Evaluating the Risk of Psilocybin for the Treatment of Bipolar Depression: A Systematic Review of Published Case Studies

This review (2021; pre-print) finds that in the current literature there are some known, but limited, risks of activating mania with psilocybin for those with bipolar depression (BD). The review describes 15 cases of BD and the use of a range of psychedelics.


Objective: Given the treatment limitations of depression in bipolar disorder, we evaluated the known risks of using psilocybin (and similar substances) in this population, including a systematic assessment of published case histories, to assess the risk of psilocybin as a treatment of depression in bipolar disorder.

Data Sources: A comprehensive search of case studies published through December 31, 2020 was conducted using the following electronic databases: PubMed, Web of Science, and PsychInfo, focusing on classic psychedelics and case studies or case histories.

Study Selection: Our search terms resulted in 541 hits, of which 43 were non-duplicates of case studies with individuals having an adverse reaction to a psychedelic substance. Of those, 15 case studies indicated some form of adverse event involving mania or manic like behavior that persisted beyond the acute intoxication of the substance.

Data Extraction: Two independent evaluators assessed all possible cases, focusing on manic behavior based on DSM criteria. Two separate evaluators convened to evaluate cases where the case information was unclear.

Results: Of the 15 cases, four involved psilocybin, two cases involved individuals with a likely pre-existing diagnosis of bipolar disorder, and three involved individuals without a history of polysubstance abuse or concurrent polysubstance use.

Conclusions: We conclude that there is some evidence of risk of activating mania with these substances, but that the risk does not appear to be strong or overwhelming. Instead a careful prospective study, such as an open-label treatment protocol with careful controls, appears warranted in this population.

Authors: David Gard, Mollie M. Pleet, Ellen R. Bradley, Andrew Penn, Matthew L. Gallenstein, Lauren S. Riley, Meghan DellaCrosse, Emily Garfinkle, Erin E. Michalak & Joshua D. Woolley

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