The food industry has a rich history of improving public health through nutrient fortification and enrichment. However, doubts exist about the benefits of fortification with B vitamins.

Epidemiological data from the National Health and Nutrition Examination Surveys suggest that reduced plasma folic acid and vitamin B-6 and hyperhomocysteinemia are associated with an increased risk of cardiovascular disease (Selhub et al., 1995). Additional epidemiological data support the earlier observations with respect to elevated total plasma homocysteine (tHcy) level and increased risk of a cardiovascular event (Homocysteine Studies Collaboration, 2002). However, questions on possible mechanisms, the issue of causality, and the very definition of clinically significant homocysteinemia remain unresolved.

Despite these questions, virtually every primary care physician in the U.S. insists on folic acid and vitamin B complex supplementation for any patient in whom atherosclerotic or coronary disease is suspected. The typical dosing and combination is 2.2 mg of folic acid, 25 mg of vitamin B-6, and 1 mg of vitamin B-12 per day, even though folic acid in doses >0.1 mg/day may mask pernicious anemia. These doses may resolve hematologic parameters, yet neurological manifestations that are sometimes mistaken for multiple sclerosis, such as paresthesias, weakness, clumsiness, and an unsteady gait, may progress.

Recent evidence from a 3.5-year clinical trial among 3,749 Norwegian patients (Bonaa, 2005) suggests that the administration of prophylactic doses of these B vitamins may not reduce the risk of cardiovascular events. Subjects were assigned to daily doses of either 0.8 mg of folic acid, 40 mg of vitamin B-6, both, or a placebo during hospitalization following an acute myocardial infarction.

The primary endpoint of this study was a composite of fatal and nonfatal myocardial infarction and stroke. While the subjects on the folic acid arms experienced a 28% mean reduction in tHcy, the primary endpoint was recorded in 18% of the placebo group and those assigned to either folic acid or vitamin B-6 alone. Subjects receiving both B vitamins experienced a 20% increase in relative risk of the endpoints and a 30% increase in cancer.

These data suggest that none of the study groups benefited from supplementation with folic acid and vitamin B-6. While the study was statistically underpowered, it questions the certainty of this kind of supplementation to reduce risk of cardiovascular and peripheral vascular disease, and begs the question as to the suggested role of folic acid as a protectant against certain cancers.

Epidemiological studies suggest that elevated tHcy, a direct neurotoxin, may be associated with cognitive impairment and dementia. In a 4-year study among 937 dementia-free Italians over age 65, Ravaglia et al. (2005) found that elevated plasma tHcy and low serum folate were independent predictors of the development of dementia and Alzheimer’s disease. Tucker et al. (2005) reported similar results in a 3-year study assessing the cognitive function of 321 elderly men. What remains uncertain, of course, is whether the relationship of elevated plasma tHcy and decreased serum folate to cognitive decline is causal or reflects some independent and overarching metabolic perturbation.

The intervention of folic acid fortification to reduce the risk of neural tube defects, while benefiting one population, may in fact, exacerbate “hidden” health issues. These kinds of epidemiological studies must be translated to clinical trials to fully evaluate the homocysteine hypothesis, and to adequately assess the potential impact that nutritional intervention with folic acid and vitamin B-6 may have in the general population in reducing the risk of cardiovascular events and declining cognitive function. Intervention policies cannot rest on epidemiological data alone.

by Roger Clemens, Dr.P.H.,
Contributing Editor 
Professor, Molecular Pharmacology & Toxicology, USC School of Pharmacy, Los Angeles,Calif.
[email protected]

by Peter Pressman, M.D.,
Contributing Editor 
Attending Staff, Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, Calif.
[email protected]


Bonaa, K.H. 2005. NORVIT: Randomized trial of homocysteinelowering with B-vitamins for secondary prevention of cardiovascular disease after acute myocardial infarction. Presented at European Society of Cardiology Congress, Stockholm, Sweden, Sept. 5.

Homocysteine Studies Collaboration. 2002. Homocysteine and risk of ischemic heart disease and stroke: A meta-analysis. J. Am. Med. Assn. 288: 2015-2022.

Ravaglia, G., Forti, P., Maioli, F., Martelli, M., Servadei, L., Brunetti, N., Porcellini, E., and Licastro, F. 2005. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am. J. Clin. Nutr. 82:636-643.

Selhub, J., Jaques, P.F., Bostom, A.G., D’Agostino, R.B., Wilson, P.W.F., Belanger, A.J., O’Leary, D.H., Wolf, P.A., Schaefer, E.J., and Rosenbert, I.H. 1995. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. New Eng. J. Med. 332: 286-291.

Tucker, K.L., Qiao, N., Scott, T., Rosenberg, I., and Spiro, A. III. 2005. High homocysteine and low B vitamins predict cognitive decline in aging men: The Veterans Affairs Normative Aging Study. Am. J. Clin. Nutr. 82: 627-635.