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

NSI-189, a neurogenic nootropic compound developed by Neuralstem Inc., functions as a potential cognitive enhancer through documented brain pathways that stimulate neural growth in the hippocampus.

NSI-189 phosphate, the phosphate salt form of the compound, has demonstrated promising results in research settings due to its enhanced stability, improved bioavailability, and water-soluble properties that make it the preferred form for clinical studies.

NSI-189’s mechanisms target neural growth and brain function support, making it a notable subject in nootropic research circles.

What is NSI-189?

NSI-189 (also known as NSI-189 phosphate, and scientifically as (4-benzylpiperazin-1-yl)-(2-(3-methylbutylamino)pyridin-3-yl)methanone is a novel and promising pharmaceutical compound that has generated significant interest in the field of neurology and psychiatry.

Primarily known for its potential as a neurogenic and nootropic agent, NSI-189 has been the subject of various studies, particularly for its potential effects on major depressive disorder (MDD) and cognitive impairments.

NSI-189 is believed to work by stimulating neurogenesis, specifically in the hippocampus, a key area of the brain involved in memory and emotional regulation. Neurogenesis, the process of generating new neurons, is crucial for maintaining cognitive function.

As a nootropic, NSI-189 enhances cognitive functions, with research showing NSI-189 benefits include improved memory formation, enhanced learning capacity, increased mental clarity, and reduced symptoms of depression through its neurogenic properties. NSI-189 has also shown potential as a treatment for major depressive disorder. By promoting the growth of new neurons in the hippocampus, NSI-189 addresses the brain changes associated with depression.

Pros:

• Promotes neurogenesis in the hippocampus
• Enhances cognition and mental alertness
• Promotes emotional well-being
• Improves memory and learning capabilities

Cons:

• Not approved by the FDA (Food and Drug Administration)
• Lacking human trails to determine long-term safety profile

NSI-189 Forms: Phosphate vs Freebase

NSI-189 exists in two primary forms: the phosphate salt and freebase. While NSI-189 phosphate is the most studied form, understanding the differences between these variants is important.

Chemical Differences

NSI-189 freebase is the basic form of the compound, while NSI-189 phosphate is the phosphate salt form. The phosphate salt form was specifically developed to improve the compound’s stability and bioavailability.

Properties of NSI-189 Freebase

NSI-189 freebase represents the basic, non-salt form of the compound that exhibits higher lipophilicity (fat-solubility) than its phosphate counterpart, which allows NSI-189 freebase to cross the blood-brain barrier more readily while requiring more careful storage conditions. The freebase form:

• Has higher lipid solubility
• May cross the blood-brain barrier more readily
• Is often available in liquid form
• Generally requires more careful storage conditions

NSI-189 freebase liquid formulations dissolve the pure compound in a carrier solution, typically propylene glycol or similar solvents, which allows for precise dosing through dropper administration while maintaining the lipophilic properties that facilitate efficient absorption when taken sublingually.

Storage Requirements

NSI-189 freebase requires specific storage conditions to maintain stability:

• Store in an airtight container
• Keep away from light and moisture
• For liquid freebase solutions, refrigeration is typically recommended
• Follow the same general storage guidelines as the phosphate form (-20°C for powder, -80°C in solvent)

Bioavailability Considerations

While both forms of NSI-189 are biologically active, they may have different absorption profiles:

• The phosphate form is generally more water-soluble
• The freebase form may have different absorption characteristics due to its lipophilic nature
• Both forms ultimately provide the active compound to the body, though onset and duration may vary

Mechanism of Action

NSI-189’s mechanism of action works through stimulating neurogenesis in the hippocampus, where the compound promotes neural stem cell proliferation, enhances synaptic plasticity, modulates neurotransmitter systems, and potentially increases levels of Brain-Derived Neurotrophic Factor (BDNF).

While the exact molecular mechanisms are still under investigation, the current understanding is based on preclinical studies and clinical trials.

Here’s a look at the key points of NSI-189’s mechanism of action:

• Stimulation of Neurogenesis: NSI-189 is believed to promote the growth of new neurons in the hippocampus. The hippocampus is one of the few areas in the adult brain where neurogenesis occurs and is a region often associated with depression and cognitive disorders when it becomes atrophied or dysfunctional. By fostering the growth of new neurons, NSI-189 may help reverse these conditions.
• Increase in Hippocampal Volume: Research suggests that NSI-189 may increase the volume of the hippocampus. Changes in hippocampal volume are often observed in patients with major depressive disorder (MDD), and this enlargement could correlate with improvements in depressive symptoms and cognitive function.
• Enhancement of Synaptic Plasticity: NSI-189 might improve synaptic plasticity, which is the ability of synapses (the connections between neurons) to strengthen or weaken over time. Enhanced synaptic plasticity is crucial for learning and memory formation.
• Impact on Neurotrophic Factors: It’s hypothesized that NSI-189 may influence the levels of various neurotrophic factors, such as Brain-Derived Neurotrophic Factor (BDNF). These factors play a vital role in the survival, development, and function of neurons. Increasing BDNF levels can support neuron growth and resilience.
• Neural Stem Cell Proliferation: NSI-189 is thought to originate from compounds that were identified to promote the proliferation of human hippocampus-derived neural stem cells in vitro. This proliferation could translate into neurogenic effects in vivo.
• Modulation of Neurotransmitter Systems: While less clear, NSI-189 might also interact with neurotransmitter systems, such as serotonin or glutamate, which are implicated in mood regulation and cognitive functions.
• Anti-Inflammatory Effects: There’s also a possibility that NSI-189 has anti-inflammatory properties, which could contribute to its therapeutic effects, given the link between inflammation and depression.

Nootropic Benefits of NSI-189

By potentially increasing hippocampal volume and improving neural plasticity, NSI-189 offers various cognitive benefits, especially for individuals experiencing cognitive decline related to psychiatric disorders or other neurological conditions.

But, how exactly does this potential antidepressant meet our expectations as a nootropic compound? How does it improve our cognitive abilities?

Let’s take a closer look.

1. Enhanced Memory Function

By promoting neurogenesis in the hippocampus, NSI-189 improves memory formation and recall, a critical aspect of cognitive functioning.⁽¹⁾

2. Improved Learning Ability

Enhanced synaptic plasticity, a potential effect of NSI-189, is fundamental for learning. This leads to improved learning capabilities.⁽²⁾

3. Mood Stabilization

Given its investigation as a treatment for MDD, NSI-189 has mood-stabilizing effects, which are essential for overall cognitive wellness.⁽³⁾

4. Increased Neuroplasticity

Improved neuroplasticity, the brain’s ability to reorganize and form new neural connections, is crucial for cognitive flexibility and adaptation.⁽⁴⁾

5. Reduction in Cognitive Symptoms of Depression

For individuals with MDD, cognitive impairments are common. NSI-189 helps alleviate these symptoms, enhancing overall cognitive function.

6. Alleviation of Stress-Related Cognitive Impairment

By potentially modulating stress responses, NSI-189 is able to protect the brain from stress-induced cognitive impairments.

These neuroprotective effects are beneficial for long-term cognitive health.

7. Improvement in Attention and Concentration

Through its effects of NSI-189 on neurogenesis and neurotransmitter modulation, NSI-189 enhances focus and attention span. This is particularly beneficial for people with ADHD, as this tool allows for improved mental alertness.

Uses of NSI-189

NSI-189, as a novel neurogenic and potential nootropic compound, has been explored for a variety of uses, particularly in the realm of mental health and cognitive enhancement.

Here are some of the key uses of the neuroprotective compound NSI-189:

1. Cognitive Enhancement: NSI-189 is being explored for its potential to improve cognitive functions, including memory, learning, and overall cognitive performance, making it a promising nootropic.
2. Treatment of Major Depressive Disorder (MDD): One of the primary uses of NSI-189 is for treating MDD. By promoting neurogenesis in the hippocampus, NSI-189 helps alleviate depressive symptoms and address the cognitive impairments often associated with depression.
3. Neurological Disorders: NSI-189’s neurogenic properties suggest applications in treating various neurological disorders that involve neuronal loss or impairment.⁽⁵⁾
4. Brain Injury Recovery: NSI-189 aids in recovery from traumatic brain injury (TBI) or stroke by fostering the growth of new neurons and enhancing synaptic plasticity.
5. Age-Related Cognitive Decline: By promoting the formation of new neurons and improving neural plasticity, NSI-189 could be used to combat cognitive decline associated with aging.
6. Stress-Related Cognitive Impairment: NSI-189 is beneficial in addressing cognitive impairments that are a consequence of chronic stress or anxiety.

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NSI-189 Dosage

In clinical trials, particularly in the study of NSI-189 for Major Depressive Disorder (MDD), dosages have varied. The recommended NSI-189 dosage ranges from 40 mg once daily to 120 mg daily (divided into three 40 mg doses), with clinical trials demonstrating both safety and efficacy within this dosage range for most users.⁽⁶⁾

An early-phase clinical trial (Phase 1b) investigating NSI-189’s safety and efficacy in patients with major depressive disorder tested doses of 40 mg, 80 mg, and 120 mg daily.⁽⁷⁾

These trials primarily aimed to assess the safety and tolerability of NSI-189 at different dosages, alongside its potential therapeutic effects.

A standard practice is to begin with a lower dosage and gradually increase the dosage according to your tolerance.

NSI-189 Side Effects and Safety

NSI-189, being an experimental neurogenic compound, has undergone clinical trials primarily to assess its safety and efficacy.

Based on clinical trial data and research, here are the known side effects and safety considerations:

• Headache
• Fatigue
• Dizziness
• Nausea
• Insomnia

Overall, NSI-189 has been tolerated well by clinical trial participants, with most experiencing only mild side effects.

As NSI-189 is still experimental, long-term safety data is limited. Ongoing and future studies are needed to fully understand the long-term implications of its use, including any potential chronic side effects or risks.

Summary

In conclusion, NSI-189 emerges not just as a molecule of interest but as a beacon of hope in the complex and challenging world of neurological and psychiatric disorders. Its potential to revolutionize the treatment of conditions like major depressive disorder and to enhance cognitive function places it at the forefront of neuroscientific research.

As we have explored, NSI-189’s unique neurogenic properties, particularly its ability to stimulate neurogenesis in the hippocampus, set it apart from traditional antidepressants and cognitive enhancers.

The journey of NSI-189, from its conception to the promising results of clinical trials, underscores a significant leap forward in our understanding of the brain’s capacity to regenerate and repair.

However, as with any frontier in medical science, caution and patience are paramount. NSI-189 is still on its path to potential approval and widespread use.

Remember to consult with a healthcare professional before adding NSI-198 to your mental wellness regimen.

FAQs

1. Jolivalt, C G et al. “Enhancement 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.” Journal of diabetes research vol. 2022 8566970. 4 Jul. 2022, doi:10.1155/2022/8566970↩
2. Liu, Yan et al. “Enhancement 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.” Neuropharmacology vol. 144 (2019): 337-344. doi:10.1016/j.neuropharm.2018.10.038↩
3. McIntyre, 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↩
4. Tajiri, 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↩
5. Allen, Barrett D et al. “Remediation of Radiation-Induced Cognitive Dysfunction through Oral Administration of the Neuroprotective Compound NSI-189.” Radiation research vol. 189,4 (2018): 345-353. doi:10.1667/RR14879.1↩
6. Papakostas, 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↩
7. Fava, 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↩