Folic acid causes higher prevalence of detectable unmetabolized folic acid in serum than B-complex: a randomized trial

Eur J Nutr. 2016 Apr;55(3):1021-8. doi: 10.1007/s00394-015-0916-z. Epub 2015 May 6.


Purpose: Unmetabolized folic acid (UMFA) is common in serum of elderly individuals receiving folic acid (FA)-fortified foods or supplements. We studied the effect of supplementing FA or B-complex on serum concentrations of (6S)-5-methyltetrahydropteroylglutamate [(6S)-5-CH3-H4Pte] and UMFA in elderly people and explored factors associated with detectable UMFA post-supplementation.

Methods: This is a randomized single-blind non-controlled trial on 58 elderly people using daily 400 µg FA (n = 31) or 400 µg FA, 10 µg cyanocob(III)alamin and 8 mg pyridoxine (n = 27) for a median of 23 days. Main outcome includes changes in concentrations of serum (6S)-5-CH3-H4Pte and UMFA.

Results: Total homocysteine declined by a median of 1.6 (p = 0.074) in the FA and 1.3 µmol/L (p = 0.009) in the B-complex arms (p = 0.66 between the arms). Serum (6S)-5-CH3-H4Pte significantly (p < 0.001 vs. baseline) increased by a median of 9.2 and 6.5 nmol/L in the FA and B-complex groups, respectively (p = 0.152 between the groups). Compared to FA, B-complex reduced cystathionine and caused lower post-intervention serum UMFA, percentage of UMFA to (6S)-5-CH3-H4Pte and prevalence of UMFA ≥ 0.21 nmol/L. Higher serum cystathionine and whole-blood folate predicted higher post-intervention serum UMFA.

Conclusions: FA caused higher UMFA as compared to B-complex. Pyridoxine appears to improve folate recycling. Data on serum UMFA should be interpreted in relation to other vitamins involved in folate metabolism. Serum UMFA is suggested to play a sensory role through which the cell recognizes FA available for metabolism via dihydrofolate reductase.

Trial registration: NCT01105351.

Keywords: Elderly; Serum folate; Supplementation; Unmetabolized folic acid; Vitamin B12; Vitamin B6.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Biomarkers / blood
  • Cystathionine / blood
  • Dietary Supplements*
  • Dose-Response Relationship, Drug
  • Female
  • Folic Acid / administration & dosage
  • Folic Acid / blood*
  • Humans
  • Male
  • Sample Size
  • Single-Blind Method
  • Treatment Outcome
  • Vitamin B Complex / administration & dosage
  • Vitamin B Complex / blood*


  • Biomarkers
  • Vitamin B Complex
  • Cystathionine
  • Folic Acid

Associated data