Psilocybin for Cocaine Use Disorder in a Randomized Trial

Key Takeaways

• Psilocybin with psychotherapy was associated with more cocaine-abstinent time than diphenhydramine with the same psychotherapy.
• Complete abstinence was more frequent and time to first lapse was longer in the psilocybin group.
• Serious adverse events were not reported, and the findings were interpreted cautiously because of blinding challenges and small-sample uncertainty.

Complete abstinence through day 180 was seen in 6 of 20 adults given psilocybin and in 0 of 20 given diphenhydramine in a randomized clinical trial in JAMA Network Open. All participants received the same psychotherapy framework, making this a comparison of psilocybin versus active placebo within a shared behavioral program. Participants were adults with cocaine use disorder followed through day 180 after treatment. Serious adverse events were not observed during the study. The findings reflect trial outcomes within this setting.

The quadruple-blind, active placebo-controlled trial used a parallel-group design at a major medical research center in the Deep South of the US. Researchers randomized 40 adults with cocaine use disorder in a 1:1 ratio to psilocybin or diphenhydramine. Participants were aged 25 years or older, met DSM-IV criteria for cocaine dependence, wanted complete abstinence, and were mostly Black men with lower income. They received a single oral dose of psilocybin 25 mg per 70 kg or diphenhydramine 100 mg, plus manualized psychotherapy incorporating cognitive-behavioral treatment before and after an all-day drug session. Prespecified outcomes were cocaine-abstinent days, complete abstinence, and time to first lapse through day 180, assessed by timeline followback and confirmed with urinalysis.

Psilocybin recipients had a higher percentage of cocaine-abstinent days after randomization, with beta 28.95, 95% CI 18.22 to 39.67, and P < .001. Complete abstinence was also more likely with an odds ratio of 18.37, 95% CI 1.92 to 2468.17, and P = .007. Time to cocaine lapse favored psilocybin, with a hazard ratio of 0.28, 95% CI 0.13 to 0.60, and P = .001. Kaplan-Meier estimates showed 90-day survival probabilities of 55.0% with psilocybin and 21.05% with placebo. Across the prespecified efficacy measures, results favored psilocybin through 180 days.

Serious adverse events and serious treatment-related adverse events were not observed, no rescue medications were administered, and most events were expected session-day occurrences that resolved without sequelae. Adverse events occurred in 13 of 20 psilocybin participants and 2 of 20 placebo participants; most occurred during the all-day session, with hypertension in 6 and 2, respectively. Emotional distress and crying each occurred in 5 of 20 psilocybin participants, headache in 3, and one post-session suicidal ideation event was judged unrelated. The investigators cautioned that small sample size, wide confidence intervals, salient drug effects that challenged blinding, reliance partly on self-report, therapist allegiance bias, and limited generalizability constrained certainty. They described the results as hypothesis-generating, while stating that the regimen appeared safe and efficacious in this trial and required replication and extension.