Psilocybin in Treatment-Resistant Depression: Weighing Rapid Antidepressant Effects Against Uncertain Durability

Background/Objectives: Treatment-resistant depression (TRD) is heterogeneous and recurrent. Psilocybin administered with structured psychological support can reduce symptoms rapidly. Support protocols differ in content and intensity, and trial design complicates estimates of the specific drug effect and durability. We reviewed efficacy, durability, mechanisms, safety, and clinical delivery in TRD. Methods: This structured narrative review covered PubMed/MEDLINE literature through 8 August 2026 and preliminary phase 3 reports through 9 August. September checks concerned only COMP360 development status (25 September) and regulatory access (30 September), without extending the clinical evidence cut-off. Priority was given to primary unipolar TRD studies, follow-up reports, and evidence on masking, medication management, safety, and delivery. Sponsor-reported phase 3 findings were considered preliminary because incomplete reporting and the absence of peer review limited independent appraisal. No meta-analysis or formal risk-of-bias assessment was performed. Results: COMP001 met its prespecified week-3 primary endpoint for 25 mg versus 1 mg. EPISODE did not confirm its prespecified week-6 response hypothesis, although prespecified secondary continuous outcomes favored 25 mg and remain exploratory. Psilocybin in Depression Resistant to Standard Treatments (PsiDeR) provided exploratory efficacy estimates, including differences from the inert placebo, at weeks 3 and 6 within a feasibility trial. Differences in comparators, treatment guessing, endpoints, and psychological support limit generalization of effect estimates. Long-term follow-up showed improved group means, but sustained response was less common. Additional treatment during follow-up limited attribution to psilocybin alone. Mechanistic studies support 5-hydroxytryptamine receptor 2A (5-HT2A) receptor engagement, plasticity, and network changes. No validated biomarker guides selection or retreatment. Safety requires screening, repeated assessment of suicidality, continuous observation during dosing, defined medical and psychiatric emergency pathways, and structured follow-up after discharge. Conclusions: Psilocybin administered with structured psychological support shows short-term antidepressant activity in carefully selected adults with TRD. The specific drug effect, durability, retreatment strategy, and comparative place in care remain uncertain. Confirmatory trials should assess masking, standardize psychological support, and measure sustained remission, functioning, rescue treatment, and cumulative safety.