Background In June 2023, the FDA released a First Draft Guidance on Clinical Trials with Psychedelic Drugs, reflecting a reemerging interest in using psychoactive compounds like psilocybin to treat conditions such as depression, PTSD, and substance use disorders. Psilocybin, specifically, has shown promising efficacy in treating unipolar depression, with ongoing studies exploring its safety in bipolar II depression. However, its significant serotonergic activity raises concerns about potentially triggering manic episodes in susceptible individuals. Existing clinical trials of psilocybin have historically excluded patients with bipolar disorder, and literature is scarce regarding psilocybin-induced mania.

Case Presentation The patient is a 16-year-old male with a history of depression, was brought to the emergency department by police following erratic behavior reported by his family. He had new-onset decreased need for sleep, pressured speech, grandiosity, and paranoia. On exam, he reported high energy and made several grandiose statements, such as that he believed he could achieve anything and fly if he wanted to. He admitted to consuming chocolates infused with magic mushrooms and cannabis. Despite his regular cannabis use, there had been no recent change in frequency or type. Lab work, including urine drug screen (UDS) and liver panel, were positive for THC and mildly elevated LFTs, respectively. Due to safety concerns related to his high-rise living situation, he was hospitalized. The patient was initiated on risperidone due to signs of both mania and psychosis being present and was recommended for transfer to an inpatient psychiatric facility. On day three, he continued to demonstrate elevated mood, grandiosity, tangential speech, and distractibility, although there were improvements in his sleep. The patient was then accepted for transfer to an external psychiatric facility, and the remainder of his clinical course is not known.

Discussion This case underscores the potential of psilocybin to induce manic episodes, especially in individuals with a personal or family history of bipolar disorder. Healthcare providers should prioritize obtaining comprehensive substance use histories and evaluating past medical and family histories when assessing patients presenting with acute manic or psychotic symptoms. Such practices are essential for assessing the risk of psilocybin-induced mania and formulating appropriate management strategies. Future research is critical to elucidate the safety profile of psilocybin, particularly in populations with existing bipolar disorder or heightened susceptibility to mania. Understanding these risks is paramount for informing clinical decisions regarding the therapeutic use of psilocybin and mitigating potential adverse outcomes, as highlighted by this case.