Doctor in a white coat holding a digital pill containing DNA to represent differences in drug metabolism for psychedelic drugs
Credit: LeoWolfert/Getty Images

Research from the University of North Carolina at Chapel Hill School of Medicine shows that gene mutations can impact how effective psychedelic drugs are for treating conditions such as anxiety and depression.

Recent clinical trials have shown that psychedelic drugs such as psilocin and LSD have beneficial effects for people with neurological conditions like depression, anxiety, and cluster headaches.

“For example, psilocybin, the prodrug to the active compound psilocin found in Psilocybe cubensis mushrooms, has been granted breakthrough drug status by the Food and Drug Administration due to its potential as a treatment for treatment-resistant depression and anxiety,” write lead researcher Bryan Roth, a professor at the University of North Carolina School of Pharmacy, and co-authors of an article in the journal ACS Chemical Neuroscience.

However, not everyone with these conditions appears to benefit from these drugs. “The reasons for such inter-individual variability in psychedelic drug response are unknown. At the molecular level, random sequence variations in genes (single-nucleotide polymorphisms, SNPs) could explain inter-individual differences in drug response, and such activities are highly relevant as psychedelics become more prevalent in clinical practice,” write the study authors.

Roth and colleagues think this may have to do with genetic variation in the HTR2A gene, which encodes the serotonin receptor 5-Hydroxytryptamine Receptor 2A. The team tested the effects of seven single-nucleotide polymorphisms (SNPs) in the HTR2A gene, which result in changes to the protein sequence, on the metabolism of four psychedelics that have therapeutic potential.

The researchers used an assay to test how the changed HTR2A proteins would respond to psilocin, LSD, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and mescaline.

The results showed that these mutations do change the way psychedelics are metabolized, albeit to a modest degree. Some of the mutations increased and some decreased the efficacy and potency of the drugs. The effects varied depending on the drug, with the most significant variations from controls seen for mescaline and the least for LSD.

“The major finding of this study is that certain 5-HT2A [HTR2A] receptor non-synonymous SNPs can alter the in vitro pharmacology of the tested psychedelics,” write the authors.

“Given that several psychedelic drugs are in clinical trials, including the ones in this study, this information can aid in the design and ultimate interpretation of clinical studies.”

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