Non-psychedelic compound has similar antidepressant effect as psychedelics in mice

By The Science Advisory Board staff writers

September 29, 2022 -- A collaborative research team has developed a new non-psychedelic compound that hits the same brain cell target as psychedelic drugs, triggering lasting antidepressant effects in mice but without the hallucinations.

Researchers from Duke University, Stanford University, University of North Carolina (UNC) at Chapel Hill , University of California, San Francisco (UCSF), and Yale University published results of their study on September 28 in the journal Nature, which demonstrated that the compound hits the same target as psychedelic drugs -- the 5-HT2A serotonin receptors on the surface of specific neurons -- but minus the hallucinations when given to mice.

Years of chemistry experiments were required to create a compound that selectively hits 5-HT2A serotonin receptors on the surface of specific neurons, without the psychedelic effects. The scientists used in silico modeling and generated 3D iterations of more than 75 million lysergic acid diethylamide (LSD)-related molecules, ultimately coming up with two they tested in mice.

In mouse models, the new compound triggers the same antidepressant action that researchers have long observed in mice treated with selective serotonin reuptake inhibitors (SSRIs). But by contrast, the new compound avoids SSRI-related side effects, and the antidepressant effect is immediate and long-lasting after one dose.

"This compound was effective in all mouse models after a single dose," said co-senior author Dr. Bryan Roth, PhD, a professor at the UNC School of Medicine. "We don't know if we'll see the same effects in people. But we hope to find out. It would be a game changer to create a one-dose, long-acting therapy to help people with treatment-resistant depression and other conditions."

The new compound is patented by Yale, UNC-Chapel Hill, and UCSF and licensed to Onsero Therapeutics, a biopharmaceutical company focused on discovery and development of small molecule drugs for treating a range of neuropsychiatric and mental health conditions.

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