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

This pharmacogenetic study (n=81) found that the lack of a functional CYP2D6 gene correlated with a longer half-life and higher blood plasma of LSD (metabolites). The same effect was found for the subjective effects experienced, which were longer and stronger than those with a functional CYP2D6 gene.


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.

Authors: Patrick Vizeli, Isabelle Straumann, Friederike Holze, Yasmin Schmid, Patrick C. Dolder & Matthias E. Liechti


This paper was also analyzed by the excellent The TAB by Tyler Quigley.

We all know that one person who’s able to drink four beers and not feel a thing. Or that friend who becomes giggly after barely touching their first drink. We know a lot about which genes influence how our body processes alcohol (pharmacogenetics). The current study, by the team at the University Hospital Basel, is taking the first step to uncover genetic influences on our reaction to LSD.

In this study, which pooled data from 81 participants, the team looked specifically at genetic variants of the CYP gene. This gene is responsible for making enzymes that deal with things our body doesn’t normally encounter (it metabolises xenobiotics). And without a functional version of the CYP2D6 gene (and thus no enzymes), your trip will be longer and more intense.

This is what we know about LSD pharmacogenetics

  • Those without CYP2D6 showed higher concentrations of LSD in their blood plasma (75% more total exposure)
  • And had more intense and longer-lasting trips as measured on a visual distortion and a mysticism scale
  • This is the very first study to show this in humans, at the same time only 7 participants didn’t have the CYP2D6 enzymes

The current study is one step forward in understanding more of the (biological) differences between people and their reactions to LSD. Although this information alone isn’t enough to predict someone’s exact trip intensity, it does provide more information that healthcare professionals could possibly use in the future to determine dosage.

The same gene (expression) has also been found to play a role in the absorption of MDMA and ibogaine. Although for MDMA the effect was less pronounced as for LSD. It should also be noted that SSRIs could inhibit the effects of the gene, thus possibly making a trip more intense (or a lower dose could be administrated) for those who are taking antidepressants.


Lysergic acid diethylamide (LSD) is a classic psychedelic that was rediscovered by modern psychiatric research. Its metabolism is not fully understood, but several cytochrome P450 (CYP) enzymes are involved in its metabolism, and the pharmacokinetics of LSD may also be influenced by CYP pharmacogenetics.

This study investigated the influence of prominent genetic polymorphisms of several CYPs involved in the metabolism of LSD on the pharmacokinetic parameters of LSD and its acute subjective effects.

This study was a pooled secondary analysis of four Phase 1 studies that used a randomized, double-blind, placebo-controlled, crossover design and included 84 healthy subjects. The studies used mean data from the four LSD doses that were used within the same subject in Study 4. All four studies were approved by the local ethics committee and were conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all subjects, and they were under constant supervision while they experienced acute drug effects.

A total of 81 healthy subjects were recruited from the University of Basel campus or word-of-mouth advertising. Two participants withdrew from the study before the first test session and two participants did not give consent for genotyping. Twenty-two subjects had prior hallucinogenic drug experiences, of which 16 subjects had previously used LSD (1 – 3 times), five subjects had previously used psilocybin (1 – 3 times), and one subject had previously used dimethyltryptamine (4 times), mescaline (1 time), and salvia divinorum (3 times).


In Studies 1 and 2, LSD base was taken orally as gelatin capsules, and in Studies 3 and 417, LSD base was taken as a drinking solution in 96% ethanol. The doses that were used in each study are shown in Supplementary Table S1.

Pharmacokinetic analyses were performed using Phoenix WinNonlin 6.4 (Certara, Princeton, NJ, USA). The pharmacokinetic parameters were calculated using non-compartmental analysis and a one-compartment model with first-order input, first-order elimination, and no lag time was used.

Physiological effects of LSD were assessed before and repeatedly after administration. Mean arterial pressure, rate pressure product, and core temperature were measured.

Subjective effects were assessed using Visual Analog Scales (VASs) and the 5 Dimensions of Altered States of Consciousness (5D-ASC) at the end of the acute drug effects.

We genotyped the CYPs in whole blood using commercial TaqMan SNP genotyping assays. We also covered SNPs with a minor allele frequency (MAF) 1% to catch mutations with substantial impact. We assayed the following SNPs and respective alleles for CYP1A21F, CYP2B6, CYP2C92, CYP2C9*3 and CYP2D6, and determined the effects of CYP2D6 functionality on the pharmacokinetics and pharmacodynamics of LSD.

Genetically determined non-functional CYP2D6 and functional CYP2C9 were significantly different in their plasma LSD concentration – time curves over 24 h after LSD administration. The non-functional CYP2D6 subjects had a longer half-life and higher AUC values compared to the functional CYP2C9 subjects.

We used one-way analysis of variance (ANOVA) to test for genotype effects on the pharmacokinetics and effects of LSD, and confirmed the results with nonparametric statistics to minimize the effect of outliers and non-normal data distributions on the parametric statistics.


Subjects with CYP2D6 mutations had higher plasma LSD exposure, longer T1/2 values, and higher O-H-LSD AUC values compared with functional CYP2D6 carriers. Lower CYP2D6 activity was also associated with significantly higher exposure to LSD.

CYP2D6 PMs exhibited a longer duration of the acute subjective response to LSD and significantly greater alterations of mind compared with functional CYP2D6 subjects. CYP2D6 genotype had no relevant effect on the autonomic response to LSD.


LSD is metabolized almost completely in the human body, and CYP2D6 is involved in the N-demethylation of LSD to nor-LSD. Polymorphisms of the CYP2D6 gene influence both the metabolism of LSD and acute response to LSD in humans. LSD may be used therapeutically in patients with psychiatric disorders and using a serotonin reuptake inhibitor (SSRI) treatment, but the dose of LSD should be reduced in the presence of CYP2D6 inhibitors.

We investigated the influence of CYP enzyme genotype on the pharmacokinetics of LSD. We found no influence of CYP enzyme genotype on the pharmacokinetics of LSD in humans, but CYP enzyme genotype may influence the pharmacokinetics of other drugs.

Genetically determined function of cytochromes P450 2D6 affects the pharmacokinetics and response to LSD. The effects were assessed using the area under the time-concentration curve and the Wilcoxon signed-rank test.

The pharmacogenetic influence of metabolizing enzymes on LSD appears quite similar to MDMA, with CYP2D6 polymorphisms substantially impacting pharmacokinetics and subjective effects. However, the effect of CYP2D6 genotype variations on MDMA is limited and evident only during the onset of MDMA’s effects.

Genetic effects on the acute subjective response to LSD may be clinically relevant. CYP2D6 PMs may have an overall more challenging acute experience, with higher acute anxiety and possibly even lower therapeutic effects, than functional CYP2D6 individuals.

The present study has limitations, such as a small sample size and the possibility of type I errors. Additional studies with different selective CYP inducers/inhibitors are needed to confirm the present findings.

The present study used validated psychometric tools and used statistical methods to address possible confounders. It also used z-transformed values to account for between-study differences in genotype distribution and doses used.

In conclusion, the present study revealed that genetic polymorphisms of CYP2D6 significantly influenced the pharmacokinetics and acute subjective effects of LSD in humans. No effect was observed with other CYPs.


The authors acknowledge several people who helped them with the study, including F. Müller, L. Ley, and S. Harder. They also acknowledge the Swiss National Science Foundation for funding the study.

Competing interests

Mind Medicine, Inc. licensed the knowhow and data associated with this study from the University Hospital Basel.

Additional information

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, provided you give appropriate credit to the original author(s) and the source.

Study details

Compounds studied

Topics studied

Study characteristics
Placebo-Controlled Double-Blind Bio/Neuro



Authors associated with this publication with profiles on Blossom

Matthias Liechti
Matthias Emanuel Liechti is the research group leader at the Liechti Lab at the University of Basel.

Yasmin Schmid
Yasmin Schmid is a physician who previously worked at the University of Basil Liechti Lab.


Institutes associated with this publication

University of Basel
The University of Basel Department of Biomedicine hosts the Liechti Lab research group, headed by Matthias Liechti.

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