Psilocybin for Treatment-Resistant OCD: A Randomised Controlled Trial

Background: Obsessive-compulsive disorder (OCD) affects 2–3% of the population worldwide, and 40–60% of patients do not respond to first-line treatments. We evaluated the efficacy and safety of a single dose of psilocybin in adults with treatment-resistant OCD.<br><br>Methods: In this phase 2, randomised, double-blind, placebo-controlled trial at the Connecticut Mental Health Center, Yale University (New Haven, CT, USA), adults aged 18–65 years with treatment-resistant OCD (Y-BOCS score ≥19 and ≥2 failed adequate treatment trials) were randomly assigned (1:1) using permuted blocks to receive a single dose of psilocybin (0·25 mg/kg orally) or niacin (250 mg orally). Independent raters were masked to treatment assignment through 1-week assessments. The primary analysis followed intention-to-treat principles. Primary outcomes were change in A-YBOCS from baseline to 48 hours and Y-BOCS from baseline to 1 week. This trial is registered at ClinicalTrials.gov, NCT03356483, and is now complete.<br><br>Findings: Between Nov 1, 2018, and June 30, 2023, 194 individuals were assessed for eligibility; 28 enrolled and randomly assigned (14 to psilocybin, 14 to niacin; 14 female, 13 male, one non-binary). At 48 hours, A-YBOCS scores decreased by 9·76 points (95% CI 6·00–13·52) in the psilocybin group versus +0·07 (−2·21 to 2·35) in the niacin group (between-group difference 9·83 points (95% CI 5·04–14·62); p&lt;0·0001). At 1 week, 69·2% (9/13) of psilocybin participants achieved response (≥35% Y-BOCS reduction) versus 0% (0/14) of niacin participants (p&lt;0·0001; number needed to treat 1·4). Benefits persisted through 12 weeks. In open-label crossover, 35·7% (5/14) achieved response at 1 week. One serious adverse event (suicidal ideation) occurred; no treatment-related deaths occurred.<br><br>Interpretation: A single dose of psilocybin produced rapid, clinically meaningful, and sustained OCD symptom reductions, suggesting a novel interventional paradigm for treatment-resistant OCD warranting larger confirmatory trials.