Psychedelic Drugs' Interaction with Serotonin Receptors for Potential Therapies

Researchers at the Icahn School of Medicine at Mount Sinai have uncovered significant insights into how a particular class of psychedelic drugs interacts with serotonin receptors, potentially offering therapeutic benefits for individuals suffering from neuropsychiatric conditions such as depression and anxiety. Published in Nature on May 8, the study reveals that specific psychedelic substances engage with a less-recognized serotonin receptor in the brain, known as 5-HT1A, to produce therapeutic effects in animal models.

The research, led by PhD candidate Audrey Warren, highlights the intricate ways in which psychedelics like LSD and psilocybin impact various molecular targets in the brain. These drugs have shown promising results in early clinical trials, but the precise mechanisms through which they exert their therapeutic effects remain largely unknown. "Our study is the first to show how serotonin receptors, particularly 5-HT1A, likely influence the subjective experience of psychedelics and their therapeutic outcomes," Warren explained.

LSD and 5-MeO-DMT—a psychedelic found in the secretions of the Colorado River Toad—are primarily known for their hallucinogenic effects mediated through the serotonin receptor 5-HT2A. However, these substances also activate the 5-HT1A receptor, which is a validated target for treating depression and anxiety. Collaborating with Professor Dalibor Sames from Columbia University's Department of Chemistry, the research team synthesized and tested derivatives of 5-MeO-DMT in cell signaling assays and cryo-electron microscopy. Their goal was to pinpoint the chemical components that make a drug favor the 5-HT1A receptor over the 5-HT2A receptor. This led to the identification of a compound called 4-F, 5-MeO-PyrT, the most selective for 5-HT1A in their series of tests.

Lyonna Parise, an instructor in Scott Russo's lab at Icahn Mount Sinai, tested this leading compound in a mouse model of depression. The results showed that 4-F, 5-MeO-PyrT produced antidepressant-like effects predominantly mediated by the 5-HT1A receptor. "We managed to fine-tune the 5-MeO-DMT/serotonin scaffold to achieve maximum activity at the 5-HT1A interface while minimizing activity at 5-HT2A," noted senior author Daniel Wacker, Assistant Professor of Pharmacological Sciences and Neuroscience at Icahn Mount Sinai. "Our findings indicate that receptors other than 5-HT2A not only influence the behavioral effects of psychedelics but may also significantly contribute to their therapeutic potential. We were pleasantly surprised by the strong contribution of 5-HT1A to the effects of 5-MeO-DMT, which is undergoing clinical trials for depression."

The study’s promising results suggest that it may soon be possible to develop new medications derived from psychedelics that do not have the hallucinogenic properties of current drugs. The discovery of the 5-HT1A-selective compound with antidepressant effects but without the hallucinogenic consequences associated with 5-HT2A activation raises researchers' expectations. The near-term focus will likely be on studying the impact of 5-MeO-DMT in preclinical models of depression, given the current research restrictions around psychedelic substances.

"Our research demonstrates that psychedelics have multifaceted physiological effects that engage various receptor types," emphasized Audrey Warren. "We are now in a position to expand on this knowledge to develop better therapeutics for a range of mental health disorders."