A non-hallucinogenic psychedelic analogue with therapeutic potential

Lindsay P. Cameron, Robert J. Tombari, Ju Lu, Alexander J. Pell, Zefan Q. Hurley, Yann Ehinger, Maxemiliano V. Vargas, Matthew N. McCarroll, Jack C. Taylor, Douglas Myers-Turnbull, Taohui Liu, Bianca Yaghoobi, Lauren J. Laskowski, Emilie I. Anderson, Guoliang Zhang, Jayashri Viswanathan, Brandon M. Brown, Michelle Tjia, Lee E. Dunlap, Zachary T. Rabow, Oliver Fiehn, Heike Wulff, John D. McCorvy, Pamela J. Lein, David Kokel, Dorit Ron, Jamie Peters, Yi Zuo and David E. Olson ()
Additional contact information
Lindsay P. Cameron: University of California, Davis
Robert J. Tombari: University of California, Davis
Ju Lu: University of California, Santa Cruz
Alexander J. Pell: University of California, Davis
Zefan Q. Hurley: University of California, Davis
Yann Ehinger: University of California, San Francisco
Maxemiliano V. Vargas: University of California, Davis
Matthew N. McCarroll: University of California, San Francisco
Jack C. Taylor: University of California, San Francisco
Douglas Myers-Turnbull: University of California, San Francisco
Taohui Liu: University of California, Santa Cruz
Bianca Yaghoobi: University of California, Davis
Lauren J. Laskowski: and Anatomy, Medical College of Wisconsin
Emilie I. Anderson: and Anatomy, Medical College of Wisconsin
Guoliang Zhang: University of California, Davis
Jayashri Viswanathan: University of California, Davis
Brandon M. Brown: University of California, Davis
Michelle Tjia: University of California, Santa Cruz
Lee E. Dunlap: University of California, Davis
Zachary T. Rabow: University of California, Davis
Oliver Fiehn: University of California, Davis
Heike Wulff: University of California, Davis
John D. McCorvy: and Anatomy, Medical College of Wisconsin
Pamela J. Lein: University of California, Davis
David Kokel: University of California, San Francisco
Dorit Ron: University of California, San Francisco
Jamie Peters: University of Colorado Denver, Anschutz Medical Campus
Yi Zuo: University of California, Santa Cruz
David E. Olson: University of California, Davis

Nature, 2021, vol. 589, issue 7842, 474-479

Abstract: Abstract The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. 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-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. 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.

Date: 2021
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DOI: 10.1038/s41586-020-3008-z

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