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By promoting the growth of dendritic spines (red) on neurons (blue), a nonhallucinogenic compound called tabernanthalog may help neurons in the brain recover their communication skills and combat depression and addiction.

Lindsay P. Cameron

Chemists re-engineer a psychedelic to treat depression and addiction in rodents

The Bwiti tribe in Gabon has used the hallucinogen ibogaine for centuries in spiritual ceremonies. But it wasn’t until the 1950s that the drug caught on in the West—not as a psychedelic, but as a treatment for addiction and depression, conditions that today’s medical interventions still struggle to treat.

Unfortunately, ibogaine isn’t much of a medicine. Besides triggering hallucinations, it can cause heart attacks and is illegal in much of the world. An alternative may be on the way, however.

Researchers report today that they’ve created a nontoxic and nonhallucinogenic chemical cousin of ibogaine that combats depression and addictive behaviors in rodents. The work provides new hope that chemists may one day be able to create medicines for people that offer the purported therapeutic benefits of ibogaine and other psychoactive compounds without their side effects.

“This is really cool work” that could be a “game changer” for the field, says Matthew Johnson, an experimental psychologist and expert in hallucinogens at Johns Hopkins University who was not involved with the study.

Ibogaine and other psychedelics, such as LSD and psilocybin, have long been hailed as potentially powerful treatments for sufferers of addiction and depression. Psychoactives appear to have a different mechanism of action from other psychiatric medicines out, which offers hope that they could treat more people. They also seem to produce lasting effects after only a few doses.

Though the biology of depression and addiction is complex, people with these diseases tend to lose some synaptic connections in their prefrontal cortex. This region of the brain is linked to personality, decision-making, and social behavior. Two psychoactive compounds that combat depression and addiction in some people—LSD and ketamine—seem to help the neurons in this part of the brain communicate better by promoting the growth of dendritic spines, small protrusions from neurons that help neurons talk to each other.

In an attempt to find a nonhallucinogen that would do the same thing, researchers led by David Olson, a chemical neuroscientist at the University of California, Davis, started with ibogaine. The team synthesized 20 different chemical analogs of the hallucinogen, retaining a central ring-shaped portion that proved to be involved with some of the desired effects, but losing other fragments that proved toxic and hallucinogenic. The most promising result was a compound called tabernanthalog (TBG).

TBG promoted dendritic spine growth in both cells and rodents. The compound appeared safe in cell cultures and zebrafish and sharply reduced both alcohol- and heroin-seeking behavior in mice and rats. A single injection of the compound protected against relapse of heroin use for up to 14 days. TBG also doesn’t appear to stimulate the brain’s reward centers, as do drugs such as cocaine, indicating it may not cause dependency, the team reports today in Nature.

Bryan Roth, a pharmacologist at the University of North Carolina, Chapel Hill, says the results are noteworthy in part because they show TBG binds to a subset of receptors for the neurotransmitter serotonin—receptors also targeted by LSD and psilocybin. That suggests TBG might use a similar mechanism, providing the beneficial effects of psychoactive drugs without hallucinations. However, he cautions that many other serotonin-affecting compounds showed promise in animal studies but have not worked in humans.

Olson also notes that TBG isn’t particularly potent, as the animals had to be given large doses to see beneficial effects. That can be a warning flag for potential medicines, because drugs given at large doses often produce more side effects. So, he says, his lab will look for more potent versions. If they succeed, it could bring much needed help to sufferers of conditions that currently have limited medical treatments.