In this systematic review, we examined 7 systematic reviews and 68 trials of a variety of pharmacotherapies for stimulant use disorder (46 for cocaine, 14 for amphetamine and/or methamphetamine), and found largely disappointing results. We found no strong, consistent evidence that any drug class was effective in increasing abstinence, reducing use, or improving study retention rates. As the summary of evidence table shows, a key issue was the absence of good quality evidence: we found insufficient to low strength evidence for all drug classes in amphetamine/methamphetamine use disorder and most of the drug classes in cocaine use disorder, suggesting that further research in these areas may alter conclusions. On the other hand, we also found some areas in which there was consistent evidence of no effect, or negative effect. For patients with cocaine use disorder, we found moderate to high strength evidence that antidepressants (specifically, SSRIs and TCAs) do not improve abstinence, use, or retention; moderate strength evidence that anticonvulsants do not improve use or retention; and low to moderate strength evidence that dopamine agonists do not improve abstinence or retention. We found moderate strength of evidence that SSRIs increase risk of study withdrawal due to adverse events and that disulfiram treatment was associated with lower retention than placebo.

A motivating factor behind this review was to find promising treatments for a devastating condition that has been historically difficult to treat with pharmacotherapy. We identified several potentially effective treatments, though the strength of evidence is low, underscoring the need for further research to strengthen conclusions. First, psychostimulants as a class, and the antidepressant bupropion, may improve abstinence in cocaine use disorder, though the same studies did not find an improvement in reducing cocaine use or treatment retention.⁵ The anticonvulsant topiramate may also be effective for continuous cocaine abstinence.^18,66,67 Second, antidepressants and psychostimulants may be effective in patients with comorbid opioid use disorder.¹¹ Third, topiramate has the potential to be beneficial in those with methamphetamine use disorder (based on the finding from 1 larger, well-done trial).⁸⁷ Finally, antidepressants may decrease the risk of relapse in patients who have already achieved abstinence from cocaine.^41,96 The use of pharmacotherapy for relapse prevention is an intriguing finding that warrants exploration. In subgroup analyses, we found that 2-or-more-week abstinence at baseline (confirmed by UA), or a negative UA at screening, were more likely to predict success.^19,46 It is possible that those who are actively using stimulants are not engaged enough in treatment for pharmacotherapy to be effective. Retention rates varied widely across studies (24–97%), but overall low rates of retention could potentially affect the assessment of treatment effectiveness in the majority of studies (attrition was greater than 20% in 68% of the studies reporting retention rates). Unfortunately, pharmacotherapy itself does not appear to be effective in improving retention rates. Two areas of promise that are notable include those in which patients have already demonstrated engagement in treatment, or may have another rationale for ongoing engagement (as is the case for some patients with comorbid opiate use disorder, or tobacco use disorders). Perhaps the neurobiology of stimulant use disorders makes it more difficult for some to engage in treatment.⁹⁷ Whether the negative results we found reflect the biology of disease or lack of efficacy of the pharmacological interventions is unclear.

As such, behavioral interventions (ie, contingency management, cognitive behavioral therapy, and community reinforcement approach) continue to be mainstays of treatment and management of stimulant use disorders.^98–100 A systematic review by Minozzi et al found that any psychosocial treatment likely reduces drop-out rates, and may increase the period of abstinence (most of the studies reviewed involved contingency management in addition to treatment as usual).¹⁰⁰ In our comparison of all included studies with and without CM, we found that pharmacotherapeutic effects were similar in studies with and without a CM co-intervention.

The decision to consider any treatment depends on the anticipated balance of benefits and harms. One might consider use of a medication with lower strength evidence of benefit if the potential for adverse effects was known to be low. In this body of evidence, however, data on harms was poorly reported, resulting in insufficient evidence to draw conclusions about harms for most of the drugs examined in this population. None of these drugs are FDA-approved for this indication. Most have been widely used for other indications for many years and many have well-known adverse effect profiles. There was moderate strength evidence that SSRIs may be associated with a higher rate of treatment withdrawal due to adverse effects, but very few studies reported on the nature and rate of severe adverse effects.

Conclusions

We found no strong, consistent evidence that any drug class was effective in increasing abstinence, reducing use, or improving retention rates. We found moderate to high strength evidence that antidepressants, disulfiram, and anticonvulsants (with the exception of topiramate) are unlikely to be effective in non-abstinent patients. There are several promising areas deserving of further research including the use of bupropion, topiramate, treatment of abstinent patients to prevent relapse, and treatment of patients with comorbid opioid use disorder.

Conclusions Table A

Summary of the evidence on mental health pharmacotherapies for cocaine use disorder, stratified by drug class.

Conclusions Table B

Summary of the evidence on pharmacotherapies that are prescribed for other stimulant use disorders in studies of patients with cocaine use disorder, stratified by drug.

Conclusions Table C

Summary of the evidence on anticonvulsants/muscle relaxants for cocaine use disorder, stratified by drug.

Conclusions Table D

Summary of the evidence on dopamine agonists for cocaine use disorder.

Conclusions Table E

Summary of the evidence on mental health pharmacotherapies for comorbid cocaine and opioid use disorders, stratified by drug class.

Conclusions Table F

Summary of the evidence on the use of pharmacotherapies prescribed for other stimulant use disorders in studies of patients with comorbid cocaine and opioid use disorders, stratified by drug.

Conclusions Table G

Summary of the evidence on mental health pharmacotherapies for amphetamine/methamphetamine use disorder.

Conclusions Table H

Summary of the evidence on anticonvulsants/muscle relaxants for amphetamine/methamphetamine use disorder.

Conclusions Table I

Summary of the evidence on pharmacotherapies used for other stimulant use disorders in studies of patients with amphetamine/methamphetamine use disorder.

Conclusions Table J

Summary of the evidence on pharmacotherapies in patients with comorbid amphetamine/methamphetamine and opioid use disorders.