Long-Term Efficacy of Psilocybin with Adjunct Psychotherapy in Treatment-Resistant Major Depression (EPIsoDE): 6- and 12-Month Naturalistic Follow-Up of a Phase 2b Trial
This paper reports the longest and largest follow-up dataset from the EPIsoDE trial, examining whether the antidepressant effects of psilocybin-assisted psychotherapy persist for up to 12 months in people with treatment-resistant depression (TRD)
This paper reports the longest and largest follow-up dataset from the EPIsoDE trial, examining whether the antidepressant effects of psilocybin-assisted psychotherapy persist for up to 12 months in people with treatment-resistant depression (TRD)
Abstract
Introduction: Psilocybin shows promise for treatment-resistant depression (TRD), but long-term data are limited. This study examined the antidepressant effect of one or two psilocybin doses with adjunct psychotherapy in TRD until twelve months.
Methods: This is a naturalistic follow-up of a phase 2b, randomized, active placebo-controlled trial, where participants were randomized to receive two drug administrations six weeks apart, embedded within seven psychotherapeutic sessions: (1) active placebo (100 mg nicotinamide) then 25 mg psilocybin, (2) 5 mg psilocybin then 25 mg psilocybin, (3a) 25 mg psilocybin then 5 mg psilocybin, or (3b) 25 mg psilocybin twice. The controlled phase ended at twelve weeks, after which participants could pursue other treatments, with follow-ups at six- and twelve-months.
The primary follow-up endpoint was change from baseline on the Hamilton Rating Scale for Depression (HAMD17).
Results: 126/144 randomized participants (51 females, 40%) completed at least one follow-up visit. A generalized additive mixed regression model for change in HAMD17 scores showed a significant time effect across groups for both follow-up time points, with estimated average changes from baseline of -7.93 (95% CI: -9.17, -6.70, adj. p<0.0001) at six months and -7.74 (95% CI: -9.04, -6.43, adj. p<0.0001) at twelve months, without significant group differences. Results were consistent when controlling for antidepressant pharmacotherapy and psychedelic use. Re-initiation of antidepressant pharmacotherapy during follow-up was strongly associated with higher HAMD17 scores (β=3.79, 95% CI: 1.98, 5.60).
Conclusion: This is the largest and most complete follow-up of any clinical psychedelic trial. The findings demonstrate a stable and clinically meaningful long-lasting antidepressant effect of one or two 25 mg doses psilocybin with adjunct psychotherapy up to twelve months in TRD.
A key finding was that one or two 25 mg psilocybin sessions combined with psychotherapy produced antidepressant improvements that remained largely stable for 12 months in patients with treatment-resistant depression. The durability of effect is striking compared with many conventional interventions, although the original trial's mixed efficacy findings and the need for specialized psychological support mean that larger Phase 3 studies are still required before firm conclusions can be drawn.
Mertens LJ, Betzler F, Brand M, Evens R, Jungaberle A, Jungaberle H, et al. Long-term efficacy of psilocybin with adjunct psychotherapy in treatment-resistant major depression (EPIsoDE): 6- and 12-month naturalistic follow-up of a Phase 2b trial. Psychother Psychosom. 2026. doi:10.1159/000552272. Read Paper
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