What is the recommended dosage of biologically active folic acid, specifically 5-methyltetrahydrofolate (5-MTHF), for patients requiring supplementation?

How to Prescribe Biologically Active Folic Acid (5-MTHF)

For most clinical situations requiring folate supplementation, prescribe 400-800 μg of 5-methyltetrahydrofolate (5-MTHF) daily, which is equivalent to or superior to standard folic acid and avoids the risk of masking vitamin B12 deficiency. 1, 2

Critical Pre-Treatment Assessment

Before initiating any form of folate supplementation, you must exclude vitamin B12 deficiency first by checking both serum B12 and folate levels, as folic acid (and to a lesser extent 5-MTHF) can mask B12 deficiency hematologically while allowing neurological complications like subacute combined degeneration of the spinal cord to progress. 1, 3

Standard Dosing by Clinical Indication

For Women of Childbearing Age (Neural Tube Defect Prevention)

Average-risk women:

• 400-800 μg daily of 5-MTHF (equivalent to 416 μg of calcium-L-methylfolate) 1
• Start at least 4 weeks (ideally 12 weeks) before planned conception through first trimester 1, 4
• 5-MTHF increases red blood cell folate concentrations more effectively than folic acid, suggesting superior bioavailability 4

High-risk women (personal/family history of NTDs, type 1 diabetes, exposure to valproic acid/carbamazepine):

• 4,000 μg (4 mg) daily starting 12 weeks before conception 1
• Reduce to 400 μg daily after 12 weeks gestation 1
• This high-dose approach minimizes long-term exposure risks while providing maximal protection during critical organogenesis 1

For MTHFR Gene Variant Carriers

For patients with MTHFR C677T or A1298C polymorphisms:

• 600-800 μg of 5-MTHF daily 5
• 5-MTHF bypasses the MTHFR enzymatic block entirely, making it the preferred form over folic acid 5
• Avoid high-dose folic acid (5 mg) in these patients, as it leads to unmetabolized folic acid (UMFA) syndrome with potential immune dysfunction 5
• Treat for at least 4 months before attempting conception (corresponding to complete spermatogenesis cycle) 5

For Cardiovascular Disease/Homocysteine Lowering

For moderate hyperhomocysteinemia (15-30 μmol/L):

• 400 μg of 5-MTHF daily achieves maximal vascular benefit 1
• Higher doses provide no additional benefit on endothelial function or intracellular 5-MTHF levels 1
• In MTHFR 677TT genotype specifically, oral 5-MTHF should be considered as it requires no MTHFR conversion 1

For Enteral and Parenteral Nutrition

Enteral nutrition:

• At least 30 μg biotin per day in 1500 kcal (note: this appears to be a biotin recommendation from the evidence) 1
• For folate: 125-200 μg/day of 5-MTHF (equivalent to 250-400 μg dietary folate equivalents) 1

Parenteral nutrition:

• 125-200 μg/day of 5-MTHF intravenously 1

Bioavailability Conversion Factors

Understanding dietary folate equivalents (DFE) is essential for proper dosing:

For intakes <400 μg/day:

• 1 μg 5-MTHF = 1.7 μg food folate 6
• Use the same conversion as folic acid 6

For intakes ≥400 μg/day:

• 1 μg 5-MTHF = 2.0 μg food folate 6
• 5-MTHF is MORE bioavailable than folic acid at these higher doses 6

This means 208 μg of 5-MTHF is equivalent to 400 μg of folic acid in terms of homocysteine-lowering effect. 2, 7

Monitoring Parameters

Initial monitoring:

• Measure serum B12 and folate at baseline 1, 3
• Check plasma homocysteine if treating for cardiovascular indications 1, 7

Follow-up monitoring:

• In diseases with increased folate needs, measure folate status every 3 months until stabilization, then annually 3
• Plasma folate plateaus after 12 weeks of supplementation 4
• Red blood cell folate continues to rise beyond 24 weeks without plateau 4

Key Advantages of 5-MTHF Over Folic Acid

1. Does not mask B12 deficiency as readily as folic acid 1, 5
2. Superior bioavailability at doses ≥400 μg, with greater increases in red blood cell folate 4, 6
3. Bypasses MTHFR enzyme, making it effective in patients with MTHFR polymorphisms 5
4. Avoids UMFA syndrome associated with high-dose folic acid 5
5. More effective homocysteine lowering at equivalent low doses 7

Common Pitfalls to Avoid

• Never start folate without checking B12 first - this is the most critical error 1, 3
• Do not use high-dose folic acid (5 mg) in MTHFR carriers - switch to 5-MTHF instead 5
• Do not assume 4 weeks of preconception supplementation is sufficient - red blood cell folate continues rising beyond 24 weeks, suggesting longer preconception periods may be beneficial 4
• Do not exceed 400 μg in populations with food fortification when treating cardiovascular disease - no additional vascular benefit occurs 1

Safety Profile

The cost of 5-MTHF supplementation is minimal and adverse effects at standard doses (400-800 μg daily) are negligible. 3 Excess 5-MTHF is excreted in urine, making toxicity unlikely at recommended doses. 3