Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential.

Publication Type Academic Article
Authors Tuck J, Dunlap L, Khatib Y, Hatzipantelis C, Weiser Novak S, Rahn R, Davis A, Mosswood A, Vernier A, Fenton E, Aarrestad I, Tombari R, Carter S, Deane Z, Wang Y, Sheridan A, Gonzalez M, Avanes A, Powell N, Chytil M, Engel S, Fettinger J, Jenkins A, Carlezon W, Nord A, Kangas B, Rasmussen K, Liston C, Manor U, Olson D
Journal Proc Natl Acad Sci U S A
Volume 122
Issue 16
Pagination e2416106122
Date Published 04/14/2025
ISSN 1091-6490
Keywords Lysergic Acid Diethylamide, Hallucinogens, Drug Design
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.
DOI 10.1073/pnas.2416106122
PubMed ID 40228113
PubMed Central ID PMC12037037
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