The Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria for substance-induced psychosis requires the presence of delusions, hallucinations, or both, that developed during or within one month of substance intoxication or withdrawal. The disturbance must not be better accounted for by another diagnosis or occur exclusively during delirium. The disturbance must also cause clinically significant distress or impairment in functioning [3]. A literature search of PubMed, using the keywords “psilocybin-induced psychosis” and “hallucinogen-induced psychosis,” yielded eight published case reports describing nine cases of psilocybin-induced psychosis (Table 1) [4-11].

Of these nine cases, six had known histories of cannabis use, and an additional two cases had a history of substance use that may or may not have included cannabis [4,6-11]. Every case had a personal history of either substance use disorders, symptoms of psychiatric disorders, or both. Six of the cases involved either repeated doses or unusually high doses, or both [4,6,8-11]; the remaining three cases used unknown quantities [5,7,8]. For one of the cases, acute encephalopathy better explained the symptoms, but a substance-induced psychotic disorder could not be ruled out [7]. Two of the cases reported catatonic symptoms associated with the psychosis [4,11]. Cases of psilocybin-induced mood disorders in the absence of psychotic symptoms were outside the scope of this review.

The primary predisposing factors among these cases were a personal and/or family history of psychiatric disorders and a personal history of cannabis use. Most patients had also consumed unusually large quantities of mushrooms. Our case furthers this emerging pattern. The patient in our case report had a possible history of schizoid and avoidant traits, two personality disorders which have long been considered likely antecedents for schizophrenia, and a history of years of cannabis use, a known risk factor for schizophrenia and psychosis [12,13]. Additionally, he was ingesting 150 mg of psilocybin multiple times a week over the course of months leading up to this episode. By comparison, in research, an oral dose above 25 mg is considered high [1].

Limitations to this case include that it is unclear what role his cannabis use played in his developing psychotic symptoms and that his history of depression and interpersonal difficulties may have masked prodromal symptoms of schizophrenia, characterized by social withdrawal and cognitive decline. Notably, these new onset psychotic symptoms occurred only after the patient began using psilocybin heavily, and he had not experienced any prior psychotic symptoms during his years of cannabis use. While his cannabis use was likely a predisposing factor, it is far less likely that this presentation represented cannabis-induced psychosis than psilocybin-induced psychosis given the timing of the onset of symptoms. Distinguishing subtle prodromal symptoms of schizophrenia from co-morbid depressive symptoms is always challenging, especially in the context of a severe substance use disorder. That a patient may have been experiencing prodromal symptoms prior to developing a substance-induced psychotic disorder can very rarely be ruled out completely due to the confounding effects of intoxication and withdrawal symptoms from substance use.

Interest in research for psilocybin as a treatment for psychiatric illness has grown considerably over recent years. Psilocybin is already being studied as a potential treatment for anxiety and depression in patients with advanced cancer, major depressive disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and tobacco and alcohol dependence, and even more indications are being explored with new research. Psilocin, for which psilocybin is a prodrug, probably acts primarily through agonism of 5-HT_2a serotonin receptors, and this is also the likely mechanism for the proposed anxiolytic and antidepressive effects. Current findings are encouraging, with potential benefits being found for anxiety, obsessive-compulsive disorder, depression, and suicidality, among others, with few adverse effects. However, though the body of literature is growing, small study size and paucity of comparison studies currently significantly limits the quality of evidence for the benefits of psilocybin [14].

Given this increasing popularity of psilocybin, both therapeutically and recreationally, the risks of its use need to be studied as extensively as the benefits. Our case report and associated review serves as a warning that psilocybin use is not without risks and predisposing risk factors for psilocybin-induced psychosis may include common psychiatric conditions such as depression, anxiety, and personality disorder traits. However, that these cases occurred primarily among those using doses much higher than those used in a therapeutic setting will be reassuring to researchers studying the medicinal uses.