Psychedelic and non-hallucinogenic drugs promote neuroplasticity through shared pathways

Understanding exactly how psychedelics promote new connections in the brain is critical to developing targeted, non-hallucinogenic therapeutics that can treat neurodegenerative and neuropsychiatric diseases. To achieve this, researchers are mapping the biochemical pathways involved in both neuroplasticity and hallucinations.

In new research led by the University of California, Davis, researchers found that non-hallucinogenic versions of psychedelic drugs promote neuroplasticity through the same biochemical pathway as psychedelics. However, unlike psychedelics, they don't activate genes long thought to be key players in that process.

The research, published Aug. 4 in Nature Neuroscience, compared the biochemical pathways activated by the hallucinogenic compound 5-MeO-DMT and its non-hallucinogenic analog tabernanthalog (TBG).

The prevailing hypothesis in the field was that psychedelics promote neuroplasticity by causing this big burst of glutamate in the brain, which then turns on intermediate early genes. We now know that non-hallucinogenic compounds like TBG can promote neuroplasticity without inducing a glutamate burst or immediate early gene activation."

David E. Olson, director of the Institute for Psychedelics and Neurotherapeutics and a professor of chemistry and of biochemistry and molecular medicine at UC Davis

"This work challenges the current dogma in the field," said John A. Gray, a co-author of the study and the associate director of the Institute for Psychedelics and Neurotherapeutics as well as a professor in the Center for Neuroscience at UC Davis.

The team found that TBG promotes neuroplasticity by activating the same psychedelic receptor as 5-MeO-DMT, but the difference is the extent of the activation.

The researchers also provide the first direct evidence that a non-hallucinogenic psychedelic analog like TBG, produces sustained antidepressant-like effects through the growth of dendritic spines in the brain's prefrontal cortex.

Following the biochemical flow

Using pharmacological and genetic tools in rodents, the team found that both TBG and 5-MeO-DMT promoted cortical neuroplasticity by activating the serotonin 2A receptor (5-HT2A). Both drugs then induced the downstream activation of the same receptors and proteins, including TrkB, mTOR and AMPA. 

This means that that despite TBG being non-hallucinogenic, it turns on one of the same biochemical pathways that psychedelics do. Whereas 5-MeO-DMT is a full agonist, TBG is a partial agonist.

Olson likened agonists to water faucets. Full agonists turn on the faucet all the way, allowing for a full flow of water, while partial agonists only allow for drips and limited streams. 

"Full agonists turn on hallucinations and they also turn on plasticity," Olson said. "Partial agonists only turn on the receptor part way and that seems to be sufficient to turn on plasticity." 

Link between neuroplasticity and antidepressant effects 

The study addressed an open question in psychedelic science. While the activation of 5-HT2A receptors by psychedelics is known to promote neuroplasticity, the link between this and psychedelics' sustained antidepressant effects was unclear. 

"Are the neuroplasticity-promoting effects - the growth of these dendritic spines in the prefrontal cortex - responsible for the antidepressant effects?" Olson wondered.

It turns out, they are. 

With advanced genetic tools, the team tagged the dendritic spines that grew in the prefrontal cortex after TBG dosing. They then used lasers to erase those spines.

"When we erased those spines, the antidepressant effect went away," Olson said. 

Previously, this kind of experiment was conducted with ketamine to demonstrate that its sustained antidepressant-like properties required the growth of these dendritic spines.

"This is the first time that we've done this with a serotonergic agent," Olson said. "And we find that cortical neuroplasticity is at least responsible for some of the compound's antidepressant-like effects." 

Similarities and differences

While 5-MeO-DMT and TBG boasted similarities in their effects on neuroplasticity, there were critical differences. Unlike 5-MeO-DMT, TBG didn't promote bursts of glutamate or turn on immediate early genes - genes long thought to be critical for the neuroplasticity-promoting effects of psychedelics. 

"It was kind of shocking that TBG promoted plasticity, but the glutamate burst and immediate early genes were not required," Olson said. The team used a combination of whole brain imaging and single-nucleus RNA sequencing to profile gene expression patterns following treatment with 5-MeO-DMT and TBG. "What we found is that glutamate bursts and immediate early gene expression are probably more related to the hallucinogenic properties of psychedelics rather than their plasticity-promoting effects."

"Science is full of surprises," said Gray. "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."

 Additional co-authors include 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 and Christina K. Kim.

The research reported here was supported by grants from the National Institutes of Health, the Camille and Henry Dreyfus Foundation, a Hellman Fellowship, the Boone Family Foundation, the WoodNext Foundation and a sponsored research agreement with Delix Therapeutics. Olson is co-founder and chief innovation officer of Delix Therapeutics.