A randomized clinical trial of repeated doses of psilocybin for the treatment of obsessive-compulsive disorder.

Current treatments for obsessive-compulsive disorder (OCD), including serotonin reuptake inhibitors and cognitive-behavioral therapy, are often insufficient. Psilocybin, a 5HT2a agonist psychedelic, has shown promise for treating OCD, but rigorous evidence is still needed. This randomized clinical trial evaluated safety, tolerability, and benefit of multiple psilocybin doses in OCD patients. Fifteen participants were randomized to receive 4 weekly sessions of high-dose (300 g/kg), low-dose (100 g/kg) psilocybin, or active placebo (lorazepam) in a double-blind Phase 1 (n = 5 per condition), followed by four additional high-dose sessions (single-blind Phase 2). OCD severity was assessed with the Yale-Brown Obsessive Compulsive Scale (YBOCS) following each session, and prospectively for 6 months. Safety was evaluated via adverse event systematic assessment, suicide severity rating, and psychosis screening. Psilocybin was generally well-tolerated, with no serious adverse events, or psychotic symptoms, and no significant changes in suicide severity scores. Psilocybin but not placebo significantly reduced YBOCS scores. At the end of 8-week treatment, after participants had received at least four high doses of psilocybin, 73.3% were responders ( 35% reduction in YBOCS scores), with 40% in remission. These effects diminished but remained substantial at 6 months. Post hoc analysis of cumulative dosing correlated with YBOCS score reductions at the end of treatment. Administration of up to eight doses of psilocybin in a clinical research setting appears to be safe and potentially effective for patients with OCD. Larger trials are needed to further support efficacy and refine treatment protocols. ClinicalTrials.gov ID NCT03300947.