Harnessing Pharmacogenomics in Clinical Research on Psychedelic-Assisted Therapy

Abstract

Psychedelics have recently re-emerged as potential treatments for various psychiatric conditions that impose major public health costs and for which current treatment options have limited efficacy. At the same time, personalized medicine is increasingly being implemented in psychiatry to provide individualized drug dosing recommendations based on genetics. This review brings together these topics to explore the utility of pharmacogenomics (a key component of personalized medicine) in psychedelic-assisted therapies. We summarized the literature and explored the potential implications of genetic variability on the pharmacodynamics and pharmacokinetics of psychedelic drugs including lysergic acid diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), ibogaine and 3,4-methylenedioxymethamphetamine (MDMA). Although existing evidence is limited, particularly concerning pharmacodynamics, studies investigating pharmacokinetics indicate that genetic variants in drug-metabolizing enzymes, such as cytochrome P450, impact the intensity of acute psychedelic effects for LSD and ibogaine, and that a dose reduction for CYP2D6 poor metabolizers may be appropriate. Furthermore, based on the preclinical evidence, it can be hypothesized that CYP2D6 metabolizer status might contribute to altered acute psychedelic experiences with 5-MeO-DMT and psilocybin when combined with monoamine oxidase inhibitors. In conclusion, considering early evidence that genetic factors can influence the effects of certain psychedelics, we suggest that pharmacogenomic testing should be further investigated in clinical research. This is necessary to evaluate its utility in improving the safety and therapeutic profile of psychedelic therapies and a potential future role in personalizing psychedelic-assisted therapies, should these treatments become available.

Figure 1

The suggested metabolism of LSD, psilocin, DMT, β‐carbolines, 5‐MeO‐DMT, ibogaine and MDMA. This figure is based on the literature discussed (LSD,, psilocin,, , DMT,, , β‐carbolines, 5‐MeO‐DMT,, , ibogaine, and MDMA ⁷² ). *Indicates the major pathway where known, and † denotes the main contributing enzymes if multiple are specified. LSD, lysergic acid diethylamide; DMT, N,N‐dimethyltryptamine; 5‐MeO‐DMT, 5‐methoxy‐N,N‐dimethyltryptamine; MDMA, 3,4‐methylenedioxymethamphetamine; MAO‐A, monoamine oxidase A; ALDH, aldehyde dehydrogenase; ADH, alcohol dehydrogenase; UGT, UDP‐glucuronosyltransferases; COMT, catechol‐O‐methyltransferase.