This Psychedelic Heals the Brain Without the Trip

In a new study from the University of California, Davis, scientists have shown that a non-hallucinogenic compound can trigger brain growth through the same receptor as psychedelics, without activating the genes long thought essential to that process.

The compound, called tabernanthalog (TBG), mimics the antidepressant and neuroplastic effects of classic psychedelics like 5-MeO-DMT, but skips the mind-altering side effects. Published August 4 in Nature Neuroscience, the findings challenge decades of assumptions about how psychedelics work in the brain and could lead to safer, more accessible treatments for depression and other psychiatric conditions.

Rewiring Without the Trip

For years, researchers believed psychedelics promoted neuroplasticity—the brain’s ability to rewire itself—by triggering a cascade of gene activity via a glutamate surge. But TBG appears to sidestep that route entirely. While it activates the same serotonin 2A receptor (5-HT2A) as 5-MeO-DMT, TBG functions as a partial agonist, producing dendritic spine growth in the prefrontal cortex without flooding the brain with glutamate or turning on immediate early genes like c-Fos and Arc.

“We now know that non-hallucinogenic compounds like TBG can promote neuroplasticity without inducing a glutamate burst or immediate early gene activation,” said David E. Olson, senior author and director of UC Davis’s Institute for Psychedelics and Neurotherapeutics.

Key Findings at a Glance

• TBG triggers structural and functional plasticity via 5-HT2A receptor activation.
• Unlike psychedelics, TBG does not cause glutamate surges or immediate early gene (IEG) activation.
• Antidepressant-like effects from TBG depend on dendritic spine growth in the prefrontal cortex.
• TBG blocks hallucinogenic responses in animal models, suggesting low psychedelic liability.

Following the Biochemical Trail

The researchers used a combination of genetic knockout mice, brain imaging, and fiber photometry to track how TBG affects cortical neurons. In wild-type mice, a single dose of TBG boosted dendritic spine density and increased excitatory signals. But in mice lacking 5-HT2A receptors, those effects disappeared.

The team also used laser ablation to erase the newly formed dendritic spines in the prefrontal cortex. When they did, the antidepressant effect vanished. This confirmed what researchers had suspected but never proven for serotonergic compounds: that physical neuron growth in specific brain regions is required for their therapeutic impact.

Disentangling Plasticity From Hallucinations

“This work challenges the current dogma in the field,” said co-author John A. Gray, associate director of the institute. While both TBG and 5-MeO-DMT boosted calcium signaling in the same prefrontal neurons, only 5-MeO induced the burst of extracellular glutamate and triggered a spike in IEG expression.

Using single-nucleus RNA sequencing, the researchers found that 5-MeO upregulated dozens of genes across key neuronal populations, something TBG did not do. This suggests that IEG activation is more likely tied to hallucinogenic effects than to structural brain changes.

The Road Ahead for Psychedelic-Inspired Therapies

The study adds to growing interest in “psychoplastogens,” compounds that stimulate brain plasticity without producing hallucinations. TBG, BOL-148, AAZ-A-154, and lisuride now join the short list of candidates capable of promoting neural regeneration without triggering acute psychedelic effects.

“Science is full of surprises,” Gray said. “There is still so much we don’t know about how psychedelics impact the brain, and it feels like we learn something new every day.”

With major implications for depression, PTSD, and addiction treatment, the findings suggest that future drug development could bypass the challenges of managing a psychedelic experience. Partial activation of 5-HT2A may offer a therapeutic sweet spot: enough to regrow neurons, not enough to warp reality.

Journal Reference

Nature Neuroscience, August 4, 2025
DOI: 10.1038/s41593-025-02021-1