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 <i>N,N</i>-dimethyltryptamine, suggesting that zalsupindole might represent a safer and more scalable neuroplasticity-promoting compound for treating conditions like depression.