Short-Term and Late-Term Effects of Psilocybin on Symptoms in Major Depression

Importance: Psilocybin has been proposed as a rapid-acting antidepressant (onset 6 weeks), but evidence from randomized clinical trials remains limited, particularly in the broader major depressive disorder (MDD) population. Objective: To assess short-term and long-term antidepressant effects of psilocybin therapy in patients with MDD. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial of participants diagnosed with moderate to severe recurrent MDD was conducted at the Northern Stockholm Psychiatric Clinic between January 26, 2021, and February 19, 2024. Statistical analysis was performed from February 20, 2024, to June 20, 2025. Interventions: Participants received a single dose of psilocybin (25 mg) or active placebo (niacin, 100 mg) and 5 psychotherapeutic support sessions during 17 days. Main Outcomes and Measures: The primary end point was between-group difference in change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 8. Secondary end points included MADRS scores on days 15, 42, and 365, as well as monthly self-reports (MADRS-S) of depressive symptoms, disability, quality of life, and anxiety throughout the 365-day follow-up. Results: The study included 35 participants (21 [60%] female; mean [SD] age, 41.0 [10.1] years) diagnosed with moderate to severe recurrent MDD, with 17 randomized to the psilocybin group and 18 to the niacin group. The study met its primary end point with a significant mean between-group difference (model estimated) in change in MADRS score on day 8 (-7.27; 95% CI, -12.89 to -1.65; P =.01) in favor of psilocybin. The between-group difference was significant also on days 15 (mean difference, -11.03; 95% CI, -16.65 to -5.42; P