NSI-189

Quick Facts

• Full Name: NSI-189 Phosphate
• Aliases: NSI-189, Neuralstem compound 189
• Category: Cognitive Enhancement / Neurogenesis / Antidepressant
• Type: Synthetic neurogenic compound (benzyl-piperazine / nicotinamide derivative)
• Molecular Weight: 473.6 Da (free base)
• Administration: Oral
• Typical Dose: 20–40 mg/day
• Frequency: Once daily or divided (20 mg BID)
• Half-Life: ~6–8 hours
• Status: Research Only (Phase II trials completed; not FDA-approved)
• WADA Status: Not listed

What It Does

NSI-189 is a neurogenic compound developed by Neuralstem Inc. that promotes hippocampal neurogenesis — the growth of new neurons in the hippocampus. It increases hippocampal volume, enhances BDNF signaling, and demonstrated antidepressant effects in Phase I/II clinical trials for major depressive disorder (MDD). Unlike traditional antidepressants, it works via neuroregeneration rather than monoamine modulation, making it a novel approach to both depression and cognitive enhancement.

Mechanism of Action

1. Hippocampal neurogenesis: NSI-189 promotes proliferation and differentiation of neural stem cells in the hippocampal dentate gyrus → measurable hippocampal volume increase (MRI-verified in human trials)
2. BDNF upregulation: Increases BDNF mRNA and protein in hippocampus → supports new neuron survival and synaptic integration
3. Antidepressant mechanism: Neurogenic hypothesis of depression — hippocampal volume restoration reverses depressive symptoms independently of monoamine pathways
4. Cognitive improvement: Larger, more connected hippocampus → improved episodic memory, spatial navigation, emotional regulation
5. Neuroinflammation reduction: Anti-inflammatory effects in hippocampal microglia

Dosing Protocols

Standard Protocol

• Dose: 40 mg/day (40 mg once daily, or 20 mg BID)
• Frequency: Once or twice daily
• Duration: 8–12 week minimum (neurogenesis takes time to manifest clinically)
• Cycling: 8–12 weeks on, 4–6 weeks off; assess benefits before repeat
• Start: Some begin at 20 mg/day for first 2 weeks to assess tolerance
• Source: The Peptides Bible, Phase II trial data (Fava et al.)

Cognitive Enhancement Protocol

• Dose: 20–40 mg/day
• Duration: 12 weeks minimum
• Stack with Selank or P21 for enhanced neurogenesis

Stacks Well With

• Cerebrolysin + RG3 – advanced neuroprotective and neurogenic stack
• Selank + P21 – neurogenesis and BDNF support stack
• Semax – BDNF synergy for cognitive enhancement
• Dihexa – HGF + hippocampal neurogenesis dual-pathway stack
• Noopept – neurotrophin upregulation complement

Use Cases

• Depression (MDD, treatment-resistant depression)
• Neurogenesis (hippocampal volume restoration)
• Cognitive Enhancement (memory, executive function)
• Age-Related Cognitive Decline
• PTSD (hippocampal-dependent fear memory processing)
• Anxiety (hippocampal regulation of stress response)

Contraindications & Safety

• Active malignancy — neurogenic compound; theoretical stem cell concern; avoid
• Bipolar disorder — neurogenic antidepressants may trigger mania; caution
• Interaction with SSRIs/SNRIs — additive serotonergic/neurogenic effects; monitor
• Generally well-tolerated in Phase II trials
• Common side effects: Headache, mild fatigue, vivid dreams; generally manageable

Storage

• Capsules/powder: Room temperature; away from moisture and light; 1–2 year shelf life
• Stability: Stable small molecule; no special cold storage required

PubMed Research

Research links will be added after PubMed search

Sources

• The Peptides Bible – Neurogenic compounds section
• Peptide Protocols Master Bible – Cognitive and neurological protocols
• Fava et al., Mol Psychiatry 2016 — Phase I/II NSI-189 trial

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