Psilocybin-assisted therapy linked to reduced depression in people with bipolar disorder, small study finds

A small pilot study published in the journal Psychedelic Medicine suggests that psilocybin-assisted psychotherapy might help reduce depressive symptoms in people with bipolar II disorder who have not responded to conventional treatments. The treatment was also not associated with an increase in manic or psychotic symptoms, which are typically a concern in bipolar disorder. While the findings are preliminary and based on just four participants, they highlight a potential avenue for addressing a form of depression that is often difficult to treat.

Psilocybin is a naturally occurring psychedelic compound found in certain species of mushrooms. When used under structured and supervised conditions, it has been associated with rapid improvements in depressive symptoms. Most clinical research to date, however, has excluded people with bipolar disorders due to concerns that psychedelics could trigger manic episodes. This has left a significant gap in understanding whether psilocybin could be safely and effectively used in this population, particularly for those with bipolar II disorder, which is often marked by long-lasting depressive episodes and a lack of effective treatment options.

“Psilocybin has shown very promising results for treatment-resistant depression. However, previous studies have excluded patients with bipolar disorder. I see a lot of patients with bipolar depression and know they need better treatments, so I was very interested to see if psilocybin was feasible to study for treatment-resistant bipolar depression,” said study author Joshua D. Rosenblat, an associate professor of psychiatry at the University of Toronto.

The new analysis focused on a subgroup of participants from a previously published trial on treatment-resistant depression. The researchers specifically examined four individuals diagnosed with bipolar II disorder. These participants had been experiencing major depressive episodes lasting at least three months and had failed to respond to at least two standard pharmacological treatments. The average length of their current depressive episode was nearly 16 years. This subgroup included two men and two women, with an average age of about 38. Three identified as white and one as Arab. All had some post-secondary education, and one was married.

Before beginning the study, participants were required to taper off antidepressants and antipsychotics, though they were allowed to continue taking mood stabilizers under medical supervision. Each participant received one or two supervised psilocybin sessions at a dose of 25 milligrams. These sessions were embedded within a broader treatment framework that included preparatory and integrative psychotherapy conducted by licensed professionals. The researchers used several standard tools to track symptoms, including the Montgomery–Åsberg Depression Rating Scale (MADRS), the Quick Inventory of Depressive Symptoms–Self Report (QIDS-SR), and the Young Mania Rating Scale (YMRS). Assessments took place frequently over the course of the 24-week study.

At the beginning of the study, the participants’ average MADRS score was 32.5, indicating moderate to severe depression. Two weeks after the first psilocybin session, the average score had dropped to 20.3, and two weeks after the second session, it dropped slightly more to 19. At the end of the 6-month study period, the average score was 21.3, suggesting that the reductions in depressive symptoms had persisted to some degree.

A similar trend was seen with self-reported symptoms on the QIDS-SR. At baseline, participants scored an average of 18. Two weeks after the first psilocybin session, the average score had dropped to 10.3, and after the second session, it remained around 10. By the end of the study, scores had risen slightly to 15.7. These patterns suggest that depressive symptoms improved during the treatment period and may have partially returned afterward, though not to the original severity.

“This small pilot study suggested that psilocybin-assisted psychotherapy is feasible to study in bipolar II disorder,” Rosenblat told PsyPost. “We cannot yet comment on safety and efficacy, but can say that the pilot study was promising and no safety concerns arose. There was evidence of improvement (i.e., reduction in depressive symptom severity) in this small study with no serious adverse events. Of note, this was the first randomized controlled trial of psilocybin therapy to include bipolar disorder.”

Crucially, none of the participants experienced a switch into mania or hypomania, a concern that has often led researchers to exclude people with bipolar disorder from psychedelic studies. The YMRS scores, which measure manic symptoms, remained at a stable mean of 1 across all time points. There were also no reports of psychosis or suicidal behavior. This stability is important, as mania can be highly disruptive and potentially dangerous, especially if triggered by an intervention intended to treat depression.

“I was surprised that we had no cases of mania, hypomania, or psychosis,” Rosenblat said. “There are major concerns that psilocybin will trigger mania and psychosis, so it was reassuring that we did not see any of this.”

The findings appear to align with results from another recent pilot study involving 15 people with bipolar II depression. In that earlier study, participants also experienced reduced depressive symptoms following a single 25 mg dose of psilocybin, without any signs of treatment-emergent mania or psychosis. The consistency between the two studies, though preliminary, lends some support to the idea that psilocybin might be safe under controlled conditions for certain individuals with bipolar II disorder.

At the same time, the study has several limitations. Most significantly, it was conducted with only four participants, making it difficult to generalize the findings. The open-label design means that both participants and researchers knew what treatment was being administered, which can influence expectations and perceived outcomes. The small sample also included people with diverse psychiatric histories and varying degrees of treatment resistance, which may affect how individuals respond to psilocybin.

Because of these factors, “we cannot draw any conclusions about safety or efficacy,” Rosenblat said. “It is just too early to say, but we can say that further study is merited and feasible.”

Larger trials are already underway, according to the research team, with the goal of more rigorously testing both the safety and antidepressant effects of psilocybin in people with bipolar II disorder.

“We are currently conducting two larger clinical trials to more thoroughly evaluate psilocybin for treatment-resistant bipolar depression,” Rosenblat explained. “If safety and efficacy are demonstrated in these larger trials, then psilocybin might become a treatment option for this group of difficult-to-treat patients where other treatments are often ineffective.”

“We are currently only studying psilocybin for bipolar II disorder, but if safety and efficacy are demonstrated, we may even explore it in bipolar I disorder, where the risk of mania and psychosis is higher. We need to demonstrate safety in bipolar II disorder first, but I am keen to explore this in other groups also.”

The study, “Psilocybin-Assisted Psychotherapy for Treatment-Resistant Depression in Bipolar II Disorder,” was authored by Shakila Meshkat, Erica Kaczmarek, Zoe Doyle, Ryan M. Brudner, Fabiano A. Gomes, Marc G. Blainey, Geneva Weiglein, Roger S. McIntyre, Rodrigo B. Mansur, and Joshua D. Rosenblat.