Daily doses of folic acid as low as 0.2 milligrams are sufficient to lower homocysteine levels – an amino acid linked to increased risks of heart disease and dementia, says a new study.
The dose – similar to levels currently attained under the current US fortification program – is sufficiently low to allay concerns associated potential adverse effects of long-term exposure to high folic acid intakes, according to findings published in the American Journal of Clinical Nutrition.
Supplementing the diets of 101 with heart disease and 71 without the condition with varying doses of folic acid, ranging from 0.2 to 0.8 milligrams per week for six months, showed that the lowest dose was adequate to lower homocysteine levels, and that no additional benefits were observed at the higher doses.
“The potency of folic acid at low doses given chronically, as demonstrated in this study, should not be underestimated, and it is possible that doses lower than those investigated here would also be effective over a longer time period,” report researchers led by Helene McNulty from the University of Ulster, Coleraine in Northern Ireland.
B for baby benefits
An overwhelming body of evidence links folate deficiency in early pregnancy to increased risk of neural tube defects (NTDs) - most commonly spina bifida and anencephaly - in infants.
This connection led to the 1998 introduction of public health measures in the US and Canada, where all grain products are fortified with folic acid - the synthetic, bioavailable form of folate.
Preliminary evidence indicates that the measure is having an effect with a reported 15 to 50 per cent reduction in NTD incidence. A total of 51 countries now have some degree of mandatory fortification of flour with folic acid.
Similar measures in other countries are on the table, but concerns remain over the potential to mask vitamin B12 deficiency in the elderly, as well as reports linking folic acid to an increased risk of colorectal cancer.
In an accompanying editorial, Petra Verhoef from Unilever R&D Vlaardingen in the Netherlands said that folic acid ‘supplementation’ at a level of about 0.2 mg/d is likely to lower the risk of NTDs.
“Whether lower fortification levels are as effective or safer is currently still unknown. Folate status is low among young women of childbearing age in many developing and emerging countries, where it contributes to maternal and childhood mortality,” she added.
“In those countries, folic acid fortification of foods may be the best approach to reach the groups at risk. In the developed countries where mandatory folic acid fortification is not yet in place, targeted supplementation of women of childbearing age has become ever so important.”
McNulty and her co-workers conducted their double-blind, randomized, placebo-controlled trial with 101 adults with heart disease (average age 64) and 71 adults free of the disease (average age 60). Participants were randomly assigned to one of four groups, and received daily supplements containing 0, 0.2, 0.4, or 0.8 mg folic acid.
After 26 weeks of intervention the researchers reported that the higher doses of folic acid produced higher blood levels of the B vitamin. However, there were no significant differences between the homocysteine reductions in the 0.2, 0.4, and 0.8 milligrams per day groups.
The greatest homocysteine reductions were observed in individuals with the highest levels of the amino acid at the start of the study, added the researchers.
“The finding in this study that 0.2 mg folic acid/d given for 26 weeks was effective at lowering homocysteine is important for emerging folic acid fortification policy in different countries. This is because food fortification is untargeted, and ensuring that the effective dose is reached in a population inevitably means that some people will be exposed to much higher levels,” said the researchers.
“A dose of 0.2 mg/d is similar to the estimated increment in folic acid intake in the United States (ie, 215–249 micrograms per day), arising from the introduction of mandatory fortification in 1998.
“Mandatory folic acid fortification was formally proposed in the United Kingdom in 2000 and again in 2006 after an extensive review of the available evidence; however, in 2007, implementation of a new policy was further postponed to allow consideration of new evidence in relation to potential adverse effects of folic acid and cancer risk—a process just completed,” said the researchers
The current findings suggest that the additional intake of 0.2 mg folic acid/d now being proposed for implementation, although primarily aimed at reducing neural tube defects (NTDs), is likely to also have other benefits,” they concluded.
The homocysteine hypothesis
Previously, high levels of the amino acid, hyperhomocysteinemia, were said to be a marker for heart disease and thought to be a risk factor for atherosclerotic disease, which contributes to heart attacks.
The link was founded on the observation that children with homocystinuria – a rare genetic condition causing extreme elevations in homocysteine levels – have higher rates of cardiovascular disease. Such an observation was therefore generalized to the wider population, with the hypothesis indicating that supplementation with B vitamins may reduce blood homocysteine levels and reduce the risk of heart disease.
The link between homocysteine and cardiovascular events was questioned recently with results of a meta-analysis of eight folic acid trials involving 37,485 participants finding no benefits on the risk of major vascular events, cancer, or deaths, despite reducing homocysteine levels by 25 per cent.
Researchers from the University of Oxford reported their findings in the Archives of Internal Medicine (Vol. 170, pp. 1622-1631).
Source: American Journal of Clinical Nutrition
2011, Volume 93, Pages 11-18, doi:10.3945/ajcn.2010.29427
“A dose-finding trial of the effect of long-term folic acid intervention: implications for food fortification policy”
Authors: P. Tighe, M. Ward, H. McNulty, et al.
Editorial: American Journal of Clinical Nutrition
2011, Volume 93, Pages 1-2, doi:10.3945/ajcn.110.006387
“New insights on the lowest dose for mandatory folic acid fortification?”
Author: P. Verhoef