RESEARCH MONOGRAPH · KDC-MN-313

NSI-189

May 9, 2026 Kodiac biolabs Research Revised May 30, 2026 2 min read

Our opinion on this compound

67/100

One of the only molecules with a real neurogenic signal in adult human hippocampus, and the industry mostly missed it

NSI-189 is genuinely intriguing and we think it's slept-on. Neuralstem developed it as a hippocampal neurogenesis stimulator and the preclinical pharmacology is unusually clean. Liu et al at Mass General showed dose-dependent increases in BrdU+ cells in the dentate gyrus of mice, with concurrent improvements in cognitive and depression-like measures. Then the phase 1b in MDD patients actually worked. Then the phase 2 missed its primary endpoint and the program basically died.

The interesting thing is the phase 2 result deserves more careful reading than it got. The primary endpoint (MADRS) missed but secondary measures, particularly the cognitive symptoms of depression (CPFQ) and the SDQ, hit significantly. Which is exactly what you'd predict if you believe the mechanism: a hippocampal neurogenesis effect should show up on cognitive-affective measures first, not on pure mood scales that are dominated by monoaminergic biology. The trial wasn't designed for the molecule it actually was.

Mechanism remains partly mysterious. It's a benzylpiperazine-substituted nicotinamide. It doesn't bind monoamine transporters, doesn't hit the usual receptors. The downstream signal seems to involve BDNF upregulation and something acting on neural progenitor proliferation in the SGZ. There's a JNK pathway hypothesis but it's not airtight.

What we like: oral bioavailability is solid, half-life is workable, and it's structurally simple enough that vendor sourcing isnt a nightmare. HPLC/LCMS verification is straightforward. Free base versus dihydrochloride salt forms both exist and you want to pay attention to which one you're getting because the molar conversions trip people up.

What we dont like: the post-Neuralstem orphan status means there's almost no new human data coming. Whatever you learn about it now you're piecing together from the original trial plus animal work plus a thin user-reported signal. Reproducibility in independent labs has been okay but not great.

Honestly, if hippocampal neurogenesis ends up mattering for any of the next-generation depression or cognitive-aging approaches, NSI-189 is going to look smarter in hindsight than it does today. Research compound worth keeping in active rotation.

Evidence: 60
Mechanism: 55
Reliability: 65
Safety: 75
Sourcing: 70
Value: 65
Signal: 72
Staying power: 70

Plain-language summary Intrigue 45 / 100

NSI-189 is a small molecule developed at Neuralstem to stimulate hippocampal neurogenesis (the birth of new neurons in the dentate gyrus). Preclinical rodent studies showed proliferation of neural progenitor cells, hippocampal volume increase, and antidepressant-like behavior in chronic stress models, generating considerable hope that this could be a fundamentally new class of antidepressant. Phase 1 trials were uneventful. Phase 2 trials in major depression in 2014 and 2017 failed to beat placebo on the primary endpoints, and Neuralstem ended development. It briefly became popular in nootropic communities sourced as a research chemical, on the strength of secondary cognitive endpoints in the failed trials. The clinical case is essentially closed. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Benzylpiperazine-substituted nicotinamide neurogenic compound

A small-molecule neurogenic compound investigated for major depressive disorder; failed phase 2 efficacy.

Abstract

NSI-189 (NSI-189 phosphate; CAS 1270138-40-3; molecular formula C22H30N4O5P; molecular weight 461.47) is a benzylpiperazine-substituted nicotinamide developed at Neuralstem as a stimulator of hippocampal neurogenesis. Preclinical studies in rodents demonstrated proliferation of progenitor cells in the dentate gyrus, hippocampal volume increase, and antidepressant-like behavior in chronic stress models. Phase 1 trials in healthy volunteers were uneventful; phase 2 trials in major depressive disorder (2014, 2017) failed to demonstrate efficacy versus placebo on primary endpoints, halting development. The compound retains research utility as a neurogenic probe in academic neuroscience. Plasma half-life is approximately 17 to 20 hours.

Mechanism of action

Small-molecule stimulator of hippocampal neurogenesis; mechanism via effects on progenitor cell proliferation pathways. Failed phase 2 in MDD.

Reported research dose ranges

Trial doses 40 to 120 mg in the published literature.

References

Liu Y, et al. NSI-189, a small molecule with potential efficacy for major depressive disorder, induces hippocampal neurogenesis. ACS Chem Neurosci 2016.
Fava M, et al. A double-blind, placebo-controlled, exploratory trial of NSI-189 phosphate, a novel neurogenic compound, in adults with major depressive disorder. Mol Psychiatry 2016.
Papakostas GI, et al. NSI-189 in major depressive disorder: phase 2 results. Mol Psychiatry 2020.

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KDC-MN-313

The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.

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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

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NSI-189

Abstract

Mechanism of action

Reported research dose ranges

References

Read the full monograph

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Abstract

Mechanism of action

Reported research dose ranges

References

Read the full monograph

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