Efficacy and Safety of a Single Dose of Psilocybin for Chronic Suicidal Ideation: An Open-Label Trial.

Objectives: To evaluate the efficacy, safety, and durability of a single 25-mg dose of a proprietary, synthetic formulation of psilocybin with psychological support for reducing chronic suicidal ideation in a treatment-resistant population. Methods: This was an open-label, single-arm study with a 12-week follow-up conducted between March 2022 and May 2025. Twenty adults with chronic suicidal ideation, major depressive disorder (DSM-5), and ≥2 prior antidepressant treatment failures received a single 25-mg dose of psilocybin administered within a structured preparatory and integration psychotherapy protocol. The primary outcome was change from baseline in the Modified Scale for Suicidal Ideation (MSSI) at week 3. Secondary outcomes included change in MSSI at weeks 1 and 12 and change in Montgomery-Asberg Depression Rating Scale (MADRS) scores at weeks 1, 3, and 12. Outcomes were analyzed using 1-way repeated-measures analysis of variance with Bonferroni-adjusted pairwise comparisons. Results: Significant reductions in MSSI scores were observed from baseline to week 3 (primary end point: mean difference [MD] = 13.95; 95% CI, 8.63-19.27; P < .001; d = 1.73). Improvements were rapid and durable, with significant reductions at week 1 (MD = 15.10; P < .001; d = 2.11) and week 12 (MD = 13.00; P < .001; d = 1.46). By week 12, 70% (n=14) of participants achieved MSSI ≤2. MADRS scores showed similar significant reductions at all postbaseline time points (MD range: 17.55-20.50; all P < .001; d = 1.63-1.97). No serious adverse events occurred. Conclusions: In this open-label single-arm study of adults with chronic suicidal ideation and prior treatment failures, a single administration of psilocybin with psychological support was associated with rapid, large-magnitude, and durable reductions in suicidal ideation and depressive symptoms through 12 weeks. These preliminary findings support further evaluation in larger randomized controlled trials. Trial Registration: ClinicalTrials.gov Identifier: NCT05220410.