Randomized trial of folic acid supplementation and serum homocysteine levels

Background: Lowering serum homocysteine levels with folic acid is expected to reduce mortality from ischemic heart disease. Homocysteine reduction is known to be maximal at a folic acid dosage of 1 mg/d, but the effect of low er doses (relevant to Food fortification) is unclear. Methods: We randomized 151 patients with ischemic heart disease to 1 of 5 d osages of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo. Fasting blood samples for serum homocysteine and serum folate analysis were taken initially, after 3 months of supplementation, and 3 months after folic acid use was discontinued. Results: Median serum homocysteine level decreased with increasing folic ac id dosage, to a maximum at 0.8 mg of folic acid per day, when the homocyste ine reduction (placebo adjusted) was 2.7 mu mol/L (23%), similar to the kno wn effect of folic acid dosages of 1 mg/d and above. The higher a person's initial serum homocysteine level, the greater was the response to folic aci d, but there were statistically significant reductions regardless of the in itial level. Serum folate level increased approximately linearly (5.5 nmol/ L for every 0.1 mg of folic acid). Within-person fluctuations over time in serum homocysteine levels, measured in the placebo group, were large compar ed with the effect of folic acid, indicating that monitoring of the reducti on in an individual is impractical. Conclusions: A dosage of folic acid of 0.8 mg/d appears necessary to achiev e the maximum reduction in serum homocysteine level across the range of hom ocysteine levels in the population. Current US food fortification levels wi ll achieve only a small proportion of the achievable homocysteine reduction .