Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential
Jeremy R Tuck, Lee E. Dunlap, 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, Alex S Nord, Brian D Kangas, Kurt Rasmussen, Conor Liston, Uri Manor, David E. Olson
Proceedings of the National Academy of Sciences April 14, 2025 DOI: 10.1073/pnas.2416106122 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Rodents (rats and/or mice, implied by behavioral assays) |
| Intervention | (+)-JRT |
| Topics | LSD Neuroplasticity |
| Keywords | Neuropsychiatric disease Nonhallucinogenic Psychedelics hallucinogens Entheogens Psychoactive drugs Psychological medicine Behavioral health Neuroscience brain research Neural science Neurobiology Drug development pharmaceutical |
| Citations | 32 |
| Key points | The nonhallucinogenic LSD analogue (+)-JRT promotes cortical spinogenesis and produces therapeutic effects in behavioral assays relevant to depression and cognition without exacerbating psychosis-related signatures. |
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.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cited by 26
- Emerging mechanisms of psilocybin-induced neuroplasticity TIPS - Trends in Pharmacological Sciences September 16, 2025
- Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics ACS Chemical Neuroscience October 13, 2025
- Should we skip the trip? Clinical implications of psychedelic-associated subjective effects and the potential role of non-hallucinogenic alternatives. General Hospital Psychiatry July 3, 2025
- LSD: Mechanisms and relevance to the treatment of depression Neuroscience & Biobehavioral Reviews October 10, 2025
- Zalsupindole: A Non-Hallucinogenic Psychoplastogen Advancing Psychedelic-Inspired Therapeutics. ACS Chemical Neuroscience January 21, 2026
and 21 more in the library
Cites 33
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 28 more in the library