NSI-189 Review: Nootropic Benefits, Dosage, & Side Effects

Updated on December 14, 2022
 by — reviewed by Jason Williams, PhD (Contributor: George Collins / Editor: Yoko Hill)

In this NSI-189 review, we'll take an in-depth look at this popular nootropic. We'll also go over how NSI-189 works in the brain, information about the benefits, side effects, and where you can buy it online.

NSI-189, developed by Neuralstem, Inc., is a novel experimental pharmaceutical compound that has gained traction in the nootropic community for its potential to improve mood, energy levels, and cognitive performance.

It is being researched as a possible treatment for major depressive disorder (MDD) and other forms of cognitive impairment or neurodegenerative conditions.

Evidence suggests that NSI-189 encourages the growth of new neurons, known as neurogenesis, in vitro and provides neuroprotection.

Let's take a closer look at how NSI-189 works and what Science says about its effectiveness as a nootropic.

NSI-189 Review Summary

NSI-189 phosphate is a novel experimental compound that shows promise as a treatment for major depressive disorder (MDD) and other forms of cognitive impairment or neurodegenerative conditions.

Although evidence is still limited, there are some promising results from both in vitro and animal studies showing how NSI-189 works to promote neurogenesis and protect the brain from damage.

Pros:

  • Works extremely well as an antidepressant
  • Has procognitive benefits
  • Improves memory and learning
  • Stimulates neurogenesis (growth of new brain cells)

Cons:

  • Limited evidence for effectiveness in humans

What Is NSI-189?

nsi-189 structure

NSI-189 is an experimental antidepressant that was developed by an American biotechnology company called Neuralstem Inc. for the treatment of major depressive disorder (MDD).

It has also been investigated for its potential benefit in cognitive impairment and neurodegenerative diseases. A phase II clinical trial conducted in July 2017, failed to meet the primary endpoint for MDD but showed statistically significant improvement on several secondary endpoints, including depression and cognition [1].

Subsequently, a phase I trial, administered to 41 healthy volunteers in 2011, demonstrated no major adverse effects [2].

This was followed by a phase Ib clinical trial with 24 participants, which started in 2012 and was completed in July 2014, with results published in December 2015 [3].

These trials all highlighted NSI-189's safety profile. More recently, in August 2020, a further phase 2 study involving 220 participants demonstrated NSI-189's efficacy as an adjunct therapy in people with MDD with few side effects.

In addition to MDD, NSI-189 is being studied for its potential therapeutic effects in traumatic brain injury (TBI), Alzheimer's disease (AD), post-traumatic stress disorder (PTSD), stroke, and cognitive and memory decline related to aging.

Imagebuy nsi-189 phosphate online
NameNSI-189 Phosphate
ClassNootropic
EffectsImproved depression and cognition
Potential Side EffectsHeadache, dizziness, dry mouth
Half-Life17.4 - 20.5 hours
Common Dosage40 mg daily
Content1 g
Price$29.99
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As such, NSI-189 continues to be investigated for its potential as an effective antidepressant and nootropic with minimal associated risks or toxicity.  

How Does NSI-189 Work In The Brain?

NSI-189 is believed to have neurogenic properties that may help treat depression and other neurological conditions. It works by stimulating the growth of new neurons in the brain, known as neurogenesis [4].

review of nsi-189

This process helps to rebuild connections between damaged brain cells and create new pathways for communication. This has been shown by histopathological assessments, which is a microscopic examinations of tissue samples to determine whether cells or tissue structures have been altered due to trauma, infection, or disease.

A study revealed increased neurite outgrowth as evidenced by MAP2 immunoreactivity when NSI-189 was administered orally to adult rats starting at 6 hours after middle cerebral artery occlusion and daily thereafter over the next 12 weeks [5].

The exact mechanism by which NSI-189 stimulates neurogenesis is still not fully understood. However, it is thought to modulate the activity of neural stem cells (NSCs) and progenitor cells (PCs). NSCs are immature stem cells that can grow into various types of neurons, while PCs are more developed neural precursors.

By modulating these cells’ activity, researchers hypothesize that NSI-189 can increase their ability to produce new neurons, thus promoting neuron growth and repair in brain areas that have been affected by a stroke or other injury.

In addition to its effect on neuron growth, research suggests that NSI-189 may also help protect existing neurons from further damage. It appears to do this through its antioxidant effects, which can reduce oxidative stress in the brain caused by toxins or inflammations associated with injury or neurological diseases.

What Is NSI-189 Used For?

According to the scientific literature available on NSI-189, the main research focus has been to investigate its potential use as an adjunct therapy to treat MDD, a debilitating mental illness marked by a constant low mood and lack of interest or pleasure in previously enjoyable activities.

Here's an overview of some of the clinical uses as well as other potential functions of NSI-189:

Major Depression Disorder (MDD)

One study looked at NSI-189 as monotherapy for major depressive disorder (MDD). 220 subjects were randomized to receive either 40 mg or 80 mg of NSI-189, or a placebo, for 12 weeks [6].

The primary outcome measure was the Montgomery–Åsberg Depression Rating Scale (MADRS), which is an observation-based scale used to assess the severity of depression in adults.

Results indicated that although there was no significant reduction in MADRS scores when compared to placebo for either dose, there were overall reductions in SDQ (Symptoms of Depression Questionnaire) using the 40 mg dose. This suggests that using NSI-189 may still benefit MDD sufferers, with further research necessary to determine its efficacy.

Besides the potential cognitive benefits, previous studies examining neurogenic compounds such as NSI-189 have also found promising results regarding mood improvements, further emphasizing its potential utility as a therapeutic agent in treating MDD.

The Blood-Brain Barrier (BBB)

The BBB is a semi-permeable membrane that acts as a protective shield around the brain, which separates neurons from circulating blood cells.

An MCAo (Middle Cerebral Artery occlusion) stroke causes disruption of the BBB, allowing both toxins and antibodies to enter the nervous system and cause further damage. NSI-189's ability to penetrate the BBB even before stroke-induced BBB breakdown is one of the key factors that makes it so effective.

This trait enables NSI-189 to remain in the brain for longer and be more effective at initiating tissue remodeling processes that can help repair damaged areas after a stroke.

Furthermore, the continued behavioral improvement seen in animals when NSI-189 was terminated at 12 weeks post-stroke suggests that this drug may also promote long-term healing and recovery, even without daily treatment.

Enhanced Neurogenesis

Naoki et al. showed that treatment with NSI-189 successfully reversed cell death caused by oxygen-glucose deprivation (OGD). Additionally, it increased the expression of Ki67 protein and levels of MAP2 density, implying that neural activity was maintained throughout [7].

NSI-189 stimulated the upregulation of several key neurogenic factors, such as BDNF (Brain-Derived Neurotrophic Factor) and SCF (Stem Cell Factor). Moreover, antibodies directed against these two factors blocked the rescue of cell viability against OGD caused by NSI-189 treatment.

These findings indicate that NSI-189 could provide a viable solution to preserving and restoring neuronal health by stimulating neurogenesis. Notably, Naoki et al. found that the hippocampal cells appeared to be especially sensitive to the effects of NSI-189; the experiments revealed increased BDNF and SCF after treatment with NSI-189.

What Are The Benefits Of NSI-189 For Cognition?

Preclinical studies have shown that NSI-189 has numerous beneficial properties, including:

  • Antidepressant
  • Procognitive
  • Synaptoplastic
  • Neurotrophic activities

This novel compound is remarkably beneficial, not only in treating depression but also providing powerful cognitive advantages. NSI-189 has been proven to induce neurogenesis within the hippocampus, thereby influencing learning and memory enhancement.

This makes it a great nootropic for those looking to improve their cognitive function and prevent age-related cognitive decline.

Overall, NSI-189 is an exciting new smart drug that has the potential to revolutionize the treatment of MDD as well as other debilitating mental health disorders.

Where To Buy NSI-189 Online?

It is challenging to find NSI-189 for sale due to its scarcity. If there is availability in the market, there are still things you have to check to ensure that your chosen vendor is reliable and that what you are buying is legitimate.

Some supplements and compounds are priced very high, while some are too low. To avoid any problems with NSI-189, buy from reliable sources and check the following:

  • Credentials: The vendor has evidence of independent laboratory testing.
  • Trustworthiness: There are good reviews about the vendor.
  • Availability: There should be customer service support

We at WholisticResearch recommend Chemyo, which is an American-based vendor. Their NSI-189 comes in powdered form, making it easy to measure.

Chemyo is the ideal choice for those seeking efficient and affordable NSI-189, as their price of $29.99 (USD) per 1g cannot be beaten! Additionally, they provide third-party testing to ensure that your product meets a high standard in terms of 'identity & purity.'

What Do People Say About NSI-189 On Reddit?

Let's take a look at what some people on Reddit have to say about NSI-189:

According to elasticoder:

"I've been using it for a month in conjunction with a consistent exercising routine and vitamins. I must say that the results are amazing. I mix 40 mg in coffee or orange juice every morning. You will feel the effects within 15 minutes. At first, you will feel stimulated and motivated. The feeling is similar to Adderall but less intense and healthier...The best part about NSI-189 is that there is no withdrawal if you stop taking it at any point. Last but not least, this compound is very hard to find. I managed to find a legit vendor with authentic signed lab reports. You can check out their site ->https://science.bio/."

According to falre1028us:

"Personally, I've found NSI-189 to be very useful. I'm taking 50mg freebase once daily in the morning. The acute effects for me are a gentle wave of calmness, improved long-term memory, and notably improved vision."

According to ThechanceW:

"So I started taking NSI-189 a little bit over a month ago, freebase, sourced from science.bio...The first day I took 40mg sublingually in the morning, to very little effect… The second and third days I did the same, with no effects. The fourth day I swallowed down 40mg with water, and noticed a slight mood boost. The fifth, and all subsequent days, I've taken between 80 and 110mg orally in the morning, sometimes on an empty stomach, sometimes not, and I feel as though I've been brought back to life."

How Do You Take NSI-189 For Cognitive Enhancement?

NSI-189 is typically taken in powder form once or twice daily for cognitive enhancement. Some people prefer splitting the dosage between morning and afternoon, while others choose to take the whole dose at once.

NSI-189 can be taken with or without food. That said, some anecdotal evidence suggests that it may be more effective when taken on an empty stomach. If you experience any side effects, such as gastrointestinal discomfort, try taking your dose with food, preferably a high-fat meal.

Because the data on NSI-189 is still limited, it's important to start slowly and gradually increase your dose over time. It can take a few weeks for NSI-189 to reach its full potential in terms of enhancing cognitive function, so be patient and consistent with your dosage schedule.

We recommend cycling NSI-189 on and off every few months, as long-term use may lead to issues with tolerance and dependence. One way to do this could be to take NSI-189 for 4 weeks and then take a break for 2 weeks before starting again.

Talk to your doctor before starting a new supplement regimen, especially if you are taking any other medications or have a medical condition.

The recommended dosage for NSI-189 depends on several factors, including your age and health status and the specific benefits you hope to achieve.

As a general rule, it is recommended that you start with a low dose of 20-40 mg per day and gradually increase this over time. If no side effects are experienced, you can increase the dose to a maximum of 80-120 mg daily in divided doses.

If you're completely new to NSI-189, we don't recommend stacking it with other cognitive-enhancing compounds or medications, as this can increase your risk of experiencing unwanted side effects.

What Are The Side Effects Of NSI-189?

Although NSI-189 is generally well tolerated, some people do experience side effects like headaches, fatigue, dry mouth, nausea, and dizziness.

It's also important to be aware that taking NSI-189 may increase your risk of developing drug dependence and tolerance. That said, there is limited research on the safety and long-term effects of using NSI-189.

Pregnant and breastfeeding women should not use this product, and it is important to talk to your doctor before taking NSI-189 if you have a history of mental health problems or heart conditions.

What Nootropics Are Similar To NSI-189?

Several other nootropics may have similar effects to NSI-189. These include Noopept, Piracetam, and Phenylpiracetam.

  • Like NSI-189, noopept has been shown to boost BDNF levels, increase neuroplasticity, and protect against cognitive decline. It is also similar to NSI-189's ability to improve memory and enhance focus [8].
  • Piracetam is another popular nootropic that has similar effects to NSI-189. It has been shown to promote neurogenesis, protect against age-related cognitive decline, and enhance memory [9].
  • Phenylpiracetam is a phenylated analog of Piracetam, which means it contains a phenyl group attached to the pyrrolidone nucleus. Like NSI-189, it has been shown to be neuroprotective and improve cognition [10].

Noopept, Piracetam, and Phenylpiracetam all have solid evidence backing their ability to support brain health and enhance cognitive function, making them good alternatives to NSI-189. That said, NSI-189 is showing promising results in early clinical trials.

What Brain Supplements Can NSI-189 Be Stacked With?

Stacking NSI-189 with other nootropics is a common practice, as can help you get even more benefits from the supplement. Some popular options include Caffeine, L-theanine, NooCube, and Alpha-GPC.

  • Caffeine blocks adenosine receptors in the brain, increasing alertness and reducing fatigue. When stacked with NSI-189, it can help improve focus and boost energy levels.
  • L-Theanine works by increasing alpha brain waves and promoting relaxation. When paired with NSI-189, it can reduce stress and improve mood.
  • Alpha-GPC is a precursor to acetylcholine (ACh), which is important for memory and learning. When stacked with NSI-189, it can enhance cognition and support long-term brain health.

If you're looking for a solid foundation to stack NSI-189 with, NooCube is an excellent choice. It contains a blend of 13 synergistic nootropic ingredients that have been shown to support cognitive function and brain health.

With ingredients like Alpha-GPC, Huperzine A, L-Theanine, Bacopa Monnieri, and Cat's Claw Extract, it can help improve focus, boost energy levels, and enhance memory. Plus, it is made in an FDA-registered facility that follows GMP guidelines for quality assurance.

With NooCube, you get more bang for your buck, as it is a cost-effective and high-quality nootropic supplement. You can read more about NooCube right here:

Frequently Asked Questions (FAQ)

Let's take a closer look at some of the most common questions people have about NSI-189.

How Long Does It Take For NSI-189 To Work?

NSI-189 kicks in fairly quickly, typically within 15-30 minutes. However, the full effects may take several weeks to develop and continue building over time.

How Does NSI-189 Make You Feel?

NSI-189 makes you feel more focused and energized. As the full benefits develop over time, you will notice a mood and cognitive function boost. People who take NSI-189 for depression report feeling more positive and motivated.

Does NSI-189 Show Up On A Drug Test?

NSI-189 is not likely to show up on a drug test. It does not contain any psychoactive ingredients and is unlikely to trigger a false positive for illicit or illegal substances.

What's The Half-Life Of NSI-189?

The half-life of NSI-189 is approximately 17.4 to 20.5 hours, which means that it takes this amount of time for the drug to reduce by 50% in the bloodstream.

Is It Safe To Use NSI-189?

The limited clinical trial data available suggests that NSI-189 is safe to use with a low risk of side effects. However, long-term effects are unknown, and further research is needed to confirm its safety in humans.

Is NSI-189 Legal?

The legal status of NSI-189 is currently being investigated by the United States Food and Drug Administration (FDA). At this time, NSI-189 has been granted Investigational New Drug status by the FDA, which means that it can be used in investigational clinical trials. This does not mean that the drug is approved for sale or use in humans. 

Conclusion

So what do we know about NSI-189?

NSI-189 is an experimental antidepressant Neuralstem Inc. developed to treat major depressive disorder (MDD). NSI-189 has been investigated for its potential benefit in cognitive impairment and neurodegenerative diseases. 

A phase II clinical trial conducted in July 2017 failed to meet the primary endpoint for MDD but showed statistically significant improvement on several secondary endpoints, including depression and cognition.

Subsequently, a phase I trial, administered to 41 healthy volunteers in 2011, demonstrated no major adverse effects. However, further clinical research is needed to fully understand the safety and efficacy of NSI-189.

Despite its limitations, NSI-189 is quickly becoming a popular option in the nootropic community due to rising interest in this novel antidepressant and its potential applications for cognitive impairment and neurodegenerative diseases.

References

References
1“Neuralstem: NSI-189 Phase 2 Trial Fails to Meet Primary Efficacy Endpoint.” Business Insider, Business Insider, https://markets.businessinsider.com/news/stocks/neuralstem-nsi-189-phase-2-trial-fails-to-meet-primary-efficacy-endpoint-1002202000?miRedirects=1.
2“Single-Dose Pharmacokinetics (PK) Study of Novel Neurogenic Compound NSI-189 - Full Text View.” Full Text View - ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01310881.
3Fava, M et al. “A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients.” Molecular psychiatry vol. 21,10 (2016): 1372-80. doi:10.1038/mp.2015.178
4McIntyre, Roger S et al. “The neurogenic compound, NSI-189 phosphate: a novel multi-domain treatment capable of pro-cognitive and antidepressant effects.” Expert opinion on investigational drugs vol. 26,6 (2017): 767-770. doi:10.1080/13543784.2017.1324847
5, 7Tajiri, Naoki et al. “NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats.” Journal of cellular physiology vol. 232,10 (2017): 2731-2740. doi:10.1002/jcp.25847
6Papakostas, G I et al. “A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder.” Molecular psychiatry vol. 25,7 (2020): 1569-1579. doi:10.1038/s41380-018-0334-8
8Ostrovskaya, R U et al. “Noopept stimulates the expression of NGF and BDNF in rat hippocampus.” Bulletin of experimental biology and medicine vol. 146,3 (2008): 334-7. doi:10.1007/s10517-008-0297-x
9Taupin, Philippe. “Nootropic agents stimulate neurogenesis. Brain Cells, Inc.: WO2007104035.” Expert opinion on therapeutic patents vol. 19,5 (2009): 727-30. doi:10.1517/13543770902721303
10Zvejniece, Liga et al. “Neuroprotective and anti-inflammatory activity of DAT inhibitor R-phenylpiracetam in experimental models of inflammation in male mice.” Inflammopharmacology vol. 28,5 (2020): 1283-1292. doi:10.1007/s10787-020-00705-7
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