Folic acid

Vitamins. Haemopoietic stimulants

ATC code: B03BB01 (Folic acid)

Brand names – drugs

Folvite, Deplin

Brand names – supplements

Thorne 5-MTHF, Solgar Folate

Supplements are not tested in clinical trials and are not registered as medications.

Mechanism of action

Folic acid (vitamin B9) is reduced in the body to tetrahydrofolate – a one-carbon group carrier in purine, thymidine, and amino acid (methionine, serine, glycine) synthesis. Required for DNA synthesis and division of rapidly proliferating cells (bone marrow, GI epithelium, foetus). Deficiency causes megaloblastic anaemia and, in early embryogenesis, neural tube defects.

Indications

Folate deficiency anaemia

First line

Folic acid 1–5 mg daily for 1–4 months is first-line for folate deficiency anaemia. Clinical response: reticulocyte crisis at 5–10 days, haemoglobin normalisation over 1–2 months. Co-existing B12 deficiency must be excluded before starting therapy – isolated folate use in unrecognised B12 deficiency masks anaemia but does not prevent neurological degeneration.

Sources

ГРЛС: Фолиевая кислота – Государственный реестр лекарственных средств (2026)

Methotrexate-related adverse event prevention

First line

Concurrent folic acid 5 mg once weekly (day after methotrexate) is a required component of low-dose methotrexate therapy in rheumatoid arthritis, psoriatic arthritis, and psoriasis. EULAR 2023 includes folic acid in the standard protocol. Reduces hepatotoxicity, nausea, stomatitis, and cytopenias without compromising methotrexate's anti-inflammatory effect.

Sources

EULAR: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological DMARDs (2023)

Neural tube defect prevention

First line

Folic acid 400 µg daily in all women planning pregnancy and through the first 12 weeks of pregnancy is foundational neural tube defect prevention. USPSTF 2023 reaffirmed recommendation A. In women with a prior NTD pregnancy, diabetes, epilepsy, obesity, or on antiepileptics, the dose is increased to 4–5 mg daily. The Cochrane review confirmed a 70% reduction in open neural tube defects.

Supplementation starts 1–3 months before conception. Most NTDs form by day 28 of embryogenesis, before the woman may be aware of pregnancy.

Sources

Major depressive disorder

Not recommended

The 2019 Cochrane review (3 RCTs, 247 participants) did not find a clinically meaningful effect of folic acid or L-methylfolate as monotherapy or adjunct in major depression. Small positive RCTs in patients with folate deficiency or MTHFR polymorphism have not been reproduced. APA and NICE mental health do not include folate in depression treatment standards.

Sources

Cochrane: Folate and folic acid for depression (2019)

Anti-aging and longevity (marketed indication)

Not recommended

Folic acid for slowing ageing or extending lifespan is not mentioned in international guidelines. Homocysteine-lowering therapy (folate, B6, B12) in patients without inherited homocystinuria has not shown an effect on cardiovascular outcomes or all-cause mortality in several large RCTs. High-dose folic acid in older adults is discussed as a possible risk factor for progression of early cancers – data are mixed.

Sources

Cochrane: Folate and folic acid for depression (2019)

Practical notes

Timing and administration

Take regardless of meals at any time of day. With methotrexate, take the day after methotrexate, not concurrently. Well absorbed from the small intestine regardless of pH.

Dose titration

NTD prevention: 400 µg daily, 4–5 mg daily in high-risk groups. Folate deficiency anaemia treatment: 1–5 mg daily for 1–4 months. With methotrexate: 5 mg once weekly. RDA for healthy adults: 400 µg.

Monitoring

In folate deficiency anaemia treatment, check reticulocytes at 1 week and haemoglobin and MCV at 4 weeks. Before prescribing high-dose folic acid, exclude concurrent B12 deficiency – check serum B12 or methylmalonic acid. In pregnant women on standard prophylactic doses, no additional monitoring is needed.

Food and drinks

Dietary sources: green leafy vegetables (spinach, chard), legumes (lentils, chickpeas), citrus, avocado, liver. Natural folates degrade during cooking (30–60% loss). Synthetic folic acid from fortified foods and supplements is 85% bioavailable, natural folate 50%. In women with MTHFR polymorphism, L-methylfolate is sometimes considered – but routine genotyping is not required, as 5 mg folic acid provides sufficient active form.

Common myths

Myth: “folic acid is only for pregnant women”. Fact: supplementation is recommended for all women of reproductive age who may become pregnant – most unintended pregnancies are unplanned, and the critical neural tube window is the first 28 days.

Myth: “methylfolate is better than folic acid for everyone”. Fact: for most women, folic acid 400 µg is fully effective. Methylfolate costs 5–10 times more without proven advantage in general populations. There may be benefit in women with homozygous MTHFR polymorphism and high homocysteine – but this is a narrow group.

Myth: “folic acid causes cancer”. Fact: there are observational data linking high doses with progression of pre-existing tumours in older adults – clinically significant effect not confirmed. In reproductive-age women at prophylactic doses, cancer risk is not increased.

Safety

Contraindications

Hypersensitivity to folic acid
Untreated B12 deficiency anaemia (risk of masking and neurological progression)
Pernicious anaemia without B12 (same reason)
Malignancy (relative contraindication for high doses)

Serious adverse effects

Masking of B12 deficiency with progression of subacute combined degeneration
Anaphylactic reactions (very rare)

Common adverse effects

Epigastric discomfort at high doses
Altered taste

Uncommon adverse effects

Allergic reactions (urticaria, pruritus, bronchospasm)
Sleep disturbance, irritability at doses above 15 mg daily

PregnancyFDA A

FDA category A at neural tube defect prevention doses. High-dose therapy (4–5 mg) in pregnant women with epilepsy, diabetes, or obesity is safe and is encouraged by international obstetric societies.

Breastfeeding

Transfers into breast milk. Supplementation at the RDA of 500 µg is safe and encouraged.