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.
Lea J Mertens, Felix Betzler, Manuela Brand, Ricarda Evens, Andrea Jungaberle, Henrik Jungaberle, Laura Kärtner, Tomislav Majić, Christian N Schmitz, Andreas Ströhle, Dennis Scharf, Moritz Spangemacher, Max Wolff, Zahra Assadi, Scharif Bahri, Lilith Becher, Luca V Färber, Henry Harder, Niklas Kirchen, Eugenia Kulakova, Linda C Kunz, Andy Meijer, Barbara Rohrmoser, Stefan Wellek, Moritz M Berger, Michael Koslowski, Gerhard Gründer
Psychotherapy and psychosomatics May 27, 2026 DOI: 10.1159/000552272 via PubMed
Summary
AI-generated from the abstractA single 25 mg dose of psilocybin, or two such doses given six weeks apart, combined with psychotherapy produced a stable and clinically meaningful reduction in depression symptoms for up to twelve months in people with treatment-resistant depression. The average improvement on the Hamilton Rating Scale for Depression was about 7.9 points at six months and 7.7 points at twelve months, with no significant difference between dosing groups. Restarting standard antidepressant medication during follow-up was strongly linked to higher depression scores. This naturalistic follow-up of a phase 2b trial is the largest and most complete long-term assessment of psilocybin for depression to date.
Study at a glance
| Characteristics | Naturalistic follow-up of a phase 2b, randomized, active placebo-controlled trial Peer reviewed |
|---|---|
| Sample size | 126 |
| Population | Adults with treatment-resistant depression |
| Interventions | Psilocybin Nicotinamide |
| Dose | 25 mg, 5 mg, 100 mg |
| Duration | Twelve-month follow-up |
| Key finding | One or two 25 mg doses of psilocybin with adjunct psychotherapy produced a stable and clinically meaningful antidepressant effect lasting up to twelve months in treatment-resistant depression. |
Abstract
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. 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). 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). 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.