Researchers at the Icahn School of Medicine at Mount Sinai have provided insight into the intricate ways that a group of psychedelic drugs bind to and trigger serotonin receptors. This could lead to potential therapeutic benefits for patients with neuropsychiatric disorders like depression and anxiety. The study was published on May 8 in Nature.The research team announced that specific psychedelic drugs interact with a lesser-known serotonin receptor in the brain called 5-HT1A to provide therapeutic benefits in animal models.
“Substances such as LSD and psilocybin are being tested in clinical trials and showing promising early results, but we still don’t fully comprehend how they target different molecules in the brain to produce their therapeutic effects,” explains lead author Audrey Warren, a PhD candidate at Icahn Mount Sinai’s Graduate School of Biomedical Sciences. “Our study sheds light on how serotonin receptors like 5-5-HT1A is likely to influence how people feel during a psychedelic experience and may also have an important role in their therapeutic effects when used clinically.”
LSD and 5-MeO-DMT, a psychedelic substance found in the secretions of the Colorado River Toad, are known to produce their hallucinogenic effects by acting on the serotonin receptor 5-HT2A. However, these drugs also activate 5-HT1A, which is a known target for treating depression and anxiety. In collaboration with Dalibor Sames, PhD, a Professor in the Department of Chemistry at Columbia University, the team created and tested variations of 5-MeO-DMT in cell signaling experiments.The researchers used cryo-electron microscopy to pinpoint the specific chemical components responsible for a drug’s preference for activating 5-HT1A over 5-HT2A. Through this process, they discovered that a compound called 4-F, 5-MeO-PyrT exhibited the highest selectivity for 5-HT1A in this series. Dr. Lyonna Parise, an instructor in Dr. Scott Russo’s lab at the Center for Affective Neuroscience and the Brain and Body Research Center at Icahn Mount Sinai, then tested this lead compound in a mouse model of depression. The results showed that 4-F, 5-MeO-PyrT had antidepressant-like effects that were effectively mediated by 5-HT1A.
“We were able to fine-tune the chemical structure of the compound to achieve these targeted effects,” noted Dr. Parise.According to Daniel Wacker, who is an Assistant Professor of Pharmacological Sciences and Neuroscience at Icahn Mount Sinai, they used the 5-MeO-DMT/serotonin structure to maximize activity at the 5-HT1A interface and minimize activity at 5-HT2A. Their research suggests that receptors other than 5-HT2A not only influence the behavioral effects of psychedelics, but also play a significant role in their therapeutic potential. They were surprised by how much these receptors contributed to the effects of 5-MeO-DMT, which is currently being studied in clinical trials for depression. They believe that their study will improve our understanding of the therapeutic potential of psychedelics.Pharmacologists are studying the complex effects of psychedelics on various receptor types. Their promising findings suggest that they may soon be able to create new psychedelic-based medications that do not have the hallucinatory effects of current drugs. This hope is fueled by the discovery that their primary compound, which is the most 5-HT1A-selective analog to 5-MeO-DMT, has shown antidepressant effects without causing hallucinations related to 5-HT2A. Additionally, researchers are looking into the impact of 5-MeO-DMT on preclinical models of depression.The research has shown that psychedelic drugs have a wide range of physiological effects on different receptor types. This suggests that there is potential to develop improved treatments for various mental health disorders.
