Response to Psychedelic Drugs May Be Determined by Genetic Variations in Serotonin Receptor

Genetic variations in the 5-hydroxytryptamine serotonin receptor uniquely impacted the receptor’s response to psychedelic drugs, including LSD and psilocin, possibly explaining why patients have varied success with psychedelic treatment for psychiatric conditions.

Common genetic variations in the serotonin receptor 5-hydroxytryptamine receptor (5-HT2A) may impact how a patient responds to psychedelic drugs, according to the authors of a study published in ACS Chemical Neuroscience. These genetic variations in the 5-HT2A receptor may help to explain why psychedelic therapies are more effective in certain patients than others.

Though clinical research has shown that psychedelic drugs can help treat individuals with conditions such as alcoholism, severe depression, anxiety, and cluster headaches, there have been decades of sociocultural stigma around the use of psychedelic drugs more broadly, impacting investigation into the potential therapeutic benefit psychotropic drugs may hold.

Today, researchers have a renewed interest in investigating psychotropic drugs for the treatment of neuropsychiatric disorders, like major depressive disorder, because the drugs have been found to stimulate serotonin receptors in the brain. These receptors then bind the neurotransmitter serotonin and other similar amine-containing molecules, helping to regulate people’s moods, emotions, and appetite.

In total, there are 7 naturally occurring, random genetic variations known as single nucleotide polymorphisms (SNPs) can affect the function and structure of the 5-HT2A receptor. To investigate the role of these receptors further, researchers from the University of North Carolina at Chapel Hill (UNC Chapel Hill) School of Medicine explored how these variations in the 5-HT2A serotonin receptor change the activity of 4 psychedelic therapies: psilocin; LSD; 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT); and mescaline.

The researchers used a series of experimental assays to measure the effect that 7 different SNPs had on in vitro binding and signaling of the 5-HT2A serotonin receptor when in the presence of one of the psychedelic drugs. The study results showed that some genetic variants uniquely and differentially impacted the 5-HT2A serotonin receptor’s response to the 4 psychedelic drugs.

For example, the SNP Ala230Th demonstrated a decreased response to psilocin, while the Ala447Val mutation showed a reduced response to 2 of the drugs.

"Based on our study, we expect that patients with different genetic variations will react differently to psychedelic-assisted treatments," NIH Psychotropic Drug Screening Program lead Bryan Roth, MD, PhD, Michael Hooker Distinguished professor of pharmacology, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry in the Eshelman School of Pharmacy, UNC Chapel Hill, said in a press release. "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."

Further, the study findings showed that some gene variations may alter the way that the receptor interacts with psychedelic drugs, even in variations that are far from the exact location where the drug binds to the receptor.

"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 in the press release. "Further research will help us continue to find the best ways to help individual patients."

Reference

Research reveals role of genetic variants on psychedelics' therapeutic effects. News Release. University of North Carolina Health Care; July 27, 2022. Accessed August 1, 2022. https://www.sciencedaily.com/releases/2022/07/220727153626.htm