Faculty Collaboration Database

A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021 Jan;589(7842):474-479

Date

12/11/2020

Pubmed ID

33299186

Pubmed Central ID

PMC7874389

DOI

10.1038/s41586-020-3008-z

Scopus ID

2-s2.0-85097312071 (requires institutional sign-in at Scopus site)   188 Citations

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 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.

Author List

Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, Vargas MV, McCarroll MN, Taylor JC, Myers-Turnbull D, Liu T, Yaghoobi B, Laskowski LJ, Anderson EI, Zhang G, Viswanathan J, Brown BM, Tjia M, Dunlap LE, Rabow ZT, Fiehn O, Wulff H, McCorvy JD, Lein PJ, Kokel D, Ron D, Peters J, Zuo Y, Olson DE

Author

John McCorvy PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alcoholism
Animals
Antidepressive Agents
Arrhythmias, Cardiac
Behavior, Addictive
Chemistry Techniques, Synthetic
Depression
Disease Models, Animal
Drug Design
Female
Hallucinogens
Heroin Dependence
Ibogaine
Male
Mice
Mice, Inbred C57BL
Neuronal Plasticity
Patient Safety
Receptor, Serotonin, 5-HT2A
Serotonin 5-HT2 Receptor Agonists
Substance-Related Disorders
Swimming
Tabernaemontana