BACKGROUND AND AIMS: Cocaine use disorder (CUD) is an increasingly widespread concern worldwide. Various pharmacological treatments have been investigated for CUD, but their efficacy remains unclear, and none have been licensed for treatment. Therefore, we assessed the comparative effectiveness, safety and acceptability of pharmacological interventions for the treatment of CUD and prevention of relapse.

METHODS: Systematic review and network meta-analyses (PROSPERO: CRD42024596434) of double-blind randomized controlled trials (RCTs) of pharmacological interventions specifically tested for the treatment of CUD with a minimum follow-up of 4 weeks in any in/outpatient setting, with no restriction on geographic location. Participants included adults with diagnosed CUD. Participants with co-occurring substance use disorders and/or common mental health conditions were eligible. We assessed risk of bias using the Cochrane Risk of Bias 2 tool and certainty of evidence was assessed using the Confidence in Network Meta-analysis framework. We assessed 12 effectiveness, three acceptability and two safety outcomes. Our primary outcomes were continuous abstinence, point abstinence, dropout for any reason and serious adverse events. We also examined longest duration of continuous abstinence, extent of cocaine use, craving, severity of dependence, dropout due to adverse events, adherence and mortality.

RESULTS: We included 218 reports of 163 studies (14 871 participants) assessing 89 unique medications, grouped into 8 categories (agonist/replacement approaches; antidepressants and other serotonergic agents; glutamate modulators; anticonvulsants and GABAergic agents; antagonist/blocker approaches; opioid agonists and antagonists; combination pharmacotherapy; other neuroactive agents). Most study results had some concerns or high risk of bias, and the results of syntheses were generally judged to be very low certainty evidence. As such, the findings ought to be interpreted with caution. No single treatment type showed consistent beneficial effects across all effectiveness outcomes and there was limited evidence that results varied by intervention type or presence of co-occurring comorbidity.

CONCLUSIONS: In a comprehensive network meta-analysis, we found no convincing evidence for the effectiveness of any pharmacological treatments for cocaine use disorder.