The role of genetic variants in the therapeutic effects of psychedelics

Summary: Genetic variants of the 5-HT2A serotonin receptor may explain why some respond to psychedelic therapy for the treatment of mental health disorders while others do not.

A source: UNC

When all else fails, some patients turn to psychedelic drugs in an attempt to relieve alcoholism, severe depression or anxiety, or even cluster headaches, which clinical studies show can help treat people with these disorders, sometimes with dramatic positive results. However, sometimes, as with any therapy, psychological treatment does not work. It just takes the patient on a long strange journey.

Now, UNC School of Medicine researchers led by Brian Roth, Michael Hooker Distinguished Professor of Pharmacology, report that one reason for the treatment disparity may be common genetic variations in a serotonin receptor.

published in the magazine ACS Chemical Neurosciencelaboratory studies in cells show that seven variants specifically and differentially affect the receptor’s response to four psychedelic drugs—psilocin, LSD, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and mescaline.

“Based on our research, we expect that patients with different genetic variations will respond differently to psychedelic treatment,” said Roth, who directs the NIH Psychotropic Drug Review Program.

“We think doctors should look at the patient’s serotonin receptor genetics to determine which psychedelic compound might be the most effective treatment in future clinical trials.”

After decades of denial about the potential therapeutic benefits of psychotropic drugs, there has been renewed interest and research in the use of such compounds in the treatment of neuropsychiatric disorders, such as major depressive disorder, because the drugs stimulate serotonin receptors in the brain.

These receptors bind to the neurotransmitter serotonin and other similar amine-containing molecules, helping to regulate mood and emotions in humans, as well as appetite. In particular, the 5-hydroxytryptamine receptor, known as 5-HT2A, is responsible for mediating the human response to psychedelic drugs.

However, there are several naturally occurring, random genetic variations known as single nucleotide polymorphisms, or SNPs, that can affect the function and structure of the 5-HT2A receptor.

Roth and colleagues wanted to study how variations in this single serotonin receptor could alter the activity of four psychedelic therapies.

Roth and colleagues wanted to study how variations in this single serotonin receptor could alter the activity of four psychedelic therapies. Image is in the public domain

UNC graduate student Gavin Schmitz and postdoctoral researchers Manish Jain, PhD, and Samuel Slocum, PhD, used a series of experimental assays to measure the effects of seven different SNPs. in vitro 5-HT2A serotonin receptor binding and signaling in the presence of one of four drugs.

Their results show that certain gene variations, even remote from the exact site where the drug binds to the receptor, can alter how the receptor interacts with psychedelic drugs.

For example, the SNP Ala230Th decreased response to one of four drugs (psilocybin is the active metabolite of psilocybin), whereas the Ala447Val mutation affected only two drugs.

“It’s another piece of the puzzle that we need to be aware of when deciding to prescribe different therapeutics that have such an amazing effect, beyond the therapeutic effect,” Roth said. “Further research will help us find better ways to help individual patients.”

Funding: The research was funded by the National Institutes of Health and the Defense Advanced Research Projects Agency (DARPA).

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About it Psychopharmacology and Serotonin Research News

Author: Mark Derevich
A source: UNC
The connection: Mark Derevich – UNC
Photo: Image is in the public domain

Original research: Open access.
“5-HT2A SNPs Alter Pharmacological Signaling of Potentially Therapeutic Psychedelics” Brian Roth et al. ACS Chemical Neuroscience


Abstract

5-HT2A SNPs alter pharmacological signaling of potentially therapeutic psychedelics

Serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR) signaling is critical for the actions of classical psychoactive drugs. In this study, we investigated whether sequence variations in the 5-HT2AR gene affect the signaling of four commonly used psychedelic drugs.

We have reviewed in vitro Pharmacology of seven non-synonymous single nucleotide polymorphisms (SNPs) causing Ser12Asn, Thr25Asn, Asp48Asn, Ile197Val4.47Ala230Thr, Ala447Val, and His452Tyr variant 5-HT2A serotonin receptors.

We found that these non-synonymous SNPs have modest but statistically significant effects on the efficacy and potency of four therapeutically relevant psychedelics. It should be noted that in vitro The pharmacological effects of SNP drug actions on 5-HT2AR are drug specific.

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