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

⚠️ Small Study / Early Comparative Evidence

This open-label, single-arm pilot trial administered a single 25-mg dose of synthetic psilocybin (COMP360) with structured preparatory and integration psychotherapy to 20 adults with chronic SI, MDD, and at least two prior antidepressant failures. MSSI scores declined significantly by week 1 and remained below baseline through week 12.

Clinical Considerations

• 70% of participants achieved near-complete SI remission (MSSI ≤2) at week 12; within-group effect sizes (Cohen d = 1.46–2.11) are among the largest reported for any psychiatric SI intervention, though open-label design substantially limits interpretation
• Two participants (10%) experienced SI worsening; one showed a clinically significant MSSI increase from 17 to 23 at week 12, a critical safety signal in this high-risk population
• MSSI and MADRS reductions were strongly correlated (r = 0.70), but the numerically larger SI effect size at week 1 raises the possibility of a partially independent antisuicidal mechanism
• Entrenched negative expectancy (“Things will never get better”) and prior ECT history were associated with nonresponse in exploratory analyses; prior psilocybin exposure was associated with response

Practice Applications

• Recognize these findings as hypothesis-generating only; no comparator arm means placebo and expectancy effects cannot be separated from pharmacologic signal
• Monitor for heterogeneous response in treatment-resistant suicidal patients; a meaningful minority may experience worsening, even in controlled settings
• Anticipate that patients may present awareness of this research; counsel that structured therapeutic support and careful screening were integral to the protocol, not psilocybin alone
• Consider that 60% of participants restarted adjunctive pharmacotherapy by week 12, complicating interpretation of durability claims