Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: A randomized placebo-controlled study

Bernard J. Venn, Tim Green, Rudolf Moser, Jim I. Mann

Research output: Contribution to journalArticle

72 Citations (Scopus)


Background: Food fortification with folic acid has been introduced in several countries for the prevention of neural tube defects. Fortification has lowered total homocysteine (tHcy) concentrations in the US population, a consequence that may have health benefits. However, folic acid fortification could mask vitamin B-12 deficiency. Synthetic L-5-methyltetrahydrofolate (L-MTHF) may be more appropriate than folic acid as a fortificant because it is unlikely to mask the hematologic indicators of vitamin B-12 deficiency. Objective: The objective of the study was to compare the effectiveness of 100 μg folic acid/d with that of equimdlar L-MTHF in lowering tHcy in healthy volunteers. Design: The study was designed as a 24-wk, randomized, placebo-controlled intervention. Free-living healthy volunteers (n = 167) were randomly assigned to receive a daily supplement containing folic acid (100 μg), L-MTHF (113 μg), or placebo. Blood collected at baseline and at 8, 16, and 24 wk was analyzed for tHcy, plasma folate, and red blood cell folate (RCF) concentrations. Results: At 24 wk, after adjustment for baseline values, mean (95% CI) tHcy was 14.6% (9.3, 19.5%) and 9.3% (3.7, 14.6%) lower, mean plasma folate was 34% (14, 56%) and 52% (30, 78%) higher, and mean RCF was 23% (12, 35%) and 31% (19, 44%) higher in the L-MTHF and folic acid groups, respectively, than in the placebo group. L-MTHF was more effective than was folic acid in lowering tHcy (P < 0.05). At 24 wk, the increases in plasma folate and RCF concentrations did not differ significantly between the 2 supplemented groups. Conclusion: Low-dose L-MTHF is at least as effective as is folic acid in reducing tHcy concentrations in healthy persons.

Original languageEnglish
Pages (from-to)658-662
Number of pages5
JournalAmerican Journal of Clinical Nutrition
Issue number3
Publication statusPublished - 1 Mar 2003
Externally publishedYes


  • Cardiovascular disease
  • Clinical trial
  • Folic acid
  • Homocysteine
  • L-5-Methyltetrahydrofolate
  • L-MTHF
  • Plasma folate
  • Red blood cell folate

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Food Science

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