Psilocybin for Treatment-Resistant OCD: A Randomized Control Trial
Kelemndi, B., et al. (2026). Psilocybin for Treatment-Resistant OCD: A Randomized Control Trial. The Lancet - PREPRINT (https://papers.ssrn.com/sol3/papers.cfm?abstract_id=6218466). This trial is registered at ClinicalTrials.gov, NCT03356483, and is now complete.
Abstract with select article content
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.
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; weight-adjusted, standardised to 70 kg; mean dose 18.34 (SD 4.63) mg [range 11.0–28.6 mg]) 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.
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<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<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.
Secondary Measures: Depression - MADRS improved significantly in the psilocybin group. At 1 week, MADRS scores decreased by 9.46 (95% CI 6.36–12.56) in the psilocybin group versus 0.57 (−2.13 to 3.27) in the niacin group (between-group difference 8.89 (95% CI 4.79–12.99); p<0.0001).
Self-reported disability on the SDS improved significantly from baseline to 12 weeks in the psilocybin group (mean improvement 8.27 (95% CI 4.12–12.43); p=0.001), representing a 42% reduction in functional impairment.
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.
Discussion: In this phase 2 trial in individuals with treatment-resistant OCD, a single dose of psilocybin produced a 10-point A-YBOCS reduction at 48 hours, more than double the minimal clinically important difference of 4.9 points, with an effect size (Cohen’s d=1.64) exceeding those of conventional treatments (d=0.5–0.8). The rapid onset within 48 hours—compared with weeks or months for standard treatments—suggests that psilocybin engages therapeutic mechanisms distinct from established interventions for OCD. Similar large benefits were seen in the Y-BOCS at 1 week and persisted in most participants for 12 weeks following dosing.