Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics
Rajiv Agrawal, Daniel J. Gillie, Alison E. Mungenast, Milan Chytil, Sharon Engel, Michael C. Wu, Kurt Rasmussen, Eliseo Salinas, David E. Olson
ACS Chemical Neuroscience October 13, 2025 DOI: 10.1021/acschemneuro.5c00667 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | zalsupindole |
| Topics | Esketamine Ketamine |
| Citations | 8 |
| Key points | Zalsupindole produced robust effects on structural and functional neuroplasticity in the prefrontal cortex of rats and sustained antidepressant-like responses without hallucinogenic or dissociative properties. |
Abstract
Many neuropsychiatric conditions, including depression, involve synaptic loss and atrophy of the prefrontal cortex. The rapid regrowth of cortical neurons has been hypothesized to explain the rapid and enduring therapeutic effects of psychedelics and the dissociative anesthetic ketamine. However, safety concerns related to hallucinogenic/dissociative properties have limited the addressable patient population that could potentially be treated with these compounds. Thus, substantial efforts have focused on the development of neuroplastogens─compounds that can produce similar effects on structural and functional neuroplasticity as well as rapid and sustained therapeutic behavioral effects without inducing hallucinations or dissociation. Here, we describe the preclinical pharmacology and efficacy of zalsupindole─the first neuroplastogen to be administered to patients with major depressive disorder. Despite lacking any of the acute cellular and behavioral characteristics of hallucinogenic/dissociative compounds, zalsupindole produced robust effects on structural and functional neuroplasticity in the prefrontal cortex of rats as well as sustained antidepressant-like responses. These effects were comparable to or greater than those of ketamine, psilocybin, and N,N-dimethyltryptamine, suggesting that zalsupindole might represent a safer and more scalable neuroplasticity-promoting compound for treating conditions like depression.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 10
- Zalsupindole: A Non-Hallucinogenic Psychoplastogen Advancing Psychedelic-Inspired Therapeutics. ACS Chemical Neuroscience January 21, 2026
- Psychedelics for treatment of negative symptoms and depressive symptoms in schizophrenia spectrum disorder: A narrative review Schizophrenia Research March 13, 2026
- Psychoplastogens to Reduce Persistent Cognitive Symptoms for Traumatic Brain Injury as a Chronic Condition Journal of Neurotrauma October 19, 2026
- The Emergence of Isotryptamine Analogs as Novel Serotonergic Agents with Psychotherapeutic Potential ACS Pharmacology & Translational Science August 18, 2026
- Redefining the real problem in psychedelic trials: Why fighting the Lessebo matters more than blinding integrity. International Journal of Drug Policy July 8, 2026
and 5 more in the library
Cites 32
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- 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
and 27 more in the library