Photographic and video evidence shows that a single dose of a synthetic compound that’s a non-hallucinogenic counterpart to a hallucinogenic one can repair stress-damaged neurons and brain circuitry in mice — all while reducing their anxious and depressive behaviors and curbing their addictions.
The compound is tabernanthalog (TBG), synthesized from the hallucinogen ibogaine by UC Santa Cruz chemical neuroscientist David E. Olson. Ibogaine is an extract of the naturally-growing African plant, iboga. A drug for medicinal use in humans is in development; clinical trials are anticipated.
An article in the May 25, 2021, issue of Molecular Psychiatry depicts the work by Olson and collaborators and the rationale behind modeling TBG on ibogaine’s key structural elements. While ibogaine has demonstrated anti-anxiety and anti-depression effects and is used in some drug and alcohol rehab clinics around the world, it will probably never be licensed for use in the United States. This is because, at therapeutic doses, it can cause dangerous heart arrhythmias and fatal heart attacks. At high doses, it is neurotoxic. Enter Olson’s new TBG. His hope for the new synthetic compound is that, in humans, it will prove to have all of ibogaine’s benefits and none of its toxicity or hallucinogenic potential. While the compound is still untested in humans, Olson’s Molecular Psychiatry paper about it shows that sort of promise.
Anxiety, Depression, Addiction, and the Psychedelic Connection
Over the past several years, neuroscientists and mental health professionals have become intrigued with the potential of psychedelics to open people’s minds to healthy change and to combat mental illness. Ibogaine’s successes —as well as the successes of psilocybin and ketamine — suggest that psychedelics may one day be recognized as powerful medicines. Even so, some are dangerous. Hallucinations present a risk for patients with a history of psychosis or mania. Some people otherwise drawn to the therapeutic benefits of psychedelics remain afraid of the very prospect of hallucinating. Realizing all of this, in his lab at UC Davis Olson wondered whether the psychedelic effects of drugs like psilocybin and ketamine are necessary contributors to their efficacy as psychiatric medicines. Would treatment work just as well without the drugs’ “trippy” aspects?
TBG does not induce hallucinations, or at least that’s the impression that Olson and colleagues have drawn from their studies with mice. Typically, mice given a hallucinogen develop a characteristic side-to-side head movement referred to as a “head twitch response.” Mice given TBG don’t twitch their heads.
TBG Reverses Stress Behaviors in Mice
The new Molecular Psychiatry article was preceded by a paper published in January 2021 in Nature. Part of the purpose of that study was to investigate whether TBG is safer than ibogaine. Working with young zebrafish, Olson and colleagues found that ibogaine caused disabling changes in shape, while TBG did not. The study was also designed to determine whether TBG, like ibogaine, is useful in treating mental illness. They found that, in mice, it reduced alcohol- and heroin-seeking behavior and it reversed post-stress behaviors associated with depression.
Five months after the publication of that Nature article, the study described in Molecular Psychiatry demonstrated the anti-anxiety benefits of TBG and revealed the breakthrough neuronal and brain circuitry repair benefits of the compound.
In the newer study, Olson and his colleagues worked with two-month-old lab mice, exposing them for several days to unpredictable mild stress such as illumination changes, forced swimming, and extra handling. At the end of the period of stressful days, the mice were put through challenges meant to reveal whether stress had changed behavior, sensory processing abilities, or cognitive flexibility.
Indeed, it had. The consecutive days of stress had made mice reluctant to move about in heights and had reduced their ability to learn diverse and novel stimulus-response associations. When stressed-out mice rubbed their whiskers on textures that were new to them, the level of excitation in the sensory processing area of the brain was unusually low.
Then the mice were given TBG. Within one day, the behavioral, learning, and sensory processing changes wrought by stress were reversed, and no toxic effects on heart or brain were evident.
Looking inside the living mice’s brains, the researchers also saw that damage to neurons’s dendrites and to neuronal communication had been righted. (Dendrites are the spined branches extending out of a neuron. Electrical impulses flow through them into and out of the neuronal network.)
Looking Inside a Living Mouse’s Brain
One month before the experiment began, the researchers had created a single “cranial window” at the top of each mouse’s skull. Having anesthetized the mice, they drilled a 2.3 mm diameter hole into the head, and then replaced the missing bone and tissue with glass glued in place with dental cement. This is a common procedure in labs studying neurology in live rodents. It’s considered humane because skulls have few nerves and, for any given rodent, the large mass of remaining bone plus the tiny cranial window create a stable skull.
Using high-powered microscopes and special lights, Olson’s team shot photos and video through the cranial windows. They saw evidence of damaged dendritic spines, which they speculated lay at the root of behavior, sensory, and cognitive deficits. They also noted a lack of calcium bursts within the neural networks. This indicated that electrical communication among neurons had ebbed. After giving mice a single dose of TBG, they saw improvements in spine growth and density. Calcium bursts indicated that communication was back at par.
The Possibility of a Permanent Cure
How does TBG repair neurons and neural circuits? Could it be that psilocybin, ketamine, and other psychedelics can also facilitate brain repair?
In a Zoom interview, Olson explained his original interest in creating a synthetic counterpart to ibogaine, and also spoke of what the future might hold.
“I’d learned from the work of others that sometimes a single administration of a psychedelic substance can produce long-lasting effects. For example, studies conducted by other researchers had suggested that an initial dose of ibogaine can keep heroin addicts drug free for up to six months.”
Olson also spoke of wondering whether stress or addiction had produced neuronal changes that the drugs were reversing.
“The idea that a substance can quickly rescue structural and functional deficits in neural networks is a new concept in pharmacological research and intervention,” he explained. “Such substances are called ‘psychoplastogens.’ Ketamine, ibogaine, and psilocybin are all psychoplastogens. The non-hallucinogenic analog TBG is also, but it repairs damage without creating hallucinations or injuring hearts.”
The concept of psychoplastogenesis seems beyond revolutionary. For, if some drugs are capable of truly repairing what has gone wrong in a brain, they may not just treat mental illness. They may cure it.
In conversation, Olson speculated that safe, non-hallucinogenic psychoplastogens might even one day be approved for weekly, monthly, or annual home use.
“In which case,” he said, “people could keep ’cures’ in their medicine cabinets. Psychiatry would never be the same.”
To date, there are no data suggesting efficacy or safety for TBG in humans. Olson’s research has led to the founding of Delix Therapeutics, which is advancing TBG through preclinical and clinical development.