In an open-label, single-arm dose-escalation pilot (n=14) of psilocybin-assisted therapy for bipolar II depression, psilocybin (10 mg, with 25 mg if needed) was generally well tolerated and produced significant, sustained reductions in depressive symptoms and improved quality of life up to 90 days, with adverse events (including transient anxiety, nausea, headache and three notable psychiatric events) broadly comparable to other psilocybin studies. The authors conclude that randomised, placebo-controlled trials are needed to confirm efficacy and refine dosing protocols in this vulnerable population.
Papers cited by this study that are also in Blossom
Morton, E., Sakai, K., Ashtari, A. et al. · Journal of Psychopharmacology (2022)
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.
Downey and colleagues situate the study within a clinical context in which bipolar II disorder (BD-II) presents persistent depressive episodes, high psychiatric comorbidity, and limited effective treatments. Earlier clinical trials of psilocybin plus psychotherapy have shown antidepressant effects in other populations, but people with BD-II and those with family histories of bipolar disorder have largely been excluded because of theoretical concerns about precipitating mania or psychosis. The authors note that adverse event reporting in psychedelic trials has been inconsistent and that restrictive eligibility criteria limit generalisability to real-world, comorbid populations. This paper reports an open-label, single-arm, dose-escalation pilot designed to evaluate safety, tolerability, and preliminary efficacy of psilocybin-assisted therapy for individuals with BD-II currently experiencing at least moderate depression. The trial emphasises systematic adverse-event capture, a conservative dosing strategy (initial 10 mg with optional 25 mg if depressive symptoms persisted), and inclusion of participants with greater psychiatric complexity than in many prior trials, with the aim of informing whether larger, randomized studies are warranted.
The study used an open-label, single-arm dose-escalation design. Eligible participants were adults aged 18–70 with DSM-defined BD-II in a current major depressive episode lasting more than four weeks and a baseline MADRS score >18; they were required to have had at least one prior unsuccessful medication trial of >6 weeks. Key psychiatric exclusions included current hypomania, history of psychotic disorder, recent (past 12 months) moderate-or-worse substance use disorder, psychedelic use in the past six months, and imminent suicide risk on the C-SSRS. Medical exclusions included serious cardiovascular or central nervous system disease. Four participants were taking medications with potential psilocybin interactions; these were tapered under psychiatric supervision to achieve clearance (≥5 half-lives) before dosing. To support safety, participants identified a support person who saw them at least five days per week. Diagnostic and baseline assessments included serum labs, ECG, physical exam, vital signs, and the SCID-5; the investigators used an adapted hypomania criterion of ≥2 consecutive days of symptoms to diagnose BD-II. Each participant received preparatory psychotherapy with a licensed therapist, then an initial oral dose of synthetic psilocybin (10 mg). If the 10 mg session was well tolerated and MADRS remained ≥7 at day 21, participants could receive a second administration of 25 mg. Participants were not told the specific MADRS threshold used to determine progression to the second session. Administration took place in a standardised, comfortable setting with a lead and assisting therapist present; vital signs and urine drug screens were checked before dosing and rescue medications were available to the on-site medical provider. Regulatory approvals included the FDA, DEA, relevant state regulators, and the UCSF IRB. Outcome assessments were scheduled at 7, 14, and 21 days after each administration (A7/A14/A21 for 10 mg; B7/B14/B21 for 25 mg), with a long-term follow-up 90 days after the participant's final session (AB90). Safety and tolerability were the primary focus: adverse events were captured prospectively at every visit, the Clinical Global Impression of Improvement (CGII) was used, suicidality was measured with the C-SSRS (including Ideation severity subscale), and treatment-emergent (hypo)mania, psychosis, and insomnia were assessed with the YMRS, PANSS, and ISI. The primary preliminary efficacy endpoint was change in MADRS from baseline to 21 days after the final administration; quality of life used the QoL-BD. Exploratory measures included treatment expectations (SETS), PTSD symptoms (PCL-5), attachment style (ECR-M16), adverse childhood experiences (ACE), and the MEQ, EBI and CEQ to characterise the acute psychedelic experience. For statistical analysis, mixed-effects linear models were fitted with timepoint as a fixed effect and participant ID as a random effect; model assumptions were checked but small sample size limited confirmatory inferences. Paired Wilcoxon signed-rank tests were used as a non-parametric check, and Spearman correlations (with Pearson and Kendall checks) examined associations between baseline/acute-experience measures and outcomes. Paired t-tests compared phenomenological scores between 10 mg and 25 mg sessions. Results are reported as estimated mean differences (standard errors) with Hedges' g effect sizes where applicable; analysis scripts were noted as available but the detailed statistical analysis plan was not finalised prior to database lock, so analyses are presented as exploratory.
To assess change in outcome scores from baseline, we used mixed effects linear models with score as dependent variable, timepoint as fixed effect, and patient ID as random effect. All models were constructed in R (v4.1.2) using the lme4 (v1.1-27.1) and lmerTest (v3.1-3) packages. Normality of residuals was checked from QQ-plots and homeoskedasticity was assessed with scale-location plots. While no major violation of assumptions was observed, normality could also not be confirmed due to the small sample size. To mitigate this concern, paired Wilcoxon signed rank tests, which do not require normality, were also implemented. Wilcoxon models yielded the same overall pattern of results as the mixed-effects models, see Supplementary Materials for details. All test statistics are reported in the Supplementary Tables, along with Hedges' g effect sizes, (i.e. standardized mean difference). To assess associations between baseline characteristics or acute psilocybin experience measures and treatment efficacy, we used Spearman correlations, supplemented by Pearson and Kendall correlations to evaluate robustness. Phenomenological characteristics of the psychedelic experience, as quantified by the MEQ, EBI, and CEQ, was compared between the 10 mg and 25 mg sessions using paired t-tests. All baseline variables are presented as means (standard deviations). For analyses evaluating change from baseline, results are reported as estimated mean differences (standard errors) unless otherwise specified. Analysis scripts available on the project's GitHub repo, the clinical data can be requested by qualified researchers.
This open-label, dose-escalation trial evaluated the safety and tolerability of psilocybin therapy in individuals with treatment-resistant, moderate-to-severe BD-II depression. Feared outcomes reported in case reports and naturalistic surveys, such as acute mania and psychosis, were not observed. A structured and proactive approach to adverse event capture revealed a significant burden of adverse events. Prior to psilocybin administration, nearly two-thirds of participants experienced a mild adverse event possibly related to trial procedures. Nearly all participants experienced at least one adverse event during the trial, with highest frequency noted on the day of psilocybin administration, including headache, nausea, and anxiety. While most were mild, three participants experienced concerning exacerbations of their psychiatric conditions including suicidality and hypomania. These rates and distribution of adverse events are consistent with reports from other psilocybin trials. Depression symptoms (MADRS) -the primary, albeit preliminary, clinical outcome -and quality of life (QoL-BD) both showed large and sustained improvements over the 90-day follow-up period. These findings are consistent with other psilocybin trials in unipolar depressionand BD-II. Our results offer initial evidence that psilocybin therapy may be clinically beneficial in BD-II when administered under controlled conditions with a safety profile similar to studies in other patient populations, but randomized, double-blind, placebo-controlled trials are needed to confirm these effects. There were three notable psychiatric adverse events: active suicidal ideation 37 days after an administration session, passive suicidal ideation 11 days after an administration session, and a hypomanic episode two weeks after an administration session. The relationship of these events to psilocybin remains unclear given the clinical complexity of the sample, recent medication tapers, and the cyclical nature of BD-II. In a large trial of psilocybin therapy for treatment resistant depression, worsened suicidality was reported in 15.2% / 16.0% / 15.2% of participants in the 25 / 10 / 1 mg psilocybin groups, respectively, through week 12. Together these data highlight the importance of monitoring for emerging suicidality weeks to months after psilocybin administration, regardless of dose. Although participants were informed they would receive one or two psilocybin administrations, the use of a pre-specified remission threshold to determine eligibility for the second session was not disclosed, to minimize demand characteristics. While this approach prioritized safety, several participants experienced disappointment or confusion when they were not offered a second administration session, feeling abruptly disconnected from a potentially beneficial intervention. Future designs may benefit from more flexible, transparent decision-making processes that balance safety, demand characteristics, and participant engagement. Our study population had clinically significant PTSD symptoms and moderate-to-elevated attachment insecurity at baseline. Given the promising results of 3,4methylenedioxymethampheatmine (MDMA)-assisted psychotherapy for PTSD, few trials have investigated classic psychedelics for this indication-potentially reflecting the widespread perception that PTSD was already being addressed through MDMA-focused efforts. In our trial, psilocybin therapy was associated with sustained reductions in PTSD symptoms and attachment-related anxiety and avoidance. These effects mirror those observed in our earlier study of long-term AIDS survivors, where a single administration also improved both domains. Notably, neither intervention specifically targeted PTSD or attachment-two domains that are typically resistant to treatment. Together, these results suggest psilocybin therapy may hold promise for addressing trauma-related and attachment-based psychopathology. In our study, 4/14 participants experienced remission of depression after a 10mg dose of psilocybin, suggesting that some individuals with BD-II may achieve remission of depression following this lower dose, potentially reducing the need for higher doses and associated risks. Participants reported subjective experiences on the MEQ, EBI, and CEQ following 10 mg that were similar to those observed after 25 mg-both within this trial and in a prior study of psilocybin for unipolar depression, see Supplementary Figures. These relatively intense experiences may have contributed to therapeutic improvement, offering a possible explanation for the clinical effects observed at this lower dose. However, it is also possible that some or all of the observed remissions after the 10 mg session reflect placebo responses. We acknowledge several limitations. First, the small sample size and open-label design warrant cautious interpretation. The placebo response likely explains some of the observed benefits. However, while critiques of psilocybin therapy often highlight expectancy biases associated with the favorable media coverage of the treatment (15), our baseline expectancy was not associated with clinical outcomes, see Supplementary Materials for details. This lack of relationship between self-reported expectancies and outcomes is consistent with the only other psilocybin trial that measured expectancy. Second, our exclusion criteria reduce generalizability to more complex psychiatric presentations and to those with BD-I. Third, most concomitant psychotropic medications were exclusionary, further reducing the generalizability of our findings. Psilocin, the active metabolite of psilocybin, acts via serotonergic pathways. To mitigate the risk of treatment-emergent mania, concurrent serotonergic agents such as SSRIs were tapered prior to psilocybin administration. However, emerging safety data support cautious co-administration with serotonergic antidepressantswhich future trials may explore with appropriate safeguards. In summary, results of this open-label, dose escalation study suggest that psilocybin therapy may be a safe, feasible, and possibly efficacious treatment for BD-II depression. Randomized, placebo-controlled trials are warranted to examine efficacy in larger samples with common psychiatric comorbidities observed with BD-II. Dose-response studies are important to further optimize efficacy while mitigating psychological and physiologic risks, particularly considering our observed four remissions following the 10 mg dose. We join others in calling for transparent, complete, and standardized characterization of adverse events in psychedelic clinical trials.
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Fourteen of 58 screened participants received at least one psilocybin administration; mean baseline MADRS was 27.7 (SD 6.6). All 14 completed the 21-day assessment after 10 mg; nine received a second (25 mg) session and completed the corresponding 21-day follow-up. Mean positive expectancy on the SETS was low (2.0 [1.4]) while negative expectancy items averaged 4.4 (1.8). Physiologic effects were transient and self-limiting: mean peak heart rate was 84.8 (17.0) bpm after 10 mg and 84.4 (17.3) bpm after 25 mg; peak systolic/diastolic pressures averaged 141.6 (15.5)/86.3 (8.9) mmHg for 10 mg and 144.7 (18.3)/88.9 (8.3) mmHg for 25 mg. Eight of eleven respondents (73%) to the Treatment Satisfaction Questionnaire said they would recommend the treatment. Adverse events (AEs) were frequent but mostly mild: of 143 total AEs, 83% were mild, 15% moderate, and one was severe; no events were classified as serious. Most events occurred within 24 hours of dosing and commonly included mild-to-moderate anxiety, nausea and headache. On the C-SSRS Ideation severity subscale there was no increase at A21/B21 versus baseline; rather a small average reduction (~0.7 points) was observed at post-administration timepoints. Notably, three psychiatric adverse events were judged concerning: one participant experienced worsening suicidal ideation with intent 37 days after a challenging 10 mg session (this participant declined the 25 mg session and later accessed external mental health care); a second participant had suicidal ideation 11 days after 10 mg that resolved in two days with therapist support; and a third participant showed elevated YMRS scores consistent with hypomania 14 days after 25 mg that returned to baseline by B21 without emergency services. Mean YMRS and PANSS scores did not show significant group-level worsening. On the primary preliminary efficacy outcome, MADRS scores improved significantly. After the 10 mg session participants showed a mean change at A21 of -12.7 (SE 2.7), n=14, p<0.001, with 4/14 (28.5%) meeting remission criteria (MADRS ≤6) and therefore not proceeding to the 25 mg session. Among those receiving 25 mg, B21 change was -18.6 (3.1), n=9, p<0.001. At the 90-day follow-up (AB90) sustained improvement versus baseline was observed (AB90: -14.3 [2.8], n=12, p<0.001), with Hedges' g=1.9. Quality of life (QoL-BD) also improved substantially at A21 and B21 (A21 reported as 35.5, p<0.001; B21 55.9 [10.9], p<0.001) and remained improved at AB90 (31.2 [10.2], p=0.004; Hedges' g=1.6). Exploratory analyses noted baseline PTSD symptom burden in many participants (mean PCL-5 31.9 [20.9]), with a significant reduction at AB90 (change -13.9 [6.1], p=0.048; Hedges' g=-0.87). Phenomenological measures of the acute experience (MEQ, EBI, CEQ) were numerically similar between 10 mg and 25 mg sessions; normalized MEQ scores were 0.53 (0.28) vs 0.63 (0.29), CEQ 0.20 (0.13) vs 0.30 (0.19), and EBI 0.78 (0.14) vs 0.76 (0.18). Attachment anxiety and avoidance on the ECR-M16 decreased at A21 and B21; avoidance remained significantly lower at AB90 while anxious attachment showed a non-significant trend at AB90. No robust associations emerged between baseline measures (ACE, SETS, PCL-5) or acute-experience measures (EBI/MEQ/CEQ) and clinical outcomes.
Downey and colleagues interpret the trial as providing initial evidence that psilocybin-assisted therapy can be administered to people with BD-II depression under controlled conditions with a safety profile broadly comparable to that reported in other psilocybin trials. Group-level worsening to frank mania or psychosis was not observed, but systematic adverse-event monitoring revealed a substantial burden of mostly mild, transient events concentrated around the day of administration. The authors highlight three psychiatric adverse events of concern—one case of worsening suicidal ideation with intent, one brief episode of suicidal ideation, and one transient hypomanic episode—and acknowledge that attributing these events to psilocybin is complicated by participants' clinical complexity, recent medication tapers, and the natural course of BD-II. The investigators emphasise the sizeable and sustained reductions in depressive symptoms (MADRS) and improvements in quality of life through 90 days, and note that 4 of 14 participants remitted after a single 10 mg session. They caution that some remissions after the low dose may reflect placebo responses, but point out that baseline expectancies were not associated with outcomes in this sample. Additional exploratory findings included reductions in PTSD symptoms and attachment insecurity, which the authors suggest may merit further study given the resistance of these domains to standard treatments. Limitations acknowledged by the study team include the small sample size, open-label design, and exclusionary criteria that reduce generalisability to BD-I or more complex presentations; the required tapering of most serotonergic medications further limits applicability to routine clinical populations. The absence of a finalised statistical analysis plan prior to database lock led the authors to present analyses as exploratory. Practical and ethical lessons for future trials are discussed: the authors recommend routine, extended monitoring for suicidality in the weeks to months after dosing, greater transparency and flexibility in decisions about additional dosing to reduce participant distress, standardised and complete adverse-event reporting in psychedelic trials, and randomised, placebo-controlled and dose-response studies to confirm efficacy and refine safety protocols.