{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T10:22:19Z","timestamp":1792059739052,"version":"4.4.0"},"reference-count":23,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Current Research Funds 2026","doi-asserted-by":"publisher","award":["RRC-2026-23688274"],"award-info":[{"award-number":["RRC-2026-23688274"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministry of Health, Italy","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The clinical renaissance of psychedelic medicine has highlighted the therapeutic potential of rapid-acting neuroplastogens, or \u201cpsychoplastogens,\u201d for psychiatric disorders. However, the widespread application of classical psychedelics\u2014such as psilocybin and LSD\u2014and the atypical dissociative ibogaine is severely limited by their hallucinogenic properties and, particularly in the case of ibogaine, life-threatening cardiotoxicity. Addressing these limitations, Tabernanthalog (TBG) has emerged as a frontrunner in the field. This non-hallucinogenic analog of ibogaine was rationally designed to eliminate interactions with the human ether-\u00e0-go-go-related gene (hERG, KCNH2) potassium channel, thereby mitigating cardiotoxic risks. While initially characterized for its anti-addictive and antidepressant-like properties, recent data from 2024\u20132025 have significantly expanded its therapeutic horizon. TBG demonstrates robust efficacy in preclinical models of neuropathic and visceral pain, as well as in the rescue of cognitive deficits associated with cancer-related cognitive impairment (CRCI). TBG has shown efficacy in reversing cognitive impairments induced directly by the presence of a tumor in preclinical models, rather than by chemotherapy-specific neurotoxicity. Crucially, emerging evidence suggests that TBG\u2019s mechanism extends beyond simple 5-HT2A receptor agonism. New findings point to a multi-target profile involving the inhibition of nicotinic acetylcholine receptors (nAChRs), positive modulation of NMDA receptors, and functional crosstalk with mGlu2 receptors. Furthermore, TBG appears to induce structural neuroplasticity without the widespread induction of immediate early genes (IEGs) seen with classical hallucinogens, suggesting a decoupling of therapeutic rewiring from the subjective psychedelic experience. This review synthesizes current preclinical evidence to discuss TBG as a promising chemical scaffold for next-generation neurotherapeutics targeting the intersection of psychiatry and neurology.<\/jats:p>","DOI":"10.3390\/ijms27062811","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T09:44:41Z","timestamp":1773999881000},"page":"2811","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Beyond the Genomic Storm: Evaluating Tabernanthalog as a Potential Scaffold for Silent Neuroplasticity and Broad-Spectrum Therapy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0215-2174","authenticated-orcid":false,"given":"Ivan","family":"Anchesi","sequence":"first","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3999-0286","authenticated-orcid":false,"given":"Ivana","family":"Raffaele","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7882-2432","authenticated-orcid":false,"given":"Maria Francesca","family":"Astorino","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morpho Functional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3694-5287","authenticated-orcid":false,"given":"Maria","family":"Lui","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2082-9855","authenticated-orcid":false,"given":"Marco","family":"Calabr\u00f2","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morpho Functional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0823-1455","authenticated-orcid":false,"given":"Giovanni Luca","family":"Cipriano","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gao, K., Oruc, E.B., and Koparal, B. (2025). Pharmacological Monotherapy for Depressive Disorders: Current and Future-A Narrative Review. Medicina, 61.","DOI":"10.3390\/medicina61040558"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1007\/s10571-021-01064-9","article-title":"The Roles of Serotonin in Neuropsychiatric Disorders","volume":"42","author":"Pourhamzeh","year":"2022","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"de Vos, C.M.H., Mason, N.L., and Kuypers, K.P.C. (2021). Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. Front. Psychiatry, 12.","DOI":"10.3389\/fpsyt.2021.724606"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"26331055211033847","DOI":"10.1177\/26331055211033847","article-title":"Engineering Safer Psychedelics for Treating Addiction","volume":"16","author":"Peters","year":"2021","journal-title":"Neurosci. Insights"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1126\/science.adf0435","article-title":"Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors","volume":"379","author":"Vargas","year":"2023","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1089\/psymed.2023.0009","article-title":"Tabernanthalog Reduces Motivation for Heroin and Alcohol in a Polydrug Use Model","volume":"1","author":"Heinsbroek","year":"2023","journal-title":"Psychedelic Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6237","DOI":"10.1038\/s41380-021-01159-1","article-title":"An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress","volume":"26","author":"Lu","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"116183","DOI":"10.1016\/j.bcp.2024.116183","article-title":"Tabernanthalog and ibogainalog inhibit the \u03b17 and \u03b19\u03b110 nicotinic acetylcholine receptors via different mechanisms and with higher potency than the GABA(A) receptor and Ca(V)2.2 channel","volume":"223","author":"Tae","year":"2024","journal-title":"Biochem. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"117887","DOI":"10.1016\/j.biopha.2025.117887","article-title":"Ibogalogs decrease neuropathic pain in mice through a mechanism involving crosstalk between 5-HT(2A) and mGlu(2) receptors","volume":"184","author":"Arias","year":"2025","journal-title":"Biomed. Pharmacother. Biomed. Pharmacother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"118742","DOI":"10.1016\/j.biopha.2025.118742","article-title":"Ibogalogs improve spatial and recognition memory in rodents through a mechanism involving 5-HT(2A) receptor activation-enhanced NMDA receptor activity in hippocampal pyramidal CA1 neurons","volume":"193","author":"Chagraoui","year":"2025","journal-title":"Biomed. Pharmacother. Biomed. Pharmacother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"116867","DOI":"10.1016\/j.biopha.2024.116867","article-title":"Non-hallucinogenic compounds derived from iboga alkaloids alleviate neuropathic and visceral pain in mice through a mechanism involving 5-HT(2A) receptor activation","volume":"177","author":"Arias","year":"2024","journal-title":"Biomed. Pharmacother. Biomed. Pharmacother."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Arinaga, M., Yamada, J., Maeda, S., Okamura, A., Oshima, Y., Zhang, L., Han, Y., Iinuma, K.M., and Jinno, S. (2025). Tabernanthalog, a Non-Hallucinogenic Psychedelic, Alleviates Cancer-Induced Cognitive Deficits via Serotonergic Pathways. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26157519"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1038\/s41593-025-02021-1","article-title":"The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation","volume":"28","author":"Aarrestad","year":"2025","journal-title":"Nat. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1177\/02698811231200882","article-title":"Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview","volume":"37","author":"Ona","year":"2023","journal-title":"J. Psychopharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/j.1369-1600.2012.00447.x","article-title":"Anti-addiction drug ibogaine inhibits hERG channels: A cardiac arrhythmia risk","volume":"19","author":"Koenig","year":"2014","journal-title":"Addict. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/s41586-020-3008-z","article-title":"A non-hallucinogenic psychedelic analogue with therapeutic potential","volume":"589","author":"Cameron","year":"2021","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1007\/s00213-013-3006-z","article-title":"Characterization of the head-twitch response induced by hallucinogens in mice: Detection of the behavior based on the dynamics of head movement","volume":"227","author":"Halberstadt","year":"2013","journal-title":"Psychopharmacology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"113612","DOI":"10.1016\/j.biopha.2022.113612","article-title":"Serotonin 5-HT(2A), 5-HT(2c) and 5-HT(1A) receptor involvement in the acute effects of psilocybin in mice. In vitro pharmacological profile and modulation of thermoregulation and head-twich response","volume":"154","author":"Horrillo","year":"2022","journal-title":"Biomed. Pharmacother. Biomed. Pharmacother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1038\/s41593-023-01316-5","article-title":"Psychedelics promote plasticity by directly binding to BDNF receptor TrkB","volume":"26","author":"Moliner","year":"2023","journal-title":"Nat. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lerer, E., Botvinnik, A., Shahar, O., Grad, M., Blakolmer, K., Shomron, N., Lotan, A., Lerer, B., and Lifschytz, T. (2024). Effects of psilocybin, psychedelic mushroom extract and 5-hydroxytryptophan on brain immediate early gene expression: Interaction with serotonergic receptor modulators. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1391412"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1021\/acschemneuro.5c00707","article-title":"Zalsupindole: A Non-Hallucinogenic Psychoplastogen Advancing Psychedelic-Inspired Therapeutics","volume":"17","author":"Salfiti","year":"2026","journal-title":"ACS Chem. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4388","DOI":"10.1021\/acschemneuro.5c00667","article-title":"Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics","volume":"16","author":"Agrawal","year":"2025","journal-title":"ACS Chem. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2836","DOI":"10.1161\/01.CIR.102.23.2836","article-title":"Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications","volume":"102","author":"Rothman","year":"2000","journal-title":"Circulation"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2811\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T05:12:54Z","timestamp":1774156374000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2811"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,20]]},"references-count":23,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062811"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062811","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,20]]}}}