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Cited by 473Psychedelics and Drug StudiesAlkaloids: synthesis and pharmacologySynthesis and bioactivity of alkaloids

A non-hallucinogenic psychedelic analogue with therapeutic potential

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Cameron, Lindsay P., Tombari, Robert J., Lu, Ju, Pell, Alexander J., Hurley, Zefan Q., Ehinger, Yann, Vargas, Maxemiliano V., McCarroll, Matthew N. +21 more·2021·Nature
DOI 10.1038/s41586-020-3008-zPMC PMC7874389
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Abstract

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.

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Crossref · 10.1038/s41586-020-3008-z

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  • AAZ and TBG have demonstrated robust plasticity-promoting properties.

    “Our two most advanced compounds—AAZ and TBG—have demonstrated robust plasticity-promoting properties”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [250]

    The ‘Effect of TBG on Neural Plasticity’ section reports increased dendritic complexity and spine density in cultured neurons, as well as increased spine formation in mice. Our copy does not identify AAZ or establish its plasticity-promoting properties (searched: AAZ), so it supports the claim for TBG only. The supplied passages have no page numbers. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • We engineered several non-hallucinogenic analogs of psychedelics with beneficial properties.

    “we were able to engineer several non-hallucinogenic analogs of psychedelics with beneficial properties”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [250]

    The Abstract reports that the authors engineered TBG, a non-hallucinogenic ibogaine analog with beneficial effects in rodents. But the section “TBG is a Safer, Non-Hallucinogenic 5-HT2A Agonist” says the other tested analog, IBG, had reduced hallucinogenic potential, while TBG was devoid of it in the head-twitch assay. The copy therefore supports one non-hallucinogenic analog with beneficial properties, not several. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • AAZ and TBG produce sustained (>1 week) antidepressant-like effects following a single administration in both environmental (chronic unpredictable stress) and genetic (VMAT2 heterozygous mice) models of depression as measured via behavioral tests relevant to motivation, anhedonia, anxiety, and cognitive flexibility.

    “produce sustained (>1 week) antidepressant-like effects following a single administration in both environmental (chronic unpredictable stress) and genetic (VMAT2 heterozygous mice) models of depression as measured via behavioral tests relevant to motivation, anhedonia, anxiety, and cognitive flexibility”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [250]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • The psychoplastogenic effects of TBG and AAZ may involve activation of 5-HT2 receptors.

    “The psychoplastogenic effects of TBG and AAZ may involve activation of 5-HT2 receptors”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [250]

    The ‘Effect of TBG on Neural Plasticity’ section reports that TBG increased dendritic arbor complexity and that a 5-HT2A antagonist blocked this effect, supporting the proposed receptor involvement for TBG. The passages from our copy do not establish the corresponding claim for AAZ. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Non-hallucinogenic psychoplastogens, like their hallucinogenic counterparts, produce sustained therapeutic behavioral responses in preclinical animal models after a single administration.

    “non-hallucinogenic psychoplastogens, like their hallucinogenic counterparts, produce sustained therapeutic behavioral responses in preclinical animal models after a single administration”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [250]

    The section ‘Effect of TBG on Alcohol- and Heroin-Seeking Behavior’ reports that a single administration of the non-hallucinogenic compound TBG reduced cue-induced heroin seeking in rats for up to 12–14 days. That supports a sustained behavioral effect in a preclinical model, but the paper does not establish the claim for non-hallucinogenic psychoplastogens as a class or show the same single-dose animal-model result for their hallucinogenic counterparts. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cites

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Cited by

Sorted by citations

Authors
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., Fiehn, O., Wulff, H., McCorvy, J. D., Lein, P. J., Kokel, D., Ron, D., Peters, J., Zuo, Y., & Olson, D. E.
Affiliations
  • University of California, Davis (US)
  • University of California, Santa Cruz (US)
  • University of California, San Francisco (US)
  • Medical College of Wisconsin (US)
  • University of Colorado Anschutz (US)
Corresponding author
Olson, David E.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-12-09
Volume
589
Issue
7842
Pages
474-479
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-020-3008-z
PMC
PMC7874389
OpenAlex
W3112535936
Cited by
473
References
4
Citations by year
2026: 70 · 2025: 101 · 2024: 108 · 2023: 93 · 2022: 54 · 2021: 41 · 2020: 5
FWCI
19.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • MIND Institute, University of California, Davis (U54 HD 079125, HD079125)
  • Nature
  • National Institutes of Health (4T32 GM6754714, R37 AA01684, TR001860, UL1TR001860, TL1TR001861)
  • Genentech
  • University of California, Davis (T32GM113770, UL1 TR001860, U54 HD079125, 5T32GM099608)
  • National Institute on Alcohol Abuse and Alcoholism (R01AA022583, R37AA016848)
  • National Institute on Aging (UH3AG064706, U19AG023122)
  • National Institute of Mental Health (R01MH109475, R01MH104227, T32MH112507)
  • National Institute on Drug Abuse (R01DA045836)
  • National Institute of General Medical Sciences (T32GM099608, T32GM113770, R01GM128997)
  • National Institute of Neurological Disorders and Stroke (R01NS104950)
  • National Center for Research Resources (S10RR019266)
  • National Center for Advancing Translational Sciences (TR001860, TR001861)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD079125, P50HD103526, P30HD003352)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Synthesis and bioactivity of alkaloids
Keywords
ibogaine, addiction treatment, substance use disorders, antidepressant-like effects, pharmacophore design, cardiac arrhythmias
MeSH terms
Alcoholism, Animals, Antidepressive Agents, Arrhythmias, Cardiac, Depression, Disease Models, Animal, Female, Hallucinogens, Heroin Dependence, Ibogaine, Male, Mice, Inbred C57BL, Neuronal Plasticity, Swimming, Drug Design, Behavior, Addictive, Substance-Related Disorders, Tabernaemontana, Receptor, Serotonin, 5-HT2A, Mice, Serotonin 5-HT2 Receptor Agonists, Chemistry Techniques, Synthetic, Patient Safety

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