For MIGRAINES, the amino acid L-arginine has been shown to decrease pain and headache frequency. Clinically, our patients have fewer and less severe headaches. There are several theories about how L-arginine works, including the classic understanding that it is a circulation tonic that helps normalize healthy blood flow and improves the tone of brain blood vessels. Thus, arginine eases restricted blood flow and pain sensitivity, especially for migraines. Newer research indicates that it also works by decreasing or balancing chemical compounds and hormones–such as serotonin and estrogen–that often play a role in pain sensitivity for migraine sufferers.

What causes migraines?

Migraines are a common chronic inflammatory neurological condition frequently characterized by intense, debilitating headaches. Migraines can cause throbbing in one particular area that can vary in intensity. Visual disturbances, nausea, vomiting, dizziness, extreme sensitivity to sound, light, touch, and smell, and tingling or numbness in the extremities or face are also common symptoms. Ocular migraines may involve flashing lights or visual disturbances without a headache. The underlying process of migraines involves nerve inflammation and dysfunction of the vascular endothelial cells. Much evidence confirms the role of inflammation in the pathogenesis of migraines.

Vascular instability and neurological dysfunction are both likely to play roles in causing migraines. Inflammation can trigger vasodilation–where blood vessels dilate and blood rushes in with a drop of pressure; or vasoconstriction–where blood vessels are narrowed, blood flow slows, and pressure inside arteries and veins increases. Sudden narrowing and then dilation of blood vessels is common with migraines.

Inflammation and oxidative damage can also injure neurons by increasing free radicals. An imbalance of neurotransmitters including GABA, serotonin, and acetylcholine affects blood flow. Likewise, hormones are linked with either vasodilation or vasoconstriction, and imbalances of cortisol, melatonin, testosterone, and estrogen can disturb brain blood flow and aggravate migraines.

What is arginine?

Arginine is a semi-essential amino acid because it is needed for a child’s rapid growth spurt, but it is considered nonessential for healthy adults whose bodies produce adequate amounts. In adults, arginine’s production depends on different factors such as age, and mental or physical stress. A deficiency is possible when these factors outstrip the body’s production requirements, and also in these situations: pre-term infants, bowel or kidney disease, and specific genetic disorders.

Arginine has important functions in cell division, growth, wound healing, ammonia excretion, immune function, and hormone release. L-arginine is found in modest amounts in most protein-rich foods including fish, red meat, and poultry; and small amounts are found in nuts, seeds, and legumes.

How does arginine help with migraines?

The cranial blood vessel is considered an integral player in the pathophysiology of migraine, but its perceived role has been the subject of much discussion and controversy. An underlying theme is the intimate relation between vascular activity and neural function, and recent developments have clarified the role of cranial blood vessels in what is called the trigemino-vascular system. Migraine is accompanied by significant derangements in vascular function that represent important targets for investigation and treatment. Fortunately, L-arginine can benefit the tone of brain blood vessels.

In the body, the amino acid arginine has several functions:

• L-arginine converts to monomethyl-L-arginine, a specific inhibitor of the enzyme nitric oxide synthase, which is involved in the central processing of pain, the regulation of blood vessel tone, and vasodilatation in the central nervous system.
• L-arginine was found to be correlated with serotonin and estrogen levels which are found to play a role in the pathogenesis of migraines.
• It reduces clotting risk, discouraging tiny blood cell or platelet clumps that could impede blood flow and trigger migraines.

L-arginine clinically helps patients who report fewer and less severe headaches. Older theories about migraines suggested that symptoms were possibly due to fluctuations in blood flow to the brain. Now many headache researchers realize that changes in blood flow and blood vessels do not initiate the pain but may contribute to it. Today, it is widely understood that chemical compounds and hormones, such as serotonin and estrogen, often play a role in pain sensitivity for migraine sufferers.

Past and present theories about migraine causes

The vascular theory of migraine, as proposed by Graham and Wolff in 1938, was long accepted as a plausible explanation of the characteristic sensory and motor disturbances in migraine with aura. The vascular theory views migraine as having 2 phases:

1. The first prodromal phase is characterized by vasospasm, which causes focal cerebral ischemia and transient neurologic symptoms.
2. The second phase results from compensatory vasodilation of the intracranial and extracranial vasculature. Brain acidosis and stretching of pain fibers in arterial walls would then cause a pulsating headache.

Although the vascular theory influenced medical literature for many decades, the involvement of the cranial vessels in the initiation and pathogenesis of migraine may not be the whole story and is now under considerable debate.

At present, the most widely accepted model of migraine is the trigemino-vascular theory. This theory proposes that migraine results from a loss of normal electrical charge in nervous tissue called depolarization of cortical neurons, followed by reduced blood flow in the posterior cerebral part of the brain.

According to the trigemino-vascular theory, migraineurs have a hyperexcitable cerebral cortex. Genetic factors cause disturbances in neuronal ion channels, which allow a variety of external or internal factors to trigger episodes of greater and then lower electrical activity, known as regional neuronal excitation, followed by cortical depression.

The initial phase is a wave of spreading cortical depression associated with reduced spontaneous brainwave activity measured by EEG and a regional reduction of blood volume in the peripheral circulation. Cortical depression begins in the occipital region, moves anteriorly during an attack, and is thought to be responsible for a patient’s aura, focal neurologic symptoms, or both.

Cortical depression spreads to the meningeal trigeminal nerve fibers, causing headaches. Brain ion homeostasis falters, allowing an outflow of excitatory amino acids from nerve cells and enhanced energy metabolism. Decreased blood flow to the occipital cortex of the brain follows in response to the decreased neuronal activity.

The science behind arginine and migraines

This is where serotonin comes into play. One aspect of migraine pain theory explains that migraine pain happens due to waves of activity by groups of excitable brain cells. These trigger chemicals, such as serotonin, to narrow blood vessels. Serotonin is a neurotransmitter necessary for communication between nerve cells, but it can also cause narrowing of blood vessels throughout the body. This discharge of serotonin causes a wave of spreading excitation followed by depression of neuronal activity. L-arginine provides a counterbalance to reduce the migraine-triggering influence of serotonin.

During a migraine attack, urine levels of a serotonin breakdown substance increase significantly. Serotonin is released from platelets at the beginning of an attack. After onset and for the duration of the headache, intraplatelet serotonin levels decrease. Serotonin turnover is also reduced during a migraine attack. Between attacks, however, migraineurs have increased synthesis of serotonin.¹

When serotonin or estrogen levels change, the result for some is a migraine. Serotonin levels may affect both sexes, for men a drop in testosterone may be a factor, while fluctuating estrogen levels affect women only. For women, estrogen levels naturally vary over the life cycle, with increases during fertile years and decrease afterward. Women of childbearing age also experience monthly changes in estrogen levels. Migraines in women are often associated with these fluctuating hormone levels and may explain why women are more likely to have migraines than men.

Some research suggests that when estrogen levels rise and then fall, contractions in blood vessels may be set off. This leads to throbbing pain. Other data suggest that lower levels of estrogen make facial and scalp nerves more sensitive to pain.

Migraine, especially migraine with aura, is also consistently linked with micro- or macrovascular changes, meaning in tiny or large blood vessels, during the attack. Recent work on two key models of migraine–the trigemino-vascular model and cortical spreading depression–bears this out. Alterations in vascular function may or may not be the first event in a migraine attack: we would argue that the initial step can vary, with several possible pathways that lead to the generation of pain. But migraine cannot be understood without a clear view of how blood vessel dynamics can exacerbate headaches.^2,3

Conversely, several lines of evidence attest that serotonin metabolism is substantially impaired in migraine patients, triggering or enhancing vasoconstriction with reduced blood flow and hypersensitization of neurons. Published data so far suggests that nitric oxide may be effective in amplifying the reactive vasodilatation that follows the initial reduction of cerebral blood flow, relieving migraine pain. Abnormalities of nitric oxide metabolism are awaiting confirmation in larger studies.

Nitric oxide (NO) is a potent endogenous vasodilator, meaning that it naturally occurs in the body and opens up blood vessels. It is involved in pain transmission, hyperalgesia or over-sensitivity to pain, chronic pain, inflammation, and central sensitization where the central nervous system has structural and biochemical changes that worsen pain sensitivity. Nitric oxide is also involved in migraine pathogenesis, causing an immediate headache in all migraine patients and less often in healthy subjects.³ In addition, NO is released during cortical spreading depression (CSD), playing a significant role in changes in blood flow associated with this phenomenon.⁴

Studies show that migraine patients seem to have an arterial super-sensitivity to NO.
Today, migraine is considered a neurovascular disorder and classified into migraine without aura (MwoA) and migraine with aura (MwA). One study enrolled 21 migraineurs (10 with aura, 11 without aura, and 13 controls. Researchers investigated whether migraine patients present an altered response to NO in the cerebral circulation as well as the peripheral artery system. They concluded that migraineurs with aura have an excessive arterial response to blood flow in the vessels that supply the brain, likely due to an increased sensitivity to endothelium-derived nitric oxide.⁵

Another important study of migraine patients (25 with aura, 35 without aura, and 30 age-matched control subjects) supported the hypothesis of activation of the L-arginine/NO pathway in migraine patients, especially those with aura. This research also verified previous findings that increased levels of L-arginine in the platelets of migraine patients coincide with headache-free periods.⁶ Monomethyl-L-arginine, a specific inhibitor of NO synthase, is an effective treatment for migraine pain.

We can conclude that taking L-arginine eases migraines by maintaining normal brain biochemistry and nerve conduction, by balancing serotonin, and by modulating nitric oxide’s influence on brain blood flow.

Given its good track record for relieving migraine, we recommend a sustained-release L-arginine preparation, because the body breaks it down rapidly. We like a base of slow-release methylcellulose, to maintain ample tissue and platelet levels of L-arginine over 24 hours with just 500mg twice daily.

Recommendation: L-arginine in a base of slow-release methylcellulose, 500mg to 1,000mg two times daily, with or between meals; or as directed by your healthcare provider.

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