Low Dose Folic Acid Not As Effective for Migraine Treatment

An earlier study examined the efficacy of 2 mg folic acid.

Supplementation with 1 mg of folic acid with B6 and B12 was not as effective as 2 mg of folic acid in decreasing migraine symptoms, according to data published in the Journal of Headache and Pain.

The pathophysiology of migraine is not fully understood but it is thought to be tied to vasodilation of intracranial blood vessels via activation of the trigeminovascular system. A variant of the methylenetetrahydrofolate reductase (MTHFR) gene and elevated homocysteine levels are also associated with migraines, possibly related to endothelial dysfunction.

In earlier phases of this study, patients with migraine with aura received folic acid 2 mg, vitamin B6 25 mg, and vitamin B12 400 μg. The investigators reported reductions of homocysteine levels and migraine disability scores and noted that response to treatment was affected by the MTHFR variant.

In this study, Saras Menon, PhD, of the Genomics Research Centre, Institute of Health and Biomedical Innovation at Queensland University of Technology in Australia, and colleagues sought to investigate if a lower dose of folic acid would be as effective in reducing migraine disability and homocysteine levels.

The study participants were randomized to receive a daily supplement of 1 mg of folic acid, 25 mg of vitamin B6, and 400 μg of vitamin B12 or placebo for 6 months. Patients were assessed with the Migraine Disability Assessment Score (MIDAS) instrument, headache diaries, and serum samples of homocysteine, folate, vitamin B6 and B12. Genotyping and genomic DNA extraction was also performed.

After exclusions, dropouts, and losses to follow-up, the study included 189 participants who completed the study with 126 in the vitamin group and 63 in the placebo group. The groups were similar for serum studies however, there was a higher proportion of participants in the placebo group with a high migraine disability than in the treatment group (91% vs 79%).

At the 6 month follow-up, the treatment group demonstrated significantly higher levels of folate, B6, and B12 levels (P< .0001). Plasma homocysteine levels decreased in the treatment group but not significantly (9.4 to 8.5 μmols/l, P=.02).

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Although not statistically significant, the treatment group demonstrated fewer participants with high severity, frequency, and disability scores than the placebo group (P> .1). A similar non-significant decrease in high severity, frequency, and disability scores in the treatment group was observed when stratified by the MTHFR C677T genotypes (P> .1).

“This current study has provided evidence that the folic acid dosage in the proposed vitamin supplementation for migraine treatment plays a pertinent part in reducing homocysteine levels and migraine associated symptoms,” the authors wrote.

They highlighted limited evidence of folic acid toxicity at high levels except for epigenetic studies that suggest a possible promotion of existing tumor growth with high folic acid intake. However, this association was not observed in a meta-analysis of the use of B-vitamins in patients with cardiovascular disease. Further studies are needed to better understand the impact of folic acid supplementation, the authors wrote.

The authors reported no disclosures. The study was supported by grants from the Queensland Government Smart State CIF grant.


Menon S, Nasir B, Avgan N, et al. The effect of 1 mg folic acid supplementation on clinical outcomes in female migraine with aura patients. J Headache Pain. 2016;17(1):60.