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Supercharge Your Brain, Mood, and Sexual Health with Nitric Oxide

(Arginine vs Citrulline vs Agmatine)

  • nNOS vs iNOS vs eNOS*
  • Optimize Your Blood Flow with Nitric Oxide Synthase 3.


[References to this Article]

Blood flow is critically important.

Our blood pressure, mood, brain function, and even sexual health depends on nitric oxide.

While the role of nitric oxide is less clear on unipolar depression, it appears to play a role with cognition, anxiety, and bipolar depression.

Popular sexual function drugs, Levitra, Viagra, and Cialis are now being explored for their effects on the brain and mood, through their effects on superior blood circulation.

False Myth:

Nitric oxide only affects male sexual function.

As more and more health optimizers, ask, “what can I do for my brain-fog”, with others struggling with depression, anxiety, and hypertension, nitric oxide is not to be ignored.

Instead it needs much more attention by all health optimizers.

Comprising nitrogen and oxygen, nitric oxide relaxes blood vessels throughout the body.

[Related Article: The Top 9 Science-Backed Blood Pressure Supplements]

Nitric oxide (NO) is a gas-based molecule we naturally create from L-arginine using nitric oxide synthase (NOS), a “family” of three enzymes.

Nitric Oxide: Four Fun Facts

#1) While the primary purpose of nitric oxide is blood flow, it also functions as a neurotransmitter.

#2) It differs from other neurotransmitters in its unique gaseous form, allowing it to rapidly and easily penetrate through cellular membranes.

#3) With a blood vessel relaxation focus, nitric oxide-increasing blood flow optimizes brain blood flow, which might therapeutically target “brain fog”, and mood disorders.

#4) Blood vessel relaxation promotes optimal blood pressure and other smooth muscle actions such as digestive and function.

Diseases of Nitric Oxide Synthase Function

  • Alzheimer’s Disease
  • Anxiety *
  • “Brain-Fog” *
  • Coronary Spasm
  • Depression *
  • Diabetes *
  • Hair Loss *
  • Hypertension
  • Immunity
  • Ischemic Stroke
  • Metabolic Disease *
  • Preeclampsia/ Eclampsia
  • Sexual Function (Male and Female)

*Still under investigation.

Three Types of Blood Circulation

As a reactive free radical, nitric oxide regulates a variety of bodily systems and processes, such as neurotransmitters while providing antimicrobial and antitumor actions.

Our bodies undergo three types of blood circulation.

  1. Systemic Circulation: blood movement from the heart via arteries to the periphery and back to the heart via veins.
  2. Pulmonary Circulation: movement of deoxygenated blood from the right ventricle to the lungs, with moving oxygenated blood back to the left ventricle and atrium.
  3. Portal Circulation: movement of blood from the small intestine to the liver, the right half of the colon, and the spleen via the portal vein.



Nitric Oxide Synthase: The Three Enzymes

Three different nitric oxide enzymes comprise nitric oxide synthase in regulating nitric oxide.

The three forms are inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS).

These enzymes, or “protein isoforms”, produce nitric oxide from the amino acid arginine:

1)Neuronal Nitric Oxide: (nNOS) (NOS1)

2)Inducible Nitric Oxide: (iNOS) (NOS2)

3)Endothelial Nitric Oxide (eNOS) (NOS3)

Nitric oxide synthase 3 (NOS3) produces NO in our endothelial cells or inner blood vessel lining, which may control cardiovascular disease (CVD).

The study of NOS3 polymorphisms or SNPs is associating NOS3 gene variants and cardiovascular disease.

This means hypertension and CVD might be because of a genetic polymorphism or SNP in the NOS3 gene.

#1 Neuronal Nitric Oxide Synthase: (nNOS) (NOS1)

Operates brain communication, as too much nNOS activation can inhibit neuronal growth and repair.

nNOS produces nitric oxide in neurons throughout the nervous system.

Enhancing neuroplasticity, nNOS centrally regulates blood pressure and relaxation of smooth muscle cells.

#2 Inducible Nitric Oxide Synthase: (iNOS) (NOS2)

Operates with the immune system by targeting harmful bacteria.

But unregulated levels of iNOS can increase inflammation.

#3 Endothelial Nitric Oxide Synthase (eNOS) (NOS3)

Increases blood flow, lowering blood pressure, and removal of cellular waste.

eNOS is the most common form of NOS expression form of NOS we have throughout our blood vessels.

To be clear, when we discuss improving NOS function, we are typically discussing eNOS for its vasodilation effects.

This increases vascular smooth muscle relaxation through our cGMP-mediated signal transduction pathway.

The result is the production of healthy blood vessels, platelet-activated blood clotting, and vascular endothelial growth factor (VEGF), and angiogenesis in blood vessels.

The Nervous System and Nitric Oxide



Nitric oxide benefits extend beyond just sports, as we often overlook the role of blood flow to major organs, most notably the brain.

“Brain fog” is one of the most common complaints amongst individuals searching for supplements and solutions.

As in the body’s case, nitric oxide delivers blood flow to the brain.

Playing a major role in learning and memory, nitric oxide coordinates activities with the glutamate system.

Through this interaction with the glutamate systems, nitric oxide can also be neurotoxic when unchecked.

Glutamate, our most common CNS neurotransmitter, is an initiator of the body’s nitric oxide reaction.

Nitric oxide also acts on inhibitory gamma-Aminobutyric acid (GABA) activity, which means nitric oxide fills the role of both excitatory or inhibitory neurotransmitter activity in the brain.

Nitric Oxide Effects on Immune System


With a major role in our immune system, nitric oxide, specifically iNOS, plays a heavy hand in the body’s inflammatory response.

Our body’s phagocytes, white blood cells contain sizable amounts of nitric oxide and when activated, they release pathogenic-destroying nitric oxide onto bacteria.

Only recently are we realizing just how underrated and undervalued nitric oxide can be as a versatile immune system leading actor.

iNOS acts as an important immune protector during inflammatory states, but unregulated nitric oxide (NO) contributes to several serious pathological consequences.

Nitric Oxide Boosting Supplements


As one of the most popular sports supplements, nitric oxide boosters are popular amongst athletes.

Popularized by Arnold Schwarzenegger, in “Pumping Iron”, we view nitric oxide supplements as muscle pump supplements.

But for sports performance alone, the benefits go well beyond this.

In improving muscular blood supply, we can move lactic acid from the muscles, while transporting various nutrients into the muscles.

This fuels slight gains while increasing recovery.

Comparing Nitric Oxide Boosting Supplements:

Arginine vs Citrulline vs Agmatine

For some time, supplements enthusiasts have solely analyzed arginine versus citrulline, but now we have a few other options to consider.

Citrulline, an arginine precursor is about twice as potent as arginine.

Both arginine and citrulline lower blood pressure over 5 over 2 points, which puts them on a par level with significant diet and lifestyle changes.

Some studies believe combining the two produces a greater effect on nitric oxide.

Other studies show arginine can activate viral activity, because of increasing iNOS levels.

L-Arginine side effects include gastrointestinal side effects.

L-Arginine vs L-Citrulline vs Agmatine and NOS3


Increases: eNOS + nNOS + iNOS

L-Citrulline: (Arginine precursor: better absorbed)

Increases: eNOS

Decreases: iNOS

Agmatine: (Metabolite of L-Arginine)

Increases: eNOS

Decreases: iNOS + nNOS


Agmatine might be the overall best-kept secret in the supplement industry.

An increasingly popular method of increasing L-Arginine bioavailability is the counterintuitive use of L-Arginine metabolite, agmatine.

Our mitochondria naturally produce agmatine, from our beneficial gut microflora, (bacteria), which means foods with fermented probiotics contain trace amounts of agmatine

More than enhancing L-Arginine, agmatine is a novel NMDA-antagonist neurotransmitter, impeding nitric oxide synthase (NOS) through its influence on all three enzymes: iNOS (NOS2), nNOS (NOS1), and eNOS (NOS3).

Turning NOS on and off, like a switch, agmatine inhibits or decreases nNOS, (NOS1) and iNOS, (NOS2), while inducing or increasing eNOS, (NOS3).

The over activation of iNOS and nNOS can lead to inflammatory states and the eNOS activity is preserved which produces the vasodilation we are after.

In rodent studies, agmatine rivals diabetic kidney disease drug pimagedine (aminoguanidine) for iNOS inhibition.

In cytokine-stimulated cell studies, agmatine inhibits iNOS.

As the sole human studies support its effectiveness with neuropathic pain, (with a hypothetical synergy with marijuana), and serotonin synthesis for depression, we need more agmatine studies.

Useful for drug addictions such as alcohol, fentanyl, and methamphetamine, agmatine is synergistic with opioids such as morphine and even opioid agonists, such as kratom, increasinganalgesic effects, lowering tolerance, and addictive properties.

Agmatine is also synergistic with antidepressants, such as SSRIs.

Delivering antianxiety and antidepressant actions, agmatine is also neuroprotective against stroke and excitotoxicity.

The latter two are likely because of agmatine enhancing signaling of naturally occurring anxiolytic and antidepressant compounds.

Producing higher cerebral cortex and hippocampus processing, agmatine improves behavioral and procedural memory.

Researchers are exploring how agmatine may coordinate the early nitric oxide phases along with the later inflammation model repair phases.

With its imidazoline, NMDA, nicotinic, and acetylcholine receptor-binding actions, we believe agmatine offers the potential for tremendous value as a neuroprotective agent.

The result is a reduction of over-activation of inflammation, neurons, and oxidative damage.

Citrulline Malate and Alpha Ketoglutarate (AAKG)


Adding either malic acid (malate) to citrulline or Alpha-Ketoglutarate (AAKG), a urea cycle molecule to L-Arginine, we can add additional ATP-stimulating benefits through enhancing mitochondrial function.

Besides L-Arginine, L-citrulline, and agmatine, L-ornithine is the other common urea cycle supplement we see sometimes included in L-Arginine combinations.

Adding AAKG can increase L-Arginine’s nitric oxide efficiency, in a similar method adding malate increases citrulline’s efficiency.

Two Other Notable Nitric Oxide Supplements



Significantly greater than many supplements, a mere 80 mg of bioavailable-enhanced curcumin increases nitric oxide up to 40%. The mechanism of action is through believed NF-kB activation.



The lone study assessing nitric oxide and garlic noted a raw garlic clove of 2 grams increases nitric oxide by 224% in healthy individuals within 2 to 4 hours with potency not decreasing after seven days.

Aged garlic extract of 600 mg two times daily can be used and might be a better substitute if you are going to be having some sexy time later.

Alternatively, milk fats and green tea have been discovered to bind to raw garlic odor.


Cocoa extract, dietary fiber, fish oil, cod liver oil, omega-3, krill oil, algae oil, DHA, EPA, ginkgo Biloba, L-carnitine, Gotu kola, COQ10, ubiquinol, green tea, vitamin C, alpha-lipoic acid, ALCAR, melatonin, artichoke extract, resveratrol, pterostilbene, psyllium, grape seed extract, pine bark (pycnogenol), taurine, hesperidin, panax ginseng.




  • Agmatine performs as the top overall nitric oxide boosting supplement.
  • Some users report agmatine produces a better “pump” for sports performance.
  • Agmatine dosages range from 2 to 3 grams per day in divided doses.
  • Agmatine redirects nitric oxide from iNOS and nNOS while increasing nitric oxide via eNOS, which is exactly what we want to happen.
  • Aged garlic extract and bioavailable curcumin are overall top 5 supplement choices and can also act as excellent nitric oxide boosters.
  • If one is still seeking even greater sports-related performance and eNOS activity, combining citrulline-malate with agmatine can be a solid choice.


Your Friend in Health

Mark Stein

[Get The Essential 3 Sugars and Fat for Every Health Optimizer]