Ibogalogs, Drug Discovery, and the New Psychedelic Era
/The Past and Present of Psychedelic Medicine
In 1943, the Swiss chemist Albert Hofmann discovered by self-experimentation that LSD had psychedelic (literally, “mind manifesting”) effects. In the following decades, research on psychedelic compounds such as LSD, MDMA, psilocybin, and ibogaine proliferated in the hands of psychiatrists, counterculture academics, and even the CIA. Numerous studies in this era showed great promise for several psychedelic compounds as potential treatments for addiction, depression, and other psychiatric conditions, likely by changing the strength and number of connections between neurons (a process called plasticity). However, research in this area decreased sharply in the latter part of the twentieth century largely due to increasingly stringent restrictions on the use of psychedelic drugs (Doblin et al., 2019).
Now, psychedelic medicine is in its renaissance. In 2017, the FDA expedited clinical review of MDMA for PTSD by designating it as a Breakthrough Therapy, a designation reserved for experimental drugs that are expected to demonstrate substantial improvement over available therapies (Feduccia et al., 2019). In 2020, Oregon became the first state to legalize psilocybin-assisted psychotherapy. As research and therapeutic application of these substances regains traction, the goal is to determine how best to safely and effectively use these substances in a clinical context.
Ibogaine and Ibogalogs
One psychedelic substance which has great therapeutic potential but also unique barriers to clinical translation is ibogaine. Limited studies and anecdotal accounts have indicated that ibogaine is effective for countering opioid withdrawal; however, larger studies have been terminated due to evidence that the drug causes heart problems, such as arrhythmias and cardiotoxicity. Ibogaine is also scarce, as it only naturally occurs in a family of tropical shrubs and is difficult to synthesize.
In 2020, a group of researchers from five universities published a thorough study exploring whether the therapeutic effects of ibogaine could be induced by similar chemicals which are simpler to make in a laboratory and do not cause heart problems (Cameron et al., 2021). They identified three major structural features of the ibogaine molecule, and then they synthesized 15 different molecules (termed “ibogalogs”) which each had two of the three major structural features. They identify two of these ibogalogs – ibogainalog and tabernanthalog – as particularly promising based on their induction of plasticity in cultured neurons and also based on chemical features which tend to be associated with lack of cardiotoxicity.
Ibogainalog and tabernanthalog both seem relatively safe. When the authors exposed zebrafish to either chemical, the fish did not exhibit arrhythmias or developmental issues as was the case with ibogaine. Mice injected with tabernanthalog did not show head twitching behavior, a feature that might indicate that the mice are experiencing hallucinations. The authors also measured tabernanthalog’s tendency to interact with 81 different kinds of receptors in the body, since broad interactions with many kinds of receptors may indicate that a drug will produce undesirable side effects. What they found was that tabernanthalog has a strong preference for interacting with a certain kind of receptor for the neurotransmitter serotonin, which is a brain signaling chemical involved in mood, learning, and other physiological processes. This tendency for tabernanthalog to preferentially interact with serotonin receptors was similar to but a bit stronger than the other hallucinogenic drugs’ preference for serotonin receptors, which bodes well for the specificity of tabernanthalog.
After showing the safety of their “ibogalogs”, the authors transition to assessing whether tabernanthalog in particular might actually be effective for treating depression and addiction like ibogaine. For this, the authors used a variety of mouse behavioral tests. Mice injected with tabernanthalog showed reduced depressive-like behavior, alcohol binge drinking, and heroin-seeking behavior. Taken together with the safety experiments, this suggests that tabernanthalog could potentially have similar therapeutic effects to ibogaine but with fewer adverse side effects.
Looking Ahead
The drug discovery approach of starting from a molecule (e.g., ibogaine) and borrowing its structural features to identify potentially more suitable drugs (e.g., tabernanthalog) does have drawbacks. Many psychedelic drugs (and other psychiatric medications) are molecularly promiscuous, interacting with many molecules in the body and thus causing many side effects. While tabernanthalog does preferentially interact with serotonin receptors, it also still interacts at a lower level with a number of other random receptors in the body. Other researchers have alternatively tried creating new drugs solely based on how well they interact with receptors of interest in the body (rather than starting from some other drug, like ibogaine) and have produced more specific drugs than tabernanthalog this way (Roth et al., 2017). Moreover, seeking to capture the desired behavioral effects of a particular drug with a new drug requires a good way of measuring behavioral effects, and some researchers argue that rodent behavioral experiments may be too oversimplified as a model of human behaviors and psychiatric illness.
Even so, the ibagolog study did succeed in identifying intriguing and safer ibogaine alternatives. One could imagine the same approach being applied to other psychedelic substances which either have concerning side effect profiles (e.g., MDMA’s neurotoxic effects) or are naturally scarce (e.g., mescaline, a cactus-derived hallucinogen). Innovative approaches like those used in this paper could potentially mitigate some of the biggest criticisms of psychedelic medicine and provide a path toward more effective treatments for addiction and depression.
Edited by Arielle Keller
Works Cited
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., et al. (2021). A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature.
Doblin, R.E., Christiansen, M., Jerome, L., and Burge, B. (2019). The Past and Future of Psychedelic Science: An Introduction to This Issue. J. Psychoactive Drugs.
Feduccia, A.A., Jerome, L., Yazar-Klosinski, B., Emerson, A., Mithoefer, M.C., and Doblin, R. (2019). Breakthrough for trauma treatment: Safety and efficacy of MDMA-assisted psychotherapy compared to paroxetine and sertraline. Front. Psychiatry.
Roth, B.L., Irwin, J.J., and Shoichet, B.K. (2017). Discovery of new GPCR ligands to illuminate new biology. Nat. Chem. Biol.
