Feeling stressed? New research might help, as we’ve identified a substance that can revert stress-induced behavioral deficits and restore neural circuits affected by stress in the brain — in mice, so far.

The compound tabernanthalog (TBG) is similar in structure to ibogaine, a psychedelic drug. However, it lacks its toxic and hallucinogenic effects and has been found to quickly reverse stress-related issues in mice. A single dose of TBG is enough for the job, the authors add, to address issues such as anxiety and cognitive inflexibility, regrow neuronal connections, and restore neural circuits — all possible effects of stress.

Stress-B-gone

“It was very surprising that a single treatment with a low dose had such dramatic effects within a day,” said corresponding author Yi Zuo, professor of molecular, cell, and developmental biology at UC Santa Cruz.

“I had a hard time believing it even when I saw the initial data.”

TBG was developed in the lab of David Olson at UC Davis, a co-author on the current paper, and was first reported on in 2020. The study focused on its activity against the effects of stress, using a protocol in which lab mice were subjected to mild but unpredictable sources of stress over a period of a few days.

Stress, the team explains, especially sustained over longer periods of time, can lead to increased levels of anxiety, difficulty in processing sensory input, and reduced flexibility in decision-making. In the brain, it can lead to disruptions between neurons and changes in the structure of our neuronal circuitry — which, overall, impacts how well our brain can function on a day-to-day basis.

One dose of TBG, however, had reversed all of these effects in the mice used in this study. The team also performed imaging studies to assess changes in the brains of the mice at the neuronal level.

“This study provides significant insights into neural mechanisms underlying the therapeutic effects of psychedelic analogs on mental illnesses and paves the way for future investigations to understand their cellular and circuit mechanisms,” adds Zuo.

Psychedelic drugs have been receiving a lot of attention lately as they might be useful in treating addiction, depression, anxiety, and post traumatic stress disorder. However, their hallucinogenic effects can be quite impairing for some patients and remain a point of concern.

Ibogaine is one such compound that showed promise in the treatment of addiction. It does, however, also cause heart arrhythmia and is a very strong hallucinogenic substance. TBG is chemically and biochemically similar to Ibogaine, but seems to lack its toxic and hallucinogenic effects in mice. The compound has not yet been tested on humans, so we can’t be sure, but it doesn’t induce head-twitching behaviors in mice after administration, as known hallucinogens do.

Previous research on mice has shown that TBG can act as an antidepressant and can reduce addictive behavior. The current study was meant to expand on these initial findings by evaluating its potential in the treatment of stress and its symptoms.

Initial studies of TBG found that it had antidepressant effects and reduced addictive behaviors in rodents. The new study was initiated by co-first author Michelle Tjia, then a graduate student in Zuo’s lab studying the effects of stress. After Tjia left for a postdoctoral position, co-first author Ju Lu, a project scientist in the lab, led additional studies. The researchers conducted a range of tests to evaluate behavioral responses to stress and the effects of treatment with TBG.

The paper “An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress” has been published in the journal Molecular Psychiatry.