In brief
- An open-label trial of 15 people, published in JAMA Psychiatry (2023), tested a single 25 mg dose of synthetic psilocybin combined with psychotherapy for treatment-resistant bipolar II depression.
- Most participants responded and entered remission by week three, with effects largely sustained through week 12, without increases in mania/hypomania or suicidal ideation.
- These are promising but preliminary results: the sample size is small, there was no placebo group, participants were carefully screened, and the intensive clinical support is difficult to separate from the drug’s effects.
Bipolar II disorder involves depressive episodes that are often resistant to standard treatments. Furthermore, there is a classic clinical caution: the fear that an antidepressant or a psychedelic might trigger a switch into mania. This is why a trial published in JAMA Psychiatry in late 2023 drew attention; for the first time in a regulated setting, it explored psilocybin in this specific population. The results were notable, but they should be read with equal honesty in both directions: it is neither a miracle nor a cause for alarm.
The study
This was an open-label, non-randomized trial (all participants knew they were receiving psilocybin, and there was no placebo group), led by Scott T. Aaronson and his team at the Sheppard Pratt Hospital in the United States, with funding from Compass Pathways. It was published in JAMA Psychiatry in December 2023. The study included 15 people between the ages of 18 and 65 (average age near 38) with bipolar II disorder and a depressive episode lasting more than three months, considered treatment-resistant because they had not improved sufficiently with at least two previous treatments during that same episode. The average duration of the episode exceeded two years. All participants tapered off their psychotropic medication at least two weeks prior. Each participant received a single 25 mg dose of synthetic psilocybin, supported by three preparatory sessions, an administration day of about eight hours with clinical support, and three subsequent integration sessions. The primary measure was the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) between baseline and week three.
What was found
At three weeks, the average depression score dropped by 24 points from baseline, a 76% reduction and a very large effect size. Twelve of the fifteen participants met the criteria for response (a drop of at least half the score), and eleven achieved remission (a score of 10 or less, indicating minimal or absent depression). Furthermore, this benefit was well-sustained over time: at week 12, twelve of the fifteen continued to meet both response and remission criteria. Secondary measures of self-reported symptoms and quality of life also improved. Regarding safety—the great unknown—no significant increases in mania or hypomania scales were observed (in fact, the trend was downward), nor were there increases in suicidal ideation, and there were no suicide attempts during the study. The most frequent adverse effect was a headache on the day of dosing, which resolved within 24 hours.
What it means (and what it doesn’t)
An optimistic reading is legitimate: in a group of people with long-term depression who had already failed several treatments, a brief intervention produced broad and lasting improvements without signs of the manic switch that was so feared. For a disorder with limited options, this is a lead worth following. However, the study design itself necessitates caution. There were only fifteen people, with no comparison group: when someone knows they have taken a psychedelic and receives intensive attention for weeks, the placebo effect and expectations can be enormous, and there is no way to discount them here. The sample was highly selected—for example, people with bipolar I, who are at higher risk of mania, were excluded—so these data cannot be extrapolated to everyone with bipolar disorder. Additionally, the drug was inseparably linked to a careful therapeutic framework: it was not “a mushroom and go home,” but rather preparation, support during the session, and subsequent integration, all of which are part of the result and cannot be replicated by self-administration.
It is worth emphasizing this last point without moralizing. Psilocybin remains a controlled substance in most countries, and its use in bipolar depression is still in the early stages of research, not an approved treatment. Self-experimenting with a condition like bipolar disorder, without a refined diagnosis, without supervised tapering of other drugs, and without support, is precisely the scenario this trial carefully avoided. Recognizing the potential of a molecule and recognizing the risks of using it without a framework are not contradictory positions; they are two halves of the same honesty. The reasonable approach, in light of these data, is cautious enthusiasm while awaiting larger, randomized, controlled studies that confirm—or refine—what this first step suggests.
Source
- Aaronson ST, van der Vaart A, Miller T, et al. Single-Dose Synthetic Psilocybin With Psychotherapy for Treatment-Resistant Bipolar Type II Major Depressive Episodes: A Nonrandomized Open-Label Trial. JAMA Psychiatry, 2023. DOI: 10.1001/jamapsychiatry.2023.4685 (ClinicalTrials.gov NCT04433845)
Educational content written from a harm reduction perspective and with respect for individual freedom. It is not a substitute for advice from a healthcare professional and is not intended to encourage or condemn any drug use.
