A psychedelic substance found in the secretions of the Colorado River Toad or Sonoran Desert toad could be modified to become an effective therapy against depression and anxiety, a study conducted by researchers at the Icahn School of Medicine in Mt. Sinai. These scientists have elucidated the complex mechanisms by which a category of psychedelic drugs bind and activate serotonin receptors to generate potential therapeutic effects in patients with neuropsychiatric disorders such as depression and anxiety.
Researchers found that certain psychedelic drugs interact with a little-known member of the serotonin receptor family in the brain, known as 5-HT1A, to produce therapeutic benefits in animal models (mice) and that specifically the hallucinogen 5-MeO- DMT, which contains the venom of the Sonoran Desert toad and is associated with intense psychedelic experiences, interacts with the serotonin 5-HT1A receptor.
“Psychedelics such as LSD and psilocybin have entered clinical trials with promising initial results, although we do not yet understand how they interact with different molecular targets in the brain to trigger their therapeutic effects,” says lead author Audrey Warren, a doctoral candidate at the School of Biomedical Sciences at Icahn Mount Sinai.
“Our study highlights, for the first time, how serotonin receptors such as 5-HT1A likely modulate the subjective effects of the psychedelic experience and also play a potentially crucial role in its clinically observed therapeutic outcome,” adds the expert. Her findings have been published in Nature.
Drugs derived from psychedelics with antidepressant effects
LSD and 5-MeO-DMT, a psychedelic found in the secretions of the Colorado River Toad, are known to mediate their hallucinogenic effects through the 5-HT2A serotonin receptor, although these drugs also activate 5-HT1A, a validated therapeutic target to treat depression and anxiety. Working in collaboration with co-author Dalibor Sames, Ph.D., professor in the Department of Chemistry at Columbia University, the team synthesized and tested 5-MeO-DMT derivatives in cell signaling assays and cryo-electron microscopy to identify the most important chemical components. prone to cause a drug to preferentially activate 5-HT1A over 5-HT2A.
This process led to the discovery that a compound called 4-F,5-MeO-PyrT was the most selective compound for 5-HT1A in this series. Lyonna Parise, a doctor and instructor in the laboratory of Scott Russo, director of the Center for Affective Neuroscience and the Center for Brain and Body Research at Icahn Mount Sinai, then tested that lead compound in a mouse model of depression and showed that 4- F, 5-MeO-PyrT had antidepressant-like effects that are effectively mediated by 5-HT1A.
“We have shown that psychedelics have complex physiological effects that span many different types of receptors and we are ready to develop better therapies for a variety of mental health disorders”
“We were able to tune the structure of 5-MeO-DMT/serotonin to obtain maximum activity at the 5-HT1A interface and minimal activity at the 5-HT2A interface,” explains senior author Daniel Wacker, Ph.D., assistant professor of pharmacological sciences. and neuroscience at Icahn Mount Sinai. “Our findings suggest that receptors other than 5-HT2A not only modulate the behavioral effects derived from psychedelics, but may contribute substantially to their therapeutic potential. In fact, we were pleasantly surprised by the strength of that contribution from 5-MeO-DMT, which is currently being tested in several clinical trials for depression. “We believe our study will lead to a better understanding of the complex pharmacology of psychedelics involving many types of receptors.”
In fact, the researchers are hopeful that, based on their revolutionary findings, it will soon be possible to design psychedelic-derived medications that do not possess the hallucinogenic properties of current drugs. The discovery that its lead compound – the most selective 5-HT1A analogue of 5-MeO-DMT – showed antidepressant effects without the hallucinations associated with 5-HT2A has raised expectations.
Another near-term goal for scientists is to investigate the impact of 5-MeO-DMT in preclinical models of depression (due to research restrictions around psychedelic drugs, studies involving a 5-MeO-DMT derivative have been limited to animal models). “We have shown that psychedelics have complex physiological effects that span many different types of receptors,” emphasizes first author Warren, “and now we are ready to take advantage of that finding and develop better therapies for a variety of mental health disorders.”
