summary: A new LSD-derived compound called JRT is committed to treating schizophrenia and other brain disorders without inducing hallucinations. Developed by researchers who have altered only two atoms in the LSD structure, JRT avoids the risks associated with psychemy, while maintaining the neuroplastic effect of psychedelics.
In a mouse model, JRT promoted synaptic growth, increased antidepressant effects, and improved cognitive flexibility. Key challenges in schizophrenia treatment. These findings support the idea that psychedelics can be safely redesigned to unlock brain repair without perceptual side effects.
Important facts:
- Enhanced Neuroplasticity: JRT increased dendritic spine density by 46% and synaptic density by 18%.
- There are no hallucination effects: Unlike LSD, JRT produced no hallucinosis behavior or schizophrenia-related gene expression in mice.
- Powerful antidepressants: JRT showed 100 times more potent antidepressant effects than ketamine.
sauce: UC Davis
Researchers at the University of California, Davis have developed a new neuroplastic promoter that is closely related to LSD that harnesses the therapeutic power of psychedelics with reduced hallucination abilities.
Research published in Proceedings of the National Academy of Sciences, It highlights the potential for new drugs as a treatment option for conditions like schizophrenia, where psychedelics are not prescribed for safety reasons.
This compound may also be useful in the treatment of other neuropsychiatric and neurodegenerative diseases characterized by synaptic loss and brain atrophy.
To design a drug called JRT, researchers reversed the position of only two atoms in the molecular structure of LSD.
Chemical flips reduced the hallucinogenic potential of JRT while maintaining neurotherapeutic properties, including the ability to promote neuronal growth and repair neuronal growth, which is often observed in neuropsychiatry and neurodegenerative disease brains.
“Essentially, what we did here is the rotation of the tires,” says corresponding author David E. Olson, director of the Institute for Psychedelics and Neurotherapy, professor of chemistry and professor of biochemistry and molecular medicine at UC Davis.
“Just transposed two atoms into the LSD significantly improved the selectivity profile of JRTs and reduced the likelihood of hallucinogens.”
JRT showed potent neuroplastic effects and improved measures in mice associated with negative and cognitive symptoms of schizophrenia without exacerbating behavior and gene expression associated with psychosis.
“No one really wants to give a schizophrenia patient a hallucinating molecule like LSD,” says Olson, co-founder and chief innovation officer at Delix Therapeutics, which aims to bring neuroplastics to the market.
“The development of JRT emphasizes that psychedelics like LSD can be used as a starting point to make better medicines. We may be able to create drugs that can be used in patient populations where psychedelics are prevented.”
Testing the possibilities of JRT
Olson said it took nearly five years to complete the 12-stage synthesis process to produce JRT. The molecule is named after Jeremy R. Tuck, a former graduate student at Olson’s Institute. He was the first to integrate it, and is the co-first author of the study along with Lee E. Dunlap, another former graduate student at Olson’s Institute.
Following the successful synthesis of JRT, researchers performed batteries of cellular and mouse assays that improved the neuroplastic effects and safety profile of the drug compared to LSD.
Important findings:
- JRT and LSD have exactly the same molecular weight and overall shape, but have different pharmacological properties.
- JRT is extremely potent and highly selective for binding to serotonin receptors, particularly 5-HT2A receptors, and its activation is key to promoting cortical neuronal growth.
- JRT promoted neuroplasticity, or growth between brain cell connections, resulting in a 46% increase in dendritic spinal density and an 18% increase in prefrontal cortex synaptic density.
- JRT did not produce the hallucinogen-like behavior that is normally seen when administered LSD to mice.
- JRT did not promote gene expression associated with schizophrenia. Such gene expression is usually amplified using LSD.
- JRT has a robust antidepressant effect and is about 100 times more potent than ketamine, the cutting-edge, rapid antidepressant.
- JRT promoted cognitive flexibility and successfully addressed impairments to inverted learning defects associated with schizophrenia.
“JRT has a very high therapeutic potential. We are currently testing it in other disease models, improving its synthesis and creating even better new analogs of JRT,” Olson said.
More effective treatment for schizophrenia
Olson highlighted the possibility of JRT to treat negative and cognitive symptoms of schizophrenia. This is because most current treatments have limited effects on anhedonia, which is unable to feel pleasure and cognitive function.
Clozapine is one exception, but it is not the first choice of drug for people suffering from side effects and suffering severely from schizophrenia.
Olson and his team are currently testing the potential of JRT for other neurodegenerative and neuropsychiatric disorders.
Additional co-authors include Yara A. Khatib, Cassandra J. Hatzipantelis, Sammy Weiser Novak, Rachel M. Rahn, Alexis R. Davis, Adam Mosswood, Anna MM Vernier, Ethan M. Fenton, Isak K. Aarrestad, Robert J. Tombari, Samuel J. Carter, Zachar Gonzalez, Arab A. Avanes, Noel A. Powell. Milan Chitil, Sharon Engel, James C. Fettinger, Amaya R. Jenkins, William A. Karaison Jr., Alex S. Nord, Brian D. Kangas, Kurt Rasmussen, Connorliston and Uri Manners.
Funding: The research reported here was funded by the request of the National Institutes of Health, UC Davis Provost undergraduate fellowship, the Camille and Henried Refuss Foundation, the Mosennajaffy Research Award in Pharmaceutical Chemistry, the Boone Family Foundation, the Depression Research Foundation’s hopes, the Pretzker Neuropsychiatric Disorders Research Conditions, the Imector of Initiatives, and the Zinichi City’s Scholarship Association. Awards and the National Science Foundation Neuron Awards.
About this psychopharmacology research news
author: Andrew fell
sauce: UC Davis
contact: Andrew Fell – UC Davis
image: This image is credited to Neuroscience News
Original research: Open access.
“Molecular design of therapeutic LSD analogues with reduced hallucination.” David E. Olson et al. pnas
Abstract
Molecular design of therapeutic LSD analogues with reduced hallucination.
Reduced dendritic spinal density in the cortex is an important pathological feature of neuropsychiatric disorders, including depression, addiction and schizophrenia (SCZ).
Psychedelics have the remarkable ability to promote cortical neuronal growth and increase spinal density. However, these compounds are contraindicated in patients with a family history of SCZ or psychosis.
Here we report the molecular design and de novo synthesis of (+)-JRT. It is a structural analogue of lyserformate diethylamide (LSD) with hallucination potential and potent neuroplastic promoting properties.
In addition to promoting spindle formation in the cortex, (+)-JRT generates therapeutic effects on behavioral assays related to depression and cognition without exacerbating behavioral and gene expression signatures associated with psychosis.
This study highlights the potential of non-forcinogenic psychotic cells to treat diseases where psychedelic use poses serious safety concerns.
