Clinical Summary: Results From a Long-Term Observational Follow-Up Study of a Single Dose of Psilocybin for a Treatment-Resistant Episode of Major Depressive Disorder
Patients with treatment-resistant depression often cycle through multiple antidepressant trials with limited remission and delayed benefit, so durability matters as much as initial response. This follow-up study asks a practical question for psychiatrists: after a single dose of psilocybin with psychological support, how long do benefits last, when do patients need additional treatment, and what safety issues emerge over 52 weeks?
Key Findings
- In the primary analysis including all participants from COMP 001, median time to depression related event was 92 days (49–199) in the 25 mg group, 83 days (39–142) in the 10 mg group, and 62 days (28–NE) in the 1 mg group.
- Among all participants from COMP 001, the proportion with any depression-related event was similar across groups: 54.4%, n=43 with 25 mg; 54.7%, n=41 with 10 mg; and 57.0%, n=45 with 1 mg.
- The most frequently reported depression-related events were initiation of new antidepressant treatment and worsening MADRS total scores: initiation of new antidepressant treatment occurred in 48.1%, n=38 with 25 mg, 38.7%, n=29 with 10 mg, and 43.0%, n=34 with 1 mg; worsening MADRS total scores occurred in 21.5%, n=17, 18.7%, n=14, and 22.8%, n=18, respectively.
- Among COMP 001 completers entering COMP 004 at 12 weeks post-psilocybin administration, 27.3% (n=6) in the 25 mg group, 47.4% (n=9) in the 10 mg group, and 58.8% (n=10) in the 1 mg group had started a new antidepressant treatment; by Week 52, 54.5% [n=12] in the 25 mg group and 57.9% [n=11] in the 10 mg group had started a new antidepressant treatment, while the 1 mg group was numerically greater at 76.5% (n=13).
- After entry into COMP 004, 61 TEAEs occurred in 27 participants, the most common was COVID-19 in 13.8% (n = 8), and 4 TESAEs were reported by 3 participants; all TESAEs were deemed not related to study drug.
A single 25 mg dose of psilocybin with psychological support was associated with longer time to depression-related event and later need for new antidepressant treatment than 1 mg, with no new long-term safety signal identified over 52 weeks. In practice, the benefit appears durable for some patients but often not sufficient to prevent additional treatment within a year.
Practice Implications
- When discussing psilocybin for treatment-resistant depression, set expectations around durability: median time to depression related event was 92 days with 25 mg, so follow-up planning should extend well beyond the acute response window.
- Monitor for relapse pragmatically by tracking need for new antidepressant treatment and MADRS worsening, since these were the most common depression-related events in long-term follow-up.
- Plan early reassessment of ongoing treatment needs within 12 weeks after administration, because new antidepressant treatment had already been started by 27.3% (n=6) of the 25 mg group and 58.8% (n=10) of the 1 mg group at that point.
- Reassure patients that late serious safety events were uncommon and all 4 TESAEs in 3 participants were judged unrelated to study drug, while still maintaining routine monitoring for suicidal ideation given reported events in the 25 mg and 1 mg groups.
