The UNC School of Medicine lab of Bryan Roth, MD, PhD, found that variants in a small serotonin receptor in neurons may be the reason why some patients do much better after psychedelic therapy than others.
CHAPEL HILL, NC — When all else fails, some patients trying to overcome alcoholism, severe depression or anxiety, and even cluster headaches turn to psychedelic drugs, which clinical research has shown can help treat individuals with these conditions , sometimes with dramatically positive results. But sometimes, like any therapy, the psychedelic treatment doesn’t work. It just takes a patient a long strange journey.
Now, UNC School of Medicine researchers led by Bryan Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology, report that one reason for treatment disparities could be common genetic variations in one serotonin receptor.
Published in the magazine ACS Chemical NeuroscienceLaboratory studies in cells show that seven variants have a unique and differential influence on 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 treatments,” said Roth, chief of the NIH Psychotropic Drug Screening Program. “We think doctors should consider the genetics of a patient’s serotonin receptors to determine which psychedelic compound is likely to be the most effective treatment in future clinical trials.”
After decades of taboo regarding potential therapeutic benefits of psychotropic drugs, there is renewed interest and research in the use of such compounds to treat neuropsychiatric disorders, such as major depressive disorder, because the drugs stimulate serotonin receptors in the brain. These receptors bind the neurotransmitter serotonin and other similar amine-containing molecules, helping to regulate people’s mood and emotions, as well as their appetite. In particular, the 5-hydroxytryptamine receptor, known as 5-HT2A, is responsible for how a person responds 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 investigate how variations in this single serotonin receptor alter the activity of four psychedelic therapies.
UNC graduate student Gavin Schmitz and postdoctoral researchers Manish Jain, PhD, and Samuel Slocum, PhD, used a battery of experimental tests to measure the effect that seven different SNPs had on in vitro binding and signaling of the 5-HT2A serotonin receptor in the presence of one of the four drugs. Their results indicated that some gene variations — even those that are far from the exact location where the drug binds to the receptor — alter the way the receptor interacts with the psychedelic drugs.
For example, the SNP Ala230Th had a reduced response to one of the four drugs (psilocin, the active metabolite of psilocybin), while the Ala447Val mutation only showed reduced effects on two of the drugs.
“This is another piece of the puzzle that we need to know when we decide to prescribe a therapy with such a dramatic effect, aside from the therapeutic effect,” Roth said. “Further research will help us find the best ways to help individual patients.”
The National Institutes of Health and the Defense Advanced Research Projects Agency (DARPA) funded this research.
Media contact: Mark Derewicz