Zalsupindole: A Non-Hallucinogenic Psychoplastogen Advancing Psychedelic-Inspired Therapeutics.
Miguel Salfiti, Marios Kyriazis, Georgios Mikellides
ACS Chemical Neuroscience January 21, 2026 DOI: 10.1021/acschemneuro.5c00707 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Population | Preclinical and early clinical data on zalsupindole |
| Topics | Neuroplasticity |
| Keywords | 5-ht2a Aaz-a-154 Dlx-001 Biased agonism Psychedelics Psychoplastogens Zalsupindole |
| Citations | 2 |
| Key findings | Zalsupindole promotes neuroplasticity via 5-HT2A biased agonism without hallucinogenic effects, showing rapid antidepressant-like activity in animal models and good tolerability in Phase 1 trials. |
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.
Comparable studies
Other narrative reviews on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists | 2012 | Review | |
| Towards an understanding of psychedelic-induced neuroplasticity. Review of preclinical and clinical studies | 2023 | Review | |
| Buddha's Brain: Neuroplasticity and Meditation [In the Spotlight] | 2008 | Review | |
| Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics | 2021 | Review | |
| Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms | 2020 | Review |
Citations in the library
Cited by 5
- 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
- Beyond the Genomic Storm: Evaluating Tabernanthalog as a Potential Scaffold for Silent Neuroplasticity and Broad-Spectrum Therapy International Journal of Molecular Sciences March 20, 2026
- Next-Generation Psychedelic Drug Development ACS Chemical Neuroscience September 15, 2026
- Multidimensional characterization of the physiological and behavioral effects of TCB-2 in mice bioRxiv August 6, 2026
Cites 26
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
and 21 more in the library