Psychedelics without the trip: a potential breakthrough for depression treatment

When lab mice take psychedelics, their heads twitch, a telltale sign they’re seeing cats or cheese or whatever else rodents hallucinate while tripping.

But when Dr. Bryan Roth’s research group injected mice with their newly created psychedelic compound, they noticed something strange: the mice didn’t twitch or show any other signs they were hallucinating.

Roth, a UNC-Chapel Hill researcher, could see the drug had made its way into the mice’s brains. Furthermore, the compound was effectively treating depression in mice, as other psychedelics have been shown to do.

Inadvertently, Roth realized, he had created a completely new drug that appears to provide all the therapeutic benefits of psychedelic drugs without the trip. The discovery, funded by NIH and DARPA grants, was published Wednesday in Nature with researchers at UC-San Francisco and Yale.

If the drug proves effective in humans — which to many scientists, including Roth, is a big “if” — it could make psychedelic treatments palatable to a broader audience who don’t necessarily want an out-of-body experience during medical treatment.

One and done

In 2016, scientists began clinical trials in humans to test the therapeutic effects of psilocybin, the active ingredient in “magic” mushrooms.

Participants with cancer-related depression were given a “cosmic dose” of psilocybin and guided through a psychedelic experience with therapists.

Seven months later, after only a single dose, 80% of the participants were significantly less depressed.

Roth said while the study was small, the results were unprecedented for a psychiatric treatment. Medications typically prescribed for depression, like Prozac or Celexa, require patients to take pills every day and work maybe 50% of the time, he said.

“This is a case where it’s basically one and done,” he said. “ You take the take the drug, you get the effect and you’re fine.”

Other trials since then have found similar, long-lasting benefits in patients with depression. Anecdotal reports also suggest that psychedelics could be used to treat anxiety, migraines, obsessive compulsive disorder and substance abuse.

The compound Roth’s team created appears to strip psychedelics of their hallucinogenic properties while still causing long-lasting antidepressant effects in mice — similar to the one caused by psilocybin.

“That was an astounding finding, something we had not expected at all,” Roth said.

That doesn’t necessarily mean the drug will be effective in people. There are many drugs that have antidepressant effects in mice that don’t work on humans, Roth said.

Roth’s lab isn’t the first to create a non-hallucinogenic psychedelic compound.

A research group out of UC Davis and Roth’s former trainee, Sheng Wang, published articles describing similar molecules in the last two years. However, both of the compounds were derived from existing medications.

Roth’s new compound, generated using a computational program that vets millions of chemical structures, is entirely novel. That means a company could bring the medication to market without infringing on other patents.

UNC-Chapel Hill, which holds a patent on the compound with UCSF and Yale, has a provisional licensing agreement with Onsero Therapeutics to ready the drug for clinical trials.

What are psychedelics without the trip?

Researchers still disagree about what role hallucinations play in psychedelic treatment.

Some scientists believe that the psychedelic experience is what makes the drugs therapeutic. Several participants in the 2016 psilocybin study told The New York Times that they experienced epiphanies during their hallucinations.

“Why are you letting yourself be terrorized by cancer coming back?” one participant said. “That’s when I saw black smoke rising from my body.”

Other scientists believe hallucinations are an inconsequential side effect of psychedelics that can be rooted out without impacting their effectiveness.

Much of the disagreement stems from the fact that researchers still don’t know exactly why psychedelics cause antidepressant effects. Though they know the compounds bind to the 5-HT-2A receptor in brain cells, they don’t know how they create such a robust, long-lasting mental benefit.

“It’s unclear really what the heck is going on,” he said.

Roth considers himself to be a part of a third, “wait-and-see” camp in the hallucination debate. Future trials with Roth’s new compound could help answer questions about how central hallucinations are to the therapeutic effect of psychedelics.

“It could be either, right?” he said. “It’s a testable hypothesis and so we’re trying to test that hypothesis.”

Teddy Rosenbluth covers science for The News & Observer in a position funded by Duke Health and the Burroughs Wellcome Fund. The N&O maintains full editorial control of the work.