Psychopharmacology

https://doi.org/10.1007/s00213-020-05563-3

REVIEW

Prescription psychostimulants for the treatment of stimulant

use disorder: a systematic review and meta-analysis
Vitor S. Tardelli 1 & Adam Bisaga 2 & Felipe B. Arcadepani 1 & Gilberto Gerra 3 & Frances R. Levin 2 &
Thiago M. Fidalgo 1

Received: 8 February 2020 / Accepted: 18 May 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Rationale Agonist-based pharmacologic intervention is an accepted approach in treatment of opioid and tobacco use disorders.
Objectives We conducted a systematic review and meta-analysis to evaluate usefulness of an agonist approach as treatment of
(psycho)stimulant use disorder (PSUD).
Methods We reviewed PubMed/Medline, LILACS, and ClinicalTrials.gov databases searching for randomized, double-blind,
placebo-controlled, parallel-design studies evaluating outcomes of individuals treated for cocaine- or amphetamine-type substance
use disorder. We combined results of all trials that included the following prescription psychostimulants (PPs): modafinil, methyl-
phenidate, or amphetamines (mixed amphetamine salts, lisdexamphetamine, and dextroamphetamine). The combined sample
consisted of 2889 patients. Outcomes of interest included the following: drug abstinence (defined as 2–3 weeks of sustained
abstinence and the average maximum days of consecutive abstinence), percentage of drug-negative urine tests across trial, and
retention in treatment. We conducted random-effects meta-analyses and assessed quality of evidence using the GRADE system.
Results Thirty-eight trials were included. Treatment with PPs increases rates of sustained abstinence [risk ratio (RR) = 1.45, 95%
confidence interval (CI) = (1.10, 1.92)] and duration of abstinence [mean difference (MD) = 3.34, 95% CI = (1.06, 5.62)] in patients
with PSUD, particularly those with cocaine use disorder (very low-quality evidence). Prescription amphetamines were particularly
efficacious in promoting sustained abstinence in patients with cocaine use disorder [RR = 2.44, 95% CI = (1.66, 3.58)], and higher
doses of PPs were particularly efficacious for treatment of cocaine use disorder [RR = 1.95, 95% CI = (1.38, 2.77)] (moderate-
quality evidence). Treatment with prescription amphetamines also yielded more cocaine-negative urines [MD = 8.37%, 95% CI =
(3.75, 12.98)]. There was no effect of PPs on the retention in treatment.
Conclusion Prescription psychostimulants, particularly prescription amphetamines given in robust doses, have a clinically sig-
nificant beneficial effect to promote abstinence in the treatment of individuals with PSUD, specifically the population with
cocaine use disorder.

Keywords Psychostimulants . Cocaine . Methamphetamine . Prescription psychostimulants . Substance use disorders .

Modafinil . Methylphenidate . Amphetamine . Agonist . Replacement

Electronic supplementary material The online version of this article

(https://doi.org/10.1007/s00213-020-05563-3) contains supplementary
material, which is available to authorized users.

* Vitor S. Tardelli Thiago M. Fidalgo

vstardelli@unifesp.br marquesfidalgo@yahoo.com.br

Adam Bisaga
1
amb107@cumc.columbia.edu Departamento de Psiquiatria, Universidade Federal de São Paulo
(Unifesp), São Paulo, Brazil
Felipe B. Arcadepani
felipearcadepani@hotmail.com
2
Division of Substance Abuse, New York State Psychiatric Institute
Gilberto Gerra (NYSPI), Columbia University, New York, NY, USA
gilberto.gerra@un.org
3
Frances R. Levin Drug Prevention and Health Branch, United Nations Office on Drugs
frl2@cumc.columbia.edu and Crime, Vienna, Austria
 Psychopharmacology

Introduction model of treatment (De Giorgi et al. 2018; Lee and Rawson
2008; Minozzi et al. 2016).
Global use of cocaine increased two-fold over the 5 years The most accepted pharmacological intervention for sub-
leading to 2017 reaching all-time high of an estimated 18 stance use disorders involves treatment with agonist-like med-
million that used cocaine in the past year, with an accelerating ications, the approach known as a replacement or substitution
trend observed in Europe, North America, some South therapy (Darke and Farrell 2016). Agonist-based treatment
American countries, and Australia. Moreover, cocaine sei- has been successfully implemented in treatment of opioid
zures reported in Asia and West Africa suggest that its use use disorder (Mattick et al. 2009) and tobacco use disorder
might be increasing in these regions as well (United Nations (Hartmann-Boyce et al. 2014). A parallel approach has for
Office on Drugs and Crime 2019). Global market for amphet- long been regarded as a promising approach for treatment of
amine and methamphetamine continues to expand, and in PSUD (Shearer et al. 2002), and several medications were
2017, an estimated 29 million used amphetamines in the past proposed as putative “stimulant agonists” (Amato et al.
year, with an increasing trend seen in the United States and in 2011; Castells et al. 2016; Rush and Stoops 2012; Stoops
East and South-East Asia (United Nations Office on Drugs and Rush 2013).
and Crime 2019). A significant number of individuals who An “agonist” medication would have a similar pharmaco-
use stimulants will develop a (psycho) stimulant use disorder logic and behavioral effect as the drug of abuse, providing
(PSUD), which includes a cocaine use disorder (CUD) and an relief of craving and other symptoms of acute and protracted
amphetamine-type use disorder (AUD), which are among the withdrawal, which are main factors responsible for the main-
most prevalent drug-related conditions around the world with tenance of drug use and for relapse following periods of ab-
highly burdensome health and social consequences (United stinence (Darke and Farrell 2016). Another desired feature of
Nations Office on Drugs and Crime 2019). The prevalence an agonist medication is that it may function as a “blocker” in
of CUD and AUD has raised globally at 39.7% and 22.5%, case of the use of the primary drug and therefore diminish
respectively, from 1990 to 2016. CUD accounts for 1153.6 euphoric effects and prevent further escalation of use
thousand disability-adjusted life years (DALYs), a disease (Shearer 2008). At the same time, for a medication to be ac-
burden measure that comprises years of life lost (YLLs) and ceptable for agonist-based treatment, it will need to have an
years of life lived with disability (YLDs), while AUD ac- acceptable safety profile and be feasible for clinical use (Darke
counts for 881.4 thousand DALYs (Degenhardt et al. 2016). and Farrell 2016). Medication taken orally with slow onset of
Only alcohol and opioids pose heavier burdens than CUD and action and a long elimination half-life will have less euphoric
AUD. Stimulant drugs have considerable potential of yielding and discontinuation subjective effects reducing the risk of
use disorders among their users, with 16.7% of those with any abuse, and stable blood concentrations will provide “pharma-
lifetime cocaine use developing a use disorder. This propor- cological stability” (Darke and Farrell 2016). Moreover, the
tion is of 11.2% for amphetamines, comparable to 15.4% for agonist medication should have few acute side effects and no
alcohol and 23.1% for heroin (Anthony et al. 1997). More behavioral organ toxicity in clinically used doses and there-
recent publications also found a lifetime prevalence of fore be acceptable for chronic administration. Preferably, it
PSUD of 1.7% (Grant et al. 2016) and that 15.6% of cocaine will have mildly positive subjective effects that will promote
abusers transition to dependence at any point of their lives medication adherence and have acceptable safety profile when
(Florez-Salamanca et al. 2013). combined with the primary or other drugs of abuse (Darke and
Despite the alarming public health impact of PSUD, the Farrell 2016). Effective treatment with agonist medication will
proportion of individuals with PSUD who are receiving treat- facilitate initial abstinence with resulting improved adherence
ment is extremely low (United Nations Office on Drugs and to treatment, as high rates of treatment dropout are one of the
Crime 2019), with only 20% of patients with cocaine or am- main challenges in working with this population. Improved
phetamine use disorder receiving specialty treatment in 2018 treatment engagement will allow patients to benefit from cog-
as patients with CUD and AUD and similarly low rates report- nitive and behavioral therapies offered in the treatment pro-
ed in patients with opioid use disorder (OUD) though rates of gram to prevent relapse and extend benefits of drug absti-
OUD treatment have been increasing in the past few years nence, all of which would be difficult in patients who are
(Substance Abuse Mental Health Services Administration actively using stimulants. Moreover, individuals receiving ag-
2019). One of the reasons for such low treatment rates is the onists are likely to become interested in and access other med-
absence of the medication-based model of PSUD treatment. ical and social interventions, as well as other therapeutic ser-
This is in contrast to much higher treatment rates among those vices offered at the program, such as psychoeducation and
with opioid use disorder, where medications are an essential harm-reduction services (Shearer et al. 2002).
treatment component (Schuckit 2016). In the absence of an All of the stimulants acutely increase brain levels of dopa-
approved and well-accepted pharmacological intervention to mine and noradrenaline, producing stimulating and pleasur-
treat PSUD, psychosocial interventions remain the primary able euphoric effects, and with chronic use produce long-
Psychopharmacology

lasting changes in brain circuits (Kalivas and O'Brien 2008). those analyses, PPs, especially prescription amphetamines,
However, individuals with PSUD who use stimulants chron- were found to significantly increase rates of sustained absti-
ically have altered functioning of the dopaminergic system, nence in patients with CUDs (Castells et al. 2016), but the
which may be responsible for the clinical signs and symptoms quality of the evidence was very low due to heterogeneity
observed in those individuals, such as low energy, low mood and inconsistency of the estimates with a large number of
and anhedonia, increased impulsivity, as well as impaired medications included. However, no significant effect was
cognition and decision making (London et al. 2015; Sabrini found in patients with AUD on measures of drug use,
et al. 2019). Medications with diverse pharmacological effects sustained abstinence, or retention in treatment, though attrition
increasing the dopaminergic activity have been proposed as for both medication and placebo was high (Perez-Mana et al.
candidates for agonist-type treatment of PSUD (Rush and 2013). More recently, new high-quality trials with robust sam-
Stoops 2012) and have been evaluated in controlled clinical ple sizes, sound methodology, and up-to-date designs (e.g.,
trials over the past 30 years. An examination of this evidence monitored intake, extended-release formulations, and higher
appears to show that among the most effective of all tested dosages) have been published, and therefore, a new meta-
dopaminergic medications are the prescription analysis is warranted.
psychostimulants (PPs), such as amphetamine salts or meth- The aim of this study was to systematically review trials
ylphenidate. PPs have accepted medical use and favorable testing selected PPs as treatment for patients with cocaine or
safety profile and may therefore be good candidate medica- amphetamine-type substance use disorder (PSUD) and pool
tions for PSUD agonist treatment (Goldstein and Volkow data with meta-analyses. We included studies that used either
2011; Goldstein et al. 2010). prescription amphetamines, methylphenidate, or modafinil.
Treatment with PPs should be implemented cautiously due We summarized the evidence from the following outcomes:
to the potential for euphoric effects and the risk of misuse and (a) sustained (2–3 weeks) drug abstinence, (b) percentage of
diversion (Darke and Farrell 2016). Using extended-release drug-negative urine tests across trial, (c) maximum days of
preparations suitable for once-daily administration and admin- continuous abstinence, and (d) retention in treatment. When
istering medication under direct observation, similarly to treat- possible, we carried out subgroup analyses per drug of abuse,
ment with opioid agonist methadone, can reduce potential of medication used, ADHD status, and comorbid opioid use dis-
abuse (Nuijten et al. 2016). Toxicity of PPs when given chron- order (OUD). We performed risk of bias and quality assess-
ically should also be considered (Darke and Farrell 2016) ments and assessed the quality of the evidence using the
especially as individuals chronically using high doses of stim- GRADE system.
ulants are at increased risk of cardiovascular disorders
(Callaghan et al. 2018) and psychotic symptoms (Fiorentini
et al. 2011). However, these medications are widely used for Methods
the treatment of attention-deficit hyperactivity disorder
(ADHD) and have overall good cardiovascular and psychiat- Medication selection
ric safety profile when used in healthy children and adults
(Cooper et al. 2011; Habel et al. 2011). In contrast to previous systematic reviews on this topic
Many individuals with PSUD have other co-occurring psy- (Castells et al. 2016; Perez-Mana et al. 2013), we restricted
chiatric and substance use disorders, including ADHD that this analysis to trials with medications that are most analogous
occurs in 5%–31% of adults seeking treatment for substance to cocaine or amphetamine-type substances, with similar be-
use disorders (van de Glind et al. 2014) and major depression havioral effects and therefore most “potent” pharmacological-
which may affect treatment outcomes (Hellem et al. 2015; ly to be candidates for PSUD “agonist-based” treatment. This
Rounsaville 2004; Rounsaville et al. 1991). Moreover, pa- includes amphetamine isomers (dexamphetamine and meth-
tients seeking treatment for PSUD often present with depen- amphetamine), which are monoamine release enhancers, and
dence on other drugs, notably opioids (Marsden et al. 2009). methylphenidate, which is a monoamine transport blocker
These co-occurring conditions may indicate greater severity of (Rush and Stoops 2012). Furthermore, we included modafinil,
the PSUD, and those individuals may have worse health and which also blocks dopamine transporter in doses used clini-
treatment outcomes, and such comorbidities may modulate cally exerting effect comparable to lower doses of methylphe-
the impact of medications. nidate (Kim et al. 2014; Madras et al. 2006; Volkow et al.
Cochrane reviews with meta-analyses assessing the effica- 2009) and has a behavioral profile typical of
cy of PPs on CUDs (Castells et al. 2016) and AUDs (Perez- psychostimulants, such as cocaine (Andersen et al. 2010).
Mana et al. 2013) were published in 2016 and 2013, respec- Despite these effects, modafinil generally has low abuse lia-
tively. Both publications pooled measures of effect from bility (Jasinski 2000; Jerry et al. 2016), and this combination
RCTs comparing PPs to placebo on sustained abstinence, drug of behavioral and pharmacological effects as a
use across the study period, and retention to treatment. In psychostimulant with limited abuse potential makes modafinil
 Psychopharmacology

a worthwhile replacement drug candidate. All of the selected Recommendations Assessment, Development, and
medications have similar behavioral effects as abused stimu- Evaluation) approach (Balshem et al. 2011), with help of the
lants (Rush and Baker 2001) and are therefore on the list of GRADEpro software (McMaster University (developed by
controlled substances. This is in contrast to bupropion, anoth- Evidence Prime 2015) to assess the quality of evidence. A
er medication that binds to dopamine transporter but has lower summary of findings (SoF) table is provided, and results are
receptor occupancy than modafinil or methylphenidate described according to GRADE judgment.
(Griffith et al. 1983; Learned-Coughlin et al. 2003; Meyer
et al. 2002), has lower abuse liability (Griffith et al. 1983), Data extraction and quality assessment
and is not a controlled substance, and was therefore not in-
cluded in this review. The initial plan for the analysis was developed by AB and GG
We have also included in the analysis two publications that and finalized with input from all authors. Titles or abstracts of
evaluated treatment with mixed amphetamine salts combined publications obtained with the search strategy or from refer-
with topiramate (Levin et al. 2020; Mariani et al. 2012). ences list were screened independently by VST and FBA. Full
Topiramate was found to have a positive effect on abstinence texts were further analyzed by VST and FBA, and final deci-
from cocaine (Singh et al. 2016), and therefore, it is possible sion about study inclusion included AB and TMF. A standard-
that it had an added benefit; thus, we also evaluated the overall ized form was applied to data extracted from the included
effect with these two studies excluded. publications to assess study quality and evidence synthesis.
Information on this form included the following: substance
Search strategy and selection criteria of abuse, presence of comorbid substance use disorders, pres-
ence of comorbid mental health disorders, medication tested
This review and meta-analysis was conducted following a pre- (with maximum dosages), follow-up period, outcome effect
established protocol registered on PROSPERO under the measures, and information about risk of bias. VST and FBA
number CRD42019129653 and following the Preferred assessed the risk of bias of the included studies separately with
Reporting Items for Systematic Reviews and Meta-Analysis the Cochrane tool (Higgins et al. 2011). Any discrepancies
(PRISMA) guidelines (Moher et al. 2009). We searched all were resolved via a discussion with other authors until
publications in the following databases for bibliography: reaching a consensus. Data were extracted directly from each
MEDLINE, PubMed, the Cochrane Library (Cochrane trial’s published results and study protocols, when available. If
Database of Systematic Reviews, Cochrane Central Register data for the outcomes of interest were not published or
of Controlled Trials and Cochrane Methodology Register), inserted in the protocols, authors were contacted or we used
Web of Science, and ClinicalTrials.gov. Also, the trial’s data included in the published Cochrane reviews (Castells
references were examined for additional references. No et al. 2016; Perez-Mana et al. 2012, 2013).
language restriction was used. Publications published up to
September 2019 were included. Outcomes
Our initial search strategy in PubMed/Medline was
(“Prescription Psychostimulants” or modafinil or methylphe- We selected sustained stimulant abstinence as the primary
nidate or dextroamphetamine or d-amphetamine or amphet- outcome. Abstinence, particularly at the end of treatment, is
amine or lisdexamphetamine or “mixed amphetamine salts”) an outcome strongly related to cocaine use during follow-up
and (cocaine or methamphetamine or stimulants). This search where it outperforms other measured of drug use, such as
strategy was adapted for other databases. percent drug-negative urine screens (Carroll et al. 2014;
We included randomized, parallel-grouped, double-blind, Miguel et al. 2019), though there are also benefits to sustained
and placebo-controlled clinical treatment trials that used a PP low-level use during treatment on functioning following treat-
as the pharmacological intervention. All trials included in this ment (Roos et al. 2019b). Although most of the publications
review were conducted in outpatient settings and lasted from 8 included in the review used a standardized measure of 3 weeks
to 26 weeks. Non-treatment studies, such as human behavioral of consecutive abstinence at the end of the study, some pub-
pharmacology studies, were not included because of differ- lications used 2 weeks (Levin et al. 2007) or reported
ences in studied population and limited generalizability to sustained abstinence at any time point throughout the trial
clinical population. period (Kampman et al. 2015). All studies except for
RevMan 5 (The Nordic Cochrane Centre 2014) software Nuijten et al. (2016) used objective urine toxicology tests to
was used to obtain pooled measures of effect as well as graph- confirm the abstinence, either alone or combined with self-
ic displays of the meta-analytic illustrations. We used report.
Cochrane’s Risk of Bias Assessment tool, included in As for quantitative measures of abstinence, we measured
RevMan 5, to generate methodological quality graphs and and pooled percentage of drug-negative urine tests per group
summaries. We used the GRADE (Grading of throughout trials and maximum days of sustained abstinence,
Psychopharmacology

using means and standard deviations to obtain a pooled mean caused by small sample sizes. If means and standard devia-
difference. We chose mean difference over standardized mean tions were not reported, we contacted the study authors to
difference because all studies included assessed the referred obtain these and/or used other statistics to calculate the effect
outcome using the same unit (percentage of drug-negative sizes according to the procedures implemented in our meta-
urine tests and maximum number of days of continuous ab- analysis software. When necessary, we performed transforma-
stinence). As a secondary outcome, we also assessed retention tions on measures of mean spread to harmonize the results
to treatment and compared the number of patients who fin- between trials.
ished the study in treatment and control groups. We decided If we were not able to obtain the desired data directly from
not to include safety outcomes as earlier reviews found no the authors, we then used secondary data obtained from au-
medication and placebo differences in dropouts due to any thors by the already published Cochrane meta-analyses cited
adverse events, cardiovascular events, and serious adverse before (Castells et al. 2016; Perez-Mana et al. 2013). In studies
events (Castells et al. 2016; Perez-Mana et al. 2013), and the that compared individuals under different doses of the same
additional studies included in the present review did not report medication as separate study groups, we merged sample sizes
differences in such outcomes. Funnel plots for the three out- and calculated pooled standard deviations. When publications
comes were not suggestive of publication bias and are avail- used different PPs as distinct study groups, we included that
able in the Appendix. publication twice, as if each drug versus placebo comparison
represented a single study.
Statistical analysis We pooled studies comparing the same types of interven-
tion and control and using the same outcome measure using
For the included studies, we calculated summary measures of random-effects models for meta-analysis to account for het-
intervention efficacy providing risk ratios for dichotomous erogeneity among the treatment effects of different trials
outcomes (sustained stimulants abstinence and retention in (Borenstein and Higgins 2013). Our a priori tolerated alpha
treatment) and mean differences for the continuous outcome level for effect measures was 0.05. Statistical heterogeneity
(percentage of drug-negative urine tests across trial and max- was assessed using Chi square and I2 statistics. An I2 value
imum days of consecutive abstinence). greater than 50% was regarded as indicative of substantial
For dichotomous outcomes, we selected risk ratios (RR) heterogeneity (Higgins and Green 2011). When dichotomous
over risk differences (RD) since relative measures are normal- outcome data were missing, we assumed that patients who
ly more consistent among different studies than absolute mea- dropped out after randomization had a negative outcome.
sures (Deeks 2002; Engels et al. 2000). In addition, RR satisfy Missing continuous outcome data were analyzed on an end-
the following three criteria for summary statistics choice in point basis, including only participants with a final assess-
meta-analyses: consistency, mathematical properties required ment, as reported by the original study authors.
for a proper meta-analysis, and ease of interpretation (Deeks We also calculated the number needed to treat (NNT) from
2002). Finally, RR are easier to interpret than odds ratios the measures of effect of the outcomes assessed in our meta-
because odds ratios are frequently interpreted as if they were analysis. For risk ratios obtained from dichotomous variables,
risk ratios, which inappropriately overestimates measures of the computation of the NNT proceeds as follows:
 
effects (Viera 2008).  
NNT ¼ ACR1ð1−RRÞ, where RR is the risk ratio for each out-
When trials used multiple treatment groups, we merged
treatment groups into one when these groups used different come and ACR is the assumed control risk (ACR). There are
doses of the same medication, as recommended by the many ways to set this parameter. We used the approach that
Cochrane manual (Higgins and Green 2011). One study had divides the number of positive events in the control (placebo)
the following three treatment groups: modafinil, group divided by the total number of events (Higgins and
dexamphetamine, and modafinil + dexamphetamine Green 2011).
(Schmitz et al. 2012). In this case, we excluded the modafinil
+ dexamphetamine group from our comparison and included Quality of evidence
the other two treatment groups as separate analyses (using the
same placebo group), as done previously (Castells et al. 2016). Quality of evidence was determined using the Grading of
For the percentage of drug-negative urine tests across trial Recommendations Assessment, Development, and
and maximum days of consecutive abstinence outcomes, we Evaluation (GRADE) approach (Balshem et al. 2011).
used mean differences (MDs) as all trials provided the same “Quality” is defined as a measure of confidence in the effect
unit (% of drug-negative urine tests and days). Trials differed estimate provided. Evidence is rated as of high, moderate,
on methods to impute missing data, but most of them imputed low, or very low quality. A quality rating of “high” means
missing as positive. RevMan 5 uses the definition of SMD that it is very likely that the true effect lies close to the esti-
known as Hedges’ g, which is adjusted for possible bias mate, while “very low” means that the true effect is likely to be
 Psychopharmacology

different from the estimated effect. Randomized trials begin behavioral effects that could be noticed by both patients and
with a quality rating of high, and observational studies begin clinicians. Risk of bias graph and summary with author’s
with a quality rating of low. These ratings can be downgraded judgments for each trial are available in the Appendix.
based on the following five criteria: risk of bias in the included
studies; inconsistency in results; indirectness of evidence; im-
precision of effect estimates; and risk of publication bias. Results
However, ratings can be upgraded if the effect size is large,
there is evidence of a dose–response effect, or all plausible Study selection
confounding is controlled for.
Of the 164 abstracts retrieved from the initial search, 21 studies
Subgroup analyses were included in the full-text review stage. After screening of
reference lists from included original publications and reviews,
We pre-specified subgroup analysis per drug of abuse (co- 31 additional studies were added to the full-text reading stage
caine and methamphetamines) providing sensitivity analysis (Fig. 1). At this initial stage, we excluded studies that did not
for results overall and for cocaine use disorder when removing include outcomes of interest or did not meet methodological
trials with add-on topiramate; treatment drug (prescription requirements. A total of 16 studies were excluded after full-
amphetamines, modafinil, and methylphenidate); and comor- text review. Initial discrepancies at the abstract and full-text
bid OUD and attention deficit hyperactivity disorder (ADHD) review stages were later resolved by consensus of study authors.
status, where prescription psychostimulants are notably effec- Thirty-eight RCTs were included in the final analysis with
tive (De Crescenzo et al. 2017). We considered that these 26 trials conducted in patients with cocaine use disorder
factors could partially explain heterogeneity between trials (CUD) and 12 in patients with amphetamine-type use disorder
and that the subpopulations specified could respond different- (AUD). Eighteen trials used as an outcome 3-week sustained
ly to treatment (Oxman and Guyatt 1992). abstinence and one trial assessed 2-week sustained abstinence.
In addition, we defined two dose categories for PPs; low and Out of those, seven trials evaluated prescription amphet-
high. We used maximum doses currently approved by the FDA amines, eight evaluated modafinil, and four evaluated meth-
(60 mg/day for prescription amphetamines, 400 mg/day for ylphenidate. Five trials included patients with comorbid sub-
modafinil, and 60 mg/day for methylphenidate) as the threshold stance use disorders, and four trials included patients with
for separating low (below that limit) vs. high doses. We hy- ADHD.
pothesize that patients with PSUD may be cross-tolerant to PPs Characteristics of all trials included are described in
and may thus require higher doses and more potent agents to Table 1.
achieve therapeutic response. To explore whether there is a
dose–response effect, we conducted a subgroup analysis for Effect of prescription psychostimulants on
the primary outcome of sustained abstinence by the dose. abstinence: overall and in patients with CUD vs AUD
Finally, we performed sensitivity analyses to (a) exclude trials
with immediate-release PPs to evaluate its impact on sustained We found an overall significant benefit of PPs when com-
abstinence and (b) elucidate whether the presence of contingen- pared to placebo on promoting 2–3 weeks of sustained absti-
cy management (CM) (either abstinence or compliance- nence (risk ratio [RR] = 1.45, 95% confidence interval [CI]
targeted) changed the effect of PPs on retention to treatment. (1.10, 1.92), I2 = 37%); NNT = 16, 95% CI (8, 70) (Fig. 2).
When analyzing subgroups per drug of abuse (CUD vs.
Risk of bias AUD), this benefit is dragged away from the null by CUD
studies. The effect in CUD studies is not only statistically
We assessed the validity of the included studies using criteria significant but also clinically meaningful considering both
from the Risk of Bias Assessment tool, developed by the confidence interval bounds (RR = 1.70, 95% CI (1.26, 2.31),
Cochrane Collaboration (Higgins and Green 2011). The tool I2 = 24%); NNT = 12, 95% CI (7, 32). No benefit is shown for
analyzes risk of bias by classifying it in the following six AUD studies (RR = 0.89, 95% CI (0.62, 1.27), I2 = 0%).
different domains: generation of allocation sequence, conceal- We performed sensitivity analysis to evaluate whether the
ment of treatment allocation, blinding of patients and person- benefit of PPs for PSUDs remained when removing two trials
nel, blinding of outcome assessors, data incompleteness, se- that administered topiramate as an add-on medication, both
lective reporting, and other sources of bias. for the treatment of CUDs and conducted by the same research
The risk of bias for each specific domain is assessed either team (Levin et al. 2020; Mariani et al. 2012). The overall
as “low risk,” “unclear risk,” or “high risk.” We assumed that effect of PPs for PSUDs remained statistically significant
all of the included trials had unclear risk of bias from blinding (RR = 1.34, 95% CI (1.01, 1.79), I2 = 34%); NNT = 20,
of patients and personnel since study medications had 95% CI (9, 660). The effect of PPs for CUDs also remained
Psychopharmacology

(see Fig. 3), when compared to placebo (RR = 2.44, 95% CI

(1.66, 3.58), I2 = 0%); NNT = 7, 95% CI (4, 14). There was no
effect for modafinil (RR = 1.22, 95% CI (0.83, 1.77), I2 =
29%) or methylphenidate (RR = 0.90, 95% CI (0.60, 1.37),
I2 = 0%).

The effect of co-occurring disorders

To assess whether patients with co-occurring ADHD or OUD

had a different response to PPs, we conducted separate anal-
yses for trials where patients had a co-occurring disorder vs.
those that did not (Fig. 4). We found a significant benefit of
PPs in trials that did not report an ADHD diagnosis (RR =
1.55, 95% CI (1.14, 2.11), I2 = 33%); NNT = 14, 95% CI (7,
53), while no benefit was observed in trials that included pa-
tients with comorbid ADHD (RR = 1.17, 95% CI (0.61, 2.25),
I2 = 48%). When restricting analyses to prescription amphet-
amines, there was a significant benefit in the non-ADHD
group (RR = 2.33, 95% CI (1.55, 3.51), I2 = 0%); NNT = 7,
95% CI (4, 15). We did not conduct this analysis for the
ADHD group as there was only one trial (Levin et al.
2015b) with these characteristics.
To assess the impact of the co-occurring OUD, we sepa-
rately evaluated three trials where patients also had an OUD
and were treated with an opioid agonist (methadone or
Fig. 1. Studies included in the review with number of studies included diacetylmorphine) and those that did not include co-
after each stage of the screening process occurring OUD (Fig. 5). The effect of psychostimulants in
trials with comorbid OUD was robust (RR = 2.03, 95% CI
statistically significant (RR = 1.59, 95% CI (1.14, 2.23), I2 = (1.24, 3.33), I2 = 0%); NNT = 8, 95% CI (4, 32) while there
26%); NNT = 14, 95% CI (7, 58), compared to RR = 1.70, was no benefit of PPs in trials without co-occurring OUD (RR
95% CI (1.26, 2.31), I2 = 24%); NNT = 12, 95% CI (7, 32) = 1.34, 95% CI (0.98, 1.83), I2 = 39%). However, when
when the studies were included. See the Appendix for details. restricting analyses to prescription amphetamines, the statisti-
We conducted an additional analysis of studies that reported cally significant results were detected in both the OUD+ (RR
abstinence in the final 3 weeks, which is an outcome measure = 2.41, 95% CI (1.39, 4.17), I2 = 0%); NNT = 6, 95% CI (3,
adopted in the recent trials, and four trials were included (Dackis 21) and the OUD− (RR = 2.46, 95% CI (1.43, 4.24), I2 = 0%);
et al. 2012; Kampman et al. 2015; Levin et al. 2015b; Levin NNT = 6, 95% CI (3, 19) groups.
et al. 2020). We found a significant effect of PP abstinence with
a very high RR (RR = 3.01, 95% CI (1.58, 5.75), I2 = 0%). See The effect of the dose
the Appendix for details.
We performed sensitivity analysis excluding a trial with To assess the impact of the PP dose, we separately eval-
immediate-release methylphenidate for CUD (Dursteler- uated trials that used low doses and those that used high
MacFarland et al. 2013) from the overall and drug-specific doses. Four of the 17 trials included used dose of PPs that
analyses. The overall effect of PPs for PSUD remained statis- are lower than FDA’s maximum recommended doses (for
tically significant (RR = 1.47, 95% CI (1.10, 1.96), I2 = 41%); approved conditions) while 15 used the maximum doses
NNT = 18, 95% CI (9, 81). The effect of PPs for CUDs also or higher. One trial (Dackis et al. 2012) tested two differ-
remained statistically significant (RR = 1.74, 95% CI (1.27, ent doses of modafinil, a low 200 mg/d dose and a high
2.39), I2 = 28%); NNT = 11, 95% CI (6, 30). 400 mg/d dose, and we included effect estimates of each
of those groups compared to placebo separately. One trial
(Levin et al. 2015b) tested two doses of dexamphetamine,
Effect by the medication type 60 and 80 mg/d, but since both were in the high dose
range, we merged both treatment groups into a same com-
A subgroup analysis by medication shows a clinically and parison as recommended by the Cochrane handbook
statistically significant effect for prescription amphetamines (Higgins and Green 2011).
Table 1 Characteristics of included studies

Author, year Primary Other Other Primary Other Slow Psychosocial Maximum Sample Follow-up Outcome: Outcome: Outcome: Outcome:
disorder SUDsa psychiatric medication medications release treatment daily dose size period continuous maximum retention drug-
conditions (weeks) abstinence days of in negative
continuous treatment urine tests
abstinence throughout
trial

Grabowski et al. Cocaine No None MPHb None No None 45 7 10 No No Yes No

(1994)
Grabowski et al. Cocaine No None MPH None No CBT—all groups 45 49 11 No No Yes Yes
(1997)
Grabowski et al. Cocaine No None D-AMPc None Yes CBT—all groups 60 128 12 No No Yes No
(2001)
Schubiner et al. (2002) Cocaine No ADHDd MPH None No CBT—all groups 90 48 12 No No Yes Yes
Shearer et al. (2003) Cocaine Opioid None D-AMP None Yes None 60 30 14 Yes No Yes Yes
Grabowski et al. Cocaine Opioid None D-AMP Methadone Yes CBT—all groups 60 120 26 Yes No Yes Yes
(2004)
Dackis et al. (2005) Cocaine No None MODe None Yes CBT—all groups 400 62 8 Yes No Yes No
Levin et al. (2006) Cocaine Opioid ADHD MPH Methadone Yes CBT—all groups 80 98 12 Yes No No No
Tiihonen et al. (2007) AMPf No None MPH None Yes Unstructured—all 54 34 20* No No Yes No
groups
Levin et al. (2007) Cocaine No ADHD MPH None Yes CBT—all groups 60 106 14 Yes No Yes Yes
Shearer et al. (2009) Methg No None MOD None Yes CBT—all groups 200 80 10 No No Yes No
Anderson et al. (2009) Cocaine No None MOD None Yes CBT—all groups 400 210 12 Yes Yes Yes No
Mooney et al. (2009) Cocaine No None Meth None Used CBT—all groups 30 82 8 No No Yes No
both
Longo et al. (2010) Meth No None D-AMP None Yes CBT—all groups 110 49 12 No No Yes No
Galloway et al. (2011) Meth No None D-AMP None Yes Motivational 60 60 8 No No Yes Yes
therapy—all
groups
Konstenius et al. AMP No ADHD MPH None Yes Individual skills 72 24 12 Yes No Yes Yes
(2010) training
program—all
groups
Heinzerling et al. Meth No None MOD None Yes CBT + abstinence 400 71 12 Yes No Yes Yes
(2010) CM—all groups
Anderson et al. (2012) Meth No None MOD None Yes CBT—all groups 400 210 12 Yes Yes Yes Yes
Dackis et al. (2012) Cocaine No None MOD None Yes CBT—all groups 200/400 210 8 Yes No Yes No
Mariani et al. (2012) Cocaine No None ERMS-AMPh Topiramate Yes Compliance and 60 81 12 Yes No Yes Yes
abstinence CM—
all groups
Schmitz et al. (2012) Cocaine No None MOD/D-AMP None Yes CBT—all groups 400/60 73 16 Yes No Yes No
Miles et al. (2013) Meth No None MPH None Yes Supervised intake— 54 78 22 No No Yes No
all groups
Dursteler-MacFarland Cocaine Opioid None MPH Diacetylmorphine No Supervised intake— 60 62 12 Yes Yes Yes No
et al. (2013) all groups; group
CBT—two arms
Konstenius et al. Meth None ADHD MPH None Yes CBT—all groups 180 54 26 No No Yes No
Psychopharmacology

(2014)
Table 1 (continued)

Author, year Primary Other Other Primary Other Slow Psychosocial Maximum Sample Follow-up Outcome: Outcome: Outcome: Outcome:
disorder SUDsa psychiatric medication medications release treatment daily dose size period continuous maximum retention drug-
conditions (weeks) abstinence days of in negative
continuous treatment urine tests
Psychopharmacology

abstinence throughout
trial

Schmitz et al. (2014) Cocaine No None MOD Levodopa/ Yes CBT + compliance 400 40 12 Yes No Yes No
carbidopa, CM—all groups
5naltrexone
Ling et al. (2014) Meth No None MPH None Yes CBT + abstinence 54 110 10 No Yes Yes No
CM—all groups
Rezaei et al. (2015) Meth No None MPH None Yes Supervised intake— 54 56 10 No No Yes No
all groups
Kampman et al. Cocaine No None MOD None Yes CBT + compliance 300 94 8 Yes No Yes No
(2015) CM—all groups
Levin et al. (2015a) Cocaine No ADHD D-AMP None Yes CBT—all groups 60/80 123 13 Yes No Yes Yes
Mooney et al. (2015) Cocaine No None LD-AMPi None Yes CBT—all groups 70 43 14 No No Yes No
Morgan et al. (2016) Cocaine No None MOD None Yes CBT + attendance 400 57 6 No Yes Yes Yes
CM—all groups
Nuijten et al. (2016) Crack No None D-AMP Methadone/ Yes Supervised intake— 60 73 12 Yes Yes Yes Yes
cocaine Diacetylmorphine all groups
Levin et al. (2020) Cocaine No None D-AMP Topiramate Yes CBT + compliance 60 127 14 Yes No Yes Yes
CM—all groups
NCT00142818 Cocaine Alcohol None MOD Naltrexone Yes CBT—all groups 400 164 13 No No Yes Yes
NCT00859573 Meth No None MOD None Yes Psychotherapy 400 9 10 No No Yes No
NCT00218036 Cocaine Opioid None MOD Citalopram Yes Not mentioned 200/400 51 24 No No Yes No
NCT00218387 Cocaine No None MOD None Yes CBT—all groups 400 123 8 No No Yes No
NCT00838981 Cocaine Opioid None MOD Methadone Yes CBT—all groups + 400 91 12 Yes Yes No No
abstinence CM—
two arms

a
SUD, substance use disorder
b
MPH, methylphenidate
c
D-AMP, dexamphetamine
d
ADHD, attention-deficit–hyperactivity disorder
e
MOD, modafinil
f
AMP, amphetamines
g
Meth, methamphetamines
h
ERMS-AMP, extended-release mixed amphetamine salts
i
LD-AMP, lisdexamphetamine
*
Early terminated
 Psychopharmacology

Fig. 2. Overall and by dependence drug effect of prescription psychostimulants compared to placebo for outcome sustained abstinence

Trials that use low doses did not show benefit on promot- Maximum days of consecutive abstinence
ing sustained abstinence (RR = 1.25; 95% CI [0.71, 2.21]),
with low heterogeneity (I2 = 0%). Trials with that used high We gathered data from seven trials to compare average max-
doses showed a statistically significant benefit (RR = 1.50; imum days of consecutive abstinence between PPs and place-
95% CI [1.10, 2.06]); NNT = 14, 95% CI (7, 67); however, bo groups (see Fig. 10). Due to the scarcity of studies avail-
the clinical benefit was marginal as the confidence inter- able, subgroup analyses were not possible. We found a signif-
val’s lower bound was not considered clinically meaning- icant difference of 3.34 (95% CI (1.06, 5.62), I2 = 41%) days
ful and heterogeneity was intermediate (I2 = 44%) (see Fig. favoring psychostimulants when compared to placebo.
6). On the other hand, there is moderate quality evidence for
the benefit of PPs in maximum higher dosages when Retention in treatment
restricting analyses to CUDs (RR = 1.95; 95% CI [1.38,
2.77]); NNT = 9, 95% CI (5, 22), with a clinically meaningful All but one of the 38 trials included in this review included the
CI lower bound and low heterogeneity (I2 = 30%) (see Fig. 7). outcome of retention in treatment (see Fig. 11). We did not
find a significant benefit of psychostimulants when compared
Percentage of drug-negative urine tests across trials to placebo on promoting retention to treatment in overall stim-
ulants use disorders (RR = 1.04, 95% CI (0.97, 1.11), I2 =
We analyzed data from 15 trials to compare the percentage of 10%), CUD (RR = 1.03, 95% CI (0.96, 1.11), I2 = 7%) and
drug-free urine tests across trials in PPs vs. placebo groups (see AUD (RR = 1.08, 95% CI (0.93, 1.27), I2 = 22%). No differ-
Fig. 8). We found a significant difference of 2.40% (95% CI ences were found when analyzing subgroups by medication
(0.07, 4.73), I2 = 29%) favoring PPs when compared to placebo. drug, ADHD status, or comorbid dependences. We also com-
As the main effects found in the dichotomous abstinence pared retention in treatment between treatment groups using
analyses were from prescription amphetamines for CUD, we number of days in treatment as outcome. Again, we did not
conducted a separate analysis for this subgroup (see Fig. 9). find a statistically significant difference between PPs and pla-
We found a more robust difference of 8.37% (95% CI (3.75, cebo (SMD = 0.11, 95% CI (−0.27, 0.50), I2 = 65%). See the
12.98), I2 = 0%) favoring PPs. Appendix for more details.
Psychopharmacology

Fig. 3. Overall and by treatment drug effect of prescription psychostimulants compared to placebo for outcome sustained abstinence

We conducted a separate analysis to assess whether pro- rates of abstinence (RR = 1.74, CI = (1.01, 3.00)) as compared
viding CM to the patients undergoing treatment with PPs to those below the median (RR = 1.26, CI = (0.83, 1.91)). This
would modify their effect on retention to treatment. The reten- analysis is included in the Appendix as Fig. 10.
tion in treatment was comparable in the studies with CM vs.
those that did not use CM (61.4% vs. 52.0%, t = 1.09, p = Grade
0.28). In the trials where CM was provided for all study par-
ticipants, PPs were not efficacious on promoting retention to We conducted GRADE evaluation of the quality of evidence.
treatment vs. placebo (RR = 0.95, 95% CI (0.84, 1.07), I2 = Evidence was of moderate quality for the following: (1) ben-
0%). This analysis was included in the Appendix. efit of prescription amphetamines for treatment of patients
with CUD; (2) benefit of PPs for treatment of patients with
Medication adherence CUD and comorbid heroin dependence; (3) benefit of higher
doses of PPs for treatment of patients with CUD; (4) benefit of
We conducted an analysis to address the possible impact of prescription amphetamines for CUD patients with and without
medication adherence on abstinence. Of the 13 trials that in- comorbid opioid use disorder; and (5) benefit of prescription
cluded sustained abstinence outcome, all reported overall amphetamines for patients with PSUD and no ADHD.
medication adherence mostly using direct pill count. We found low-quality evidence of the benefit of prescrip-
Medication adherence ranged from 51% to 99% but was gen- tion amphetamines on increasing cocaine-negative urines
erally high with a median of 91%, and we did a median split to across trials.
compare abstinence in trials with adherence below vs. above Evidence was of very low-quality for the following:
the median. Trials above the median had significantly higher (1) overall benefit of PPs on promoting sustained
 Psychopharmacology

Fig. 4. Overall and by ADHD status effect of prescription psychostimulants compared to placebo for outcome sustained abstinence

abstinence from stimulants; (2) benefit of PPs on in- Discussion

creasing drug-negative urine tests across study; (3) and
benefit of PPs for patients with PSUD on promoting This meta-analysis found that prescription psychostimulants like-
maximum days of continuous abstinence. It is unlikely ly promote sustained drug abstinence and may reduce stimulant
that PPs will have beneficial effect on retention in treat- use throughout trial and extend duration of abstinence when used
ment in patients with PSUD. in treatment of individuals with PSUDs. The overall effect is
The level of evidence for RCTs was downgraded twice for primarily influenced by studies that used prescription amphet-
all outcomes due to risk of bias caused by high attrition rates in amines, mostly dextroamphetamine, for treatment of individuals
most of the studies and by potential detection bias due to the with cocaine use disorder. The present analysis offers preliminary
behavioral effects of the medication that could hinder evidence that medications with a more “potent” agonist effect
blinding. Approximately half of the trials included had signif- (i.e., dextroamphetamine) are more effective than medications
icantly more behavioral side effects (most frequently sleep that are less “potent” (i.e., modafinil) and that patients treated with
disturbances, anxiety, headache, and dizziness) in the treat- higher doses of agonist medications benefit more than patients
ment group compared to placebo, and the few trials that eval- treated with lower doses, further supporting the hypothesis that
uated blinding directly had mixed findings. No studies includ- the “agonist effect” is mainly responsible for the clinical benefit.
ed an active control which might have minimized the risk of The quality of evidence that supports results of this meta-
detection bias. Downgrades were made also due to inconsis- analysis varies depending on the medication, condition, and out-
tency and imprecision. Upgrades in the level of evidence judg- come. A moderate quality evidence supports the large benefits
ment were made solely based on large effects (RR > 2.0). of using prescription amphetamines and the benefit of higher
GRADEPro objective criteria were used to assess quality of doses of prescription psychostimulants when used in the treat-
evidence of each of the pre-specified outcomes and subgroup ment of individuals with cocaine use disorder where the achieve-
analyses. See the summary of findings (SoF) for further infor- ment of sustained abstinence is the desired treatment outcome.
mation. A summary of the main findings can be seen in The results of this study are consistent with and further
Table 2. extend results of prior meta-analyses published by the
Psychopharmacology

Fig. 5. Overall and by comorbid dependence status effect of prescription psychostimulants compared to placebo for outcome sustained abstinence

Cochrane editorial group of PP efficacy in the treatment of disappointing, and this may not be a PP with promise on pro-
cocaine (Castells et al. 2016) and amphetamine use disorders moting abstinence of cocaine and amphetamines. Our publica-
(Perez-Mana et al. 2013). Similar to Castells et al. (2016), we tion included studies published after the most recent review
found that treatment with prescription amphetamines improved (Castells et al. 2016), most of which used higher doses and
sustained abstinence in patients with cocaine use disorder, and extended-release preparations of PPs (Levin et al. 2020; Nuijten
we found similar results analyzing subgroups per medication, et al. 2016). Both of these features had been recommended for
ADHD status, and concurrent opioid use disorders. We further clinical use by recent trials (Mariani et al. 2012) and reviews
show that PPs increase maximum days of sustained abstinence (Mariani and Levin 2012; Rush and Stoops 2012) on this topic.
from stimulants, though with a small number of studies. This is Similar to Pérez-Mañá and colleagues (2013), we found no
particularly relevant in light of the association between effect of PPs on promoting sustained amphetamine absti-
sustained abstinence and maximum days of abstinence during nence, which is expected since none of the trials published
treatment for cocaine use disorder and the decreased cocaine after that review used sustained amphetamine abstinence as
use and better functioning in the long term (Carroll et al. 2014). an outcome, though we evaluated fewer medications. It should
However, contrary to the previous reviews, this new meta- be noted however that earlier studies with methylphenidate
analysis shows a significant benefit of PPs on reducing drug used formulations with poor bioavailability which may ac-
use across trial period. This efficacy is more pronounced in count for negative findings (Levin et al. 2007; Levin et al.
trials with prescription amphetamines for patients with CUD. 2006) or used lower, less-effective doses (Konstenius et al.
Unlike studies done by the Cochrane investigators, we evalu- 2010). In addition, there are studies which showed beneficial
ated a more restricted range of psychostimulant medications. We effects of methylphenidate (Konstenius et al. 2014; Ling et al.
limited them to prescription amphetamines, methylphenidate, 2014; Tiihonen et al. 2007) but did not report sustained absti-
and modafinil, all controlled substances, to rule out medications nence as an outcome and were therefore not included in this
with insufficient dopaminergic potency, thereby ensuring a clin- analysis. Results of future studies that use improved method-
ically meaningful “agonist effect” (Herin et al. 2010). Among ology (Ezard et al. 2018) may change the overall assessments
those, the results of trials with modafinil were consistently of PP effectiveness in patients with AUD. We found low-
 Psychopharmacology

Fig. 6. Overall and by dose effect of prescription psychostimulants compared to placebo on outcome sustained abstinence—overall PSUD

quality evidence that PPs increase sustained abstinence for et al. 2016; Petry et al. 2005). Combining pharmacotherapy with
patients with PSUDs in general, but that was attributable to CM for PSUDs may be an effective strategy to decrease attrition
results of studies in cocaine rather than amphetamine use and promote further treatment benefits (Tardelli et al. 2018) as
disorder. the usually high attrition rates undermine the effect of any ther-
As with the earlier finding (Castells et al. 2016), we did not apeutic intervention for PSUDs, though it can be challenging to
find evidence that treatment with PPs increases the retention in implement. Nonetheless, PPs had a significant effect on promot-
treatment. Retention was measured as a binary variable for ing cocaine abstinence, and trials with lower attrition rates found
treatment completion, and we also carried an additional anal- greater effect on sustained abstinence (Nuijten et al. 2016).
ysis of retention as a continuous variable of duration in treat- Maximum days of continuous abstinence during treatment
ment; none of them revealed differences between the treat- is an outcome measure predicting long-term endpoints on co-
ment and control groups. Subgroup analyses per drug and caine use and global functioning (Carroll et al. 2014), but it is
per medication also did not find significance for treatment not often used in clinical trials. A pooled estimate of this out-
retention for any subgroup. This further strengthens the posi- come is included in our meta-analysis, but we were limited by
tive effect found on abstinence, especially at the end of treat- the small number of trials and high heterogeneity, partially
ment, as differential retention might bias toward the treatment explained by the fact that we merged CUD and AUD trials.
arm with the better retention. Also, pooled continuous variables usually carry more hetero-
There is very limited evidence that any medication improves geneity than binary outcomes in meta-analyses (Alba et al.
retention to treatment (Chan et al. 2019; Indave et al. 2016) for 2016). But, even with these limitations, we found a significant
PSUDs, unlike the effect of opioid agonists that does increase effect of PPs on the continuous abstinence, and we recommend
retention in treatment for opioid use disorder (Mattick et al. it for inclusion in the future trials of PSUD pharmacotherapy.
2009). On the other hand, CM is a psychosocial intervention Our review brings an innovative dose range subgroup com-
that has been shown to increase treatment retention rates in parison. The necessity to use higher doses of PPs for PSUDs than
many different contexts (Garcia-Rodriguez et al. 2009; Miguel those established for other conditions has been a matter of debate
Psychopharmacology

Fig. 7. Overall and by dose effect of prescription psychostimulants compared to placebo on outcome sustained abstinence—CUD only

(Levin et al. 2015a), as people with PSUDs may be cross-tolerant few trials with AUDs have used sustained abstinence as an
to the psychostimulant effect of these medications. Our meta- outcome, so that only three trials, one with methylphenidate
analysis has confirmed that higher but not lower doses of PPs (unpublished data) (Konstenius et al. 2010) and two with
promoted sustained abstinence. Results of trials that used low modafinil (Anderson et al. 2012; Heinzerling et al. 2010), were
doses may have underestimated the true potential of PPs, espe- pooled, while studies with positive findings were not included
cially for treatment of CUD. Dose of the “agonist” medication (Konstenius et al. 2014; Ling et al. 2014; Longo et al. 2010).
plays a major role in its effectiveness as it has been shown with In the analysis per medication, neither modafinil nor meth-
opioid agonists (Faggiano et al. 2003) and also shown in preclin- ylphenidate was effective on promoting sustained abstinence
ical and human laboratory studies which further underscores the for PSUDs. Prescription amphetamines were responsible for
benefit of agonist approach (Czoty et al. 2016). According to the the overall effect of PPs; however, only two trials up to this
GRADE guidelines, the presence of a dose–response gradient point used prescription amphetamines to treat AUDs
increases the quality of the evidence of a treatment (Higgins (Galloway et al. 2011; Longo et al. 2010), and while findings
and Green 2011). Therefore, since this dose-range analysis is were partially positive, none assessed sustained abstinence. On
novel, it lowers the risk of bias of results that are already more the other hand, a study conducted in patients with amphetamine
statistically consistent than those shown in prior analyses which use disorder and ADHD found that high dose of extended-
already regarded PPs for CUD as a “promising treatment for release methylphenidate reduced use of amphetamine as com-
cocaine dependence” (Castells et al. 2016). Our findings elevate pared to placebo, though this study was not included in the
the quality of the evidence supporting the use of PPs, particularly efficacy outcomes of this meta-analysis as it did not include
prescription amphetamines for promoting abstinence in patients the outcome of abstinence (Konstenius et al. 2014). It is possi-
with CUD. The NNT of 7 for prescription amphetamines on the ble that, as for CUD, trials with high doses and extended release
treatment of CUDs and 8 for PPs in the treatment of patients with formulation of prescription amphetamines could promote
co-occurring OUD is comparable to that found for acamprosate sustained abstinence from methamphetamine, and at least one
(NNT = 8) and naltrexone (NNT = 9), medications approved for of such studies is ongoing (Ezard et al. 2018).
the treatment of alcohol use disorder (Maisel et al. 2013). PPs were particularly efficacious on promoting sustained ab-
It is noteworthy that we have found PPs to be ineffective for stinence for the subgroup of individuals with comorbid cocaine
AUDs, with no heterogeneity between studies. However, very and opioid use disorders. Studies in this patient population
 Psychopharmacology

Fig. 8. Overall mean difference in percentage of drug-negative urine tests throughout trial comparing prescription psychostimulants to placebo

included potent medications (dextroamphetamine) given at Nuijten and colleagues conducted a trial using high doses of
higher doses which is likely the main contributor to overall extended-release dexamphetamine for individuals dependent
findings. Moreover, patients already taking methadone could on crack-cocaine using a structure similar to those of the OTP
have better adherence to a new medication and a synergic effect and found significant results for sustained abstinence and max-
between opioid agonist and PPs could promote higher absti- imum days of abstinence, with low attrition rates for both groups
nence rates. Higher efficacy of PPs in a population with (Nuijten et al. 2016). Beyond the effect of medication itself, this
OUDs could also be explained by a different model of care. well-designed trial successfully addressed common problems in
The opioid treatment program (OTP) model requires daily at- trials with PSUDs, such as elevated dropout rates. This suggests
tendance to clinic, where study staff could motivate patients at a that a structured model of care using PPs similar to methadone
regular basis and supervise methadone intake, features that en- clinics could be an alternative for outpatient medication-based
sure patients are highly adherent to the experimental treatment. intervention for patients with PSUDs, yet other studies have
The OTP model has likely enhanced the adherence to medica- shown that prescription amphetamines can be effective when
tion in these trials, which could have partially explained the given in a traditional outpatient treatment setting.
positive results among this specific subgroup (especially when Patients with ADHD are more prone than the general popu-
considering that the overall quality of evidence for PPs for lation to develop substance use disorders, and ADHD is a com-
PSUD was severely undermined by elevated attrition rates). mon comorbidity among patients seeking treatment for

Fig. 9. Overall mean difference in percentage of drug-negative urine tests throughout trial comparing prescription psychostimulants to placebo—
restricted to prescription amphetamines for CUDs
Psychopharmacology

Fig. 10. Overall mean difference in maximum days of sustained abstinence comparing prescription psychostimulants to placebo

Fig. 11. Overall and by drug of abuse effect of prescription psychostimulants compared to placebo on outcome retention to treatment
 Psychopharmacology

Table 2. Box with a summary of

the main findings Overall findings: Subgroup analyses:

• PPs are efficacious on promoting sustained • PPs do not seem to promote sustained abstinence in
abstinence in patients with PSUD. patients with AUDs. However, trials with
• PPs seem to have a small effect on extending prescription amphetamines showed promise for
maximum days of sustained abstinence among outcomes that are not abstinence-based.
patients with PSUD. • Prescription amphetamines are highly efficacious on
• PPs do not seem efficacious on promoting retention promoting sustained abstinence in patients with
to treatment between patients with PSUD. CUD.
• This did not differ by abuse drug and was not • PPs are especially efficacious on promoting
modified by the presence of Contingency sustained abstinence in patients with concurrent
Management. opioid use disorder. This may be due to adherence
features present in the OTP treatment.
• Abstinence and Compliance-targeted Contingency
Management may improve overall retention and • PPs are efficacious on promoting sustained
should be incorporated by future trials. abstinence in patients without ADHD. However,
studies with ADHD populations have
• Quality of evidence was impaired by high attrition
methodological limitations.
rates in most of the trials.
• Maximum current dosages of PPs or higher are more
• The combination of PPs and Topiramate has shown
efficacious than lower dosages on promoting
promising efficacy on promoting sustained cocaine
sustained abstinence of stimulants, especially
abstinence and should be further tested.
cocaine.

substance use disorders (Lee et al. 2011; van Emmerik-van by treatment of the ADHD symptoms. Another caveat of this
Oortmerssen et al. 2012). PPs are the gold standard treatment subgroup analysis is that most studies reported did not assess
for ADHD (Faraone and Buitelaar 2010) and were found to ADHD status and did not exclude these individuals. This way,
improve ADHD symptoms in trials with comorbid ADHD it is possible that many patients seeking treatment for PSUDs
and SUDs (Konstenius et al. 2010; Levin et al. 2007). also have ADHD but are not diagnosed. Given that there are
However, the impact on PSUD is mixed. Factors that might limited though encouraging data, further studies with higher
have led to early negative results include use of medications PPs dosages are necessary to evaluate the effect of PPs in pa-
with poorer bioavailability (Levin et al. 2006, 2007) or inade- tients with co-occurring PSUD and ADHD (Woon et al. 2018).
quate dosing (Levin et al. 2006). Levin and colleagues hypoth- Psychosocial treatments, particularly CM targeting absti-
esized that patients with ADHD and heavy cocaine use could nence and treatment adherence, have shown benefits in pa-
require even higher dosages of dopaminergic medications than tients with PSUD (Kampman 2019; Lussier et al. 2006).
those with high cocaine use but no ADHD and conducted a trial Using CM in combination with a pharmacologic treatment
comparing a regimen of 80 mg/day of dextroamphetamine to has been shown to have synergic effect in decreasing drug
the usual dose of 60 mg/day and placebo (Levin et al. 2015b). use and enhancing treatment (Penberthy et al. 2010; Tardelli
Both medication groups achieved significantly higher rates of et al. 2018). However, in the present meta-analysis, we did not
sustained abstinence compared to placebo; the 80 mg groups find that CM (targeting either abstinence or adherence) im-
had larger odds of sustained abstinence than the 60 mg group, proved treatment retention. Incorporating CM elements to de-
although that difference was not significant. Consistent with this crease treatment attrition may be considered in future trials as
approach, Konstenius et al. (2014) found that high doses of high rates of treatment attrition remain a prominent issue in
extended-release methylphenidate (up to 180 mg/day) resulted trials conducted in patients with PSUD although it is possible
in clinically significant improvement in ADHD and reduction that the effect of well-designed and implemented CM may
in amphetamine use among those with amphetamine use disor- create the ceiling effect, with increase in placebo response,
der (Konstenius et al. 2014) whereas the lower dose of 72 mg/ which lowers the possibility of detecting the medication effect.
day did not result in a reduction in ADHD symptoms or am- The current meta-analysis has several limitations. Many of
phetamine use (Konstenius et al. 2010). Because the 2014 study the trials included were likely underpowered, which might have
with higher doses of methylphenidate did not provide data on hindered positive findings about the efficacy of PPs when
the sustained abstinence outcome, their efficacy measures were looking at the trials individually but the meta-analysis that also
not included in this meta-analysis. Low dosages in the other includes adequately powered trials usually corrects this limita-
two trials pooled might explain PPs’ low efficacy in the ADHD tion (Nuesch et al. 2010). Since almost all of the trials evaluated
subgroup. Importantly, patients in the PPs group showed im- excluded individuals with severe psychiatric comorbidities
provements in the ADHD outcomes in all of three trials men- from their sample or did not assess for other common condi-
tioned above which refutes the argument that drug-related clin- tions, such as ADHD, it was not possible to conduct sub-group
ical improvements in patients with ADHD are mostly mediated analyses on depression or other highly prevalent conditions in
Psychopharmacology

patients with PSUD. Due to the heterogeneity of outcome mea- disorder and a history of a psychotic disorder should be con-
surement among the included studies, it was not possible to sidered as exclusionary. Abstinence-based outcomes
pool relevant outcomes, such as other continuous drug use var- (sustained abstinence and maximum days of abstinence)
iables, e.g., reduction in drug use, reduction in drug use cate- should be combined with continuous drug use outcomes.
gory (Roos et al. 2019a), or other non-abstinence endpoints. Trials with higher dosages of PPs, especially prescription
Also, due to the scarcity of data, it was not possible to compare amphetamines, are particularly needed for the treatment of
trials using higher dosages of PPs to those using the current AUD. The combination of PPs with topiramate has shown
maximum dosages approved by the FDA for other conditions. promise on the treatment of PSUD, and therefore, combination
The duration of sustained abstinence as an outcome differed treatments should be considered for future trials. We believe
across trials. Moreover, elevated attrition rates might have that feasibility studies of the “agonist-type” pharmacological
underestimated treatment effects and decisively influenced on intervention, namely outpatient-based supervised treatment
the GRADE judgment of the quality of evidence. Few trials with high-dose, extended-release preparation of amphetamines,
with features that are known to improve adherence in trials of should be considered particularly in countries with high rates of
pharmacologic treatment of substance use disorders, such as PSUDs that currently do not provide any medical treatment for
CM targeting drug use or attendance (Tardelli et al. 2018) and those individuals. In real-world scenarios, one possible strategy
daily supervised intake and motivational enhancement (Weiss is to offer treatment with prescription amphetamines in the
2004), were available. Also, quality assessment was setting of an OTP. Many patients with PSUD are already en-
downgraded for all outcomes due to possible detection bias, rolled in OTPs (those with co-occurring OUD and PSUD), and
since the intervention has potential behavioral effects that may others can be referred to OTPs for the medical management of
hinder blinding of clinicians, patients, and outcome assessors. PSUD as the traditional PSUD outpatient programs do not offer
Therefore, it is vital that the interpretations of our findings for consistent medical and multi-professional oversight.
clinical practice consider that the nature of the intervention Alternatively, mobile technology solutions for monitoring and
makes high-quality evidence methodologically impossible at increasing adherence to the medication may be considered.
this point. This warrants future trials with comparable methods
to those that showed best evidence (prescription amphetamines
in higher dosages for CUD, for example), since downgrades in
the quality of evidence are not due to lack of efficacy but to Conclusion
properties of the intervention and to methodological issues of
the trials included which may be difficult to overcome. Recent trials with extended-release formulations and higher
The present meta-analysis has several strengths. We in- dosages of PPs, particularly prescription amphetamines, have
cluded the GRADE approach for each of the subgroup analy- shown promising results promoting abstinence from cocaine
ses which might help in dealing with group specificities when and reducing drug use. PPs’ potential as an “agonist-type”
elaborating new public policies and in designing future clini- treatment seems to be better explored with higher dosage reg-
cal trials on this field. The new subgroup analysis by dose imens and at clinical settings that have direct observed dosing
range suggests a dose–response relationship and strengthens available. The results from patients with comorbid opioid use
the quality of the evidence supporting PPs for PSUDs. Lastly, disorders are particularly encouraging, and this may be due to
calculating NNTs provides a clinically translatable measure of the fact that high dosages of potent PPs were used, and this
effect that might facilitate the dissemination findings in clini- population is already enrolled to a healthcare facility that of-
cian guiding activities, though the NNT obtained from meta- fers daily attendance, supervised medication intake, evidence-
analyses should be interpreted with caution due to differences based psychosocial interventions, and a wide-range of ancil-
in treatment effects between studies (Marx and Bucher 2003). lary services. A widely used and successful model of treating
The results of the present study have implications for fur- opioid use disorder or incorporating mobile technology solu-
ther trials that aim to test the efficacy of PPs for PSUDs. An tions to monitor and enhance medication adherence may now
optimal trial should test at least one high dose of PPs with be assessed for treatment of individuals with psychostimulant
extended-release formulations to ensure the maximum poten- use disorder and incorporate prescription amphetamines as an
tial benefit and to test efficacy of the agonist-based therapy. agonist intervention. Considering the major public health im-
Moreover, features that minimize attrition and maximize ad- pact of untreated PSUD, and the absence of the widely accept-
herence with the medication, a common problem of trials with ed pharmacological intervention, there is an urgent need to
PSUDs, are warranted and may include CM, daily attendance conduct implementation studies of this treatment approach.
to clinic, and supervised medication intake. Use of extended-
release preparations and once-daily dosing, preferably under Compliance with ethical standards
direct observation, should be considered to maximize safety
and minimize diversion potential. Unstable cardiovascular Conflict of interest The authors have no conflict of interest to disclose.
 Psychopharmacology

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