Vitamin B9 (Folic Acid) | Supplementopedia

Overview

Vitamin B9, commonly known as folic acid when synthesized for supplements, is a water‑soluble B‑vitamin that functions as a co-factor in one-carbon metabolism. Its primary purpose is to donate and accept single‑carbon units, which are essential for nucleic‑acid synthesis, amino‑acid metabolism, and the methylation of DNA, proteins, and lipids.

Benefits

Prenatal health: Adequate folic acid (≥400 µg DFE daily) reduces the risk of neural‑tube defects (NTDs) such as spina bifida by up to 70 % (WHO, 2022).
Cardiovascular support: 0.8–1 mg/day lowers plasma homocysteine by ~20 % and modestly reduces stroke risk in meta‑analyses of ≥30 k participants.
Red blood cell formation: Essential for synthesis of purines and pyrimidines; deficiency leads to megaloblastic anemia, which resolves with supplementation.
Cognitive function: Observational studies link higher folate status to slower age‑related cognitive decline, and randomized trials show modest improvement in memory tests when deficient subjects receive 400–800 µg/day.
Pregnancy outcomes: Adequate folate reduces pre‑eclampsia, low birth weight, and preterm birth, especially when started pre‑conception.
Metabolic health: Folate contributes to the conversion of homocysteine to methionine, supporting methyl‑group availability for DNA repair and cellular energy regulation.

How It Works

Folic acid is reduced to tetrahydrofolate (THF) by dihydrofolate reductase (DHFR). THF acts as a carrier of one‑carbon units in three oxidation states: 5‑methyltetrahydrofolate (5‑MTHF), 5,10‑methylene‑THF, and 10‑formyl‑THF. These forms participate in:

Purine & pyrimidine synthesis: 5,10‑methylene‑THF donates a carbon to thymidylate synthase, forming dTMP for DNA replication.
Methionine cycle: 5‑MTHF donates a methyl group to homocysteine via methionine synthase (B12‑dependent), producing methionine and S‑adenosyl‑methionine (SAM), the universal methyl donor for DNA, protein, and lipid methylation.
Amino‑acid metabolism: Folate‑linked tetrahydrofolate derivatives transfer one‑carbon units to serine, glycine, and histidine pathways, influencing neurotransmitter synthesis.
These biochemical actions underpin folate’s role in cell division, DNA repair, and methylation‑dependent gene regulation.

Dosage

General adult population: 400 µg DFE (≈400 µg folic acid) per day, meeting the RDA.
Women of child‑bearing age / pregnancy: 600 µg (pre‑conception) to 800 µg (pregnancy) to achieve plasma folate >15 nmol/L, a level linked to NTD prevention.
Therapeutic/deficiency correction: 1–5 mg daily for 4–8 weeks to normalize serum folate (>10 ng/mL) and resolve anemia.
High‑risk cardiovascular or hyperhomocysteinemia: 0.8–1 mg/day often combined with vitamins B6 and B12; higher doses (up to 5 mg) are used in clinical trials but should be medically supervised.
Timing: Oral tablets taken with food improve absorption; split doses (e.g., 400 µg twice daily) may enhance plasma levels in individuals with malabsorption.

Safety & Side Effects

Folic acid is well‑tolerated; adverse effects are rare and usually gastrointestinal (nausea, bloating) at doses >5 g/day. The main safety concern is masking of vitamin B12 deficiency, potentially leading to irreversible neurologic damage; thus, individuals >60 yr or with malabsorption should be screened for B12 before high‑dose supplementation. Drug interactions: Anticonvulsants (e.g., phenytoin, carbamazepine) accelerate folate metabolism, possibly requiring higher doses. Methotrexate, a DHFR inhibitor, can be antagonized by folic acid, so timing (e.g., 24 h after methotrexate) is critical. Contraindications: None for dietary intake, but caution in patients with cancer where high folate may theoretically promote tumor growth; current evidence is inconclusive, so oncologic patients should follow oncologist guidance.

Chemistry

Folic acid (IUPAC: 5‑[(2‑S‑hydroxymethyl)‑4‑[[(2‑amino‑4‑oxo‑1,3‑dihydro‑2‑H‑pyrimidin‑5‑yl)‑methyl]‑amino]‑5‑oxo‑2‑pyridinecarboxylic acid) has the formula C₁₉H₁₉N₇O₆ (M = 441.4 g mol⁻¹). It comprises a pteridine ring, a para‑aminobenzoic acid (PABA) moiety, and a glutamate residue (p‑aminobenzoic acid linked via an amide to L‑glutamic acid). The molecule is amphoteric: the p‑carboxyl group (pKa ≈ 2.0) is de‑protonated at physiological pH, while the pterin nitrogen (pKa ≈ 5.0) remains partially protonated, giving folic acid modest water solubility (≈0.5 mg mL⁻¹). The reduced form, tetrahydrofolate, is the active co‑factor; the synthetic folic acid lacks the reduced pteridine ring and thus requires reduction by DHFR to become biologically active.

Sources & Quality

Natural sources: Leafy greens (spinach, kale), legumes (lentils, peas), citrus fruits, and fortified grains contain naturally occurring folate as polyglutamate forms.
Extraction: Folate is isolated from plant tissues via aqueous extraction, followed by enzymatic de-polymerization to monoglutamate (the form used in supplements).
Synthetic production: Industrially, folic acid is synthesized chemically from p‑aminobenzoic acid and 2‑amino‑4‑hydroxy‑6‑methoxy‑pyrimidine, followed by condensation with L‑glutamic acid. This method yields >99 % purity and is the standard for pharmaceutical‑grade supplements.
Quality considerations: USP‑NF or USP‑USP standards require ≥95 % purity, low heavy‑metal content, and stability testing (e.g., light and heat stability). Certifications such as GMP, ISO 9001, and third‑party testing (e.g., NSF, USP) ensure consistency and absence of contaminants such as cyanide or heavy metals.