Name: Folic acid, Vitamin B9
Goes well with: Vitamin B6, Vitamin B12
Number of scientific references: 32
Level of Evidence: Level II What is this?
Note: The presence of MTHFR C677T gene variant disturbs folate metabolism and increases the susceptibility of developing migraine with aura. Folic acid supplementation with other members from vitamin B complex helps reduce migraine severity and disability. There is a debate on whether to use folic acid or 5-MTHF, but studies to date have examined the efficacy of folic acid supplementation in case of migraine. Consult your doctor for the dose and type of supplement.
A migraine is identified as a complex brain disorder, and this complexity arises from the number of pathways and systems involved.
Burstein et al. state that the number of variable symptoms that are present from the prodromal to the headache phase (these are stages of a migraine) suggests that many neuronal groups will be functioning abnormally in this disorder.
Among the various hypothesis for migraine causes, the concept of genetic predisposition to a migraine seems to account for most of the symptoms. It is not about a particular gene but multiple sets of susceptibility genes.
And these genes, when abnormally expressed, cause increased neurotransmission (alterations in brain chemistry and electrical activity), increased excitability of brain cells, increased pain sensitivity and other alterations that take place in the brain during a migraine but at a cellular and biochemical level.
A recent study published in The Lancet, Neurology, 2015 states that 13 genetic variants are associated with migraine development. Complex interactions occur within these variants that contribute to the different symptoms of the disorder.
Folic acid belongs to Vitamin B complex group and is referred to as Vitamin B9. It is essential for the development of red blood cells and is advised as an important supplement in pregnancy for healthy development of the baby.
Folic acid plays an important role in the functioning of the brain and nervous system. It is also involved in the production of genetic material.
Table of Contents
- 1 Suggested Folic Acid/Folate Supplements For Migraine
- 2 What is the role of MTHFR gene in the occurrence of a migraine?
- 3 How Folic Acid Supplementation Helps In A Migraine
- 4 Folic Acid vs. Folate Debate: Which should you take for a migraine?
- 5 Dosage of Folic Acid For Migraine Relief
- 6 Precautions with Folic Acid Use
- 7 Conclusion
As discussed prior, genes play an important role in the susceptibility of a migraine.
Some of these genes affect folate metabolism, and when abnormally expressed they impair folate metabolism, increase homocysteine levels and increase the risk of developing migraine with aura. Folic acid supplementation helps to compensate for the abnormal gene expression and benefits in migraine by reducing homocysteine levels and migraine severity.
Folic acid’s effectiveness in relieving migraine symptoms is linked with expression of certain genes. Let’s understand that better in the upcoming sections.
Suggested Folic Acid/Folate Supplements For Migraine
Please consult a health practitioner before taking any health supplements.
If you have been tested positive for MTHFR mutation and experience migraines, then it is advised to supplement with folate as well other B vitamins. This is one supplement that I came across that helps support methylation status and is reported to be beneficial for MTHFR mutation by users.
|Thorne Research Methyl-Guard Plus|
|This supplement contains folate, vitamin B6, riboflavin, vitamin B12 and betaine packed in veg capsules.
Dosage: 1-2 capsules per day or follow manufacturer’s recommended dosage
Buy from Amazon (US, UK, Canada)
Buy from iHerb (Global)
Image Credit: Thorne Research, Inc.
Individual Folic Acid Supplements
If you are looking for individual supplements then here are a few suggested folic acid and folate supplements. You may even consider taking a complete B-complex supplement in addition to this (Buy from Amazon or Buy from iHerb).
|Solgar Folic Acid 800mcg capsules||Thorne Research-5-MTHF- 1mg Folate|
Image Credit: Solgar Inc.
Image Credit: Thorne Research, Inc.
|Contains 800mcg folic acid in veg capsules||Contains 1 mg 5-MTHF or folate per veg capsule|
|Buy from Amazon (US, UK, Canada)
Buy from iHerb (Global)
|Buy from Amazon (US, UK, Canada)
Buy from iHerb (Global)
What is the role of MTHFR gene in the occurrence of a migraine?
If you have read quite a bit on the role of genes in a migraine, you must have heard of MTHFR gene aka ‘the migraine gene, ’ and in that case, you can skip this section.
Various genes have been linked to the development of a migraine and its symptoms, and they can be broadly classified as genes involved with:
• Neurological pathways (linked with neurotransmission)
• Vascular pathways (linked with blood flow)
• Hormonal pathways (linked with hormones especially in females)
What is MTHFR gene and its function?
MTHFR is a gene involved in the vascular pathway and is known as methylene-tetra-hydro-folate reductase gene (the first four units are one word, and the hyphen is just to make the pronunciation simpler).
The expression of this gene leads to the production of MTHFR enzyme which is important for reactions involving folate or vitamin B9. It converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, and this product is required for conversion of homocysteine to methionine.
High homocysteine levels are linked with the development of heart diseases. Increased homocysteine levels affect the cells of blood vessels, firing of certain neurons (trigeminal neurons) and the blood’s coagulation status.
The firing of trigeminal neurons and altered blood circulation can contribute to pain and other symptoms in a migraine.
Variants in MTHFR gene lead to reduced enzymatic activity and increased homocysteine levels. To reduce these homocysteine levels, folate supplementation is necessary.
What are the variants in the MTHFR gene?
Two variations have been studied in this gene (these are changes or replacement in nitrogenous bases which is different from what normal individuals have):
• A to C change at position 1298
• C to T change at position 677
And the second one is found to impact and lessen enzymatic activity more significantly than the first one. The MTHFR C677T variant is found to be linked with high risk of a migraine with aura.
Further, there are other subtypes in MTHFR C677T gene variant:
• CC genotype: normal
• CT genotype: heterozygous type with a single copy
• TT genotype: homozygous type with two copies
How does MTHFR C677T genetic variant affect migraine symptoms?
A study was conducted to assess the difference in symptoms of a migraine based when on these genetic variants subtypes.
The TT genotype was found to have:
• A migraine with aura
• Unilateral head pain (a headache restricted to only one side left or right)
• High frequency of a unilateral headache
• Did not find stress as a trigger factor
The CT genotype was found to have following characteristics:
• Physical discomfort prior or during a migraine
• Found stress as a trigger factor
• Had an intermediate response to a unilateral headache
• Highly susceptible to stress-induced trigger of a migraine
Coming to gender differences, females with TT were significantly associated with a unilateral headache while those with CT has nausea, osmophobia (aversion to smell) and were likely to use natural remedies.
Men with TT genotype had a higher incidence of a bilateral headache and were less likely to use natural therapies.
Some studies have found that MTHFR C677T genetic variant is not linked with migraine occurrence. They found that patients with these variants have equal chances of developing migraine with aura or without aura. Also, they found that this genetic variant is as frequently observed in normal individuals as in migraineurs.
These differences could be due to the presence or absence of certain other genetic alterations which influence the ability of MTHFR C677T to increase the risk of a migraine.
Can vitamin supplementation help in a migraine if you have MTHFR C677T genetic variant?
In 2009, researchers from Genomics Research Centre, Griffith University, Australia conducted a study to examine whether vitamin supplementation helps in a migraine and does the presence of MTHFR C677T genetic variant affect treatment response.
52 individuals with a migraine with aura were enrolled in the study. They were given the following vitamins: 2mg folic acid, 25 mg vitamin B6, 400 microgram vitamin B12 for six months.
Vitamin supplementation was found to reduce homocysteine levels by 39% and the disability score reduced from 60 to 30% in 6 months. The frequency of a headache and pain intensity reduced significantly with vitamin therapy.
Reduction in homocysteine levels and disability scores was more pronounced in individuals with CT genotype than TT genotype.
Methionine synthase reductase (MTRR) gene is another gene that is involved in methylation or conversion of homocysteine. Abnormal expression of this gene and resultant deficiency in the enzyme (MTRR) can disturb the metabolism of folate and cobalamin and cause an increase in levels of homocysteine.
MTRR gene also has a genetic variant known as MTRR A66G. The presence of this variant in combination with MTHFR C677T worsens the effect of MTHFR variant and increases the risk of experiencing migraine with aura by eight folds in migraineurs.
In 2012, researchers from Griffth University, Australia conducted another study where they examined the effect of vitamin B supplementation in patients with MTRR and MTHFR genetic variants and experiencing migraine with aura.
Vitamin treatment reduced the severity of a headache, homocysteine levels, and migraine disability. Treatment response was more pronounced in CT genotype than TT genotype as well as in AG genotype than GG.
Also, it was observed that both gene variants independently influenced treatment response in female migraineurs.
How Folic Acid Supplementation Helps In A Migraine
There are a few studies that have found folic acid supplementation beneficial in migraine treatment. MTHFR gene variant reduces the usable form of folic acid in the body and makes it difficult to utilize dietary folic acid.
This leads to increased homocysteine levels which contribute to migraine development.
In 2007, Di Rosa et al. reported that folic acid supplementation successfully resolved or reduced a migraine in children with MTHFR gene variants.
In the 2009 study, Lea et al. found 2mg of folic acid, 25 mg vitamin B6 and 400microgram vitamin B12 effective in reducing migraine severity and homocysteine levels in patients with a migraine with aura.
In 2015, researchers belonging to the same group reported that dietary folate intake (in the form of folic acid) influenced migraine frequency in females diagnosed with a migraine with aura.
Dietary folate intake was associated with reduced migraine frequency, and this effect was more pronounced in the CC genotype or normal genotype of MTHFR gene.
Further, their study published in 2016 revealed that 1mg folic acid was ineffective in reducing migraine severity, migraine disability, and homocysteine levels.
Recently a study published in Nutrition 2017 demonstrated that a combination of folic acid (5mg/day) and pyridoxine (80mg/day) for three months was more effective than folic acid alone in reducing frequency and severity of the attack.
Here are a few other therapeutic benefits of folic acid that can help in migraine therapy:
1. A multivitamin supplement containing folic acid and prepared from fruits and vegetables exert a neuroprotective action and prevents neurodegenerative processes in healthy individuals. B complex vitamins have a neuroprotective action.
2. Folate and cobalamin levels in the body can influence inflammation and oxidative stress in the central nervous system.
3. Folic acid protects antioxidant defenses which are otherwise disturbed in case of high homocysteine levels.
Quick Gist: The presence of MTHFR C677T genetic variant increases the risk of developing migraine with aura. This genetic variant can influence folic acid levels in the body and lead to high homocysteine levels.
Folic acid supplementation with vitamin B6 and vitamin B12 is proven to reduce migraine severity, disability and homocysteine levels in patients with a migraine with aura. A dose of 2mg folic acid with 25 mg vitamin B6 and 400microgram vitamin B12 is found to be effective.
Folic Acid vs. Folate Debate: Which should you take for a migraine?
Now the terms folic acid and folate are used interchangeably, but folate refers to the natural form of vitamin B9 as present in diet while Folic acid refers to the synthetic version prepared in labs.
There is quite a bit of debate on whether one should supplement with folic acid or folate; most authorities suggest that one should go with the natural one which is 5-methyltetrahydrofolate.
The reason for this is that gut can easily transform 5-methyltetrahydrofolate and not folic acid; folic acid needs to be converted into a usable form by the liver and chronic exposure to folic acid may cause saturation of the liver.
Apart from that high dose of folic acid may have some health concerns as demonstrated by evidence listed by MTHFR Support Australia. And 5-methyltetrahydrofolate and folic acid are said to have comparable bioavailability.
A few other advantages of 5-methyltetrahydrofolate over folic acid are :
• It may prevent masking of anemia like symptoms caused by vitamin B12 deficiency.
• It may have a reduced interaction with drugs that inhibit dihydrofolate reductase.
Both folic acid and 5-methyltetrahydrofolate are found to be equally effective in reducing homocysteine levels in healthy women. 400microgram folic acid and 416 micrograms of 5-MTHF were equally effective in increasing plasma folate levels (151% increase by folic acid and 164% increase by 5-MTHF).
However, the same group of researchers found that 5-MTHF supplementation is more effective than folic acid in improving folate status in women irrespective of MTHFR C677T gene variant.
Regarding the efficacy of reducing homocysteine and increasing folate levels, 416 microgram of 5-MTHF is equivalent to 400 micrograms folic acid.
Most studies till date that have explored folate deficiency or conditions that are affected by folate levels have used folic acid supplements and have demonstrated positive results. Migraine related studies in humans have also used folic acid supplements.
It would be interesting to compare both folic acid and folate supplementation in migraine patients with MTHFR C677T mutation. More research and definitive evidence is required.
I would be updating this section when I get better data on this matter, but till then it is best to consult a health practitioner whether to take 5-MTHF or folic acid for a migraine.
Quick Gist: 5-MTHF is the natural form of vitamin B9 while folic acid is derived in the lab. There are some health concerns associated with high dose folic acid which still needs to be addressed, and hence various sources suggest taking 5-MTHF.
There has been no long-term study assessing which of the two forms are better. Also, there is no study which examines the efficacy of 5-MTHF in migraine relief. Studies to date have used folic acid successfully for a migraine.
Please consult a health practitioner before taking 5-MTHF or folic acid for a migraine.
Dosage of Folic Acid For Migraine Relief
As per research 2mg folic acid is found to be an effective dose for reduction of migraines in combination with other B vitamins (25 mg vitamin B6 and 400microgram vitamin B12).
No study to date examines the efficacy of 5-MTHF in a migraine. A study examining the benefits of 5-MTHF vs. Folic acid in patients with MTHFR C677T found 5-MTHF better in improving folate levels than folic acid. In this study, 416 micrograms of 5-MTHF is equivalent to 400 micrograms folic acid in terms of efficacy.
Please consult a health practitioner to identify the dose and type of folic acid or folate supplement that would suit you.
Precautions with Folic Acid Use
Side effects from dietary folic acid are rare. Very high dose of folic acid may cause side effects like:
• Loss of appetite
• Stomach issues
• Sleep disturbances
• Confusion or reduction in mental function
• Kidney damage
• Allergic reaction
Folic acid tends to hide symptoms of vitamin B12 deficiency or anemia. So if you have been diagnosed with either of these, you should consult a health practitioner before taking folic acid.
Individuals being treated for cancer or seizures should consult a health practitioner before taking folic acid supplements.
Folic acid may interact with certain medications: oral contraceptives, antibiotics, anti-seizure medicines, chemotherapeutic agents, pyrimethamine, pentamidine, trimethoprim, triamterene and certain medications that lower folic acid levels. Please check the full list noted by UMM.
B complex vitamins play an important role in neuroprotection. Mutation in the MTHFR gene reduces the body’s ability to convert dietary folic acid to a usable form, increases homocysteine levels and increases the tendency to develop a migraine with aura.
Studies have found that folic acid supplementation in such cases helps reduce homocysteine levels and reduces migraine severity and disability. These studies have utilized folic acid in combination with other vitamin B group members.
There is a debate on the use of synthetic folic acid versus natural 5-MTHF, but no study to date has examined the efficacy of 5-MTHF in a migraine. It is best to consult a health practitioner about this.
If you have tried folic acid supplementation for migraine, please share your experience here as comments. Do share the article if you have found it beneficial.