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 people with these conditions, sometimes with dramatically positive results. But sometimes, as with any therapy, psychedelic treatment doesn’t work. He just needs a patient on 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 the treatment disparity could be common genetic variations in a serotonin receptor .
Published in the journal ACS Chemical Neuroscience, laboratory research in cells shows that seven variants uniquely 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 study, we expect that patients with different genetic variations will react differently to psychedelic treatments,” said Roth, who directs the NIH’s Psychotropic Drug Screening Program. “We believe that clinicians should consider a patient’s serotonin receptor genetics to identify which psychedelic compound is likely to be the most effective treatment in future clinical trials.”
After decades of taboo about the potential therapeutic benefit of psychotropics, there has been renewed interest and research in the use of these compounds to treat neuropsychiatric disorders, such as major depressive disorder, because the drugs stimulate receptors of serotonin in the brain. These receptors bind to 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 mediating how a person reacts to psychedelic drugs. However, there are several random and naturally occurring genetic variations, known as single nucleotide polymorphisms or SNPs, that can affect the function and structure of the 5-HT2A receptor.
Roth and his colleagues wanted to explore how variations in this serotonin receptor change the activity of four psychedelic therapies.
UNC graduate student Gavin Schmitz and postdoctoral researchers Manish Jain, PhD, and Samuel Slocum, PhD, used a series of experimental assays to measure the effect that seven different SNPs had on binding and signaling in in vitro of the serotonin 5-HT2A receptor when in the presence of one of the four drugs. Their results indicated that some gene variations, even away from the exact location where the drug binds to the receptor, alter the way the receptor interacts with psychedelic drugs.
For example, the Ala230Th SNP had decreased response to one of the four drugs (psilocin, the active metabolite of psilocybin), while the Ala447Val mutation only showed reduced effects to two of the drugs.
This is another piece of the puzzle that we need to know when deciding to prescribe any therapeutic with such a dramatic effect apart from the therapeutic effect. Further research will help us continue to find the best ways to help individual patients.”
Bryan Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology
Source:
University of North Carolina School of Medicine
Journal reference:
Schmitz, GP, et al. (2022) 5-HT2A SNPs alter pharmacological signaling of potentially therapeutic psychedelics. ACS Chemical Neuroscience. doi.org/10.1021/acschemneuro.1c00815