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) via PubMed
Summary
AI-generated from the abstractNonhallucinogenic psychoplastogens like tabernanthalog (TBG) promote cortical neuroplasticity through the same biochemical pathway as classic psychedelics—involving 5-HT2A, TrkB, mTOR, and AMPA receptor activation—but without inducing an immediate glutamate burst or immediate early gene activation. TBG-induced cortical spinogenesis is required for its sustained antidepressant-like behavioral effect in rodents. These findings clarify how certain psychoplastogens can produce neuroplasticity without hallucinogenic effects, challenging assumptions that glutamate burst and IEG activation are necessary for psychedelic-induced neuroplasticity.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Rodents |
| Intervention | Tabernanthalog (TBG) |
| Key finding | 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.