European Journal of Nutrition

, Volume 55, Issue 3, pp 1021–1028 | Cite as

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

  • Rima ObeidEmail author
  • Susanne H. Kirsch
  • Sarah Dilmann
  • Cosima Klein
  • Rudolf Eckert
  • Jürgen Geisel
  • Wolfgang Herrmann
Original Contribution



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.


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.


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.


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.


Unmetabolized folic acid Elderly Supplementation Vitamin B6 Vitamin B12 Serum folate 



Betaine hydroxymethyl transferase


Dihydrofolate reductase


Glomerular filtration rate


Folic acid




Mean corpuscular volume










Serine hydroxymethyl transferase




Total homocysteine


Unmetabolized folic acid



The study was registered: Clinical Trials NCT01105351.

Conflict of interest

The authors have no conflict of interest to declare.

Supplementary material

394_2015_916_MOESM1_ESM.doc (30 kb)
Supplementary material 1 (DOC 30 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Rima Obeid
    • 1
    • 2
    Email author
  • Susanne H. Kirsch
    • 1
  • Sarah Dilmann
    • 1
  • Cosima Klein
    • 1
  • Rudolf Eckert
    • 3
  • Jürgen Geisel
    • 1
  • Wolfgang Herrmann
    • 1
  1. 1.Department of Clinical Chemistry and Laboratory MedicineUniversity Hospital of the SaarlandHomburgGermany
  2. 2.Aarhus Institute of Advanced StudiesUniversity of AarhusÅrhus CDenmark
  3. 3.Marien Hospital Geriatric CentreSt. WendelGermany

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