What supplements should be avoided in individuals with the MTHFR (methylenetetrahydrofolate reductase) C677T gene variant?

Supplements to Avoid with MTHFR C677T Gene Variant

Individuals with the MTHFR C677T variant should avoid regular folic acid supplementation and cyanocobalamin (the synthetic form of vitamin B12), as these require enzymatic conversion that is impaired by the mutation. 1

Specific Supplements to Avoid

Folic Acid (Synthetic Folate)

• Regular folic acid should be avoided because it requires conversion by the deficient MTHFR enzyme to become biologically active, making it significantly less effective in individuals with the C677T variant, particularly those with the TT genotype 1
• Folic acid increases plasma 5-MTHF levels but has only modest effects on intracellular 5-MTHF concentrations, whereas direct 5-MTHF supplementation more effectively raises intracellular levels 1
• The European Society of Cardiology specifically recommends against using folic acid in favor of 5-methyltetrahydrofolate (5-MTHF) for individuals with MTHFR mutations, particularly the 677TT genotype 1

Cyanocobalamin (Synthetic B12)

• Cyanocobalamin should be avoided as it is less effective in reducing homocysteine levels compared to methylcobalamin or hydroxycobalamin 1
• The American Heart Association recommends using methylcobalamin or hydroxycobalamin instead of cyanocobalamin for stroke prevention in patients with hyperhomocysteinemia 1

What to Use Instead

Recommended Folate Form

• Use 5-methyltetrahydrofolate (5-MTHF) at doses of 0.4-5 mg daily, which bypasses the enzymatic defect entirely and reduces homocysteine levels by 25-30% 1
• 5-MTHF is immediately bioavailable as it is already in the active form, requiring no conversion 1
• The FDA-approved methylfolate is indicated regardless of MTHFR C677T polymorphism genotype 2

Recommended B12 Forms

• Use methylcobalamin or hydroxycobalamin at 0.02-1 mg daily (or 1 mg weekly), which provides an additional 7% reduction in homocysteine levels when combined with 5-MTHF 1
• TT homozygotes respond better when both folate and B12 levels are above median values, suggesting they need higher doses or active forms 1

Additional Beneficial Supplements

• Vitamin B6 (pyridoxine) at 50 mg daily supports the transsulfuration pathway of homocysteine metabolism 1
• Riboflavin (vitamin B2) supplementation appears particularly effective for individuals with the TT genotype 1, 3
• Betaine (trimethylglycine) acts as a methyl donor that remethylates homocysteine to methionine, particularly useful when response to B vitamins is insufficient 3

Critical Pre-Supplementation Warning

• Never start folate supplementation without first ruling out vitamin B12 deficiency by measuring serum cobalamin and methylmalonic acid 1, 3
• Folate alone can mask the hematologic manifestations of B12 deficiency while allowing irreversible neurological damage to progress, which is particularly dangerous in elderly populations and those with MTHFR mutations 1
• The American College of Medical Genetics specifically recommends measuring serum and erythrocyte folate, serum cobalamin, and serum/urine methylmalonic acid before starting folate supplementation 1

Common Pitfalls to Avoid

• Do not use standard multivitamins containing folic acid if you have the TT genotype—look specifically for products containing 5-MTHF instead 1
• Avoid fortified foods with synthetic folic acid—focus instead on foods naturally rich in folate such as leafy greens, legumes, fruits, and vegetables 1
• Do not supplement with folate alone—comprehensive B vitamin supplementation (5-MTHF, methylcobalamin/hydroxycobalamin, B6, and riboflavin) is necessary rather than focusing solely on folate 1

Monitoring Considerations

• Plasma homocysteine measurement is more informative than molecular testing alone, as homozygosity for MTHFR mutations accounts for only about one-third of hyperhomocysteinemia cases 1, 3
• Treatment should be based on both homocysteine levels and MTHFR genotype, with fasting plasma homocysteine measured after at least 8 hours of fasting 1, 3