Single-Dose Synthetic Psilocybin With Psychotherapy for Treatment-Resistant Bipolar Type II Major Depressive Episodes

Bipolar II disorder (BDII) is a chronic condition marked by recurrent hypomanic and depressive episodes that often produce functional impairment comparable to bipolar I disorder. Earlier research indicates that depressive episodes in BDII are frequently protracted and difficult to treat, with limited evidence to guide treatment because many trials have not enrolled sufficient numbers of BDII patients. Conventional antidepressant strategies have shown inconsistent benefits and ongoing debate exists about their risk–benefit balance in BDII. There is therefore a compelling need for novel therapies for treatment-resistant BDII depression. Psilocybin, a 5-HT2A receptor agonist with putative effects on associative learning, cognitive flexibility and neuroplasticity, has shown rapid and sometimes durable antidepressant effects in trials of major depressive disorder. However, clinical data are lacking for its use in bipolar depression, and there are safety concerns specific to bipolar populations (notably induction of mania, hypomania, mixed states, psychosis or increased suicidality). This study aimed to provide a first prospective, systematic evaluation of the safety and efficacy of a single 25-mg dose of synthetic psilocybin given with psychological support in patients with treatment-resistant BDII currently in a major depressive episode, with the primary endpoint at 3 weeks posttreatment and follow-up to 12 weeks.

Aaronson and colleagues carried out a 12-week, open-label trial at the Sheppard Pratt Health System of a single 25-mg oral dose of synthetic psilocybin administered to participants meeting DSM-5 criteria for BDII in a current depressive episode. The trial enrolled 15 participants between April 2021 and January 2023 under an FDA investigational new drug protocol. All participants provided informed consent and the study protocol was registered and approved by institutional review. Eligible participants were aged 18–65, had a current depressive episode longer than 3 months, and had documented insufficient benefit from at least two adequate pharmacologic treatments during the index episode (ascertained with the Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire criteria, expanded to include FDA-approved mood stabilisers). At screening and baseline participants required a Hamilton Rating Scale for Depression-17 score of at least 18 and a Young Mania Rating Scale (YMRS) score below 10. Key exclusions included prior bipolar I disorder, schizophrenia, psychotic disorders, borderline personality disorder, recent substance use disorder, and other major psychiatric exclusions. All participants had normal screening bloodwork and ECG. Medication taper and psychological support were integral to the protocol: psychotropic medications (including mood stabilisers, stimulants and benzodiazepines) were tapered during a 3–6 week run-in and discontinued at least 2 weeks before dosing. Lead and assistant therapists provided at least 3 pretreatment hours, onsite support during the 8–9 hour dosing day, and three integration sessions (the day after dosing and in the subsequent two weeks). The dosing environment was nonclinical and supportive; participants were encouraged to use eyeshades and a curated playlist. The study physician assessed participants the day after dosing and at scheduled follow-ups. Primary and secondary outcomes were clinician- and self-rated depression scales: the primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 3. Secondary endpoints included MADRS at other time points, response (≥50% MADRS reduction) and remission (MADRS ≤10) rates, Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) and Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF). Safety assessments comprised the Columbia Suicide Severity Rating Scale (C-SSRS) and the YMRS at each visit. An exploratory outcome measured acute subjective psychedelic effects using the Five Dimension Altered States of Consciousness Questionnaire (5D-ASC) administered postdosing. Statistical analysis used repeated-measures general linear models (one-way repeated-measures ANOVA for key scales), Bonferroni-corrected post hoc tests, and Pearson correlations to explore associations between 5D-ASC scores and antidepressant outcomes. One participant withdrew after week 6 and last-observation-carried-forward was used for missing data for that individual.

Fifteen participants (9 female, 6 male; mean age 37.8 years) received psilocybin and were included in the analysed cohort; one additional screened individual withdrew prior to dosing during medication taper. Many participants had long current depressive episodes (mean duration reported as 2.5 years) and baseline depression scales indicated moderate-to-severe symptom severity. For the primary clinical outcome, the trial reports that most participants met response and remission criteria: at week 3, 12 of 15 participants met the response threshold (≥50% reduction in MADRS) and 11 met remission (MADRS ≤10). At the 12-week end point, 12 participants met both response and remission criteria. The extracted Results text does not clearly report the mean change in MADRS score from baseline to week 3 within the Results section; counts of responders and remitters are the primary MADRS outcomes presented here. Self-rated depressive symptoms (QIDS-SR) decreased significantly over time. A one-way repeated-measures ANOVA on QIDS-SR at baseline and weeks 1, 3 and 12 yielded a robust main effect of time (F(3,42) = 21.78; P < .001). Significant reductions from baseline were observed at week 1 (Cohen d = 2.26; 95% CI, -15.58 to -6.95; adjusted P < .001), week 3 (Cohen d = 2.00; 95% CI, -16.77 to -4.03; adjusted P = .001), and week 12 (Cohen d = 2.19; 95% CI, -19.13 to -5.67; adjusted P < .001); follow-up weeks did not differ significantly from one another. Quality of life (Q-LES-Q-SF) scores increased significantly from baseline (F(2,28) = 28.29; P < .001), with large effect sizes at week 3 (Cohen d = 1.80; 95% CI, 8.14 to 24.39; adjusted P < .001) and week 12 (Cohen d = 2.30; 95% CI, 11.11 to 29.69; adjusted P < .001). Mania symptoms measured by the YMRS showed an overall trend toward reduction over time (F(3,42) = 2.85; P = .049), but post hoc comparisons did not identify significant pairwise differences. Suicidality as measured by the C-SSRS did not show a significant main effect across time points (F(3,42) = 2.29; P = .09). No participants attempted or died by suicide during the study. Acute subjective effects on the 5D-ASC were intercorrelated across subscales. Several 5D-ASC dimensions correlated with the MADRS end point: oceanic boundlessness (OB) r = -0.66 (P = .008), anxious ego dissolution (AED) r = -0.55 (P = .03), visionary restructuralization (VR) r = -0.79 (P < .001) and reduction of vigilance (RV) r = -0.59 (P = .02); auditory alterations (AA) did not reach conventional significance (r = -0.51; P = .06). A global 5D-ASC score summing subscales correlated with MADRS at week 12 (Pearson r = -0.69; P = .005), suggesting greater intensity of the psychedelic experience was associated with larger antidepressant effects. Safety findings indicated no significant adverse events related to dosing. The most frequently reported adverse event was headache in 4 of 15 participants on the dosing day, resolving within 24 hours. All participants were tapered off psychotropic medications at least 2 weeks prior to dosing; nine participants did not restart medications during the 12-week period while six resumed at least one prior agent at various time points. The text describes specific cases where medication restart was associated with nonresponse or relapse and how those participants were coded in analyses.

Aaronson and colleagues present this study as the first prospective, systematic report of single-dose psilocybin with psychological support in a cohort of patients with treatment-resistant BDII depression. Participants experienced rapid and, in many cases, sustained reductions in depressive symptoms, with most remitting within one week and many remaining remitted through the 12-week follow-up. Importantly, the investigators did not observe emergence of manic, hypomanic, mixed, psychotic symptoms or a signal of increased suicidality in this carefully screened and closely monitored sample. The authors contrast these controlled findings with survey-based anecdotal reports in people with bipolar diagnoses that have described both beneficial and adverse effects after recreational psychedelic use; they note that differences in setting, comedication or substance use, diagnostic certainty and reporting may account for divergent outcomes. The observed correlation between the intensity of the acute psychedelic experience (5D-ASC) and longer-term antidepressant benefit is highlighted, supporting the view—debated in the field—that subjective intensity may predict clinical response. Acknowledged limitations include the uncontrolled, open-label design, small sample size, selected and motivated participant population, and relatively short 12-week follow-up. The authors caution that expectation effects, intensive therapeutic contact and selection bias could have influenced outcomes, and that a single-dose protocol does not inform effects of repeated dosing. They also state these findings cannot be generalised to bipolar I disorder or to patients in mixed or hypomanic states. The study team recommends further investigation in randomised clinical trials to better define safety and efficacy in BDII, and they advise caution before expanding the paradigm to bipolar I given higher associated risks.

The investigators conclude that these preliminary open-label findings support further study of psilocybin-assisted therapy in the BDII population. They recommend attention to whether psilocybin administration affects the elevated risk of substance use disorders in people with bipolar disorder and caution against extrapolating these results to bipolar I disorder, where risks of mania and psychosis are higher.