Cytochrome P450 enzymes contribute to the metabolism of LSD to nor-LSD and 2-oxo-3-hydroxy-LSD: Implications for clinical LSD use.

Summary

LSD is metabolized in the human liver into two main metabolites, nor-LSD and O-H-LSD, but only in small amounts—less than 1% of the parent compound was converted over four hours in laboratory experiments using human liver microsomes. Several cytochrome P450 enzymes contribute to this metabolism: CYP2D6, 2E1, and 3A4 for nor-LSD, and CYP1A2, 2C9, 2E1, and 3A4 for O-H-LSD. Enzyme induction by rifampicin increased metabolite formation, while omeprazole had a minor effect on nor-LSD. LSD and nor-LSD both activate serotonin receptors (5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C), with nor-LSD showing lower affinity at the 5-HT2C receptor. O-H-LSD had much weaker receptor activity, suggesting it is inactive. Genetic variations or drug interactions affecting these enzymes could alter LSD's effects.

Study at a glance

Abstract

In recent years, experimental research on lysergic acid diethylamide (LSD) in humans has gained new momentum. In humans, LSD is metabolized rapidly into several metabolites but knowledge of the involved metabolizing enzymes is limited. The aim of the current study was to identify the cytochrome P450 (CYP) isoforms involved in the metabolism of LSD to 6-norlysergic acid diethylamide (nor-LSD) and 2-oxo-3-hydroxy-LSD (O-H-LSD) in vitro, in order to evaluate potential effects of enzyme polymorphisms or prescription drugs on LSD pharmacokinetics. Additionally, interactions of LSD and both metabolites with 5-hydroxytryptamine (5-HT) receptors were assessed. LSD was incubated with human liver microsomes over 4 h and the production of nor-LSD and O-H-LSD was quantified by liquid chromatography tandem mass spectrometry. Metabolism was inhibited by the addition of specific CYP inhibitors. Additionally, recombinant CYPs were used to verify the inhibition results obtained with microsomes and induction of metabolism was investigated in human hepatocyte-derived cells. Radioligand binding and calcium mobilization assays were used to determine 5-HT receptor affinities and activities, respectively. Human liver microsomes displayed minor metabolite formation (<1% metabolized) over 4 h. CYP2D6, 2E1, and 3A4 significantly contributed to the formation of nor-LSD, and CYP1A2, 2C9, 2E1, and 3A4 were significantly involved in the formation of O-H-LSD. These findings could be verified using recombinant CYPs. Enzyme induction with rifampicin distinctly increased the formation of both metabolites, whereas treatment with omeprazole only slightly increased formation of nor-LSD. LSD and nor-LSD were pharmacologically active at the 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors. Nor-LSD mainly differed from the parent compound by having a lower affinity to the 5-HT2C receptor. O-H-LSD displayed substantially weaker affinity and activity at serotonergic receptors in comparison to LSD. To conclude, human liver microsomes converted only small amounts of LSD to nor-LSD and O-H-LSD but several CYPs significantly contributed. Genetic polymorphisms and drug interactions could therefore influence pharmacokinetics and pharmacodynamics of LSD. Nor-LSD likely has hallucinogenic activity similar to LSD, whereas O-H-LSD is inactive. Drug-drug interaction studies in humans are required to further assess the clinical relevance of these findings.