Summary: Common genetic variants of the 5-HT2A serotonin receptor may help explain why some patients benefit from psychedelic-assisted therapies while others see little or no improvement.
Source: UNC
Psychedelic drugs have re-emerged as promising treatments for difficult-to-treat conditions such as severe depression, anxiety, alcoholism, and even cluster headaches. Clinical studies have demonstrated dramatic improvements in some patients following psychedelic-assisted therapy, yet responses vary widely: some patients improve markedly while others do not respond. New laboratory research from the UNC School of Medicine suggests that genetic variation in a single serotonin receptor could be one important factor behind these differing outcomes.
A research team led by Bryan Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology, investigated how naturally occurring variations in the 5-hydroxytryptamine 2A receptor (5-HT2A)—a key brain receptor mediating psychedelic effects—alter the receptor’s response to several commonly studied psychedelic compounds.
Published in ACS Chemical Neuroscience, the study used cell-based assays to examine seven non-synonymous single nucleotide polymorphisms (SNPs) in the 5-HT2A receptor and measured how each variant influenced receptor binding and signaling in the presence of four psychedelic drugs: psilocin (the active metabolite of psilocybin), lysergic acid diethylamide (LSD), 5-methoxy-N,N-dimethyltryptamine (5‑MeO‑DMT), and mescaline.
“Based on our study, we expect that patients with different genetic variations will react differently to psychedelic-assisted treatments,” said Roth, who directs the NIH Psychotropic Drug Screening Program. “We think physicians should consider the genetics of a patient’s serotonin receptors to identify which psychedelic compound is likely to be the most effective treatment in future clinical trials.”
Serotonin receptors help regulate mood, emotion and appetite by binding serotonin and related amine-containing molecules. The 5-HT2A subtype in particular is central to the characteristic subjective and therapeutic effects produced by classical psychedelics. However, several naturally occurring SNPs change the amino acid sequence of the 5-HT2A receptor and can therefore modify its structure and function.
Graduate student Gavin Schmitz together with postdoctoral researchers Manish Jain, PhD, and Samuel Slocum, PhD, conducted a suite of in vitro experiments to quantify how seven specific SNPs affected drug binding and downstream signaling of 5-HT2A. The variants studied were Ser12Asn, Thr25Asn, Asp48Asn, Ile197Val, Ala230Thr, Ala447Val, and His452Tyr.
The results showed that these amino acid substitutions produced statistically significant, though generally modest, changes in both the potency and efficacy of the psychedelics tested. Importantly, the effects were drug-specific: a given SNP could alter responses to one psychedelic more than to another, indicating that genetic variation can change the pharmacological profile of 5-HT2A in compound-dependent ways.
For example, the Ala230Thr variant displayed a reduced response to psilocin, while the Ala447Val change led to diminished responses for two of the four drugs tested. Notably, some SNPs exerted functional effects even when located far from the receptor sites where drugs directly bind, suggesting that distant structural changes can influence receptor behavior.
These findings point to a genetic component that could partly account for variability in clinical outcomes from psychedelic therapies. “This is another piece of the puzzle we must know when deciding to prescribe any therapeutic with such dramatic effect aside from the therapeutic effect,” Roth said. He emphasized that further research will be needed to translate these in vitro observations into clinical practice and to identify how genetic screening might guide treatment selection for individual patients.
Funding: The work was supported by the National Institutes of Health and the Defense Advanced Research Projects Agency (DARPA).
About this psychopharmacology and serotonin research news
Author: Mark Derewicz
Source: UNC
Contact: Mark Derewicz – UNC
Image: The image is in the public domain
Original Research: Open access. “5-HT2A SNPs Alter the Pharmacological Signaling of Potentially Therapeutic Psychedelics” by Bryan Roth et al., ACS Chemical Neuroscience
Abstract
5-HT2A SNPs Alter the Pharmacological Signaling of Potentially Therapeutic Psychedelics
Signaling through the serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR) is essential for the actions of classical psychedelic drugs. This study tested whether naturally occurring sequence variations in the 5-HT2AR gene influence the pharmacology of four commonly examined psychedelics.
We evaluated the in vitro pharmacology of seven non-synonymous single-nucleotide polymorphisms (SNPs) that produce the Ser12Asn, Thr25Asn, Asp48Asn, Ile197Val (4.47), Ala230Thr, Ala447Val, and His452Tyr variants of the 5-HT2A receptor. The data indicate that these SNPs exert statistically significant, though generally modest, effects on the potency and efficacy of the tested psychedelics and that these effects are drug specific.