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 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 in humans.
  • 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 with 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 derivative have been ignored. This leaves lingering questions as to whether they behave similarly to psilocybin/psilocin — or whether 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 does its metabolism and elimination compare to that for psilocybin/psilocin?

 

 

Psilocybin and Psilocin Metabolism References

  • Hasler, F. et al; J Pharm Biomed Anal 30 (2): 331-9 (2002)
  • Martin, R. et al;  Int J Legal Med.  126(6): 845-9 (2012)
  • Shoda, T. et al.; Drug Test Anal. 2011 Sep;3(9):594-6
  • Manevski, N. et al; Drug Metab Dispos. 2010 Mar;38(3):386-95
  • Aboul-Enein, HY; Am J Pharm Sci Support Public Health. 1974 May-Jun;146(3):91-5
  • Ricardo Jorge Dinis-Oliveira (2017) , Drug Metabolism Reviews, 49:1, 84-91.