Real-World Psilocybin Therapy for Treatment-Resistant Depression: a Retrospective Observational Study

Psilocybin has demonstrated promising antidepressant effects in depression and treatment-resistant depression (TRD) in controlled clinical trials. However, its effectiveness and safety in real-world therapeutic settings remain largely unknown. Although psilocybin is not yet approved as an antidepressant treatment, Switzerland’s unique legal framework allows its limited medical use for TRD. We conducted a retrospective analysis of medical records from 19 TRD patients treated with psilocybin (20–35mg) across one to four dosing sessions at the Psychiatric University Hospital Zurich. Depression severity was assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Beck Depression Inventory II (BDI). Changes from baseline to interim and post-treatment were analyzed, including response, remission, and the reliable change index. MADRS scores significantly decreased from baseline ( M  = 30.78) to post-treatment ( M  = 19.89), with a large effect size (Hedges’ g  = 1.37, p  < .001). BDI scores also decreased significantly ( M  = 32.33 to M  = 23.28), with a large effect ( r  = .80, p  = .003). Response and remission rates were 33.3% and 22.2% (MADRS), and 27.8% and 27.8% (BDI). No additive effect of multiple dosing was found. No serious adverse events occurred. We observed a significant and clinically meaningful reduction in depressive symptoms after psilocybin treatment, with response and remission rates below those reported in previous trials. Although observational and limited by its sample size, this study provides some of the first real-world evidence on psilocybin. Larger, prospective trials are needed to confirm our findings and identify predictors to increase treatment effectiveness.