Folic acid is one of those great public health success stories. In the decade that followed the fortification of cereal grains and other foods, along with educational campaigns, the rate of certain birth defects dropped dramatically.
As studies beginning in the 1980s started showing that folic acid could also help prevent some cancers, it started to seem like a wonder-vitamin.
Now, however, folic acid's heyday may be over. New studies suggest that getting too much folic acid might fuel certain cancers in some people.
And with the vitamin showing up in ready-to-eat cereals, bread, snack bars, multivitamins and more, some health experts fear that it's easy to far exceed the recommended daily intake of 400 micrograms.
There is now an urgent need, experts say, to figure out how much folate is enough but not too much for different segments of the population.
"Too little folic acid we know is not good, and too much folic acid is probably not good," said Connie Motter, a genetic counselor at Akron Children's Hospital in Ohio and co-chair of the National Council for Folic Acid, a coalition of advocacy groups. "The answer is not going to be easy."
Folic acid is the synthetic version of folate, or vitamin B9, one of eight B vitamins. The vitamin -- found naturally in leafy greens, orange juice and legumes, among other foods -- helps the body make and maintain new cells. That's important for a number of processes, including growing a baby.
The United States began requiring the fortification of flour, and several other cereal grains in 1998, after clinical trials linked folic acid deficiency with spina bifida and anencephaly, two potentially devastating birth defects. Since then, the rate of both defects has declined by 20% to 50%, depending on which studies you look at.
No one disputes the need for women to have adequate amounts of folic acid in their bodies at the time of conception. The first few weeks of pregnancy, in particular, are a critical period for a baby's brain and spine development. And because more than half of pregnancies are unplanned, doctors recommend that all women of childbearing age take a daily supplement of up to 800 micrograms of folic acid.
But for other people, the evidence for folate's benefits is mixed.
On the plus side, getting enough folate protects against anemia. It may promote heart health, though that link is controversial. And it keeps hair, skin and nails healthy.
On the downside, scientists know that excess folic acid can cover up a shortage of the vitamin B12. B12 deficiency is a common condition in older patients that can cause dementia if not addressed.
The story grows even more complex in the case of cancer.
"For the last 20 years, I've been publishing papers and doing research that demonstrates that if you don't get enough folate, you have a higher risk for several types of cancer," said Joel B. Mason, professor of nutrition science and policy at Tufts University in Boston. "More recently, what has emerged is that it's not as simple of a relationship as we thought."
In some ways, folic acid appears protective. The vitamin plays an essential role in the formation and repair of DNA and can help prevent development of certain cancers, particularly in the colon, where cells replicate especially fast.
Studies show that people who get plenty of folic acid reduce their risk of developing colorectal cancer and precancerous polyps by 40% to 60%. But folic acid doesn't just help healthy cells grow. It also helps cancerous cells grow. Studies in animals have shown that once cells are on the path to becoming cancers, the vitamin makes things worse.
As far back as the 1940s, folic acid supplements were found to accelerate leukemia in children who were given the vitamin in the hope that it might help. (Such studies helped lead to a class of antifolate drugs that are among today's most common cancer treatments.)
More recently, researchers noticed that rates of colorectal cancer went up in North America around the same time that fortification began. One study, published by Mason and colleagues in 2007 in the journal Cancer Epidemiology Biomarkers & Prevention, acknowledged that the link could be a coincidence. But according to another study published this year, the same thing happened in Chile after fortification began there in 2000.
Mason estimates that excess folic acid consumption may cause an extra 15,000 cases of colorectal cancer each year in the U.S. and Canada. By comparison, fortification with the vitamin prevents an estimated 2,000 to 3,000 brain and spinal cord defects in both countries.
Folic acid's effects have also been tested in clinical trials. In the largest one completed, scientists studied almost 1,000 people who had had precancerous polyps removed from their colons. Half of the patients were randomly assigned to take a daily supplement of 1 milligram of folic acid (2.5 times the recommended intake of 400 micrograms). The others took a placebo.