Cocaine use disorder has no approved pharmacotherapy, and contingency management remains the only intervention consistently associated with improved abstinence outcomes. Against that backdrop, a small randomized clinical trial published in JAMA Network Open found that psilocybin combined with intensive psychotherapy was associated with more cocaine-abstinent days and a lower risk of cocaine lapse compared with active placebo plus the same psychotherapy regimen.
The findings, however, should be considered preliminary and hypothesis-generating, according to both the study researchers and an accompanying invited commentary, because the trial included only 40 patients, had no prespecified power calculation, and faced substantial challenges with blinding and treatment attribution.
Researchers at the University of Alabama at Birmingham randomized 40 adults with cocaine use disorder to receive a single oral dose of psilocybin, 25 mg per 70 kg of body weight, or diphenhydramine, 100 mg, as active placebo. All patients received manualized psychotherapy incorporating cognitive behavioral treatment, including four to five preparation sessions, one all-day investigational drug session, and five postsession integration sessions.
The quadruple-blind, active placebo-controlled trial enrolled patients from May 2015 through August 2023, with data collection completed in May 2024. Enrollment therefore spanned nearly a decade, including the COVID-19 pandemic and substantial shifts in the stimulant overdose landscape in the US.
Eligible patients were aged 25 years or older, wanted to stop cocaine use, and had no significant comorbidities. The study excluded patients with current psychiatric disorders other than substance abuse or nicotine dependence, current hypertension, use of certain psychotropic medications, pregnancy or breastfeeding, and personal or family history of psychotic or bipolar disorders.
The primary outcomes were urinalysis-verified percentage of cocaine-abstinent days, complete cocaine abstinence, and time to first cocaine lapse through 180 days following treatment. Complete abstinence was defined as no cocaine use following the all-day drug session through day 180, verified by urinalysis, with patients lost to follow-up counted as nonabstinent.
Across postrandomization periods, patients who received psilocybin had approximately 29 more percentage points of cocaine-abstinent days than patients who received placebo, based on the study’s mixed-model analysis across follow-up periods. Pairwise comparisons showed 26 more percentage points during the integration period, 36 more percentage points from the final integration session through day 90, and 28 more percentage points from day 90 through day 180.
Complete abstinence through day 180 occurred in six of 20 patients who received psilocybin and none of the 20 patients who received placebo. Researchers reported that patients who received psilocybin were approximately 18 times more likely to achieve complete abstinence (odds ratio, 18.37; 95% CI, 1.92-2,468), with a number needed to treat of 3, although the estimate was derived from a small sample with wide uncertainty around effect estimates.
At 90 days, Kaplan-Meier estimates for remaining free of cocaine lapse were 55% among patients who received psilocybin and 21% among those who received placebo. Patients who received psilocybin also had a lower risk of cocaine lapse over time.
No serious adverse events were reported. Adverse events occurred in 13 of 20 patients who received psilocybin and two of 20 patients who received placebo. Events reported with psilocybin included hypertension, emotional distress, crying, headache, agitation, altered perception, and heightened visual imagery. One patient also reported suicidal ideation more than 1 month following the psilocybin session following cocaine relapse; investigators did not attribute the event directly to psilocybin, and it resolved without sequelae.
Most adverse events occurred during the all-day drug session and resolved without sequelae. The researchers also noted that only potentially serious or drug-related adverse events were systematically documented, meaning mild or unrelated adverse events may have been underreported.
The study population differed from many prior psychedelic trials, which have often enrolled predominantly White and higher-income participants. Of the 40 patients in the current trial, 33 were Black, seven were White, and 26 reported annual income of $20,000 or less. Most patients smoked cocaine, and cocaine use histories extended for more than 2 decades.
Still, several methodological limitations complicate interpretation of the findings.
Blinding was substantially compromised. Eighteen of 20 patients who received psilocybin correctly guessed their treatment assignment compared with nine of 19 patients who received placebo. The primary and secondary therapists each correctly identified treatment assignment in 39 of 40 cases.
Psilocybin recipients also reported higher expectancy scores during follow-up, raising concern that expectancy effects may have contributed to observed efficacy differences between groups.
The trial also lacked psychotherapy fidelity monitoring, and lead study researcher Peter S. Hendricks, PhD, of the University of Alabama at Birmingham Heersink School of Medicine, served as the primary therapist for all patients, creating potential allegiance bias that could not be formally assessed.
The researchers acknowledged additional limitations, including reliance on self-reported cocaine use supplemented by urinalysis, lack of adjustment for multiple comparisons, small sample size, and limited generalizability to routine clinical populations.
No subgroup efficacy analyses were reported, and the study did not report secondary substance use outcomes or broader functional recovery measures.
In an invited commentary, Erin E. Bonar, PhD, of Michigan Innovations in Addiction Care through Research and Education Program, University of Michigan Department of Psychiatry, wrote that the findings “may offer a path forward for rigorous research,” but cautioned that psychotherapy fidelity monitoring was absent and that implementation challenges remain substantial.
Dr. Bonar noted that contingency management remains the most effective current treatment for stimulant use disorders under American Society of Addiction Medicine and American Academy of Addiction Psychiatry guidelines.
By contrast, psilocybin-assisted therapy remains difficult to implement clinically because psilocybin is a Schedule I substance in the US and the intervention required extensive psychotherapy, an all-day monitored administration session, and two therapists.
“It remains important to explore treatments using rigorous methods with the populations that are most likely to benefit, while also deploying existing efficacious care models,” Dr. Bonar concluded.
Dr. Hendricks reported grants, consulting fees, equity interests, patents, and company leadership roles related to psychedelic therapeutics outside the submitted work. Multiple co-researchers also reported industry relationships.
Separately, Filament Health was granted rights to use the trial data toward potential US Food and Drug Administration authorization efforts, and associated intellectual property was licensed to the company.
The study was funded by the University of Alabama at Birmingham and the Heffter Research Institute. Dr. Bonar reported no conflicts of interest.
Source: JAMA Network Open
