Psilocybin for Treatment-Resistant OCD: A Randomized Controlled Trial

Background: Obsessive-compulsive disorder (OCD) affects 2-3% of the population worldwide. 40-60% of patients do not respond to first-line interventions. We evaluated the efficacy and safety of a single dose of psilocybin in patients with treatment-resistant OCD.Methods: In this phase 2, randomized, double-blind trial, we randomly assigned 28 adults with treatment-resistant OCD to receive a single dose of psilocybin (0.25 mg/kg; n=14) or niacin (250 mg; n=14), in a supportive controlled setting. Primary outcomes were Acute Yale-Brown Obsessive-Compulsive Scale (A-YBOCS) from baseline to 48 hours post-treatment and weekly Y-BOCS assessments through 12 weeks. Secondary outcomes included depression symptoms (MADRS) and functional disability (SDS). All participants initially assigned to niacin crossed over to open-label psilocybin after 1 week.Results: At 48 hours, A-YBOCS scores decreased from 24.07±6.02 to 14.31±8.83 in the psilocybin group versus no change (24.29±4.81 to 24.36±3.95) in the niacin group (between-group difference, 9.83 points; 95% CI, 5.19-14.91; P<0.001; Cohen's d=1.64). At one week, 69.2% (9/13) of psilocybin participants achieved response (≥35% Y-BOCS reduction) versus 0% (0/14) of niacin participants (P<0.001; number needed to treat, 1.4). Benefits persisted through 12 weeks in the psilocybin group. One serious adverse event occurred. In open-label treatment, A-YBOCS decreased by 6.14 points at 48 hours (95% CI, 2.56-9.72; P=0.003), with 35.7% achieving response at one week.Conclusions: A single dose of psilocybin with unstructured support produced rapid, clinically meaningful, and sustained reductions in OCD symptoms. This profile suggests a novel interventional paradigm for treatment-resistant OCD warranting larger confirmatory trials.Trial Registration: ClinicalTrials.gov number, NCT03356483.