Abstract
Lysergic acid diethylamide (LSD) is a classic psychedelic substance that is used recreationally and investigated in psychiatric research. There are no pharmacogenetic studies on LSD. In vitro metabolic studies indicate that several cytochrome P450 (CYP) isoforms (e.g., CYP2D6, CYP1A2, and CYP2C9) are involved in LSD metabolism, but in vivo data are scarce. The present study examined the influence of genetic polymorphisms of CYP genes on the pharmacokinetics and acute effects of LSD in healthy subjects. We identified common genetic variants of CYPs (CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP2B6) in 81 healthy subjects who were pooled from four randomized, placebo-controlled, double-blind Phase 1 studies. We found that genetically determined CYP2D6 functionality significantly influenced the pharmacokinetics of LSD. Individuals with no functional CYP2D6 (i.e., poor metabolizers) had longer LSD half-lives and approximately 75% higher parent drug and main metabolite 2-oxo-3-hydroxy LSD area-under-the-curve blood plasma concentrations compared with carriers of functional CYP2D6. Non-functional CYP2D6 metabolizers also exhibited greater alterations of mind and longer subjective effect durations in response to LSD compared with functional CYP2D6 metabolizers. No effect on the pharmacokinetics or acute effects of LSD were observed with other CYPs. These findings indicate that genetic polymorphisms of CYP2D6 significantly influence the pharmacokinetic and subjective effects of LSD. Given the potential therapeutic use of psychedelics, including LSD, the role of pharmacogenetic tests prior to LSD-assisted psychotherapy needs to be further investigated.
Highlights
Lysergic acid diethylamide (LSD) is a classic psychedelic
One study of human liver microsomes showed that CYP2D6, CYP3A4, and CYP2E1 contribute to the N-demethylation of LSD to 6-nor-LSD, whereas CYP2C9, CYP1A2, CYP2E1, and CYP3A4 participate in the formation of LSD’s main metabolite 2-oxo-3-hydroxy-LSD (O-H-LSD)[8]
Subjects who were genetically classified as CYP2D6 poor metabolizers (PMs) exhibited higher plasma LSD exposure (Fig. 1), reflected by significantly larger AUC∞ and AUC10 values compared with functional CYP2D6 carriers (Table 1)
Summary
Lysergic acid diethylamide (LSD) is a classic psychedelic. After early psychiatric research, recreational use, and prohibition, LSD was rediscovered by modern psychiatric research and may be useful for LSD-assisted psychotherapy[1,2,3,4,5,6]. Another study of human liver S9 fractions reported that CYP2C19 and CYP3A4 were involved in the formation of nor-LSD, and CYP1A2 and CYP3A4 contributed to the hydroxylation of L SD7. Some CYP enzymes (e.g., CYP2D6, CYP1A2, CYP2C9, and CYP2C19) have common functional genetic polymorphisms that result in different p henotypes[9,10,11,12,13,14]. Genetic variants of LSD-metabolizing CYPs, especially CYP2D68, may influence the pharmacokinetics of LSD. The present study investigated the influence of prominent genetic polymorphisms of several CYPs involved in the metabolism of LSD (i.e., CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP2B6) on pharmacokinetic parameters of LSD and its acute subjective effects. Based on in vitro studies with LSD, we hypothesized that CYP2D6 PMs would exhibit higher LSD concentrations and acute effects compared with individuals with functional CYP2D6. The quality and extent of subjective effects of psychedelics are interesting because more intense and more positive acute psychedelic effects are thought to predict long-term therapeutic outcome in patients who receive psychedelic-assisted therapy[20,21,22] and positive long-term effects in healthy subjects[23,24]
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