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NSI-189 1g

NSI-189 1g

€27,50 EUR
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                                         NOT FOR HUMAN CONSUMPTION

NSI-189 is an orally bioavailable, benzylpiperazine-aminopyridine small molecule originally developed to stimulate hippocampal neurogenesis and improve mood and cognition. It is not approved by any regulator. After Phase 1 safety and signal-finding studies in major depressive disorder (MDD), a Phase 2 program did not meet its primary endpoint; development has largely stalled. Preclinical data indicate pro-neurogenic, synaptogenic, and neurotrophic effects in hippocampus with downstream impacts on stress circuitry and cognition.

Additional Benefits of NSI-189 Now Under Investigation

Benefit Key take-aways
1 Hippocampal neurogenesis In vitro and rodent studies show proliferation/differentiation of hippocampal precursors and spine density increases; memory behaviors improve in stress/lesion models. Stem Cell Reports; Journal of Neuroscience
2 Antidepressant signal (MDD) Early Phase 1b showed exploratory improvements on depression scales; the Phase 2RCT failed its primary endpoint but suggested subset/time-course signals—insufficient for approval. Molecular Psychiatry; Depression & Anxiety
3 Cognitive enhancement (processing speed/working memory) Rodent data and small human exploratory tasks suggested modest cognitive benefits, especially in processing speed and verbal learning domains. Neuropsychopharmacology; CNS Drugs
4 Anhedonia & motivation Preclinical stress paradigms show sucrose preference and effort-based tasksimprovements consistent with mesolimbic normalization. Biological Psychiatry; Translational Psychiatry
5 Neuroprotection after ischemia/TBI In stroke/TBI models, NSI-189 reduced lesion-associated behavioral deficits and supported neurite/synapse recovery. Brain Research; Experimental Neurology
6 Anti-inflammatory/neuroimmune modulation Down-shift of microglial NF-κB and cytokines (IL-1β, TNF-α) reported alongside neurogenesis; causal links remain exploratory. Glia; Journal of Neuroinflammation
7 Stress-axis normalization Rodent work shows HPA-axis re-tuning with lower corticosterone reactivity and improved hippocampal feedback. Endocrinology; Psychoneuroendocrinology
8 Neuroplasticity in aging Signals for hippocampal volume preservation and memory tasks in aged rodents; human aging data absent. Aging Cell; Neurobiology of Aging
9 Adjunct in PTSD/cognitive syndromes Concept: pair neurogenesis with psychotherapy/rehab to consolidate learning; only preclinical or hypothesis-driven studies so far. Frontiers in Psychiatry; Behavioural Brain Research

2. Molecular Mechanism of Action

2.1 Pharmacodynamics (working model)

  • Neurogenesis & synaptogenesis: Up-regulates BDNF, CREB, MAPK/ERK, and PI3K–Akt–mTOR pathways → progenitor proliferation, dendritic spine formation, and synaptic proteins (PSD-95, synapsin).

  • Neuroimmune & HPA modulation: Restraint of NF-κB signaling and improved glucocorticoid feedback in hippocampus → stress resilience.

  • Not a monoaminergic reuptake inhibitor/MAOI. Any serotonergic/dopaminergic effects appear downstream of plasticity cascades.

2.2 Down-stream biology

Pathway Functional outcome Context
BDNF–TrkB → ERK/CREB Plasticity gene induction, mood/cognition Hippocampus
PI3K–Akt–mTOR Cell survival, dendritic growth Hippo/cortex
NF-κB restraint ↓ Pro-inflammatory cytokines Microglia
HPA re-tuning Stress reactivity ↓ Limbic loop

3. Pharmacokinetics

  • Route: Oral (phosphate salt).

  • Brain penetration: Demonstrated in animals; human CNS levels not published.

  • Half-life/steady state: Hours to low-teens half-life reported; once- or twice-daily regimens used in trials.

  • Metabolism: Hepatic oxidative pathways (exact CYP liabilities not fully characterized).

  • Food effect/interactions: Limited public data; not a classic CYP inducer/inhibitor.

4. Clinical Evidence (high-level)

  • Phase 1b in MDD: Generally well tolerated; exploratory antidepressant and cognitive signals across several scales.

  • Phase 2 in MDD: Did not meet primary endpoint vs placebo; some secondary/exploratory outcomes hinted at benefit in subgroups/time windows—insufficient for advancement.

  • Imaging/biomarkers: Small datasets explored hippocampal volumetrics and peripheral BDNF—inconclusive.

Evidence quality note: Strong preclinical plausibility with neurogenesis/circuit biology; human efficacy unproven after a negative Phase 2. Any clinical use should be confined to research settings.

5. Emerging Clinical Interests (conceptual)

Field Rationale Status
Treatment-resistant depression Plasticity beyond monoamines Concept
Post-stroke/TBI cognitive rehab Pairing synaptogenesis with therapy Preclinical/early concept
PTSD Extinction learning support Concept
Age-related cognitive decline Hippocampal neurogenesis Preclinical concept

6. Safety and Tolerability

  • Common AEs in trials: Headache, dizziness, somnolence/insomnia, nausea, fatigue—generally mild to moderate.

  • Vitals/labs/ECG: No consistent safety signal in short-term studies.

  • Neuropsychiatric: Activation/insomnia in a subset; monitor for anxiety or agitation early in dosing.

  • Suicidality monitoring: Standard for antidepressant investigations—no clear excess signal reported, but vigilance required.

  • Long-term safety: Unknown (no lengthy exposure datasets).

  • Drug interactions: Limited data; because the MOA is non-monoaminergic, risk of serotonin syndrome appears low when combined with SSRIs/SNRIs, but combination evidence is sparse—use caution in research settings.

Comparative snapshot (neuroplasticity-oriented antidepressants)

Feature NSI-189 Ketamine/Esketamine SSRIs/SNRIs
Primary action Neurogenesis/BDNF–CREB (putative) Rapid glutamatergic plasticity Monoamine transport
Onset Gradual (weeks) Rapid (hours–days) Weeks
Evidence Negative Phase 2 primary Robust TRD efficacy Robust MDD efficacy
Abuse liability Low (expected) Moderate (controlled) Low

7. Regulatory Landscape

  • Not approved (no active late-stage programs publicly ongoing).

  • Any availability is via research channels; consumer “nootropic” products are unregulated and may be misidentified—avoid outside formal trials.

8. Practical Take & Future Directions

  • Current stance: NSI-189 remains experimental with insufficient clinical efficacy.

  • If pursued scientifically: Target biotype-enriched populations (low hippocampal volume, high inflammation, high anhedonia), use adaptive trial designs, and anchor outcomes with objective cognition, digital phenotyping, and MRI/EEG biomarkers.

  • Combination hypotheses: Pair with psychotherapy/rehab, exercise, or sleep-based plasticity protocols to exploit a pro-neurogenic state.

  • Translational needs: Clear target engagement biomarkers, refined PK/PD, and longer blinded trials in precisely defined cohorts.

Selected References

  • Stem Cell Reports; Journal of Neuroscience — NSI-189-driven neurogenesis and synaptogenesis in vitro/in vivo.

  • Molecular Psychiatry; Depression & Anxiety; CNS Drugs — Phase 1/2 clinical results in MDD (safety, exploratory signals, Phase 2 miss).

  • Neuropsychopharmacology; Translational Psychiatry — Plasticity markers, cognition, and stress-model outcomes.

  • Glia; Journal of Neuroinflammation — Neuroimmune modulation accompanying neurogenesis.

  • Endocrinology; Psychoneuroendocrinology — HPA-axis changes linked to hippocampal plasticity.

  • Brain Research; Experimental Neurology — Post-stroke/TBI recovery paradigms.