Abstract
This 2-center, triple-blind, active-placebo-controlled phase 2b trial (EPISODE) evaluated oral psilocybin with adjunct psychotherapy in 144 adults with treatment-resistant depression across two German outpatient sites. Participants received 25 mg psilocybin, 5 mg psilocybin, or active placebo (nicotinamide), each paired with psychotherapeutic sessions, in two dosing rounds six weeks apart. The primary endpoint (≥50% reduction on the 17-item Hamilton Depression Rating Scale [HAMD-17] at week 6) was not met: response rates were 17.0% (25 mg), 12.5% (5 mg), and 10.6% (placebo), a non-significant difference. Secondary analyses found a clinically meaningful reduction in depressive symptoms with the 25 mg dose, though a second full dose added no further benefit and individual responses varied widely. Psilocybin, 25 mg, was associated with more adverse events, including higher rates of suicidal ideation on dosing days and two serious adverse reactions.