Importance Psilocybin has been proposed as a rapid-acting antidepressant (onset lt;2 weeks) with sustained effects (gt;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 lt; .001) and 42 (mean difference, −8.33; −13.94 to −2.71; P = .004) but no longer on day 365 (mean difference, −3.68; −9.30 to 1.94; P = .20). For MADRS-S, the psilocybin group had a significantly greater reduction beginning at day 2 (mean difference, −9.58; 95% CI, −16.05 to −3.11; P = .004), with group differences persisting through day 102 (mean difference, −6.60; 95% CI, −13.01 to −0.19; P = .04) and then isolated effects at days 283 and 343. Most reported treatment-emergent adverse events were transient and of mild to moderate severity. No drug-related serious adverse events were reported. Two participants in the psilocybin group reported persistent, severe anxiety that required medical attention. Conclusions and Relevance In this randomized clinical trial of MDD, a single dose of psilocybin was associated with rapid antidepressant effects, observed by day 2 and persisting for more than 3 months on secondary outcomes; psilocybin was generally well tolerated, but some individuals required additional support after dosing due to anxiety. These results suggest that psilocybin may provide a rapid and relatively long-lasting antidepressant effect on major depressive disorder, warranting further investigation into repeated dosing or adjunctive treatment strategies. Trial Registration ClinicalTrials.gov Identifier: NCT04630964
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