5-MTHF Titration Schedule for MTHFR Mutation
Start with 5-methyltetrahydrofolate (5-MTHF) 400-800 mcg daily and titrate up to 5,000 mcg (5 mg) daily over 4-8 weeks, combined with methylcobalamin 1 mg weekly, vitamin B6 50 mg daily, and riboflavin 1.6 mg daily. 1, 2
Initial Assessment Before Starting
- Measure baseline fasting homocysteine levels (after at least 8 hours fasting) to establish severity and guide dosing 1, 3
- Check serum B12, folate, and methylmalonic acid to rule out B12 deficiency before initiating treatment 3, 4
- Confirm MTHFR genotype (677CT heterozygous, 677TT homozygous, or A1298C variants) as this affects dosing strategy 1, 4
Week-by-Week Titration Protocol
Weeks 1-2: Initiation Phase
- 5-MTHF: 400-800 mcg once daily (standard starting dose for general population) 1
- Methylcobalamin: 1 mg once weekly (provides additional 7% homocysteine reduction) 1, 2
- Vitamin B6: 50 mg once daily (supports transsulfuration pathway) 1, 2
- Riboflavin: 1.6 mg once daily (particularly effective for TT genotype) 1, 4
Weeks 3-4: First Escalation
- Increase 5-MTHF to 1,000-1,500 mcg daily if well tolerated 5
- Continue all other supplements at same doses 2
- Monitor for gastrointestinal symptoms (rare with 5-MTHF compared to folic acid) 6
Weeks 5-6: Second Escalation
- Increase 5-MTHF to 2,000-3,000 mcg daily for moderate hyperhomocysteinemia (15-30 μmol/L) 3, 5
- Continue methylcobalamin, B6, and riboflavin unchanged 2
Weeks 7-8: Target Dose Achievement
- Increase 5-MTHF to 5,000 mcg (5 mg) daily for homozygous 677TT genotype or severe hyperhomocysteinemia 2, 7
- This dose has been shown to reduce homocysteine from 19.4±5.3 μmol/L to 6.9±2.2 μmol/L 2
Genotype-Specific Dosing Adjustments
For Heterozygous MTHFR (677CT or A1298C)
- Target dose: 800-1,500 mcg daily is typically sufficient 4, 5
- Riboflavin 1.6 mg daily is particularly important for normalizing homocysteine 4
For Homozygous MTHFR (677TT)
- Target dose: 5,000 mcg (5 mg) daily due to significantly reduced enzyme activity 1, 2, 7
- This bypasses the deficient MTHFR enzyme and reduces homocysteine by 25-30% 1
For Combined Heterozygous (C677T/A1298C)
Monitoring Schedule
- Recheck fasting homocysteine at 8 weeks after reaching target dose 3, 2
- Goal: Homocysteine <10-15 μmol/L (threshold for hyperhomocysteinemia is 15 μM) 3, 4
- If homocysteine remains elevated, increase 5-MTHF by 1,000-2,000 mcg increments every 4 weeks up to maximum 5,000 mcg daily 2, 5
- Monitor every 3 months once stable therapeutic levels achieved 3
Critical Pitfalls to Avoid
Never use standard folic acid instead of 5-MTHF in patients with MTHFR mutations, as it requires conversion by the deficient enzyme and may lead to unmetabolized folic acid (UMFA) syndrome with potential immune dysfunction 1, 6, 7
Never supplement with folic acid alone without ruling out B12 deficiency, as this can mask hematologic manifestations while allowing neurological damage to progress 3, 4
Never use cyanocobalamin - always use methylcobalamin or hydroxycobalamin, especially in patients with renal dysfunction 1, 3
Do not omit riboflavin supplementation - it is particularly critical for TT homozygotes and independently lowers blood pressure in hypertensive patients with MTHFR mutations 1, 4
Maintenance Therapy
- Continue target dose indefinitely for patients with documented hyperhomocysteinemia or cardiovascular risk factors 1, 3
- For pregnancy planning: Maintain 5-MTHF 5,000 mcg daily for 4 months before conception (duration of complete spermatogenesis cycle is 74 days) 7
- Long-term monitoring: Homocysteine levels every 6-12 months once stable 3
Special Populations
Pregnancy and Preconception
- Start 5-MTHF 5,000 mcg daily 4 months before attempting conception 7
- This has shown successful pregnancy outcomes in 87% of couples with recurrent pregnancy loss and MTHFR mutations 2
Cardiovascular Disease
- Target homocysteine <10 μmol/L as B vitamins reduce ischemic stroke by 43% in patients with elevated homocysteine 3, 4