Photo credit: www.sciencedaily.com

Breakthrough in Neuropharmacology: New Drug Mirrors LSD’s Benefits Without Hallucinations

Researchers at the University of California, Davis have introduced an innovative drug, JRT, that promotes neuroplasticity and is structurally related to LSD. This new compound aims to leverage the therapeutic effects of psychedelics while minimizing their hallucinogenic properties.

Published in the Proceedings of the National Academy of Sciences, the study reveals that JRT could serve as a promising treatment for conditions such as schizophrenia, where traditional psychedelics are avoided due to safety concerns. Additionally, this compound may have applications in addressing various neuropsychiatric and neurodegenerative disorders characterized by synaptic damage and brain shrinkage.

In developing JRT, scientists modified the LSD molecule by repositioning just two atoms within its structure. This change successfully diminished the hallucinogenic effects while preserving the drug’s neurotherapeutic qualities, such as facilitating neuronal growth and repairing damaged cells often seen in individuals with neuropsychiatric conditions.

“Essentially, what we accomplished is akin to a tire rotation,” explained David E. Olson, the corresponding author of the study and professor at UC Davis. “By merely rearranging two atoms in LSD, we markedly enhanced JRT’s selectivity profile and lessened its potential for hallucinations.”

In experimental scenarios, JRT exhibited significant neuroplastic effects and yielded promising results in mouse models related to the cognitive and negative symptoms associated with schizophrenia, without aggravating psychosis-related behaviors and gene expression.

“There’s a widespread reluctance to administer a hallucinogenic agent, such as LSD, to individuals diagnosed with schizophrenia,” Olson noted, who is also the co-founder and chief innovation officer at Delix Therapeutics, a firm focused on designing neuroplastogens for clinical application. “The development of JRT illustrates our ability to utilize psychedelics like LSD as foundational compounds to create safer, more effective medications for patient populations that cannot use psychedelics.”

Investigating JRT’s Efficacy

Olson’s team dedicated nearly five years to the complex 12-step process necessary to synthesize JRT. The compound was named after Jeremy R. Tuck, a former graduate student in Olson’s lab who first produced it, sharing co-first author credit with Lee E. Dunlap, another former graduate student.

Once synthesized, JRT underwent an array of cellular studies and tests in mouse models, demonstrating its neuroplastic capabilities and enhanced safety profile compared to LSD. Key findings from the studies included:

• JRT and LSD share the same molecular weight and overall structure, yet differ significantly in their pharmacological effects.
• JRT demonstrates potent and selective binding to serotonin receptors, particularly the 5-HT2A receptors, crucial for inducing growth in cortical neurons.
• The compound fosters neuroplasticity, resulting in a 46% increase in dendritic spine density and an 18% increase in synapse density within the prefrontal cortex.
• Unlike LSD, JRT does not lead to hallucinogenic-like behaviors in mice.
• JRT does not trigger the enhanced gene expression linked to schizophrenia that is typically observed with LSD use.
• The drug exhibits substantial antidepressant effects, being approximately 100 times more effective than ketamine, known for its rapid antidepressant properties.
• JRT enhances cognitive flexibility, improving deficits in reversal learning connected with schizophrenia.

“JRT displays exceptional therapeutic promise. We are currently exploring its efficacy in other disease models, refining the synthesis process, and developing new analogs that might enhance its performance,” Olson stated.

Paving the Way for Schizophrenia Treatment

Olson highlighted JRT’s potential for addressing the negative and cognitive symptoms of schizophrenia, a realm where existing treatments often fall short, especially regarding conditions like anhedonia — the inability to feel pleasure. While clozapine remains an exception due to its effectiveness, it is seldom the first choice for those severely impacted by schizophrenia due to its side effects.

Looking ahead, Olson and his research team are actively investigating JRT’s capabilities in treating other neurodegenerative and neuropsychiatric disorders.

Additional contributors to the study include 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, and Uri Manor.

The research was supported through various grants from organizations including the National Institutes of Health, the UC Davis Provost’s Undergraduate Fellowship, and multiple foundations focused on enhancing mental health and neuropsychiatric research.

Source
www.sciencedaily.com