Ibogaine inspires potential neuropsychiatric treatment

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By systematically tweaking the structure of the psychedelic compound ibogaine, chemists have created a molecule that may someday find use as a treatment for neuropsychiatric disorders, including depression and addiction. The compound, which the researchers call tabernanthalog, also has a simpler structure than ibogaine, making it easier to synthesize.

Researchers in David E. Olson’s lab at the University of California, Davis have been exploring psychedelic compounds as potential therapeutics for neuropsychiatric conditions. They think that psychedelics can regrow neurons and reestablish synaptic connections in an area of the brain that degenerates in these illnesses. Olson points to the recent success of the psychedelic drug ketamine as a treatment for depression. But ketamine has hallucinogenic properties and therefore must be given to patients by a healthcare professional, which usually means an hours-long stay in a clinical setting to ensure safety.

“We really wanted to see if we could use chemistry to engineer a psychedelic compound to lack the hallucinogenic effects but retain the beneficial effects,” says Olson. Ibogaine stood out as a target because while there are hints it could be useful in treating addiction, its hallucinogenic properties are compounded by toxicity: people have died from cardiac arrhythmias after taking ibogaine.

Olson and coworkers found that by removing ibogaine’s isoquinuclidine and moving its methoxy group, they could make a compound, tabernanthalog, that didn’t cause hallucinations in mice and didn’t inhibit the potassium channels that are linked to ibogaine’s cardiotoxicity. Tabernanthalog made neurons grow in a petri dish, and in experiments with rodents, the compound reduced both alcohol- and heroin-seeking behavior and had antidepressant effects (Nature 2020, DOI: 10.1038/s41586-020-3008-z).

Olson points out that tabernanthalog’s mechanism likely modifies the circuitry in the brain that causes addictive behaviors, so it should work across a range of addictive disorders. Olson cofounded Delix Therapeutics to develop non-hallucinogenic psychedelic analogs as drugs. The company is exploring the posssibility of moving tabernanthalog or a related molecule into the clinic.

“It’s always fascinating when a compound written off as a menace to humans is thoughtfully revisited, studied from a unique perspective, modified if necessary, and repurposed as a valuable therapeutic,” Long Island University’s Christopher K. Surratt, an expert in pharmaceutical sciences, says in an email. He points to botulinum neurotoxin and thalidomide—both now used to treat a range of medical conditions—as examples of these menace molecules that have become success stories. “Hopefully an ibogaine derivative like tabernanthalog can one day be added to that list,” Surratt says.

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