Chemists re-engineer a psychedelic to deal with melancholy and dependancy in rodents | Science


By encouraging dendritic spines (red) to grow on neurons (blue), a non-hallucinogenic compound called tabernanthalog can help neurons in the brain restore their communication skills and fight depression and addiction.

Lindsay P. Cameron

By Robert F. ServiceDec. 9, 2020, 11:45 a.m.

The Bwiti tribe in Gabon have used the hallucinogen ibogaine in spiritual ceremonies for centuries. 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 are still difficult to treat.

Unfortunately, ibogaine isn’t a great medicine. Not only does it induce hallucinations, but it can cause heart attacks and is illegal in much of the world. However, an alternative might be on the way.

Researchers today report that they created a non-toxic and non-hallucinogenic chemical cousin to ibogaine that combats depression and addictive behavior in rodents. The work gives new hope that one day chemists may be able to develop drugs for people that offer the supposed therapeutic benefits of ibogaine and other psychoactive compounds without their side effects.

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

Ibogaine and other psychedelics such as LSD and psilocybin have long been recognized as potentially effective treatments for addicts and depression sufferers. Psychoactive substances appear to have a different mechanism of action than other psychiatric drugs, which gives hope that they could treat more people. They seem to have a lasting effect even after a few doses.

Although 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 associated with personality, decision making, and social behavior. Two psychoactive compounds that work against depression and addiction in some people – LSD and ketamine – appear to help neurons in this part of the brain communicate better by encouraging the growth of dendritic spines, small protrusions of neurons that help neurons to talk to each other.

In an attempt to find a non-hallucinogen that does the same thing, researchers under the direction of David Olson, a chemical neuroscientist at the University of California at Davis, began using ibogaine. The team synthesized 20 different chemical analogues of the hallucinogen, leaving a central ring-shaped part that dealt with some of the desired effects, but lost other fragments that were found to be 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 to be safe in cell cultures and zebrafish and greatly reduced both alcohol and heroin-seeking behavior in mice and rats. A single injection of the compound protected from relapse of heroin use for up to 14 days. TBG also doesn’t seem to stimulate the brain’s reward centers, nor does drugs like cocaine, suggesting it may not cause addiction, the team reports in Nature today.

Bryan Roth, a pharmacologist at the University of North Carolina, Chapel Hill, says the results are noteworthy in part because they show that TBG binds to a subset of receptors for the neurotransmitter serotonin – receptors that LSD and psilocybin also target . This suggests that TBG could use a similar mechanism that provides the beneficial effects of psychiatric drugs without hallucinations. However, he warns that many other serotonin-affecting compounds have shown promise in animal studies but have not worked in humans.

Olson also notes that TBG is not particularly effective because the animals had to be given large doses in order to see beneficial effects. This can be a warning flag for potential drugs, as drugs given in large doses often produce more side effects. So, he says, his lab will be looking for more effective versions. If successful, it could bring much-needed help to patients with conditions that currently receive limited medical treatment.