NSI-189 Dosage: The 40-80 mg/day Trial Figure

NSI-189's most-referenced figure is about 40-80 mg per day, taken orally once daily. Unlike most research nootropics, that range is not pulled from forum guesswork: it is inherited directly from the doses used in NSI-189's human depression trials, which ran 40 mg and 80 mg/day arms. The catch is what those trials found. The pivotal Phase 2 study failed its primary endpoint, and the drug was never approved, so the dose people use is trial-derived but not validated for cognitive enhancement in anyone.

NSI-189 is also not a peptide. It is a synthetic small molecule (a benzylpiperazine-aminopyridine) originally developed by Neuralstem as a neurogenic candidate for major depressive disorder. This guide reports the dose figures community sources reference, where they trace back to, and the trial record behind them — not a recommended protocol.

Research-context information only. NSI-189 is an investigational drug not approved by the FDA; its clinical program was discontinued, and material sold today is a research chemical labeled not for human consumption. Protocols, doses, and reactions reported below come from published clinical trials and self-reported community sources. This article reports what has been documented, not what should be done. Possession or use of investigational drugs outside an authorized clinical trial may be illegal in your jurisdiction. Consult a licensed physician for personal medical decisions.

Quick Reference: Protocol

There is no clinically-established cognitive-enhancement protocol to publish, because no trial has validated one. What does exist is a community-used range that maps cleanly onto the doses used in the depression trials. The table below reports the figures that appear in vendor listings and forum discussion, organized by the forms NSI-189 is sold in. Every value is trial-derived or vendor-reported, not enhancement-validated.

The 40 mg and 80 mg figures are exactly the two active-arm doses tested in the Phase 2 trial; the Phase 1B study also ran a 120 mg/day arm. Community sources commonly describe time-limited courses and on/off cycling, loosely mirroring the trial windows (28 days in Phase 1B, up to 12 weeks in Phase 2) — but no human safety data exists for any cycle length beyond those ≤12-week trial exposures.

Routes of Administration

NSI-189 is an oral small molecule, and the oral route is both the dominant community route and the route used in every human trial. That alignment is unusual for a research nootropic and is worth noting.

• Oral (capsules or powder): Capsules at 20 mg each and loose phosphate or free-base powder are the standard forms. Once-daily oral dosing matches the trial protocol. The phosphate salt is the form used in the clinical trials and is described by vendors as having better solubility and stability than the free base.
• Sublingual: Occasionally mentioned in forums, but it has no pharmacokinetic basis in the published record and was not a route studied in the trials.

There is no injectable or reconstituted route in the documented record, and no human data supports anything other than oral use.

Reconstitution Quick Reference

NSI-189 does not have a reconstitution step. It is an oral small molecule sold as phosphate powder, free-base powder, or 20 mg capsules — not a lyophilized peptide that gets mixed with bacteriostatic water — so no vial/diluent/concentration dilution table applies to it.

Powder is generally described as being kept dry, sealed, and stored cool away from light. Purity and identity depend entirely on the supplier's certificate of analysis; vendor copy commonly claims roughly 98-99% by HPLC, which should be verified against the current COA. The material is labeled not for human consumption.

Affiliate disclosure: vendor links in this article are affiliate links — The Peptide Catalog may earn a commission if you buy through them, at no additional cost to you.

Where These Numbers Come From

The 40-80 mg/day figure is not a forum invention, and it is not an enhancement-validated dose either. It comes from the doses used in NSI-189's human depression trials, which is what makes NSI-189 different from most research nootropics: the community dose maps onto real trial doses rather than being reverse-engineered from vendor copy alone.

In a Phase 1B multiple-dose-escalation study in patients with major depressive disorder (Fava et al., 2016, PMID 26643541), NSI-189 phosphate was tested at 40 mg once daily, 80 mg/day, and 120 mg/day over 28 days. It was reported to be relatively well tolerated at all doses with no serious adverse effects. That established the dose range the community later adopted.

The pivotal trial is the part that has to be reported prominently. In a 220-patient, 12-week Phase 2 monotherapy study in outpatients with MDD (Papakostas et al., 2020, PMID 30626911), NSI-189 was tested at 40 mg/day and 80 mg/day against placebo. The primary endpoint — change in the Montgomery-Åsberg Depression Rating Scale (MADRS) — was not met at either dose (40 mg, p = 0.224; 80 mg, p = 0.344). Some subject-rated secondary scales favored the 40 mg arm (the Symptoms of Depression Questionnaire and the Cognitive and Physical Functioning Questionnaire, pooled SDQ p = 0.044), and a small hippocampal-volume increase was reported, but those are secondary, subject-rated signals that do not rescue a failed primary endpoint. On the July 2017 top-line miss, Neuralstem's stock fell sharply and the depression program did not advance to a successful Phase 3.

A later post-hoc subgroup analysis of the same dataset (Johe et al., 2020, PMID 32722729) reported that the 80 mg dose benefited the moderately-depressed subgroup (baseline MADRS < 30) but not severely-depressed patients. Post-hoc subgroup findings are hypothesis-generating only; they do not change the fact that the prospectively-defined primary endpoint failed, and they are not evidence that NSI-189 "works for moderate depression."

The preclinical record is animal and in-vitro only. In rodents, NSI-189 has been reported to improve recovery in a stroke model with increased BDNF and neurite outgrowth (Tajiri et al., 2017, PMID 28181668) and to enhance long-term potentiation and reverse cognitive and motor deficits in an Angelman-syndrome mouse model via TrkB and Akt pathway activation (Liu et al., 2019, PMID 30408487). These are directionally consistent with the "neurogenic compound" descriptor, but they are not human-efficacy evidence and did not translate into a positive human primary endpoint.

The honest bottom line: there is no trial that tested NSI-189 for cognitive enhancement in healthy people, so the dose people use is trial-derived but not enhancement-validated.

Stacking Protocols

Community sources sometimes describe pairing NSI-189 with other nootropic compounds, but there is no trial-validated stacking protocol and no human safety data for any combination. The only human dosing data that exists is the monotherapy used in the depression trials. Because no trial has validated NSI-189 even for enhancement on its own, layering additional unapproved research chemicals compounds the uncertainty rather than resolving it. This guide does not report specific stack doses, as none rest on documented human evidence.

Side Effects & Safety

NSI-189's short-term tolerability record is, unusually for this category, one of its stronger data points — but it covers only up to 12 weeks of exposure.

• Documented in trials: Phase 1B (PMID 26643541) reported it was relatively well tolerated at up to 120 mg/day with no serious adverse effects; the most common adverse events were headache, dizziness, and somnolence. Phase 2 (PMID 30626911) described it as safe and well tolerated with no serious adverse events attributable to NSI-189. This is one of the better-documented short-term tolerability records among research nootropics.
• No long-term human data: the longest trial exposure was about 12 weeks. Nothing in the published record speaks to safety beyond that window.
• Theoretical (mechanistic): a compound promoting neurogenesis and cell proliferation has, in principle, unknown long-term proliferative-signaling implications. This is mechanistic reasoning, not a documented adverse effect observed in the trials.
• Community-reported (anecdotal): headache, irritability or anxiety, fatigue or a "flat"/blunted affect, sleep changes, and GI upset. Reports are inconsistent — some community users describe no noticeable effect at all. None of this is placebo-controlled.

The accurate framing is that the trials reported NSI-189 was well tolerated with no serious adverse events at ≤12 weeks, while the efficacy primary endpoint still failed and no long-term human safety data exists.