Psilocin inhibits CYP450 metabolism of isoforms 2A6 and 3A4

Psilocybin is a hallucinogen produced by several “magic mushrooms”. This prodrug is rapidly metabolized in the organism by alkaline phosphatases and esterases into psilocin. A scientific gap exists regarding the possible interactions between psilocybin/psilocin and CYP450 enzymes. Given their biological importance, and since the binding of drugs to CYP450 enzymes can interfere with the metabolism of other substrates leading to drug-drug interactions, this research topic is of utmost importance. This study aimed to assess potential inhibitory interactions between psilocybin/psilocin and CYP2A6, 2B6, 2D6, 2E1 and 3A4.
The in vitro assessment of CYP450 inhibition was performed using the Vivid®CYP450 screening kits, following the user’s guide. Concentrations of psilocybin and psilocin ranged between 3.8x10-6-6.8 mM (n=28) and 1.0x10-8-1.0 mM (n=26) for CYP2A6, 2.4x10-4-8.0 mM (n=28) and 7.7x10-6-1.0 mM (n=32) for CYP2B6, 1.71x10-13-8.0 mM (n=55) and 6.1x10-5-1.0 mM (n=16) for CYP2D6, 1.2x10-4-4.0 mM (n=32) and 1.7x10-5-1.0 mM (n=32) for CYP2E1, and 1.1x10-13-4.0 mM (n=47) and 6.1x10-5-1.0 mM (n=18) for CYP3A4, respectively. Each test condition was mixed with baculosomes expressing the specific CYP, Vivid® regeneration system, NADP+, and a non-fluorescent substrate. A solvent control and a positive control of inhibition (tranylcypromine for CYP2A6 and 2E1, miconazole for CYP2B6, quinidine for CYP2D6, and ketoconazole for CYP3A4) were used. Fluorescence was measured for 60 minutes using the Biotek® Synergy Mx monochromator-based microplate reader (Ex=415/20 nm; Em=460/20 nm). The half-maximal inhibitory concentration (IC50) was calculated using GraphPad prism 9.3.0. For CYP2A6 and CYP3A4 a minimum of five independent experiments were performed, four independent experiments for CYP2B6 and CYP2E1, and three independent experiments for CYP2D6.
IC50 values of 800.49 uM/ 2.06 uM for CYP2A6, 2349.84 uM/ 6.17 uM for CYP2B6, 2089.19 uM/ 11.89 uM for CYP2D6, 429.99 uM/ 6.37 uM for CYP2E1, and 65.27 uM/ 2.36 uM for CYP3A4 were attained for psilocybin and psilocin, respectively. The results suggest a potential for psilocin to be an inhibitor of all the enzymes evaluated, especially CYP2A6 and CYP3A4, contrary to psilocybin which does not seem to have the potential to inhibit any of the CYP450 enzymes evaluated.