Non-hallucinogenic psychedelic analog boosts brain plasticity in an unexpected way

New research published in Nature Neuroscience provides evidence that a non-hallucinogenic analog of psychedelic drugs can stimulate brain cell growth through the same molecular pathway as traditional psychedelics—but without the need for gene activation typically thought to be part of the process. The study focused on tabernanthalog (TBG), a compound structurally related to serotonergic psychedelics such as psilocybin and 5-MeO-DMT.

Psychoplastogens are a class of small molecules that rapidly enhance brain plasticity and may provide long-lasting relief from conditions such as depression, post-traumatic stress disorder, and addiction. Classic psychedelics like LSD and psilocybin are among the most potent psychoplastogens known, and they are currently being explored for therapeutic use. However, their hallucinogenic properties raise concerns about safety and accessibility.

TBG and similar compounds have been developed as alternatives that might deliver the therapeutic benefits of psychedelics without inducing hallucinations. Yet, the exact molecular mechanisms underlying their action remained unclear. In particular, it was unknown whether TBG promotes cortical neuroplasticity by engaging the same brain receptors and signaling pathways as hallucinogens, or whether it operates through a distinct route.

Previous studies suggested that activation of serotonin 2A receptors (5-HT2A) is necessary for the psychedelic experience, but the role of these receptors in promoting plasticity was still debated. Some research proposed that other proteins, like the brain-derived neurotrophic factor receptor TrkB, might play a larger role in the therapeutic effects. The new study sought to directly test whether TBG engages 5-HT2A receptors and whether it could promote brain changes independently of hallucinatory side effects.

“By better understanding the mechanisms of non-hallucinogenic psychedelic analogues like TBG, we hope to create safer, more scalable neurotherapeutics that can help a larger number of people,” said study author David E. Olson, the director of the UC Davis Institute for Psychedelics and Neurotherapeutics.

To explore these questions, the researchers used a wide range of experimental approaches. They began by assessing how TBG binds to various serotonin receptors in cell-based assays. They found that TBG functions as a partial agonist of 5-HT2A receptors, meaning it activates the receptor but to a lesser degree than full psychedelic compounds.

Next, they examined whether 5-HT2A activation was required for TBG’s effects on brain structure and behavior. In both wild-type and genetically modified mice that lack the 5-HT2A receptor, they assessed the growth of dendritic spines—small protrusions on neurons associated with synaptic plasticity.

After administering TBG, they observed increased spine density and synaptic activity in the prefrontal cortex of normal mice, but not in those without the receptor. Behavioral tests, such as the tail suspension test commonly used to evaluate antidepressant effects, showed that TBG reduced immobility time in normal mice but had no effect in receptor knockout animals.

To determine whether the growth of new dendritic spines was required for TBG’s antidepressant-like effects, the researchers used an innovative light-based method to selectively remove newly formed spines after TBG administration. Mice that underwent this targeted photoablation no longer showed the behavioral benefits of TBG, indicating that the structural changes in the brain were necessary for its lasting effects.

The study also investigated whether TBG and psychedelics activate similar signaling pathways. They compared the effects of TBG with those of compounds like LSD and 5-MeO-DMT across multiple assays. All of the tested compounds increased dendritic complexity and required activation of the same downstream signaling cascade, involving the mTOR pathway, TrkB receptors, and AMPA receptors. These pathways are known to regulate protein synthesis and support structural plasticity in the brain.

However, there was a key difference. Classic psychedelics trigger a burst of glutamate—a neurotransmitter linked to excitatory signaling—and strongly increase the expression of immediate early genes (IEGs), which are associated with neuronal activation and plasticity. Using advanced imaging techniques, such as light-sheet microscopy and single-nucleus RNA sequencing, the researchers showed that TBG did not significantly elevate glutamate levels or induce IEG expression. Despite this, it still promoted the same degree of spine growth and behavioral improvement, suggesting that these molecular events may not be required for therapeutic plasticity.

“I was surprised that the neuroplasticity-promoting effects of TBG did not depend on a glutamate burst, as this has been assumed to be critical for psychedelic-induced neuroplasticity,” Olson told PsyPost.

To confirm this dissociation, they examined the effects of TBG in other animal models. In pigs, TBG occupied a substantial portion of 5-HT2A receptors in the brain without triggering the behavioral markers of hallucinogenic activity, such as head shakes or scratching. In mice, TBG was even able to block the head-twitch response normally induced by psychedelics, further supporting its non-hallucinogenic profile.

The researchers also showed that TBG and psychedelics activated largely overlapping populations of neurons in the prefrontal cortex, as revealed through two-photon calcium imaging. Both drugs increased calcium signaling in similar cells, although TBG did not enhance glutamate bursts. This suggests that partial activation of 5-HT2A receptors may be sufficient to promote plasticity without triggering the chain of events that leads to hallucinations.

“Our study provides further evidence that it is possible to decouple the hallucinogenic effects of psychedelics from their beneficial effects on neuroplasticity,” Olson said.

The findings offer new insight into the neurobiology of psychedelic-inspired compounds, but there are some limitations to consider. Most of the data come from rodent and pig models, and the extent to which these findings translate to humans remains to be seen. Although TBG was shown to occupy serotonin receptors and promote brain changes in animals, human trials will be needed to determine whether it has therapeutic effects without unwanted side effects.

“At the moment, TBG has not yet been tested in humans, so we don’t know for sure if it is truly non-hallucinogenic,” Olson noted.

The researchers also note that the absence of immediate early gene activation at the tested time points does not rule out more delayed gene responses. It remains possible that TBG triggers a different transcriptional program that supports structural changes over time. Future studies may examine whether TBG affects other gene networks or cellular mechanisms involved in memory, learning, or mood regulation.

Another area for exploration is the exact threshold of 5-HT2A receptor activation needed to achieve therapeutic plasticity. TBG’s status as a partial agonist suggests that the strength and duration of receptor activation may shape the balance between plasticity and hallucinations. Identifying the optimal engagement of this receptor could help guide the design of next-generation compounds.

“We are hoping that non-hallucinogenic psychoplastogens, or neuroplastogens, will become broadly useful therapeutics for a variety of brain conditions,” Olson said.

The study, “The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation,” was authored by 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, and David E. Olson.