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Researchers Uncover How Psychedelics Interact With Serotonin Receptors

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Researchers have shed light on how some psychedelic drugs – which show promise in patients with neuropsychiatric disorders such as depression and anxiety – bind to and activate serotonin receptors.

Understanding how these drugs exert potential therapeutic effects may help to design therapeutics for mental health disorders.

The study was published in Nature.

Understanding the molecular effects of psychedelics

Drugs based on psychedelics – such as LSD and psilocybin – have shown promise for various psychological conditions in a number of clinical trials, with more underway.

Clinical trials have found that such psychedelics-inspired drugs – often administered alongside more conventional talking therapies – show promise for conditions such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD).

Yet exactly how these drugs exert their potentially therapeutic effects has been unclear. Evidence has pointed towards 5-HT2A, a type of serotonin receptor. But more has been emerging to suggest some psychedelics – such as 5-MeO-DMT, produced by the Colorado River Toad – may work through another serotonin receptor, 5-HT1A, an established therapeutic target for depression and anxiety.

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With this in mind, the researchers in the new study delved deeper into how psychedelics interact with 5-HT1A in animal models, shedding light on how it produces potentially therapeutic effects.

A potential therapeutic target

The team synthesized derivatives of 5-MeO-DMT, which they tested in cell culture and with cryo-electron microscopy to identify the chemical components most likely to cause a drug to activate 5-HT1A over 5-HT2A.

One compound, 4-F, 5-MeO-PyrT, was discovered to be the most selective for 5-HT1A.

“We were able to fine-tune the 5-MeO-DMT/serotonin scaffold to obtain the maximum activity at the 5-HT1A interface and minimal activity at 5-HT2A,” explained senior author Dr. Daniel Wacker, an assistant professor of Pharmacological Sciences and Neuroscience at Icahn Mount Sinai.

Experiments using a mouse model of depression revealed that 4-F, 5-MeO-PyrT exerted antidepressant-like effects mediated by 5-HT1A.

“Our findings suggest that receptors other than 5-HT2A not only modulate behavioral effects stemming from psychedelics, but may substantially contribute to their therapeutic potential,” he added. “In fact, we were pleasantly surprised by the strength of that contribution to 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 that involve many receptor types.”

Additionally, the researchers’ lead compound – the most 5-HT1A-selective analog to 5-MeO-DMT – showed antidepressant effects without the hallucinations related to 5-HT2A activation. This finding may boost hopes of the development of non-hallucinogenic psychedelic-derived medications, which could prove more suitable for use in at-home settings.

“We’ve demonstrated that psychedelics have complex physiological effects that span many different receptor types, and are now ready to build on that finding to develop improved therapeutics for a range of mental health disorders,” Warren explained.

Reference: Warren AL, Lankri D, Cunningham MJ, et al. Structural pharmacology and therapeutic potential of 5-methoxytryptamines. Nature. 2024:1-10. doi: 10.1038/s41586-024-07403-2

This article is a rework of a press release issued by Mount Sinai. Material has been edited for length and content.