Psilocybin Revisited: The Science Behind the Drug and Its Surprising Therapeutic Potential.

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Author: Michael W. Jann
Date: Mar. 2021
From: Psychiatric Times(Vol. 38, Issue 3)
Publisher: Intellisphere, LLC
Document Type: Article
Length: 4,876 words
Lexile Measure: 1670L

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Psilocybin and psilocin are the main psychedelic agents of the psychoactive mushroom genus Psilocybe. (1) Historical and cultural use of these psychoactive mushrooms dates back 3000 years in Mexico and the Southwestern regional areas of the present-day United States. Scientifically, psilocybin was isolated and identified in 1958, synthesized in 1959, and used in various experimental research studies in the early 1960s. During that time, psilocybin and other psychedelic agents such as lysergic acid diethylamide (LSD) generated considerable controversy. Outside of recreational use, could they be used safely as therapeutic interventions?

The pharmaceutical company Sandoz ceased LSD and psilocybin manufacturing in 1965, and in 1970, the Controlled Substances Act placed psilocybin, LSD, and other psychedelic drugs under the Schedule I designation. (1,2) This action resulted in a cessation of research associated with these agents. The revival of research into psilocybin and LSD began 25 years later under strict restrictions, when preliminary findings displayed promising results for a variety of psychiatric disorders. In the past several years, there have been more research studies on psychedelics than at any previous time.

The FDA approved the psychedelic agent, esketamine nasal spray for treatment-resistant depression (TRD) in 2019; this opened the door to the novel therapeutic approaches of psychedelic agents. In 2018, the FDA designated psilocybin for TRD and 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post traumatic stress disorder (PTSD) as breakthrough therapies. (3) Based on these recent studies and approvals, psilocybin may have a growing role in the treatment of TRD and other psychiatric disorders.

Psilocybin reportedly has a low abuse potential and yields no physical dependence, based on the 8 factors of the Controlled Substances Act. It was recommended to be rescheduled as a Controlled Substance Schedule IV drug with a risk evaluation mitigation strategy (REMS) if approved by the regulatory agencies. (4,5)


The structures of psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine) and its active metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine) are shown in the Figure, and they both belong to the group of tryptamine/indolamine hallucinogens that are related to serotonin.1,6 Psilocybin can be considered a prodrug, as it is rapidly converted to psilocin in the gastrointestinal (GI) tract by alkaline phosphatase and nonspecific esterases, where 1.0 mol of psilocin is equal to 1.4 mol of psilocybin. (1) Psilocin is the active molecule that produces the pharmacologic effects of a selective agonist of serotonin (5-HT) receptors, which include 5-[HT.sub.1A], 5-[HT.sub.2A], 5-[HT.sub.2B], and 5-[HT.sub.2C] receptor subtypes. (1,7) Compared to other similar 4-OH substituted tryptamines, psilocin has the most potent binding affinity (Ki) for 5-[HT.sub.2A] receptors (6.0 nM), 5-[HT.sub.2C] receptors (10 nM), and to a lesser extent, 5-[HT.sub.2B] receptors (410 nM). (1,8)

Preclinical studies have shown that 5-HT2A receptor activation in the cortical and subcortical structures is the unifying mechanism by which psychedelics exert their hallucinogenic and other assorted psychological actions. (7) Depending upon the dose used, the specific psychedelic agent, and possibly, the 5-HT2A receptor density in the different neuronal areas, psilocybin and other psychedelic agents can exert different modulatory actions across the various cortical regions. The administration of ketanserin (a 5-HT2A...

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