This preclinical pharmacology study in rats found that zalsupindole (third-generation psychedelic) produced robust effects on structural and functional neuroplasticity in the prefrontal cortex as well as sustained antidepressant-like responses comparable to or greater than those of ketamine, psilocybin, and DMT, despite lacking any of the acute cellular and behavioural characteristics of hallucinogenic or dissociative compounds.
Abstract of Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics
“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.”
Authors: Rajiv Agrawal, Daniel Gillie, Alison Mungenast, Milan Chytil, Sharon Engel, Michael C. Wu, Kurt Rasmussen, Eliseo Salinas & David E. Olson
Summary of Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics
Agrawal and colleagues introduce zalsupindole (ZAL), a new compound developed to promote neuroplasticity—the brain’s ability to form and reorganise connections—without causing hallucinations or dissociation. Many psychiatric conditions, particularly major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and substance use disorder (SUD), are associated with the loss of neurons and synapses in the prefrontal cortex (PFC), a region responsible for mood regulation and decision-making. Traditional antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), can reverse this process, but they typically require weeks of continuous administration before any clinical improvement is seen. Their slow mechanism is linked to the gradual promotion of neuroplasticity over time.
By contrast, newer classes of drugs such as ketamine, psilocybin, and DMT can induce rapid changes in both structural and functional neuroplasticity, often producing significant mood improvements within hours or days. These substances, referred to as psychoplastogens, are believed to stimulate neuronal growth and connectivity in the PFC. However, their dissociative or hallucinogenic effects, as well as potential safety and abuse concerns, limit their use in broader clinical populations. To overcome these challenges, scientists have sought to develop neuroplastogens—compounds capable of promoting neuroplasticity without the mind-altering effects associated with psychedelics.
Zalsupindole (also called AAZ-A-154) emerged from medicinal chemistry research on isotryptamine analogues of 5-MeO-DMT. Previous work suggested that zalsupindole can promote cortical neuron growth and produce antidepressant-like effects in rodents without causing hallucinations or dissociation. The current study sought to thoroughly characterise the pharmacological, neuroplastic, and behavioural properties of zalsupindole in preclinical models and compare its efficacy to established psychoplastogens such as ketamine, psilocybin, and DMT.
Results
Ketamine and psilocybin promote cortical neuroplasticity
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https://doi.org/10.1021/acschemneuro.5c00667
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Agrawal, R., Gillie, D., Mungenast, A., Chytil, M., Engel, S., Wu, M. C., ... & Olson, D. E. (2025). Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics. ACS Chemical Neuroscience.