Beyond Exclusion: Why Psychedelics May Be Safe and Effective for Bipolar Disorder

For years, people with bipolar disorder have been systematically excluded from clinical trials of psychedelic therapy. Despite promising results for psychedelics in treating depression, anxiety, and other mental health conditions, researchers have been hesitant to include bipolar patients due to concerns about triggering manic episodes. But what if this exclusion has been based more on caution than evidence? Recent research is challenging these long-held assumptions and suggesting that psychedelics might actually be safe and effective for many people with bipolar disorder.

The Bipolar Treatment Challenge

Bipolar disorder affects up to 4% of adults at some point in their lives and is notoriously difficult to treat. The condition is characterized by cyclical episodes of abnormally elevated or irritable mood known as (hypo)mania, often alternating with episodes of depression. While the dramatic highs of mania often come to mind when thinking about bipolar disorder, the illness is usually dominated by depressive episodes that can be particularly stubborn and debilitating. The stakes are high: individuals with bipolar disorder often experience lower quality of life and functioning, and the condition accounts for a substantial portion of suicides globally. Studies indicate that 30% of affected individuals attempt suicide, and 5-15% die by suicide. Current treatments for bipolar depression are limited and problematic. Psychiatric treatment faces the challenge of addressing depressive symptoms without triggering mania, or vice versa. Treatment is further complicated by the large variability in patients' responses to pharmacological treatments such as lithium and lamotrigine. Additionally, these medications often cause troublesome side effects, including cardiovascular conditions, extreme restlessness or fatigue, and metabolic disorders. Given these challenges, the need for novel treatments is clear. Could psychedelics offer a solution?

Why the Hesitation?

The exclusion of people with bipolar disorder from psychedelic research stems from several concerns:

1. Fear of inducing mania: There's concern that the powerful serotonergic effects of psychedelics could trigger a manic episode, similar to how some antidepressants can cause a "switch" from depression to mania in bipolar patients.
2. Limited safety data: Without controlled studies, researchers have relied on case reports and theoretical concerns rather than systematic evidence.
3. Historical caution: The field of psychedelic research is still rebuilding its reputation after decades of restrictions, leading to extra caution with potentially vulnerable populations.

These concerns are understandable. However, a closer look at the available evidence suggests they may be overstated.

What the Research Actually Shows

A systematic review published in the Journal of Affective Disorders Reports examined the risk of psilocybin for treating bipolar depression by analyzing published case studies. The researchers found only 17 cases of adverse events possibly involving mania across all psychedelics, with just five involving psilocybin specifically. Only two of these cases involved individuals with a likely pre-existing diagnosis of bipolar disorder. The authors concluded that while there is reason for caution, "the risks may be low relative to the treatment needs of this population." They noted that epidemiological data and religious ceremony data do not provide strong evidence for excluding people with bipolar disorder from carefully designed clinical trials. More recently, two groundbreaking studies have provided direct evidence challenging the assumption that psychedelics are necessarily dangerous for people with bipolar disorder.

New Evidence: Recreational Use Study

A 2024 study published in the Journal of Affective Disorders systematically examined the effects of recreational psychedelic use in individuals with bipolar disorder. Using the Timeline Followback method, researchers assessed mood symptoms, substance use, and other mental health-related variables in the month before and three months following participants' most recent psychedelic experience. The results were striking: participants showed a significant reduction in depressive symptoms and cannabis use, an increase in the number of days without mental health symptoms, and an increase in the number of days with hallucinogen use. Most importantly, no significant changes in (hypo)manic, psychotic, or anxiety symptoms were observed. This suggests that, at least in some contexts, psychedelics may not trigger the feared manic episodes in people with bipolar disorder.

The Sheppard Pratt Trial: First Clinical Evidence

Even more compelling is a recent clinical trial conducted at Sheppard Pratt Hospital. This open-label study, published in JAMA Psychiatry, investigated the safety and efficacy of a single 25-mg dose of synthetic psilocybin with psychotherapy for depressive episodes in individuals with bipolar II disorder. The results were remarkable. Of the 15 participants, all had lower depression scores at week 3, with a mean change of −24.00 points on the Montgomery-Åsberg Depression Rating Scale (MADRS). At week 3, 12 participants met the response criterion (50% decrease in MADRS), and 11 met remission criterion (MADRS score ≤10). At the study end point (12 weeks), 12 patients met both response and remission criteria. Most importantly from a safety perspective, there was no significant increase in mania/hypomania symptoms or suicidality. The Young Mania Rating Scale (YMRS) and Columbia Suicide Severity Rating Scale (CSSRS) scores did not change significantly at any point compared to baseline. Lead researcher Dr. Scott Aaronson and colleagues concluded that the findings "suggest efficacy and safety of psilocybin with psychotherapy in BDII depression and supports further study of psychedelics in this population."

Why Might Psychedelics Be Safe for Some Bipolar Patients?

Several factors may explain why psychedelics might not trigger mania in bipolar patients as often as feared:

1. Controlled settings: Modern psychedelic therapy protocols emphasize careful preparation, monitoring, and integration, which may reduce risks compared to recreational use.
2. Patient selection: The Sheppard Pratt trial focused specifically on bipolar II disorder, which has a lower risk of severe mania compared to bipolar I.
3. Medication-free approach: Participants discontinued other psychiatric medications before receiving psilocybin, potentially reducing drug interaction risks.
4. Therapeutic support: The presence of trained therapists throughout the experience may help manage any challenging psychological content that emerges.
5. Different mechanism: Unlike traditional antidepressants that are taken daily and can gradually build up in the system, psilocybin is typically administered as a single dose with effects that resolve within hours.

Who Might Benefit Most?

Based on current evidence, certain individuals with bipolar disorder may be better candidates for psychedelic therapy than others:

• People with bipolar II disorder: The existing clinical trial focused on bipolar II, which is characterized by hypomania rather than full mania, suggesting this subtype may be safer to treat.
• Those with treatment-resistant depression: Individuals who haven't responded to multiple conventional treatments may have more to gain from novel approaches.
• Patients in a stable phase: Those not currently experiencing active mania or severe depression may be better positioned to benefit from psychedelic therapy.
• People with good support systems: Strong social support and access to ongoing mental health care are important safety factors.

It's worth noting that even within these categories, individual responses may vary, and careful screening and monitoring would be essential in any treatment protocol.

The Path Forward

While the emerging evidence is promising, it's important to recognize that research in this area is still in its early stages. The Sheppard Pratt trial, while groundbreaking, was small and open-label, meaning there was no control group or blinding. Larger, randomized controlled trials are needed to confirm these initial findings. Several important questions remain to be answered:

• Are the results similar for people with bipolar I disorder, who experience more severe manic episodes?
• What is the optimal dose and frequency of administration for bipolar depression?
• How do psychedelics interact with commonly prescribed mood stabilizers?
• What factors might predict who will respond well versus who might experience adverse effects?

Researchers at the University of California, San Francisco are currently conducting a clinical trial specifically designed to determine the safety, tolerability, and feasibility of psilocybin therapy in people with Bipolar II Disorder. This and other upcoming studies will help answer these critical questions.

Practical Implications

For now, it's important to emphasize that self-medication with psychedelics is not recommended for people with bipolar disorder. The promising results seen in research settings involve careful screening, preparation, monitoring during the experience, and integration afterward—elements that are typically absent in recreational use. However, the emerging evidence suggests that blanket exclusion of all bipolar patients from psychedelic research and potential future treatments may not be justified. As one research team put it, "the relative lack of systematic data or common case examples indicating risk appears to show that a cautious trial, using modern trial methods focusing on appropriate 'set' and 'setting', targeted at those lowest at risk for mania in the bipolar spectrum (e.g., bipolar 2 disorder), is very much needed, especially given the degree to which depression impacts this population."

A New Hope

For people with bipolar disorder who struggle with persistent depression despite trying multiple treatments, these research developments offer a glimmer of hope. The possibility that psychedelic therapy might one day be a safe and effective option for bipolar depression could represent a significant advance in treatment options. As one participant in the Sheppard Pratt trial described their experience: "It was like a reset button for my brain. For the first time in years, I felt like the cloud had lifted, and I could see clearly again. "While more research is needed before psychedelic therapy becomes a mainstream treatment option for bipolar disorder, the early results challenge long-held assumptions and open the door to new possibilities. For a condition that has seen few treatment innovations in recent decades, this represents a potentially important breakthrough.

Disclaimer: Psychedelic Assisted Psychotherapy has not been approved by any regulatory agencies in the United States, and the safety and efficacy are still not formally established at the time of this writing. 

References

Aaronson, S. T., van der Vaart, A., Miller, T., LaPratt, J., Swartz, K., Shoultz, A., Lauterbach, M., Sackeim, H. A., & Suppes, T. (2023). Single-Dose Synthetic Psilocybin With Psychotherapy for Treatment-Resistant Bipolar Type II Major Depressive Episodes: A Nonrandomized Open-Label Trial. JAMA Psychiatry, 81(6), 634. https://doi.org/10.1001/jamapsychiatry.2023.4685

Gard, D. E., Pleet, M. M., Bradley, E. R., Penn, A. D., Gallenstein, M. L., Riley, L. S., DellaCrosse, M., Garfinkle, E. M., Michalak, E. E., & Woolley, J. D. (2021). Evaluating the risk of psilocybin for the treatment of bipolar depression: A review of the research literature and published case studies. Journal of Affective Disorders Reports, 6, 100240. https://doi.org/10.1016/j.jadr.2021.100240

Meyer, T. D., Ibrahim, M., Vale, L. N., & Soares, J. C. (2024). Psychedelic use and bipolar disorder – An investigation of recreational use and its impact on mental health. Journal of Affective Disorders, 373, 505-511. https://doi.org/10.1016/j.jad.2024.12.044