Nataliya Vorobyeva 1 ,* † and  Alena A. Kozlova 2 , †

Pharmacokinetics

“Magic mushrooms” are usually taken per os in the form of herbal preparations or smoked. The effective oral dose of psilocybin is about 0.045 mg/kg (Hasler et al., 1997). Depending on the individual’s body weight and the species of psychedelic mushroom, this can be an equivalent of 0.25–1.5 g of dry mushroom (Hasler et al., 1997).

After oral intake psilocybin is rapidly dephosphorylated to psilocin (4-hydroxy-N,N-dimethyltryptamine) in the acidic milieu of the stomach or the intestinal mucosa by both alkaline phosphatase and non-specific esterase (Tylš et al., 2014). Rapid dephosphorylation of psilocybin was determined after its parenteral administration (Johnson et al., 2008). Psilocin is thought to be the active agent in the CNS responsible for the manifestation of psychoactive effects, as it easily crosses the blood-brain barrier (Hasler et al., 1997; Johnson and Griffiths, 2017). Interestingly, both inactive psilocybin (dephosphorylated) and bioactive psilocin were naturally found in varying amounts in psychedelic mushrooms (Kamata et al., 2010). Since psilocin is structurally related to the neurotransmitter serotonin, it undergoes a comparable metabolism in the human body (Helsley et al., 1998). However, the complete metabolic pathway of psilocybin remains largely unknown, and much information must be obtained to identify the exact mechanisms implicated in its metabolism. After dephosphorylating, psilocin is subjected to either glucuronidation or oxidation and deamination (Passie et al., 2002). Glucuronidation occurs through the activity of 19 endoplasmic enzymes classified as uridine 5′-diphospho-glucuronosyltransferase UDP-glucuronosyltransferases (UGTs) (Manevski et al., 2010). In particular, psilocin glucuronidation is carried out by two UGT1A10 in the small intestine and UGT1A9 in the liver, resulting in the formation of the psilocin-O-glucuronide (glucuronide) conjugate (Manevski et al., 2010). The majority of the absorbed psilocin (approximately 80%) is eliminated from the body with urine (Kamata et al., 2003). Several pharmacologic studies have shown instant hydrolysis of psilocybin after a single oral dose to its active metabolite psilocin, which has a half-life of 163 min, and the presence of approximately 67% of psilocin glucuronide form in the urine (Hasler et al., 1997, Hasler et al., 2002). Thus, psilocin-O-glucuronide is the key urinary metabolite with clinical and diagnostic relevance. The remaining 20% of the absorbed psilocin is metabolized by oxidation, where the compound usually undertakes demethylation and deamination to form 4 hydroxyindole—3—acetaldehyde and 4—hydroxyindole—3—acetic acid or 4—hydroxytryptophol (Brown et al., 2017). These metabolites are excreted by the liver and kidney, however, enzymes involved in these reactions are unknown (Brown et al., 2017; Dinis-Oliveira, 2017). The half-life of psilocin is 3 h (±1.1 h) in healthy individuals, depending on specific characteristics and route of administration (Brown et al., 2017).

Psilocybin and psilocin, similarly to serotonin, have an indole ring structure, a fused double ring encompassing both a pyrrole ring and a benzene ring, linked to an amino group by a two-carbon side chain (Hasler et al., 2004) (refer to Figure 1). They differ from each other in position 4 carbohydrates, which contain phosphate and hydroxyl groups, respectively. An overview of the characteristics of psilocybin. The diagram includes the chemical structures of psilocybin and its metabolite. The bold lines indicate similarities in the chemical structure between this psychedelic and serotonin. In addition, the enzymes and major organs involved in the metabolism and excretion of psilocybin are indicated. The mechanism of action represents the targets of the psychedelic, both the region of the brain affected by the psychedelic and the receptors with which it interacts (pink circle for agonist). 5HT—serotonin receptors (2Ar, 1Ar, 2Cr, – subtypes). IP3, inositol-3-phosphate; cAMP, cyclic adenosine monophosphate.