JAMA Netw Open
Psilocybin plus therapy shows promise in cocaine use disorder
Clinical Takeaway: Psilocybin-assisted psychotherapy may emerge as a future option for cocaine use disorder, but the findings are early.
Cocaine use disorder remains one of the few major substance use disorders without an approved pharmacotherapy, and psychosocial interventions have produced only modest gains. This trial tested whether a single dose of psilocybin combined with manualized psychotherapy could improve abstinence in motivated patients.
In this study of 40 randomized adults, psilocybin recipients were abstinent on about 29 more days out of every 100 than placebo recipients, with large effect sizes across each follow-up window. Six of 20 psilocybin participants (30%) achieved complete abstinence through 180 days of follow-up, compared with none of the placebo participants. Risk of cocaine lapse was reduced by 72%.
The participants were 82.5% Black and 65% reported annual income of $20,000 or less, groups historically underrepresented in psychedelic research. Median age was 50, and cocaine use had typically spanned more than two decades.
The randomized, quadruple-blind, single-site trial enrolled adults with DSM-IV cocaine dependence at the University of Alabama at Birmingham between 2015 and 2023. Participants received four to five preparation psychotherapy sessions, then a single oral dose of psilocybin (25 mg per 70 kg) or 100 mg diphenhydramine as active placebo, followed by five integration sessions.
Cocaine abstinence was confirmed by urinalysis at each visit. No serious adverse events occurred; expected effects during the drug session included transient hypertension, emotional distress, and headache.
If replicated in larger and more diverse trials, the findings could open a therapeutic avenue for a condition that has resisted decades of pharmacologic development. Practical questions remain about dosing, optimal psychotherapy structure, and how psilocybin-assisted treatment could be implemented in the populations most affected.
Psilocybin remains investigational with no FDA-approved indication. Positive Phase 3 data has been reported in treatment-resistant depression and a rolling NDA is being submitted to FDA under a national priority voucher. Use of the treatment in major depressive disorder is in late-stage testing, while substance use indications remain earlier stage.
The authors conclude, "Psilocybin appeared to be safe and efficacious for treating cocaine use disorder among individuals from underrepresented and vulnerable populations. Further research is warranted to replicate and expand these findings."
Source: Hendricks PS. JAMA Netw Open. 2026 May 7. Psilocybin in the Treatment of Cocaine Use Disorder