NSI-189 (Amdiglurax): The Complete Guide

NSI-189 (INN: amdiglurax; later development code ALTO-100) is a small-molecule investigational drug, not a peptide. The molecule is a synthetic organic heterocycle — specifically a (4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone — with no peptide bonds.

Identity correction: the existing StackTrax encyclopedia describes NSI-189 as a "pyrazolo-pyrazine derivative." That’s wrong. The molecule is a benzylpiperazine–pyridine methanone with no pyrazolopyrazine core. Free base molecular formula C₂₂H₃₀N₄O, MW 366.5 g/mol, CAS 1270138-40-3.

Origin:

• Identified by Neuralstem, Inc. through an in vitro phenotypic screen of ~10,269 compounds against a stable line of human fetal hippocampal neural stem cells, scoring on neurogenic proliferation.
• Lead chemist: Karl Johe (Neuralstem CSO).
• "NSI" = NeuralStem Inc.; "189" is the library entry.

Sponsor history (this matters):

• Neuralstem, Inc. → renamed Seneca Biopharma (Oct 2019)
• Seneca → reverse-merger into Palisade Bio (Apr 2021)
• Palisade Bio sold the asset (2021) for up to $4.9M cash + milestones
• Buyer: Alto Neuroscience, which re-coded the molecule as ALTO-100
• INN amdiglurax assigned post-Alto

Regulatory status:

• FDA (US): never approved. No NDA filed. Not on Drugs@FDA. Not a controlled substance.
• EMA (EU), MHRA, PMDA, Health Canada: no approvals.
• WADA 2026: not specifically named on the Prohibited List. As an unapproved investigational substance, S0 (non-approved substances) catch-all applies. Athletes should consult their governing body.

NSI-189 was identified in a phenotypic screen — scored on a cellular outcome (NSC proliferation in hippocampal culture), not by binding to a defined target.

What is established (preclinical):

• In rodent models, oral NSI-189 has been associated with increased dentate-gyrus neurogenesis, increased hippocampal volume on MRI, enhanced LTP in hippocampal slices, and behavioral improvements in stress, stroke, Angelman syndrome, and diabetic neuropathy models.
• Downstream signaling reported: TrkB and Akt phosphorylation increase (Liu 2019, PMID 30408487). BDNF and SCF protein levels rise in stroke-model brain tissue (Tajiri 2017, PMID 28181668).

What is NOT established:

• The receptor / direct molecular target has not been publicly identified. No published study reports an X-ray co-crystal structure, a confirmed primary binding partner, or a knockout that abolishes NSI-189 activity.
• Statements that NSI-189 "activates TrkB" should be read as "increases TrkB activity downstream," not as direct TrkB agonism.

What NSI-189 is NOT:

• Not a 5-HT (SSRI/SNRI-type) reuptake inhibitor. Does not target SERT.
• Not a norepinephrine reuptake inhibitor. Does not target NET.
• Not a stimulant. No DAT inhibition or amphetamine-like activity.
• Not a monoamine receptor agonist or antagonist at meaningful affinity.
• Not an NMDA antagonist. Mechanistically distinct from ketamine and esketamine (Spravato).
• Not an angiotensin IV / HGF system modulator. Mechanistically distinct from dihexa.

Audit-defensible mechanism statement:

"NSI-189 is a small-molecule investigational compound originally identified by phenotypic screening for hippocampal neural-stem-cell proliferation in vitro. In rodent models it has been associated with increased dentate-gyrus neurogenesis, hippocampal volume, and synaptic plasticity, with downstream activation of TrkB/Akt signaling. The direct molecular target remains uncharacterized in the public literature."

NSI-189 has been tested in two registration-grade MDD trials and missed the primary endpoint in both. Plus an Alto Phase 2b in 2024 that also missed. There has never been a positive pivotal trial.

Phase 1b — Fava 2016 (signal-finding only)

Fava M, Johe K, Ereshefsky L, et al. Mol Psychiatry 2016. PMID 26643541 (erratum PMID 27528461).

• Double-blind, randomized, placebo-controlled, multiple-dose-escalation.
• Inpatient MDD; n = 24; 28 days dosing.
• Doses: 40 mg QD, 40 mg BID, 40 mg TID (40 / 80 / 120 mg/day) vs placebo.
• Primary read: safety, tolerability, PK. No serious adverse events.
• PK: half-life ~17.4–20.5 h; AUC dose-proportional; steady state by 96–120 h. Compatible with once-daily dosing.
• Exploratory: reductions on MADRS, HAM-D, CGI-S, CGI-I, SDQ, CPFQ vs placebo on multiple scales. SDQ/CPFQ effects persisted post-dosing.
• Caveat: n=24 is signal-finding, not confirmatory. Sponsor-funded; Karl Johe is a Neuralstem author.

Briefing PMID error: the original audit briefing listed PMID 27434236 for the Phase 1b paper. That PMID is a 2016 PLoS One paper on benzathine penicillin for antenatal syphilis — not the NSI-189 paper. The correct anchor is PMID 26643541.

Phase 2 — Papakostas 2020 (FAILED primary endpoint)

Papakostas GI, Johe K, Hand H, et al. Mol Psychiatry 2020. PMID 30626911.

• 12-week double-blind, randomized, placebo-controlled, sequential parallel comparison design (SPCD).
• n = 220 outpatients with MDD.
• Doses: NSI-189 40 mg/day, 80 mg/day, or placebo. Monotherapy.
• Primary endpoint: MADRS change from baseline.
• Result: NEGATIVE. Pooled mean MADRS difference vs placebo: 40 mg arm −1.8 (p = 0.22); 80 mg arm −1.4 (p = 0.34). HAM-D17 also did not separate.
• Secondary self-rated SDQ and CPFQ showed nominal advantages for 40 mg/day — exploratory in the absence of primary-endpoint significance.
• Safety: well tolerated; no new safety signals.

Phase 2 post-hoc — Johe 2020

Johe K, Hand H, Heintz N, et al. Ann Clin Psychiatry 2020. PMID 32722729. Re-analysis of the same 220-patient dataset with severity dichotomization. 80 mg/day showed effect in moderately depressed subgroup (MADRS <30) but not severely depressed.

Methodological caveat: post-hoc dichotomized subgroup analysis. First author is Karl Johe (sponsor employee). Hypothesis-generating only; cannot rescue a negative primary endpoint per FDA review standards.

Alto Neuroscience era (ALTO-100):

• 2023 Phase 2 (precision-psychiatry-stratified): Alto press releases reported a biomarker-defined responder subgroup outperforming non-responders on MADRS at week 6. No peer-reviewed publication located.
• 2024 Phase 2b: MISSED PRIMARY ENDPOINT (MADRS vs placebo) per Alto IR disclosure October 2024.

Cognitive enhancement in healthy adults:

There is no published controlled trial of NSI-189 in cognitively normal adults for nootropic / cognitive-enhancement use. All efficacy data come from MDD populations or rodent models. Marketing claims of cognitive enhancement in healthy users are extrapolations from rodent and depressed-patient data only.

From Fava 2016 Phase 1b (PMID 26643541):

• Route: oral (capsule).
• Half-life (t½): 17.4–20.5 h.
• AUC: dose-proportional across 40 / 80 / 120 mg/day.
• Steady state: reached by 96–120 h of repeat dosing.
• BBB penetration: inferred from CNS pharmacodynamic effects; quantitative human CSF / PET data not published.
• Trial doses: 40 or 80 mg/day in Phase 2.
• Food effect, drug interactions, metabolism, excretion: not fully characterized in published literature.

StackTrax does not endorse NSI-189 use. Two MDD trials missed primary endpoints. The dosing below is community / vendor convention.

Parameter	Range
Dose	20–80 mg/day oral (community); the trial doses were 40 and 80 mg/day
Cycle length	4–12 weeks (community); the longest published trial was 12 weeks
Route	Oral (capsule, sometimes sublingual per vendor instructions)

No long-term human safety data exist beyond 12 weeks. There has been no Phase 3 of any kind. No real-world registry.

From the trial record:

Across Phase 1, Phase 1b, and Phase 2 (a combined total of ~280 patients with up to 12 weeks of dosing): generally well tolerated, no serious adverse events. The trials failed on efficacy, not safety.

Common (community / trial reports):

• Mild irritability or paradoxical mood effects (community reports; not consistently in trial data).
• Headache.
• Mild GI effects.
• Sleep disturbance with later-day dosing (community).

Theoretical / unaddressed:

• Long-term safety beyond 12 weeks: not characterized in any published study.
• Receptor target uncharacterized: by definition, off-target effects can’t be ruled out for an undefined molecular target.
• Cancer-axis: a "neurogenesis enhancer" mechanism that drives neural-stem-cell proliferation is theoretically aligned with proliferative pathways; long-term carcinogenicity data do not exist.
• Pregnancy / breastfeeding: not studied.

• Pregnancy / breastfeeding — no safety data.
• Active or prior cancer — theoretical caution given the proliferation-enhancer phenotype with an undefined molecular target.
• Active major depressive disorder — especially if depression is severe. The published Phase 2 post-hoc suggested benefit was concentrated in moderate depression and absent in severe depression. Severe MDD users should not rely on NSI-189 instead of evidence-based treatment.
• Suicidal ideation — not a substitute for evidence-based MDD treatment.
• Concurrent SSRIs / SNRIs / mood stabilizers — uncharacterized interactions; sponsor data did not test combinations systematically.
• Athletes subject to anti-doping testing — consult your governing body. WADA S0 catch-all may apply.
• Anyone seeking an "approved antidepressant" — NSI-189 has never been approved.

Compound	Class / Mechanism	Difference
SSRIs / SNRIs	Serotonin / NE reuptake inhibitors	NSI-189 has NO reuptake activity; not a monoamine modulator
Ketamine / esketamine (Spravato)	NMDA antagonist; rapid-acting via glutamate / synaptogenesis	Ketamine works in hours; NSI-189 acts over weeks via a phenotypic-neurogenic mechanism with no NMDA activity
Bupropion	NDRI / nicotinic modulator	NSI-189 is not a stimulant
Tianeptine	µ-opioid agonist (rebadged historically)	NSI-189 has no opioid activity; no abuse potential reported
Cerebrolysin	Porcine-brain-derived peptide mixture	Peptide mixture given IM; NSI-189 is a single small molecule oral
Semax / Selank	Russian heptapeptide nootropics (ACTH-derived)	True peptides; intranasal; mechanism distinct
Dihexa	HGF/c-Met positive modulator (peptide-derived)	Different chemistry, different target. Dihexa’s foundational papers have been retracted; NSI-189’s primary literature is intact but trials failed.
BDNF / 7,8-dihydroxyflavone	Direct TrkB agonists	NSI-189’s TrkB activation is downstream / indirect, not direct agonism
Spadin / PE-22-28	TREK-1 K-channel blocker peptides	Peptide; ion-channel target; unrelated mechanism
Modafinil / armodafinil	Wake-promoting (DAT / orexin)	NSI-189 is not stimulant-like; does not promote wakefulness via DAT
Racetams	Putative cholinergic / AMPA modulators	Different chemistry; racetam efficacy itself controversial

ALTO-100 / amdiglurax — same molecule under different names. The Alto Phase 2b 2024 missed primary endpoint; this isn’t a different drug, just a re-coding by a new sponsor.