Folate (Vitamin B9)
Critical for pregnancy and DNA synthesis — but the form you take matters more than you think
Also known as: Folic Acid • Methylfolate • 5-MTHF • Vitamin B9 • Folinic Acid
Overview
Folate is a water-soluble B vitamin (B9) essential for DNA synthesis, cell division, and amino acid metabolism. It is perhaps best known for preventing neural tube defects (NTDs) in pregnancy — the mandatory fortification of grain products with folic acid in the US since 1998 reduced NTD rates by 25-50%. However, there is growing awareness that the synthetic form (folic acid) and the natural/active form (methylfolate/5-MTHF) are not equivalent for everyone. Approximately 30-40% of the population carries variants in the MTHFR gene that reduce the ability to convert folic acid to its active form. For these individuals, methylfolate (5-MTHF) supplementation may be more effective. The debate between folic acid and methylfolate is one of the most active discussions in nutritional science.
Key Benefits
Neural Tube Defect Prevention
Adequate folate before and during early pregnancy reduces the risk of neural tube defects (spina bifida, anencephaly) by 50-70%. This is one of the most well-established supplement benefits in all of medicine. The CDC recommends all women of childbearing age consume 400 mcg of folic acid daily.
DNA Synthesis & Cell Division
Folate is essential for the synthesis of DNA and RNA, making it critical for rapidly dividing cells. This is why folate is especially important during pregnancy, infancy, and adolescence. Folate deficiency leads to megaloblastic anemia — abnormally large red blood cells that can't function properly.
Homocysteine Metabolism
Folate, along with vitamins B6 and B12, is required to convert homocysteine to methionine. Elevated homocysteine is an independent risk factor for cardiovascular disease, stroke, and cognitive decline. Folate supplementation effectively lowers homocysteine levels.
Mood & Mental Health
L-methylfolate is involved in the synthesis of serotonin, dopamine, and norepinephrine. Low folate status is associated with depression, and L-methylfolate (as Deplin, a prescription medical food) is used as an adjunct to antidepressants. Several studies show improved response rates when methylfolate is added to SSRI therapy.
Dosage & How to Take
The RDA is 400 mcg DFE for adults, 600 mcg DFE during pregnancy, and 500 mcg DFE during lactation. For MTHFR carriers, 400-800 mcg of L-methylfolate is often recommended instead of folic acid.
| Purpose | Dose | Notes |
|---|---|---|
| General health (RDA) | 400 mcg DFE daily | Easily met through fortified foods + diet |
| Pregnancy prevention of NTDs | 400-800 mcg daily (start 1 month before conception) | Continue through first trimester minimum |
| MTHFR carriers | 400-800 mcg L-methylfolate | Active form bypasses MTHFR conversion |
| Depression adjunct (Deplin) | 7.5-15 mg L-methylfolate | Prescription medical food, under medical supervision |
Best Time to Take
Can be taken any time of day. No significant timing preference. Consistency is more important than timing.
With or Without Food
Can be taken with or without food. Folic acid is actually slightly better absorbed on an empty stomach, but the difference is minimal.
Forms & Bioavailability
| Form | Absorption | Best For | Notes |
|---|---|---|---|
| Folic Acid (Synthetic) | High (in most people) | General population, fortified foods | Must be converted to active form by MTHFR enzyme. Cheap and well-studied. |
| L-Methylfolate (5-MTHF) | Very High (bypasses MTHFR) | MTHFR carriers, depression adjunct | Active form. More expensive. Branded as Metafolin or Quatrefolic. |
| Folinic Acid (5-Formyl THF) | High | Alternative active form | Bypasses MTHFR but through a different pathway than methylfolate. |
Side Effects & Safety
Common
- Generally very well tolerated
- Mild GI upset at high doses
Rare
- High-dose folic acid (>1000 mcg) may mask vitamin B12 deficiency
- Potential concern about unmetabolized folic acid and cancer risk (debated)
Contraindications
- High-dose folic acid may mask B12 deficiency — always check B12 status
- Some concerns about high-dose folic acid in individuals with existing cancer (may promote growth)
Interactions
Folate supplementation may reduce methotrexate efficacy for cancer treatment (but is often prescribed to reduce side effects in autoimmune use)
These medications deplete folate; supplementation is often recommended
High-dose folic acid can mask B12 deficiency by correcting anemia while neurological damage progresses
Scientific Research
US Folic Acid Fortification Impact
Mandatory folic acid fortification of grain products reduced neural tube defects by 25-50% in the US
MTHFR and Folate Metabolism
The MTHFR C677T variant (present in 30-40% of the population) reduces folic acid conversion to active folate by 30-70%
L-Methylfolate for Depression
15mg L-methylfolate as adjunct to SSRI improved response rates by 2x compared to placebo in treatment-resistant depression
Food Sources
Frequently Asked Questions
Medical Disclaimer
This content is for educational and informational purposes only and is not intended as medical advice. Always consult with a qualified healthcare professional before starting any supplement regimen, especially if you have pre-existing health conditions or are taking medications. The statements on this page have not been evaluated by the Food and Drug Administration.