Five-year outcomes of psilocybin-assisted therapy for Major Depressive Disorder

Abstract Background Major Depressive Disorder (MDD) is a leading cause of disability and economic loss, with high recurrence and treatment resistance. Psilocybin-assisted therapy (PAT) shows promise in reducing depressive symptoms, but long-term effects are unknown. We aimed to determine the long-term safety and efficacy of PAT for MDD over a five-year follow-up period. Methods Individuals who previously participated in an RCT studying the effects of PAT for patients with MDD were contacted for a long-term follow-up (LTFU) study. This study uses a parallel convergent mixed methods design. Of the original 24 RCT participants, 21 enrolled in the LTFU study, with 18 (75%) completing it. For the six non-completers, baseline scores were used in quantitative analyses as conservative estimates. The primary outcome was clinician-rated change in depression severity from baseline to LTFU. Secondary outcomes included anxiety, functional impairment, and qualitative assessments of participants' experiences and mental health. Results Significant and sustained reductions in depression were observed, with 67% in remission for at least five years post-treatment. Anxiety and functional impairment also improved. Qualitative interviews revealed lasting positive changes in mindset, emotional health, and relationships. Participants reported enhanced empathy, self-acceptance, and improved interpersonal relationships. No severe adverse events were reported. Conclusion This study supports the long-term efficacy and safety of PAT in reducing depressive symptoms and improving mental health in patients with MDD. Further research is needed to determine if these findings can be replicated, and to explore the mechanisms behind the sustained benefits of PAT, potentially validating an approach that could transform the treatment of MDD.