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 (QoLBD), 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<0.001); 21 days after 25 mg (-18.6 [3.1], p<0.001) and 90 days after the final dose (-14.3 [2.8], p<0.001). Quality of life also improved at 90 days (31.2 [10.2], p=0.004). Conclusions: Psilocybin therapy under controlled conditions may be safe and effective in reducing depressive symptoms and improving quality of life in individuals with BD-II depression, and feared outcomes—mania, psychosis, and suicidality—do not appear elevated relative to other clinical populations treated with psilocybin. Given the high psychiatric comorbidity and general vulnerability to adverse events in this population, randomized, placebo-controlled trials are needed to confirm efficacy and refine dosing protocols in larger samples.