An open-label, dose-escalation trial of psilocybin-assisted therapy for bipolar 2 depression

Background: Individuals with bipolar II disorder (BD-II) and depression face limited treatment options and are often excluded from psilocybin therapy trials due to theoretical concerns of precipitating mania or psychosis. Although psilocybin has demonstrated antidepressant effects when combined with psychotherapy, adverse event reporting is inconsistent, and restrictive eligibility criteria limit generalizability. Aims: To evaluate the safety, tolerability, and preliminary efficacy of psilocybin therapy in individuals with BD-II experiencing moderate-to-severe depression. Method: In this open-label, single-arm pilot trial, 14 participants received 10 mg of psilocybin, followed by 25 mg if depressive symptoms persisted. Participants underwent psychotherapy before, during, and after psilocybin administration sessions and were proactively monitored for adverse events. Depression and quality of life were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and Quality of Life in Bipolar Disorder Questionnaire (QoL BD), along with exploratory measures. Results: Psilocybin was well tolerated, with transient increases in heart rate and blood pressure and no serious adverse events. Common adverse events included mild-to-moderate anxiety, nausea, and headache. Three participants experienced notable psychiatric adverse events (suicidal ideation and hypomania) which resolved with support. The frequency and nature of both serious and non-serious adverse events were broadly comparable to those reported in psilocybin studies for other conditions. MADRS scores improved at all timepoints: 21 days after 10 mg (-12.7 [2.7], p