Scientists create non-psychedelic compound with same anti-depressant effect: Researcheres develop new compound that hits the same brain cell target as psychedelic drugs, triggering long-lasting anti-depressant action without psychedelic effects in mice

While illegal for recreational use, psychedelic drugs are showing great promise as treatments for severe depression and anxiety, as well as alcohol addiction and other conditions. Some advocates and scientists believe the actual psychedelic trip — hallucinations and profound emotional experiences- is what leads to long-lasting therapeutic effects. Other scientists speculate that if the ‘trip’ could be eliminated from such drugs, then only the therapeutic effects might remain. Researchers at UNC-Chapel Hill, UC San Francisco, Yale, Duke, and Stanford have taken a major step toward answering that question.

Published in Nature, this research in animal models show it’s possible to create a compound that hits the same exact target as psychedelic drugs hit — the 5-HT2A serotonin receptors on the surface of specific neurons — but does not cause the same psychedelic effects when given to mice. The new compound triggers the same anti-depressant action that researchers have long observed in mice treated with SSRI drugs over the past two decades, with just two differences: the anti-depressant action of the new compound was immediate and long-lasting after just one dose.

“We were very surprised the compound had any anti-depressant activity similar to ketamine and psilocybin, both rapidly acting antidepressant psychedelic drugs,” said co-senior author Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology at the UNC School of Medicine and director of the NIMH Psychoactive Drug Screening Program. “We were basically running a chemistry experiment to see if we could create a compound to activate 5-HT2A. Once we achieved that, we decided to run experiments in mice.”

The compound is patented by Yale, UNC-Chapel Hill, and UCSF and licensed to Onsero, a company created to fine-tune experimental compounds before they can be further tested in clinical trials.

“We don’t know if we’ll see the same effects in people,” Roth said. “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 Case for Psychedelics

When someone eats a magic mushroom, the active ingredient pscilocin — which is derived from psilocybin — binds tightly to the 5-HT2A serotonin receptors on the surface of neurons. The receptor is activated for a long time, triggering a cascade of chemical signals inside cells. These cells then communicate to other cells throughout the brain, sending the person on a long, strange hallucinogenic trip for hours. For those who are treatment-resistant, psychedelic drugs can immediately alleviate depression, and the effect lasts for many months.

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