Clinical Summary: An Open-Label, Dose-Escalation Trial of Psilocybin-Assisted Therapy for Bipolar II Depression
Patients with bipolar II depression have few effective options, and they have largely been excluded from psilocybin trials because of concern about mania risk. This study addresses the practical question clinicians face: whether psilocybin-assisted therapy can improve bipolar II depression without unacceptable psychiatric destabilization when used with structured psychotherapy and longitudinal monitoring.
Key Findings
- Depression scores improved from baseline at the primary end point after the final administration session, with MADRS change of −12.7 [2.7], n=14, P<.001 at A21 and −19.2 [3.0], n=9, P <.001 at B21.
- Improvement persisted at follow-up: MADRS scores remained improved at AB90 (−14.3 [2.8], n = 12, P < .001; Hedges g = 1.9), and QoL-BD scores also improved at AB90 (31.2 [10.2], P=.004; Hedges g=1.6).
- Four participants (28.5%) met remission criteria (MADRS ≤6) at A21 after 10 mg and did not proceed to 25 mg; at B21, 3 out of 9 patients met remission criteria (33%). Using MADRS≤10, remission rates were 36% at A21 and 56% at B21, and response rates (≥50% improvement relative to baseline) were also 36% and 56%, respectively.
- Tolerability was favorable overall: of the 143 total adverse events, 83% of events were mild, 15% were moderate, and a single event was severe; no serious adverse events were observed.
- Clinically important psychiatric adverse events still occurred after dosing: 1 participant had worsening suicidal ideation with intent but no plan 37 days after the 10 mg session, 1 had suicidal ideation 11 days after the 10 mg session, and 1 had hypomanic symptoms 14 days following the 25 mg session that resolved without pharmacologic intervention.
Psilocybin-assisted therapy produced large short-term and 90-day improvements in bipolar II depression in this small open-label sample, with no serious adverse events and only 1 transient hypomanic episode. The key clinical message is not same-day tolerability alone, but the need for structured follow-up for suicidality and mood elevation for weeks after administration.
Practice Implications
- If psilocybin-assisted therapy is considered in bipolar II depression research or specialty settings, monitor beyond the dosing day: the most concerning psychiatric events occurred 11 days, 14 days, and 37 days after administration.
- Do not rely only on acute session safety markers; incorporate longitudinal assessment of suicidality, sleep, and hypomanic symptoms using structured follow-up after each administration.
- A lower initial dose may be clinically informative in a dose-escalation approach, as 4 participants (28.5%) met remission criteria (MADRS ≤6) after 10 mg and did not require 25 mg per protocol.
- Set expectations clearly before treatment decisions about whether a second session will occur, because one participant experienced significant emotional distress when not advancing to the second administration after meeting remission criteria.
