Relieving depression with LSD-like drugs without causing hallucinations

Psychedelics such as LSD and psilocybin from “magic mushrooms” have been proposed to ease depression. But the hallucination side effect makes these powerful drugs less ideal as therapeutics. Now, scientists in China have designed LSD analogs that appear to have solved the hallucination problem.

By studying the psychedelics’ activity, researchers from the Chinese Academy of Sciences and ShanghaiTech University have managed to tell apart the pathways by which the drugs exert the antidepressive effects and the hallucinations. New compounds designed based on this knowledge alleviated depression in mice without triggering hallucinations, according to results published in Science.

The discovery could accelerate the development of similar psychedelic analogs to treat depression more safely in humans, the researchers said.

Psychedelics bind to the 5-HT2AR receptor. The researchers examined the binding activity of several compounds to 5-HT2AR: LSD, psilocin—which psilocybin becomes once consumed inside the body—5-HT2AR’s natural binder, serotonin and also Bayer’s nonhallucinogenic drug Dopergin (lisuride).

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A 2017 Cell study found that LSD occupied a pocket within 5-HT2AR called the orthosteric binding pocket (OBP). Sheng Wang, Ph.D., of the Chinese Academy of Sciences, a co-senior author of the current study, was a co-first author on that study. This time, Wang and colleagues found that psilocin and serotonin also touched upon a neighboring site called the extended binding pocket (EBP) in a process mediated by lipids.

In behavioral studies in mice, compounds that occupied more EBP than OBP were linked to antidepressive activity without hallucinations. With that knowledge, the researchers designed new compounds with favorable EBP binding based on Intra-Cellular Therapies’ marketed antipsychotic Caplyta.

Two compounds, dubbed IHCH-7086 and IHCH-7079, stood out. Mice treated with the meds didn’t show head twitches, which were indicative of hallucinations in humans. The animals did show reduced freezing behavior, suggesting the drugs had effective antidepression power similar to LSD.

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Psychedelics could be powerful antidepressants. Compass Pathways recently reported promising midstage trial results showing a 25-mg dose of its psilocybin candidate, dubbed COMP360, significantly decreased depressive symptoms in patients with treatment-resistant depression compared with a control group that used the drug at a mere 1-mg strength.

But side effects remain a major concern of therapeutic use of psychedelics. In the search for better options, researchers at the University of California, Davis synthesized a nonhallucinogenic version of the psychedelic drug ibogaine. That compound, called tabernanthalog, showed promising effects in treating depression and addiction as well as unpredictable mild stress in mice. Tabernanthalog and its related science formed the scientific base of Fierce 15 winner Delix Therapeutics.

The Chinese scientists now suggest their discovery around the structure of 5-HT2AR and its interaction with psychedelics could inform the design of new drugs that retain antidepressant effects without causing hallucinations. The team is further perfecting its drug design in the hope of bringing a candidate into human testing in the future.