Frequently Asked Questions

The trial found that psilocybin-assisted therapy was associated with significant improvements in depressive symptoms in this small open-label sample of adults with bipolar II depression. MADRS scores improved from baseline by 12.7 points at 21 days after the 10 mg session (A21; n=14; P<.001) and by 19.2 points at 21 days after the final session among those who received 25 mg (B21; n=9; P<.001). Improvements were also sustained at 90 days after the final session, with a MADRS change of -14.3 points (n=12; P<.001; Hedges g=1.9), and quality of life improved at A21, B21, and AB90.

Using the study's remission threshold of MADRS ≤6, 4 of 14 participants (28.5%) remitted after the initial 10 mg session at A21 and therefore did not proceed to 25 mg, while 3 of 9 participants (33%) met remission criteria at B21 after receiving 25 mg. Using the more traditional remission definition of MADRS ≤10, remission rates were 36% at A21 and 56% at B21. Response rates, defined as at least 50% improvement from baseline, were also 36% at A21 and 56% at B21.

No cases of acute mania or psychosis were observed in this trial, and mean YMRS and PANSS scores did not significantly worsen. However, 1 participant developed symptoms concerning for hypomania 14 days after the 25 mg session, including mildly elevated mood, increased energy, and reduced sleep of about 5 hours per night lasting nearly 3 days. The episode was less severe and shorter than the participant's prior hypomanic episodes, resolved without pharmacologic treatment, and YMRS returned to baseline by B21.

The most concerning psychiatric adverse events occurred days to weeks after dosing rather than during the administration sessions. One participant had a severe adverse event of worsening suicidal ideation with intent but no plan 37 days after a challenging 10 mg session; the participant declined emergency services, accessed outside mental health care the next day, and the suicidal ideation resolved. One additional participant experienced suicidal ideation 11 days after the 10 mg session that resolved within 2 days with therapist support, and another participant experienced significant emotional distress after learning they would not proceed to the second session because they had already met remission criteria.

No serious adverse events were observed by regulatory criteria, and no participant had a higher C-SSRS Ideation Severity score at 21 days after their final administration session than at baseline.

Overall tolerability was favorable in this small pilot study, with no serious adverse events observed. Of the 143 total adverse events, 83% were mild, 15% were moderate, and 1 event was severe. Most adverse events occurred within 24 hours of psilocybin administration and were most commonly mild-to-moderate anxiety, nausea, and headache; no medications were required during administration sessions to manage adverse effects.

Psilocybin also produced transient increases in heart rate and blood pressure, with mean peak heart rate of 84.8 bpm after 10 mg and 84.4 bpm after 25 mg, and mean peak blood pressure of 141.6/86.3 mm Hg after 10 mg and 144.7/88.9 mm Hg after 25 mg.

The study used a cautious dose-escalation design because of theoretical concern that psilocybin could induce mania in bipolar II disorder. All participants first received 10 mg, and they became eligible for 25 mg only if the 10 mg dose was well tolerated and depressive symptoms persisted, defined as MADRS ≥7 at day 21. This approach was intended to minimize exposure to a higher psilocybin dose in participants who were no longer depressed after the initial session.

This was an open-label, dose-escalation pilot study in 14 adults aged 18 to 70 years with bipolar II disorder who were in a current major depressive episode lasting more than 4 weeks and had at least moderate depression severity, defined as MADRS >18. All participants had at least 1 prior unsuccessful medication trial for bipolar II depression lasting at least 6 weeks.

Participants received psychotherapy before, during, and after psilocybin administration. Everyone received an initial 10 mg oral synthetic psilocybin session, and 9 participants later received 25 mg if they remained depressed at day 21 and had tolerated the first session. The primary efficacy end point was change in MADRS from baseline to 21 days after the final administration session, and follow-up extended to 90 days after the final session.

No. In this study, insomnia scores improved rather than worsened after psilocybin-assisted therapy. ISI scores improved from baseline at every posttreatment time point, including A21 (-5 [1.4], P<.001), B21 (-7.0 [1.6], P<.001), and AB90 (-3.1 [1.4], P=.036), with an overall Hedges g of 1.0.

In this trial, PTSD symptoms were reduced at the 90-day follow-up among the participants assessed on the PCL-5. At baseline, 10 of 14 participants reported events likely meeting DSM-5 Criterion A for PTSD, 2 others described possibly qualifying events, and the mean baseline PCL-5 score was 31.9, which met the National Center for PTSD threshold for clinically significant PTSD. At AB90, PCL-5 scores decreased by 13.9 points (P=.048; Hedges g=-0.87).

The study also found reductions in attachment-related anxiety and avoidance at A21 and B21, with avoidance still significantly reduced at AB90.

The main limitations are that it was a small, open-label pilot study with 14 treated participants, so the findings require cautious interpretation. The authors state that placebo response likely explains some of the observed benefit. They also note that exclusion criteria reduced generalizability to more complex psychiatric presentations and to bipolar I disorder, and that most concomitant psychotropic medications were exclusionary, which further limits generalizability.