Folic Acid and Heart Disease

Folate may prevent hypertension in women
BOSTON, MASSACHUSETTS. Hypertension is a major risk factor for cardiovascular disease, so insights into its development are always valuable. Folate intake may have a role to play through reducing levels of homocysteine, a blood component which some studies suggest may damage blood vessels.

Researchers from Brigham and Women’s Hospital and Harvard Medical School looked at folate intake and hypertension in two cohorts of healthy participants - the Nurses Health Study I, including 62,260 women aged 43-70 and the Nurses Health Study II, including 93,803 women aged 27-44. Intake of dietary folate and supplemental folic acid was measured by questionnaire at the start and every four years. Blood pressure was checked every two years. After eight years, 19,720 cases of hypertension were identified. Once many relevant factors were taken into account, younger women (aged 27 to 44 years) who consumed at least 1,000 micrograms a day of total folate had a 46 per cent lower risk of hypertension than those consuming less than 200 micrograms a day. The equivalent intake in older women (aged 43 to 70 years) reduced risk by 18 per cent. In this study, the benefit of folate was unrelated to other factors which are known to influence risk of hypertension including exercise, salt intake and diet.

The researchers also looked at the effect of folic acid supplementation through analysing data on the women with a folate intake from the diet of less than 200 micrograms a day. Among the younger women in this group, those who consumed 800 micrograms a day or more of folate (through supplementation), had a 48 per cent reduction in hypertension risk compared to those whose folate intake was less than 200 micrograms a day. The same intake produced a 40 per cent reduction in women in the older cohort. The research team concludes that supplemental folic acid may reduce the risk of hypertension and encourages future trials to examine folic acid supplementation as a means of lowering blood pressure in young women.
Forman, J P et al. Folate Intake and the Risk of Incident Hypertension Among US Women. Journal of the American Medical Association, Vol. 293, January 2005, pp:320-329

Vitamin therapy reduces restenosis after angioplasty
ENCINITAS, CALIFORNIA. Angioplasty (percutaneous coronary intervention or PCI) is used to open up (dilate) coronary arteries so as to produce a more abundant blood supply to the heart. The beneficial effect of angioplasty is, unfortunately, often short-lived with 40% or more of the opened artery segments closing up again (restenosis) within 6 months of the operation.

A team of American researchers now reports that the incidence of restenosis in smaller coronary arteries can be markedly reduced by decreasing homocysteine levels through supplementation with folic acid and vitamins B6 and B12. Their double-blind, randomized clinical trial involved 205 patients who underwent angioplasty to open up small (diameter less than 3 mm) coronary arteries that were at least 50% blocked (stenosis). Half the participants received 1 mg folic acid, 400 micrograms vitamin-B12, and 10 mg vitamin-B6 on a daily basis while the other half received a placebo. After 28 weeks (plus or minus 6 weeks) 42% of the control group had experienced restenosis as compared to only 15% of the vitamin-treated patients; this is a relative reduction in restenosis rate of 66%. The benefit of homocysteine lowering therapy was highest among patients treated with balloon angioplasty only (82% relative risk reduction) and significantly less in patients who had stents implanted. The benefits were also higher among patients with high levels of low-density lipoprotein cholesterol.

The researchers conclude that homocysteine lowering therapy with vitamins significantly reduces the risk of restenosis in patients treated with PCI for stenosis of small coronary arteries.
Schnyder, Guido, et al. Effect of homocysteine-lowering therapy on restenosis after percutaneous coronary intervention for narrowing in small coronary arteries. American Journal of Cardiology, Vol. 91, May 15, 2003, pp. 1265-69

Congestive heart failure and homocysteine
FRAMINGHAM, MASSACHUSETTS. Congestive heart failure (CHF) is a serious health problem among the elderly. The main risk factors are advancing age, high blood pressure (hypertension), diabetes, obesity, heart valve disease, and having experienced a heart attack. Researchers involved with the Framingham Heart Study now report that a high blood level of homocysteine, a sulfur-containing amino acid, is an independent risk factor for CHF. Their study involved 1547 women and 944 men between the ages of 60 and 95 years. All participants were free of CHF and had not suffered a heart attack at the start of the study. After 8 years of follow-up 156 (6.2%) participants (88 women) had developed CHF. The researchers found that women in the highest quartile of homocysteine level (13.7 – 64.6 micromol/L) had a 4 times higher risk of CHF than did those in the lowest quartile (3.5 – 8.9 micromol/L). Even women with only slightly elevated homocysteine levels (9.0 – 11.0) had twice the risk of women in the lowest quartile. The risk for men in the highest quartile (14.5 – 219.8 micromol/L) was 50% higher than for men in the lowest quartile (4.1 – 9.5 micromol/L); however, a significant increase was not observed until the level exceeded 11.8 micromol/L. The risk estimates are those obtained after adjusting for age, smoking, valve disease, systolic blood pressure, antihypertensive medication use, echocardiographic left ventricular hypertrophy, diabetes, ratio of total cholesterol to high-density lipoprotein, alcohol intake, body mass index, serum creatinine, interim recognized or unrecognized myocardial infarction, and baseline examination.

The researchers urge further trials to determine if reducing elevated homocysteine levels through supplementation with folic acid, vitamin B6 and vitamins B12 will reduce the risk of CHF.
Vasan, Ramachandran S., et al. Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction. Journal of the American Medical Association, Vol. 289, March 12, 2003, pp. 1251-57

Editor’s comment: Homocysteine levels can be safely and effectively lowered by daily supplementation with 400-800 micrograms of folic acid, 50-100 mg of vitamin-B6 (pyridoxine) and 1 mg of vitamin-B12 (cyanocobalamin) taken sublingually.

Folic acid and heart disease
HYATTSVILLE, MARYLAND. High homocysteine levels are associated with an increased risk of heart disease. High homocysteine levels have also been linked to a relative folic acid deficiency. Researchers at the Centers for Disease Control and Prevention now report that low blood levels of folic acid are associated with a substantially increased risk of dying from cardiovascular disease. Their study involved 689 adults aged between 30 and 75 years who were free of heart disease at the start of the study in 1976-1980. After 12 to 16 years of follow-up 122 of the participants without diabetes had died - 49 of them from heart disease. Among the participants with diabetes, 52 in all, 25 died - 12 of them from heart disease.
In the non-diabetic group there was a clear association between blood levels of folate and death from heart disease. The participants with folate levels below 10 nmol/L had a 2.64 times higher age and sex adjusted risk of dying from cardiovascular disease than did the participants with levels above 16.8 nmol/L. Even when adjusting for other risk factors (education level, race, cigarette smoking, alcohol consumption, cholesterol levels, blood pressure, and body mass index) the death rate among the participants with low folate status was still 2.28 times higher than among the people with higher levels. The observations made in the non-diabetic group tended to parallel those in the diabetes group, but because of the small sample size in the diabetes group the observed trends were not statistically significant.
The researchers conclude that at least a third of the participants had folate levels at baseline (1976-1980) so low that they would be in the high-risk category for dying from cardiovascular disease. They urge further work to determine if recent efforts to fortify the US food supply with folic acid are sufficient to decrease the proportion of the population at risk for heart disease because of insufficient folate levels.
Loria, Catherine M., et al. Serum folate and cardiovascular disease mortality among US men and women. Archives of Internal Medicine, Vol. 160, November 27, 2000, pp. 3258-62

Folic acid helps heart disease patients
HALIFAX, CANADA. Several studies have concluded that high homocysteine levels are associated with coronary artery disease (CAD). It is believed that homocysteine promotes atherosclerosis through increased oxidative stress and by “encouraging” dysfunction of the lining of the arteries (endothelial dysfunction). It is generally accepted that folic acid supplementation will lower homocysteine levels, but whether folic acid supplementation will also reduce the endothelial dysfunction responsible for the initiation and progression of atherosclerosis is less certain.
Medical researchers at the Queen Elizabeth II Health Sciences Centre now report that supplementation with 5 mg/day of folic acid significantly decreases endothelial dysfunction. The extent of endothelial dysfunction is determined by measuring the blood flow through the brachial artery in the arm (flow-mediated dilation or FMD). The clinical trial included 75 patients with CAD. The patients were randomized into three groups. One group took 5 mg of folic acid daily for four months; the second group took 5 mg of folic acid plus 2000 mg of vitamin C plus 800 IU of vitamin E per day; the third group was given a placebo. At the end of the trial patients in the folic acid group had increased their blood plasma level of folate by 475 per cent (from 14 nmol/L to 80 nmol/L) and decreased their homocysteine level by about 11 per cent. FMD improved significantly as well (from 3.2 to 5.2 per cent). Patients in the folic acid plus antioxidant group increased their folate level by 438 per cent, reduced homocysteine by 9 per cent, and improved FMD from 2.6 to 4.0 per cent.
The researchers point out that the FMD improvement seen in the folic acid supplemented groups is similar to that seen with statin drugs and ACE inhibitors. They conclude that four months of folic acid supplementation is safe and significantly reduces endothelial dysfunction in patients with established coronary atherosclerosis. [61 references]
Title, Lawrence M., et al. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. Journal of the American College of Cardiology, Vol. 36, September 2000, pp. 758-65

Atherosclerosis and folic acid
AMSTERDAM, THE NETHERLANDS. A high blood level of homocysteine (a sulfur-containing amino acid derived from methionine) has been associated with the development of atherosclerosis. High homocysteine levels can be reduced by supplementation with folic acid; however, it is still uncertain whether this reduction actually lowers the risk of atherosclerosis. Now researchers at the University Hospital Vrije Universiteit report evidence that supplementation with folic acid and vitamin B6 is associated with a decreased occurrence of abnormal exercise electrocardiographs - important markers for atherosclerosis. The study involved 158 siblings of 167 patients with premature atherothrombotic disease. The study participants (siblings) had no signs of arterial disease when entering the study, but were obviously at greater risk of developing atherosclerosis than normal. The participants underwent a methionine-loading test at the start of the study and were subsequently divided into two groups. One group of 104 had high homocysteine levels after the methionine-loading test while the second group of 54 siblings had normal levels. Each group was subsequently randomized to receive either 5 mg folic acid plus 250 mg vitamin B6 daily for a two-year period while the other group received a placebo. At the end of two years all participants had an electrocardiogram, an ultrasound measurement of the carotid and femoral arteries, and a determination of their ankle-brachial pressure index at rest and after exercise. As expected, the vitamin treatment was associated with a significant drop in both fasting homocysteine concentration and postmethionine homocysteine concentration. Blood plasma content of folic acid increased 13-fold and that of vitamin B6 9-fold in the supplement group. There was no apparent effect of vitamin treatment on ankle-brachial pressure indices or ultrasound measurements; however, the incidence of new abnormal exercise electrocardiograms was much lower in the vitamin group (6 versus 14 in the placebo group). The researchers conclude that vitamin therapy lowers the risk of an abnormal exercise electrocardiogram by 60 per cent independent of other risk factors such as age, sex, baseline level of postmethionine homocysteine, cholesterol levels, smoking habits, and the presence of hypertension or diabetes. Although the trial involved participants at high risk for atherosclerosis the researchers see no reason why the results should not be applicable to healthy individuals.
Vermeulen, E.G.J., et al. Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial. The Lancet, Vol. 355, February 12, 2000, pp. 517-22

B vitamins and atherosclerosis
TAIPEI, TAIWAN. High blood levels of the amino acid homocysteine have been associated with an increased risk of atherosclerosis. Homocysteine is formed in the body from methionine (an amino acid found in proteins) in a process that can be blocked by folic acid and vitamins B6 and B12. High homocysteine levels can induce endothelial dysfunction (a narrowing of the arteries) which in turn is believed to be a precursor of atherosclerosis. Researchers at the National Taiwan University Hospital now report that homocysteine-induced endothelial dysfunction can be avoided or very significantly ameliorated by supplementing with folic acid and vitamins B6 and B12.

The study involved two men and fourteen women between the ages of 41 and 55 years. At the start of the study all participants had their blood levels of homocysteine and their blood flow through the brachial artery measured after a 10-14 hour overnight fast. They were then given an oral methionine loading test to simulate the intake of a high protein meal. Four hours later their average homocysteine level had increased from 7 micromol/L to 22.7 micromol/L and the blood flow (flow-mediated vasodilation) had decreased by 40 per cent. The experiment was repeated, but this time 5 mg of folic acid was given together with the methionine; the results were similar to those obtained in the first experiment indicating that folic acid does not act immediately as an "antidote" to a high intake of methionine. The participants were then given 5 mg of folic acid, 100 mg of vitamin B6, and 0.5 mg of vitamin B12 daily for five weeks. At the end of the five weeks their average homocysteine level had decreased to 5.2 micromol/L. The methionine loading test was repeated. Four hours later the average homocysteine level among the participants had increased to 17 micromol/L, but there was no statistically significant difference in blood flow before and after the methionine loading test. The researchers conclude that short-term (five weeks) administration of folic acid and vitamins B6 and B12 will reduce post-methionine load homocysteine levels and eliminate or ameliorate endothelial dysfunction (an early manifestation of atherosclerosis).
Chao, Chia-Lun, et al. Effect of short-term vitamin (folic acid, vitamins B6 and B12) administration on endothelial dysfunction induced by post-methionine load hyperhomocysteinemia. American Journal of Cardiology, Vol. 84, December 1, 1999, pp. 1359-61

A daily vitamin pill helps combat atherosclerosis
CLEVELAND, OHIO. A high blood level of the amino acid homocysteine has been linked to an increased risk of atherosclerosis and thrombosis. It is known that oral supplementation with folic acid will lower homocysteine levels to acceptable norms, but it is not clear just how much folic acid is required to achieve this effect. Now researchers at the Cleveland Clinic Foundation report that the amount of folic acid (400 micrograms) found in most multivitamin preparations is sufficient to lower homocysteine levels in heart disease patients. Their experiment involved 95 patients who had either had a heart attack or suffered from advanced atherosclerosis. The patients were divided into four groups with one group receiving 400 micrograms/day (0.4 mg/day) of folic acid, one group receiving 1 mg/day, one group receiving 5 mg/day, and the fourth group receiving a placebo. All patients receiving folic acid also received 12.5 mg of vitamin B6 per day and 500 micrograms of vitamin B12. After 90 days the plasma homocysteine levels had dropped from 13.8 to 9.6 micromol/L in the 400 micrograms/day folic acid group, from 13.0 to 9.8 micromol/L in the 1 mg/day group, and from 14.8 to 9.7 micromol/L in the 5 mg/day group. Also after 90 days the plasma levels of folic acid had risen from 28 nanomol/L in the placebo group to 63 nmol/L in the 400 micrograms/day supplement group, to 80 nmol/L in the 1 mg/day group, and to 162 nmol/L in the 5 mg/day group. Vitamin B6 levels rose from 75 nmol/L to about 250 nmol/L in the supplemented groups and vitamin B12 levels rose from about 300 picomol/L to 525 picomol/L. The researchers conclude that a daily dose of 400 micrograms of folic acid combined with vitamins B6 and B12 will normalize homocysteine levels in heart disease patients.
Lobo, Arlene, et al. Reduction of homocysteine levels in coronary artery disease by low-dose folic acid combined with vitamins B6 and B12. American Journal of Cardiology, Vol. 83, March 15, 1999, pp. 821-25

Low folate levels link to strokes and dementia
CALGARY, CANADA. Researchers at the University of Calgary report that elderly people with low blood levels of folic acid (folate) are more likely to suffer a stroke than are people with normal to high levels. Their study involved 1171 subjects aged 65 years and older who were enrolled in the Canadian Study of Health and Aging. The researchers found that participants with a folate level below 9.3 nmol/L had a relative risk for ischemic stroke of 1.37. They also discovered that people with low folate levels were more likely to be depressed or demented, tended to have a history of weight loss, and were more apt to rate their health as poor. The researchers conclude that folate deficiencies in elderly people can have serious implications and point out that these deficiencies are easily, inexpensively, and rapidly correctable through supplementation.
Ebly, Erika M., et al. Folate status, vascular disease and cognition in elderly Canadians. Age and Aging, Vol. 27, July 1998, pp. 485-91

Folic acid and vitamin B-6 prevent heart attacks
BOSTON, MASSACHUSETTS. Researchers at the Harvard School of Public Health have just released a major study which shows that a higher intake of folic acid and vitamin B-6 (pyridoxine) protects women against nonfatal heart attacks (myocardial infarction) and fatal coronary heart disease (CHD). The study involved over 80,000 female nurses who in 1980 completed food frequency questionnaires. The questionnaires were updated in 1984, 1986 and 1990 and also gathered information on the use of vitamin supplements. By 1994 658 of the women had suffered a nonfatal heart attack (MI) and 281 had died of coronary heart disease. Statistical analysis showed that women whose intake of folate (folic acid) exceeded 545 micrograms/day had a 31 per cent lower risk of having a heart attack or fatal CHD than did women whose intake was less than 153 micrograms/day. Similarly, women whose intake of vitamin B-6 was greater than 5.9 milligrams/day had a 33 per cent lower risk. Women with the highest intake of both folate and vitamin B-6 had a 45 per cent lower risk than women with the lowest combined intake. These risk reductions were independent of other cardiovascular risk factors such as smoking, hypertension, alcohol consumption, and the intake of fiber, vitamin E and saturated, polyunsaturated and trans- fatty acids. Multivitamins and other vitamin supplements were by far the largest contributors to the intakes of both folate and vitamin B-6.

The researchers found a linear decline in the risk of CHD with increased folate intake (5.8 per cent decrease for each 100 micrograms/day increase in intake) in the range between 150 to 700 micrograms/day. They conclude that the lowest risk was among women whose folate intake was above 400 micrograms/day and whose vitamin B-6 intake was above 3 milligrams/day. These values are considerably higher than the current Recommended Daily Allowances (RDAs) of 200 micrograms and 1.6 milligrams respectively. The researchers also point out that almost 90 per cent of all American women have a folate intake below 400 micrograms/day with the average national intake being only 224 micrograms/day. A high folate intake was found to be particularly important among women who consumed one or more alcoholic drinks per day. In this group those with the highest folate intake reduced their risk of MI and CHD by an astounding 73 per cent when compared to women with a low intake. The researchers were not able to evaluate the benefits of supplementation with more than 1000 micrograms/day of folate.
Rimm, Eric B., et al. Folate and vitamin B-6 from diet and supplements in relation to risk of coronary heart disease among women. Journal of the American Medical Association, Vol. 279, February 4, 1998, pp. 359-64
McCully, Kilmer S. Homocysteine, folate, vitamin B-6, and cardiovascular disease. Journal of the American Medical Association, Vol. 279, February 4, 1998, pp. 392-93 (editorial)

Heart disease linked to folate deficiency
OTTAWA, CANADA. Researchers at Health Canada report that a lack of folate (folic acid) increases the risk of death from coronary heart disease (CHD) significantly. Their study began in 1970 and involved 5056 men and women aged 35 to 79 years. During the 15-year follow-up period there were 165 deaths from CHD. The researchers conclude that people with low folate levels (<6.8 nmol/L [3 ng/mL]) have a 69 per cent greater risk of dying from CHD than do people with high levels (>13.6 nmol/L [6 ng/mL]). They also confirm that smoking, hypertension, diabetes, and high cholesterol levels are potent risk factors for cardiac death with relative risk rates of 1.72, 2.37, 2.26, and 2.91 respectively. Low folate levels have also been linked to an increased risk of carotid artery stenosis, neural tube defects, cervical dysplasia, and rectal cancer. It is believed that an adequate level of folate is required in order to avoid high blood levels of homocysteine, a known risk factor for both CHD and cerebrovascular disease. The researchers point out that an estimated 88 per cent of American adults consume less folate than required to produce low, stable homocysteine levels. They also point out that the bioavailability (absorption) of folate from food is significantly less than that from folic acid supplements.
Morrison, Howard I., et al. Serum folate and risk of fatal coronary heart disease. Journal of the American Medical Association, Vol. 275, No. 24, June 26, 1996, pp. 1893-96

Vitamins prevent heart attacks
BOSTON, MASSACHUSETTS. Researchers at the Harvard Medical School confirm that a high blood level of homocysteine is a potent risk factor for a first heart attack (myocardial infarction). Homocysteine is an amino acid formed during the metabolism of methionine (an amino acid found in proteins). The researchers measured the blood plasma levels of homocysteine, vitamin B-6, vitamin B-12, and folate (folic acid) in 130 Boston area residents who had suffered a first heart attack. The results were compared to levels found in 118 matched controls. The homocysteine levels were an average 11 per cent higher in the heart attack victims than in the controls. A high homocysteine level (>11.2 micromol/L) corresponded to a five-fold increase in heart attack risk over the incidence rate at a low level (<7.2 micromol/L). The increase in risk was linear with a 3 micromol/L increase in homocysteine level corresponding to a 35 per cent increase in heart attack risk. The researchers also found that high blood levels of vitamin B-6 and folic acid provide significant protection against heart attacks. No clear association was found between vitamin B-12 levels and heart attack risk. There was a strong inverse relationship between homocysteine levels and folate levels indicating that an adequate folate intake is essential to normalizing homocysteine levels. The researchers found that homocysteine levels were lowest at a folate intake of 350-400 micrograms/day and recommend a daily folate intake of 400 micrograms/day (the current RDA is 200 micrograms/day).
Verhoef, Petra, et al. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B-6, B-12, and folate. American Journal of Epidemiology, Vol. 143, No. 9, May 1, 1996, pp. 845-59

Folic Acid and Homocysteine

Homocysteine reduction with folic acid
WAGENINGEN, THE NETHERLANDS. There is growing evidence that a high blood level of the amino acid homocysteine is associated with an increased risk for heart attack, stroke, atherosclerosis, Raynaud’s phenomenon, and Alzheimer’s disease. Folic acid is known to reduce homocysteine levels and is also effective in preventing neural tube defects. However, it has not been clearly established exactly how much folic acid is needed on a daily basis in order to achieve maximum homocysteine reduction.

Researchers at Wageningen University now report that a daily intake of 400 micrograms of folic acid will reduce homocysteine levels by an average of about 22%. The clinical trial involved 308 Dutch men and women between the ages of 50 and 75 years. The participants were randomized to receive a placebo or 50, 100, 200, 400, 600 or 800 mcg/day of folic acid for a 12-week period. At the end of the trial homocysteine concentrations had dropped by about 10% in the groups receiving 50 or 100 mcg/day, by 22% in the 400 mcg/day group, and by about 25% in the groups receiving 600 and 800 mcg/day. The researchers conclude that about 90% of the maximum homocysteine reduction obtainable through folic acid supplementation can be achieved by supplementing with 400 micrograms daily.
van Oort, Floor VA, et al. Folic acid and reduction of plasma homocysteine concentrations in older adults: a dose-response study. American Journal of Clinical Nutrition, Vol. 77, May 2003, pp. 1318-23

Low-dose folic acid supplementation is effective
NIJMEGEN, NETHERLANDS. An elevated level of homocysteine is a risk factor for cardiovascular disease, stroke, and Alzheimer's disease and also increases the risk of a pregnant woman giving birth to a baby with neural tube defects. Supplementation with folic acid is known to lower homocysteine levels, but it is not known exactly how much is required and how long it takes to become effective. Researchers at the Nijmegen University Hospital have just completed a study aimed at answering these questions. The trial involved 144 healthy women (with normal homocysteine levels) between the ages of 18 and 40 years. The women were randomly allocated to one of three groups. Group 1 received 500 micrograms of folic acid daily for a four-week period, group 2 received 500 micrograms every second day (250 micrograms/day), and group 3 received a placebo. Blood samples were taken at the start of the trial and after one, two and four weeks when the supplementation phase ended. Samples were also taken four and eight weeks after the end of the supplementation to see how long its effect would last. Supplementation with both 500 micrograms/day and 500 micrograms every second day was found to be effective. Homocysteine levels decreased by an average 22 per cent in the women taking 500 micrograms/day and by 11 per cent in the ones taking 500 micrograms every second day. The level of folate in plasma and red blood cells also increased significantly. The homocysteine levels increased again when supplementation was stopped, but were still well below original levels eight weeks later. The major part of the drop in homocysteine level in the 500 micrograms/day group took place within the first two weeks. In view of the fact that neural tube defects develop in the third or fourth week of pregnancy it may be worthwhile to start taking folic acid immediately after missing the first period; although, of course, it would be better to start four weeks before a planned pregnancy. The magnitude of the observed drop in homocysteine concentration upon supplementation was found to be highly dependent on the initial level. Women with high levels (14.3 micromol/L) experienced a drop of around 4 micromol/L while women with lower initial levels only experienced drops of about 1 micromol/L.
Brouwer, Ingeborg A., et al. Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomized trial. American Journal of Clinical Nutrition, Vol. 69, January 1999, pp. 99-104

Vitamin B-12 increases efficiency of folic acid
BONN, GERMANY. There is increasing evidence that high blood levels of the amino acid homocysteine increases the risk of vascular disease, coronary heart disease, neural tube defects, and Alzheimer's disease. Folic acid supplementation is known to lower homocysteine levels and laws have recently been passed in the United States mandating folic acid fortification of bread and cereal. Now researchers at the University of Bonn report that folic acid's homocysteine lowering capacity can be markedly increased by also supplementing with vitamin B-12 (cobalamin). Their study involved 150 young, healthy women (average age of 24 years) who after a four-week washout period were randomized into three groups. Group 1 received a daily supplement of 400 micrograms of folic acid, group 2 received 400 micrograms/day of folic acid and 6 micrograms/day of vitamin B-12, and group 3 received 400 micrograms/day of folic acid and 400 micrograms/day of vitamin B-12. After four weeks the average concentration of plasma homocysteine had dropped by 11 per cent in group 1, 15 per cent in group 2, and 18 per cent in group 3. The researchers noted that study participants with high initial homocysteine concentrations benefited more from supplementation than did women with lower initial homocysteine levels. It was also noted that vitamin B-12 levels increased significantly over the four-week period in the women whose supplements included vitamin B-12. This provides further proof that oral vitamin B-12 is indeed adequately absorbed. The researchers conclude that the benefits of folate supplementation can be markedly enhanced by the addition of vitamin B-12. They point out that vitamin B-12 deficiency is widespread especially among the elderly. The addition of vitamin B-12 to folic acid supplements also prevents the possibility that supplementation with just folic acid could mask pernicious anemia resulting from a vitamin B-12 deficiency which in turn may lead to irreversible nerve damage.
Bronstrup, Anja, et al. Effects of folic acid and combinations of folic acid and vitamin B-12 on plasma homocysteine concentrations in healthy, young women. American Journal of Clinical Nutrition, Vol. 68, November 1998, pp. 1104-10

Folic acid and homocysteine
OXFORD, ENGLAND. Many studies have shown that patients with vascular disease, especially coronary heart disease, have higher blood homocysteine levels than do healthy controls. It is clear that the elevated homocysteine levels precede the onset of disease and is unrelated to other risk factors. Epidemiological studies have shown that a prolonged lowering of homocysteine levels of just 1 micromol/liter (in the range of 10-15 micromol/l) could theoretically result in a 10 per cent reduction in risk. It is known that homocysteine concentrations are inversely proportional to blood levels of folic acid (folate), vitamin B-12, and vitamin B-6 and that homocysteine levels can be lowered by supplementing with these vitamins. Medical researchers at the Radcliffe Infirmary have reviewed the results of trials aimed at lowering homocysteine levels by vitamin supplementation. The trials involved 1114 people with a mean age of 52 years (23 to 75 years); the average (mean) duration of treatment was six weeks and the median baseline blood concentrations of homocysteine and folate were 11.8 micromol/l and 11.6 nanomol/l respectively.

The researchers found that daily supplementation with 0.5-5.0 mg of folic acid reduces homocysteine concentrations by 25 per cent. The reduction was significantly greater among patients with high initial homocysteine levels, but did not seem correlated with the amount of folic acid taken in the range of 0.5 to 5.0 mg. Supplementation with vitamin B-12 (0.5 mg/daily on average) lowers homocysteine levels by an additional seven per cent, but no effect was noted for vitamin B-6 supplementation with an average (mean) intake of 16.5 mg/daily. The researchers conclude that oral supplementation with at least 0.5 mg of folic acid and 1.0 mg of vitamin B-12 on a daily basis would lower homocysteine concentration by 3-4 micromol/l theoretically corresponding to a 30-40 per cent reduction in the risk of developing vascular disease. They recommend that further large scale studies be done to evaluate the efficacy and safety of long term use of folic acid and vitamin B-12 as a means of reducing the incidence of vascular disease among high risk subjects.
Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. British Medical Journal, Vol. 316, March 21, 1998, pp. 894-98

Major new risk factor for heart disease discovered
VANCOUVER, CANADA. It is becoming increasingly evident that an elevated blood level of homocysteine is a potent risk factor for cardiovascular disease. Recent studies also suggest that high homocysteine levels may be associated with kidney disease, psoriasis, breast cancer, and acute lymphoblastic leukemia. Extensive past research has shown a close link between the development of neural-tube defects in babies and the mother's homocysteine level prior to and during pregnancy. Researchers at the University of British Columbia have just released a major report which summarizes the current knowledge about homocysteine and its effect on health. Homocysteine is formed in human tissues during the metabolism of methionine, a sulfur- containing essential amino acid. A normal, desirable level is 10 micromol/L or less. A level of 12 micromol/L is considered borderline and levels of 15 micromol/L or above are considered to be indicative of increased risk for cardiovascular disease. Several factors (age, smoking, vitamin deficiencies, and genetic abnormalities) have been linked to increased homocysteine levels. Medications that interact with folate such as methotrexate, carbamazepine, phenytoin, and colestipol/niacin combinations have also been linked to increased homocysteine levels. The researchers reviewed 23 studies dealing with the association between atherosclerosis and homocysteine levels and found that patients with vascular diseases had an average level of homocysteine that was 26 per cent higher than the level in healthy subjects. One study found that a homocysteine level of 4 micromol/L above normal corresponds to a 41 per cent increase in the risk of developing vascular disease. Another study estimates that the lives of 56,000 Americans could be saved every year if average homocysteine levels were lowered by 5 micromol/L. The researchers conclude that abnormally high homocysteine levels are a potent risk factor for cardiovascular and several other diseases. They point out that elevated homocysteine levels can, in most cases, be safely and effectively lowered by supplementation with as little as 400 micrograms per day of folic acid. Other researchers have found that a combination of folic acid (0.4-10 mg/day), vitamin B-12 (50-1000 micrograms/day), and vitamin B-6 (10-300 mg/day) is highly effective in lowering homocysteine levels. (153 references). Medical doctors at the University of Wisconsin echo the findings of the Canadian researchers in a separate report and describe a case of a 57-year-old man who lowered his homocysteine level from 29 micromol/L to 2 micromol/L by supplementing with 800 micrograms/day of folic acid for two months.
Moghadasian, Mohammed H., et al. Homocysteine and coronary artery disease. Archives of Internal Medicine, Vol. 157, November 10, 1997, pp. 2299-2308
Fallest-Strobl, Patricia C., et al. Homocysteine: A new risk factor for atherosclerosis. American Family Physician, Vol. 56, October 15, 1997, pp. 1607-12

Vitamins may help prevent strokes in lupus patients
BALTIMORE, MARYLAND. Systemic lupus erythematosus (SLE) patients have an increased risk of suffering strokes, heart attacks, and other arterial thrombotic events such as gangrene of the fingers. It is believed that this higher risk is at least partially related to a greater propensity among SLE patients to develop premature atherosclerosis. High concentrations of homocysteine (a sulphur-containing amino acid) have previously been linked to an increased risk of stroke and coronary artery disease. Now researchers at the Johns Hopkins Medical Institutions report that many SLE patients have high homocysteine levels and that these higher levels correspond to a significantly increased risk for stroke and other thrombotic events. The study involved 337 SLE patients who were followed for an average of 4.8 years. The average age of the patients was 35 years and 93 per cent of them were women. The researchers found that 15 per cent of the patients had raised homocysteine levels (greater than 14.1 micromol/liter). They also noted a strong inverse correlation between homocysteine levels and the levels of folic acid and vitamin B- 6 in the blood. After adjusting for other relevant risk factors the researchers conclude that SLE patients with elevated homocysteine levels have a 2.4 times higher risk of having a stroke and a 3.5 times higher risk of having an arterial thrombotic event. The researchers suggest that supplementation with folic acid and vitamin B-6 may help prevent thrombotic events in SLE patients. Other studies have found a clear inverse correlation between homocysteine levels and vitamin B-12 levels. This correlation was not observed in the present study - most likely because the patients were relatively young and therefore less likely to be deficient in vitamin B-12.
Petri, Michelle, et al. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. The Lancet, Vol. 348, October 26, 1996, pp. 1120-24

Elevated homocysteine levels linked to stroke risk
LONDON, ENGLAND. Evidence is rapidly accumulating to the effect that a high homocysteine level in the blood is a potent risk factor for cardiovascular disease. Homocysteine is an amino acid formed in the metabolism of methionine. A high level of homocysteine can be inherited, but far more often is due to a deficiency of the vitamins required to metabolize it (folic acid, vitamin B- 6, and vitamin B-12). A team of British and Norwegian medical researchers now report that men with a high homocysteine level have a vastly increased risk of suffering a stroke (ischemic). Their study involved 5,661 middle-aged men whose blood was sampled in the period 1978 to 1980. By 1991 141 of the men had suffered a stroke. The researchers compared the homocysteine level in the blood from the stroke victims with the level in blood from matched controls who had not had a stroke or heart attack during the follow-up period. They found that men with a total homocysteine level of more than 15.4 micromol/liter had an almost five times greater risk of having a stroke than did men with a more normal level of less than 10.3 micromol/liter. The increased stroke risk held true even after adjusting for obesity, hypertension, diabetes, cigarette smoking, alcohol consumption, social class, lung capacity, and level of HDL cholesterol. Elevated homocysteine levels can be normalized by ensuring an adequate intake of folic acid and other B vitamins.
Perry, I.J., et al. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. The Lancet, Vol. 346, November 25, 1995, pp. 1395-98

Homocysteine linked to known cardiovascular risk factors
BERGEN, NORWAY. It is generally accepted that a high blood level of homocysteine is a significant risk factor for cardiovascular disease. Several studies have found that patients with coronary heart disease have homocysteine levels which are 20 to 30 per cent (2 to 3 micromol/liter) higher than those of healthy control subjects. A recent study found that a 5 micromol/l increase in homocysteine level is associated with a 60 to 80 per cent increase in the risk of coronary artery disease and a 50 per cent increase in the risk of cerebrovascular disease (stroke). Researchers from the University of Bergen now report that homocysteine levels are closely linked with other known risk factors for cardiovascular disease. Their study involved a total of 7,591 men and 8,585 women between the ages of 40 and 67 years. None of the participants had a previous history of diabetes, hypertension, coronary heart disease or cerebrovascular disease. The researchers found that men tend to have higher homocysteine levels than women and that these levels increase significantly with age. Cigarette smoking is closely connected with homocysteine levels and women smokers tend to have higher levels than male smokers. When age, sex, and cigarette smoking is combined the effect becomes vastly magnified. A 65-67 year old man who is a heavy smoker has a homocysteine level 4.8 micromol/l higher than a never-smoking woman aged 40-42 years; this would correspond to a 60 to 80 per cent higher risk for coronary heart disease.

Exercise has a beneficial effect on homocysteine levels with vigorous exercise in the 40-42 year age group having homocysteine levels 0.8-0.9 micromol/l lower than sedentary people. A low diastolic blood pressure and heart rate were both associated with benefically lower homocysteine levels. Serum cholesterol levels were also found to be related to homocysteine levels with lower cholesterol levels corresponding to lower homocysteine levels. People who took vitamin supplements, which usually contain folic acid, were found to have an average 1.35 micromol/l lower homocysteine level than people who did not supplement. A diet rich in fresh fruit and vegetables was also found to be beneficial with people eating fruit and vegetables at least six times a week having a 0.79 micromol/l lower homocysteine level than people eating fruit and vegetables once a week or less. The researchers conclude their report by raising the crucial question "Is a high homocysteine level the cause of cardiovascular disease or merely a marker of susceptibility to cardiovascular disease?" The Norwegian team believe that high homocysteine levels actually may cause vascular disease and raise the intriguing possibility that people who are at an elevated risk for cardiovascular disease (smokers, sedentary people, people with high blood pressure and cholesterol levels, and older people) may actually lower their risk by increasing their intake of vitamins or more specifically, folic acid.
Nygard, Ottar, et al. Total plasma homocysteine and cardiovascular risk profile. Journal of the American Medical Association, Vol. 274, No. 19, November 15, 1995, pp. 1526-33

Folic acid helps prevent coronary heart disease
SEATTLE, WASHINGTON. A high level of homocysteine in the blood has been clearly implicated in heart disease, stroke and peripheral vascular disease. Homocysteine is an amino acid which is not found in protein as such, but is involved in the metabolism of other amino acids (methionine and cysteine). The average blood level of total homocysteine in male adults is about 10 micromol/L. Now researchers at the University of Washington confirm that people with a higher than normal level of homocysteine have a greater risk of developing vascular disease. The researchers evaluated 17 studies dealing with the link between homocysteine levels and the risk of coronary artery disease (CAD). They found that men with a level of 15 micromol/L had a 60 per cent greater risk of developing CAD while the increased risk for women was 80 per cent. The risk for cerebrovascular disease (stroke) was found to be almost twice as high in men and women with elevated (15 micromol/L) homocysteine levels. The risk of developing peripheral vascular disease (eg. intermittent claudication) was found to be almost seven times higher among people with elevated homocysteine levels. The researchers conclude that a high homocysteine level is an independent risk factor for vascular disease and that a 5 micromol/L elevation results in the same increase in CAD risk as a cholesterol increase of 0.5 mmol/L (20 mg/dL).

The researchers also evaluated 12 studies concerning the connection between dietary intake of folic acid and homocysteine level. They found that folic acid is very effective in lowering homocysteine levels. An intake of 400 micrograms per day (the level found in most supplements) lowers the homocysteine level by about 6 micromol/L. The researchers conclude that over 44,000 lives could be saved every year if just half the population of the United States were to supplement with 400 micrograms per day of folic acid. Unfortunately, recent surveys have shown that 88 per cent of American adults have a daily intake of folic acid below 400 micrograms. The researchers warn that an increased intake of folic acid may mask a vitamin B-12 deficiency and recommend that 1 mg of vitamin B-12 be added to all supplements containing 400 micrograms of folic acid. They also recommend that consideration be given to fortifying grain products with 350 micrograms of folic acid per 100 grams of grains. This strategy would have the added advantage of making it easier to prevent neural tube defects in new born babies.
Boushey, Carol J., et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Journal of the American Medical Association, Vol. 274, No. 13, October 4, 1995, pp. 1049-57

Folate helps prevent heart disease
BOSTON, MASSACHUSETTS. Several recent studies on the causes of coronary disease have concluded that a high blood level of homocysteine is an important risk factor. A recently completed study, the Physicians' Health Study, showed that men with a high homocysteine level had a three times higher risk of suffering a myocardial infarction (heart attack) than did men with lower levels. Elevations of homocysteine levels can be due to relatively rare genetic defects but are most likely caused by a lack of folate (folic acid) in the diet. Studies have shown that the level of homocysteine in the blood is inversely proportional with the level and dietary intake of folate. A minimum daily intake of 400 micrograms per day of folate is required to maintain a stable low level of homocysteine. A folate intake of 1 to 2 mg per day, which is generally safe, is usually sufficient to reduce high homocysteine levels even if they are not due to inadequate folate consumption. It is estimated that 40 per cent of Americans get too little folate and that over 20 per cent have homocysteine levels high enough to result in vascular disease.
Stampfer, Meir J. and Malinow, M. Rene. Can lowering homocysteine levels reduce cardiovascular risk? The New England Journal of Medicine, Vol. 332, No. 5, February 2, 1995, pp. 328-29

Folic Acid and Cancer

Folic acid and B vitamins help prevent breast cancer
BOSTON, MASSACHUSETTS. Researchers at the Harvard School of Public Health have released the results of a major study aimed at evaluating the association between blood (plasma) levels of folate (folic acid), vitamins B6 and B12 and the risk of breast cancer. The study involved 32,826 female nurses who had blood samples drawn during 1989 and 1990. At the end of 1996 712 of the participants had developed breast cancer.

The researchers found the women with the highest plasma levels of folate (greater than 14 ng/mL) had a 27% lower risk of breast cancer than did women with a lower level (less than 6.4 ng/mL). The protective effect of folic acid was found to be even more pronounced in women who regularly consumed alcohol (one drink per day or more). Here those with the highest folate levels had an 89% lower risk of breast cancer than did women with low levels.

High plasma levels of vitamin-B6 (greater than 95.3 pmol/mL) were associated with a 30% risk reduction as compared to low levels (less than 28.5 pmol/mL). High vitamin B12 levels were associated with a lower breast cancer risk among premenopausal women, but not among postmenopausal women. This finding contradicts that of earlier studies which found a protective effect only among postmenopausal women. It is interesting that no correlation was observed between the intake of vitamin B12 from food and plasma levels; a significant correlation was noticed between vitamin-B12 intake from supplements and plasma levels. Plasma homocysteine levels were not associated with breast cancer risk. The researchers conclude that folic acid and vitamin B6 may help prevent breast cancer and that ensuring an adequate intake of these vitamins either from food or supplements may reduce breast cancer risk.
Zhang, SM, et al. Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. Journal of the National Cancer Institute, Vol. 95, March 5, 2003, pp. 373-80

Folic acid protects against leukemia
SYDNEY, AUSTRALIA. Leukemia is the most common cancer among children in developed countries. The causes of childhood leukemia are largely unknown, but there is some indication that environmental factors and exposure to radiation could play a role. Researchers at the Cancer Foundation of Western Australia now report the results of a comprehensive study aimed at determining the risk factors for acute lymphoblastic leukemia. The researchers compared 83 children under the age of 14 years with leukemia with 166 healthy children matched for sex, date of birth, and broad region of residence. They interviewed both the mother and father of each child and also determined the child’s exposure to various expected risk factors. As an add-on they also asked the mothers about their use of medicines and supplements during pregnancy.
Not unexpectedly, they found that children who had been exposed to pesticides and x-rays had a three-fold increased risk of leukemia. A mother’s exposure to agricultural chemicals, glues or resins during pregnancy increased the risk by a factor of three or four. A father’s exposure to paints or pigments (at work) or to solvents, degreasers or cleansing agents or other industrial chemicals, in the five-year period prior to the child’s birth, was associated with a three-fold risk increase. Completely unexpected was the finding that children born to women who had supplemented with iron and folic acid during pregnancy had a three times (0.37 odds ratio) lower risk of developing leukemia than did children born to mothers who had not supplemented.
The researchers believe that the folic acid is responsible for the protective effect, but could not separate the effects of iron and folic acid as they were always taken together. They point out though that folic acid has been associated with a reduced risk of colon cancer. The researchers conclude that folic acid supplementation during pregnancy reduces the risk of childhood leukemia. NOTE: The RDA for iron and folic acid during pregnancy is 30 mg/day and 400 micrograms/day respectively.
Thompson, Judith R., et al. Maternal folate supplementation in pregnancy and protection against acute lymphoblastic leukemia in childhood: a case-control study. The Lancet, Vol. 358, December 8, 2001, pp. 1935-40

Folic acid prevents breast cancer
SHANGHAI, CHINA. A team of American and Chinese researchers has discovered that folic acid (folate) is highly effective in preventing breast cancer in both pre- and postmenopausal women. Their investigation involved 1321 women with breast cancer and 1382 healthy controls. The women were between the ages of 25 and 64 years when they enrolled in the Shanghai Breast Cancer Study during 1996-98.
The researchers found a clear correlation between dietary intake of folic acid and the risk of breast cancer. Women with a daily intake of 345 micrograms or higher had a 38 per cent lower risk than did women with an intake of less than 195 micrograms – after adjustment for total vegetable, fruit and animal food intake. The protective effect of folic acid was even more pronounced in women who also had a high dietary intake of vitamin B6, vitamin B12 and methionine. Women with a daily intake equal to or higher than 345 micrograms of folic acid, 8.47 micrograms of vitamin B12, 2 mg of vitamin B6, and 1.9 grams of methionine had a 53 per cent lower risk of breast cancer than did women with daily intakes at or below 195 micrograms of folic acid, 1.32 micrograms of vitamin B12, 1.35 mg of vitamin B6, and 1.27 grams of methionine.
Researchers believe that folic acid exerts its protective effect by preventing errors in DNA replication and by helping to regenerate methionine, a vital component in DNA synthesis. They also point out that both vitamin B12 and vitamin B6 are vital cofactors required for folic acid to “do its job”. NOTE: Most multivitamins have levels of folic acid, vitamin B6 and vitamin B12 well above the levels found to be beneficial in the Shanghai study.
Shrubsole, Martha J., et al. Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Research, Vol. 61, October 1, 2001, pp. 7136-41

Folic acid protects against pancreatic cancer
BETHESDA, MARYLAND. Although pancreatic cancer accounts for only 2 per cent of all cancers worldwide it is the fifth leading cause of cancer deaths in the US. The five-year survival rate is less than 5 per cent. Researchers at the National Cancer Institute and the Finnish National Public Health Institute now report that an adequate folic acid intake can materially reduce the risk of developing the cancer. Their study included over 27,000 healthy male smokers aged 50 to 69 years when enrolled in 1985. Thirteen years later 157 of the men had developed cancer of the pancreas. A review of dietary records revealed that the men with a daily dietary folate intake of more than 373 micrograms/day had half the risk of pancreatic cancer than did the men with an intake of less than 280 micrograms/day. This significant risk reduction held true even after adjusting for other potential risk factors. As expected, the most serious risk factor was smoking. Men who smoked more than 25 cigarettes a day had an 82 per cent higher risk than men who smoked less than 14 a day. The researchers found no correlation between the risk of pancreatic cancer and alcohol consumption or dietary intake of methionine, vitamin B6 or vitamin B12.
Supplementing with folic acid seemed to have a slightly negative effect. The researchers point out that the supplement takers had significantly more health and alcohol-related problems than did the non-takers and that the number of supplement takers was too small to draw statistically significant conclusions. They caution that the issue could be clouded by earlier findings from animal experiments that, while folic acid supplementation may be effective in preventing cancer from starting, it may actually enhance tumor development at a later stage.
Stolzenberg-Solomon, Rachael Z., et al. Dietary and other methyl-group availability factors and pancreatic cancer risk in a cohort of male smokers. American Journal of Epidemiology, Vol. 153, April 1, 2001, pp. 680-87 [51 references]

Folates and cancer prevention
TORONTO, CANADA. Folates (derivatives of folic acid) play a key role in the synthesis, repair, and methylation of DNA. It is therefore not surprising that a deficiency in this essential B vitamin has been implicated in Alzheimer's disease, atherosclerosis, heart attack, stroke, osteoporosis, depression, dementia, cleft lip and palate, hearing loss, Raynaud's phenomenon, and of course, neural tube defects.
There is now also evidence that a folate deficiency may be involved in the development of certain cancers. Dr. Young-In Kim, MD of the University of Toronto presents an overview of the current knowledge regarding the role of folates in cancer prevention. Some 20 studies have been published regarding the association between colorectal cancer (cancer of the colon or rectum) and folate status. Collectively, these studies suggest that people with a high intake of folates can reduce their risk of developing colorectal cancer by about 40 per cent when compared to people with low intakes. A study involving almost 90,000 American female nurses concluded that nurses who had been supplementing with 400 micrograms/day or more of folic acid for 15 years or more had a 75 per cent reduction in the risk of colorectal cancer when compared to people who did not supplement. The evidence concerning folates and breast cancer is not quite as clear. Studies have shown that even moderate alcohol consumption increases the risk of breast cancer and that this risk can be counteracted by supplementing with folic acid. The jury is still out on whether folate supplementation reduces the risk among non-drinkers although one study did show that postmenopausal women could decrease their risk of developing breast cancer by supplementing with folic acid. Another study involving 300 premenopausal women found a 50 per cent lower risk among women whose intake exceeded 304 micrograms/day. Other studies, however, have failed to confirm this effect.
A major study involving over 29,000 male, Finnish smokers found that those who developed pancreatic cancer had a significantly lower blood serum level of folate than did those who did not. A baseline serum folate level above 4.45 ng/mL was associated with a 55 per cent risk reduction when compared to levels below 3.33 ng/mL. An Australian study found a 64 per cent difference in risk between men with the highest folate intake and those with the lowest intake.
Dr. Kim concludes that a moderate increase in folate intake can materially help reduce the risk of certain cancers, but cautions that people who already have cancer should not increase their folate intake as there is evidence that high folate levels may accelerate the growth of existing tumours.
Kim, Young-In. Folate and cancer prevention: a new medical application of folate beyond hyperhomocysteinemia and neural tube defects. Nutrition Reviews, Vol. 57, October 1999, pp. 314-21

Folic acid and colon cancer
NEW YORK, NY. Colorectal cancer (cancer of the colon or rectum) is the third-leading cancer in the United States with more than 130,000 new cases reported every year. Previous research has shown that a high consumption of meat and a low intake of fruits and vegetables substantially increase the risk of developing colorectal cancer. Now researchers at the New York University School of Medicine report that women with a low level of folate (folic acid) in their blood serum have twice the risk of colorectal cancer than do women with higher levels. Their study involved 15,785 women who were part of the New York University Women's Health Study begun in 1985. By the end of 1994 105 of the women had developed colorectal cancer. These women were matched with 523 controls and folate intake and blood levels of folate and homocysteine were compared. Women with the highest serum level of folate (more than 31 nanomol/L) had about half the risk of developing colorectal cancer than did women with levels below 12 nanomol/L. Women with the highest levels of homocysteine (more than 12 micromol/L) had a 70 per cent increase in risk compared with women whose levels were below 8 micromol/L. About 39 per cent of the total folate intake reported came from vitamin/mineral supplements. The researchers conclude that folates may protect against colorectal cancer, but recommend larger clinical trials to further support this contention.
Kato, I., et al. Serum folate, homocysteine and colorectal cancer risk in women: a nested case- control study. British Journal of Cancer, Vol. 79, No. 11/12, April 1999, pp. 1917-21

Multivitamin use and colon cancer
BOSTON, MASSACHUSETTS. A deficiency of folate (folic acid) prior to and during preganancy increases the risk of giving birth to a baby with neural tube defects. A lack of folate has also been linked to an increased risk of cardiovascular disease. Now researchers at the Harvard Medical School report that women with a high folate intake decrease their risk of developing colon cancer by as much as 75 per cent. Their study which began in 1980 involved 88,756 female nurses. The nurses completed food frequency questionnaires in 1980, 1984, 1986, and 1990 and also provided information about their use of vitamins, lifestyle factors, and family history which could affect their risk of colon cancer. During the period from 1980 to June 1994 442 of the women developed colon cancer. Statistical analysis showed that women who had supplemented with multivitamins containing folic acid (>400 micrograms/day) for 15 years or more had a four times lower risk of colon cancer than did women whose daily intake had been 200 micrograms/day or less. This association remained true after adjusting for age, family history of colorectal cancer, aspirin use, smoking, weight, degree of physical activity, and intake of red meat, alcohol, methionine and fiber. Adjustment for intake of vitamins A, C, D, E and calcium did not alter the folate/colon cancer correlation. However, it was clear that the benefits of folate became evident only after 15 years or more of supplement use although smaller statistically non-significant risk reductions were noted after five years. The risk reduction associated with folate supplementation was particularly evident among women with low methionine levels. Folate is essential in the regeneration of methionine and a deficiency may lead to abnormalities in DNA synthesis and repair - mechanisms which may influence the development of colon cancer. The researchers found a significantly stronger correlation between the intake of folate from supplements and a reduced colon cancer risk than between the intake of dietary folate and reduced risk. They ascribe this to the relatively low bioavailability of folate from food sources and conclude that long term use of multivitamins containing folic acid reduces the risk of colon cancer in women. Other studies have shown that folic acid supplementation also reduces colon cancer risk in men. NOTE: Certain birth control pills and drugs such as methotrexate can markedly lower folate levels in the body.
Giovannucci, Edward, et al. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Annals of Internal Medicine, Vol. 129, October 1, 1998, pp. 517-24

Folate levels and colon cancer risk
TORONTO, CANADA. Cancer of the colon or rectum is now the second most common cause of cancer deaths in the United States. There were almost 200,000 new cases and over 59,000 deaths from colorectal cancer in 1996 alone. Colon cancer is preceded by the occurrence of malignant polyps (adenomatous polyps); non-malignant polyps (hyperplastic polyps) may also be present in the colon and rectal area. Researchers at the University of Toronto have just completed a study which shows that the folate (folic acid) level in the lining (mucosa) of the colon is significantly lower among patients with malignant polyps than among patients with benign polyps. Their study involved 30 patients over the age of 18 years who had been referred to the New England Medical Center for colonoscopy. Biopsies of normal mucosa (at least 10 cm from polyps) showed that the presence of adenomatous polyps was associated with a significantly lower mucosal folate level than was the presence of hyperplastic polyps. Although mucosal folate levels correlated reasonably well with the folate concentration in blood serum and red blood cells, these indicators were not sufficiently sensitive to predict whether polyps would be malignant or not. Blood levels of homocysteine were found to correlate well with mucosal folate levels and an elevated homocysteine level was also found to correlate with the presence of adenomatous polyps. The researchers suggest that people with malignant polyps may have an impairment in their folate metabolism which would account for their higher homocysteine levels.
Weir, Donald G. and Scott, John M. Colonic mucosal folate concentrations and their association with colorectal cancer. American Journal of Clinical Nutrition, Vol. 68, October 1998, pp. 763-64 (editorial)
Kim, Young-In, et al. Colonic mucosal concentrations of folate correlate well with blood measurements of folate status in persons with colerectal polyps. American Journal of Clinical Nutrition, Vol. 68, October 1998, pp. 866-72

Folate and vitamin E protect against colon cancer
CHAPEL HILL, NORTH CAROLINA. Colorectal adenomas are benign tumors (polyps) in the large intestine that are believed to be precursors of colon cancer. Researchers at the University of North Carolina now report that women with a high intake of folate (folic acid) and men with a high intake of vitamin E have a much reduced risk of developing colorectal adenomas. Their study involved 645 patients who underwent colonoscopy in the period between July 1988 and March 1991. Of these patients, 236 were found to have adenomas or cancer while 409 had no polyps and were used as a control group. After adjusting for other variables the researchers conclude that women with an average (mean) daily intake of 398 micrograms or more of folate have a 60 per cent reduced risk of developing colorectal adenomas as compared to women with a mean daily intake of 130 micrograms or less. The RDA of folate is only 180 micrograms. High intakes of iron (25 mg/day or more) and vitamin C (278 mg/day or more) were also found to have a protective effect among women. Among men the most protective micronutrient was vitamin E. Men whose daily vitamin E intake averaged 34 IU or higher were found to have a 65 per cent reduction in their risk of developing colorectal adenomas as compared to men with a mean daily intake of 5 IU or less. The RDA of vitamin E for men is only 10 IU. A high intake of calcium was also found to have a significant protective effect among men. Men whose average daily intake was 1400 mg or more reduced their risk by 56 per cent as compared to men whose daily intake was 400 mg or less. The researchers point out that many of the patients with high intakes of the protective micronutrients were using supplements and question whether the normal American diet contains enough of these micronutrients to offer any significant protection.
Tseng, Marilyn, et al. Micronutrients and the risk of colorectal andenomas. American Journal of Epidemiology, Vol. 144, No. 11, December 1, 1996, pp. 1005-14

Heavy drinkers need folate
BOSTON, MASSACHUSETTS. Researchers at the Harvard Medical School report that heavy drinking (more than two drinks a day) combined with a low intake of folate and methionine triples the risk of developing colon cancer. Their study involved almost 48,000 male health professionals in the United States and covered the period 1986 to 1992. During this period 205 new cases of colon cancer were diagnosed in the study group. The researchers also discovered that men who drank more than two drinks per day, but had a high folate or methionine intake, had no greater risk of developing colon cancer than did non-drinkers. The greatest protective effect was found with a methionine intake in excess of 2.44 grams/day and a folate intake of 646 micrograms/day or greater. A high methionine and folate intake did not significantly lower the risk of getting colon cancer among light drinkers and non-drinkers. The risk of getting colon cancer was somewhat higher among wine drinkers than among beer and liquor drinkers. The researchers recommend that alcohol drinkers increase their intake of methionine-rich foods (poultry, fish, and low-fat dairy products); they do not recommend supplementation with methionine as an excess can increase blood homocysteine levels. A high homocysteine level is now believed to be a risk factor for coronary heart disease. A high intake of folate-rich foods (fresh fruit, vegetables, and whole-grain foods) is also recommended including the use of multivitamin supplements if necessary. The researchers believe that the combination of large amounts of alcohol and insufficient amounts of methionine and folate in the diet leads to abnormalities in the methylation of DNA. This may contribute to the development of cancer by activating tumor development genes and deactivating tumor suppressor genes. (88 references)
Giovannucci, Edward, et al. Alcohol, low-methionine-low-folate diets, and risk of colon cancer in men. Journal of the National Cancer Institute, Vol. 87, No. 4, February 15, 1995, pp. 265- 73

Vitamin A may protect against breast cancer
BOSTON, MASSACHUSETTS. Evidence is mounting that a high intake of fruits and vegetables is protective against most cancers. It is not entirely clear which components of the fruits and vegetables provide the protection but vitamin C and beta carotene have long been top contenders. Now researchers at the Harvard Medical School report that folic acid may provide significant protection against colon cancer. The scientists found that men and women with a high intake of folic acid (including supplements) had a 35 per cent less risk of developing adenomatous colon polyps (the precursors to colon cancer) than did people with a low intake. A high fiber intake was also found to lower the colon adenoma risk. Thus people who consumed about 30 grams/day of fiber had a 50 per cent lower risk than did people who consumed about 12 grams/day. The researchers also report on the latest findings in the Nurses' Health Study concerning breast cancer. Between 1980 and 1988 about 1500 cases of breast cancer occurred in the study group. The scientists found no correlation between the risk of breast cancer and the intake of fat or the intake of vitamins C and E. However, a high intake of vitamin A was found to correspond to a 20 to 30 per cent reduction in breast cancer risk. The researchers believe that both beta carotene and preformed vitamin A from animal sources (including supplements) have a protective effect. They point out that women who already have a high dietary intake of vitamin A may benefit little from further supplementation; however, among women whose dietary intake was low, the scientists found a 50 per cent reduction in breast cancer risk associated with the use of vitamin A supplements.
Willett, Walter C. Micronutrients and cancer risk. American Journal of Clinical Nutrition, Vol. 59 (suppl), May 1994, pp. 1162S-65S

Folic Acid and Depression and Alzheimer’s Disease

Folic acid and depression
LONDON, UNITED KINGDOM. Dr. E.H. Reynolds, a consulting neurologist at King’s College, has produced a comprehensive review of the association between folic acid and neuropsychiatric disorders such as depression and dementia. Dr. Reynolds points out that a folate deficiency is quite common, especially in older people. Severe folate deficiency is associated with megaloblastic anemia and it is estimated that some two thirds of patients with megaloblastic anemia also have a neuropsychiatric disorder. In elderly people a close association has been noted between a folate deficiency and apathy, depression, dementia, withdrawal, and a lack of motivation. In a study of 164 Alzheimer’s patients cognitive decline was significantly associated with raised plasma homocysteine levels and lowered folic acid and vitamin B12 levels. Significant improvements were noted in 24 folate-deficient, depressed persons who were given 15 mg/day of folic acid for a four-month period. Other studies have shown that supplementation with as little as 0.5 mg/day of folic acid increases the effectiveness of fluoxetine (Prozac). Dr. Reynolds points out that folic acid can excite the nervous system so should be used with caution in epileptics. It should also be used with caution if a vitamin-B12 deficiency is suspected.
Reynolds, E.H. Folic acid, ageing, depression, and dementia. British Medical Journal, Vol. 324, June 22, 2002, pp. 1512-15

Is Alzheimer’s disease preventable?
BOSTON, MASSACHUSETTS. A high blood level of the sulfur-containing amino acid homocysteine is a potent risk factor for both stroke and cardiovascular disease. It has been estimated that exceeding normal levels (5-15 micromol/L) by as little as 5 micromol/L increases the risk of coronary artery disease by 60 per cent in men and 80 per cent in women.
Researchers at the Boston University School of Medicine now provide convincing evidence that high homocysteine levels are an equally potent risk factor for Alzheimer’s disease. Their study involved 1092 men and women with an average age of 76 years who were deemed to be free of dementia when examined (as part of the Framingham Study) between 1986 and 1990. After an average eight years of follow-up 111 of the study participants had developed dementia of which 83 were given a diagnosis of Alzheimer’s disease. The researchers found that people with a blood plasma homocysteine level above 14 micromol/L had nearly twice the risk of developing Alzheimer’s disease as did people with lower levels. They also determined that a 5 micromol/L increase in homocysteine level corresponds to a 40 per cent increased risk of Alzheimer’s disease.
Dr. Joseph Loscalzo, MD, in commenting on the findings, suggests that it may be possible to substantially reduce one’s risk of Alzheimer’s disease by supplementing with folic acid, vitamin-B6 and vitamin-B12. Such supplementation has, in numerous clinical trials, been found highly effective in lowering homocysteine levels.
Seshadri, Sudha, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. New England Journal of Medicine, Vol. 346, February 14, 2002, pp. 476-83 [56 references]
Loscalzo, Joseph. Homocysteine and dementias. New England Journal of Medicine, Vol. 346, February 14, 2002, pp. 466-68 (perspective)

Vitamin deficiency implicated in Alzheimer’s disease
STOCKHOLM, SWEDEN. Some studies have found a correlation between low vitamin B12 levels and the development of Alzheimer’s disease (AD) and dementia; other studies have found no such correlation. Researchers at the Karolinska Institute now provide convincing evidence that a deficiency of either vitamin B12 or folic acid (folate) is associated with an increased risk of AD and dementia.
Their study involved 370 non-demented people aged 75 years and older who were not supplementing with vitamin B12 or folate. The participants were tested at baseline to determine mental status and had blood samples drawn for analysis of vitamin-B12 and folate levels. Only subjects who showed no signs of dementia were included in the follow-up group. Three years later 77 of the participants had developed dementia; of these 59 were diagnosed with AD. Compared with participants with normal levels of vitamin B12 and folate the participants with low levels of at least one of the vitamins had a 2.3 times higher risk of AD and a 1.7 times risk of any kind of dementia. These risk estimates were obtained after adjusting for other risk factors such as age, sex, and educational attainment.
The researchers speculate that homocysteine, a known neurotoxin, may be involved in the development of AD and that vitamin B12 and folic acid help prevent this effect by reducing homocysteine levels in the body.
Wang, H-X, et al. Vitamin B12 and folate in relation to the development of Alzheimer’s disease. Neurology, Vol. 56, No. 9, May 8, 2001, pp. 1188-94

Folate deficiency linked to Alzheimer's disease
LEXINGTON, KENTUCKY. Studies have shown that low concentrations of folic acid (folates) in the blood are associated with an increased risk of dementia and Alzheimer's disease (AD). Researchers at the University of Kentucky now report that low folate levels are directly associated with a high degree of atrophy of the cerebral cortex. Their study involved 30 nuns who had blood samples drawn and analyzed prior to their death between the ages of 78 and 101 years. Autopsies of the brains showed a clear negative association between folate levels and atrophy of the neocortex and this association was especially strong among the nuns who had been diagnosed with Alzheimer's disease. The average folate level in the nuns with significant AD was 45 nmol/L as compared to 61 nmol/L in the nuns without significant AD. It is interesting that the average blood levels of folate was 104 nmol/L in the nuns taking multivitamin pills as compared to only 36 nmol/L in those not taking supplements.

The researchers also found that the nuns with moderate to severe atherosclerosis in the arteries supplying the brain had an average blood folate level of only 34 nmol/L while those with minimal atherosclerosis had a level of 75 nmol/L. They conclude that a folate deficiency is associated with increased atrophy of the neocortex, particularly in patients with Alzheimer's disease.
Snowdon, David A., et al. Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun Study. American Journal of Clinical Nutrition, Vol. 71, April 2000, pp. 993-98
Weir, Donald G. and Molloy, Anne M. Microvascular disease and dementia in the elderly: are they related to hyperhomocysteinemia? American Journal of Clinical Nutrition, Vol. 71, April 2000, pp. 859-60 (editorial)

Alzheimer's disease and folic acid
OXFORD, UNITED KINGDOM. An inadequate intake of folic acid is firmly associated with an increased risk of vascular disease and, among women of childbearing age, with a significantly heightened risk of giving birth to a baby with neural tube defects. Now a team of researchers from the universities of Oxford and Bergen (Norway) report that low folate levels are associated with an increased risk of developing Alzheimer's disease (AD). Their study which spanned the period 1988 to 1996 involved 164 patients with a clinical diagnosis of AD and 108 control subjects. The AD diagnosis was confirmed by autopsy in 76 of the 164 patients who died during the study. The researchers found that AD patients had significantly lower blood levels of folic acid and vitamin B12 (cobalamin) than did controls. They also had significantly higher levels of the amino acid homocysteine. Homocysteine is a strong risk factor for vascular disease and its level has been found to be inversely proportional to the level of folic acid in the blood. Study participants with homocysteine concentrations equal to or higher than 14 micromol/liter were found to have a 4.5 fold higher risk of AD than did participants with a homocysteine level at or below 11 micromol/liter. This association held true even when corrected for age, sex, social class, cigarette smoking, and level of apolipoprotein E epsilon 4 (a known risk factor for the development of AD). Study participants with folate levels in the lower third of the overall distribution had a 3.3 fold higher risk of AD when compared to subjects in the upper third. Similarly, participants in the lower third of vitamin B12 levels had a 4.3 times higher risk of AD as compared to subjects in the upper third. The researchers also observed that disease progression was more rapid among AD patients with high initial homocysteine levels. They conclude that high homocysteine levels are an important risk factor for AD and that this risk can be significantly reduced by ensuring an adequate intake of folic acid and vitamin B12. They suggest that daily supplementation with 0.5 to 5 mg of folic acid and 0.5 mg of vitamin B12 (cyanocobalamin) will lower the typical homocysteine levels found in Western populations by about a third. NOTE: This study was partially funded by Bristol-Myers Squibb.
Clarke, Robert, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Archives of Neurology, Vol. 55, November 1998, pp. 1449-55
Diaz-Arrastia, Ramon. Hyperhomocysteinemia - A new risk factor for Alzheimer disease? Archives of Neurology, Vol. 55, November 1998, pp. 1407-08 (editorial)

Folate deficiency linked to depression
BOSTON, MASSACHUSETTS. A low or deficient blood level of folate (folic acid) has been detected in 15 to 38 per cent of adults suffering from depression. There is now increasing evidence that supplementation with therapeutic amounts of folate can significantly improve the condition of depressed patients. In a recent trial involving 20 elderly patients with depressive disorders, treatment with 50 mg/day of methylfolate was associated with an 81 per cent response rate within six weeks. Folate supplementation (15 mg/day of methylfolate) has also been found to markedly improve the effect of treatment with standard antidepressants. Researchers at the Harvard Medical School point out that many drugs, some chronic diseases (eg. rheumatoid arthritis), certain cancer treatments, alcoholism, and a poor diet can all lead to a folate deficiency and the potential for depression. They conclude that folate supplementation may play a useful role in the treatment of depression, but caution that the daily dosage required has to be carefully determined as too high a dose may cause sleeping problems, irritability, and hyperactivity.
Alpert, Jonathan E. and Fava, Maurizio. Nutrition and depression: the role of folate. Nutrition Reviews, Vol. 55, May 1997, pp. 145-49

Folic Acid and Other Disorders

Folic acid and multiple births.
Folic acid supplementation in women of childbearing age is becoming increasingly popular as an effective means of preventing neural tube defects in their offspring. At least three studies have indicated the possibility that supplementation may be associated with an increased incidence of multiple births (twins or triplets). A major study in China questions this association. Over 242,000 women were randomized to receive a placebo or 400 mcg/day of folic acid prior to conception and during pregnancy. The Chinese researchers found no difference in the number of multiple births between the two groups, but actually noted a lower incidence of multiple births in women who took folic acid (0.59%) than in women who did not (0.65%).
The Lancet, Vol. 361, February 1, 2003, pp. 380-84

Fathers-to-be need folic acid too
An increasing number of couples have difficulty conceiving a child. A major reason for this is the declining sperm quality in men. Dutch researchers have just discovered that supplementing with a combination of folic acid and zinc can increase the sperm count in infertile men by as much as 74 per cent. “An importance advance”, says Dr. Bruce Ames of the University of California who last year found not only that a folic acid deficiency is associated with low sperm count and quality, but that a lack of vitamin-C, especially in smokers, can lead to a poor sperm as well. Folic acid supplementation has also been found to reduce homocysteine levels and thus help prevent stroke and heart attack. There is also evidence that folic acid reduces the risk of Alzheimer’s disease and colon cancer.
New Scientist, March 23, 2002, p. 11

Folic acid helps prevent pneumonia
SENDAI, JAPAN. Older people often have difficulty swallowing and this problem in turn may lead to the development of aspiration pneumonia. Researchers at the Tohoku University School of Medicine now report that supplementation with folic acid is highly effective in preventing pneumonia. Their clinical trial involved 15 institutionalized patients who had been diagnosed with aspiration pneumonia on at least two separate occasions during the preceding two years. The patients, with an average age of 71 years, were matched with a control group of 12 healthy 72- years-olds with no history of pneumonia.
The researchers measured baseline levels of folic acid, vitamin-B12, vitamin-B6, and homocysteine in the two groups. Thirteen of the 15 in the pneumonia group were found to be deficient in folic acid (average plasma level of 2.4 ng/mL versus 8.3 ng/mL in the controls). The patients also had excessively high homocysteine levels (18.2 micromol/L versus 6.4 micromol/L for the controls). There were no significant differences in vitamin B6 or vitamin B12 levels. However, the patients took significantly longer to swallow – average of 6 seconds versus 1.8 seconds for the controls.
The patients then received a 5-mg folic acid tablet twice a day for eight weeks. At the end of this period their homocysteine and folate (folic acid) levels were normal and their swallowing reflex had improved to 1.7 seconds (equivalent to the controls). The supplementation was continued for two years during which time not a single case of pneumonia was observed. The researchers conclude that folic acid supplementation may prevent the incidence of pneumonia and improve swallowing function in older people.
Sato, Emi, et al. Folate deficiency and risk of pneumonia in older people. Journal of the American Geriatrics Society, Vol. 49, December 2001, pp. 1739-40 (letter to the editor)

Crohn’s disease patients need folic acid
TEL-HASHOMER, ISRAEL. People with inflammatory bowel disease (Crohn’s disease and ulcerative colitis) tend to be at greater risk for thromboembolic events (blood clots) such as stroke and peripheral venous thrombosis. Researchers at the Chaim Sheba Medical Center believe they may have found the reason for this. They studied 105 men and women with active Crohn’s disease and compared their blood levels of homocysteine (a known risk factor for blood clots), folic acid and vitamin B12 to the levels found in 105 healthy controls. They found that homocysteine levels were significantly higher in patients with mild to moderately active Crohn’s disease and that folic acid and vitamin B12 levels were significantly lower. The average level of folic acid was 5.9 pg/mL (normal range is 5 to 17 pg/mL). The researchers point out that it is well established that increased folate levels correspond to lower homocysteine levels. They conclude that patients with Crohn’s disease may benefit from supplementing with folic acid.
Chowers, Yehuda, et al. Increased levels of homocysteine in patients with Crohn’s disease are related to folate levels. American Journal of Gastroenterology, Vol. 95, December 2000, pp. 3498-3502

Supplement recommendations for chronic fatigue syndrome
BERKELEY, CALIFORNIA. Dr. Melvyn Werbach, MD of the UCLA School of Medicine has just published a thorough review of nutritional deficiencies involved in chronic fatigue syndrome (CFS). These include deficiencies in vitamin C, coenzyme Q10, magnesium, zinc, sodium, l-tryptophan, l- carnitine, essential fatty acids, and various B vitamins. He points out that there is some evidence that the deficiencies are caused by the disease itself rather than by an inadequate diet. He suggests that the deficiencies not only contribute to the symptoms of CFS but also impair the healing process. Although the results of supplementation trials involving CFS patients have been inconclusive so far Dr. Werbach nevertheless recommends that CFS patients be given large doses of certain supplements for at least a trial period to see if their symptoms improve. His recommendations are:

• Folic acid: 1-10 mg/day for 3 months
• Vitamin B12: 6-70 mg (intramuscular injection) per week for 3 weeks
• Vitamin C: 10-15 grams/day
• Magnesium: 600 mg/day + 2400 mg/day of malic acid for 8 weeks
• Zinc: 135 mg/day for 15 days
• 5-hydroxytryptophan: 100 mg three times daily for 3 months (if fibromyalgia is present)
• L-carnitine: 1-2 grams three times daily for 3 months
• Coenzyme Q10: 100 mg/day for 3 months
• Essential fatty acids: 280 mg GLA and 135 mg EPA daily for 3 months

The supplements should be administered with medical supervision and accompanied by a high- potency vitamin/mineral supplement for the duration of the trial. [95 references]
Werbach, Melvyn R. Nutritional strategies for treating chronic fatigue syndrome. Alternative Medicine Review, Vol. 5, No. 2 April 2000, pp. 93-108

Parkinson's patients on l-dopa need folic acid
BOCHUM, GERMANY. People suffering from Parkinson's disease have an increased risk of heart attacks and strokes. A team of German and Swiss medical researchers believe they have uncovered the reason for this and propose a simple solution to the problem. The researchers studied a group of 48- to 73-year-old people. Fifteen of them had Parkinson's disease and were treated with levodopa plus decarboxylase inhibitor (Sinemet), 15 had Parkinson's disease, but were not treated as yet, and 15 were healthy controls. All study participants had their homocysteine levels measured after a 10-hour fast. The drug-treated Parkinson's patients had an average level of 17.3 micromol/L as compared to 9.1 micromol/L in the untreated group, and 9.2 micromol/L in the group of healthy controls. Other research has found that men with a level of 15 micromol/L increase their risk of coronary heart disease by 60 per cent while women increase it by 80 per cent. The risk of a stroke at the 15 micromol/L is two to five times higher than at the 10 micromol/L level in both men and women and the risk of peripheral vascular disease (eg. intermittent claudication) is seven times higher among people with elevated levels. The researchers believe that prolonged treatment with levodopa and decarboxylase inhibitor increases the blood level of homocysteine resulting in a greater risk for heart disease and stroke. They point out that elevated homocysteine levels can be lowered easily and effectively by supplementation with folic acid (400-800 micrograms per day or more depending on homocysteine level). The research team concludes that Parkinson's patients who are treated with levopoda should have their homocysteine levels monitored on a regular basis and should supplement with folic acid as required. (Editor's Note: Folic acid is non-toxic and no cases of overdosing have ever been reported. In these times of tight medical resources it would seem reasonable to suggest that Parkinson's patients on levopoda routinely supplement with 400-800 micrograms per day - unless, of course, their physician has specific objections to this).
Muller, Thomas, et al. Nigral endothelial dysfunction, homocysteine, and Parkinson's disease. The Lancet, Vol. 354, July 10, 1999, pp. 126-27 (research letter)

Folic acid deficiency implicated in hearing loss
ATHENS, GEORGIA. Hearing loss is the most common impairment among the elderly after heart problems, hypertension, and arthritis and affects more than 28 million Americans. Researchers from the Centers for Disease Control and Prevention and the University of Georgia believe that age-related hearing loss may be partially caused by vitamin deficiencies. They have just released a report which supports this hypothesis. Their study involved 55 healthy women between the ages of 60 and 71 years. The women were all given a hearing test using a diagnostic audiometer according to Standard S3.6 of the American National Standards Institute and also had fasting blood samples taken. The blood samples were analyzed for serum vitamin B12, serum folate, and folate levels in the red blood cells. The researchers discovered that women with impaired hearing (less than 20 dB hearing level) had a 38 per cent lower serum level of vitamin B12, a 31 per cent lower folate level in the red blood cells, and a 25 per cent lower folate level in the blood serum. They speculate that poor folate and vitamin B12 status may somehow lead to deterioration of the nerves and blood vessels supplying the auditory system perhaps through a mechanism involving homocysteine.
Houston, Denise K., et al. Age-related hearing loss, vitamin B-12, and folate in elderly women. American Journal of Clinical Nutrition, Vol. 69, March 1999, pp. 564-71

Folic acid important for kidney patients
CLEVELAND, OHIO. Patients with end-stage renal disease often die from a heart attack or other cardiovascular complications. Researchers at the Cleveland Clinic Foundation now provide compelling evidence that this increased risk of cardiovascular disease among kidney patients is, to a large extent, due to the fact that they tend to have high blood concentrations of homocysteine (an amino acid formed in the metabolism of methionine). The study involved 176 dialysis patients with end-stage renal disease. The researchers found that the kidney patients had much higher homocysteine concentrations in their blood than does the normal population (26.6 versus 10.1 micromol/liter). They also discovered that kidney patients who had a homocysteine level above 27.8 micromol/liter were three times more likely to suffer a cardiovascular event than were kidney patients with lower concentrations. Not surprisingly, the researchers also found that kidney patients who suffered cardiovascular events had lower levels of folate, vitamin B-12, and vitamin B-6 (pyridoxine) than did kidney patients who did not suffer such events. The researchers conclude that kidney patients may need more vitamin B-6 supplementation than previously thought. They also suggest that supplementation with folic acid (15 mg/day or more) together with adequate doses of vitamins B-12 and B-6 may be effective in counteracting the increased risk of cardiovascular disease found among patients with end-stage renal disease.
Robinson, Killian, et al. Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations. Circulation, Vol. 94, No. 11, December 1, 1996, pp. 2743-48

Folic acid helps prevent cleft lip and palate
OAKLAND, CALIFORNIA. Researchers at the California Birth Defects Monitoring Program and the Oakland Children's Hospital report that mothers can decrease their risk of giving birth to a child with orofacial clefts (cleft lip or palate) by increasing their intake of folic acid prior to and immediately following conception. The investigation involved 731 mothers who had given birth to a child with an orofacial cleft and 734 mothers with a non-malformed child. The researchers found that mothers who had taken multivitamins containing folic acid (0.4-0.8 mg) during the period from one month before through two months after conception had a 25 to 50 per cent reduction in the risk of giving birth to a child with orofacial clefts. Earlier research has shown that a mother who has already given birth to one child with orofacial clefts can reduce her risk of having another child with orofacial clefts by a factor of six if she takes multivitamin pills and 10 mg/day of folic acid.
Shaw, Gary M., et al. Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. The Lancet, Vol. 346, August 12, 1995, pp. 393-96

Requirements and Supplementation

Grain fortification with vitamin B12?
DUBLIN, IRELAND. Since 1998 it has been mandatory to fortify grain-based foods with folic acid in the United States. Recent reports indicate that this measure has resulted in a 19 per cent decrease in the incidence of neural tube defects. A similar fortification program is being considered in the UK. Irish researchers now suggest that the fortification protocol should include not only folic acid, but also vitamin B12. They point out that folic acid supplementation also lowers the level of homocysteine, a potent risk factor for heart and vascular disease. However, a recent trial carried out by the Dublin researchers clearly showed that as blood levels of folic acid increased through supplementation, blood levels of vitamin-B12 became the limiting factor. In other words, additional folic acid as well as additional vitamin B12 is required in order to attain the maximum reduction in homocysteine levels. Four to five hundred micrograms per day of folic acid were found to increase folic acid levels by 80 to 180 per cent and lower homocysteine levels by about 30 per cent in both men and women. Both folate and homocysteine levels tended to revert to their pre-supplementation levels after 10 weeks of no supplementation; this shows that continuous supplementation is necessary in order to keep homocysteine levels under control.
Quinlivan, E.P., et al. Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. The Lancet, Vol. 359, January 19, 2002, pp. 227-28 (research letter)

Older people need folic acid
High blood levels of homocysteine are associated with an increased risk of cardiovascular disease, particularly among the elderly. Folic acid will lower homocysteine levels, but how much is needed? Scottish researchers conclude that a total intake of 926 micrograms/day is required to remove the homocysteine-related risk from 95 per cent of people between the ages of 65 and 75 years. It would be very difficult to obtain this amount from the diet so supplementation or fortification is required. NOTE: Folic acid supplements should always be taken in conjunction with vitamin-B12 and preferably vitamin-B6 as well.
Quarterly Journal of Medicine, Vol. 95, January 2002, pp. 27-35

Folic acid requirements defined
CHICHESTER, UNITED KINGDOM. The U.S. government has mandated the fortification of all cereal grains with 0.14 mg (140 micrograms) of folic acid per 100 grams of grain. The aim of this measure is to reduce the risk of women giving birth to babies with neural tube defects (spina bifida). The fortification would theoretically supplement a person’s diet with about 0.1 mg (100 micrograms) of folic acid per day.
Folic acid supplementation has also been found useful in lowering homocysteine levels and thereby reducing the incidence and mortality from ischemic heart disease (angina and heart attack). A dosage of 1 mg (1000 micrograms) per day has been found to result in about a 25 per cent decrease in homocysteine concentration; this is estimated to correspond to a 15 per cent reduction in mortality from ischemic heart disease. Higher dosages (up to 5 mg/day) have not been found to have any greater effect than the 1 mg/day dose. British researchers have now addressed the question of how much folic acid (in supplement form) is needed to achieve the maximum homocysteine reduction. Their clinical trial involved 151 patients with ischemic heart disease who were randomized to receive 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1 mg or a placebo daily for a three-month period. The participants’ blood levels of folate and homocysteine were measured before the start of supplementation, at the end of the supplementation period, and three months later. The maximum median reduction in homocysteine levels (23 per cent) was observed at a supplementation level of 0.8 mg/day. The currently recommended daily intake of 200-400 micrograms/day achieved only a 10 per cent reduction in homocysteine levels. Homocysteine levels returned to their pre-trial levels after three months without supplementation indicating that folic acid supplementation must be continuous and indefinite if homocysteine levels are to be kept in check. The researchers conclude “It would be reasonable for clinicians to consider advising patients with ischemic heart disease to take 0.8 mg (800 micrograms) of folic acid each day.”
Wald, David S., et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Archives of Internal Medicine, Vol. 161, March 12, 2001, pp. 695-700

New RDAs for folate
GAINESVILLE, FLORIDA. Folates occur naturally in foods such as spinach and broccoli. Folic acid is a synthetic form of folate used in supplements and fortified foods. A folate deficiency has been linked to neural tube defects, cardiovascular disease, and colon cancer. The Food and Nutrition Board of the US Academy of Sciences has recently updated the Recommended Dietary Allowances for folate. They are now 400 micrograms/day for adults, 600 micrograms/day for pregnant women, and 500 micrograms/day for lactating women. Folic acid has been found to be 1.7 times more bioavailable than folate from food so 100 micrograms of folic acid has the equivalent effect of 170 micrograms of food folate. The Tolerable Upper Intake Level for supplemental folic acid has been set at 1000 micrograms/day based on the observation that an intake of 5 mg or more per day may hide the progression of neurologic disorders in patients suffering from a deficiency of vitamin B12.
Bailey, Lynn B. Dietary reference intake for folate: the debut of dietary folate equivalents. Nutrition Reviews, Vol. 56, October 1998, pp. 294-99

Vitamin supplementation could save billions in health care costs
PARAMUS, NEW JERSEY. It is estimated that the treatment of preventable illnesses absorbs as much as 70 per cent of total health care costs in the United States. Researchers at the Roche Vitamins Laboratory have just published a study which clearly demonstrates that nearly $20 billion in hospital charges alone could be saved every year if all women of childbearing age were to supplement with zinc and folic acid and if all people over 50 years of age were to supplement with vitamin E. The researchers evaluated all reports available in the MEDLINE database dealing with the association between vitamin intake and the incidence of disease. There are more than 4600 babies born every year in the United States with neural tube defects. Research has shown that 70 per cent of these cases could be prevented if all women of childbearing age were to supplement with 0.4-0.8 mg of folic acid daily in addition to having a daily dietary intake of 0.15-0.2 mg folate. Cardiovascular birth defects and complications associated with low birth weight incur hospital charges of almost $6 billion/year. These conditions could be largely prevented if women of childbearing age supplemented with folic acid plus 15-20 mg of zinc per day. Vitamin E supplementation is an effective preventive measure against coronary heart disease and heart attacks. Several large-scale studies have shown that men and women who supplement with 100 IU/day of vitamin E for two or more years reduce their risk of fatal coronary disease and non-fatal heart attacks by 40 per cent. Another large study found that older people (mean age: 62 years) can reduce their risk of having a heart attack by over 75 per cent by supplementing with 400 IU/day or more of vitamin E for 1.4 years or more. The researchers point out that in addition to major health care cost savings other benefits of supplementation include better quality of life, longer life, and increased productivity. They also point out that the level of supplements required for effective disease protection cannot be obtained through even the most healthful diet. NOTE: This work was funded and performed by Hoffmann-LaRoche Inc., a major manufacturer of vitamins and pharmaceuticals.
Bendich, Adrianne, et al. Potential health economic benefits of vitamin supplementation. Western Journal of Medicine, Vol. 166, May 1997, pp. 306-12

Broccoli is not enough
COLERAINE, NORTHERN IRELAND. A team of researchers from the University of Ulster and Trinity College in Dublin report that eating folate-rich foods such as broccoli and spinach does not result in improved folate status. An adequate folate status is especially important in women of child-bearing age as low folate levels in the blood can lead to the birth of babies with neural tube defects. Recent research has also shown that an adequate folate status is crucial in the prevention of heart disease. The study involved 41 women aged 17 to 40 years. The women were randomly assigned to one of five groups. Group I was given 400 micrograms/day of a folic acid supplement, Group II received 400 micrograms/day of folate by eating folic-acid-fortified foods, Group III received 400 micrograms/day of folate through the consumption of folate-rich food, Group IV received dietary advice on how to increase their intake of folate from food, and Group V served as a control group. At the end of the three-month experiment only the women in Groups I and II showed a significant increase in the folate content of their red blood cells. The researchers conclude that it is misleading to advise women to rely on the consumption of folate- rich foods as a means of maintaining an adequate folate status. The only way an adequate status can be ensured is by taking supplements or by consuming foods fortified with folic acid.
Cuskelly, Geraldine J., et al. Effect of increasing dietary folate on red-cell folate: implications for prevention of neural tube defects. The Lancet, Vol. 347, March 9, 1996, pp. 657-59

Supplementation urged
BERKELEY, CALIFORNIA. It is becoming increasingly clear that fruits, vegetables, fiber, and antioxidant vitamins are potent protectors against many forms of cancer. Now folic acid has been added to the list. A recent study shows that increased dietary intake of folic acid significantly reduces the risk of developing adenomas (tumors) of the colon and rectum. Dr. Gladys Block of the University of California points out that only 9% of all Americans consume the recommended five or more servings a day of fruits and vegetables. She recommends that serious consideration be given to fortifying food and/or urging people to use antioxidant supplements so as to reduce the incidence of cancer.
Block, Gladys Micronutrients and cancer: time for action? Journal of the National Cancer Institute, Vol. 85, No. 11, June 2, 1993, pp. 846-47

Women urged to supplement with folic acid
ATLANTA, GEORGIA. The Public Health Service in the U.S.A. recently issued a statement urging women of child-bearing age to ensure that they consume 400 micrograms of folic acid a day. Folic acid is present in leafy dark vegetables and citrus fruits, but even a well balanced diet may not provide 400 micrograms per day; thus the need for supplementation. Recent studies in England and Hungary have shown that folic acid is important in preventing neural tube defects. Dr. Godfrey Oakley of the Centers for Disease Control estimates that 2,500 children are born with neural tube defects in the United States each year. He predicts that one half to three quarters of these cases can be prevented if women of child-bearing age ensure an adequate intake of folic acid at all times. NOTE: Neural tube defects usually occur before a woman realizes that she is pregnant.
Science, September 25, 1992, p. 1857

Vitamin C supplementation may increase vitamin E and folate stores in elderly people
BOSTON, MASSACHUSETTS. A study of the vitamin C status of 677 noninstitutionalized elderly people (age 60 to 98 years) was carried out in the Greater Boston area between August 1981 and December 1983. The study was based on detailed blood analyses and three-day food intake and nutrient supplement records. The study involved 235 males (82 of whom used vitamin C supplements) and 442 females (195 of whom used supplements). The average daily vitamin C intake from diet alone was 142 and 136 mg/day for males and females respectively. The mean daily supplement dose was 300 mg. The study found no significant correlation between plasma ascorbic acid (AA) level and age; however, there was a clear correlation between vitamin C intake and plasma AA level. None of the subjects taking supplements were found to be deficient in plasma AA levels; however, 6% of male non-users and 3% of female non-users were found to be marginally deficient. There was no significant correlation between vitamin B-6 status and plasma AA level nor was vitamin B-12 status affected. The study supports the hypothesis that vitamin C spares vitamin E in elderly people. Neither copper nor iron absorption seemed to be affected by plasma AA levels. However, the folate status was substantially better (by 25%) in supplement users as compared to non-users.
Jacob, Robert A. Vitamin C status and nutrient interactions in a healthy elderly population. American Journal of Clinical Nutrition, Vol. 48, No. 6, December 1988, pp. 1436-42