For MIGRAINES, SAMe exerts pain-relieving and preventive effects, and the benefits build up over the long term. SAMe reduces inflammation, maintains healthy folic acid levels, and helps the body clear homocysteine, a natural waste product that can exacerbate migraines. Clinical trials have shown that SAMe, as a methyl donor, reduces the incidence and severity of migraine attacks.

What is SAMe?

S-adenosyl-L-methionine (SAMe) is a naturally occurring amino acid derivative distributed throughout virtually all body tissues and fluids. It is of fundamental importance in several critical biochemical reactions involving methylation contributing to the synthesis, activation, or metabolism of such compounds as hormones, neurotransmitters, nucleic acids, proteins, and phospholipids.

SAMe is normally produced in the liver from the amino acid methionine which is abundant in most diets. Folic acid and vitamin B12 are necessary for the synthesis of SAMe, and deficiencies of these vitamins result in low concentrations of SAMe in the central nervous system. Low blood or central nervous system levels of SAMe have been detected in people who suffer from migraine pain.

What causes migraines?

Migraines are a common inflammatory neurological disorder characterized by multiple symptoms including intense, debilitating head pain, nausea, vomiting, and extreme sensitivity to light and sound with attacks lasting from 4 to 72 hours. Migraines can cause throbbing in one particular area that can vary in intensity. Visual disturbances, dizziness, extreme sensitivity to 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 processes of migraines involve nerve inflammation and dysfunction of blood flow and vascular endothelial cells. Much evidence confirms the role of inflammation in the pathogenesis of migraines.

Migraines are ranked as the 7th most disabling condition by the World Health Organization and are thought to be one of the symptoms of poor methylation, an important biochemical process in the body. Migraines affect approximately 12% of the population, about 66% of which are female; the condition causes a large amount of lost productivity in the workplace.

Both vascular instability and neurological dysfunction play roles in the cause of migraines, and poor methylation is also a factor. 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 methylation and how does it affect migraines?

 Methylation is an important metabolic event that uses vitamin B12 and folic acid (or folate) to help remove homocysteine, a waste product our bodies naturally make. Methylation is a cyclical process in the body. To simplify, your body derives vitamin B12 and folate from the foods you eat or from nutritional supplements, and those nutrients are used to create a molecule called SAMe. SAMe has a methyl group attached to it, which it donates to homocysteine. Then homocysteine is converted into the amino acid, methionine, which eventually becomes SAMe again, and the cycle continues.

The methylation cycle is important because it takes nutrients from food and supplements to make the energy our bodies need for daily metabolism. If one process is faulty, it influences the next like a domino effect. When the cycle breaks, it affects our moods, energy, and overall physiological function. Several neurotransmitters, fatty acids, phospholipids, and other chemicals must accept methyl groups from SAMe to become active. Sometimes the brain can produce all the SAMe it needs, but patients who are depressed or in pain often cannot make enough of their own, and thus their methylation functions are lacking.

When the methylation cycle is disrupted, excess homocysteine accumulates in the body. Research has found migraines with aura to be associated with mutations in the gene that encodes the MTHFR enzyme leading to elevated homocysteine levels.¹

Although much is being learned about genetic variants and their relation to disease, migraine with aura may be related to a rare genetic inability to process folate. Researchers are seeing that elevated levels of homocysteine are due to an inadequate supply of folate, and not the result of a migraine attack. Co-factors in the biochemical function of folate include vitamin B12 which is of great importance in the regulation of serum homocysteine levels. The L-methionine produced in the reaction can participate in protein synthesis and is also a major source for the synthesis of S-adenosyl-L-methionine (SAMe) circling back to its importance in folate-based migraine treatment.²

Why is B12 also important for migraine relief?

B12 itself helps migraine headaches in several ways:

• Firstly, low blood levels of B12 are linked with more migraines. Boosting serum B12 to above 643 pg./mL can reduce the chance of developing a migraine by a huge 80%.³
• Secondly, vitamin B12 enhances mitochondria within our cells and their energy production. Patients with lower mitochondrial energy reserves are more at risk for migraines.
• And thirdly, vitamin B12 helps to reduce homocysteine. This is a waste product naturally made by the body, but if it is not cleared efficiently, its accumulation can worsen migraine pain.²

The science behind SAMe’s necessary co-factors

One study, which measured the amount of folate and folic acid consumed by people who experience migraines, found that the more folic acid people consumed, the less frequent their migraines were. Researchers noted that folic acid, vitamin B6, and B12 supplementation have been previously shown to reduce levels of homocysteine and decrease migraine symptoms. However, the influence of dietary folate intake on migraine has taken longer to clarify. This 2015 study assessed the dietary intake of these vitamins in 141 adult females and paired this with migraine frequency, severity, and disability. The results from this study indicate that if folate intake and methylation cycles were functioning well, the study participants experienced fewer migraines.³

Simply providing the body with the vitamins and cofactors essential for optimal methylation can be an effective option. Supplementing with folate or folic acid, vitamin B6, and vitamin B12 can reduce homocysteine levels, thus benefitting migraine sufferers.⁴

The more we learn about methylation and genetics, the more intriguing the current research becomes as it relates to novel therapies for migraines. We know that SAMe has been shown to lower expression of the inflammation-causing, or pro-inflammatory, cytokine TNF-α and to increase the expression of the anti-inflammatory cytokine IL-10 in macrophages. From this position, a 2014 study sought to assess whether epigenetic mechanisms mediate the anti-inflammatory effects of SAMe. Their data indicated that SAMe modulates the expression of inflammatory genes in association with changes in specific gene promoter DNA methylation. This is a complex way of stating that SAMe has a positive effect on the methylation cycle and it calms inflammation, reducing migraines.⁵

Folic acid intake alone does not significantly decrease migraine attacks compared with placebo. Folic acid requires B6 to bring a significant decrease in all characteristics of migraine attacks compared with folate or placebo intake. An important double-blind, randomized, placebo-controlled clinical trial was conducted on 95 migraine patients with aura (age range 18 to 65 years) in Isfahan, Islamic Republic of Iran. Patients were randomly allocated to receive folic acid plus pyridoxine, vitamin B6, folic acid alone, or placebo for 3 months. Only folic acid with pyridoxine decreased the characteristics of migraine attacks including headache severity and attack frequency.⁶

Our clinical experience with SAMe formulations

SAMe is highly hygroscopic and a very unstable compound, meaning that it absorbs moisture from the air which could easily denature it. We shun the many SAMe supplements that attempt to keep SAMe stable in coated tablets with shellacs, waxes, and plastics containing phthalates, which are known endocrine disruptors. In our clinic, we want only a pure formulation with calcium and magnesium chelates to keep SAMe stable without unhealthy additives.

Furthermore, we prefer a SAMe formula that includes cofactors, the necessary amounts of 500mcg vitamin B12, and 200mg folic acid in the right proportions for SAMe to work. These cofactors are required with SAMe for the methylation functions and sulfur-reactions that bring mood, nervous system, joint, and liver benefits. We also want a formula that includes 2 to 3mg of vitamin B6 to ensure that SAMe is efficiently cleared and to prevent homocysteine elevations.

In our clinic, our patients taking SAMe with correct cofactors have reported fewer migraines and less pain, and noticed the effectiveness building up over long-term use of 3 or more months.

Recommendation: 200 to 400mg of SAMe daily between meals or as directed by your healthcare provider. We ideally like to see cofactor doses of 500mcg vitamin B12, 200mg folic acid, and 2 to 3mg of vitamin B6.

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