Addiction Medicine 978-3-030-86430-9 Compressed

Psychiatry Update 2
Series Editor: Michelle B. Riba
Jonathan D. Avery
David Hankins Editors
Addiction
Medicine
A Case and Evidence-Based Guide
Psychiatry Update 2
Series Editor
Michelle B. Riba
University of Michigan, Department of Psychiatry
University of Michigan Eisenberg Family Depression Center
Ann Arbor, MI, USA
Psychiatry Update will encompass all areas of psychiatry research and clinical
diagnosis and treatment. Chapters will publish randomly though out the year
culminating in volumes throughout the year.
More information about this series at http://www.springer.com/series/16222

Jonathan D. Avery • David Hankins
Editors
Addiction Medicine
A Case and Evidence-Based Guide
Editors
Jonathan D. Avery David Hankins
Weill Cornell Medicine Weill Cornell Medicine
NewYork-Presbyterian Hospital NewYork-Presbyterian Hospital
New York, NY New York, NY
USA USA
ISSN 2524-8316 ISSN 2524-8324 (electronic)

Psychiatry Update 2
ISBN 978-3-030-86429-3 ISBN 978-3-030-86430-9 (eBook)
https://doi.org/10.1007/978-3-030-86430-9
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Introduction by Series Editor
It is an honor to welcome this edited book by Drs. Avery, Hankins, et al. on addic-
tion medicine to this series.
Substance use disorders and other mental health conditions are a growing prob-
lem, especially during the recent COVID pandemic. We are learning more and more
about the interrelationship between the neurobiology of addiction, behavioral mani-
festations, co-occurrence with other psychiatric problems, and associated social,
economic, and intergenerational issues.
Training in this specific field is a complicated but necessary part of mental health
care, with growing numbers of healthcare professionals recognizing the need to
equip students, residents, and fellows with the necessary tools for maintaining com-
petence in addiction medicine treatment.
In this edited book, we are delighted to present, along with seasoned authors,
residents and fellows who validate the interest and trajectory of trainees who want
to specialize in this area. This book contributes to the shared goals of clinicians who
wish to attain improved clinical knowledge and proficiency on various topics in
addiction medicine.
As we see more states in the USA legalize or allow the use of substances for
medicinal or recreational purposes, it is incumbent upon health-care providers to
better understand how to prevent, educate, recognize, evaluate, and treat substance
use problems in a timely manner; this is a public health matter and mandate.
We thank the many authors who have contributed to this volume and Dr. Avery
and Dr. Hankins for their leadership in organizing such a clinically valuable and
comprehensive text.
v
Introduction
Medical providers regardless of specialty encounter the effects of substance use and
other addictive disorders on a daily basis. These effects of addictive behaviors, both
direct and indirect, are responsible for vast morbidity and mortality globally as well
as significant economic costs. Attitudes about substance use are rapidly shifting,
leading to massive public policy and legal changes at the local, state, and national
levels. These broader consequences make the value of discussing addiction with
individual patients clear, but those conversations can be challenging for many rea-
sons. Patients may feel hesitant to discuss their substance use related to shame and
pervasive stigma. Providers may not be confident in their knowledge and skill level
with assessing these disorders and so may do so incompletely or not at all. And both
provider and patient may feel uneasy in navigating treatment options once a sub-
stance use disorder diagnosis has been made.
Luckily, this book has been written at a time when treatment options for sub-
stance use disorders continue to expand. Novel pharmacologic approaches are
emerging for a variety of disorders, and there continue to be many well-studied,
evidence-based medications available for some substance use disorders that remain
underutilized. Options for psychotherapy, group treatment, and other psychosocial
interventions are expanding as the treatment of addiction becomes a higher priority
for the medical system and policymakers. There are excellent treatment options
available for substance use disorders, and a physician may be the first person a
patient turns to for help in these cases.
This book attempts to counter some of the potential pitfalls in the clinical encoun-
ter by the use of clinical cases in addiction. It primarily follows the structure of the
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM 5), with
each substance use disorder featured in one chapter which centers on a clinical
vignette (or vignettes) and provides helpful background on the etiology and treat-
ment options for each disorder. If you are looking for help with a specific patient or
a specific kind of addiction, you can jump immediately to the chapter about that
disorder. We have also included chapters on the assessment of substance use disor-
ders, their neurobiology, behavioral addictions, and the management of co-occurring
psychiatric and substance use disorders, to provide additional context to those who
would like to explore these topics at greater depth.
The cases presented in the book are not the stories of individual, real patients.
They are intended to be “typical” cases, however, so may share similarities with
vii
viii Introduction
patients the authors and readers have encountered. The cases are a mixture of some
elements of the histories of patients treated by the authors as well as fictionalized
elements included to facilitate broader discussion of each disorder. The names cho-
sen by the authors are unrelated to any real patients treated by them.
All of the chapter authors wish you much success as you broach these at times
difficult – but often lifesaving – discussions with your patients.
Contents
1 Assessment of Substance Use Disorders�� 1

Anil Abraham Thomas and Keriann Shalvoy
2 Neurobiology of Substance Use Disorders �� 11
Manesh Gopaldas and Kristopher A. Kast
3 Alcohol Use Disorder �� 21
Kseniya Svyatets
4 Cannabis Use Disorder�� 33
Dhruti Patel
5 Hallucinogen-Related Disorders�� 41
Katherine Kim and Daniel Roberts
6 Inhalant Use Disorders�� 57
Rosemary Busch Conn
7 Opioid Use Disorder�� 67
Sierra Ferguson and Aviva Teitelbaum
8 Sedative-, Hypnotic-, or Anxiolytic-Related Disorders�� 81
Emily Dumas
9 Stimulant-Related Disorders�� 91
Matthew Boyer
10 Nicotine Dependence and Tobacco Use Disorder Treatment �� 101
Noel Carrillo
11 Behavioral Addictions�� 113
Daniel Sugrue
12 Co-occurring Substance Use Disorders and Mental Illness�� 123
Jonathan D. Avery and David Hankins
Index�� 131
ix
Contributors
Jonathan D. Avery, MD Weill Cornell Medicine, NewYork–Presbyterian

Hospital, New York, NY, USA
Matthew Boyer, MD Rogers Behavioral Health, Philadelphia, PA, USA
Noel Carrillo, MD Weill Cornell Medicine, NewYork-Presbyterian Hospital,
New York, NY, USA
Rosemary Busch Conn, MD Weill Cornell Medicine, NewYork-Presbyterian
Hospital, New York, NY, USA
Emily Dumas, MD Weill Cornell Medicine, NewYork-Presbyterian Hospital,
New York, NY, USA
Sierra Ferguson, MD Icahn School of Medicine at Mount Sinai, Mount Sinai
Health System, New York, NY, USA
Manesh Gopaldas, MD Vanderbilt University Medical Center, Nashville, TN, USA
David Hankins, MD Weill Cornell Medicine, NewYork-Presbyterian Hospital,
New York, NY, USA
Kristopher A. Kast, MD Vanderbilt University School of Medicine, Addiction
Consult Service, Vanderbilt University Medical Center, Nashville, TN, USA
Katherine Kim, MD New York University Grossman School of Medicine,
New York, NY, USA
Dhruti Patel, MD University of Miami Miller School of Medicine, Miami, FL, USA
Daniel Roberts, MD, MSW New York University Grossman School of Medicine,
New York, NY, USA
Keriann Shalvoy, MD New York University Grossman School of Medicine,
New York, NY, USA
Daniel Sugrue, MD Weill Cornell Medicine, NewYork-Presbyterian Hospital,
New York, NY, USA
xi
xii Contributors
Kseniya Svyatets, DO New York University Grossman School of Medicine,

New York, NY, USA
Aviva Teitelbaum, MD New York University Grossman School of Medicine,
New York, NY, USA
Anil Abraham Thomas, MD New York University Grossman School of Medicine,
New York, NY, USA
Assessment of Substance Use Disorders
1
Anil Abraham Thomas and Keriann Shalvoy
Substance use disorders are complex, chronic, relapsing and remitting diseases
resulting in significant morbidity and mortality. The assessment of a possible sub-
stance use disorder or disorders is a fluid process that is the continuation of a posi-
tive triage screen. The assessment should clarify the diagnosis, type and extent of
the disorder and should help determine the appropriate level of care. The assessment
should also identify comorbid medical and psychiatric issues and help determine
appropriate treatments [1]. Substance use assessment should use multiple avenues
to collect the necessary clinical information, including clinical records, self-
assessment instruments, structured clinical interviews, and collateral information
whenever possible [2, 3].
Gathering the History
Patients should be assessed along three domains: the medical domain, the psychiat-
ric domain, and the substance use domain. Objective assessment includes the initial
screening, mental status exam, physical exam, and diagnostic tools including order-
ing necessary laboratory and imaging studies. The mental status and physical exams
can indicate whether the patient is currently intoxicated or in withdrawal. Pertinent
positives and negatives differ depending on the substance being used by the patient
and are discussed in more detail in later chapters of this book. Similarly, screening
and diagnostic scales as well as laboratory and imaging studies can also be tailored
to the differential diagnosis.
Assessing a patient along a medical domain is important particularly since a
number of medical conditions can mimic various stages of a substance use disorder
from intoxication, to withdrawal, to chronic use. For example, essential tremor in a
A. A. Thomas (*) · K. Shalvoy

New York University Grossman School of Medicine, New York, NY, USA
e-mail: anil.thomas@nyulangone.org
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 1

J. D. Avery, D. Hankins (eds.), Addiction Medicine, Psychiatry Update 2,
https://doi.org/10.1007/978-3-030-86430-9_1
2 A. A. Thomas and K. Shalvoy
social alcohol user can be mistaken for acute alcohol withdrawal, or a gait abnor-
mality attributed to substance abuse and not a neurological issue, if a detailed
assessment is not completed. Table 1.1 highlights a selection of medical issues that
might present similarly to a substance use disorder; keep in mind that this table is
not exhaustive and that contributions from medical and psychiatric issues, as well as
substance use, often remain on the differential diagnosis without it being possible to
firmly eliminate one. Medical assessment enables one to quantify the comorbid
issues that can influence treatment; it also helps to determine the extent of any medi-
cal complications as a result of the substance use disorder [4, 5]. The reverse is also
true—substance use disorders can also mimic or precipitate common medical con-
ditions. Common examples include nasal ulcers or perforated septum, skin track
marks, skin abscesses, alcohol on breath, ascites, enlarged liver, obesity, uncon-
trolled hypertension, chronic pain, blackouts, accidental overdose, withdrawal
symptoms, premature labor, and vague somatic complaints [6].
Assessing along the psychiatric domain is equally important; here again there are
psychiatric conditions that can mimic substance use disorders. For example,
untreated anxiety might be mistaken for alcohol withdrawal or cocaine intoxication
if the patient endorses any recent use of one of these substances, leading to a missed
diagnosis of generalized anxiety disorder or panic disorder. As with medical issues,
substance use disorders can also mimic common psychiatric conditions. Common
symptoms that can be associated with a wide range of substance intoxication and
withdrawal syndromes include depression, anxiety, paranoia, hallucinations, irrita-
bility, insomnia, flashbacks, suicidal ideations, vagueness, memory and concentra-
tion issues, and defensiveness when questioned about substance use. Brain imaging
Table 1.1 Examples of medical “mimics” of substance use disorders and their complications
Head, eyes, ears, nose, Rhinorrhea seen in patients with upper respiratory infections
and throat (HEENT) (similar to that seen in opioid withdrawal)
Cardiovascular Palpitations seen in patients with atrial fibrillation with rapid
ventricular response (similar to that seen with stimulant intoxication
or alcohol withdrawal)
Respiratory Shortness of breath seen in patients with coronavirus disease 2019
(COVID-19) (similar to that seen with chronic cigarette smoking)
Gastrointestinal Vomiting seen in patients with acute appendicitis (similar to that
seen with alcohol intoxication)
Genitourinary Dysuria seen in patients with acute urinary tract infections (similar
to that seen with chronic ketamine use)
Dermatologic Facial and oral lesions seen in patients with fixed drug eruption
(similar to those seen with inhalant abuse)
Neurologic Gait disturbance and dysarthria seen in patients with posterior
circulation stroke (similar to that seen with alcohol intoxication)
Endocrine Diarrhea seen in patients with hyperthyroidism (similar to that seen
in opioid withdrawal)
Hematologic Paranoia seen in patients with acute intermittent porphyria (similar
to that seen with methamphetamine intoxication)
Allergy/immunology Conjunctival injection from allergic rhinitis (similar to that seen
with cannabis use)
1 Assessment of Substance Use Disorders 3
of people who have substance use disorders has shown changes in areas responsible
for decision-making, learning, memory, judgment, behavioral control, and overall
body functioning, any one of which could also be attributed to a primary psychiatric
issue in a certain context [7]. Screening for suicidal ideation and depression should
be included in all substance-related disorder assessments, e.g., the Columbia Suicide
Severity Rating Scale (C-SSRS) and the Patient Health Questionnaire-9 (PHQ-9) [8].
Fully considering medical and psychiatric issues potentially at play can help pre-
vent premature closure and false attribution of symptoms to substance use alone,
which can have serious consequences. However, a comprehensive assessment of sub-
stance use is always essential along with the other two domains. The substance use
history should begin with open-ended questioning (“Have you ever used any sub-
stances, regularly or socially, including using prescription drugs that you don’t get
from a doctor or use differently or for longer periods than they are prescribed?”) and
move toward a systematic approach to specifically address each substance individu-
ally. Assessment of the substance use domain should determine all the substances the
person uses, the extent or quantity of use for each substance (whether in money spent
or other kinds of quantity data such as cigarettes smoked or bags of heroin used), the
length of time of use for each substance including the timing of first lifetime use of
the substance and last time the substance was used, the pattern of use (daily, binging,
occasional, social, etc.), and the route of administration: oral, intranasal, smoking,
intraocular, or intravenous. These questions and others can be thought of on a spec-
trum of urgency as illustrated in Table 1.2. Certain questions must be asked immedi-
ately to prevent life-threatening consequences, while other questions may be part of
a more comprehensive assessment or longer-term treatment and can help assess the
patient’s relationship to substances and willingness to change.
It is helpful to discuss the social situations that might have predisposed, precipi-
tated, and perpetuated the patient’s substance use, given the link between psychoso-
cial stressors (divorce, loss of employment, housing instability) and worsening
substance abuse [4]. As much as possible, the assessment should also determine the
patient’s level of interest in engaging in treatment and any particular barriers
(whether practical or psychological) that might interfere. This can include
Table 1.2 Question domains for the substance use history sorted by urgency
Facts to gather during Facts and feelings to gather
Facts needed immediately the assessment eventually
• Substances used • Age of first use • Does patient see substance use as
• Frequency and amount used • Changes in pattern a problem
most recently of use • Likes/dislikes about substance use
• Route of administration • Longest period of • Reasons to change
• Exact time of last use abstinence • Financial consequences
• Any history of complicated • Treatment history • Triggers for use/relapse and
alcohol or benzodiazepine • Family history with adaptive strategies that have
withdrawal substances worked in the past
• History of overdoses
discussion of the longest period of sobriety and interventions that aided in sobriety,
as well as the causes of relapse.
If a thorough substance history is obtained, commonly used screening tools such as
the CAGE (felt you should Cut down on use; people Annoyed you by criticizing your
use; felt bad or Guilty about use; ever use first thing in the morning to steady nerves or
to get rid of any early withdrawal—“Eye opener”), or other questionnaires that are
directed toward primary care or general psychiatric interviews, will be unnecessary [9].
In most cases, a basic urine drug screen involving qualitative opiate, methadone,
cocaine, benzodiazepine, and barbiturates is indicated. If additional substance use is
suspected, by the initial assessment, further toxicology diagnostics should be ordered.
Routine medical labs including complete blood count, basic metabolic panel, hepatic
function panel, hemoglobin A1c, and thyroid-stimulating hormone/free T4 are also
indicated and can be tailored to the differential diagnosis. All women of child-bear-
ing age should be given a pregnancy test given the significant risk for complications
in pregnant women with comorbid substance use disorders. For patients with higher-
risk sexual behaviors, a sexually transmitted infections (STI) panel including human
immunodeficiency virus (HIV) testing should be ordered. For patients who use intra-
venous drugs, HIV, hepatitis B, and hepatitis C serologies should also be obtained.
Tuberculosis testing may be indicated if the patient has a history of untreated HIV or
is at high risk of it because of social circumstances [10].
Making a Substance Use Disorder Diagnosis
Subsequent to gathering and analyzing the information, a diagnosis must be formu-

lated. Diagnosis of a substance use disorder follows the criteria set forth in the
Diagnostic and Statistical Manual 5 (DSM 5), with these general diagnostic criteria
applied across the board to each specific substance use disorders (Table 1.3). The
diagnosis requires “a problematic pattern of substance use leading to clinically sig-
nificant impairment or distress as manifested be at least two of the 11 criteria, occur-
ring within a 12 month period” [11]. To clarify the diagnosis, one needs to incorporate
questions that address the DSM 5 criteria for substance use disorders (Table 1.3).
Some patients may find reviewing these DSM-5 criteria directly helpful as part
of shared decision-making; others may bristle at the clinical language or reject that
any of them apply to the patient’s specific situation. As always, clinical judgment of
the individual patient is essential.
Discussing Treatment Options
If you have made a determination that the patient is likely to meet criteria for a sub-
stance use disorder, it is important at the initial assessment to determine the patient’s
readiness to change. The stages of change include pre-contemplation (unaware or
unwilling to change; in denial), contemplation (considering change; ambivalent
about change), preparation (experimenting with small changes), action (definite
action to change), maintenance (maintaining new behavior), and relapse prevention
Table 1.3 DSM-5 criteria for substance use disorder [11]

At least two criteria occurring within a 12-month period
1 Social and interpersonal problems
2 Craving or strong desire to use
3 Use in physically hazardous situations
4 Failure to fulfill major role obligations
5 Use larger amounts or for longer periods than intended
6 Desire or unsuccessful efforts to cut down
7 Important social, occupational, and recreational activities given up or reduced
8 Greater time spent to obtain, use, and recover
9 Use despite persistent or recurrent physical and psychological problems
10 Tolerance
11 Withdrawal
Severity modifier:
Mild: 2–3 criteria
Moderate: 4–5 criteria
Severe: 6 or more criteria
[12, 13]. These stages for most are gradual, and it is expected that the patient will
make advances and at times regress. One should also determine the positive and
negative impact on the patient’s quality of life; this includes understanding why
using the substance is positively reinforcing for the patient or what benefits it pro-
vides [10, 14]. Working to understand the perceived positive aspects of substance
use can help reduce feelings of judgment and stigma that the patient may have
experienced in previous clinical encounters and may facilitate a fuller discussion of
the more negative aspects of the substance use.
Discussion about treatment options must be handled carefully, as it requires the
patient to have some understanding and agreement that there is a substance use
disorder diagnosis at play. Prematurely discussing future treatment options with
patients who do not have insight into having a substance use disorder (e.g., those at
the pre-contemplation stage) may cause these patients to become angry and to stop
engaging with the assessment.
Common Challenges in the Substance Use Assessment
All substance use assessments should be informed by the possibility that patients
may be acutely intoxicated or in withdrawal, influencing their ability or willingness
to engage in a discussion. A patient who is intoxicated on phencyclidine (PCP) may
be too agitated to participate in any sort of meaningful discussion; a patient who is
withdrawing from heroin may become irritated if the conversation lasts too long and
veers into less immediately relevant territory.
All conversations with the patient should be direct, empathic, and nonjudgmental
in order to present information without alienating the patient who may be ashamed,
in denial, ambivalent, or resistant to change. The approach can have a significant
impact on whether the patient will leave the assessment in a position to take the next
step forward [10].
All aspects of gathering a substance use history must be informed by the fact that
patients often are reluctant to reveal substance use issues. There is a fear of negative
judgment, being embarrassed by their inability to control their lives, or denial about
the extent of the problem. These are the norm, not the exception. Patients avoid
disclosing information in a variety of ways both subtle and more overt: minimizing
use, minimizing consequences of use, changing topics, seeming not to listen, or
discouraging questions with irritation and at times lying. The dropout rate within
30 days of initial assessment across substance use disorders is approximately 50%,
with estimates ranging from 26% to 80% [15].
Providers should also be aware of how their own negative views of people who
use substances—not always overt but often subtly informed by personal experi-
ences and messages from superiors during medical training—may be affecting the
quality of their relationship with the patient in the initial assessment. These biases
toward patients with substance use disorders have the potential to negatively affect
the likelihood of successful treatment. Physicians have higher rates of stigma toward
substance-related disorders as compared to other illness, as well as pessimism about
the role of treatment, which leads to decreased empathy toward patients with
substance-related disorders [16].
Using multiple substances is common, although the patient may only view one
as problematic. A patient who is perfectly content to discuss his significant daily use
of intravenous heroin may angrily shut down any discussion of smoking cessation.
Bearing in mind that a single patient’s readiness to change on two different sub-
stances can be drastically different can help avoid an approach that damages the
therapeutic alliance.
The involvement of family, friends, and previous providers can be useful in clari-
fying the patient’s history and can be an essential part of a patient making the deci-
sion to begin treatment. When gathering collateral information or involving social
supports in other ways, it is important to maintain the patient’s trust and autonomy
by obtaining written consent. You should encourage collateral information sources
to share the extent of what they know about the patient’s substance use, since
patients themselves may be unreliable historians. Bringing support into the assess-
ment whether by phone, video, or in person can be helpful in understanding the full
extent of substance use. For example, patients may admit to more problematic
aspects of substance use when directly confronted by a family member in ways that
a provider cannot do. This can also be an opportunity to assess the family or other
social support structures and the ways in which these could be beneficial in planning
for next steps in treatment.
Finally, frequent reassessment is critical given the natural course of substance
use disorders. The complexity and idiosyncratic features of substance withdrawal,
cravings for the substance, and lingering chronic effects of long-time use are among
the many factors that can make recovery from substance use so challenging and the
presentation so varied at different points even for the same patient. Treatment
adjustment is essential as needs of the patient evolve.
Case Study: Patient Lilly
This patient case highlights some of the key considerations for substance use assess-
ment discussed in this chapter.
History of Present Illness (HPI): 42-year-old woman in the emergency depart-
ment (ED) requesting treatment for anxiety, insomnia, and methadone for with-
drawal from heroin use. Patient indicates she “is tired of using and wants to change.”
Medical Domain: Patient reports a diagnosis of hepatitis C for which she is not
currently in treatment. She is vague about how she acquired it. She has a history of
long-standing hypertension for which she is not in treatment, as well as psoriasis
with flare-ups when stressed.
Psychiatric Domain: Patient complains of anxiety which is described as being
continuous. She struggles to identify specific domains of anxiety, describing a much
more generalized feeling of unease. She also complains of insomnia; she states she
only sleeps for a “few hours” a day, and she is continuously tired. She denied any
suicidal ideation currently (C-SSRS score is 0), and she denied any history of any
suicide attempts. She has not followed up with a mental health professional.
Substance Use Domain: Opioids: heroin, using intravenously, currently using
about 15 “bags” per day (equivalent to about 1.5 g per day although the amount of
heroin per bag can vary in different communities). First opioid use at the age of
25 years—prescription pills after wisdom tooth removal—transitioned to using
heroin at the age of 28. Last use was night prior to ED visit at around 10 pm, used
10 “bags” IV. She reports two prior accidental overdoses both requiring naloxone
use and hospital stay. She denies any medical complications including endocarditis;
however as noted she reports a history of hepatitis C. She has had multiple attempts
at cutting down the use of heroin, by herself and also in treatment programs includ-
ing two methadone maintenance program admissions. Longest period of sobriety
since initial use of opioids was 2.5 years while in the methadone program, ending
1 year ago. Cocaine: ~$50 per day (~0.5 g), IV-“speedballs” (IV cocaine and heroin
together), and first use was at the age of 26 and last use was night prior to ED visit,
unknown amount. Tobacco: smokes one pack of cigarettes per day for the last
25 years. Denies use of other substances.
Family History: Patient denies any significant history; however she is vague
about this.
Social History: She states she was born and raised in New York City, undomi-
ciled, no contact with parents or siblings who also live in New York City. Not in any
relationship. She has some college level education, no vocational training. She
works odd jobs at times currently and has a history of sex work. She admits to a
pending court case for shoplifting and has spent a total of 4 years in prison. No his-
tory of military service.
Objective Diagnostics: Positive urine toxicology for opioids and cocaine; posi-
tive serology for hepatitis C. Negative pregnancy test, negative HIV, mild elevation
of transaminases.
Physical Exam: Suboptimal hygiene and grooming, cachectic, “track marks”

secondary to IV drug use present on both arms and hands, chronic cough, and mildly
elevated blood pressure.
Mental Status Exam (MSE): Most notable for superficially cooperative attitude,
at times vague thought process, mild subjective anxiety, no hallucinations/delu-
sions, no suicidal ideation currently, partial insight, impaired judgment.
Discussion: Patient Lilly came to the emergency department for anxiety, insom-
nia, and opioid withdrawal. It quickly becomes clear that she meets DSM-5 criteria
for opioid use disorder, severe. She also likely meets criteria for cocaine use disor-
der, severe (under the category of stimulant use disorders), and tobacco use disor-
der, severe. The chronic nature of her medical and psychiatric issues raises the
possibility of some significant contribution from either or both of these domains to
her current presentation. For example, she may have any number of undiagnosed
medical conditions exacerbating her insomnia and anxiety, particularly in light of
her lack of engagement in medical care. Patients with chronic mental illness often
have co-occurring substance use disorders, so while it is difficult to make a conclu-
sive diagnosis of, for example, a generalized anxiety disorder in a patient with such
significant substance use, further questioning could help illuminate to what extent
anxiety symptoms predated any substance use. All of her medical, psychiatric, and
substance use challenges are exacerbated by psychosocial stressors. She is estranged
from her family and has no significant community support system. She has legal
issues and has apparently struggled to sustain employment. She is undomiciled
which is a significant cause of stress and anxiety for those experiencing it and a
significant barrier to engagement in any kind of treatment. Due to her substance use
pattern and psychosocial stressors, she is at an increased chronic safety risk; how-
ever, she is not an acute safety risk as she is not expressing any suicidal ideation nor
does she have any known history of suicide attempts. Securing her agreement to
contact collateral sources of information (although it appears unlikely from her
description of her level of support) could be helpful in verifying the key data inform-
ing this assessment. A comprehensive treatment plan for Lilly should address the
issues mentioned above in order to provide her with the best possibility for sus-
tained abstinence from substances.
Conclusion
When a patient presents for assessment of a substance-related disorder, it is a criti-

cal opportunity to intervene. Ineffective assessments of substance-related disorders
frequently stem from too narrow a focus on substance use, neglecting the medical
and psychiatric domains and failing to consider how these three areas may interact.
Successful assessments of substance use consider these dimensions and incorporate
the patient’s readiness to change. Patients must navigate a multitude of barriers to
care including psychosocial stressors, complex treatment systems, and fear of being
disbelieved or stigmatized while in substance use treatment, all of which can make
the substance use assessment particularly challenging. Ultimately, however, a
thorough and compassionate assessment of the medical, psychiatric, and substance

use domains could be the catalyst for a patient making the decision to change an
unhealthy pattern of substance use [17, 18].
Key Points
• A comprehensive substance use assessment must include attention to the medical

and psychiatric domains, either or both of which may be contributing to the cur-
rent presentation in addition to any substance use.
• Gathering a substance use history must include attention to the basic facts about
use—some of which may be urgently needed for lifesaving purposes—as well as
the patient’s subjective experience of their use and thoughts about change.
• Patients who use substances may be reluctant to discuss their use in depth, par-
ticularly at an initial encounter.
References
1. Woody GE, Cacciola J. Diagnosis and classification of DSM-IV-TR and ICD-10. In: Ruiz P,
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Neurobiology of Substance
Use Disorders 2
Manesh Gopaldas and Kristopher A. Kast
Introduction
The past two decades of neuroscience research in preclinical and clinical models
have significantly enhanced our understanding of the neurobiology of addiction.
Koob and Volkow have summarized a large and growing body of literature, propos-
ing a three-stage model of substance-related and addictive disorders [1]. Recently,
Kwako and colleagues proposed that this three-stage model could provide a clini-
cally applicable framework for diagnosis and treatment [2]. In this chapter, we pres-
ent a clinical case, review the three-stage model, and apply this neuroscience-based
framework to clinical care.
Clinical Case
We begin with a case to illustrate some problems confronting the clinician caring
for individuals with substance use and related disorders. This case calls attention to
observational data that are helpfully organized and made clinically useful by a
neuroscience-based framework.
M. Gopaldas
Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center,
Nashville, TN, USA
e-mail: manesh.m.gopaldas@vumc.org
K. A. Kast (*)
Department of Psychiatry and Behavioral Sciences, Vanderbilt University School of
Medicine, Addiction Consult Service, Vanderbilt University Medical Center,
Nashville, TN, USA
e-mail: kristopher.a.kast@vumc.org

https://doi.org/10.1007/978-3-030-86430-9_2
12 M. Gopaldas and K. A. Kast
History of Present Illness
You are asked to assess “Mr. M,” a 35-year-old man with a history of unspecified
anxiety and depressive disorders who presents to the emergency department in dis-
tress, requesting hospitalization to address worsening suicidal ideation. Your open-
ended questions elicit prominent, unrelenting symptoms of anxiety and sleep-onset
insomnia that are “only” relieved by alcohol use – though he ruminates aloud that
his drinking “to get going” in the morning is now affecting his work and personal
responsibilities.
You find that Mr. M’s alcohol intake escalated over preceding months to five
12-ounce beers four times per week, with one or two “heavier” binges causing epi-
sodic amnesia. As if anticipating chastisement, he reports “And every time I try to
stop, I can’t sleep – I start shaking – and my body just starts to feel like it is shutting
down… like I’m going to die.”
Psychosocial History
Mr. M’s neurodevelopmental history is notable for significant childhood adver-

sity, including emotional and physical abuse by an older brother, with subsequent
impairing anxiety in nearly all social situations “for as long as [he] could remem-
ber.” He worries about how others perceive him and engages in self-evaluative
thoughts and post-event processing. His intense ruminations often result in hope-
lessness and anticipatory worry about future social interactions, though these
symptoms have gone undiagnosed and untreated throughout his child- and early
adulthood.
He recalls first trying alcohol in college, quickly learning that drinking alleviated
many of his anxiety symptoms. He began to identify with an intoxicated self-state:
“It let me be myself.” Initially, Mr. M consumed alcohol only in social settings, but
his use extended over time to drinking alone, especially when overwhelmed with
ruminative generalized worries. He tells you, “I noticed that I didn’t really enjoy
drinking anymore… but when I started worrying, I would be drinking before I even
realized what I was doing.”
Mr. M took a leave of absence midway through his second collegiate semester
due to his symptoms, and he did not return. He now lives alone with few relation-
ships, continuing to work in sales despite job dissatisfaction.
Inpatient Hospital Course
After reviewing your diagnostic assessment and treatment recommendations, Mr. M

agrees to voluntary inpatient admission for acute stabilization. Given his heavy
alcohol use, presenting blood alcohol level (<100 mg/dL), and history of moderate
withdrawal symptoms, you begin a symptom-triggered protocol for alcohol with-
drawal treatment. Moderate doses of diazepam provide acute withdrawal symptom
2 Neurobiology of Substance Use Disorders 13
relief and allow you to discuss further post-acute treatment options for his comorbid
alcohol use and anxiety disorders. He chooses extended-release naltrexone with
close outpatient follow-up in your addiction clinic, deferring other interventions:
“I’m a lot less anxious after the [diazepam].”
Outpatient Clinic Management
Two weeks post-discharge, Mr. M presents to your office. He arrives late and
appears apprehensive, with psychomotor activation (fidgeting, frequent reposition-
ing), avoidant eye contact, and brisk speech, at times fumbling over his words. He
reports muscle tension, restlessness, sweating, and trouble concentrating since dis-
charge, with associated racing thoughts, excessive worrying, and panic-like epi-
sodes in public settings – “like being here.” Despite having “urges” to use alcohol,
he has remained abstinent, citing his strong “willpower.” With guided questions,
you are also able to identify limited adaptive coping strategies he has utilized (e.g.,
exercise, reading).
You review his untreated anxiety symptoms, their relationship to relapse risk,
and recommend additional pharmacological and behavioral treatments to facilitate
his recovery.
Discussion
In this section, we introduce the chronic disease model of addiction and review the
three neurofunctional domains implicated in the development and maintenance of
substance use and related disorders.
Addiction Cycle
Addiction is a chronic, relapsing illness that involves distress or functional impair-

ment due to intense desire for a drug, loss of control over its use, and profound
discomfort with abstinence [3]. Individuals with substance-related and addictive
disorders experience this maladaptive pattern of use repetitively and compulsively,
often despite harmful consequences.
Koob and Volkow have characterized addiction as a recurring cycle of three dis-
tinct stages: (1) binge/intoxication, (2) withdrawal/negative affect, and (3) preoc-
cupation/anticipation [1]. The binge/intoxication stage is marked by reward and
positive reinforcement, where the drug serves to promote positive subjective experi-
ence [4]. The withdrawal/negative affect stage is an aversive, stress-like state marked
by negative reinforcement, where drug consumption serves to remove the discom-
fort experienced during abstinence [4]. The preoccupation/anticipation stage is
characterized by executive function deficits and impulsivity, which contribute to
drug craving and increase risk of relapse.
Neuroanatomy and Circuits
The neurocircuitry of each stage has been well characterized in rodent studies, with
corroborating human subject evidence [1]. We review this overlapping neurocir-
cuitry in detail below.
Binge/Intoxication
All known substances associated with addictive syndromes affect the reward sys-
tem – centered around a group of structures located in the basal ganglia [5]. Midbrain
neurons projecting to the striatum (and the prefrontal cortex) release dopamine toni-
cally and, to a lesser extent, opioid peptides [1]. These neurotransmitters are respon-
sible for (1) positively valenced emotions (e.g., euphoria) with increased firing in
the ventromedial striatum and (2) increased behaviors that seek anticipated reward
via the dorsolateral striatum. These midbrain-originating circuits are termed (1) the
mesolimbic dopamine pathway, which projects to the nucleus accumbens (NAcc)
and mediates reward and reinforcement, and (2) the nigrostriatal dopamine path-
way, which projects to the dorsolateral striatum, controlling habitual motor func-
tions [5].
Repeated substance-induced dopamine release in the NAcc leads to anticipatory
dopamine activity in the reward circuit when re-exposed to substance-related cues,
producing incentive salience for these cues [1]. Repeated use further results in com-
pensatory neuroadaptations that attenuate substance-induced dopamine release. A
new, lowered set point for tonic dopaminergic activity is established (a process
termed allostasis), with the downstream effect of diminished reward response to
natural reinforcers. Ultimately, most patients presenting for treatment experience
heightened cue-related incentive salience, less substance-induced euphoria, and low
expectations of reward from non-substance activities (e.g., relationships, work).
Withdrawal/Negative Affect
Two neurobiological mechanisms – within- and between-system neuroadapta-
tions – are thought to underlie the experience of acute and post-acute withdrawal
[6]. With chronic substance use, within-system changes counter rewarding effects
by downregulating reward signaling in the NAcc via allostasis, producing a relative
dopaminergic deficit. The between-system changes, in contrast, are characterized
by enhanced recruitment of stress circuits in the extended amygdala – sometimes
termed the “anti-reward” system. The extended amygdala consists of several struc-
tures including the central nucleus of the amygdala (CeA), bed nucleus of the stria
terminalis (BNST), and shell of the NAcc.
This anti-reward system upregulation results in elevated levels of amygdalar
corticotropin-releasing factor (CRF), norepinephrine (NE), and dynorphin, as well
as activation of the hypothalamic-pituitary-adrenal (HPA) axis [7]. Acute and post-
acute withdrawals are associated with relative upregulation of the HPA axis, result-
ing in increased adrenocorticotropic hormone, corticosterone, and amygdalar
CRF. These neuroadaptations collectively produce a stress-like state marked by

negative affect (i.e., irritability, emotional pain, anxiety, and dysphoria) that is pro-
longed beyond the acute withdrawal state (lasting from weeks to years) and also
drives negative reinforcement processes responsible for craving and relapse [4].
Preoccupation/Anticipation
Impairments in decision-making, self-regulation, and behavioral inhibition are
often observed in individuals with substance use disorders. These executive func-
tion deficits contribute significantly to relapsing behavior despite accumulating
negative consequences.
To conceptualize cognitive control of impulsive and compulsive behavior, two
heuristically useful and opposing prefrontal cortical circuits have been proposed: a
“Go system” mediated by the anterior cingulate and dorsolateral prefrontal cortex
and a “Stop system” mediated by the ventrolateral and orbitofrontal cortex [1].
When presented with the incentive salience of a substance-related cue (e.g., reward
craving when passing a liquor store) or the aversive withdrawal state (e.g., relief
craving when waking the morning after a binge), these two systems engage (Go
system) or inhibit (Stop system) the associated habitual substance-seeking behavior.
In the above examples, the Go system would initiate recurrent drinking, while the
Stop system may prioritize an abstinence goal. A relatively upregulated Go system
and downregulated Stop system result in a decisional balance tipped toward relaps-
ing behaviors.
Treatment
In this section, we interpret Mr. M’s clinical case within the three-stage model and
describe the utility of the Addictions Neuroclinical Assessment. Select pharmaco-
logical and behavioral treatments for substance use disorders are then reviewed
within this neuroscience framework.
Translating Neuroscience into Clinical Practice
Developed by the National Institute on Alcohol Abuse and Alcoholism (NIAAA),

the Addictions Neuroclinical Assessment (ANA) provides the building blocks of the
Alcohol and Addiction Research Domain Criteria (AARDoC) [8]. The ANA is a
neuroscience-based assessment tool that incorporates the three-stage model of
addiction. It includes behavioral, self-report, and neuroimaging measures for each
stage, allowing for more precise diagnosis and treatment of addictive disorders.
Kwako and colleagues evaluated the ANA framework in a sample of patients
with alcohol use disorders (AUDs), showing that the three-stage model corresponds
to three clinically identifiable neurofunctional domains: incentive salience, negative
emotionality, and executive (dys)function [2]. Furthermore, the study identified fac-
tors that either predicted development or indicated the presence of dysregulation
within the three neurofunctional domains. These findings help us to better under-
stand how AUD may develop and to begin to classify different subtypes of AUD.
Further, applying the three-stage neurobiological framework to a specific case
provides a clinically useful heuristic for diagnostic assessment and treatment plan-
ning. For example, Mr. M reports significant cravings for alcohol prior to attending
social events, illustrating an associative learning process involved in incentive
salience: socially cued anxiety and alcohol use become a learned association, with
resulting reinforced and intensified subjective experience of “wanting” alcohol
when exposed to social cues. Mr. M’s worsened anxiety and insomnia when attempt-
ing to reduce his drinking further demonstrate compensatory allostatic changes in
stress-response systems corresponding with negative emotionality: abstinence states
lead to acute and post-acute withdrawal symptoms elicited by within-system down-
regulation of normal dopaminergic functioning and between-system upregulation of
the anti-reward circuitry. And finally, his relapsing alcohol use – despite his own
concern for its sequelae – in response to relief cravings during anxious rumination
shows a relative imbalance between his Go and Stop systems, expressing executive
(dys)function.
In addition, Mr. M’s case overlapped with several predictors and indicators of
vulnerability in each neurofunctional domain as identified in the AUD cohort stud-
ied by Kwako and colleagues. His history of emotional abuse predicts risk across all
three domains, perhaps mediated by epigenetic mechanisms [8]. Among the identi-
fied indicators of current dysfunction, Mr. M’s elevated anxiety and depressive
symptoms are associated with the incentive salience and negative emotionality
domains, perhaps mediated by the maladaptive learning and anti-reward system
upregulation described above.
Mr. M’s treatment course may be understood as targeting each of these neuro-
functional domains. As with most patients presenting for substance use treatment,
his withdrawal/negative emotionality features prominently at the outset. Immediate
attention is paid to stabilizing acute withdrawal symptoms via agonist therapy, a
concept applicable to several substance categories (including nicotine, opioid, and
alcohol, among others). Restoring relative GABA-ergic tone via benzodiazepine
therapy reduces acute withdrawal symptoms (and mitigates risk of severe with-
drawal, including seizure or delirium). Other acute withdrawal treatments target the
upregulated stress-response/anti-reward system directly, as with lofexidine and
clonidine targeting noradrenergic hyperactivity in opioid withdrawal.
Ameliorating the immediate aversive state allows for initial engagement in edu-
cational, motivational, and relapse-prevention interventions. No longer over-
whelmed by relief cravings, an imbalanced Go/Stop cognitive control system may
be engaged by psychosocial and psychotherapeutic interventions in a targeted way.
Education and cue avoidance feature prominently in early treatment. Identifying
high-risk situations is an early goal in cognitive-behavioral treatment of substance
use disorders, similar to the 12-step directive to change “people, places, and things”
associated with prior use. Both interventions diminish the contribution of incentive
salience to relapse risk and intend to allow this maladaptive learning to extinguish
over time, while new associations form in the context of substance-abstaining activ-
ities and relationships.
However, avoidance of all cue-related incentive salience is rarely achievable,
and often relapse prevention is further aided by pharmacotherapy that reduces
reward- and relief-craving experiences. Effective maintenance agonist and antago-
nist therapies – such as nicotine, methadone, buprenorphine, and naltrexone – typi-
cally occupy a target receptor for the relevant substance, partly reducing the effect
of dopaminergic firing with re-exposure to cues or recurrent substance use. For
individuals with AUD, the mu-opioid receptor antagonist naltrexone reduces crav-
ings and risk of relapse or heavy use – demonstrating a link between the opioider-
gic system and alcohol use in this population [9]. Overall, patients on these
therapies report reduced cravings and cognitive preoccupation with substance-
related themes, theoretically creating cognitive space for engagement in psychoso-
cial interventions.
Diagnosis and treatment of co-occuring psychiatric disorders further address
dysfunction within each neurofunctional domain. As in Mr. M’s case, targeted
medication and psychotherapeutic treatment of anxiety and depressive symptoms
implicated in the negative emotionality domain may further mitigate risk of
relapse and/or facilitate engagement in an ongoing treatment relationship.
Behavioral activation and engagement with a recovery-supportive social network
may further improve mood and anxiety symptoms while simultaneously reducing
exposure to high-risk contexts (e.g., social isolation or use-associated environ-
ments and contacts). And cognitive behavioral interventions, like identification
and reappraisal of cognitive distortions, engage cognitive control networks in
adaptive learning that may mitigate imbalanced Go/Stop system decision-making
(see Fig. 2.1).
Negative emotionality Executive dysfunction
Alcohol withdrawal
↑Stress-response systems
↓ STOP
Social anxiety diathesis ↑ GO
Insomnia
Avoidant coping
↓Behavioral activtion
Depressive symptoms ↓Self-efficacy
Incentive salience Social context
Cues ↑Active use network

NAcc dopamine
↓Recovery network
response
+
Alcohol ↑High-risk contexts
↑Cue exposure
Time
Fig. 2.1 The interaction of three neurobiological domains with social context in Mr. M, an indi-
vidual with alcohol use disorder. The three neurobiological domains include (1) negative emotion-
ality, (2) executive dysfunction, and (3) incentive salience; each interacts with components of the
other domains and surrounding social context to contribute to the risk of relapsing alcohol use.
Within negative emotionality, an upregulated stress-response system occurs in the context of acute
and post-acute alcohol withdrawal, which exacerbates Mr. M’s insomnia and underlying social
anxiety and depressive symptoms. Executive dysfunction, with imbalanced Go/Stop cognitive
control, reinforces avoidant coping and reduces behavioral activation, decreasing Mr. M’s self-
efficacy and contributing to learned helplessness. Over time, allostatic changes in the reward sys-
tem lead to reduced response to alcohol itself, with relatively heightened response to its associated
cues; in Mr. M’s case, incentive salience becomes associated with negative internal emotional
states and high-risk social contexts, further increasing risk of relapse when exposed to these cues
References
1. Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry.
2016;3(8):760–73.
2. Kwako LE, Schwandt ML, Ramchandani VA, et al. Neurofunctional domains derived from
deep behavioral phenotyping in alcohol use disorder. Am J Psychiatry. 2019;176(9):744–53.
3. McLellan AT, Lewis DC, O’Brien CP, et al. Drug dependence, a chronic medical illness: impli-
cations for treatment, insurance, and outcomes evaluation. JAMA. 2000;284:1689–95.
4. Koob GF, Mason BJ. Existing and future drugs for the treatment of the dark side of addiction.
Annu Rev Pharmacol Toxicol. 2016;56(1):299–322.
5. Ries RK, et al. The ASAM principles of addiction medicine. Wolters Kluwer Health,
Philadelphia, PA; 2014.
6. Koob GF. The dark side of emotion: the addiction perspective. Eur J Pharmacol. 2015;753:73–87.
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based framework for addictive disorders. Biol Psychiatry. 2016;80(3):179–89.
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administration and craving: meta-analysis of human laboratory studies. Addict Biol.
2016;22:1515–27.
Alcohol Use Disorder
3
Kseniya Svyatets
Introduction
Alcohol use disorder is a highly prevalent illness, with tremendous morbidity, mor-
tality, and strain on the healthcare system. In 2019, approximately 14 million adults
and 400,000 adolescents met criteria for alcohol use disorder [1]. Recent data shows
that alcoholism is the third leading cause of death in the United States [1, 2]. An
estimated 261 deaths occur daily from alcohol use, with a loss of 29 years of life per
death [3]. Alcohol abuse carries a significant socioeconomic burden as well. In
2010, alcohol misuse cost the United States $249.0 billion [1, 3], which included
economic losses in workplace productivity, healthcare spending, law enforcement
costs, and motor vehicle accidents [4]. An estimated two out of every five dollars
spent on alcohol-related costs are covered by taxpayers [4]. There is no question
that alcohol addiction directly and indirectly affects every member of our society.
With the pervasiveness of substance use disorders and their medical sequelae,
addiction has become one of the most commonly encountered domains of illness in
healthcare. A 2016 survey shows that approximately 80% of hospitalists and 35% of
primary care providers reported routinely treating patients with addiction. This
same survey showed that only 27% of hospitalists and 18% of primary care doctors
felt fully confident in their ability to screen patients for substance use, 35% of hos-
pitalists and 17% of primary care doctors considered themselves very prepared to
diagnose addiction, and most notably only 12% of hospitalists and 9% of primary
care physicians felt thoroughly prepared to engage patients in brief interventions
[5]. Why do physicians feel such discomfort in treating this spectrum of illnesses?
The same 2016 survey also showed that a large proportion of physicians believe that
addiction is a choice, many find caring for patients with addiction less satisfying,
and the majority of physicians consider disorders of addiction to be more
K. Svyatets (*)
Addiction Psychiatry Fellow, New York University, New York, NY, USA
e-mail: Kseniya.Svyatets@nyulangone.org

https://doi.org/10.1007/978-3-030-86430-9_3
22 K. Svyatets
challenging to manage than other illnesses [5]. Substance use disorders remain
highly stigmatized in our society, and healthcare personnel are not immune to these
biases. These attitudes contribute to the numerous barriers to care that patients with
addiction experience.
Psychiatrists are often consulted on patients struggling with alcohol use disorder.
Common reasons for such consults include the high rate of comorbidities with pri-
mary psychiatric illness and discomfort of primary care/internal medicine doctors in
working with this population. This chapter highlights the clinical case of a middle-
aged man with severe alcohol use disorder and comorbid psychiatric pathology.
This case serves to illustrate the numerous biopsychosocial factors at play in alcohol
use disorder, the complexity of dual diagnosis, and the treatment options available
for alcohol dependence.
Case
Mr. B is a 42-year-old male, recently separated from his wife and children, employed
in finance, with no prior psychiatric history, who was brought in to the emergency
department by his brother for abdominal pain, intractable vomiting, lethargy, and
dizziness. He was found to have alcoholic ketoacidosis and admitted to the medical
unit for rehydration and electrolyte repletion. This was Mr. B’s second admission
for alcoholic ketoacidosis and fifth time in the hospital for alcohol-related compli-
cations. The other three were emergency room visits for trauma due to falls while
intoxicated. Despite multiple hospital visits, Mr. B had never received counseling
from his medical providers or referrals for addiction treatment. On his most recent
admission, the hospitalist noted Mr. B’s nonchalant attitude about his numerous
hospitalizations and requested a psychiatric assessment.
Throughout the evaluation, Mr. B minimized his alcohol use and showed a lim-
ited understanding of the toll his addiction had taken on his life. He said that he
came from a family of “casual drinkers.” His parents would routinely have multiple
glasses of wine with dinner and were often intoxicated after work. Mr. B recalled a
childhood of frequent outbursts at home and occasional physical violence between
his parents. His father had a lucrative job in finance and his mother was a manager
in a prominent public relations firm. There was never any acknowledgment that his
parents might have an unhealthy dependence on alcohol and potentially underlying
mental health struggles. Mr. B’s brother had several admissions to rehabs and con-
tinues in outpatient treatment for addiction, and he was characterized as the “black
sheep” of the family.
Mr. B recalled that he had always been an anxious and “moody” person. As a
teenager, he constantly worried over his future, whether he would get into a good
college and live up to his parents’ expectations. He would often find himself unable
to relax and lose sleep over his worries. At times, he would be unable to eat due to his
stress. He began having panic attacks in his senior year of high school. During these
attacks, he would feel as if the walls were closing in on him; he could not breathe or
focus. He says he has felt sad and empty for most of his life. There were multiple
3 Alcohol Use Disorder 23
episodes throughout his life, during which he “fell into a dark hole.” In those times,
he would isolate himself in his room, avoid school and work, and spend days lying in
bed. He occasionally had thoughts of not wanting to live anymore, but never formu-
lated a plan to harm himself. These mood symptoms continued into adulthood, yet
Mr. B never thought to seek mental health treatment. He believed that most people
struggled with similar thoughts, and it was a matter of willpower to overcome them.
Mr. B began drinking with friends at age 15. His drinking was primarily social at
first, but he soon realized that alcohol had a blunting effect on his anxiety and sad-
ness. As he began his own career in finance, Mr. B’s alcohol use increased exponen-
tially. His career demanded perfectionism, long hours, and a competitive attitude.
Alcohol helped him cope with his fear of failure and self-doubt. As Mr. B’s drinking
increased, he became more irritable with his family members, frequently intoxi-
cated at family functions, and would occasionally sleep through events such as his
children’s sporting games. Mr. B reported experiencing tremulousness and anxiety
when he attempted to cut back on his alcohol use. He denied a history of seizures,
delirium tremens, or other episodes of complicated withdrawal. His wife expressed
concerns many times over his increasing alcohol use, and several months ago, she
separated from him. The week prior to his hospitalization, Mr. B had been drinking
nearly a 750 mL bottle of whiskey daily.
Mr. B was reticent to discuss the notion that he may have a severe substance use
disorder. He understood that his drinking had escalated into unhealthy patterns, yet he
believed that alcohol played a significant role in helping him manage his stress. He
expressed a goal of decreasing his alcohol intake but was not interested in complete
alcohol cessation. The consulting psychiatrist provided psychoeducation on the nature
of alcohol addiction and introduced treatment options including inpatient rehab, out-
patient referrals, and medication-assisted treatment for alcohol use. Mr. B was strongly
urged to consider inpatient rehab; however, he did not feel his alcohol use was severe
enough to warrant inpatient care or medications. Mr. B did accept the psychiatrist’s
assessment that he likely meets criteria for generalized anxiety disorder and recurrent
major depression, and he accepted a referral for an outpatient dual diagnosis clinic.
Discussion
Mr. B’s case illustrates how addiction develops gradually over time and negatively
affects numerous aspects of a person’s life. An awareness of the biopsychosocial
factors at play can help build rapport, empathy, and understanding of the patient, as
well as aid in the prompt diagnosis and treatment of patients, including those who
may feel uncomfortable disclosing the full extent of their substance use. Mr. B’s
history includes several determinants which increased his risk for substance abuse.
From a biological perspective, Mr. B has significant genetic loading toward alcohol
use. His brother struggled with a severe alcohol use disorder, and both parents had
substantial alcohol misuse, the full extent of which is unclear. Some literature esti-
mates that genetics are 60% responsible for the formation of alcoholism, while the
other 40% is determined by psychological and social factors. Other biological
24 K. Svyatets
theories postulate that family history of alcoholism increases the risk of a patient
developing alcohol use disorder by three to four times [6]. Mr. B also reports long-
standing untreated symptoms of anxiety and depression. Mood disorders are a well-
documented risk factor for developing substance use disorders. An estimated
30–40% of people with alcohol addiction have comorbid depression, 25–50% meet
criteria for an anxiety disorder, and approximately 10–15% have a history of suicid-
ality [6].
There are multiple psychological theories about personality structures which
predispose to addiction. Classic psychoanalysis postulates that patients with alcohol
addiction are fixed in the oral stage of development [6]. Kohut and Balint theorized
that patients with addiction utilize alcohol as a means to replace missing self-esteem
and inner peace [7]. Other psychodynamic theories claim that addiction to sub-
stances may be an attempt to control unacceptable affective states including anger,
guilt, shame, and sadness [7]. An initial psychiatric consultation is insufficient for
appreciating the full psychodynamic influences at play. However, from Mr. B’s his-
tory, it is reasonable to hypothesize that self-esteem and painful emotional states
may have been another predisposing factor for him to addiction. Lastly, societal
attitudes strongly affect a patient’s propensity toward alcohol use. Mr. B grew up in
an environment where his parents frequently drank to the point of intoxication. He
continued in a career where colleagues were frequently socializing with one another
outside of work and using alcohol and drugs while doing so. He was constantly
exposed to a social normalization of severe alcohol use, and these experiences likely
hindered his realization of how problematic his own alcohol use had become.
An integral aspect of any psychiatric evaluation in a patient with suspected alco-
hol use disorder is assessment for comorbid psychiatric pathology. Chronic sub-
stance use can induce numerous mood states including depression, anxiety,
neurovegetative symptoms, mania, and psychosis. Alcohol intoxication is specifi-
cally known to precipitate mood lability, while alcohol withdrawal exacerbates
anxiety and insomnia [8]. Differentiating between alcohol-induced mood states and
primary psychiatric disorders is often a challenge for even the seasoned psychiatrist.
In order to make the distinction, it is important to obtain a timeline of the onset of
mood symptoms and substance use. If the patient has had significant periods of
sobriety during which he experienced mood symptoms, he would likely meet crite-
ria for a primary psychiatric disorder such as major depressive disorder. Another
clue is that substance-induced mood symptoms will resolve or at least significantly
decrease in the first few weeks of abstinence while primary psychiatric symptoms
will persist. For this reason, some psychiatrists choose to defer treatment for pri-
mary mood states, barring any acute need, until after a few weeks of sobriety are
achieved. Mr. B reports a clear childhood history of anxiety and depression, which
began prior to his onset of alcohol use. He also notes that he used alcohol to help
him manage these symptoms. In his case, he would meet criteria for a primary anxi-
ety and depressive disorder, and initiation of an SSRI would have been reasonable,
had he been amenable.
Treatment
Medical Complications
Treatment of alcohol use disorder is multifaceted and includes assessment for acute
medical complications, evaluation for psychiatric comorbidities, and discussion of
medication-assisted and psychosocial treatment options. The following discussion
lists several medical complications which providers commonly encounter when
consulting on patients with alcohol abuse. The full list of medical complications of
chronic alcohol use is vast and beyond the scope of this chapter.
The first step in providing treatment for a patient struggling with chronic alcohol
abuse is to effectively manage withdrawal. Symptoms to monitor include nausea,
vomiting, increased anxiety, tremors, sensory disturbances, and disorientation. The
Clinical Institute Withdrawal Assessment for Alcohol (CIWA) scale is the measure
of alcohol withdrawal most commonly used by healthcare professionals and incor-
porates both objective and subjective data on the above domains of withdrawal
symptoms. Long-acting benzodiazepines are the treatment of choice for withdrawal;
however in patients with liver compromise, it is safer to use benzodiazepines that do
not undergo hepatic conjugation such as lorazepam and oxazepam [2].
Inadequate treatment of alcohol withdrawal can lead to serious medical compli-
cations including seizures and delirium tremens. Seizures occur in about 1% of
patients who are untreated for withdrawal, and patients are at highest risk in the first
three days of withdrawal [2]. Delirium tremens (DTs) is a rare phenomenon marked
by autonomic instability, delirium, and hallucinations. Approximately 5% of
patients in alcohol withdrawal develop DTs, and the risk is again highest within the
first three days of withdrawal [2]. Previously, DTs had a mortality rate of about
30%; however with medical advances, the mortality rate has decreased to 1% [9].
Both DTs and seizures are treated with high-dose rapid-onset IV benzodiazepines.
ICU management is often required for patients in DTs as they require constant
monitoring and can deteriorate rapidly. Patients in withdrawal refractory to benzo-
diazepines are often administered phenobarbital [2]. Antiepileptic medications are
sometimes used prophylactically to prevent seizures; however data is limited.
Some patients may ultimately be referred for inpatient detoxification (“detox”)
treatment. The patients referred for inpatient detoxification are typically those who
have expressed an interest in stopping alcohol after chronic use and for whom there
is some concern—either through high volume of use or due to past complicated
alcohol withdrawal—that the early phase of alcohol cessation could result in com-
plicated withdrawal. Inpatient detoxification typically lasts no more than one week
and incorporates medical treatment for withdrawal symptoms and various psycho-
social and psychotherapeutic substance abuse treatment modalities. Treatment with
inpatient detoxification is generally not an effective long-term treatment for alcohol
use disorder; over half of those who participate are using alcohol again within
two weeks of discharge, with over 80% ultimately drinking again [15].
26 K. Svyatets
Alcohol hallucinosis is a syndrome sometimes mistaken for DTs. Patients with

alcohol hallucinosis experience visual hallucinations without delirium or autonomic
instability, although other kinds of hallucinations have been reported as well.
Alcohol hallucinosis is usually time limited; although most situations will eventu-
ally resolve without pharmacological management, short-term antipsychotics are
often helpful for the comfort of the patient [2].
Wernicke-Korsakoff syndrome is another set of medical complications that psy-
chiatrists may encounter in chronic alcohol users. Wernicke-Korsakoff is in reality
two distinct syndromes caused by thiamine deficiency, as a result of decreased oral
intake in the context of chronic alcohol abuse. Wernicke’s disease is characterized
by symptoms of ocular dysfunction, gait disturbances, and mental status changes.
Most patients do not present with all three symptoms; therefore, Wernicke’s should
be suspected in all alcoholic patients who present with an acute development of any
of these symptoms. Wernicke’s is a medical emergency, as lack of prompt treatment
can lead to Korsakoff syndrome or death in a significant number of patients.
Korsakoff syndrome is a chronic memory disorder, marked by retrograde and
anterograde amnesia, which occurs as a result of long-standing thiamine deficiency.
Wernicke’s is treated with high-dose intravenous thiamine, as oral thiamine is not
absorbed well, and multivitamins [2]. Korsakoff syndrome is considered irrevers-
ible and there is limited data on treatment options; however, high-dose thiamine is
typically used.
Medication-Assisted Treatment
Patients with moderate to severe alcohol use disorder would benefit from a conver-
sation about medication-assisted treatment options. Currently, the three medications
approved by the US Food and Drug Administration (FDA) for alcohol use disorder
are naltrexone, disulfiram, and acamprosate. Naltrexone is an opioid receptor antag-
onist and is also FDA approved for opiate addiction. By blocking the opioid recep-
tors, naltrexone is believed to reduce the dopamine-enhancing effects of alcohol,
thereby reducing cravings and feelings of intoxication [10]. Patients who initiate
naltrexone must not have taken opiates for 7–10 days prior; otherwise, the opioid
blockade of naltrexone will precipitate withdrawal. Naltrexone is often a first-line
choice for patients due to the easy once a day dosing. Naltrexone also comes in a
monthly depot formation, improving efficacy in patients who have difficulty taking
pills daily. Notable side effects of naltrexone include nausea, abdominal pain, vom-
iting, CNS disturbances, hepatotoxicity, and rarely suicidal ideation. Due to the risk
of hepatotoxicity, routine monitoring of liver function tests is highly recommended.
Acamprosate is an alternative medication to naltrexone, often used when patients
are unable to tolerate the side effects of naltrexone or have liver compromise, since
it is renally cleared. The mechanism of acamprosate is not fully understood; how-
ever it is believed to counter the hyperglutamatergic state that emerges in the brain
after repeated cycles of alcohol intoxication and withdrawal. Acamprosate has few
side effects and few drug interactions [10]. It is not known to cause hepatotoxicity
and is a good option for patients with significant liver dysfunction, although it can-
not be used in patients with renal impairment. One downside to acamprosate is the
requirement for three times daily dosing, which can be challenging for some patients
to manage. Disulfiram is the third and oldest FDA-approved medication for alcohol
use disorder. Disulfiram blocks aldehyde dehydrogenase, creating a buildup of toxic
acetaldehyde when patients consume alcohol. When a patient drinks while taking
disulfiram, they experience a highly unpleasant reaction to the acetaldehyde which
may include nausea, vomiting, sweating, flushing, blood pressure fluctuations, pal-
pitations, and rarely cardiac issues [10]. Evidence for the efficacy of disulfiram for
alcohol cessation is inconsistent; however, it is a good option for highly motivated
patients for whom the prospect of the disulfiram reaction is an effective deterrent to
alcohol use.
FDA-approved medications for alcohol use disorder

Medication FDA year
name of approval Dosing Common side effects
Disulfiram 1951 Once daily Nausea, vomiting, sweating, flushing, blood
pressure fluctuations, palpitations, and rarely
cardiac issues when ingested with alcohol
Naltrexone 1984 Once daily or Nausea, abdominal pain, vomiting, CNS
monthly IM disturbances, hepatotoxicity, and rarely suicidal
depot ideation
Acamprosate 2004 TID dosing Few side effects, most commonly diarrhea
Gabapentin, topiramate, and valproic acid are not approved by the FDA but are
common second-line agents for alcohol use disorder. Gabapentin is particularly
helpful for patients with alcohol use disorder and comorbid anxiety or neuropathic
pain. Topiramate has some data for efficacy in both alcohol use disorder and cocaine
use disorder and is sometimes used for patients who struggle with comorbid sub-
stance abuse. Valproic acid is an appropriate choice to consider in patients with
bipolar disorder or severe mood lability and alcohol use disorder. It is best to utilize
FDA-approved treatment options as the first-line management for alcohol use disor-
der; however, these agents can be helpful adjuncts to consider.
Inpatient Treatments
As discussed earlier, inpatient detoxification may be considered for some patients

where there is concern for medically complicated acute alcohol withdrawal and
who want additional support and treatment in the early phase of cessation. Longer-
term treatments, often colloquially referred to as “rehab,” may last from weeks to
months and typically offer intensive treatment in a variety of modalities (including
psychotherapy and medication-assisted treatment) to support abstinence from alco-
hol. Patients will often need to be medically cleared for admission to these rehabili-
tation facilities out of concern for their ability to manage severe alcohol withdrawal,
either by completing a brief detoxification first or by confirmation that the patient
28 K. Svyatets
has not experienced complicated alcohol withdrawal in the past when stopping.
Important considerations for helping a patient select one of these longer-term reha-
bilitation facilities include treatment modalities offered, length of the program,
insurance coverage, and cost. Finally, some patients who have severe alcohol use
disorder and a decompensated co-occurring mental health diagnosis (such as major
depression, bipolar disorder, or a psychotic illness) should be considered for admis-
sion to a dual-diagnosis psychiatric unit that can treat both alcohol and other sub-
stance use disorders as well as the co-occurring psychiatric disorder. These units are
becoming less common, however, as the overall number of inpatient psychiatric
beds is gradually being reduced.
Psychosocial Interventions
Mr. B had been admitted five times for alcohol-related complications, yet the con-
sulting psychiatrist was the first physician to provide counseling for addiction. This
is not an uncommon scenario for patients. In contrast to other chronic medical con-
ditions, such as diabetes, hypertension, and cancer, physicians feel uncomfortable
and ill-prepared to provide counseling on addiction and too often avoid the topic
altogether. Yet, evidence has shown that even brief time-limited interventions can
have a significant impact on a patient’s motivation to change. A Cochrane review
from 2019 examined data from 69 studies and found that brief interventions by
primary care physicians can reduce the average weekly amount of alcohol con-
sumed in patients followed for up to a year after [11]. Brief interventions for alcohol
use are varied and can encompass assessment of motivation for change, feedback
about current use, and psychoeducation about pharmacological and behavioral
options for behavioral modification [11]. One example of a straightforward brief
intervention which can be done in any time-limited setting is known as the 5A
framework: Ask about the use, advise to quit, assess desire to change, assist in quit-
ting with medication and therapy, and arrange follow-up.
Motivational interviewing (MI) is known as the quintessential interviewing tech-
nique for patients struggling with ambivalence about alcohol and/or other substance
use. MI aims to elicit patients’ motivations for change through four core compo-
nents: engaging the patient in conversation, focusing on an agenda, evoking patients’
motivations for change, and planning for change if the patient is ready and agree-
able. MI utilizes the core skills of open-ended questions, affirming patients’
strengths and beliefs, reflective listening, and summarizing [12]. MI is a collabora-
tive, non-confrontational style of interviewing and can be successfully utilized both
in brief interventions and longer-standing therapeutic relationships.
For longer-term treatment, there is an ever-growing number of psychotherapeu-
tic modalities that have been shown to be effective with addiction disorders.
Cognitive behavioral therapy (CBT) is one of the most commonly used psycho-
therapy techniques, applicable to a wide range of mental illnesses. In CBT, thera-
pists and clients collaboratively examine connections between thoughts, behaviors,
and emotions. The cognitive component of CBT for alcohol use focuses on identify-
ing and reframing cognitive distortions surrounding substance use, tracking the cir-
cumstances present at the time of cravings to drink, managing painful emotions that
may lead to alcohol use, and exploring the significance of dysfunctional beliefs
about alcohol and their relationship to patients’ core beliefs about themselves.
Behavioral techniques center around avoiding and managing triggers, tolerating
cravings, and building healthy coping skills and new rituals without alcohol.
Network Therapy, created by Dr. Marc Galanter in the 1990s, is a modality which
brings the patients’ loved ones into sessions, utilizing social support and community
reinforcement as powerful motivational tools in the mutual goal of sobriety [13].
Acceptance and Commitment Therapy has gained traction in recent years, as a ther-
apeutic technique that clarifies clients’ values for committed action and utilizes
mindfulness and cognitive defusion to manage triggers for alcohol use and painful
emotions.
Group therapies are also powerful tools for patients with alcohol use disorder,
providing clients with social support, peer mentorship, and reduction of stigma.
Alcoholics Anonymous (AA) is one of the oldest and most well-known forms of
group therapy, widely utilized in all states and many countries. A 2020 meta-
analysis showed that AA performs at least as well if not better than other psycho-
therapeutic treatment options and may be particularly cost-effective compared to
other treatments [14]. AA meetings focus on the 12 steps to recovery, which include
admitting to powerlessness over alcohol, asking a higher power for forgiveness,
and taking personal inventory of shortcomings. AA meetings also facilitate con-
nections among individuals with alcohol use disorder at different points in their
recovery; this kind of mutual support and use of personal experience can be par-
ticularly helpful for patients newly provided with a diagnosis of alcohol use disor-
der and questioning whether a life without regular alcohol use is possible. Different
AA groups take different approaches to helping participants navigate the 12 steps,
so if a patient with alcohol use disorder mentions a dislike for AA based on prior
experience, it can be helpful to inquire about the specific issue that person had with
AA and to mention that other AA groups might be a more positive experience for
the patient. SMART Recovery groups are another group treatment option for
patients. SMART Recovery uses a more cognitive-behavioral framework and may
be particularly appealing for those patients who want a group treatment but have
negative views on AA’s focus on connecting with a higher power as part of treat-
ment. Both AA and SMART Recovery are widely available and have options for
in-person and virtual meetings.
It often takes numerous attempts at intervention before a patient moves for-
ward from the precontemplative stage of addiction. In Mr. B’s case, while the
initial intervention by the psychiatrist did not result in an acceptance of treatment
(a very common initial response to a medical provider’s expression of concern
about alcohol use), we can hope that it planted seeds of understanding of the
nature of his addiction to alcohol and may result in more willingness to seek treat-
ment in the future.
30 K. Svyatets
Conclusion
Alcohol use disorder is a complex and varied illness which requires an interdisci-
plinary approach. Effective treatment combines medication-assisted treatment, psy-
chosocial interventions, and management of comorbidities. Alcohol use disorder is
a difficult illness to manage; however, given the vast associated morbidity and mor-
tality, it is vital that the medical community continue to assess and treat it wherever
possible in order to improve patient outcomes.
Key Points
• Alcohol use disorder is one of the costliest illnesses in the United States and
around the world both in terms of lives lost and its economic consequences.
• Every opportunity should be taken to screen and potentially intervene for patients
for whom alcohol use disorder is suspected.
• Effective treatments for alcohol use disorder include three FDA-approved medi-
cations (disulfiram, acamprosate, and naltrexone) as well as other medication
options that may help target co-occurring symptoms in addition to alcohol use
disorder.
• Psychosocial treatments, including individual psychotherapy and groups, are
effective for many people with alcohol use disorder and should be offered as an
option along with medication-assisted treatments.
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Cannabis Use Disorder
4
Dhruti Patel
Introduction
Cannabis continues to be the most widely used illicit substance in the United States.
During the past decade, cannabis use disorders have increased in all age groups and
sociodemographic groups [17]. This is partially reflective of a major shift in atti-
tudes that is occurring in the United States and around the world both at the indi-
vidual and at the broader policy level. In 1988, 24% of Americans supported
legalization of cannabis; three decades later in 2018 that figure was 66% supporting
legalization [10]. Although still illegal at the federal level, as of 2020 cannabis was
legal in 11 US states plus the District of Columbia, with medical marijuana legal in
dozens more states. Several states where legislative efforts have stopped short of full
legalization have pursued a policy of decriminalization, eliminating penalties for
possession of small amounts of cannabis for personal use.
Cannabis is available in multiple forms with varying concentrations of chemical
compounds known as cannabinoids. Cannabinoids exert their effects through the
endocannabinoid system by binding to cannabinoid receptors CB1 and CB2. The
highest density of CB1 receptors is found in part of the brain that influences mem-
ory, concentration, pleasure, coordinated movements, and sensory and time percep-
tion [13]. The main cannabinoids are delta-9-tetrahydrocannabinol (THC) and
cannabidiol (CBD). CBD, which is non-intoxicating, is FDA approved to treat two
rare forms of childhood epilepsy. Its popularity has exploded in recent years as a
largely unregulated treatment for a variety of ailments, particularly anxiety and sev-
eral forms of chronic pain. The evidence to support its use for these other indica-
tions is mostly inconclusive, and patients interested in hearing more about CBD
should be counseled on the lack of consistency among various preparations and the
difficulty of knowing what these products actually contain. THC is the psychotropic
D. Patel (*)
University of Miami Miller School of Medicine, Miami, FL, USA
e-mail: dhruti.patel@jhsmiami.org

https://doi.org/10.1007/978-3-030-86430-9_4
34 D. Patel
substance in cannabis primarily responsible for its intoxicating and psychogenic

effects. THC activates the brain’s reward system to release dopamine, and this flood
of dopamine contributes to the pleasurable “high” that those who use seek. Long-
term use, however, is associated with blunting of the dopamine system [3].
Acute cannabis intoxication for many people includes euphoria and sense of
relaxation. However, potential adverse effects include anxiety, fear, paranoia, and
acute psychosis with hallucinations and delusions. These effects are temporary in
most cases, but appear to play a role in a subset of individuals in either precipitating
or exacerbating chronic psychotic disorders. The risk of adverse effects increases
with frequent use and with exposure to high concentrations of THC. The cannabis
available today is much more potent than what was available in the past, with a THC
to CBD ratio that has grown quickly in recent decades. One study of samples seized
by the DEA between 1995 and 2014 showed an increase in potency from 4% to 12%
and a THC to CBD ratio that increased from 14 to 80 over those two decades [8]. It
is important to inquire about the method of use as concentrated products, commonly
known as dabs or waxes, typically contain higher doses of THC and are more likely
to produce adverse psychological symptoms. Use of edible cannabis can increase
the risk of unintentional overdose due to its longer absorption time and delayed
effect, often prompting the user to take a second dose. In addition, chronic users of
cannabis are at risk for developing a condition known as cannabinoid hyperemesis
syndrome (CHS), which is marked by severe cycles of nausea and vomiting which
can lead individuals to make frequent trips to the emergency room. Supportive ther-
apy is the mainstay of treatment for the syndrome, with patients reporting benefits
from taking hot showers. It is shown to resolve when a person stops using can-
nabis [9].
While many people can use cannabis use without harm, a cannabis use disorder
develops in approximately 9% of regular cannabis users [19, 20]. The DSM-5
defines cannabis dependence as a disorder characterized by continued problematic
pattern of use leading to negative consequences that cause significant impairment or
distress. For the full criteria based on the Diagnostic and Statistical Manual of
Mental Disorders – Fifth Edition (DSM-5) criteria, see Table 4.1.
Table 4.1 DSM criteria for cannabis use disorder

Using cannabis in larger amounts or over a longer period than was prescribed or intended
Making unsuccessful efforts to cut down or control cannabis use
Spending a lot of time in activities necessary to obtain, use, or recover from cannabis effects
Craving cannabis or feeling an urge to use cannabis
Failing to fulfill major life obligations at work, school, or home
Continuing to use cannabis despite persistent or recurrent social or interpersonal problems
Giving up or reducing involvement in important social, occupational, or recreational activities
Using cannabis in physically hazardous circumstances
Continuing to use cannabis despite having a persistent or recurrent physical or psychological
problem
Tolerance, as defined by a need for markedly increased amounts of cannabis or a markedly
diminished effect with continued use of the same amount of cannabis
Withdrawal, as manifested by the characteristic withdrawal syndrome
Mild: 2–3 symptoms; moderate: 4–5 symptoms; severe: >6 symptoms
4 Cannabis Use Disorder 35
Cannabis use places individuals at risk for various adverse health consequences
and may be associated with cognitive impairment, poor school or work perfor-
mance, and psychiatric comorbidity such as mood disorders and psychosis. Common
consequences include relationship and family problems, guilt associated with use of
the drug, financial difficulties, low energy and self-esteem, dissatisfaction with pro-
ductivity levels, sleep and memory problems, and low life satisfaction [7]. Most
who use cannabis to the extent that they can be diagnosed with a use disorder per-
ceive themselves as unable to stop, and most experience a withdrawal syndrome
upon cessation.
Cannabis withdrawal is defined in the DSM-5 as clinically significant distress or
impairment of social or occupational functioning seen approximately one week
after cessation of heavy and prolonged use. Individuals typically experience irrita-
bility, anger, depression, sleep difficulty, craving, and decreased appetite. Onset of
symptoms typically appears about 24 to 48 hours after the last cannabis use, peaks
within four to six days, and lasts from one to three weeks, although significant indi-
vidual differences occur in withdrawal expression [4]. The negative reinforcing
effect of withdrawal makes relapse common in this period. Many indicate that these
symptoms adversely impact their attempts to quit and motivate use of cannabis [6].
Clinical Case
Anne is a 21-year-old college student, who was referred to the mental health clinic
by her primary care physician for reporting changes in her mood. She says her mood
is “okay” but reports having a high level of anxiety and has recently had a few epi-
sodes of overwhelming anxiety, shortness of breath, and chest pain.
As part of your assessment you inquire about her cannabis use. She tells you she
smokes cannabis “socially.” Upon further questioning she reveals that she smokes
about one joint per day during the week and two or more joints per day on the week-
end. She does not smoke tobacco and drinks “a few beers” weekly when at parties.
She does not use any other substances. She first used cannabis in high school and
initially only smoked in social settings. Over time, she has needed more cannabis to
“take the edge off” and has strong cravings to use daily. She reports liking how can-
nabis decreases his anxiety and helps her fall asleep, although she thinks the can-
nabis sometimes makes her “paranoid,” which results in her keeping away from
friends and family at times. Furthermore, she explains she is failing two of her
classes this year but was an excellent student in the past.
Anne has met the criteria for cannabis use disorder, and it is evident that her can-
nabis use is problematic and is likely causing or contributing to some of her school
difficulties and medical conditions. After summarizing Anne’s symptoms and coun-
seling her on cannabis use disorder, Anne expresses that she was not aware of the
addictive qualities of cannabis.
36 D. Patel
Discussion
The public’s increasing openness toward cannabis use has contributed to an increase
in the number of cannabis users, which means more people who need treatment and
intervention. Although more people are seeking help for problems with cannabis
today, most who need treatment do not feel their use is problematic and are typically
referred to treatment by others. There are also barriers to accessing help which com-
monly include fear of judgment, lack of knowledge of treatment options, long wait
times for help, and lack of perceived need for help. Addressing a patient’s cannabis
use is often an ongoing process, requiring comprehensive assessment before a diag-
nosis can be made and in most cases frequent revisiting of the topic to assess shifts
in the patient’s attitude toward use.
Screening
Medical providers for patients who struggle with cannabis use must become able to
identify and characterize cannabis use disorders, provide education, and offer
evidence-based treatments. The most basic facts to be obtained include amount used
and frequency, duration of use, and route of administration. Taking a nonjudgmental
and curious approach will facilitate patients being more forthcoming about their
use. Terminology that may be familiar to regular users of cannabis such as blunts,
spliffs, bowls, joints, dime bags, etc. may be unfamiliar to the provider who is per-
forming the assessment; it is critically important to become comfortable asking
follow-up questions when something is not clear, to ensure an accurate picture of
the pattern of the patient’s use. Patients may be able to quantify their use another
way, such as in terms of money spent or amount used over a certain time period. A
urine drug screen (UDS) is helpful in identifying the extent of substance use beyond
solely cannabis. Also, general health and possible co-occurring mental health con-
ditions should be assessed to differentiate between symptoms that could be attribut-
able to other substances or other physical and mental health conditions.
Screening, Brief Intervention, and Referral to Treatment (SBIRT) Model

• Screening people helps determine their severity of cannabis use.
• Brief interventions use motivational interviewing to raise awareness of the
consequences of use and to provide an incentive toward making posi-
tive change.
• High-risk individuals are referred for further assessment and treatment.
Screening allows the provider to assess the severity of the use in order to identify
the appropriate level of treatment. Screening, brief intervention, and referral to
treatment (SBIRT) is an evidence-based approach to the delivery of early interven-
tion and treatment services to people with substance use disorders and those at risk
of developing these disorders. The benefit of SBIRT is that it can be delivered in
many clinical care settings. Providers should ask all patients about cannabis use,
even if their use is reported as occasional and not problematic. This can also include
monitoring patients for the signs and symptoms of problematic cannabis use even if
use is denied by the patient. As a baseline, providers should specifically ask all
patients in their practices if they have used cannabis in any form in the past year.
Brief intervention focuses on increasing insight and awareness regarding substance
use and motivation toward behavioral change. Brief interventions should be person-
alized and offered in a supportive, nonjudgmental manner. Referral to treatment
provides those identified as needing more extensive treatment with access to spe-
cialty care [2].
Higher-risk groups include adolescents and young adults; patients with mood,
anxiety, or psychotic disorders; and patients who use other substances. These indi-
viduals should be asked about cannabis use during routine visits, at least annually.
Patients with poorly controlled chronic pain should be asked about cannabis use for
analgesia. Another scenario is screening for synthetic “marijuana” products such as
K2 and spice. Although these products are chemically distinct from the psychoac-
tive compounds in the traditional cannabis plant, some cannabis users have tried
synthetic “marijuana” products because of their gross physical similarity to canna-
bis plant matter.
A number of studies link chronic cannabis use and mental illness, and cannabis
use is widespread among psychiatric patients. Effectively treating a co-occurring
mental health disorder with standard treatments involving medications and behav-
ioral therapies may help reduce cannabis use, particularly among those involved
with heavy use and those with more chronic mental disorders [19, 20]. A series of
large, longitudinal studies showed a link between cannabis and the development of
psychosis. Use of the drug can also worsen the course of illness for patients who
have schizophrenia [14]. It is not yet known to what extent cannabis is a causative
agent in psychosis and to what extent it may simply exacerbate symptoms in indi-
viduals with a predisposition to psychotic symptoms. The relationship between can-
nabis and anxiety disorders is unsettled; while one meta-analysis showed a small
positive association between cannabis use and anxiety disorders, other data has not
shown this [18]. Cannabis use is common among patients with post-traumatic stress
disorder (PTSD). Animal studies have found that cannabinoids can prevent stress-
induced emotional and memory effects, and preliminary studies have found reduc-
tion in some PTSD symptoms in humans. There have, however, been no large-scale,
controlled studies [1]. Assessing patients who use cannabis and also suffer anxiety
or trauma-related disorders should be done on a case-by-case basis, with a focus on
exploring the relationship of their symptoms to cannabis use.
Treatment
Brief interventions might be useful for mild to moderate cannabis users for reducing
cannabis use and/or associated consequences and have demonstrated potential for
reducing cannabis use-related risk or harm indicators when compared with untreated
38 D. Patel
controls [12]. There are six elements important for a brief intervention to be effec-
tive: Feedback (about personal impairment/risks), Responsibility (for change,
placed on client), Advice (to change, given by clinician), Menu (of various options
available, given to patient), Empathy (a style adopted by clinician), and Self-efficacy
(optimistic empowerment of the client) and are commonly summarized with acro-
nym FRAMES [11].
Psychosocial treatments of cannabinoid dependence have been tested in several
studies. Supportive treatment may be provided to allow addressing underlying dis-
orders and to aid in developing healthier coping skills when facing stressors.
Motivational enhancement therapy (MET), cognitive-behavioral therapy (CBT),
and contingency management (CM) have been carefully evaluated and have all
shown promising results. Generally, MET is effective at engaging individuals who
are ambivalent about treatment; CM can lead to longer periods of abstinence during
treatment by incentivizing abstinence; and CBT can work to enhance abstinence
following treatment (preventing relapse). These interventions can be delivered indi-
vidually or in groups and focus on the individual or the social environment, and the
focus of the therapy is to teach coping strategies and problem-solving skills [15].
Longer duration of psychotherapy is associated with better outcomes [16]. Findings
also indicate that integrating all three approaches—MET, CBT, and CM—is most
likely to produce positive outcomes, especially as measured by rates of abstinence
from cannabis [16]. These psychosocial approaches for substance use disorders aim
to build motivation, identify patterns of use and triggers that lead to use, and man-
age and promote substitution of substance-related behaviors with healthier activities.
Currently, there is no medication that is FDA-approved to treat cannabis use
disorder, but research is active in this area and pharmacotherapy trials have been
conducted as adjunctive interventions to psychosocial treatment. Studies in particu-
lar are targeting medication treatment for cannabis withdrawal symptoms; reducing
or alleviating withdrawal symptoms during cessation from regular cannabis use
may result in the individual being less likely to resume cannabis use and have better
treatment outcomes. N-Acetylcysteine and gabapentin are two of the most promis-
ing medications, although no pharmacologic treatment has emerged as clearly effi-
cacious [12]. Studies have also shown that oral THC, nabiximols, and nabilone have
evidence for targeting multiple withdrawal symptoms, including cravings.
Quetiapine, zolpidem, and mirtazapine may help with sleep disturbances associated
with cannabis withdrawal [5].
Conclusion
Rates of cannabis use and cannabis use disorder are on the rise in the United States
resulting in an increase in number of people in need for treatment. This parallels the
changes in the legal and political climate favoring legalization along with the
decreased perception that cannabis use poses a significant risk of negative conse-
quences. Screening and brief interventions can be delivered in various healthcare
settings in order to identify at-risk groups and allow for treatment implantation.
Several studies have highlighted the benefit of psychosocial interventions and have
concluded that a combination of CBT and MET represents the best approach to treat
cannabis use disorder and that abstinence-based CM (incentives) can enhance effec-
tiveness. Several pharmacological interventions have also been investigated; how-
ever, only a few have shown encouraging results. Future directions depend on
increased research funding, greater accessibility of treatment options, and height-
ened awareness not only of the consequences of heavy cannabis use but the avail-
ability of specific treatments.
Key Points
• While many people can use cannabis use without harm, cannabis use places indi-
viduals at risk for various adverse health consequences.
• It is imperative to screen regularly for cannabis use and to characterize the use,
provide education, and offer evidence-based treatments.
• Psychotherapeutic treatments, including motivational enhancement treatment
(MET), cognitive-behavioral therapy (CBT), and contingency management
(CM), have demonstrated effectiveness in reducing frequency and quantity of
cannabis use.
• Pharmalogical treatments are targeted to decrease withdrawal symptoms.
However, their effectiveness to reduce cannabis use and prevent relapse still
needs further investigation.
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Hallucinogen-Related Disorders
5
Katherine Kim and Daniel Roberts
Introduction
Hallucinogens comprise a diverse group of substances with differing chemical

structures and mechanisms of action, but are classified together for their similar
subjective effects, including alterations in perception, mood, and cognition (see
Table 5.1). Many names have been proposed for this class of drugs, including
psychotomimetic (meaning “mimicking psychosis”), entheogen (“bringing into
being the god within”), and psychedelic (“mind- or soul-manifesting”). Hallucinogen
has been its common designation in the scientific literature. However, the term
psychedelic, which has prevailed in the lay press for decades, is increasingly the
preferred term even in research settings [1, 2]. For the purposes of consistency with
DSM-5 nomenclature, we use the term hallucinogens to refer to this group of
substances in this chapter.
This diverse group of substances includes indoleamines (e.g., psilocybin, N,N-
dimethyltryptamine [DMT], and the admixture ayahuasca which contains DMT),
ergolines (e.g., lysergic acid diethylamide [LSD] and lysergic acid amide [LSA],
which is found in morning glory seeds), phenethylamines (e.g., 3,4-methylenediox
ymethamphetamine [MDMA] and mescaline), NMDA antagonists (e.g.,
phencyclidine [PCP] and ketamine), as well as other ethnobotanical compounds
such as Salvia divinorum and jimsonweed [3]. Many hallucinogens are ingested
orally, either swallowed as tablets, pills, or liquids; consumed raw or dried; or
brewed into teas; though some can be inhaled (DMT, PCP, Salvia), snorted
(ketamine, PCP), or injected (ketamine, PCP) [4].
K. Kim · D. Roberts (*)

Department of Psychiatry, New York University School of Medicine, New York, NY, USA
e-mail: katherine.kim@nyulangone.org; dan.roberts@nyulangone.org

https://doi.org/10.1007/978-3-030-86430-9_5
42 K. Kim and D. Roberts
Table 5.1 Signs and symptoms associated with hallucinogen intoxication

Autonomic arousal (e.g., dilated pupils, hypertension, hyperthermia, gastrointestinal distress,
tachycardia, tachypnea)
Depersonalization
Derealization
Distortions in one’s sense of time
Ego death/dissolution (i.e., reduction in normal self-referential awareness leading to an
increased feeling of unity with others and one’s surroundings)
Mood changes (both perceived as good and bad and can be quite variable during the course of
intoxication)
Impaired judgment
Impaired motor coordination
Mystical-type experiences
Perceptual changes (e.g., intensification of sensations, illusions or visual hallucinations (rarer),
synesthesia)
Thought process changes
Table 5.2 Hallucinogen-related disorders (as described in the DSM-5 [3])
Phencyclidine use disorder

Other hallucinogen use disorder
Phencyclidine intoxication
Other hallucinogen intoxication
Hallucinogen persisting perception disorder
Other phencyclidine-induced disorders
Other hallucinogen-induced disorders
Unspecified phencyclidine-related disorder
Unspecified hallucinogen-related disorder
Though a comprehensive discussion of the history of these substances is beyond

the scope of this clinical text, there exists a notable history, documented on most
continents, of the use of various preparations of hallucinogenic plants as part of
religious and spiritual ceremonies. Substances used in this context include, but are
not limited to: hallucinogenic mushrooms, used by the Aztecs and other indigenous
groups from Central and North America; the DMT-containing brew ayahuasca, used
by indigenous tribes in the Amazon; and mescaline-containing peyote cactus, used
by indigenous peoples of Mexico and North America [5–7].
Under the category of hallucinogen-related disorders, the DSM-5 describes hal-
lucinogen use disorders, hallucinogen-induced disorders, and acute intoxication
(see Table 5.2). Although maladaptive patterns of drug use can be seen in users of
PCP and ketamine, hallucinogen use disorders generally are rare, with a lifetime
prevalence estimated at around 0.1–0.6% in the United States [3, 8]. Lifetime use,
however, is relatively common (9.32%) [8]. Recreational use of classical
hallucinogens, a group of serotonergic substances that includes LSD and
5 Hallucinogen-Related Disorders 43
psilocybin, has been found to be relatively safe from a physiologic perspective, and
their use is associated with lower utilization of emergency medical treatment com-
pared to the use of methamphetamine, cannabis, and alcohol [9–12]. Lifetime use of
classical hallucinogens is not associated with the development of mental health dis-
orders, increased rates of panic attacks, or decreased cognitive function [9].
In light of their physiological safety and their unique psychological effects, the
therapeutic potential of hallucinogens has emerged as an area of clinical research [1,
2, 13]. Recent phase 1 and phase 2 clinical studies have investigated the utility of
psilocybin for a number of psychiatric disorders including, but not limited to, major
depressive disorder [13, 14], end-of-life psychological distress [15], and alcohol use
disorder [16]; and the use of MDMA for post-traumatic stress disorder [17].
Moreover, research over the last 10 years has established a substantial evidence base
for the therapeutic utility of ketamine in the treatment of acute suicidal ideation [18]
as well as unipolar and bipolar depression [19]. Although thought to be physically
safe for consumption for most adults, hallucinogens cause a temporary disruption to
ordinary mind states, which, for some, can cause psychological distress during the
experience. Other adverse effects can include physiological toxicity, physiological
tolerance, and prolonged psychopathology [20], which we explore in the case exam-
ples below.
Clinicians may encounter patients presenting with either acute intoxication or
complications related to hallucinogen use. Acute hallucinogen intoxication may
present with symptoms that overlap to some extent with endogenous manic,
psychotic, or dissociative states. Other conditions that may cause hallucinations,
delusions, and cognitive impairment, such as traumatic brain injury, delirium, and
acute mania, psychosis, or dissociation, should also be considered. A history of
recent consumption of a hallucinogenic substance, as well as what is typically the
very transient nature of these presenting symptoms, should help to clarify the
diagnosis. In making the diagnosis of hallucinogen intoxication, other conditions
that may cause hallucinations, delusions, and cognitive impairment, such as
traumatic brain injury, delirium, and acute mania, psychosis, or dissociation, should
also be considered. Severe adverse effects and fatalities associated with hallucinogens
are usually due to illicit drug impurities and/or coingestion of other drugs or
alcohol [21].
The cases outlined in this chapter depict a variety of clinical scenarios related to
the use of hallucinogens. They illustrate a comprehensive approach to treatment,
including the stabilization of patients in the acute phase of intoxication with
supportive psychological interventions. Should such an intervention fail to relieve
the acute distress, psychopharmacological interventions can be used. We also
discuss how to meet the long-term needs of patients with hallucinogen-related
disorders, including the management of potential complications, and counseling
patients in ongoing treatment.
Clinical Cases
Case 1
Angel is a 32-year-old man brought to the emergency room (ER) by emergency

medical services (EMS) with a police escort after being agitated in public, where he
had been yelling at passersby and attempting to fight with police officers when
approached. This is his fifth visit in the past six months under similar circumstances.
The clinical impression in his prior visits had been acute intoxication of various
substances, including PCP, which was occasionally confirmed by urine toxicology
when Angel was more agreeable to diagnostic workup. On initial assessment at
triage, Angel is oddly related, paranoid, and endorses various delusions. His heart
rate and blood pressure are elevated, and he has prominent nystagmus. Shortly into
the triage process, while awaiting assessment in the busy ER milieu, Angel becomes
increasingly agitated and verbally threatening. Despite the staff’s efforts at verbal
de-escalation, he begins swinging his fists at them and ultimately requires
intramuscular medication and physical restraints to ensure safety.
Discussion
Angel is presenting with signs of altered mental status, paranoid ideation, delu-
sional thoughts, autonomic hyperactivity, nystagmus, and acute aggression. Given
his history of similar clinical presentations, many of which objectively confirmed
recent PCP use, phencyclidine intoxication is high on the differential diagnosis (see
Table 5.3). This diagnosis is made based upon the history and clinical evaluation.
However, because a clear history can be difficult to obtain in these circumstances, a
Table 5.3 Phencyclidine intoxication diagnostic criteria (excerpt from the DSM-5 [3])
A. Recent use of phencyclidine (or a pharmacologically similar substance).
B. Clinically significant problematic behavioral changes (e.g., belligerence, assaultiveness,
impulsiveness, unpredictability, psychomotor agitation, impaired judgment) that developed
during, or shortly after, phencyclidine use.
C. Within 1 hour, two (or more) of the following signs or symptoms:
Note: When the drug is smoked, “snorted,” or used intravenously, the onset may be particularly
rapid.
1. Vertical or horizontal nystagmus.
2. Hypertension or tachycardia.
3. Numbness or diminished responsiveness to pain.
4. Ataxia.
5. Dysarthria.
6. Muscle rigidity.
7. Seizures or coma.
8. Hyperacusis.
D. The signs or symptoms are not attributable to another medical condition and are not better
explained by another mental disorder, including intoxication with another substance
working diagnosis must suffice until safety has been established and the altered
mental status and impulsive, dangerous behavior have improved.
Other etiologies that might present with similar symptoms include substance
withdrawal from alcohol or benzodiazepines, toxidromes, or infections (such as
encephalitis, meningitis, or sepsis), particularly given the combination of altered
mental status and vital sign abnormalities. Metabolic abnormalities that may cause
altered mental status, including hypoglycemia, hyponatremia, or hyperthyroidism,
as well as seizure disorders and vascular pathologies, should also be ruled out with
the appropriate medical workup. Additionally, given the variable symptoms
associated with intoxication, and because both intentional and unintentional
coingestion of multiple substances are common, the differential diagnosis should
include intoxication with other psychoactive substances, including not only those
commonly presenting with agitation and altered mental status (e.g., amphetamines,
cocaine), but also novel psychoactive substances, particularly given the growing
online market for various synthetic (“designer”) drugs, most of which cannot be
detected on standard urine drug screens.
As the DSM-5 points out, the combination of nystagmus, elevated heart rate and/
or blood pressure, and bizarre and aggressive behavior often helps to distinguish
PCP intoxication from intoxication due to other substances, particularly other
hallucinogens. Urine toxicology may be useful in the diagnostic workup, especially
in a setting that allows for extended observation, where a clinician might have the
benefit of longitudinal observation to distinguish between a short-term, substance-
induced etiology and a primary psychotic or affective illness that warrants hospital
admission. With respect to diagnostic workup, PCP is detectable in the urine, but
may be detected up to approximately 8 days after use, so its presence is not
necessarily diagnostic. Other common laboratory abnormalities associated with
PCP intoxication include an elevated creatine kinase (CK or CPK) and elevated
hepatic transaminases [3]. As noted above, if clinical suspicion for a medical
etiology is high, then the appropriate laboratory tests should also be performed.
In this particular case example, Angel is presenting as paranoid with delusional
content, and so, per the DSM-5, an additional diagnosis of phencyclidine-induced
psychotic disorder should be considered in a patient presenting with the symptoms
of PCP intoxication with the noted absence of intact reality testing. Moreover, a
review of Angel’s history, particularly his repeated presentations and continued use
of PCP despite consequences within a 12-month period, suggests that phencyclidine
use disorder should also be considered.
As noted in the case introduction, Angel’s behavior quickly escalated to the point
of serious concern for safety to both staff and the patient. In cases of PCP intoxication
with agitation, particularly in busy medical settings, a supportive approach to reduce
agitation would include efforts to reduce external stimulation, for example, by
placing the patient in a darker, quieter space that still allows for adequate monitoring.
Offering a patient a benzodiazepine, particularly in a quiet, calm, environment, can
be an effective strategy that may eliminate the need for involuntary medication and/
or physical restraints. However, if these measures are unavailable or ineffective, and
patient or staff safety is at risk, safe and efficient symptom reduction is essential.
Physical restraints may be initially necessary to safely administer sedating

medications. Safe and effective physical restraint may require several staff members,
given PCP’s propensity to cause both significant activation and reduced perception
of pain.
Based upon observational reports and clinical experience, antipsychotics and/or
benzodiazepines are often the preferred types of sedating agents. Regarding
benzodiazepines, general clinical consensus recommends lorazepam 4 mg
intravenously (IV) or midazolam 5 mg IV, or by intramuscular (IM) injection if IV
access is not available [22]. Regarding antipsychotics, droperidol 2.5 mg or
haloperidol 5 mg IM or IV can be used as adjunctive therapy if benzodiazepines do
not adequately control symptoms [22]. These doses may be repeated until adequate
sedation is achieved to establish safety. In reviewing the literature, there is some
anecdotal caution to avoid antipsychotics such as droperidol or haloperidol due to
the potential concern of lowering a patient’s seizure threshold or that these agents
may impair heat dissipation in patients experiencing hyperthermia. However, there
do not appear to be any high-quality human studies to support these claims, and
significant clinical experience suggests that antipsychotics or the coadministration
with benzodiazepines can be safely utilized.
Clinicians should be aware of multiple serious complications that can occur with
PCP intoxication and the attendant behaviors, particularly with ingestion of large
quantities of PCP. These include rhabdomyolysis, seizures, hypoglycemia, trauma,
and coma. Any patient with such significant complications should be triaged to an
appropriate medical setting and likely requires admission to an intensive care setting
for monitoring and treatment.
Given the variable presentation of PCP toxicity and the potentially problematic
behavioral issues associated with intoxication, most patients presenting in the
emergency setting benefit from observation. The intoxication period from PCP
usually lasts for several hours, so a patient presenting early following ingestion
could quickly escalate in terms of problematic behaviors and safety concerns, and
so should be retained in an appropriate setting where they can be safely monitored
while metabolizing any ingested substances. Of note, in individuals with a
co-occurring mental illness, other substance use disorders, genetic loading for
mental illness, or other psychiatric or behavioral vulnerabilities, the hallucinogenic
effects of PCP may last beyond the typical time period and may precipitate a
persistent psychotic episode resembling schizophrenia spectrum illness.
PCP use disorder is defined by the same criteria as other substance use disorders
in the DSM-5. The use of motivational interviewing can be helpful in assisting
patients to become aware of and resolving ambivalence of decreasing or stopping
PCP use [23]. One large study found the incidence of PCP intoxication-related
injuries to be 13%, with self-inflicted injuries representing 22% of those [24]. As
such, when counseling active PCP users, a harm-reduction approach that emphasizes
the maintenance of physical safety is important. Although pharmacological
treatments for any co-occurring substance use or psychiatric disorders may be
helpful in this patient population, there are no FDA-approved treatments for PCP
use disorder. However, enrollment in outpatient counseling or inpatient rehabilitation
centers may be helpful in patients who are motivated for treatment. Additionally,
12-step support programs are a widely available and free community resource that
may assist in supporting abstinence.
Case 2
Phil is a 22-year-old man that comes into the ER accompanied by his friend, who
informs staff that the patient had ingested some “shrooms” a couple hours earlier
with a group of friends. The friend notes that shortly thereafter, Phil became acutely
anxious and paranoid. He reported visions of frightening figures on the wall and
began repeatedly announcing that the “world is corrupt.” Given his level of distress,
he asked his friend to take him to the ER. During the assessment, Phil is able to
provide a narrative of the day’s events and his mushroom ingestion, but he appears
anxious and guarded and states that he is afraid that these experiences and feelings
will never go away. His heart rate and blood pressure are elevated, and his pupils
appear dilated. He responds to verbal reassurance and is taken to a quiet room,
where he is offered medications, which appear to calm him. Some hours later, after
a subjective report of improvement in symptoms and apparent return to his physical,
cognitive, and psychological baseline, he is discharged from the ER.
One month later, Phil presents to his primary care doctor complaining of visual
abnormalities, including visual trailing, spontaneous flashes of color, and illusory
palinopsia (a persistence of a visual image after the stimulus has been removed). He
reports that he has not used any substances since his ER visit.
Discussion
At his initial visit, Phil is presenting with the acute onset of significant psychologi-
cal changes (e.g., marked anxiety, fear of losing control, and paranoia), alterations
in sensory perception, and abnormal vital signs following ingestion of presumed
psilocybin-containing mushrooms. His signs and symptoms meet the DSM-5
diagnostic criteria for other hallucinogen intoxication.
The overall effect of any psychoactive drug is a complex interaction of many
elements beyond direct pharmacological mechanisms, including physiological,
psychological, cultural, and environmental factors [20]. Although we assess for the
influence of these factors with any patient, they may have an especially important
role in the experience of a person who has ingested a hallucinogenic compound. A
group of influences in this context has been collectively termed “set and setting.”
“Set” refers to individual factors such as one’s mindset, personality structure, and
expectations; “setting” includes environmental factors, such as the physical location,
the situation, and the cultural context in which the hallucinogen use occurs. These
elements are thought to underlie the differences in emotional valence, level of
anxiety, and overall experience of different users at different times despite ingesting
the same substance. Colloquially, the subjective experience of acute intoxication is
referred to as a “trip,” and a “bad trip” refers to those experiences predominantly

marked by anxiety, dysphoria, fear, or agitation. Neuropsychiatric effects occur in
response to administration of any hallucinogen, and although the various substances
(e.g., LSD versus MDMA) differ in their onset, duration, and intensity of effects,
their acute psychological and behavioral symptoms can be quite similar (see
Table 5.1).
As in both Angel’s and Phil’s cases, many hallucinogens produce sympathomi-
metic effects such as dilated pupils, elevations in blood pressure and heart rate, and,
on rare occasions, hyperthermia. The DSM-5 requires at least two physiologic
signs, in addition to psychological and perceptual changes, to meet diagnostic crite-
ria for other hallucinogen intoxication (in this case, with psilocybin). Though mild
vital sign fluctuations can occur with psilocybin intoxication, significant vital sign
abnormalities are uncommon and should prompt consideration of another intoxicant
(e.g., PCP, amphetamines, or cocaine) or other medical etiologies. Hyperthermia
rarely occurs with isolated hallucinogen intoxication, and this is a sign of severe
toxicity. It can also be a sign of serotonin toxicity (“serotonin syndrome”), a
condition characterized by the presence of altered mental status, neuromuscular
abnormalities, and autonomic hyperactivity that typically occurs in the setting of
coingestion of serotonergic hallucinogens (e.g., LSD, MDMA, or psilocybin) and
other serotonergic medications such as antidepressants (e.g., SSRIs or MAOIs),
analgesics (e.g., meperidine), antiemetics (e.g., ondansetron), or herbal supplements
(e.g., St. John’s wort). A patient presenting with signs and symptoms concerning for
serotonin syndrome, especially with hyperthermia, should be promptly triaged to an
appropriate medical setting and likely requires admission to an intensive care setting
for monitoring and treatment.
Of note, most patients presenting with hallucinogen intoxication are awake and
oriented, are able to provide a coherent history of preceding events including
hallucinogen use, and have good insight that their symptoms are substance-induced.
These patients, in the absence of severe symptoms, typically do not require, nor
benefit, from routine laboratory tests, especially given the fact that most
hallucinogens are not detectable on routine urine toxicology screens. However, the
presence of altered mental status, overt psychosis (especially with auditory
hallucinations), severe agitation, or bizarre behavior should prompt further medical
workup to rule out other medical etiologies [25].
In most cases of intoxication, supportive care is all that is needed to manage a
patient’s distress. The general clinical consensus suggests embracing a nondirective
and nonconfrontational approach while allowing the patient to relax in a calming
environment until the substance’s effects subside. In Phil’s case, he was offered
medications in the ER, which is often done. Psychopharmacological interventions,
such as benzodiazepines and/or antipsychotics, are generally only necessary if there
is concern for the safety of the patient or others. Some clinicians who have had
significant experience in working with patients having difficult psychological
experiences while intoxicated from hallucinogens have cautioned that
pharmacologically terminating a “bad trip” can potentially have a negative
psychological impact on a patient [25, 26], although this has not been explored in
clinical trials.
Most cases of other hallucinogen intoxication are time-limited and resolve over
the course of several hours, ultimately resulting in a patient returning to their
neuropsychiatric baseline and being able to leave the ER without residual symptoms
or complications. However, in the case of Phil, he began to experience some
distressing symptoms some weeks later, consistent with the unique disorder of
hallucinogen persisting perception disorder (HPPD).
Hallucinogen Persisting Perception Disorder (HPPD)
HPPD is a relatively rare and poorly understood phenomenon, with anecdotal

reports associating this diagnosis primarily, though not exclusively, with LSD use
[3]. HPPD is described in the DSM-5 as the reexperiencing of one or more perceptual
symptoms after cessation of hallucinogen use. Of note, these perceptual disturbances
may not have been experienced during the acute intoxication experience, a period
typically not lasting more than several hours maximum [27]. Visual symptoms can
include geometric hallucinations, false perceptions of movement in the peripheral
visual fields, flashes or intensification of colors, trailing images of moving objects,
positive afterimages, halos around objects, and misperceptions of relative size
(macropsia, micropsia). HPPD may co-occur with dissociative phenomena. The
symptoms can emerge after one-time use or at any point after more frequent use and
may be experienced episodically or persistently [28]. The symptoms can begin after
a latent period of days to months or even years, and they may last for months to
years. Interestingly, without treatment, both spontaneous improvement and persis-
tent symptoms have been reported [29, 30].
HPPD is a diagnosis of exclusion. Patients need to be carefully evaluated for
other causes of perceptual disturbances, such as anatomical brain lesions and central
nervous system infections, seizure disorders, migraines, head trauma, hypnopompic/
hypnagogic hallucinations, delirium, major neurocognitive disorders, primary
psychotic disorders, substance intoxication, and substance-induced psychotic
disorders. Given the relatively low incidence of HPPD, a neurological evaluation
that includes an EEG and brain MRI may be warranted to rule out neurological
causes. In addition to ruling out psychiatric disorders that may better explain the
visual symptoms, screening for concurrent psychiatric comorbidities such as
depression, anxiety, panic disorder, and psychotic disorders is critical, as HPPD can
cause significant distress and clinical impairment. As with any psychiatric
presentation, the patient should also be assessed for suicidality [31].
Counseling provided to patients with HPPD should include recommendations to
avoid further use of hallucinogens and to limit the use of other substances.
Assessment of the triggers for visual symptoms may prevent further exacerbation.
The use of motivational interviewing may be helpful in those who, despite persisting
symptoms of HPPD, appear unmotivated or ambivalent around the recommendation
to limit their use of hallucinogenic substances [23]. Educating patients on the
possible outcomes of HPPD, which include spontaneous remission or persistent

symptoms with unpredictable frequency and intensity, can be helpful in managing
expectations. To this end, psychotherapeutic interventions, including the use of
mindfulness- and acceptance-based psychotherapies, may also be helpful. Cognitive-
behavioral approaches can also be used to target any distorted cognitions, depres-
sion, and/or anxiety that might occur secondary to HPPD symptoms.
Lastly, judicious use of psychotropic medications may be of some utility in
patients whose symptoms cause persistent and clinically significant distress despite
non-pharmacologic therapies. However, given the paucity of data regarding efficacy
of psychotropic medications in HPPD and the possibility of spontaneous remission,
a thorough discussion of the risks and benefits of pharmacologic treatment is
particularly important in these cases. Open-label studies and case reports suggest
possible benefit from treatment with benzodiazepines, anticonvulsants, and alpha-2-
agonists, while results from studies of selective serotonin reuptake inhibitors
(SSRIs) and antipsychotics are mixed. Among the latter, risperidone appears to
worsen symptoms [32, 33]. However, given the low prevalence of HPPD, a
meaningful interpretation of these findings is limited by a very small sample size.
Given the potential side effects of medications, a shorter course of treatment should
be considered; however, the risk of rebound symptoms after withdrawing such
treatment has not been studied.
Integration
It is worth emphasizing that, although hallucinogen intoxication is generally an

acute, time-limited experience that does not result in chronic adverse effects and
hallucinogen use disorders are rare, these experiences can be very challenging and
cause significant psychological distress that can leave a person feeling unsettled for
some time after the acute intoxication has resolved. Additionally, even the visions
and insights one may experience during a so-called “good trip” can be challenging
to understand, and it can be difficult to incorporate these experiences into one’s
daily life. In response to this perceived need, there is a growing number of licensed
mental health clinicians that offer ongoing psychotherapeutic services, often
referred to as “Psychedelic Integration Therapy,” focused on providing
psychoeducation, and to help individuals process and integrate their experiences
with hallucinogens.
The resurgence of scientific research focused on hallucinogen-assisted psycho-
therapy has generated significant positive media coverage in the recent years. As a
result, it is possible that there may be an increase in the number of individuals that
decide to experiment with hallucinogens. Future studies will likely focus on how to
optimize experiences with hallucinogens, and, in particular, explore if, how, and to
what extent integration work factors into the overall positive results observed in
recent hallucinogen-assisted psychotherapy studies. Given the increased awareness
of these substances and the potential for growing prevalence and incidence of use,
it will be important for clinicians to be able to provide accurate psychoeducation
about these substances and for there to be resources that can offer appropriate psy-
chotherapeutic support for patients in need.
Case 3
Sasha is a 21-year-old woman who was brought to the emergency department by

EMS after being found unconscious at a dance club. She is accompanied by a friend
who reported that Sasha had used “Molly” and ketamine during the course of the
evening. On physical exam, the patient appears lethargic. Vital signs are notable for
mild hypertension and tachycardia. Neurologic exam showed no signs of myoclonus,
hyperreflexia, nystagmus, or tremor. Laboratory results show a mild hyponatremia
but are otherwise within normal limits. Sasha was admitted to the inpatient medicine
service for monitoring and supportive treatment with IV fluids, which corrected her
hyponatremia, and her vital signs and mental status normalized. Now returned to
baseline, she is discharged home shortly thereafter.
Discussion
MDMA (“Molly” or “Ecstasy”) and ketamine are commonly used in the recre-
ational setting, where they are often referred to as “club drugs.” MDMA has both
hallucinogenic and stimulant-like properties and is used to achieve these and other
effects, including a sense of tranquility, euphoria, and increased emotional openness
and empathy. Ketamine, which has FDA approval for use as an anesthetic agent, is
also used recreationally, as subanesthetic doses induce prominent dissociative and
hallucinogenic effects. Like PCP, MDMA and ketamine may have higher abuse
potential compared to other hallucinogens [34, 35].
Acute treatment of MDMA and/or ketamine intoxication begins with medical
assessment and stabilization, given the potential complications of unmonitored use.
Adverse effects of acute MDMA intoxication are well established. MDMA
intoxication may cause acute hypertension, tachycardia, and/or hyperthermia.
Cardiac complications of MDMA intoxication can include hypertensive
emergencies, arrhythmias, heart failure, and myocardial infarction [36].
Hyperthermia may be caused by direct drug effects on the central nervous system,
as well as from physical exertion or environmental conditions, and can be lethal. As
such, these patients may require rapid cooling to stabilize their temperature and to
mitigate downstream adverse effects, including rhabdomyolysis, myoglobinuria,
renal failure, and disseminated intravascular coagulopathy, among others [37, 38].
In a patient with autonomic instability, altered cognition, and symptoms of
myoclonus, hyperreflexia, or tremor, there should be a high suspicion for serotonin
syndrome (see Case 2 above for details regarding serotonin toxicity). In addition to
serotonin syndrome, hyponatremia may occur in intoxicated patients (as it did in
Sasha’s case). This is largely the result of increased fluid intake due to the polydipsia
that is commonly caused by MDMA, though syndrome of inappropriate antidiuretic
hormone (SIADH) may also contribute. Significant hyponatremia can lead to

nausea, malaise, encephalopathy, seizures, and death [39]. Hepatotoxicity is another
possible adverse effect, and laboratory values should be closely monitored [40].
Patients who present to the emergency room with complications of acute MDMA
intoxication may require admission to the hospital for appropriate monitoring and
treatment.
Various authors have proposed that environmental or behavioral factors sur-
rounding MDMA use likely play more of a contributory role in the development of
reported adverse events, such as vigorous dancing or physical activity, inadvertent
disregard of physical cues, and excessive or reduced hydration resulting in
hyperthermia or hyponatremia [41]. There has also been much concern raised
through the years in the lay press, as well as by some researchers, about the potential
neurotoxic effects of MDMA in humans [42, 43]; however subsequent reviews of
these initial reports with follow-up analyses have countered that the concerning
claims are based on animal studies that included unrealistically high doses of
MDMA and on human studies comparing repeated use of MDMA, often concurrently
with other substances [41, 44, 45]. This debate is ongoing, but from growing studies
including MDMA-assisted psychotherapy, it does not appear that cognitive function
is negatively impacted [41, 44, 45].
Like MDMA, ketamine can be used in the recreational setting, either alone or in
combination with other drugs. At higher doses (like those used in anesthesia), it can
suppress consciousness or induce coma. However, in smaller doses, it can cause
reduced alertness, altered sensory perception, ataxia, cognitive impairment, and
mild increases in heart rate and blood pressure [34]. Nystagmus can be seen but is
less common than that seen in PCP intoxication. Chronic use can lead to urologic
injury including ketamine-induced ulcerative cystitis, with symptoms of increased
frequency and urgency of urination, dysuria, urge incontinence, and hematuria, and
which may be irreversible even after cessation of use [46]. Frequent ketamine use
can also be rarely associated with hydronephrosis or papillary necrosis [46].
Abdominal pain is a common complaint among chronic, heavy users of ketamine
and may be associated with liver injury [46, 47]. Like with MDMA, chronic use of
ketamine may also lead to cognitive deficits [48].
As with other substance use disorders, enrolling in an outpatient treatment pro-
gram or inpatient rehabilitation center may be helpful for patients who want to
decrease or stop use. Psychotherapeutic interventions including motivational
interviewing can help patients understand the role that substance use plays in their
lives [23]. Psychoeducation on adverse consequences may help patients recognize
and seek help for any medical complications of their use; it is especially important
for patients to be able to recognize life-threatening conditions such as malignant
hyperthermia and serotonin syndrome. Pharmacologically, there are no FDA-
approved treatments for hallucinogen use disorders. Pharmacological treatments for
co-occurring substance use disorders, as well as treatment of any psychiatric
comorbidities, may likely be helpful in these patients. And, as discussed above in
Angel’s case, 12-step support programs are a widely available and free community
resource that may assist in supporting one’s desire for abstinence.
Conclusion
In this chapter, we discussed scenarios clinicians may encounter with patients pre-
senting with hallucinogen-related disorders. In acute intoxication of most hallucino-
gens (not including PCP), supportive care is often all that is needed to manage a
patient’s time-limited distress while waiting for the substance to metabolize over the
typical course of several hours. Patients typically return to their neuropsychiatric
and physical baseline without any residual symptoms or complications. However,
acute PCP intoxication can present with altered mental status and bizarre and
aggressive behavior that puts the patient and others at serious risk of harm, and so
this condition often requires pharmacological intervention and continued observa-
tion. Additionally, it is imperative for patients presenting with altered mental status
or severe vital sign abnormalities to be assessed for medical complications and to be
triaged to the appropriate medical setting including an intensive care unit if appro-
priate. In the outpatient setting, being able to provide psychoeducation and harm
reduction strategies for patients may also be useful, including education on the com-
plications of chronic use of hallucinogens. In general, pharmacological treatments
are limited for hallucinogen use disorders, but assessment and treatment of co-
occurring substance use disorders and other psychiatric disorders are important.
Outpatient substance use settings, community-based 12-step support groups, and
inpatient rehabilitation programs may be helpful for patients who are struggling, but
motivated, to decrease or abstain from use of hallucinogens.
Key Points
• Hallucinogens comprise a diverse group of substances with differing chemical

structures and mechanisms of action but are classified together for producing
similar subjective alterations in perception, mood, and cognition and for
producing altered states of consciousness.
• Maladaptive patterns of drug use can be seen with PCP and ketamine, but hal-
lucinogen use disorders, in general, are rare.
• PCP intoxication can produce significant medical complications and unpredict-
able neuropsychiatric symptoms that place both the patient and others at risk of
harm and may warrant proper medical workup and observation with appropriate
treatment to minimize serious complications and safety risks.
• “Set” (individual factors) and “setting” (environmental factors) can greatly
impact one’s overall experience with hallucinogens.
• Distress associated with other hallucinogen intoxication is often time-limited
and can be generally managed with supportive care.
• There is a resurgence of scientific research focused on hallucinogens and hallu-
cinogen-assisted psychotherapy, with numerous positive preliminary reports
including safety and tolerability in targeting various psychiatric conditions, but
there is much still to be learned about this class of substances.
• There are growing numbers of licensed mental health clinicians and facilities
that offer psychotherapeutic services for individuals seeking assistance in
processing and integrating difficult experiences with hallucinogens.
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Inhalant Use Disorders
6
Rosemary Busch Conn
Introduction
Though a less common substance use disorder, the unique features of inhalant use
disorder create significant potential for severe morbidity and mortality. As defined
by the DSM 5, inhalant use disorder is a problematic pattern of use of a hydrocarbon-
based inhalant substance leading to clinically significant impairment or distress, as
manifested by at least two of the ten criteria listed in Table 6.1 and occurring in a
12-month period [1].
Unique among its class and adding to its inconspicuous nature, inhalant use dis-
order has no corresponding withdrawal disorder. The differential diagnosis for
inhalant use disorder includes unintentional inhalant exposure from industrial or
other accidents; intentional inhalant use or intoxication that does not meet criteria
for inhalant use disorder; inhalant-induced disorders (such as psychotic or depres-
sive disorders); other substance use disorders, especially those involving sedating
substances; other toxic, metabolic, traumatic, neoplastic, or infectious disorders
impairing central or peripheral nervous system function; and disorders of other
organ systems. Included among this class of substances are volatile solvents, aero-
sols, gases, and nitrites [1].
This chapter includes background information and epidemiology, two clinical
cases on the topic at hand, physiologic consequences, and ends with treatment and
prevention measures. Distinct features of this disorder include the multitude of sub-
stances which it encompasses and the variation of usage by population. The volume
of specific substances in the category of inhalants results in difficulty classifying
specific traits of this disorder and contributes to limited understanding of pharmaco-
logic effects.
R. B. Conn (*)
Adult Psychiatry Resident, New York Presbyterian – Weill Cornell Medicine,
New York, NY, USA
e-mail: Rvb9002@nyp.org

https://doi.org/10.1007/978-3-030-86430-9_6
58 R. B. Conn
Table 6.1 Criteria of inhalant use disorder from DSM-5

Inhalant Use Disorder: a problematic pattern of use of a hydrocarbon-based inhalant substance
leading to clinically significant impairment or distress
Occurs within a 12-month period
Includes at least two of the following criteria:
1. The inhalant substance is often taken in larger amounts or over a longer period than was
intended.
2. There is a persistent desire or unsuccessful efforts to cut down or control use of the inhalant
substance.
3. A great deal of time is spent in activities necessary to obtain the inhalant substance, use it,
or recover from its effects.
4. Craving, or a strong desire or urge to use the inhalant substance.
5. Recurrent use of the inhalant substance resulting in a failure to fulfill major role obligations
at work, school, or home.
6. Continued use of the inhalant substance despite having persistent or recurrent social or
interpersonal problems caused or exacerbated by the effects of its use.
7. Important social, occupational, or recreational activities are given up or reduced because of
use of the inhalant substance.
8. Recurrent use of the inhalant substance in situations in which it is physically hazardous.
9. Use of the inhalant substance is continued despite knowledge of having a persistent or
recurrent physical or psychological problem that is likely to have been caused or
exacerbated by the substance.
10. Tolerance, as defined by either of the following:
(a) A need for markedly increased amounts of the inhalant substance to achieve intoxication
or desired effect
(b) A markedly diminished effect with continued use of the same amount of the inhalant
substance
Epidemiology
There is some difficulty in establishing who meets criteria for inhalant use disorder,
which is among the least prevalent substance use disorders. Broadly, inhalant use is
most common among adolescents, with younger girls initially more likely to use
than younger boys. This pattern eventually reverses with age, and young men are
more likely to use inhalants than young women. Inhalant use occurs with higher
prevalence in rural areas [2, 3].
According to the 2019 National Survey on Drug Use and Health, 807,000 people
age 12 or older used inhalants in the prior month. That number increased to 2.1 mil-
lion people (0.8% of the population) when the time frame was extended to a year,
more than methamphetamine (2.0 million) and heroin (745,000). Estimates of the
past year use increased since 2016 for people age 12 or above, with the primary shift
seen in those aged 12–17 (from 2.2 percent in 2016 to 3.0 percent in 2019). Rates of
use in young adults (ages 18–25) and adults above age 26 remained stable from
2015 to 2019. Of the 730,000 individuals who initiated inhalant use in 2019, slightly
more than half were adolescents aged 12–17 (381,000) with an average of 1,000
adolescents initiating use each day. Across age groups, the number diagnosed with
6 Inhalant Use Disorders 59
inhalant use disorder has remained stable at 0.4% since 2017 with adolescents con-
stituting the highest proportion (0.3%) [4].
According to the national Youth Risk Behavior Survey (YRBS) published by the
Centers for Disease Control and Prevention, the percentage of teens in grades 9–12
who have ever used inhalants– which is defined as having sniffed glue, breathed the
contents of aerosol spray cans, or inhaled any paints or sprays to get high one or
more times during their life– has decreased since 1995 (earliest data available). The
percentage of lifetime use was 6.4% in 2019 [5].
Case 1
Helen is a 14-year-old female with no significant medical history. She is preparing

to begin 9th grade and lives in a rural part of her home state with her grandmother,
who works as a cashier at the local grocery store, and two younger siblings. Both of
Helen’s parents have unknown substance use disorders. Her grandfather had bipolar
I disorder and died 20 years prior from suicide.
Helen presents to her pediatrician, Dr. Chen, for her pre-high school physical
exam. Before walking into the exam room where Helen and her grandmother are
waiting, Dr. Chen looks over Helen’s intake assessment. He immediately notices
Helen’s weight has dropped from the 40th percentile last year to below the 5th per-
centile. Her height has remained in the 50th percentile. Dr. Chen makes a note to
evaluate for an eating disorder, as well as two things he sees more often than he
would like in his rural pediatric practice: inadequate access to nutritious food and
substance misuse.
Dr. Chen, Helen, and her grandmother discuss how things have been going since
they met last winter when Helen was sick with a cold. He is relieved to know the
grandmother is still working at the grocery store, where he knows she receives a
discount on food. Helen describes that she spent the summer, “hanging out with my
friends,” and shrugs when pressed for details about how they were spending their
time. Dr. Chen examines Helen, noticing as he checks her oropharynx that there are
small erythematous papules on the skin surrounding her mouth. The remainder of
Helen’s exam is normal.
Dr. Chen tells Helen and her grandmother that he would like to speak with Helen
individually. Helen opens up a little more and tells him that it has been difficult to
have both of her parents away. Helen is open about having tried smoking a cigarette
but did not like that it made her cough. She denies alcohol or cannabis use. When
asked about other substances, she looks down and states that she started “bagging.”
Helen reports some friends were sniffing glue six months ago, since then she has
been inhaling fumes, mostly from spray paint, out of a paper bag at least once a day.
Dr. Chen asks Helen if she would be okay discussing this with her grandmother
present. Helen is hesitant but agrees.
With Helen and her grandmother, Dr. Chen discusses the dangerous nature of
using inhalants, answers their questions about it, and provides information about
peer support groups for teenagers. Additionally, Dr. Chen makes a referral for Helen
60 R. B. Conn
to see the child and adolescent psychiatrist in the closest nearby city, about half an
hour from their rural town. He explains the importance of seeing the psychiatrist for
additional help with inhalant use management and for psychiatric screening, espe-
cially with Helen’s family history. When ordering lab tests, Dr. Chen includes urine
hippuric acid and benzylmercapturic acid tests as well as a broad urine toxicology
screen [2, 6, 7].
Case 2
Benny is a 33-year-old gay male who works as a high school chemistry teacher. His
medical history includes asthma and alcohol use disorder, which has been in remis-
sion since age 27. Following graduate school, Benny’s alcohol use increased to the
point that he was drinking every day and found he was unable to go without alcohol
ingestion for more than a few days. But it was only after narrowly avoiding a car
accident while driving intoxicated that he realized he needed to get professional
help to stop using alcohol. Benny met with an addiction specialist who offered him
a 30-day detoxification and rehabilitation program, as well as monthly injections of
intramuscular naltrexone (Vivitrol). With an active Alcoholics Anonymous program
and this medication, Benny has been able to refrain from using alcohol for over
5 years.
Benny lives in a large city with his dog. His family history includes alcohol use
disorder in his father and grandfather. When his long-term relationship abruptly
ended last year, Benny started attending parties with some younger friends to “blow
off steam.” At these parties he was introduced to “poppers.” In addition to making
him feel euphoric, the poppers were an enhancement to his sexual encounters.
Since the effects of poppers lasted only several minutes, Benny found that he was
not impaired by them like he had been with alcohol. After attending a few parties
where he used them, he learned the ease of buying them himself. His usage increased
from occasional social use, to then using at home alone, and then bringing them to
work. Inconspicuous and with a lingering odor indistinguishable from others in his
chemistry laboratory classroom, Benny regularly used poppers at work between
classes or on his lunch break.
This occurred for several weeks, until one Tuesday afternoon when Benny woke
up confused in an ambulance. Another teacher found him unconscious and immedi-
ately called 911. In the emergency department, the EMS worker informed Dr. Willis
that Benny was found holding a small canister of “liquid gold.” He complained of a
headache and gave inappropriate answers to orientation questions. On exam, he was
tachycardic with a heart rate in the 140’s and hypoxic with an oxygen saturation of
88% on room air. When nurse Chris drew his blood, he noticed how dark it appeared
and informed Dr. Willis of this anomaly. Dr. Willis requested a nitrate test and a
hemolysis panel in addition to basic lab tests. Due to a high index of suspicion for
methemoglobinemia, she treated Benny with supplemental oxygen and IV methy-
lene blue.
After recovery, Dr. Willis helped Benny call his addiction specialist and schedule
an appointment for the following day [6, 8].
I nhalant Classification, Psychosocial Impacts, Physiologic

Effects, and Proposed Mechanisms
As a result of the wide range of products which vaporize, there were more than 200
different categories of inhalants reported between 1993 and 2008. To organize and
classify the variety of inhalants, Storck et al. grouped them by chemical properties.
In Group I are aliphatic, aromatic, or halogenated hydrocarbons, including propel-
lants. Examples are fuels, such as toluene and gasoline, and computer sprays, which
have seen a substantial increase in use since the early 2000s. Group II includes
gases and other aerosols such as nitrous oxide, found in whipped cream dispensers
and referred to colloquially as “whippets.” Least used are inhalants in Group III
which are the alkyl nitrates such as chlorohexyl nitrite [6].
The psychosocial impacts of inhalant use disorder are numerous though little is
known about the natural history of inhalant use disorders and comorbidities in the
general population. A common thread through the cases above is the association of
inhalant use disorder with psychiatric conditions and, as in the second case, with
other substance use disorders. Psychiatric conditions and symptoms notably more
common among inhalant users include depressive disorders, anxiety disorders, sui-
cidal ideation, and suicide attempts. Rates of depression and anxiety were higher in
groups studied with occupational exposure to inhaled hydrocarbons. Though evi-
dent, differentiating whether this association is due to a similar spectrum of risk
factors or if one is premorbid to the other is unclear. One hypothesis remarks on
inhalant use as a global vulnerability marker, rather than a direct precipitant of psy-
chiatric illness [6].
As there are many types of inhalants, the mechanism of use as well as signs and
symptoms of intoxication or recent use can vary. The most common methods by
which a vapor is inhaled are through direct inhalation from a container, inhalation
from a product vaporized into a bag, or inhalation of fumes from a soaked cloth that
covers the nose and/or mouth [8]. Signs of use can directly correlate to the method
of ingestion. In the case of Helen, a perioral rash was evidence of recent use by
inhaling fumes out of a paper bag, also known as “bagging.”
Physiologic effects of inhalants correlate specifically to the substance ingested
and broadly affect every organ system. Systems impacted are neurocognitive, meta-
bolic, hepatic, renal, cardiovascular, hematopoietic, neuromuscular (including
peripheral nerves), and reproductive. It is difficult to distinguish acute effects from
those that result from sustained use as there have been reports of long-term impacts,
such as in memory and processing speed, from a single occupational exposure.
Occupational exposure studies allowed for the discovery of the effects of these sub-
stances on the body; however, these data serve only as a model due to higher expo-
sure level in intentional inhalant use (whether by quantity, duration, or repetitious
use) [6].
62 R. B. Conn
Acute physiologic effects mimic those of alcohol intoxication, such as dizziness,

dysarthria, tremor, vision changes and involuntary eye movement, stupor, and coma,
as well as impairments in cognition, coordination, and reflexes. With repetitive use,
these temporary consequences progress to the development of encephalopathy, par-
kinsonism, cerebral atrophy, ataxia, and decreased cerebral perfusion. On brain
imaging, hypointensities are visible in the thalamus and basal ganglia. Pulmonary
dysfunction and disease are also highly common, with associations noted between
duration of inhalant use and development of bronchitis, asthma, sinusitis, and tuber-
culosis. One study demonstrated an accelerated rate of radioisotope pulmonary
clearance in those who were using inhaled solvents, indicating dysfunction at the
level of the alveolar capillary membrane [6]. A particular example of physiologic
impact relates to Benny from Case 2, which is that of amyl nitrate and its potential
to cause methemoglobinemia; this can be fatal without recognition and timely treat-
ment [8].
Additional adverse consequences of inhalant use are chemical and thermal burns,
persistent mental illness, and medical emergencies. Severe and imminent life-
threatening consequences of inhalant use are sudden sniffing death, asphyxiation,
and unintentional injuries. Sudden sniffing death refers to heart failure precipitated
by fatal arrhythmia [2, 6].
Cognitive and neurological effects can be temporary though with repeated expo-
sure compounded deficits can be long-lasting. Global brain atrophy, as seen in
Image B in Fig. 6.1, can occur in those with chronic toluene use [9]. Other effects
of prolonged toluene exposure include impaired growth such that a person with
a b
Fig. 6.1 Normal brain (a) and brain with chronic exposure to inhalant (b). (Image a features the
brain of a patient with no history of inhalant use. Image b features the brain of an individual who
chronically uses toluene. The brain in image b has atrophied, evidenced by the smaller appearance
and increased space inside the skull (the white outer circle in each image). This image is used with
permission from NIDA, Courtesy of Neil Rosenberg, M.D., NIDA Research Report (NIH
05-3818) [9])
repeated use can develop failure to thrive, such as Helen in Case 1 [10]. Systemically,
toluene inhalation can cause imminently harmful problems such as lactic acidosis,
rhabdomyolysis, and acute hepatorenal injury [11].
Teratogenic effects occur with intrauterine exposure to inhaled substances. The
presentation is similar to fetal alcohol syndrome with prominent features of facial
and cranial deformities, poor brain development, low birth weight, developmental
delays, as well as a variety of additional complications [4, 6].
The proposed mechanism for the neurobiology of inhalant use again varies by
substance. Toluene and trichloroethylene promote motor excitation at low concen-
trations, whereas at high concentrations they potentiate anesthesia, sedation, coma,
and even death. A proposed mechanism for toluene is that it blocks NMDA recep-
tors in a similar way to PCP [4]. In studies with rats, toluene exposure increased
dopamine levels in the prefrontal cortex and striatum, leading to increased neuron
firing in the ventral tegmental area. This mechanism is similar to other substances
which are misused. Benzene and diethyl ether work as depressants to the central
nervous system as positive modulators to GABA-a receptors [4].
Treatment
Treatment options for inhalant use disorder are limited; psychosocial treatments
have shown some efficacy and pharmacologic options are minimal. Inadequate ini-
tiatives to develop treatment options can be attributed to lack of research, inadequate
screening, and underreporting of use [4]. As with the case of Dr. Chen and Helen,
directly approaching the patient is the foundation of treatment of inhalant use disor-
der. This method begins with the implementation of screening at every opportunity
as well as looking out for signs of use, such as Helen’s perioral dermatitis and fail-
ure to thrive. The SBIRT model offers a standardized approach to screening and
intervention that includes questions on topics of frequency and amount of use, as
well as impacts of use on personal and interpersonal functioning [12]. As with other
substance use disorders, the motivational interview is crucial in determining the
state of readiness of change for a particular patient, as well as guiding them along in
the process [13]. Outpatient and inpatient substance use treatment programs, which
utilize structured environments, peer support, individual and group counseling, edu-
cation, and accountability, can be useful in the treatment of inhalant use disorder [4].
Primary prevention methods aim to deter the use of commonly used volatile
compounds and are a key area of focus in reducing harm from inhalant abuse [4].
Examples of primary prevention include clearer labeling for misused products and
chemicals, changing the composition of products so the volatile chemicals causing
intoxication are replaced or masked, monitoring quantity of particular products pur-
chased, and the addition of age restrictions. Other harm reduction strategies are to
make usage safer, such as advising persons to avoid the use of compounds contain-
ing propane and butane, refrain from placing a plastic bag over one’s head, and take
precautions to avoid burns, overdose, and aspiration of vomitus.
64 R. B. Conn
Treatment at the community level is multipart. Nearly every rural community

needs increased access to mental health care and substance use treatment.
Educational initiatives and outreach programs directly addressing substance use are
imperative in prevention of all substance use disorders, including inhalants.
Opportunities for youth engagement such as recreational programs offer a means of
alternative time spent for youth most vulnerable to early substance use. Culturally
sensitive outreach and education may be critical in certain vulnerable communities.
In Canada and Australia, for example, holistic approaches that utilize components
drawn from indigenous cultures have been shown to be efficacious treatment options
for inhalant use disorder in indigenous populations [4].
Pharmacological treatments for inhalant use disorder have not been well
researched, though some antipsychotics and antiepileptic agents demonstrate ben-
efit for symptom relief. In one case report of a patient who developed psychotic
symptoms after repeated gasoline inhalation, the administration of risperidone led
to both decreased psychotic symptoms and decreased cravings. Haloperidol and
carbamazepine similarly have some limited evidence for decreasing symptoms in
those with inhalant-induced psychotic disorders. A case report showed reduction in
cravings and increased abstinence with lamotrigine [4].
Conclusion
Although inhalant use disorder is relatively rare compared to other substance use
disorders, it can nevertheless cause significant injury to those affected by it, includ-
ing several potentially fatal complications. Inhalant use should be part of any com-
prehensive substance use screening, particularly when working with populations
with higher prevalence of the disorder. Although treatment options are limited,
some of the psychosocial treatments with efficacy in other substance use disorders
have also been shown to work in this patient population.
Key Points
• Inhalant use disorder describes problematic use of a heterogeneous group of sub-

stances including volatile solvents, aerosols, gases, and nitrites.
• Inhalants can exert their effects across body systems both acutely (including life-
threatening hematologic, respiratory, and cardiac risks) and more chronically.
• Careful screening, harm reduction, and community-level interventions are criti-
cal to reducing the burden of disease.
• Treatment options for inhalant use are primarily psychosocial and overlap with
those for other substance use disorders.
References
1. Kalai. Diagnostic and statistical manual of mental disorders: DSM-5. Arlington: American
Psychiatric Association; 2017. p. 533–40.
2. Storck M, Black L, Liddell M. Inhalant abuse and dextromethorphan. Child Adolesc Psychiatr
Clin N Am. 2016;25:497–508.
3. Crossin R, Scott D, Witt KG, Duncan JR, Smith K, Lubman DI. Acute harms associated
with inhalant misuse: co-morbidities and trends relative to age and gender among ambulance
attendees. Drug Alcohol Depend. 2018;190:46–53.
4. National Institute on Drug Abuse. Inhalants trends & statistics. National Institute on Drug
Abuse; 2020. https://www.drugabuse.gov/drug-topics/inhalants/inhalants-trends-statistics.
Accessed 15 Feb 2021.
5. Kalai. Trends in the prevalence of marijuana, cocaine, and other illegal drug use national
YRBS: 1991–2019. Centers for Disease Control and Prevention; 2020. https://www.cdc.gov/
healthyyouth/data/yrbs/factsheets/2019_us_drug_trend_yrbs.htm
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disorders in the United States. Addiction Science & Clinical Practice; 2011. https://www.ncbi.
nlm.nih.gov/pmc/articles/PMC3188822/
7. Crossin R, Cairney S, Lawrence AJ, Duncan JR. Adolescent inhalant abuse leads to other
drug use and impaired growth; implications for diagnosis. Aust N Z J Public Health.
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8. Hunter L, Gordge L, Dargan PI, Wood DM. Methaemoglobinaemia associated with the
use of cocaine and volatile nitrites as recreational drugs: a review. Br J Clin Pharmacol.
2011;72:18–26.
9. National Institute on Drug Abuse. What are the other medical consequences of inhalant
abuse? National Institute on Drug Abuse; 2020. https://www.drugabuse.gov/publications/
research-reports/inhalants/what-are-other-medical-consequences-inhalant-abuse
10. Crossin R, Qama A, Andrews ZB, Lawrence AJ, Duncan JR. The effect of adolescent inhalant
abuse on energy balance and growth. Pharmacol Res Perspect. 2019;7(4):e00498. https://doi.
org/10.1002/prp2.498.
11. Camara-Lemarroy CR, Rodríguez-Gutiérrez R, Monreal-Robles R, González-González

JG. Acute toluene intoxication–clinical presentation, management and prognosis: a prospec-
tive observational study. BMC Emerg Med. 2015;15:19. https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC4539858/
12. Tools. Clinician tools – SBIRT for substance abuse. https://www.sbirt.care/tools.aspx.

Accessed 15 Feb 2021.
13.
Empowering change: motivational interviewing. SAMHSA. https://www.samhsa.gov/
homelessness-programs-resources/hpr-resources/empowering-change. Accessed 15 Feb 2021.
Opioid Use Disorder
7
Sierra Ferguson and Aviva Teitelbaum
Introduction
Opioid use disorder is defined by the chronic use of opioids that leads to clinically
significant impairment or distress [1]. Opioid use disorder is diagnosed when an
individual meets two or more of the 11 criteria in the table below within a one-year
period, and severity is based on the number of symptoms present (Table 7.1). An
estimated 26.8 million people globally have opioid use disorder with over 100,000
overdose deaths reported each year [2]. In 2018, 10.3 million people or 3.7% of the
US population aged 12 or older were estimated to have misused opioids, and two
million of these individuals met criteria for opioid use disorder [3]. An estimated
446,000 American died from an opioid overdose from 1999 to 2018 and of those
233,000 died from a prescription opioid overdose [4]. During this same time period,
there was a tenfold increase in overdose deaths caused by fentanyl [4], a synthetic
opioid 30–50 times more potent than heroin [5, 6]. The prevalence of heroin use in
the United States has increased significantly over the past two decades, doubling in
number from 2002 to 2018 [7], and two thirds of individuals who use heroin also
report use of prescription opioids [8]. Given the increasing rates of opioid overdose
deaths and the human toll caused by this “opioid epidemic,” in 2017, the US
Department of Health and Human Services declared the opioid crisis a public health
emergency, which increased public funding for treatment, overdose prevention, and
training of first responders and other medical professionals to respond to the
crisis [9].
S. Ferguson
Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, NY, USA
e-mail: Sierra.Ferguson@mountsinai.org
A. Teitelbaum (*)
NYU Grossman School of Medicine, New York, NY, USA
e-mail: Aviva.Teitelbaum@nyulangone.org

https://doi.org/10.1007/978-3-030-86430-9_7
68 S. Ferguson and A. Teitelbaum
Table 7.1 DSM-5 diagnostic criteria for opioid use disorder [1]
Opioids are often taken in larger amounts or over a longer period of time than intended
There is a persistent desire or unsuccessful efforts to cut down or control opioid use
A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or
recover from its effects
Craving, or a strong desire to use opioids
Recurrent opioid use resulting in failure to fulfill major role obligations at work, school, or
home
Continued opioid use despite having persistent or recurrent social or interpersonal problems
caused or exacerbated by the effects of opioids
Important social, occupational, or recreational activities are given up or reduced because of
opioid use
Recurrent opioid use in situations in which it is physically hazardous
Continued use despite knowledge of having a persistent or recurrent physical or psychological
problem that is likely to have been caused or exacerbated by opioids
Tolerance, as defined by either of the following: (a) a need for markedly increased amounts of
opioids to achieve intoxication or desired effect or (b) a markedly diminished effect with
continued use of the same amount of an opioid
Withdrawal, as manifested by either of the following: (a) the characteristic opioid withdrawal
syndrome or (b) the same (or a closely related) substance is taken to relieve or avoid withdrawal
symptoms
Individuals develop opioid use disorder through a variety of pathways including

legitimate use or abuse of prescription analgesics such as oxycodone and hydroco-
done or through use of illicit substances such as heroin. Individuals at risk for devel-
oping opioid use disorder frequently have risk factors including current or past
history of substance abuse, introduction to opioids at a younger age, untreated psy-
chiatric disorders, and social and familial contexts where substance use is common-
place [10].
Medication-assisted treatment for opioid use disorder, when used in conjunction
with psychosocial interventions and counseling, shows superior treatment outcomes
in terms of treatment retention, lower mortality, and improved quality of life [11–
14]. Despite strong evidence in support of MAT, it is underutilized [15, 16]. This
can be explained in part due to stigma held by both patients and providers, lack of
training for providers particularly in rural areas, and limited access to opioid treat-
ment programs [17, 18]. One study found that less than 50% of privately funded
substance use disorder treatment programs offer MAT as part of their treatment
programs and of those only 34.4% of patients with opioid use disorder received
MAT [19]. The goal of this chapter is to illustrate the evolution of an opioid use
disorder (OUD) through a clinical case and to outline the pharmacologic treatment
options to treat this illness including methadone, an opioid agonist; buprenorphine,
an opioid partial agonist; and naltrexone, an opioid antagonist.
7 Opioid Use Disorder 69
Clinical Case
Joe is a 45-year-old married man, working in construction, who sustained a work-

related injury; while using a circular saw to cut a piece of wood, he accidentally
sliced off his index finger. Fortunately, he salvaged his finger, and it was reattached
at a nearby hospital. Dr. Frank, the surgeon who performed the procedure, pre-
scribed Joe a one-month supply of oxycodone-acetaminophen (commonly known
as Percocet) to treat his postoperative pain.
Prior to receiving this prescription for oxycodone-acetaminophen, Joe had never
used any opioid analgesics nor any illicit opioids. He considered himself a “social
drinker,” but never drank on a daily basis, infrequently got drunk, and never blacked
out from alcohol. His wife, however, did have a remote history of heroin addiction
and was on methadone prescribed by an opioid treatment program (OTP) in a nearby
town. Joe did not have any chronic medical conditions, nor did he have any relevant
psychiatric history. He recalls his father being “an angry drunk,” but his parents
divorced at a young age, and he never maintained a relationship with his father after
he left.
Joe began taking the opioid analgesic as his doctor had prescribed it. Initially, the
medication adequately controlled Joe’s pain, but within a few weeks, the pain in his
finger became more intense. In an attempt to help alleviate Joe’s pain, Dr. Frank
renewed Joe’s prescription and doubled his supply during the following 2 months.
Four months after Joe’s procedure, despite ongoing complaints of intense
“dagger-like” pain in his reattached index finger, Dr. Frank informed Joe that he
could no longer continue to prescribe oxycodone-acetaminophen, explaining “the
medical community is cracking down on narcotic prescriptions, so you should try to
cope without the medication.” At this point, Joe had been consuming oxycodone-
acetaminophen 5–325 mg up to six times daily for several months. He was worried
about being suddenly cut off from his prescription, recalling a time when he had
forgotten his pain medication at home during a work day, and he experienced flu-
like symptoms of opioid withdrawal. He expressed these concerns to his doctor who
offered to refer him to a pain management specialist, but the next available appoint-
ment was in 3 months’ time.
In the week following his last appointment with Dr. Frank, Joe attempted to cut
back on his oxycodone-acetaminophen use. He had about 30 pills remaining, and he
attempted to reduce his use from six pills daily to three pills daily. He succeeded at
this, despite enduring numerous symptoms of opioid withdrawal: chills, muscle
aches, nausea, and diarrhea. Joe felt like he had come down with a terrible bout of
influenza. His wife, concerned about his state, suggested he enroll at her opioid
treatment program and initiate methadone. Joe refused. He had always regarded
methadone as “legal heroin” and had been encouraging his wife to taper off of it.
As he only had a few days’ supply of pain medications remaining, and his pain
management appointment was still ten weeks away, Joe felt that he had to find an
interim solution. He took to the Internet to search his options, and he found a com-
pound called kratom (Mitragyna speciosa), which could be bought legally, mar-
keted itself as an effective painkiller, and had opioid-like properties that would
soften the impact of opioid withdrawal.
Joe found relief in kratom – a powder he brewed into hot water – which he con-
sumed multiple times daily. It lessened his symptoms of opioid withdrawal and
dulled the pain in his finger. He noticed, however, that he quickly became tolerant
of kratom. He began by drinking three cups of kratom daily, and within a few weeks,
he was drinking six cups daily to achieve the same desired effect.
Joe started to worry about the financial implications of his new kratom habit. His
wife approached him again and suggested that he come to her Opioid Treatment
Program and hear about the available treatment options, assuring him that metha-
done is not the only option for his condition. Joe agreed.
Pharmacologic Interventions
When Joe arrives at the clinic, he meets with a psychiatrist to discuss treatment
options and shares that he last used kratom yesterday morning and is already expe-
riencing withdrawal symptoms and cravings to use again. During the visit a Clinical
Opiate Withdrawal Scale (COWS) is administered, which is an 11-item scale
designed to assess withdrawal symptoms over time, rating withdrawal symptoms
from mild, moderate, moderately severe, and severe [20]. Joe’s vitals are taken and
blood pressure is 125/90 mm Hg and pulse rate 110 beats per minute. He blows his
nose several times as he enters the exam room and reports feeling anxious and rest-
less with strong urges to use kratom. He is noted to be sweating and yawns twice
during the session. He also reports experiencing severe muscle and bone pain and
gets up several times during the interview to use the bathroom due to nausea and
severe diarrhea. Based on these symptoms of opioid withdrawal, Joe’s COWS score
is 16, indicating moderate withdrawal. He is not noted to have any tremor or goose-
flesh skin, and pupils appear normal-sized. Joe initially states he wants to “tough it
out” and detox from kratom without MAT due to concern for “getting addicted to
something else.” Detox options are discussed, specifically non-opioid symptomatic
treatment of opioid withdrawal including clonidine 0.1–0.2 mg four times daily to
treat Joe’s tachycardia, anxiety, sweating, and hypertension. Metoclopramide 10 mg
every 6 hours as needed is offered for nausea and loperamide 4 mg initially, and
then 2 mg thereafter (up to 16 mg/day) is offered for diarrhea. Ibuprofen 400 mg
three times daily as needed is offered for pain, and he is also prescribed trazodone
50 mg nightly as needed for insomnia which he also reported experiencing due to
the withdrawal [21].
By the end of the 45-minute session, Joe appeared even more restless and was
noted to have a new onset tremor and a COWS score of 23. As he rose to leave the
Table 7.2 Pros and cons of the three FDA-approved treatments for OUD
Medication Pros Cons
Methadone Medication cost is affordable [50] Initially 6 day/week attendance expected at
Straightforward induction process most OTPs
Reduction in infectious disease No office-based treatment, must have
transmission and criminal activity access to OTP [24]
[51] Cardiac arrhythmias [53]
Safely used in pregnancy [52] Overdose risk [24]
Some find benefit to the structure Stigmatized
of an OTP High abuse potential
Low risk of diversion due to strictAt high doses: sedation, constipation,
initial frequent attendance policy sexual dysfunction [54]
Buprenorphine Ceiling effect: low risk of Costly: medication is moderately
overdose, less abuse potential expensive, and DEA-X waivered
Daily or alternate-day dosing physicians usually in private practice
Increased flexibility: office-basedModerate abuse potential [55]
prescribing Diversion risk with office-based
Less stigmatized than methadone prescribing
Safely used in pregnancy [55] Risk of precipitated withdrawal during
induction [55]
Naltrexone Blocks high from any opioid use Risk of precipitated withdrawal during
Relieves cravings induction
No risk of naltrexone withdrawal Decreases tolerance, therefore increases
Less stigmatized than methadone overdose risk
Minimal abuse potential Common side effect: nausea
office, he walked to the door then stopped and turned around and said “I’d actually
like to hear about the other treatment options. I can’t continue withdrawing like this.”
The psychiatrist welcomed Joe back into the room and provided supportive lis-
tening about how much Joe has struggled with his chronic pain and resultant opioid
dependence. She then reviewed the three FDA-approved medication options for
opioid use disorder that work by reducing cravings: methadone, buprenorphine, and
naltrexone [22].
The psychiatrist, aware that Joe’s wife was treated with methadone for opioid use
disorder, began by discussing this option. Methadone, she explained, is a long-
acting opioid agonist that is FDA-approved for both opioid use disorder and pain
management, which could be helpful for Joe’s finger pain [23]. She also shared that
methadone can only be dispensed by a SAMHSA-certified Opioid Treatment
Program (OTP) that would provide on-site administration of methadone in liquid
form six days a week along with individual sessions with a counselor, regular urine
toxicology, and group therapy. Additional pros and cons of methadone were
reviewed with Joe (Table 7.2) [24].
Joe expressed interest in the pain management aspects of methadone though
expressed hesitance that methadone was not for him, saying “it seems like yet
another drug to abuse.”
Next the psychiatrist reviewed naltrexone, a synthetic opioid antagonist, as a
treatment option given that there is no abuse potential with this medication [25]. She
explained how this medication was available as a tablet or in an extended-release
monthly injection called Vivitrol that could be prescribed in an outpatient clinic set-
ting. Naltrexone functions by binding to and blocking the opioid receptor [25] and
by extension would block opioid-like substances such as kratom, which has agonist
effects on the opioid receptor. Naltrexone therefore reduces opioid cravings and
compulsive opioid use [3]. Joe seemed interested initially, though when he learned
that he would have to remain abstinent from opioids or opioid-like substances for
6 days prior to induction on naltrexone, he declined this option.
Aware that Joe was seeking a more immediate treatment for his opioid cravings
and withdrawal, the psychiatrist then recommended buprenorphine, an opioid par-
tial agonist that can be prescribed in an outpatient clinic setting. Given Joe’s current
withdrawal symptoms, he could safely be induced on buprenorphine today in the
office. The treatment, it was explained, would reduce his opioid cravings and with-
drawal symptoms as well as reduce some of his finger pain given its action at the
opioid receptor. The pros and cons of this treatment were reviewed with Joe includ-
ing risk for precipitated withdrawal – if he had recently consumed opioids – and
potential side effects. Various formulation options were reviewed including
buprenorphine sublingual tablets (Subutex), buprenorphine-naloxone combination
sublingual films (Suboxone) and tablets (Zubsolv), as well as longer-acting forms of
buprenorphine such as extended-release injection (Sublocade). Given Joe’s concern
about the abuse potential of his treatment, he opted to try a buprenorphine-naloxone
compound, since naloxone reduces misuse of buprenorphine. Joe agreed to start
buprenorphine-naloxone combination sublingual films (Suboxone) 4 mg in the
office and would return home with an additional 4 mg to take that evening if with-
drawal symptoms persisted. He agreed to return the following morning for assess-
ment and potential dose adjustment. See treatment Algorithm 7.1 for additional
guidance of initiating MAT for the treatment of opioid use disorder.
Discussion
Joe’s story is similar to that of many thousands of Americans who have developed
an opioid use disorder over the past 30 years. In 1995, the American Pain Society
(APS) set out guidelines that encouraged medical providers to record patients’
reports of pain, with the goal of improving the diagnosis and treatment of pain. They
recommended that patients’ reports of pain should be taken as seriously as vital sign
measurements, thereby coining this initiative pain as the fifth vital sign [32]. Not
surprisingly, an increase in pain assessments brought on an increase in opioid anal-
gesic prescribing; opioid prescriptions increased from 76 million in 1991 to 219 mil-
lion in 2011. Unfortunately, during this time of widespread opioid prescribing,
pharmaceutical companies marketed opioid analgesics to the medical community as
non-addictive [33], which we now recognize is not the case. The increase in opioid
prescriptions led to an increase in opioid-related emergency room visits, treatment
admissions, and overdose fatalities [34].
In response to the increasing rates of controlled substance misuse in the United
States, prescription drug monitoring programs (PDMPs) were implemented in most
American states. With the implementation of PDMPs, there was a corresponding 30

percent decrease in the rates of prescribing Schedule II opioids (which includes
most prescription opioids) [35]. Physicians became increasingly aware of the addic-
tive nature of prescription opioids, and many abruptly changed their prescribing
practices, sometimes to the detriment of their patients.
Naloxone, a rapid-acting opioid receptor antagonist, was introduced to the mar-
ket in a more user-friendly form in recent years. In the past, this medication had
been used only in medical settings such as emergency rooms, since it was only
available in intravenous or intramuscular form. Importantly, the key to reversing an
opioid overdose is prompt timing of naloxone administration, so the recent creation
and wider distribution of an easy-to-use intranasal naloxone spray have been an
important step in overdose prevention [36]. Naloxone should be prescribed to any-
one considered high risk of opioid overdose – such as individuals with an opioid use
disorder who have recently been released from a period of incarceration or those
who are prescribed high doses of long-acting opioid analgesics – and a doctor or
pharmacist can show patients, their family members, or caregivers how to adminis-
ter intranasal naloxone [37].
As was seen in Joe’s case, his doctor abruptly stopped his opioid prescription,
leaving Joe without access to a medication he was physiologically dependent on. It
is at this juncture that many people make the transition to heroin due to its wide-
spread availability, adequate analgesic effect, and affordability. In Joe’s case, how-
ever, he harbored considerable stigma about illicit drugs and their treatments, such
as methadone, so he sought out kratom, an opioid-like compound that is sold legally
online and in head shops. Kratom (Mitragyna speciosa) is harvested from a tree
indigenous to Southeast Asia and is a relative of the coffee plant. It is sold as a pow-
der that can be stirred into a beverage or put in individual capsules for consumption.
At lower doses, kratom has stimulant-like properties, and at higher doses it behaves
like an opioid, and in fact is an agonist on the major opioid receptors. In recent years
it has gained popularity as a recreational drug that is marketed to improve mood,
relieve pain, and may provide benefit in opioid addiction [38]. As we saw in the
above case, Joe became tolerant of kratom and began to use higher doses to achieve
the same effect. Upon recognizing this, he agreed to visit his wife’s OTP and con-
sider a medication-assisted treatment for opioid use disorder.
Upon learning about the three FDA-approved treatments for opioid use disorder,
Joe found himself most partial to buprenorphine-naloxone combination therapy
(Suboxone). He told the psychiatrist that he heard that methadone causes dental and
bone decay. The OTP psychiatrist explained that methadone can reduce the produc-
tion of saliva, which prevents dental caries. Therefore, initiating methadone can
cause dry mouth, which may increase risk of cavities; however, methadone does not
directly act on the teeth to cause dental decay. Additionally, until arriving at a thera-
peutic dose of methadone, opioid withdrawal symptoms may cause musculoskeletal
pain, which may be misconstrued as bone breakdown. Methadone does not directly
act on bones to break them down, however. Joe mentioned that he is also worried
that people would regard him as “weak and without willpower” if he agreed to
methadone or another MAT [39]. His wife has been on methadone for nearly a
decade, and he is worried that if he were to start it, he would never get off. While the
OTP psychiatrist understood that there is considerable stigma against people with
substance use disorders and those on MAT, she assured Joe that most providers he
would be working with at the clinic would see his seeking treatment as a sign of
willpower: he is asking for help with a habit that has become destructive. She also
assured Joe that every patient is different: some patients use MAT as a bridge to
transitioning off opioids altogether, and others need to be on MAT for many years,
given how susceptible they are to relapse on opioids.
Despite the OTP psychiatrist debunking many of Joe’s preconceived notions
about methadone, and recommending it for the dual treatment of opioid use disorder
and pain management, Joe opted to initiate suboxone. While he could initiate sub-
oxone at his wife’s OTP, he preferred to find an office-based suboxone provider in
the future, so he would not be subject to the initial six-day-per-week pickup sched-
ule of the OTP.
Despite substantial evidence for its efficacy, safety, and relative ease of use,
buprenorphine remains vastly underutilized [40]. In order to become a licensed
buprenorphine prescriber, one must provide MAT in a qualified practice setting or
hold board certification in addiction medicine or addiction psychiatry. Buprenorphine
training is typically eight hours in duration and grants those a DEA X waiver to
prescribe buprenorphine [41]. As of 2017, more than half (56.3%) of US counties
were without a buprenorphine prescriber [42]. In addition, most waivered physi-
cians treat far fewer than the potential maximum of 275 patients they are eligible to
treat. Studies suggest a lack of prescriber experience and education in the use of
buprenorphine as a reason for its underutilization [43]. Buprenorphine has also been
criticized as being marketed to a specifically white, affluent, college-educated popu-
lation [44]. Notably its advertising campaigns do not target an underserved popula-
tion with low socioeconomic status, where rates of substance use disorders are
highest. In addition, many state-funded Medicaid programs do not cover reimburse-
ments for buprenorphine, thereby narrowing the scope of prescribing to more afflu-
ent subsections of the population with private insurance [45].
Psychotherapeutic and Psychosocial Interventions
The treatment of opioid use disorder includes medication-assisted treatment as well

as a range of behavioral interventions aimed at helping patients to reduce urges to
use opioids, maintain abstinence, and develop coping skills [46]. Studies have
shown superior clinical outcomes in the treatment of opioid use disorder when med-
ication management was combined with psychosocial interventions [47]. These
interventions take the form of individual and group therapies including cognitive
behavioral therapy, acceptance and commitment therapy, couples and family
therapy including network therapy, contingency management, motivational inter-

viewing, social skills training, harm reduction counseling, and 12-step facilitation
therapy [48]. Some treatments such as 12-step facilitation therapy (such as Narcotics
Anonymous, with almost 20,000 groups worldwide) promote an abstinence-only
recovery approach, while others such as harm reduction counseling seek primarily
to reduce the negative sequelae of substance use, such as infectious disease trans-
mission or criminal behavior.
Joe’s case provides a good example of where motivational interviewing could be
used to help Joe recognize problems associated with his kratom use, explore and
resolve ambivalence about his use, and explore both the benefits of changing his
addictive behaviors and the costs of not changing. In this case, the OTP psychiatrist
could take a nonjudgmental stance and use empathy to align with Joe in his struggle
to stop using kratom. She could employ open-ended questioning and reflections to
help Joe to see the gap between his kratom use and his personal goals and values.
The psychiatrist could elicit Joe’s own reasons for change referred to as “change
talk” rather than trying to persuade him that he should stop using kratom. She could
also explore his belief about MAT being a sign of weakness rather than as a sign of
strength in his recovery.
Conclusion
The opioid epidemic is one of the most profound public health crises that the United
States has faced over the course of its history. An increase in opioid analgesic pre-
scribing in the late 1990s and early 2000s led to an increase in misuse and abuse of
prescription opioids, which commonly became a gateway to developing a heroin
addiction [49]. There are three medication-assisted treatments [13] for opioid use
disorder – methadone, buprenorphine, and naltrexone – and they are all underpre-
scribed and heavily stigmatized, both by the lay public, by patients with opioid use
disorders, and even by medical providers. This chapter has attempted to illustrate
how a middle-aged man without a prior history of addiction developed an opioid use
disorder through a legitimate prescription by his own physician. Within a short
period of time, he was physiologically dependent on opioid analgesics and later on
kratom, an opioid-like compound that reduces opioid withdrawal symptoms. The
patient’s own long-held beliefs about MAT prevented him from seeking treatment
immediately and from weighing all three approved treatment options equally. While
the psychiatrist in this case was well-versed on each approved MAT for the patient’s
opioid use disorder, MAT in general is vastly underprescribed, possibly due to pre-
scriber lack of training and experience in MAT prescribing. Additional efforts in
educating medical providers and the general public on the disease of addiction and
its treatments are a necessary step in tackling the opioid epidemic.
Algorithm 7.1 Treatment of Opioid Use Disorder
Assess whether patient meets

criteria for Opioid Use Disorder
and discuss MAT options
Full detox
MAT
without MAT
Methadone Buprenorphrine Naltrexone
Observe for signs of withdrawal

prior to initiation. For short Ensure patient has been
Day 1: Start 20-30 mg. acting opioids (heroin, abstinent from short
Wait 2-4 hrs. If symptoms hydrocodone, oxycodone IR) acting opioids for 7 days
of withdrawal continue wait 12-16 hrs, for intermediate and from long acting
given another 5-10mg up acting opiods (oxycodone SR) opioids for 10 days to
to 40 mg [27]. wait 17-24 hrs, for long acting prevent precipitated
opioids (methadone) wait withdrawal [28].
30-48 hrs. (32) Ensure
COWS>6-10 [31].
Day 6: Increase dose by

Day 7-10: Ensure no
5 mg or less. Can
symptoms of
continue 5 mg increases
Day 1:Give withdrawal. Can use
every 5 or more days
buprenorphine 4 mg. naloxone challenge
until no symptoms of
Wait 2-4 hrs and observe prior to dosing. Give
withdrawal. Limited
for signs of withdrawal. naltrexone 25 mg [30].
safety data above
120 mg/day though some Can increase dose up to
patients require higher 8 mg [29].
doses [26].
Day 2: Assess for

Day after initation
withdrawal and If signs of precipitated
dosing: If no
cravings. If they withdrawal, stop and
symptoms of
persist give up to treat symptoms prior
withdrawal, give 50 mg
double the dose given to resuming.
[30].
on Day 1 [30].
Day 3: Reach target

dose of 12-16 mg.
Some patients require
doses up to 32 mg [30].
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medication-assisted-treatment/medications-counseling-related-conditions/buprenorphine
Sedative-, Hypnotic-, or
Anxiolytic-Related Disorders 8
Emily Dumas
Introduction
Sedative, hypnotic, and anxiolytic substances include benzodiazepines, barbitu-

rates, and non-benzodiazepine hypnotics. Phenobarbital was introduced in 1912,
but due to its potential for toxicity and abuse, was largely supplanted by the benzo-
diazepines, when chlordiazepoxide came into existence in the early 1960s [5, 13].
The non-benzodiazepines, the so-called Z-drugs, are a newer class, initially thought
to occupy a lower level of abuse liability than benzodiazepines, though it has since
been demonstrated that they too pose a significant risk of dependence.
The clearest indications for benzodiazepines are in panic disorder, generalized
and social anxiety disorders, simple phobias, and for short-term use in acute anxiety
and acute insomnia. They are also utilized as the core treatment of alcohol with-
drawal in the inpatient setting. It has been estimated that up to 50% of regular ben-
zodiazepine users will experience clinically significant signs of withdrawal with
sudden discontinuation [21]. Dose-dependent side effects of benzodiazepines
include drowsiness, lethargy, fatigue, sedation, disturbances in concentration and
attention, development of dependence, and rebound of insomnia or anxiety after
lowering doses [2]. The Z-drugs come with their own set of adverse experiences
such as anterograde amnesia, somnambulism, difficulty acquiring new learning,
agitation, and hallucinations [4]. Currently, benzodiazepines are considered rela-
tively safe for short-term use in most populations, but their safety has not been
established beyond two to four weeks of treatment.
The number of benzodiazepine prescriptions in the United States has increased
substantially since the mid-1990s [1, 19]. Dependence develops in approximately
half of patients who use benzodiazepines for longer than 1 month [6, 13]. High-risk
groups for developing dependence include those with chronic pain syndromes,
E. Dumas (*)
PGY-2 Psychiatry Resident, Weill Cornell Medical College, New York, NY, USA
e-mail: esd9012@nyp.org

https://doi.org/10.1007/978-3-030-86430-9_8
82 E. Dumas
alcohol or opioid use disorders, chronic sleep disorders, or personality disorders

[19]. Additionally, females have an elevated risk of dependence [4]. Among those
prescribed benzodiazepines for psychiatric disorders, individuals with anxiety dis-
orders are not as likely to develop use disorders compared to those with affective
disorders [4]. Sedative-hypnotic use disorders can also be associated with other
substance use disorders, as substance users will often turn to sedatives to mitigate
undesirable side effects of other substances or to use synergistically with their pri-
mary substance of abuse for mood enhancement. For example, studies have shown
that approximately 15–20% of alcoholic patients presenting for treatment may be
abusing benzodiazepines [4].
Understanding the mechanism of action of benzodiazepines is critical to grasp-
ing their clinical effects, side effects, and pathways to development of a use disor-
der. The agents in the sedative-hypnotics class have similar mechanisms of action in
that they bind to allosteric sites on the gamma-aminobutyric acid subtype A
(GABAA) receptor, increasing the frequency of the chloride channel opening. This
results in enhancing the inhibitory effect of GABA, translating to the clinical effects
of decreased anxiety, increased sedation, muscle relaxation, amnesia, hypnosis, and
anticonvulsion [19]. Long-term benzodiazepine use leads to tolerance through
downregulation of GABA receptors and upregulation of the excitatory glutamate
system [11]. More recent findings show that benzodiazepines may increase the
activity of dopaminergic neurons in the ventral tegmental area (VTA), indicating
that benzodiazepines may have a mechanism in common with opioids in terms of
dopamine release [19]. The benzodiazepines that have the greatest abuse potential
have a quick onset of action due to their lipophilicity, enabling them to produce
hedonic effects rapidly [6].
Within both the patient and clinician populations, there are barriers to recogniz-
ing patterns of misuse and thus diagnosing sedative-hypnotic use disorders. In con-
trast to opioid intoxication and alcohol withdrawal, benzodiazepines, when ingested
alone or being withdrawn from, are rarely fatal. As a result, misuse of these benzo-
diazepines, in contrast to opioids or alcohol, does not often draw as intensive inter-
ventions and treatments. Additionally, sedative, hypnotic, and anxiolytic use
disorders are often iatrogenic, arising in the setting of benzodiazepines being taken
in doses within the therapeutic range, causing both the prescriber and patient to not
view use patterns as problematic. Additionally, some clinicians believe that benzo-
diazepines are more effective than first-line pharmacologic and nonpharmacologic
approaches for insomnia and anxiety, and certain individuals, in particular older
people, are less willing to try alternative, more labor-intensive treatments such as
cognitive behavioral therapy (CBT). This unwillingness to consider reducing or dis-
continuing benzodiazepines for an alternative treatment method, along with there
being limited resources for alternative treatments such as CBT, leads to benzodiaz-
epine use disorders going unaddressed [8, 15].
The clinical case in this chapter will illustrate many of the key points about ben-
zodiazepine use disorder, highlighting the signs and symptoms of dependence and
withdrawal. The case will also give cause for further discussion about how to
8 Sedative-, Hypnotic-, or Anxiolytic-Related Disorders 83
prescribe and taper benzodiazepines while being mindful of the challenges of

achieving abstinence.
Clinical Case
Dr. Smith is a psychiatry resident in her second year of training, rotating through the
Consultation-Liaison Psychiatry service at a hospital in a large urban area. On Dr.
Smith’s list of consults for the day is a 43-year-old woman, Maya, admitted to a
general medicine floor for management of altered mental status. She has a history
of generalized anxiety disorder, depression, and anorexia nervosa, in remission, but
no significant past medical history. She has been treated by outpatient psychiatrists
for a decade. When Maya started seeing her current outpatient psychiatrist two years
ago, she was on a regimen consisting of multiple benzodiazepines, including alpra-
zolam, clonazepam, and lorazepam (exact amounts unknown). Since being under
the care of her current psychiatrist, Maya’s medication regimen has been consoli-
dated to alprazolam 1 mg daily and clonazepam 6.5 mg daily.
Maya was brought by ambulance to the hospital’s emergency after her outpatient
psychiatrist noticed that earlier that day, during their weekly virtual check-in
appointment, Maya presented as disorganized, inattentive, and not oriented to time
or place. Upon this evaluation, Maya slurred her speech, exhibited paranoid delu-
sions (e.g., she accused her psychiatrist of posting about her on social media), and
reported having not slept in three days. Per collateral from Maya’s parents, who live
in Florida, Maya started behaving bizarrely four days ago, when she sent several
aggressively worded text messages to her father, which was uncharacteristic of her.
After Maya was admitted to the medicine floor, the primary team of doctors initi-
ated an altered mental status workup, including a metabolic panel, ammonia level,
carboxyhemoglobin level, and head imaging, none of which had pathological find-
ings. Additionally, Maya’s urine toxicology screen and blood alcohol level were
insignificant. The primary team gave her fluids and placed orders for a Clinical
Institute Withdrawal Assessment (CIWA) to be completed every four hours to moni-
tor for benzodiazepine withdrawal.
When Dr. Smith first came to see Maya the day following her admission, Maya
presented as a thin woman lying calmly in bed who appeared stated age, but was
disheveled and displayed limited eye contact. Maya reported a “scared” mood and
had an anxious affect. Her thought process was linear but vague. No paranoia, delu-
sions, or perceptual disturbances were elicited in her thought content. She denied
auditory and visual hallucinations. Maya explained that she had not taken her alpra-
zolam or clonazepam in over a week because she had abruptly run out of pills and
could not manage to get them refilled for unclear reasons. Maya did not recall send-
ing text messages to her father or speaking with her psychiatrist the day she was
brought to the emergency department.
Dr. Smith recommended starting Maya on clonazepam 1.5 mg every 8 h in the
hospital, to be held for sedation, and keeping Maya on CIWA for benzodiazepine
withdrawal precautions. After two days in the hospital, Maya became clearer and
84 E. Dumas
cognitively intact. She denied using any illicit substances, though admitted that in
the last few months she was drinking alone more often, consuming at least one or
two glasses of wine most nights, and sometimes up to a bottle of wine on a week-
end. She explained that the social isolation she was experiencing was making her
anxious, so she took it upon herself to self-medicate with tablets of alprazolam and
clonazepam every day. She recalled that approximately one day after she ran out of
her benzodiazepine prescriptions, she began to experience heightened anxiety, irri-
tability, and confusion. She described feeling as though she were in a fog and having
an “out of body experience.” During this time, she stopped running her usual daily
six miles. Maya discussed multiple life stressors including her father’s recent diag-
nosis with lymphoma, her dog’s illness, migraines, and social isolation in the setting
of the pandemic, compounded by the loss of her job in the setting of layoffs early in
the pandemic. Her mother, who had arrived in the city by time of discharge, was
planning on staying with her for at least the next couple of weeks. The discharge
plan was for Maya to follow up with her outpatient psychiatrist the next day.
Discussion
Maya’s initial presentation was consistent with delirium secondary to benzodiaze-

pine withdrawal, in the setting of benzodiazepine use disorder. Within days of sud-
denly stopping her benzodiazepines, Maya experienced a concurrent acute change
in mental status, marked by escalating confusion, disorientation, and memory
impairment. This evolved into disorganization and frank psychosis, as evidenced by
her paranoia that her psychiatrist was posting about her on social media. The dif-
ferential diagnosis included benzodiazepine or alcohol acute intoxication, alcohol
withdrawal, and unspecified psychosis.
Maya’s delirious presentation was characteristic of the moderate-to-severe with-
drawal that is usually experienced by individuals who abruptly stop taking medium-
to-high doses of benzodiazepines after regularly taking them for at least two to
six months. Maya’s outpatient regimen of alprazolam 1 mg and clonazepam 6.5 mg
daily, doses approximately equivalent to lorazepam 15 mg daily, was a high amount
of benzodiazepines, relative to the average prescriptions of benzodiazepines. The
severity and duration of withdrawal is multifactorial, depending upon the potency
and half-life of the benzodiazepine, the amount taken, and the duration of use prior
to discontinuation. Some sources suggest it may take as little as four weeks of regu-
lar use to develop withdrawal symptoms; others report that rebound insomnia can
be seen after two weeks of daily use [7, 9]. With shorter half-life agents like alpra-
zolam, symptoms can develop as early as 24 hours after discontinuation, and the
severity of withdrawal peaks on average between one and three days. In contrast, for
longer half-life agents like clonazepam, symptoms of withdrawal can begin later
and peak as late as four to seven days after drug discontinuation [5]. For Maya, who
was taking a combination of alprazolam and clonazepam, the onset of withdrawal
symptoms is more difficult to predict, but based on her presentation, her withdrawal
symptoms likely occurred within one or two days after sudden discontinuation. The
withdrawal from short-acting benzodiazepines tends to be experienced as more

intense than that associated with long-acting benzodiazepines, but indeed, there is
variability in the sensitivity of individuals to discontinuation. Variation among indi-
viduals is dependent upon several factors, including any that influence the metabo-
lism of drugs, such as age and medical health. Furthermore, underlying
psychopathology, for example, Maya’s depression and anxiety, can elevate the
severity of the withdrawal symptoms. Conversely, when benzodiazepines are
administered for short periods and at therapeutic doses, the withdrawal syndrome is
usually mild, consisting of anxiety, headache, insomnia, dysphoria, and tremor or
muscle twitching. In individuals experiencing acute withdrawal like Maya, pharma-
cologic management is often recommended because of the risk of serious conse-
quences, including seizures and delirium tremens. Thus, Maya was placed on
standing benzodiazepines (clonazepam 1.5 mg every eight hours) as well as CIWA
precautions, which would have also protected her had she been experiencing alco-
hol withdrawal, a syndrome that can mimic the appearance of benzodiazepine with-
drawal. It is worth noting that the abrupt discontinuation of barbiturates, in contrast
to that of benzodiazepines or alcohol, has the greatest propensity to result in severe
symptoms, including grand mal seizures [7]. As such, barbiturates are considered
less safe and tolerable than benzodiazepines, and thus the prescription of benzodi-
azepines has largely replaced that of barbiturates for inducing sleep and anxiolysis.
Maya’s history of depression, anxiety, and an eating disorder made her vulnera-
ble to developing benzodiazepine dependence. The risk of dependence on benzodi-
azepines is associated with a history of mental illness and with higher doses of
drugs taken [10]. The greatest risk factors for benzodiazepine dependence include a
longer duration of treatment with these agents, treatment at higher doses, and con-
current substance misuse [3, 12].
Among individuals who abuse substances, it is uncommon for benzodiazepines
to be the primary drug of use [7]. Individuals with current or remote alcohol and/or
opioid use disorders comprise two groups with high rates of benzodiazepine abuse-
related problems. Concurrent use of other substances, such as opioids or stimulants,
can conflate or exacerbate the benzodiazepine withdrawal and intoxication presen-
tation, as their intoxication syndromes can present similarly with impaired motor
performance and sedation. If a clinician suspects opioid use in a patient who has
altered mental status, naloxone can be administered without any negative repercus-
sions. Although Maya’s blood alcohol level was negligible on her admission labs,
her increased alcohol intake in recent months should be addressed in subsequent
treatment to prevent a potentially fatal overdose if she were to combine alcohol with
benzodiazepines. Such poor outcomes underscore the importance that clinicians
screen for benzodiazepine use in patients with co-occurring substance use disor-
ders [7].
Lower on the differential for Maya’s clinical presentation was intoxication with
benzodiazepines or alcohol, as well as other metabolic disturbances, given that her
metabolic panel, blood alcohol level, and urine toxicology screen were unremark-
able. Severe toxicity with benzodiazepines can manifest, in the most severe cases,
as stupor, coma, respiratory arrest, or cardiovascular collapse [7]. Management in
86 E. Dumas
severely intoxicated patients is largely supportive, with the goal of maintaining the
airway. Flumazenil is indicated only in those with confirmed benzodiazepine toxic-
ity who are losing consciousness; however, it has limited use due to its risk of pre-
cipitating seizures [5]. Mild-to-moderate acute toxicity of benzodiazepines—which
can occur even within a therapeutic context of benzodiazepine use—is character-
ized by sedation, slurred speech, psychomotor impairment, ataxia, altered visuospa-
tial skills, and memory problems [4]. Maya exhibited lapses in memory, but this was
more likely secondary to her delirious state, not necessarily a result of benzodiaze-
pine use. The cognitive side effects of benzodiazepines, such as difficulty with
attention, concentration, and acquiring new learning, tend to be insidious, rather
than acute [20]. Benzodiazepines, as well as Z-drugs, have the potential to produce
acute anterograde amnesia; in fact, impairment of learning new information is a
drawback of this class of medications. There is a multitude of documented cases of
zolpidem and zaleplon, especially at high doses, being associated with bizarre
behaviors like somnambulism and nocturnal eating, shopping, and driving. Tolerance
can develop to some of these cognitive effects, but not in all patients, and not always
to the same degree. Although benzodiazepines can contribute to cognitive impair-
ment, the association between benzodiazepine use and late-life cognitive disorders
such as dementia remains controversial [17].
Treatment
Benzodiazepine discontinuation plans are heterogeneous; the approach taken is

largely determined by the severity of benzodiazepine dependence. Benzodiazepine
discontinuation can be managed in either the inpatient setting, where rapid dose
reduction may occur, or in the outpatient setting, with close monitoring and a slower
taper over weeks to months. Individuals with medical comorbidities, comorbid use
of other substances, high-dose sedative-hypnotic use, or extensive mental health
issues are best managed in inpatient facilities for detoxification [19]. The outpatient
setting is best suited for those with long-term use and physical dependence at thera-
peutic doses, as well as for individuals who do not have significant comorbid sub-
stance use disorders and can reliably present for outpatient appointments.
Prior to determining the discontinuation protocol in an individual, a thorough
sedative-hypnotic history is recommended, encompassing the doses taken, the dura-
tion of use, and the overall clinical response to these agents throughout the course
of use [7]. To complete this history, it is necessary to find out all of the sources from
which the individual is obtaining benzodiazepines from, as some individuals may
be using a combination of prescribed and non-prescribed benzodiazepines, the latter
of which may be related to a form of diversion, such as taken from family members
or friends or purchased off the street. It is key for the provider to be cognizant that
the prescription monitoring database is not necessarily comprehensive and probe
about other avenues of obtaining benzodiazepines. It is also imperative to know
which other psychoactive substances are currently being taken, as other substances
can conflate the withdrawal picture. This can be further ascertained with regular
drug screens at appointments. Prior to discontinuing, it is important to provide psy-

choeducation, including the reasons for discontinuation, the signs and symptoms
likely to be experienced, and the pros and cons of the various withdrawal strategies.
The method of withdrawal considered to be most effective and safe features a
fixed taper, usually occurring over a period ranging from 4 to 12 weeks [22]. The
taper is extended weeks to months in order to prevent severe withdrawal symptoms
such as seizures and delirium. If an individual is using multiple benzodiazepines,
as was the case for Maya, the clinician can consolidate to a single agent. More
specifically, the clinician may substitute short-acting benzodiazepines (e.g., alpra-
zolam or lorazepam) for longer-acting benzodiazepines (e.g., chlordiazepoxide or
clonazepam) at equivalent doses, since longer-acting benzodiazepines minimize
the interdose withdrawal symptoms [19]. The dose can then be decreased on a
weekly or every-other-week basis over the course of 4–12 weeks [5, 7].
Recommendations range from reducing the initial benzodiazepine dose by 50%
approximately every week to reducing by between 10% and 25% every two weeks
[19]. Prolonged reductions over many months should be avoided to prevent the
withdrawal treatment from becoming the individual’s “morbid focus” [14]. Lastly,
the rate of withdrawal is often determined by the individuals’ ability to tolerate
symptoms, but generally, the first 50% of the taper is experienced as smoother and
mildly symptomatic, in contrast to the last 50% of the taper [16, 18, 19]. If intoler-
able symptoms of withdrawal do occur, the dose can be increased slightly until the
symptoms resolve. Following the development of intolerable withdrawal symp-
toms, subsequent dose reductions should be more conservative in terms of amount
and speed of reduction [5].
Clinicians conducting benzodiazepine discontinuation should be prepared to
manage the emergence of psychiatric disorders—such as insomnia or anxiety—dur-
ing the withdrawal period. Concomitant psychopharmacotherapy for withdrawal
lacks robust evidence, but is generally symptom-based. Medications to mitigate
withdrawal symptoms include sleep-inducing agents such as mirtazapine and trazo-
done, as well as anxiolytic agents such as pregabalin, gabapentin, hydroxyzine, or
diphenhydramine [19]. Individuals can also experience a state known as “pseudo
withdrawal,” defined as “overinterpretation of symptoms secondary to the expecta-
tions of withdrawal” [11]. Additionally, individuals undergoing tapering may
experience rebound symptoms, in which their pre-benzodiazepine symptoms of
anxiety or insomnia return but are experienced more intensely than their original
symptoms were [5]. It is key that clinicians counsel individuals about the variety of
potential adverse responses during the withdrawal period and provide reassurance
that rebound symptoms usually dissipate or return to original levels within weeks.
Additionally, employing psychotherapeutic treatments, such as cognitive behavioral
therapy, helps the individual manage psychosocial stress factors and likewise
addresses situations that are high risk for relapse [19].
Although benzodiazepines are rarely the first-line treatment for anxiety and sleep
disorders, when the first-line approaches fail to control symptoms, benzodiazepines
should not be withheld. After trialing first-line treatment modalities, such as
88 E. Dumas
cognitive behavioral therapy, group therapy, relaxation therapy, stress management,

antidepressants, and buspirone, benzodiazepines may be considered as adjunctive
treatments for individuals experiencing refractory anxiety, panic, or phobias, at least
for the short term. Particularly important for the aging and elderly in these cases, the
goal when administering benzodiazepines is to use the lowest possible dose for the
shortest period of time [7]. However, for individuals with current or history of sub-
stance use disorder, benzodiazepines should be avoided at all costs due to the higher
risk of fatal overdose. If there is uncertainty about how effective a benzodiazepine
is for the refractory symptoms once the individual begins taking it, a brief taper can
be tried to determine whether continued administration of the benzodiazepine is
indeed indicated [16]. When selecting a benzodiazepine agent, one can consider
both the potency and pharmacokinetics (e.g., speed of onset and duration of action
of the agent). Clinicians should aim to prescribe the lowest potency and longest-
acting agents (e.g., clonazepam instead of alprazolam) at the lowest effective doses,
because these qualities decrease the abuse potential. See Table 8.1 for a list of com-
monly used benzodiazepines, their half-lives, and dose equivalencies. In the outpa-
tient setting, clinicians typically prescribe to achieve a steady state, so the critical
variable to consider when selecting a benzodiazepine is elimination half-life. In
contrast, in the emergency setting, the critical variable is the distribution half-life,
with the goal being fastest onset of action.
In order to prevent iatrogenic benzodiazepine dependence when prescribing ben-
zodiazepines, clinicians can check the state’s prescription drug monitoring program,
available in the vast majority of states in the United States, as this helps to avoid
situations in which multiple providers are prescribing controlled substances.
Further, clinicians can educate individuals about the regulation of benzodiazepines,
specifically about the policies of no early refills and no prescriptions for benzodiaz-
epines from multiple physicians. See Table 8.2 for a list of signs and symptoms of
benzodiazepine use disorder. Furthermore, providers should explain that benzodiaz-
epines are viewed as short-term therapies, the need for which will be re-evaluated at
frequent intervals and be discontinued as soon as clinical symptoms improve or if
the indication changes [7]. In situations that allow for it, family members can be
educated about the risks of combining benzodiazepines with opioids or alcohol,
since family members are often the first to recognize misuse.
Table 8.1 Benzodiazepine doses and equivalencies

Distribution Elimination Dose
Benzodiazepine Onset after oral dose half-life half-life (h) equivalency
Diazepam Fastest Fast Slow (30–100 h) 5 mg
(Valium)
Lorazepam Fast (IV), Intermediate Fast (10–20 h) 1 mg
(Ativan) intermediate (PO)
Alprazolam Intermediate-fast Intermediate Fast (6–20 h) 0.5 mg
(Xanax)
Clonazepam Intermediate Intermediate Intermediate 0.25 mg
(Klonopin) (18–50 h)
Table 8.2 Signs and symptoms of sedative-, hypnotic-, and anxiolytic-related use disorders
History of sedative overdose
History of or current prescription misuse
History of taking benzodiazepines for years, especially with history of increasing dose instead
of tapering
History of “doctor shopping” as evidenced by multiple providers listed in prescription
monitoring database
History of emergency room visits for prescriptions
Concurrent substance misuse
Patient initially reporting improvement in anxiety symptoms and at a later date seeking to
increase dose for anxiety
Patient reporting lost or stolen prescriptions >1 time
Patient refusal to accept alternative non-benzodiazepine treatments (e.g., buspirone, pregabalin,
antidepressant, hydroxyzine, CBT) for anxiety
Conclusion
Sedative-, hypnotic, and anxiolytic-related disorders can develop in a variety of

individuals, including those taking them at therapeutic doses for anxiety or phobia
disorders, as well as those seeking them for different motives, such as mood
enhancement or to mitigate unwanted side effects from other substance misuse. The
withdrawal symptoms are often experienced as unpleasant if not intolerable, and a
monitored discontinuation protocol is the optimal management for long-term suc-
cess in overcoming a use disorder. Individuals taking these agents must be educated
about the signs of dependence and symptoms of withdrawal prior to initiating their
use. If the medications are prescribed at reasonable doses for limited periods of
time, sedative hypnotics can be used safely and effectively to treat severe anxiety,
panic, and phobia disorders.
Key Points
• For individuals prescribed with benzodiazepines, the continued need for these
medications should be reassessed on a regular basis.
• Benzodiazepine withdrawal can be inadvertently initiated by a physician due to
concerns of misuse, dependence, or co-occurring substance use disorders.
• For discontinuation of benzodiazepines, the consensus is a slow taper over a
period of 4–12 weeks, largely dependent upon the individual’s ability to tolerate
dose reduction.
• Clinicians should discuss the risks in prescribing sedative hypnotics, such as
dependence and withdrawal, and counsel individuals about benzodiazepines’
potentially lethal interactions with other substances such as opioids and alcohol.
90 E. Dumas
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Stimulant-Related Disorders
9
Matthew Boyer
Introduction
The substances of abuse in stimulant-related disorders include cocaine, methamphet-

amine, amphetamines, and synthetic cathinones. Users enjoy stimulants because of
the effects of euphoria, increased energy, and elevated libido stimulants can bring
about. The stimulant withdrawal syndrome, known as a crash, can be marked by dys-
phoria and hypersomnia. For many users, withdrawal can be unpleasant enough to
trigger cravings for continued use of stimulants. Cravings, in turn, can lead to repeated
use of stimulants, paving the way to development of a stimulant-related disorder.
Data from a national survey in the United States show that about 977,000 people
aged 12 or older met criteria in 2018 for cocaine use disorder [1]. More people use
cocaine than any other illegal drug in the United States aside from cannabis, with an
additional four million people using cocaine in the past year but not meeting criteria
for a use disorder [2]. Prevalence of cocaine use is highest among white men in their
20s, those who were previously married, those unemployed, those living in nonrural
areas, and those who did not complete high school [3].
About 1.1 million people aged 12 or older met criteria in 2018 for methamphet-
amine use disorder [1]. It has been reported that 4.7 million Americans have tried
methamphetamine at some point in their lives [4]. Men have been found to have a
higher three-year prevalence rate than women [5]. In the United States, rates of
methamphetamine use have historically been highest in the western and mid-west-
ern regions [6].
About 561,000 people aged 12 or older met criteria in 2018 for prescription
stimulant use disorder [1]. Amphetamines are prescribed for several conditions,
including attention-deficit/hyperactivity disorder, narcolepsy, and weight loss.
Diversion of prescribed amphetamines can contribute to misuse and abuse of
M. Boyer (*)
Psychiatrist, Rogers Behavioral Health, Philadelphia, PA, USA
e-mail: matthew.boyer@rogersbh.org

https://doi.org/10.1007/978-3-030-86430-9_9
92 M. Boyer
amphetamines. An estimated 5.3 million people in the United States had misused

prescription stimulants within the preceding year [2]. Measures have been taken to
create long-acting formulations of prescribed stimulants to lower their potential
for abuse.
Use of synthetic cathinones (bath salts) is much lower in prevalence compared to
that of the other three types of stimulants.
Patients with stimulant-related disorders can present for care in the outpatient
setting or be admitted to an inpatient unit for treatment. For example, patients can
present to ambulatory substance abuse clinics on their own volition, with encour-
agement from loved ones, or be referred there by the courts. Patients with stimulant-
related disorders can also present to emergency departments and then be admitted
to inpatient units. For example, during the intoxication phase, some stimulant users
can become aggressive or experience psychosis characterized by paranoid ideation
and auditory hallucinations. During the withdrawal phase, dysphoria can be so pro-
found that some stimulant users present to emergency departments with suicidal
ideation. In the case described next, emergency medical services were activated for
a patient expressing homicidal ideation while intoxicated on methamphetamine.
Clinical Case
Simon is a 30-year-old man who has sex with men and has no prior psychiatric his-
tory. Emergency medical services transported Simon from his home to the emer-
gency department after his roommate called 911 to report that Simon was making
homicidal comments.
Upon entering the patient’s room in the emergency department, Simon is
observed to be talking to himself. On interview, the patient describes a scheme
whereby his neighbor has hacked his webcam to intercept private masturbation vid-
eos he shares on a group sex website. Simon says there is evidence to support the
notion that he’s been hacked. For example, he notices delays when he livestreams
his videos. Sometimes, he says, the videos fail to stream altogether. He reports that
his neighbor is using a “data beam” she has aimed through his window into his
apartment in order to intercept his videos. The patient reports hearing his neighbor
speaking to him at the time of the interview.
Collateral is obtained from the roommate who called 911. The roommate says
that the patient has been fixated on a window in the patient’s room at home. The
roommate recalls that Simon first put up tin foil to cover the window for no apparent
reason. He then moved a heavy bookshelf in front of the window to block the win-
dow altogether. Asked what happened that the roommate decided to call 911, the
roommate says the patient started repeating “I’m going to kill her” and was pacing
anxiously in their small apartment. The roommate states that the patient in recent
weeks has been smoking increasing amounts of “tina,” not sleeping, and
hardly eating.
On mental status exam, the patient is malnourished, and his hair is unkempt.
Thought content is notable for delusions of persecution. Perceptual disturbances are
9 Stimulant-Related Disorders 93
present, notably auditory hallucinations. The patient’s speech is rapid but interrupt-
ible, and his thought process is linear. He is alert and grossly oriented. On workup,
labs and electrocardiogram (EKG) are unremarkable. Simon’s urine toxicology is
positive for methamphetamine when the results came back a short time later.
The treating physician suspects a stimulant-related disorder based on the pre-
senting history and objective findings. Given the severity of Simon’s psychosis,
Simon is admitted to the inpatient psychiatric service. Provided below is additional
discussion about Simon’s case and treatment.
Discussion
Simon is having auditory hallucinations and delusions of persecution in the setting

of increased use of methamphetamine. His psychosis is most likely substance-
induced. Also on the differential is a psychotic disorder such as schizophrenia.
Psychosis in the setting of stimulant abuse can present a diagnostic challenge;
stimulant-induced psychosis is sometimes misdiagnosed as schizophrenia [7].
Diagnostic ambiguity can be compounded by the fact that some individuals with
chronic psychotic disorders also have stimulant use disorders. In this case, how-
ever, schizophrenia is less likely than methamphetamine-induced psychosis
because of the relatively acute onset of symptoms in a patient with no known prior
history of psychotic symptoms. Additional features of the case making schizophre-
nia less likely are the patient’s linear thought process and the absence of negative
symptoms.
Episodes of methamphetamine-induced psychosis typically are short-lived,
although for some, episodes have been known to last six months or longer [8]. Even
though they were not present in Simon’s presentation, tactile hallucinations are
common in stimulant-induced psychosis, especially formication (the sensation that
insects are crawling under or on one’s skin). When patients present in the intoxica-
tion phase, stimulant users typically have intact orientation.
Workup should include urine toxicology to evaluate for other potential sub-
stances of abuse. Labs should be ordered to rule out possible medical explanations
for the patient’s presentation, such as hyperthyroidism or hypoglycemia. Workup
should also include EKG due to risk for cardiac arrhythmias. Physical exam should
include evaluation of injection sites for signs of infection if patients are using
intravenously.
Aside from methamphetamine-induced psychosis, the patient also meets criteria
for methamphetamine use disorder based on additional history gathered from the
patient during his hospitalization. For example, Simon later reported problematic
use of methamphetamine for the previous two years. His problematic use had been
marked by an inability to cut back on his use of methamphetamine, having cravings
to use methamphetamine, losing two jobs in the catering industry due to his meth-
amphetamine use, and experiencing both tolerance and withdrawal. He also admit-
ted that his use in recent months had escalated from smoking methamphetamine to
injecting it and to using more than he had intended.
94 M. Boyer
Table 9.1 Stimulants and their street names, routes of administration, and effects of intoxication
and withdrawal
StreetRoutes of
Substance names administration Intoxication Withdrawal
Cocaine Coke, Intranasal, Euphoria, increased Dysphoria, anhedonia,
snow, smoking, energy, heightened fatigue, poor
blow injection, alertness, increased concentration,
suppository sociability, hypersomnolence,
Methamphetamine Crystal, Oral, decreased need for increased dreaming,
tina, ice, intranasal, sleep, poor appetite. increased appetite,
speed smoking, The intoxication arthralgias, chills,
injection phase can also tremors, and involuntary
Amphetamine Addys, Oral, intranasal include unwanted motor movements
smart effects such as
pills anxiety, irritability,
Synthetic Bath Oral, hypervigilance,
cathinones salts, intranasal, suspiciousness,
cloud smoking, grandiosity,
nine, injecting stereotyped
vanilla behaviors, delusions,
sky and hallucinations
The substance of methamphetamine itself can take on the physical appearance of

shards of glass. Hence, it is commonly referred to as crystal meth. It is also known
on the street as “speed,” “ice,” “crank,” “glass,” or “tina.” Methamphetamine and
other stimulants have sympathomimetic effects. The increase in catecholamine neu-
rotransmitter activity has downstream physical effects, including tachycardia,
tachypnea, hyperthermia, hypertension, and anorexia. Psychiatrically, patients can
experience anxiety, insomnia, or, as seen in Simon’s case, psychosis. Withdrawal
from stimulants can include dysphoria, increased appetite, and hypersomnia. See
Table 9.1.
In light of the struggles he has been experiencing personally and professionally
now culminating in a hospitalization for psychosis, Simon could benefit from a
number of available pharmacologic and nonpharmacologic treatment options.
Treatment
While on the inpatient unit, Simon was started on risperidone, and the dose was
titrated to 2 mg at nighttime. Simon’s symptoms of psychosis resolved quickly.
Because of some evidence demonstrating that mirtazapine can be helpful in patients
with methamphetamine use disorder, the patient was started on mirtazapine on an
off-label basis and titrated to a nighttime dose of 30 mg. The patient reported toler-
ating both risperidone and mirtazapine well. Inpatient treatment lasted for six days.
The patient’s social worker lined up an intake appointment for the patient at the
treating hospital’s affiliated chemical dependency outpatient clinic. Unfortunately,
he did not present for that appointment. When contacted by telephone for
post-hospitalization tracking, the patient stated he was no longer taking either the
risperidone or the mirtazapine. He said he had returned to using methamphetamine,
albeit reportedly in doses smaller than he had previously been using. He declined
re-referral to outpatient substance treatment.
When treating patients with stimulant-related disorders, it is important to iden-
tify goals of treatment. Reduction or elimination of psychotic symptoms, return to
school or re-entry into the workforce, maintaining abstinence from any stimulant
use, and merely cutting back on stimulant use are goals worth discussing with
patients.
In Simon’s case, had he followed up with outpatient care, the treating psychia-
trist would have needed to talk to him about the use of the antipsychotic. Long-term
treatment with an antipsychotic is not required in cases of methamphetamine-
induced psychosis if the symptoms of psychosis remit. An antipsychotic should
only be prescribed to a patient with methamphetamine-induced psychosis who is
still experiencing psychosis or who has had less than 3–6 months of stability on the
antipsychotic. If the patient is psychiatrically stable after six months of use of an
antipsychotic, the psychiatrist should consider tapering off the antipsychotic with
continued close monitoring of the patient. Long-term treatment with an antipsy-
chotic in resolved methamphetamine-induced psychosis is not indicated.
Unlike tobacco, opioid, and alcohol use disorders for which treatment options
include FDA-approved medications, there is no FDA-approved medication for
treatment of stimulant-related disorders. Simon was started on mirtazapine on an
off-label basis. The rationale for prescribing mirtazapine was based on a study
showing that men who have sex with men (MSM) prescribed mirtazapine had
decreased use of methamphetamine [9]. The number needed to treat was 3.1. An
expanded replication trial showed that the addition of mirtazapine in methamphet-
amine users reduced methamphetamine use as well as some human immunodefi-
ciency virus (HIV) risk [10]. Another study has shown that more patients with
methamphetamine use disorder responded to the combination of extended-release
injectable naltrexone plus oral extended-release bupropion than those given placebo
[11]. The number needed to treat was nine. Regarding cocaine use disorder research,
the combination of extended release mixed amphetamine salts and topiramate has
been found to be efficacious in promoting abstinence among adults with cocaine use
disorder [12].
In the absence of an FDA-approved medication for stimulant-related disorders,
psychotherapeutic approaches are critical. Several psychotherapeutic modalities
have demonstrated efficacy. Drug counseling consists of individual and group ses-
sions that center around topics of education and recovery. Drug counseling has dem-
onstrated efficacy in reducing cocaine use among people with cocaine use disorder
[13]. Cognitive behavioral therapy (CBT) has been shown to be efficacious in
patients with cocaine use disorder [14] and methamphetamine use disorder [15].
CBT can be used to build skills helpful in maintaining abstinence [16]. See Table 9.2
for a sample of coping skills useful in the management of cravings for substances.
Because of the link between stimulant-related disorders and high-risk sexual
96 M. Boyer
Table 9.2 A sample of coping skills useful in the management of cravings for substances
Skill Comment
Urge surfing [22] Cravings peak and then pass. Patients practice imagining themselves
surfing on a large wave
Distraction [23] Patients identify activities (especially physical activities) to engage in
to distract them from intense urges to use
Recall of negative Patients practice asking themselves, “How do I feel the day after
consequences [23] using?” “What effect does using have on my relationships?”
Talking about craving Sharing the burden of cravings with a confidant or sponsor can offer
[23] relief. Patients can call an anonymous helpline (1-800-622-HELP) if a
supportive contact is not available
Using self-talk [23] Using positive rather than negative self-talk to challenge automatic
thoughts about cravings and the perceived urgency to use
Normalize [23] Patients practice recognizing that cravings are uncomfortable, expected,
and can be experienced without resorting to use
Table 9.3 Motivational interviewing [24] concepts and examples of questions

Concept Examples of possible questions
Open-ended “Tell me about your use of crystal meth.”
questions “What are the benefits of using cocaine?”
Affirmations “I see how hard you’re working at cutting back.”
“You’re demonstrating good insight about your triggers to use.”
Reflections “You sense there may be a connection between your moods and your use of
cocaine.”
“You’ve noticed more conflict with your partner when you exceed the
prescribed dose of your stimulant medication.”
Summary “Let me make sure I understand. You just explained how.…”
statements
behavior in MSM, some treatment programs include a concurrent focus on address-

ing high-risk sexual behaviors.
Other interventions include contingency management and aerobic exercise.
Contingency management has demonstrated efficacy among patients with stimulant-
related disorders in maintaining abstinence from stimulants [17]. Contingency man-
agement is a behavioral intervention used to augment other psychotherapeutic
interventions. It relies on rewards to incentivize attainment of treatment goals.
Voucher reinforcement and intermittent prize reinforcement are two strategies used
in contingency management. Data also support implementing a program of aerobic
exercise in patients with methamphetamine use disorder [18].
Employment of the tenets of motivational interviewing when speaking to patients
with stimulant-related disorders is helpful. Maintenance of a non-judgmental stance
with patients who abuse stimulants can build an alliance and foster openness. A
strong alliance and openness may be features of treatment especially important to
patients who experience shame or face stigma. When gathering a history, it can be
helpful to normalize behaviors. For example, you might try asking the following,
“Some people enjoy crystal meth because it is known to enhance sexual experiences.
I am curious to understand the ways crystal meth affects your sex life.” Also ask
about other substances with which stimulant users may be inclined to experiment or
abuse, including gamma-hydroxybutyrate (GHB), 3,4-methylenedioxymethamphet-
amine (MDMA), and ketamine. Use the principles of motivational interviewing. See
Table 9.3 for motivational interviewing concepts and examples.
Harm reduction is an important strategy to employ in patients with stimulant-
related disorders for at least two reasons. First, relapse is common. In the case of
methamphetamine use disorder, the relapse rate is 61% within the first 12 months
[19]. The second reason that harm reduction is important in stimulant-related disor-
ders is that stimulants in high doses can be cardiotoxic. Harm reduction can help to
mitigate risks from relapse. In keeping with a harm-reduction approach, try to ask
patients presenting with stimulant-related disorders about sex work, condomless
sex, routine screening for sexually transmitted illnesses (STIs), and pre-exposure
prophylaxis (PrEP) to decrease the risk for HIV. Patients should be referred for STI
screening along with screening for PrEP (or post-exposure prophylaxis, if indi-
cated). Speedballing, the practice of combining a stimulant with an opioid, puts
patients with stimulant-related disorders at risk for opioid overdoses. For this rea-
son, it is appropriate to educate patients with stimulant-related disorders about the
use of naloxone and to prescribe naloxone as a harm-reduction measure.
Some patients diagnosed with stimulant-related disorders suffer from comorbid
psychiatric illness. For example, among patients with methamphetamine use disor-
der, 16% have a comorbid mood disorder and 7% have a comorbid anxiety disorder
[20]. A tenet of treatment of stimulant-related disorders – and of substance use dis-
orders more broadly – is to optimize treatment of any comorbid psychiatric disor-
ders. Providers should also be careful to consider the role of early-life trauma.
Early-life trauma has been shown to affect treatment success in methamphetamine
use disorder [21].
Finally, support services are available. The Substance Abuse and Mental Health
Services Administration (SAMHSA) operates a national helpline for people inter-
ested in referrals for substance treatment. The number is 1-800-662-HELP. Crystal
Meth Anonymous is a 12-step recovery program. It runs a 24-hour helpline at
1-855-Meth-Free (1-855-638-4373). The organization’s website (https://www.crys-
talmeth.org/) has a map feature to help patients find local meetings. Cocaine
Anonymous is another option for patients with stimulant-related disorders.
Conclusion
The substances of abuse in stimulant-related disorders include cocaine, metham-

phetamine, amphetamines, and synthetic cathinones. Mental health workers aware
of patients abusing stimulants should assess whether patients meet criteria for a
stimulant-related disorder and screen for abuse of other substances. Although there
is no FDA-approved medication for stimulant-related disorders, there is some
evidence to support the use of certain medications and of psychotherapeutic inter-
ventions. Relapse rates are high.
98 M. Boyer
Key Points
• Motivational interviewing is a psychotherapeutic technique that can be used to

target ambivalence and assess readiness for change in patients with stimulant-
related disorders.
• Be sure to screen for use of other substances in patients who abuse stimulants.
• Use harm-reduction techniques.
• Optimize treatment of psychiatric comorbidities.
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Nicotine Dependence and Tobacco Use
Disorder Treatment 10
Noel Carrillo
According to the 2013–2014 National Adult Tobacco Survey (NATS), the preva-
lence of tobacco use in the United States during that time was 21.3% of adults age
18 and over [1]. About 17% of US adults consumed tobacco via cigarette smoking,
which delivers a high amount of nicotine to the brain and the rest of the body [11].
Even though the prevalence of tobacco use and smoking has decreased compared to
prior decades, millions of people who are actively smoking will eventually develop
medical complications as a result of it. More recently, electronic cigarettes or
e-cigarettes have skyrocketed in popularity, introducing a new vehicle for nicotine
addiction, raising the specter of a reversal in decades-long efforts to reduce nicotine
use, and creating a host of uncertain health effects for users given the paucity of
available longitudinal evidence. In an effort to combat tobacco and nicotine addic-
tion, many pharmacological treatments have been developed to treat tobacco use
disorder and help facilitate smoking cessation. In this chapter, we will discuss the
current treatment options available for tobacco use disorder and smoking cessation
by incorporating clinical vignettes and highlighting research data that supports
these treatments.
Aside from cigarette smoking, tobacco and nicotine can come in various other
forms including cigars, pipes, water pipes (hookah), electronic cigarettes (e-cigs),
and formulations developed for chewing, dipping, or snuffing [18]. However, smok-
ing still remains the most popular method of nicotine consumption at this time.
E-cigarettes and vaping have rapidly gained popularity since their appearance on
the market more than a decade ago. According to the 2011–2018 National Youth
Tobacco Survey (NYTS), e-cigarette use increased among high school students
from 1.5% in 2011 to 20.8% in 2018 [4]. E-cigarettes are also regularly used as a
smoking cessation tool, with some emerging evidence confirming that this can lead
to prolonged abstinence from cigarettes for some [15]. Despite the rise in
N. Carrillo (*)
PGY-3 Psychiatry Resident, New York Presbyterian/Weill Cornell, New York, NY, USA
e-mail: noc9036@nyp.org
https://doi.org/10.1007/978-3-030-86430-9_10
102 N. Carrillo
e-cigarettes’ popularity and popular conceptions of vaping as a harm reduction

strategy, health and safety data remain limited. E-cigarettes create known exposure
to a number of other toxic compounds [19].
Regardless of the formulation, all tobacco-related products have nicotine, which
is a naturally produced alkaloid found in the tobacco plant that acts as an agonist in
the nicotinic cholinergic receptors of the autonomic ganglia and other areas of the
central nervous system [18]. The effects of nicotine are dose-dependent and medi-
ated by the release of several neurotransmitters including acetylcholine, beta-
endorphins, dopamine, norepinephrine, serotonin, and adrenocorticotropic hormone
(ACTH). Stimulant effects of nicotine can include both vascular effects – such as
peripheral vasoconstriction, hypertension, tachycardia, and increased cardiac out-
put – and cognitive effects including increased alertness and insomnia. Nicotine
also produces depressant effects, such as muscle relaxation and anxiety reduction.
Withdrawal symptoms of nicotine include anxiety, poor concentration, irritability,
and cravings for tobacco.
In addition to its short-term effects, nicotine has long-term effects associated
with poor health outcomes, related to its delivery by tobacco products [18, 21].
About 400,000 people in the United States die prematurely as a result of smoking,
which accounts for about one of every five deaths in the United States. Free radicals
found in cigarettes and other tobacco products cause oxidative stress, inflammation,
and DNA damage to the human body across multiple organ systems. The most com-
mon types of cancer associated with smoking include lung, head, neck, gastrointes-
tinal, and cervical malignancies. Smoking also causes cardiovascular conditions
including coronary artery disease, stroke, aortic aneurysms, and peripheral arterial
disease, prompted by chemical products found in cigarettes that cause endothelial
dysfunction, changes in lipid metabolism, increased myocardial oxygen demand,
and prothrombic effects. Lung diseases, such as chronic obstructive pulmonary dis-
ease (COPD), are also commonly associated with smoking. When smoke enters the
lungs, it causes inflammation, cilia destruction, and mucous gland hyperplasia
resulting in pulmonary pathology. The reproductive system is also affected by
smoking in both men and women. In pregnant women, smoking can lead to low
birth weight, premature birth, ectopic pregnancy, teratogenic effects, and sudden
infant death syndrome, while in men it causes erectile dysfunction. Additional
effects from smoking include impaired immune functioning, increased infection
risk, peptic ulcers, bone fractures, and diabetes-related complications.
The prevalence of tobacco use differs among various subgroups, reflecting both
historical consumption patterns and socioeconomic and racial disparities. In 2015,
the prevalence of cigarette smoking was 16.7% in men and 13.6% in women;
decades ago many more men than women smoked, but this gap by sex has been
gradually closing [14]. Smoking rates also differ by race, with American Indian/
Alaska Natives having the highest prevalence of 21.9% and Asians having the low-
est at 7.0%. Increased rates of smoking have been consistently noted in
10 Nicotine Dependence and Tobacco Use Disorder Treatment 103
communities with lower incomes, lower education levels, and higher unemploy-
ment, among many other socioeconomic correlates [10]. Those with mental illness
or other substance use disorders have higher rates of cigarette smoking compared to
the general population.
Due to addictive properties of nicotine, many individuals who smoke or consume
tobacco, eventually develop tobacco use disorder. According to [5], in order to meet
criteria for tobacco use disorder, a person must have a problematic pattern of tobacco
use that leads to clinical impairment or distress within a 12-month period. The per-
son must meet at least two criteria that are listed under that definition. Please see
Table 10.1 for criteria listed by the DSM-5.
In terms of treatment, there are both pharmacologic and non-pharmacologic
approaches to tobacco use disorder and smoking cessation. Most of the discussion
of the rest of this chapter will focus on the evidence-based medication treatments
currently available, which include nicotine replacement therapy (NRT), varenicline
(also known as Chantix), and bupropion (also known as Wellbutrin). Please see
Table 10.2 for a list of the medications as well as common doses for smoking cessa-
tion [21]. The following clinical cases will illustrate practical approaches to using
these medications.
Table 10.1 DSM-5 criteria for tobacco use disorder

A. A problematic pattern of tobacco use leading to clinically significant impairment or distress,
as manifested by at least two of the following, occurring within a 12-month period:
1. Tobacco is often taken in larger amounts or over a longer period than was intended
2. There is a persistent desire or unsuccessful efforts to cut down or control tobacco use
3. A great deal of time is spent in activities necessary to obtain or use tobacco
4. Craving, or a strong desire or urge to use tobacco
5. Recurrent tobacco use resulting in a failure to fulfill major role obligations at work,
school, or home
6. Continued tobacco use despite having persistent or recurrent social or interpersonal
problems caused or exacerbated by the effects of tobacco (e.g., arguments with others
about tobacco use)
7. Important social, occupational, or recreational activities are given up or reduced because
of tobacco use
8. Recurrent tobacco use in situations in which it is physically hazardous (e.g., smoking in
bed)
9. Tobacco use is continued despite knowledge of having a persistent or recurrent physical
or psychological problem that is likely to have been caused or exacerbated by tobacco
10. Tolerance, as defined by either of the following:
(a). A need for markedly increased amounts of tobacco to achieve the desired effect
(b) A markedly diminished effect with continued use of the same amount of tobacco
11. Withdrawal, as manifested by either of the following:
(a) The characteristic withdrawal syndrome for tobacco (refer to Criteria A and B of the
criteria set for tobacco withdrawal)
(b) Tobacco (or a closely related substance, such as nicotine) is taken to relieve or avoid
withdrawal symptoms
104 N. Carrillo
Table 10.2 Psychopharmacology of tobacco use disorders and dosing

Name of medication Dosing
Varenicline (Chantix) Dosing: 0.5 mg, 1 mg
Frequency: 0.5 mg daily for days 1–3, then twice a day for days 4–7,
then 1 mg twice a day starting day 8 and thereafter
Note: start 1 week before quit date
Bupropion (Wellbutrin, Dosing: 150 mg of the sustained-release formulation
Zyban) Frequency: daily for days 1–3, then twice a day starting day 4 and
thereafter
Note: start 1 week before quit date
Nicotine replacement Transdermal patch:
therapies Doses: 7 mg, 14 mg, 21 mg
Frequency: every 24 hours
gum:
Doses: 2 mg, 4 mg
Frequency: every 1–2 h
Lozenge:
Doses: 2 mg, 4 mg
Sublingual tablet:
Doses: 2 mg, 4 mg
Inhalation:
Doses: 1 cartridge
Frequency: continuously every 20 minutes but no more than 16
cartridges/day
Nasal spray:
Doses: 1 mg per dose (2 sprays)
Frequency: 1–2 doses per hour
Clinical Cases
Dr. Ramos recently completed residency in psychiatry and started an addiction psy-
chiatry fellowship. During her first week as a fellow, she discusses three cases with
her attending related to tobacco use disorder and her proposed treatments. Her first
case, Jonathan, is a 39-year-old man with a history of anxiety, who has never seen a
therapist before and has never taken medication in the past because of “trouble
swallowing pills.” Jonathan reports that he has been smoking about two packs a day
and is interested in quitting. He is willing to try “anything,” including therapy and
medication.
Her next case is Xavier, a 65-year-old-man with a history of depression, previ-
ously on SSRIs but stopped due to sexual side effects. Lately he has been feeling
more depressed with low energy, increased sleep, and weight gain. He attributes his
low mood to the fact that he has failed to quit smoking in the past but is thinking of
attempting to quit again. He has been smoking a pack of cigarettes a day almost
every day for the last 20 years. He reports wanting to quit because recently he was
diagnosed with coronary artery disease and hypertension. Xavier is now interested
in medication that can help him in both smoking cessation and his depression.
Dr. Ramos’s final patient is Nataly, a 20-year-old woman with a history of an

eating disorder in the past and seizures. She began smoking half a pack of cigarettes
a day two years ago when she turned 18 and started college. She has attempted to
quit in the past by using nicotine gum and patch, but her attempts were unsuccess-
ful. Lately, she has been vaping and using e-cigarettes, which help to reduce her
cravings but at times she continues to smoke cigarettes, especially during her final
examinations. Nataly is interested in trying another medication to help her quit
before next month when school starts again.
Discussion
Dr. Ramos’s patients are presenting with nicotine dependence and would benefit
from treatment. Each of the available treatments has strengths and weaknesses,
detailed in Table 10.3 [21, 24]. For each of these cases, there are specific factors in
the history and presentation of these patients that might persuade a provider to
choose one medication over another. For the rest of the chapter, we will discuss the
current treatments available for tobacco use disorder and why Dr. Ramos might
choose that particular treatment over the others.
Non-pharmacological Intervention
In our first case, Jonathan is interested in both therapy and medication. After a per-
son stops smoking, there are many psychological factors that can lead someone to
relapse including intermittent negative thoughts and emotions, multiple urges to
smoke, decreased motivation, and self-efficacy about quitting. Therefore, there are
a variety of interventions that have been shown to be effective in helping to prevent
relapse of smoking and tobacco use [21]. Some of these non-pharmaceutical inter-
ventions include cognitive behavioral therapy (CBT), motivational interviewing,
and acceptance and commitment therapy. These therapies can be individual or group
based and vary in intensity. Nicotine Anonymous is another option, with hundreds
of 12-step meetings available worldwide. They can also vary by mode of delivery,
which can include delivery by a clinician, counselor, telephone, or computer. Most
research supports their efficacy in increasing smoking cessation rates, but data com-
paring each of these modes is limited. However, data does show that effectiveness is
dose-responsive, so higher amounts of exposure to these behavioral strategies yield
longer periods of sustained cessation.
Nicotine Replacement Treatment
Another option for Jonathan is nicotine replacement therapy (NRT), which helps by
reducing nicotine cravings in those that smoke or use tobacco. NRT comes in five
forms including a transdermal patch, gum, lozenge, nasal spray, and inhaler [22].
106 N. Carrillo
Table 10.3 Comparison of different treatments in smoking cessation

Intervention Advantages Disadvantages
Psychosocial treatment only Can address psychological Does not address biological
factors and motivation to
(brief provider interventions, dependence, cravings, or
individual psychological quit withdrawal symptoms
interventions, telephone Brief interventions still Less intensive interventions
support, Nicotine effective shown to be less effective
Anonymous, etc.) Maximizes social support
to help patient quit
More effective than
self-help
Nicotine replacement therapy Low cost More frequent dosing for
Different formulations short-acting forms
chosen based on patient Irritation of the skin, mouth, or
preference nose depending on formulation
Has both short-acting and used
long-acting forms, which Less effective than varenicline
can help with withdrawal
and craving symptoms
Mimics hand to mouth
ritual
Few side effects
Bupropion Simple twice a day dosing Adverse effects can include
No weight gain insomnia, anxiety, dry mouth
Can help with depression Contraindicated in patients with
Can be combined with history of eating disorder or
NRT seizures or concurrent use of
monoamine oxidase inhibitors
(MAOIs)
Must monitor neuropsychiatric
symptoms
Less effective than varenicline
Varenicline Simple dosing of twice a Adverse effects include nausea,
day vomiting, constipation, sleep
Different mechanism of disturbances
action for patient who have Must monitor neuropsychiatric
failed other treatments symptoms
Most effective treatment Limited data suggests
cardiovascular effects
This is particularly convenient for someone like Jonathan, who doesn’t like “swal-
lowing pills.” These formulations work by providing nicotine without the other haz-
ardous chemicals found in cigarettes or tobacco. NRT provides lower doses of
nicotine that normally last longer than nicotine found in cigarettes or tobacco. The
nicotine patch provides the longest release of nicotine [22].
All forms of NRT increase rate of quitting by 50–60%, and efficacy is compa-
rable among the different formulations [9]. However, based on research, combining
the long-acting nicotine patch with a short-acting form is more effective than a
single NRT agent. A Cochrane meta-analysis found that this combined approach
made quitting 15–36% more likely. [16]. Therefore, Dr. Ramos may want to
prescribe Jonathan a long-acting patch with a short-acting form, such as nicotine

gum, in hopes that this will be more effective in helping Jonathan quit smoking.
In general, NRT has a low side effect profile, including heart palpitations and
chest pains, nausea and vomiting, insomnia, as well as irritation of the mouth and
skin depending on route of administration [17]. Therefore, NRT is the safest phar-
macological treatment to prescribe, particularly since most individuals prescribed
NRT will already be habituated to these physiologic effects of nicotine.
Bupropion
Bupropion is an effective medication for smoking cessation and tobacco use disor-
der that is also a treatment for depression [8]. Therefore, Xavier might benefit from
this medication as it would help both with his tobacco use disorder and his mood.
The mechanism of this drug related to smoking cessation is not totally clear [23].
When nicotine crosses the blood-brain barrier, it causes a release of dopamine into
the synaptic cleft of the dopaminergic, pleasure-seeking pathways of the brain.
Similarly, bupropion blocks the reuptake of dopamine. Additionally, it is thought
that dopamine deficiency in the nucleus accumbens leads to nicotine withdrawal
when smoking is stopped. Therefore, bupropion might increase dopamine in the
nucleus accumbens, which leads to attenuation of nicotine withdrawal symptoms.
Bupropion is also a noncompetitive blocker of the postsynaptic acetylcholine nico-
tine receptor, which stops the reinforcing effect of nicotine use [23].
Bupropion appears to be an effective treatment of tobacco use disorder. A meta-
analysis of 65 RCTs found that bupropion as a monotherapy significantly increased
long-term cessation of 6 months or greater (RR = 1.62; 95% CI, 1.49–1.76) relative
to placebo, which was comparable to NRT (RR = 0.96; 95% CI, 0.85–1.09) [13]. A
Cochrane meta-analysis also found that both bupropion and NRT are comparable in
efficacy [3].
Bupropion’s most common side effects include headache, insomnia, dry mouth,
and agitation [12]. However, one of the most notable adverse effects is seizures [12].
The risk of seizures depends both on dose and on preparation. The higher the dose,
the higher the risk of developing seizures. Additionally, the sustained-release for-
mulation has a lower risk of seizures compared to the immediate-release formula-
tion. Therefore, seizure disorder is a major contraindication to use, as well as any
other factors that predispose someone to seizures including discontinuation of alco-
hol or sedatives, arteriovenous malformations, severe headache injury, stroke, brain
tumor, or any other significant central nervous system disease. Bupropion should
also not be used in someone with a history of an eating disorder or bipolar disorder
or who is on monoamine oxidase inhibitors [12]. Therefore bupropion would not be
an appropriate medication to use in someone like Nataly, who has a history of an
eating disorder and seizures.
The FDA requires all antidepressants to carry a boxed warning that antidepres-
sants can increase risk of suicide in those under 25 years of age, including bupro-
pion. However, suicidal behavior is less of a concern in smoking cessation. In
108 N. Carrillo
December 2016, data from a large clinical trial convinced the FDA that serious
mood and suicidal behaviors were not as severe as previously thought of and the
FDA removed the black box warning for smoking cessation [19]. The report still
advises to use with caution and to monitor behavioral symptoms, especially in
patients with co-occurring mood or psychotic disorders.
Varenicline
Another medication option for tobacco use disorder is varenicline, which may be an
ideal option for Nataly. This drug works as a partial agonist of the alpha-4-beta-2
nicotinic acetylcholine receptor subtype (nACh) [20]. When the drug attaches to the
receptor, it produces less effect of dopamine release than it would with nicotine.
This leads to decreased nicotine addiction, and it also decreases the cravings and
withdrawal syndrome associated with cessation of tobacco use.
Varenicline appears to be the most effective option for tobacco use disorder. A
study assessing the effectiveness of varenicline in smokers who had no intention to
quit in the next 30 days found that 32.1% of smokers were biochemically confirmed
to have been continuously abstinent by weeks 15–24 after starting varenicline [6].
On the other hand, the placebo group only had an abstinence of 6.9% during that
time period. Additionally, by weeks 21–52 after initiation of the trial, 27% of the
varenicline group remained abstinent, compared to only 9% in the placebo group. A
Cochrane review also found that varenicline is more effective than either NRT or
bupropion [3]. The odds ratio of effectiveness compared to placebo was 1.84 (95%
CI of 1.71–1.99) for NRT, 1.82 (95% CI 1.60–2.06) for bupropion, and 2.88 (95%
CI 2.40–3.47) for varenicline.
The most common side effect of varenicline is nausea, which is seen in almost
30% of people taking it [7]. Other less common side effects include headache,
insomnia, vivid dreams, constipation, and other gastrointestinal symptoms. In 2009,
the US FDA required that varenicline carries a boxed warning that the drug should
be stopped if there were any changes in behavior. This was done in response to post-
marketing reports carried out by the FDA that found increased suicidality risk and
suicidal behavior among people using varenicline for smoking cessation. However,
many systematic reviews have been conducted that have found no increased suicide
risk or neuropsychiatric side effects. In 2016, the FDA removed the black box warn-
ing as it did for bupropion, but the FDA continues to recommend monitoring patients
for these side effects [19]. In June 2011, the US FDA also issued a safety announce-
ment about varenicline potentially causing a small increase of cardiovascular
adverse events in people with cardiovascular disease. This was based on a review
that showed increased risk of cardiovascular events in people using varenicline
compared to placebo. However, multiple reviews and meta-analyses afterward have
found no increase in cardiovascular events associated with varenicline use [6].
Given that Xavier already has history of cardiovascular disease, it may be prudent
to try a medication other than varenicline given possible risk of cardiovascu-
lar events.
A number of studies have also looked at combination therapies combining vare-

nicline with other smoking cessation medications [2]. A study showed higher con-
tinuous abstinence in those who combined varenicline with a 15 mg nicotine patch
compared to those who were on varenicline alone. However, another study found no
difference. In another study that looked at varenicline plus bupropion, there were no
differences found between the two groups in terms of abstinence. However, a sub-
group analysis found significantly higher rates of abstinence in those who smoked
more than 20 cigarettes per day [2]. Therefore, combining varenicline with bupro-
pion might be another option for some patients.
Conclusion
Although prevalence rates for tobacco use disorder are decreasing around the world,
millions of people worldwide continue to consume tobacco and are at increased risk
of serious illness and death as a result of it. Providers must continue to discuss
tobacco and nicotine use with their patients, keeping in mind the variety of potential
nicotine delivery methods and the recent surge in popularity of e-cigarettes. A treat-
ment plan including psychosocial and/or pharmacologic interventions for tobacco
use disorder can be individually tailored to a patient’s preferences and relevant addi-
tional information in the history that might make certain options a better fit
than others.
Key Points
• Nicotine use remains a major cause of morbidity and mortality around the world,
primarily because of its delivery through harmful tobacco products.
• Tobacco use disorder is a DSM-5 diagnosis that can be made based on an indi-
vidual’s pattern of problematic tobacco use.
• Both behavioral and pharmacological interventions on their own, or in combina-
tion, can be used to treat tobacco use disorder.
• Currently, there are three medication options to help with smoking cessation:
nicotine replacement therapy, bupropion, and varenicline.
• The differences in these medications’ required frequency, side effect profiles,
contraindications, and effectiveness should all be considered when working with
a patient to craft a plan for nicotine cessation.
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Behavioral Addictions
11
Daniel Sugrue
In the past, addiction mainly referred to the recurrent compulsive and maladaptive
use of alcohol or other substances with associated functional impairment. However,
a growing body of research has shown significant overlap between substance use
disorders (SUDs) and the compulsive engagement of problematic behaviors. These
behaviors include gambling, Internet gaming, sexual behavior, eating, and shop-
ping, among others. Given this overlap, some have come to classify the recurrent
dysfunctional engagement of these behaviors as behavioral addictions. However,
debate about whether these behaviors should be recognized as actual addictive dis-
orders continues to this day [1]. Several behaviors have been shown to have signifi-
cant overlap with SUDs and have been described using the addiction model. These
include gambling disorder, Internet gaming disorder, and hypersexual disorder. This
chapter will focus on these three conditions and discuss their clinical characteris-
tics, including diagnostic criteria and prevalent psychiatric comorbidities, as well as
their potential treatment options.
Gambling disorder is the only non-substance-related disorder found in the
“Substance Related and Addictive Disorders” section in the Fifth Edition of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-5). This categoriza-
tion is different from the previous DSM-IV, in which the American Psychiatric
Association (APA) had recognized disordered gambling, previously known as path-
ological gambling, as an impulse-control disorder. This alteration not only rein-
forced the similarities between gambling disorder and SUDs, but also supported the
notion that maladaptive engagement of a behavior could be classified as an addic-
tive disorder [1]. Similar to the APA, the World Health Organization (WHO) also
recognized disordered gambling as an addictive disorder in the eleventh revision of
the International Classification of Diseases (ICD-11) [2].
D. Sugrue (*)
General Adult Psychiatry Resident, Weill Cornell Medical College, New York, NY, USA
e-mail: das2045@nyp.org
https://doi.org/10.1007/978-3-030-86430-9_11
114 D. Sugrue
According to the DSM-5, patients with gambling disorder may often be preoc-
cupied with gambling, increase the amount of money they gamble to experience the
same level of excitement, try to cover up their amount of gambling from others,
gamble in response to stress or to recover previous losses, and rely on others finan-
cially to continue their gambling. Patients with the disorder may also experience
negative mood states when not gambling, risk or lose relationships or career oppor-
tunities due to gambling, and have failed to quit gambling on numerous occasions.
To meet a diagnosis of gambling disorder, one needs to exhibit at least four of the
above symptoms in a 12-month period, and their behavior cannot be attributed to a
manic episode [1, 2].
The lifetime prevalence of disordered gambling in the United States has been
found to range from 0.4% to 0.6% and has been associated with reduced quality of
life and significant patient distress. Patients with gambling disorder are more likely
to experience bankruptcy, legal trouble, marital problems, and medical ailments
such as cirrhosis and other forms of liver disease due to comorbid alcohol abuse.
Indeed, disordered gambling has been associated with a high prevalence of comor-
bid SUDs as well as comorbid mood and anxiety disorders, personality disorders,
and impulse control disorders. Between 17% and 24% of patients with gambling
disorder have reported attempting suicide because of distress tied to their gambling.
Despite the significant impairment associated with gambling disorder, however,
only about 10% of individuals seek treatment, with their motivation being often tied
to legal, financial, or interpersonal difficulties [2]. These clinical characteristics
highlight the importance of screening patients with gambling disorder for comorbid
psychiatric symptoms, as well as screening for symptoms of disordered gambling
among patients seeking help for other psychiatric symptoms. In addition, physicians
should keep in mind that patients with gambling disorder may also have other prob-
lematic behaviors, which are often linked, as in the case of gambling and Internet
gaming [3].
Gaming, similar to gambling, was recognized by the WHO as an addictive
behavior, which eventually included gaming disorder as a medical condition in the
ICD-11. In the ICD-11, this disorder is characterized by excessive gaming that is
difficult to control, persists despite negative consequences, and is associated with
functional impairment over at least a year period [4]. The APA, on the other hand,
categorized Internet gaming disorder in Section III of the DSM-5, which requires
that further research be done before the condition can be officially recognized as a
disorder. The proposed symptoms of Internet gaming disorder include a preoccupa-
tion with gaming, a loss of interest in other activities due to gaming, and an inability
to stop gaming despite negative consequences. Patients with this condition may also
try to cover up their amount of gaming from others, experience distress when not
gaming, spend increasing amounts of time gaming to achieve the same level of
excitement, game in response to stress, and jeopardize relationships or career oppor-
tunities due to gaming. In order to receive a diagnosis of Internet gaming disorder,
one needs to exhibit at least five of these symptoms in a one-year period [5].
In the midst of the controversy over whether gaming ought to be considered an
addictive behavior, an increasing number of studies have looked at the prevalence
11 Behavioral Addictions 115
rates and clinical characteristics of Internet gaming disorder. Prevalence rates have
been found to range between 1% and 10% in European and North American popula-
tions and 10% and 15% in East and Southeast Asian populations. Internet gaming
disorder is more common among males and younger individuals and has been asso-
ciated with increased social difficulties, physical aggression, and poor academic
performance. The physical well-being of individuals has also been shown to be
jeopardized in certain cases due to sleep disturbances and decreased food and fluid
intake [6]. In addition, Internet gaming disorder has been associated with SUDs and
other comorbid psychiatric disorders including mood, anxiety, and personality dis-
orders [7]. Hence, similar to the approach to gambling disorder, providers should
screen for these comorbid psychiatric symptoms in patients presenting with Internet
gaming disorder symptoms, in addition to other associated problematic behaviors,
such as hypersexual behavior.
Hypersexual disorder, a term that has been used interchangeably with hypersexu-
ality, compulsive sexual behavior disorder, and sexual addiction, was proposed for
addition to the DSM-5, with an addiction model framework. The proposed diagnos-
tic criteria included recurrent sexual thoughts, urges, and behaviors that are difficult
to control, often occur in response to negative mood states, take up excessive time,
and impair an individual’s functioning. In addition, the condition can include par-
ticipation in sexual behaviors that endanger the safety of the patient or others. These
behaviors may include cybersex, pornography use, masturbation, and sexual activ-
ity with multiple partners, among others. Furthermore, these symptoms cannot be
attributed to mania, substance abuse, or drug side effects [8]. The APA ultimately
did not recognize hypersexual disorder as an addictive disorder in the DSM-5, how-
ever, stating that more supporting evidence for its inclusion was needed. The WHO,
meanwhile, categorized hypersexual behavior as an impulse-control disorder in the
ICD-11, using the term compulsive sexual behavior disorder [8]. Despite the ongo-
ing debate over its characterization, many clinicians recognize hypersexual disorder
as an addictive disorder that can have detrimental effects on patients’ careers, per-
sonal lives, and physical health [9]. The latter may be jeopardized due to increased
risk for sexually transmitted diseases (STDs) and injury secondary to repeated inter-
course. However, despite the associated impairment, hypersexual disorder often
goes undiagnosed, and many patients don’t seek treatment until well into their 30s
(even though symptoms often start around 18 years of age) [9]. Also, similar to
gambling disorder, the motivation to seek treatment is often tied to professional or
legal troubles or related to their comorbid psychiatric disorders [9]. Given the delay
among patients in seeking treatment for their hypersexual disorder, providers ought
to screen for problematic sexual behaviors, in addition to others (i.e., gambling and
gaming), in patients presenting with other psychiatric symptoms.
Gambling disorder, Internet gaming disorder, and hypersexual disorder often
occur in individuals with other co-occurring disorders. These include SUDs,
mood and anxiety disorders, impulse-control disorders, and personality disor-
ders, among others. Table 11.1 highlights the prevalence rates of different psy-
chiatric comorbidities among patients with these problematic behaviors, based
on several epidemiological studies [9–11]. This association with other
116 D. Sugrue
Table 11.1 Prevalence rates of comorbid psychiatric disorders in behavioral addictions

Pathological gambling Internet gaming disorder Hypersexual disorder
Alcohol use disorder Anxiety (92%) Mood disorders (72%)
(73.2%)
Personality disorder Depression (89%) Other addictive disorders
(60.8%) (40–71%)
Nicotine dependence Attention-Deficit/Hyperactivity Anxiety disorders (38%)
(60.4%) Disorder (ADHD) (87%)
Mood disorder Social phobia/anxiety and obsessive ADHD (17–19%)
(49.6%) compulsive symptoms (75%)
Anxiety disorder – Personality disorders (17%)
(41.3%)
Drug use disorder – Obsessive-Compulsive
(38.1%) Disorder (OCD) (12–14%)
– – Impulse control disorders
(5–6%)
psychiatric disorders calls attention to the importance of obtaining a comprehen-

sive history from patients to not only rule out other primary causes for their
symptoms (i.e., mania, substance use), but also screen for comorbid psychiatric
diagnoses to treat [2, 9].
An increasing number of studies have examined evidence-based treatments for
gaming disorder, Internet gaming disorder, and hypersexual disorder that include
pharmacologic and psychosocial interventions. When used in combination, these
interventions have shown some promising results in improving patients’ symptoms
for these disorders. Furthermore, medications that have been able to improve these
behavioral addictions have also been able to target comorbid psychiatric symptoms
[2, 5, 9]. Treatment approaches are discussed later.
The following three clinical cases exemplify the benefit in screening patients for
symptoms of both behavioral addictions and other psychiatric disorders to inform
optimal treatment. In particular, a thorough assessment of these symptoms can
inform a provider’s medication selection to target both problematic behaviors and
comorbid psychiatric symptoms.
Clinical Cases
Dr. Jones is a psychiatry resident treating patients at his hospital’s outpatient clinic.
He is scheduled to conduct an initial evaluation of three patients who were referred
to the clinic and develop individualized treatment plans for each case.
The first patient Dr. Jones interviews is Mr. F., a 57-year-old married man,
employed as an attorney, with a family history notable for alcohol use disorder, not
currently on any medications, who presents at the behest of his wife to request help
in stopping gambling. Over the last year, he describes having gambled five nights
out of the week at the casino near his home, which he has tried to hide from his
wife and the rest of his family. He reports experiencing a persistent and intense
urge to gamble, has lost nearly all of his savings from gambling this past year, and
has had to borrow money from his brother to continue gambling. He has been
unable to stop on his own, despite multiple attempts, and has come seeking help
only after his wife threatened to divorce him if he did not seek counseling. On
screening for substance use, Dr. Jones learns that Mr. F. has a history of binge
drinking a six-pack of beer three nights out of the week for several decades, which
has increased to six nights over the past year. He denies having received any treat-
ment in the past to reduce his alcohol consumption but is open to considering
options to help curb his drinking.
The second patient Dr. Jones evaluates is Ms. C., a 20-year-old woman, cur-
rently enrolled as a junior in college, with no significant psychiatric history, who
was referred to the clinic by her academic advisor, who expressed concern about
Ms. C.’s apparent low mood, loss of interest in activities, and associated decline
in school performance over the past year. On interview, Ms. C. reports feeling
depressed for the past 2 months with associated poor sleep, energy, and appetite
and has had thoughts that life is not worth living. When asked about her interest
in activities, she reports that she had previously enjoyed spending time with
friends and participating in extracurricular activities, but that she gradually gave
these up in favor of playing an online video game. Ms. C. reports having been
introduced to the game a little over a year ago, which she initially played for
one hour each day, but has since progressed to about nine hours a day. She reports
heightened irritability and restlessness when not gaming and has kept the extent
of her gaming hidden from her family. She reports, however, that her grades have
suffered because of her gaming and is now at risk of academic probation. She
reports having tried to quit gaming multiple times, but hasn’t been successful. She
now expresses interest in receiving treatment for both her mood symptoms and
problematic gaming.
The third case of the day is Mr. R., a 31-year-old single man, currently employed
as a consultant, with a history of generalized anxiety disorder, not on medications,
who was referred to the clinic for mandated treatment after being caught masturbat-
ing to pornography at work. On interview, he expresses significant distress about his
masturbatory habits over the past couple of years, which he describes as excessive.
He reports experiencing the intense urge to masturbate throughout most of the day,
finds this urge difficult to control, and often experiences the urge more often when
under stress. When Dr. Jones asks about his anxiety, Mr. R. reports having felt anx-
ious throughout his life, including constantly feeling “on edge.” He also describes
having difficulty making simple decisions, has trouble falling asleep most nights,
and finds it difficult to concentrate. He reports being interested in receiving treat-
ment to reduce his anxiety and the frequency he masturbates and uses
pornography.
After seeing each patient, Dr. Jones reviews each case to prepare individualized
treatment plans to include medications that target both the patients’ problematic
behaviors and comorbid psychiatric symptoms.
118 D. Sugrue
Discussion of Clinical Cases
Dr. Jones’ patients presented to the clinic for various reasons, and after a thorough
assessment, he has elicited symptoms of behavioral addictions and some of their
common psychiatric comorbidities. Each of these cases illustrates the significant
interpersonal, academic, and professional problems that may occur with behavioral
addictions and the resultant personal distress. Furthermore, they highlight that the
problems associated with these conditions are often the reason patients are either
referred to treatment or seek help on their own. Given the history he obtained on the
interviews, Dr. Jones can now consider a combined approach with the available
pharmacologic and psychosocial interventions to treat each patient. In particular, he
can discuss medication options with the patients that target both their problematic
behavior and comorbid psychiatric symptoms, as discussed in the following section.
Gambling Disorder
Mr. F.’s description of his gambling behavior and the significant impairment this has
caused in his life is consistent with a diagnosis of gambling disorder. His motivation
to seek treatment due to the interpersonal difficulties his gambling disorder has
caused with his wife is also one of the common reasons patients seek treatment for
this disorder [2]. His alcohol use, combined with his family history, is also concern-
ing for alcohol use disorder, and he would likely benefit from further discussion
about his motivation to quit.
Currently, there is no medication approved by the US Food and Drug
Administration (FDA) for the treatment of gambling disorder, but research has
shown numerous medications to be effective, which is outlined in Table 11.2 [2].
With respect to this particular case, Dr. Jones may wish to consider an opioid recep-
tor antagonist, such as naltrexone or nalmefene (the latter available in Europe), to
treat both Mr. F.’s gambling disorder and alcohol use disorder [2]. An opioid antago-
nist may also lead to a better treatment outcome for this particular patient, in light
of his intense gambling urges and family history of alcohol use disorder, both of
Table 11.2 Preferred pharmacologic agents for gambling disorder based on psychiatric

comorbidities
Pharmacologic agent(s) Psychiatric comorbidities targeted
Opioid antagonists (naltrexone, Alcohol use disorder Opioid use disorder
nalmefene)
Mood stabilizers (lithium and Bipolar disorder or –
valproate) bipolar spectrum
disorders
Glutamatergic agents Nicotine dependence –
(n-acetylcysteine)
Selective serotonin reuptake Mood disorders other Anxiety disorders (generalized
inhibitors (escitalopram, paroxetine, than bipolar spectrum anxiety disorder, social anxiety
fluvoxamine) disorders disorder, etc.)
which have been associated with positive outcomes for patients on these medica-
tions [1, 2].
In his approach to other patients, Dr. Jones may wish to consider other pharma-
cotherapy that has been studied in the treatment of gambling disorder. These include
selective serotonin reuptake inhibitors (SSRIs), mood stabilizers, and glutamatergic
agents. Escitalopram, an SSRI indicated for certain mood and anxiety disorders,
may be an option for Dr. Jones to consider for patients with problematic gambling
and comorbid mood and anxiety symptoms. However, the studies of SSRIs in treat-
ing gambling disorder, in particular paroxetine and fluvoxamine, have been equivo-
cal. Meanwhile, in his approach to patients with comorbid bipolar disorder, mood
stabilizers like lithium and valproate may be beneficial. Lastly, N-acetylcysteine
(NAC), a glutamatergic agent, may be helpful for patients with gambling disorder
and concurrent tobacco use, given that NAC has been shown to improve nicotine
dependence and gambling disorder symptoms, when administered along with
behavioral treatment [2].
In addition to pharmacotherapy, Dr. Jones should discuss the available psychoso-
cial treatments for gambling disorder with Mr. F. These include Gamblers
Anonymous, cognitive behavioral therapy (CBT), and motivational interviewing,
all of which have been shown to effectively improve gambling disorder symptoms.
Given the severity of Mr. F.’s gambling, he would likely benefit from a combination
of Gamblers Anonymous and CBT, with the option of motivational interviewing.
However, if he were not willing to commit to multiple modalities, Dr. Jones can
assess his interest in engaging in at least one of them [2].
Internet Gaming Disorder
Ms. C. was initially referred for treatment of her mood symptoms, which were
thought to be associated with her decline in academic performance. However upon
further assessment, Dr. Jones elicited information about the negative impact her
problematic gaming behaviors has had, which dates back starting before her depres-
sive symptoms. After obtaining a thorough history, he suspects a diagnosis of
Internet gaming disorder with comorbid major depression, and her interest in receiv-
ing treatment gives Dr. Jones the opportunity to discuss a medication that can pos-
sibly target both issues. Bupropion is a medication that’s indicated for the treatment
of depression and has also been shown to be effective in improving Internet gaming
disorder symptoms [5]. Hence, this may be an appropriate agent to consider for Ms.
C. to improve her symptoms and her functioning. However, other medication
options are limited, given that studies of the effectiveness of medications like esci-
talopram, methylphenidate, and atomoxetine, in the treatment of Internet gaming
disorder, were not placebo controlled [5].
Similar to his treatment of gambling disorder, Dr. Jones should also discuss the
benefit of a combined treatment approach with psychosocial interventions for Ms.
C.’s Internet gaming disorder. Despite the limited studies, CBT has been shown to
improve symptoms of Internet gaming disorder when administered alone or in
120 D. Sugrue
tandem with bupropion. A combination of CBT and bupropion, in particular, was

shown to be more effective than bupropion alone and may result in a better treat-
ment outcome for Ms. C. In his approach to adolescent patients with Internet gam-
ing disorder, Dr. Jones may also wish to consider family-based treatments, which
are effective in treating SUDs in adolescents, but more research on their effective-
ness for Internet gaming disorder is needed [5].
Hypersexual Disorder
Mr. R. presents with hypersexual urges and behaviors consistent with hypersexual
disorder, as well as chronic anxiety likely secondary to his generalized anxiety dis-
order. His motivation to treat his sexual behaviors stems from the professional dif-
ficulties they have caused him, which is a common reason patients with this
condition seek help [9]. Dr. Jones can discuss the medication options listed in
Table 11.3, which have been shown to improve symptoms of both hypersexual dis-
order and common psychiatric comorbidities. In his approach to Mr. R.’s case, Dr.
Jones may wish to consider SSRIs, which are used in the treatment of several anxi-
ety disorders, including generalized anxiety disorder, and have been shown to effec-
tively reduce hypersexual disorder symptoms [9]. In particular, he may wish to offer
citalopram, which has been shown to improve masturbation frequency and pornog-
raphy use in men, and may also help with anxiety. Other SSRIs to consider that have
been shown to improve symptoms of hypersexual disorder, include fluoxetine, ser-
traline, and paroxetine. If Mr. R.’s hypersexual disorder symptoms show only partial
improvement to SSRIs, Dr. Jones may also wish to consider adding naltrexone. This
opioid antagonist may improve symptoms of hypersexual disorder when used alone
or in combination with SSRIs and may be particularly beneficial for patients with
co-occurring alcohol or opioid use disorders. Topiramate, on the other hand, which
is an antiepileptic medication, may be beneficial for patients with comorbid alcohol
use disorder, binge eating, or kleptomania. Lastly, in his approach to patients with
comorbid bipolar disorder or schizophrenia, Dr. Jones could consider mood
Table 11.3 Preferred pharmacologic agents for hypersexual disorder based on psychiatric
comorbidities
Pharmacologic agent(s) Psychiatric comorbidities targeted
Selective serotonin reuptake Mood disorders other Anxiety disorders –
inhibitors (citalopram, than bipolar spectrum (generalized anxiety
sertraline, paroxetine, disorders disorder, social anxiety
fluoxetine) disorder, etc.)
Topiramate Alcohol use disorder Binge eating Kleptomania
Mood stabilizers (lithium, Bipolar disorder or Schizophrenia –
valproate) bipolar spectrum
disorders
Antipsychotics Schizophrenia Bipolar disorder or bipolar –
spectrum disorders
Naltrexone Alcohol use disorder Opioid use disorder –
stabilizers (i.e., lithium and valproate) or antipsychotics. However, he would need

to exercise caution when choosing an antipsychotic, as certain agents such as aripip-
razole can actually induce hypersexual symptoms [9].
In addition to an appropriate pharmacologic agent, Dr. Jones should discuss with
Mr. R. the benefit of combination treatment, as discussed in the previous cases,
including either CBT, referrals for self-help groups, or both [9].
Conclusion
Controversy may continue about whether behavioral addictions should be recog-

nized as mental disorders and how to categorize them, but the clinical cases in this
chapter highlight the negative outcomes associated with these conditions when left
untreated. Given the high rates of comorbid psychiatric disorders among gaming
disorder, Internet gaming disorder, and hypersexual disorder, it is important for
mental health providers to screen for other psychiatric symptoms when assessing
patients with these conditions, as well as screen for problematic behaviors in patients
presenting with various psychiatric complaints. A thorough assessment can subse-
quently guide medication selection to target the symptoms of both the behavioral
addiction and any psychiatric comorbidities, which can be administered in tandem
with psychosocial interventions.
Key Points
• Gambling disorder, Internet gaming disorder, and hypersexual disorder can neg-
atively impact patients’ personal and professional lives, resulting in personal dis-
tress, and have been associated with high rates of comorbid psychiatric disorders.
• Combination treatment with available pharmacologic and psychosocial interven-
tions has shown promise in improving the symptoms of these conditions.
• A comprehensive assessment of patients that screens for problematic behaviors
and other psychiatric symptoms can inform the selection of optimal medications
to target both behavioral addictions and their psychiatric comorbidities.
References
1. Yau YH, Potenza MN. Gambling disorder and other behavioral addictions: recognition and
treatment. Harv Rev Psychiatry. 2015;23(2):134–46.
2. Potenza MN, Balodis IM, Derevensky J, Grant JE, Petry NM, Verdejo-Garcia A, Yip
SW. Gambling disorder. Nat Rev Dis Primers. 2019;5:51–1.
3. Ford M, Håkansson A. Problem gambling, associations with comorbid health conditions, sub-
stance use, and behavioural addictions: opportunities for pathways to treatment. PLoS One.
2020;15(1):e0227644. https://doi.org/10.1371/journal.pone.0227644.
122 D. Sugrue
4. Jo YS, Bhang SY, Choi JS, Lee HK, Lee SY, Kweon YS. Clinical characteristics of diagnosis
for internet gaming disorder: comparison of DSM-5 IGD and ICD-11 GD diagnosis. J Clin
Med. 2019;8(7):945. https://doi.org/10.3390/jcm8070945.
5. Zajac K, Ginley MK, Chang R, Petry NM. Treatments for internet gaming disorder and inter-
net addiction: a systematic review. Psychol Addict Behav. 2017;31(8):979–94. https://doi.
org/10.1037/adb0000315.
6. Saunders JB, et al. Gaming disorder: its delineation as an important condition for diagnosis,
management, and prevention. J Behav Addict. 2017;6:271–9.
7. Burleigh TL, Griffiths MD, Sumich A, Stavropoulos V, Kuss DJ. A systematic review of the
co-occurrence of Gaming Disorder and other potentially addictive behaviors. Curr Addict Rep.
2019;6:383–401.
8. Grubbs JB, Hoagland KC, Lee BN, Grant JT, Davison PM, Reid R, Kraus SW. Sexual addic-
tion 25 years on: a systematic and methodological review of empirical literature and an agenda
for future research. Clin Psychol Rev. 2020;82:101925.
9. Malandain L, Blanc JV, Ferreri F, Thibaut F. Pharmacotherapy of sexual addiction. Curr
Psychiatry Rep. 2020;22:1–8.
10. Petry NM, Stinson FS, Grant BF. Comorbidity of DSM-IV pathological gambling and other
psychiatric disorders: results from the National Epidemiologic Survey on Alcohol and Related
Conditions. J Clin Psychiatry. 2005;66(5):564–74.
11. González-Bueno V, Santamaría JJ, Fernández D, Merino L, Montero E, Ribas J. Association
between internet gaming disorder or pathological video-game use and comorbid psychopa-
thology: a comprehensive review. Int J Environ Res Public Health. 2018;15(4):668.
Co-occurring Substance Use Disorders
and Mental Illness 12
Jonathan D. Avery and David Hankins
Only about 17% of individuals who need substance use treatment actually receive it
[11]. The barriers that prevent those with substance use disorders from seeking care
are both individual (e.g., shame, lack of insight, personal finances) and structural
(e.g., lack of providers, stigma, high costs). These same barriers exist for those who
need help for other mental health problems, compounding the difficulties that indi-
viduals who have both a substance use disorder and another mental illness can expe-
rience in seeking care [8]. In the United States alone, nine million people
experiencing mental illness also have a co-occurring substance use disorder (SUD),
and nearly half of them receive treatment for neither [11]. In this chapter, we discuss
medication treatment for individuals with co-occurring disorders (CODs), with a
particular focus on patients for whom medication would be indicated both for a
mental illness and for a SUD.
Rates of all forms of substance use are higher in those with a co-occurring mental
illness. Substance use in this population appears to be correlated with severity of
mental illness, with those with more severe forms of mental illness the most likely
to use substances. In 2018, 16% of adults without mental illness used any illicit drug
in the United States, compared to 37% of adults with any mental illness and 49% of
those with a serious mental illness (one that substantially limited one or more major
life activities). Given the opioid crisis, it is particularly notable that those with seri-
ous mental illness use opioids at over five times the rate of those without mental
illness, with 14.6% past year use compared to 2.6% [11]. Only 25% of adults with
both opioid use disorder and another mental illness receive treatment for both [7].
The differences with alcohol are less stark but still statistically significant; 25% of
J. D. Avery · D. Hankins (*)

Weill Cornell Medicine, NewYork–Presbyterian Hospital, New York, NY, USA
e-mail: joa9070@med.cornell.edu; dgh7001@med.cornell.edu
https://doi.org/10.1007/978-3-030-86430-9_12
124 J. D. Avery and D. Hankins
those without mental illness engaged in binge alcohol consumption in the past
month, compared to 32% of those with serious mental illness [7].
The consequences of untreated CODs have been consistently demonstrated.
Among individuals with mental illness, all-cause mortality is two to three times
higher in those with a COD than those without [6]. Individuals with co-occurring
major depression and a SUD have more severe depressive episodes more often,
more suicide attempts, and greater risk of experiencing other mental illnesses com-
pared to those who have major depression without a SUD [4]. Patients with schizo-
phrenia and a COD have two to three times more psychiatric hospitalizations than
those with schizophrenia alone [9]. Taken together, these studies and many others
emphasize the importance of treating both mental illnesses and CODs.
Psychosocial interventions (such as 12-step programs and brief interventions at
office visits) are an important component of treatment for SUDs. Utilizing only
psychosocial interventions, however, misses an opportunity for the use of a range of
safe and effective medication treatments for SUDs. This can happen even in cases
where both patient and psychiatrist feel comfortable with medication treatment for
a mental illness; barriers often cited to the initiation of such treatment include lab
monitoring requirements, concern for risk of diversion, and perceived lack of
time [1].
The three substance use disorders for which there is the strongest evidence in
support of pharmacology as a key treatment modality are alcohol, nicotine, and
opioid use. Note that the Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition (DSM-5) was released before the widespread use of non-tobacco nico-
tine products, such as electronic cigarettes; in this chapter we retain the DSM-5
terminology of tobacco use disorder. These three substances represent, along with
cannabis, the most commonly used and abused substances in the United States [11].
Table 12.1 highlights some of the evidence-based medication treatments for alco-
hol, opioid, and tobacco use disorders [2].
The clinical case in this chapter will illustrate how a comprehensive approach to
individuals with CODs can include the use of medications for both substance use
disorders and a range of other psychiatric diagnoses.
Clinical Case
Dr. Walker is a psychiatry resident early in her third year of training, working at an
outpatient clinic in a large urban area. Dr. Walker’s schedule for the day includes
three patients she has met for the first time recently but does not yet know well. Her
first patient, Deborah, is a 42-year-old woman with a history of schizophrenia, who
has been treated in the outpatient clinic for over a decade. She has tried several
antipsychotics during that time but is now stable on risperidone. Deborah reports
that she has been binge drinking recently up to two six packs of beer nightly,
although on some days she does not drink at all. She says this has been her pattern
of alcohol consumption for many years and is unsure if the frequency or amount of
her alcohol use has changed recently. She did not discuss this at their first
12 Co-occurring Substance Use Disorders and Mental Illness 125
Table 12.1 Psychopharmacology for substance use disorders, with average doses
Alcohol use disorder Opioid use disorder Tobacco use disorder
Naltrexone (ReVia) Buprenorphinea Varenicline (Chantix)
50 mg PO QD (Suboxone) 1 mg PO BID
8–16 mg SL QD
Naltrexone (Vivitrol) Methadone (Dolophine, Bupropion (Wellbutrin, Zyban)
380 mg IM monthly Methadose) 150 mg PO BID of sustained release, or
60–120 mg PO QD 300 mg PO QD of extended release
Acamprosate (Campral) Naltrexone (ReVia) Nicotine replacement therapies
666 mg PO TID 50 mg PO QD
Disulfiram (Antabuse) Naltrexone (Vivitrol)
125–500 mg PO QD 380 mg IM monthly
Gabapentin (Neurontin)
600–2400 mg PO QD
Topiramate (Topamax)
75–150 mg PO BID
Note. PO orally, QD once daily, TID three times daily, SL sublingual
a
Usually combined with naloxone and available in several forms and preparations (film, tablet,
implants)
appointment together a month ago and has never received any kind of alcohol-spe-
cific treatment.
Second on the schedule for the day is Kay, a 27-year-old woman with generally
well-controlled bipolar I disorder. Kay has had severe manic and depressive epi-
sodes in the past, requiring hospitalization five times. Kay began using oxycodone
ten months ago after a back surgery and four months ago began injecting heroin.
She is interested in stopping but is wary of treatment options given that her regimen
of lithium and quetiapine already leaves her at times feeling in her words “over-
medicated.” Her lithium levels have been erratic over the past several months despite
no change in her dose.
Dr. Walker’s final patient, Zack, is a 53-year-old man who has been in treatment
for major depressive disorder and without full remission of symptoms on sertraline
for the past five months. Dr. Walker has used a brief motivational approach at each
visit to discuss Zack’s cigarette smoking, which is currently at 30 cigarettes per day.
After seeing these patients, Dr. Walker prepares to discuss the cases with her
attending and considers how she might be able to manage these individuals’ CODs.
Discussion
Dr. Walker’s patients for the day present with three of the most common substance
use disorders, in the setting of existing psychiatric diagnoses which are likely the
primary reason that they are coming to see a psychiatrist. Given the amount that
must be covered in a single psychiatric appointment, the temptation to focus solely
on the primary psychiatric issue and thus neglect any CODs is understandable.
However, given the beneficial effects that can come from stopping these substances
in terms of patients’ physical and mental health, taking some time at each visit to
review current substance use and available medication treatment options can pay
substantial dividends.
Some of the hesitation in discussing medication treatments for CODs with
patients likely emerges from provider mindsets about substance use disorders more
broadly. Society at large and many individual providers have tended to view SUDs
as primarily behavioral or a reflection of moral failing on the part of the patient and
thus best addressed with psychosocial interventions [3]. An approach that combines
psychosocial and pharmacologic interventions is likely to be more beneficial for
patients, with a particular focus on medication treatments for the three substance
use disorders highlighted in this chapter.
Treatment
Alcohol Use Disorder
Deborah’s pattern of alcohol use warrants further discussion at her psychiatry

appointments and would likely benefit from the initiation of medication treatment.
One important consideration for Dr. Walker will be her assessment of Deborah’s
overall level of adherence to her prescribed schizophrenia regimen of oral risperi-
done. If Deborah has been adherent, Dr. Walker might consider the addition of any
of the oral agents mentioned in Table 12.1. However, Dr. Walker should also con-
sider and discuss with Deborah long-acting intramuscular naltrexone, which could
help reduce pill burden and improve adherence in any patient, but particularly those
with the risk factors for cognitive impairment that come from both problematic
alcohol use and from schizophrenia. Given Deborah’s history of schizophrenia, for
which long-acting injectable formulations are one of the mainstays of treatment, Dr.
Walker might be able to initiate the conversation by exploring Deborah’s history
with injections, if any, and her thoughts on oral versus injectable medications.
Deborah’s reported pattern of binge alcohol use with days of abstinence may also
make her a candidate for the “Sinclair method” of oral naltrexone use, in which
naltrexone is taken only on days when a patient is drinking, to reduce the amount of
alcohol consumed [10]. Baseline laboratory tests to measure liver and kidney func-
tion could help narrow the list of acceptable options; acamprosate can cause kidney
damage, and naltrexone and disulfiram are implicated in liver disease (Table 12.2).
Opioid Use Disorder
Kay presents to Dr. Walker with the relatively recent onset of a COD, in this case
use of prescription painkillers and heroin, and a clearly stated desire to stop using,
creating a unique opportunity to collaboratively pursue medication-assisted treat-
ment. The ambivalence she expressed about being on another medication is worth
further exploration, so that Dr. Walker can understand if this is related to forgetting
to take her medications, side effects, cost, or any number of other potential factors.
Table 12.2 Advantages and contraindications to medications for alcohol use disorder
Medication Advantages Contraindications
Naltrexone Oral or injectable Liver disease
formulations Active opioid use
Oral form can be taken daily
or only on days when patient
is drinking
Strong evidence base
Acamprosate Useful for those patients Kidney disease
with liver damage (renally
cleared)
Typically very well tolerated
Disulfiram Useful particularly for Concurrent alcohol use
highly motivated patients Coadministration with any of several antibiotics,
and a few rarer drugs can compound the
“disulfiram reaction” if taken with alcohol
Severe liver or heart disease
Gabapentin Can treat anxiety disorders None
Topiramate Mood stabilizing properties None
The variation in her lithium level could suggest some degree of nonadherence, par-
ticularly if other causes have been excluded.
Dr. Walker could propose the main treatment options for opioid use disorder to
Kay: methadone, buprenorphine, or the long-acting intramuscular formulation of
naltrexone. Methadone would require referral to a specialty clinic and, if initiated,
attention to a number of potentially serious drug-drug interactions including for
several commonly used psychiatric medications (benzodiazepines and some antide-
pressants can raise methadone levels, while carbamazepine among others can lower
levels). Office inductions onto buprenorphine are becoming more widespread as
provider training in its use is growing. Since Dr. Walker has completed buprenor-
phine training, initiating buprenorphine might be a particularly appealing option to
take advantage of Kay’s expressed desire to stop using opioids. Buprenorphine has
considerably fewer clinically significant drug-drug interactions than methadone as
well, potentially making the path forward easier if Kay were to need adjustments to
the medication regimen for her bipolar I disorder in the future. Long-acting intra-
muscular naltrexone is also an option in this case, especially if an injectable formu-
lation is sought either for patient preference or to improve adherence. However
since Kay’s opioid use originated from a surgery, methadone or buprenorphine may
be preferable to long-acting naltrexone in this case due to their analgesic effects.
Tobacco Use Disorder
Zack, who has both major depressive disorder and tobacco use disorder, also has
many medication treatments available to treat his COD. In this case, one medication
is indicated for both diagnoses: bupropion. Dr. Walker could discuss with Zack
whether he has ever tried bupropion before or if it was previously stopped should
explore dosing (to ensure a high enough treatment dose was attempted), side effects,
and duration of the trial. This is a particularly attractive option since Zack’s depres-
sion has not achieved remission with sertraline; bupropion could be considered for
either a new monotherapy or as an adjunctive agent for sertraline [5].
In addition to bupropion, other medication options for the management of Zack’s
tobacco use disorder include nicotine replacement therapy (available in a variety of
delivery systems including patches, gum, lozenges, inhalers, and others) and
varenicline.
Although this would not be the case for Zack, it is important to keep in mind for
other patients that by-products from tobacco smoke induce cytochrome P450 (CYP)
1A2, lowering the serum drug levels for antipsychotics including haloperidol, olan-
zapine, and clozapine. This induction does not happen with nicotine-only products.
Thus if a patient is abstinent from tobacco for a time (including with the aid of nico-
tine replacement therapy) and then resumes smoking, this can lead to a rapid emer-
gence of psychotic symptoms. Given high rates of relapse back to nicotine, patients
with tobacco use disorder as a COD should continue to be asked about their tobacco
use even after a period of abstinence.
Conclusion
The high number of patients with mental illness who also have a COD should
prompt mental health providers to carefully screen for substance use disorders and
to consider pharmacologic treatments for their patients’ CODs. Each medication
comes with its own profile of advantages and risks, giving providers options to tailor
treatments to patients’ unique needs and preferences.
Key Points
• Individuals with co-occurring disorders (CODs) are at risk of having their sub-
stance use disorder (SUD) go untreated even if they are in psychiatric care.
• A range of effective psychopharmacologic options are available to treat alcohol,
opioid, and tobacco use disorders, which are three of the most common sub-
stance use disorders.
• Medication treatments for CODs typically interact minimally with pharmaco-
logic agents for other psychiatric diagnoses or have drug-drug interactions that
can be considered and adapted to.
References
1. Albright J, et al. Psychiatrist characteristics that influence use of buprenorphine medication-
assisted treatment. J Addiction Med. 2010;4(4):197–203. https://doi.org/10.1097/
ADM.0b013e3181c816f3.
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Index
A C
Acamprosate, 127 Cannabis use disorder, 33, 35
Addiction, 11, 101, 104 chemical compounds, 33
Adrenocorticotropic hormone (ACTH), 102 DSM-5, 35
Affirmations, 96 screening, 36, 37
Alcoholics anonymous (AA), 29 THC, 34
Alcohol use disorder, 21–23 treatment, 38
addiction, 22 Cardiovascular, 2
anxiety, 23 Cathinones, 91, 97
electrolyte repletion, 22 Chronic obstructive pulmonary disease
inpatient treatments, 27, 28 (COPD), 102
medical complications, 25, 26 Clinical opiate withdrawal scale
medication-assisted treatment, 26, 27 (COWS), 70
mood, 22, 24 Cocaine, 91, 94, 97
psychodynamic theories, 24 Cognitive behavioral therapy
psychosocial interventions, 28, 29 (CBT), 28, 119
rehydration, 22 Columbia Suicide Severity Rating Scale
Amphetamine, 91, 94 (C-SSRS), 3
Analgesia, 37 Co-occurring disorders (CODs), 123–126
Anxiolytic-related use disorders, 89 alcohol use disorder, 126, 127
Anxiolytics, 81, 87, 89 DSM-5, 124
opioid use disorder, 127
psychopharmacology, 125
B tobacco use disorder, 128
Behavioral addictions, 113 Corticotropin-releasing factor (CRF), 14
gambling, 115, 116, 118 Craving, 13, 15
gaming, 113
hypersexual disorder, 120, 121
internet gaming disorder, 119, 120 D
mood symptoms, 117 Delta-9-tetrahydrocannabinol (THC), 33
pharmacologic agents, 118 Dependence, 81, 82
psychiatric comorbidities, 120 Diagnostic and Statistical Manual of Mental
psychiatric disorders, 116 Disorders (DSM-5), 4, 113, 114
SSRI, 119 Disulfiram, 127
Benzodiazepine, 81–85, 87, 88 Domains, 3
Bupropion, 106, 107
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer 131
Nature Switzerland AG 2022
https://doi.org/10.1007/978-3-030-86430-9
132 Index
E binge/intoxication, 14
Emergency room (ER), 44 clinical models, 11
illness, 12
inpatient hospital course, 12
G outpatient clinic management, 13
Gabapentin, 127 preoccupation/anticipation, 15
Gambling, 113 psychosocial history, 12
Gaming, 113, 114 treatment, 15–17
Gamma-aminobutyric acid subtype A withdrawal/negative affect, 14, 15
(GABAA), 82 Nicotine, 101, 102
dependence, 105
replacement therapies, 104
H Nitrous oxide, 61
Hallucinogen, 41, 43, 47–49
DSM-5, 42
harm reduction, 46 O
integration, 50 Opioid use disorder (OUD), 68–70
ketamine, 42 chronic use, 67
MDMA, 51, 52 legitimate use, 68
phencyclidine, 44–46 MAT, 75
psychedelic, 41, 50 pharmacologic interventions, 70–74
signs and symptoms, 42 psychosocial interventions, 74, 75
Hallucinogen persisting perception disorder
(HPPD), 49
Hydrocarbons, 61 P
Hypersexual disorder, 115, 120, 121 Pharmacotherapy, 119
Hypnotics, 81, 89 Prescription drug monitoring programs
(PDMPs), 72
Psychopharmacology, 104
I
Incentive salience, 14
Inhalant use disorder, 57, 59, 60 R
epidemiology, 58, 59 Reflections, 96
inhalant classification, 61 Respiratory, 2
proposed mechanisms, 63
psychosocial effects, 62
psychosocial impacts, 61 S
treatment, 63, 64 Sedative, 81, 82, 86, 89
Initial assessment, 4 Selective serotonin reuptake inhibitors
(SSRIs), 119
Sexually transmitted diseases (STDs), 115
M Stimulant-related disorders, 91–93, 96
Marijuana, 37 amphetamines, 92
Medication-assisted treatment, 23 cathinones, 91
Mental status exam (MSE), 7, 8 cocaine, 91, 97
Methamphetamine, 93, 94 psychosis, 92
Motivational interviewing (MI), 28 treatment, 94–97
Substance use disorders, 1, 8
assessments, 5, 6
N diagnosis, 4
Negative emotionality, 17, 18 history, 1–4
Neurobiology mimic, 2
addiction cycle, 13 treatment, 5
Index 133
T V
Three-stage model, 11 Varenicline, 106, 108
Tobacco use disorder, 101, 102, 106, 128 Ventral tegmental area (VTA), 82
bupropion, 107, 108
DSM-5, 103
nicotine replacement therapy, 105–107 W
non-pharmacological intervention, 105 Withdrawal, 81, 82
psychiatry, 104
psychopharmacology, 104
varenicline, 108, 109 Y
Tolerance, 82, 86 Youth Risk Behavior Survey (YRBS), 59
Toluene, 61, 62

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What are some of the main substance use disorders discussed in the text?

What are some of the main substance use disorders discussed in the text?

What are some treatment approaches mentioned for substance use disorders?

What are some treatment approaches mentioned for substance use disorders?

Psychiatry Update 2

Series Editor: Michelle B. Riba

More information about this series at http://www.springer.com/series/16222

ISSN 2524-8316 ISSN 2524-8324 (electronic)

1 Assessment of Substance Use Disorders�������������������������������������������������� 1

Jonathan D. Avery, MD Weill Cornell Medicine, NewYork–Presbyterian

Kseniya Svyatets, DO New York University Grossman School of Medicine,

A. A. Thomas (*) · K. Shalvoy

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 1

Making a Substance Use Disorder Diagnosis

Subsequent to gathering and analyzing the information, a diagnosis must be formu-

Discussing Treatment Options

Table 1.3 DSM-5 criteria for substance use disorder [11]

Common Challenges in the Substance Use Assessment

Case Study: Patient Lilly

Physical Exam: Suboptimal hygiene and grooming, cachectic, “track marks”

When a patient presents for assessment of a substance-related disorder, it is a criti-

thorough and compassionate assessment of the medical, psychiatric, and substance

• A comprehensive substance use assessment must include attention to the medical

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 11

History of Present Illness

Mr. M’s neurodevelopmental history is notable for significant childhood adver-

Inpatient Hospital Course

After reviewing your diagnostic assessment and treatment recommendations, Mr. M

Outpatient Clinic Management

Addiction is a chronic, relapsing illness that involves distress or functional impair-

CRF. These neuroadaptations collectively produce a stress-like state marked by

Translating Neuroscience into Clinical Practice

Developed by the National Institute on Alcohol Abuse and Alcoholism (NIAAA),

Negative emotionality Executive dysfunction

Incentive salience Social context

Cues ↑Active use network

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 21

Alcohol hallucinosis is a syndrome sometimes mistaken for DTs. Patients with

FDA-approved medications for alcohol use disorder

As discussed earlier, inpatient detoxification may be considered for some patients

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 33

substance in cannabis primarily responsible for its intoxicating and psychogenic

Table 4.1 DSM criteria for cannabis use disorder

Screening, Brief Intervention, and Referral to Treatment (SBIRT) Model

Hallucinogens comprise a diverse group of substances with differing chemical

K. Kim · D. Roberts (*)

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 41

Table 5.1 Signs and symptoms associated with hallucinogen intoxication

Table 5.2 Hallucinogen-related disorders (as described in the DSM-5 [3])

Phencyclidine use disorder

Though a comprehensive discussion of the history of these substances is beyond

Angel is a 32-year-old man brought to the emergency room (ER) by emergency

Physical restraints may be initially necessary to safely administer sedating

referred to as a “trip,” and a “bad trip” refers to those experiences predominantly

Hallucinogen Persisting Perception Disorder (HPPD)

HPPD is a relatively rare and poorly understood phenomenon, with anecdotal

possible outcomes of HPPD, which include spontaneous remission or persistent

It is worth emphasizing that, although hallucinogen intoxication is generally an

Sasha is a 21-year-old woman who was brought to the emergency department by

hormone (SIADH) may also contribute. Significant hyponatremia can lead to

1 Assessment of Substance Use Disorders�� 1

Making a Substance Use Disorder Diagnosis

Discussing Treatment Options

Common Challenges in the Substance Use Assessment

Case Study: Patient Lilly

History of Present Illness

Inpatient Hospital Course

Outpatient Clinic Management

Translating Neuroscience into Clinical Practice

Hallucinogen Persisting Perception Disorder (HPPD)

I nhalant Classification, Psychosocial Impacts, Physiologic

Joe is a 45-year-old married man, working in construction, who sustained a work-

Psychotherapeutic and Psychosocial Interventions

Nicotine Replacement Treatment

Discussion of Clinical Cases

Internet Gaming Disorder

Alcohol Use Disorder

Opioid Use Disorder

Tobacco Use Disorder