Pharmacologic analysis of non-synonymous coding 5-HT2A SNPs reveals alterations psychedelic drug potencies and efficacies
Gavin P. Schmitz, Manish K. Jain, Samuel T. Slocum, Bryan L. Roth
bioRxiv Preprint Server December 9, 2021 preprint DOI: 10.1101/2021.12.09.472000 via bioRxiv
Summary
Variations in the gene encoding the serotonin 2A receptor (5-HT2AR) can modestly affect how four psychedelic drugs work. Seven specific genetic variations were studied, and while they had statistically significant effects on drug efficacy and potency, these effects varied depending on the specific drug. The findings suggest that individual genetic differences may influence responses to psychedelics.
Study at a glance
| Population | in vitro models of serotonin receptors |
|---|---|
| Key finding | Non-synonymous SNPs in the 5-HT2AR gene have modest but statistically significant effects on the efficacy and potency of four commonly used psychedelic drugs. |
Abstract
Serotonin (5-Hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR) signaling is essential for the actions of classical psychedelic drugs. In this study, we examined whether random sequence variations in the gene (single nucleotide polymorphisms, SNPs) encoding the 5-HT2AR affect the signaling of four commonly used psychedelic drugs. We examined the in vitro pharmacology of seven non-synonymous SNPs, which give rise to S12N, T25N, D48N, I197V, A230T, A447V, and H452Y variant 5-HT2A serotonin receptors. We found that these non-synonymous SNPs exert statistically significant, although modest, effects on the efficacy and potency of four therapeutically relevant hallucinogens. Significantly, the in vitro pharmacological effects of the SNPs drug actions at 5-HT2AR are drug specific.