The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation.
Isak K Aarrestad, Lindsay P. Cameron, Ethan M Fenton, Austen B Casey, Daniel R Rijsketic, Seona D Patel, Rohini Sambyal, Shane B Johnson, Calvin Ly, Jayashri Viswanathan, Eden V Barragan, Stephanie A Lozano, Nicolas Seban, Hongru Hu, Noel A Powell, Milan Chytil, Retsina Meyer, David Rose, Chris Hempel, Eric Olson, Hanne D. Hansen, Clara A Madsen, Gitte M. Knudsen, Chase Redd, Damian G Wheeler, Nathaniel Guanzon, Jessie Muir, Joseph J. Hennessey, Gerald Quon, John D. Mccorvy, Sunil P Gandhi, Kurt Rasmussen, Conor Liston, John A Gray, Boris D. Heifets, Alex S Nord, Christina K Kim, David E. Olson
Nature Neuroscience September 1, 2025 DOI: 10.1038/s41593-025-02021-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Rodents |
| Intervention | Tabernanthalog (TBG) |
| Topics | Neuroplasticity |
| Key points | Nonhallucinogenic psychoplastogens promote cortical neuroplasticity through the same biochemical pathway as classic psychedelics but without glutamate burst or immediate early gene activation, and TBG-induced spinogenesis is required for sustained antidepressant-like effects. |
Abstract
Nonhallucinogenic psychoplastogens, such as tabernanthalog (TBG), are being developed as potentially safer, more scalable alternatives to psychedelics for promoting neuronal growth and treating various brain conditions. Currently, it is unclear whether 5-hydroxytryptamine 2A (5-HT2A) receptors and immediate early gene (IEG) activation have a role in the neuroplasticity-promoting effects of nonhallucinogenic psychoplastogens. Here, we use pharmacological and genetic tools in rodents to show that nonhallucinogenic psychoplastogens promote cortical neuroplasticity through the same biochemical pathway-involving 5-HT2A, TrkB, mTOR and AMPA receptor activation-as classic psychedelics and that TBG-induced cortical spinogenesis is required for the sustained antidepressant-like behavioral effect of TBG. In contrast to psychedelics, TBG does not induce an immediate glutamate burst or IEG activation. As these effects have been assumed to be necessary for psychedelic-induced neuroplasticity, our results shed light on the mechanisms by which certain psychoplastogens can promote cortical neuroplasticity in the absence of hallucinogenic effects.
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cited by 20
- Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics ACS Chemical Neuroscience October 13, 2025
- Ibogalogs improve spatial and recognition memory in rodents through a mechanism involving 5-HT2A receptor activation-enhanced NMDA receptor activity in hippocampal pyramidal CA1 neurons Biomedicine & Pharmacotherapy November 13, 2025
- Psilocybin as a fast-acting and long-lasting antidepressant for adolescence: Proposing NeuroD1 as a biomarker of its long-term plasticity Biomedicine & Pharmacotherapy October 30, 2025
- Pathway-selective signaling of serotonergic psychedelics at 5-HT receptors: Implications for psychoactivity, safety, and therapeutic potential European Neuropsychopharmacology April 10, 2026
- Zalsupindole: A Non-Hallucinogenic Psychoplastogen Advancing Psychedelic-Inspired Therapeutics. ACS Chemical Neuroscience January 21, 2026
and 15 more in the library
Cites 57
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and 52 more in the library