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.

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.

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

Notes

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.

Become a psychedelic insider!

With a free Blossom membership you will always be in the know.

📰 Weekly newsletter about the psychedelic research

✔️ Unlimited access to our database and original articles

🖊️ Add (private) notes and comments to each page

Make an account
0 Comments
Inline Feedbacks
View all comments
0
Would love your thoughts, please comment.x
()
x