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

Am J Clin Nutr. 2003 Mar;77(3):658-62. doi: 10.1093/ajcn/77.3.658.


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 micro g folic acid/d with that of equimolar 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 microg), L-MTHF (113 microg), 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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Dietary Supplements*
  • Double-Blind Method
  • Erythrocytes / chemistry
  • Female
  • Folic Acid / administration & dosage*
  • Folic Acid / blood
  • Food, Fortified
  • Homocysteine / blood*
  • Homocysteine / drug effects
  • Humans
  • Male
  • Middle Aged
  • Neural Tube Defects / prevention & control
  • Placebos
  • Tetrahydrofolates / administration & dosage*
  • Treatment Outcome
  • Vitamin B 12 Deficiency / diagnosis


  • Placebos
  • Tetrahydrofolates
  • Homocysteine
  • Folic Acid
  • 5-methyltetrahydrofolate