Psilocybin in Treatment-Resistant Depression: EPISODE Trial Readout

Key Takeaways

• The primary end point was treatment response at week 6 before the second dose, and the first hierarchical comparison of psilocybin 25 mg versus nicotinamide was nonsignificant.
• Exploratory mean-change secondary analyses were described as showing a clinically meaningful reduction in depressive symptoms with psilocybin 25 mg.
• Adverse events were reported mainly acutely; suicidal ideation on dosing days was more often reported with psilocybin 25 mg, and two serious adverse reactions were described, although the treatment was reported as well tolerated by most participants.

In the EPISODE randomized clinical trial, psilocybin 25 mg produced a 17.0% week-6 response rate, but the prespecified primary efficacy comparison was nonsignificant. This 2-center, triple-blinded, phase 2b, active placebo-controlled randomized clinical trial enrolled adults aged 25 to 65 years with treatment-resistant depression after antidepressant withdrawal. Participants received oral synthetic dosing with psychotherapeutic sessions across two planned dosing visits. The overall readout was inconclusive, with separate secondary outcome patterns and safety findings.

Adults 25 to 65 years old with treatment-resistant depression were recruited predominantly from 2 outpatient settings in Germany after discontinuing antidepressant medication. Investigators randomized 144 participants, and 142 were included in the primary efficacy analysis, across 4 dosing-sequence groups assigned in a 2:2:1:1 ratio. The dosing framework included oral synthetic psilocybin 25 mg, psilocybin 5 mg, or nicotinamide 100 mg, each administered with psychotherapeutic sessions. Two doses were given 6 weeks apart, and the randomized cohort had a mean age of 42.6 years, with 59.0% male participants. Week 6, before the second dose, was the key time point for the primary analysis.

Treatment response for the primary end point was defined as at least a 50% reduction on HAMD17 at week 6 before the second dose. Response rates were 17.0% with psilocybin 25 mg, 12.5% with psilocybin 5 mg, and 10.6% with nicotinamide. The first hierarchical comparison between psilocybin 25 mg and nicotinamide was nonsignificant, with an adjusted odds ratio of 1.73, 95% CI 0.53-6.23, and P = .19. Because that result did not cross the 1-sided alpha threshold of P = .03, further formal testing was not performed. The prespecified primary efficacy test was therefore not met.

Key secondary end points included BDI-II response and mean change from baseline on HAMD17 and BDI-II at week 6. Mean-change analyses were characterized as exploratory and described as consistent with a clinically meaningful effect of psilocybin 25 mg. Even with that symptom reduction, the trial was framed as inconclusive overall because the prespecified primary comparison was nonsignificant.

Safety findings centered on adverse events with psilocybin 25 mg, mainly during the acute period around dosing. Suicidal ideation on dosing days was reported in 4% of the psilocybin 25 mg group and 1% to 2% of comparator conditions. Two serious adverse reactions were described after psilocybin 25 mg, including one case of hallucinogen persisting perception disorder. Study data were analyzed from April 2024 to November 2025. Overall, the readout combined exploratory symptom signals with acute and serious safety observations, although the treatment was described as well tolerated by most participants.