Synopsis

Source of validity: Scientific
Rating (out of 5): 2

L-5-methyltetrahydrofolate (5-MTHF) is the biologically active form of folate, often used as a dietary supplement, including in the form of its glucosamine salt. There is emerging scientific interest in the potential role of folate metabolism in migraine, particularly in individuals with genetic polymorphisms such as MTHFR (methylenetetrahydrofolate reductase) mutations. Some studies suggest that these mutations may impair folate metabolism, increase homocysteine levels, and potentially contribute to migraine pathophysiology. A few small-scale randomized controlled trials and observational studies have explored the use of folate (including 5-MTHF), often in combination with other B vitamins (B6 and B12), for migraine prophylaxis. These studies have reported modest reductions in migraine frequency or severity, particularly in individuals with specific MTHFR genotypes. However, the evidence is limited by small sample sizes, short durations, and variability in outcomes. The use of 5-MTHF for migraine is not yet supported by large, high-quality clinical trials, and major guidelines do not currently endorse it as a first-line treatment. Nevertheless, it may be considered in select cases, especially for patients with confirmed MTHFR polymorphisms or elevated homocysteine. Overall, while there is a scientific rationale and preliminary data supporting its use, the evidence remains weak-to-moderate and further research is needed to establish clear recommendations.

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