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A research team including the Roth Lab from UNC-Chapel Hill, along with collaborators from UC San Francisco, Yale, Duke, and Stanford developed a new compound that hits the same brain cell target as psychedelic drugs, triggering long-lasting anti-depressant action without psychedelic effects in mice.

Bryan Roth, MD, PhD

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.

Representation of the serotonin 2A Receptor (5HT2AR) signaling protein complex bound with the novel compound R-69 (in subset, magenta).
Representation of the serotonin 2A Receptor (5HT2AR) signaling protein complex bound with the novel compound R-69 (in subset, magenta).

“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.”

Then Roth’s UNC lab, led by co-first author Kuglae Kim, PhD, selected and tested several actual compounds to see how they bind to the serotonin receptors in cell cultures. This part also took years. Receptors are complex and delicate bunches of perfectly situated proteins. To be able to observe a compound’s effect on them is a laborious process involving various experimental techniques, including x-ray crystallography.

“What we saw was completely unexpected,” Roth said. “Not only did the compound bind the 5-HT2A serotonin receptor like we thought it would, but it had the same anti-depressant drug action as does ketamine but not the same hallucinogenic drug action.”

“It was more than a little remarkable to us is that this compound was effective in all mouse models after a single dose, and the effect was long lasting, similar to psilocybin,” Roth said. “We were lucky. And we know we’re not finished.”

~The above is excerpted from the original article of same title published Sept. 28, 2022 on UNC Health News, which goes into more detail about the case for using psychedelics to create treatments for depression and the years of collaborative research that led to this discovery.

Read the journal article in Nature, 2022 Sep 28. doi: 10.1038/s41586-022-05258-z. Online ahead of print.

Duke’s William C Wetsel and Stanford’s Georgios Skiniotis are co-senior authors on the Nature paper. Other authors are Ximena Barros-Álvarez, Ramona M. Rodriguiz, Ying Yang, Oh Sang Kweon, Tao Che, John McCorvy, David N. Kamber, James P. Phelan, Luan Carvalho Martins, Vladimir M. Pogorelov, Jeffrey F. DiBerto, Samuel T. Slocum, Xi-Ping Huang, Jain Manish Kumar, Michael J. Robertson, Ouliana Panova, Alpay B. Seven, and Autumn Q. Wetsel.