Fol?c ac?d: B vitamin baffles researchers.

"Contrary to expectations, B vitamins may do more harm than good," declared the press release from the European Society of Cardiology Congress in Stockholm in early September.

There, professor Kaare Harald Bonaa of the University of Tromsa reported preliminary results from the Norwegian Vitamin Trial (NORVIT).

"Folic acid and vitamin B-6 in combination may increase the risk of cardiovascular disease," he concluded. And, he added, "further studies are needed to find out whether folic acid accelerates the growth of cancer cells."

Should you stop taking multivitamins? Rummage through your pantry to get rid of any cereals or energy bars with extra folic acid and B-6? Avoid the hundreds of foods made with "enriched wheat flour," which contains added folic acid? No.

Here's a clearer picture of what we know--and don't know--about folate (a B vitamin that occurs naturally in food) and folic acid (a well-absorbed form of folate that's added to supplements and many fortified foods).

Birth Defects

It's clear that folic acid can prevent devastating birth defects.

"Nobody now questions folic acid's protective effect against spina bifida and anencephaly," says Godfrey Oakley, former director of the Division of Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention in Atlanta.

Within the first few weeks of pregnancy, the neural tube is supposed to encase the spinal cord. If the tube fails to close, the fetus is left without a brain (anencephaly) or with an exposed spinal cord (spina bifida), which can cause paralysis, learning disabilities, and bowel or bladder problems.

The body needs folate to make DNA and RNA, both essential for rapidly dividing cells. "If you don't have the building blocks for DNA, you can't build the neural tube fast enough," explains Oakley, now a visiting professor of epidemiology at the Rollins School of Public Health at Emory University in Atlanta.

In 1992, a clinical trial found that women who were given a multi-vitamin with folic acid were less likely to have children with neural tube defects than women who got a mineral supplement. (1)

By 1998, the Food and Drug Administration required the food industry to add folic acid (along with three other B vitamins and iron) to the "enriched" flour that's used to make most breads, cereals, and pasta, and to rice, grits, and other grain foods.

"Since fortification, neural tube defects have dropped from 4,000 a year to 3,000," says Oakley. (2) And the drop occurred even though the average woman gets only 100 micrograms a day of folic acid from fortification.

"That's far less than the 400 mcg of folate that the Public Health Service recommends for all women of childbearing age," Oakley notes. (Since neural tube defects often occur before a woman knows that she is pregnant, women can't wait until then to start taking it.)

"Putting folic acid into flour has made a remarkable difference," says Oakley. What's more, he adds, by boosting intakes among people who got the least folate from food, "fortification wiped out folate deficiency anemia in the U.S."

Could extra folate also wipe out heart attacks and strokes?

Heart Attacks & Strokes

If folate protects arteries, researchers believe, it's by lowering blood levels of an amino acid called homocysteine.

"We have very strong evidence from prospective studies that homocysteine is a strong, graded, independent risk factor for cardiovascular events," says J. David Spence, director of the Stroke Prevention and Atherosclerosis Research Centre at the Robarts Research Institute in London, Ontario, in Canada.

Study after study has found a higher risk of heart attacks and strokes in people with high homocysteine levels. (3) Yet that evidence isn't enough to prove that it's homocysteine--and not something associated with the amino acid--that causes heart disease.

So researchers in the U.S., Canada, Europe, Australia, and elsewhere have launched a number of trials to see if high doses of folic acid, vitamin B-12, and vitamin B-6 can reduce the risk of heart attacks or strokes (see "Still in Progress"). (4) (Even though all three B vitamins can lower homocysteine, folate is considered the key player.)

But the few trials that have been published are inconsistent. "We've had positive, negative, and null trials, which adds to the controversy and complexity," says Meir Stampfer, chair of the epidemiology department at the Harvard School of Public Health in Boston.

Among the results to date:

* The Swiss Heart Study. Roughly 200 heart disease patients were given either a placebo or B vitamins (l,000 mcg of folic acid, 400 mcg of B-12, and 10 mg of B-6) every day for six months after their angioptasties. The vitamin takers were more likely to keep their arteries open than those given a placebo. (5)

* Dutch/German restenosis study. More than 600 heart disease patients were given either a placebo or B vitamins (1,200 mcg of folic acid, 60 mcg of B-f2, and 48 mg of B-6) every day for six months after surgery to insert a coronary stent. The men who were given vitamins were less likely to keep their arteries open. However, the vitamins didn't hurt--and there were signs they might have helped--women, as well as anyone who started out with diabetes or high homocysteine levels. (6)

* Vitamin Intervention for Stroke Prevention Trial (VISP). More than 3,600 patients who had suffered a stroke were given B vitamins in either high doses (2,S00 mcg of folic acid, 400 mcg of B-12, and 25 mg of B-6) or low doses (20 mcg of folic acid, 6 mcg of B-12, and 0.2 mg of B-6) every day for two years. The results were null--that is, the two groups had the same risk of a second stroke or other cardiovascular event. (7)

Looking back, the authors weren't entirely surprised. "In VISP, we shot ourselves in the foot in several ways," says Spence, who co-authored the study.

First, 'frolic acid fortification of grain products coincided with the beginning of the trial," he explains. With extra folic acid in the food supply, the difference between the high-dose and low-dose groups may have shrunk enough to obscure a difference in stroke rates.

Since both groups were getting enough folate, only a lack of vitamin B-12 would keep homocysteine elevated. But the trial erred there, too.

"Being neurologists, we didn't want to give people B-12 deficiency, which could damage their nerves and spinal cords," says Spence. "So instead of a placebo, we gave low-dose vitamins and B-12 injections to anyone with low B-12 levels." That also minimized the difference between groups.

The researchers later re-analyzed the VISP data after excluding people who were probably taking B-12 on their own or unable to absorb B-12. (8)

"In the 2,155 patients left, we found a 21 percent lower risk of stroke, coronary events, and death in those who took high doses of the B vitamins," says Spence.

But a re-analysis doesn't carry much weight unless other trials agree. NORVIT didn't.

Too Soon to Know

The 3,749 people in the Norwegian Vitamin Trial weren't the healthiest bunch.

Nearly half were smokers, all had suffered a heart attack during the week before they entered the study, roughly 90 percent were taking aspirin (to prevent blood clots) and beta-blockers (to lower blood pressure), and 80 percent were on statins (to lower cholesterol).

Each got a daily placebo or one or more B vitamins (800 mcg of folic acid, 400 mcg of B-12, and 40 mg of B-6). After 3 1/2 years, those who had been given folic acid plus B-6 had a 21 percent higher risk of a heart attack or stroke than those who got the placebo.

Why? Since the B vitamins lowered homocysteine levels, suggests the University of Tromso's Kaare Harald Bonaa, maybe homocysteine is just "an innocent bystander" that's linked to whatever actually damages blood vessels.

And the hint that folic acid takers in the NORVIT study had more cancers--though not statistically significant--wasn't reassuring either.

Others hesitate to say anything about unpublished results like NORVIT's.

"Until I read the published paper, I wouldn't make a fuss," says Emory's Godfrey Oakley. "When they analyze the complete data, the differences may disappear."

Heart attack, stroke, and cancer death rates haven't climbed since manufacturers started adding folic acid to foods, he notes. On the contrary, "the CDC data suggests that we've had 50,000 fewer stroke and heart attack deaths per year after fortification began."

What's more, adds Harvard's Meir Stampfer, "If folate isn't useful in preventing a second heart attack in patients who are taking statins and other drugs, that doesn't mean it won't prevent a first heart attack. The situations aren't comparable."

Cancer

Preliminary results from the NORVIT study showed slightly more cancers in people who took folic acid, but the difference wasn't statistically significant. Was it due to chance?

Studies that track people who consume more folate on their own have found a lower risk of colon cancer, especially in women who take multivitamins that contain folic acid. (9)

"There's still pretty compelling evidence that a higher intake of folate is protective against colon cancer," says Joel Mason, director of the Vitamins and Carcinogenesis Laboratory at the Jean Mayer U.S.

Department of Agriculture Human Nutrition Research Center on Aging at Tufts University in Boston.

But again, the strongest evidence would come from studies that give B vitamins to people at risk for cancer. Two studies have done that with people who have had at least one precancerous colon polyp.

A Harvard trial is still under way, while researchers at Dartmouth Medical School in New Hampshire reported their preliminary results at a scientific meeting last April. After giving roughly 1,000 people either a placebo or 1,000 mcg a day of folic acid for three years, "we found no effect on the number of people with polyps," says John Baron, a professor of medicine at Dartmouth.

But a follow-up on roughly 500 people three to five years later found "weak evidence" that folic acid increased the risk that someone with polyps had more than one. "We're not ringing bells about it, but it may be time to be a little cautious," says Baron.

Experts aren't quite sure how to interpret those results. In a study that tracked 80,000 nurses, "we saw a lower risk of colon cancer only in people who got more folate for 10 or 15 years," says Harvard's Meir Stampfer. "That's how long it takes for a polyp to turn into a cancer."

Timing also makes him skeptical about the NORVIT results.

"It's hard to believe that folic acid would increase cancer incidence that quickly. But it's possible that folic acid could be enhancing the growth of tumors that are already present, so they get diagnosed earlier."

Researchers have known for decades that folate is a growth factor for cells, including cancer cells.

"The evidence suggests that providing adequate folate protects cells from becoming cancerous," says Tufts University's Joel Mason. "But once cells pass an invisible threshold beyond which they're going to become cancer cells regardless, the more folate you give, the more quickly the cells will grow."

Mason also wonders whether the 800 mcg of folic acid used in the NORVIT study was too much. "There's some concern that we're overdoing it," he notes.

"Folic acid is the fully oxidized, pharmaceutical form of the vitamin. It may not be as optimal as folate's natural forms, but that's all speculation."

In the meantime, neither colon nor breast cancer death rates in the U.S. have climbed since fortification. "In the Nurses' Health Study," says Stampfer, "we've looked at folate and breast cancer over the long term, with lots of women taking typical doses from food and supplements. There's no hint of an increased risk."

In fact, two studies found a lower risk of estrogen-negative breast cancer (the kind that doesn't respond to estrogen) in women who got the most folate from all foods and supplements. (10,11)

"If anything, folate seems to get rid of the excess risk of breast cancer that's associated with alcohol," says Stampfer.

Fear of Folate

"It would be a big mistake to fear folate" because of NORVIT's preliminary results, says the University of Western Ontario's J. David Spence.

He notes that researchers haven't stopped any of the major trials in progress, and that they would have if scientists who monitor the studies saw a jump in disease.

"The monitoring board for the VITA-TOPS study explicitly decided not to stop its trial after NORVIT," he notes. Nor have Harvard researchers halted the Women's Antioxidant Cardiovascular Study, which is due this spring (see "Still in Progress," p. 9).

Until those and other trials are done--and published in full--most researchers aren't worried.

"I wouldn't stop taking my multi," says Stampfer. "But beyond that, I wouldn't look for any extra folate, apart from what's in foods like fruits and vegetables."

The Bottom Line

* Take an ordinary multivitamin-and-mineral supplement to make sure you get enough folic acid (400 mcg) and a dozen or so other nutrients. (If you're pregnant, take a prenatal vitamin, which has 800 mcg.)

* Make sure your multi (or a separate supplement) has at least 25 mcg of vitamin B-12 if you're over 50, and at least 250 to 500 mcg if you take an acid blocker.

* Eat 5 to 10 servings of fruits and vegetables each day to lower your risk of heart disease, stroke, and obesity.

B Vitamins & the Brain

Folate is a hot research topic, not just to prevent heart attacks and strokes, but to keep your mind sharp as you age.

For example, a study that tracked more than 300 healthy aging men for three years found that the ability to copy shapes declined more rapidly in those with lower blood folate levels than in those with higher levels. (1) (Spatial copying reflects how easily people become lost, a common problem in those who are moving towards Alzheimer's.)

"The evidence suggests that folate may prevent or delay some of the early cognitive decline that people would just write off to aging," says Katherine Tucker of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston.

It's too early to say if folate can prevent either Alzheimer's or the usual cognitive decline that occurs with aging. And so far, people who already have Alzheimer's or other dementias haven't improved after taking folic acid or vitamins B-6 or B-12. (2) Nevertheless, the results are promising.

"In addition to preventing vascular damage, folate could affect neurotransmitters or DNA repair of neuron linkages," says Tucker. "But at this point, we need more studies to know."

Also promising: researchers in Japan found a steep drop in the risk of hip fractures in older stroke victims who were given massive daily doses of folic acid (5,000 mcg) and vitamin B-12 (1,500 mcg) for two years. (3)

With companies adding folic acid to dozens of foods, most older Americans get enough folate, especially if they also take a multivitamin and eat folate-rich foods (see "Full of Folate"). But that may not be true for vitamin B-12.

Short on B-12

"In the Framingham Offspring Study, 40 percent of the elderly had B-12 levels under 350 picograms per milliliter, which is when a metabolic deficiency begins to develop," says J. David Spence of the Robarts Research Institute and the University of Western Ontario in Canada. The study also found low B-12 levels in nearly 18 percent of people in their 40s and 50s. (4)

"It's much more common than people realize," adds Spence. The problem, he explains, is that "there are about eight ways for vitamin B-12 absorption to go wrong as people age." The most common: many people secrete less stomach acid as they grow older, even as early as their 50s.

"People who don't make enough stomach acid can't separate the B-12 from protein," explains Tucker. To make matters worse, a growing number of people are taking acid blockers like Prilosec, Prevacid, Tagamet, Pepcid, and Zantac.

"There haven't been good studies to look at acid blockers and B-12," adds Tucker. "But logically, you would need a much larger dose of B-12 for enough to be absorbed."

How much? "If I were on an acid blocker, I'd be taking 250 to 500 micrograms a day," says Tucker. "Most other people are probably fine with the 25 mcg that you get in many senior-formula multivitamins."

Those levels are higher than the Recommended Dietary Allowance (2.4 mcg) and the Daily Value (6 mcg), she notes, "but it's inexpensive and harmless to take B-12."

Getting too little B-12 is not. "B-12 deficiency damages the nervous system," explains Spence.

The symptoms of early deficiency vary says Tucker. "Some people lose vibration sense, which doctors test with a tuning fork. Others lose sensation in their fingertips, get mood disorders, or start to lose their balance."

With such a variety of symptoms, she notes, "it's safer to just get your B-12 tested." But, she adds, "that's a major problem because doctors use the old-fashioned cutoff for deficiency. Many people are told that their B-12 is normal because it's over 200."

In fact, if your B-12 is between 200 and 350 picograms per milliliter (pg/mL), you need a different blood test to see if you're deficient. "The best way to diagnose a B-12 deficiency is to look for a rise in methylmalonic acid," says Spence.

It's critical not to wait. "If you catch the symptoms in the first year, they may be reversible, but after that, you get a poor response," says Tucker. And the damage can progress to irritability, numbness, difficulty walking, and dementia.

To protect the older population, says Godfrey Oakley of Emory University in Atlanta, the government should require companies to add B-12 to foods that are enriched with folic acid.

"In 1998, the Institute of Medicine advised everybody over 50 to get 2.4 micrograms of B-12 a day from a supplement or fortified foods," he notes. (You need stomach acid to absorb the B-12 that's bound to protein in foods, but not to absorb the B-12 in supplements and fortified foods.)

"The FDA ought to require companies to put enough B-12 into flour to make the problem caused by too little stomach acid go away," says Oakley. "But instead, the FDA has been sitting on its thumbs since 1998."

(1) Amer. J. Clinical Nutrition 82. 627, 2005.

(2) Cochrane Database Syst. Rev. 4: CD004514, 2003.

(3) J. Amer. Medical Assoc. 293: 1082, 2005.

(4) Amer. J. Clinical Nutrition 60: 2, 1994.

(1) New England Journal of Medicine 327: 1832, 1992.

(2) Morbid. Mortal. Weekly Report 53: 362, 2004

(3) J. Amer. Med. Assoc 288: 2015, 2002

(4) Annals of Internal Medicine 131: 363, 1999

(5) New England Journal of Medicine 345: 1593, 2001.

(6) New England Journal of Medicine 350: 2673, 2004.

(7) J. Amer. Med. Assoc. 291: 565, 2004

(8) Stroke 36: 2404, 2005

(9) Cancer Epidem. Biomarkers Prev. 11: 227, 2002.

(10) Cancer Epidem. Biomarkers Prev. 14: 2004, 2005.

(11) Cancer Epidem. Biomarkers Prev. 11: 1104, 2002.

Still in Progress
Can B vitamins prevent heart attacks and strokes? Here are some of the
largest trials under way. Others are testing B vitamins on memory,
attention, and cognitive ability.

Trial              Daily doses (vs. placebo)   Participants

Women's            Folic acid (2,500 mcg)      5,400 women with a
Antioxidant        B-6 (25 mg)                 history of heart disease
Cardiovascular     B-12 (1,000 mcg)
Study (WACS)

Heart Outcomes     Folic acid (2,500 mcg)      500 people with heart
Prevention         B-6 (50 mg)                 disease or diabetes
Evaluation--The    B-12 (1,000 mcg)
Ongoing Outcomes
(HOPE-TOO)

Vitamins to        Folic acid (2,000 mcg)      8,000 people with a
Prevent Stroke     B-6 (25 mg)                 history of stroke or
(VITATOPS)         B-12 (500 mcg)              transient ischemic
                                               attack (TIA)

Study of the       Folic acid (2,000 mcg)      12,000 people with a
Effectiveness of   B-12 (1,000 mcg)            history of heart attack
Additional         Zocor (20 mg or 80 mg)
Reductions in
Cholesterol and
Homocysteine
(SEARCH)

SU.FOL.OM3 Trial   Folate (500 mcg)            3,000 people with a
                   B-6 (3 mg)                  history of heart attack,
                   B-12 (20 mcg)               stroke, or unstable
                   Fish oil (600 mg)           angina

Full of Folate

Beans, vegetables, and fruit are the
best sources of naturally occurring
folate. You can get folic acid in "enriched"
grains (most breads, pasta, rice,
crackers, pancakes, etc.), but cereals
have the highest levels. Check the
label to see which have 100 micrograms
(25% of the Daily Value) or less
per serving, and which bump it up to
400 mcg (100% of the DV).

Food                                             Folate
(1/2 cup, unless noted)                    (micrograms)

Kashi Heart to Heart cereal (3/cup)               400 *
Life cereal (3/4 cup) (1)                         400 *
Product 19 cereal (1 cup)                         400 *
Quaker Take Heart Oatmeal (1 packet) (1)          400 *
Total cereal (3/4 cup)                            400 *
Lentils, cooked                                   180
Pinto beans, cooked                               145
Chickpeas, cooked                                 140
Black beans, cooked                               130
Rice, enriched, cooked (1 cup)                    130
Spinach, cooked                                   130
Red kidney beans, cooked                          115
Asparagus, cooked (5 spears)                      110
Chex cereal (1 cup) (1)                       100-400 *
Smart Start cereal (1 cup) (1)                100-400 *
Pasta, enriched, cooked (1 cup)                   100 *
Soybeans, cooked                                  100
Wheat germ, toasted (1/4 cup)                     100
Collards, cooked                                   90
Broccoli, cooked                                   85
Avocado (1/2)                                      80
Sunflower seeds (1/4 cup)                          75
Romaine lettuce (1 cup)                            65
Orange juice (1 cup)                               60
Spinach, raw (1 cup)                               60
Papaya (1 cup)                                     55
Peanuts, shelled (1/4 cup)                         55
Green peas, cooked                                 50
Orange (1)                                         40
White bread (1 slice)                              35 *
Whole wheat bread (1 slice)                        15

* Includes added folic acid.

(1) Average of all varieties.

Sources: manufacturers and USDA Nutrient
Database for Standard Reference.