Tabernanthalog, which is a recently discovered novel compound, is an analog (similar structure) of ibogaine, with the difference that it lacks the toxic and hallucinatory effects observed in ibogaine cases (1).

Ibogaine is a psychoactive element found in plants, Apocynaceae families, such as Tabernanthe iboga, Tabernaemontana undulata, Vocanga Africana, and Tabernaemontana. Studies regarding this drug are reported to help counter drug addiction and can treat stress-induced psychiatric disorders (2). However, this drug has serious side effects (3). Therefore, with Tabernanthalog, researchers designed the new compound with a similar structure but removed the part responsible for the side effects.

Many psychiatric conditions that include mood, substance use disorders, and anxiety arise when the neuronal circuits or connections weaken, leading to abnormal behavior. Compounds that facilitate the functional reorganization of neuronal circuits and displayed positive effects in behavior are of greater interest, as claimed by researchers in Tabernanthalog’s studies. Several compounds are known to have this effect, but most of them follow an indirect mechanism and produce slow effects (3). Tabernanthalog belongs to a class of fast-acting compounds and has quicker output. Studies on animal models reported that a single dose of this compound reversed the stress-induced effects (1).

Mechanism of action

Studies demonstrated that administration of Tabernanthalog in stress-induced rodents is associated with the growth of dendritic spines on neurons (a spike located on neurons which is crucial for learning and memory). Researchers used two-photon microscopy to assess the growth pattern of those spikes. 7 days UMS increased elimination of spines, while a single dose of Tabernanthalog significantly increased the spine formation (4).

Synaptic changes alter neural networks and their functions, researchers analyzed cortical neurons activities with wide-field and 2P calcium imaging and found that Tabernanthalog significantly increased whisking modulation of mesoscopic neural activity and restore the calcium activity in pyramidal neurons of the brain. Tabernanthalog was also found to rescues the excitability of parvalbumin-expressing inhibitory interneurons (PV+ INs) in the stressed brain of mice (4).

Animal studies

Stress is associated with anxiety which further leads to sensory deficits in the brain. In animal models, Tabernanthalog has been found to repair stress-induced effects. The environment in brain cells is strongly interconnected through the synapse, which is the junctions between neurons and plays an essential role in carrying messages. This connection gets disrupted in stress/anxiety or in a depressive situation. Tabernanthalog has been tested in animal models and found that it possesses the capability to recover those damaged connections of brain cells.

Researchers have tested the effect of Tabernanthalog on alcohol intake in animal studies assessed by a 2-bottle choice experiment that mimics drinking behavior in humans and found that this compound plays a role in reducing alcohol intake. Researchers injected Tabernanthalog in mice, and observed that it reduced alcohol intake and preference for at least two days without changing the water intake and total liquid consumption, reflecting an important role of Tabernanthalog on alcohol intake. Similar results have been reported previously for ibogaine, but the side effects of ibogaine limit its use in humans (1).

The animal study was performed to analyze heroin intake and found that Tabernanthalog was able to significantly reduce acute heroin seeking behavior in mice models. Tabernanthalog did not produce side effects of hallucination and locomotor deficits (1).

Forced swim test was another behavioral test used to evaluate the effect of Tabernanthalog on stress levels in mice. Immobility time was increased significantly after 7 days of UMS, and this effect was rescued by a moderate dose 50 mg/kg but not with 10 mg/kg dose of Tabernanthalog. Preliminary data showed that 50 mg/kg dose of Tabernanthalog in animals produced a significant positive response in the brains of mice compared to 10 mg/kg (1).

Researchers have extended the studies to check the efficacy of Tabernanthalog on a wide range of stress tests using animal models. Researchers induced unpredictable mild stress (UMS) to animals, which is the combination of different stressors and attempts to represent real-life stress. After 7 days period of UMS, researchers administered Tabernanthalog and analyzed stress levels, and found that Tabernanthalog reduced stress levels in mice assessed by open arms, elevated plus maze test, in which spending higher times in open arm indicating a higher anxiety level. The outcome observed that Tabernanthalog was found to rescue stress-induced anxiety in rodents (4).

Toxicity studies

Animal studies did not report side effects of Tabernanthalog (3). Researchers tested its toxicity in animal models and found that, unlike ibogaine, Tabernanthalog did not produce any head-twitch response, which is used as a hallucinatory side effect test in rodents (5, 6). Studies reported so far, showed promising results in stress alleviation and restore the changes in the brain that were induced by stress.

Functional reorganization of neurons and structural plasticity in the prefrontal cortex of the brain has been shown to associate with antidepressant like effects of ketamine in mouse models and suggesting to play a critical role in therapeutic effects of 5-HT2A agonists. Compounds that induced hallucinations mainly used the serotonergic system. Activation of serotonin 5-HT2A receptors (HT2ARs) in the prefrontal and limbic cortex is considered the common factor for the production of hallucinations effects (7, 8), suggesting that TBG is not producing hallucinatory side effects.

Human studies

No studies on humans have been reported yet.

Literature references

1. Cameron, L. P., Tombari, R. J., Lu, J., Pell, A. J., Hurley, Z. Q., Ehinger, Y., Vargas, M. V., McCarroll, M. N., Taylor, J. C., Myers-Turnbull, D., Liu, T., Yaghoobi, B., Laskowski, L. J., Anderson, E. I., Zhang, G., Viswanathan, J., Brown, B. M., Tjia, M., Dunlap, L. E., Rabow, Z. T., … Olson, D. E. (2021). A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature, 589(7842), 474–479. https://doi.org/10.1038/s41586-020-3008-z
2. Koenig, X., & Hilber, K. (2015). The anti-addiction drug ibogaine and the heart: a delicate relation. Molecules (Basel, Switzerland), 20(2), 2208–2228. https://doi.org/10.3390/molecules20022208
3. Olson DE. The subjective effects of psychedelics may not be necessary for their enduring therapeutic effects. ACS Pharm Transl Sci. 2020;4:563–7.
4. Lu, J., Tjia, M., Mullen, B., Cao, B., Lukasiewicz, K., Shah-Morales, S., Weiser, S., Cameron, L. P., Olson, D. E., Chen, L., & Zuo, Y. (2021). An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress. Molecular psychiatry, 10.1038/s41380-021-01159-1. Advance online publication. https://doi.org/10.1038/s41380-021-01159-1
5. Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature. 2021;589:474–9.
6. Gonzalez-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, et al. Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron. 2007;53:439–52.
7. Geyer, M. A., & Vollenweider, F. X. (2008). Serotonin research: contributions to understanding psychoses. Trends in pharmacological sciences, 29(9), 445–453. https://doi.org/10.1016/j.tips.2008.06.006
8. Eggers A. E. (2013). A serotonin hypothesis of schizophrenia. Medical hypotheses, 80(6), 791–794. https://doi.org/10.1016/j.mehy.2013.03.013