain, S.R., Goudriaan, A.E., Stein, D.J.,
treatment of addictions. Prog. Neuro-Psychopharmacol. Biol. Psy-
Vanderschuren, L.J., et al., 2014. New developments in human neu-
chiatry 64, 250e258.
rocognition: clinical, genetic, and brain imaging correlates of impul-
Bogenschutz, M.P., Forcehimes, A.A., Pommy, J.A., Wilcox, C.E.,
sivity and compulsivity. CNS Spectr. 19 (1), 69e89.
Barbosa, P., Strassman, R.J., 2015. Psilocybin-assisted treatment for
Frazer, K.M., Richards, Q., Keith, D.R., 2018. The long-term effects of
alcohol dependence: a proof-of-concept study. J. Psychopharmacol.
cocaine use on cognitive functioning: a systematic critical review.
29 (3), 289e299.
Behav. Brain Res. 348 (1), 241e262.
Botticelli, M., 2014. National Blueprint for Drug Policy Reform Released
Freyer, F.J., 2018. Director of Drug Abuse Institute Offers Words of
Today in Roanoake, VA. https://obamawhitehouse.archives.gov/blog/
Caution on Marijuana. https://www.bostonglobe.com/metro/2018/05/
2014/07/09/national-blueprint-drug-policy-reform-released-today-
03/words-caution-marijuana/mvdlHOrEjmtiQXFG0U66MJ/story.
roanoke-va.
html.
Brandstätter, V., Lengfelder, A., Gollwitzer, P.M., 2001. Implementation
Goldstein, R.Z., Volkow, N.D., 2011. Dysfunction of the prefrontal cortex
intentions and efficient action initiation. J. Personal. Soc. Psychol. 81
in addiction: neuroimaging findings and clinical implications. Nat.
(5), 946e960.
Rev. Neurosci. 12 (11), 652e669.
Broyd, S.J., van Hell, H.H., Beale, C., Yücel, M., Solowij, N., 2016. Acute
Gollwitzer, P.M., 1999. Implementation intentions: strong effects of sim-
and chronic effects of cannabinoids on human cognition e a sys-
ple plans. Am. Psychol. 54, 493e503.
tematic review. Biol. Psychiatry 79 (7), 557e567.
Grant, I., Gonzalez, R., Carey, C.L., Natarajan, L., Wolfson, T., 2003.
Busch, S.H., Epstein, A.J., Harhay, M.O., Fiellin, D.A., Un, H.,
Non-acute (residual) neurocognitive effects of cannabis use: a meta-
Barry, C.L., 2014. The effects of federal parity on substance use
analytic study. J. Int. Neuropsychol. Soc. 9 (5), 679e689.
disorder treatment. Am. J. Manag. Care 20 (1), 76e82.
Hall, W., Carter, A., 2013. How may neuroscience affect the way that the
Carter, A., Hall, W., 2018. From coerced to compulsory treatment of
criminal courts deal with addicted offenders? In: Vincent, N.A. (Ed.),
addiction in the patient’s best interests: is it supported by the evi-
Neuroscience and Legal Responsibility. Oxford University Press,
dence? In: Spivakovsky, C., Seear, K., Carter, A. (Eds.), Critical
Oxford, New York.
Perspectives on Coercive Interventions. Routledge, London.
Hall, W., Carter, A., Forlini, C., 2015. The brain disease model of Lewis, M., 2015. The Biology of Desire: Why Addiction Is Not a Disease.
addiction: is it supported by the evidence and has it delivered on its Scribe, Melbourne.
promises? Lancet Psychiatry 2 (1), 105e110. MacKillop, J., 2013. Integrating behavioral economics and behavioral
Hall, W., Lynskey, M., 2016. Evaluating the public health impacts of genetics: delayed reward discounting as an endophenotype for
legalizing recreational cannabis use in the United States. Addiction addictive disorders. J. Exp. Anal. Behav. 99 (1), 14e31.
111 (10), 1764e1773. March, J.C., Oviedo-Joekes, E., Perea-Milla, E., Carrasco, F., PEPSA
Hamilton, K.R., Littlefield, A.K., Anastasio, N.C., Cunningham, K.A., team, 2006. Controlled trial of prescribed heroin in the treatment of
Fink, L.H., et al., 2015a. Rapid-response impulsivity: definitions, opioid addiction. J. Subst. Abus. Treat. 31 (2), 203e211.
measurement issues, and clinical implications. Personal. Disord. 6 (2), Mattick, R.P., Breen, C., Kimber, J., Davoli, M., 2014. Buprenorphine
168e181. maintenance versus placebo or methadone maintenance for opioid
Hamilton, K.R., Mitchell, M.R., Wing, V.C., Balodis, I.M., Bickel, W.K., dependence. Cochrane Database Syst. Rev. 2, CD002207.
Fillmore, M., et al., 2015b. Choice impulsivity: definitions, measure- McKim, T.H., Bauer, D.J., Boettiger, C.A., 2016. Addiction history as-
ment issues, and clinical implications. Personal. Disord. 6 (2), 182e198. sociates with propensity to form habits. J. Cogn. Neurosci. 28,
Hart, C.L., Marvin, C.B., Silver, R., Smith, E.E., 2012. Is cognitive 1024e1038.
functioning impaired in methamphetamine users? A critical review. Midgette, G., 2016. A New Approach to Reducing Heavy Drinking and
Neuropsychopharmacology 37, 586e608. Alcohol-Involved Crime? Insights from RAND Research on 24/7
Heather, N., 2017. Q: is addiction a brain disease or a moral failing? A: Sobriety Programs. RAND Corporation, Santa Monica.
neither. Neuroethics 10 (1), 115e124. Morein-Zamir, S., Robbins, T.W., 2015. Fronto-striatal circuits in
Heyman, G., 2009. Addiction: A Disorder of Choice. Harvard University response-inhibition: relevance to addiction. Brain Res. 1628 (Pt A),
Press, Cambridge, MA. 117e129.
Higgins, S.T., Petry, N.M., 1999. Contingency management: incentives for Morgan, C., McAndrew, A., Stevens, T., Nutt, D., Lawn, W., 2017.
sobriety. Alcohol Res. Health 23 (2), 122e127. Tripping up addiction: the use of psychedelic drugs in the treatment of
Higgins, S.T., Washio, Y., Heil, S.H., Solomon, L.J., Gaalema, D.E., problematic drug and alcohol use. Curr. Opin. Behav. Sci. 13,
Higgins, T.M., Bernstein, I.M., 2012. Financial incentives for smok- 71e76.
ing cessation among pregnant and newly postpartum women. Prev. Murray, R.M., Quigley, H., Quattrone, D., Englund, A., Di Forti, M.,
Med. 55, s33es40/. 2016. Traditional marijuana, high-potency cannabis and synthetic
Hogarth, L., Lam-Cassettari, C., Pacitti, H., Currah, T., Mahlberg, J., et al., cannabinoids: increasing risk for psychosis. World Psychiatry 15 (3),
May 22, 2018. Intact goal-directed control in treatment-seeking drug 195e204.
users indexed by outcome-devaluation and Pavlovian to instrumental Nadelmann, E., LaSalle, L., 2017. Two steps forward, one step back:
transfer: critique of habit theory. Eur. J. Neurosci. [Epub ahead of current harm reduction policy and politics in the United States. Harm
print]. http://doi.10.1111/ejn.13961. Reduct. J. 14, 37.
Humphreys, K., Malenka, R.C., Knutson, B., MacCoun, R.J., 2017. Nutt, D.J., King, L.A., Phillips, L.D., 2010. Drug harms in the UK: a
Brains, environments, and policy responses to addiction. Science 356 multicriteria decision analysis. Lancet 376 (9752), 1558e1565.
(6344), 1237e1238. Nutt, D., King, L.A., Saulsbury, W., Blakemore, C., 2007. Development of
Humphreys, K., Piot, P., 2012. Scientific evidence alone is not sufficient a rational scale to assess the harm of drugs of potential misuse. Lancet
basis for health policy. BMJ 344, e1316. 369 (9566), 1047e1053.
Hyman, S., Malenka, R.C., Nestler, E.J., 2006. Neural mechanisms of Nutt, D., McLellan, A.T., 2014. Can neuroscience improve addiction
addiction: the role of reward-related learning and memory. Annu. Rev. treatment and policies? Publ. Health Rev. 35 (2), 1e12.
Neurosci. 29, 565e598. Perry Jr., E.B., Cramer, J.A., Cho, H.-S., Petrakis, I.L., Karper, L.P., Yale
Jones, J.L., Mateus, C.F., Malcolm, R.J., Brady, K.T., Back, S.E., 2018. Ketamine Study Group, 2007. Psychiatric safety of ketamine in psy-
Efficacy of ketamine in the treatment of substance use disorders: a chopharmacology research. Psychopharmacology 192 (2),
systematic review. Front. Psychiatry 9, 277. 253e260.
Kalant, H., 2010. Drug classification: science, politics, both or neither? Perucca, E., 2017. Cannabinoids in the treatment of epilepsy: hard evi-
Addiction 105 (7), 1146e1149. dence at last? J. Epilepsy Res. 7 (2), 61e76.
Kleiman, M., 2009. When Brute Force Fails: How to Have Less Crime and Pescosolido, B.A., Martin, J.K., Long, J.S., Medina, T.R., Phelan, J.,
Less Punishment. Princeton University Press, Princeton. Link, B., 2010. “A disease like any other?”: a decade of change in
Krebs, T.S., Johansen, P.O., 2012. Lysergic acid diethylamide (LSD) for public reactions to schizophrenia, depression, and alcohol depen-
alcoholism: meta-analysis of randomized controlled trials. dence. Am. J. Psychiatry 167, 1321e1330.
J. Psychopharmacol. 26 (7), 994e1002. Potvin, S., Pelletier, J., Grot, S., Hébert, C., Barr, A.M., Lecomte, T., 2018.
Ladouceur, R., Blaszczynski, A., Lalande, D.R., 2012. Pre-commitment in Cognitive deficits in individuals with methamphetamine use disorder:
gambling: a review of the empirical evidence. Int. Gambl. Stud. 12 a meta-analysis. Addict. Behav. 80, 154e160.
(2), 215e230. Potvin, S., Stavro, K., Rizkallah, E., Pelletier, J., 2014. Cocaine and
Le Berre, A.-P., Fama, R., Sullivan, E.V., 2017. Executive functions, cognition: a systematic quantitative review. J. Addict. Med. 8 (5),
memory, and social cognitive deficits and recovery in chronic alco- 368e376.
holism: a critical review to inform future research. Alcohol Clin. Exp. Robbins, T.W., James, M., Owen, A.M., Sahakian, B.J., McInnes, L.,
Res. 41 (8), 1432e1443. Rabbitt, P., 1994. Cambridge Neuropsychological Test Automated
Leshner, A.I., 1997. Addiction is a brain disease, and it matters. Science Battery (CANTAB): a factor analytic study of a large sample of
278 (5335), 45e47. normal elderly volunteers. Dementia 5 (5), 266e281.
Satel, S.L., Lilienfeld, S.O., 2017. If addiction is not best conceptualised a Van Timmeren, T., Daams, J.G., van Holst, R.J., Goudriaan, A.E., 2018.
brain disease, then what kind of disease is it? Neuroethics 10 (1), 19e24. Compulsivity-related neurocognitive performance deficits in gambling
Savage, C., McCabe, O.L., 1973. Residential psychedelic (LSD) therapy disorder: a systematic review and meta-analysis. Neurosci. Biobehav.
for the narcotic addict: a controlled study. Arch. Gen. Psychiatry 28, Rev. 84, 204e217.
808e814. Verdejo-Garcia, A., 2016. Cognitive training for substance use disorders:
Sebold, M., Deserno, L., Nebe, S., Schad, D.J., Garbusow, M., et al., 2014. neuroscientific mechanisms. Neurosci. Biobehav. Rev. 68,
Model-based and model-free decisions in alcohol dependence. Neu- 270e281.
ropsychobiology 70 (2), 122e131. Verdejo-Garcia, A., Chong, T.J., Stout, J.C., Yücel, M., London, E.D.,
Sebold, M., Nebe, S., Garbusow, M., Guggenmos, M., Schad, D.J., 2018. Stages of dysfunctional decision-making in addiction. Phar-
Heinz, A., 2017. When habits are dangerous: alcohol expectancies and macol. Biochem. Behav. 164, 99e105.
habitual decision making predict relapse in alcohol dependence. Biol. Volkow, N.D., Koob, G., 2015. Brain disease model of addiction: why is it
Psychiatry 82 (11), 847e856. so controversial? Lancet Psychiatry 2 (8), 677e679.
Sjoerds, Z., de Wit, S., van den Brink, W., Robbins, T.W., Beekman, A.T., Volkow, N.D., Koob, G.F., McLellan, A.T., 2016. Neurobiologic ad-
Veltman, D.J., 2013. Behavioral and neuroimaging evidence for vances from the brain disease model of addiction. N. Engl. J. Med.
overreliance on habit learning in alcohol-dependent patients. Transl. 374, 363e371.
Psychiatry 3, e337. Voon, V., Derbyshire, K., Ruck, C., Irvine, M.A., Worbe, Y.,
Sjoerds, Z., Luigjes, J., van den Brink, W., Denys, D., Yücel, M., 2014. Bullmore, E.T., 2015. Disorders of compulsivity: a common bias to-
The role of habits and motivation in human drug addiction: a reflec- wards learning habits. Mol. Psychiatry 20 (3), 345e352.
tion. Front. Psychiatry 5, 8. Vrecko, S., 2010. Birth of a brain disease: science, the state and addiction
Snyder, H.R., Miyake, A., Hankin, B.L., 2015. Advancing understanding neuropolitics. Hist. Hum. Sci. 23 (4), 52e67.
of executive function impairments and psychopathology: bridging the Washio, Y., Higgins, S.T., Heil, S.H., McKerchar, T.L., Badger, G.J.,
gap between clinical and cognitive approaches. Front. Psychol. 6, 328. Skelly, J.M., Dantona, R.L., 2011. Delay discounting is associated
Stephan, R.A., Alhassoon, O.M., Allen, K.E., Wollman, S.C., Hall, M., with treatment response among cocaine-dependent outpatients. Exp.
Grant, I., 2017. Meta-analyses of clinical neuropsychological tests of Clin. Psychopharmacol 19 (3), 243e248.
executive dysfunction and impulsivity in alcohol use disorder. Am. J. Williams, T., 2015. Police Leaders Join Call to Cut Prison Rosters. https://
Drug Alcohol Abuse 43 (1), 24e43. www.nytimes.com/2015/10/21/us/police-leaders-join-call-to-cut-
Sznitman, S.R., Bretteville-Jensen, A.L., 2015. Public opinion and medical prison-rosters.html.
cannabis policies: examining the role of underlying beliefs and
national medical cannabis policies. Harm Reduct. J. 12, 46.
Chapter 25
Population neuroscience in addiction

research
Tomás Paus
Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada; Departments of Psychology and Psychiatry,
University of Toronto, Toronto, ON, Canada
This chapter provides an introduction to population organization to a different one (e.g., behavior to gene
neuroscience, a combination of epidemiology, genetics, and regulation and vice versa);
neuroscience, and its use in addiction research. We start (3) Structural and functional complexity of the human
with a general overview of population neuroscience, its brain.”
goals, and approaches. We then identify motivations for
The three challenges can be met by conducting our
applying this approach in the context of addiction research
pursuits in large samples of participants drawn from the
and describe the design of two ongoing cohorts focusing on
general population and evaluated with state-of-the-art tools
adolescence and youth: the Saguenay Youth Study and the
for assessing (a) genes and their regulation; (b) external and
IMAGEN Study. After a brief overview of the findings
internal environments; and (c) brain properties, all done in
generated by these two studies, we focus on challenges
an integrative fashion and across life span (Fig. 25.1).
associated with the interpretation of such observations.
Next, I will describe briefly basic concepts pertinent for
We conclude with an outlook for future research in this
the assessment of (a) genes and their regulation;
area.
(b) physical and social environment; and (c) the brain
structure and function. For a detailed treatment of these
Population neuroscience: an overview topics, see Paus, 2016.
Let us begin by stating the obvious: human behavior is
complex and so are the forces that shape it. The same of Genes and gene regulation
course applies to the organ generating our behavior: the We differ from each other by thousands to millions of
human brain. Behavioral and brain traits provide comple- variants in the DNA sequence (Manolio et al., 2009). These
mentary explanatory levels, focusing on one or the other variants include single-nucleotide polymorphisms (SNPs),
reflects questions being asked. The main goal of population copy number variants, as well as copy number neutral
neuroscience is to gain understanding of the forces shaping inversions and translocations. It is not surprising that
the human brain from conception forward (Paus, 2010, discovering new associations between common SNPs and
2013, 2016). complex traits requires large samples. For example, recent
As pointed out elsewhere (Paus, 2016), “practitioners of efforts by the CHARGE and ENIGMA Consortia, and their
population neuroscience are cognizant of three key mutual replications, identified molecular architecture
challenges inherent in their pursuits: underlying cortical thickness and surface area of the human
(1) An infinite combination of factors influencing the brain cerebral cortex by metaanalyzing data obtained in over
from within (genes and their regulation) and the outside 40,000 individuals (BioRxiv 399402, 404558). Similarly,
(social and physical environment); a genome-wide association study (GWAS) carried out by
(2) Presence of developmental cascades that carry such the Psychiatric Genomics Consortium identified 128 SNPs
influences from one time point to the next (108 independent loci) associated with schizophrenia by
(e.g., prenatal to postnatal), from one organ to another comparing 36,989 cases with 113,075 controls (Biological
(e.g., cardiometabolic to brain), and from one level of insights from 108 schizophrenia-associated genetic loci,

FIGURE 25.1 Population Neuroscience: assessing (A) genes and their regulation; (B) external and internal environments; and (C) the brain properties
across the life span and generations. From (Paus, 2016).
2014). As expected, however, the amount of phenotypic DHS regions (5.1 enrichment). At the same time, SNP-
variance explained by these SNPs is small. Polygenic based heritability estimates are the highest for the DHS
scores calculated from the 108 genome-wide significant partition (79% SNP heritability), as compared with the
loci explained 3.4% variation on the liability scale to coding regions (8% SNP heritability) (Gusev et al., 2014).
schizophrenia (Biological insights from 108 schizophrenia- Thus, knowledge of genome biology is beginning to guide
associated genetic loci, 2014). This (low) number is the interpretation of GWAS-based findings. The key word
consistent with the highly polygenic nature of complex here is regulation of gene expression, either globally or in a
traits. tissue-specific manner. One can use the classical GWAS
Would considering all common SNPs explain more approach to search for genetic variants associated with
variance in a given phenotype? This is indeed the case, as interindividual variations in gene expression: expression
demonstrated for 49 different traits using the genome-wide Quantitative Trait Loci, eQTLs (Albert and Kruglyak,
complex trait analysis (Yang et al., 2011, 2013). We have 2015). Here, the level of gene expression represents a trait,
shown that an overall pattern of genotypic variations across with expression levels of 20,000þ genes measured in each
w500,000 SNPs explains up to 50% of phenotypic varia- sample either through expression microarrays or RNA
tions in the brain structure (Toro et al., 2015) and function sequencing. A GWAS approach is then used to identify
(Dickie et al., 2014). It is unlikely, however, that each of associations between genetic variations (SNPs) and
the 500,000 SNPs contributes equally, each adding expression levels, thus identifying eQTLs. Such GWAS-
0.0001% to the total of 50% of variance explained; not all based analyses of gene expression have been carried out
genomic locations are created equal. This brings us to in a number of different tissues, including the human brain
genome biology and the knowledge gained from projects (Ramasamy et al., 2014).
such as the Encyclopedia of DNA Elements, ENCODE In the human cerebral cortex, the regional pattern of
(Kellis et al., 2014). their expression isdfor some genesdhighly consistent
Genomes can be partitioned into a number of functional across individuals. As we describe below, this allows us to
domains. For example, all SNPs included in the 1000 Ge- use resources such as the Allen Human Brain Atlas
nomes dataset can be annotated (classified) as belonging to (Hawrylycz et al., 2012) to facilitate interpretations of
one of the following six partitions: coding region (0.9% of various MRI-derived phenotypes (see “Challenges and
all SNPs), untranslated region (0.9%), promoter (2.6%), outlook”).
DNase I hypersensitivity site (DHS; 16.4%), intron
(28.6%), and intergenic region (50.5%)dsee Table S4 in
Gusev et al., 2014. Genetic variants located in the different
Built and social environment
partitions may be over- or underrepresented among SNPs We are both recipients and creators of our environment
associated with a given trait. For example, across 11 (Kendler et al., 2003). There are countless variations and
common diseases, the top hits are highly enriched in the permutations of physical, built, and social environments
coding regions (13.8-fold enrichment) and less so in the that surround us in space and time. The physical and social
Population neuroscience in addiction research Chapter | 25 333
ecology contributesdtogether with genesdto many envi- Brain structure and function
ronments that exist in an individual’s body: on the body
Over the past 30þ years, MRI has become the method of
surfaces (e.g., microbes on our skin and in the gut) and in
choice for studying both structure and function of the
the circulating blood (e.g., micronutrients, toxins, inflam-
human brain across the life span. This is due to its versa-
matory molecules). Measuring these “body” environments
tility (same scanner used for measuring a variety of brain
is straightforward: one needs a biological sample (stool,
phenotypes), availability (e.g., w11,000 MRI units in the
urine, blood) and an appropriate high-throughput assay for
United States), and the noninvasive nature of MRI
assessing a particular part of the metabolome, a catalog
technology, namely no exposure to ionizing radiation. The
containing at least w8500 endogenous and w40,000
noninvasiveness makes MRI particularly suitable for
exogenous compounds (Wishart, 2011). Assessing
research studies of brain development and maturation in
individual’s ecosystem is more challenging. Asking a series
general (nonclinical) population. As pointed out above, the
of questions using a standard survey is the most common
majority of MRI scanners come equipped with basic
way for collecting information about the individual’s
hardware and software allowing one to acquire a wide
physical, built, and social environment. Although valuable,
variety of brain “images” using a particular temporal
there are two main disadvantages of the survey-based
sequence of radiofrequency pulses, gradients, and readouts
approach: (1) participant’s time (many hours required to
- a “scan” (Moore and Chung, 2017). These scans allow
cover multiple domains) and (2) self-reported nature of the
one to capture different types of MR signal, which is based
collected information and, therefore, possible biases and
on electromagnetic energy emitted by precessing nuclei of
errors. Alternative approaches are being developed by data
hydrogen; the most common types of images acquired in
scientists for extracting information about built and social
population-based studies include T1-weighted and
environment from various digital sources (See “Where do
T2-weighted images, diffusion tensor images (DTI), and
we go next”). Smartphones and other mobile technologies
functional MRI.
equipped with a GPS device, accelerometers, heart rate
Multimodal imaging of the brain structure, that is, a
monitors, or even sweat-based monitors of metabolites and
combination of multiple “scans” of the person’s brain
electrolytes (Gao et al., 2016) provide new opportunities
during a single session, is particularly helpful for deriving
for sampling individual’s behavior and physiology in time
multiple brain phenotypes and triangulating their neurobi-
and space, evaluating this individual-based metric against
ological underpinnings. Fig. 25.2 shows a particular
physical and social context using aggregate data. For
example of such a multimodal protocol, as employed in one
example, Hurvitz and colleagues used mobile technology
of our population-based studies of the human brain
(accelerometers, GPS devices, and/or a multimodal sensor)
(Bjornholm et al., 2017).
to create “LifeLogs” containing data derived from these
Using these images, one can derive a number of char-
devices that are, in turn, visualized in geospace with
acteristics informative with regard to normal and abnormal
“LifeLog Views” (Hurvitz et al., 2014).
brain development and maturation. Thus, owing to the high
In summary, technological advances are expanding our
contrast between gray and white matter, T1-weighted
abilities to assess the individual’s internal and external
images are particularly useful for estimatingdusing auto-
environments with an increasing breadth and precision.
matic image-processing toolsdthe size of the cerebral
Together with aggregate data mapped in well-defined
cortex (thickness, surface area) and its subdivisions (Fischl
geospatial units with high granularity, these tools allow
and Dale, 2000) and volumes of various subcortical struc-
us to relate the individual’s enviroment to his/her
tures, such as the hippocampus (Pipitone et al., 2014).
phenome.
FIGURE 25.2 Coronal slices of multimodal images of the brain structure acquired in members of a birth cohort when they reached 20 years of age. T1W,
T1-weighted image; qT1, T1 relaxation time; qT2, T2 relaxation time; MWF, myelin water fraction; FA, fractional anisotropy; MD, mean diffusivity;
MTR, magnetization transfer ratio. From Lerch, J.P., van der Kouwe, A.J., Raznahan, A., et al., 2017. Studying neuroanatomy using MRI. Nat. Neurosci.
20, 314e326.
Quantitative estimates of T1 and T2 relaxation times Labeling atlas (Tzourio-Mazoyer et al., 2002)), probabi-
provide valuable information about tissue properties of listic maps of cytoarchitecture (Eickhoff et al., 2007), or
various gray-matter (e.g., cerebral cortex) and white-matter metaanalyses of structural imaging studies (Cheung et al.,
(e.g., corpus callosum) structures. Images of myelin water 2010).
fraction and magnetization transfer ratio (MTR) captured The network structure of our brains implies constant
in a complementary fashiondrelative amount of myelin in functional interactions across various spatially segregated
a given 3D voxel; relative to other types of tissue occu- modules. Functional imaging studies provide a unique
pying the same voxel, such as the axon (Bjornholm et al., opportunity to quantify such interregional interactions by
2017). Finally, DTI-derived estimates of mean diffusivity virtue of measuring BOLD signals across the entire brain
and fractional anisotropy reflect constraints imposed on simultaneously. The primary tool for exploring the
water diffusion by the geometry (and biological properties) so-called functional connectivity has been a statistical
of cellular elements that make up a given voxel of imaged analysis of concurrent fluctuations in the BOLD signal over
tissue. Taking advantage of this feature when modeling time, with or without the engagement of a participant in a
spatial patterns of water motion across voxels, the so-called particular paradigm. Various methods have been introduced
tractography is used commonly to identify bundles of fibers to measure functional and effective connectivity, from
(Jbabdi et al., 2015); note that this approach works well for simple interregional correlations to multivariate techniques
long-range fibers that constitute, however, only w4% of all (reviewed in Friston, 2011).
axons (Schüz and Braitenberg, 2002). The above
MRI-derived metrics provide a toolbox with which one can Population neuroscience: addiction
embark on mapping the development and maturation of the
brain structure in vivo.
research
When mapping brain function, the most common MR A growing number of studies are asking questions about
signal used as an indirect index of neuronal activity, most the human brain and addiction; a total of 7376 items are
likely excitatory postsynaptic potentials (Logothetis et al., identified when searching PubMed (brain AND addiction,
2001), is the blood oxygenation leveledependent (BOLD) filtered for “humans,” April 2, 2019), increasing from 30
contrast; it arises from the disproportionate increase of items in 1990 to 449 items in 2018. What motivates this
blood flow into the region engaged functionally at a given work?
moment. In most fMRI studies, the degree of engagement Substance use and substance use disorders are among
of a particular brain region is measured simply by tracking the greatest contributors to preventable morbidity and
the BOLD signal over time and calculating the difference mortality worldwide (Rehm et al., 2009; Whiteford et al.,
between time segments that differ from each other with 2013; The Health Consequences of Smoking e 50 Years of
regard to the presence or absence of a particular stimulus Progress: A Report of the Surgeon General, 2014). A per-
ordin more general termsda difference in a particular son’s liability to develop and sustain a substance use dis-
well-defined behavioral state (e.g., anticipation of reward). order is unfolding during two periods: (1) adolescence,
This calculation is carried out throughout the brain voxel- when substance use emerges (Johnston et al., 2011) and
by-voxel, typically after a number of preprocessing steps; (2) young adulthood, when substance use peaks (Johnston
the main outputs of such analyses are statistical maps that et al., 2009; Sussman and Arnett, 2014; Chen and Jacob-
indicate in which voxels (regions) the BOLD signal son, 2012). Substance use disorders contribute to about 5%
measured during one state differs from that in another state. of years lived with disability (Whiteford et al., 2013); they
Although voxel-wise analyses of fMRI data allow for an also represent one of the most common comorbid condi-
unbiased search for (group) differences throughout the tions associated with other psychiatric disorders (Krishnan,
brain, it can be useful to restrict the “search space” to a set 2005). This public health imperative motivates research on
of specific brain regions in some instances. In particular, interindividual variations in the risk for developing
such a region-of-interest (ROI) approach is suitable for substance use (and its progression), as well as research on
testing specific hypothesis in large population-based studies possible consequences of substance use on mental and
in which one models a brain response in the context of a physical health. Population neuroscience represents a use-
variety of genetic and environmental influences. There are ful framework for (1) bringing together “external”
various ways in which one can define a priori such ROIs, (environment) and “internal” (genes) factors thatdin
both functionally and anatomically. The former can be combinationdmay influence person’s liability for devel-
achieved through metaanalyses of published reports oping substance use disorder and (2) providing a phenotype
(Eickhoff et al., 2009) or by constructing probabilistic maps (brain structure and function) that may help us understand
using large datasets (Tahmasebi et al., 2012), while the the nature of such influences. Note, however, that
latter can take advantage of various anatomical parcella- observational studies cannot infer causality and direction-
tions of the human brain (e.g., the Automatic Anatomical ality in the relationship between environment (or genes)
and brain phenotypes. Given the emergence of substance (12e18 years) and both biological parents of the French-
use during adolescence, this period of human development Canadian origin born in the region. In Wave 1
represents the main focus of several ongoing studies. I will (November 2003eFebruary 2012), phenotyping of the ad-
now describe two such studies: the Saguenay Youth Study olescents took place over several sessions (15 h in total)
(SYS) and the IMAGEN Study. and included a number of brain and cardiometabolic
domains detailed in Table 25.1 (further details in Pausova
et al., 2007; Pausova et al., 2017 and www.saguenay-
The Saguenay Youth Study
youth-study.org). During this Wave, we asked the parents
The SYS cohort includes 1029 adolescents and their 962 to fill out a number of questionnaires about the family
parents (at first assessment). This single-site cohort was environment, their mental health, and substance use and
recruited via adolescents attending high schools in the provide a blood sample. Between 2012 and 2015, we have
SaguenayeLac-Saint-Jean region of Quebec, Canada. This carried out full phenotyping of the parents using virtually
region is home to the largest genetic founder population in the same protocol used in adolescents in Wave 1. Fasting
North America (Peltonen et al., 2000; De Braekeleer, 1991; (morning) blood samples were drawn on the day of the
Grompe et al., 1994; De Braekeleer et al., 1998). Both hospital visit during which we acquired MRIs, complete
maternal and paternal grandparents of the adolescents were cardiovascular and metabolic assessments, cognitive
required to be of French-Canadian ancestry born in the testing, and psychiatric interviews (Pausova et al., 2016).
region; as such, all adolescents and their parents are of a In 2018, we initiated a follow-up assessment of the
single ethnicity (European [French] ancestry). Half of the young people (Wave 2). The follow-up consists of the
adolescents were exposed prenatally to maternal cigarette following elements: (1) an Internet-based self-assessment
smoking; the other half (“nonexposed”) were matched to of substance use, mental health, life events, and other
the “exposed” by maternal education and school attended. health-related domains; (2) a face-to-face structured
The cohort is family-based (481 families), including only psychiatric interview, a follow-back assessment of cannabis
adolescents who have one or more siblings of similar age use and computer-based assessment of cognition;
TABLE 25.1 Saguenay Youth Study (Adolescents; Wave 1)dPhenotypes.
Domain Tool Phenotypes

Brain MRI Global and regional volumes; cortical surface and thickness; MTR
Cognition 6-h battery PIQ and VIQ; memory; executive functioning, phonological and motor skills; social
cognition
Mental health DPS, GRIP Epidemiological diagnoses; symptom counts
Substance use GRIPado Cigarette smoking, cannabis, alcohol use, drug experimentation (age of initiation, life-
time history, last 30 days, binge drinking)
Personality NEO-PI-R Neuroticism, extroversion, openness, agreeableness, conscientiousness
Sexual maturation PDS Tanner stages
Lifestyle Lerner Sleep, nutrient intake, physical activity, extracurricular activities, sexuality, vocational
aspirations
Family environment FamEnvi Stressful life events, financial difficulties, SES (family income, parental education)
Body MRI, bioimpedance Subcutaneous and visceral fat; total body fat and muscle mass
Cardiovascular Finometer Beat-by-beat systolic and diastolic blood pressure; heart rate; sympathetic and para-
sympathetic tone
Hormones Blood Testosterone, estrogen, cortisol
Biochemistry Blood Glucose, insulin, cholesterol, triglycerides, HDL, leptin, CRP, free fatty acids
Lipidomics LC-ESI-MS w750 lipid species (in progress)
CRP, C-reactive protein; DPS, DISC predictive scales; GRIP, Groupe de Recherche sur l’Inadaptation Psychosociale, adolescent self-assessment of
mental health and substance use developed for the SYS by J. Séguin based on validated National Longitudinal Survey of Children and Youth (NLSCY)
and Quebec Longitudinal Study of Child Development (QLSCD) protocols; HDL, high-density lipoprotein; LC-ESI-MS, liquid chromatography electro-
spray ionization mass spectrometry; Lerner, adolescent self-assessment developed by Richard Lerner. MTR, magnetization transfer ratio; NEO-PI, neuroti-
cism, extraversion, opennessdpersonality inventory; PDS, Puberty Development Scale; PIQ, performance IQ; VIQ, verbal IQ.
TABLE 25.2 Assessment of cannabis, alcohol, and cigarette smoking in young adulthood.
Last Substance use

Lifetime 12 months Last 30 days Instruments disorders Instruments
Cannabis Number Number of Number of Mental health and addiction, Cannabis use Mini Plus,
of uses use days use days GRIP, ESPAD, CUPIT disorder CUPIT
Alcohol Number Number of Number of Mental health and addiction, Alcohol use Mini Plus,
of drinks drinking days drinking days ESPA, ASR disorder AUDIT
Cigarettes Number Number of Number of Mental health and addiction, Tobacco use FTND,
of smokes smoking days smoking days GRIP, ASR disorder SSAGA
ASR, Adult Self Report; AUDIT, Alcohol Use Disorders Identification Test; CUPIT, Cannabis Use Problems Identification Test; ESPAD, European School
Survey Project on Alcohol and Other Drug; FTND, Fagerstrom Test for Nicotine Dependence; GRIP, Groupe de recherche sur l’inadaptation psychoso-
ciale chez l’enfant; MINI Plus, Mini-International Neuropsychiatric Interview; SRE, Subjective Response to Ethanol; SSAGA, Semi-Structured Assessment
for the Genetics of Alcoholism. Instruments compiled by the SYS team.
(3) cardiometabolic assessment; (4) magnetic resonance assessments have been carried out, each including an MRI
imaging; and (5) a blood sample. The key substance use session, a cognitive assessment, and blood draw. In addi-
variables and instruments are summarized in Table 25.2. tion, adolescents and their parents completed internet-based
Given the long initial period of phenotyping (November self-assessments of their substance use, mental health,
2003eFebruary 2012), we are able to stagger these family environment, and stressful life events (https://
assessments so that participants’ age (at follow-up) will imagen-europe.com/). These visits took place at the
vary between 25 and 35 years (median age: 30 years). following ages: Visit 1 at 14 years of age (n ¼ 2000), Visit
In Wave 2, we are readministering (on line) family 2 at 19 years of age (n ¼ 1500), and Visit 3 at 23 years of
environment, lifestyle, and mental health/substance use age (n ¼ 1,100, ongoing). In addition, an internet-based
(GRIP, life habits) questionnaires, as well as several other self-assessment of substance use took place between
questionnaires that were administered to the parents. Note Visits 1 and 2 at 16 years of age (n ¼ 1700).
in particular the use of instruments relevant for the Cognitive assessments were carried out with the Cam-
assessment of cannabis (Cannabis Use Problems Identifi- bridge Neuropsychological Test Automated Battery
cation Test, GRIPado) and alcohol use (Alcohol Use (CANTAB) and six subtests of WISC (Visit 1 only), mental
Disorders Identification Test [AUDIT], Subjective health was assessed with the Development and Well-Being
Response to Ethanol, GRIPado), as well as other illegal Assessment interview (Goodman et al., 2000) and
substances (European School Survey Project on Alcohol Strengths and Difficulties Questionnaire (Goodman, 1997),
and Other Drug [ESPAD], Drug Abuse Screening Test and substance use with a number of questionnaires
[DAST]). During a visit, we draw a blood sample (after (e.g., AUDIT, ESPAD, FTND; see Table 25.2 for
overnight fasting) for future “omics” analyses abbreviations).
(e.g., genomics, transcriptomics, metabolomics), carry out a At all sites, the MRI session included a series of
structured psychiatric interview (Mini-International structural (T1-weighted images, DTI) and functional
Neuropsychiatric Interview (Sheehan et al., 1997)) and (Monetary Incentive Delay [MID] task, Stop-Signal Task
the University of California, Los Angeles (UCLA) Natural [SST], Face Task) scans. The three functional paradigms
History Interview (cannabis section only; Murphy et al., have been selected to engage brain networks relevant for
2010), assess cognitive abilities using a validated reward anticipation and processing (MID task; Knutson
computer-based battery comprising 12 tests of executive et al., 2001), cognitive control and impulsivity (SST;
function, memory, learning, and attention (www. Logan, 1994), and processing of social signals from
cambridgebrainscience.com), and acquire a series of MRI biological motion (Face task; Grosbras and Paus, 2006).
scans. The latter include T1-weighted images, MTR, DTI, In addition, resting-state scans were acquired at the
and abdominal scans (1.5T, Siemens Avanto). majority of sites, while MTR and abdominal scans were
acquired at a single site.
IMAGEN study
Findings
The IMAGEN cohort is a multisite study that includes 2000
adolescents (at first assessment) recruited via high schools Over the past 10 years, the two studies have reported a
in eight European cities including Berlin, Dresden, number of findings about brain maturation during adoles-
Hamburg, Mannheim (Germany), London, Nottingham cence in general, as well as observations that speak to the
(United Kingdom), Paris (France), and Dublin (Ireland) relationship between genes, environment, and substance
(Schumann et al., 2010). Three waves of face-to-face use/addiction. Table 25.3 provides an overview of these
TABLE 25.3 Summary of relevant publications from the Saguenay Youth Study and the IMAGEN Study. MTR,
Magnetization Transfer Ratio; PEMCS, Prenatal Exposure to Maternal Cigarette Smoking; VBM, Voxel Based
Morphometry; OFC, orbitofrontal cortex; ACC, anterior cingulate cortex; DL-FC, dorsolateral frontal cortex;
PFC, prefrontal cortex; PAG, periaqueductal grey; BMI, body mass index; ICV, intracranial volume
First Pub
Exposures Outcomes Author Journal year PMID
Androgens Volume of white matter, Perrin Journal of neuroscience 2008 18799683
MTR
PEMCS Cortical thickness, Positive Toro Neuropsychopharmacology 2008 17609681
youth development
PEMCS Corpus callosum (volume, Paus Neuroimage 2008 18221892
MTR)
Peer influence Cortical thickness, Positive Grosbras Social Neuroscience 2008 18979383
youth development, IQ
Androgens, Puberty Fiber-tract structural Herve Human Brain Mapping 2009 19235881
properties
Puberty Volume of white matter, Perrin NeuroImage 2009 19349224
MTR
PEMCS Cognitive abilities Kafouri Int J Epidemiology 2009 19039007
PEMCS Visceral fat Syme Obesity 2010 19851308
PEMCS Orbitofrontal cortex (thick- Lotfipour Arch Gen Psychiatry 2009 19884612
ness), substance use
PEMCS Striatum (volume), drug use Lotfipour Molecular Psychiatry 2010 20029407
PEMCS DNA methylation (BDNF) Toledo- Am J Med Genet B Neuro- 2010 20583129
Rodriguez psychiatr Genet
Video gaming Striatum (volume, response Kuhn Transl Psychiatry 2011 22833208
to feedback), Cambridge
Gambling Task
Cigarette smoking Striatum (reward anticipa- Peters Am J Psychiatry 2011 21362742
tion), impulsivity, novelty
seeking
Risk taking Striatum (volume, reward Schneider Am J Psychiatry 2012 21955931
anticipation), Cambridge
Gambling Task
RASGRF2 haplotype Striatum (reward anticipa- Stacey PNAS 2012 23223532
tion), drinking
Initiation of early drinking Brain response to reward Nees Neuropsychopharmacology 2012 22113088
anticipation
PEMCS Cortical surface area and Paus Cerebral Cortex 2012 22156575
folding
Impulsivity Neural correlates of inhibi- Whelan Nature Neuroscience 2012 22544311
tory control (Stop-Signal
Task [SST])
Impulsiveness Cortical thickness (“prefron- Schilling Molecular Psychiatry 2013 22665261
tal cortex")
Impulsiveness Brain structure (VBM) Schilling Human Brain Mapping 2013 22076840
PEMCS Amygdala (volume), fat Haghighi JAMA Psychiatry 2013 22945562
intake
Breastfeeding Cortical thickness Kafouri Int J Epidemiology 2013 23175518
Continued
Morphometry; OFC, orbitofrontal cortex; ACC, anterior cingulate cortex; DL-FC, dorsolateral frontal cortex; PFC,
prefrontal cortex; PAG, periaqueductal grey; BMI, body mass index; ICV, intracranial volumedcont’d
First Pub
AMBRA1 Impulsivity, Brain response Heinrich Eur J Neurosci 2013 23551272
in SST (in OFC)
ODZ4 Amygdala (response to Heinrich Bipolar Disord 2013 23611537
reward)
CHRNA5-CHRNA3-CHRNB4 Striatum, OFC, ACC Nees Neuropsychopharmacology 2013 23689675
cluster (response to reward), anxi-
ety sensitivity
PEMCS Striatum (reward Muller JAMA Psychiatry 2013 23784668
anticipation)
Visceral fat Executive functions, Schwartz Int J Obesity 2013 23797144
memory
PEMCS Fetal organ volumes (Brain, Anblagan PLOS One 2013 23843995
kidney, lungs, liver)
Compulsive behavior OFC, DL-FC, striatum Montigny PLOS One 2013 24244633
(volumes)
OPRM1 (opioid receptor mu Fat intake, amygdala (vol- Haghighi Molecular Psychiatry 2014 23337944
1) ume), Obesity
Puberty, sex hormones Pituitary volume Wong NeuroImage 2014 24632090
Video gaming Cortical thickness Kuhn PLOS One 2014 24633348
COMT Brain response in SST (in White Neuropsychopharmacology 2014 24820538
PFC)
PEMCS Drug use, externalizing Lotfipour Addiction 2014 24942256
behavior
Cigarette smoking Anxiety, depression Taylor BMJ Open 2014 25293386
Neuropsychosocial profiles Alcohol misuse Whelan Nature 2014 25043041
Family history of alcoholism Striatum (reward Muller Addict Biol 2015 24903627
anticipation)
PEMCS Fat dietary preference Lee J Psychiatry Neurosci 2015 25266401
PEMCS DNA methylation (genome Lee Environ Heatlh Perspect 2015 25325234
wide)
BDNF Alcohol use, striatum Nees Alcohol 2015 25650137
(response to reward
anticipation)
DNA methylation (PPM1G) Alcohol use disorder, Brain Ruggeri Am J Psychiatry 2015 25982659
response (Stop Tasks) in sub-
thalamic nucleus
RSU1 Alcohol use, Brain response Ojelade PNAS 2015 26170296
to reward anticipation
(striatum)
Cannabis, PRSsch Cortical thickness French JAMA Psychiatry 2015 26308966
Cannabis Brain response to faces Spechler Dev Cogn Neurosci 2015 26347227
(amygdala)
Personality (SURPS) Substance use (alcohol use, Jurk Alcohol Clin exp Res 2015 26463560
smoking, and cannabis use)
First Pub
OFC (gyrification) Drinking behavior Kuhn Addiction Biology 2016 25913102
CNR1 Brain response to faces Ewald Eur J Neurosci 2016 26527537
Accumbens genes (e.g.,EHD4) Binge drinking, Brain Stacey J Psychiatry Neurosci 2016 26679926
response to reward
(striatum)
Reward processing “nodes” Hyperactivity, alcohol use Jia PNAS 2016 27001827
(striatal and cortical), VPS4A
GWAS Lifetime cannabis use Stringer Transl Psychiatry 2016 27023175
Striatum (reward anticipation): Cigarette smoking Jollans Dev Neuropsychol 2016 27074029
functional connectivity
KALRN Brain response to reward Pena- Front Genet 2016 27092175
(striatum), Binge drinking Oliver
Personality (TCI), Cambridge Alcohol use Heinrich Biol Psychol 2016 27180911
Gambling Task, Brain
response to reward (MID),
ANKK1, HOMER1
Polygenic Risk Score Brain response to reward, Lancaster JAMA Psychiatry 2016 27384424
(schizophrenia) IQ, impulsivity
PEMCS Cognitive abilities (WAIS Ramsay BMC Psychiatry 2016 27908296
subtests, CANTAB subtests)
Sex, age Disordered eating Behaviour Bartholdy Eur Child Adolesc 2017 28050706
Psychiatry
OPRM1 Brain response to reward Nees Pain 2017 28092323
(PAG, striatum), pain
complaints
Brain response to reward Problematic drug use Buchel Nat Commun 2017 28221370
(striatum, PFC), personality (defined as the intake of
increased amounts of licit
and/or illicit drugs; cigs: 1þ
cigs per days, alcohol: 20þ
drinks per month [last
30 days], cannabis: 39þ
lifetime occasions, other
drugs: 3þ lifetime
occasions)
GABRB1 Brain response to reward Duka Front Behav Neurosci 2017 28261068
(MID) and cognition control
(SST)
Sex hormones Cortical thickness and Wong Cerebral Cortex 2018 28334178
thinning
EFHD2 (Swiprosin-1) Alcohol use, anxiety Mielenz Mol Psychiatry 2018 28397836
PSD3 Alcohol use, Binge drinking, Gonzalez Mol Psychiatry 2018 28607459
BOLD response in SST (in
PFC)
OPRL1 (opioid Receptorelike Binge drinking, Brain Ruggeri J Child Psychol Psychiatry 2018 29197086
1) methylation status response to reward anticipa-
tion (striatum)
Continued
First Pub
PEMCS Offspring overweight Albers Int J Obesity 2018 29717267
Psychosocial, brain, and ge- Initiation of cannabis use Spechler Eur J Neurosci 2018 29889330
netic features
DRD1, DRD2 Alcohol misuse, brain Baker Psychol Med 2019 29909784
response to reward (stria-
tum, OFC)
Ventromedial PFC (volume) Hyperactive/inattention Albaugh Cerebral Cortex 2018 29912404
symptoms
GWAS Age at first cannabis use Minica Addiction 2018 30003630
PEMCS Offspring BMI Albers Obes Rev 2018 30035359
TTC12-ANKK1-DRD2 Cigarette smoking, Brain Macare Eur 2018 30104163
response to reward Neuropsychopharmacol
(striatum)
Brain structure Symptoms of attention Bayard Mol Psychiatry 2018 30108313
deficit hyperactivity disorder
or conduct disorder
COMT Attention deficit hyperactivi- Millenet Front Genet 2018 30108607
ty symptoms
White matter (FA, MD) Concurrent subthreshold Vulser Am J Psychiatry 2018 30111185
depression and depression
at 2-yr follow-up
GWAS Cannabis use Pasman Nature Neuroscience 2018 30150663
DRD2 methylation status IQ, gray matter (striatum), Kaminski Transl Psychiatry 2018 30166545
brain response to reward
(striatum)
Age, delta age, cell-specific Cortical MTR Patel Cerebral Cortex 2018 30169567
gene expression
Visceral fat, White matter (T1W signal Syme Int J Obesity 2018 30206338
glycerophosphocholines intensity, MTR), Processing
speed
Functional connectivity Reward anticipation and Cao Human Brain Mapping 2018 30240509
receipt (MID task)
Polygenic Risk Score (psycho- Psychotic experiences (at Velthorts Transl Psychiatry 2018 30258131
sis), Brain response to faces 18)
(at 14)
16p11.2 distal CNV ICV, subcortical volumes, Sonderby Molecular Psychiatry 2018 30283035
IQ
Psychosocial stress, alcohol DNA methylation (EWAS) Tay Am J Psychiatry 2019 30525907
use, smoking
Breastfeeding IQ Hartwig IJE 2018 30541029
Peer victimization Psychopathology Quinlan Molecular Psychiatry 2018 30542059
Cannabis (extremely low Gray matter Orr Journal of Neuroscience 2019 30643026
levels of use)
First Pub
GWAS Gray matter (voxel wise) Luo JAMA Psychiatry 2019 30649180
TANK gene Brain response to reward Muller Cerebral Cortex 2019 30721969
(MID), cognition control
(SST), and social cues (Face)
Puberty Resting-state connectivity, Ernst Transl Psychiatry 2019 30804326

psychopathology
reports ordered by their year of publication. In this table, associations with lower (exposed vs. nonexposed) cortical
the first two columns identify the key “exposures” and thickness (Lotfipour et al., 2009; Toro et al., 2008), smaller
“outcomes” addressed in a given report. These termsdand corpus callosum (Paus et al., 2008), higher adiposity (Syme
their equivalents (e.g., “independent” and “dependent” et al., 2010), and its relationship to fat intake and the
variables, as used in experimental studies)dshould be amygdala volume (Haghighi et al., 2013), or differences in
interpreted against the background of observational studies DNA methylation (Lee et al., 2015; Toledo-Rodriguez
and their limitations: even if one can be certain about et al., 2010). Some of our findings suggest that prenatal
temporal order in some instances (e.g., exposure to exposure to maternal cigarette smoking is associated with
maternal smoking during pregnancy, substance use during reward deficiency rather than higher sensitivity to reward
adolescence), one cannot infer causality from the mere (Lotfipour et al., 2009; Muller et al., 2013). Again, we need
presence of (statistical) associations between “exposures” to keep in mind that no causality can be inferred from these
and “outcomes.” Furthermore, in cases of brainebehavior associations.
relationshipsdsuch as cannabis use and cortical thickness The concurrent assessment of substance use and func-
measured at the same time pointdassignment of the two tional engagement of neural circuits involved in reward and
variables as “exposures” and “outcomes” is arbitrary, as we cognitive control provided initial insights into relevant
cannot establish directionality in their relationships. brainebehavior relationships. For example, a differential
Let us now highlight a few of these findings. Given the BOLD response to anticipated reward in (ventral) striatum,
puberty-associated changes in hormonal environment, it is as assessed by the MID task, is one of the most consistent
not surprising to see a number of structural correlates of findings across a number of traits including cigarette
sexual maturation, including variations in cortical gray- smoking (Peters et al., 2011; Jollans et al., 2016), risk
matter (Paus et al., 2010), the overall volume and structural taking (Schneider et al., 2012), video gaming (Kuhn et al.,
properties of white matter (Perrin et al., 2008, 2009), and 2011), compulsive behavior (Montigny et al., 2013), and
the volume of the pituitary gland (Wong et al., 2014). problematic drug use (Buchel et al., 2017). At the same
Furthermore, we took advantage of the head MRIs to time, a number of genetic variations are associated with the
quantify a number of nonbrain phenotypes, namely brain response to anticipated reward assessed by the same
morphology of the face (Mareckova et al., 2011) and the task (RASGRF276, CHRNA5-CHRNA3-CHRNB4 cluster
voice box (Markova et al., 2016), and relate these to (Nees et al., 2013), BDNF (Nees et al., 2015), RSU1
pubertal stages (and hormone levels). (Ojelade et al., 2015), EHD4 (Stacey et al., 2016), KALRN
The multidomain nature of the Saguenay Youth Study (Pena-Oliver et al., 2016), DRD1, DRD2, TTC12-ANKK1-
allowed us to evaluate sex differences in the adolescent DRD2 (Baker et al., 2019; Macare C et al., 2018). This
brain and body. Table 25.4 provides a summary of effects series of observations made over the years awaits a
sizes of these differences for a total of 66 traits; 59 of these synthesis that, together with parallel work in experimental
traits showed sex differences (at a nominal P < 0.05), models, promises to integrate the role of the genetic and
with small (32), medium (13), and large (11) effects environmental factors in shaping the reward system of the
(Paus et al., 2017). human brain and their significance for the risk of addiction.
A number of observations have been made with regard Our work in the Saguenay Youth Study and the
to the prenatal exposure to maternal smoking including IMAGEN Study, together with that in other cohorts such as
TABLE 25.4 Sex differences in phenotypes assessed across a number of brain and body domains in the Saguenay Youth Study. Phenotypes are
ordered by their effect size, from the largest positive values (indicating mean values higher in males than females) to the largest negative values
(indicating mean values higher in females than males). d, Cohen’s d. Threshold for corrected P value: P [ 7.50Ee04.
Sex (d; M Sex 3 Age r r n n

Domain Variable Sex (P) eF) (P) Male Female Male Female
Brain Cortical area 4.59E 1.52 1.76Ee01 0.01 0.08 479 509
e100
Brain Brain volume 7.25Ee95 1.47 4.86Ee01 0.03 0.01 476 509
Brain White matter volume (lobar) 2.81Ee87 1.40 6.69Ee03 0.29 0.16 476 509
Brain Gray matter volume (lobar) 2.74Ee66 1.18 1.85Ee03 0.37 0.24 476 509
Anthropometry Lean body mass (log) 1.28Ee56 1.08 5.12Ee25 0.62 0.32 467 512
Anthropometry Body water (log) 1.99Ee55 1.07 1.22Ee24 0.61 0.31 471 511
Anthropometry Visceral fat to total body fat (ratio, log) 2.70Ee40 0.90 1.19Ee01 0.15 0.28 453 502
Voice Formant position 3.73Ee10 0.87 1.18Ee01 0.22 0.03 94 144
Anthropometry Height 6.46Ee36 0.81 5.98Ee29 0.67 0.33 495 531
Face Perceived maleness 1.28Ee29 0.81 1.46Ee03 0.33 0.07 407 431
Food intake Food recall: Energy intake (log) 3.56Ee28 0.72 1.42Ee03 0.22 0.04 478 509
Food intake Food recall: Protein (log) 4.22Ee24 0.66 8.82Ee02 0.17 0.08 479 512
Food intake Food recall: Carbohydrates (log) 3.25Ee20 0.60 5.01Ee02 0.15 0.03 468 504
Food intake Food recall: Fat (log) 8.83Ee19 0.57 3.51Ee02 0.18 0.07 481 514
Metabolic Food recall: Polyunsaturated FAs (log) 5.52Ee14 0.49 2.24Ee01 0.15 0.09 477 513
Metabolic Food recall: Saturated FAs (log) 9.92Ee14 0.48 1.46Ee02 0.19 0.05 481 513
Body image Body esteem: Weight (log) 1.02Ee13 0.48 9.53Ee02 0.04 0.13 494 502
Body image Body esteem: Appearance (log) 9.13Ee11 0.42 8.04Ee01 0.09 0.10 486 500
Cardiovascular Diastolic blood pressure (averaged time series) 1.74Ee09 0.40 3.24Ee01 0.07 0.01 444 478
Cardiovascular Diastolic blood pressure (clinical) 8.62Ee10 0.39 1.03Ee01 0.09 0.01 482 511
Anthropometry Waist circumference (log) 1.28Ee09 0.39 5.43Ee03 0.30 0.14 482 529
Cardiovascular Systolic blood pressure (clinical) 2.60Ee09 0.38 8.10Ee02 0.18 0.09 485 515
Metabolic Glucose (log) 2.94Ee09 0.38 1.52Ee04 0.03 0.27 488 519
Cardiovascular Systolic blood pressure (averaged time series) 3.18Ee07 0.34 2.31Ee01 0.17 0.13 444 478
Physical Exercise (log) 4.94Ee07 0.32 2.01Ee01 0.10 0.19 477 518
activity
Anthropometry Weight (log) 1.96Ee06 0.30 4.19Ee07 0.52 0.35 490 529
Cardiovascular Parasympathetic tone (high-frequency interbeat interval, 3.36Ee06 0.29 4.26Ee01 0.11 0.07 489 525
log)
Substance use Binge drinking (5þ drinks on same occasion in last 4.60Ee02 0.21 1.21Ee02 0.34 0.08 158 199
30 days)
Autonomic Sympathetic tone (low-frequency diastolic blood pressure, 1.89Ee03 0.20 5.68Ee01 0.05 0.01 490 525
log)
Substance use Smoking: Negative life history 1.97Ee03 0.19 7.56Ee01 0.26 0.27 491 523
Face PC1 1.55Ee01 0.15 5.35Ee01 0.14 0.07 183 199
Food intake Food recall: Fat percentage (%) 6.95Ee02 0.12 4.21Ee01 0.08 0.04 482 517
Voice Vocal tract length (log) 1.28Ee01 0.10 4.38Ee03 0.28 0.11 411 460
Food intake Food recall: Protein percentage (log) 3.00Ee01 0.07 6.80Ee01 0.02 0.05 479 514
Anthropometry Body mass index (log) 4.45Ee01 0.05 4.94Ee01 0.26 0.25 488 524
Substance use Marijuana (ever, never) 1.58Ee01 0.09 7.41Ee01 0.42 0.39 488 524
Body image Body esteem: Attribution 1.12Ee01 0.10 2.82Ee01 0.05 0.12 494 533
Food intake Food recall: Carbohydrate percentage (%) 4.28Ee02 0.13 5.46Ee01 0.07 0.05 482 517
Population neuroscience in addiction research Chapter | 25

Anthropometry Visceral fat volume (log) 3.46Ee02 0.14 8.41Ee01 0.12 0.14 466 519
Sleep Nap during day 1.29Ee02 0.16 7.47Ee01 0.29 0.31 495 532
Personality Conscientiousness 1.11Ee03 0.21 4.72Ee01 0.00 0.05 488 522
Substance use Alcohol (ever tried) 6.75Ee04 0.21 2.31Ee02 0.58 0.53 491 524
Metabolic Triglycerides (log) 4.11Ee04 0.22 7.85Ee01 0.18 0.18 487 525
Metabolic Low-density lipoprotein (log) 2.77Ee04 0.23 5.98Ee01 0.10 0.07 485 522
Metabolic Insulin resistance (HOMA index, log) 7.71Ee05 0.25 9.31Ee02 0.06 0.19 479 516
Brain Cortical thickness 5.28Ee05 0.26 6.44Ee06 0.53 0.33 479 509
Sleep Sleeping quality 3.21Ee05 0.26 7.19Ee01 0.12 0.10 495 532
Metabolic C-reactive protein (log) 4.14Ee05 0.26 3.23Ee08 0.09 0.40 479 513
Voice Vocal fold length 8.32Ee04 0.27 1.08Ee07 0.45 0.29 237 411
Sleep Tired during day 6.98Ee07 0.31 1.57Ee01 0.13 0.23 495 532
Metabolic Insulin (log) 3.36Ee07 0.32 1.53Ee01 0.04 0.14 481 523
Sleep Night wake 1.13Ee07 0.33 9.22Ee01 0.01 0.01 494 530
Personality Resistance to peer influence (log) 6.66Ee08 0.37 2.82Ee01 0.14 0.25 399 464
Cardiovascular Heart rate (averaged time series) 2.02Ee09 0.38 8.14Ee03 0.32 0.19 491 525
343
Continued
TABLE 25.4 Sex differences in phenotypes assessed across a number of brain and body domains in the Saguenay Youth Study. Phenotypes are ordered
by their effect size, from the largest positive values (indicating mean values higher in males than females) to the largest negative values (indicating
mean values higher in females than males). d, Cohen’s d. Threshold for corrected P value: P [ 7.50Ee04.dcont’d
Sex (d; M Sex 3 Age r r n n

Domain Variable Sex (P) eF) (P) Male Female Male Female
Personality Neuroticism 2.69Ee11 0.42 1.78Ee03 0.11 0.09 488 519
Metabolic Cholesterol (log) 9.96Ee12 0.43 1.82Ee01 0.04 0.13 490 521
Personality Extroversion 1.61Ee12 0.45 1.95Ee01 0.14 0.07 489 522
Brain Corticospinal tract: MTR 4.86Ee12 0.51 1.23Ee02 0.09 0.08 361 409
Metabolic High-density lipoprotein (log) 8.56Ee16 0.51 2.36Ee07 0.19 0.13 492 522
Metabolic Insulin resistance (HOMA-B, log) 8.73Ee21 0.61 1.40Ee01 0.02 0.08 478 516
Personality Openness 3.61Ee22 0.62 8.30Ee01 0.26 0.23 488 522
Personality Agreeableness 5.86Ee23 0.64 6.27Ee01 0.05 0.08 488 522
Brain Pituitary volume (log) 6.13Ee23 0.65 3.57Ee05 0.48 0.31 472 506
Anthropometry Total body fat (log) 6.73Ee24 0.67 5.03Ee01 0.22 0.32 452 506
Anthropometry Subcutaneous abdominal fat volume (log) 3.89Ee25 0.67 4.82Ee02 0.06 0.23 481 521
Voice Fundamental frequency (log) 2.20Ee71 1.87 1.03Ee40 0.71 0.29 204 328
From Paus, T., Wong, A.P., Syme, C., Pausova, Z., 2017. Sex differences in the adolescent brain and body: findings from the saguenay youth study. J. Neurosci. Res. 95, 362e370.
the Avon Longitudinal Study of Parents and Children Challenges and outlook
(ALSPAC; Boyd et al., 2013), allowed us to discover and
replicate a subtle interactive relationship between genes and As any other approach, population neuroscience comes
environment. We close this section by describing a report in with its own challenges. In addition to the time and effort it
which we asked whether the use of cannabis during early takes to recruit and assess large (>1000) numbers of
adolescence (by age 16) is associated with variations in participants, as well as the cost of deep phenotyping and
brain maturation as a function of genetic risk of schizo- omics-based assays, the key challenges lie in the interpre-
phrenia (French et al., 2015). We addressed this question in tation of the findings. These exist at two different levels.
three samples of typically developing youth, namely SYS At a design level, the majority of research taking this
(n ¼ 949; both sexes), ALSPAC (n ¼ 295; males only), approach is based on data collected in observational
and IMAGEN (n ¼ 333; both sexes), for whom we studies. As detailed elsewhere (Paus, 2013), the way
obtained (1) information about their cannabis use during participants are recruited represents a possible source of
adolescence; (2) structural images of their brains; and ascertainment biases and, consequently, deviations from the
(3) their polygenic risk score of schizophrenia (PRSSCH). composition of general population. For example, selecting
The polygenic risk scores were calculated from 114 SNPs adolescents who used cannabis from a large birth cohort by
identified by the Psychiatric Genomics Consortium in a reviewing answers to questionnaires administered to all
genome-wide comparison of 36,989 patients with schizo- cohort members would yield a more representative sample
phrenia and 113,075 controls (Biological insights from 108 than when recruiting from a community by a targeted
schizophrenia-associated genetic loci, 2014). Note that this (cannabis-related) advertisement. Other less obvious but
score is based on common genetic variants and, as such, it more common biases relate to self-selection when volun-
has a normal distribution in general population. In SYS teering in time-demanding longitudinal studies (e.g., family
males, we observed an interaction between cannabis use income, education). Furthermore, and as discussed above,
and the risk score on age-adjusted cortical thickness; higher observational studies do not allow us to infer causality and,
risk score is associated with lower cortical thickness in with a few exceptions, directionality of statistical associa-
cannabis “ever users” but not in “nonusers.” This was not tions between “exposures” and “outcomes”. Nonetheless,
the case in SYS females. In ALSPAC and IMAGEN, we when combined with molecular genetics, one can
assessed relationships between cumulative cannabis strengthen interpretations along these lines. For example,
frequency and cortical thickness in individuals with high- we showed thatdin male adolescentsdthe relationship
or low-risk score. In the ALSPAC high-risk group, “heavy between testosterone levels and white matter is moderated
users” (61 occasions) had lower cortical thickness than by a functional polymorphism in androgen receptor gene
both the “never users” and “light users.” No such differ- (i.e., gene x environment interaction), thus supporting our
ences were observed in the ALSPAC low-risk group. In the conclusion that testosterone indeed drives the growth of
IMAGEN high-risk group of males, “heavy users” (20 white-matter volume (Perrin et al., 2008). A subsequent
occasions) showed a larger decrease in cortical thickness experimental study (in rats) confirmed this conclusion
(between 14 and 19 years of age) than “never users”; this (Pesaresi et al., 2015). In recent years, the use of genetic
was also true for the comparison of “medium users” (3e19 variations as “instrumental variables” has gained popularity
occasions) with “never users” (Fig. 25.3). No such differ- in a framework of Mendelian randomization (Smith et al.,
ences were found in IMAGEN females. Across the three 2008). In the context of addition research, a rather
samples, the relationship between cannabis use and cortical surprising reinterpretation of the directionality in
thickness was highly significant in male adolescents a cannabiseschizophrenia relationship has emerged,
belonging to the high-risk groups (the Stouffer’s meta namely evidence for a causal positive influence of schizo-
P-value ¼ 2.3E-6). This was not the case for low-risk phrenia risk on cannabis use (Pasman et al., 2018).
males, or either the low-risk or high-risk female groups At a level of specific brain phenotypes, the field is also
(meta P-value > 0.05). Finally, we showed that regional beginning to take advantage of advances in molecular
variations in the magnitude of a group difference (never vs. genetics, and publicly available resources, to facilitate
ever users) in cortical thickness vary as a function of interpretations of MRI-based findings. In our work, for
regional differences in the expression of cannabinoid example, we use interregional profiles of gene expression in
receptor 1 (CNR1) gene, as provided by the Allen Human the human cerebral cortex, provided in the Allen Human
Brain Atlas (Hawrylycz et al., 2012) and calculated for each Brain Atlas (Hawrylycz et al., 2012) and remapped to the
cortical region using an approach developed in our labo- Desikan-Killany parcellation of FreeSurfer (French and
ratory (French and Paus, 2015). This finding supports the Paus, 2015), to asses which genes relate to a phenotype of
possibility that cannabinoids indeed play a role in the interest. As mentioned above, we showed that differences
observed relationship between cannabis use, PRSSCH, and between cannabis “users” and “nonusers” in regional
cortical thickness. values of cortical thickness varieddacross 34 “FreeSurfer”
FIGURE 25.3 Dot plots of mean cortical thickness for different groups of male cannabis users at high and low risk. Thickness values are binned and
stacked horizontally within each grouping. Mean thickness values are marked with thick black lines. Significant group differences are marked with lines
and Cohen d statistics. (A), Age-adjusted cortical thickness is presented in male participants who ever and never used cannabis. (B), Change in cortical
thickness (Time 2 Time 1) by number of occasions of use. (C), Age-adjusted cortical thickness is presented by number of occasions of use. ALSPAC,
Avon Longitudinal Study of Parents and Children; SYS, Saguenay Youth Study. Cortical thickness is presented in arbitrary units (residuals). a, P < 0.005,
t test. b, P < 0.05, t test. From French, L., Gray, C., Leonard, G., et al., 2005. Early cannabis use, polygenic risk score for schizophrenia and brain
maturation in adolescence. JAMA Psychiatry 7, 1002e1011.
regions (left hemisphere)das a function of regional values Haythornthwaite, 2013). Twitter-based studies of social
of expression CNR1, a gene coding for a cannabinoid behavior include, for example, a cyclic nature of coordi-
receptor 1; cortical regions with higher CNR1 expression nated social activity (Morales et al., 2017) or public
show a bigger difference in thickness (French et al., 2015). attention and temporal patterns of tweets on specific social
Similarly, we used NR3C1 gene (coding for glucocorticoid issues (Peng et al., 2017). To start, such informationd
receptor) to facilitate interpretations of age-related changes mapped in space and timedcan be considered at an
in cortical thickness during adolescence (Wong et al., 2018; aggregate level (e.g., neighborhood, census tract) and
Parker et al., 2017) and the relationship between stressful related to the individual member of a cohort through a
life events and brain response to faces (Lieslehto et al., geospatial information system (Paus, 2016).
2017). We have extended this approach into the so-called Third, as mentioned above, there is a great desire to
virtual histology, whereby cell-specific gene markers are uncover causal influences shaping the developing brain.
used to identify cellular correlates of MRI-based metrics Some would argue that the ultimate test of a causal
(Shin et al., 2018; Patel et al., 2018). Finally, a number of hypothesis is an experiment. In studies of human devel-
reports listed in Table 25.3 combined population and opment, interventions represent unique opportunities for
experimental neuroscience to advance our understanding of examining causal effects of a variety of influences tested by
causal mechanisms underlying addiction, in particular, in randomizing individuals (or groups of individuals) into
relation to alcohol use (Stacey et al., 2012, 2016; Pena- “experimental” and “control” arms and measuring
Oliver et al., 2016; Mielenz et al., 2018). outcomes before and after the intervention. Randomized
control trials and quasiexperimental designs have been
Where do we go next? used, for example, to evaluate effects of breastfeeding on
cognitive development (Kramer et al., 2008) or effective-
First, in addition to the ongoing cohort studies, such as the ness of various psychosocial interventions on mental health
Saguenay Youth Study and IMAGEN Study, and longitu- in children and adolescents (Sandler et al., 2014). Incor-
dinal birth cohorts, such as ALSPAC (Boyd et al., 2013), porating state-of-the-art assessment of brain and behavior
the Northern Finland Birth Cohort (Jarvelin et al., 1993), in future interventions has the potential to provide insights
and the Generation R Study (Jaddoe et al., 2012), new relevant for understanding brain development as well as
population-based studies with a strong neuroimaging mechanisms underlying the success (or failure) of a given
component have been initiated in recent years. Most intervention. Clearly, interventions aimed at reducing the
notably, the Adolescent Brain Cognitive Development risk of substance use disorders represent an ideal meeting
(ABCD) Study has recruited over 11,000 children (9e10 point between science and public health.
years old) to participate in longitudinal (every 2 years) as-
sessments of their brains and behavior throughout adoles-
cence (Garavan et al., 2018). Similar to the IMAGEN Acknowledgments
Study, the ABCD Study will provide new knowledge about The work described in this chapter was made possible by our funders,
brain characteristics that precede (possible risks) or follow including the Canadian Institutes of Health Research and the National
(possible consequences) the onset of substance use in Institutes of Health (USA). I am grateful to my students, fellows, and
general population. colleagues for their contributions made in the course of our studies of
Second, we need to enhance assessment of the envi- the adolescent brain. I very much appreciate the collaborative spirit of
my academic colleagues associated with a number of cohorts,
ronment surrounding participants in our studies throughout
including the IMAGEN Study, ALSPAC, Northern Finland Birth
their lives. As pointed out above, the developing human
Cohort, and the Porto Alegre-São Paulo High Risk Cohort Study for
being is under a myriad of influences related to his/her the Development of Childhood Psychiatric Disorders. My work on
physical environment (e.g., air, trees), built environment population neuroscience would not be possible without Dr. Zdenka
(e.g., transportation) and, most importantly, social envi- Pausova. Over more than 20 years, Zdenka has provided me the
ronment (e.g., family, peers, neighbors) (Ruiz Jdel et al., inspiration and knowledge necessary for embarking on studies in
2016). There is a growing number of examples whereby genetics and epigenetics. Together, we built the Saguenay Youth
data science in general, and “population informatics” in Study, which provides the template for most of the ideas and concepts
particular (Kum et al., 2014), show the power of extracting described here.
information about social and built environment from
various digital sources (e.g., satellite images, social media, References
patterns of mobile phone use) and relating it to phenomena Abnousi, F., Rumsfeld, J.S., Krumholz, H.M., 2019. Social determinants
such as brain maturation (Parker et al., 2017), well-being of health in the digital age: determining the source code for nurture.
(Kardan et al., 2015), obesity (Maharana and Okanyene JAMA 321, 247e248.
Nsoesie, 2018), health (Abnousi et al., 2019), and social Albert, F.W., Kruglyak, L., 2015. The role of regulatory variation in
relationships (David-Barrett et al., 2016; Gruzd and complex traits and disease. Nat. Rev. Genet. 16, 197e212.
Baker, T.E., Castellanos-Ryan, N., Schumann, G., et al., 2019. Modulation Goodman, R., Ford, T., Richards, H., Gatward, R., Meltzer, H., 2000.
of orbitofrontal-striatal reward activity by dopaminergic functional The development and well-being assessment: description and
polymorphisms contributes to a predisposition to alcohol misuse in initial validation of an integrated assessment of child and
early adolescence. Psychol. Med. 49, 801e810. adolescent psychopathology. J. Child Psychol. Psychiatry 41,
Schizophrenia Working Group of the Psychiatric Genomics C, 2014. 645e655.
Biological insights from 108 schizophrenia-associated genetic loci. Grompe, M., St-Louis, M., Demers, S.I., al-Dhalimy, M., Leclerc, B.,
Nature 511, 421e427. Tanguay, R.M., 1994. A single mutation of the fumarylacetoacetate
Bjornholm, L., Nikkinen, J., Kiviniemi, V., et al., 2017. Structural prop- hydrolase gene in French Canadians with hereditary tyrosinemia type
erties of the human corpus callosum: multimodal assessment and sex I. N. Engl. J. Med. 331, 353e357.
differences. Neuroimage 152, 108e118. Grosbras, M.H., Paus, T., 2006. Brain networks involved in viewing angry
Boyd, A., Golding, J., Macleod, J., et al., 2013. Cohort profile: the hands or faces. Cerebr. Cortex 16, 1087e1096.
“children of the 90s”dthe index offspring of the Avon longitudinal Gruzd, A., Haythornthwaite, C., 2013. Enabling community through social
study of parents and children. Int. J. Epidemiol. 42, 111e127. media. J. Med. Internet Res. 15, e248.
Buchel, C., Peters, J., Banaschewski, T., et al., 2017. Blunted ventral Gusev, A., Lee, S.H., Trynka, G., et al., 2014. Partitioning heritability of
striatal responses to anticipated rewards foreshadow problematic drug regulatory and cell-type-specific variants across 11 common diseases.
use in novelty-seeking adolescents. Nat. Commun. 8, 14140. Am. J. Hum. Genet. 95, 535e552.
Chen, P., Jacobson, K.C., 2012. Developmental trajectories of substance Haghighi, A., Schwartz, D.H., Abrahamowicz, M., et al., 2013. Prenatal
use from early adolescence to young adulthood: gender and racial/ exposure to maternal cigarette smoking, amygdala volume, and fat
ethnic differences. J. Adolesc. Health 50, 154e163. intake in adolescence. JAMA Psychiatry 70, 98e105.
Cheung, C., Yu, K., Fung, G., et al., 2010. Autistic disorders and Hawrylycz, M.J., Lein, E.S., Guillozet-Bongaarts, A.L., et al., 2012. An
schizophrenia: related or remote? An anatomical likelihood estima- anatomically comprehensive atlas of the adult human brain tran-
tion. PLoS One 5, e12233. scriptome. Nature 489, 391e399.
David-Barrett, T., Kertesz, J., Rotkirch, A., et al., 2016. Communication Hurvitz, P.M., Moudon, A.V., Kang, B., Saelens, B.E., Duncan, G.E.,
with family and friends across the life course. PLoS One 11, 2014. Emerging technologies for assessing physical activity behaviors
e0165687. in space and time. Front. Public health 2, 2.
De Braekeleer, M., 1991. Hereditary disorders in saguenay-Lac-St-Jean Jaddoe, V.W., van Duijn, C.M., Franco, O.H., et al., 2012. The Generation
(Quebec, Canada). Hum. Hered. 41, 141e146. R Study: design and cohort update 2012. Eur. J. Epidemiol. 27,
De Braekeleer, M., Mari, C., Verlingue, C., et al., 1998. Complete iden- 739e756.
tification of cystic fibrosis transmembrane conductance regulator Jarvelin, M.R., Hartikainen-Sorri, A.L., Rantakallio, P., 1993. Labour in-
mutations in the CF population of Saguenay Lac-Saint-Jean (Quebec, duction policy in hospitals of different levels of specialisation. Br. J.
Canada). Clin. Genet. 53, 44e46. Obstet. Gynaecol. 100, 310e315.
Dickie, E.W., Tahmasebi, A., French, L., et al., 2014. Global genetic Jbabdi, S., Sotiropoulos, S.N., Haber, S.N., Van Essen, D.C.,
variations predict brain response to faces. PLoS Genet. 10, e1004523. Behrens, T.E., 2015. Measuring macroscopic brain connections
Eickhoff, S.B., Paus, T., Caspers, S., et al., 2007. Assignment of functional in vivo. Nat. Neurosci. 18, 1546e1555.
activations to probabilistic cytoarchitectonic areas revisited. Neuro- Johnston, L.D.O.M.P., Bachman, J.G., Schulenberg, J.E., December 14,
image 36, 511e521. 2011. Marijuana Continues to Rise Among U.S. Teens, While Alcohol
Eickhoff, S.B., Laird, A.R., Grefkes, C., Wang, L.E., Zilles, K., Fox, P.T., Use Hits Historic Lws. University of Michigen News Service, Ann
2009. Coordinate-based activation likelihood estimation meta-analysis Arbor, MI, p. 2011.
of neuroimaging data: a random-effects approach based on empirical Johnston, L.D.O.M.P., Bachman, J.G., Schulenberg, J.E., 2009. Moni-
estimates of spatial uncertainty. Hum. Brain Mapp. 30, 2907e2926. toring the Future National Survey Results on Drug Use, 1975e2007.
Fischl, B., Dale, A.M., 2000. Measuring the thickness of the human ce- Bethesda, MD.
rebral cortex from magnetic resonance images. Proc. Natl. Acad. Sci. Jollans, L., Zhipeng, C., Icke, I., et al., 2016. Ventral striatum connectivity
U.S.A. 97, 11050e11055. during reward anticipation in adolescent smokers. Dev. Neuropsychol.
French, L., Paus, T., 2015. A FreeSurfer view of the cortical transcriptome 41, 6e21.
generated from the allen human brain atlas. Front. Neurosci. 9, 323. Kardan, O., Gozdyra, P., Misic, B., et al., 2015. Neighborhood greenspace
French, L., Gray, C., Leonard, G., et al., 2015. Early cannabis use, poly- and health in a large urban center. Sci. Rep. 5, 11610.
genic risk score for schizophrenia and brain maturation in adoles- Kellis, M., Wold, B., Snyder, M.P., et al., 2014. Defining functional DNA
cence. JAMA Psychiatry 72, 1002e1011. elements in the human genome. Proc. Natl. Acad. Sci. U.S.A. 111,
Friston, K.J., 2011. Functional and effective connectivity: a review. Brain 6131e6138.
Connect. 1, 13e36. Kendler, K.S., Gardner, C.O., Prescott, C.A., 2003. Personality and the
Gao, W., Emaminejad, S., Nyein, H.Y., et al., 2016. Fully integrated experience of environmental adversity. Psychol. Med. 33,
wearable sensor arrays for multiplexed in situ perspiration analysis. 1193e1202.
Nature 529, 509e514. Knutson, B., Fong, G.W., Adams, C.M., Varner, J.L., Hommer, D., 2001.
Garavan, H., Bartsch, H., Conway, K., et al., 2018. Recruiting the ABCD Dissociation of reward anticipation and outcome with event-related
sample: design considerations and procedures. Dev. Cognit. Neurosci. fMRI. Neuroreport 12, 3683e3687.
32, 16e22. Kramer, M.S., Aboud, F., Mironova, E., et al., 2008. Breastfeeding and
Goodman, R., 1997. The strengths and difficulties questionnaire: a child cognitive development: new evidence from a large randomized
research note. J. Child Psychol. Psychiatry 38, 581e586. trial. Arch. Gen. Psychiatry 65, 578e584.
Krishnan, K.R., 2005. Psychiatric and medical comorbidities of bipolar natural history interview and the addiction severity index. J. Drug
disorder. Psychosom. Med. 67, 1e8. Issues 40, 495e516.
Kuhn, S., Romanowski, A., Schilling, C., et al., 2011. The neural basis of Nees, F., Witt, S.H., Lourdusamy, A., et al., 2013. Genetic risk for nicotine
video gaming. Transl. Psychiatry 1, e53. dependence in the cholinergic system and activation of the brain
Kum, H.C., Krishnamurthy, A., Machanavajjhala, A., Ahalt, S., 2014. reward system in healthy adolescents. Neuropsychopharmacology 38,
Social Genome: Putting Big Data to Work for Population Informatics. 2081e2089.
IEEE Computer Special Outlook Issue, pp. 56e63. Nees, F., Witt, S.H., Dinu-Biringer, R., et al., 2015. BDNF Val66Met and
Lee, K.W., Richmond, R., Hu, P., et al., 2015. Prenatal exposure to reward-related brain function in adolescents: role for early alcohol
maternal cigarette smoking and DNA methylation: epigenome-wide consumption. Alcohol 49, 103e110.
association in a discovery sample of adolescents and replication in Ojelade, S.A., Jia, T., Rodan, A.R., et al., 2015. Rsu1 regulates ethanol
an independent cohort at birth through 17 years of age. Environ. consumption in Drosophila and humans. Proc. Natl. Acad. Sci. U.S.A.
Health Perspect. 123, 193e199. 112, E4085eE4093.
Lerch, J.P., van der Kouwe, A.J., Raznahan, A., et al., 2017. Studying Parker, N., Wong, A.P., Leonard, G., et al., 2017. Income inequality, gene
neuroanatomy using MRI. Nat. Neurosci. 20, 314e326. expression, and brain maturation during adolescence. Sci. Rep. 7,
Lieslehto, J., Kiviniemi, V., Maki, P., et al., 2017. Early adversity and 7397.
brain response to faces in young adulthood. Hum. Brain Mapp. 38, Pasman, J.A., Verweij, K.J.H., Gerring, Z., et al., 2018. GWAS of lifetime
4470e4478. cannabis use reveals new risk loci, genetic overlap with psychiatric
Logan, G., 1994. On the ability to inhibit thought and action: a user’s traits, and a causal influence of schizophrenia. Nat. Neurosci. 21,
guide to the stop signal paradigm. In: Dagenbach, D.C.T. (Ed.), 1161e1170.
Inhibitory Processes in Attention, Memory and Language. Academic Patel, Y., Shin, J., Gowland, P.A., Pausova, Z., Paus, T., consortium, I.,
Press, San Diego, pp. 189e236. 2018. Maturation of the human cerebral cortex during adolescence:
Logothetis, N.K., Pauls, J., Augath, M., Trinath, T., Oeltermann, A., 2001. myelin or dendritic arbor? Cerebr. Cortex.
Neurophysiological investigation of the basis of the fMRI signal. Paus, T., 2010. Population neuroscience: why and how. Hum. Brain Mapp.
Nature 412, 150e157. 31, 891e903.
Lotfipour, S., Ferguson, E., Leonard, G., et al., 2009. Orbitofrontal cortex Paus, T., 2013. Population Neuroscience. Springer-Verlag, Berlin
and drug use during adolescence: role of prenatal exposure to maternal Heidelberg.
smoking and BDNF genotype. Arch. Gen. Psychiatry 66, 1244e1252. Paus, T., 2016. Population neuroscience. Handb. Clin. Neurol. 138,
Macare, C., Ducci, F., Zhang, Y., et al., 2018. A neurobiological pathway 17e37.
to smoking in adolescence: TTC12-ANKK1-DRD2 variants and Paus, T., Nawazkhan, I., Leonard, G., et al., 2008. Corpus callosum in
reward response. Eur. Neuropsychopharmacol. 28, 1103e1114. adolescent offspring exposed prenatally to maternal cigarette smoking.
Maharana, A., Okanyene Nsoesie, E., 2018. Use of deep learning to Neuroimage 40, 435e441.
examine the association of the built environment with prevalence of Paus, T., Nawaz-Khan, I., Leonard, G., et al., 2010. Sexual dimorphism in
neighborhood adult obesity. JAMA Netw. Open 1, e181535. the adolescent brain: role of testosterone and androgen receptor in
Manolio, T.A., Collins, F.S., Cox, N.J., et al., 2009. Finding the missing global and local volumes of grey and white matter. Horm. Behav. 57,
heritability of complex diseases. Nature 461, 747e753. 63e75.
Mareckova, K., Weinbrand, Z., Chakravarty, M.M., et al., 2011. Paus, T., Wong, A.P., Syme, C., Pausova, Z., 2017. Sex differences in the
Testosterone-mediated sex differences in the face shape during adolescent brain and body: findings from the saguenay youth study.
adolescence: subjective impressions and objective features. Horm. J. Neurosci. Res. 95, 362e370.
Behav. 60, 681e690. Pausova, Z., Paus, T., Abrahamowicz, M., et al., 2007. Genes, maternal
Markova, D., Richer, L., Pangelinan, M., et al., 2016. Age- and sex-related smoking, and the offspring brain and body during adolescence: design
variations in vocal-tract morphology and voice acoustics during of the Saguenay youth study. Hum. Brain Mapp. 28, 502e518.
adolescence. Horm. Behav. 81, 84e96. Pausova, Z., Paus, T., Abrahamowicz, M., et al., 2017. Cohort profile: the
Mielenz, D., Reichel, M., Jia, T., et al., 2018. EFhd2/Swiprosin-1 is a saguenay youth study (SYS). Int. J. Epidemiol. 46, e19.
common genetic determinator for sensation-seeking/low anxiety and Peltonen, L., Palotie, A., Lange, K., 2000. Use of population isolates for
alcohol addiction. Mol. Psychiatry 23, 1303e1319. mapping complex traits. Nat. Rev. Genet. 1, 182e190.
Montigny, C., Castellanos-Ryan, N., Whelan, R., et al., 2013. Pena-Oliver, Y., Carvalho, F.M., Sanchez-Roige, S., et al., 2016. Mouse
A phenotypic structure and neural correlates of compulsive behaviors and human genetic analyses associate Kalirin with ventral striatal
in adolescents. PLoS One 8, e80151. activation during impulsivity and with alcohol misuse. Front. Genet. 7,
Moore, M.M., Chung, T., 2017. Review of key concepts in magnetic 52.
resonance physics. Pediatr. Radiol. 47, 497e506. Peng, T.Q., Sun, G., Wu, Y., 2017. Interplay between public attention and
Morales, A.J., Vavilala, V., Benito, R.M., Bar-Yam, Y., 2017. Global public emotion toward multiple social issues on twitter. PLoS One 12,
patterns of synchronization in human communications. J. R. Soc. e0167896.
Interface 14. Perrin, J.S., Herve, P.Y., Leonard, G., et al., 2008. Growth of white matter
Muller, K.U., Mennigen, E., Ripke, S., et al., 2013. Altered reward pro- in the adolescent brain: role of testosterone and androgen receptor.
cessing in adolescents with prenatal exposure to maternal cigarette J. Neurosci. 28, 9519e9524.
smoking. JAMA Psychiatry 70, 847e856. Perrin, J.S., Leonard, G., Perron, M., et al., 2009. Sex differences in the
Murphy, D.A., Hser, Y.I., Huang, D., Brecht, M.L., Herbeck, D.M., 2010. growth of white matter during adolescence. Neuroimage 45,
Self-report of longitudinal substance use: a comparison of the UCLA 1055e1066.
Pesaresi, M., Soon-Shiong, R., French, L., Kaplan, D.R., Miller, F.D., Sussman, S., Arnett, J.J., 2014. Emerging adulthood: developmental
Paus, T., 2015. Axon diameter and axonal transport: in vivo and period facilitative of the addictions. Eval. Health Prof. 37,
in vitro effects of androgens. Neuroimage 115, 191e201. 147e155.
Peters, J., Bromberg, U., Schneider, S., et al., 2011. Lower ventral striatal Syme, C., Abrahamowicz, M., Mahboubi, A., et al., 2010. Prenatal
activation during reward anticipation in adolescent smokers. Am. J. exposure to maternal cigarette smoking and accumulation of intra-
Psychiatry 168, 540e549. abdominal fat during adolescence. Obesity (SilverSpring) 18,
Pipitone, J., Park, M.T., Winterburn, J., et al., 2014. Multi-atlas segmen- 1021e1025.
tation of the whole hippocampus and subfields using multiple auto- Tahmasebi, A.M., Artiges, E., Banaschewski, T., et al., 2012. Creating
matically generated templates. Neuroimage 101, 494e512. probabilistic maps of the face network in the adolescent brain: a
Ramasamy, A., Trabzuni, D., Guelfi, S., et al., 2014. Genetic variability in multicentre functional MRI study. Hum. Brain Mapp. 33,
the regulation of gene expression in ten regions of the human brain. 938e957.
Nat. Neurosci. 17, 1418e1428. U.S. Department of Health and Human Services, 2014. The Health Con-
Rehm, J., Mathers, C., Popova, S., Thavorncharoensap, M., sequences of Smoking e 50 Years of Progress: A Report of the
Teerawattananon, Y., Patra, J., 2009. Global burden of disease and Surgeon General. US Department of Health and Human Services,
injury and economic cost attributable to alcohol use and alcohol-use Centers for Disease Control and Prevention, National Center for
disorders. Lancet 373, 2223e2233. Chronic Disease Prevention and Health Promotion, Office on Smok-
Ruiz Jdel, C., Quackenboss, J.J., Tulve, N.S., 2016. Contributions of a ing and Health, Atlanta.
child’s built, natural, and social environments to their general cogni- Toledo-Rodriguez, M., Lotfipour, S., Leonard, G., et al., 2010. Maternal
tive ability: a systematic scoping review. PLoS One 11, e0147741. smoking during pregnancy is associated with epigenetic modifications
Sandler, I., Wolchik, S.A., Cruden, G., et al., 2014. Overview of meta- of the brain-derived neurotrophic factor-6 exon in adolescent
analyses of the prevention of mental health, substance use, and offspring. Am. J. Med. Genet. B. Neuropsychiatry Genet. 153B,
conduct problems. Annu. Rev. Clin. Psychol. 10, 243e273. 1350e1354.
Schneider, S., Peters, J., Bromberg, U., et al., 2012. Risk taking and the Toro, R., Leonard, G., Lerner, J.V., et al., 2008. Prenatal exposure to
adolescent reward system: a potential common link to substance maternal cigarette smoking and the adolescent cerebral cortex. Neu-
abuse. Am. J. Psychiatry 169, 39e46. ropsychopharmacology 33, 1019e1027.
Schumann, G., Loth, E., Banaschewski, T., et al., 2010. The IMAGEN Toro, R., Poline, J.B., Huguet, G., et al., 2015. Genomic architecture of
study: reinforcement-related behaviour in normal brain function and human neuroanatomical diversity. Mol. Psychiatry 20, 1011e1016.
psychopathology. Mol. Psychiatry 15, 1128e1139. Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., et al., 2002.
Schüz, A., Braitenberg, V., 2002. The Human Cortical White Matter: Automated anatomical labeling of activations in SPM using a
Quantitative Aspects of Cortico-Cortical Long-Range Connectivity. macroscopic anatomical parcellation of the MNI MRI single-subject
Taylor & Francis, London and New York. brain. Neuroimage 15, 273e289.
Sheehan, D.V., Lecrubier, Y., Harnett-Sheehan, K., Janavs, J., Weiller, E., Whiteford, H.A., Degenhardt, L., Rehm, J., et al., 2013. Global burden of
Bonara, L.I., Keskiner, A., Schinka, J., Knapp, E., Sheehan, M.F., disease attributable to mental and substance use disorders: findings
Dunbar, G.C., 1997. Reliability and validity of the MINI international from the Global Burden of Disease Study 2010. Lancet 382,
neuropsychiatric interview (M.I.N.I.): according to the SCID-P. Eur. 1575e1586.
Psychiatry 12. Wishart, D.S., 2011. Advances in metabolite identification. Bioanalysis 3,
Shin, J., French, L., Xu, T., et al., 2018. Cell-specific gene-expression 1769e1782.
profiles and cortical thickness in the human brain. Cerebr. Cortex Wong, A.P., Pipitone, J., Park, M.T., et al., 2014. Estimating volumes of
28, 3267e3277. the pituitary gland from T1-weighted magnetic-resonance images:
Smith, G.D., Timpson, N., Ebrahim, S., 2008. Strengthening causal effects of age, puberty, testosterone, and estradiol. Neuroimage 94C,
inference in cardiovascular epidemiology through Mendelian 216e221.
randomization. Ann. Med. 40, 524e541. Wong, A.P., French, L., Leonard, G., et al., 2018. Inter-regional variations
Stacey, D., Bilbao, A., Maroteaux, M., et al., 2012. RASGRF2 regulates in gene expression and age-related cortical thinning in the adolescent
alcohol-induced reinforcement by influencing mesolimbic dopamine brain. Cerebr. Cortex 28, 1272e1281.
neuron activity and dopamine release. Proc. Natl. Acad. Sci. U.S.A. Yang, J., Lee, S.H., Goddard, M.E., Visscher, P.M., 2011. GCTA: a tool
109, 21128e21133. for genome-wide complex trait analysis. Am. J. Hum. Genet. 88,
Stacey, D., Lourdusamy, A., Ruggeri, B., et al., 2016. A translational 76e82.
systems biology approach in both animals and humans identifies a Yang, J., Lee, T., Kim, J., et al., 2013. Ubiquitous polygenicity of human
functionally related module of accumbal genes involved in the regu- complex traits: genome-wide analysis of 49 traits in Koreans. PLoS
lation of reward processing and binge drinking in males. J. Psychiatry Genet. 9, e1003355.
Neurosci. 41, 192e202.
Chapter 26
Drug use and self-awareness of

treatment need: an exemplar of how
population-based survey studies can
address questions relevant to the
neuroscience of insight
Scott J. Moeller1, Renee D. Goodwin2, 3, Ryan M. Sullivan1, 4 and Antonio Verdejo-Garcia5
1
Department of Psychiatry, Stony Brook University School of Medicine, Stony Brook, NY, United States; 2Department of Epidemiology and
Biostatistics, School of Public Health, The City University of New York, New York, NY, United States; 3Department of Epidemiology, Mailman
School of Public Health, Columbia University, New York, NY, United States; 4Department of Psychology, University of Wisconsin-Milwaukee,
Milwaukee, WI, United States; 5School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne,
VIC, Australia
Introduction may involve impaired insight into illness severity, such that
individuals with SUDs may have decreased metacognitive
Substance use disorders (SUDs) contribute to global access to the severity of their drug-related problems or need for
morbidity and mortality (Degenhardt and Hall, 2012). In the treatment (Goldstein et al., 2009; Moeller and Goldstein,
United States, 3.9% and 9.9% of the population meet criteria 2014; Verdejo-Garcia et al., 2013; Williams et al., 2015).
for 12-month and lifetime SUD, respectively, and these Supporting this perspective, laboratory studies have shown
prevalences may be increasing (Grant et al., 2016). SUDs are individuals with SUDs have a decreased capacity to self-
also highly comorbid with other forms of psychopathology monitor ongoing task performance (Hester et al., 2007,
(Lai et al., 2015) and co-occurring polysubstance use 2009; Moeller et al., 2016) or interoceptive experiences
(McCabe et al., 2017). Yet, despite the effectiveness, at least in (Naqvi et al., 2007; Stewart et al., 2014); individuals with
the short-term, of behavioral (Benishek et al., 2014; Magill SUDs also exhibit discrepancies between self-reports and
and Ray, 2009; Oikonomou et al., 2017) and pharmacological objective behavior (Moeller et al., 2010, 2014) and between
(Donoghue et al., 2015; Nosyk et al., 2015) therapies, only a self-reports and informant reports of behavioral symptoms
minority of individuals with an SUD ultimately seek treatment linked to addiction (Moreno-Lopez et al., 2017;
(Blanco et al., 2015; Compton et al., 2007; Grant et al., 2016; Verdejo-Garcia and Perez-Garcia, 2008). In some of these
Hedden and Gfroerer, 2011; Mojtabai and Crum, 2013). These same laboratory studies, the observed behavioral deficits have
low treatment prevalences may reflect, among many factors, correlated with functional and/or structural abnormalities in
pessimistic efficacy beliefs (Mojtabai and Crum, 2013), lack the anterior cingulate cortex (ACC), ventromedial prefrontal
of adequate health insurance for substance use treatment cortex (vmPFC), insula, and dorsal striatum. Involvement of
(Ilgen et al., 2011), cultural norms (Gopalkrishnan and these regions is consistent with studies conducted in pop-
Babacan, 2015), the potential for stigmatization (Kulesza ulations with other psychiatric disorders more classically
et al., 2014), and/or a paucity of resources (Bobrova et al., characterized by impaired insight, including schizophrenia
2006; McLellan and Meyers, 2004). (van der Meer et al., 2013), Alzheimer’s disease (Amanzio
Beyond these well-recognized treatment barriers, we et al., 2011), frontotemporal dementia (Shany-Ur et al., 2014),
and others have suggested that another mechanism that may and traumatic brain injury (Ham et al., 2014).
help to explain low rates of treatment seeking for SUDs

However, prior clinical studies primarily have included of insight. Using a publicly available epidemiological
individuals who are dependent on a single substance dataset, we are unable to reach the richness of clinical
(e.g., stimulants or alcohol). When study inclusion is research data, but we are able to derive answers to
opened to polysubstance dependence or substance-related circumscribed questions while testing large numbers of
comorbidities, there is usually insufficient statistical individuals efficiently and at low cost. In doing so, we can
power to dissect the contributions of individual drugs to the explore questions that are currently unanswerable in
insight-related impairments. Therefore, in the clinical clinical neuroscience research, including whether treatment
neuroscience literature, a question persists with respect to need awareness differs by the substance that is misused
which substances (and their respective patterns of use) are (e.g., alcohol vs. marijuana). Our study echoes the
associated with the highest propensity for denying a need approach of “population neuroscience” (Falk et al., 2013;
for SUD treatment and/or exhibiting other insight-related Paus, 2010), leveraging interdisciplinary capabilities at the
impairments. The question regarding the association intersection of neuroscience (which emphasizes the
between drug use and treatment need awareness is perhaps fundamental mechanisms underlying complex behavior)
best addressed using a large-scale, population-based and population science (which emphasizes large, repre-
approach. Indeed, epidemiology has a longstanding interest sentative samples to make generalizable conclusions about
in documenting the various predictors of treatment need a phenomenon of interest).
awareness, including predictors related to sociodemographics,
mental health comorbidities, and/or legal factors (Booth et al.,
2013, 2014; Borders et al., 2015; Edlund et al., 2006; Grella
Methods
et al., 2009; Mojtabai and Crum, 2013; Mojtabai et al., 2002; Sample
Oleski et al., 2010), as well predictors related to select sub-
Data were drawn from the National Survey on Drug Use
stance use variables (Edlund et al., 2009; Falck et al., 2007;
and Health (NSDUH), sponsored by the Substance Abuse
Glass et al., 2015; Wu and Ringwalt, 2004). Thus, the idea
and Mental Health Service Administration, spanning
explored in this chapter is that epidemiological measures can
2004e13 (see Appendix for citations); this multiyear
be used to inform cognitive questions that otherwise would be
intractable in the small sample sizes typically seen in clinical approach ensured a large number of individuals with SUD.
The NSDUH uses a combination of audio computer-
neuroscience studies.
assisted self-interview, computer-assisted personal inter-
In the current study, we examined a nationally represen-
view, and computer-assisted self-interview techniques to
tative, multiyear sample of individuals with at least one SUD,
measure the prevalences and correlates of substance use
testing whether the use of certain substances would be asso-
and SUDs (as defined by the Diagnostic and Statistical
ciated with reduced treatment need awareness, one component
Manual of Mental Disorders, fourth edition [DSM-IV]
(among others) of clinical insight impairment (Amador and
[American Psychiatric Association, 2000]) among the
David, 1998). In our analyses, we also statistically adjusted for
relevant sociodemographics and for proxies of physical general population of the United States; relevant socio-
demographic information was also collected. The target
health, mental health, legal problems, and the general ten-
population was noninstitutionalized respondents 12 years
dency to seek treatment of any kind, which together could
or older, incorporating a multistage area probability sample
influence one’s decision or prompt a court mandate to seek
for all 50 states and the District of Columbia. Respondents
SUD treatment. Compared with prior studies that examined
gave verbal consent in accordance with the RTI Interna-
drug use predictors specifically (Edlund et al., 2009; Falck
tional (formerly: Research Triangle Institute) Institutional
et al., 2007; Glass et al., 2015; Wu and Ringwalt, 2004), the
Review Board (IRB) and received $30 for participation. To
current study used a larger sample of respondents that allowed
us to examine a more comprehensive list of drug use predictors obtain our final analytical sample, we filtered the dataset by
removing respondents without an SUD, duplicate identi-
for a more comprehensive list of substances. For example, it is
fiers, minors below age 18 (whose sociodemographic
currently unknown whether recency of substance use, inde-
information would not be comparable with adults), and
pendently of its overall frequency and use disorder, predict
individuals for whom treatment-seeking data were unavai-
treatment need unawareness; such a relationship would pre-
lable (for SUD, but also for nonsubstance mental health
sent an important translational parallel to prior clinical work
treatment) (Fig. 26.1).
(Martinez-Gonzalez et al., 2016; Moeller et al., 2010, 2016;
Verdejo-Garcia and Perez-Garcia, 2008).
The present study can contribute knowledge to the Outcome variable
epidemiological links between drug use and treatment need
The NSDUH asks respondents: “During the past
awareness and simultaneously provide a potentially inter-
12 months, did you need treatment or counseling for your
esting, albeit still speculative at this stage, link to an
alcohol or drug use?” and “During the past 12 months, that
important outstanding question in the clinical neuroscience
Drug use and self-awareness of treatment need Chapter | 26 353
FIGURE 26.1 Derivation of the National Survey on Drug Use and Health (NSDUH) analytical sample, with data collected from 2004 through 2013
inclusive.
is since [DATEFILL], have you received treatment or within 30 min of waking). In addition to diagnostic criteria,
counseling for your use of alcohol or any drug, not we analyzed past-year number of days used (use frequency;
counting cigarettes?” From these two variables, we derived categorical levels), past-month use (use recency; yes/no),
three levels of treatment need awareness: no perception of and substance use before age 18 (early initiation; yes/no).
treatment need (TxUnaware), perception of treatment need We conducted these analyses for alcohol, cigarettes, and
but no treatment sought (TxAware), and treatment sought marijuana; we also conducted these analyses for a fourth
(TxSought), respectively. category we created, labeled as “other drugs,” which
collapsed across cocaine/crack, heroin, hallucinogens,
analgesics, tranquilizers, and noncocaine stimulants; these
Drug use variables drugs were less frequently used, and preliminary analyses
For a given substance, we analyzed the presence (yes/no) of with the illicit drugs considered separately (e.g., heroin vs.
past-year dependence (e.g., the presence of withdrawal cocaine) were underpowered.
symptoms when use is discontinued) and (separately) past-
year abuse (e.g., use in hazardous situations, such as
driving while impaired). DSM-IV criteria established abuse
Sociodemographic and general health
and dependence for all drugs except cigarettes, for which covariates
Fagerstrom criteria were used (i.e., nicotine dependence Sociodemographic covariates included sex, race/ethnicity,
was recorded if the respondent reported smoking cigarettes age, marital status, education, employment status, income, and
in the past month and if the first cigarette was smoked
whether the individual had been arrested (with the latter cross in all tables, are reported and interpreted in the text.
potentially being relevant to court-mandated treatment). We Finally, for variables that showed similar effects in the TxU-
also included a variable assessing presence of dysphoric mood naware and TxAware subgroups (i.e., significant and in the
symptoms (i.e., feeling sad/blue much of the day and/or losing same direction, consistent with proportional odds), follow-up
pleasure in enjoyable activities) and respondents’ self- ordinal logistical regressions examined whether the particular
reported overall health, ranging from excellent to poor. variable exerted graded effects on the extent of treatment need
Finally, we included variables relevant to the receipt of mental perception (with TxSought, TxAware, and TxUnaware,
health treatment (i.e., apart from SUD treatment): whether respectively, reflecting decreasing treatment need percep-
individuals sought nonsubstance mental health treatment and tions). Significant effects for these ordinal logistic regressions
(separately) whether individuals were found to need, but not are indicated by a double cross in all tables.
receive, mental health treatment. Prior treatment seeking has
been associated with greater odds of future treatment seeking
(Blanco et al., 2015), and comorbid mood/anxiety disorders
Results
have been associated with greater odds of reporting an unmet Table 26.1 displays the sociodemographics of the sample.
need for SUD treatment (Melchior et al., 2014). Tables 26.2e26.3 display the frequencies, percentages, and
RRRs for all drug-related variables (Table 26.2: substance
diagnoses; Table 26.3: substance use) by study group
Statistical analyses (TxUnaware: not perceiving a need for treatment, TxA-
We obtained relative risk ratios (RRRs) from two sets of ware: perceiving a need for treatment but not seeking it, and
multinomial regression analyses, which estimated the asso- TxSought [the reference group in the analyses]: seeking
ciations between each substance use variable and treatment treatment).
need perception. Analyses were performed using Stata/MP
14, which accommodates the complex survey design of the Drug use predictors of TxUnaware status
NSDUH. The first set of RRRs examined the relationship
between drug use predictors and reporting no awareness of Diagnostic status: Individuals who abused alcohol, but not
treatment need (TxUnaware) (N ¼ 36,466; 89.1% of the individuals who were dependent on alcohol, were more
sample). The second set of RRRs examined the relationship likely to perceive no need for treatment (i.e., to belong to
between drug use predictors, reporting an awareness of the TxUnaware group vs. the TxSought group). In contrast,
treatment need but without seeking treatment (TxAware) individuals who were dependent on nicotine or illicit drugs
(N ¼ 1755; 4.3% of the sample). Individuals who sought were less likely to perceive no need for treatment.
treatment (TxSought) (N ¼ 2711; 6.6% of the sample) were Substance use initiation: When examining initiation into
considered the reference group in both sets of RRRs. substance use, individuals who used any substances before
For all analyses, each substance (alcohol, nicotine, mari- age 18 were less likely to belong to the TxUnaware group.
juana, and “other drugs”) was considered separately. Each Substance use frequency: Individuals who used all
analysis was conducted across the entire available sample, not substances frequently (vs. no use within the past year) were
just within a particular substance (e.g., marijuana use could also less likely to belong to the TxUnaware group, with
predict treatment need awareness among individuals with such relationships reaching significance for moderate use of
alcohol problems). All analyses also adjusted for the socio- alcohol (50e99 days) and marijuana (12e49 days) and
demographic/health characteristics included in Table 26.1, all heavy use of “other drugs” (100e299 and 300e365 days).
other substances use variables examined for each substance, An exception to this pattern, however, was observed for the
and the survey year as a categorical variable. heaviest use of marijuana (300e365 days), in which the
We also conducted the following supporting analyses to direction of association was reversed.
bolster conclusions and lessen the influence of potential con- Substance use recency: Independent of frequency, in-
founds. First, to protect against issues associated with unbal- dividuals who used substances recently (i.e., within the last
anced cell counts (i.e., most of the sample belonged to the month) were more likely to belong to the TxUnaware group
TxUnaware subgroup), we repeated all analyses using a (note that recency analyses could not be conducted for
randomly selected subsample of 3050 TxUnaware cigarettes due to data collinearity).
respondents (approximately 1.75 times the size of the smallest
group). Second, to lessen the possibility that effects of recent Drug use predictors of TxAware status
drug use represent artifacts of treatment-seeking individuals
reducing their recent drug use, we repeated all analyses after Diagnostic status: Individuals with nicotine dependence
excluding individuals who reported no attempt to reduce or and individuals with marijuana abuse were less likely to
stop their drug use over the past year. Only effects that reached belong to the TxAware group (i.e., perceive a need for
significance in these supporting analyses, as marked with a treatment but not seek it, compared with seeking treatment).
TABLE 26.1 Sociodemographic and wellness characteristics and perceived need for treatment.
Sought treatment (N [ 2711) Perceived need, did not seek No perceived need for treat-
(reference category) treatment (N [ 1755) ment (N [ 36466)
Characteristic N(%) N(%) N(%)
Sex
Male 1,693 (62.4) 1,001 (57.0) 22,206 (60.9)
Female 1,018 (37.6) 754 (43.0) 14,260 (39.1)
Race/ethnicity
Caucasian 1,891 (69.8) 1072 (61.1) 24,556 (67.3)
African American 293 (10.8) 238 (13.6) 3,654 (10.0)
Hispanic 281 (10.4) 282 (16.1) 5,213 (14.3)
Asian 20 (0.7) 16 (0.9) 840 (2.3)
Pacific Islander 9 (0.3) 10 (0.6) 232 (0.6)
Native American 100 (3.7) 73 (4.2) 817 (2.2)
More than one race 117 (4.3) 64 (3.6) 1,154 (3.2)
(non-Hispanic)
Age, y
50 104 (3.8) 107 (6.1) 1,412 (3.9)
35e49 504 (18.6) 344 (19.6) 4,561 (12.5)
26e34 397 (14.6) 284 (16.2) 4,902 (13.4)
18e25 1706 (62.9) 1,020 (58.1) 25,591 (70.2)
Marital status
Married 333 (12.3) 323 (18.4) 6,107 (16.7)
Widowed 19 (0.7) 25 (1.4) 189 (0.5)
Divorced/separated 417 (15.4) 260 (14.8) 2,710 (7.4)
Never married 1942 (71.6) 1,147 (65.4) 27,460 (75.3)
Education
<High school 801 (29.5) 487 (27.7) 6,541 (17.9)
graduate
High school graduate 1064 (39.2) 593 (33.8) 11,695 (32.1)
Some college 669 (24.7) 485 (27.6) 11,898 (32.6)
College graduate 177 (6.5) 190 (10.8) 6,332 (17.4)
Employment status
Other (or not in labor 753 (27.8) 379 (21.6) 6,061 (16.6)
force)
Unemployed 461 (17.0) 277 (15.8) 3,587 (9.8)
Part time 454 (16.7) 302 (17.2) 7,876 (21.6)
Full time 1,043 (38.5) 797 (45.4) 18,942 (51.9)
Income, $
<20,000 1,096 (40.4) 660 (37.6) 11,477 (31.5)
20,000e49,999 915 (33.8) 625 (35.6) 12,358 (33.9)
50,000e74,999 293 (10.8) 233 (13.3) 5,122 (14.0)
75,000 407 (15.0) 237 (13.5) 7,509 (20.6)
Continued
TABLE 26.1 Sociodemographic and wellness characteristics and perceived need for treatment.dcont’d
Sought treatment (N [ 2711) Perceived need, did not seek No perceived need for treat-
(reference category) treatment (N [ 1755) ment (N [ 36466)
Characteristic N(%) N(%) N(%)
Overall health status (n [ 36460, n [ 1754, n [ 2711)
Poor 76 (2.8) 70 (4.0) 410 (1.1)
Fair 374 (13.8) 282 (16.1) 2,835 (7.8)
Good 984 (36.3) 635 (36.2) 10,068 (27.6)
Very good 925 (34.1) 548 (31.2) 15,019 (41.2)
Excellent 352 (13.0) 219 (12.5) 8,128 (22.3)
Dysphoric symptoms (n [ 36413, n [ 1752, n [ 2704)
Yes 1,684 (62.3) 1,251 (71.4) 18,593 (51.1)
No 1,020 (37.7) 501 (28.6) 17,820 (48.9)
Needed mental health treatment went unmet (n [ 36414, n [ 1751, n [ 2704)
Yes 691 (25.6) 728 (41.6) 5,058 (13.9)
No 2,013 (74.4) 1,023 (58.4) 31,356 (86.1)
Received mental health treatment
Yes 986 (36.4) 364 (20.7) 3,795 (10.4)
No 1,725 (63.6) 1,391 (79.3) 32,671 (89.6)
Arrested/charged (n [ 36411, n [ 1751, n [ 2706)
Yes 2,108 (77.9) 1,032 (58.9) 13,481 (37.0)
No 598 (22.1) 719 (41.1) 22,930 (63.0)
Numbers are frequencies and percentages.
Substance use initiation: Age of initiation did not relate Substance use frequency: Individuals who used mari-
to TxAware status, for any substances. juana for 300e365 days in the last year had decreased
Substance use frequency: Individuals who used marijuana awareness of treatment need, compared with those who
very frequently (300e365 days, vs. no use) were more likely reported no use. That is, individuals with very frequent
to belong to the TxAware group (vs. the TxSought group). marijuana use were most likely to belong to the TxUnaware
However, individuals with moderate marijuana use frequency group, followed respectively by their likelihood of
(i.e., 100e299 days, vs. no use within the past year) were less belonging to the TxAware group and the TxSought group.
likely to belong to the TxAware group. Substance use recency: Individuals who used alcohol,
Substance use recency: Individuals who used any sub- marijuana, and illicit drugs within the past month,
stances in the past month were more likely to belong to the compared with those who had not used these substances
TxAware group (vs. the TxSought group). within the past month, had decreased awareness of treat-
ment need (most likely to belong to the TxUnaware group,
Graded effects on treatment need awareness followed respectively by their likelihood of belonging to
the TxAware group and the TxSought group).
Diagnostic status: Individuals with nicotine dependence had
increased awareness of treatment need, compared with those
without nicotine dependence. That is, individuals with nico- Discussion
tine dependence were least likely to belong to the TxUnaware
Using NSDUH survey data collected between 2004 and
group, followed respectively by their likelihood of belonging
2013, we examined whether certain SUDs and patterns of
the TxAware group and the TxSought group.
substance use were associated with reduced awareness of
Substance use initiation: No graded analyses with sub- treatment need in a nationally representative, multiyear
stance use initiation were conducted, as there were no
sample of individuals with SUDs. This is the first study, to
plausible candidate effects.
TABLE 26.2 Associations between alcohol and drug use disorders and the perceived need for substance use
treatment among adults with substance use disorders in the United Statesa.
Sought treatment Perceived

(N [ 2711) need,
(reference did not seek No perceived need
category) treatment for treatment
(N [ 1755) (N [ 36466)
Relative risk Relative risk
Substance N(%) N(%) ratio (95% CI) N (%) ratio (95% CI)
Alcohol dependence
Yes 1,262 (46.6) 1,012 (57.7) 1.06 (0.78e1.43) 12,610 (34.6) 0.97 (0.80e1.18)
No 1,449 (53.4) 743 (42.3) Reference 23,856 (65.4) Reference
Alcohol Abuse
Yes 643 (23.7) 303 (17.3) 0.78 (0.52e1.16) 17,665 (48.4) 2.76 (2.21e3.43)
***b
No 2,068 (76.3) 1,452 (82.7) Reference 18,801 (51.6) Reference
Nicotine dependence (Fagerstrom)
Yesc 1,411 (52.0) 730 (41.6) 0.69 (0.52e0.92)*b 8,255 (22.6) 0.54 (0.43e0.67)
***b
Marijuana Dependence
Yes 522 (19.3) 417 (23.8) 0.95 (0.69e1.31) 5,183 (14.2) 0.78 (0.60e1.01)
Marijuana Abuse
Yes 226 (8.3) 112 (6.4) 0.50 (0.32e0.78)**b 2,723 (7.5) 0.92 (0.68e1.24)
d
Other Drugs Dependence
Yes 1,044 (38.5) 667 (38.0) 0.83 (0.63e1.08) 3,053 (8.4) 0.30 (0.24e0.37)
***b
Other Drugs Abuse
Yes 289 (10.7) 187 (10.7) 0.85 (0.58e1.23) 1,858 (5.1) 0.80 (0.63e1.03)
Numbers are frequencies or odds ratios, with respective percentages or 95% confidence intervals in parentheses;
a
Adjusted relative risk ratios corrected for year of survey, sex, age, race/ethnicity, education, family income, marital status, employment status, overall
health, depression symptoms, unmet need for mental health treatment, received mental health treatment, and arrest history; *, P < 0.05, **, P < 0.01,
***, P < 0.001;
b
Remained significant (P < 0.05) after rerunning the analyses to account for potential confounds, that is, after excluding individuals who did not attempt
to reduce their drug use during the past year and after using a random subsample of respondents who reported no perceived need for treatment;
c
Significant using ordinal logistic regression (with the three groups comprising individuals who sought treatment, individuals who perceived a need for
treatment but did not seek it, and individuals who did not perceive a need for treatment, respectively);
d
Other drugs of abuse included cocaine/crack, heroin, hallucinogens, analgesics, tranquilizers, and noncocaine stimulants (e.g., methamphetamine).
our knowledge, to incorporate the presence of use disorder, questions but with fewer drug use variables (Edlund et al.,
recency, frequency, and age of initiation together in the 2009; Falck et al., 2007; Glass et al., 2015; Wu and
same models in predicting awareness of treatment need. In Ringwalt, 2004). This is also the first study to propose
this way, we were able to isolate the effects of each drug theoretical links between the epidemiology of treatment
use variable, for each substance of abuse, thus extending need perception and the clinical neuroscience literature on
prior studies that have addressed similar epidemiological treatment need perception as relevant to insight. This study,
TABLE 26.3 Associations between alcohol and drug use frequency, recency, and initiation and the perceived
need for substance use treatment among adults with substance use disorders in the United Statesa.
Perceived need, No perceived

Sought treatment did not seek need for
(N [ 2711) treatment Relative treatment Relative risk
(reference category) (N [ 1755) risk ratio (N [ 36466) ratio (95%
Substance N(%) N(%) (95% CI) N(%) CI)
Alcohol
Used last month
(n ¼ 36465, n ¼ 1755,
n ¼ 2711)
Yesc 1,878 (69.3) 1,431 (81.5) 2.46 (1.87 32,235 (88.4) 3.41 (2.65
e3.23)***b e4.39)***b
No 833 (30.7) 324 (18.5) Reference 4,230 (11.6) Reference
Used before age 18
Yes 2,447 (90.3) 1,542 (87.9) 0.82 (0.55 30,547 (83.8) 0.58 (0.46
e1.21) e0.74)***b
Past-year use frequency,
days (n ¼ 36149, n ¼ 1723,
n ¼ 2645)
None 149 (5.6) 68 (3.9) Reference 742 (2.1) Reference
1e11 236 (8.9) 103 (6.0) 0.82 (0.43 1,444 (4.0) 0.66 (0.45
e1.55) e0.98)*
12e49 448 (16.9) 229 (13.3) 0.62 (0.35 6,151 (17.0) 0.49 (0.32
e1.09) e0.75)**
50e99 436 (16.5) 226 (13.1) 0.64 (0.34 6,148 (17.0) 0.48 (0.30
e1.20) e0.76)**b
100e299 1,154 (43.6) 863 (50.1) 0.74 (0.39 18,967 (52.5) 0.53 (0.33
e1.39) e0.85)**
300e365 222 (8.4) 234 (13.6) 1.14 (0.59 2,697 (7.5) 0.54 (0.31
e2.22) e0.94)*
Cigarettes
Used last monthd
Yes 2,200 (81.2) 1,336 (76.1) e 21,234 (58.2) e
No 511 (18.8) 419 (23.9) e 15,232 (41.8) e
Used before age 18
Yes 1620 (59.8) 912 (52.0) 0.93 (0.73 11,756 (32.2) 0.75 (0.64
e1.19) e0.89)**b
days (n ¼ 36348, n ¼ 1745,
n ¼ 2702)e
None 511 (18.9) 419 (24.0) Reference 15,222 (41.9) Reference
1e11 e e e e e
12e49 172 (6.4) 141 (8.1) 1.02 (0.66 3,598 (9.9) 0.86 (0.62
e1.60) e1.18)
50e99 94 (3.5) 66 (3.8) 0.87 (0.49 1,639 (4.5) 0.81 (0.52
e1.55) e1.26)
Continued
TABLE 26.3 Associations between alcohol and drug use frequency, recency, and initiation and the perceived need
for substance use treatment among adults with substance use disorders in the United Statesa.dcont’d

100e299 270 (10.0) 186 (10.7) 1.17 (0.78 3,583 (9.9) 0.72 (0.54
e1.75) e0.96)*
300e365 1,655 (61.3) 933 (53.5) 1.34 (0.91 12,306 (33.9) 0.76 (0.59
e1.98) (0.99)*
Marijuana
Used last month
(n ¼ 36450, n ¼ 1755,
n ¼ 2710)
Yesc 1,037 (38.3) 810 (46.2) 2.02 (1.58 13,169 (36.1) 1.59 (1.36
e2.60)***b e1.89)***b
Used before age 18
Yes 2,230 (82.3) 1,353 (77.1) 0.74 (0.54 22,813 (62.6) 0.49 (0.40
e1.02) e0.61)***b
days (n ¼ 36084, n ¼ 1729,
n ¼ 2625)
None 2,143 (81.6) 1,420 (82.1) Reference 29,731 (82.4) Reference
1e11 263 (10.0) 179 (10.4) 1.20 (0.84 4,468 (12.4) 0.94 (0.73
e1.71) e1.21)
12e49 101 (3.8) 49 (2.8) 0.63 (0.34 851 (2.4) 0.64 (0.42
e1.16) e0.96)*b
50e99 32 (1.2) 17 (1.0) 0.60 (0.25 139 (0.4) 0.50 (0.25
e1.44) e0.99)*
100e299 46 (1.8) 10 (0.6) 0.14 (0.05 233 (0.6) 0.57 (0.29
e0.40)***b e1.14)
300-365c 40 (1.5) 54 (3.1) 2.18 (1.22 662 (1.8) 2.65 (1.65
e3.90)**b e4.25)***b
Other Drugsf
Used last month
(n ¼ 36322, n ¼ 1741,
n ¼ 2689)
Yesc 939 (34.9) 713 (41.0) 1.70 (1.21 6,886 (19.0) 1.92 (1.52
e2.39)**b e2.43)***b
Used before age 18
Yes 1,668 (61.5) 986 (56.2) 0.85 (0.66 13334 (36.6) 0.67 (0.55
e1.10) e0.82)**b
Continued
TABLE 26.3 Associations between alcohol and drug use frequency, recency, and initiation and the perceived need
for substance use treatment among adults with substance use disorders in the United Statesa.dcont’d

days
None 947 (34.9) 612 (34.9) Reference 22,097 (60.6) Reference
1e11 362 (13.4) 234 (13.3) 1.05 (0.72 6,126 (16.8) 0.98 (0.77
e1.54) e1.25)
12e49 365 (13.5) 229 (13.0) 0.88 (0.60 3,672 (10.1) 0.70 (0.55
e1.29) e0.90)**
50e99 243 (9.0) 154 (8.8) 0.92 (0.56 1,754 (4.8) 0.63 (0.48
e1.51) e0.83)**
100e299 583 (21.5) 381 (21.7) 0.81 (0.53 2,379 (6.5) 0.49 (0.37
e1.22) e0.67)***b
300e365 211 (7.8) 145 (8.3) 0.82 (0.49 438 (1.2) 0.23 (0.16
e1.38) e0.34)***b
Numbers are frequencies or odds ratios, with respective percentages or 95% confidence intervals in parentheses;
a
Adjusted relative risk ratios corrected for year of survey, sex, age, race/ethnicity, education, family income, marital status, employment status, overall
health, depression symptoms, unmet need for mental health treatment, received mental health treatment, and arrest history; *, P < 0.05; **, P < 0.01,
***, P < 0.001;
b
Remained significant (P < 0.05) after rerunning the analyses to account for potential confounds, that is, after excluding individuals who did not attempt
to reduce their drug use during the past year and after using a random subsample of respondents who reported no perceived need for treatment;
c
Significant using ordinal logistic regression (with the three groups comprising individuals who sought treatment, individuals who perceived a need for
treatment but did not seek it, and individuals who did not perceive a need for treatment, respectively);
d
Not included in the model due to collinearity with those who used 300e365 days;
e
Extrapolated from past month data;
f
Other drugs of abuse included cocaine/crack, heroin, hallucinogens, analgesics, tranquilizers, and noncocaine stimulants (e.g., methamphetamine).
by employing and integrating concepts and approaches (Verdejo-Garcia and Perez-Garcia, 2008). Future studies will
from neuroscience and epidemiology, is consistent with the need to adjudicate among several plausible mechanisms.
emerging and exciting field of population neuroscience First, individuals with AUD may experience less psycho-
(Falk et al., 2013; Paus, 2010). social disruptions than individuals with other SUDs
Our primary finding was that alcohol abuse was associ- (Fernandez-Calderon et al., 2015) and thus the perceived
ated with a lower likelihood of reporting a need for treatment need (or actual need) for treatment may be less stark (Tuithof
(i.e., higher likelihood of belonging to the TxUnaware et al., 2016). Second, or in combination, the failure to seek
group), compared with those without alcohol abuse. treatment in AUD could represent a manifestation of
Although alcohol dependence was not similarly associated neurotoxic effects of alcohol on cortical structure/functions
with a lower likelihood of reporting a need for treatment, it relevant to self-awareness. For example, deficits in PFC-
was not associated with a higher likelihood of reporting a related function and structure in AUD correlated with
need for treatment either (which contrasts with other sub- decreased readiness to change problematic alcohol use (Le
stances; see next paragraph). Other studies using different Berre et al., 2013) and low treatment engagement (Rinn
data sources have similarly reported that individuals with et al., 2002).
alcohol use disorder (AUD) often do not perceive a need for Interestingly, nicotine and drug dependence (and mari-
treatment (Edlund et al., 2009), and they seek treatment less juana abuse) were associated with greater awareness of
often than do individuals with other SUDs (Blanco et al., treatment need (i.e., a higher likelihood of seeking treat-
2015). In clinical studies, individuals with AUD have also ment in the last year). These findings were somewhat un-
exhibited impaired treatment need awareness (example expected, considering that prior research has reported
questionnaire item: “I can control my drinking any time I impairments in insight-related functions in other SUDs
want to”) (Kim et al., 1998), and they have shown self/ (especially, stimulants). For example, relative to healthy
informant discrepancy scores of neurocognitive impairment controls, individuals with cocaine use disorder exhibited
impairments on tasks assessing the capability to self-monitor necessarily over the past month. Second, the effects of recent
task behavior (Hester et al., 2007; Moeller et al., 2010, 2016), drug use followed an ordinal relationship as a function of
and these impairments correlated with functional and struc- treatment need awareness, consistent with the idea that recent
tural abnormalities in the rostral ACC and vmPFC (Moeller drug use is accentuating awareness problems in an expected,
et al., 2014, 2016). Furthermore, using measures similar to stepwise fashion. Third, our findings remained significant
those described above (Le Berre et al., 2013), vmPFC gray after limiting the analyses to individuals who reported
matter volume correlated with increased readiness to change attempting to cut down or stop drug use at least once over the
problematic drug use as further modulated by the presence of past year (i.e., whether or not treatment was sought). Fourth, at
personality disorders (Moreno-Lopez et al., 2014). Although least for marijuana, the highest frequencies of use in the past
the mechanisms underlying the current unexpected finding year (300e365 days) were associated with a lower likelihood
(i.e., better treatment need awareness in SUDs other than of seeking treatment. This finding speaks against treatment-
AUD) require further investigation, one plausible explana- related reductions in drug use, and it also speaks against the
tion relates to the different sampling scopes (i.e., population- possibility that recent users are also necessarily the heaviest
based case-only study vs. clinically based caseecontrol users who simply do not wish to stop.
studies), which are core considerations of population A methodological limitation of the study is that
neuroscience research (Falk et al., 2013). If indeed AUD is respondents may have had varying conceptions of drug
characterized by the lowest treatment need perceptions, and “treatment,” perhaps introducing variance into the dependent
if indeed these lowered perceptions are validly captured by measure. For example, some individuals may have believed
the current NSDUH questions, then applying some of the the treatment questions referred to classical inpatient
same sensitive, neuroscience-based measures in AUD that approaches, and they may have responded “no” to these
have been used in other addictions could yield especially questions despite wanting some kind of help nonetheless.
robust and informative effects. In this way, clinical neuro- Another methodological limitation is that we are unable to
science can be informed by epidemiological findings. determine the directionality of effects: treatment need
The most consistent findings in the current study were that, unawareness may have predated problematic drug use,
at least after accounting for other drug use measures including followed problematic drug use, or contributed as part of a
frequency of drug use and early initiation (both of which were bidirectional relationship. Prospective investigations are
typically, though not always, associated with a higher likeli- needed to address the issue. A final methodological limitation
hood of seeking treatment), past-month drug use was associ- is that the contributions of psychiatric comorbidities
ated with less awareness of treatment need. Thus, those who (e.g., mood disorders) to these results require further study, as
are actively using substances may seek treatment less readily comorbidities and their severity might covary with socio-
despite potentially needing treatment more imminently, which demographic or drug use variables. However, we note that, in
underscores the need to implement programs and policies to all analyses, we controlled for dysphoric symptoms and psy-
attract individuals who have current/recent use into treatment chiatric, nonesubstance-related treatment seeking, which are
services. These findings also present a very interesting parallel proxies for mental health problems and general treatment
to prior laboratory-based work, which has shown that recency, seeking.
rather than severity per se, of drug use is an important Beyond the study-specific methodological limitations,
modulator of impaired insight and self-awareness in SUDs there are also more general, conceptual challenges to
(Martinez-Gonzalez et al., 2016; Moeller et al., 2010, 2016; adopting an epidemiological approach to clinical neuro-
Verdejo-Garcia and Perez-Garcia, 2008). More specifically, science questions. For example, treatment need perception
discrepancies between self-reports and informant reports in as a variable does not perfectly map onto the concept of
polysubstance abusers were evident during active drug use, insight as defined in the clinical literature, both because it
but not during abstinence (Verdejo-Garcia and Perez-Garcia, was measured in the NSDUH with only two self-report
2008). Also in polysubstance abuse, one’s ability to recognize items and more generally because it is viewed as only
the adverse effects of one’s substance use problem correlated one component or aspect of insight; other components of
with longer abstinence length (Martinez-Gonzalez et al., clinical insight, not measured here, have included aware-
2016). In cocaine use disorder, greater impairments in ness of having a disorder, awareness of symptoms,
self-monitoring one’s own task performance were accentuated attribution of symptoms to the disorder, and recognizing the
in cocaine users who tested positive for cocaine in urine, consequences of symptoms (David et al., 2012). Further-
indicating recent use within 72 h (Moeller et al., 2010, 2016). more, and relatedly, the link posited between treatment
One potential confound in the current recency effects is that need unawareness and the effects of substance use on
individuals who sought treatment may have, in parallel, also neurocognitive functioning implicated in insight is
reduced their recent drug use. However, several pieces of currently speculative, as no direct data on neurocognitive
evidence bolster the fidelity of these findings. First, treatment functioning were available in this survey. Therefore, it will
seeking could have occurred any time over the past year, not take time, persistence, and multiple triangulated studies of
this kind to advance the idea that, for example, a concept as and does not necessarily represent the official views of the National
complicated as insight can be (at least partially) meaning- Institutes of Health. Other support came from a strategic research
fully informed by one or two survey questions. It will also grant from Monash University (SGS2014/026) and the program grant
require cross-disciplinary collaboration between clinical RETICS from the Institute of Health Carlos III, Spanish of Ministry of
Health, cofunded by FEDER funds of the European Unionda way to
neuroscientists and epidemiologists, who have quite
build Europed(RD12/0028/0017) to AVG. The funders had no role
different trainings and modes of thinking. The same chal-
in the design and conduct of the study; collection, management,
lenges would likely apply to other neuroscience-informed analysis, and interpretation of the data; preparation, review, or
constructs beyond insight, if a similar approach to ours is approval of the manuscript; and decision to submit the manuscript for
adopted in other domains. If these challenges can be publication. We thank Keren Bachi and Muhammad A. Parvaz for
overcome, however, the current approach allows the helpful discussions on concepts presented in this manuscript.
examination of provocative, clinically informed research
questions at very low costs. It opens the door for contri-
butions from able and motivated investigators, even if they
References
do not have plentiful funding or well-staffed laboratories. American Psychiatric Association, 2000, fourth ed., Text Revision.
In conclusion, our findings reflect an attempt to interrogate Diagnostic and Statistical Manual of Mental Disorders. American
a question of relevance to the clinical neuroscience literature Psychiatric Association, Washington DC.
using epidemiological methods. This initial effort provides Ahmadi, J., Kampman, K.M., Oslin, D.M., Pettinati, H.M., Dackis, C.A.,
feasibility for future translational research to bridge these Sparkman, T., 2009. Predictors of treatment outcome in outpatient
cocaine and alcohol dependence treatment. Am. J. Addict. 18, 81e86.
respective fields. Future studies conducted in the community
Amador, X.F., David, A.S., 1998. Insight and Psychosis. Oxford Uni-
or clinic are clearly warranted, including those that are
versity Press, New York, NY.
informed by the current epidemiological data, that include Amanzio, M., Torta, D.M., Sacco, K., Cauda, F., D’Agata, F., Duca, S.,
insight, self-awareness, and/or neurocognition variables in the Leotta, D., Palermo, S., Geminiani, G.C., 2011. Unawareness of
same community or population-based survey, and that probe deficits in Alzheimer’s disease: role of the cingulate cortex. Brain 134,
why individuals do not perceive a need for help. Supporting 1061e1076.
the potential linkage between insight and cognition, laboratory Benishek, L.A., Dugosh, K.L., Kirby, K.C., Matejkowski, J.,
findings have reported that greater “denial” of the need for Clements, N.T., Seymour, B.L., Festinger, D.S., 2014. Prize-based
methamphetamine treatment was associated with lower neu- contingency management for the treatment of substance abusers: a
rocognitive function (Dean et al., 2015) and that functional meta-analysis. Addiction 109, 1426e1436.
alternations of the self-awareness network in chronic cannabis Blanco, C., Iza, M., Rodriguez-Fernandez, J.M., Baca-Garcia, E.,
Wang, S., Olfson, M., 2015. Probability and predictors of treatment-
users were associated with memory deficits (Pujol et al.,
seeking for substance use disorders in the U.S. Drug Alcohol
2014). It would also be interesting to conduct more studies on
Depend. 149, 136e144.
treatment need awareness studies in AUD, and to further study Bobrova, N., Rhodes, T., Power, R., Alcorn, R., Neifeld, E.,
the effects of recent drug use, which, for example, might help Krasiukov, N., Latyshevskaia, N., Maksimova, S., 2006. Barriers to
clarify why positive urine status predicts poor prognosis in accessing drug treatment in Russia: a qualitative study among
treatment outcome studies (Ahmadi et al., 2009; Poling et al., injecting drug users in two cities. Drug Alcohol Depend. 82 (Suppl.
2007). Finally, it will be important to craft strategies for 1), S57e63.
encouraging individuals with a less severe SUD to seek help or Booth, B.M., Curran, G.M., Han, X., Edlund, M.J., 2013. Criminal justice
otherwise reduce problematic use before experiencing more and alcohol treatment: results from a national sample. J. Subst. Abus.
severe substance-related problems, which are far more costly Treat. 44, 249e255.
to individuals, their families, and society than treatment Booth, B.M., Stewart, K.E., Curran, G.M., Cheney, A.M., Borders, T.F.,
2014. Beliefs and attitudes regarding drug treatment: application of the
(Ettner et al., 2006). More broadly, future research needs to
theory of planned behavior in African-American cocaine users.
examine the complex relationships that likely exist between
Addict. Behav. 39, 1441e1446.
treatment need perception and the larger individual and Borders, T.F., Booth, B.M., Stewart, K.E., Cheney, A.M., Curran, G.M.,
sociocultural factors shaping the decision to seek substance 2015. Rural/urban residence, access, and perceived need for treatment
use treatment. An improved understanding of which drug(s) among African American cocaine users. J. Rural Health 31, 98e107.
(and their patterns of use) increases the likelihood for prob- Compton, W.M., Thomas, Y.F., Stinson, F.S., Grant, B.F., 2007. Preva-
lems of insight and self-awareness can enable better tailoring lence, correlates, disability, and comorbidity of DSM-IV drug abuse
of scarce research and clinical resources and can provide and dependence in the United States: results from the national
translation between diverse research fields within a population epidemiologic survey on alcohol and related conditions. Arch. Gen.
neuroscience framework. Psychiatry 64, 566e576.
David, A.S., Bedford, N., Wiffen, B., Gilleen, J., 2012. Failures of
metacognition and lack of insight in neuropsychiatric disorders.
Acknowledgments Philos. Trans. R. Soc. Lond. B Biol. Sci. 367, 1379e1390.
Dean, A.C., Kohno, M., Morales, A.M., Ghahremani, D.G., London, E.D.,
This work was supported by grants from the National Institute on
2015. Denial in methamphetamine users: associations with cognition
Drug Abuse (to SJM K01DA037452 and R21DA040046; to RDG:
and functional connectivity in brain. Drug Alcohol Depend. 151,
R01DA20892). The content is solely the responsibility of the authors
84e91.
Degenhardt, L., Hall, W., 2012. Extent of illicit drug use and dependence, Hester, R., Simões-Franklin, C., Garavan, H., 2007. Post-error behavior in
and their contribution to the global burden of disease. Lancet 379, active cocaine users: poor awareness of errors in the presence of intact
55e70. performance adjustments. Neuropsychopharmacology 32,
Donoghue, K., Elzerbi, C., Saunders, R., Whittington, C., Pilling, S., 1974e1984.
Drummond, C., 2015. The efficacy of acamprosate and naltrexone in Ilgen, M.A., Price, A.M., Burnett-Zeigler, I., Perron, B., Islam, K.,
the treatment of alcohol dependence, Europe versus the rest of the Bohnert, A.S., Zivin, K., 2011. Longitudinal predictors of addictions
world: a meta-analysis. Addiction 110, 920e930. treatment utilization in treatment-naive adults with alcohol use dis-
Edlund, M.J., Booth, B.M., Feldman, Z.L., 2009. Perceived need for orders. Drug Alcohol Depend. 113, 215e221.
treatment for alcohol use disorders: results from two national surveys. Kim, J.S., Kim, G.J., Lee, J.M., Lee, C.S., Oh, J.K., 1998. HAIS (Hanil
Psychiatr. Serv. 60, 1618e1628. Alcohol Insight Scale): validation of an insight-evaluation instrument
Edlund, M.J., Unutzer, J., Curran, G.M., 2006. Perceived need for alcohol, for practical use in alcoholism. J. Stud. Alcohol 59, 52e55.
drug, and mental health treatment. Soc. Psychiatr. Psychiatr. Epi- Kulesza, M., Ramsey, S., Brown, R., Larimer, M., 2014. Stigma among
demiol. 41, 480e487. individuals with substance use disorders: does it predict substance use,
Ettner, S.L., Huang, D., Evans, E., Ash, D.R., Hardy, M., Jourabchi, M., and does it diminish with treatment? J. Addict. Behav. Ther. Rehabil.
Hser, Y.I., 2006. Benefit-cost in the California treatment outcome 3, 1000115.
project: does substance abuse treatment “pay for itself”? Health Serv. Lai, H.M.X., Cleary, M., Sitharthan, T., Hunt, G.E., 2015. Prevalence of
Res. 41, 192e213. comorbid substance use, anxiety and mood disorders in epidemio-
Falck, R.S., Wang, J., Carlson, R.G., Krishnan, L.L., Leukefeld, C., logical surveys, 1990e2014: a systematic review and meta-analysis.
Booth, B.M., 2007. Perceived need for substance abuse treatment Drug Alcohol Depend. 154, 1e13.
among illicit stimulant drug users in rural areas of Ohio, Arkansas, and Le Berre, A.P., Rauchs, G., La Joie, R., Segobin, S., Mezenge, F.,
Kentucky. Drug Alcohol Depend. 91, 107e114. Boudehent, C., Vabret, F., Viader, F., Eustache, F., Pitel, A.L.,
Falk, E.B., Hyde, L.W., Mitchell, C., Faul, J., Gonzalez, R., Beaunieux, H., 2013. Readiness to change and brain damage in pa-
Heitzeg, M.M., Keating, D.P., Langa, K.M., Martz, M.E., tients with chronic alcoholism. Psychiatr. Res. 213, 202e209.
Maslowsky, J., Morrison, F.J., Noll, D.C., Patrick, M.E., Pfeffer, F.T., Magill, M., Ray, L.A., 2009. Cognitive-behavioral treatment with adult
Reuter-Lorenz, P.A., Thomason, M.E., Davis-Kean, P., Monk, C.S., alcohol and illicit drug users: a meta-analysis of randomized
Schulenberg, J., 2013. What is a representative brain? Neuroscience controlled trials. J. Stud. Alcohol Drugs 70, 516e527.
meets population science. Proc. Natl. Acad. Sci. U.S.A. 110, Martinez-Gonzalez, J.M., Vilar Lopez, R., Becona Iglesias, E., Verdejo-
17615e17622. Garcia, A., 2016. Self-deception as a mechanism for the mainte-
Fernandez-Calderon, D., Fernandez, F., Ruiz-Curado, S., Verdejo- nance of drug addiction. Psicothema 28, 13e19.
Garcia, A., Lozano, O.M., 2015. Profiles of substance use disorders McCabe, S.E., West, B.T., Jutkiewicz, E.M., Boyd, C.J., 2017. Multiple
in patients of therapeutic communities: link to social, medical and DSM-5 substance use disorders: a national study of US adults. Hum.
psychiatric characteristics. Drug Alcohol Depend. 149, 31e39. Psychopharmacol. Clin. Exp. 32, 1e10.
Glass, J.E., Grant, J.D., Yoon, H.Y., Bucholz, K.K., 2015. Alcohol McLellan, A.T., Meyers, K., 2004. Contemporary addiction treatment: a
problem recognition and help seeking in adolescents and young adults review of systems problems for adults and adolescents. Biol. Psy-
at varying genetic and environmental risk. Drug Alcohol Depend. 153, chiatry 56, 764e770.
250e257. Melchior, M., Prokofyeva, E., Younes, N., Surkan, P.J., Martins, S.S.,
Goldstein, R.Z., Craig, A.D., Bechara, A., Garavan, H., Childress, A.R., 2014. Treatment for illegal drug use disorders: the role of comorbid
Paulus, M.P., Volkow, N.D., 2009. The neurocircuitry of impaired mood and anxiety disorders. BMC Psychiatry 14, 89.
insight in drug addiction. Trends Cognit. Sci. 13, 372e380. Moeller, S.J., Fleming, S.M., Gan, G., Zilverstand, A., Malaker, P.,
Gopalkrishnan, N., Babacan, H., 2015. Cultural diversity and mental dOleire Uquillas, F., Schneider, K.E., Preston-Campbell, R.N.,
health. Australas. Psychiatry 23, 6e8. Parvaz, M.A., Maloney, T., Alia-Klein, N., Goldstein, R.Z., 2016.
Grant, B.F., Saha, T.D., Ruan, W.J., Goldstein, R.B., Chou, S.P., Jung, J., Metacognitive impairment in active cocaine use disorder is associated
Zhang, H., Smith, S.M., Pickering, R.P., Huang, B., Hasin, D.S., with individual differences in brain structure. Eur. Neuro-
2016. Epidemiology of DSM-5 drug use disorder: results from the psychopharmacol. 26, 653e662.
national epidemiologic survey on alcohol and related conditions-III. Moeller, S.J., Goldstein, R.Z., 2014. Impaired self-awareness in human
JAMA Psychiatry 73, 39e47. addiction: deficient attribution of personal relevance. Trends Cognit.
Grella, C.E., Karno, M.P., Warda, U.S., Moore, A.A., Niv, N., 2009. Sci. 18, 635e641.
Perceptions of need and help received for substance dependence in a Moeller, S.J., Konova, A.B., Parvaz, M.A., Tomasi, D., Lane, R.D., Fort, C.,
national probability survey. Psychiatr. Serv. 60, 1068e1074. Goldstein, R.Z., 2014. Functional, structural, and emotional correlates
Ham, T.E., Bonnelle, V., Hellyer, P., Jilka, S., Robertson, I.H., Leech, R., of impaired insight in cocaine addiction. JAMA Psychiatry 71, 61e70.
Sharp, D.J., 2014. The neural basis of impaired self-awareness after Moeller, S.J., Maloney, T., Parvaz, M.A., Alia-Klein, N., Woicik, P.A.,
traumatic brain injury. Brain 137, 586e597. Telang, F., Wang, G.J., Volkow, N.D., Goldstein, R.Z., 2010.
Hedden, S.L., Gfroerer, J.C., 2011. Correlates of perceiving a need for Impaired insight in cocaine addiction: laboratory evidence and effects
treatment among adults with substance use disorder: results from a on cocaine-seeking behaviour. Brain 133, 1484e1493.
national survey. Addict. Behav. 36, 1213e1222. Mojtabai, R., Crum, R.M., 2013. Perceived unmet need for alcohol and
Hester, R., Nestor, L., Garavan, H., 2009. Impaired error awareness and drug use treatments and future use of services: results from a longi-
anterior cingulate cortex hypoactivity in chronic cannabis users. tudinal study. Drug Alcohol Depend. 127, 59e64.
Neuropsychopharmacology 34, 2450e2458.
Mojtabai, R., Olfson, M., Mechanic, D., 2002. Perceived need and help- Verdejo-Garcia, A., Fernandez-Serrano, M.J., Tirapu-Ustarroz, J., 2013.
seeking in adults with mood, anxiety, or substance use disorders. Denial and lack of awareness in substance dependence: insights from
Arch. Gen. Psychiatry 59, 77e84. the neuropsychology of addiction. In: Miller, P.M., Ball, S.A.,
Moreno-Lopez, L., Albein-Urios, N., Martinez-Gonzalez, J.M., Soriano- Blume, A.W., Kavanagh, D., Kampman, K., Bates, M.E.,
Mas, C., Verdejo-Garcia, A., 2014. Prefrontal gray matter and moti- Larimer, M., Petry, N.M., de Witte, P. (Eds.), Principles of Addiction:
vation for treatment in cocaine-dependent individuals with and without Comprehensive Addictive Behaviors and Disorders. Academic Press,
personality disorders. Front. Psychiatry/Front. Res. Found. 5, 52. San Diego, CA.
Moreno-Lopez, L., Albein-Urios, N., Martinez-Gonzalez, J.M., Soriano- Verdejo-Garcia, A., Perez-Garcia, M., 2008. Substance abusers’ self-
Mas, C., Verdejo-Garcia, A., 2017. Neural correlates of impaired awareness of the neurobehavioral consequences of addiction. Psy-
self-awareness of apathy, disinhibition and dysexecutive deficits in chiatry Res. 158, 172e180.
cocaine-dependent individuals. Addict. Biol. 22, 1438e1448. Williams, A.R., Olfson, M., Galanter, M., 2015. Assessing and improving
Naqvi, N.H., Rudrauf, D., Damasio, H., Bechara, A., 2007. Damage to the clinical insight among patients “in denial”. JAMA Psychiatry 72,
insula disrupts addiction to cigarette smoking. Science 315, 531e534. 303e304.
Nosyk, B., Bray, J.W., Wittenberg, E., Aden, B., Eggman, A.A., Wu, L.T., Ringwalt, C.L., 2004. Alcohol dependence and use of treatment
Weiss, R.D., Potter, J., Ang, A., Hser, Y.I., Ling, W., services among women in the community. Am. J. Psychiatry 161,
Schackman, B.R., 2015. Short term health-related quality of life 1790e1797.
improvement during opioid agonist treatment. Drug Alcohol Depend.
157, 121e128.
Oikonomou, M.T., Arvanitis, M., Sokolove, R.L., 2017. Mindfulness Appendix
training for smoking cessation: a meta-analysis of randomized- SAMHSA (2004) National Survey on Drug Use and Health (ICPSR04373-
controlled trials. J. Health Psychol. 22, 1841e1850.
v4). Inter-university Consortium for Political and Social Research
Oleski, J., Mota, N., Cox, B.J., Sareen, J., 2010. Perceived need for care,
[distributor], Ann Arbor, MI.
help seeking, and perceived barriers to care for alcohol use disorders
in a national sample. Psychiatr. Serv. 61, 1223e1231. SAMHSA (2005) National Survey on Drug Use and Health
Paus, T., 2010. Population neuroscience: why and how. Hum. Brain Mapp. (ICPSR04596-v5). Inter-university Consortium for Political and Social
31, 891e903. Research [distributor], Ann Arbor, MI.
Poling, J., Kosten, T.R., Sofuoglu, M., 2007. Treatment outcome pre- SAMHSA (2006) National Survey on Drug Use and Health
dictors for cocaine dependence. Am. J. Drug Alcohol Abuse 33, (ICPSR21240-v6). Inter-university Consortium for Political and Social
191e206. Research [distributor], Ann Arbor, MI.
Pujol, J., Blanco-Hinojo, L., Batalla, A., Lopez-Sola, M., Harrison, B.J., SAMHSA (2007) National Survey on Drug Use and Health
Soriano-Mas, C., Crippa, J.A., Fagundo, A.B., Deus, J., de la (ICPSR23782-v5). Inter-university Consortium for Political and Social
Torre, R., Nogue, S., Farre, M., Torrens, M., Martin-Santos, R., 2014. Research [distributor], Ann Arbor, MI.
Functional connectivity alterations in brain networks relevant to self-
SAMHSA (2008) National Survey on Drug Use and Health
awareness in chronic cannabis users. J. Psychiatr. Res. 51, 68e78.
(ICPSR26701-v6). Inter-university Consortium for Political and Social
Rinn, W., Desai, N., Rosenblatt, H., Gastfriend, D.R., 2002. Addiction
denial and cognitive dysfunction: a preliminary investigation. Research [distributor], Ann Arbor, MI.
J. Neuropsychiatry Clin. Neurosci. 14, 52e57. SAMHSA (2009) National Survey on Drug Use and Health
Shany-Ur, T., Lin, N., Rosen, H.J., Sollberger, M., Miller, B.L., (ICPSR29621-v6). Inter-university Consortium for Political and Social
Rankin, K.P., 2014. Self-awareness in neurodegenerative disease re- Research [distributor], Ann Arbor, MI.
lies on neural structures mediating reward-driven attention. Brain 137, SAMHSA (2010) National Survey on Drug Use and Health
2368e2381. (ICPSR32722-v6). Inter-university Consortium for Political and Social
Stewart, J.L., May, A.C., Poppa, T., Davenport, P.W., Tapert, S.F., Research [distributor], Ann Arbor, MI.
Paulus, M.P., 2014. You are the danger: attenuated insula response in SAMHSA (2011) National Survey on Drug Use and Health
methamphetamine users during aversive interoceptive decision-
making. Drug Alcohol Depend. 142, 110e119.
Research [distributor], Ann Arbor, MI.
Tuithof, M., Ten Have, M., van den Brink, W., Vollebergh, W., de
SAMHSA (2012) National Survey on Drug Use and Health
Graaf, R., 2016. Treatment seeking for alcohol use disorders: treat-
ment gap or adequate self-selection? Eur. Addict. Res. 22, 277e285.
van der Meer, L., de Vos, A.E., Stiekema, A.P., Pijnenborg, G.H., van Research [distributor], Ann Arbor, MI.
Tol, M.J., Nolen, W.A., David, A.S., Aleman, A., 2013. Insight in SAMHSA (2013) National Survey on Drug Use and Health
schizophrenia: involvement of self-reflection networks? Schizophr. (ICPSR35509-v3). Inter-university Consortium for Political and Social
Bull. 39, 1288e1295. Research [distributor], Ann Arbor, MI.
Chapter 27
Genetics, imaging, and cognition: big

data approaches to addiction research
Robert Whelan1, Zhipeng Cao2, Laura O’Halloran1 and Brian Pennie1
1
School of Psychology, Trinity College Dublin, Dublin, Ireland; 2School of Psychology, University College Dublin, Dublin, Ireland
The etiology and trajectory of addictions is complex, in geneticsdmeta- and megaanalysesdthat may provide
caused and moderated by individual differences in breakthroughs in our understanding of the genetics of
cognition that are themselves a function of genetics and of addiction.
environment. In this chapter, we will discuss how methods
from other disciplines, under the rubric of “Big Data,” can
shed light on the cognitive correlates of addiction.
Cognition: online-based research
Addiction research has traditionally been conducted using Big Data approachesdby definitiondrequire big data. The
methods developed within the natural sciences; that is, cognitive neuroscience of addiction has generally relied on
hypothesis-driven research typically based on assays of laboratory-based research, an approach that is time-
single cognitive functions, with more participants than consuming and labor-intensive and therefore constrains
data points and the use of null hypothesis significance sample sizes (Henrich et al., 2010). Furthermore, given a need
testing to quantify the likelihood of the observed effect to acquire data in a laboratory setting, cognitive neuroscience
occurring by chance. “Big Data” approaches are different. has had an overreliance on samples comprised of undergrad-
There is no single definition of Big Data (Diebold, 2012), uate students (Henrich et al., 2010), reducing generalizability.
but here, as others have done (Chen et al., 2014; Cheung Broad claims about human psychology are often based on
and Jak, 2016), the term Big Data denotes datasets that samples drawn entirely from Western, Educated, Industrial-
cannot be acquired or processed in a reasonable time ized, Rich, and Democratic (WEIRD) societies (Henrich et al.,
frame on standard computers. In contrast to traditional 2010), whereas individuals suffering from addiction are pre-
approaches (see Bzdok et al., 2018, for a summary of the dominately from lower socioeconomic backgrounds and have
differences), Big Data is primarily data-driven, using lower education (Henkel and Zemlin, 2016). Recently, online-
algorithms that search for patterns in data. Many different based research (we use this as an omnibus term for both
types of data can be included in a model and there are internet- and app-based protocols) has provided alternative
usually more data points than there are participants. The methods for both participant recruitment and for implement-
metric of success in Big Data approaches is usually the ing psychological interventions relevant to addiction. Online
ability of a model to make accurate predictions on previ- methods range from public social networking sites
ously unseen data, rather than a comparison against the (e.g., Twitter, Facebook) to general crowdsourcing platforms
null hypothesis. Thus, Big Data is not merely a bigger (e.g., Amazon’s Mechanical Turk) to research-specific plat-
version of the traditional scientific method, but can offer a forms such as TurkPrime (www.turkprime.com) and Prolific
substantially different perspective on addiction. Our goal in (www.prolific.ac). Here, we first outline various challenges
this chapter is to introduce and to provide practical advice on and benefits to online-based research; next, we review several
Big Data approaches for addiction. In the first part of this addiction studies that recruited large online samples; finally,
chapter, we describe how online methods of data collection we describe online-based interventions that have been used to
facilitate the collection of large datasets. In the second sec- treat addiction.
tion, we outline some recent advances in neuroimaging, with Online research can be particularly useful for recruiting
a focus on prediction of substance use using machine participants with addiction. While in-laboratory participant
learning methods. In the final section, we present advances recruitment for addiction research can be both costly and

difficult (Ramo and Prochaska, 2012; Thornton et al., on completion of the study and by pretesting to avoid
2016), online recruitment methods can successfully target frustration caused by technical problems (Simcox and Fiez,
these specialized groups (Nosek et al., 2002). Online 2014). Motivation and adherence can be increased by
research provides a level of anonymity for people unwilling incorporating gamification featuresdfeatures of game
to participate in face-to-face research, typically because of design embedded in non-game contextsdsuch as the
embarrassment and stigma (Chebli et al., 2016; Gainsbury inclusion of stories/themes or providing “trophies” for
et al., 2014). Online approaches can also overcome logis- completing specific tasks (Brown et al., 2016). Finally,
tical barriers that prevent face-to-face participation, such as repeated participation can be neutralized by tracking
physical disability, transport issues, or geographical Internet protocol (IP) addresses and rejecting the data from
remoteness (Proudfoot et al., 2011). Recruiting participants the same address. Moreover, participants on research-
through social networking sites can facilitate the inclusion specific platforms such as Mechanical Turk are given
of low-incidence or hidden populations (Ramo et al., 2014), fixed ID codes that can be monitored by the researcher
such as young adult smokers (Ramo et al., 2014), (Litman et al., 2017). To assess the quality of data in online
individuals involved in alcohol-related domestic violence addiction research, Kim and Hodgins (2017) evaluated the
(Crane, 2018), low-income populations (Lohse and Wam- validity and reliability of data obtained from Mechanical
boldt, 2013), and cannabis cultivators (Barratt et al., 2015). Turk. Current drinkers (N ¼ 208), cannabis users
As an example of online-based addiction recruitment, (N ¼ 200), and gamblers (N ¼ 200) completed a range of
Thornton et al. (2016) recruited 524 participants via self-report measures associated with alcohol and cannabis
Facebook at a cost of $1.86 per participant, many of whom had use, addiction severity, impulsivity, as well as measures for
high-severity substance use and mental health issues. When valid responding and motivations for participating in
compared with a non-Facebook sample, Facebook partici- Mechanical Turk studies. Internal consistency ranged from
pants reported significantly more current use (including a ¼ 0.75 to 0.93 on the addiction severity measures. Over
harmful use) of tobacco and cannabis and more high-severity 80% of participants provided valid responses, and financial
cannabis use (Facebook ¼ 24%, non-Facebook ¼ 4%). motives were the most commonly reported motivation to
Online methods have also been successfully used to acquire participate. After the exclusion of invalid responding,
longitudinal addiction data. Strickland and Stoops (2018) significant differences were only observed in the cannabis
explored the feasibility, acceptability, and validity of collect- sample, suggesting that high-quality data were only
ing longitudinal alcohol use data using Mechanical Turk. acquired from alcohol and gambling populations. In
Daily alcohol and soda use (N ¼ 278) was recorded weekly general, data obtained from online methods are comparable
over 18 weeks. Response rates were high (64.1%e86.8%) in quality to data collected from the laboratory; this is also
across the 18-week period, and expected associations between the case specifically for addiction.
frequent and heavier drinking with higher scores on the The scale of online-based addiction research can be
AUDIT were also observed. Online research, therefore, is a orders of magnitude larger than in-laboratory research. For
promising tool for addiction recruitment. example, Cunningham et al. (2017) recruited 11,107 par-
Obvious concerns about online research include ticipants on Mechanical Turk ($1.50 each) who reported
reduced experimental control and a possible reduction in hazardous patterns of alcohol use over four intervention
reliability (Litman et al., 2017). However, with appropriate trials. For each trial, they invited participants to complete a
controls, internet-based research is, in some ways, superior survey about alcohol consumption and invited those who
to laboratory-based protocols for studying addiction for drank in a hazardous fashion to complete follow-up surveys
both experimental (Germine et al., 2012; Lewis et al., 2011) ($10 payment). Participants who fit the criteria were then
and correlational designs (Briones and Benham, 2017; A. randomized to be either given or not given access to an
Weigold, Weigold and Russell, 2013), although this is not online intervention for hazardous alcohol use. Interestingly,
always the case (Dandurand et al., 2008; Weigold et al., although it was possible to recruit a large sample of par-
2016). For instance, online approaches may diminish ticipants who used alcohol in a problematic fashion, the rate
response bias in sensitive research areas such as substance of recruitment decreased substantially over time. In addi-
use (Thornton et al., 2016), perhaps because online tion, demographic characteristics (e.g., age, sex, marital
experiments do not require someone to provide instructions status) varied across recruitment waves, but patterns of
or present experimental manipulations (Kraut et al., 2004) alcohol consumption did not. Although the online-based
and therefore demand characteristics are likely to be research discussed thus far used self-report measures,
reduced (Reips, 2002). Malingering can be assessed by nearly all cognitive tasks work equally well when presented
utilizing “faking bad” questionnaires such as the Minnesota online. Indeed, Crump et al. (2013) replicated a variety of
Multiphasic Personality Inventorye2 (MMPIe2) F(p) cognitive tasks including attentional and learning tasks
scale (Arbisi and Ben-Porath, 1995). Attrition rates and utilizing online methods, with the exception of paradigms
demotivation can be reduced by providing bonus payments requiring stimuli to be presented at a resolution of less than
Genetics, imaging, and cognition: big data approaches to addiction research Chapter | 27 367
approximately 50 ms. In the context of addiction, Gillan Online-based interventions are particularly effective for
et al. (2016) used an online taskdtwo-step reinforcement smoking cessation interventions because of their low cost
learningdto assess individual differences in goal-directed and potential to reach individuals with limited access to
versus habitual (automatic) responding, recruiting just healthcare (Cheung et al., 2017) and who traditionally have
under 2000 participants across two experiments via not been served by face-to-face methods (McLellan, 2006).
Mechanical Turk. Crucially, by utilizing online methods to Moreover, these interventions may be more attractive to
recruit such a large sample, Gillan et al. were able to young smokers or for individuals who may not be aware of
identify three transdiagnostic dimensions defined by self- conventional treatment methods (Taylor et al., 2017). A
report measures: compulsive behavior, anxious depres- recent Cochrane review by Taylor et al. (2017) assessed the
sion, and social withdrawal. Only the set of compulsive effectiveness of Internet-based interventions for smoking
symptoms, which incorporated alcohol addiction, eating cessation, and whether or not tailored or interactive features
disorders, and impulsivity, were associated with the improve treatment outcomes. Having pooled data from
propensity for habit-based learning during the task. These 45,194 participants across a range of interventions
data showcase online methods as a powerful, efficient, and (e.g., email, mobile phone, interactive, personalized
cost-effective approach to recruit large numbers for messaging), they found that interactive and tailored online
psychological research, including addiction. interventions led to greater quit rates than nonactive controls
Online-based interventions: Internet-based interventions at 6 months or longer, but were no better than other active
have emerged as a promising new treatment modality for smoking treatments. Despite overall positive treatment ef-
psychological disorders (Chebli et al., 2016). There are fects across the majority of studies, several methodological
several benefits for both client and practitioner: online weaknesses were observed, including a reliance on self-
interventions are more cost-effective than their face-to-face report, absence of a control group, and inconsistencies
counterparts (McCrone et al., 2004), data can be continu- across intervention type. In an example of a methodologi-
ously recorded (Proudfoot et al., 2011), and the anonymity cally strong smoking cessation study, Nguyen Thanh et al.
of online interventions benefits people reluctant to seek (2018) recruited 2478 smokers to assess the effectiveness of a
traditional forms of treatment because of embarrassment or personalized Internet-based cessation program versus a
stigma or who have transport issues or physical disabilities traditional self-help booklet. The online intervention was an
(Chebli et al., 2016). Moreover, the convenience and flexi- automated “e-coaching” program comprised of 45 emails
bility of online-based interventions improves treatment sent over a 3-month period. The control group received a
retention, especially in populations with high attrition rates booklet on smoking cessation in which self-reported absti-
such as addiction (Cunningham, 2007). A systematic review nence was measured at 3, 6, and 12 months of follow-ups.
by Chebli et al. (2016) assessed the effectiveness of online Using an intention-to-treat approach (i.e., all participants
interventions for smoking cessation, alcohol misuse, analyzed regardless of intervention adherence), they found
substance abuse, and gambling. Positive treatment outcomes that the online program was superior to the self-help booklet
were observed for several addictive behaviors including at postintervention and after 3 months, but not at 6 and
problem gambling and smoking cessation. For gambling, 12 months, follow-up. However, per-protocol analysis (i.e.,
Myrseth et al. (2013) found that combining online those who actually adhered to the program) revealed signif-
interventions with other treatment options (i.e., telephone icant effects were still evident after 6 months, suggesting that
consultations) was both time-efficient and cost-effective, adherence is a key factor for online smoking cessation
especially when compared to face-to-face treatment options. programs.
In contrast, however, Hester et al. (2013) found that face-to- In sum, online-based research provides a great oppor-
face interventions were slightly more effective than online tunity for addiction researchers to collect big data. Online
treatments for problematic drinking. Additionally, some methods are less time-consuming, less labor-intensive,
interventions that work well in clinical practice may not suc- permit much larger sample sizes, and provide greater
cessfully translate to online platforms (Andersson and Titov, generalizability when compared with traditional laboratory-
2014). For example, cognitive bias modification (CBM) based studies. With appropriate controls for reliability and
interventions, which target automatic processes, are consid- validity, online research may even be superior to traditional
ered particularly promising for treating addiction (Boffo et al., methods. Anonymity is increased, logistical barriers are
2015). However, online CBM interventions may be less removed, and specialized groups can be more easily
effective than in clinical practice, with dropout during the captured through dedicated online recruitment platforms.
intervention as one important factor (Wiers et al., 2015). A Finally, online-based interventions have emerged as a
potential solution might be to utilize more motivationally viable new approach for addiction treatment, and the scal-
engaging methods, such as gamification, which has been ability of this approach means that interventions can reach a
successfully used in other populations (Dovis et al., 2012). wide range of individuals.
Big data and neuroimaging such as the NEO-FFI (Costa and McCrea, 1992), and those
specific to addition, such as the Substance Use Risk Pro-
Functional magnetic resonance imaging (fMRI; hereafter file Scale (SURPS; Woicik et al., 2009). Neuroimaging
neuroimaging) allows us to observe brain activity in vivo. measures assay impulsivity via the Stop-Signal Task
Therefore, neuroimaging data have potential for gaining (SST; Whelan et al., 2012), reward processing via the
important insights into the neurocognition of addiction. Monetary Incentive Delay task (MID; Peters et al., 2011;
Traditionally, neuroimaging has been used to compare Cao et al., 2018), and emotional reactivity via the Faces
differences in average brain activity across groups using null Task (Tahmasebi et al., 2012). The cVEDA project is a
hypothesis significance testing. Recently, however, the com- joint Indian-UK study that uses an accelerated longitudi-
bination of large neuroimaging datasets (see Table 27.1 for an nal design with planned missingness, obtaining data from
overview), often under the rubric of “population neurosci- overlapping cohorts aged 6e23 years over a 3-year span,
ence” (Paus, 2010; see Chapter 25 for a chapter-length treat- with a projected final sample size of 10,000. The sample
ment of this topic), and the application of methods such as includes both those at high risk of substance misuse and a
machine learning have enabled predictions about individuals community sample from seven sites in five Indian regions.
(Dubois and Adolphs, 2016). Briefly, population neurosci- Neuroimaging data on a subsample of approximately 1500
ence seeks to measure individual differences across members participants in cVEDA will include structural (gray and
of the population by integrating biological, social, and white matter) and functional (resting state) MRI.
environmental influences that shape the course of brain The ABCD study is an American multisite longitudinal
development and function. In this section of the chapter, we study with the goal of following 10,000 individuals,
orient the reader to these methods by focusing on a key goal of including twin cohorts, for 10 years (see Vol. 32 of
addiction research: why do some individuals, and not others, Developmental Cognitive Neuroscience, which is dedicated
initiate substance misuse? We know that substance use typi- to the ABCD study). Participants were recruited at the age
cally begins during adolescence (Degenhardt et al., 2016), of 9e10 years. The ABCD study examines risk and resil-
with early-onset use predictive of dependence later in adult- ience factors influencing substance use trajectories, as well
hood (Behrendt et al., 2009). At the same time, despite broad as the impact of substance use on neurocognitive, health,
exposure to early substance use, many individuals remain and psychosocial development and outcomes (Morris et al.,
resilient to addiction or problematic use in later life 2018; Lisdahl et al., 2018). The baseline ABCD sample is
(Ostaszewski and Zimmerman, 2006). In humans, experi- largely substance-naïve; however, measures sensitive to
mental studies of addiction initiation are not possible for low-level exposures are included (e.g., iSay Sip Inventory;
ethical reasons, and cross-sectional designs in humans cannot Jackson et al., 2015) because children as young as 9 may
disentangle cause and effect in any behavioral or neural var- initiate or try substances (e.g., sipping alcohol, first puffs of
iables. Understanding causal neurocognitive factors for cannabis and nicotine; Lisdahl et al., 2018). The ABCD
addiction therefore requires data to be acquired before initia- imaging protocol measures brain structure and function,
tion of substance use, with longitudinal follow-up. In practice, including resting state and task-based fMRI. Neuroimaging
this involves recruiting large samples of young adolescents to, assays six behavioral domainsdreward processing, moti-
first, ensure sufficient numbers of individuals with and without vation, impulsivity, impulse control, working memory, and
substance use at follow-up and, second, to account for the emotion regulation. (SST, MID, and an emotional version
myriad intraindividual and environmental variables that of the n-back task; see Casey et al., 2018). An important
influence human brain development. Here, we give an over- aspect of the ABCD study is the intentional recruitment of
view of three longitudinal neuroimaging studies: IMAGEN an American community sample that accounts for socio-
(Schumann et al., 2010), the Adolescent Brain Cognitive demographic variation (Garavan et al., 2018). Special
Development (ABCD) Study (https://abcdstudy.org/), and attention has been given to recruiting and retaining under-
Consortium on Vulnerability to Externalizing Disorders and represented samples in addiction research, such as African-
Addictions (cVEDA; https://cveda.org/), before describing Americans and lower socioeconomic White populations
how methods such as machine learning can be applied to these (the latter are particularly vulnerable to prescription opioid
types of neuroimaging datasets. abuse). Data from the ABCD study will be publicly
The IMAGEN project is a European multicenter study available, through the National Institute of Mental Health
with a baseline cohort of 2,250 14-year-olds, with neuro- (NIMH) Data Archive (https://www.nimh.nih.gov), and
imaging follow-up assessments at 19 and 23 years old. In will be released in both raw and curated data format.
addition to gathering demographic, genetic, and neuro- The existence of large neuroimaging datasets cannot
imaging data, the test battery also includes several self-report advance addiction research on their own, however: a
measures of substance misuse, including any harmful pressing challenge is to develop and utilize methods that
prenatal exposures to tobacco or alcohol. Behavioral and can best interrogate these data. There are likely to be
cognitive assessments include broad personality measures,
TABLE 27.1 A comparison of IMAGEN, ABCD, and cVEDA studies.
Study IMAGEN ABCD cVEDA

MRI baseline 2,250 11,500 1,500
cohort sizea
Starting age (years) 14 9e10 6e11, 12e17, 18e23
End age (years) 23 19e20 8e13, 14e18, 20e25
MRI frequency 4 2 1 or 2 years (planned missingness)
(years)
Number of MRI 8 21 4
sites
b
Structural MRI T1, T2, diffusion T1, T2, diffusion T1, T2, diffusion
fMRI Resting 1 6.2 min run 4 5 min runs 6.07 min run
state
Inhibitory Stop-signal task Stop-signal task e

control
Reward Monetary Incentive Delay Monetary Incentive Delay e

processing
Emotional Face processing Emotional n-back e

regulation
Working e Emotional n-back e

memory
c
Key addiction European School Survey Project Lifetime Use Interview iSay Sip Alcohol, Smoking and Substance
measures on Alcohol and Drugs Inventory Involvement Screening Test
Fagerstrom Test for Nicotine Web Timeline Followback Interview (ASSIST)-Plus
Dependence
Alcohol Use Disorders
Identification Test
Timeline Followback Interview
d
Key behavioral Cambridge Neuropsychological Rey Auditory Verbal Learning Test Cambridge Neuropsychological
assays Test Automated Battery Little Man Task Test Automated Battery (CANTAB)
(CANTAB) Cash Choice Task Test Balloon analogue risk task
Emotional dot Probe NIH Toolbox (e.g., Flanker, Facial emotion recognition task
Passive Avoidance Learning Working Memory, Picture Theory of Mind task
Paradigm Vocabulary Test)
Wechsler Abbr. Scale of
Intelligence
Key personality Substance Use Risk Profile Modified UPPS-P for Children 6e11: Children’s Behavior
measures Scale Child Behavioral Inhibition and Questionnaire
Temperament and Character Behavioral Activation 12e17: Adolescent Temperament
Inventory Questionnaire
NEO-PI-R 18e23: Adult Temperament
Q’aire, Big Five Inv.
e
Psychiatric Development and Well-Being Kiddie Schedule for Affective M.I.N.I Kid
symptoms Assessment (DAWBA) Disorders andSchizophrenia, Development and Well-Being
DSM-5 Assessment (DAWBA)
Achenbach Child Behavior
Checklist
Processing pipeline Custom (based on SPM) Open source (incl. FreeSurfer Same as IMAGEN
Volumetrix and summary statistics
in Gordon Parcels)
Data access Not public as of 2018 Ongoing curated and raw data Full baseline data will be released
release on September 2019
a
Numbers are approximate because of quality control, ongoing data collection, etc.
b
Casey, B. J., Cannonier, T., Conley, M. I., Cohen, A. O., Barch, D. M., Heitzeg, M. M., et al. (2018). The adolescent brain cognitive development
(ABCD) study: imaging acquisition across 21 sites. Dev. Cogn. Neurosci.
c
Lisdahl, K. M., Sher, K. J., Conway, K. P., Gonzalez, R., Ewing, S. W. F., Nixon, S. J., et al. (2018). Adolescent brain cognitive development (ABCD)
study: Overview of substance use assessment methods. Dev. Cogn. Neurosci.
d
Luciana, M., Bjork, J. M., Nagel, B., Barch, D. M., Gonzalez, R., Nixon, S. J., and Banich, M. T. (2018). Adolescent neurocognitive development and
impacts of substance use: overview of the adolescent brain cognitive development (ABCD) baseline neurocognition battery. Dev. Cogn. Neurosci.
e
Barch, D. M., Albaugh, M. D., Avenevoli, S., Chang, L., Clark, D. B., Glantz, M. D., et al. (2017). Demographic, physical and mental health
assessments in the adolescent brain and cognitive development study: Rationale and description. Dev. Cogn. Neurosci.
thousands of potentially informative predictors of substance Conducting machine learning analyses may seem
use outcomes, such as demographic, personality, behavioral, daunting at first, but implementing machine learning
neurobiological, and genetic variables. Neuroimaging data are methods is no longer only for those with advanced pro-
high dimensional (in excess of 10,000 data points per partic- gramming skills (although some programming knowledge
ipant), with generally weak effect sizes (Button et al., 2013) is nearly always advantageous). Common methods, such as
and highly collinear structure. Acquiring neuroimaging data is cross-validation or penalized regression, are available as
expensive and neuroimaging studies often test small sample easy-to-use functions in many software packages. For
sizes (typically less than 50 participants). When generating example, scikit-learn (Pedregosa et al., 2011; http://scikit-
predictive models using neuroimaging data using standard learn.org/) is an open source software toolbox containing
methods, the high ratio of predictors to participants will result many machine learning algorithms, which is implemented
in “overfitting,” even in relatively large samples (see Whelan in Python, a general-purpose programming language. There
and Garavan, 2014, for a discussion of this issue with respect is a large community of scikit-learn users, and there exist
to neuroimaging). Therefore, apparently accurate predictions many training opportunities and extensive documentation.
will reflect idiosyncrasies of the training sample and will fail to Commercial software, such as Matlab (MathWorks, Natick,
predict accurately when presented with previously unseen MA), also has extensive machine learning toolboxes. In the
data. Fortunately, principles and techniques developed within era of Open Science, machine learning publications are
the field of machine learning are well-suited for analyzing often accompanied by the code used to analyze the data.
neuroimaging data. Due to the extensive availability of machine learning
There are many reviews of machine learning approaches packages, the barrier to entry into machine learning has
in the context of neuroimaging (e.g., Woo et al., 2017; been lowered substantially.
Jollans and Whelan, 2016), including with specific refer- Several studies of substance use have already applied
ence to substance misuse (O’Halloran et al., 2017), but we machine learning methods to large neuroimaging datasets.
briefly outline the basic principles here. The tendency to For example, a 2-year prospective MRI study in the
overfit can be attenuated by methods that penalize regres- IMAGEN cohort (total n ¼ 692; Whelan et al., 2014)
sion weights (e.g., the Elastic Net; Zou and Hastie, 2005), showed that a combination of factors (demographic, life
and therefore it is possible to include many more predictors history, personality, cognitive, and brain data) could predict
than participants in a model. Many machine learning binge drinking at 16 years old based on data collected at 14
approaches can select the most important predictors, termed years old, with moderate accuracy (73% of abstainers and
“feature selection,” in a principled way that also attenuates 66% of future binge drinkers correctly classified).
overfitting. Unlike null hypothesis significance testing, Predictors of future binge drinking included neuroimaging
from a machine learning perspective, the ability of a model data from tasks assaying reward processing, behavioral
accurately to predict previously unseen data quantifies inhibition, and affective face processing. By iteratively
success (Bzdok et al., 2018), often termed “out-of-sample” omitting each domain (e.g., brain, personality, or life his-
validation. Using a separate dataset is the gold standard in tory) from the model and repeating the analysis, insights
terms of assessing out-of-sample validation. However, a were gained into the relative contributions of different
more cost-effective method is cross-validation, which factors for binge drinking. Life history was most important
involves the division of a dataset into multiple training and predictor, followed by personality, with brain data ranking
test sets. The training set is used to generate a model which is third. Similarly, Squeglia et al. (2016) collected neuro-
subsequently applied to the test data. The test set can be imaging data, both structural (cortical thickness) and
comprised of one observation (leave-one-out cross- functional (a visual working memory task), from 137
validation) or of one of k equal partitions of the dataset 12e14-year-old substance-naive adolescents. A machine
(k-fold cross-validation). Machine learning approaches also learning approach, using a method called Random Forest,
include quite sophisticated methods to increase prediction was able to predict alcohol use initiation by age 18 years,
accuracy. For example, boosting or stacked generalization with 74% sensitivity and 73% specificity. Adolescents with
(stacking) is types of ensemble learners that can train a lower performance on tests of executive functioning tests
diverse set of models and learn from misclassified cases. In and who were faster on sustained attention tests were more
this way, results from a number of weak learnersdperhaps likely to initiate alcohol use. Another longitudinal neuro-
neuroimaging data from a single cognitive system such as imaging study from the IMAGEN reported that decreased
inhibitory control or reward processingdcan be aggregated activity to anticipated rewards in mesolimbic and prefrontal
to produce a better prediction than any single model. In sum, cortical regions predicted if novelty-seeking adolescents
addiction research can benefit from years of research in the would later develop problematic drug use (Büchel et al.,
field of Big Data research; methods do not need to be 2017). Out-of-sample prediction accuracy was higher for a
discovered de novo, and many difficult methodological model that brain measures when compared to a model with
issues (e.g., overfitting) have already been addressed. only behavioral measures.
The studies described in the preceding paragraph show disorders and the specific genetic variants that cause them (the
the potential utility of neuroimaging for prediction of “missing heritability problem”; Eichler et al., 2010). For
substance use initiation. It is worth noting that, first, a wide example, in the Collaborative Genetic Study of Nicotine
range of data were collected and analyzed and, second, that Dependence (COGEND; Saccone et al., 2010), only 5%e7%
no single type of predictor was very accurate on its own. of the phenotypic variance in the sample (n ¼ 2062) was
These findings underscore the need for a wide range of data to explained. Addiction is a particularly difficult challenge from
be obtained. Indeed, there is growing utilization of mobile a genetic perspective: it is likely that a variety of genetic
and wearable technology for monitoring cognition and variants underlie several different addiction etiologies, each of
measuring substance use (see Bagot et al., 2018 for a which may be modulated by a myriad of environmental factors
discussion of this issue with respect to the ABCD study). For (Kendler et al., 2003). Similar to neuroimaging, in genetics
example, it is possible to detect smoking relapse using there are typically many more data points than participants,
wearable sensors that detect respiration patterns and arm with hundreds of thousands of single-nucleotide poly-
movements (Saleheen et al., 2015) and to detect cocaine use morphisms (SNPs) examined in the standard human genome
using a biosensor wristband (Carreiro et al., 2015). Future assay. Each common-variant SNP has a small effect on
work in predicting substance use may therefore combine addictive behaviors, and there may be rare variants that have
several complementary measures with MRI, such as magne- large effects. As with many genetic studies in a range of
toencephalography or electroencephalography, which can scientific fields, early candidate gene studies relevant to
measure brain activity with better temporal resolution (in the addiction have typically failed to replicate (Hart et al., 2013).
order of milliseconds). Gabrieli et al. (2015) have commented More recent studies have employed genome-wide association
that biological markersdneuromarkersdindicating presence studies (GWAS) approaches in which a large number of
or risk of addiction may ultimately be sufficiently cost- genetic variants are examined. Given the number of statistical
effective to provide an improvement in diagnostic or prog- tests, the conventional P value threshold for any one SNP in a
nostic accuracy, although several hurdles must be first crossed. common-variant GWAS is P <5 108 (Pe’er et al., 2008).
A robust neuromarker should fulfill the following criteria (see However, this threshold can cause both Type I and Type II
Jollans and Whelan, 2018; Woo et al., 2017 for longer treat- errors. Given the difficulty of finding specific genetic variants
ments of this topic). First, it should be observable even with for specific addictive phenotypes, here we focus on results
slight deviations in data collection or preprocessing steps. derived from collaborations among large-scale genetics
Second, it should account for heterogeneity within the popu- consortia with large samples or where a finding was replicated
lation when making individual predictions. Third, in a separate study. In particular, we introduce meta- and
neuromarkers should have good construct validity (i.e., if a megaanalyses of GWAS data that have promise for generating
neuromarker accurately classifies alcoholics from abstainers, replicable and novel discoveries in addiction-related pheno-
it should also perform reasonably well identifying non- types (Agrawal et al., 2016). Genetic metaanalyses use
disordered drinkers from abstainers). Rich datasets, such as summary statistics from different studies to increase statistical
IMAGEN, cVEDA, and ABCD, will help to advance our power, whereas megaanalyses use pooled raw data. The
understanding of substance use initiation and ultimately our metaanalytic strategy is used in large-scale studies, such as the
understanding of addiction. These large consortia studies ENIGMA consortium (Enhancing Neuroimaging Genetics
require a high degree of coordination and are costly through Meta-Analysis), which has an addiction-specific
(e.g., ABCD budget is approximately $300 million), but the working group (Mackey et al., 2016). GWAS studies are
scientific benefit is that findings are more robust and gener- conducted locally with regression model in which regression
alizable. Given the open-access nature of some datasets and coefficient, standard error, and P-value are computed. The site
increased availability of machine learning tools, addiction level results rather than the raw data are forwarded to the
researchers, and in particular early career researchers, have coordinating site where a unifying metaanalysis weights
greater opportunity to engage in Big Data research. the SNP coefficients by their standard error. Worldwide
collaborations such as ENIGMA (McMahon and Thompson,
2017), the database of Genotypes and Phenotypes dbGaP
Genetics and addiction: meta- and (Mailman et al., 2007), the Tobacco and Genetics consortium
megaanalyses (Tobacco and Genetics, 2010), the Psychiatric Genomics
Numerous large twin studies have shown that addictions are Consortium (PGC; Sullivan, 2010), and the international
highly heritable (Bierut, 2011; Vink, 2016), with mono- cannabis consortium (Stringer et al., 2016) have been estab-
zygotic:dizygotic ratio of 2:1 (Ducci and Goldman, 2012). lished to facilitate research on genetic risk factors associated
Although progress has been made in the characterization of with addiction.
genetic vulnerability to addictions (Bierut, 2011), there There has been some success in understanding the
remains a gap between the known heritability of addiction genetic underpinnings of alcohol use. Alcohol dehydroge-
nase (ADH) and aldehyde dehydrogenase (ALDH) are two
major enzymes of alcohol metabolism that influence an ventral striatum, and reduced dopamine neuron excitability
individual’s level of alcohol consumption and risk of in the ventral tegmental area (Stacey et al., 2012), both
alcoholism. Genetic studies on alcohol dependence focused areas closely associated with reward processing. The
on ADH- and ALDH-related gene variants: ADH1B, RASGRF2 gene showed significant association with
ADH1C, and ALDH2 (Edenberg, 2007). A strong associ- ventral striatum activity during reward anticipation in 663
ation between a variant of the ADH1B gene (Arg48His) 14-year-old male adolescents, as well as their number of
and alcohol dependence and abuse was reported in a met- drinking episodes at age 16 (Stacey et al., 2012). Thus,
aanalysis with 9638 cases and 9517 controls (allelic there is strong evidence of RASGRF2’s relevance to
P ¼ 1 1036), and the association was strongest in alcohol use because of the large sample size in the human
various Asian samples with allelic P value being 7 1042 studies and converging evidence in nonhuman animals.
(Li et al., 2011). The variant of the Arg48His is associated Nicotine is the major substance in tobacco products and
with altered ADH enzyme activity. ADH enzymes with b2 has a biological effect through nicotinic acetylcholine
protein encoded by His48 oxidize ethanol approximately receptors (nAChRs), which are proteins responding to
70- to 80-fold faster than those with b1 protein encoded by neurotransmitter acetylcholine (Wu, 2009). The nAChRs
Arg48 (Edenberg, 2007). A protective effect of point participate in diverse brain functions such as reward,
mutation at rs671 of ALDH2 (i.e., ALDH2*2) against learning, and memory (Miwa et al., 2011), and its subtype
alcoholism in Asians has been reported by two meta- receptors (e.g., nAChRa3 and nAChRa5) are encoded by
analytic studies, the first with 2250 cases and 2200 controls different genes (e.g., CHRNA3 and CHRNA5). There has
from 15 studies (Luczak et al., 2006) and the second with been some success in identifying genetic variants associ-
9678 cases and 7331 controls from 53 studies with allelic P ated with nicotine addiction. Converging evidence from
value being 3 1056 (Li et al., 2012). The ALDH2*2 large GWAS metaanalyses revealed strong association
variant encodes an almost-inactive ALHD2 enzyme that no between variations within a region of chromosome 15
longer oxidizes acetaldehyde. This results in an aversive containing nAChRs genes and nicotine addiction as well as
reaction (including nausea and flushing) triggered by other smoking-related traits (Loukola et al., 2014; Treutlein
acetaldehyde accumulation and is hypothesized to be the and Rietschel, 2011). The associations between risk for
protective mechanism of ALDH2*2 (Edenberg, 2007). smoking and nicotine addiction and variants in CHRNA3
Regulation of ADH1C genotype was associated with (rs1051730) and CHRNA5 (rs16969968) were consistently
alcohol consumption in men, which was reported in the reported in consortium studies with large initial and repli-
examination of 974 maleefemale pairs from different cation sample size such as the Oxford-GlaxoSmithKline
European countries (Latella et al., 2009). This association study (Ox-GSK) with 41,150 initial and 120,516 replica-
was further replicated in another GWAS study with 808 tion samples (Liu et al., 2010), the European Network of
alcohol-dependent cases and 1248 controls (Biernacka Genetic and Genomic Epidemiology (ENGAGE)
et al., 2013). A large-scale GWAS study with 16,087 sub- consortium with 31,266 initial and 54,731 replication
jects have associated SNPs of ADH1B with alcohol samples (Thorgeirsson et al., 2010), and the Tobacco and
dependence in European-American (Arg48His, Genetics consortium (TAG) with 74,035 initial and 68,988
P ¼ 1 1031) and African-American (Arg369Cys, replication samples (Tobacco and Genetics, 2010). In
P ¼ 6 1031) populations and ADH1C (Thr151Thr, particular, evidence from animal models show that mice
P ¼ 5 1010) with alcohol dependence in African- with nAChR subunit alpha-5 knocked out had greater
American samples (Gelernter et al., 2014). In a later large- nicotine intake, suggesting that nAChRa5 encoded by
scale GWAS study with 112,117 white British individuals CHRNA5 may regulate nicotine-induced aversion and thus
from the UK Biobank, SNPs in ADH1B and ADH1C were further influence vulnerability to tobacco addiction (Fowler
associated with alcohol consumption (Clarke et al., 2017). and Kenny, 2014). The brain-derived neurotrophic factor
There are a limited number of studies that have inte- (BDNF), which has a role in modulation of dopamine activity
grated genetics, neuroimaging, and cognition. For example, (Hyman et al., 1991), and its variants have been associated
genes related to alcohol-induced reward reinforcement have with substance-related disorders (Barker et al., 2015;
been investigated. A metaanalysis of alcohol-intake rele- Gratacos et al., 2007; Zhang et al., 2006), eating disorders
vant SNPs among 47,501 European individuals reported an and schizophrenia (Gratacos et al., 2007), and obesity
association between RASGRF2 and alcohol consumption (Thorleifsson et al., 2009). Several novel SNPs in BDNF
(Schumann et al., 2011), although a replication sample in gene associated with smoking initiation (ever vs. never
21,185 individuals approached, but did not surpass, the smokers) have been reported in metaanalysis with a combi-
multiple comparison corrected significance threshold. nation of samples of Ox-GSK, TAG, and ENGAGE
Evidence from an animal model showed that mice with consortium studies including up to 143,023 individuals
RASGRF2 knocked out had decreased ethanol consump- (Treutlein and Rietschel, 2011).
tion, impaired ethanol-induced dopamine release in the
In this section, we have described genetic analyses of et al., 2011), leading to increased false positives. Data-
addiction that, as with all genetic analyses, are challenging. driven approaches, such as supervised machine learning,
Nevertheless, there are some encouraging trends in the have potentially fewer researcher degrees of freedom
literature: genetic variants in the alcohol metabolizing because the best algorithm is automatically selected during
genes, such as ALDH2, ADH1B, and ADH1C, and in the the training process. Furthermore, because the machine
cholinergic genes, such as CHRNA5 and CHRNA3, are the learning criterion for success is performance on unseen
most replicated gene variants associated with alcohol and data, idiosyncratic decisions by researchers are unlikely to
nicotine addiction, respectively. Smaller sample sizes and be rewarded.
heterogeneity in the definition of addiction have hampered An additional advantage of Big Data is that a more
genetic studies on opioid, heroin, and cocaine addiction. It representative cross section of society can be recruited.
is possible, however, that future work will address this Psychology has been criticized for relying on undergraduates
shortfall. A first impression may be that genetic analyses from high-income Western societies to derive most theories of
are beyond the scope of all but the specialized researcher, human behavior. Online crowdsourcing platforms provide an
with huge sample sizes required and methodological issues avenue to recruit a more diverse sample of participants than
pervading the field of genetics in general. However, it is have traditionally been unavailable; most people on the planet
likely that research in the genetic bases of addiction will be now have access to a mobile phone (Poushter, 2016). Large
advanced by many smaller research groups working in consortium studies of addiction, such as ABCD, are actively
collaboration. Genetic information can be very easy to recruiting from traditionally underrepresented populations
collect. Data from blood are preferable from the perspective (Garavan et al., 2018), such as African-American, Asian, and
of data quality (e.g., saliva typically contains microbial lower socioeconomic White populations. Collecting and
DNA), but genetic data can be easily obtained from effectively analyzing individual difference measures from a
salivadgenetic data are quite robustdand commercially wide range of factorsdgenetics, environment, biology, and
available collection tubes can keep the saliva samples stable cognitiondmay move addiction research toward the field of
for up to 5 years at room temperature. Furthermore, the cost “personalized medicine” (Hamburg and Collins, 2010). This
of genetic analysis is steadily falling. There are also may facilitate the prediction of substance use trajectories
addiction-specific genetic chips, such as Smokescreen based on individual differences, which could result in earlier
(Baurley et al., 2016), which is used in ABCD (Uban et al., diagnosis and better prognosis for substance use disorders.
2018). Smokescreen is an enriched chip, meaning that it has To conclude, although Big Data is, in essence, a
better coverage for genetic variants associated with addic- collection of ones and zeros, the success of these
tion, in particular for nicotine addiction. In short, approaches relies on successful human interaction. Big
researchers can collect genetic information in parallel with Data requires coordination among researchers, either via
ongoing research. These genetic data can then be uploaded large consortia (e.g., IMAGEN, ABCD) or post hoc
to public databases (e.g., dbGap) or consortia aggregation of data (e.g., dbGAP). While there will always
(e.g., ENIGMA Addiction) along with phenotyping be a place for smaller, hypothesis-driven addiction studies,
information. large-scale multi-authored addiction papers are likely to
become more prevalent in the Big Data era. The scientific
benefits of these collaborations have the potential to yield
General discussion new insights into cognitive processes in addiction.
In this chapter, we have outlined the application of Big
Data approaches to addiction research with respect to
cognition, neuroimaging, and genetics. At this juncture, it is
References
worth considering the distinct advantages that Big Data Agrawal, A., Edenberg, H.J., Gelernter, J., 2016. Meta-analyses of
confers over traditional approaches. Possibly the main genome-wide association data hold new promise for addiction
advantage of a Big Data approach is that it affords greater genetics. J. Stud. Alcohol Drugs 77 (5), 676e680.
replicability of findings. It is known that psychology in Andersson, G., Titov, N., 2014. Advantages and limitations of Internet-
based interventions for common mental disorders. World Psychiatry
general, and cognitive psychology in particular, does not
13 (1), 4e11. https://doi.org/10.1002/wps.20083.
have high replicability (Open Science Collaboration, 2015).
Arbisi, P.A., Ben-Porath, Y.S., 1995. An MMPI-2 infrequent response
Studies of cognition have been underpowered, particularly scale for use with psychopathological populations: the infrequency-
for neuroimaging (Button et al., 2013) and genetics (Sham psychopathology scale, F(p). Psychol. Assess. 7 (4), 424e431.
and Purcell, 2014): Big Data, almost by definition, can Bagot, K.S., Matthews, S.A., Mason, M., Squeglia, L., Fowler, J.,
solve this problem by increasing sample size. Poor repli- Gray, K., et al., 2018. Current, future and potential use of mobile and
cability is also often a result of “researcher degrees of wearable technologies and social media data in the ABCD study to
freedom,” in which researchers test several different com- increase understanding of contributors to child health. Dev. Cogn.
binations of approaches and statistical thresholds (Simmons Neurosci. 32, 121e129. https://doi.org/10.1016/j.dcn.2018.03.008.
Barker, J.M., Taylor, J.R., De Vries, T.J., Peters, J., 2015. Brain-derived development (ABCD) study: imaging acquisition across 21 sites. Dev.
neurotrophic factor and addiction: pathological versus therapeutic Cogn. Neurosci. 31, 43e54.
effects on drug seeking. Brain Res. 1628 (Pt A), 68e81. https://doi.org/ Chebli, J.L., Blaszczynski, A., Gainsbury, S.M., 2016. Internet-based
10.1016/j.brainres.2014.10.058. interventions for addictive behaviours: a systematic review.
Barratt, M.J., Potter, G.R., Wouters, M., Wilkins, C., Werse, B., Perala, J., J. Gambl. Stud. 32 (4), 1279e1304. https://doi.org/10.1007/s10899-
et al., 2015. Lessons from conducting trans-national Internet-mediated 016-9599-5.
participatory research with hidden populations of cannabis cultivators. Chen, M., Mao, S., Liu, Y., 2014. Big data: a survey. Mob. Netw. Appl. 19
Int. J. Drug Policy 26 (3), 238e249. https://doi.org/10.1016/ (2), 171e209.
j.drugpo.2014.12.004. Cheung, M.W.L., Jak, S., 2016. Analyzing big data in psychology: a split/
Baurley, J.W., Edlund, C.K., Pardamean, C.I., Conti, D.V., Bergen, A.W., analyze/meta-analyze approach. Front. Psychol. 7, 738.
2016. Smokescreen: a targeted genotyping array for addiction Cheung, K.L., Wijnen, B.F.M., Hiligsmann, M., Coyle, K., Coyle, D.,
research. BMC Genomics 17, 145. https://doi.org/10.1186/s12864- Pokhrel, S., et al., 2017. Is it cost-effective to provide internet-based
016-2495-7. interventions to complement the current provision of smoking cessa-
Behrendt, S., Wittchen, H.U., Höfler, M., Lieb, R., Beesdo, K., 2009. tion services in The Netherlands? An analysis based on the EQUI-
Transitions from first substance use to substance use disorders in PTMOD. Addiction. https://doi.org/10.1111/add.14069.
adolescence: is early onset associated with a rapid escalation? Drug Clarke, T.K., Adams, M.J., Davies, G., Howard, D.M., Hall, L.S.,
Alcohol Depend. 99 (1e3), 68e78. Padmanabhan, S., et al., 2017. Genome-wide association study of
Biernacka, J.M., Geske, J.R., Schneekloth, T.D., Frye, M.A., alcohol consumption and genetic overlap with other health-related
Cunningham, J.M., Choi, D.S., et al., 2013. Replication of genome wide traits in UK Biobank (N¼112 117). Mol. Psychiatry 22 (10),
association studies of alcohol dependence: support for association with 1376e1384. https://doi.org/10.1038/mp.2017.153.
variation in ADH1C. PLoS One 8 (3), e58798. https://doi.org/10.1371/ Costa, P.T., McCrea, R.R., 1992. Revised neo personality inventory (neo
journal.pone.0058798. pi-r) and neo five-factor inventory (neo-ffi). Professional manual.
Bierut, L.J., 2011. Genetic vulnerability and susceptibility to substance Odessa, FL: Psychol. Assess. Resour.
dependence. Neuron 69 (4), 618e627. https://doi.org/10.1016/ Crane, C.A., 2018. Crowdsourcing as a method for collecting data
j.neuron.2011.02.015. pertaining to the effects of alcohol on perceptions of partner aggres-
Boffo, M., Pronk, T., Wiers, R.W., Mannarini, S., 2015. Combining sion. Am. J. Drug Alcohol Abuse 1e8. https://doi.org/10.1080/
cognitive bias modification training with motivational support in 00952990.2018.1436178.
alcohol dependent outpatients: study protocol for a randomised Crump, M.J., McDonnell, J.V., Gureckis, T.M., 2013. Evaluating Ama-
controlled trial. Trials 16, 63. https://doi.org/10.1186/s13063-015- zon’s Mechanical Turk as a tool for experimental behavioral research.
0576-6. PLoS One 8 (3), e57410. https://doi.org/10.1371/
Briones, E.M., Benham, G., 2017. An examination of the equivalency of journal.pone.0057410.
self-report measures obtained from crowdsourced versus undergraduate Cunningham, J., 2007. Translation of addictions science into practice. In:
student samples. Behav. Res. Methods 49 (1), 320e334. https://doi.org/ Miller, P., Kavanagh, D. (Eds.), Internet-Based Interventions for
10.3758/s13428-016-0710-8. Alcohol, Tobacco and Other Substances of Abuse.
Brown, M., O’Neill, N., van Woerden, H., Eslambolchilar, P., Jones, M., Elsevier-Pergamon, New York, pp. 399e438.
John, A., 2016. Gamification and adherence to web-based mental Cunningham, J.A., Godinho, A., Kushnir, V., 2017. Using Mechanical
health interventions: a systematic review. JMIR Mental Health 3 (3), Turk to recruit participants for internet intervention research: experi-
e39. https://doi.org/10.2196/mental.5710. ence from recruitment for four trials targeting hazardous alcohol
Büchel, C., Peters, J., Banaschewski, T., Bokde, A.L., Bromberg, U., consumption. BMC Med. Res. Methodol. 17 (1), 156. https://doi.org/
Conrod, P.J., et al., 2017. Blunted ventral striatal responses to antic- 10.1186/s12874-017-0440-3.
ipated rewards foreshadow problematic drug use in novelty-seeking Dandurand, F., Shultz, T.R., Onishi, K.H., 2008. Comparing online and
adolescents. Nat. Commun. 8, 14140. lab methods in a problem-solving experiment. Behav. Res. Methods
Button, K.S., Ioannidis, J.P., Mokrysz, C., Nosek, B.A., Flint, J., 40 (2), 428e434.
Robinson, E.S., Munafò, M.R., 2013. Power failure: why small Degenhardt, L., Stockings, E., Patton, G., Hall, W.D., Lynskey, M., 2016.
sample size undermines the reliability of neuroscience. Nat. Rev. The increasing global health priority of substance use in young people.
Neurosci. 14 (5), 365. Lancet Psychiatry 3 (3), 251e264.
Bzdok, D., Krzywinski, M., Altman, N., 2018. Points of significance: Dovis, S., Van der Oord, S., Wiers, R.W., Prins, P.J., 2012. Can
machine learning: supervised methods. Nat. Methods 15 (5). https://doi. motivation normalize working memory and task persistence in
org/10.1038/nmeth.4551. children with attention-deficit/hyperactivity disorder? The effects of
Cao, Z., Bennett, M., Orr, C., Icke, I., Banaschewski, T., Barker, G.J., money and computer-gaming. J. Abnorm. Child Psychol. 40 (5),
et al., 2018. Mapping Adolescent Reward Anticipation, Receipt, and 669e681. https://doi.org/10.1007/s10802-011-9601-8.
Prediction Error during the Monetary Incentive Delay Task. Human Dubois, J., Adolphs, R., 2016. Building a science of individual differences
Brain Mapping. https://doi.org/10.1002/hbm.24370. from fMRI. Trends Cogn. Sci. 20 (6), 425e443.
Carreiro, S., Fang, H., Zhang, J., Wittbold, K., Weng, S., Mullins, R., Ducci, F., Goldman, D., 2012. The genetic basis of addictive disorders.
et al., 2015. iMStrong: deployment of a biosensor system to detect Psychiatr. Clin. 35 (2), 495e519. https://doi.org/10.1016/
cocaine use. J. Med. Syst. 39, 186. j.psc.2012.03.010.
Casey, B.J., Cannonier, T., Conley, M.I., Cohen, A.O., Barch, D.M.,
Heitzeg, M.M., et al., 2018. The adolescent brain cognitive
Edenberg, H.J., 2007. The genetics of alcohol metabolism: role of alcohol drinkers, part 1: three-month outcomes of a randomized controlled
dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res. trial. J. Med. Internet Res. 15 (7).
Health 30 (1), 5. Hyman, C., Hofer, M., Barde, Y.-A., Juhasz, M., Yancopoulos, G.D.,
Eichler, E.E., Flint, J., Gibson, G., Kong, A., Leal, S.M., Moore, J.H., Squinto, S.P., Lindsay, R.M., 1991. BDNF is a neurotrophic factor for
Nadeau, J.H., 2010. Missing heritability and strategies for finding the dopaminergic neurons of the substantia nigra. Nature 350 (6315), 230.
underlying causes of complex disease. Nat. Rev. Genet. 11 (6), Jackson, K.M., Barnett, N.P., Colby, S.M., Rogers, M.L., 2015. The
446e450. https://doi.org/10.1038/nrg2809. prospective association between sipping alcohol by the sixth grade and
Fowler, C.D., Kenny, P.J., 2014. Nicotine aversion: neurobiological later substance use. J. Stud. Alcohol Drugs 76 (2), 212e221.
mechanisms and relevance to tobacco dependence vulnerability. Jollans, L., Whelan, R., 2016. The clinical added value of imaging: a
Neuropharmacology 76 Pt B, 533e544. https://doi.org/10.1016/ perspective from outcome prediction. Biol. Psychiatry Cogn. Neuro-
j.neuropharm.2013.09.008. sci. Neuroimaging 1 (5), 423e432.
Gabrieli, J.D., Ghosh, S.S., Whitfield-Gabrieli, S., 2015. Prediction as a Jollans, L., Whelan, R., 2018. Neuromarkers for mental disorders:
humanitarian and pragmatic contribution from human cognitive harnessing population neuroscience. Front. Psychiatry 9.
neuroscience. Neuron 85 (1), 11e26. Kendler, K.S., Jacobson, K.C., Prescott, C.A., Neale, M.C., 2003. Speci-
Gainsbury, S., Hing, N., Suhonen, N., 2014. Professional help-seeking for ficity of genetic and environmental risk factors for use and abuse/
gambling problems: awareness, barriers and motivators for treatment. dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants,
J. Gambl. Stud. 30 (2), 503e519. https://doi.org/10.1007/s10899-013- and opiates in male twins. Am. J. Psychiatry 160 (4), 687e695.
9373-x. Kim, H.S., Hodgins, D.C., 2017. Reliability and validity of data obtained
Gelernter, J., Kranzler, H.R., Sherva, R., Almasy, L., Koesterer, R., from alcohol, cannabis, and gambling populations on Amazon’s
Smith, A.H., et al., 2014. Genome-wide association study of alcohol Mechanical Turk. Psychol. Addict. Behav. 31 (1), 85e94. https://
dependence:significant findings in African- and European-Americans doi.org/10.1037/adb0000219.
including novel risk loci. Mol. Psychiatry 19 (1), 41e49. https:// Kraut, R., Olson, J., Banaji, M., Bruckman, A., Cohen, J., Couper, M.,
doi.org/10.1038/mp.2013.145. 2004. Psychological research online: report of board of scientific
Garavan, H., Bartsch, H., Conway, K., Decastro, A., Goldstein, R.Z., affairs’ advisory group on the conduct of research on the internet. Am.
Heeringa, S., et al., 2018. Recruiting the ABCD sample: design Psychol. 59 (2), 105e117. https://doi.org/10.1037/0003-
considerations and procedures. Dev. Cogn. Neurosci. 32, 16e22. 066X.59.2.105.
Germine, L., Nakayama, K., Duchaine, B.C., Chabris, C.F., Chatterjee, G., Latella, M.C., Di Castelnuovo, A., de Lorgeril, M., Arnout, J.,
Wilmer, J.B., 2012. Is the Web as good as the lab? Comparable Cappuccio, F.P., Krogh, V., et al., 2009. Genetic variation of alcohol
performance from Web and lab in cognitive/perceptual experiments. dehydrogenase type 1C (ADH1C), alcohol consumption, and
Psychonomic Bull. Rev. 19 (5), 847e857. https://doi.org/10.3758/ metabolic cardiovascular risk factors: results from the IMMIDIET
s13423-012-0296-9. study. Atherosclerosis 207 (1), 284e290. https://doi.org/10.1016/
Gillan, C.M., Kosinski, M., Whelan, R., Phelps, E.A., Daw, N.D., 2016. j.atherosclerosis.2009.04.022.
Characterizing a psychiatric symptom dimension related to deficits in Lewis, I., Watson, B., White Katherine, M., 2011. Internet versus paper
goal-directed control. Elife 5. https://doi.org/10.7554/eLife.11305. and pencil survey methods in psychological experiments: equivalence
Gratacos, M., Gonzalez, J.R., Mercader, J.M., de Cid, R., testing of participant responses to health related messages. Aust. J.
Urretavizcaya, M., Estivill, X., 2007. Brain-derived neurotrophic Psychol. 61 (2), 107e116. https://doi.org/10.1080/
factor Val66Met and psychiatric disorders: meta-analysis of case- 00049530802105865.
control studies confirm association to substance-related disorders, Li, D., Zhao, H., Gelernter, J., 2011. Strong association of the alcohol
eating disorders, and schizophrenia. Biol. Psychiatry 61 (7), 911e922. dehydrogenase 1B gene (ADH1B) with alcohol dependence and
https://doi.org/10.1016/j.biopsych.2006.08.025. alcohol-induced medical diseases. Biol. Psychiatry 70 (6), 504e512.
Hamburg, M.A., Collins, F.S., 2010. The path to personalized medicine. https://doi.org/10.1016/j.biopsych.2011.02.024.
N. Engl. J. Med. 363 (4), 301e304. https://doi.org/10.1056/ Li, D., Zhao, H., Gelernter, J., 2012. Strong protective effect of the
NEJMp1006304. aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against
Hart, A.B., de Wit, H., Palmer, A.A., 2013. Candidate gene studies of a alcoholism and alcohol-induced medical diseases in Asians. Hum.
promising intermediate phenotype: failure to replicate. Neuro- Genet. 131 (5), 725e737. https://doi.org/10.1007/s00439-011-1116-4.
psychopharmacology 38 (5), 802e816. https://doi.org/10.1038/ Lisdahl, K.M., Sher, K.J., Conway, K.P., Gonzalez, R., Ewing, S.W.F.,
npp.2012.245. Nixon, S.J., et al., 2018. Adolescent brain cognitive development
Henkel, D., Zemlin, U., 2016. Social inequality and substance use and (ABCD) study: overview of substance use assessment methods. Dev.
problematic gambling among adolescents and young adults: a review Cogn. Neurosci. 32, 80e96.
of epidemiological surveys in Germany. Curr. Drug Abuse Rev. 9, Litman, L., Robinson, J., Abberbock, T., 2017. TurkPrime.com: a versatile
26e48. crowdsourcing data acquisition platform for the behavioral sciences.
Henrich, J., Heine, S.J., Norenzayan, A., 2010. The weirdest people in the Behav. Res. Methods 49 (2), 433e442. https://doi.org/10.3758/
world? Behav. Brain Sci. 33 (2e3), 61e83. https://doi.org/10.1017/ s13428-016-0727-z.
S0140525X0999152X. Discussion 83e135. Liu, J.Z., Tozzi, F., Waterworth, D.M., Pillai, S.G., Muglia, P.,
Hester, R.K., Lenberg, K.L., Campbell, W., Delaney, H.D., 2013. Middleton, L., et al., 2010. Meta-analysis and imputation refines the
Overcoming addictions, a web-based application, and SMART association of 15q25 with smoking quantity. Nat. Genet. 42 (5),
recovery, an online and in-person mutual help group for problem 436e440. https://doi.org/10.1038/ng.572.
Lohse, B., Wamboldt, P., 2013. Purposive facebook recruitment endows Pedregosa, F., Varoquaux, G., Gramfort, A., Michel, V., Thirion, B.,
cost-effective nutrition education program evaluation. J. Med. Inter. Grisel, O., et al., 2011. Scikit-learn: machine learning in Python.
Res. Protoc. 2 (2), e27. https://doi.org/10.2196/resprot.2713. J. Mach. Learn. Res. 12 (Oct), 2825e2830.
Loukola, A., Hallfors, J., Korhonen, T., Kaprio, J., 2014. Genetics and Peters, J., Bromberg, U., Schneider, S., Brassen, S., Menz, M.,
smoking. Curr. Addict. Rep. 1 (1), 75e82. https://doi.org/10.1007/ Banaschewski, T., et al., 2011. Lower ventral striatal activation during
s40429-013-0006-3. reward anticipation in adolescent smokers. Am. J. Psychiatry 168 (5),
Luczak, S.E., Glatt, S.J., Wall, T.L., 2006. Meta-analyses of ALDH2 and 540e549.
ADH1B with alcohol dependence in Asians. Psychol. Bull. 132 (4), Poushter, J., 2016. Smartphone ownership and internet usage continues to
607e621. https://doi.org/10.1037/0033-2909.132.4.607. climb in emerging economies. Pew Res. Center 22, 1e44.
Mackey, S., Kan, K.J., Chaarani, B., Alia-Klein, N., Batalla, A., Proudfoot, J., Klein, B., Barak, A., Carlbring, P., Cuijpers, P., Lange, A.,
Brooks, S., et al., 2016. Genetic imaging consortium for addiction et al., 2011. Establishing guidelines for executing and reporting
medicine: from neuroimaging to genes. Prog. Brain Res. 224, Internet intervention research. Cogn. Behav. Ther. 40 (2), 82e97.
203e223. https://doi.org/10.1080/16506073.2011.573807.
Mailman, M.D., Feolo, M., Jin, Y., Kimura, M., Tryka, K., Ramo, D.E., Prochaska, J.J., 2012. Broad reach and targeted recruitment
Bagoutdinov, R., et al., 2007. The NCBI dbGaP database of genotypes using Facebook for an online survey of young adult substance use.
and phenotypes. Nat. Genet. 39 (10), 1181e1186. J. Med. Internet Res. 14 (1), e28. https://doi.org/10.2196/jmir.1878.
McCrone, P., Knapp, M., Proudfoot, J., Ryden, C., Cavanagh, K., Ramo, D.E., Rodriguez, T.M., Chavez, K., Sommer, M.J., Prochaska, J.J.,
Shapiro, D.A., et al., 2004. Cost-effectiveness of computerised 2014. Facebook recruitment of young adult smokers for a cessation
cognitive-behavioural therapy for anxiety and depression in primary trial: methods, metrics, and lessons learned. Internet Interv. 1 (2),
care: randomised controlled trial. Br. J. Psychiatry 185, 55e62. 58e64. https://doi.org/10.1016/j.invent.2014.05.001.
McLellan, A., 2006. What we need is a system: creating a responsive and Reips, U.D., 2002. Standards for internet-based experimenting. Exp.
effective substance abuse treatment system. In: Miller, R., Psychol. 49, 243e256. https://doi.org/10.1026//1618-3169.49.4.243.
Carroll, K.M. (Eds.), Rethinking Substance Abuse: What the Science Saccone, N.L., Schwantes-An, T.H., Wang, J.C., Grucza, R.A.,
Shows, and what We Should Do About it. Guildford Press, New York. Breslau, N., Hatsukami, D., et al., 2010. Multiple cholinergic nicotinic
McMahon, M., Thompson, P., 2017. Enhancing neuro imaging genetics receptor genes affect nicotine dependence risk in African and Euro-
through meta analysis: global collaborations in psychiatry by the pean Americans. Genes Brain Behav. 9 (7), 741e750. https://doi.org/
ENIGMA consortium. Eur. Neuropsychopharmacol. 27, S715. 10.1111/j.1601-183X.2010.00608.x.
Miwa, J.M., Freedman, R., Lester, H.A., 2011. Neural systems governed Saleheen, N., Ali, A.A., Hossain, S.M., Sarker, H., Chatterjee, S.,
by nicotinic acetylcholine receptors: emerging hypotheses. Neuron 70 Marlin, B., et al., 2015. puffMarker: a multi-sensor approach for
(1), 20e33. https://doi.org/10.1016/j.neuron.2011.03.014. pinpointing the timing of first lapse in smoking cessation. Proceedings
Morris, A.S., Squeglia, L.M., Jacobus, J., Silk, J.S., 2018. Adolescent of the 2015 ACM International Joint Conference on Pervasive and
brain development: implications for understanding risk and resilience Ubiquitous Computing, pp. 999e1010.
processes through neuroimaging research. J. Res. Adolesc. 28 (1), Schumann, G., Loth, E., Banaschewski, T., Barbot, A., Barker, G.,
4e9. Büchel, C., et al., 2010. The IMAGEN study: reinforcement-related
Myrseth, H., Brunborg, G.S., Eidem, M., Pallesen, S., 2013. Description behaviour in normal brain function and psychopathology. Mol. Psy-
and pre-post evaluation of a telephone and Internet based treatment chiatry 15 (12), 1128.
programme for pathological gambling in Norway: a pilot study. Int. Schumann, G., Coin, L.J., Lourdusamy, A., Charoen, P., Berger, K.H.,
Gambl. Stud. 13 (2), 205e220. https://doi.org/10.1080/ Stacey, D., et al., 2011. Genome-wide association and genetic func-
14459795.2012.759610. tional studies identify autism susceptibility candidate 2 gene (AUTS2)
Nosek, B.A., Banaji, M.R., Greenwald, A.G., 2002. Harvesting implicit in the regulation of alcohol consumption. Proc. Natl. Acad. Sci.
group attitudes and beliefs from a demonstration web site. Group Dyn. U.S.A. 108 (17), 7119e7124. https://doi.org/10.1073/
6 (1), 101e115. https://doi.org/10.1037/1089-2699.6.1.101. pnas.1017288108.
O’Halloran, L., Nymberg, C., Jollans, L., Garavan, H., Whelan, R., 2017. Sham, P.C., Purcell, S.M., 2014. Statistical power and significance testing
The potential of neuroimaging for identifying predictors of adolescent in large-scale genetic studies. Nat. Rev. Genet. 15 (5), 335e346.
alcohol use initiation and misuse. Addiction 112 (4), 719e726. Simcox, T., Fiez, J.A., 2014. Collecting response times using Amazon
Open Science Collaboration, 2015. Estimating the reproducibility of mechanical Turk and adobe flash. Behav. Res. Methods 46 (1),
psychological science. Science 349. https://doi.org/10.1126/ 95e111. https://doi.org/10.3758/s13428-013-0345-y.
science.aac4716. Simmons, J.P., Nelson, L.D., Simonsohn, U., 2011. False-positive
Ostaszewski, K., Zimmerman, M.A., 2006. The effects of cumulative risks psychology: Undisclosed flexibility in data collection and analysis
and promotive factors on urban adolescent alcohol and other drug use: allows presenting anything as significant. Psychol. Sci. 22 (11),
a longitudinal study of resiliency. Am. J. Community Psychol. 38 1359e1366.
(3e4), 251e262. Squeglia, L.M., Ball, T.M., Jacobus, J., Brumback, T., McKenna, B.S.,
Paus, T., 2010. Population neuroscience: why and how. Hum. Brain Mapp. Nguyen-Louie, T.T., Sorg, S.F., Paulus, M.P., Tapert, S.F., 2016.
31 (6), 891e903. Neural predictors of initiating alcohol use during adolescence. Am. J.
Pe’er, I., Yelensk, R., Altshuler, D., Daly, M.J., 2008. Estimation of the Psychiatry 174 (2), 172e185.
multiple testing burden for genomewide association studies of nearly all
common variants. Genet. Epidemiol. 32 (4), 381e385. https://doi.org/
10.1002/gepi.20303.
Stacey, D., Bilbao, A., Maroteaux, M., Jia, T., Easton, A.C., Uban, K.A., Horton, M.K., Jacobus, J., Heyser, C., Thompson, W.K.,
Longueville, S., et al., 2012. RASGRF2 regulates alcohol-induced Tapert, S.F., et al., 2018. Biospecimens and the ABCD Study:
reinforcement by influencing mesolimbic dopamine neuron activity Rationale, Methods of Collection, Measurement and Early Data.
and dopamine release. Proc. Natl. Acad. Sci. U.S.A. 109 (51), Developmental cognitive neuroscience.
21128e21133. https://doi.org/10.1073/pnas.1211844110. Vink, J.M., 2016. Genetics of addiction: future focus on gene x environ-
Strickland, J.C., Stoops, W.W., 2018. Feasibility, acceptability, and ment interaction? J. Stud. Alcohol Drugs 77 (5), 684e687.
validity of crowdsourcing for collecting longitudinal alcohol use data. Weigold, A., Weigold, I.K., Russell, E.J., 2013. Examination of the
J. Exp. Anal. Behav. https://doi.org/10.1002/jeab.445. equivalence of self-report survey-based paper-and-pencil and internet
Stringer, S., Minica, C.C., Verweij, K.J., Mbarek, H., Bernard, M., data collection methods. Psychol. Methods 18 (1), 53e70. https://
Derringer, J., et al., 2016. Genome-wide association study of lifetime doi.org/10.1037/a0031607.
cannabis use based on a large meta-analytic sample of 32,330 subjects Weigold, A., Weigold, I.K., Drakeford, N.M., Dykema, S.A., Smith, C.A.,
from the International Cannabis Consortium. Transl. Psychiatry 6, 2016. Equivalence of paper-and-pencil and computerized self-report
e769. https://doi.org/10.1038/tp.2016.36. surveys in older adults. Comput. Hum. Behav. 54, 407e413. https://
Sullivan, P.F., 2010. The psychiatric GWAS consortium: big science doi.org/10.1016/j.chb.2015.08.033.
comes to psychiatry. Neuron 68 (2), 182e186. Whelan, R., Garavan, H., 2014. When optimism hurts: inflated predictions
Tahmasebi, A.M., Artiges, E., Banaschewski, T., Barker, G.J., Bruehl, R., in psychiatric neuroimaging. Biol. Psychiatry 75 (9), 746e748.
Büchel, C., et al., 2012. Creating probabilistic maps of the face Whelan, R., Conrod, P.J., Poline, J.B., Lourdusamy, A., Banaschewski, T.,
network in the adolescent brain: a multicentre functional MRI study. Barker, G.J., et al., 2012. Adolescent impulsivity phenotypes
Hum. Brain Mapp. 33 (4), 938e957. characterized by distinct brain networks. Nat. Neurosci. 15 (6), 920.
Taylor, G.M.J., Dalili, M.N., Semwal, M., Civljak, M., Sheikh, A., Car, J., Whelan, R., Watts, R., Orr, C.A., Althoff, R.R., Artiges, E.,
2017. Internet-based interventions for smoking cessation. Cochrane Banaschewski, T., et al., 2014. Neuropsychosocial profiles of current
Database Syst. Rev. 9, Cd007078 https://doi.org/10.1002/ and future adolescent alcohol misusers. Nature 512 (7513), 185.
14651858.CD007078.pub5. Wiers, R.W., Houben, K., Fadardi, J.S., van Beek, P., Rhemtulla, M.,
Thanh, V.N., Guignard, R., Lancrenon, S., Bertrand, C., Delva, C., Cox, W.M., 2015. Alcohol cognitive bias modification training for
Berlin, I., et al., 2018. Effectiveness of a Fully Automated Internet- problem drinkers over the web. Addict. Behav. 40, 21e26. https://doi.
Based Smoking Cessation Program: A Randomized Controlled Trial org/10.1016/j.addbeh.2014.08.010.
(STAMP). Nicotine and Tobacco Research. https://doi.org/10.1093/ Woicik, P.A., Stewart, S.H., Pihl, R.O., Conrod, P.J., 2009. The substance
ntr/nty016. use risk profile scale: a scale measuring traits linked to reinforcement-
Thorgeirsson, T.E., Gudbjartsson, D.F., Surakka, I., Vink, J.M., Amin, N., specific substance use profiles. Addict. Behav. 34 (12), 1042e1055.
Geller, F., et al., 2010. Sequence variants at CHRNB3-CHRNA6 and Woo, C.W., Chang, L.J., Lindquist, M.A., Wager, T.D., 2017. Building
CYP2A6 affect smoking behavior. Nat. Genet. 42 (5), 448e453. better biomarkers: brain models in translational neuroimaging. Nat.
https://doi.org/10.1038/ng.573. Neurosci. 20 (3), 365.
Thorleifsson, G., Walters, G.B., Gudbjartsson, D.F., Steinthorsdottir, V., Wu, J., 2009. Understanding of nicotinic acetylcholine receptors. Acta
Sulem, P., Helgadottir, A., et al., 2009. Genome-wide association Pharmacol. Sin. 30 (6), 653e655. https://doi.org/10.1038/
yields new sequence variants at seven loci that associate with aps.2009.89.
measures of obesity. Nat. Genet. 41 (1), 18. Zhang, H., Ozbay, F., Lappalainen, J., Kranzler, H.R., van Dyck, C.H.,
Thornton, L.K., Harris, K., Baker, A.L., Johnson, M., Kay-Lambkin, F.J., Charney, D.S., et al., 2006. Brain derived neurotrophic factor (BDNF)
2016. Recruiting for addiction research via Facebook. Drug Alcohol gene variants and Alzheimer’s disease, affective disorders, post-
Rev. 35 (4), 494e502. https://doi.org/10.1111/dar.12305. traumatic stress disorder, schizophrenia, and substance dependence.
Tobacco, Genetics, C., 2010. Genome-wide meta-analyses identify Am. J. Med. Genet. B Neuropsychiatr. Genet. 141B (4), 387e393.
multiple loci associated with smoking behavior. Nat. Genet. 42 (5), https://doi.org/10.1002/ajmg.b.30332.
441e447. https://doi.org/10.1038/ng.571. Zou, H., Hastie, T., 2005. Regularization and variable selection via the
Treutlein, J., Rietschel, M., 2011. Genome-wide association studies of elastic net. J. R. Stat. Soc. Ser. B 67 (2), 301e320.
alcohol dependence and substance use disorders. Curr. Psychiatr. Rep.
13 (2), 147e155. https://doi.org/10.1007/s11920-011-0176-4.
Chapter 28
Modeling neurocognitive and

neurobiological recovery in addiction
Dieter J. Meyerhoff1 and Timothy C. Durazzo2
1
University of California San Francisco and San Francisco VA Medical Center; 2Stanford University and Palo Alto VA Medical Center
Modeling neurocognitive and primarily in the domains of learning/memory, working

memory, and other executive-based skills, including
neurobiological recovery in addiction cognitive/inhibitory control (extensively reviewed in pre-
Neurocognitive dysfunction associated with alcohol and vious chapters). Persons with alcohol use disorder (AUD)
substance use disorders (SUDs) has been well-established have been studied most, with the nature and level of
and is the topic of most chapters in this book. However, impairment showing considerable variability (for recent
neurocognitive changes occurring during abstinence from reviews, see Stavro et al., 2013; Bernardin et al., 2014;
alcohol and substances have been less frequently described. Oscar-Berman et al., 2014; Le Berre, Fama et al., 2017).
This chapter first summarizes the main neurocognitive and Approximately 55% of AUD manifest clinically significant
neurobiological abnormalities associated with alcohol and neurocognitive deficits after acute detoxification (i.e., >1.5
SUDs, before reviewing more extensively the neuro- standard deviations below the level in healthy controls), but
cognitive and neurobiological changes that occur with some degree of recovery from these deficits is apparent
abstinence from alcohol and other substances. As a recent with short-term (i.e., 1 month), intermediate-term (i.e.,
review focused on findings from functional magnetic 1e12 months), and long-term (i.e., >1 year) abstinence
resonance imaging (fMRI) and positron emission tomog- from alcohol (Rourke and Grant, 2009; Durazzo et al.,
raphy studies during abstinence from alcohol (Charlet et al., 2014b). Some dysfunction has been reported to persist into
2018), the neurobiological descriptions here focus on brain long-term abstinence from alcohol, particularly in the
morphological and spectroscopic MR studies of individuals domains of executive and visuospatial skills, learning and
with alcohol and/or SUDs. While the neurocognitive and memory, and postural stability (Durazzo and Meyerhoff,
neurobiological abnormalities associated with addiction 2007; Rourke and Grant, 2009; Stavro et al., 2013;
increase mortality and morbidity for the afflicted individual Le Berre, Fama et al., 2017). The degree of cognitive
and the society, there is also clear evidence of adaptive and dysfunction and the rate of recovery during abstinence
variable recovery from these abnormalities. A better appear to be influenced by many factors such as age, sex,
understanding of the specific changes associated with family history of AUD, treatment history, pretreatment
abstinence, their trajectories over time, and of their poten- alcohol consumption level, number of detoxifications,
tial mechanisms will inform more efficacious interventions nutritional status, comorbid psychiatric and biomedical
for alcohol and SUDs in future. Additionally, a better conditions, and comorbid SUD (Durazzo and Meyerhoff,
understanding of the course of neurobiological changes 2007; Oscar-Berman and Marinkovic, 2007; Rourke and
associated with abstinence can ultimately serve as powerful Grant, 2009; Schulte et al., 2014).
psychoeducational information for those considering and Most treatment-seeking substance users today concur-
seeking treatment for alcohol and SUDs. rently and/or simultaneously consume more than one illicit/
licit compound, so-called polysubstance users (PSU)
(Hasin and Grant, 2015). Among PSU, comorbid tobacco
Neurocognitive deficits in addiction use disorder is most prevalent in AUD (Durazzo and
Alcohol and SUDs in general (cocaine, methamphetamine, Meyerhoff, 2007; Weinberger et al., 2016), and chronic
cannabis, or tobacco) are associated with dysfunction, cigarette smoking itself is associated with significant

neurocognitive deficiencies (e.g., visuospatial memory, (Durazzo et al., 2008b). In comparisons to 1-month-absti-
motor impulsivity) in both AUD and non-AUD cohorts nent AUD, 1-month-abstinent PSU performed worse on
(e.g., Brody, 2006; Glass et al., 2006; Durazzo et al., measures of auditory verbal memory and learning and
2006b; Gazdzinski et al., 2006; Durazzo and Meyerhoff, general intelligence (Schmidt et al., 2017), suggesting a
2007; Almeida et al., 2008; Durazzo et al., 2010a; Durazzo diminished capacity (compared to AUD) of learning,
et al., 2011; Durazzo et al., 2012; Morales et al., 2012; memorizing, and integrating new skills presented in clinical
Pennington et al., 2013; Durazzo et al., 2014b; Durazzo treatment settings. In addition, PSU exhibited worse
et al., 2015). Smoking AUD performed worse than their decision-making and higher self-reported impulsivity than
nonsmoking counterparts on domains of auditory verbal AUD, potentially placing them at a greater relapse risk
learning and memory, processing speed, cognitive effi- during early recovery. Finally, PSU between the ages of 25
ciency, and working memory during the first month of and 70 years showed greater age-related declines in
abstinence from alcohol (Durazzo et al., 2006b; Pennington processing speed, general intelligence, cognitive efficiency,
et al., 2013). Smoking AUD also demonstrated poorer and global intelligence than controls, indicating the
neurocognition with increasing age than never-smoking detrimental cumulative effects of polysubstance use on
AUD, and the performance of former-smoking AUD on neurocognition (Schmidt et al., 2017).
several domains was intermediate to that of never-smoking As described, the degree and nature of neurocognitive
and actively smoking AUD (Durazzo et al., 2013; Pen- deficits varies considerably among substance-using groups
nington et al., 2013). investigated, critically related to the combination of both
Particularly common among PSU is the simultaneous illicit and licit substances abused and their use histories.
and/or concurrent abuse of alcohol, tobacco, and psychos- However, it is noteworthy that even mild neurocognitive
timulants (Moss et al., 2015). Therefore, in many published deficits can impact quality of life and relapse risk (Gold-
research reports on the neurobiological and neurocognitive stein et al., 2004; Bates et al., 2013). Impaired neuro-
consequences of AUD, many individuals were also likely cognition and inhibition may adversely affect maintenance
nicotine-dependent, and in studies of cocaine use disorder, of abstinence during treatment and long-term treatment
participants were also likely heavy drinkers. This was both efficacy (Aharonovich et al., 2006; Passetti et al., 2008;
likely and most apparent in literature from before 2010, Streeter et al., 2008; de Wit, 2009; Bates et al., 2013;
when polysubstance abuse had not been attended to more Stevens et al., 2014; Rupp et al., 2016); specifically,
widely in substance abuse research, and other substance use neurocognitive deficits can interfere with treatment efficacy
was largely treated as a nuisance variable. More recently, by reducing the individual’s ability to encode, process,
poorer health outcomes and greater treatment resistance recall, integrate, and apply program information during and
have been reported for PSU compared to monosubstance following treatment (Durazzo et al., 2008b; Dominguez-
users (Walitzer et al., 2015; Weinberger et al., 2017). Salas et al., 2016; Rezapour et al., 2016). As such,
Despite its prevalence, however, few studies have directly assessment of cognitive abilities during treatment may
examined the neuropsychological or neurobiological con- improve treatment outcomes by providing clinicians an
sequences of polysubstance abuse. In early studies, understanding of the individual’s capabilities during treat-
cocaine-dependent individuals with and without AUD ment and inform appropriate posttreatment follow-up care
showed cognitive deficits at 3 months of abstinence (Di (Bates et al., 2013).
Sclafani, Bloomer et al., 1998), and decision-making was
still impaired in similar individuals abstinent for 8 months Neurocognitive changes during abstinence
(Verdejo-Garcia et al., 2007). Even after several years of
abstinence, psychostimulant-related deficits of episodic Studies of longitudinal neurocognitive changes during
memory, planning, and cognitive flexibility were persistent abstinence from alcohol and other substances are far less
in PSU (Fernandez-Serrano et al., 2011). These relatively common than cross-sectional studies (e.g., Fernandez-
persistent cognitive deficits were associated with the Serrano et al., 2011). Most longitudinal studies assessed
amount of cocaine and cannabis consumed (Fernandez- neurocognition several weeks after detoxification and then
Serrano et al., 2010; Schmidt et al., 2017) as well as with 6e12 months later; they demonstrated several neuro-
relapse risk (Verdejo-Garcia et al., 2007; Verdejo-Garcia cognitive functions improve at least partially during
et al., 2012). Cognitive efficiency, processing speed, and sustained abstinence, whereas some cognitive dysfunction
visuospatial learning were less impaired in 1-month-absti- persists for years after detoxification (for recent reviews,
nent PSU who continued to abstain versus those who see Bernardin et al., 2014; Oscar-Berman et al., 2014;
subsequently relapsed between 1 and 4 months of absti- Le Berre et al., 2017). Psychological changes in AUD
nence (Schmidt et al., 2017); similarly, 1-month-abstinent during a residential rehabilitation program have recently
AUD with the lowest processing speed showed a signifi- been documented and include significant decreases in
cantly increased risk for relapse following treatment anxiety, depression, and psychological distress within
Modeling neurocognitive and neurobiological recovery in addiction Chapter | 28 381
about 1 month of detoxification in those with substance- functions in cocaine users improved in those who decreased
induced mood disorders (Giorgi et al., 2015). In studies their cocaine use over a 1-year interval and normalized in
on the effects of comorbid tobacco use on neurocognitive those who were abstinent for 1 year (Vonmoos et al., 2014).
recovery in AUD (Durazzo et al. 2006a, 2007b; Durazzo Decline of working memory over 1 year was associated
et al., 2010a; Pennington et al., 2013), we found that with increased cocaine use in these individuals and with
smoking was associated with significantly diminished younger age of onset of cocaine use. In abstinent PSU,
improvement of visuospatial learning and processing speed cross-sectional studies with different durations of absti-
within the first year of abstinence from alcohol (Pennington nence did (Verdejo-Garcia et al., 2004; Fernandez-Serrano
et al., 2013; Durazzo et al., 2014b). et al., 2011) or did not (Medina et al., 2004) suggest
We analyzed neurocognition across three different time recovery from neurocognitive dysfunction. The additive
points during abstinence from alcohol (1 week, 1 month, detrimental effects of concurrent cocaine and alcohol
and 8 months) and as a function of smoking status (never- dependence persisted over 1 month of abstinence (Bolla
smoking, former-smoking, and actively smoking AUD) et al., 2000). However, over 6 months of abstinence,
(Durazzo et al., 2014b). Over 8 months of abstinence, AUD individuals with comorbid alcohol and stimulant use dis-
as a group showed significant improvements of visuospatial orders demonstrated improvements on measures of imme-
learning and memory, processing speed, and working diate memory (Fein et al., 2002), and improvements
memory, with less pronounced changes in executive func- in verbal short-term memory were also observed over
tions, postural stability, and auditory verbal learning and 3e4 months of abstinence from substances (Block et al.,
memory. Overall, the recovery rates were nonlinear over 2002). Concurrent use of substances in those with AUD
time, showing faster recovery between 1 and 4 weeks than (i.e., PSU) hampered neurocognitive recovery (Schulte
between 1 and 8 months of abstinence. Improvements in et al., 2014), consistent with the detrimental effects of
the foregoing domains in AUD were driven by never- comorbid tobacco use in AUD. Nevertheless, in treatment-
smoking AUD, where both former-smoking and actively seeking PSU who maintained abstinence (other than
smoking AUD showed significantly less recovery than tobacco) for 3 months after their baseline assessment at
never-smoking AUD. Additionally, active smokers showed 1 month of sobriety (Schmidt et al., 2017), we observed
significantly less improvement with increasing age than significant improvements in executive functions, cognitive
never-smoking AUD over 8 months on measures of pro- efficiency and processing speed, working memory, and
cessing speed, learning and memory. At 8 months of reductions in self-reported impulsivity (Dominguez-Salas
abstinence, currently smoking AUD remained inferior to et al., 2016; Rezapour et al., 2016). These improvements
controls and never-smoking AUD on multiple measures, likely aid in treatment adherence and reduce relapse risk.
former smokers performed worse than never-smoking AUD Fine motor skills, learning, and memory, however,
on several tests, but never-smoking AUD were not signif- remained deficient after 4 months of abstinence, especially
icantly different from controls on any measure. Thus, in in smoking PSU. During abstinence, self-reported impul-
this AUD cohort over 8 months of abstinence from alcohol, sivity decreased in PSU, whereas performance on a mea-
smoking status interacted with both abstinence duration and sure of decision-making/risk-taking did not improve,
age to robustly moderate recovery on measures of auditory commensurate with findings for long-term abstinent AUD
verbal and visuospatial learning and memory, as well as (Fein et al., 2004) (but see Loeber et al., 2010). Thus,
processing speed. The above findings were adjusted for although some deficits appear to be more enduring (and
education, estimated premorbid verbal intelligence, lifetime may be potentially premorbid and serve as risk factors for
drinking severity, and medical, psychiatric, and substance development of an addictive disorder (Rezapour et al.,
misuse comorbidities. Importantly, in actively smoking 2016)), PSU showed significant recovery across multiple
AUD, more lifetime years of tobacco use were related to neurocognitive domains over 3 months of sustained absti-
poorer recovery of auditory verbal memory over 8 months nence, despite decades of substance abuse.
of abstinence (Durazzo et al., 2014b). For a discussion of Taken together, significant neurocognitive improve-
smoking-related neurobiological mechanisms potentially ments are generally observed beyond about 1 month of
underlying the differential recovery observed in AUD abstinence in those with SUD, whereas abstinent in-
subgroups, see Durazzo et al. (2010a) and Durazzo et al. dividuals with AUD appear to show a more rapid recovery
(2014a). trajectory. However, the research dedicated to studying the
In studies of neurocognitive recovery during abstinence short-term and long-term neurocognitive recovery in AUD
from substances, neurocognition was largely unchanged is considerably greater than that in SUD, and more longi-
over 1 month of abstinence from methamphetamine (Simon tudinal research is required to more fully explicate the
et al., 2010), but improved somewhat over longer periods course of neurocognitive recovery with abstinence in those
of sustained abstinence (Iudicello et al., 2010). Attention, with SUD. These neurocognitive recoveries during absti-
working memory, declarative memory, and executive nence suggest that the deficits are largely a consequence of
chronic alcohol and/or substance use and the associated individuals (Ersche et al., 2011) (as well as their unaffected
maladaptive lifestyle (i.e., poor diet/nutrition, physical siblings (Ersche et al., 2013)) have all been shown to have
activity, sleep); some persistent deficits may be premorbid enlarged striatal volumes. Additionally, prescription opioid
and may have contributed to initiation of alcohol or sub- analgesics are associated with both decreases and increases
stance abuse in the first place or are related to clinically of regional brain volumes after only 1 month of opioid
significant comorbid conditions. The neurocognitive administration, with many of the changes persisting for
changes during abstinence suggest parallel adaptive neu- 5 months after discontinuation (Younger et al., 2011).
roplasticity, which may present a critical window of Consistent with the above reports on (ostensibly)
opportunity for augmenting recovery in AUD and SUD monosubstance users, structural brain abnormalities have
with plasticity-based neurocognitive remediation, mag- also been described in PSU, who are the largest but most
netic/electric stimulation methods, or targeted pharma- understudied SUD group. Greater years of polysubstance
cology (Rabin et al., 2015; Klein, 2016; Rezapour et al., use were related to lobar cortical and thalamic gray matter
2016), in particular during the initial months of abstinence volume loss (Noyan et al., 2016). In comparison to AUD,
(Durazzo et al., 2014b). The corresponding neurocognitive PSU had larger lobar white matter volumes in the absence
improvements in these individuals (and neurobiology, of the widespread gray matter volume loss typically
discussed next) will likely promote better treatment observed in AUD with comparable lifetime drinking and
responsedas demonstrated for AUD (Bates et al., 2013) smoking histories (Pennington et al., 2015). Furthermore,
dand ultimately longer abstinence. PSU exhibited distinct relationships between regional brain
volumes and processing speed, cognitive efficiency,
Neurobiological abnormalities in addiction working memory, and inhibitory control, which were not
observed in AUD or controls; this suggests potential
Underlying the neurocognitive deficits in AUD and SUD as alterations/compensations in neural circuits of PSU that are
well as their changes with abstinence from alcohol and/or classically associated with the above functional domains.
substances are neurobiological adaptations and their Taken together, neuronal atrophy in PSU may be countered
changes during abstinence. Here, we first review MR-based by the adverse effects of reactive gliosis and neuro-
studies of brain alterations in addiction, followed by review inflammation (as reflected in the subcortical volume
of serial MR studies performed to better understand the enlargements of psychostimulant users), possibly masking
neuroadaptations associated with recovery during absti- atrophy typically observed in AUD.
nence. We focus on descriptions of MR structural and Other neuroimaging methods help assess functional
spectroscopic findings in addiction, with the vast fMRI alterations or neurobiological mechanisms underlying brain
field not covered (but see Charlet et al., 2018). structural alterations in addiction. They include functionally
Magnetic resonance (MR)ebased neuroimaging studies relevant low cerebral blood flow (Rogers et al., 1983;
of individuals with use disorders of alcohol, cocaine, Tunving et al., 1986; Volkow et al., 1988; Nicolas et al.,
amphetamines, marijuana, or tobacco have revealed 1993; Oishi et al., 1999; Ernst et al., 2000b; Gansler et al.,
regional brain atrophy as correlates of neurocognitive 2000; Chang et al., 2002; Hwang et al., 2006; Heinz et al.,
dysfunction (for reviews, see Goldstein and Volkow, 2011; 2009; Murray et al., 2018), altered brain glucose meta-
Wang et al., 2015; Buhler and Mann, 2011; Sneider et al., bolism (Volkow et al., 1993; Volkow et al., 1994; Volkow
2013; Xiao et al., 2015; Sullivan et al., 2018). Atrophy is et al., 2001; Eldreth et al., 2004; Kim et al., 2005), and
observed throughout the brain with a prefrontal preference altered brain metabolite levels measured by proton mag-
and is likely driven by loss of, or damage to, neuronal cell netic resonance spectroscopy (MRS). MRS studies revealed
bodies, dendrites (including dendritic spines, axons/tele- regional metabolic abnormalities in those with alcohol and
dendria/terminal endings as demonstrated neuro- SUDs that are consistent with abnormal markers of
pathologically), and/or glial cells (Crews and Boettiger, neuronal integrity (as measured by lower concentrations of
2009; Zahr et al., 2011). However, abused substances may N-acetylaspartate [NAA] or glutamate [Glu]), cellular
affect brain structures differentially, potentially related to bioenergetics (as indicated by lower concentrations of
the distribution of specific receptors (such as cannabinoid creatine-containing metabolites, Cr), glial or cell membrane
or cholinergic receptors) throughout the brain and/or to the turnover/synthesis (as indicated by altered levels of
heterogeneity of substance use severities across the choline-containing metabolites, Cho), and glial content/
different brain imaging studies published. In addition to gliosis or osmoregulation (as reflected in altered levels of
variable and regionally varying cortical atrophy, psychos- myo-inositol [mI]) (Meyerhoff et al., 1994; Fein et al.,
timulant studies describe enlargement of subcortical struc- 1995; Meyerhoff et al., 1999; Ernst et al., 2000a; O’Neill
tures: For example, methamphetamine users (Chang et al., et al., 2001; Parks et al., 2002; Durazzo et al., 2004; Ke
2007), heavy cannabis users (Moreno-Alcázar et al., 2018; et al., 2004; Meyerhoff et al., 2004; Nordahl et al., 2005;
Nader and Sanchez, 2018), and cocaine-dependent Chang et al., 2007; Hermann et al., 2007; Durazzo et al.,
2008a; Durazzo et al., 2010b; Sailasuta et al., 2010; Prescot in these PSU, GABA tended to be reduced in the ACC, and
et al., 2011; Prescot et al., 2013; Murray et al., 2016) (also lower GABA in the dorsolateral PFC was associated with
reviewed by Meyerhoff et al., 2013). These studies indicate greater cocaine consumption. In contrast, dorsolateral PFC
that alcohol and illicit substances alter regional neuronal metabolite levels and prefrontal GABA levels were normal
integrity, energy metabolism, membrane synthesis/turn- in age-equivalent AUD with similar lifetime drinking his-
over, the metabolic pools of Glu and gamma-aminobutyric tories, and initially low NAA, Cr, and mI levels in the ACC
acid (GABA) that are in equilibrium with their neuro- of these AUD had all normalized by 1 month of abstinence
transmitter pools, and gliotic/inflammatory processes (Yang from alcohol (Mon et al., 2012). As such, metabolite
et al., 2009; Licata and Renshaw, 2010). In several of the alterations appear to be regionally different in abstinent
MRS reports cited here, the brain metabolite abnormalities PSU and AUD, more pronounced in the dorsolateral PFC
correlated with the duration of substance use and neuro- of PSU, which may signal more enduring brain injury
cognitive deficits (e.g., Murray et al., 2016). during abstinence in PSU. The detected metabolite abnor-
Furthermore, in addition to neurocognitive dysfunction malities in PSU were unrelated to age, alcohol consump-
(described above), chronic cigarette smoking also amplifies tion, body mass index, smoking status, as well as comorbid
regional brain metabolite abnormalities observed in AUD depression and anxiety symptomatologies; the abnormal-
(Meyerhoff, 2007; Wang et al., 2009; Durazzo et al., 2013). ities were likely related to the misuse of illicit drugs in
The chronic abuse of different substances is associated with PSU. Such cross-sectional comparisons of brain alterations
tissue alterations in largely similar brain regions, primarily across different substance-using groups suggest slightly
in the prefrontal cortex (PFC), the underlying white matter, different brain injuries and recovery dynamics that suggest
the thalami, and the basal ganglia including striatal struc- better targeted approaches for optimal treatment.
tures (Holman et al., 1991; Volkow et al., 1992; Weber
et al., 1993; Ernst et al., 2000a; Sullivan, 2000; Sullivan Neurobiological changes during abstinence
et al., 2000; Franklin et al., 2002; Matochik et al., 2003;
Eldreth et al., 2004; Thompson et al., 2004; Dom et al., The cross-sectional neuroimaging abnormalities described
2005; Matochik et al., 2005; Nordahl et al., 2005; Bae above were reported to either relate or not relate to absti-
et al., 2006; Hermann et al., 2007; Sorg et al., 2012; Wang nence duration (e.g., Hanlon et al., 2013; Yucel et al.,
et al., 2015; Murray et al., 2016). Specifically, the dorso- 2016); thus, they could be a consequence of alcohol/sub-
lateral PFC is implicated in executive functions involving stance abuse and the associated lifestyle, a premorbid risk
planning and organization, response inhibition, working factor for its development, or both. Only serial studies
memory, reasoning, problem solving, set shifting, and goal- focusing on neurobiological recovery during sustained
directed behavior (e.g., Goldstein and Volkow, 2011). The abstinence can distinguish between these interpretations by
collective subregions of the anterior cingulate cortex (ACC) providing evidence of recovery from brain abnormalities
and orbitofrontal cortex (OFC) combine to subserve pro- during abstinence. Poor subject retention, however
cessing of affective or emotional stimuli or contexts, (Morales et al., 2012; Salo and Fassbender, 2012; Hanlon
conflict monitoring, interoceptive-autonomic and reward- et al., 2013; Mackey and Paulus, 2013), has limited the
processing aspects of reward processing, switching execution of longitudinal neuroimaging studies in treatment
between habitual (overlearned) and goal-directed behavior seekers during abstinence, especially in illicit substance
based on consequences of actions, and reward identification abusers.
and acquisition (Volkow and Baler, 2014; Williams, 2016; The best evidence for beneficial neuroadaptation during
Moorman, 2018). As such, the affected brain regions are all sobriety is available from longitudinal morphometric neu-
critically important for the initiation and maintenance of roimaging studies of treatment seekers abstinent from
addictive behaviors (Volkow et al. 2012, 2013; Volkow alcohol (see reviews by Buhler and Mann, 2011; Meyerh-
and Baler, 2014). off, 2014; Zahr, 2014; Durazzo et al., 2015b; Charlet et al.,
We have also studied the neurobiological consequences 2018). Brain volume increases can be demonstrated by
of polysubstance use via brain MRS. Early studies sug- quantitative MRI within as few as 14 days of abstinence
gested that alcohol-dependent individuals with and without (van Eijk et al., 2013; Durazzo et al., 2015b; Zou et al.,
cocaine dependence differed in their regional metabolite 2018), driven by increases in regional frontal, occipital, and
concentrations and the brain regions primarily affected parietal cortical thickness but not surface area (Wang et al.,
(Meyerhoff et al., 1999). More recent studies compared 2016); reduced subcortical volumes did not recover over
1-month-abstinent PSU to drug-free controls and found the first 2 weeks of abstinence (van Eijk et al., 2013).
lower NAA, Cr, and mI in the dorsolateral PFC of PSU, Volume increases were also observed over a 6-month
with lower prefrontal NAA in PSU related to poorer follow-up period in a few select brain regions (including
visuospatial learning/memory and working memory cerebellar vermis and cingulate gyrus) in those who did not
(Abé et al., 2013). While prefrontal Glu levels were normal manage to achieve complete abstinence (i.e., those who
engaged in some low-level drinking after treatment with no dependent treatment seekers, PFC volume recovered
resumption of heavy consumption) (Segobin et al., 2014), between months 5 and 9 of abstinence; increases in inferior
supporting the harm reduction theory in AUD treatment. frontal gyrus as well as ventromedial PFC volumes were
Hippocampal volume recovery within the first month of associated with improvements in cognitive flexibility and
alcohol abstinence was a function of brain-derived neuro- decision-making, respectively (Parvaz et al., 2017). In this
trophic factor genotype (Hoefer et al., 2014) and associated study, lapses did not necessarily impede cortical volume
with improvements in visual short- and long-term memory recovery. Similarly, reducing (not ceasing) cocaine use in
(Gazdzinski et al., 2008). When investigated, repeat studies heavy users over 19 months was associated with thickening
in abstinent individuals often indicate positive associations of the lateral frontal cortices that related to better attention
between volumetric and neurocognitive recoveries (Hirsiger et al., 2019). These latter studies lend initial
(Durazzo and Meyerhoff, 2007; Meyerhoff, 2008). support for a harm reduction model also in cocaine use
Almost all longitudinal neuroimaging studies in addic- disorder treatment.
tion involved one follow-up examination after a few weeks In unpublished neuroimaging studies of 20 PSU
of abstinence; only a few studies used at least three patients between 1 and 4 months of abstinence (a subgroup
assessment points (Pfefferbaum et al., 1995; Agartz et al., of individuals described in the cross-sectional PSU neuro-
2003; Gazdzinski et al., 2005a; Yeh et al., 2007; Hoefer imaging analyses above) (Pennington et al., 2015), we
et al., 2014; Durazzo et al., 2015b; Zou et al., 2018) to found evidence for widespread volumetric change also in
investigate the trajectory of brain volume recovery over a individuals who co-abused alcohol and stimulants for more
longer period of abstinence from alcohol. In an early study than 20 years: an increase in left caudate volume, a
of the temporal dynamics of volume recovery (Gazdzinski decrease in right superior temporal lobe volume, and trends
et al., 2005a), we observed that approximately 50% of the to decreasing insula and entorhinal cortex volumes
tissue volume recovery of the entire brain over v(unpublished). These changes, however, were much less
7e12 months of continuous abstinence occurred during the dramatic than observed in short-term abstinent AUD
first month of abstinence. We also showed that a nonlinear described above. Given that abnormalities in PSU involved
mathematical formula predicted very well the experimen- both smaller and larger regional tissue volumes (purport-
tally observed data for lobar gray and white matter volume edly from competing neural mechanismsdsee cross-
changes (Mon et al., 2011). Further analyses of structural sectional review above), observing both volume increases
imaging data from a similar cohort (Durazzo et al., 2015b) and decreases across different brain regions during sus-
revealed that gray matter volumes increased significantly in tained abstinence is not surprising and may relate to the
the frontal, parietal, and occipital lobes of AUD between competing morphometric processes and altered functional
1 week and 7.5 months of abstinence. However, the connectivity postulated among these brain regions.
monthly gray matter volume change rates of the frontal and Longitudinal MRS studies have been used to try to
parietal lobes were significantly greater between 1 week further understand the tissue changes that underlie volume
and 1 month of abstinence than between 1 and 7.5 months changes during recovery. We showed in a series of studies
of abstinence, suggesting a nonlinear gray matter volume in recovering AUD that after correcting for parallel tissue
recovery trajectory with faster recovery in earlier phases of volume changes, NAA and Cho concentrations throughout
sobriety. In a follow-up study, we observed that the func- the brain recovered significantly, but variably over 5 weeks
tionally distinct dorsolateral PFC, OFC, and insula had of abstinence, with some of the metabolite changes related
nonlinear volume recovery trajectories over long-term to improvements in specific neurocognitive domains
abstinence, whereas the trajectories for the ACC and hip- (Durazzo et al., 2006a, Gazdzinski et al. 2008). The brain
pocampus were linear over the entire observation period metabolite recovery was generally greater in nonsmoking
(Zou et al., 2018). This gray matter plasticity apparent than smoking AUD (Meyerhoff, 2007), with less frontal
during alcohol abstinence and its timing may have impor- white matter NAA recovery related to longer smoking
tant treatment implications. Specifically, the degree of duration (Durazzo et al., 2006a). In an MRS study of
regional structural recovery during early and later phases of recently abstinent methamphetamine abusers, low Glu in
abstinence may identify those at increased risk for relapse ACC recovered over 5 months of abstinence, together with
and inform the type and timing of interventions that pro- a reduction of craving (Ernst and Chang, 2008). Over just
mote the most efficient adaptive neuroplasticity during 4 weeks of abstinence, however, prefrontal NAA and Cho
early recovery (Seo and Sinha, 2015; Seo et al., 2015; in intravenous methamphetamine users did not change
Durazzo and Meyerhoff, 2017). significantly (Yoon et al., 2010), in contrast to observations
Methamphetamine-dependent individuals showed in short-term abstinent AUD. In our small cohort of absti-
volume increases in inferior frontal, angular, and superior nent PSU, regional metabolite concentrations recovered
temporal gyri, precuneus, insula, and occipital pole over between 1 and 3 months of abstinence to levels commen-
4 weeks of abstinence (Morales et al., 2012). In cocaine- surate with controls (unpublished). Specifically, NAA and
Cho in the dorsolateral PFC and GABA and NAA in the injury and recovery in AUD. Finally, a critical determinant
ACC significantly increased, while Glu and mI in the ACC of brain injury is the age of onset of substance use, with
and mI in the parieto-occipital gray matter decreased; the substance-associated brain changes in adolescents being
NAA increases in ACC and dorsolateral PFC correlated different both qualitatively and quantitatively from those in
with improvements in visuospatial learning and working adults, as they likely interact with brain development.
memory, respectively. Studying the effects of substance use cessation in the
The observed brain tissue volume and metabolite level developing brain is in its infancy, with the current
changes during abstinence from alcohol and/or substances Adolescent Brain Cognitive Development (ABCD) Study,
may partially reflect the reversal of maladaptive neuro- a longitudinal, observational study of over 10,000 youth
plastic processes associated with chronic long-term alcohol/ recruited throughout the United States, promising to
substance abuse (Koob, 2009). While initial significant address this issue.
neurobiological changes have been observed within the first
month of abstinence in AUD, fewer studies describe such
early processes in illicit substance users, reminiscent of the
Conclusions and outlook
dynamics of potentially related neurocognitive improve- Given these many modulators of neurobiology in alcohol
ments (see above). Neurobiological improvements are and SUDs, some of which are also risk factors for relapse
observable over many months, even years after initiation of (Durazzo et al., 2010b; Rando et al., 2011; Seo and Sinha,
abstinence. They are likely not the result of a single neural 2015; Seo et al., 2015; Durazzo and Meyerhoff, 2017),
process but of several different processes involving neurobiological and neurocognitive recovery with absti-
different cell types and populations to various degreesd nence from alcohol and other substances is complex and
sometimes potentially with opposing effects on regional not trivial to study and interpret in a meaningful way. Even
MR-based outcome measures and with various temporal more challenging will be to incorporate some of these
dynamics. Given the demonstrated associations between research findings into clinical practice. One successful
neurobiological and neurocognitive measures, this may example of such development is the emerging integration
give rise to the relatively large variability observed for of smoking cessation into substance abuse treatment: to-
neurocognitive recovery across different substance-using bacco use, a significant but modifiable health risk for both
groups and among individuals in the same substance- relapse and common psychiatric comorbidities in AUD, has
using group during abstinence. Data from humans and a greater annual mortality than SUD and AUD combined,
animal models suggest the tissue volume recovery in AUD and we can ill afford to continue ignoring it in addiction
during early and extended abstinence is related to increases treatment (Weinberger et al., 2015). It has been demon-
in neuronal dendritic arbor, soma/cell volume, synaptic strated that treating tobacco use effectively in those seeking
density, nonreactive glial proliferation (particularly micro- treatment for their (other) substance abuse may promote
glia), and remyelination (e.g., Dlugos and Pentney, 1997; better long-term outcomes (Kalman et al., 2010; Cavazos-
Sullivan and Pfefferbaum, 2005; Crews and Nixon, 2009; Rehg et al., 2014; Durazzo and Meyerhoff, 2017). But
Anderson, 2011; Zatorre et al., 2012), which are all our efforts cannot end here, as newer forms of nicotine
intrinsic neuroadaptations that are also instrumental in delivery (e.g., vaping/e-cigarettes) also need to be consid-
experience-based learning and memory (Anderson, 2011; ered carefully regarding their addictive and brain-altering
Zatorre et al., 2012). The metabolite concentration changes potentials.
that often accompany morphometric changes during Despite the seemingly overwhelming complexities in
abstinence may also be related to these mechanisms. studying brain function, morphometry, and recovery in
Clinically relevant modulators of the degree of regional human addiction, demonstrating specific neuroadaptations
volume reduction in adult AUD and of the extent of after detoxification, their time courses, and their depen-
structural recovery during abstinence have been identified; dence on critical modulators are important for several rea-
they include age, gender, family history of problem sons: (1) There might be an optimal window of opportunity
drinking and genetic factors, degree of baseline atrophy, for augmenting such intrinsic neurobiological repair pro-
number of detoxifications, and comorbid medical (hepatitis cesses (neuroplasticity) via interventions such as plasticity-
C and hypertension), psychiatric (depression, anxiety), and based cognitive remediation, magnetic/electrical stimula-
SUDs including tobacco use disorder (Duka et al., 2003; tion, or pharmacotherapy; (2) many neurocognitive deficits
Cardenas et al. 2005, 2007; Gazdzinski et al., 2005b; and/or their neurobiological correlates are not premorbid/
Durazzo et al., 2007a,b; Demirakca et al., 2011; Mon et al., risk factors of abuse, but rather consequences of abuse, and
2013; Hoefer et al., 2014; Pennington et al., 2015; Durazzo brain function and tissue integrity can improve with
and Meyerhoff, 2017; Sullivan et al., 2018). The same sustained abstinence; and (3) relapse risk likely decreases
factors as well as stress and stress response (Blaine and over time with abstinence as brain neurobiology and
Sinha, 2017) also modulate metabolic and functional brain functions recover from injury (adaptive neuroplasticity).
Identifying the specific neurobiological mechanisms asso- Bae, S.C., Lyoo, I.K., Sung, Y.H., Yoo, J., Chung, A., Yoon, S.J., et al.,
ciated with such improvements, their mitigating factors, 2006. Increased white matter hyperintensities in male methamphet-
time courses, and trajectories can critically inform amine abusers. Drug Alcohol Depend. 81 (1), 83e88.
Bates, M.E., Buckman, J.F., Nguyen, T.T., 2013. A role for cognitive
interventions aimed at facilitating brain repair and recovery
rehabilitation in increasing the effectiveness of treatment for alcohol
processes, such as strengthening prefrontal neural connec-
use disorders. Neuropsychol. Rev. 23 (1), 27e47. https://doi.org/
tivity or employing GABAergic therapy to improve 10.1007/s11065-013-9228-3.
inhibitory control. A recent opinion piece (Humphreys and Bernardin, F., Maheut-Bosser, A., Paille, F., 2014. Cognitive impairments
Bickel, 2018) calls for “expanding and deepening the in alcohol-dependent subjects. Front. Psychiatry 5, 78. https://doi.org/
neuroscience of recovery from addiction” to improve 10.3389/fpsyt.2014.00078.
addiction-focused clinical care and public policy. In that Blaine, S.K., Sinha, R., 2017. Alcohol, stress, and glucocorticoids: from
spirit, we hope that this chapter contributes to describing a risk to dependence and relapse in alcohol use disorders. Neurophar-
critical part of the current state of addiction recovery macology 122, 136e147. https://doi.org/10.1016/
research. j.neuropharm.2017.01.037.
Finally, it is noteworthy that all recovery research Block, R.I., Erwin, W.J., Ghoneim, M.M., 2002. Chronic drug use and
cognitive impairments. Pharmacol. Biochem. Behav. 73 (3),
described in this chapter has been conducted in individuals
491e504.
having (ostensibly) achieved complete abstinence from
Bolla, K.I., Funderburk, F.R., Cadet, J.L., 2000. Differential effects of
alcohol and other substances. Research has rarely examined cocaine and cocaine alcohol on neurocognitive performance.
psychological or physical functioning in moderation- Neurology 54 (12), 2285e2292.
focused treatment approaches (see, e.g., Witkiewitz et al., Brody, A.L., 2006. Functional brain imaging of tobacco use and depen-
2019). Given the increasing consideration of treatment dence. J. Psychiatr. Res. 40 (5), 404e418.
outcome endpoints other than complete abstinence, future Buhler, M., Mann, K., 2011. Alcohol and the human brain: a systematic
research will almost certainly be conducted to better un- review of different neuroimaging methods. Alcohol Clin. Exp. Res. 35
derstand the degree of neurobiological recovery associated (10), 1771e1793. https://doi.org/10.1111/j.1530-0277.2011.01540.x.
with reduced substance use (harm reduction from Cardenas, V.A., Studholme, C., Gazdzinski, S., Durazzo, T.C.,
nonabstinence-based recovery). Additional research might Meyerhoff, D.J., 2007. Deformation-based morphometry of brain
changes in alcohol dependence and abstinence. Neuroimage 34 (3),
focus on recovery processes that go beyond the standard
879e887.
treatment durations of several months described here, to
Cardenas, V.A., Studholme, C., Meyerhoff, D.J., Song, E., Weiner, M.W.,
better understand neuropsychological and neurobiological 2005. Chronic active heavy drinking and family history of problem
factors associated with sustained recovery in later years drinking modulate regional brain tissue volumes. Psychiatr. Res. 138
when treated individuals remain at some degree of relapse (2), 115e130.
risk. Cavazos-Rehg, P.A., Breslau, N., Hatsukami, D., Krauss, M.J.,
Spitznagel, E.L., Grucza, R.A., et al., 2014. Smoking cessation is
associated with lower rates of mood/anxiety and alcohol use disorders.
References Psychol. Med. 44 (12), 2523e2535. https://doi.org/10.1017/
Abé, C., Mon, A., Durazzo, T.C., Pennington, D.L., Schmidt, T.P., s0033291713003206.
Meyerhoff, D.J., 2013. Polysubstance and alcohol dependence: unique Chang, L., Alicata, D., Ernst, T., Volkow, N., 2007. Structural and
abnormalities of magnetic resonance-derived brain metabolite levels. metabolic brain changes in the striatum associated with metham-
Drug Alcohol Depend. 130 (1e3), 30e37. https://doi.org/10.1016/ phetamine abuse. Addiction 102 (Suppl. 1), 16e32. https://doi.org/
j.drugalcdep.2012.10.004. 10.1111/j.1360-0443.2006.01782.x.
Agartz, I., Brag, S., Franck, J., Hammarberg, A., Okugawa, G., Chang, L., Ernst, T., Speck, O., Patel, H., DeSilva, M., Leonido-Yee, M.,
Svinhufvud, K., Bergman, H., 2003. Mr volumetry during acute Miller, E.N., 2002. Perfusion MRI and computerized cognitive test
alcohol withdrawal and abstinence: a descriptive study. Alcohol abnormalities in abstinent methamphetamine users. Psychiatr. Res.
Alcohol. 38 (1), 71e78. 114 (2), 65e79.
Aharonovich, E., Hasin, D.S., Brooks, A.C., Liu, X., Bisaga, A., Charlet, K., Rosenthal, A., Lohoff, F.W., Heinz, A., Beck, A., 2018. Im-
Nunes, E.V., 2006. Cognitive deficits predict low treatment retention aging resilience and recovery in alcohol dependence. Addiction 113
in cocaine dependent patients. Drug Alcohol Depend. 81 (3), (10), 1933e1950. https://doi.org/10.1111/add.14259.
313e322. https://doi.org/10.1016/j.drugalcdep.2005.08.003. Crews, F.T., Boettiger, C.A., 2009. Impulsivity, frontal lobes and risk for
Almeida, O.P., Garrido, G.J., Lautenschlager, N.T., Hulse, G.K., addiction. Pharmacol. Biochem. Behav. 93 (3), 237e247. https://
Jamrozik, K., Flicker, L., 2008. Smoking is associated with reduced doi.org/10.1016/j.pbb.2009.04.018.
cortical regional gray matter density in brain regions associated with Crews, F.T., Nixon, K., 2009. Mechanisms of neurodegeneration and
incipient Alzheimer disease. Am. J. Geriatr. Psychiatry 16 (1), regeneration in alcoholism. Alcohol Alcohol. 44 (2), 115e127. https://
92e98. doi.org/10.1093/alcalc/agn079 agn079 [pii].
Anderson, B.J., 2011. Plasticity of gray matter volume: the cellular and de Wit, H., 2009. Impulsivity as a determinant and consequence of drug
synaptic plasticity that underlies volumetric change. Dev. Psychobiol. use: a review of underlying processes. Addict. Biol. 14 (1), 22e31.
53 (5), 456e465. https://doi.org/10.1002/dev.20563. https://doi.org/10.1111/j.1369-1600.2008.00129.x.
Demirakca, T., Ende, G., Kammerer, N., Welzel-Marquez, H., Durazzo, T.C., Meyerhoff, D.J., 2017. Psychiatric, demographic, and brain
Hermann, D., Heinz, A., Mann, K., 2011. Effects of alcoholism and morphological predictors of relapse after treatment for an alcohol use
continued abstinence on brain volumes in both genders. Alcohol Clin. disorder. Alcohol Clin. Exp. Res. 41 (1), 107e116. https://doi.org/
Exp. Res. 35 (9), 1678e1685. https://doi.org/10.1111/j.1530- 10.1111/acer.13267.
0277.2011.01514.x. Durazzo, T.C., Meyerhoff, D.J., Nixon, S.J., 2010a. Chronic cigarette
Di Sclafani, V., Bloomer, C., Clark, H., Norman, D., Hannauer, D., smoking: implications for neurocognition and brain neurobiology. Int.
Fein, G., 1998. Abstinent chronic cocaine and cocaine/alcohol abusers J. Environ. Res. Public Health 7 (10), 3760e3791. https://doi.org/
evidence normal hippocampal volumes on MRI despite cognitive 10.3390/ijerph7103760.
impairments. Addict. Biol. 3, 261e270. Durazzo, T.C., Mon, A., Gazdzinski, S., Meyerhoff, D.J., 2011. Chronic
Dlugos, C.A., Pentney, R.J., 1997. Morphometric evidence that the total cigarette smoking in alcohol dependence: associations with cortical
number of synapses on Purkinje neurons of old F344 rats is reduced thickness and N-acetylaspartate levels in the extended brain reward
after long-term ethanol treatment and restored to control levels after system. Addict. Biol. 18 (2), 379e391. https://doi.org/10.1111/j.1369-
recovery. Alcohol Alcohol. 32 (2), 161e172. 1600.2011.00407.x.
Dom, G., Sabbe, B., Hulstijn, W., van den Brink, W., 2005. Substance use Durazzo, T.C., Mon, A., Gazdzinski, S., Meyerhoff, D.J., 2013a. Chronic
disorders and the orbitofrontal cortex: systematic review of behavioral cigarette smoking in alcohol dependence: associations with cortical
decision-making and neuroimaging studies. Br. J. Psychiatry 187, thickness and N-acetylaspartate levels in the extended brain reward
209e220. system. Addict. Biol. 18 (2), 379e391. https://doi.org/10.1111/j.1369-
Dominguez-Salas, S., Diaz-Batanero, C., Lozano-Rojas, O.M., Verdejo- 1600.2011.00407.x.
Garcia, A., 2016. Impact of general cognition and executive func- Durazzo, T.C., Mon, A., Gazdzinski, S., Yeh, P.H., Meyerhoff, D.J.,
tion deficits on addiction treatment outcomes: systematic review and 2015b. Serial longitudinal magnetic resonance imaging data indicate
discussion of neurocognitive pathways. Neurosci. Biobehav. Rev. 71, non-linear regional gray matter volume recovery in abstinent alcohol-
772e801. https://doi.org/10.1016/j.neubiorev.2016.09.030. dependent individuals. Addict. Biol. 20 (5), 956e967. https://doi.org/
Duka, T., Townshend, J.M., Collier, K., Stephens, D.N., 2003. Impairment 10.1111/adb.12180.
in cognitive functions after multiple detoxifications in alcoholic in- Durazzo, T.C., Mon, A., Pennington, D., Abe, C., Gazdzinski, S.,
patients. Alcohol Clin. Exp. Res. 27 (10), 1563e1572. Meyerhoff, D.J., 2014a. Interactive effects of chronic cigarette
Durazzo, T., Insel, P.S., Weiner, M.W., The Alzheimer’s Disease Neu- smoking and age on brain volumes in controls and alcohol-dependent
roimaging Initiative, A., 2012. Greater regional brain atrophy rate in individuals in early abstinence. Addict. Biol. 19 (1), 132e143. https://
healthy elders with a history of cigarette smoking. Alzheimer’s doi.org/10.1111/j.1369-1600.2012.00492.x.
Dement. 8, 513e519. Durazzo, T.C., Pathak, V., Gazdzinski, S., Mon, A., Meyerhoff, D.J.,
Durazzo, T., Mattsson, N., Weiner, M., 2015. Interaction of Cigarette 2010b. Metabolite levels in the brain reward pathway discriminate
Smoking History With APOE Genotype and Age on Amyloid Level, those who remain abstinent from those who resume hazardous alcohol
Glucose Metabolism, and Neurocognition in Cognitively Normal El- consumption after treatment for alcohol dependence. J. Stud. Alcohol
ders, vol. 4. Drugs 71 (2), 278e289.
Durazzo, T.C., Cardenas, V.A., Studholme, C., Weiner, M.W., Durazzo, T.C., Pennington, D.L., Schmidt, T.P., Meyerhoff, D.J., 2014b.
Meyerhoff, D.J., 2007a. Non-treatment-seeking heavy drinkers: ef- Effects of cigarette smoking history on neurocognitive recovery over
fects of chronic cigarette smoking on brain structure. Drug Alcohol 8 months of abstinence in alcohol-dependent individuals. Alcohol Clin.
Depend. 87 (1), 76e82. Exp. Res. 38 (11), 2816e2825. https://doi.org/10.1111/acer.12552.
Durazzo, T.C., Gazdzinski, S., Banys, P., Meyerhoff, D.J., 2004. Cigarette Durazzo, T.C., Pennington, D.L., Schmidt, T.P., Mon, A., Abe, C.,
smoking exacerbates chronic alcohol-induced brain damage: a pre- Meyerhoff, D.J., 2013. Neurocognition in 1-month-abstinent
liminary metabolite imaging study. Alcohol Clin. Exp. Res. 28 (12), treatment-seeking alcohol-dependent individuals: interactive effects of
1849e1860. age and chronic cigarette smoking. Alcohol Clin. Exp. Res. 37 (10),
Durazzo, T.C., Gazdzinski, S., Banys, P., Meyerhoff, D.J., 2006a. Brain 1794e1803. https://doi.org/10.1111/acer.12140.
metabolite concentrations and neurocognition during short-term re- Durazzo, T.C., Rothlind, J.C., Gazdzinski, S., Banys, P., Meyerhoff, D.J.,
covery from alcohol dependence: preliminary evidence of the effects 2006b. A comparison of neurocognitive function in nonsmoking and
of concurrent chronic cigarette smoking. Alcohol. Clin. Exp. Res. 30 chronically smoking short-term abstinent alcoholics. Alcohol 39 (1), 1e11.
(3), 539e551. Durazzo, T.C., Rothlind, J.C., Gazdzinski, S., Meyerhoff, D.J., 2008b. The
Durazzo, T.C., Gazdzinski, S., Meyerhoff, D.J., 2007b. The neurobio- relationships of sociodemographic factors, medical, psychiatric, and
logical and neurocognitive consequences of chronic cigarette smoking substance-misuse co-morbidities to neurocognition in short-term
in alcohol use disorders. Alcohol Alcohol. 42 (3), 174e185. abstinent alcohol-dependent individuals. Alcohol 42 (6), 439e449.
Durazzo, T.C., Gazdzinski, S., Yeh, P.H., Meyerhoff, D.J., 2008a. Com- https://doi.org/10.1016/j.alcohol.2008.06.001. S0741-8329(08)00247-
bined neuroimaging, neurocognitive and psychiatric factors to predict 4 [pii].
alcohol consumption following treatment for alcohol dependence. Eldreth, D.A., Matochik, J.A., Cadet, J.L., Bolla, K.I., 2004. Abnormal
Alcohol Alcohol. 43 (6), 683e691. https://doi.org/10.1093/alcalc/ brain activity in prefrontal brain regions in abstinent marijuana users.
agn078 agn078 [pii]. Neuroimage 23 (3), 914e920.
Durazzo, T.C., Meyerhoff, D.J., 2007. Neurobiological and neurocognitive Ernst, T., Chang, L., 2008. Adaptation of brain glutamate plus glutamine
effects of chronic cigarette smoking and alcoholism. Front. Biosci. 12, during abstinence from chronic methamphetamine use.
4079e4100. J. Neuroimmune Pharmacol. 3 (3), 165e172. https://doi.org/10.1007/
s11481-008-9108-4.
Ernst, T., Chang, L., Leonido-Yee, M., Speck, O., 2000a. Evidence for Giorgi, I., Ottonello, M., Vittadini, G., Bertolotti, G., 2015. Psychological
long-term neurotoxicity associated with methamphetamine abuse: a changes in alcohol-dependent patients during a residential rehabilita-
1H MRS study. Neurology 54 (6), 1344e1349. tion program. Neuropsychiatr. Dis. Treat. 11, 2989e2996. https://
Ernst, T., Chang, L., Oropilla, G., Gustavson, A., Speck, O., 2000b. Ce- doi.org/10.2147/NDT.S93520.
rebral perfusion abnormalities in abstinent cocaine abusers: a perfu- Glass, J.M., Adams, K.M., Nigg, J.T., Wong, M.M., Puttler, L.I., Buu, A.,
sion MRI and SPECT study. Psychiatr. Res. 99 (2), 63e74. et al., 2006. Smoking is associated with neurocognitive deficits in
Ersche, K.D., Barnes, A., Jones, P.S., Morein-Zamir, S., Robbins, T.W., alcoholism. Drug Alcohol Depend. 82 (2), 119e126.
Bullmore, E.T., 2011. Abnormal structure of frontostriatal brain sys- Goldstein, R.Z., Leskovjan, A.C., Hoff, A.L., Hitzemann, R., Bashan, F.,
tems is associated with aspects of impulsivity and compulsivity in Khalsa, S.S., et al., 2004. Severity of neuropsychological impairment
cocaine dependence. Brain 134 (Pt 7), 2013e2024. https://doi.org/ in cocaine and alcohol addiction: association with metabolism in the
10.1093/brain/awr138. prefrontal cortex. Neuropsychologia 42 (11), 1447e1458.
Ersche, K.D., Jones, P.S., Williams, G.B., Smith, D.G., Bullmore, E.T., Goldstein, R.Z., Volkow, N.D., 2011. Dysfunction of the prefrontal cortex
Robbins, T.W., 2013. Distinctive personality traits and neural corre- in addiction: neuroimaging findings and clinical implications. Nat.
lates associated with stimulant drug use versus familial risk of stim- Rev. Neurosci. 12 (11), 652e669. https://doi.org/10.1038/nrn3119.
ulant dependence. Biol. Psychiatry 74 (2), 137e144. https://doi.org/ Hanlon, C.A., Beveridge, T.J., Porrino, L.J., 2013. Recovering from
10.1016/j.biopsych.2012.11.016. cocaine: insights from clinical and preclinical investigations. Neuro-
Fein, G., Di Sclafani, V., Meyerhoff, D.J., 2002. Prefrontal cortical volume sci. Biobehav. Rev. 37 (9), 2037e2046. https://doi.org/10.1016/
reduction associated with frontal cortex function deficit in 6-week j.neubiorev.2013.04.007. S0149-7634(13)00103-6 [pii].
abstinent crack-cocaine dependent men. Drug Alcohol Depend. 68 Hasin, D.S., Grant, B.F., 2015. The national epidemiologic survey on
(1), 87e93. alcohol and related conditions (NESARC) waves 1 and 2: review and
Fein, G., Klein, L., Finn, P., 2004. Impairment on a simulated gambling summary of findings. Soc. Psychiatry Psychiatr. Epidemiol. 50 (11),
task in long-term abstinent alcoholics. Alcohol Clin. Exp. Res. 28 1609e1640. https://doi.org/10.1007/s00127-015-1088-0.
(10), 1487e1491. Heinz, A., Beck, A., Grusser, S.M., Grace, A.A., Wrase, J., 2009. Iden-
Fein, G., Meyerhoff, D.J., Weiner, M.W., 1995. Magnetic resonance tifying the neural circuitry of alcohol craving and relapse vulnera-
spectroscopy of the brain in alcohol abuse. Alcohol Health Res. World bility. Addict. Biol. 14 (1), 108e118. https://doi.org/10.1111/j.1369-
19 (4), 306e314. 1600.2008.00136.x. ADB136 [pii].
Fernandez-Serrano, M.J., Perez-Garcia, M., Schmidt Rio-Valle, J., Hermann, D., Sartorius, A., Welzel, H., Walter, S., Skopp, G., Ende, G.,
Verdejo-Garcia, A., 2010. Neuropsychological consequences of Mann, K., 2007. Dorsolateral prefrontal cortex N-acetylaspartate/total
alcohol and drug abuse on different components of executive func- creatine (NAA/tCr) loss in male recreational cannabis users. Biol.
tions. J. Psychopharmacol. 24 (9), 1317e1332. https://doi.org/ Psychiatry 61 (11), 1281e1289.
10.1177/0269881109349841. Hirsiger, S., Hanggi, J., Germann, J., Vonmoos, M., Preller, K.H.,
Fernandez-Serrano, M.J., Perez-Garcia, M., Verdejo-Garcia, A., 2011. Engeli, E.J.E., et al., 2019. Longitudinal changes in cocaine intake and
What are the specific vs. generalized effects of drugs of abuse on cognition are linked to cortical thickness adaptations in cocaine users.
neuropsychological performance? Neurosci. Biobehav. Rev. 35 (3), Neuroimage Clin. 101652. https://doi.org/10.1016/j.nicl.2019.101652.
377e406. https://doi.org/10.1016/j.neubiorev.2010.04.008. S0149- Hoefer, M.E., Pennington, D.L., Durazzo, T.C., Mon, A., Abe, C.,
7634(10)00092-8 [pii]. Truran, D., et al., 2014. Genetic and behavioral determinants of hip-
Franklin, T.R., Acton, P.D., Maldjian, J.A., Gray, J.D., Croft, J.R., pocampal volume recovery during abstinence from alcohol. Alcohol
Dackis, C.A., et al., 2002. Decreased gray matter concentration in the 48 (7), 631e638. https://doi.org/10.1016/j.alcohol.2014.08.007.
insular, orbitofrontal, cingulate, and temporal cortices of cocaine pa- Holman, B.L., Carvalho, P.A., Mendelson, J., Teoh, S.K., Nardin, R.,
tients. Biol. Psychiatry 51 (2), 134e142. Hallgring, E., et al., 1991. Brain perfusion is abnormal in cocaine-
Gansler, D.A., Harris, G.J., Oscar-Berman, M., Streeter, C., Lewis, R.F., dependent polydrug users: a study using technetium-99m-HMPAO
Ahmed, I., Achong, D., 2000. Hypoperfusion of inferior frontal brain and ASPECT. J. Nucl. Med. 32 (6), 1206e1210.
regions in abstinent alcoholics: a pilot SPECT study. J. Stud. Alcohol Humphreys, K., Bickel, W.K., 2018. Toward a neuroscience of long-term
61 (1), 32e37. recovery from addiction. JAMA Psychiatry 75 (9), 875e876. https://
Gazdzinski, S., Durazzo, T., Jahng, G.H., Ezekiel, F., Banys, P., doi.org/10.1001/jamapsychiatry.2018.0956.
Meyerhoff, D., 2006. Effects of chronic alcohol dependence and Hwang, J., Lyoo, I.K., Kim, S.J., Sung, Y.H., Bae, S., Cho, S.N., et al.,
chronic cigarette smoking on cerebral perfusion: a preliminary mag- 2006. Decreased cerebral blood flow of the right anterior cingulate
netic resonance study. Alcohol Clin. Exp. Res. 30 (6), 947e958. cortex in long-term and short-term abstinent methamphetamine users.
Gazdzinski, S., Durazzo, T.C., Meyerhoff, D.J., 2005a. Temporal dynamics Drug Alcohol Depend. 82 (2), 177e181.
and determinants of whole brain tissue volume changes during recovery Iudicello, J.E., Woods, S.P., Vigil, O., Scott, J.C., Cherner, M.,
from alcohol dependence. Drug Alcohol Depend. 78 (3), 263e273. Heaton, R.K., et al., 2010. Longer term improvement in neuro-
Gazdzinski, S., Durazzo, T.C., Studholme, C., Song, E., Banys, P., cognitive functioning and affective distress among methamphet-
Meyerhoff, D.J., 2005b. Quantitative brain MRI in alcohol depen- amine users who achieve stable abstinence. J. Clin. Exp.
dence: preliminary evidence for effects of concurrent chronic cigarette Neuropsychol. 32 (7), 704e718. https://doi.org/10.1080/
smoking on regional brain volumes. Alcohol Clin. Exp. Res. 29 (8), 13803390903512637, 919610692 [pii].
1484e1495. Kalman, D., Kim, S., DiGirolamo, G., Smelson, D., Ziedonis, D., 2010.
Gazdzinski, S., Durazzo, T.C., Yeh, P.H., Hardin, D., Banys, P., Addressing tobacco use disorder in smokers in early remission from
Meyerhoff, D.J., 2008. Chronic cigarette smoking modulates injury alcohol dependence: the case for integrating smoking cessation ser-
and short-term recovery of the medial temporal lobe in alcoholics. vices in substance use disorder treatment programs. Clin. Psychol.
Psychiatr. Res. 162 (2), 133e145. https://doi.org/10.1016/j.pscy- Rev. 30 (1), 12e24. https://doi.org/10.1016/j.cpr.2009.08.009.
chresns.2007.04.003. S0925-4927(07)00086-8 [pii].
Ke, Y., Streeter, C.C., Nassar, L.E., Sarid-Segal, O., Hennen, J., Yurgelun- Meyerhoff, D.J., Durazzo, T.C., Ende, G., 2013. Chronic alcohol con-
Todd, D.A., et al., 2004. Frontal lobe GABA levels in cocaine sumption, abstinence and relapse: brain proton magnetic resonance
dependence: a two-dimensional, J-resolved magnetic resonance spectroscopy studies in animals and humans. Behavioral Neurobi-
spectroscopy study. Psychiatr. Res. 130 (3), 283e293. ology of Alcohol Addiction. Springer, pp. 511e540.
Kim, S.J., Lyoo, I.K., Hwang, J., Sung, Y.H., Lee, H.Y., Lee, D.S., et al., Meyerhoff, D.J., MacKay, S., Weiner, M.W., Fein, G., 1994. Reduced
2005. Frontal glucose hypometabolism in abstinent methamphetamine Phospholipid Resonances in Chronic Alcoholics. Paper presented at
users. Neuropsychopharmacology 30 (7), 1383e1391. the Research Society on Alcoholism Meeting.
Klein, J.W., 2016. Pharmacotherapy for substance use disorders. Med. Mon, A., Delucchi, K., Durazzo, T.C., Gazdzinski, S., Meyerhoff, D.J.,
Clin. North Am. 100 (4), 891e910. https://doi.org/10.1016/ 2011. A mathematical formula for prediction of gray and white matter
j.mcna.2016.03.011. volume recovery in abstinent alcohol dependent individuals. Psychi-
Koob, G.F., 2009. Neurobiological substrates for the dark side of atry Res. 194 (2), 198e204. https://doi.org/10.1016/
compulsivity in addiction. Neuropharmacology 56 (Suppl. 1), 18e31. j.pscychresns.2011.05.003.
https://doi.org/10.1016/j.neuropharm.2008.07.043. Mon, A., Durazzo, T.C., Gazdzinski, S., Hutchison, K.E., Pennington, D.,
Le Berre, A.P., Fama, R., Sullivan, E.V., 2017. Executive functions, Meyerhoff, D.J., 2013. Brain-derived neurotrophic factor genotype is
memory, and social cognitive deficits and recovery in chronic alco- associated with brain gray and white matter tissue volumes recovery in
holism: a critical review to inform future research. Alcohol Clin. Exp. abstinent alcohol-dependent individuals. Genes Brain Behav. 12 (1),
Res. 41 (8), 1432e1443. https://doi.org/10.1111/acer.13431. 98e107. https://doi.org/10.1111/j.1601-183X.2012.00854.x.
Licata, S.C., Renshaw, P.F., 2010. Neurochemistry of drug action: insights Mon, A., Durazzo, T.C., Meyerhoff, D.J., 2012. Glutamate, GABA, and
from proton magnetic resonance spectroscopic imaging and their other cortical metabolite concentrations during early abstinence from
relevance to addiction. Ann. N. Y. Acad. Sci. 1187, 148e171. https:// alcohol and their associations with neurocognitive changes. Drug
doi.org/10.1111/j.1749-6632.2009.05143.x. NYAS5143 [pii]. Alcohol Depend. 125 (1e2), 27e36. https://doi.org/10.1016/
Loeber, S., Duka, T., Welzel Marquez, H., Nakovics, H., Heinz, A., j.drugalcdep.2012.03.012.
Mann, K., Flor, H., 2010. Effects of repeated withdrawal from alcohol Moorman, D.E., 2018. The role of the orbitofrontal cortex in alcohol use,
on recovery of cognitive impairment under abstinence and rate of abuse, and dependence. Prog. Neuro Psychopharmacol. Biol. Psy-
relapse. Alcohol Alcohol. 45 (6), 541e547. https://doi.org/10.1093/ chiatry 87, 85e107. https://doi.org/10.1016/j.pnpbp.2018.01.010.
alcalc/agq065. Morales, A.M., Lee, B., Hellemann, G., O’Neill, J., London, E.D., 2012.
Mackey, S., Paulus, M., 2013. Are there volumetric brain differences Gray-matter volume in methamphetamine dependence: cigarette
associated with the use of cocaine and amphetamine-type stimulants? smoking and changes with abstinence from methamphetamine. Drug
Neurosci. Biobehav. Rev. 37 (3), 300e316. https://doi.org/10.1016/ Alcohol Depend. 125 (3), 230e238. https://doi.org/10.1016/j.dru-
j.neubiorev.2012.12.003. galcdep.2012.02.017. S0376-8716(12)00069-5 [pii].
Matochik, J.A., Eldreth, D.A., Cadet, J.L., Bolla, K.I., 2005. Altered brain Moreno-Alcázar, A., Gonzalvo, B., Canales-Rodríguez, E.J., Blanco, L.,
tissue composition in heavy marijuana users. Drug Alcohol Depend. Bachiller, D., Romaguera, A., et al., 2018. Larger gray matter volume
77 (1), 23e30. in the basal ganglia of heavy cannabis users detected by voxel-based
Matochik, J.A., London, E.D., Eldreth, D.A., Cadet, J.L., Bolla, K.I., morphometry and subcortical volumetric analysis. Front. Psychiatry 9
2003. Frontal cortical tissue composition in abstinent cocaine abusers: (175). https://doi.org/10.3389/fpsyt.2018.00175.
a magnetic resonance imaging study. Neuroimage 19 (3), 1095e1102. Moss, H.B., Goldstein, R.B., Chen, C.M., Yi, H.Y., 2015. Patterns of use
Medina, K.L., Shear, P.K., Schafer, J., Armstrong, T.G., Dyer, P., 2004. of other drugs among those with alcohol dependence: associations
Cognitive functioning and length of abstinence in polysubstance with drinking behavior and psychopathology. Addict. Behav. 50,
dependent men. Arch. Clin. Neuropsychol. 19 (2), 245e258. 192e198. https://doi.org/10.1016/j.addbeh.2015.06.041.
Meyerhoff, D., Blumenfeld, R., Truran, D., Lindgren, J., Flenniken, D., Murray, D.E., Durazzo, T.C., Schmidt, T.P., Abé, C., Guydish, J.,
Cardenas, V., et al., 2004. Effects of heavy drinking, binge drinking, Meyerhoff, D.J., 2016. Frontal metabolite concentration deficits in
and family history of alcoholism on regional brain metabolites. opiate dependence relate to substance use, cognition, and self-
Alcohol Clin. Exp. Res. 28 (4), 650e661. regulation. J. Addict. Res. Ther. 7 (4), 286. https://doi.org/10.4172/
Meyerhoff, D.J., 2007. The neurobiological and neurocognitive conse- 2155-6105.1000286.
quences of chronic cigarette smoking in alcohol use disorders. Front. Murray, D.E., Durazzo, T.C., Schmidt, T.P., Murray, T.A., Abe, C.,
Biosci. 42 (3), 174e185. Guydish, J., Meyerhoff, D.J., 2018. Regional cerebral blood flow in
Meyerhoff, D.J., 2008. Proton magnetic resonance spectroscopy in alcohol opiate dependence relates to substance use and neuropsychological
use disorders: a potential new endophenotype? Alcohol 32 (7), performance. Addict. Biol. 23 (2), 781e795. https://doi.org/10.1111/
1146e1158. https://doi.org/10.1016/j.alcohol.2008.06.001 10.1111/ adb.12523.
j.1530-0277.2008.00695.x. Nader, D.A., Sanchez, Z.M., 2018. Effects of regular cannabis use on
Meyerhoff, D.J., 2014. Brain proton magnetic resonance spectroscopy of neurocognition, brain structure, and function: a systematic review of
alcohol use disorders. Handb. Clin. Neurol. 125, 313e337. https:// findings in adults. Am. J. Drug Alcohol Abuse 44 (1), 4e18. https://
doi.org/10.1016/B978-0-444-62619-6.00019-7. doi.org/10.1080/00952990.2017.1306746.
Meyerhoff, D.J., Bloomer, C., Schuff, N., Ezekiel, F., Norman, D., Nicolas, J.M., Catafau, A.M., Estruch, R., Lomena, F.J., Salamero, M.,
Clark, W., et al., 1999. Cortical metabolite alterations in abstinent Herranz, R., et al., 1993. Regional cerebral blood flow-SPECT in
cocaine and cocaine/alcohol-dependent subjects: proton magnetic chronic alcoholism: relation to neuropsychological testing. J. Nucl.
resonance spectroscopic imaging. Addict. Biol. 4 (4), 405e419. Med. 34 (9), 1452e1459.
https://doi.org/10.1080/13556219971399.
Nordahl, T.E., Salo, R., Natsuaki, Y., Galloway, G.P., Waters, C., stimulation to treat addiction. In: Ewing, S.W.F., Witkiewitz, K.,
Moore, C.D., et al., 2005. Methamphetamine users in sustained Filbey, F.M. (Eds.), Neuroimaging and Psychosocial Addiction
abstinence: a proton magnetic resonance spectroscopy study. Arch. Treatment: An Integrative Guide for Researchers and Clinicians.
Gen. Psychiatry 62 (4), 444e452. Palgrave Macmillan UK, London, pp. 67e84.
Noyan, C.O., Kose, S., Nurmedov, S., Metin, B., Darcin, A.E., Dilbaz, N., Rando, K., Hong, K.I., Bhagwagar, Z., Li, C.S., Bergquist, K.,
2016. Volumetric brain abnormalities in polysubstance use disorder Guarnaccia, J., Sinha, R., 2011. Association of frontal and posterior
patients. Neuropsychiatric Dis. Treat. (12), 1355e1363. cortical gray matter volume with time to alcohol relapse: a prospective
O’Neill, J., Cardenas, V.A., Meyerhoff, D.J., 2001. Separate and interac- study. Am. J. Psychiatry 168 (2), 183e192. https://doi.org/10.1176/
tive effects of cocaine and alcohol dependence on brain structures and appi.ajp.2010.10020233.
metabolites: quantitative MRI and proton MR spectroscopic imaging. Rezapour, T., DeVito, E.E., Sofuoglu, M., Ekhtiari, H., 2016. Chapter 16
Addict. Biol. 6, 347e361. e perspectives on neurocognitive rehabilitation as an adjunct treat-
Oishi, M., Mochizuki, Y., Shikata, E., 1999. Corpus callosum atrophy and ment for addictive disorders: from cognitive improvement to relapse
cerebral blood flow in chronic alcoholics. J. Neurol. Sci. 162 (1), prevention. In: Ekhtiari, H., Paulus, M.P. (Eds.), Progress in Brain
51e55. Research, vol. 224. Elsevier, pp. 345e369.
Oscar-Berman, M., Marinkovic, K., 2007. Alcohol: effects on neuro- Rogers, R.L., Meyer, J.S., Shaw, T.G., Mortel, K.F., 1983. Reductions in
behavioral functions and the brain. Neuropsychol. Rev. 17 (3), regional cerebral blood flow associated with chronic consumption of
239e257. https://doi.org/10.1007/s11065-007-9038-6. alcohol. J. Am. Geriatr. Soc. 31, 540e543.
Oscar-Berman, M., Valmas, M.M., Sawyer, K.S., Ruiz, S.M., Luhar, R.B., Rourke, S.B., Grant, I., 2009. The neurobehavior correlates of alcoholism.
Gravitz, Z.R., 2014. Profiles of impaired, spared, and recovered In: Neuropsychological Assessment of Neuropsychiatric and Neuro-
neuropsychologic processes in alcoholism. Handb. Clin. Neurol. 125, medical Disorders, third ed. Oxford University Press, New York, NY,
183e210. https://doi.org/10.1016/B978-0-444-62619-6.00012-4. pp. 398e454.
Parks, M.H., Dawant, B.M., Riddle, W.R., Hartmann, S.L., Dietrich, M.S., Rupp, C.I., Beck, J.K., Heinz, A., Kemmler, G., Manz, S., Tempel, K.,
Nickel, M.K., et al., 2002. Longitudinal brain metabolic character- Fleischhacker, W.W., 2016. Impulsivity and alcohol dependence
ization of chronic alcoholics with proton magnetic resonance spec- treatment completion: is there a neurocognitive risk factor at treatment
troscopy. Alcohol Clin. Exp. Res. 26 (9), 1368e1380. entry? Alcohol. Clin. Exp. Res. 40 (1), 152e160. https://doi.org/
Parvaz, M.A., Moeller, S.J., d’Oleire Uquillas, F., Pflumm, A., 10.1111/acer.12924.
Maloney, T., Alia-Klein, N., Goldstein, R.Z., 2017. Prefrontal gray Sailasuta, N., Abulseoud, O., Hernandez, M., Haghani, P., Ross, B.D.,
matter volume recovery in treatment-seeking cocaine-addicted in- 2010. Metabolic abnormalities in abstinent methamphetamine
dividuals: a longitudinal study. Addict. Biol. 22 (5), 1391e1401. dependent subjects. Subst. Abuse 4, 9e20.
https://doi.org/10.1111/adb.12403. Salo, R., Fassbender, C., 2012. Structural, functional and spectroscopic
Passetti, F., Clark, L., Mehta, M.A., Joyce, E., King, M., 2008. Neuro- MRI studies of methamphetamine addiction. Curr. Top Behav. Neu-
psychological predictors of clinical outcome in opiate addiction. Drug rosci. 11, 321e364. https://doi.org/10.1007/7854_2011_172.
Alcohol Depend. 94 (1e3), 82e91. https://doi.org/10.1016/j.dru- Schmidt, T.P., Pennington, D.L., Cardoos, S.L., Durazzo, T.C.,
galcdep.2007.10.008. S0376-8716(07)00421-8 [pii]. Meyerhoff, D.J., 2017. Neurocognition and inhibitory control in
Pennington, D.L., Durazzo, T.C., Schmidt, T., Mon, A., Abe, C., polysubstance use disorders: comparison with alcohol use disorders
Meyerhoff, D.J., 2013. The effects of chronic cigarette smoking on and changes with abstinence. J. Clin. Exp. Neuropsychol. 39 (1),
cognitive recovery during early abstinence from alcohol. Alcohol. 22e34. https://doi.org/10.1080/13803395.2016.1196165.
Clin. Exp. Res. 37 (7), 1220e1227. https://doi.org/10.1111/ Schulte, M.H., Cousijn, J., den Uyl, T.E., Goudriaan, A.E., van den
acer.12089. Brink, W., Veltman, D.J., et al., 2014. Recovery of neurocognitive
Pennington, D.L., Durazzo, T.C., Schmidt, T.P., Abe, C., Mon, A., functions following sustained abstinence after substance dependence
Meyerhoff, D.J., 2015. Alcohol use disorder with and without stim- and implications for treatment. Clin. Psychol. Rev. 34 (7), 531e550.
ulant use: brain morphometry and its associations with cigarette https://doi.org/10.1016/j.cpr.2014.08.002.
smoking, cognition, and inhibitory control. PLoS One 10 (3), Segobin, S.H., Chetelat, G., Le Berre, A.P., Lannuzel, C., Boudehent, C.,
e0122505. https://doi.org/10.1371/journal.pone.0122505. Vabret, F., et al., 2014. Relationship between brain volumetric
Pfefferbaum, A., Sullivan, E.V., Mathalon, D.H., Shear, P.K., changes and interim drinking at six months in alcohol-dependent
Rosenbloom, M.J., Lim, K.O., 1995. Longitudinal changes in mag- patients. Alcohol Clin. Exp. Res. 38 (3), 739e748. https://doi.org/
netic resonance imaging brain volumes in abstinent and relapsed al- 10.1111/acer.12300.
coholics. Alcohol Clin. Exp. Res. 19 (5), 1177e1191. Seo, D., Sinha, R., 2015. Neuroplasticity and predictors of alcohol re-
Prescot, A.P., Locatelli, A.E., Renshaw, P.F., Yurgelun-Todd, D.A., 2011. covery. Alcohol. Res. 37 (1), 143e152.
Neurochemical alterations in adolescent chronic marijuana smokers: a Seo, S., Mohr, J., Beck, A., Wustenberg, T., Heinz, A., Obermayer, K.,
proton MRS study. Neuroimage 57 (1), 69e75. https://doi.org/ 2015. Predicting the future relapse of alcohol-dependent patients from
10.1016/j.neuroimage.2011.02.044. structural and functional brain images. Addict. Biol. 20 (6),
Prescot, A.P., Renshaw, P.F., Yurgelun-Todd, D.A., 2013. gamma-Amino 1042e1055. https://doi.org/10.1111/adb.12302.
butyric acid and glutamate abnormalities in adolescent chronic mari- Simon, S.L., Dean, A.C., Cordova, X., Monterosso, J.R., London, E.D.,
juana smokers. Drug Alcohol Depend. 129 (3), 232e239. https:// 2010. Methamphetamine dependence and neuropsychological func-
doi.org/10.1016/j.drugalcdep.2013.02.028. tioning: evaluating change during early abstinence. J. Stud. Alcohol
Rabin, R.A., Blumberger, D.M., Daskalakis, Z.J., George, T.P., Drugs 71 (3), 335e344.
Barr, M.S., 2015. The promise of repetitive transcranial magnetic
Sneider, J.T., Mashhoon, Y., Silveri, M.M., 2013. A review of magnetic Verdejo-Garcia, A., Rivas-Perez, C., Vilar-Lopez, R., Perez-Garcia, M.,
resonance spectroscopy studies in marijuana using adolescents and 2007. Strategic self-regulation, decision-making and emotion pro-
adults. J. Addict. Res. Ther. (Suppl. 4) https://doi.org/10.4172/2155- cessing in poly-substance abusers in their first year of abstinence.
6105.S4-010. Drug Alcohol Depend. 86 (2e3), 139e146. https://doi.org/10.1016/
Sorg, S.F., Taylor, M.J., Alhassoon, O.M., Gongvatana, A., j.drugalcdep.2006.05.024. S0376-8716(06)00208-0 [pii].
Theilmann, R.J., Frank, L.R., Grant, I., 2012. Frontal white matter Volkow, N.D., Baler, R.D., 2014. Addiction science: uncovering neuro-
integrity predictors of adult alcohol treatment outcome. Biol. Psy- biological complexity. Neuropharmacology 76 Pt B, 235e249. https://
chiatry 71 (3), 262e268. https://doi.org/10.1016/ doi.org/10.1016/j.neuropharm.2013.05.007.
j.biopsych.2011.09.022. Volkow, N.D., Chang, L., Wang, G.J., Fowler, J.S., Franceschi, D.,
Stavro, K., Pelletier, J., Potvin, S., 2013. Widespread and sustained Sedler, M.J., et al., 2001. Higher cortical and lower subcortical
cognitive deficits in alcoholism: a meta-analysis. Addict. Biol. 18 (2), metabolism in detoxified methamphetamine abusers. Am. J. Psychi-
203e213. https://doi.org/10.1111/j.1369-1600.2011.00418.x. atry 158 (3), 383e389.
Stevens, L., Verdejo-Garcia, A., Goudriaan, A.E., Roeyers, H., Dom, G., Volkow, N.D., Fowler, J.S., Wang, G.J., Hitzemann, R., Logan, J.,
Vanderplasschen, W., 2014. Impulsivity as a vulnerability factor for Schlyer, D.J., et al., 1993. Decreased dopamine D2 receptor avail-
poor addiction treatment outcomes: a review of neurocognitive find- ability is associated with reduced frontal metabolism in cocaine
ings among individuals with substance use disorders. J. Subst. Abuse abusers. Synapse 14 (2), 169e177.
Treat. 47 (1), 58e72. https://doi.org/10.1016/j.jsat.2014.01.008. Volkow, N.D., Hitzemann, R., Wang, G.J., Fowler, J.S., Wolf, A.P.,
Streeter, C.C., Terhune, D.B., Whitfield, T.H., Gruber, S., Sarid-Segal, O., Dewey, S.L., Handlesman, L., 1992. Long-term frontal brain meta-
Silveri, M.M., et al., 2008. Performance on the Stroop predicts treat- bolic changes in cocaine abusers. Synapse 11 (3), 184e190.
ment compliance in cocaine-dependent individuals. Neuro- Volkow, N.D., Mullani, N., Gould, K.L., Adler, S., Krajewski, K., 1988.
psychopharmacology 33 (4), 827e836. https://doi.org/10.1038/ Cerebral blood flow in chronic cocaine users: a study with positron
sj.npp.1301465. emission tomography. Br. J. Psychiatry 152, 641e648.
Sullivan, E.V., 2000. NIAAA Research Monograph No. 34: human brain Volkow, N.D., Wang, G.J., Fowler, J.S., Tomasi, D., 2012. Addiction
vulnerability to alcoholism: evidence from neuroimaging studies. In: circuitry in the human brain. Annu. Rev. Pharmacol. Toxicol. 52,
Noronha, A., Eckardt, M., Warren, K. (Eds.), Review of NIAAA’s 321e336. https://doi.org/10.1146/annurev-pharmtox-010611-134625.
Neuroscience and Behavioral Research Portfolio. National Institute on Volkow, N.D., Wang, G.J., Hitzemann, R., Fowler, J.S., Overall, J.E.,
Alcohol Abuse and Alcoholism, Bethesda, MD, pp. 473e508. Burr, G., Wolf, A.P., 1994. Recovery of brain glucose metabolism in
Sullivan, E.V., Pfefferbaum, A., 2005. Neurocircuitry in alcoholism: a detoxified alcoholics. Am. J. Psychiatry 151 (2), 178e183.
substrate of disruption and repair. Psychopharmacology (Berl.) 180 Volkow, N.D., Wang, G.J., Tomasi, D., Baler, R.D., 2013. Unbalanced
(4), 583e594. neuronal circuits in addiction. Curr. Opin. Neurobiol. 23 (4),
Sullivan, E.V., Rosenbloom, M.J., Pfefferbaum, A., 2000. Brain Vulner- 639e648. https://doi.org/10.1016/j.conb.2013.01.002.
ability to Alcoholism: Evidence from Neuroimaging Studies. Vonmoos, M., Hulka, L.M., Preller, K.H., Minder, F., Baumgartner, M.R.,
Retrieved from: Quednow, B.B., 2014. Cognitive impairment in cocaine users is drug-
Sullivan, E.V., Zahr, N.M., Sassoon, S.A., Thompson, W.K., Kwon, D., induced but partially reversible: evidence from a longitudinal study.
Pohl, K.M., Pfefferbaum, A., 2018. The role of aging, drug depen- Neuropsychopharmacology 39 (9), 2200e2210. https://doi.org/
dence, and hepatitis C comorbidity in alcoholism cortical compromise. 10.1038/npp.2014.71.
JAMA Psychiatry 75 (5), 474e483. https://doi.org/10.1001/ Walitzer, K.S., Dearing, R.L., Barrick, C., Shyhalla, K., 2015. Tobacco
jamapsychiatry.2018.0021. smoking among male and female alcohol treatment-seekers: clinical
Thompson, P.M., Hayashi, K.M., Simon, S.L., Geaga, J.A., Hong, M.S., complexities, treatment length of stay, and goal achievement. Subst. Use
Sui, Y., et al., 2004. Structural abnormalities in the brains of human Misuse 50 (2), 166e173. https://doi.org/10.3109/10826084.2014.962050.
subjects who use methamphetamine. J. Neurosci. 24 (26), Wang, C., Xu, X., Qian, W., Shen, Z., Zhang, M., 2015. Altered human
6028e6036. brain anatomy in chronic smokers: a review of magnetic resonance
Tunving, K., Thulin, S.O., Risberg, J., Warkentin, S., 1986. Regional imaging studies. Neurol. Sci. 36 (4), 497e504. https://doi.org/
cerebral blood flow in long-term heavy cannabis use. Psychiatr. Res. 10.1007/s10072-015-2065-9.
17 (1), 15e21. Wang, G.Y., Demirakca, T., van Eijk, J., Frischknecht, U., Ruf, M.,
van Eijk, J., Demirakca, T., Frischknecht, U., Hermann, D., Mann, K., Ucar, S., et al., 2016. Longitudinal mapping of gyral and Sulcal pat-
Ende, G., 2013. Rapid partial regeneration of brain volume during the terns of cortical thickness and brain volume Regain during early
first 14 days of abstinence from alcohol. Alcohol. Clin. Exp. Res. 37 alcohol abstinence. Eur. Addict. Res. 22 (2), 80e89. https://doi.org/
(1), 67e74. https://doi.org/10.1111/j.1530-0277.2012.01853.x. 10.1159/000438456.
Verdejo-Garcia, A., Betanzos-Espinosa, P., Lozano, O.M., Vergara- Wang, J.J., Durazzo, T.C., Gazdzinski, S., Yeh, P.H., Mon, A.,
Moragues, E., Gonzalez-Saiz, F., Fernandez-Calderon, F., et al., Meyerhoff, D.J., 2009. MRSI and DTI: a multimodal approach for
2012. Self-regulation and treatment retention in cocaine dependent improved detection of white matter abnormalities in alcohol and
individuals: a longitudinal study. Drug Alcohol Depend. 122 (1e2), nicotine dependence. NMR Biomed. 22 (5), 516e522. https://doi.org/
142e148. https://doi.org/10.1016/j.drugalcdep.2011.09.025. 10.1002/nbm.1363.
Verdejo-Garcia, A., Lopez-Torrecillas, F., Gimenez, C.O., Perez- Weber, D.A., Franceschi, D., Ivanovic, M., Atkins, H.L., Cabahug, C.,
Garcia, M., 2004. Clinical implications and methodological chal- Wong, C.T., Susskind, H., 1993. SPECT and planar brain imaging in
lenges in the study of the neuropsychological correlates of cannabis, crack abuse: iodine-123-iodoamphetamine uptake and localization.
stimulant, and opioid abuse. Neuropsychol. Rev. 14 (1), 1e41. J. Nucl. Med. 34 (6), 899e907.
Weinberger, A.H., Funk, A.P., Goodwin, R.D., 2016. A review of Yeh, P.H., Gazdzinski, S., Durazzo, T.C., Sjostrand, K., Meyerhoff, D.J.,
epidemiologic research on smoking behavior among persons with 2007. Hierarchical linear modeling (HLM) of longitudinal brain
alcohol and illicit substance use disorders. Prev. Med. 92, 148e159. structural and cognitive changes in alcohol-dependent individuals
https://doi.org/10.1016/j.ypmed.2016.05.011. during sobriety. Drug Alcohol Depend. 91 (2e3), 195e204.
Weinberger, A.H., Platt, J., Esan, H., Galea, S., Erlich, D., Goodwin, R.D., Yoon, S.J., Lyoo, I.K., Kim, H.J., Kim, T.S., Sung, Y.H., Kim, N., et al.,
2017. Cigarette smoking is associated with increased risk of substance 2010. Neurochemical alterations in methamphetamine-dependent pa-
use disorder relapse: a nationally representative, prospective longitu- tients treated with cytidine-5’-diphosphate choline: a longitudinal
dinal investigation. J. Clin. Psychiatry 78 (2), e152ee160. https:// proton magnetic resonance spectroscopy study. Neuro-
doi.org/10.4088/JCP.15m10062. psychopharmacology 35 (5), 1165e1173. https://doi.org/10.1038/
Weinberger, A.H., Platt, J., Jiang, B., Goodwin, R.D., 2015. Cigarette npp.2009.221 npp2009221 [pii].
smoking and risk of alcohol use relapse among adults in recovery from Younger, J.W., Chu, L.F., D’Arcy, N.T., Trott, K.E., Jastrzab, L.E.,
alcohol use disorders. Alcohol Clin. Exp. Res. 39 (10), 1989e1996. Mackey, S.C., 2011. Prescription opioid analgesics rapidly change the
https://doi.org/10.1111/acer.12840. human brain. Pain 152 (8), 1803e1810. https://doi.org/10.1016/
Williams, L.M., 2016. Precision psychiatry: a neural circuit taxonomy for j.pain.2011.03.028.
depression and anxiety. Lancet Psychiatry 3 (5), 472e480. https:// Yucel, M., Lorenzetti, V., Suo, C., Zalesky, A., Fornito, A., Takagi, M.J.,
doi.org/10.1016/S2215-0366(15)00579-9. et al., 2016. Hippocampal harms, protection and recovery following
Witkiewitz, K., Wilson, A.D., Pearson, M.R., Montes, K.S., Kirouac, M., regular cannabis use. Transl. Psychiatry 6, e710. https://doi.org/
Roos, C.R., et al., 2019. Profiles of recovery from alcohol use disorder 10.1038/tp.2015.201.
at three years following treatment: can the definition of recovery be Zahr, N.M., 2014. Structural and microstructral imaging of the brain in
extended to include high functioning heavy drinkers? Addiction 114 alcohol use disorders. Handb. Clin. Neurol. 125, 275e290. https://
(1), 69e80. https://doi.org/10.1111/add.14403. doi.org/10.1016/B978-0-444-62619-6.00017-3.
Xiao, P., Dai, Z., Zhong, J., Zhu, Y., Shi, H., Pan, P., 2015. Regional gray Zahr, N.M., Kaufman, K.L., Harper, C.G., 2011. Clinical and pathological
matter deficits in alcohol dependence: a meta-analysis of voxel-based features of alcohol-related brain damage. Nat. Rev. Neurol. 7 (5),
morphometry studies. Drug Alcohol Depend. 153, 22e28. https:// 284e294. https://doi.org/10.1038/nrneurol.2011.42.
doi.org/10.1016/j.drugalcdep.2015.05.030. Zatorre, R.J., Fields, R.D., Johansen-Berg, H., 2012. Plasticity in gray and
Yang, S., Salmeron, B.J., Ross, T.J., Xi, Z.X., Stein, E.A., Yang, Y., 2009. white: neuroimaging changes in brain structure during learning. Nat.
Lower glutamate levels in rostral anterior cingulate of chronic cocaine Neurosci. 15 (4), 528e536. https://doi.org/10.1038/nn.3045.
users e a (1)H-MRS study using TE-averaged PRESS at 3 T with an Zou, X., Durazzo, T.C., Meyerhoff, D.J., 2018. Regional brain volume
optimized quantification strategy. Psychiatr. Res. 174 (3), 171e176. changes in alcohol-dependent individuals during short-term and long-
https://doi.org/10.1016/j.pscychresns.2009.05.004. S0925-4927(09) term abstinence. Alcohol Clin. Exp. Res. 42 (6), 1062e1072. https://
00140-1 [pii]. doi.org/10.1111/acer.13757.
Chapter 29
Clinical translation and implementation

neuroscience for novel cognitive
interventions in addiction medicine
Tara Rezapour1, 2, Robin L. Aupperle3, Martin P. Paulus3 and Hamed Ekhtiari3
1
Institute for Cognitive Science Studies, Tehran, Iran; 2Iranian National Center for Addiction Studies, Tehran University of Medical Sciences,
Tehran, Iran; 3Laureate Institute for Brain Research, Tulsa, OK, United States
Introduction substance users that could be potentially revised with

cognitive modifications (e.g., attention bias modification)
Recent advances in the neuroscience of drug addiction (Ekhtiari et al., 2017b; Rezapour et al., 2017). In the
motivate questions concerning whether and how clinical second category, there is a varied profile of CDs experi-
practice may be based on or inspired by these new advances. enced by substance users, thought to be caused by
In this chapter, we will provide a framework for summari- “neurotoxic effects” of drugs. These deficits have been
zing novel, neuroscience-informed, cognitive interventions described in a variety of domains, including learning and
that are under investigation and/or in the process of trans- memory, attention and concentration, executive func-
lation to clinical practice. We will provide more specific tioning, and visuospatial processing (Baldacchino et al.,
information concerning our experience in developing a new 2018). Cognitive rehabilitation may be a promising strat-
integrative package of interventions inspired by this frame- egy for targeting these functions (Rezapour et al., 2017a).
work. At the end of the chapter, we will discuss the next It is clear that there are neurocognitive disorders that have
steps in the clinical translation and implementation of both neurotoxic and neuroadaptive mechanisms involved,
neuroscience-based cognitive interventions. and the lines between these two categories can quickly
start to blur. As an example, lack of proper insight (ano-
Neuroscience-based cognitive sognosia) and metacognition about one’s own substance
use disorder (SUD) may be considered either a cognitive
interventions maladaptation relating to a preference to sustain drug use
Chronic and prolonged use of various substances or neuropsychological deficits caused by neurotoxic
(including alcohol) may change or induce damages in effects. Regardless of cause, these symptoms can lead
different brain regions and networks including subcortical users to deny addiction as a health problem and reduce
(Nagel et al., 2005), frontal (Koester et al., 2012), orbi- motivation to seek or accept treatment (Ekhtiari et al.,
tofrontal (Tanabe et al., 2009), cingulate, limbic, and 2017a). Thus, CDs and CMs associated with drug use
paralimbic cortices (Thompson et al., 2004). These iden- would potentially benefit more from integrating different
tified structural alterations have been associated with cognitive-based interventions (cognitive modifications
several cognitive-related functional pathologies, which and cognitive rehabilitations) into a holistic program
can be classified into two distinct but interacting rather than employing each separately. Drug users could
categories: cognitive maladaptation (CM) and cognitive also benefit from structured psychoeducation programs
deficits (CDs). Cognitive maladaptation is an umbrella aiming to transfer knowledge about different aspects of
term for any “neuroadaptation” resulting from extreme addiction and increase insight and motivation for recov-
saliency of drug rewards. High sensitivity to short-term ery. The following sections provide more detailed
rewards and preference for processing drug-related cues descriptions for these interventions.
are some examples of cognitive maladaptation in

Neuroscience-informed psychoeducation and or problems (e.g., difficulty in shifting attention or imme-

metacognitive training diately forgetting new information) would be a promising
therapeutic intervention in this context (Skidmore et al.,
The ability to reflect about and regulate one’s internal world 2018). Other strategies that enhance awareness of one’s
of thoughts, feelings, and mental processes is termed internal bodily states or processes and the external world
“metacognition” (Flavell, 1979; Roebers, 2017; Sadeghi (i.e., mindfulness) could also be promising for enhancing
et al., 2017). Distortion of this higher-order function is insight and metacognition (Shapiro et al., 2006). Common
apparent in the observation that people with SUDs often to all these approaches is a core focus on supporting the
underestimate or inaccurately report on their symptoms integration of both internal and external relevant cues to
(Inchausti et al., 2016; Moeller et al., 2016; Verdejo-Garcia create a self-representation that is close to the true state.
et al., 2012). These deficits are thought to potentially arise
because of damages in neural networks that include the
anterior cingulate cortex (ACC) and insula (Fleming et al., Neuroscience-informed cognitive modifications
2012). Poor metacognitive functions relate to reduced Having a conceptual framework that provides specific tar-
consistency between subjective symptoms and real objec- gets for neuroscience-informed interventions is critical. The
tive states (e.g., self-report craving and actual arousal dynamic craving model (DCM) as depicted in Fig. 29.1 can
states) (Castine et al., 2018), denial of problems associated be considered a potential framework to define targets and
with drug use (Moeller and Goldstein, 2014), and decreased categorize interventions as well as for providing guidance in
interoceptive sensations or awareness (Ates Col et al., measuring the efficacy of such interventions (Ekhtiari et al.,
2016). A recent study in cocaine users reported an associ- 2016). The traditional cognitive behavioral therapyebased
ation between metacognition impairment and poor treat- model (Beck, 1997) adapted for drug craving, which is often
ment outcome because of reduced treatment motivation used to guide relapse prevention packages, involves four
(Castine et al., 2018). These evidences suggest a need to main elements: triggers, thoughts/affect, craving, and drug
embed interventions that directly target metacognition into use (Larimer et al., 1999; Oei et al., 1991). In the DCM,
the context of addiction medicine. Accordingly, there are thoughts and craving are delineated into five major cognitive
different interventions that may enhance metacognition for processes, namely, attention, saliency valuation, memory,
substance use. This includes motivational interviewing, interoception, and executive control modules. Each of these
which could enhance metacognition through the enhance- modules has subprocesses, reflected to some extent in the
ment of insight and motivation for change(Apodaca and top/bottom of each cell of Fig. 29.1. As it has been indicated
Longabaugh, 2009), as well as psychoeducation programs in the model, exposure to the environmental stimuli (E)
aiming to improve subject’s awareness about their own (including both internal and external cues) activates the
mental health disorder and related problems (Ekhtiari et al., process of drug craving. These cues then elicit distinct yet
2017a). Improved insight may change negative attitudes to collaborative bottom-up and top-down attentional processes
recovery and reduce potential stigma that is an important that increase the focus of attention on drug-relevant cues (A).
impediment to addiction treatment (Hasan et al., 2015). This attentional deployment activates saliency evaluation
Moreover, training patients to use self-assessment and self- processes (S) related to drug-associated cues. The retrieval of
monitoring in daily life activities to identify their symptoms memories (M) linked to the drug cues provides relevant
Drug-related Top-down Explicit Compulsive Control Abstinence

Cues Attention Processing State
E A S I Co Re
Emotional/ Bottom-up Implicit Appetitive
Stress Cues Attention Precessing State Execution Drug Use
Emotional
E: Environment M: Memory
A: Attention I: Interoception
M S: Saliency processing CO: Control
(Significance) Re: Response
Procedural
FIGURE 29.1 Dynamic model of craving. A neuroscience-informed conceptual framework to define the major targets in the dynamic response to drug-
related or emotional salient cues.
Clinical translation and implementation Chapter | 29 395
information during saliency processing. Saliency evaluation responses to emotionally salient cues. Hence, impairments
can result in an interoceptive state that represents the sub- in ER could lead to improper behavioral actions
jective feeling of craving, leading to the engagement of (e.g., avoidance or appetitive reaction) due to misinter-
executive control (Co) processes to take execute actions pretation or decreased tolerance of an emotional experi-
supporting drug-taking behavior or abstinence (response) ence (Pietrek et al., 2012). CR strategies for saliency
(Ekhtiari et al., 2016). Below, we will further discuss these modification in negative affect (i.e., anxiety, depression)
five modules and cognitive interventions that may target have been adapted in attempts to target appetitive re-
each. sponses to drug-related salient cues for the purposes of
craving management and relapse prevention. It has also
Attention bias interventions been well-established that people with SUDs have
different degrees of ER impairments that may contribute
The unconscious orientation of attention toward substance-
to increased cue-induced craving and poor treatment
related cues is termed “attentional bias” and is considered
response (Berking et al., 2011; Daughters et al., 2005;
among the most prominent cognitive maladaptive changes
Hopwood et al., 2015; Strong, 2012; Wilcox et al., 2016).
in chronic drug/alcohol users (Cox et al., 2014). Attentional
Hence, embedding CR could provide added value to
bias is thought to result from an increase in the brain’s
standard treatments. CR can be used to target cognitions
automatic attentional processes and a decrease in the
concerning drug use and feelings of craving, or it can be
reflective ones (Stacy and Wiers, 2010). Attentional bias used to target affective states or stress that may serve as
has been considered as a potential “early warning signal,”
cues or triggers for subsequent use. Although there is a
as it seems to occur automatically when substance users are
plethora of studies supporting the use of cognitive therapy
exposed to drug-related cues and can lead to relapse for
for conditions often comorbid with substance use
subjects with SUDs who are undergoing treatment (Field
(e.g., anxiety, mood, and trauma-related disorders) (Butler
et al., 2014). In fact, recent findings suggest that substance
et al., 2006), there is less evidence supporting the efficacy
users who have greater attentional bias toward drug-related
of CR for targeting substance use specifically. One study
cues (measured by modified Stroop tasks) are more likely
among cigarette users suggests that CR may be associated
to drop out from the treatment, have shorter length of stay with weaker expectancies that smoking alleviates negative
in treatment, and have greater subsequent drug consump-
feelings and induces positive mood (Fucito et al., 2010).
tion (Diaz-Batanero et al., 2018; Streeter et al., 2008). In
Moreover, based on the previous findings on ER, it should
this context, a series of interventions has been applied to
be noted that the successful implementation of saliency
retrain biases away from substance-related cues toward
modification strategies may directly depend on patients’
more neutral ones in the environment. These computer-
awareness of their emotions and internal bodily states (i.e.,
based interventions, referred to as Attention Bias Modifi-
urges, cravings) as well as their capacity to control their
cation (ABM), are based on the well-known visual dot
behaviors (Hopwood et al., 2015). Interoceptive aware-
probe implicit association tasks. In brief, one drug-related ness (IA) and self-control will be discussed in more detail
and one neutral stimulus are shown on the screen simul-
in subsequent sections of this chapter.
taneously, after which a “probe” target stimulus (i.e., an X)
Contingency management is one of the most efficacious
is displayed in the location of one of the stimuli. For ABM,
treatments for substance use and could be viewed as tar-
the probe is shown in the location of the neutral stimuli
geting saliency processing. This intervention attempts to
with a higher probability (e.g., 80%), thus training partic-
combat the saliency and reward of drug use or cues with
ipants to disengage their attention from drug-related stimuli
rewards that are contingent on abstinence and incompatible
and shift it toward the paired neutral ones (Cristea et al.,
with drug use (e.g., a prize or voucher) (Potenza et al., 2011;
2016; Heitmann et al., 2018). Stanger et al., 2013). Contingency management takes
advantage of the fact that the brain processes immediate
Saliency-based interventions rewards as more salient and motivating than longer-term
The ability to properly attenuate, amplify, and maintain an rewards, providing a briefer immediate reward (voucher or
emotional response is termed as emotional regulation (ER) prize) for continued abstinence (Kiluk and Carroll, 2013).
(Axelrod et al., 2011). Among ER strategies, cognitive
reappraisal (CR) has received particular attention in the Memory-based interventions
field of drug addiction. By using CR strategies, patients
Repeated pairing of drug-related cues (e.g., sight of a
learn how to reevaluate and reinterpret emotional experi- syringe) with rewarding outcomes (hedonic state) forms a
ences to alter the meaning given to them and potentially
type of learning (instrumental/operant) whereby the cue
reduce the saliency of affect experienced (Steinberger et al.,
becomes the reward anticipator (salient stimulus) that can
2011). CR is critical for managing emotional situations and
trigger drug-seeking and drug-taking behaviors (Hogarth prospective memory neuropsychological deficits docu-
et al., 2013). One prominent neural change in response to mented in SUDs (Heffernan, 2008; Rendell et al., 2009).
such drug-related operant cues is increased dopamine
release, which is linked to increased emotional arousal Interoceptive-based interventions
(e.g., increased heart rate) as well as learning and memory
When we come across an emotional/appetitive stimulus or
consolidation about the drug-related cue. Reexposure to
cue (either internal or external), interoception helps us to
these cues and retrieval of related emotional memories
accurately receive, process, and integrate different body-
(via hippocampal/amygdala connections to various brain
relevant signals originating from our visceral organs
structures/networks) promote craving followed by relaps-
ing behaviors (Torregrossa et al., 2011; Torregrossa and (e.g., heart, stomach) to inform decision-making (Paulus
et al., 2013; Stewart et al., 2015). In healthy subjects,
Taylor, 2013). Hence, the interventions that modulate
afferent neural signals about interoceptive changes
encoding and retrieval of emotionalemotivational mem-
(e.g., increased heart rate) serve as warnings about sub-
ories could attenuate the intensity of both positive and
optimal conditions (e.g., being in danger) and prompt
negative affective-appetitive states (Sorg, 2012). Recent
approach or avoidance behavior to respond appropriately
studies have begun to examine the potential benefit of
to the danger and return the body to an equilibrium state.
treatments aimed at reshaping addiction memories in the
This communication flows between peripheral receptors,
process of selective retrieval and targeted reconsolidation
(Liddie and Itzhak, 2016; Sorg, 2012). According to the c-fiber afferents, spinothalamic projections, specific
thalamic nuclei, posterior and anterior insula, and ACC
memory reconsolidation hypothesis, previous memories
(Paulus et al., 2013). There has been consistent evidence
become pliable and susceptible to disruption immediately
concerning disrupted IA in drug users (Berk et al., 2015).
after they are retrieved (Shi et al., 2015). Thus, during
Specifically, it has been proposed that drug users develop
active retrieval, it may be possible to modify or alter the
increased or decreased IA to different salient stimuli
affective salience of memories by incorporating new and
following chronic drug use (Ates Col et al., 2016;
somehow interfering information (Lee et al., 2017;
Verdejo-Garcia et al., 2012). In the case of decreased IA,
Torregrossa and Taylor, 2013). For example, when a
drug-related memory is reactivated by the presence of a subjects may become less aware of aversive bodily signals
evoked in response to drug-related cues. In the case of
drug-related cue, a patient could potentially add or modify
increased IA, subjects may become hyperaware of their
this memory with new information (e.g., imagining the
bodily states but do not interpret them accurately. Instead,
negative outcomes for the drug use, considering what
any visceral changes (e.g., increased heart rate) experi-
would have happened if they would have abstained and
enced might be perceived as either a symptom of with-
went home to their family instead, etc.) preferentially in a
drawal or distress, thereby triggering substance use to
controlled environment and with the guidance of a thera-
alleviate this negative affective state with positive emo-
pist. Doing so could diminish the salient value of the
initial memory. Another strategy during reconsolidation is tions (e.g., relief, pleasure). This repeated pattern further
embeds the negative reinforcement properties of substance
to broaden the “memory tunnel” by orienting their atten-
use (Baker et al., 2004). The discrepancy between the
tion toward more peripheral details (e.g., spatial and
person’s ideal state (experienced during drug use) and the
temporal details) of the memory rather than only focusing
actual one (experienced during states of craving or
on their emotional aspects (Rimmele et al., 2011). These
distress) is thought to generate body prediction error sig-
types of memory trade-offs (between new and old,
nals. Interventions suggested to be potentially effective in
emotional and nonemotional) could deliberately interfere
modulating interoceptive processes for drug users include
with memory processes to suppress cue-induced craving.
In addition to reconsolidation and extension of retro- mindfulness and physical exercise (Paulus et al., 2013). In
mindfulness-based exercises, participants are trained to
spective memories, patients with SUDs may also benefit
focus attention on their bodily states in the present
from strategies modulating prospective memory. Episodic
moment without judging them (Price and Hooven, 2018).
future thinking (EFT) is defined as the ability to mentally
There has been some initial evidence of efficacy for
travel in time and vividly preexperience future events
mindfulness interventions with alcohol and drug use
(Snider et al., 2016). EFT has been shown to modify delay
(Witkiewitz et al., 2013; Zgierska et al., 2008). With
discounting behaviors, purportedly through expanding the
physical exercise, subjects learn how to adjust their
temporal window in which individuals are considering
consequences of their decisions (Bromberg et al., 2015). exertion based on feedforward (expectations) and feed-
back (body-relevant sensing) information (Paulus et al.,
EFT has been shown to be effective in reducing delay dis-
2013). Although there is lack of evidence for the neural
counting and demand rate in alcohol users (Bulley and
mechanisms that underlie the beneficial effects of physical
Gullo, 2017; Snider et al., 2016, 2018). EFT strategies could
exercise on drug-taking behavior in substance users
also theoretically be helpful in targeting the planning and
(Rawson et al., 2015; Robertson et al., 2016), it is hy- engage in avoidance actions in response to drug cues
pothesized that repeated engagement in controlled, inter- (e.g., 80% of trials), it is thought that this may modify the
oceptive goal action (exercise) could enhance functioning individual’s automatic responses to drug cues in their daily
of interoceptive-related networks (i.e., insula, ACC) and life. Although the ApBM is a novel approach in the field of
help patients be more prepared to interpret and respond to addiction treatment, there are a few studies suggesting it
body-relevant information triggered by drug-related may have promise for decreasing relapse rates (Eberl et al.,
stimuli (Paulus et al., 2013). 2013; Wiers et al., 2011), subjective craving (Wiers et al.,
2015), as well as neural activity in brain regions involved in
Inhibitory control interventions reward processing of drug-related stimuli (e.g., medial
prefrontal cortex and nucleus accumbens) in alcohol (Wiers
Substance and alcohol use have consistently been associ- et al., 2014) and cannabis users (Cousijn et al., 2012) (more
ated with deficits in cognitive control and response inhi- details on ApBM in Chapter 17). In addition to ApBM,
bition, including tendencies to act prematurely and repeated practice with inhibitory control paradigms such as
impulsively. This includes engaging automatically in drug- go/no-go or Stroop-related tasks may increase one’s ability
related habitual behaviors despite negative consequences to withhold prepotent responses to engage in more goal-
for the behavior (Sherman et al., 2018). Cognitive control is directed behaviors (Houben et al., 2012). These types of
likely impacted by many different neurocognitive pro- training paradigms have been successful in experimental
cesses, including attentional biases or dysregulation, settings for reducing implicit attitudes and alcohol intake
memory processes, salience of cues and outcomes, or acutely, though the pragmatic application and efficacy in
misinterpretation of interoceptive signals. Thus, many of real clinical settings needs further investigation (Bowley
the interventions discussed above could potentially impact et al., 2013; Houben et al., 2012). You can find more details
cognitive control abilities as well. However, there are also on inhibitory control training in Chapter 19.
interventions that more specifically target cognitive control.
Many interventions aim to decrease automatic, habitual
Neurocognitive rehabilitation
drug-use behaviors by enhancing self-awareness of these
behaviors and their cues and the forming of new habits As mentioned above, individuals with SUDs suffer from
(Cleo et al., 2018). This is usually accomplished via self- various deficits in more general neuropsychological func-
monitoring (e.g., of cues, emotions, behaviors), identi- tions, including flexibility, visuospatial skills, psychomotor
fying alternative behaviors to drug use, planning and goal speed, attention, concentration, verbal fluency, reasoning,
setting, and reviewing progress (Kliemann et al., 2017; problem solving, and episodic memory (Rezapour et al.,
McGowan, 2013). One such strategy for enhancing plan- 2016). These impairments can interfere with treatment by
ning and problem solving is goal management training reducing the ability of a user to receive, encode, integrate,
(Alfonso et al., 2011). Realistic expectations and patient and employ therapeutic strategies, both in the context of
motivation are crucial for successful implementation of treatment sessions and in their everyday lives (Rezapour
these interventions (Gardner et al., 2012). et al., 2016). Therefore, SUDs could potentially benefit
Approach bias modification (ApBM) is a more recently from therapeutic interventions similar to cognitive reha-
investigated approach for modifying automatic behaviors to bilitation programs for other populations (e.g., traumatic
drug-related cues. These are similar to ABMs in that they brain injury, severe mental illness), which support
are computer-based training of responses to drug-related compensatory and/or restorative strategies. These types of
stimuli, but while ABMs focus on training visual atten- interventions have been successfully employed for stimu-
tion to drug-related versus neutral cues, ApBMs focus on lant, opiate, and alcohol users (Bell et al., 2016; Bickel
training behavioral approach-avoidance responses to drug- et al., 2011; Gamito et al., 2014; Goldstein et al., 2005;
related cues (Cousijn et al., 2011; Wiers et al., 2014). Marceau et al., 2017; Rass et al., 2015; Rezapour et al.,
One of the most well-known ApBM means is the approach- 2017b; Rupp et al., 2012; Snider et al., 2018; Wanmaker
avoidance paradigm in which different pictures (including et al., 2018; Zhu et al., 2018). The finding from these
neutral and drug-related cues) are shown to subjects on studies show initial promise that cognitive rehabilitation
computer screen (Wiers et al., 2015). Participants are asked programs may enhance cognitive function and increase
to respond to a stimulus feature unrelated to the contents of efficacy of broader SUD treatment programs (Bates et al.,
the picture (landscape/portrait format, left/right rotation) by 2013). However, these studies have primarily relied on
pulling or pushing the joystick (Eberl et al., 2013). By small samples and there has been a relative lack of repli-
pushing the joystick (resembling avoidance action), the cation outside the development team or to real-world
picture size decreases, whereas by pulling it (resembling clinical settings. Thus, there remains much work to be
approach action), the picture size increases (Neumann and done for these interventions to be more broadly adopted
Strack, 2000). By having the subject disproportionately into the daily practice of addiction medicine.
To summarize, the DCM model (Fig. 29.1) provides a transference of training effects to daily functioning and
neuroscience-informed way of conceptualizing different treatment outcome. As a neuroscience-based program,
cognitive components that can potentially be targeted in NEAT (as well as the DCM model) was developed in the
substance use treatment. The most robust clinical effects spirit of the Research Domain Criteria (RDoC) model,
could potentially be supported through integration of both provided by National Institute of Mental Health (Insel
cognitive modification and rehabilitation strategies that et al., 2010). RDoC supports the examination of
target different aspects of the DCM model. Ideally, such a dimensions of function rather than discrete categorical
model could eventually be used to identify areas of definitions (i.e., diagnoses). NEAT was developed with
strengths and weaknesses for each individual and inform the idea of targeting various domains of functioning,
customized treatments to meet individual patients’ needs. including the RDoC domains of cognitive systems
In the following section, we will discuss an example (e.g., attention, executive control, and working memory),
program that attempts to integrate different cognitive edu- positive/negative valence processing (e.g., reward/threat
cation, modification, and rehabilitation strategies into a processing), and arousal/modulatory systems (e.g., sleep-
program that targets various aspects of the DCM model. wake cycles, alertness).
In terms of content, the NEAT program is organized
into five main parts as follows:
Integrative cognitive interventions: Part 1: Brain education: The main purpose of these
introducing NEAT program components is to promote patient’s awareness about the
Based on research concerning the various cognitive cognitive impairments often associated with drug addiction.
maladaptive responses and deficits associated with SUD Patients are provided with information concerning common
and the various strategies that have shown potential for behavioral manifestations of these impairments in daily life
targeting aspects of the DCM model, we have developed a activities. They are informed about lifestyle changes
new program titled “Neurocognitive Empowerment for (e.g., nutrition, physical exercise) that can facilitate brain
Addiction Treatment (NEAT).” NEAT incorporates psy- recovery. To improve learning and consolidation, the edu-
choeducation, cognitive rehabilitation, and modification cation components are accompanied by colorful and comic
strategies with materials that are specifically designed to cartoons (H. Ekhtiari et al., 2017a,b). Fig. 29.2 illustrates a
be relevant for SUDs and thus increase the potential for sample of used cartoons.
FIGURE 29.2 Cartoon development pipeline for the Neurocognitive Empowerment for Addiction Treatment (NEAT) package starting from character
development and selection (panel A), ideas development (panel B), and finalized cartoons depicting cognitive deficits in SUDs including attentional bias,
memory, and executive control (panel C) (Cartoons by Naeem Tadayon and Joshua Donbar, courtesy of Laureate Institute for Brain Research).
Part 2: Compensatory strategies: The main purpose Other neuroscience-informed

of these components is to provide specific cognitive stra-
interventions
tegies for supporting optimal cognitive function or
compensating for deficits; for example, providing strategies In addition to the interventions that have been addressed
and practice for expanding tunnel memory for drug-related earlier in this chapter, there are other groups of
or emotional memories or mnemonic aids and goal man- interventions that may target neuroscience-informed bio-
agement training for memory- and planning-related prob- markers. For example, administration of atomoxetine and
lems. These components are integrated with the brain propranolol has been shown to reduce attentional biases
exercises discussed next to illustrate and practice each and affect drug-related memories in cocaine and heroin
cognitive function and compensatory strategy. users, respectively (Passamonti et al., 2017; Zhao et al.,
Part 3: Brain exercises: According to our previous 2011), and brain stimulation or neurofeedback techniques
experiences in another cognitive rehabilitation package may be used to target neural networks more directly
named NECOREDA (Neurocognitive Rehabilitation for (Yavari et al., 2016). Many of these are covered in previous
Disease of Addiction) (Rezapour et al., 2015), using brain chapters of this book. Ideally, cognitive-based interventions
exercises with different gradients of game-based features discussed herein would be integrated with these other types
could be useful for restoration of brain functions among of interventions in a holistic and personalized medicine
people with SUDs. These game-based exercises include such approach to optimize treatment for individual patients.
things as Stroop-like tasks, mazes, target cancellation tasks,
and so on. In NEAT, these games are used not only as a
Future directions
potential way of practicing and improving specific brain
functions but also for providing a foundation for discussions In the more advanced fields of medicine, such as cardiology
to enhance metacognition (the next component). or oncology, patients are assessed based on quantitative
Part 4: Metacognitive training: Metacognition biomarkers that are reliable and reflecting disease patho-
awareness is trained in this program by providing infor- genesis. Then, the most effective treatment for the indi-
mation about the cognitive functions engaged in each brain vidual is selected or even personally designed based on the
exercise and the role that these functions (and the associ- biomarker profile. Furthermore, the efficacy of these indi-
ated compensatory strategies) play in their day-to-day vidualized interventions is monitored with these same or
functioning and substance use recovery. This part targets new biomarkers to assess long-term trajectory of recovery.
insight toward the cognitive foundations of the training Currently, this seems like a dream in psychiatry in general
program and aims to enhance motivation to implement and addiction medicine in particular. However, recent ad-
skills and generalization of learning. vances in human brain mapping, genome analysis, blood
Part 5: Brain planner: Training patients to keep biochemistry, and continuous peripheral physiological
records of their daily activities, including both retrospec- recording (e.g., heart rate variability, sleep/awake behavior
tive (e.g., past events) and prospective forms (e.g., future and skin conductance response), combined with the
goals), is another critical aspect of NEAT. This supports development of novel cognitive interventions that may
higher-order cognitive functions such as self-monitoring target many of these biomarkers, provide hope for the
and planning (which are trained within compensatory future of neuroscience-informed addiction treatment.
strategies) as well as basic cognitive functions including In the ideal scenario, neuroscience-based interventions
memory and EFT in the context of daily life activities. The in addiction medicine should address following four fea-
use of a planner also supports compliance with NEAT and tures. Here, we have also provided ideas based on our new
other SU treatment activities. Each training session of trials for the NEAT package on how these features could be
NEAT has time dedicated to learning and practicing using met in the development of a neuroscience-informed
the planner. cognitive intervention.
As a paper-based training program, NEAT has 14
1. Targets a specific neuroscience-based mechanism or
sessions that include both in-session materials and
set of mechanisms informed by previous studies.
homework. The sessions are presented in an additive DCM model as a neuroscience-informed modular
structure in which basic cognitive functions (i.e., attention, model provides core mechanisms that NEAT targets
working memory) are presented before higher-order (e.g., attention, salience, interoception, memory, and
cognitive functions (i.e., inhibition, planning, prospec- cognitive control processing and the associated
tive memory). New concepts and skills are added gradu-
prefrontalelimbic networks).
ally throughout the sessions. Fig. 29.3 shows the
architecture of the 14 sessions of NEAT.
FIGURE 29.3 Architecture of Neurocognitive Empowerment for Addiction Treatment (NEAT) for 14 sessions.
2. Has a neuroscience-based biomarker based on the in abstinent polysubstance abusers. Drug Alcohol Depend. 117 (1),
targeted mechanism(s) to predict response to treat- 78e81. https://doi.org/10.1016/j.drugalcdep.2010.12.025.
ment or to help with treatment selection. In the devel- Apodaca, T.R., Longabaugh, R., 2009. Mechanisms of change in moti-
vational interviewing: a review and preliminary evaluation of the
opment of NEAT, we are utilizing baseline and
evidence. Addiction 104 (5), 705e715. https://doi.org/10.1111/
posttreatment functional magnetic resonance imaging
j.1360-0443.2009.02527.x.
(fMRI) assessments of neural reactivity during cue reac- Ates Col, I., Sonmez, M.B., Vardar, M.E., 2016. Evaluation of intero-
tivity, interoception, and response inhibition. This will ceptive awareness in alcohol-addicted patients. Noro Psikiyatr Ars 53
allow us to potentially identify and validate fMRI bio- (1), 17e22. https://doi.org/10.5152/npa.2015.9898.
markers for prediction and/or monitoring. Axelrod, S.R., Perepletchikova, F., Holtzman, K., Sinha, R., 2011.
3. Has a neuroscience-based biomarker based on the Emotion regulation and substance use frequency in women with
targeted mechanism as an outcome measure to substance dependence and borderline personality disorder receiving
monitor the efficacy of intervention over time. dialectical behavior therapy. Am. J. Drug Alcohol Abuse 37 (1),
Considering fMRI outcome measures along with clin- 37e42. https://doi.org/10.3109/00952990.2010.535582.
ical outcome measures in our ongoing NEAT trials al- Baker, T.B., Piper, M.E., McCarthy, D.E., Majeskie, M.R., Fiore, M.C.,
2004. Addiction motivation reformulated: an affective processing
lows us to assess mechanistic target engagement.
model of negative reinforcement. Psychol. Rev. 111 (1), 33e51.
4. Has the potential to be optimized or modified based
Baldacchino, A., Tolomeo, S., Balfour, D.J., Matthews, K., 2018. Profiles
on observed values of the targeted neuroscience- of visuospatial memory dysfunction in opioid-exposed and dependent
based biomarker. Based on the self-report, cognitive, populations. Psychol. Med. 1e11. https://doi.org/10.1017/
and fMRI assessments included in our initial trials, S0033291718003318.
the hope would be that eventually these same assess- Bates, M.E., Buckman, J.F., Nguyen, T.T., 2013. A role for cognitive
ments could be used to inform the personalization of rehabilitation in increasing the effectiveness of treatment for alcohol
NEAT. Participants could be providing feedback based use disorders. Neuropsychol. Rev. 23 (1), 27e47. https://doi.org/
on pretreatment, multilevel assessments that could be 10.1007/s11065-013-9228-3.
used to motivate their treatment engagement and point Beck, A.T., 1997. The past and future of cognitive therapy. J. Psychother.
to specific domains of function to be addressed. Pract. Res. 6 (4), 276e284.
Bell, M.D., Vissicchio, N.A., Weinstein, A.J., 2016. Cognitive training
While advancements in biomarkers and interventions and work therapy for the treatment of verbal learning and memory
continue, we need to continually be aware of how we can deficits in veterans with alcohol use disorders. J. Dual Diagnosis 12
bridge the gap between laboratory research and clinical (1), 83e89. https://doi.org/10.1080/15504263.2016.1145779.
implementation. Such translation can only be accomplished Berk, L., Stewart, J.L., May, A.C., Wiers, R.W., Davenport, P.W.,
through pragmatic clinical trials that test effects identified Paulus, M.P., Tapert, S.F., 2015. Under pressure: adolescent substance
users show exaggerated neural processing of aversive
in experimental settings on a larger scale. We should not
interoceptive stimuli. Addiction 110 (12), 2025e2036. https://doi.org/
forget that even in the ideal scenarios we referred to in
10.1111/add.13090.
cardiology and oncology, it takes years to translate from Berking, M., Margraf, M., Ebert, D., Wupperman, P., Hofmann, S.G.,
initial basic laboratory findings to clinical efficacy and Junghanns, K., 2011. Deficits in emotion-regulation skills predict
finally to treatment effectiveness in real-world settings. alcohol use during and after cognitive-behavioral therapy for alcohol
Thus, neuroscience-informed cognitive interventions are dependence. J. Consult. Clin. Psychol. 79 (3), 307e318. https://
unlikely to be a quick silver bullet cure for addiction. doi.org/10.1037/a0023421.
However, with continual translation between neuroscience, Bickel, W.K., Yi, R., Landes, R.D., Hill, P.F., Baxter, C., 2011.
controlled laboratory settings, and real-world clinical Remember the future: working memory training decreases delay dis-
implementation, we will hopefully continue to significantly counting among stimulant addicts. Biol. Psychiatry 69 (3), 260e265.
improve the landscape of treatment options for individuals https://doi.org/10.1016/j.biopsych.2010.08.017.
Bowley, C., Faricy, C., Hegarty, B., J Johnstone, S., L Smith, J., J
suffering from substance use.
Kelly, P., A Rushby, J., 2013. The effects of inhibitory control
training on alcohol consumption, implicit alcohol-related cognitions
Acknowledgments and brain electrical activity. Int. J. Psychophysiol. 89 (3), 342e348.
https://doi.org/10.1016/j.ijpsycho.2013.04.011.
Authors would like to thank Dr. Stacey Daughters for her invaluable Bromberg, U., Wiehler, A., Peters, J., 2015. Episodic future thinking is
feedback on the manuscript. related to impulsive decision making in healthy adolescents. Child
Dev. 86 (5), 1458e1468. https://doi.org/10.1111/cdev.12390.
References Bulley, A., Gullo, M.J., 2017. The influence of episodic foresight on delay
discounting and demand for alcohol. Addict. Behav. 66, 1e6. https://
Alfonso, J.P., Caracuel, A., Delgado-Pastor, L.C., Verdejo-Garcia, A., doi.org/10.1016/j.addbeh.2016.11.003.
2011. Combined Goal Management Training and Mindfulness medi-
tation improve executive functions and decision-making performance
Butler, A.C., Chapman, J.E., Forman, E.M., Beck, A.T., 2006. The Flavell, J.H., 1979. Metacognition and cognitive monitoring. Am. Psychol.
empirical status of cognitive-behavioral therapy: a review of meta- 34 (10), 906e911.
analyses. Clin. Psychol. Rev. 26 (1), 17e31. https://doi.org/10.1016/ Fleming, S.M., Huijgen, J., Dolan, R.J., 2012. Prefrontal contributions to
j.cpr.2005.07.003. metacognition in perceptual decision making. J. Neurosci. 32 (18),
Castine, B.R., Albein-Urios, N., Lozano-Rojas, O., Martinez- 6117e6125. https://doi.org/10.1523/JNEUROSCI.6489-11.2012.
Gonzalez, J.M., Hohwy, J., Verdejo-Garcia, A., 2018. Self- Fucito, L.M., Juliano, L.M., Toll, B.A., 2010. Cognitive reappraisal and
awareness deficits associated with lower treatment motivation in expressive suppression emotion regulation strategies in cigarette
cocaine addiction. Am. J. Drug Alcohol Abuse 1e7. https://doi.org/ smokers. Nicotine Tob. Res. 12 (11), 1156e1161. https://doi.org/
10.1080/00952990.2018.1511725. 10.1093/ntr/ntq146.
Cleo, G., Glasziou, P., Beller, E., Isenring, E., Thomas, R., 2018. Habit- Gamito, P., Oliveira, J., Lopes, P., Brito, R., Morais, D., Silva, D., et al.,
based interventions for weight loss maintenance in adults with over- 2014. Executive functioning in alcoholics following an mHealth
weight and obesity: a randomized controlled trial. Int J. Obes. (Lond.). cognitive stimulation program: randomized controlled trial. J. Med.
https://doi.org/10.1038/s41366-018-0067-4. Internet Res. 16 (4), e102. https://doi.org/10.2196/jmir.2923.
Cousijn, J., Goudriaan, A.E., Wiers, R.W., 2011. Reaching out towards Gardner, B., Lally, P., Wardle, J., 2012. Making health habitual the psy-
cannabis: approach-bias in heavy cannabis users predicts changes in chology of habit-formation and general practice. Br. J. Gen. Pract. 62
cannabis use. Addiction 106 (9), 1667e1674. https://doi.org/10.1111/ (605), 664e666.
j.1360-0443.2011.03475.x. Goldstein, G., Haas, G., Shemansky, W., Barnett, B., Salmon-Cox, S.,
Cousijn, J., Goudriaan, A.E., Ridderinkhof, K.R., van den Brink, W., 2005. Rehabilitation during alcohol detoxication in comorbid neuro-
Veltman, D.J., Wiers, R.W., 2012. Approach-bias predicts develop- psychiatric patients. J. Rehabil. Res. Dev. 42 (2), 225e234. https://
ment of cannabis problem severity in heavy cannabis users: results doi.org/10.1682/JRRD.2004.03.0040.
from a prospective FMRI study. PLoS One 7 (9), e42394. https:// Hasan, A., Falkai, P., Wobrock, T., Lieberman, J., Glenthoj, B.,
doi.org/10.1371/journal.pone.0042394. Gattaz, W.F., et al., 2015. World federation of societies of biological
Cox, W.M., Fadardi, J.S., Intriligator, J.M., Klinger, E., 2014. Attentional psychiatry (WFSBP) guidelines for biological treatment of schizo-
bias modification for addictive behaviors: clinical implications. CNS phrenia. Part 3: update 2015 management of special circumstances:
Spectr. 19 (3), 215e224. https://doi.org/10.1017/S1092852914000091. depression, suicidality, substance use disorders and pregnancy and
Cristea, I.A., Kok, R.N., Cuijpers, P., 2016. The effectiveness of cognitive lactation. World J. Biol. Psychiatr. 16 (3), 142e170. https://doi.org/
bias modification interventions for substance addictions: a meta- 10.3109/15622975.2015.1009163.
analysis. PLoS One 11 (9), e0162226. https://doi.org/10.1371/ Heffernan, T.M., 2008. The impact of excessive alcohol use on prospective
journal.pone.0162226. memory: a brief review. Curr. Drug Abuse Rev. 1 (1), 36e41.
Daughters, S.B., Lejuez, C.W., Bornovalova, M.A., Kahler, C.W., Heitmann, J., Bennik, E.C., van Hemel-Ruiter, M.E., de Jong, P.J., 2018.
Strong, D.R., Brown, R.A., 2005. Distress tolerance as a predictor of The effectiveness of attentional bias modification for substance use
early treatment dropout in a residential substance abuse treatment disorder symptoms in adults: a systematic review. Syst. Rev. 7 (1),
facility. J. Abnorm. Psychol. 114 (4), 729e734. 160. https://doi.org/10.1186/s13643-018-0822-6.
Diaz-Batanero, C., Dominguez-Salas, S., Moraleda, E., Fernandez- Hogarth, L., Balleine, B.W., Corbit, L.H., Killcross, S., 2013. Associative
Calderon, F., Lozano, O.M., 2018. Attentional bias toward alcohol learning mechanisms underpinning the transition from recreational
stimuli as a predictor of treatment retention in cocaine dependence and drug use to addiction. Ann. N. Y. Acad. Sci. 1282, 12e24. https://
alcohol user patients. Drug Alcohol Depend. 182, 40e47. https:// doi.org/10.1111/j.1749-6632.2012.06768.x.
doi.org/10.1016/j.drugalcdep.2017.10.005. Hopwood, C.J., Schade, N., Matusiewicz, A., Daughters, S.B.,
Eberl, C., Wiers, R.W., Pawelczack, S., Rinck, M., Becker, E.S., Lejuez, C.W., 2015. Emotion regulation promotes persistence in a
Lindenmeyer, J., 2013. Approach bias modification in alcohol residential substance abuse treatment. Subst. Use Misuse 50 (2),
dependence: do clinical effects replicate and for whom does it work 251e256. https://doi.org/10.3109/10826084.2014.977393.
best? Dev. Cogn. Neurosci. 4, 38e51. https://doi.org/10.1016/ Houben, K., Havermans, R.C., Nederkoorn, C., Jansen, A., 2012. Beer a
j.dcn.2012.11.002. no-go: learning to stop responding to alcohol cues reduces alcohol
Ekhtiari, H., Nasseri, P., Yavari, F., Mokri, A., Monterosso, J., 2016. intake via reduced affective associations rather than increased
Neuroscience of drug craving for addiction medicine: from circuits to response inhibition. Addiction 107 (7), 1280e1287. https://doi.org/
therapies. Prog. Brain Res. 223, 115e141. https://doi.org/10.1016/ 10.1111/j.1360-0443.2012.03827.x.
bs.pbr.2015.10.002. Inchausti, F., Ortuño-Sierra, J., García-Poveda, N., Ballesteros-Prados, A.,
Ekhtiari, H., Rezapour, T., Aupperle, R.L., Paulus, M.P., 2017a. 2016. Metacognitive abilities in adults with substance abuse treated in
Neuroscience-informed psychoeducation for addiction medicine: a therapeutic community. Adicciones 29 (2), 74e82.
neurocognitive perspective. Prog. Brain Res. 235, 239e264. https:// Insel, T., Cuthbert, B., Garvey, M., Heinssen, R., Pine, D., Quinn, K.,
doi.org/10.1016/bs.pbr.2017.08.013. et al., 2010. Research domain Criteria (RDoC)Toward a new classi-
Ekhtiari, H., Victor, T.A., Paulus, M.P., 2017b. Aberrant decision-making fication framework for research on mental disorders. Am. J. Psychiatry
and drug addiction d how strong is the evidence? Curr. Opin. Behav. 167 (7), 748e751.
Sci. 13, 25e33. https://doi.org/10.1016/j.cobeha.2016.09.002. Kiluk, B.D., Carroll, K.M., 2013. New developments in behavioral treat-
Field, M., Marhe, R., Franken, I.H., 2014. The clinical relevance of ments for substance use disorders. Curr. Psychiatry Rep. 15 (12), 420.
attentional bias in substance use disorders. CNS Spectr. 19 (3), https://doi.org/10.1007/s11920-013-0420-1.
225e230. https://doi.org/10.1017/S1092852913000321.
Kliemann, N., Vickerstaff, V., Croker, H., Johnson, F., Nazareth, I., addictions. Neuron 69 (4), 695e712. https://doi.org/10.1016/
Beeken, R.J., 2017. The role of self-regulatory skills and automaticity j.neuron.2011.02.009.
on the effectiveness of a brief weight loss habit-based intervention: Price, C.J., Hooven, C., 2018. Interoceptive awareness skills for emotion
secondary analysis of the 10 top tips randomised trial. Int. J. Behav. regulation: theory and approach of mindful awareness in body-
Nutr. Phys. Act. 14 (1), 119. https://doi.org/10.1186/s12966-017- oriented therapy (MABT). Front. Psychol. 9, 798. https://doi.org/
0578-8. 10.3389/fpsyg.2018.00798.
Koester, P., Tittgemeyer, M., Wagner, D., Becker, B., Gouzoulis- Rass, O., Schacht, R.L., Buckheit, K., Johnson, M.W., Strain, E.C.,
Mayfrank, E., Daumann, J., 2012. Cortical thinning in amphetamine- Mintzer, M.Z., 2015. A randomized controlled trial of the effects of
type stimulant users. Neuroscience 221, 182e192. https://doi.org/ working memory training in methadone maintenance patients. Drug
10.1016/j.neuroscience.2012.06.049. Alcohol Depend. 156, 38e46. https://doi.org/10.1016/
Larimer, M.E., Palmer, R.S., Marlatt, G.A., 1999. Relapse prevention. An j.drugalcdep.2015.08.012.
overview of Marlatt’s cognitive-behavioral model. Alcohol Res. Rawson, R.A., Chudzynski, J., Mooney, L., Gonzales, R., Ang, A.,
Health 23 (2), 151e160. Dickerson, D., et al., 2015. Impact of an exercise intervention on
Lee, J.L.C., Nader, K., Schiller, D., 2017. An update on memory recon- methamphetamine use outcomes post-residential treatment care. Drug
solidation updating. Trends Cognit. Sci. 21 (7), 531e545. https:// Alcohol Depend. 156, 21e28. https://doi.org/10.1016/
doi.org/10.1016/j.tics.2017.04.006. j.drugalcdep.2015.08.029.
Liddie, S., Itzhak, Y., 2016. Variations in the stimulus salience of cocaine Rendell, P.G., Mazur, M., Henry, J.D., 2009. Prospective memory
reward influences drug-associated contextual memory. Addict. Biol. impairment in former users of methamphetamine. Psychopharmacol-
21 (2), 242e254. https://doi.org/10.1111/adb.12191. ogy (Berl.) 203 (3), 609e616. https://doi.org/10.1007/s00213-008-
Marceau, E.M., Berry, J., Lunn, J., Kelly, P.J., Solowij, N., 2017. 1408-0.
Cognitive remediation improves executive functions, self-regulation Rezapour, T., Hatami, J., Farhoudian, A., Sofuoglu, M., Noroozi, A.,
and quality of life in residents of a substance use disorder therapeu- Daneshmand, R., et al., 2015. Research domain Criteria (RDoC)To-
tic community. Drug Alcohol Depend. 178, 150e158. https://doi.org/ ward a new classification framework for research on mental disorders.
10.1016/j.drugalcdep.2017.04.023. Basic Clin. Neurosci. 6 (4), 291e298.
McGowan, P., 2013. The challenge of integrating self-management sup- Rezapour, T., DeVito, E.E., Sofuoglu, M., Ekhtiari, H., 2016. Perspectives
port into clinical settings. Can. J. Diabetes 37 (1), 45e50. https:// on neurocognitive rehabilitation as an adjunct treatment for addictive
doi.org/10.1016/j.jcjd.2013.01.004. disorders: from cognitive improvement to relapse prevention. Prog.
Moeller, S.J., Goldstein, R.Z., 2014. Impaired self-awareness in human Brain Res. 224, 345e369. https://doi.org/10.1016/bs.pbr.2015.07.022.
addiction: deficient attribution of personal relevance. Trends Cognit. Rezapour, T., Wurfel, B., Simblett, S.K., Ekhtiari, H., 2017. Neuropsy-
Sci. 18 (12), 635e641. https://doi.org/10.1016/j.tics.2014.09.003. chological Rehabilitation of Psychiatric Disorders. Neuropsychologi-
Moeller, S.J., Fleming, S.M., Gan, G., Zilverstand, A., Malaker, P., cal Rehabilitation: The International Handbook.
d’Oleire Uquillas, F., et al., 2016. Metacognitive impairment in active Rezapour, T., Hatami, J., Farhoudian, A., Sofuoglu, M., Noroozi, A.,
cocaine use disorder is associated with individual differences in brain Daneshmand, R., et al., 2017a. Cognitive rehabilitation for individuals
structure. Eur. Neuropsychopharmacol. 26 (4), 653e662. https:// with opioid use disorder: A randomized controlled trial. Neuro-
doi.org/10.1016/j.euroneuro.2016.02.009. psychol. Rehabil. 1e17.
Nagel, B.J., Schweinsburg, A.D., Phan, V., Tapert, S.F., 2005. Reduced Rezapour, T., Hatami, J., Farhoudian, A., Sofuoglu, M., Noroozi, A.,
hippocampal volume among adolescents with alcohol use disorders Daneshmand, R., et al., 2017b. Cognitive rehabilitation for individuals
without psychiatric comorbidity. Psychiatr. Res. 139 (3), 181e190. with opioid use disorder: a randomized controlled trial. Neuropsychol.
Neumann, R., Strack, F., 2000. Approach and avoidance the influence of Rehabil. 1e17. https://doi.org/10.1080/09602011.2017.1391103.
proprioceptive and exteroceptive cues on encoding of affective in- Rimmele, U., Davachi, L., Petrov, R., Dougal, S., Phelps, E.A., 2011.
formation. J. Personal. Soc. Psychol. 79 (1), 39e48. Emotion enhances the subjective feeling of remembering, despite
Oei, T.P., Lim, B., Young, R.M., 1991. Cognitive processes and cognitive lower accuracy for contextual details. Emotion 11 (3), 553e562.
behavior therapy in the treatment of problem drinking. J. Addict. Dis. https://doi.org/10.1037/a0024246.
10 (3), 63e80. https://doi.org/10.1300/J069v10n03_07. Robertson, C.L., Ishibashi, K., Chudzynski, J., Mooney, L.J.,
Passamonti, L., Luijten, M., Ziauddeen, H., Coyle-Gilchrist, I.T.S., Rawson, R.A., Dolezal, B.A., et al., 2016. Effect of exercise training
Rittman, T., Brain, S.A.E., et al., 2017. Atomoxetine effects on on striatal dopamine D2/D3 receptors in methamphetamine users
attentional bias to drug-related cues in cocaine dependent individuals. during behavioral treatment. Neuropsychopharmacology 41 (6),
Psychopharmacology (Berl.) 234 (15), 2289e2297. https://doi.org/ 1629e1636. https://doi.org/10.1038/npp.2015.331.
10.1007/s00213-017-4643-4. Roebers, C.M., 2017. Executive function and metacognitionTowards a
Paulus, M.P., Stewart, J.L., Haase, L., 2013. Treatment approaches for unifying framework of cognitive self-regulation. Dev. Rev. 45,
interoceptive dysfunctions in drug addiction. Front. Psychiatry 4, 137. 31e51. https://doi.org/10.1016/j.dr.2017.04.001.
https://doi.org/10.3389/fpsyt.2013.00137. Rupp, C., Kemmler, G., Kurz, M., Hinterhuber, H., Fleischhacker, W.,
Pietrek, C., Popov, T., Steffen, A., Miller, G.A., Rockstroh, B., 2012. 2012. Cognitive remediation therapy during treatment for alcohol
Neuromagnetic indication of dysfunctional emotion regulation in af- dependence. J. Stud. Alcohol Drugs 73 (4).
fective disorders. Depress Res Treat 156529. https://doi.org/10.1155/ Sadeghi, S., Ekhtiari, H., Bahrami, B., Ahmadabadi, M.N., 2017. Meta-
2012/156529. cognitive deficiency in a perceptual but not a memory task in meth-
Potenza, M.N., Sofuoglu, M., Carroll, K.M., Rounsaville, B.J., 2011. adone maintenance patients. Sci. Rep. 7 (1), 7052. https://doi.org/
Neuroscience of behavioral and pharmacological treatments for 10.1038/s41598-017-06707-w.
Shapiro, S.L., Carlson, L.E., Astin, J.A., Freedman, B., 2006. Mechanisms Torregrossa, M.M., Taylor, J.R., 2013. Learning to forget: manipulating
of mindfulness. J. Clin. Psychol. 62 (3), 373e386. https://doi.org/ extinction and reconsolidation processes to treat addiction. Psycho-
10.1002/jclp.20237. pharmacology (Berl.) 226 (4), 659e672. https://doi.org/10.1007/
Sherman, B.J., Baker, N.L., Squeglia, L.M., McRae-Clark, A.L., 2018. s00213-012-2750-9.
Approach bias modification for cannabis use disorder: a proof-of- Torregrossa, M.M., Corlett, P.R., Taylor, J.R., 2011. Aberrant learning and
principle study. J. Subst. Abus. Treat. 87, 16e22. https://doi.org/ memory in addiction. Neurobiol. Learn. Mem. 96 (4), 609e623.
10.1016/j.jsat.2018.01.012. https://doi.org/10.1016/j.nlm.2011.02.014.
Shi, H.S., Luo, Y.X., Yin, X., Wu, H.H., Xue, G., Geng, X.H., Hou, Y.N., Verdejo-Garcia, A., Clark, L., Dunn, B.D., 2012. The role of interoception
2015. Reconsolidation of a cocaine associated memory requires DNA in addiction: a critical review. Neurosci. Biobehav. Rev. 36 (8),
methyltransferase activity in the basolateral amygdala. Sci. Rep. 5, 1857e1869. https://doi.org/10.1016/j.neubiorev.2012.05.007.
13327. https://doi.org/10.1038/srep13327. Wanmaker, S., Leijdesdorff, S.M.J., Geraerts, E., van de Wetering, B.J.M.,
Skidmore, E.R., Swafford, M., Juengst, S.B., Terhorst, L., 2018. Self- Renkema, P.J., Franken, I.H.A., 2018. The efficacy of a working
awareness and recovery of independence with strategy training. Am. memory training in substance use patients: a randomized double-blind
J. Occup. Ther. 72 (1) https://doi.org/10.5014/ajot.2018.023556, placebo-controlled clinical trial. J. Clin. Exp. Neuropsychol. 40 (5),
7201345010p7201345011e7201345010p7201345015. 473e486. https://doi.org/10.1080/13803395.2017.1372367.
Snider, S.E., LaConte, S.M., Bickel, W.K., 2016. Episodic future thinking: Wiers, R.W., Eberl, C., Rinck, M., Becker, E.S., Lindenmeyer, J., 2011.
expansion of the temporal window in individuals with alcohol Retraining automatic action tendencies changes alcoholic
dependence. Alcohol Clin. Exp. Res. 40 (7), 1558e1566. https:// patients’ approach bias for alcohol and improves treatment outcome.
doi.org/10.1111/acer.13112. Psychol. Sci. 22 (4), 490e497. https://doi.org/10.1177/
Snider, S.E., Deshpande, H.U., Lisinski, J.M., Koffarnus, M.N., 0956797611400615.
LaConte, S.M., Bickel, W.K., 2018. Working memory training im- Wiers, C.E., Stelzel, C., Park, S.Q., Gawron, C.K., Ludwig, V.U.,
proves alcohol users’ episodic future thinking: a rate-dependent Gutwinski, S., et al., 2014. Neural correlates of alcohol-approach bias
analysis. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 3 (2), in alcohol addiction: the spirit is willing but the flesh is weak for
160e167. https://doi.org/10.1016/j.bpsc.2017.11.002. spirits. Neuropsychopharmacology 39 (3), 688e697. https://doi.org/
Sorg, B.A., 2012. Reconsolidation of drug memories. Neurosci. Biobehav. 10.1038/npp.2013.252.
Rev. 36 (5), 1400e1417. https://doi.org/10.1016/j.neubiorev.2012. Wiers, R.W., Houben, K., Fadardi, J.S., van Beek, P., Rhemtulla, M.,
02.004. Cox, W.M., 2015. Alcohol cognitive bias modification training for
Stacy, A.W., Wiers, R.W., 2010. Implicit cognition and addiction: a tool problem drinkers over the web. Addict. Behav. 40, 21e26. https://
for explaining paradoxical behavior. Annu. Rev. Clin. Psychol. 6, doi.org/10.1016/j.addbeh.2014.08.010.
551e575. https://doi.org/10.1146/annurev.clinpsy.121208.131444. Wilcox, C.E., Pommy, J.M., Adinoff, B., 2016. Neural circuitry of
Stanger, C., Budney, A.J., Bickel, W.K., 2013. A developmental impaired emotion regulation in substance use disorders. Am. J. Psy-
perspective on neuroeconomic mechanisms of contingency manage- chiatry 173 (4), 344e361. https://doi.org/10.1176/
ment. Psychol. Addict. Behav. 27 (2), 403e415. https://doi.org/ appi.ajp.2015.15060710.
10.1037/a0028748. Witkiewitz, K., Lustyk, M.K.B., Bowen, S., 2013. Retraining the addicted
Steinberger, A., Payne, J.D., Kensinger, E.A., 2011. The effect of cogni- brain: a review of hypothesized neurobiological mechanisms of
tive reappraisal on the emotional memory trade-off. Cogn. Emot. 25 mindfulness-based relapse prevention. Psychol. Addict. Behav. 27 (2),
(7), 1237e1245. https://doi.org/10.1080/02699931.2010.538373. 351e365. https://doi.org/10.1037/a0029258.
Stewart, J.L., May, A.C., Tapert, S.F., Paulus, M.P., 2015. Hyperactivation Yavari, F., Shahbabaie, A., Leite, J., Carvalho, S., Ekhtiari, H., Fregni, F.,
to pleasant interoceptive stimuli characterizes the transition to stimu- 2016. Noninvasive brain stimulation for addiction medicine: from
lant addiction. Drug Alcohol Depend. 154, 264e270. https://doi.org/ monitoring to modulation. Prog. Brain Res. 224, 371e399. https://
10.1016/j.drugalcdep.2015.07.009. doi.org/10.1016/bs.pbr.2015.08.007.
Streeter, C.C., Terhune, D.B., Whitfield, T.H., Gruber, S., Sarid-Segal, O., Zgierska, A., Rabago, D., Zuelsdorff, M., Coe, C., Miller, M.,
Silveri, M.M., et al., 2008. Performance on the Stroop predicts treat- Fleming, M., 2008. Mindfulness meditation for alcohol relapse pre-
ment compliance in cocaine-dependent individuals. Neuro- vention: a feasibility pilot study. J. Addict. Med. 2 (3), 165e173.
psychopharmacology 33 (4), 827e836. https://doi.org/10.1038/ https://doi.org/10.1097/ADM.0b013e31816f8546.
sj.npp.1301465. Zhao, L.Y., Sun, L.L., Shi, J., Li, P., Zhang, Y., Lu, L., 2011. Effects of
Strong, D.R., 2012. Persistence on a stress-challenge task before initiating beta-adrenergic receptor blockade on drug-related memory reconso-
buprenorphine treatment was associated with successful transition lidation in abstinent heroin addicts. Drug Alcohol Depend. 118 (2e3),
from opioid use to early abstinence. J. Addict. Med. 6 (3), 219. 224e229. https://doi.org/10.1016/j.drugalcdep.2011.03.025.
Tanabe, J., Tregellas, J.R., Dalwani, M., Thompson, L., Owens, E., Zhu, Y., Jiang, H., Su, H., Zhong, N., Li, R., Li, X., et al., 2018. A newly
Crowley, T., Banich, M., 2009. Medial orbitofrontal cortex gray matter designed mobile-based computerized cognitive addiction therapy app
is reduced in abstinent substance-dependent individuals. Biol. Psychi- for the improvement of cognition impairments and risk decision
atry 65 (2), 160e164. https://doi.org/10.1016/j.biopsych.2008.07.030. making in methamphetamine use disorder: randomized controlled
Thompson, P.M., Hayashi, K.M., Simon, S.L., Geaga, J.A., Hong, M.S., trial. JMIR Mhealth Uhealth 6 (6), e10292. https://doi.org/10.2196/
Sui, Y., et al., 2004. Structural abnormalities in the brains of human 10292.
subjects who use methamphetamine. J. Neurosci. 24 (26),
6028e6036. https://doi.org/10.1523/JNEUROSCI.0713-04.2004.
Chapter 30
Synergistic opportunities in combined

interventions for addiction treatment
Antonio Verdejo-Garcia1 and Gloria Garcia-Fernandez1, 2
1
School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia; 2Faculty of
Psychology, University of Oviedo, Oviedo, Spain
Introduction systems. We focus on both cognitive trainings and other

psychological interventions for the reward/salience system
A common tenet of neuroscience models of addiction is the and specific cognitive trainings and CBT/multicomponent
existence of an imbalance between sensitization of the brain approaches for the cognitive control/decision-making system.
systems that code the reward value and the salience of In addition to “imbalanced system models,” another
drug-related stimuli and deterioration of the systems that way of looking into addiction-related neurocognitive
orchestrate cognitive control and decision-making (Chapter dysfunction and treatment is through the lens of aberrant
3). The cognitive training and rehabilitation programs decision-making (Chapter 4). Decision-making is probably
reviewed in this book primarily tap into one of these two the most complex (and yet ubiquitously employed) cogni-
systems. Cognitive bias modification (CBM) and mindful- tive skill. Decision-making processes use inputs from the
ness practice dampen down the motivational value and the reward/salience and the cognitive control systems; for
salience of drug-related biases and automated behaviors instance, the reward values of the different options on offer
(Chapters 17, 21), whereas working memory training and and the working memory representations of the current
Goal Management Training (GMT) aim to build the context and future goals (Noël et al., 2013). In addition,
capacity of the cognitive control or decision-making sys- decision-making processes produce outputs related to pre-
tems (Chapters 18, 20). Within the traditional portfolio of diction and forecasting of selection outcomes (Verdejo-
psychological treatments for addiction, evidence-based in- García et al., 2018). For example, substance users in
terventions such as contingency management (provides treatment will often make decisions that incorporate the
rewards contingent on drug-free tests) and adjunctive value/salience of drug use, the context of recovery, and the
interventions such as physical exercise also act on the goal of abstinence (inputs) and estimate the impact of
reward/salience system (Lynch et al., 2013; Stanger et al., the available courses of action on each of these aspects
2013). Cognitive behavioral therapy (CBT) has been typi- (outputs). If drug useerelated valence/salience overrides
cally viewed as an intervention for the cognitive control/ the other inputs and/or if the outcomes of drug use are not
decision-making system, given its emphasis on goal setting adequately predicted, advantageous decision-making is
and scheduling and problem solving skills (Blume and punctured. As the decision-making process is integrative
Alan Marlatt, 2009). Multicomponent approaches such as (combines reward and goal information) and cyclic (inputs
therapeutic communities (TCs) also tap into decision- influence forecasting outputs, and the outcomes of these
making processes by promoting self-monitoring and outputs modify the value/salience of inputs), it is reason-
responsibility, as well as education in social and commu- able to focus on treatment approaches that simultaneously
nity valuesdin TCs terminology: “right living” (National target reward/salience valuation and goal-based represen-
Institute on Drug Abuse, 2015). On the basis of these tations and that do so in a continuous manner to restore
intervention principles, in the first part of this chapter, we advantageous decision-making systems. In the second part
discuss the potential to improve addiction treatment out- of this chapter, we will discuss the potential of combining
comes by combining therapies that tap into the reward/ decision-making interventions with novel technologies that
salience and the cognitive control/decision-making can boost the integration of decision-making inputs and

outputs. An example of this approach is the combination of approaches such as working memory and inhibitory control
episodic future thinking, a cognitive neuroscienceebased trainings) and contingency management could have addi-
intervention that fosters the preexperiencing of future tive or even synergistic effects on clinical outcomes.
events with immersive technologies, so that substance users Although we devote most of our discussion to the combi-
can better evaluate the outcomes of different courses of nation of top-down cognitive training and bottom-up
action on their current state and their future goals. psychosocial interventions, it is important to note that it
could be similarly promising to combine a top-down
“traditional” intervention with a bottom-up cognitive
Combining top-down and bottom-up training. That is the case of the combination of CBM
(controls automatic biases toward drug cues) and CBT
approaches
(strengthens problem solving skills), which is discussed in
We will discuss three potential approaches: (1) combining Chapter 17 and currently being tested in ongoing trials
cognitive training with existing evidence-based (Heitmann et al., 2017).
interventions; (2) combining cognitive training and exer- The second approach aims to maximize the beneficial
cise; and (3) combining two cognitive trainings. effects of physical exercise on addiction-related cognitive
In the context of the first approach, emerging evidence deficits, craving, and mental health problems (Mooney
suggests that combining cognitive training, including genet al., 2014). Although physical exercise has a long history
eral cognitive remediation and working memory training, as an adjunctive intervention within multicomponent
with contingency management (financial incentives asso- treatment approaches such as TCs, more recent neuropsy-
ciated with completion of cognitive training sessions) chological studies provided new evidence about its positive
improves the beneficial effects of training on cognitive impact on neuroplasticity and cognitive recovery (Hötting
control and decision-making abilities (Bickel et al., 2011; and Röder, 2013). With regard to neuroplasticity, a pio-
Kiluk et al., 2017). The next step in this approach is to neering study among people with methamphetamine
explore the potential of this combination to improve clinical addiction has shown that an 8-week aerobic exercise
outcomes such as craving and reduction of drug use. training program significantly increases the availability of
A promising approach in this context would be combining dopamine D2-type receptors in the striatum, linked to
GMT and contingency management. GMT trains partici- reward valuation and impulsivity (Robertson et al., 2016).
pants to apply a decision-making strategy that facilitates Moreover, exercise-related effects on myokine expression
achievement of complex goals (Alfonso et al., 2011; and neurotrophins such as brain-derived neurotrophic factor
Valls-Serrano et al., 2016), and most training-enrolled promote neuroplasticity in the hippocampus and related
participants choose reduction of drug use or abstinence as frontolimbic systems that are implicated in relational
their primary goal. The standard evidence-based version of memory (Voss et al., 2019), a cognitive process implicated
contingency management applies positive reinforcement in drug craving associative memories (Robbins et al.,
and uses financial reimbursements or community 2008). In addition, numerous studies have examined the
reinforcers to incentivize abstinence (McPherson et al., impact of different exercise regimens and timings on
2018; Rash et al., 2017; Tardelli et al., 2018). Participants subsequent cognitive performance among nonclinical
receive shopping vouchers or access to community-based populations. Systematic reviews and metaanalytic sum-
activities in exchange for negative drug tests. While maries of this evidence suggest that acute bouts of aerobic
GMT provides a clear-cut top-down strategy to regain exercise improve cognitive performance up to 15 min
cognitive control and improve goal-based decision-making, postexercise (McSween et al., 2019), whereas longer-term
contingency management regulates the reward system via exercise regimens (>6 weeks) can significantly improve
access to competitive reinforcers (Verdejo-García et al., executive functions and particularly inhibitory control (Xue
2018). Moreover, contingency management promotes et al., 2019). The benefits of high-intensity exercise on
abstinence and thus may facilitate the application of the cognition or addiction treatment outcomes are compara-
active ingredients of GMT and the self-efficacy of tively less clear at this stage (Browne et al., 2017; Colledge
treatment-enrolled participants. The community reinforce- et al., 2018). Overall, there is emerging evidence that
ment approach, an extension of contingency management suggests that the combination of aerobic exercise combined
that diversifies the type of competitive reinforcers by and inhibitory control training can have synergistic effects
incorporating items from the patients’ everyday lives on cognitive recovery and related clinical outcomes. More
(recreational, vocational, social) (De Crescenzo et al., 2018; generally, acute bouts of aerobic exercise could be sched-
De Giorgi et al., 2017), can also pave the way to practice uled before cognitively demanding addiction therapies
GMT strategies in the context of concrete goals. Therefore, (e.g., CBT) to optimize delivery of therapeutic contents.
there are sound theoretical principles to speculate that the The third approach consisting on combining bottom-up
combination of GMT (and maybe other top-down and top-down cognitive trainings sounds immediately
Synergistic opportunities in combined interventions for addiction treatment Chapter | 30 407
intuitive. However, its application is not without chal- If we focus on patients’ everyday decision-making, an
lenges. For example, we applied a combination of CBM exciting new avenue consists on overlapping cognitive
(bottom-up, efficacious in several independent randomized neuroscience informed decision-making interventions, such
trials, see Chapter 17) and working memory training as episodic future thinking, with increasingly available
(top-down, mixed evidence, see Chapter 18) in people with immersive technologies, such as augmented and mixed
alcohol use disorders and found that the combination reality, which will be routinely embedded in mobile phone
training did not improve cognitive performance or clinical devices within the next 10 years. Episodic future thinking is
outcomes (Manning et al., 2019). Working memory a cognitive exercise/training that aims to promote a future-
training even reduced the magnitude of the benefit that we oriented approach to decision-making by increasing the
had previously achieved in similar populations with CBM tangibility, personal relevance, and positive value of future
alone (e.g., Manning et al., 2016). We reasoned that one of events (Schacter et al., 2017). Emerging evidence shows
the factors explaining lack of success might be the risk of that episodic future thinking training interventions signifi-
overwhelming cognitive abilities and generating frustration. cantly reduce delay discounting (preference for immediate
Therefore, this approach should carefully consider the over delayed rewards) among people with different addic-
timing and the intensity of the “combination training,” for tions (Chiou and Wu, 2016; Snider et al., 2016; Stein et al.,
example, by alternating different trainings on different days 2016) and ad libitum tobacco consumption in smokers
and ensuring that difficulty is progressive. Timing is (Stein et al., 2018). This evidence suggests that this training
another important factor, as bottom-up interventions can be promotes long-termebased decision-making and control of
more adequate during early treatment (or even pretreat- drug use. Combining episodic future thinking and immer-
ment) to build the necessary prerequisite skills to later sive technology would enable patients to engage in con-
benefit from more complex top-down interventions such as crete future-oriented visualization exercises, assisted by
working memory training. It is also possible that other augmented or mixed reality environments (e.g., when
combinations of bottom-up and top-down trainings hold thinking about health and family, they could visualize
greater potential and thus yield better results in the future. future, “healthy versions” of themselves and their loved
For example, there are ongoing trials combining CBM and ones), to promote more personalized and realistic fore-
extinction training in alcohol users (Chapter 17), and GMT casting outputs and facilitate long-termebased decision-
has successfully incorporated mindfulness practice in making. Most importantly, this training could occur at
polysubstance users (Chapter 20). In both cases, the any time, as needed, fitting with the continuous flow of
combined trainings are implemented as an integrated decisions of daily life and providing an “ad hoc” tool for
treatment approach, enabling researchers and treatment risky situations (e.g., drug priming and stress situations,
providers to synergize and progressively pace the thera- entering “the zone” as described in gambling disorder). It is
peutic mechanisms of the two interventions. Integrating important to note that immersive technology could also be
rather than simply adding two cognitive training incorporated to other interventions such as CBM that do not
interventions is a more promising strategy to develop specifically target decision-making skills but can be
feasible and cost-effective training protocols that can be customized to adapt their therapeutic mechanisms to foster
incorporated to the treatment of substance use disorders in future-oriented choicesdfor example, by visualizing the
clinical settings. negative consequences of approaching drug-related stimuli
and the positive consequences of approaching alternative
stimuli. Goal-related interventions, such as GMT or moti-
Interventions tapping into decision- vational interview, could also benefit from immersive
making technology-aided future visualization exercises.
We make multiple decisions every single day. For people Environment modification approaches should leverage
with addiction problems, many of these decisions involve on evidence-based policies that reduce the subjective value
some degree of conflict between drug-related inputs of drug-related behaviors and increase the value of
(drug craving is a key symptom that does not subside with competitive reinforcers (see Chapter 24). In addition, it
abstinence) and conflicting goal-related inputs would be interesting to explore the potential of nudging
(e.g., abstinence, recovery, health, family) (Noël et al., initiatives, namely, implicit and minimally invasive envi-
2013). Vulnerabilities in this decision-making process are a ronmental interventions that can have a significant impact
hallmark of addiction (Redish et al., 2008; Verdejo-García on behavior change. Nudging strategies can be potentially
and Bechara, 2009). In this context, we need interventions applied to shift decision-making tendencies around drug
that (1) empower patients to resolve these decisions use in the general community and to facilitate abstinence
advantageously and in a continuous manner and/or maintenance among drug users in recovery. Specific
(2) modify the environment to reduce the conflict between nudging strategies for patients in recovery may include
competing inputs. environmental interventions in their own homes. For
example, smart lights can be used to regulate light type and References
intensity to promote circadian alignment, given the impact
Alfonso, J.P., Caracuel, A., Delgado-Pastor, L.C., Verdejo-García, A.,
of circadian disruption on motivation-based decision-
2011. Combined goal management training and mindfulness medita-
making and drug relapse (Cain et al., 2008; Doyle et al.,
tion improve executive functions and decision-making performance in
2015). Similarly, home-based remote monitoring devices abstinent polysubstance abusers. Drug Alcohol Depend. 117 (1),
could trigger personalized reminders compatible with 78e81.
future-oriented goals to strengthen goal representations Bickel, W.K., Yi, R., Landes, R.D., Hill, P.F., Baxter, C., 2011.
during everyday decision-making (Malek et al., 2018). Remember the future: working memory training decreases delay dis-
Another avenue to explore is that of increasing the counting among stimulant addicts. Biol. Psychiatry 69 (3), 260e265.
perceived value of treatment among patients, applying Blume, A.W., Alan Marlatt, G., 2009. The role of executive cognitive
knowledge of the behavioral economics of addiction. For functions in changing substance use: what we know and what we need
example, people with substance use disorders have proven to know. Ann. Behav. Med. 37 (2), 117e125.
Browne, S.E., Flynn, M.J., O’Neill, B.V., Howatson, G., Bell, P.G.,
to be exquisitely sensitive to the value of uncertain (vs.
Haskell-Ramsay, C.F., 2017. Effects of acute high-intensity exercise
certain) commodities (Vosburg et al., 2010). Thus, it is
on cognitive performance in trained individuals: a systematic review.
tempting to speculate that we could increase the subjective In: Progress in Brain Research, 234. Elsevier, pp. 161e187.
value of (and adherence to) treatment by keeping the Cain, S.W., McDonald, R.J., Ralph, M.R., 2008. Time stamp in condi-
content of therapeutic packages uncertain. Although these tioned place avoidance can be set to different circadian phases. Neu-
are still speculative ideas that require more elaboration and robiol. Learn. Mem. 89 (4), 591e594.
proper testing for safety and efficacy, the bottom line is we Chiou, W.-B., Wu, W.-H., 2016. Episodic future thinking involving the
could explore nudging-inspired interventions for behavior nonsmoking self can induce lower discounting and cigarette con-
change in the context of compensation of the decision- sumption. J. Stud. Alcohol Drugs 78 (1), 106e112.
making deficits of people with addiction. Colledge, F., Gerber, M., Pühse, U., Ludyga, S., 2018. Anaerobic exercise
training in the therapy of substance use disorders: a systematic review.
Front. Psychiatry 9, 644.
Conclusion De Crescenzo, F., Ciabattini, M., D’Alò, G.L., De Giorgi, R., Del
Giovane, C., Cassar, C., Cipriani, A., 2018. Comparative efficacy and
In this final chapter, we adopt an intentionally hypothetical
acceptability of psychosocial interventions for individuals with
and futuristic view to exploiting synergistic opportunities cocaine and amphetamine addiction: a systematic review and network
for addiction treatment derived from cognitive neurosci- meta-analysis. PLoS Med. 15 (12), e1002715.
ence knowledge. We tentatively conclude that combined De Giorgi, R., D’Alò, G.L., De Crescenzo, F., 2017. Psychosocial in-
interventions blending top-down and bottom-up terventions in stimulant use disorders: a focus on women. Curr. Opin.
approaches, when meaningfully integrated, can provide Psychiatr. 30 (4), 275e282.
more comprehensive coverage of the faulty neurocognitive Doyle, S.E., Feng, H., Garber, G., Menaker, M., Lynch, W.J., 2015. Ef-
systems involved in addiction pathophysiology and thus fects of circadian disruption on methamphetamine consumption in
improve clinical outcomes. Combinations of “top-down methamphetamine-exposed rats. Psychopharmacology 232 (12),
cognitive control trainings þ contingency management” 2169e2179.
Heitmann, J., van Hemel-Ruiter, M.E., Vermeulen, K.M., Ostafin, B.D.,
and “inhibitory control training þ aerobic exercise” seem
MacLeod, C., Wiers, R.W., de Jong, P.J., 2017. Internet-based
particularly promising, with well-established effects of
attentional bias modification training as add-on to regular treatment
“GMT þ mindfulness.” The combination of CBM (bottom- in alcohol and cannabis dependent outpatients: a study protocol of a
up) and traditional CBT (top-down) is also well founded randomized control trial. BMC Psychiatry 17 (1), 193.
and under current evaluation. Promising combined Hötting, K., Röder, B., 2013. Beneficial effects of physical exercise on
interventions should eventually progress toward fully neuroplasticity and cognition. Neurosci. Biobehav. Rev. 37 (9),
blended interventions. We need more research to identify 2243e2257.
the key therapeutic ingredients and parameters of such in- Kiluk, B.D., Buck, M.B., Devore, K.A., Babuscio, T.A., Nich, C.,
tegrated therapies. In addition, the advent of portable Carroll, K.M., 2017. Performance-based contingency management in
immersive technologies opens an exciting new avenue for cognitive remediation training: a pilot study. J. Subst. Abus. Treat. 72,
80e88.
implementation of “online/real-time” decision-making
Lynch, W.J., Peterson, A.B., Sanchez, V., Abel, J., Smith, M.A., 2013.
trainings with a focus on strengthening a goal-based
Exercise as a novel treatment for drug addiction: a neurobiological and
future thinking strategy. Finally, we speculate about novel stage-dependent hypothesis. Neurosci. Biobehav. Rev. 37 (8),
ways in which we could modify macro- and microenvi- 1622e1644.
ronments (e.g., social policies, patient’s houses, treatment Malek, H.B., Berna, F., D’Argembeau, A., 2018. Envisioning the times of
packages) to test the effects of minimally invasive nudging future events: the role of personal goals. Conscious. Cognit. 63,
interventions on patients’ decision-making abilities. 198e205.
Synergistic opportunities in combined interventions for addiction treatment Chapter | 30 409
Manning, V., Mroz, K., Garfield, J.B., Staiger, P.K., Hall, K., Schacter, D.L., Benoit, R.G., Szpunar, K.K., 2017. Episodic future
Lubman, D.I., Verdejo-García, A., 2019. Combining Approach Bias thinking: mechanisms and functions. Curr. Opin. Behav. Sci. 17,
Modification with Working Memory Training during Inpatient 41e50.
Alcohol Withdrawal: An Open-Label Pilot Trial of Feasibility and Snider, S.E., LaConte, S.M., Bickel, W.K., 2016. Episodic future thinking:
Acceptability. Substance Abuse Treatment, Prevention, and Policy in expansion of the temporal window in individuals with alcohol
submission. dependence. Alcohol Clin. Exp. Res. 40 (7), 1558e1566.
Manning, V., Staiger, P.K., Hall, K., Garfield, J.B., Flaks, G., Leung, D., Stanger, C., Budney, A.J., Bickel, W.K., 2013. A developmental
Verdejo-Garcia, A., 2016. Cognitive bias modification training during perspective on neuroeconomic mechanisms of contingency manage-
inpatient alcohol detoxification reduces early relapse: a randomized ment. Psychol. Addict. Behav. 27 (2), 403.
controlled trial. Alcohol Clin. Exp. Res. 40 (9), 2011e2019. Stein, J.S., Tegge, A.N., Turner, J.K., Bickel, W.K., 2018. Episodic future
McPherson, S.M., Burduli, E., Smith, C.L., Herron, J., Oluwoye, O., thinking reduces delay discounting and cigarette demand: an investi-
Hirchak, K., Roll, J.M., 2018. A review of contingency management gation of the good-subject effect. J. Behav. Med. 41 (2), 269e276.
for the treatment of substance-use disorders: adaptation for under- Stein, J.S., Wilson, A.G., Koffarnus, M.N., Daniel, T.O., Epstein, L.H.,
served populations, use of experimental technologies, and personal- Bickel, W.K., 2016. Unstuck in time: episodic future thinking reduces
ized optimization strategies. Subst. Abuse Rehabil. 9, 43. delay discounting and cigarette smoking. Psychopharmacology 233
McSween, M.P., Coombes, J.S., MacKay, C.P., Rodriguez, A.D., (21e22), 3771e3778.
Erickson, K.I., Copland, D.A., McMahon, K.L., 2019. The immediate Tardelli, V.S., do Lago, M.P.P., Mendez, M., Bisaga, A., Fidalgo, T.M.,
effects of acute aerobic exercise on cognition in healthy older adults: a 2018. Contingency management with pharmacologic treatment for
systematic review. Sports Med. 49 (1), 67e82. https://doi.org/ stimulant use disorders: a review. Behav. Res. Ther. 111, 57e63.
10.1007/s40279-018-01039-9. Valls-Serrano, C., Caracuel, A., Verdejo-García, A., 2016. Goal Man-
Mooney, L.J., Cooper, C., London, E.D., Chudzynski, J., Dolezal, B., agement Training and Mindfulness Meditation improve executive
Dickerson, D., Rawson, R.A., 2014. Exercise for methamphetamine functions and transfer to ecological tasks of daily life in polysubstance
dependence: rationale, design, and methodology. Contemp. Clin. users enrolled in therapeutic community treatment. Drug Alcohol
Trials 37 (1), 139e147. Depend. 165, 9e14.
National Institute on Drug Abuse, 2015. NIDA research report: therapeutic Verdejo-García, A., Alcázar-Córcoles, M., Albein-Urios, N., 2018a.
communities (series 15-4877). Retrieved from: https://www. Neuropsychological interventions for decision-making in addiction.
drugabuse.gov/publications/research-reports/therapeutic-communities. Neuropsychology Review invited submission.
Noël, X., Brevers, D., Bechara, A., 2013. A neurocognitive approach to Verdejo-García, A., Bechara, A., 2009. A somatic marker theory of
understanding the neurobiology of addiction. Curr. Opin. Neurobiol. addiction. Neuropharmacology 56, 48e62.
23 (4), 632e638. Verdejo-García, A., Chong, T.T.-J., Stout, J.C., Yücel, M., London, E.D.,
Rash, C.J., Stitzer, M., Weinstock, J., 2017. Contingency management: 2018b. Stages of dysfunctional decision-making in addiction. Phar-
new directions and remaining challenges for an evidence-based macol. Biochem. Behav. 164, 99e105.
intervention. J. Subst. Abus. Treat. 72, 10e18. Vosburg, S.K., Haney, M., Rubin, E., Foltin, R.W., 2010. Using a novel
Redish, A.D., Jensen, S., Johnson, A., 2008. Addiction as vulnerabilities in alternative to drug choice in a human laboratory model of a cocaine
the decision process. Behav. Brain Sci. 31 (4), 461e487. binge: a game of chance. Drug Alcohol Depend. 110 (1e2), 144e150.
Robbins, T., Ersche, K., Everitt, B., 2008. Drug addiction and the memory Voss, M.W., Soto, C., Yoo, S., Sodoma, M., Vivar, C., van Praag, H.,
systems of the brain. Ann. N. Y. Acad. Sci. 1141 (1), 1e21. 2019. Exercise and hippocampal memory systems. Trends Cognit.
Robertson, C.L., Ishibashi, K., Chudzynski, J., Mooney, L.J., Sci. 23 (4), 318e333. https://doi.org/10.1016/j.tics.2019.01.006.
Rawson, R.A., Dolezal, B.A., London, E.D., 2016. Effect of exercise Xue, Y., Yang, Y., Huang, T., 2019. Effects of chronic exercise in-
training on striatal dopamine D2/D3 receptors in methamphetamine terventions on executive function among children and adolescents: a
users during behavioral treatment. Neuropsychopharmacology 41 (6), systematic review with meta-analysis. Br. J. Sports Med. https://
1629. doi.org/10.1136/bjsports-2018-099825.
Index
Note: ‘Page numbers followed by “f ” indicate figures and “t” indicate table’.
A motivation, 111 behavioral task, 35e41, 39te40t

Aberrant learning, 1, 322 new complex learning, 112 Balloon Analogue Risk Task
Acetylcholine (ACh) system, 131 treatment compliance and quality of life, (BART), 36
Acquired hepatocerebral degeneration, 114 111, 112f Beads/Box Task (BT), 38
Action-outcome (A-O) mechanisms, cognitive deficits reversibility and cerebral Cambridge gambling task (CGT), 37
9e10 damage with abstinence, 109e111 Delay Discounting Task (DDT), 35e36
Active inference models, 41e42 brain recovery, 109e110 Effort Expenditure for Reward Task
Addiction treatment policy, 324 factors influencing, 111 (EEfRT), 37e38
ADHD. See Attention-deficit/hyperactivity neuropsychological recovery, 110e111 Game of Dice Task (GDT), 37
disorder (ADHD) life expectancy, 103 Iowa Gambling Task (IGT), 36e37
Adolescence, 91 neurocognitive complications, 113e116 Risk Gains Task (RGT), 38e39
Adolescent Brain Cognitive Development central pontine myelinolysis (CPM), computational modeling, 41e43
(ABCD) study, 13, 368 115e116 Bayesian-Expected Utility Model, 43
Affective empathy. See Emotional empathy hepatic encephalopathy (HE), 114e115 classification, 44f
Affect recognition, 64 Korsakoff’s syndrome (KS), 114 data-driven approaches, 41
Ageealcohol use disorder interaction, 117 MarchiafavaeBignami disease (MBD), 114 earning to maximize approach, 42
Alcohol, 379 Wernicke’s encephalopathy (WE), Expectancy-Valence Learning (EVL)
applications, 297 113e114 model, 43
emotional empathy, 66 researchers and clinicians recommendations, Prospective Valence Learning (PVL), 43
emotion recognition and cognitive 116e120 reinforcement learning (RL), 42
empathy, 65e66 differential diagnosis, 117e118 strategy-switching heuristic choice
moral decision-making, 67 neuropsychological profile heterogeneity, model, 42
perspective-taking and theory of mind 117, 118f theory-driven approaches, 41
(ToM), 66e67 neuropsychological rehabilitation, neuroimaging, 44e47
social decision-making, 67 118e120 fMRI, 44
Alcohol Attention Control Training Program screening and assessment modalities, model-based fMRI approaches, 46
(AACTP), 232e233, 273 116e117 task-based fMRI evidence, 45e46
Alcohol dehydrogenase (ADH), 371 treatment modifications, 117, 119f self-reports, 26e33, 34te35t
Alcohol dependence (AD), 63, 65, 67 Aldehyde dehydrogenase (ALDH), 371 Barratt Impulsivity Scale (BIS), 27
Alcohol-induced neurocognitive Alpha2-adrenergic agonist, 312 Consideration of future consequences
impairments, 103 Alzheimer’s disease (AD), 117e118, 132, 306 scale (CFCS), 32
Alcohol use disorder (AUD), 202, 222e223, Amphetamines Effect expectancy questionnaire, 30e31
273, 379 acute effects, 156 Eysenck impulsiveness scale, 29
altered brain structure and function, long-term effects, 156e157 Monetary choice questionnaire (MCQ),
103e109 prevalence, 155 27e28
attention, working memory, and executive Amygdata, 108e109 Reinforcement Survey Schedule (RSS),
functions, 104e106 Animal models 31e32
brain circuits, 104f devolving from prefrontal to striatal control, Rewarding events inventory (REI), 31
characteristics, 104 11e12 Sensation seeking scales (SSS), 29
emotions, 108e109 drug-seeking habits, 9e10 Sensitivity to Reinforcement of Addictive
episodic memory, 106e107 transitioning from ventral to dorsal striatum, and other Primary Rewards
perceptive memory and visuospatial 10e11 (STRAP-R), 32e33
abilities, 108 Anterior cingulate cortex (ACC), 66, Substance Use Risk Profile Scale
procedural memory, 107e108 69, 284 (SURPS), 33
semantic memory, 107 Anthropomorphism, 212e213 Temporal experience of pleasure scale
social cognition, 109 Antipsychotic, 312 (TEPS), 29e30
characteristics, 103 Antisocial personality disorders UPPS impulsive behavior scale, 28
clinical implication and relapse factors, (ASPD), 79, 82 three-dimensional matrix, 49, 49f
111e113 Apparent diffusion coefficient (ADC), 167 Atomoxetine, 312
decision-making, 111e112 Approach bias modification, 233e235 Attention
interpersonal relationships, 112e113 Assessment paradigms, in decision-making alcohol use disorder (AUD), 104e106
dysfunctions, 26 cognitive deficits, 158
411
412 Index
Attentional bias modification, 231e233 neuropharmacology, 143e144 policy impact, 322e325

Attention-deficit/hyperactivity disorder perspective-taking and theory of mind addiction treatment policy, 324
(ADHD), 68e69, 95, 200 (ToM), 68 criminal justice policy, 324e325
AUD. See Alcohol use disorder (AUD) researchers/clinicians recommendations, 149 drug policy, 323e324
Autobiographical memory (AM), 106e107 social decision-making, 68 implication, 323
Awareness of Social Inference Test (TASIT), social reward, 68 mental health, 325
70e71 Catechol-O-methyltransferase (COMT), 149, public policy, 325e326
168e169 legalization of recreational cannabis, 326
CBM. See Cognitive bias modification psychedelics use, 325e326
B (CBM) Cognitive training interventions, 231
Balloon Analogue Risk Task (BART), 36
Central pontine myelinolysis (CPM), Combining top-down and bottom-up
Barratt Impulsivity Scale (BIS), 27 115e116 approaches, 406e407
Beads/box task (BT), 38 CFCS. See Consideration of future Comorbidity, 79
BEARNI. See Brief Evaluation of Alcohol- consequences scale (CFCS) and executive functioning, 84
Related Neuropsychological
CGT. See Cambridge gambling task (CGT) Compensatory strategies, 399
Impairment (BEARNI) Chicago Word Fluency Task (CWFT), 170 Composite International Diagnostic Interview
Behavior Stimulus Interaction (BSI), 274 Cholinergic medications, 306e311 (CIDI), 193e194
Big Data approaches, 365
Chronicity, 192 Comprehensive Affect Test System
genetics, 371e373 Cirrhotic portosystemic shunting, 115 (CATS-A), 64
neuroimaging, 368e371 Cluster B personality disorders, 80e82 Compulsions, 9e10
online-based research, 365e367 Cocaine Compulsive eating, 298
BIS. See Barratt Impulsivity Scale (BIS)
acute effects, 156 Compulsive Internet use scale (CIUS), 203
Blood oxygen level dependent (BOLD), applications, 297e298 Computational modeling, in decision-making
44, 167 chronic use, 155 dysfunctions (DMDs), 41e43
Borderline personality disorders long-term effects, 156e157 Bayesian-Expected Utility Model, 43
(BPD), 79e82
long-term neuroadaptive effects, 155e156 classification, 44f
Brain disease model of addiction prevalence, 155 data-driven approaches, 41
(BDMA), 323 recovery, 157 earning to maximize approach, 42
Brain education, 398
Cocaine users, 5 Expectancy-Valence Learning (EVL)
Brain exercises, 399
Cognition, 1 model, 43
Brain planner, 399 addiction vulnerability and consequences Prospective Valence Learning (PVL), 43
Brain recovery, 109e110 dependent vs. recreational users, 4e5 reinforcement learning (RL), 42
Brain stimulation tool
endophenotype studies, 4 strategy-switching heuristic choice
noninvasive modulation of neural circuitry, longitudinal studies, 3e4 model, 42
295e296 neurotoxicity-controlled studies, 4 theory-driven approaches, 41
moving to clinic, 295 stimulant users vs. gamblers, 5 Conduct disorder (CD), 94
preclinical foundation, 295
interface between nature and nurture, 5e6 Consideration of future consequences scale
transcranial magnetic stimulation (TMS), neurobiological models, 2e3 (CFCS), 32
295e296 social accounts of addiction, 2e3 Consortium on Vulnerability to Externalizing
repetitive transcranial magnetic stimulation Cognitive behavioral therapy (CBT), Disorders and Addictions (cVEDA),
(rTMS)
214e215, 405 368
with cognitive therapy, 298e299 Cognitive bias, 224 Contemporary models, 1
pharmacotherapy, 299 attentional biases, 224e225 Controlled Oral Word Association Task
Brief Evaluation of Alcohol-Related
dysfunctional cognitions, 225 (COWAT), 170
Neuropsychological Impairment Cognitive bias modification (CBM), Control-related deficit theory, 111e112
(BEARNI), 116 231, 367, 405 CPM. See Central pontine myelinolysis
Brisbane Longitudinal Twin study, 203 approach bias modification, 233e235 (CPM)
attentional bias modification, 231e233 Criminal justice policy, 324e325
C clinical applications, 236e237 CYP2D6, 168e169
Cambridge gambling task (CGT), 37 memory bias modification, 235e236
neurocognitive effects, 236
Cambridge Neuropsychological Test
Cognitive deficits, 222e224
D
Automated Battery (CANTAB), 181
decision-making and related processes, D-amphetamine, 311e312
Cannabidiol (CBD), 143e144, 326
223e224 D-Cycloserine (DCS), 312e313
Cannabinoid receptor type 1 (CB1), Decision-making dysfunctions (DMDs), 25
143e144 goal-based interventions, 277e278
inhibitory control and other executive assessment paradigms, 26
Cannabinoid receptor type 2 (CB2), 144 behavioral task, 35e41, 39te40t
Cannabis, 143 functions, 222e223
Cognitive empathy, 64 computational modeling, 41e43
clinical significance, 149 neuroimaging, 44e47
cognitive deficits associated with Cognitive function, 92
Cognitive Remediation (CR), 277e278 self-reports, 26e33, 34te35t
intoxication effects, 144e146 three-dimensional matrix, 49, 49f
residual/long-term effects, 146e149 Cognitive research on addiction, 321
aberrant learning, 322 cognitive deficits, 159, 223e224
emotional empathy, 67 cognitive functions
emotion recognition and cognitive impaired impulse inhibition, 322
impulsivity, 322 learning, 26
empathy, 67
reward/value, 26
Index 413
risk/probability, 26 Executive network, 19e20 Goal Management Training (GMT),

temporality, 25e26 Exogenous sex steroids, 313e314 277e278, 405
three-dimensional matrix, 49, 49f Expectancy-Valence Learning (EVL) G proteinecoupled receptor (GPR), 144
dimensions, 25 model, 43 Guanfacine, 312
interventions tapping, 407e408 Eysenck impulsiveness scale, 29
levels of evidence
H
case-control studies, 47e48
cohort studies, 48
F Habit network, 20
Far transfer, 243 Haloperidol, 312
cross-sectional studies, 47
metaanalyses, 48
Fractional anisotropy (FA), 167 HE. See Hepatic encephalopathy (HE)
Framework Convention on Tobacco Control Heart rate variability (HRV), 288
randomized controlled studies, 48 (FCTC), 130e131
systematic review, 48 Hepatic encephalopathy (HE), 114e115
Frontotemporal lobar degeneration Hierarchical Taxonomy of Psychopathology
three-dimensional matrix, 49, 49f (FTLD), 118
personality disorders (PDs), 82 (HiTOP), 80e81
Functional magnetic resonance imaging 5-HTTLPR, 149
Decision-making models, 2 (fMRI), 44, 287, 368
Delay discounting, 94e95, 224
Future time perspective (FTP), 32
Delay discounting task (DDT), 35e36 I
Delta-9-tetrahydrocannabinol (THC), ICT. See Inhibitory control training (ICT)
143e144 G IGT. See Iowa gambling task (IGT)
Dependent vs. recreational users, 4e5 GABAergic medications, 313
Illusion of control, 211e212
Diffusion tensor imaging (DTI), 167 Galantamine, 306
IMAGEN, 336, 368
Distribution volume ratios (DVRs), 167e168 Gamblers Anonymous (GA), 214
Imbalanced system models, 405e406
DMDs. See Decision-making dysfunctions Gambling
Immediate Memory Task (IMT), 83
(DMDs) applications, 298
Impaired Response Inhibition and Salience
Donepezil, 306 cognitions, 201e202
Attribution (iRISA) model, 17, 18f
Dopamine b-hydroxylase (DbH), 146 cognitive distortions
Implicit Association Test (IAT), 233e234
Dorsolateral prefrontal cortex (DLPFC), 2, 5, anthropomorphism, 212e213
Impulsive personality traits, 80e81
11, 236, 280 illusion of control, 211e212
Impulsivity, 13, 81, 200
Dorsolateral striatum (DLS), 10e11 cognitive model, 210e211
cognitive deficits, 159
Dorsomedial striatum (DMS), 10e11 electronic gaming machines (EGMs),
cognitive research on addiction, 322
Drug policy, 323e324 209e210
Incentive-sensitization theory, 17
Drug reinforcers, 10 immersion, 213
Inferior frontal cortex (IFC), 66
Drug use predictors individual risk factors
Information and Communication
of TxAware status, 354e356 (neuro)cognitive factors, 201e202
Technologies (ICTs), 221
of TxUnaware status, 354 genetic risk, 202e203
Inhibitory control, 18e20
Drug use variables, 353 personality, 200e201
Inhibitory control training (ICT)
Dual models neurocognitive correlates, 211
definition, 271
of addiction, 17, 18f personal vulnerabilities, 209e210
efficacy, 272e273
neuroimaging evidence, 18e20 research, 199e200
individual differences, 271
Dynamic craving model (DCM), social and individual predictors, 203e204
mechanisms of action, 273e274, 274t
394e395, 394f treatment and intervention, 214e215
proposed mechanisms, 271e272
Game of dice task (GDT), 37, 223e224
substance use disorder (SUD), 273
Gaming disorder
E cognitive factors, 222e225
substance users’ deficit, 271
Ecstasy use, 170e171 Insular cortex, 135e136
cognitive bias, 224e225
EEfRT. See Effort expenditure for reward The Integrated Hypothesis, 166
cognitive deficit, 222e224
Integrative cognitive interventions, 398e399
task (EEfRT) definition, 222
Effect expectancy questionnaire, 30e31 Intelligence quotient (IQ), 3, 95e96
internet addiction, 221
Effort expenditure for reward task (EEfRT), International Classification of Diseases
from internet addiction, 221e222
37e38 (ICD), 199e200
recognition, 221e222
International Youth Development Study,
Electronic gaming machines (EGMs), smartphone addiction, 221
203e204
209e210, 212 GDT. See Game of dice task (GDT)
Emotional empathy, 64 Internet addiction, 221
Genome-wide association studies (GWAS)
Internet-based interventions, 367
Emotional Facial Expression Decoding Test, approaches, 371
70e71 Internet gaming disorder, 202
Glutamatergic medications, 312e313
Internet Gaming Disorder (IGD), 222e223
Emotion perception, 64 GMT. See Goal Management
Emotion recognition, 64 Iowa gambling task (IGT), 36e37, 45e46
Training (GMT)
iRISA. See Impaired Response Inhibition
Empathy, 109 Goal-based interventions
Endophenotype studies, 4 and Salience Attribution (iRISA)
for cognitive deficits, 277e278
Entactogenes, 70 model
efficacy evidence, 278e279
Episodic memory, 106e107 intervention approaches and
Estradiol, 313e314 mechanisms, 278 K
Executive functions (EF), 4e5, 92e94 neurocognitive mechanisms, 279e280 Korsakoff’s syndrome (KS), 114
alcohol use disorder (AUD), 104e106 researchers and clinicians
cognitive deficits, 158e159 recommendations, 280
414 Index
L “top-down” mechanisms Neuroscience-based cognitive interventions,

Learning theories, 1 attentional control, 286 393e398
Leisure Interest Checklist (LIC), 31 automaticity regulation, 286e287 cognitive modifications, 394e397
Levels of evidence, in decision-making inhibitory control, 287 attention bias interventions, 395
dysfunctions Mindfulness-Based Relapse Prevention inhibitory control interventions, 397
case-control studies, 47e48 (MBRP), 283e284 interoceptive-based interventions,
cohort studies, 48 Mindfulness-Based Stress Reduction 396e397
cross-sectional studies, 47 (MBSR), 283e284 memory-based interventions,
metaanalyses, 48 Mindfulness-Oriented Recovery 395e396
randomized controlled studies, 48 Enhancement (MORE), 283e284 saliency-based interventions, 395
systematic review, 48 Minnesota Twin Family Study (MTFS), 148 neurocognitive rehabilitation,
three-dimensional matrix, 49, 49f Minocycline, 313 397e398
LIC. See Leisure Interest Checklist (LIC) MoCA. See Montreal Cognitive Assessment psychoeducation and metacognitive
Longitudinal studies, 3e4 (MoCA) training, 394
Lysergic acid diethylamide (LSD), 325e326 Modafinil, 311 Neurotoxicity-controlled studies, 4
Model-based (MB) learning system, 42 Nicotine, 372
Model-free (MF) learning system, 42 cognitive effects
M Molecular neuroimaging, 290 long-term effects, 132
Magnetic resonance imaging (MRI), 167 Monetary choice questionnaire (MCQ), 27e28 short-term effects, 132
MarchiafavaeBignami disease (MBD), 114 Monoamine transporter inhibitors, 311e312 withdrawal effects, 132e133
Marijuana, 298 Montreal Cognitive Assessment neural effects, 131
MBIs. See Mindfulness-based (MoCA), 116 reinforcement
interventions (MBIs) Moral decision-making/moral judgment, 65 neural mechanisms, 133e134
MCQ. See Monetary choice Movie for the Assessment of Social reinforcement enhancement, 133
questionnaire (MCQ) Cognition (MASC), 64e65 Nonemedical prescription opioid users
Memantine, 312 MTFS. See Minnesota Twin Family Study (NMPOU), 70e71
Memory (MTFS) Novel Psychoactive Substances (NPS),
bias modification, 235e236 Multifaceted Empathy Task (MET), 64 165e166
cognitive deficits, 158 Myelinolysis, 115e116
network, 20
Mental and emotional perspective-taking, O
64e65 N Online-based research, 365e367
Metacognitive training, 399 N-acetylcysteine (NAC), 313 Opioids, 70e71, 179
Methamphetamine, 298 National Institute on Drug Abuse (NIDA), applications, 298
Methylenedioxyethylamphetamine (MDA), 322e323 combinations, 188e189
166 National Survey on Drug Use and Health long-term cognitive de?cits, 180e189
Methylenedioxymethamphetamine (MDMA), (NSDUH), 352 methodological issues, 189e194
63e64, 72, 95 drug use variables, 353 context, 190e191
clinical significance, 171 general health covariates, 353e354 data analysis, 194
cognitive deficits associated with, 169e170 outcome variable, 352e353 data gathering, 193e194
epidemiology, 165e166 sample, 352, 353f population studied, 191e192
neuropharmacological/neuroadaptive effects sociodemographic covariates, 353e354, substance misuse and dependence,
animal research, 166e167 355te356t 192e193
functional imaging, 170e171 statistical analyses, 354 neuropsychological functioning
human imaging, 167e168 National Surveys on Drug Use and Health abstinent former heroin-dependent
pharmacokinetics and (NSDUH), 179 populations, 182e183
pharmacodynamics, 166 Neurobiological models of drug buprenorphine, 187e188
pharmacologically confounding addiction, 17 illicit heroin, 181e182
factors, 168e169 Neurobiological recovery, 379 methadone users, 183e187
potential adverse effects, 168e169 Neurocognitive deficits, 379e385 mixed opioid, 180e181
researchers/clinicians recommendations, abstinence, 380e385 Optimal decision-making, 94e95
171e172 addiction, 379e385 Oral methamphetamine, 311e312
Methylphenidate, 311 Neurocognitive dysfunction, 379 Orbitofrontal cortex (OFC), 11e12
Mindfulness-based interventions (MBIs), Neuroimaging, in decision-making
dysfunctions (DMDs), 44
283e284
addiction treatment, 289 model-based fMRI approaches, 46 P
task-based fMRI evidence Peer-reviewed working memory training
clinical format and efficacy, 285
(WMT), 264e265
mechanisms, 284e285 balloon analogue risk task (BART), 45
Cambridge gambling task (CGT), 46 CogMed, 261e262
neurocognitive mechanisms,
delay discounting tasks (DDT), 45 Curb Your (C-Ya) Addition, 264
285e289, 286f
Iowa gambling task (IGT), 45e46 jungle memory (JM), 260
reward, negative emotion and cue reactivity
lumosity, 262e263
amplifying reward and positive affect, Neuropsychological recovery
apparent discrepancies, 110 N-back (n ¼ 32), 245e260
287e288
episodic memory, 110 near and far transfer effects, 265
craving and cue reactivity regulation,
NeuroNation, 263e264
288e289 executive functions, 110
visuospatial process, 110 neuroracer, 263
dampening negative affect and stress, 288
PSSCogRehab, 260e261
Index 415
Perceptive memory, 108 S moderators

Personality, 5 Saguenay youth study (SYS), 335e336, age of onset, 157
Personality disorders (PDs) 335te336t cumulative exposure, 157
broad symptoms dimensions, 80e81 Salience network, 18e20 route of administration, 157e158
clusters, 79 Selective Serotonin Reuptake Inhibitor recovery, 157
cross-sectional and longitudinal (SSRI), 169 researchers and clinicians recommendations,
evidence, 80 Self-directed network, 20 159e160
executive functioning, 82 Self-regulation, 277 state of problem, 155
impulsive personality traits, 80e81 Semantic memory, 107 stimulants neuroadaptive effects,
neurocognitive functioning, 81e82 Sensation seeking scales 155e156
preliminary neurocognitive model, 84e85 (SSS), 29 Stimulant users vs. gamblers, 5
PES. See Pleasure Events Schedule (PES) Sensitivity to Reinforcement of Addictive Stimuluseresponse (S-R) habit process,
Pharmacological cognitive enhancement and other Primary Rewards 9e10
Pleasure Events Schedule (PES), 31 (STRAP-R), 32e33 Stop-Signal Task, 4
Polydrug use, 169 Serotonin transporter (SERT), STRAP-R. See Sensitivity to Reinforcement
Polysubstance users (PSU), 71, 192, 167e168 of Addictive and other Primary
379e380 Smoking Rewards (STRAP-R)
Population neuroscience applications, 297 Stress models, 2
addiction research, 334e345 cessation, 130 Substance misuse, 192e193
IMAGEN study, 336 cessation and mood, 136 cognitive function structure, 92
Saguenay youth study (SYS), morbidity and mortality, Substance use disorders (SUDs), 25, 63, 91,
335e336, 335te336t 129e130 209, 303, 351, 379. See also
built and social environment, 332e334 prevalence, 129 Decision-making dysfunctions
brain structure and function, 333e334, Social cognition, 63, 109 (DMDs)
333f alcohol use disorder (AUD), 109 alcohol, 65e67
challenges, 331, 345e347 definitions, 64e65 applications, 296e298
genes and gene regulation, 331e332 drug-related changes, 63 broad symptoms dimensions, 80e81
Positron emission tomography (PET), interaction, 64f cannabis, 67e68
167e168 relevance for treatment, 73 clinical studies, 352
Practice of mindfulness, 284 substance use disorders (SUDs) clusters, 79
Prefrontal cortex (PFC), 11, 169e170, 284 alcohol, 65e67 cognitive deficits, 305e306
Preliminary neurocognitive model, 84e85 cannabis, 67e68 cognitive function
Procedural memory, 107e108 entactogenes, 70 automatic cognitive processes,
Progesterone, 314 opioids, 70e71 304e305
Prospective memory (PRM), 169 polysubstance use, 71 executive functioning, 303e304
Prospective Memory Questionnaire (PMQ), stimulants, 68e70 cross-sectional and longitudinal
169 Social cognition processes, evidence, 80
Prospective Valence Learning (PVL), 43 5e6 current study, 352
Psychoeducational therapy, 112 Social decision-making, 65 drug use predictors
Social reward, 65 of TxAware status, 354e356
of TxUnaware status, 354
R Social theories, 1
entactogenes, 70
Reading the Mind in the Eyes Task South Oaks Gambling Screen
(SOGS), 200 and executive functioning, 82e84
(RMET), 64e65
Spatial working memory impulsive personality traits, 80e81
REI. See Rewarding events inventory (REI) inhibitory control training (ICT), 273
Reinforcement learning (RL), 42 deficits, 170
SSS. See Sensation seeking neurocognitive functioning, 81e82
Reinforcement Survey Schedule (RSS), opioids, 70e71
31e32 scales (SSS)
State mindfulness, 284 polysubstance use, 71
Relative risk ratios (RRRs), 354 preliminary neurocognitive model, 84e85
Repetitive transcranial magnetic stimulation Stimulants
emotional empathy, 68e69 stimulants, 68e70
(rTMS), 13 target mechanisms, 306e314, 307te310t
with cognitive therapy, 298e299 emotion recognition and cognitive
empathy, 68 alpha2-adrenergic agonist, 312
pharmacotherapy, 299 antipsychotic, 312
Response inhibition, 5, 94 moral decision-making, 69
perspective-taking and theory of mind cholinergic medications, 306e311
Restructuring reward hypothesis, 287e288
(ToM), 69 exogenous sex steroids, 313e314
Reward-based decision-making, 95 GABAergic medications, 313
Reward deficit theory, 112 social decision-making, 69
social reward, 69e70 glutamatergic medications, 312e313
Rewarding events inventory (REI), 31 monoamine transporter inhibitors,
Reward network, 18, 20 Stimulant use disorders, 155
acute effects, 156 311e312
Reward system, 17 treatment need awareness, 356
Risk Factors for Antisocial Behavior clinical significance, 158e159
attention, 158 Substance Use Risk Profile Scale (SURPS),
(RFAB), 148 33
Risk gains task (RGT), 38e39 impulsivity and decision-making, 159
memory, 158 SURPS. See Substance Use Risk Profile
Rivastigmine, 306 Scale (SURPS)
RSS. See Reinforcement Survey working memory (WM) and executive
functions (EF), 158e159 Swift, certain, and fair punishment
Schedule (RSS)
long-term effects, 156e157 (SCFP), 325
416 Index
T long-term effects, 132 U

Taiwan National Health Insurance Research short-term effects, 132 UPPS impulsive behavior scale, 28
Database, 80 withdrawal effects, 132e133
Temporal experience of pleasure scale nicotine reinforcement
(TEPS), 29e30 neural mechanisms, 133e134 V
Terpenoids, 144 reinforcement enhancement, 133 Varenicline, 306e311
Tetrahydrocannabinol (THC), 326 pharmacology Ventrolateral prefrontal cortex (VLPFC), 5
Theory of Mind (ToM), 63 acetylcholine (ACh) system, 131 Ventromedial prefrontal cortex (VMPFC),
chemicals, 131 67, 69e70
Theory of mind (ToM), 109
Tiagabine, 313 liability, 131e132 Visuospatial abilities, 108
Tobacco addiction nicotine neural effects, 131
clinicians and researchers, 136e137 policy, in United States and world,
130e131
W
electronic cigarettes, 130 Wernicke’s encephalopathy (WE), 113e114
emotionesmoking relationship smoking cessation, 130
Working memory (WM), 92e94, 243
insular cortex, 135e136 smoking prevalence, 129
alcohol use disorder (AUD), 104e106
maladaptive response to negative mood, smoking-related morbidity and mortality,
cognitive deficits, 158e159
134e135 129e130
Working memory training (WMT), 243
neural mechanisms, 135 ToM. See Theory of mind (ToM)
limitations, 266e267
shared underlying mechanism, 136 Transcranial magnetic stimulation (TMS)
training and implications, 265e266
smoking cessation and mood, 136 basic electrophysiological effects, 295e296
World Drug Report (WDR), 165e166
nicotine cognitive effects modulate cortical-striatal connectivity, 296

Cognition and Addiction

Uploaded by

Copyright:

Available Formats

Cognition and Addiction

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Cognition and Addiction

Uploaded by

Copyright:

Available Formats

What is the purpose of the book?

What is the purpose of the book?

What topics are covered in the book?

What topics are covered in the book?

Cognition and Addiction

A Researcher’s Guide from Mechanisms

Copyright © 2020 Elsevier Inc. All rights reserved.

Library of Congress Cataloging-in-Publication Data

For information on all Academic Press publications visit our

Publisher: Nikki Levy

Cognition: the interface between nature

Introduction externalization among people with addiction (e.g., “I have a

Cognition and Addiction. https://doi.org/10.1016/B978-0-12-815298-0.00001-0 1

From impulses to compulsions

Introduction outcomes of such behaviors are negative (Zapata et al.,

Cognition and Addiction. https://doi.org/10.1016/B978-0-12-815298-0.00002-2 9

Dual models of drug addiction: the

Dual models of addiction that the impairments of two neuropsychological

Cognition and Addiction. https://doi.org/10.1016/B978-0-12-815298-0.00003-4 17

Decision-making deficits in substance

Introduction second dimension of the matrix of evidence, the main

Cognition and Addiction. https://doi.org/10.1016/B978-0-12-815298-0.00004-6 25

Background: Initially, Baron et al. (1981) extracted 16

Self- Format of Aspects

Self- Format of Aspects

Behavioral task aspects of impulsivity have a positive correlation with delay

Balloon analogue risk task Iowa gambling task

BART Lejuez Risk The number of pumps A B C D

pump pump pump Cash-out

et al. vantageous and disadvantageous cards Cash

(2003) of previous trial outcome 20 40 -80 20

C 1 seconds 2 seconds 3 seconds D 1 seconds 2 seconds 3 seconds

Computaonal Models for Decision-Making Deﬁcits

Neuroimaging oxygenation/deoxygenation in that speciﬁc area (or

References Baitz, H.A., 2016. Component processes of decision making in persons

Social cognition in addiction

Introduction decrease in social contacts and social support, leading to an

Cognition and Addiction. https://doi.org/10.1016/B978-0-12-815298-0.00005-8 63

Open questions socio-cognitive impairments coincide with changes, specif-

A neurocognitive model of the

Cognition and Addiction. https://doi.org/10.1016/B978-0-12-815298-0.00006-X 79

by the current diagnostic nosology. As the nosology of

Cognitive risk factors for alcohol and

Cognition and Addiction. https://doi.org/10.1016/B978-0-12-815298-0.00007-1 91

IQ is associated with SUDs among adolescents (Moss et al., Discussion

NeurocogniƟve FuncƟons Psychopathology Dimension Observed Symptoms

SelecƟve aƩenƟon and working Conduct Disorder

Other Drug Abuse

Neuropsychological deficits in alcohol

Introduction balance) but also with a variety of cognitive disorders.

Cognition and Addiction. https://doi.org/10.1016/B978-0-12-815298-0.00008-3 103

Fronto-cerebellar circuit Papez’s circuit

follow-up. A short period of sobriety (1 month) has been Episodic memory

frontal lobes thalamus

corpus callosum pons caudate hypothalamus

cerebellum hippocampus putamen amygdala

HARMFUL ALCOHOL DRINKING CESSATION

Preserved Mild-to-moderate Severe

Tobacco addiction: cognition,

Introduction lesbian/gay/bisexual community, uninsured or covered by