Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis.
Patrick Vizeli, Isabelle Straumann, Friederike Holze, Yasmin Schmid, Patrick C. Dolder, Matthias E. Liechti
Scientific Reports May 25, 2021 DOI: 10.1038/s41598-021-90343-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Pooled analysis of four randomized, placebo-controlled, double-blind Phase 1 studies Peer reviewed |
|---|---|
| Sample size | 81 |
| Population | Healthy subjects |
| Intervention | Lysergic acid diethylamide (LSD) |
| Topics | LSD |
| Keywords | Genetics Dna Heredity Genotype Drug metabolism Drug processing Pharmacokinetics Drug breakdown Drug effects Drug response Psychedelic Hallucinogen Personalized medicine Individual differences Diverse responses Personalized outcomes Precision medicine Individual variability Cyp2d6 gene Cytochrome p450 2d6 |
| Citations | 54 |
| Key points | Genetically determined CYP2D6 functionality significantly influenced LSD pharmacokinetics and subjective effects, with poor metabolizers showing higher drug exposure and stronger, longer-lasting effects. |
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.
Comparable studies
Other randomized controlled trials on LSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases Patients with anxiety associated with life-threatening diseases | 2014 | Randomized controlled trial | n = 12 |
| Dose-Response Study of N,N-Dimethyltryptamine in Humans Experienced hallucinogen users | 1994 | Double-blind, saline placebo-controlled, randomized study | n = 12 |
| Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects Healthy subjects (8 women, 8 men) | 2014 | Double-blind, randomized, placebo-controlled, crossover study | n = 16 |
| Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor Healthy human participants | 2018 | Double-blind, randomized, counterbalanced, cross-over study | n = 24 |
| LSD-induced entropic brain activity predicts subsequent personality change. Healthy adults | 2016 | Balanced-order, placebo-controlled study | n = 19 |
Citations in the library
Cited by 48
- Psilocybin-Induced Mystical-Type Experiences are Related to Persisting Positive Effects: A Quantitative and Qualitative Report Frontiers in Pharmacology March 9, 2022
- Repeated low doses of LSD in healthy adults: A placebo-controlled, dose-response study. Addiction Biology February 1, 2022
- Safety pharmacology of acute LSD administration in healthy subjects Psychopharmacology September 13, 2021
- In vitro and in vivo metabolism of psilocybin’s active metabolite psilocin Frontiers in Pharmacology April 29, 2024
- Serotonergic Psychedelics: A Comparative Review of Efficacy, Safety, Pharmacokinetics, and Binding Profile Biological Psychiatry: Cognitive Neuroscience and Neuroimaging February 1, 2024
and 43 more in the library
Cites 25
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later Journal of Psychopharmacology May 30, 2008
- Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression Frontiers in Pharmacology January 17, 2018
- Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases The Journal of Nervous and Mental Disease March 4, 2014
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