Zalsupindole: A Non-Hallucinogenic Psychoplastogen Advancing Psychedelic-Inspired Therapeutics.

Zalsupindole, a non-hallucinogenic psychoplastogen, promotes neuritogenesis and dendritic spine growth via 5-HT2-dependent mechanisms, potentially involving the mTOR pathway. In rats, it shows rapid brain penetration, no 5-HT2B agonism, no glutamate surge, and no head-twitch response. Single doses produce rapid and durable antidepressant-like effects in forced swim test and VMAT2-deficient mouse models. Phase 1 trials (2-360 mg) show good tolerability, no psychotomimetic effects, linear absorption, and dose-dependent EEG changes indicating synaptic potentiation. This biased 5-HT2A agonist may offer a new treatment for mood disorders without hallucinogenic side effects.

Study at a glance

Abstract

This review aims to evaluate the pharmacological properties, mechanistic selectivity, and early clinical development of zalsupindole, highlighting its potential as a next-generation psychiatric therapeutic. This review was conducted using a structured literature search strategy across PubMed, Google Scholar, ClinicalTrials.gov, and the official Web sites of regulatory bodies and pharmaceutical developers. Searches included combinations of keywords such as "zalsupindole," "DLX-001," "AAZ-A-154," "non-hallucinogenic psychoplastogen," "5-HT2A receptor," "biased agonism," "neuroplasticity," and "Delix Therapeutics." The inclusion criteria encompassed English-language publications between January 2019 and October 2025. Peer-reviewed articles, preclinical studies, clinical trial data, patents, regulatory documents, and officially released press materials were considered. Sources were excluded if they lacked relevance to zalsupindole's pharmacology, therapeutic positioning, or clinical development pathway. To ensure transparency, all sources have been categorized in-text according to type: Peer-reviewed literature is cited directly and forms the scientific backbone of the review. Gray literature, including press releases, conference posters, patents, and corporate briefings, is clearly identified and used only to provide supplementary context where peer-reviewed data are unavailable. No original research was conducted as part of this review. Peer-reviewed in vitro and in vivo studies confirm that zalsupindole promotes neuritogenesis and dendritic spine growth via 5-HT2-dependent mechanisms; ketanserin abolishes these effects, and rapamycin-based inhibition studies suggest potential mTOR pathway participation in zalsupindole-induced plasticity. The compound demonstrates rapid brain penetration in rats, with no measurable 5-HT2B agonism, no glutamate surge, and no head-twitch response, suggesting strong neuroplastic effects without hallucinogenic activity. In the forced swim test and VMAT2-deficient mouse models, single doses produced rapid and durable antidepressant-like effects. In Phase 1 clinical trials, oral zalsupindole was well tolerated across a dose range of 2-360 mg, with no reports of psychotomimetic effects. Pharmacokinetic assessments showed linear absorption/CNS penetration. EEG-based biomarkers revealed dose-dependent increases in power spectra associated with synaptic potentiation. The development of zalsupindole marks a significant step forward in neuropsychiatry. Its unique 5-HT2A receptor biasing and safety profile position it as a potential treatment for mood disorders. Pending future results, zalsupindole could contribute to evolving treatment strategies in psychiatry.