Psychedelics may have therapeutic benefits through effects on serotonin receptors

Researchers at the Icahn School of Medicine at Mount Sinai have shed light on the complex mechanisms by which a class of psychedelic drugs bind to and activate serotonin receptors to produce potential therapeutic effects in patients with neuropsychiatric disorders such as depression and anxiety.

In a study published in the journal Nature, the team reported that certain psychedelic drugs interact with a poorly understood member of the serotonin receptor family in the brain known as 5-HT1A to produce therapeutic benefits in animal models.

"Psychedelics such as LSD and psilocybin are undergoing clinical trials with promising early results, although we still don't understand how they interact with various molecular targets in the brain to produce their therapeutic effects," says first author Audrey Warren, a PhD candidate in the Icahn Graduate School of Biomedical Sciences at Mount Sinai.

"Our study highlights for the first time how serotonin receptors such as 5-HT1A likely modulate the subjective effects of psychedelic experiences and also play a potentially key role in their clinically observed therapeutic outcome."

LSD and 5-MeO-DMT, a psychedelic found in the secretion of the Colorado River toad, are known for their hallucinogenic effects via the 5-HT2A serotonin receptor, although these drugs also activate 5-HT1A, a proven therapeutic target for the treatment of depression and anxiety.

Working closely with co-author Dalibor Sames, Ph.D., a professor in the Department of Chemistry at Columbia University, the team synthesized and tested 5-MeO-DMT derivatives in cell signaling assays and by cryo-electron microscopy to identify the chemical components most likely to cause preferential activation of 5-HT1A over 5-HT2A.

This approach led to the discovery that a compound called 4-F,5-MeO-PyrT was the most selective for 5-HT1A in the series. Lyonna Parise, Ph.D., an instructor in the lab of Scott Russo, Ph.D., director of the Center for Affective Neuroscience and the Icahn Center for Brain and Body Research at Mount Sinai, then tested this lead compound in a mouse model of depression and showed that 4-F,5-MeO-PyrT had an antidepressant effect that was effectively modulated through 5-HT1A.

"We were able to fine-tune the 5-MeO-DMT/serotonin platform to produce maximum activity at the 5-HT1A interface and minimal activity at 5-HT2A," explains senior author Daniel Wacker, Ph.D., associate professor of pharmacological sciences and neuroscience at the Icahn School of Medicine at Mount Sinai.

"Our findings suggest that receptors other than 5-HT2A not only modulate the behavioral effects of psychedelics, but may also contribute significantly to their therapeutic potential. In fact, we were pleasantly surprised by the strength of this contribution to 5-MeO-DMT, which is currently being tested in several clinical trials for the treatment of depression. We believe that our study will lead to a better understanding of the complex pharmacology of psychedelics, which involve many receptor types."

Mount Sinai scientists have taken detailed photographs of the serotonin receptor and clinically validated drug target 5-HT1A using cryo-electron microscopy to show how the psychedelics LSD and 5-MeO-DMT, as well as the 5-HT1A-selective derivative 5-MeO-DMT (4-F, 5-MeO-PyrT), bind. The team also found that 4-F, 5-MeO-DMT exerts antidepressant effects in mouse models via 5-HT1A, potentially contributing to the therapeutic effects of psychedelics seen in clinical trials. Authors: Audre Warren, PhD, pharmacology, and Daniel Wacker, associate professor of pharmaceutical sciences and neuroscience.

The researchers hope that their breakthrough findings will soon lead to the development of new psychedelic-based drugs that lack the hallucinogenic properties of current drugs. Fueling the anticipation is the discovery that their lead compound, the most selective 5-HT1A analogue 5-MeO-DMT, showed antidepressant effects without the hallucinations associated with 5-HT2A.

Another immediate goal for the scientists is to study the effects of 5-MeO-DMT in preclinical models of depression (given the limitations of research involving psychedelic drugs, studies with 5-MeO-DMT derivatives have been limited to animal models).

"We have demonstrated that psychedelics have complex physiological effects involving many different receptor types," emphasizes first author Warren, "and are now poised to build on this discovery to develop improved therapeutics for a wide range of psychiatric disorders."