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
AI-generated from the abstractRandom genetic variations in the serotonin 2A receptor can modestly alter how four commonly used psychedelic drugs activate this receptor, with effects that differ depending on the specific drug. Seven naturally occurring receptor variants were tested in the lab; each showed small but statistically significant changes in drug potency and efficacy. These findings suggest that individual genetic differences may influence responses to psychedelic medications.
Study at a glance
| Characteristics | In vitro pharmacological study |
|---|---|
| Population | Seven non-synonymous single nucleotide polymorphisms of the 5-HT2A serotonin receptor |
| Key finding | Non-synonymous SNPs in the 5-HT2A receptor exert drug-specific, modest but statistically significant effects on the efficacy and potency of four 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.