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

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.