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CHAPEL HILL, N.C. — Psychedelics have become a popular option among scientists looking for a treatment for mental health issues like depression. While these drugs can have a beneficial effect on human patients, the psychedelic “trip” users experience are still a concerning side-effect. Now, a new study has discovered a new compound that appears to provide the same benefit psychedelics produce without causing hallucinations or other problems.

After a seven-year “chemistry experiment,” a team from UNC-Chapel Hill, UC San Francisco, Yale, Duke, and Stanford have developed a non-psychedelic drug they say hits the same brain cell target that substances like magic mushrooms or ketamine do. In experiments with mice, the compound successfully targeted the 5-HT2A serotonin receptors on the surface of specific neurons in the brain. However, mice did not experience the same psychedelic effects that illegal drugs often cause.

Moreover, researchers say the new drug triggers the same antidepressant action that SSRI drugs do, with two major differences. Unlike SSRIs, the compound started working immediately and lasted longer 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,” says co-senior author Bryan 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, in a university release.

“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.”

“We don’t know if we’ll see the same effects in people,” Roth continues. “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.”

Why are psychedelics becoming popular antidepressant candidates?

Study authors note that the active ingredient in a magic mushroom is pscilocin, a derivative of psilocybin. It binds to the 5-HT2A serotonin receptors, triggering a series of chemical signals within cells. For someone using magic mushrooms recreationally to get high, this reaction can send them on a hallucinogenic trip for hours.

Studies have shown that this same process can immediately alleviate depression in people who are resistant to standard prescription drugs relieving depression. Moreover, the effect can last for months. Scientists have found similar results in drugs like ketamine (an anesthetic), ayahuasca (a brew including two psychoactive plants), and LSD.

A class of antidepressant drugs called selective serotonin reuptake inhibitors (SSRIs) adjust serotonin signaling, but not in the same way psychedelics do. Unfortunately, SSRIs also enhance serotonin levels in a patient’s cells, which can lead to more adverse side-effects. Additionally, people taking SSRIs typically don’t start feeling the benefits of these drugs for weeks.

“So, there’s more going on than simply raising serotonin levels to treat depression,” Roth says. “SSRIs cause changes in the brain that lead to anti-depressive action. We don’t know what’s going on, exactly. But I know many people who have had their lives transformed by SSRIs and psychotherapy.”

The new study took seven years, starting with Roth’s lab solving the complex chemical arrangement of the serotonin receptors.

‘What we saw was completely unexpected’

The team focused on chemical reactions for the synthesis of tetrahydropyridines (THPs), which occur in nature and are the building blocks of many medications. Using computational simulations, they narrowed their search to compounds which only bind to 5-HT2A — just like the psilocybin in magic mushrooms.

“For us, the project began as an opportunity to expand the new virtual libraries with 75 million tricked-out molecules from the Ellman lab,” says co-senior author Brian Shoichet. “It was only when we started to see the unusual signaling from the new compounds and their amazing permeability into the brain that we as a team started to think these compounds might have interesting effects in vivo.”

Roth’s UNC lab then selected and tested several compounds to see how well they bind to serotonin receptors in live cell cultures. The work took years but allowed the team to learn more about the link between each compound and 5-HT2A. Study authors then tweaked their designs to create new compounds that bind to 5-HT2A without the psychedelic trip.

“What we saw was completely unexpected,” Roth says. “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.”

Although researchers can’t say for certain that the mice in their experiments were free of hallucinations and depression, their behavior matched the results of previous studies that tested antidepressants on mice.

“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 concludes. “We were lucky. And we know we’re not finished.”

The findings appear in the journal Nature.

About Chris Melore

Chris Melore has been a writer, researcher, editor, and producer in the New York-area since 2006. He won a local Emmy award for his work in sports television in 2011.

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