Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential
Abstract
Decreased dendritic spine density in the cortex is a key pathological feature of neuropsychiatric diseases including depression, addiction, and schizophrenia (SCZ). Psychedelics possess a remarkable ability to promote cortical neuron growth and increase spine density; however, these compounds are contraindicated for patients with SCZ or a family history of psychosis. Here, we report the molecular design and de novo total synthesis of (+)-JRT, a structural analogue of lysergic acid diethylamide (LSD) with lower hallucinogenic potential and potent neuroplasticity-promoting properties. In addition to promoting spinogenesis in the cortex, (+)-JRT produces therapeutic effects in behavioral assays relevant to depression and cognition without exacerbating behavioral and gene expression signatures relevant to psychosis. This work underscores the potential of nonhallucinogenic psychoplastogens for treating diseases where the use of psychedelics presents significant safety concerns.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (30)
Jeremy R. Tuck
Chemistry and Chemical Biology Graduate Program, University of California
Lee E. Dunlap
Chemistry and Chemical Biology Graduate Program, University of California
Yara A. Khatib
Institute for Psychedelics and Neurotherapeutics, University of California
Cassandra J. Hatzipantelis
Institute for Psychedelics and Neurotherapeutics, University of California
Sammy Weiser Novak
Waitt Advanced Biophotonic Core, Salk Institute
Rachel M. Rahn
Department of Psychiatry and Brain and Mind Research Institute, Weill Cornell Medicine
Alexis R. Davis
Chemistry and Chemical Biology Graduate Program, University of California
Adam Mosswood
Institute for Psychedelics and Neurotherapeutics, University of California
Anna M. M. Vernier
Chemistry and Chemical Biology Graduate Program, University of California
Ethan M. Fenton
Institute for Psychedelics and Neurotherapeutics, University of California
Isak K. Aarrestad
Institute for Psychedelics and Neurotherapeutics, University of California
Robert J. Tombari
Chemistry and Chemical Biology Graduate Program, University of California
Samuel J. Carter
Institute for Psychedelics and Neurotherapeutics, University of California
Zachary Deane
Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies
Yuning Wang
Shenyang National Laboratory for Materials Science, Institute of Metal Research, Chinese Academy of Sciences, 72 Wenhua Road, Shenyang 110016, China
Arlo Sheridan
Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies
Monica A. Gonzalez
Institute for Psychedelics and Neurotherapeutics, University of California
Arabo A. Avanes
Institute for Psychedelics and Neurotherapeutics, University of California
Noel A. Powell
Delix Therapeutics, Inc
Milan Chytil
Delix Therapeutics, Inc
Sharon Engel
Delix Therapeutics, Inc
James C. Fettinger
Department of Chemistry, University of California Davis, One Shields Ave. Davis, Sacramento, California 95616, United States
Amaya R. Jenkins
Jerry and Phyllis Rappaport Center of Excellence in Basic Neuroscience Research, Harvard Medical School McLean Hospital
William A. Carlezon
Jerry and Phyllis Rappaport Center of Excellence in Basic Neuroscience Research, Harvard Medical School McLean Hospital
Alex S. Nord
Institute for Psychedelics and Neurotherapeutics, University of California
Brian D. Kangas
Jerry and Phyllis Rappaport Center of Excellence in Basic Neuroscience Research, Harvard Medical School McLean Hospital
Kurt Rasmussen
Delix Therapeutics, Inc
Conor Liston
Department of Psychiatry and Brain and Mind Research Institute, Weill Cornell Medicine
Uri Manor
Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies
David E. Olson
Institute for Psychedelics and Neurotherapeutics, University of California