A single mushroom-derived compound, paired with therapy, outperforms placebo by a wide margin
STUDY: Hendricks PS et al, JAMA Network Open 2026;9(5)
STUDY TYPE: Randomized, quadruple-blind (but blind broken), placebo-controlled trial
FUNDING: University of Alabama at Birmingham; Heffter Research Institute
Background
Psilocybin, a serotonin 2A receptor agonist and psychedelic, has shown promise in alcohol use disorder and smoking cessation. This is the first trial to test it in cocaine use disorder.
The Study
- 40 adults with cocaine use disorder recruited in Birmingham, Alabama; 83% Black, 65% with annual income under $20,000.
- Randomized to a single oral dose of psilocybin (25 mg/70 kg) or active placebo (diphenhydramine 100 mg), plus manualized cognitive behavioral therapy before and after the drug session.
- Outcomes tracked through 180 days: abstinent days, complete abstinence, and time to first relapse.
Psilocybin recipients had about 29 more percentage points of abstinent days than placebo recipients across the follow-up period (effect size large, 1.4-1.9; number needed to treat = 3.3).
Complete abstinence from the end of treatment through day 180 was achieved by 30% on psilocybin versus 0% on placebo, with psilocybin patients about 18 times more likely to remain abstinent (odds ratio 18.4). Risk of relapse was 72% lower in the psilocybin group (hazard ratio 0.28).
Side Effects
- Adverse events in 65% on psilocybin versus 10% on placebo, most during the drug session itself: hypertension (30%), emotional distress and crying (25% each), and headache (15%).
- One psilocybin patient had passive suicidal ideation more than a month after the session, following a cocaine relapse; it resolved without treatment.
Limitations
Only 40 participants. Blinding failed: 90% of psilocybin recipients correctly guessed their assignment. The lead investigator served as primary therapist, which could have introduced allegiance bias. Fidelity monitoring of the psychotherapy wasn’t done, making it hard to separate the drug effect from the therapy effect.
Practice Implications
- Like many psychedelic trials, the effect size is large and the unblinding is high.
- While unblinding raises questions about the science, a harm reduction approach would favor a single dose of psilocybin over continuous cocaine.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
