Journal Article

A non-hallucinogenic psychedelic analogue with therapeutic potential

Dunlap, Lee E., Peters, Jamie, Pell, Alexander J., Olson, David E., Vargas, Maxemiliano V., McCarroll, Matthew N., Liu, Taohui, Hurley, Zefan Q., Anderson, Emilie I., Zuo, Yi, Cameron, Lindsay P., Taylor, Jack C., Lein, Pamela J., Wulff, Heike, Tjia, Michelle, Viswanathan, Jayashri, Zhang, Guoliang, Ron, Dorit, Myers-Turnbull, Douglas, Fiehn, Oliver, McCorvy, John D., Tombari, Robert J., Brown, Brandon M., Yaghoobi, Bianca, Kokel, David, Rabow, Zachary T., Ehinger, Yann, Laskowski, Lauren J., Lu, Ju

2021

Overview

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals 1 . Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine—like those of other psychedelic compounds—are long-lasting 2 , which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling 3 , 4 . However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog—a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential. Psychedelic alkaloids served as lead structures for the development of tabernanthalog, a non-hallucinogenic and non-toxic analogue that reduces alcohol- and heroin-seeking behaviour and produces antidepressant-like effects in rodents.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 14/34 / 14/69 / 631/154/309 / 631/154/436 / 631/378 / 639/638/92/436 / 64/60 / Addictions / Alcohol / Alcoholism - drug therapy / Analysis / Animals / Antidepressants / Antidepressive Agents - pharmacology / Arrhythmias, Cardiac - chemically induced / Behavior, Addictive - drug therapy / Cardiac arrhythmia / Chemical properties / Chemistry Techniques, Synthetic / Circuits / Depression - drug therapy / Design modifications / Designer drugs / Detoxification (Substance abuse treatment) / Disease Models, Animal / Drug abuse / Drug Design / Female / Hallucinations / Hallucinogens / Hallucinogens - adverse effects / Heroin / Heroin Dependence - drug therapy / Humanities and Social Sciences / Ibogaine / Ibogaine - adverse effects / Ibogaine - analogs & derivatives / LSD / Lysergic acid diethylamide / Male / Methods / Mice / Mice, Inbred C57BL / multidisciplinary / Narcotics / Neural networks / Neuronal Plasticity - drug effects / Neuroplasticity / Neurotrophic factors / Opioids / Patient Safety / Psychedelic drugs / Receptor, Serotonin, 5-HT2A - metabolism / Safety and security measures / Science / Science (multidisciplinary) / Serotonin 5-HT2 Receptor Agonists - pharmacology / Structural members / Substance use / Substance-Related Disorders - drug therapy / Swimming / Tabernaemontana - chemistry / Toxicity