Is methylated folic acid (5-MTHF) better than normal folic acid for supplementation?

Methylated Folic Acid (5-MTHF) vs. Regular Folic Acid for Supplementation

For most individuals, 5-methyltetrahydrofolate (5-MTHF) is superior to regular folic acid because it bypasses enzymatic conversion requirements, increases plasma folate more effectively, and avoids accumulation of unmetabolized folic acid in the bloodstream. 1, 2, 3

Key Advantages of 5-MTHF Over Folic Acid

Bioavailability and Effectiveness

• 5-MTHF increases plasma folate concentrations more rapidly and to higher levels than folic acid, with significantly higher area under the curve (AUC) and maximum concentration (Cmax), and shorter time to reach maximum concentration (tmax) in both individuals with and without MTHFR mutations 3
• 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 methylenetetrahydrofolate reductase (MTHFR) 1, 4
• 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

Genetic Considerations

• The European Society of Cardiology specifically recommends 5-MTHF for individuals with MTHFR mutations, particularly the 677TT genotype (present in 10-15% of the general population, up to 23.6% in Chinese populations), as it bypasses the deficient enzyme and reduces homocysteine levels by 25-30% 2, 1
• A common 19-base pair deletion in dihydrofolate reductase (DHFR) occurs in approximately 73.8% of the population (del/del 29.5%, del/ins 44.3%), which impedes conversion of folic acid to active forms—5-MTHF circumvents this limitation 1
• Even in individuals with wild-type (CC) MTHFR genotype, 5-MTHF demonstrates superior pharmacokinetic parameters compared to folic acid 3

Unmetabolized Folic Acid (UMFA) Concerns

• Supplementation with 5-MTHF reduces plasma unmetabolized folic acid by approximately 50% compared to folic acid supplementation (median 0.5 nmol/L vs 1.3 nmol/L) 5
• Unmetabolized folic acid appears regularly in plasma following folic acid supplementation but rarely occurs with 5-MTHF 3, 6
• High doses of folic acid can lead to accumulation of UMFA when hepatic conversion capacity is exceeded, which does not occur with 5-MTHF 4, 6

Cardiovascular and Vascular Benefits

• 5-MTHF provides direct vascular benefits independent of homocysteine lowering, including scavenging peroxynitrite radicals, protecting tetrahydrobiopterin (BH4) from oxidation, improving endothelial nitric oxide synthase (eNOS) coupling, and reducing vascular superoxide production 1
• These antioxidant and endothelial protective effects of 5-MTHF occur through mechanisms that folic acid cannot replicate, as they are independent of homocysteine reduction 1

Clinical Scenarios Where 5-MTHF is Particularly Advantageous

Pregnancy and Neural Tube Defect Prevention

• 5-MTHF is equally effective as folic acid for neural tube defect prevention while avoiding UMFA accumulation 6, 4, 5
• 5-MTHF supplementation during pregnancy maintains maternal folate status as effectively as folic acid (erythrocyte folate: 1826 nmol/L vs 1998 nmol/L, not significantly different) while significantly reducing plasma UMFA 5
• For women with MTHFR polymorphisms, 5-MTHF is preferred as it bypasses the metabolic block in folic acid conversion 6, 4

Vitamin B12 Deficiency Risk

• 5-MTHF may reduce the risk of masking hematological symptoms of vitamin B12 deficiency compared to high-dose folic acid, though both forms should be used cautiously in this context 7, 4
• This is particularly relevant in older adults and individuals at risk for pernicious anemia 7

Drug Interactions

• 5-MTHF has reduced interaction with drugs that inhibit dihydrofolate reductase (such as methotrexate, trimethoprim, pyrimethamine) compared to folic acid 7
• However, for patients on methotrexate, standard folic acid supplementation (≥5 mg/week) remains the evidence-based recommendation to reduce gastrointestinal side effects, hepatotoxicity, and drug discontinuation 1

Cardiovascular Disease and Stroke Prevention

• The American Heart Association suggests using 5-MTHF combined with methylcobalamin (or hydroxycobalamin), vitamin B6, and riboflavin for stroke prevention in patients with hyperhomocysteinemia, rather than folic acid with cyanocobalamin 1, 2
• For individuals with both low folate and B12 (below median), combined supplementation reduces first ischemic stroke risk (HR 0.62,95% CI 0.46-0.86), with particularly strong effects in MTHFR 677 CC carriers (HR 0.24,95% CI 0.11-0.55) 1

Practical Dosing Considerations

Equivalent Dosing

• 5-MTHF and folic acid have comparable physiological activity at equimolar doses 7
• Standard supplementation: 400-800 μg daily for general population 1, 8
• For MTHFR 677TT genotype with hyperhomocysteinemia: 5-MTHF is preferred, combined with vitamin B12 (1 mg weekly provides additional 7% homocysteine reduction), vitamin B6 (50 mg daily), and riboflavin 2, 1

Safety Profile

• Both forms are safe at recommended doses, with upper limit of 1 mg/day for general supplementation 8
• Higher doses (4-5 mg/day) are reserved for specific clinical scenarios such as high-risk neural tube defect prevention 8
• 5-MTHF does not accumulate as UMFA even at higher doses, providing a safety advantage 6, 4

Common Pitfalls to Avoid

• Do not use standard folic acid in individuals with known MTHFR 677TT genotype—use 5-MTHF instead as it bypasses the enzymatic deficiency 2, 1
• Do not assume higher doses of folic acid provide additional vascular benefits—doses above 0.4 mg/day do not further improve vascular intracellular folate levels or endothelial function 1, 8
• Do not use cyanocobalamin with 5-MTHF for cardiovascular indications—methylcobalamin or hydroxycobalamin are preferred forms of B12 for homocysteine metabolism 1, 2
• Do not forget riboflavin supplementation in MTHFR TT homozygotes—it is particularly important for this genotype and often overlooked 2
• Do not rely solely on folate supplementation without checking vitamin B12 status—both deficiencies can cause elevated homocysteine, and isolated folate supplementation may mask B12 deficiency 1