Folic Acid (Vitamin B9, Folate, Folacin)

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  1. Indications & Dosing
  2. Pharmacology
  3. Safety
  4. Evidence-Based Medicine
  5. Drug Cost

Folic Acid Visual Summary

~ Indications and Dosing ~

Folate Deficiency

  • Megaloblastic Anemia: 0.4 – 1 mg/day PO (or IM/IV/SQ if enteric absorption impaired)
  • Nutritional, Prenatal, or Pediatric Anemia: 0.4 – 1 mg/day PO (or IM/IV/SQ if enteric absorption impaired)
  • FDA Recommended Dietary Allowance: 0.4 mg/day; 0.6 mg/day during pregnancy
  • Neural Tube Defect Prevention (Off-label):
    0.4 – 0.8 mg/day PO, start 1-3 months before conception, continue until 3rd month of development; increase dose if previous NTD or other high-risk


  • (Off-label): 0.5 – 5 mg/day PO

Drug Toxicities

  • Antifolate Toxicity (Off-label): 0.35 mg – 1.25 mg QD PO w/ IM cyanocobalamin
  • Methanol Poisoning (Off-label): 50 – 70 mg Q3-4h IV or PO; adjunct to antidotal therapy

Link to FDA Label

~ Pharmacology ~


Folic acid is a synthetic member of the folate (Vitamin B9) family, a group of chemically related compounds with shared biological activity. Naturally occurring folates exist primarily in reduced, methylated and/or polyglutamate-conjugated states and have relatively low oral bioavailability. Folic acid is oxidation-resistant and demonstrates increased bioavailability and stability. Dietary folates and orally administered folic acid are absorbed intestinally, reduced to dihydrofolate and tetrahydrofolate (THF) by dihydrofolate reductase (DHFR), and released into circulation.
THF acts as a one-carbon acceptor, serving as a critical substrate in the biosynthesis of glycine from serine. Methylated forms of THF act as carbon donors in the synthesis of thymidine and purine nucleotides, and facilitate the conversion of homocysteine to methionine.
Several commonly-used drugs impair folate metabolism, including methotrexate (DHFR antagonist), trimethoprim and pyrimethamine (bacterial DHFR antagonist), and sulfonamide antibiotics (bacterial folate synthesis).

Link to UN FAO Chapter


Orally consumed folic acid and natural folates are deconjugated by the intestinal brush border and subsequently absorbed, modified, and released into circulation (primarily as 5-methyltetrahydrofolate) by intestinal mucosal cells. Folic acid delivered orally in large quantities or via parenteral routes of administration is thought to undergo conversion to biologically active forms in the plasma or peripheral tissues.

Link to UN FAO Chapter


Peak folic acid plasma levels are reached within 1 hour following drug administration. Folic acid has a half-life of 1-3 hours and is renally excreted (intact and metabolic products).

Link to, Link to Pharmacokinetics Article

Folic Acid Mechanism

~ Safety ~

Adverse Effects

  • Masked B12 Deficiency
  • GI Distress
  • Irritability
  • Sleep Disturbance
  • Rash
  • Pruritus


  • Drug Hypersensitivity
  • Suspected Pernicious Anemia

Drug Interactions

  • Folate may antagonize phenytoin
  • Folate deficiency is observed in some renal dialysis patients, patients taking folate antagonists and anticonvulsants, and alcoholic and cirrhotic patients
  • Folic acid may interfere with the antimalarial drug sulfadoxine
  • Folic acid may interfere with antifolate cancer chemotherapeutic agent raltitrexed


Folic acid is classified by the FDA as a Pregnancy Category A drug (adequate and well-controlled studies have failed to demonstrate a risk to the fetus).

Link to FDA Label

~ EBM & Historical Context ~

Lucy Wills & The Marmite Factor

Lucy Wills (1888-1964), a pioneering British hemato-pathologist, first identified a component in marmite (a yeast extract) in the 1930’s that could reverse megaloblastic, “pernicious” anemia in pregnant women in Mumbai, India. This compound would eventually be identified as folate, or Vitamin B9. Folic acid, a synthetic form of folate, was first approved by the FDA as a pharmaceutical agent in 1947 as a treatment for megaloblastic anemia and anemias of pregnancy, nutritional, or pediatric origin. 40 years later the FDA would impose regulations that required folic acid fortification of enriched grain products as a preventative measure to reduce the incidence of fetal neural tube defects.


History and Foundational Studies

  • 1930-31 – Yeast extract used to correct ‘pernicious anemia of pregnancy’ and ‘tropical anemia’
  • 1932-33 – Marmite used to treat macrocytic anemia in celiac disease
  • 1941 – Folate isolated from, and named after, spinach leaves (‘folium’)
  • 1945 – Folic acid first synthesized in laboratory
  • 1946 – Folic acid found to suppress anemia, but not neurological damage in pernicious anemia patients
  • 1947 – Folic acid is approved by the United States FDA for the “treatment of megaloblastic anemias due to a deficiency of folic acid (as may be seen in tropical or nontropical sprue) and in anemias of nutritional origin, pregnancy, infancy, or childhood.”
  • 1998 – FDA mandates enriched grain fortification with folic acid

Link to Weirr, Hoffbrand Historical Review

~ Drug Cost ~