Small adjustments to LSD molecules can create powerful treatments for brain disease

Scientists have developed a promising new compound that can change how we treat diseases like schizophrenia by leveraging the therapeutic benefits of psychedelic drugs without hallucinogenic effects.

Researchers at the University of California, Davis and San Diego have created JRT, a modified version of LSD that promotes nerve growth and connectivity while eliminating hallucinogenic properties that make traditional psychedelic drugs unsuitable for patients with certain mental health conditions.

This breakthrough, published in the Proceedings of the National Academy of Sciences, depends on a very simple molecular modification, which provides only two atoms in the LSD structure.

“Basically, what we do here is tire rotation,” said David E. Olson, director of the UC Davis Institute for Psychedelic and Neurotherapeutics. By transferring two atoms only in LSD, we significantly improved the selectivity curve of JRT and reduced its hallucination potential.

This subtle change maintains the compound’s ability to promote nerve growth while eliminating the hallucinations that make it dangerous to patients with schizophrenia.

The researchers observed significant neurobiological effects using advanced 3D electron microscopy technology. In the prefrontal cortex of mice, single dose of JRT increased dendritic density (the bond structure of neural connectivity) while synaptic density increased by 18%.

Treating the effects of schizophrenia is particularly important. Current schizophrenia drugs mainly address hallucinations and delusions, but work to improve cognitive problems and emotional stationarity (ANHEDONIA).

No one really wants to give schizophrenia patients, hallucinating molecules like LSD, The famous Olson is also the co-founder of Delix Therapeutics. The development of JRT emphasizes that we can use psychedelic drugs like LSD as a starting point to make better drugs – drugs that can be used in the patient population of psychedelic use.

Unlike existing treatments, JRT showed significant efficacy in animal models – in the effect of antidepressants, ketamine has a potency of 100 times higher than ketamine. The compound also showed the ability to rescue cognitive flexibility in mice exposed to chronic stress without the need to produce sedation or other problematic side effects associated with current antipsychotics.

This study represents a significant advance in the emerging field of “spiritual phylogeny” – promoting neuroplasticity without hallucinogenic effects. This approach could potentially address potential neurobiological deficits in schizophrenia, where reduced dendritic spine density and impaired connectivity in the cortex are hallmarks of the disease.

We are very excited about the therapeutic potential of non-glucose psychedelic analogues such as JRT (e.g. JRT) Uri Manor, assistant professor at the UC San Diego School of Biological Sciences. This work is a perfect example of how cutting-edge chemistry, neuroscience and imaging come together to push the boundaries of biomedical research.

This development requires a lot of chemical innovation. Olson’s team spent nearly five years completing a 12-step synthesis process to produce JRT, named after first-time synthesis graduate student Jeremy R. Tuck.

The team is now testing the potential of JRT for other neurodegenerative and neuropsychiatric diseases, highlighting the broader implications of this scientific approach, which creates molecules that selectively target beneficial neural pathways while avoiding unnecessary effects.

The study was supported by the National Institutes of Health, the Undergraduate Scholarships from the University of California, Davis, the Camille and Henry Dreyfus Foundation, the Bhagwat Memorial Foundation, the Depression Research Foundation, the Pritzker Neuropsychiatric Institute for Disease Research Alliance, and the Chan Zuckerberg Initiative.