Long-Term Efficacy of Psilocybin with Adjunct Psychotherapy in Treatment-Resistant Major Depression: 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 doses of psilocybin with adjunct psychotherapy in TRD until 12 months. METHODS: This is a naturalistic follow-up of a phase 2b, randomized, active placebo-controlled trial in adults with TRD, where participants were randomized to receive two drug administrations 6 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 12 weeks, after which participants could pursue other treatments, with follow-ups at 6 and 12 months. The primary follow-up endpoint was change from baseline on the Hamilton Rating Scale for Depression (HAMD17). RESULTS: Overall, 126/144 randomized participants (51 females, 40%) completed at least one follow-up visit. Mean baseline HAMD17 scores across groups ranged from 21.6 to 22.2. 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 to -6.70, adj. p < 0.0001) at 6 months and -7.74 (95% CI: -9.04 to -6.43, adj. p < 0.0001) at 12 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 to 5.60). CONCLUSION: This is the largest and most complete systematic 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 12 months in TRD.