What is the role of Methylfolate (MTHFR), or 5-methyltetrahydrofolate (5-MTHF)?

From the Guidelines

Methylfolate supplementation is recommended for individuals with MTHFR gene mutations, as it can help lower homocysteine levels and improve endothelial function, particularly in those with moderate homocysteinaemia due to the MTHFR 677TT genotype 1. When considering methylfolate supplementation, it's essential to understand its role in homocysteine metabolism and its potential benefits in reducing the risk of thrombotic events.

• Methylfolate, also known as 5-MTHF, is a bioactive form of folate that can bypass the conversion step required for folic acid, making it immediately available for critical biochemical processes.
• The recommended dosage of methylfolate varies, but typical ranges are from 400-1000 mcg daily for general health maintenance, with therapeutic doses reaching 5-15 mg daily for specific conditions under medical supervision.
• Methylfolate works synergistically with vitamin B12, so concurrent B12 supplementation is often beneficial, as evidenced by studies showing that vitamin B12 supplementation can yield an additional 7% reduction in homocysteine levels 1.
• It's crucial to note that methylfolate can interact with certain medications, such as those for seizures, cancer, or autoimmune conditions, so consulting a healthcare provider before starting supplementation is essential.
• For best absorption, taking methylfolate with food is recommended, and if side effects occur, starting with a lower dose and gradually increasing as tolerated is advised.
• The benefits of methylfolate supplementation are supported by studies demonstrating its ability to improve endothelial function, reduce vascular superoxide production, and scavenge peroxynitrite radicals, leading to improved vascular BH4 bioavailability 1.

From the FDA Drug Label

L-METHYLFOLATE CALCIUM Tablets may be less likely than folic acid to mask vitamin B12 deficiency. Folate therapy alone is inadequate for the treatment of a B12 deficiency. The answer to the question about METHYL FOLATE is that L-METHYLFOLATE CALCIUM Tablets may be less likely to mask vitamin B12 deficiency compared to folic acid, but folate therapy alone is not sufficient to treat a B12 deficiency 2.

• Key points:
  • Methyl folate may not mask B12 deficiency as much as folic acid
  • Folate therapy is inadequate for treating B12 deficiency
  • L-METHYLFOLATE CALCIUM Tablets is not a replacement for B12 deficiency treatment

From the Research

Methyl Folate Studies

• The study 3 compared the efficacy of a diet rich in natural folate and of two different folic acid supplementation protocols in subjects with moderate hyperhomocysteinemia, taking into account C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene.
• The results showed that homocysteine levels were reduced after folate enriched diet, 5-MTHF or folic acid supplementation respectively by 20.1% (p < 0.002), 19.4% (p < 0.001) and 21.9% (p < 0.001), as compared to baseline levels and significantly as compared to placebo.
• Another study 4 discussed the biochemistry of folic acid, Hcy biosynthesis, Hcy and hydrogen sulfide bioavailability, pathogenesis of hyperhomocysteinemia and its role as a risk factor for disease, and treatment studies with folic acid supplementation in disease states.
• The study 5 investigated and compared the efficacy of two total homocysteine (tHcy)-lowering treatments including folinic acid or l-methylfolate in healthy Greek adults, and found that the reduction of serum tHcy levels was influenced by the existence of MTHFR C677T and not MTHFR A1298C gene polymorphisms.

Methyl Folate and Homocysteine Levels

• The study 6 found that folate and vitamin B12 deficiencies were observed in 10% and 6% respectively of unsupplemented dialysis patients, and that after folate therapy, tHcy levels decreased significantly in all patients and were identical between the three C677T MTHFR genotype subgroups.
• The study 7 found that hyperhomocysteinemia (HHcy) is common in patients with chronic venous insufficiency, especially those with ulceration, and that HHcy levels and prevalence of HHcy were negatively correlated with vitamin B(12) levels.
• The studies suggest that methyl folate supplementation can help reduce homocysteine levels, particularly in individuals with certain genetic polymorphisms, such as the MTHFR C677T polymorphism 3, 5, 6.
• However, the studies also suggest that other mechanisms may be responsible for hyperhomocysteinemia in certain populations, such as patients with chronic venous insufficiency 7.