A Plea for Nuance: Should People with a Family History of Bipolar Disorder Be Excluded from Clinical Trials of Psilocybin Therapy?

Background: As the field of psychedelic therapy grows, it is vital to consider who can safely engage with psilocybin therapy. In most modern clinical trials of psilocybin therapy, individuals with a family history of bipolar disorder (BD) have been excluded from participation because of their genetic predisposition for developing BD. Review: Case studies and survey data shed light on the risks of psilocybin therapy among those with a family history of BD in the absence of data from modern clinical trials. We review existing evidence that could inform risk stratification for these individuals, including genetic proximity to the affected relative, BD type, age at onset in the relative, and participant age. Hypothesizing that the risk of developing BD may predict the risk of developing serious adverse events when engaging with psilocybin therapy, we propose a risk stratification tool to be utilized when determining the relative risks of psilocybin therapy to those with a family history of BD in the context of clinical trials. Conclusion: Balancing the need for effective treatments against the potential for serious adverse events in those undergoing psilocybin therapy with a family history of BD, we argue for caution in psychedelic clinical trials but not outright exclusion of these individuals. Our risk stratification tool allows for more nuanced inclusion and exclusion criteria.