Preclinical evaluation of psilocybin and related compounds: Inhibition of cytochrome P450 isoforms

Abstract

Psilocybin, psilocin, 5-MeO-DMT, LSD and mescaline are classical hallucinogens whose recreational use has increased over recent decades (Brito-da-Costa et al., 2021; Dinis-Oliveira et al., 2019; Holze et al., 2021; Jiang et al., 2013). However, data on their interactions with cytochrome P450 (CYP450) enzymes remain scarce, despite the potential for clinically relevant drug–drug interactions.

The aim of this study was to evaluate in vitro the interaction of psilocybin, psilocin, 5-MeO-DMT, LSD and mescaline with CYP3A4, CYP2D6, CYP2B6 and CYP2A6 enzymes. Vivid® CYP450 kits were used, applying different concentration ranges for each compound and enzyme. At least three independent assays were performed per enzyme, and IC₅₀ values were calculated using GraphPad Prism version 9.3.0.

According to the applied classification criteria (Krippendorff et al., 2007), the obtained IC₅₀ values indicate that psilocin exhibits relevant inhibitory potential across several enzymes, acting as a moderate inhibitor of CYP3A4 and CYP2B6 and as a strong inhibitor of CYP2A6. LSD was identified as a strong inhibitor of CYP2D6, while 5-MeO-DMT showed moderate inhibition of this enzyme. The remaining compounds did not demonstrate significant inhibitory effects.

These results suggest that the consumption of these hallucinogens may alter the pharmacokinetics of substances metabolised by the involved CYP enzymes. In a forensic context, these findings indicate that hallucinogens such as psilocin, LSD and 5-MeO-DMT may interfere with the metabolism of other drugs and substances, potentially influencing toxicological interpretation in cases of intoxication, sudden death or concomitant substance use.