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

Background: 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 aimed to examine antidepressant outcomes, safety, and feasibility of real-world psilocybin therapy for TRD, including repeated dosing sessions. Methods: We conducted a retrospective analysis of medical records from 19 TRD patients treated with psilocybin (20-35 mg) 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 analysed, including response and remission. Findings: MADRS scores decreased from baseline (M = 30.78) to post-treatment (M = 19.89), with a large effect size (Hedges' g = 1.37, 95% CI [0.90, 1.84]). BDI scores also decreased (M = 32.33-M = 23.28), with a medium-to-large effect (Hedges' g = .77, 95% CI [0.46, 1.09]). Response and remission rates were 33.3% and 22.2% (MADRS), and 27.8% and 27.8% (BDI). No serious adverse events were documented. Interpretation: This study provides some of the first evidence on psilocybin outside controlled trials. Psilocybin was associated with a clinically meaningful reduction in depressive symptoms, with response and remission rates below those reported in previous trials. Findings suggest feasibility of psilocybin in real-world TRD care and should be interpreted within the limitations of small sample size, retrospective uncontrolled design, heterogeneous treatment conditions, and concomitant psychopharmacology. Funding: This research did not receive any funding.