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Sunday, July 27, 2025

Folic acid


Folic acid (also known as pteroylmonoglutamic acid) is the synthetic form of folate (vitamin B9), a water-soluble B vitamin that plays a critical role in numerous biological functions, including DNA synthesis and repair, amino acid metabolism, methylation reactions, and erythropoiesis (formation of red blood cells). It is essential for rapid cell division, especially during pregnancy and infancy, and its deficiency can result in serious hematological and developmental consequences.

Folic acid is commonly available as a nutritional supplement, in fortified foods, and as a prescription or over-the-counter medication for various clinical uses, including megaloblastic anemia, neural tube defect prevention, and adjunctive therapy in methotrexate or anticonvulsant use.

Pharmacological Classification

  • Class: Water-soluble vitamin, B-vitamin

  • ATC code: B03BB01

  • Synonyms: Folate (generic group name), vitamin B9, pteroylglutamic acid

  • Legal status: OTC (low-dose); Rx (higher doses, therapeutic use)

  • Formulations: Oral tablets (200 mcg, 400 mcg, 800 mcg, 1 mg, 5 mg), liquid drops, injectable (rarely used)

Mechanism of Action

Folic acid is metabolized in the liver and other tissues to its active tetrahydrofolate (THF) forms, especially 5-methyltetrahydrofolate (5-MTHF). These active folates serve as one-carbon donors and acceptors in various biochemical reactions.

Core biochemical functions:

  • Purine and pyrimidine synthesis → critical for DNA and RNA formation

  • Conversion of homocysteine to methionine via methylation → essential for cardiovascular health

  • Histidine metabolism and amino acid interconversions

  • Synthesis of neurotransmitters (indirectly via SAM cycle)

In pregnancy, folate is vital for neural tube development, and deficiency during the first trimester can result in anencephaly, spina bifida, and other congenital malformations.

Clinical Uses

1. Folate Deficiency Anemia (Megaloblastic Anemia)

  • Used in cases where anemia is due to inadequate dietary intake, malabsorption, or increased need

  • Common in elderly, alcoholics, and individuals with gastrointestinal disorders (e.g., celiac, IBD)

2. Pregnancy Supplementation

  • Routine supplementation recommended for all women planning pregnancy and during the first trimester to prevent neural tube defects (NTDs)

  • Often combined with iron, iodine, and other vitamins

3. Hyperhomocysteinemia

  • Folate lowers elevated homocysteine levels, which are linked to cardiovascular and thrombotic risks

  • Especially beneficial when used with vitamin B6 and vitamin B12

4. Methotrexate Toxicity Prevention

  • Administered to reduce methotrexate-related mucosal, hematologic, and hepatic toxicity (especially in rheumatoid arthritis and psoriasis patients)

5. Supplementation in Malabsorption Syndromes

  • Celiac disease, tropical sprue, short bowel syndrome

  • Bariatric surgery patients may require long-term supplementation

6. Support in Antiepileptic Therapy

  • Phenytoin, carbamazepine, phenobarbital may lower folate levels

  • Supplementation helps prevent associated megaloblastic changes and fetal risk in epileptic pregnancies

7. Adjunct in Depression and Cognitive Disorders

  • Low folate associated with poor SSRI response, cognitive decline, Alzheimer’s disease

  • Supplementation with 5-MTHF under investigation

Dosage Guidelines

General Prevention

  • Adults: 200–400 mcg/day

  • Pregnant women: 400–800 mcg/day

  • Lactating women: 500 mcg/day

Neural Tube Defect Prevention (High Risk)

  • 4–5 mg/day at least 1 month before conception and through first 12 weeks of pregnancy

  • Indicated in women with:

    • Previous NTD-affected pregnancy

    • Epilepsy

    • Diabetes

    • Obesity

    • Use of folate antagonists

Therapeutic Dose (Megaloblastic Anemia)

  • Adults: 5 mg/day until hematological response occurs (usually 4–6 weeks)

  • Maintenance: 0.4–1 mg/day as needed

Methotrexate Rescue

  • Folic acid: 1–5 mg/day, usually given on days not receiving methotrexate

Pharmacokinetics

  • Absorption: Rapid from upper small intestine; more efficiently absorbed in synthetic form

  • Bioavailability:

    • Folic acid (synthetic): ~85%

    • Natural dietary folates: ~50%

  • Peak plasma: 1–2 hours after oral administration

  • Metabolism: Hepatic to THF and derivatives

  • Half-life: ~4–5 hours

  • Excretion: Primarily urinary (as metabolites and unchanged)

Contraindications

  • Known hypersensitivity to folic acid or excipients

  • Untreated vitamin B12 deficiency: may mask hematologic symptoms of B12 deficiency while allowing neurological damage to progress

Warnings and Precautions

  • Folate alone should not be used in pernicious anemia or other B12-deficient states

  • Caution in malignancy: Folate can promote cell proliferation in certain tumors

  • Patients with seizure disorders may require dose adjustment if on anticonvulsants

Adverse Effects

Folic acid is generally very well tolerated and considered safe.

Common (but rare overall)

  • GI disturbances: nausea, flatulence, abdominal cramps

  • Bitter or unpleasant taste

Rare/Serious

  • Allergic reactions: rash, pruritus

  • Anaphylaxis (extremely rare)

  • Confusion, irritability (reported in high doses)

Drug Interactions

Drugs That Reduce Folate Levels

  • Anticonvulsants: phenytoin, phenobarbital, carbamazepine

  • Methotrexate, trimethoprim, pyrimethamine: antagonize folate metabolism

  • Sulfasalazine, cholestyramine, oral contraceptives

Folic Acid Reduces Efficacy of

  • Methotrexate (antifolate effect): Countered intentionally in non-cancer use

  • High-dose folic acid may reduce the efficacy of some antiepileptics (via enhanced hepatic clearance)

Monitoring Parameters

  • Serum folate and RBC folate levels

  • CBC: response in anemia

  • Homocysteine levels (if treating hyperhomocysteinemia)

  • B12 levels: before and during therapy to exclude concurrent deficiency

  • Pregnancy supplementation compliance

Use in Special Populations

Pregnancy

  • Strongly recommended; reduces risk of neural tube defects by >70%

  • Dose depends on risk category (standard or high-risk)

Lactation

  • Safe; also recommended during breastfeeding

Pediatrics

  • Safe in infants and children when dosed appropriately

Elderly

  • May require supplementation due to poor absorption or diet

Public Health and Fortification

  • Mandatory folic acid fortification in wheat flour and cereals is adopted in countries like the US, Canada, and Australia

  • Proven to reduce NTD incidence significantly at the population level

  • Not yet universally implemented in the UK and parts of Europe (as of 2024–2025, UK announced intentions to fortify flour)

Comparison with Natural Folate and 5-MTHF

  • Folic acid is the synthetic oxidized form, used in supplements and fortification

  • Folate refers to the naturally occurring, reduced, polyglutamated forms found in food (e.g., leafy greens, legumes)

  • 5-Methyltetrahydrofolate (5-MTHF) is the active form found in circulation; some people with MTHFR polymorphisms may benefit more from 5-MTHF supplementation

  • 5-MTHF is available as a medical food in select countries (e.g., Metafolin®, Quatrefolic®)

Patient Counseling

  • Take folic acid with or without food

  • Essential during pregnancy planning and first trimester

  • Do not self-medicate with high doses (>1 mg/day) without medical advice

  • Ensure B12 levels are checked before starting long-term therapy

  • Store supplements at room temperature, away from moisture





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