pain

NOS3

Can Too Much Nitric Oxide Trigger Migraines? (NOS2, NOS3)

Written by Jasmine Foster, BSc, BEd on August 18th, 2020

NOS2 & NOS3 produce the signalling molecule nitric oxide, but can too much of a good thing trigger migraines? Read on to learn more.

What are the Nitric Oxide Synthases?

The nitric oxide synthase (NOS) family of genes encode the NOS family of proteins, which produce nitric oxide from the amino acid arginine [R, R].

The NOS3 gene codes for the NOS3 protein, which is short for nitric oxide synthase 3. NOS3 is most abundant in the inner lining of the blood vessels [R, R].

Nitric oxide is a messenger molecule with multiple functions in the immune and nervous systems. Additionally, NOS3-derived nitric oxide increases blood flow and lowers the risk of heart disease [R, R].

Can Nitric Oxide Cause Headaches?

While nitric oxide is generally protective against conditions such as heart disease and lung failure, it may actually cause migraines [R, R, R].

Nitroglycerin, which causes the release of nitric oxide, can be used to induce migraine in experimental models. Nitric oxide is believed to cross the blood-brain barrier and set off a series of reactions that can increase oxidative stress in the brain [R, R].

NOS3 also dilates (widens) the blood vessels by activating a pathway that decreases the amount of free calcium. The low free calcium levels cause vessel relaxation [R, R, R].

For a long time, vasodilation (widening of the blood vessels) was believed to be the primary cause of migraine pain, though more recent evidence has thrown this hypothesis into question. However, researchers agree that nitric oxide itself almost certainly plays a role in migraines regardless of whether vasodilation has anything to do with it [R].

Is High Nitric Oxide Bad?

If you’ve read any of our other posts on NOS3, you may have noticed something: in many other conditions, nitric oxide is beneficial. For example, NOS3-derived NO lowers the risk of heart disease by increasing blood flow [R, R].

NO breaks down the free radical superoxide, both directly and by activating an antioxidant enzyme. By protecting the tissue lining from this molecule, it preserves its function and prevents vessel stiffness [R, R].

Increased NOS3 activity has also been suggested to prevent a dangerous respiratory condition called ARDS. In a study in mice, a hormone (omentin) that activates NOS3 was able to reduce lung damage leading to ARDS [R].

As you can see, NOS3 is beneficial for blood flow, heart health, and lung tissue protection, but potentially harmful in migraine. Because of its benefits, we don’t recommend actively trying to decrease NOS3 expression. However, if you have NOS3 variants that increase expression, you may want to avoid certain foods and supplements that increase it further.

NOS3 produces nitric oxide, which in turn reduces oxidative stress, widens blood vessels, and protects the lungs from damage. However, high nitric oxide has also been found to trigger migraines.

Nitric Oxide Gene Variants & Migraines

At least four NOS gene variants have been associated with migraine: rs2070744, rs743506, rs1799983, and rs2297518 [R, R, R, R].

At rs2070744, the minor ‘C’ allele is associated with higher NOS3 activity and greater incidence of migraines. Similarly, the minor ‘A’ allele at rs2297518 is associated with higher NOS2 and more migraines [R, R, R].

The relationship at the other two SNPs may be a little more complicated. At rs743506, at least two studies so far have found that a single copy of the minor ‘G’ allele (the heterozygous ‘AG’ genotype) may be protective against migraines. The heterozygous ‘AG’ genotype in this variant has been associated with lower rates of migraine compared to both the homozygous ‘AA’ and ‘GG’ genotypes [R, R].

Finally, at rs1799983, the ‘T’ allele has been associated with more frequent migraines in non-White patients. The homozygous minor ‘TT’ genotype has also been linked to migraines of longer duration [R, R].

Genetic variants that dramatically increase nitric oxide production have been linked to higher frequency and longer duration of migraines.

Your NOS Gene Results for Migraine

SNP Table

variant	genotype	frequency	risk allele
rs2070744
rs743506
rs1799983
rs2297518

SNP Summary and Table

NOS3 rs2070744

‘T’ = Lower expression of NOS3, not associated with migraine
‘C’ = Higher expression of NOS3, associated with migraine

NOS3 rs743506

‘AA’ or ‘GG’ = Associated with average frequency of migraine
‘AG’ = Possibly protective against migraine

NOS3 rs1799983

‘G’ = Not associated with migraine
‘T’ = Associated with longer and more frequent migraines

NOS2 rs2297518

‘G’ = Lower expression of NOS2, not associated with migraine
‘A’ = Higher expression of NOS2, associated with migraine

Recommendations

Nutrients

Magnesium

Magnesium deficiency is present in up to half of migraine patients. Magnesium is also essential for the removal of trapped nitric oxide from within the cell, which does not occur under low magnesium levels [R].

The richest dietary sources of magnesium include spinach, nuts, and legumes. Magnesium is also available as a supplement [R].

Vitamin B6

Migraines have been linked to vitamin B6 deficiency. Vitamin B6, like magnesium, modulates nitric oxide in the cell, which is another mechanism by which deficiency causes vasodilation [R].

Vitamin B6 is readily available in organ meats, legumes, fish, and potatoes, among other sources. It is also available as a supplement, often in combination with other B vitamins [R].

Coffee and Tea

Caffeine has been found to decrease the amount of nitric oxide exhaled by human subjects, suggesting that it could inhibit nitric oxide production. It may also constrict the blood vessels in the brain; this effect may be beneficial in patients whose migraines stem from vasodilation [R, R].

Caffeine is a part of different FDA-approved drugs for migraine and tension headaches, along with Tylenol, aspirin, sumatriptan, diclofenac, and others [R, R, R, R, R, R, R].

In 2 clinical trials on almost 350 people, caffeine (administered into veins or taken by mouth) helped prevent postoperative headaches [R, R].

Ironically, headache is one of the most common symptoms of caffeine withdrawal, which can be a limitation for its long-term use [R].

Caffeine is included in many migraine-specific painkiller combinations. In the diet, it is most often ingested in coffee or black tea.

Caffeine is considered effective against migraines and is often added to migraine medication. It may work by decreasing nitric oxide synthesis and constricting blood vessels in the brain.

Feverfew

Sometimes called medieval aspirin, feverfew has been traditionally used as a treatment for fever, rheumatism, arthritis, toothache, psoriasis, insect bites, asthma, stomachache, headaches, infertility, tinnitus, dizziness, nausea, vomiting, menstrual problems and migraine [R].

Feverfew extracts have been found to inhibit the production of nitric oxide in cell studies. It is unclear whether it has a similar effect in human bodies; however, it does seem to reduce the symptoms of migraine [R].

An active compound in feverfew reduces serotonin release by platelets (blood clot-forming cells) and white blood cells, and blocks serotonin receptors. During a migraine attack, increased serotonin release may cause inflammation and stimulate nerves, causing pain [R, R, R, R].

In 3 clinical trials on almost 400 people, feverfew extract reduced the number and severity of the attacks, the number of attacks requiring bed rest, and the frequency of vomiting [R, R, R].

In another trial on 69 women with frequent migraines, the combination of feverfew and acupuncture had better effects on pain management and quality of life than either of these strategies alone [R].

Combinations of feverfew and ginger (LipiGesic and Gelstat) were also effective in 2 trials of 89 people. Similarly, another combination of feverfew and willow extract (Mig-RL) prevented migraine attacks and reduced their intensity in a small trial on 12 people [R, R, R].

In a small trial on 17 people, capsules with freeze-dried feverfew prevented the worsening of headaches, nausea, and vomiting but caused a withdrawal-like syndrome with migraine symptoms and joint stiffness when participants switched from feverfew to placebo [R].

However, feverfew extract did not improve migraine symptoms in a trial on 50 people [R].

In another trial on 49 people, feverfew combined with riboflavin and magnesium had no benefit over riboflavin alone at preventing migraine attacks [R].

Feverfew, sometimes called medieval aspirin, may work in part by inhibiting the production of nitric oxide.

Jasmine Foster

BSc, BEd

Jasmine received her BS from McGill University and her BEd from Vancouver Island University.

Jasmine loves helping people understand their brains and bodies, a passion that grew out of her dual background in biology and education. From the chem lab to the classroom, everyone has the right to learn and make informed decisions about their health.

Disclaimer

The information on this website has not been evaluated by the Food & Drug Administration or any other official medical body. This information is presented for educational purposes only, and may not be used to diagnose or treat any illness or disease.

Also keep in mind that the “Risk Score” presented in this post is based only on a select number of SNPs, and therefore only represents a small portion of your total risk as an individual. Furthermore, these analyses are based primarily on associational studies, which do not necessarily imply causation. Finally, many other (non-genetic) factors can also play a significant role in the development of a disease or health condition — therefore, carrying any of the risk-associated genotypes discussed in this post does not necessarily mean you are at increased risk of developing a major health condition.

Always consult your doctor before acting on any information or recommendations discussed in this post — especially if you are pregnant, nursing, taking medication, or have been officially diagnosed with a medical condition.

More pain blogs

Can This Gene Worsen GERD Pain? (GNB3) Can This Gene Make You Prone to Chronic Pain (COMT)? The Heat Receptor’s Role in Pain Perception (TRPV1) Can This Gene Influence Your Sensitivity To Pain (COMT)? A Neurological Connection Between Stress and Migraines? (MEF2D) Can This Gene Influence Your Susceptibility To Headaches And Migraines? (BDNF) Is Excess Histamine Causing Your Migraines? (DAO) Can Too Much Nitric Oxide Trigger Migraines? (NOS2, NOS3) What Does the Cold Sensitivity Gene Have to Do With Migraines? (TRPM8) Serotonin Genetics in Migraine Development (HTR2C)

Content

What are the Nitric Oxide Synthases? Can Nitric Oxide Cause Headaches? Nitric Oxide Gene Variants & Migraines Your NOS Gene Results for Migraine

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