Psilocybin was first isolated by Albert Hofmann in 1957 from the Central American mushroom Psilocybe mexicana. The first synthetic psilocybin product was created shortly thereafter in 1958 and continues to be widely used today, both recreationally and in spiritual or religious rituals.¹ It has since been found in more than 100 mushroom species worldwide with varying potency. These mushrooms are both cultivated and found in the wild. Cultivated mushrooms tend to be more potent through selection of stronger mushroom strains with more active ingredient (up to 10 times that of some wild mushroom species).²

Psilocybin, a classic tryptamine hallucinogen, has similar properties to lysergic acid diethylamide (LSD) and mescaline with a slightly different chemical structure. Cross-tolerance between the different hallucinogens has been demonstrated, and research shows a common mechanism of action through serotonergic (5-HT) pathways. Psilocybin is a strong agonist at 5-HT_2A as well as a moderate agonist at 5-HT_1A and 5-HT_2C.³ 5-HT_2A receptors are located within the thalamus and cortex of the brain. Activation of 5-HT_2A receptors in the thalamus, the area of the brain responsible for sensory input, appears to decrease thalamic activity, thus leading to sensory alterations commonly referred to as hallucinations.^4,5 Hallucinogenic effects typically onset within the first 20 to 40 minutes of use then disappear within 3 to 6 hours. Psilocybin’s threshold for intoxication is approximately 40 mcg/kg of body weight. There is a low percentage of psilocybin in most mushroom varieties, so this corresponds to approximately 1 to 2 g of dried mushrooms.^2,6 Due to this alteration in sensory perception and serotonergic activity of the substance, much of the research for this agent has been focused on those mental health conditions with abnormalities in sensory perception, such as depressive disorders and anxiety or anxiety-related disorders. Psilocybin has also been researched for use in substance use disorders.

Since the Controlled Substance Act (CSA) of 1970, clinical studies using hallucinogens and psychedelics essentially ceased. Much of the research completed on these agents in the 1950s and 1960s was not taken seriously due to the small nature of the studies or methodology inconsistent with current research standards. However, interest in understanding the neuropsychiatric effects of these agents and their potential role in medical therapy persisted. Because of the CSA Schedule I status of these agents, clinical research in humans seemed unlikely and locating funding sources virtually impossible. In 1992, the National Institute on Drug Abuse worked with a Food and Drug Administration advisory committee that ultimately allowed for the resumption of research of psychedelic agents.⁷

The Heffter Research Institute, founded in 1993 by Nichols and colleagues, is the only institute solely dedicated to clinical research of the medicinal value of psychedelic agents. They ultimately have focused their research on psilocybin, the active ingredient in magic mushrooms or ‘shrooms.⁷ As the search for novel treatments for mental illness grows, new energy is being focused on older treatments, such as ketamine, and more Schedule I substances, such as marijuana, LSD, and psilocybin. This article will explore the literature behind psilocybin and the potential for the agent as a treatment for select mental health conditions. However, due to the CSA Schedule I nature of the substance, safety should first be reviewed.