Four B-vitamins are considered here in one monograph because of their related benefits as dietary supplement for promoting cardiovascular health – folic acid, vitamin B6 and vitamin B12 for their effects in reducing homocysteine levels, and niacin for reducing cholesterol levels.
Vitamin B6 (Pyridoxine) is a water-soluble vitamin. It is also known by the names pyridoxine, pyridoxamine, and pyridoxal. Vitamin B6 performs functions as a cofactor for about 70 different enzyme systems – most of which have something to do with amino acid and protein metabolism. Because vitamin B6 is also involved in the synthesis of neurotransmitters in the brain and nerve cells, it is frequently recommended as a nutrient to support mental function (mood) and nerve conduction. Some athletic supplements include vitamin B6 because of its role in the conversion of glycogen to glucose for energy in muscle tissue. Perhaps the best data supporting the value of B6 supplements is in the area of heart health via reduced homocysteine levels. Food sources include poultry, fish, whole grains and bananas.
Vitamin B12 (Cobalamin) is a water-soluble B vitamin. B12 is also known as cobalamin because it contains cobalt. The form of B12 most commonly used in dietary supplements is called cyanocobalamin. B12 is only produced by bacteria, so it is only found in food products of animal origin and in some fermented vegetable products such as tempeh and miso (fermented soybeans). B12 functions in a wide variety of metabolic processes, many of which are involved in transferring methyl groups between amino acids. B12 works closely with another B vitamin, folic acid, in reactions involved with DNA synthesis, blood cell formation, nervous system maintenance and heart health. B12 is also involved in the metabolism of proteins, fats, and carbohydrates, as it is needed to produce succinyl CoA, an intermediary in the Krebs cycle that generates ATP for cellular energy. Like B6, vitamin B12 has been shown to reduce elevated homocysteine levels and thus can be considered a valuable supplement for promoting heart health.
Folic acid is a B vitamin that plays an important role DNA and RNA synthesis, production of red blood cells and maintenance of the nervous system. Fruits and vegtables are the best dietary source (folic acid derives its name from “foliage”), especially for dark leafy greens, oranges and orange juice, beans and peas. Folic acid is known to reduce the risk of neural tube defects in developing fetuses and the FDA requires folate-enrichment of refined cereal grains to increase the population intake of folic acid for this purpose. At these fortification levels of folic acid intake, homocysteine is partially normalized, but further increases in dietary intake, wheteher form foods or supplements provides an additional significant reduction in homocysteine levels.
Niacin is a water-soluble B vitamin – and the common name for two very different compounds: nicotinic acid and niacinamide. Like all B-vitamins, niacin plays a role in many aspects of energy metabolism and nervous system function. One of the most common uses for supplemental niacin is cholesterol regulation (used at very high doses – see below). Rich dietary sources of niacin include many high-protein foods such as meat, chicken, tuna and other fatty fish, peanuts, pork and milk. The nicotinic acid form of niacin is effective, when used at high levels, for reducing cholesterol and triglyceride levels as well as enhancing circulation.
The dosage levels that have been associated with cardioprotective effects (reduced homocysteine and cholesterol levels) of these B-vitamins generally fall within the ranges of 2-12.5mg/day for B6, 50-800mcg/day for B12, 400-1000mcg/day for folate (though much higher milligram levels are also effective) for control of homocysteine levels, and 250-2000mg/day of niacin (a very high level that should be monitored by a physician) for cholesterol and triglyceride reduction.
Vitamins B6 and B12 are found in high concentrations inmost protein-rich foods. Because folic acid is destroyed during cooking, levels are typically highest in raw or lightly steamed vegetables. The chemical form of folic acid found in foods, mono-glutamic acid (conjugated), however, is less well absorbed (40-60% less) compared to the synthetic form, poly-glutamic acid (unconjugated), found in dietary supplements. This suggests that supplemental forms of folic acid may even be warranted in high risk individuals in addition to a well-balanced intake of fruits and vegetables.
Like the other B-vitamins covered here, niacin is very inexpensive – so its effectiveness in reducing cholesterol levels may be an affordable solution to reducing a known risk factor for cardiovascular disease. When monitored properly, niacin therapy can be almost as effective as the popular (and expensive) “statin” drugs for lowering cholesterol and triglyceride levels. It is important to note that, despite the fact that niacin is a B-vitamin, such high-dose niacin therapy should really be considered “drug” therapy and not “nutritional” therapy.
Although various “structure/function” rationales could be assigned to the value of supplementation with B6/B12/Folate, the clearest and most dramatic effects of these nutrients is in the area of reducing hyperhomocysteinemia (and niacin in reducing hypercholesterolemia) for prevention of heart disease. As such, although some of these related “structure/function” claims will be mentioned, the focus of this summary will be confined to the strongest data set – that being reduction of heart disease risk.
Vitamin B6, like most of the B-vitamins, is involved as a cofactor in a wide variety of enzyme systems. As such, "structure/function" claims can be made for virtually any health condition. For example, because B6 is needed in the conversion of the amino acid tryptophan into niacin, a common B6 claim relates to “healthy cholesterol levels” (because niacin can help lower cholesterol in some people). Because B6 also plays a role in prostaglandin synthesis, claims are often made for B6 in regulating blood pressure, heart function and pain levels (each of which is partially regulated by prostaglandins). Vitamin B6 needs are increased in those individuals consuming a high protein diet as well as in women taking oral contraceptives. Vitamin B6 supplements (in conjunction with folic acid) have been shown to have a significant effect in reducing plasma levels of homocysteine (an amino acid metabolite linked to increased risk of atherosclerosis) – see further discussion below.
Vitamin B6 is often recommended as a treatment for carpal tunnel syndrome (CTS). In the vast majority of cases, CTS is caused by repetitive hand/wrist motions (such as typing), which causes inflammation and nerve compression in a region of the wrist known as the carpal tunnel. CTS is also known to occur in some women during pregnancy, in which case the nerve compression may be related to water retention and swelling, rather than to repetitive motion. B6 is the most frequently recommended dietary supplement in cases of CTS (traditional treatments often include rest, splints, anti-inflammatory medications and surgery). In some cases of CTS, approximately 100-300 mg of vitamin B6 in divided doses has been shown to alleviate symptoms – although these results are not consistent and several studies have found no benefit of vitamin B6 in treating CTS.
Vitamin B12 is an essential cofactor for methylation reactions (including homocysteine metabolism) in the body (many in conjunction with folic acid) – so B12 have involvement in metabolic pathways related to brain function, joint health, and cardiovascular function. Absorption of B12 begins in the stomach, where it must combine with Intrinsic Factor, a compound synthesized by the stomach and required for proper absorption of B12 in the small intestine. An inadequate production of intrinsic factor and hydrochloric acid in the elderly is a common cause of vitamin B12 deficiency. Because B12 is stored in the liver, the symptoms of deficiency develop very slowly, typically not showing up for 5-10 years. Strict vegetarians (vegans), who consume only plant foods, are at the highest risk for developing B12 deficiency and should consider supplements. Elevated plasma homocysteine concentrations are considered to be a risk factor for vascular disease and birth defects such as neural tube defects. Recent studies have shown that plasma homocysteine can be lowered by folic acid (400-800mcg) combined with vitamin B12 (6mcg). The combination of B12 with folic acid is significantly more effective in reducing homocysteine levels than is folic acid alone.
Because folic acid has functions in DNA synthesis and nervous system maintenance, it has been linked to growth and development of the fetus during pregnancy. Clinical evidence clearly shows a beneficial effect of adequate folic acid intake in reducing the risk of brain and spinal cord birth defects. Due to its role in red blood cell formation, homocysteine metabolism and the fact that deficiency of folic acid results in megaloblastic anemia, supplemental levels are often associated with maintenance of energy levels and heart health.
It is abundantly clear that an adequate intake of folic acid is essential during pregnancy. Overwhelming evidence is available to show that women given folic acid supplements during pregnancy have a lower incidence of delivering babies with neural tube birth defects such as spina bifida. Oral contraceptives have been associated with lower folate levels in women who conceived soon after they stop taking the pill. In some cases, former contraceptive users and women who have previously delivered babies with neural tube defects may especially benefit from supplemental levels of folic acid in their diets.
The U.S. Department of Health recommends that pregnant women (and those trying to conceive) should take a daily folic acid supplement of 400mcg (0.4mg). The U.S. Public Health Service recommends that all women of childbearing age consume the same amount of folic acid each day to decrease the risk of having a pregnancy affected by a neural tube defect. Three strategies are available to women to achieve this goal: eat more foods with naturally occurring folic acid (fruits/veggies); eat foods fortified with folic acid (such as breakfast cereals); or use dietary supplements.
Despite the wide-ranging public health benefits of adequate folic acid intake and the widespread public awareness of these benefits, as many as 68-87% of American women of childbearing age still have folic acid intakes below the recommended 400 micrograms per day. Elderly populations are also thought to be at increased risk for folate deficiencies – which may exacerbate their already high risk of heart disease, cancer and neurological impairments. Several recent studies have suggested that folate supplementation should be considered in elderly people, especially those with elevated plasma total homocysteine levels and cardiovascular disease, as well as in those individuals who experience neuropsychiatric disorders. Because of the possibility for high dose folate supplements to mask the symptoms of vitamin B12 (cyanocobalamin) deficiencies (which are also common in the elderly), folic acid supplements should be given in conjunction with B12.
Because niacin is involved in the proper functioning of more than 200 metabolic enzymes, it plays a role in a wide range of bodily processes, including synthesis of hormones and blood cells and the release of energy from fats, carbohydrates and proteins. As a nutrient (vitamin B3) consumed at low doses (20-40mg), there is virtually no difference in overall metabolism between the different chemical forms of niacin. In the mid-1950s, however, it was shown that high doses of niacin (as nicotinic acid) could lower cholesterol levels (although the exact mechanism of action is still not known). The other form of niacin (nicotinamide or niacinamide) does not provide a cholesterol-lowering effect.
Niacin has been studied for its cardiovascular benefits in numerous clinical trials. The primary cardiovascular measures such as cholesterol and triglyceride levels, heart attacks and strokes are all significantly reduced with niacin therapy (sometimes used alone and sometimes used along with other drug therapy). Overall, the use of niacin (nicotinic acid, but not niacinamide) to prevent or treat elevated blood lipids and reduce cardiovascular disease risk is well substantiated (O-Connor et al. 1997). In a large number of clinical trials, nicotinic acid has been shown to consistently lower total and LDL cholesterol by about 15-20% and triglycerides by 10-25%, while increasing levels of HDL cholesterol by 15-25% (O’Connor et al. 1997). The downside is that the amount of niacin needed to lower cholesterol levels also tends to result in “niacin intolerance” in 15-40% of people who try it and the unpleasant side effect of “skin-flushing” (similar to hot flashes) as well as the serious risk of liver damage (see Safety considerations below). Niacin supplements are available in regular and “slow-release” forms. The slow-release forms of nicotinic acid, are intended for prolonged release of niacin during its 6-8 hour transit time in the intestines, but they are also associated with greater toxicity and safe doses are only about half of normal-release forms of niacin (Capuzzi et al. 1998, Guyton et al. 2000, Morgan et al. 1998).
Folate, B6, & B12 are often used in combination therapy to reduce serum levels of homocysteine (an amino acid produced during methionine metabolism). Plasma levels of homocysteine have been recognized in dozens of studies as an important cardiovascular risk factor that predicts adverse cardiac events in patients with established coronary atherosclerosis (Righetti et al. 2003) and influences restenosis rate after percutaneous coronary intervention (Schnyder et al. 2002). A 5-micromol/L increase in total homocysteine level is associated with an approximately 70% increase in relative risk of cardiovascular disease in adults (Chait et al. 1999). When folic acid is supplemented alone at 5-15mg/day for 1 year, there is no difference in degree of homocysteine reduction at different levels of folic acid within this range (Righetti et al. 2003), and much lower levels of folic acid (100-600mcg/day for 4 weeks) have resulted in significant reductions in plasma total homocysteine (tHcy) levels in a number of studies (Brouwer et al. 1999, Riddell et al. 2000, Silaste et al. 2003, Venn et al. 2002). Even in the face of folate enrichment of cereal grain products (at 140mcg/100g flour), which would be expected to increase the baseline folic acid intake of the population, dietary supplementation with additional folate (2.5g/day) for 12 weeks has been shown to further increase folic acid status and reduce tHyc levels in CAD patients (Bostom et al. 2002). Even at much lower levels of folic acid supplementation (400mcg/day) when combined with B12 (500mcg/day) and B6 (12.5mg/day) for 3 months, homocysteine levels are reduced by 15% in patients with documented CAD (Lobo et al. 1999). In one study by Malinow and colleagues (1998), 75 men and women with CAD were studied to determine the effect of folate-fortified foods on plasma homocysteine levels. Results showed that cereal fortified with 127mcg folate daily (approximately the level resulting from the FDA’s policy on enrichment of cereal grains) increased plasma folic acid by 31%, but reduced homocysteine by less then 4%. Cereals providing folic acid at 499mcg and 665mcg daily increased plsam folic acid levels by 65% and 106%, respectively and decreased plasma tHyc by 11% and 14%, respectively (Malinow et al. 1998) – suggesting that higher levels of folic acid fortification than currently recommended by the FDA may be needed to control homocysteine level. A similar study by Riddell and colleagues (2000) used fortified breakfast cereal or folic acid supplements to bring total daily folic acid intake to 600mcg/day – finding a 21-24% drop in tHyc that was negatively correlated to serum folate values. The increase in serum folate levels and thus in reductions in tHyc tend to be more dramatic for supplements and fortified foods and more modest for non-enriched folate-containing foods (Riddell et al. 2000, Venn et al. 2002), but dietary interventions to encourage higher intake of folate-rich foods is effective in increasing serum folate by approximately 11-14% and reducing tHyc levels by approximately 10-13% within 5-10 weeks (Chait et al. 1999, Silaste et al. 2003).
Like folic acid, vitamin B12 is an essential cofactor in methionine metabolism and an important coenzyme in various methylation reactions. In folate- and B12-replete subjects, vitamin B6 supplementation (pyridoxine at 1.6mg/day for 12 weeks) has been shown to further reduce plasma tHyc levels by an additional 7.5% (McKinley et al. 2001) and should thus be included in a cocktail of vitamins for reducing elevated plasma homocysteine levels.
Studies of various combinations of Folate, B6 and B12 (FA/B6/B12) therapy for reducing plasma tHyc levels have been nearly unanimous in their support in significantly reducing elevated homocysteine levels while other aspects of cardiovascular risk largely remain unchanged (Hirsch et al. 2002). In patients with established CAD, FA/B6/B12 therapy for 6 months has been shown to significantly reduce homocysteine, as well as reduce the incidence of fatal and non-fatal myocardial infarctions (Schnyder et al. 2002).
Lipid lowering therapy with fibrates is known to increase homocysteine levels by up to 40% (Dierkes et al. 2001) – an effect which could counteract the cardioprotective effect of lipid lowering. By combining fenofibrate treatment with daily folic acid (650mcg), B12 (50mcg), and B6 (5mg) for 6 weeks, the increase in homocysteine levels were cut by nearly half, from +47% with no vitamins to only 25% increase with vitamin supplementation (Dierkes et al. 2001). In most hemodialysis patients and patients with end-stage renal disease, levels of B-vitamins are depleted and homocysteine levels are elevated (Dierkes et al. 2001, Henning et al. 2001, Tremblay et al. 2000). In these patients, supplementation with folate, B6, B12 via either an oral or intravenous route is effective in improving B-vitamin status and resulting in a corresponding 30-50% reduction in hyperhomocysteinemia within a period of 4 weeks to 6 months (Dierkes et al. 2001, Henning et al. 2001, Tremblay et al. 2000). Metformin therapy in diabetic patients is also known to reduce serum levels of vitamin B12 and folic acid by 8-17% and increase tHyc levels by nearly 15% (Carlsen et al. 1997), suggesting that homocysteine-lowering therapy with B-vitamin supplements may be beneficial in some diabetic patients.
Safety / Dosage
As water-soluble vitamins, all fo the B-vitamins are generally considered quite safe as dietary supplements. For B6, excessive intakes (2-6 grams acutely or 500mg chronically) are associated with sensory neuropathy (loss of feeling in the extremities) – which may or may not be reversible. The RDA for vitamin B6 is less than 2 milligrams per day – an amount contained in virtually all multi-vitamin supplements. Pregnant and lactating women should not take more than 100mg of vitamin B6 per day.
There are no confirmed reports of toxic side effects associated with vitamin B12 supplements – even at the very high injected doses commonly used to restore cognitive function in elderly subjects suffering from B12 deficiency. Oral intakes as high as 3000mcg are considered non-toxic. The Daily Value for vitamin B12 is 6mcg with a lower RDA set at 2.4mcg.
Extremely high intakes of folic acid (1-5mg/day) have been associated with masking the signs and symptoms of pernicious anemia (vitamin B12 deficiency) and should be avoided. The Daily Value (and RDA) for folic acid is 400 micrograms – an amount that ALL women of childbearing age should consume each day. Like the other B vitamins, dietary needs may be somewhat elevated during times of stress and during pregnancy and lactation. In the elderly, a daily folate supplement of 500mcg may be warranted – although it should not replace the need for a diet rich in fruit and vegetables.
Although the Daily Value for niacin is only 20mg (see RDAs below) and the body can convert the amino acid tryptophan into niacin, a “cholesterol-lowering” dose of niacin (as nicotinic acid, NOT niacinamide or nicotinamide) is typically in the range of 250-2000mg/day. Dosing is usually started at the low-end (250mg/day) with increasing doses of 250mg each week or two until blood lipid levels start to normalize (or side effects develop). Side effects are usually minimized by increasing the dosage slowly to the common therapeutic range of 1000-2000mg/day and should be divided into 2-3 separate doses of no more than 500-750mg per dose. In the high doses of niacin used for controlling cholesterol levels (anything above 100mg/day), nicotinic acid can cause skin flushing and itching of the skin as well as headaches and hypotension. In some cases, the skin flushing and itching side effects can be reduced somewhat by combined use with an aspirin (which also has a beneficial cardiovascular effect via reduced blood clotting). The niacinamide form of niacin does not cause these side effects, but it is not effective in reducing cholesterol levels, so it is seldom taken in such high doses. The slow-release versions of niacin supplements for controlling blood lipids have the potential for causing liver damage (even at “lower” doses of 500mg/day) – so blood tests to monitor for liver damage are recommended and high-dose niacin supplementation should only be undertaken on the advice and guidance by a physician. The inositol hexaniacinate (Niacinol) form of niacin may be less likely to cause liver damage compared to timed-release forms. Anybody with liver disease, including those who consume more than 2 drinks of alcohol daily, should not take high-dose niacin except on specific medical advice. All niacin therapy (at doses exceeding 100mg/day) should be supervised and monitored by a physician.
UL = Tolerable Upper Limit
tHyc dose = dosage range showing positive effect in reducing total plasma homocysteine levels
NOAEL = No Observed Adverse Effect Level – levels at which the Council for Responsible Nutrition (CRN) has determined no adverse effects are likely to be observed.
LOAEL = Lowest Observed Adverse Effect Level – lowest levels at which CRN has determined that adverse effects are observed.
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EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhDand Kerry Hughes, MS.