People respond differently to psychedelic drugs genetics could be the reason

Recently, there's been renewed interest and research in using psychedelic compounds that stimulate serotonin receptors in the brain because of several promising results from clinical trials. These receptors bind serotonin (5-hydroxytryptamine; 5-HT) and other similar amine-containing molecules, helping regulate people's mood, perceptions, cognition, and emotions, as well as their appetite.

In particular, the serotonin receptor known as 5-HT2A is responsible for mediating the effects of psychedelic drugs. However, there are several naturally occurring, random genetic variations, known as single nucleotide polymorphisms, that can impact the 5-HT2A receptor's structure and function. So, Bryan Roth and colleagues wanted to explore how variations in the serotonin 5-HT2A receptor impact the in vitro activity of four psychedelic therapies.

The researchers used a series of assays to measure the effect that seven different SNPs had on in vitro binding and signaling of the 5-HT2A serotonin receptor when in the presence of psilocin, LSD, 5-MeO-DMT, or mescaline. Their results indicated that some gene variations, even ones at a distance from the binding site, alter the way the receptor interacts with the psychedelic drugs.

For example, the single nucleotide polymorphism Ala230Th had both increased and reduced responses to the drugs tested compared to the original version of the gene, whereas the His452Th mutation showed only reduced effects. Based on their results, the researchers expect that patients with different genetic variations would react differently to psychedelic-assisted treatments. They suggest that physicians consider the genetics of a patient's serotonin receptors to identify which psychedelic compound is likely to be the most effective treatment.

Ref:

5-HT2A SNPs Alter the Pharmacological Signaling of Potentially Therapeutic Psychedelics, ACS Chemical Neuroscience, 27-Jul-2022, 10.1021/acschemneuro.1c00815