OPEN Foundation

G. Zhang

A non-hallucinogenic psychedelic analogue with therapeutic potential


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.

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., Rabow, Z. T., … Olson, D. E. (2021). A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature, 589(7842), 474–479.

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Effect of a Hallucinogenic Serotonin 5-HT2A Receptor Agonist on Visually-Guided, Hippocampal-Dependent Spatial Cognition in C57BL/6J Mice


By acting on serotonin 5-HT2A receptors (5-HT2ARs), serotonergic psychedelic drugs induce perceptual and visual hallucinations by increasing neuronal excitability and altering visual-evoked neuronal responses. The present study was designed to examine whether the perceptual alterations induced by a serotonergic psychedelic drug would affect the integrity of hippocampal-dependent, visually guided spatial cognition. phenylalkylamine hallucinogen TCB-2 is a selective agonist of 5-HT2ARs. Mice received TCB-2 (1.0 mg kg−1, i.p.), and spatial behaviors and hippocampal electrophysiological responses were measured with water maze tasks and in vivosingle-unit recording, respectively. TCB-2 did not affect visual cue approach behavior in the visible platform water maze, but increased the latency of trained mice to initiate goal-directed swimming during a probe test in the hidden platform Morris water maze, which could be prevented by 5-HT2AR antagonist MDL 11,939. Interestingly, TCB-2 did not affect the efficiency of the swim path or the proper use of distal visual cues during the probe test. Hippocampal place cell activity is considered to represent spatial and context-specific episodic memory. Systemic TCB-2 did not affect previously established place fields of CA1 neurons in mice exploring a familiar environment, or the remapping of place cells when the mice explored a novel environment. However, TCB-2 impaired the long-term stability of place fields for the novel environment initially encoded under the influence of TCB-2, which could be prevented by 5-HT2AR antagonist MDL 11,939. Our data indicate that hallucinogenic 5-HT2AR agonist delays the initiation of spatial search behavior, but does not impair the use of visual cues to guide goal-directed spatial behavior. Moreover, activation of 5-HT2ARs does not impair the coding and retrieval of spatial information, but impairs the long-term stability of new formed place fields of CA1 neurons.

Zhang, G., Cinalli, D., & Stackman, R. W. (2017). Effect of a hallucinogenic serotonin 5‐HT2A receptor agonist on visually guided, hippocampal‐dependent spatial cognition in C57BL/6J mice. Hippocampus. 10.1002/hipo.22712
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4 October - Online psychedelic Q&A with Rick Doblin (founder and president of MAPS)