Lower, Not Higher, Doses of Folic Acid May Reduce Homocysteine Levels

Laurie Barclay, MD

January 07, 2011

January 7, 2011 — Doses of folic acid higher than 0.2 mg/day may not be needed to lower homocysteine levels, according to the results of a randomized, dose-finding trial reported in the January issue of the American Journal of Clinical Nutrition.

"The lowest dose of folic acid required to achieve effective reductions in homocysteine is controversial but important for food fortification policy given recent concerns about the potential adverse effects of overexposure to this vitamin," write Paula Tighe, from the Northern Ireland Centre for Food and Health, School of Biomedical Sciences, University of Ulster in Coleraine, Northern Ireland, and colleagues. "We compared the effectiveness of 0.2 mg folic acid/d with that of 0.4 and 0.8 mg/d at lowering homocysteine concentrations over a 6-mo period."

There were 203 participants screened and randomly assigned to receive placebo or folic acid (0.2, 0.4, or 0.8 mg/day) for 26 weeks. The study was completed by 101 patients with ischemic heart disease and by 71 healthy volunteers. At 6 or 12 weeks, subsamples of patients with ischemic heart disease were also evaluated.

Reductions in homocysteine concentrations in response to folic acid were greatest in participants with higher baseline homocysteine concentrations, with reductions of 220.6% seen with a daily folic acid dose of 0.2 mg, 220.7% with 0.4 mg, and 227.8% with 0.8 mg. In participants with lower concentrations of homocysteine at baseline, reductions in homocysteine levels were 28.2% with a daily folic acid dose of 0.2 mg, 28.9% with 0.4 mg, and 28.3% with 0.8 mg. Homocysteine responses to different folic acid doses were not significantly different.

The maximal homocysteine response in the patient group with ischemic heart disease tested at intervals during folic acid treatment was reached by 6 weeks in the 0.8-mg/day group and by 12 weeks in the 0.4-mg/day group. In the 0.2-mg/day group, however, the homocysteine response was suboptimal at both 6 and 12 weeks vs 26 weeks.

"A folic acid dose as low as 0.2 mg/d can, if administered for 6 mo, effectively lower homocysteine concentrations," the study authors write. "Higher doses may not be necessary because they result in no further significant lowering, whereas doses even lower than 0.2 mg/d may be effective in the longer term. Previous trials probably overestimated the folic acid dose required because of a treatment duration that was too short."

Limitations of this study include no measures of renal function, and inability to determine possible additional benefits of vitamin B12.

"[H]igher doses of folic acid may not be necessary and, in support of the recent opinion expressed elsewhere, may be inappropriate given potential adverse effects of long-term exposure to high folic acid intakes," the study authors conclude. "Finally, folic acid alone may not lower homocysteine to desirable concentrations, and further research is required to determine whether the inclusion of vitamin B-12 will have benefits over and above the effect of folic acid in existing and emerging fortification policies."

The Northern Ireland Chest Heart and Stroke Association supported this study. The study authors have disclosed no relevant financial relationships.

Am J Clin Nutr. 2011;93:11-18. Abstract


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