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One of the advances that changed the way we look at vitamins was the discovery that too little folate, one of the eight B vitamins, is linked to birth defects such as spina bifida and anencephaly.
The Institute of Medicine’s recommended intake of folate (also called vitamin B9) is 400 micrograms per day. (34) The upper limit of intake for adults is set at 1,000 micrograms per day of folic acid from fortified food or as a supplement, not including folate from food. People who regularly drink alcohol should make sure to get at least 600 micrograms of folate a day. It is best to achieve that level of intake through a healthy diet; taking a standard multivitamin (which contains 400 micrograms of folic acid) is added insurance. People should avoid taking higher doses of folic acid supplements.
Food sources: Many foods are excellent sources of folate—fruits and vegetables, whole grains, beans, breakfast cereals, and fortified grains and grain products. It’s best to avoid foods that are heavily fortified with folic acid.
Fifty years ago, no one knew what caused these birth defects, which occur when the early development of tissues that eventually become the spinal cord, the tissues that surround it, or the brain goes awry. More than three decades ago, British researchers found that mothers of children with spina bifida had low vitamin levels. () Eventually, two large trials in which women were randomly assigned to take folic acid (the form of folate added to multivitamins or fortified foods) or a placebo showed that getting too little folate increased a woman’s chances of having a baby with spina bifida or anencephaly and that getting enough folate could greatly reduce the incidence of these birth defects. ( )
Timing of folate is critical: For folate to be effective, it must be taken in the first few weeks after conception, often before a woman knows she is pregnant.
Enough folate, at least 400 micrograms a day, isn’t always easy to get from food that is not fortified. That’s why women of childbearing age are urged to take extra folic acid as a supplement. It’s also why the US Food and Drug Administration now requires that folic acid be added to most enriched breads, flour, cornmeal, pastas, rice, and other grain products, along with the iron and other micronutrients that have been added for years. (4)
Since the advent of mandatory folic acid fortification in 1998, neural tube birth defects have dropped by 20 to 30 percent, and studies have shown that far fewer people have low levels of folate in their blood. (5)
Another line of research about folate and two other B vitamins, vitamin B6 and vitamin B12, explores their roles in fighting heart disease and some types of cancer. The research findings have been mixed, to date. While some studies suggest that these three vitamins can lower the risk of these chronic diseases, some studies do not. And now, more than a decade after the start of mandatory fortification in the U.S., there’s been a heated debate about the possible risks from getting too much folic acid. Overall, the evidence suggests that the amount of folic acid in a typical multivitamin does not cause any harm—and may help prevent these diseases, especially among people who do not get enough folate through their diets, and among individuals who drink alcohol. (Read more about the.)
The Institute of Medicine’s recommended intake of vitamin B6 (also called pyridoxine) is 1.3 to 1.7 milligrams per day, depending on age and gender. (34) Somewhat higher intakes than that may protect against colon cancer, but more research is needed. ( 36) Very high-dose vitamin B6 supplements should be avoided, since they could lead to nerve damage; in light of these concerns, the Institute of Medicine set the upper limit for vitamin B6 intake in adults at 100 milligrams per day (an amount that can only be achieved through high dose supplements). (34)
In 1968, a Boston pathologist investigated the deaths of two children from massive strokes. Both had inherited conditions that caused them to have extremely high levels of a protein breakdown product in their blood, and both had arteries as clogged with cholesterol as those of a 65-year-old fast-food addict. (6) Putting one and one together, he hypothesized that lower, but still elevated levels of this breakdown product—called homocysteine—would contribute to the artery-clogging process of atherosclerosis.
How do B vitamins fit into the homocysteine picture? Folate, vitamin B6, and vitamin B12 play key roles in converting homocysteine into methionine, one of the 20 or so building blocks from which the body builds new proteins. Without enough folate, vitamin B6, and vitamin B12, this conversion process becomes inefficient and homocysteine levels increase. In turn, increasing intake of folate, vitamin B6, and vitamin B12 decreases homocysteine levels.
Since these early observations about homocysteine, most but not all studies have linked high levels of homocysteine with a modest increase in risk of heart disease and stroke. And some but not all observational studies, including the Nurses’ Health Study, show lower risks of cardiovascular disease, stroke, and hypertension among people with higher intakes of folate, those who use multivitamin supplements, or those with higher levels of serum folate (the form of folate found in the body). (712) But linking higher homocysteine levels—and lower folate levels—with heart disease risk does not necessarily mean that lowering homocysteine by taking folate and other B vitamins will lower risk. Ideally, this would be tested in randomized trials.
Several large randomized trials of B vitamins to lower homocysteine and prevent heart disease and stroke have failed to find any benefit. (16) These trials had similar designs: Adults who had a history of heart disease or stroke, or who were at a very high risk of heart disease were given a pill containing high doses of vitamins B6, B12, and folic acid or a placebo. The studies found that taking high doses of the three B vitamins lowered homocysteine levels but did not lead to a reduction in coronary heart events.
But looking at cardiovascular disease as a whole may have obscured a potential benefit of at least one of the B vitamins, and studying people who already have advanced vascular disease may be too late in the process: The most recent analysis of multiple studies suggests that folic acid supplements can reduce the risk of stroke in people who have not already suffered a stroke, but they do not reduce the risk of second stroke in people who have already had one. (17) Folic acid supplements were most protective in studies that lasted at least three years and that combined folic acid with vitamins B6 and B12. Trials that enrolled more men than women also showed more of a benefit, perhaps because men are at higher risk of stroke in general.
The Institute of Medicine’s recommended intake of vitamin B12 (also called cobalamin) is 2.4 micrograms per day. (34) No upper limit has been set.
Food sources: Vitamin B12 is found naturally in animal products (such as fish, poultry, meat, eggs, or dairy); it is also found in fortified breakfast cereals and enriched soy or rice milk. Most people have plenty of vitamin B12 in their diets. The main concern is whether vitamin B12 is adequately absorbed. Read more about .
More evidence on folate’s possible benefits comes from a study on stroke rates before and after mandatory folic acid fortification. The U.S. and Canada have seen stroke death rates fall more rapidly after fortification than they did before fortification; the U.K., which does not yet require folic acid fortification, saw no such change in stroke death rates. (18)
While several trials of B vitamins and heart disease have yet to report results (22), the current weight of the evidence suggests that there may be no benefit to B vitamin supplementation in people who already have heart disease—and who are already taking the world’s best medicines to control it. To date, no one has conducted a randomized controlled trial of folic acid supplementation and heart disease in healthy people, probably because it would take decades to yield results and would be very costly.
Ultimately, folic acid supplementation may only reduce the risk of heart disease in people who have lower levels of folate intake, most likely in countries that do not fortify their food supply with folic acid. In people who already get enough folate in their diets, further supplementation with high doses of folic acid supplements—much higher than what is found in a standard multivitamin—has not been found to be beneficial and might actually cause harm.
In addition to converting homocysteine to methionine, folate plays a key role in building DNA, the complex compound that forms our genetic blueprint. Observational studies show that people who get higher than average amounts of folate from their diets or folic acid supplements for 15 years or more have lower risks of colon cancer (23) and breast cancer. ( ) This could be especially important for those who drink alcohol, since alcohol interferes with the proper metabolism of folate and inactivates circulating folate. An interesting observation from the Nurses’ Health Study is that higher intake of folate appears to blunt the increased risk of breast cancer seen among women who have more than one alcoholic drink a day. (24) More recent studies have had similar findings, including one from Sweden that found that sufficient folate intake can protect against breast cancer even in women who have only one drink a day or less. ()
But the relationship between folate and cancer is a complicated one, especially for people at a high risk of colon cancer. (27) Colorectal adenomas, or polyps, are pre-cancerous growths in the large intestine. A recent multiyear trial looked at whether high-dose folic acid supplements could prevent new polyps in people who had a history of polyps. (28) The study found that taking a daily pill with 1,000 micrograms of folic acid offered no protection against new polyps, and, more worrisome, increased the risk of developing multiple or more serious polyps.
Keep in mind that this study tested a high dose of folic acid, more than two times higher than what is found in a standard multivitamin; furthermore, study participants were already at a very high risk of developing new polyps. This may be another case where timing of folate intake is critical: Getting adequate folate may prevent polyps in people who do not have them, but high dose folic acid supplements may speed up polyp growth in people who do. And it is reassuring that other trials of high dose B vitamin supplementation, such as the Women’s Antioxidant and Folic Acid Cardiovascular Study, have not found higher rates of cancer in supplement users. (29)
In the U.S., fortification itself has increased people’s daily folic acid intake, and one highly publicized study suggested that folic acid fortification might have caused a small increase in the incidence of colon cancer. (30) There’s another equally plausible explanation for the increase—greater detection of existing tumors in the colon and rectum due to more widespread use of colonoscopy. The steady decline in deaths from colon cancer before and after the onset of folic acid fortification suggests that screening, not folic acid fortification, is responsible for the uptick in colon cancer rates. The overall evidence from studies in humans shows a lower risk of colon and breast cancer with greater intake of folate or folic acid, rather than increased risk. (2632)
When teasing out the relationship between any vitamin supplement and cancer, it is important to remember that cancer cells are essentially our own cells on overdrive, growing and rapidly dividing, and they have a greater need for nutrients than most of our normal cells do. Studies done decades ago show that folate is needed for tumor cell growth. Indeed, one successful chemotherapy agent works as a folate antagonist, since rapidly dividing cells require folate to maintain their fast pace of cell division. So for people who have cancer or precancerous growths, nutritional supplements may be a double-edged sword. If you have cancer, make sure to check with your doctor before beginning any vitamin supplement regimen.
The definition of a healthy daily intake of B vitamins isn’t set in stone, and it is likely to change over the next few years as data from ongoing randomized trials are evaluated. In the U.S., folic acid fortification of food has increased the percentage of adults who have adequate levels of folate in their blood. () Yet still, only a fraction of U.S. adults currently get the recommended daily intake of all B vitamins by diet alone. If you are concerned about getting too much folic acid, keep the multivitamin, but skip the energy bars, cold breakfast cereals, and other processed foods that are heavily fortified with folic acid.
1. Smithells RW, Sheppard S, Schorah CJ. Vitamin deficiencies and neural tube defects.. 1976; 51:944–50.
2. Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation.. 1992; 327:1832–1835.
3.MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991; 338:131–137.
4.Federal Register. Food Standards: Amendment of Standards of Identity For Enriched Grain Products to Require Addition of Folic Acid. Final rule, 5 March 1996. Food and Drug Administration: Washington, DC, 1996.
5.Pitkin RM. Folate and neural tube defects. Am J Clin Nutr. 2007; 85:285S–288S.
6.McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969; 56:111–128.
7. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women.. 1998; 279:359–364.
8. He K, Merchant A, Rimm EB, et al. Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men.. 2004; 35:169–174.
9. Ishihara J, Iso H, Inoue M, et al. Intake of folate, vitamin B6 and vitamin B12 and the risk of CHD: the Japan Public Health Center-Based Prospective Study Cohort I.. 2008; 27:127–136.
10. Larsson SC, Mannisto S, Virtanen MJ, Kontto J, Albanes D, Virtamo J. Folate, vitamin B6, vitamin B12, and methionine intakes and risk of stroke subtypes in male smokers.. 2008; 167:954–961.
11. Forman JP, Stampfer MJ, Curhan GC. Diet and Lifestyle Risk Factors Associated With Incident Hypertension in Women.. 2009; 302:401–411.
12. Forman JP, Rimm EB, Stampfer MJ, Curhan GC. Folate intake and the risk of incident hypertension among US women.. 2005; 293:320–329.
13. Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004; 291:565–575.
14. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006; 354:1567–1577.
15. Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006; 354:1578–1588.
16. Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, Buring JE, Manson JE. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008; 299(17):2027-2036.
17. Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic acid in stroke prevention: a meta-analysis.. 2010; 41:1205-1212.
18. Yang Q, Botto LD, Erickson JD, et al. Improvement in stroke mortality in Canada and the United States, 1990 to 2002.. 2006; 113:1335–1343.
19. VITATOPS TSG. The VITATOPS (Vitamins to Prevent Stroke) Trial: rationale and design of an international, large, simple, randomised trial of homocysteine–lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke. Cerebrovasc Dis. 2002; 13:120–126.
20. Galan P, de Bree A, Mennen L, et al. Background and rationale of the SU.FOL.OM3 study: double–blind randomized placebo–controlled secondary prevention trial to test the impact of supplementation with folate, vitamin B6 and B12 and/or omega–3 fatty acids on the prevention of recurrent ischemic events in subjects with atherosclerosis in the coronary or cerebral arteries. J Nutr Health Aging. 2003; 7:428–435.
21. Bowman L, Armitage J, Bulbulia R, Parish S, Collins R. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors.. 2007; 154:815–823, 823 e1-6.
22. Bostom AG, Carpenter MA, Kusek JW, et al. Rationale and design of the Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial.. 2006; 152:448 e1–7.
23. Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate, and colon cancer in women in the Nurses’ Health Study. Ann Intern Med. 1998; 129:517–524.
24. Zhang S, Hunter DJ, Hankinson SE, et al. A prospective study of folate intake and the risk of breast cancer.. 1999; 281:1632–1637.
25. Larsson SC, Giovannucci E, Wolk A. Folate and risk of breast cancer: a meta-analysis.. 2007; 99:64–76.
26. Ericson U, Sonestedt E, Gullberg B, Olsson H, Wirfalt E. High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmo Diet and Cancer cohort. Am J Clin Nutr. 2007; 86:434–443.
27. Ulrich CM. Folate and cancer prevention: a closer look at a complex picture. Am J Clin Nutr. 2007; 86:271–273.
28. Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007; 297:2351–2359.
29. Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE. Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial.. 2008; 300:2012–2021.
30. Mason JB, Dickstein A, Jacques PF, et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis.. 2007; 16:1325–1329.
31. Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ. Folate intake and colorectal cancer risk: a meta-analytical approach.2005; 113:825–828.
32. Ferrari P, Jenab M, Norat T, et al. Lifetime and baseline alcohol intake and risk of colon and rectal cancers in the European prospective investigation into cancer and nutrition (EPIC).. 2007; 121:2065–2072.
33. Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999–2000. Am J Clin Nutr. 2005; 82:442–50.
34. Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press, 1999.
35. Wei EK, Giovannucci E, Selhub J, Fuchs CS, Hankinson SE, Ma J. Plasma vitamin B6 and the risk of colorectal cancer and adenoma in women. J Natl Cancer Inst. 2005; 97:684–692.
36. Lee JE, Li H, Giovannucci E, et al. Prospective study of plasma vitamin B6 and risk of colorectal cancer in men.. 2009; 18:1197–1202.
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