NSI-189
Mood, Neurogenesis
Human trials have been conducted for major depressive disorder, but a clean elimination half-life is not available in the accessible literature.
In short
- A benzylpiperazine-aminopyridine developed for major depressive disorder, associated with hippocampal neurogenesis in preclinical work.
- It went through phase 2 in humans, and the result was equivocal: it missed the primary endpoint while showing improvement on some secondary scales.
- Development was subsequently discontinued.
- Has real human safety data from the trials, which is uncommon in this section.
- Not approved anywhere.
Structure
How it works
NSI-189 was identified through a phenotypic screen for compounds stimulating proliferation of human hippocampal neural stem cells, rather than by designing against a known target — which is why its molecular mechanism remains poorly defined.
Preclinical work reports increased hippocampal volume and neurogenesis. The neurogenesis hypothesis of depression, which motivated the programme, holds that reduced hippocampal neurogenesis contributes to depressive states and that restoring it is therapeutic.
That hypothesis is itself contested, and NSI-189's trial results are part of why.
What the research shows
Phase 1B in major depressive disorder reported signal on several depression scales.
The larger phase 2 study did not meet its primary endpoint. Some secondary measures, particularly cognitive symptoms, showed improvement, and the sponsor emphasised these — but a missed primary endpoint is a missed primary endpoint.
Development was discontinued. Interest in cognitive rather than mood endpoints persisted informally.
Dosing in the literature
Figures below are quoted from published studies, with the species or population they were measured in. They are records of what was studied, not recommendations.
| Studied in | Amount | Route | Source |
|---|---|---|---|
| Human — phase 2 major depressive disorder trial | 40 mg once daily or 40 mg twice daily | oral | PubMed |
| Human — phase 1B dose-finding | 40, 80, or 120 mg daily | oral | PubMed |
Commonly reported ranges
These are amounts people report using. They are not from any study, have not been evaluated for safety, and are reproduced here only because they circulate widely and are better seen alongside the evidence than instead of it.
| Reported by | Amount | Route |
|---|---|---|
| Commonly reported | 20–40 mg daily, in courses of several weeks | oral |
Trial doses are available and community use broadly tracks the lower end. The trials ran for weeks to months, which is the relevant timescale for a neurogenesis-based mechanism — single doses would not be expected to do anything on that theory.
Handling and storage
Oral, as capsules or powder. Trials used daily dosing over 6–12 weeks.
If the mechanism is neurogenesis, the timescale is weeks rather than hours, and evaluating it after a few doses is measuring nothing.
Side effects
The phase 2 trials provide genuine human safety data. Most commonly reported were headache, nausea, dizziness, and irritability.
No serious safety signal emerged in the trials, though they were of limited duration and size.
Long-term safety data does not exist.
Combinations
In the trials it was studied both as monotherapy and adjunctively. No formal interaction studies have been published.
Combination with conventional antidepressants was part of the clinical context but has not been characterised for interaction.
Research status
Developed by Neuralstem, with phase 1B and phase 2 trials in major depressive disorder. The phase 2 result was the pivotal moment, and it was negative on the primary endpoint.
This is one of the better-documented compounds in this section, and what the documentation shows is a drug that did not work well enough to continue.
Legal status
Not approved in any jurisdiction. Development discontinued. Sold as a research chemical.
WADA status
Not specifically named on the Prohibited List. Falls under WADA class S0, which prohibits any pharmacological substance not currently approved by any governmental regulatory health authority for human therapeutic use. Treat it as prohibited in sport.
Conclusion
NSI-189 is a compound with real trials, real safety data, and a real negative result on its primary endpoint.
The secondary cognitive signal is what sustains interest, and it is worth being clear that secondary endpoints in a trial that missed its primary are hypothesis-generating rather than conclusive.
Sources
Track your own NSI-189 protocol
Peppers logs your doses, models your levels from this half-life, tracks your vials and tells you when you will run out. Free on iPhone.
Reference and educational information only. Not medical advice. Nothing here diagnoses, treats, or prescribes, and nothing here is a recommendation to use any compound. The compounds described are research chemicals and are not approved for human consumption. Legal and anti-doping status change — the review date above is when these claims were last checked. Talk to a qualified clinician about anything you intend to take.