Flipping two atoms in LSD turned it into a powerful treatment for damaged brain circuits

Scientists at the University of California, Davis have developed a new drug related to LSD that retains the psychedelic’s beneficial brain effects while minimizing the hallucinogenic experience. The compound, called JRT, showed strong potential to promote brain cell growth and reverse damage linked to conditions like schizophrenia. In animal experiments, JRT improved symptoms without triggering behaviors associated with hallucinations. The findings were published in the journal Proceedings of the National Academy of Sciences.

Lysergic acid diethylamide, or LSD, is best known for its powerful mind-altering effects. But in recent years, researchers have discovered that LSD and similar compounds can also promote neuroplasticity—the brain’s ability to grow new connections and repair damaged circuits. This effect makes psychedelics appealing as potential treatments for mood and cognitive disorders, including depression, substance use, and neurodegenerative diseases. However, their hallucinogenic properties pose risks for certain groups, especially people with schizophrenia or a family history of psychosis. Because of this, researchers have been exploring ways to preserve the therapeutic benefits of psychedelics without inducing hallucinations.

“One of the hallmarks of schizophrenia is atrophy of neurons in the cortex,” explained lead author David E. Olson, director of the UC Davis Institute for Psychedelics and Neurotherapeutics. “Psychedelics like LSD are extremely good at promoting cortical neuron growth, but they are typically contraindicated for patients with schizophrenia or a family history of psychosis. We decided to engineer an analogue of LSD with lower hallucinogenic potential in the hopes that this neuroplasticity-promoting compound might be useful for treating these patients.”

In the new study, the UC Davis team aimed to modify LSD’s structure in a way that would reduce its hallucinogenic potential while maintaining its effects on brain plasticity. They focused on the idea that small changes in a drug’s shape can have big effects on how it interacts with brain receptors. Specifically, they made a tiny adjustment—flipping the position of just two atoms in LSD’s molecular structure. This new version, JRT, turned out to bind to many of the same serotonin receptors as LSD but with a different pharmacological profile.

“You cannot synthesize JRT from LSD or any of the precursors used to make LSD,” Olson said. “We needed to synthesize JRT from scratch. Also, JRT was named after Jeremy R. Tuck, the graduate student who first synthesized it.”

To test JRT’s effects, the researchers conducted a series of experiments, beginning with extensive chemical synthesis and molecular modeling. They confirmed through computer simulations and lab tests that JRT could still interact with serotonin receptors in a way that supports neuroplasticity, but without triggering the signaling pathways that typically lead to hallucinations. Notably, JRT lacked a specific chemical bond (called the indole N–H bond) that LSD uses to form a key interaction in the serotonin 2A receptor—an interaction believed to play a role in producing hallucinations.

The researchers then conducted in vitro experiments using rat cortical neurons to examine how JRT affected neuronal growth. Compared to control treatments and existing drugs like clozapine, JRT promoted substantial growth in dendritic branches and spine density—hallmarks of healthy brain connectivity. These effects were even greater than those produced by LSD in the same tests.

The team followed up with in vivo studies using mice. A single dose of JRT led to a 46% increase in dendritic spine density and an 18% increase in synapse density in the medial prefrontal cortex, a brain region involved in decision-making and emotional regulation. In another experiment, the researchers showed that JRT could reverse the loss of dendritic spines induced by chronic stress, suggesting its potential to restore brain structure in conditions marked by cortical atrophy.

To assess whether JRT produced psychedelic-like behaviors, the scientists used a behavioral test called the head-twitch response in mice, which correlates with hallucinogenic activity in humans. Unlike LSD, JRT did not trigger the head-twitch response. In fact, it blocked the head-twitch response when mice were given LSD. JRT also did not impair prepulse inhibition—a measure of sensory gating that is often disrupted in schizophrenia and can be worsened by psychedelics.

The researchers also analyzed how JRT affected gene expression in the brain. After a single dose, they found that JRT did not induce gene expression changes associated with schizophrenia, while LSD did. This suggests that JRT is less likely to exacerbate symptoms or increase risk in individuals predisposed to psychotic disorders.

JRT’s effects on behavior were also promising. In rodent tests commonly used to model depression, including the forced swim test and sucrose preference test, JRT produced antidepressant-like outcomes. The animals were more active and showed restored interest in pleasurable activities after being treated with JRT. These effects were sustained even when the animals continued to experience stress, indicating that JRT’s impact on mood and motivation might be long-lasting.

Additionally, JRT improved performance on a cognitive flexibility task in mice subjected to unpredictable stress. The compound helped the animals learn and adapt when the rules of the task changed, an ability that is often impaired in individuals with schizophrenia and mood disorders. This suggests that JRT may help address cognitive symptoms, which are among the most disabling and treatment-resistant aspects of schizophrenia.

Importantly, the researchers found that JRT was highly selective for serotonin receptors and lacked affinity for other receptor types—such as dopamine, histamine, or adrenergic receptors—that are often linked to side effects in psychiatric medications. This specificity might make JRT safer and better tolerated than drugs like clozapine, which, while effective, often cause weight gain, sedation, and metabolic issues.

“I was surprised that transposing only two atoms was sufficient to drastically change the pharmacology of LSD,” Olson told PsyPost. “Not only did it lower hallucinogenic potential, it also improved selectivity across a wide range of targets in the brain. While psychedelics might have therapeutic properties, they were never engineered to be drugs for central nervous system disorders. Even small chemical alterations to the structures of psychedelics have the potential to profoundly improve their safety and efficacy profiles.”

While the results are promising, the study does have limitations. All experiments were conducted in animals, and it remains to be seen how well the findings will translate to humans. Although JRT appears to be non-hallucinogenic in rodents, human subjective experiences can differ and will need to be tested in clinical trials. The long-term safety of JRT, especially in vulnerable populations, also needs to be evaluated.

“At the moment, JRT has not yet been tested in humans, but we are working towards this goal,” Olson noted. “I would also like to test JRT in other disease models. In particular, I’m very excited about its potential to rescue neuronal atrophy in neurodegenerative conditions.”

The study, “Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential,” was authored by Jeremy R. Tuck, Lee E. Dunlap, Yara A. Khatib, Cassandra J. Hatzipantelis, Sammy Weiser Novak, Rachel M. Rahn, Alexis R. Davis, Adam Mosswood, Anna M. M. Vernier, Ethan M. Fenton, Isak K. Aarrestad, Robert J. Tombari, Samuel J. Carter, Zachary Deane, Yuning Wang, Arlo Sheridan, Monica A. Gonzalez, Arabo A. Avanes, Noel A. Powell, Milan Chytil, Sharon Engel, James C. Fettinger, Amaya R. Jenkins, William A. Carlezon Jr., Alex S. Nord, Brian D. Kangas, Kurt Rasmussen, Conor Liston, Uri Manor, and David E. Olson.