Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential
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.
Authors
- Samuel J. Carter (ORCID: https://orcid.org/0000-0002-2276-4373)
- Alex S. Nord (ORCID: https://orcid.org/0000-0003-4259-7514)
- Rachel M. Rahn (ORCID: https://orcid.org/0000-0002-9943-7573)
- William A. Carlezon (ORCID: https://orcid.org/0000-0002-4162-3947)
- Arabo A. Avanes (ORCID: https://orcid.org/0000-0001-6211-7966)
- Monica A. Gonzalez
- Cassandra J. Hatzipantelis (ORCID: https://orcid.org/0000-0001-5376-7887)
- Jeremy R. Tuck (ORCID: https://orcid.org/0000-0002-8807-3014)
- Brian D. Kangas (ORCID: https://orcid.org/0000-0002-4597-9801)
- David E. Olson (ORCID: https://orcid.org/0000-0002-4517-0543)
- Lee E. Dunlap (ORCID: https://orcid.org/0000-0002-9365-8025)
- Conor Liston (ORCID: https://orcid.org/0000-0002-1639-5401)
- Sammy Weiser Novak (ORCID: https://orcid.org/0000-0002-8344-9772)
- Arlo Sheridan (ORCID: https://orcid.org/0000-0003-2907-2254)
- Yuning Wang (ORCID: https://orcid.org/0000-0001-7386-1897)
- Robert J. Tombari (ORCID: https://orcid.org/0000-0002-6561-8181)
- Uri Manor (ORCID: https://orcid.org/0000-0002-9802-1955)
- James C. Fettinger (ORCID: https://orcid.org/0000-0002-6428-4909)
- Noel A. Powell (ORCID: https://orcid.org/0000-0002-6109-3269)
- Isak K. Aarrestad (ORCID: https://orcid.org/0000-0002-6911-5346)
- Sharon Engel
- Amaya R. Jenkins (ORCID: https://orcid.org/0000-0002-1919-9940)
- Milan Chytil
- Kurt Rasmussen
- Ashley A. Davis
- Ethan M. Fenton (ORCID: https://orcid.org/0009-0008-1945-7517)
- Zachary Deane
- Yara A. Khatib (ORCID: https://orcid.org/0000-0002-8342-7100)
- Adam Mosswood
- Anna M. M. Vernier (ORCID: https://orcid.org/0000-0001-7226-4417)
Institutions
- Salk Institute for Biological Studies (US)
- University of California, Los Angeles (US)
- Cornell University (US)
- McLean Hospital (US)
- MIND Research Institute (US)
- Multidisciplinary Association for Psychedelic Studies (US)
- Center for Neurosciences (US)
- Epix Pharmaceuticals (United States) (US)
- Weill Cornell Medicine (US)
- University of California, Berkeley (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1073/pnas.2416106122
- Citations
- 20
- Primary Topic
- Psychedelics and Drug Studies
- Type
- article
- Field-Weighted Citation Impact
- 46.14
Funders
- National Science Foundation
- Silicon Valley Community Foundation
- Camille and Henry Dreyfus Foundation
- Hope for Depression Research Foundation
- David F. and Margaret T. Grohne Family Foundation
- Chan Zuckerberg Initiative
- National Institutes of Health
- University of California, Davis
- Intellectual and Developmental Disabilities Research Center
- National Cancer Institute
- National Institute of Child Health and Human Development
- Division of Chemistry