Growing evidence suggests that psilocybin, the active ingredient in hallucinogenic mushrooms, can rapidly and durably improve symptoms of depression, leading to recent breakthrough status designation by the FDA and legalization for mental health treatment in some jurisdictions. Depression in bipolar disorder is associated with significant morbidity and has few effective treatments. However, there is little available scientific data on the risk of psilocybin use in people with bipolar disorder. Individuals with bipolar disorder have been excluded from modern clinical trials, out of understandable concerns of activating mania or worsening the illness course. As psilocybin becomes more available, people with these disorders will likely seek psilocybin treatment for depression and have likely already been doing so in unregulated settings. Our goal here is to summarize the known risks of psilocybin use (and similar substances) in bipolar disorder and to systematically evaluate examples of published case history data, in order to critically evaluate the relative risk of psilocybin as a treatment for bipolar depression. We found 17 cases suggesting that there is potential risk for activating a manic episode, thereby warranting caution. Nonetheless, 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.