Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis

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 C...

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Autores principales:	Patrick Vizeli, Isabelle Straumann, Friederike Holze, Yasmin Schmid, Patrick C. Dolder, Matthias E. Liechti
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/342782d7422a493c87509ac98ebdad74
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spelling	oai:doaj.org-article:342782d7422a493c87509ac98ebdad742021-12-02T15:00:51ZGenetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis10.1038/s41598-021-90343-y2045-2322https://doaj.org/article/342782d7422a493c87509ac98ebdad742021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90343-yhttps://doaj.org/toc/2045-2322Abstract 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.Patrick VizeliIsabelle StraumannFriederike HolzeYasmin SchmidPatrick C. DolderMatthias E. LiechtiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Patrick Vizeli Isabelle Straumann Friederike Holze Yasmin Schmid Patrick C. Dolder Matthias E. Liechti Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis
description	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.
format	article
author	Patrick Vizeli Isabelle Straumann Friederike Holze Yasmin Schmid Patrick C. Dolder Matthias E. Liechti
author_facet	Patrick Vizeli Isabelle Straumann Friederike Holze Yasmin Schmid Patrick C. Dolder Matthias E. Liechti
author_sort	Patrick Vizeli
title	Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis
title_short	Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis
title_full	Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis
title_fullStr	Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis
title_full_unstemmed	Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis
title_sort	genetic influence of cyp2d6 on pharmacokinetics and acute subjective effects of lsd in a pooled analysis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/342782d7422a493c87509ac98ebdad74
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Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis

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