Metabolism of Psilocybin and Psilocin in Humans

Metabolism of Psilocybin and Psilocin in Humans

The metabolism of psilocybin (and psilocin) is frequently cited.  But, the supporting references are seldom discussed.

The available literature supports the following conclusions:

  1. Upon ingestion, psilocybin is metabolized to psilocin, which is the active molecule, responsible for the psychedelic effects of “magic mushrooms.”
  2. Psilocybin is dephosphorylated by alkaline phosphatase, producing psilocin, which is the active metabolite. Psilocin is responsible for the psychoactive properties – not psilocybin.
  3. Psilocin is further metabolized, resulting in psilocin-O-glucuronide as the main urinary metabolite.

Summary of Psilocybin Metabolism Studies

Below are some additional details from the literature cited in the References section below.

  • In a clinical study investigating the metabolism of psilocybin and elimination kinetics of psilocin, eight volunteers received psilocybin in psychoactive oral doses of 212+ or -25 ug/kg body weight.
    • Orally administered psilocybin was rapidly metabolized to psilocin.
  • Urine was collected for 24 hr and psilocin concentrations were determined by high-performance liquid chromatography with column switching and electrochemical detection (HPLC-ECD).
    • Notably, psilocybin was administered and psilocin urine concentrations were subsequently followed.
  • Sample workup included “protection of the unstable psilocin with ascorbic acid,” freeze-drying, and extraction with methanol.
    • One unanswered question is whether the “unstable psilocin” is responsible for the “bluing reaction” observed in some psilocybin-containing mushrooms?
    • Stabilizing psilocin with ascorbic acid suggests that the degradation of psilocin proceeds via an oxidative mechanism.  (Ascorbic acid, an antioxidant “protects” against oxidation.)
  • Peak psilocin concentrations up to 870 ug/l were measured in urine samples during the 2-4 hr collection interval.
  • Psilocybin and psilocin were metabolized and excreted within 24 hours of orally administering psilocybin.
    • The psilocin excretion rate during this period was 55.5 (+/-33.8) ug/h.
    • The limit of quantitation (10 ug/L) was usually reached 24 hr after drug administration.

Unanswered Questions

While some work has been done to elucidate the metabolism and pharmacology of psilocybin/psilocin, the rest of the structurally similar derivatives have been ignored. This leaves lingering questions as to whether they behave similarly to psilocybin/psilocin — or if there are important differences in terms of pharmacology and/or metabolism.

The scientific community has yet to study the pharmacology of psilocybin derivatives other than psilocin and psilocybin.  For example, is baeocystin active?  Or does it function as a prodrug like psilocybin?  How does its potency compare to the potency of psilocybin/psilocin?  How do its metabolism and elimination compare to that for psilocybin/psilocin?

 

 

References

1. Aboul-Enein HY. Psilocybin: a pharmacological profile. Am J Pharm Sci Support Public Health. 1974;146(3):91-95.
2. Dinis-Oliveira RJ. Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance. Drug Metabolism Reviews. 2017;49(1):84-91. doi:10.1080/03602532.2016.1278228
3. Hasler F, Bourquin D, Brenneisen R, Vollenweider FX. Renal excretion profiles of psilocin following oral administration of psilocybin: a controlled study in man. Journal of pharmaceutical and biomedical analysis. 2002;30(2):331-339. doi:doi.org/10.1016/S0731-7085(02)00278-9
4. Martin R, Schürenkamp J, Pfeiffer H, Köhler H. A validated method for quantitation of psilocin in plasma by LC–MS/MS and study of stability. International journal of legal medicine. 2012;126(6):845-849.
5. Thomas K, Malcolm B, Lastra D. Psilocybin-Assisted Therapy: A Review of a Novel Treatment for Psychiatric Disorders. Journal of Psychoactive Drugs. 2017;49(5):446-455. doi:10.1080/02791072.2017.1320734