An experimental oral compound built to make the brain region governing memory and mood grow new cells. It works in animals; in people, both trials designed to prove the effect missed their main outcome. Only participants' ratings of mood and mental clarity separated from placebo. Side effects were mild. Longest anyone has been studied: twelve weeks. Supply is unregulated. (Full Review)

Protocol

Trial-derived standard regimen

40 mg once daily by mouth

The dose that outperformed both placebo and the 80 mg arm on every self-rated measure

Best time of day

Morning

Trials dosed in the daytime; a compound producing insomnia and vivid dreams in about one in six users is worst placed near bedtime

Single versus split dosing

Once daily is supported

Splitting was introduced only to blunt peak-related adverse events above 40 mg, and totals above 40 mg showed no benefit

Time to effect

4 weeks minimum

Trials measured outcomes at 4 and 12 weeks; self-rated improvement emerged mainly in the second six-week stage

Half-life and accumulation

Steady state at 96–120 hours

Half-life 17.4–20.5 hours; effects should not be judged before day five

Effects appear to outlast dosing

Still present at 8 weeks

Self-rated improvement persisted eight weeks after the last dose; the least replicated claim made for the compound

Benefits

Low: Reduction in self-reported depressive symptoms; improvement in cognitive function

Speculative: Stimulation of hippocampal neurogenesis and synaptic plasticity; reversal of diabetic peripheral neuropathy; functional recovery after ischemic stroke; protection against radiation-induced cognitive decline; recovery of motor and cognitive function in Angelman syndrome

Contraindications

Lifetime history of mania, hypomania or psychosis

Clinically significant suicidal ideation, or non-response to three or more adequate antidepressant trials in the current episode

Seizure disorder or an abnormal electroencephalogram

Alcohol or substance use disorder active within the past 12 months

Pregnancy or lactation, and anyone of either sex not using contraception

Under 18 or over 60, or body mass index below 19.5 or above 35 kg/m²

Clinically significant cardiovascular, hepatic, renal, respiratory, endocrine, neurological or immunological disease (Child-Pugh Class B or C, estimated glomerular filtration rate below 60 mL/min/1.73 m²)

Key Interactions

Prescription antidepressants (sertraline, escitalopram, venlafaxine, bupropion)

Antipsychotics (quetiapine, olanzapine, aripiprazole), lithium and buspirone

Sedatives allowed alongside in trials (benzodiazepines, zolpidem, zaleplon, eszopiclone, low-dose trazodone)

Over-the-counter sedating antihistamines (diphenhydramine, doxylamine) and alcohol

Over-the-counter stimulants (caffeine, pseudoephedrine)

Enzyme-perturbing supplements (St John's wort, grapefruit juice)

Supplements with additive effects (5-HTP, SAM-e, ashwagandha, melatonin)

Other neuroplasticity interventions (ketamine, psilocybin, repetitive transcranial magnetic stimulation)

Risk & Side Effects

High: Headache; nausea; sleep disruption and vivid dreams

Medium: Dose-related dizziness; daytime somnolence; paresthesia; dry mouth; palpitation; rash and skin discomfort

Low: Restlessness and irritability

Speculative: Unknown consequences of prolonged neurogenic stimulation; unpredictable off-target effects; contaminated, mislabelled or misdosed material

Monitoring

Marker	Target	Why
Alanine aminotransferase	10–26 U/L	Liver injury from a compound of unknown clearance route
Aspartate aminotransferase	10–26 U/L	Confirms and contextualises any alanine aminotransferase rise
Estimated glomerular filtration rate	>90 mL/min/1.73 m²	Renal clearance capacity, unmeasured for this compound
Resting heart rate	55–70 bpm	Palpitation was a recorded treatment-related event
Blood pressure	<120/80 mmHg	Baseline for any autonomic effect and a screen for the excluded cardiovascular group
Corrected QT interval	<430 ms (men), <450 ms (women)	Trials ran electrocardiograms; cardiac safety is otherwise uncharacterised
Thyroid stimulating hormone	1.0–2.0 mIU/L	Thyroid dysfunction mimics the depressed mood and cognitive dysfunction being targeted
Haemoglobin A1c	4.8–5.4%	Metabolic status, given the diabetic-model preclinical data
High-sensitivity C-reactive protein	<1.0 mg/L	Inflammation suppresses neurogenesis and blunts antidepressant response
White blood cell count	4.0–7.0 ×10⁹/L	Trials monitored haematology; no marketed comparator exists to predict effects
Serum brain-derived neurotrophic factor	No established target range exists; track the change from the individual's own baseline	The proposed mechanism runs through this protein, and baseline levels predicted response in the Phase 1b trial

Cadence: Week 1 for tolerability and vital signs, week 4 for the first full repeat panel and the first meaningful efficacy read, week 12 at the end of the studied exposure window, and every 6 months thereafter if use continues beyond the tested period.

Qualitative Assessment

Mood and emotional reactivity, tracked with the same self-report scale each time rather than by impression
Verbal memory, tested as recall of an unrelated word list
Mental clarity, concentration and the ability to make decisions
Sleep quality, sleep onset latency and dream intensity
Daytime alertness within four hours of dosing
Restlessness, irritability or anxiety in the first two weeks

NSI-189 for Health & Longevity

Protocol

Benefits

Risk & Side Effects

Monitoring

Qualitative Assessment