Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics

Introduction

Cortical atrophy and loss of synapses in the prefrontal cortex (PFC) are implicated in depression and related disorders such as PTSD and substance use disorder. Earlier research has shown that diverse interventions that promote structural neuroplasticity in the PFC — ranging from electroconvulsive therapy and exercise to fast-acting agents such as ketamine and classical psychedelics — can produce rapid and sustained therapeutic benefits. However, most of the advanced psychoplastogens produce hallucinogenic or dissociative effects, and some carry cardiotoxicity or abuse potential, limiting their scalability and suitability for many patients. This safety profile has driven interest in so-called neuroplastogens: compounds that promote structural and functional plasticity without causing hallucinations or dissociation. Agrawal and colleagues set out to characterise zalsupindole (ZAL, AAZ-A-154), an isotryptamine-derived neuroplastogen, across pharmacology, neuroplasticity, electrophysiology, and behaviour. The study aimed to compare ZAL's in vitro and in vivo effects with those of clinically relevant psychoplastogens (ketamine, psilocybin, and DMT), to profile its receptor pharmacology and pharmacokinetics, and to test whether ZAL could produce rapid and sustained antidepressant-like effects without hallucinogenic or dissociative properties. The work spans multiple preclinical assays, including neurite outgrowth assays, radioligand and functional receptor profiling, Golgi-Cox spine analysis, electrophysiology, microdialysis, and behavioural testing in rodents.