NSI-189 (also known as Amdiglurax, ALTO-100, ALTO-300)
NSI-189 phosphate (INN: Amdiglurax); synonyms: NSI-189, ALTO-100, ALTO-300; CAS 1270138-40-3 (freebase), CAS 1270138-41-4 (phosphate salt); DrugBank DB16230; UNII YVE9U408ZL
NSI-189 is a novel small molecule neurogenic compound developed for major depressive disorder (MDD) that stimulates hippocampal neurogenesis independent of monoamine reuptake inhibition. It completed Phase 1B (PMID 26643541) and Phase 2 (PMID 30626911) clinical trials in MDD, showing favorable tolerability but failing to meet its primary efficacy endpoint.
Last updated: 2026-03-13
Safety Summary
In clinical trials (Phase 1B: PMID 26643541; Phase 2: PMID 30626911; PMC7303010), NSI-189 phosphate was generally well tolerated at doses of 40-120 mg/day. No treatment-related serious adverse events (SAEs) were reported in any trial. No dose-limiting toxicities were identified. Discontinuation rates in the Phase 2 trial were lower in the NSI-189 groups than placebo. Complete adverse event frequency tables by dose cohort were not published in the publicly available manuscripts. No abuse potential has been reported (DrugBank DB16230; Wikipedia). No anti-drug antibody formation or immunogenicity concerns exist (NSI-189 is a small molecule, not a biologic). Community reports (ANECDOTAL) consistently cite anxiety as the most common adverse effect, along with paresthesia, headaches, and depersonalization, particularly during early dosing or at higher doses. These effects often abate with dose reduction or cycling. No formal drug-drug interaction data (CYP inhibition/induction, transporter effects) has been published (DrugBank DB16230;). Long-term safety data beyond 12 weeks is not available from controlled clinical studies; no tolerance, withdrawal, or carcinogenicity signals have been reported in the available data.
Known Side Effects
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Who Should NOT Use This
Clinical trials excluded pregnant/lactating women and required contraception. No human pregnancy exposure, embryofetal, or teratogenicity data available.
Excluded from clinical trials due to risk of mood destabilization.
Excluded from clinical trials. No dedicated organ-impairment PK/safety studies available.
Excluded from Phase 2 trial.
Excluded from clinical trials as a safety precaution.
Phase 2 excluded or required washout of most psychotropic medications. No formal drug interaction data exists.
Excluded from clinical trials.
No pediatric clinical data. All trials enrolled adults 18-60 only.
Talk to Your Doctor
Before considering NSI-189 (also known as Amdiglurax, ALTO-100, ALTO-300), discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-10]
Evidence Assessment
NSI-189 has completed Phase 2 clinical trials in MDD. The Phase 1B (NCT01520649, n=24, PMID 26643541) showed favorable safety and exploratory efficacy signals. The Phase 2 (NCT02695472, n=220, PMID 30626911) failed its primary MADRS endpoint but showed positive secondary outcomes (SDQ, CPFQ, cognitive measures). A Phase 2b is currently ongoing under Alto Neuroscience with ~200 biomarker-selected patients. No Phase 3 trials have been completed. The compound has not received FDA approval. Both drafts agree on Evidence Tier 3.
1A Phase 1, Randomized, Subject Single Blinded, Placebo-Controlled, Single-Dose Escalation Study Evaluating the Safety, Tolerability, and Pharmacokinetics (PK) of NSI-189 Phosphate in Healthy SubjectsNCT01310881
Neuralstem Inc. (Karl Johe, David Han) - ClinicalTrials.gov (2011) - Phase 1, Randomized, Single-blind, Placebo-controlled, Single-dose escalation - 35 (healthy volunteers)
First-in-human study. Established safety and pharmacokinetic profile of single oral doses. No results posted publicly.
Limitations: Results not published in peer-reviewed literature. Healthy volunteers only.
2A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patientsNCT01520649PMID 26643541
Fava M, Johe K, Ereshefsky L, Gertsik LG, English BA, Bilello JA, Thurmond LM, Johnstone J, Dickerson BC, Makris N, Hoeppner BB, Flynn M, Mischoulon D, Kinrys G, Freeman MP - Molecular Psychiatry (2016) - Phase 1B, Randomized, Double-blind, Placebo-controlled, Multiple-dose escalation - 24 (MDD inpatients; 6 per cohort x 3 dose cohorts + placebo)
NSI-189 was well tolerated at 40mg QD, BID, TID for 28 days. Half-life 17.4-20.5h. Tmax 1-2h. Dose-proportional PK. Exploratory efficacy: large effect sizes vs placebo on SDQ (d=0.90), MADRS (d=0.95), CPFQ (d=0.94), CGI-I (d=0.57) at day 28. Effects persisted to day 84 follow-up without continued treatment.
Limitations: Very small sample (n=24). Exploratory efficacy only (not powered for efficacy). Inpatient population may not generalize.
3A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorderNCT02695472PMID 30626911
Papakostas GI, Johe K, Hand H, Drber T, Johnson B, Russo P, Khin N, Bilello JA, Ereshefsky L, Fava M - Molecular Psychiatry (2019) - Phase 2, Randomized, Double-blind, Placebo-controlled, SPCD (Sequential Parallel Comparison Design) - 220 (MDD outpatients; 44 on 40mg, 44 on 80mg, 132 on placebo in Stage 1)
Primary endpoint (MADRS change) NOT met: 40mg MD=-1.8 (p=0.22), 80mg MD=-1.4 (p=0.34). Secondary: 40mg dose showed significant SDQ improvement (d=-0.68 Stage 2, p=0.04), positive CPFQ, QIDS-SR, and some CogScreen cognitive subtests. Well tolerated with no SAEs. Discontinuation rates lower in drug groups than placebo.
Limitations: Failed primary endpoint. Powered for large effect (d=0.5). Industry-sponsored. SPCD design complexity. No dose-response (80mg no better than 40mg). Secondary/exploratory analyses.
4NSI-189 phosphate, a novel neurogenic compound, selectively benefits moderately depressed patients: A post-hoc analysis of a phase 2 study of major depressive disorderNCT02695472PMID 32722729
Not fully listed in raw data - Annals of Clinical Psychiatry (2020) - Post-hoc analysis of Phase 2 RCT - Subset of 220 from Phase 2
NSI-189 selectively benefited moderately depressed patients (as opposed to severely depressed) in the Phase 2 trial.
Limitations: Post-hoc analysis. Hypothesis-generating only.
5NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke ratsPMID 28181668
Tajiri N, Quach DM, Kaneko Y, Wu S, Lee D, Lam T, Hayama KL, Hazel TG, Johe K, Wu MC, Borlongan CV - Journal of Cellular Physiology (2017) - Preclinical (rat stroke model) - Animal study
NSI-189 (30 mg/kg oral, 12 weeks post-stroke) produced behavioral recovery and neurostructural benefits. Increased Ki67+ (proliferating) and MAP2+ (mature) neurons in peri-infarct area. Upregulated neurogenic factors (BDNF, SCF). No organ toxicity signals.
Limitations: Animal model only. Not directly translatable to humans.
6Enhancement of synaptic plasticity and reversal of impairments in motor and cognitive functions in a mouse model of Angelman Syndrome by a small neurogenic molecule, NSI-189
Bhattacharya et al. (Baudry M) - Neuropharmacology (2019) - Preclinical (Angelman Syndrome mouse model) - Animal study
NSI-189 enhanced synaptic plasticity (LTP) and reversed motor and cognitive impairments in Angelman Syndrome mice.
Limitations: Animal model only. Angelman Syndrome is a rare condition.
7Enhancement of Mitochondrial Function by the Neurogenic Molecule NSI-189 Accompanies Reversal of Peripheral Neuropathy and Memory Impairment in a Rat Model of Type 2 Diabetes
Jolivalt CG et al. - Journal of Diabetes Research (2022) - Preclinical (Type 2 diabetes rat model) - Animal study
NSI-189 enhanced mitochondrial function (elevated complexes III/V expression, I/IV activity), reversed peripheral neuropathy and memory impairment. AMPK phosphorylation increased.
Limitations: Animal model only.
8Remediation of Radiation-Induced Cognitive Dysfunction through Oral Administration of the Neuroprotective Compound NSI-189
Acharya et al. - Radiation Research (2018) - Preclinical (radiation-induced cognitive dysfunction) - Animal study
Oral NSI-189 remediated radiation-induced cognitive dysfunction in animal models.
Limitations: Animal model only.
9The neurogenic compound, NSI-189 phosphate: a novel multi-domain treatment capable of pro-cognitive and antidepressant effectsPMID 28460574
McIntyre RS, Johe K, Rong C, Lee Y - Expert Opinion on Investigational Drugs (2017) - Review article - N/A (review)
Review characterizing NSI-189 as a novel multi-domain treatment with both pro-cognitive and antidepressant effects.
Limitations: Review, not original data.
10Experimental medication treatment approaches for depressionPMID 28323287
Ionescu DF, Papakostas GI - Translational Psychiatry (2017) - Review article - N/A (review)
NSI-189 discussed among experimental approaches for depression, highlighting its neurogenic mechanism as distinct from existing antidepressants.
Limitations: Review, not original data.