Folate (Methylfolate)
The methyl-donating workhorse of the body. Critical for DNA synthesis, neurotransmitter production, and clearing homocysteine. Methylated form only.
Prevention of neural-tube defects in pregnancy is the strongest evidence base in nutrition. Homocysteine reduction is consistent. Adjunct in depression treatment (especially in MTHFR carriers and SSRI non-responders) has good RCT support. Effects on mood / energy: 2–6 weeks. Homocysteine: 4–8 weeks.
Folate is B9 — required for synthesising DNA, dividing cells, and making serotonin, dopamine, and norepinephrine. It works in tight partnership with B12, converting homocysteine (cardiovascular risk factor) back to methionine and feeding the universal methylation cycle. ~30–50% of the population carries an MTHFR gene variant that impairs the conversion of synthetic folic acid (the cheap stuff in fortified bread and most prenatals) to the active form. For those people, taking synthetic folic acid can actually back up the system and worsen symptoms. The active methylated form bypasses the problem entirely.
- Form
- L-methylfolate (5-MTHF), branded as Metafolin or Quatrefolic. The active form, works in everyone regardless of MTHFR status. Folinic acid (calcium folinate) is a good alternative if methylfolate causes overstimulation. Avoid folic acid (synthetic) — incompletely converted, can mask B12 deficiency, may cause issues in MTHFR carriers.
- Dose
- 400–800 mcg/day for maintenance. 1,000–5,000 mcg/day for active deficiency, depression with low folate, hyperhomocysteinemia, or pregnancy. Higher doses (15 mg/day) are used clinically for refractory depression (Deplin protocol).
- Timing
- AM with food. Some people report methylfolate is energising or even mildly stimulating — don't take at night first time.
- Schedule
- Daily.
- Side effects
- Some sensitive individuals get over-methylation symptoms with methylfolate: anxiety, irritability, insomnia, headache. Start at lower dose. Switching to folinic acid often resolves.
- Interactions
- Methotrexate (cancer / autoimmune doses) — folate antagonism is the mechanism, supplementing folate undoes the drug. Anti-seizure medications (phenytoin, phenobarbital) — both deplete folate and have their levels reduced by it.
- Contraindications
- On methotrexate for cancer or rheumatoid arthritis without rheumatologist approval. Unrecognised B12 deficiency (always test or supplement both together).
- Lab markers
- RBC folate (intracellular — better than serum folate). Homocysteine — elevated with low folate, B12, or B6; target below 8 μmol/L. MTHFR genetic test (C677T and A1298C variants) — one-time test, informs lifelong supplementation choice.
- Food sources
- Dark leafy greens (the name 'folate' comes from 'foliage'): spinach, kale, romaine, asparagus. Legumes (lentils, chickpeas, black beans). Avocado. Beef liver. Brussels sprouts, broccoli. Cooking destroys ~30–50% of folate — eat some sources raw.
Pairs with
B12 (methylcobalamin) — always co-supplement. Taking folate alone with low B12 can cause neurological damage. Vitamin B6 (P5P) and TMG complete the homocysteine-clearing trio.
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