Preclinical evaluation of psilocybin and related compounds: Inhibition of cytochrome P450 isoforms
Mariana Silva‐Carvalho, Andreia Machado Brito-Da-Costa, Ricardo Dinis-Oliveira, Áurea Madureira-Carvalho, Diana Dias Da Silva
RevSALUS - Revista Científica da Rede Académica das Ciências da Saúde da Lusofonia May 1, 2026 DOI: 10.51126/revsalus.v8isupii.46635 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro laboratory study Peer reviewed |
|---|---|
| Population | Vivid® CYP450 enzyme kits (CYP3A4, CYP2D6, CYP2B6, CYP2A6) |
| Interventions | Psilocybin Psilocin 5-MeO-DMT LSD Mescaline |
| Measures | IC₅₀ |
| Topics | Psilocybin |
| Key points | Psilocin acted as a moderate inhibitor of CYP3A4 and CYP2B6 and a strong inhibitor of CYP2A6; LSD strongly inhibited CYP2D6, and 5-MeO-DMT moderately inhibited CYP2D6, while psilocybin and mescaline showed no significant inhibition. The authors suggest these interactions could alter the pharmacokinetics of other substances and may influence forensic toxicological interpretation. |
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.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |