Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial.

Importance: Psilocybin shows promise in treating depression, although limitations of previous research warrant further research. Objective: To investigate the efficacy and safety of oral psilocybin, 25 mg, with adjunct psychotherapy in treatment-resistant depression (TRD). Design, Setting, and Participants: This was a 2-center, triple-blinded (investigator, participant, rater), phase 2b, active placebo-controlled randomized clinical trial. Participants were randomized to 4 groups in ratios 2:2:1:1, receiving 2 doses 6 weeks apart (week 0, week 6) as follows: (1) placebo (nicotinamide, 100 mg) then psilocybin, 25 mg; (2) psilocybin, 5 mg, then 25 mg; and (3) psilocybin, 25 mg, then 5 mg or psilocybin, 25 mg, twice embedded in psychotherapeutic sessions. Participants aged 25 to 65 years with TRD and withdrawn from antidepressant medication were recruited predominantly from 2 outpatient settings in Germany. Study data were analyzed from April 2024 to November 2025. Interventions: Oral synthetic psilocybin, 25 mg; psilocybin, 5 mg; or nicotinamide, 100 mg administered with psychotherapeutic sessions. Main Outcomes and Measures: The primary end point was treatment response (≥50% reduction on the Hamilton Rating Scale for Depression [HAMD17]) at week 6 before the second dose. Key secondary end points were response on the Beck Depression Inventory II (BDI-II) and mean change from baseline on the HAMD17 and BDI-II at week 6. Results: A total of 144 participants (mean [SD] age, 42.6 [10.8] years; 85 male [59.0%]) were randomized, and 142 were included in the primary efficacy analysis: psilocybin, 25 mg (n = 47), psilocybin, 5 mg (n = 48), and nicotinamide (n = 47). Response rates on the primary end point were 17.0% in the group receiving psilocybin, 25 mg; 12.5% in the group receiving psilocybin, 5 mg; and 10.6% in the group receiving nicotinamide. The first hierarchical comparison was nonsignificant (psilocybin, 25 mg vs nicotinamide, adjusted odds ratio [OR], 1.73; 95% CI, 0.53-6.23; P = .19; 1-sided α P = .03); consequently, further formal testing was not performed. Analyses of key secondary end points (mean changes from baseline on HAMD17 and BDI-II) provided exploratory evidence of a clinically meaningful effect of psilocybin, 25 mg. Psilocybin, 25 mg, was linked to adverse events, predominantly acutely, and was associated with higher reports of suicidal ideation on dosing days (4% vs 1%-2% in comparator conditions). Two serious adverse reactions were reported after psilocybin, 25 mg, including 1 case of hallucinogen persisting perception disorder. Conclusion and Relevance: In this randomized clinical trial, psilocybin, 25 mg, with adjunct psychotherapy, was associated with a clinically meaningful reduction in depressive symptoms in individuals with TRD, although findings did not show a significant effect on the primary outcome. The treatment was well tolerated by most participants, although safety signals were observed. While overall this constituted an inconclusive trial, these results add to the existing evidence on the potential of psilocybin treatment for depression. Trial Registration: ClinicalTrials.gov Identifier: NCT04670081.