The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation

This rodent study found that the nonhallucinogenic psychoplastogen tabernanthalog (TBG) promotes cortical neuroplasticity and sustained antidepressant effects through the same 5-HT2A, TrkB, mTOR, and AMPA receptor pathway as psychedelics, but without inducing the immediate glutamate burst or immediate early gene activation previously thought necessary for psychedelic-induced neuroplasticity.

Abstract of The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation

“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.”

Authors: 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

Summary of The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation

Aarrestad and colleagues begin by framing their research in the context of mental health conditions such as depression, post-traumatic stress disorder, and addiction. These illnesses are often linked to cortical atrophy and impaired brain plasticity. Brain plasticity refers to the nervous system’s capacity to modify its structure and function by forming new synaptic connections. Classic psychedelics such as LSD, psilocybin, and DMT have shown strong ability to enhance this form of growth, leading to long-lasting behavioural improvements. However, their hallucinogenic properties and social stigma make them challenging to deploy as medicines.

The authors highlight that ketamine, a non-psychedelic psychoplastogen, also produces rapid and durable antidepressant-like effects. Its clinical use, however, is limited by issues of safety, dissociation, and abuse potential. This has prompted the search for nonhallucinogenic psychoplastogens that preserve beneficial effects on neuroplasticity. Tabernanthalog (TBG), a synthetic analogue of ibogaine, emerged as a promising candidate. Early studies in rodents suggested that it stimulates dendritic spine growth in the prefrontal cortex and alleviates behaviours linked to depression and addiction, without signs of hallucinations.

The central question of the present study is whether TBG achieves its plasticity-promoting effects through the same receptor systems and molecular pathways as classical psychedelics. The focus is on the serotonin 2A receptor (5-HT2AR), widely regarded as the primary target for psychedelic experiences. While 5-HT2ARs are clearly essential for hallucinations, their role in neuroplasticity has been debated. Aarrestad and colleagues therefore set out to test whether TBG requires 5-HT2ARs to induce cortical plasticity, and whether this happens independently of typical hallmarks of psychedelics, such as bursts of glutamate release and activation of immediate early genes (IEGs).

Methods

To access this content, you must purchase one of the following memberships: Pro Membership, Pro Membership Unlimited, Business Membership or Business Membership Unlimited. The membership will give you access to exclusive data, including summaries of psychedelic research papers, extended company info, and our member-only visualisations. Save yourself multiple hours each week by accessing Blossom’s resource library.

Find this paper

The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation

https://doi.org/10.1038/s41593-025-02021-1

Paywall | Google Scholar | Backup | 🕊

Cite this paper (APA)

Aarrestad, I. K., Cameron, L. P., Fenton, E. M., Casey, A. B., Rijsketic, D. R., Patel, S. D., ... & Olson, D. E. (2025). The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation. Nature Neuroscience, 1-13.

Study details

Compounds studied
Ibogaine

Topics studied
Neuroscience

Study characteristics
Animal Study Bio/Neuro