A non-hallucinogenic psychedelic analogue with therapeutic potential
This paper describes an analogue to ibogaine (tabernanthalog) with similar therapeutic potential that is non-toxic, and non-psychedelic.
Authors
- David Olson
- John McCorvy
- Lindsay Cameron
Published
Abstract
The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals. 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, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling. 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.
Research Summary of 'A non-hallucinogenic psychedelic analogue with therapeutic potential'
Introduction
Cameron and colleagues situate their work in the context of ibogaine, a psychedelic alkaloid with reported anti-addictive properties across multiple substances but with serious safety drawbacks including cardiotoxicity, long-lasting hallucinations and limited synthetic accessibility. Previous studies have implicated neurotrophic signalling and structural neural plasticity—for example, increases in GDNF and effects on BDNF signalling—as potential mechanisms that could explain ibogaine's enduring behavioural effects after single administrations. However, clinical development has been impeded by ibogaine's high lipophilicity, hERG channel inhibition, long and low-yield syntheses, and hallucinogenic profile. To address these problems the researchers applied function-oriented synthesis to identify the minimal psychoplastogenic pharmacophore of ibogaine and to design simplified analogues that retain therapeutic effects while reducing toxicity and hallucinogenic potential. Their primary aim was to produce water-soluble, non-hallucinogenic, synthetically tractable analogues, prioritising compounds that promote structural neural plasticity and that reduce drug-seeking and depressive-like behaviours in rodent models. The study therefore combines chemical design, in vitro and in vivo neuroplasticity assays, receptor profiling, safety pharmacology and behavioural models of addiction and depression to evaluate candidate analogues, notably IBG and tabernanthalog (TBG).
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Study Details
- Study Typeindividual
- Journal
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- APA Citation
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., . . . 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
References (9)
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