# L-Methylfolate (5-MTHF)
URL: https://genohealth.app/supplements/methylfolate
Type: Supplement
Evidence: Strong evidence
Last reviewed: 2025-06-30

## Intro
L-methylfolate (5-MTHF) is the form of folate that crosses the blood-brain barrier and feeds the methylation cycle directly. People with MTHFR C677T or A1298C variants often respond better to 5-MTHF than to folic acid because they can't efficiently convert the synthetic form.

## Summary
The bioactive form of folate the body actually uses. Often recommended for MTHFR variants, but not always the best fit when COMT is slow.

## Key facts
- Best form: L-5-MTHF (Quatrefolic, Metafolin)
- Typical dose: 400-1000 mcg/day
- Take with: B12, B6, riboflavin
- Time of day: Morning

## Who tends to benefit
- MTHFR C677T or A1298C carriers with elevated homocysteine
- Women planning pregnancy (preconception folate)
- People with low folate intake or malabsorption
- Anyone on medications that deplete folate (methotrexate, certain anticonvulsants)

## When to consider an alternative
Methylfolate can overstimulate sensitive nervous systems. People with slow COMT (rs4680 GG or 'Met/Met') sometimes report anxiety, irritability or insomnia from 5-MTHF — in those cases folinic acid (calcium folinate) usually delivers the same downstream benefit more gently. Geno automatically swaps the recommendation for slow-COMT users.

## Dosing notes
- Start low (200-400 mcg) and titrate up over 2-4 weeks
- Pair with B12 (preferably hydroxocobalamin for methyl-sensitive users)
- Re-test homocysteine and serum folate after 8-12 weeks
- Do not exceed 1000 mcg/day without clinician guidance

## Interactions and cautions
- Can mask B12 deficiency on standard blood tests — always pair with B12 status check
- May reduce efficacy of methotrexate (oncology dosing) — coordinate with prescriber
- Sensitivity reactions usually resolve within 24-48 h of stopping

## Related (knowledge graph)

### Biomarkers
- Homocysteine (/biomarkers/homocysteine): Active folate plus B12 reliably lowers homocysteine in deficiency or MTHFR-related elevations. [Strong evidence]

### Genes
- MTHFR (/genes/mthfr): MTHFR variants reduce folic-acid conversion; 5-MTHF is the active form and a common recommendation. [Strong evidence]

### Nutrients
- Folate (/nutrients/folate): L-methylfolate is the supplemental form of the active folate end-product. [Strong evidence]

### Pathways
- Methylation (/pathways/methylation-cycle): 5-MTHF directly supplies the methyl-donating step of the cycle. [Strong evidence]

## FAQ
**Q: Is L-methylfolate better than folic acid?**
A: For people with MTHFR variants — usually yes. For everyone else, folic acid at standard doses is fine for folate status, though 5-MTHF is closer to the active form the body uses.

**Q: Why does methylfolate make me anxious?**
A: Slow-COMT carriers can build up catecholamines (dopamine, norepinephrine) more readily, and methyl donors can amplify that. Switching to folinic acid usually resolves it within a few days.

**Q: Can I take 5-MTHF during pregnancy?**
A: Yes — major guidelines now consider 5-MTHF an acceptable preconception and prenatal folate source. Discuss dose with your obstetric clinician.

## Citations
- Pietrzik et al., Clin Pharmacokinet 2010 (PMID 20608755): 5-MTHF bypasses MTHFR-related conversion problems and raises plasma folate as effectively as folic acid.
- Greenberg et al., Rev Obstet Gynecol 2011 (PMID 22132188): 5-MTHF is appropriate for women with MTHFR variants seeking preconception folate.

Disclaimer: Informational only — not medical advice.