EFFICACY AND SAFETY OF A SINGLE DOSE OF PSILOCYBIN FOR CHRONIC ACTIVE SUICIDAL IDEATION: EXPERIENCES IN AN OPEN LABEL TRIAL

Individual Abstract Importance: Chronic suicidal ideation is a major public health concern with limited effective and rapidly acting treatments. Historically, clinical trials have excluded this high-risk population, creating a critical gap in knowledge.

Objective

To evaluate the efficacy, safety, and durability of a single dose of psilocybin with psychological support for reducing chronic suicidal ideation.

Design

Open-label, single-arm, naturalistic study with a 12-week follow-up period.

Setting

Conducted at a single academic medical center.

Participants

Twenty adults (12 male; mean age, 36.3 [11.1] years) with chronic suicidal ideation and a history of at least two prior antidepressant treatment failures.

Intervention: A single 25-mg dose of psilocybin (COMP360) administered with a structured protocol for preparatory and integration psychotherapy sessions.

Main Outcomes and Measures

The primary outcome was the change from baseline in the Modified Scale for Suicidal Ideation (MSSI) score at Week 3. Secondary outcomes included changes in MSSI at Weeks 1 and 12, and changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) scores across these timepoints.

Results

The mean (SD) baseline MSSI score was 18.6 (5.1). At the Week 3 primary endpoint, MSSI scores were significantly lower than baseline (mean difference = 13.95 ± 1.81; 95% CI [8.63–19.27]; p < .001; Cohen’s d = 1.94). Large reductions were already evident at Week 1 (d = 2.11) and remained stable through Week 12 (d = 1.87). At Week 12, 14 of 20 participants (70%) had an MSSI ≤ 2. MADRS scores showed a similarly rapid and durable improvement, with mean reductions of 18.55 points at Week 1 (d = 1.73) and 17.55 points at Week 12 (95% CI [11.93–23.17]; p < .001; d = 2.06). No serious adverse events occurred, although one participant’s MSSI increased from 17 to 23 at Week 12.

Conclusions and Relevance

In this open-label naturalistic study in a treatment-resistant population, a single administration of psilocybin with psychological support was associated with rapid, robust, and durable reductions in suicidal ideation. These promising preliminary results warrant further investigation in larger, randomized controlled trials.

References

Aaronson, S. T. et al. Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial. Am J Psychiatry 182, 104-113 (2025). https://doi.org/10.1176/appi.ajp.20231063 Goodwin, G. M. et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Engl J Med 387, 1637-1648 (2022). 11:00 a.m. - 12:30 p.m. Panel Sessions