What is the function of the 5-Methylenetetrahydrofolate (5-MTHFR) supplement?

What 5-MTHF Supplement Does

5-Methyltetrahydrofolate (5-MTHF) is the active, bioavailable form of folate that directly supports homocysteine metabolism, cardiovascular health, and cellular methylation without requiring enzymatic conversion—making it superior to synthetic folic acid, especially for individuals with MTHFR genetic variants. 1

Primary Metabolic Functions

5-MTHF serves as the essential methyl donor in converting homocysteine to methionine, a critical reaction catalyzed by methionine synthase that requires vitamin B12 as a cofactor 1. This process is fundamental to:

• Homocysteine regulation: 5-MTHF supplementation reduces homocysteine levels by 25-30%, with an additional 7% reduction when combined with vitamin B12 1, 2
• DNA methylation and gene regulation: Methionine produced from this pathway serves as a precursor for S-adenosylmethionine (SAM), the major methyl donor for DNA methylation 3
• Cellular metabolism: Folate cofactors are critical for one-carbon metabolism, supporting nucleotide synthesis and cell division 4

Cardiovascular and Vascular Protection

5-MTHF provides direct vascular benefits independent of homocysteine lowering, which distinguishes it from simple homocysteine-reduction strategies 1:

• Scavenges peroxynitrite radicals (ONOO−), protecting tetrahydrobiopterin (BH4) from oxidation 1
• Improves endothelial nitric oxide synthase (eNOS) coupling, enhancing nitric oxide bioavailability and vascular function 1
• Reduces vascular superoxide production by decreasing oxidative stress from NADPH-oxidase and inducible nitric oxide synthase 1
• Improves vascular redox state and endothelial function in coronary bypass grafts and other vascular tissues 1

Stroke Prevention Benefits

The American Heart Association recommends 5-MTHF combined with methylcobalamin, vitamin B6, and riboflavin for stroke prevention in patients with hyperhomocysteinemia, rather than folic acid with cyanocobalamin 1, 2. Evidence shows:

• Reduced ischemic stroke risk: In patients with both low folate and B12, treatment reduced first ischemic stroke from 3.6% to 2.3% (HR 0.62) 1
• Genotype-specific benefits: MTHFR 677 CC carriers showed dramatic reduction (4.9% to 1.6%, HR 0.24), while TT homozygotes responded better with both folate and B12 above median levels (HR 0.28) 1

Critical Advantages Over Folic Acid

5-MTHF is immediately bioavailable as it is already in the active form, while folic acid requires hepatic conversion through multiple enzymatic steps involving dihydrofolate reductase (DHFR) and MTHFR 2, 4. This creates several key advantages:

• Bypasses MTHFR enzyme deficiency: Individuals with MTHFR 677TT genotype (10-15% of population, 23.6% in Chinese populations) have significantly reduced enzyme activity—5-MTHF circumvents this metabolic block entirely 2, 5
• Effective regardless of genetic variants: A common 19-base pair deletion in DHFR (present in 74% of population in heterozygous or homozygous form) impedes conversion of folic acid to 5-MTHF, making direct 5-MTHF supplementation more reliable 1
• Better intracellular penetration: Folic acid increases plasma 5-MTHF but has only modest effects on intracellular concentrations, whereas direct 5-MTHF supplementation achieves 10-fold increases in intracellular levels 1, 5
• Absorption independent of GI pH: 5-MTHF is well absorbed even when gastrointestinal pH is altered, unlike folic acid 4

Avoiding Unmetabolized Folic Acid (UMFA) Syndrome

High-dose folic acid supplementation can lead to unmetabolized folic acid in circulation, which is suspected of causing immune dysfunction and potentially increasing cancer risk (especially colorectal and prostate) 6. 5-MTHF avoids this issue entirely because:

• No conversion required: 5-MTHF doesn't accumulate as unmetabolized compound 6, 4
• Doesn't mask B12 deficiency: Unlike folic acid, 5-MTHF reduces the potential for masking hematological symptoms of vitamin B12 deficiency 4
• No drug interactions with DHFR inhibitors: 5-MTHF overcomes interactions with drugs like methotrexate that inhibit dihydrofolate reductase 4

Specific Clinical Applications

For MTHFR 677TT homozygotes with hyperhomocysteinemia, the recommended regimen is 2:

• 5-MTHF: 600-800 μg daily
• Vitamin B12 (as methylcobalamin or hydroxycobalamin): 1 mg weekly
• Vitamin B6: 50 mg daily
• Riboflavin: particularly important for TT genotype

For fertility and pregnancy outcomes in MTHFR carriers: Treatment with 600 μg daily of 5-MTHF for 4 months before conception resulted in spontaneous conception in 13 of 33 couples with 4+ years of infertility, with most others succeeding with ART 6

Common Pitfalls to Avoid

• Never use standard folic acid instead of 5-MTHF in individuals with TT genotype—it requires conversion by the deficient MTHFR enzyme, making it ineffective 2
• Never use cyanocobalamin instead of methylcobalamin or hydroxycobalamin—it is less effective in reducing homocysteine levels 1, 2
• Never supplement folate without checking B12 status—both deficiencies cause elevated homocysteine, and isolated folate may mask B12 deficiency 2
• Don't rely on high-dose folic acid (5 mg/day) for MTHFR mutations—this approach is obsolete and can lead to UMFA syndrome 6