An Open-Label, Dose-Escalation Trial of Psilocybin-Assisted Therapy for Bipolar II Depression.

Abstract

<b>Objective:</b> Individuals with bipolar II disorder (BD-II) and depression face limited treatment options and are often excluded from psilocybin therapy trials due to concerns about precipitating mania or psychosis. The objective of this study was to evaluate the safety, tolerability, and preliminary efficacy of psilocybin therapy in individuals with BD-II and depression. <b>Methods:</b> We conducted an open-label, single-arm pilot trial from 2022-2025 in which 14 participants with BD-II depression, diagnosed using adapted criteria requiring &#x2265;2 consecutive days of hypomanic symptoms, received 10 mg of psilocybin, followed by 25 mg if symptoms persisted. Participants completed psychotherapy before, during, and after psilocybin sessions and were proactively monitored for adverse events. Depression and quality of life were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS; primary end point 21 days after each participant's final administration session) and the Quality of Life in Bipolar Disorder Questionnaire (QoL-BD), alongside exploratory measures. <b>Results:</b> Psilocybin was well tolerated, with only transient increases in heart rate and blood pressure and no serious adverse events. Common side effects included mild-to-moderate anxiety, nausea, and headache. Three participants experienced notable psychiatric events (suicidal ideation or hypomania), which resolved with support. Following the 10 mg session, MADRS scores improved significantly (-12.7 [2.7], <i>P</i>&lt;.001), with 4 participants (28.5%) meeting remission criteria and therefore not proceeding to the 25 mg session; 9 participants received the 25 mg dose. Among those who received the 25 mg dose, MADRS scores improved significantly 21 days following 25 mg (-18.6 [3.1], <i>P</i>&lt;.001). QoL-BD scores also improved at 90 days following the final dose (31.2 [10.2], <i>P</i>=.004). <b>Conclusion:</b> These findings suggest that psilocybin therapy may be safe, tolerable, and preliminarily efficacious for treating depression in BD-II, but randomized controlled trials are needed to confirm efficacy and optimize protocols. <b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT05065294.