Folic acid is a water-soluble vitamin of the vitamin B complex.
Folic acid (pteroylglutamic acid) is the parent compound for a large number of derivatives collectively known as folates. Folate is the generic term used to describe the compounds that exhibit the biological activity of folic acid; it is the preferred term for the vitamin present in foods that represents a mixture of related compounds (folates).
See Table 1 for Dietary Reference Values for folic acid.
In the UK, the average adult diet provides: for men, 322 µg daily; for women, 224 µg daily.
Folates are involved in a number of single carbon transfer reactions, especially in the syn-thesis of purines and pyrimidines (and hence the synthesis of DNA), glycine and methionine. They are also involved in some amino acid conversions and the formation and utilisation of formate. Deficiency leads to impaired cell division (effects most noticeable in rapidly regenerating tissues).
See Table 2 for dietary sources of folic acid.
Absorption of folate takes place mainly in the jejunum.
Folate is stored mainly in the liver. Entero-hepatic recycling is important for maintaining serum levels.
Excretion of folate is largely renal, but folates may also be eliminated in the faeces (mainly as a result of folate synthesis by the gut microflora). Folates are also found in breast milk.
Folates leach into cooking water and are destroyed by cooking or food processing at high temperatures.
Folate deficiency results in reduction of DNA synthesis and hence in reduction of cell division. While DNA synthesis occurs in all dividing cells, deficiency is most easily seen in tissues with high rates of cell turnover such as erythrocytes (red blood cells). The main clinical observation associated with folate deficiency is, therefore, megaloblastic anaemia.
The main causes of folate deficiency are as follows:
Decreased dietary intake: This occurs in people eating inadequate diets, such as some elderly people, those on low incomes, and alcoholics who substitute alcoholic drinks for good sources of nutrition.
Decreased intestinal absorption:. Patients with disorders of malabsorption (e.g. coeliac disease) may suffer folate deficiency.
Increased requirements: Increased requirement for folate, and hence an increased risk of deficiency, can occur in pregnancy, during breast-feeding, in haemolytic anaemia and leukaemia.
Alcoholism: Chronic alcoholism is a common cause of folate deficiency. This may occur as a result of poor dietary intake, reduced absorption or increased excretion by the kidney. The presence of alcoholic liver disease increases the likelihood of folate deficiency.
Drugs: Long-term use of certain drugs (e.g. phenytoin, sulfasalazine) is associated with folate deficiency.
Signs and symptoms include megaloblastic, macrocytic anaemia, weakness, tiredness, irritability, forgetfulness, dyspnoea, anorexia, diarrhoea, weight loss, headache, syncope, palpitations and glossitis. In babies and young children, growth may be affected.
Table 1 Dietary Reference Values for folic acid (µg/day)
|EU RDA = 200 µg|
- 7–9 years.
- The Department of Health recommends that all women who are pregnant or planning a pregnancy should take a folic acid supplement (see dose).
- ≤ 18 years = 800 µg daily.
EVM = Likely safe daily intake from supplements alone.
TUL = Tolerable Upper Intake Level (not determined for thiamine).
Pregnancy and pre-pregnancy
The risk of neural tube defects (NTDs) can be reduced by increased folic acid intake during the periconceptual period.1–5 These findings gave rise to recommendations in several countries
Table 2 Dietary sources of folic acid
|Food portion||Folate content|
|1 bowl All-Bran (45 g)||80|
|1 bowl Bran Flakes (45 g)||110|
|1 bowl Corn Flakes (30 g)||70|
|1 bowl muesli (95 g)||130|
|1 bowl Start (40 g)||140|
|Bread, brown, 2 slices||30|
|white, 2 slices||25|
|wholemeal 2 slices||30|
|fortified, 2 slices||70|
|Milk and dairy products||15|
|1/2 pint (280 ml) milk,|
|whole, semi-skimmed, or|
|1/2 pint (280 ml) soya milk||50|
|1 pot yoghurt (150 g)||25|
|Cheese, average (50 g)||15|
|Camembert (50 g)||50|
|Liver, lambs, cooked (90 g)||220|
|Kidney, lambs, cooked||60|
|Broccoli, boiled (100 g)||65|
|Brussels sprouts, boiled (100 g)||110|
|Cabbage, boiled (100 g)||30|
|Cauliflower, boiled (100 g)||50|
|Kale, boiled (100 g)||90|
|Lettuce (30 g)||20|
|Peas, boiled (100 g)||50|
|Potatoes, boiled (150 g)||145|
|Spinach, boiled (100 g)||100|
|1 small can baked beans||45|
|Chickpeas, cooked (105 g)||110|
|Red kidney beans (105 g)||90|
|1 large glass orange juice||40|
|Half a grapefruit||20|
|Brewer’s yeast (10 g)||400|
|Marmite, spread on 1 slice||50|
|Excellent source (bold); good source (italics).|
that women intending to become pregnant should consume additional folic acid. The reason for the beneficial effect of folic acid is unclear. Although it may be a result of deficiency, a genetic defect in the methylene tetrahydro-folate reductase (MTHFR) gene, estimated to occur in about 5–15% of white populations, appears to result in an increased requirement for folates and an increased risk of recurrent early pregnancy loss and NTDs.6,7 In addition, elevated levels of plasma homocysteine have been observed in mothers producing offspring with NTDs,8 and the possibility that this factor could have toxic effects on the foetus at the time of neural tube closure is currently under further investigation.
Whether folic acid taken throughout pregnancy has any benefit on birth outcome is unclear. Re-analysis of data from a large randomised trial, combined with trials from an updated Cochrane review, found no association between folic acid supplementation and birth weight, placental weight or gestational age. Folic acid at high dose (5 mg daily) was associated with reduced risk of low birth weight (pooled relative risk 0.73 (95% CI, 0.53 to 0.99). Overall there was no conclusive evidence of benefit for folic acid supplementation in pregnant women given from time of booking onwards.9
Results from some trials have suggested that folic acid is associated with an increase in twin pregnancies. A Hungarian study involving 38 151 women found that both pre- and post-conceptual supplementation of a high dose of folic acid and multivitamins are associated with a slight increase in the incidence of twin pregnancies.10 A British prospective cohort study involving 602 women undergoing fertility treatment found that the likelihood of a twin birth after in vitro fertilisation rose with in-creased concentrations of plasma folate and red-cell folate. There was no association between folate and vitamin B12 levels and the likelihood of a successful pregnancy, but the MTHFR genotype was associated with the women’s potential to produce healthy embryos.11
Marginal folate status is also associated with elevated plasma homocysteine levels, a known risk factor for CVD mortality.12–14 Mechanisms by which plasma homocysteine may be associated with increased risk of CVD have not been clearly established, but possibilities include:15
oxidative damage to the vascular endothelium;
inhibition of endothelial anticoagulant factors, resulting in increased clot formation;
increased platelet aggregation; and proliferation of smooth muscle cells, resulting in increased vulnerability of the arteries to obstruction.
Homocysteine is derived from dietary methionine, and it is removed by conversion to cystathionine, cysteine and pyruvate, or by remethylation to methionine. Rare inborn errors of metabolism can cause severe elevations in plasma homocysteine levels. One example is homocystinuria, which occurs as a result of a genetic defect in the enzyme, cystathione beta-synthase. Genetic changes in the enzymes involved in the remethylation pathway, including MTHFR and methionine synthase, are also associated with increase in plasma homocysteine concentrations. All such cases are associated with premature vascular disease, thrombosis and early death.
However, such genetic disorders are rare and cannot account for the raised homocysteine levels observed in many patients with CVD. However, attention is now being given to the possibility that deficiency of the various vitamins that act as cofactors for the enzymes involved in homocysteine metabolism could result in increased homocysteine concentrations. In particular, folate is required for the normal function of MTHFR, vitamin B12 for methionine synthase and vitamin B6 for cystathione beta-synthase.
In theory, lack of any one of these three vitamins could cause hyperhomocysteinaemia, and could therefore increase the risk of CVD. In the Framingham Heart Study,16 a cohort study on vascular disease, it was shown that folic acid, vitamin B6 and vitamin B12 are determinants of plasma homocysteine levels, with folic acid showing the strongest association.
The question of whether increased vitamin intake can reduce cardiovascular risk was examined in the Nurse’s Health Study,17 which showed that those with the highest intake of folate had a 31% lower incidence of heart disease than those with the lowest intake. For vitamin B6, those with the highest intake had a 33% lower risk of heart disease, while in those with the highest intake of both folate and vitamin B6, the risk of heart disease was reduced by 45%. The risk of heart disease was reduced by 24% in those who regularly used multivitamins. In a large Australian study involving 1419 men and 1531 women aged 20–90, the risk of fatal CVD was not associated with serum folate and serum B12 concentrations.18
Another question is whether homocysteine levels can be lowered with folate and other B vitamins. Folic acid (250 µg daily), in addition to usual dietary intakes of folate, significantly decreased plasma homocysteine concentrations in healthy young women,19 and breakfast cereal fortified with folic acid reduced plasma homocysteine in men and women with coronary artery disease.20 Another study has demonstrated that the addition of vitamin B12 to folic acid supplements or enriched foods (400 µg folic acid daily) maximises the reduction of homocysteine.21 Furthermore, two meta-analyses22,23 suggest that administration of folic acid reduces plasma homocysteine concentrations and that vitamin B12 but not vitamin B6 may have an additional effect.23 Vitamin B6 alone also seems to be less effective than a combination of folic acid and B12 in lowering plasma homocysteine concentrations in patients with coronary artery disease.24,25
A meta-analysis of 25 RCTs involving 2595 subjects found that the proportional reductions in plasma homocysteine concentrations produced by folic acid were greater at higher homocysteine and lower folate pretreatment concentrations. They were also greater in women than men. Vitamin B12 produced further reduction in homocysteine, but vitamin B6 had no significant effect. The conclusion of this meta-analysis was that daily doses ≥ 0.8 mg folic acid are required to achieve maximal reduction in homocysteine concentrations produced by folic acid. Doses of 0.2 mg and 0.4 mg were associated with 60% and 90% respectively, of this maximal effect.26 A more recent RCT also found that the homocysteine lowering effect of B vitamins (folate, B6 and B12) was maximal in those with high homocysteine and low B12 levels.27
Although high homocysteine levels are associated with CVD, the question as to whether lowering homocysteine reduces cardiovascular risk has not been clearly answered. A meta-analysis in 2002 found strong evidence that the association between homocysteine and CVD is causal, and calculated that lowering homocysteine concentrations by 3 µmol/L (achievable by increasing folic acid intake) would reduce the risk of ischaemic heart disease by 16%, deep vein thrombosis by 25% and stroke by 24%.28
However, a more recent meta-analysis that investigated the association between the MTHFR gene and CHD found no strong evidence to support this association, concluding that the possible benefit of folic acid in preventing CVD, through lowering homocysteine, is in some doubt.29
In addition, a recent RCT in Singaporean stroke patients found that the MTHFR gene polymorphism (MTHFR C677T) did not significantly influence the effect of vitamin therapy on homocysteine levels. In this study, the magnitude of the reduction in homocysteine levels at 12 months was similar, irrespective of MTHFR genotype.30
In another trial, moderate reduction of total homocysteine after non-disabling cerebral infarction had no effect on vascular outcomes during 2 years of follow-up.31 Further trials of homocysteine lowering with folic acid either alone or in combination with other B vitamins have shown no significant effects on biomarkers of inflammation, endothelial dysfunction and hypercoagulablity,32–34 or inflammatory and thrombogenic markers in smokers.35 One trial found that folate (5 mg daily) and B12 (500 µg daily) improved insulin resistance and endothe-lial dysfunction in patients with metabolic syndrome.36 Another study showed no improvement in markers of endothelial dysfunction and low-grade inflammation in patients with type 2 diabetes,37 while another found that short-term folic acid supplementation (5 mg daily) significantly enhances endothelial function in type 2 diabetes.38
Two large RCTs (the Heart Outcomes Pre-vention Evaluation39 and the NORVIT Trial40) found that B12, folic acid and B6 in combination reduced plasma homocysteine, but did not reduce the risk of major cardiovascular events in patients with CVD,39 and did not reduce the risk of recurrent CVD after acute myocardial infarction.40
Marginal folate status also appears to be associated with certain cancers,41 notably colon cancer, although it is at present unclear as to whether it is folate or some other nutritional factors that could be involved. Data, including those from two prospective studies42,43 and four case-control studies,44–47 indicate that inade-quate intake of folate may increase risk of colon cancer. However, a recent prospective study has indicated that low plasma folate concentrations may protect against colorectal cancer. A bell-shaped curve was observed between plasma folate and colorectal cancer risk. The MTHFR C677T polymorphism was associated with a reduced risk of colorectal cancer that was independent of folate status.48
There is some evidence – albeit limited –that use of supplements containing folic acid could reduce the risk of colon cancer.49,50 More recent studies have also found a lower incidence of colorectal adenomas in people with higher intakes of and plasma concentrations of folate and lower homocysteine.51
A meta-analysis of seven cohort and nine case-control studies also added support for the hypothesis that folate has a small protective effect against colorectal cancer.52
There is also evidence that high folate intake may have a particular effect in reducing colorectal cancer risk in people with high alcohol intake,53,54 or in smokers.55 In women with high alcohol intake, there is also a strong inverse relationship between dietary folate intake and ovarian cancer risk.56 Higher folate intake has also been shown to reduce breast cancer risk in women with loss of oestrogen receptor (ER) gene expression, but not in those with oestrogen receptor (ER+) gene expression.57 A study investigating the effect of folate taken in pregnancy on breast cancer found that women taking high doses of folate throughout preg-nancy may be more likely to die of breast cancer in later life than women taking no folate.
The authors suggested that this could be a chance finding, so further studies should be conducted.58
There is an apparent increase in mental disorders associated with reduced folate status.59 Recent studies have found that Alzheimer’s disease is associated with low blood levels of folate and vitamin B12 and elevated homocysteine levels.60–68 However, a meta-analysis of four randomised controlled intervention trials provide no evidence that folic acid, with or without vitamin B12, has a beneficial effect on cognitive function or mood in cognitively impaired older people.69
Evidence exists of a link between depression and low folate levels and some RCTs have found folate supplements helpful when added to conventional antidepressants. A recent US study amongst 110 patients with major depressive disorder compared levels of folate, B12 and homocysteine with the time taken to respond to the antidepressant fluoxetine. The 15% of patients who initially had low folate levels took longer to onset of clinical improvement than those with normal folate. Initial levels of B12 and homocysteine had no relationship to response onset.70
A systematic review of three RCTs of folate supplementation suggests that folate may have a potential role as a supplement to other treatments for depression. Low folate patients given extra folate had reduced Hamilton Depression Rating Scale scores and increased odds of a 50% score improvement compared to placebo. Folate given to patients with initially normal folate had no significant impact.71 Two other recent RCTs in which average folate status was normal or not measured also found no evidence that folate supplements helped depression.72,73
A UK study has investigated a genetic factor in the link between folate and depression. A cross-sectional observational study of 3478 women (from a heart health study) compared the presence of the MTHFR C677T genotype with the presence of depressive symptoms. Eight other similar studies were meta-analysed together with the new results. Depression was found to be associated with the C677T genotype.74
In summary, it is clear that a proportion of depressed patients have low folate status and that this can be associated with a worse response to antidepressants. Whether low folate is the cause or effect of depression in these patients is less clear. Evidence to date from RCTs of folate supplementation in depression is minimal but positive. Patients with depression should be tested for red cell folate and supplemented when folate is low, particularly if they are elderly or have coexisting nutritional risk.
Preliminary evidence from one RCT in 628 patients in Japan aged 65 or older with stroke found that daily oral treatment with folic acid 5 mg and mecobalamin 1500 µg reduced plasma homocysteine and the risk of hip fracture.75
In pernicious anaemia, folic acid will correct the haematological abnormalities, but neuropathy may be precipitated. Doses of folic acid 400 µg daily are not recommended until pernicious anaemia has been ruled out.
Pregnancy and breast-feeding
No problems have been reported. Supplements are required during pregnancy and when planning a pregnancy (see Dose).
Folic acid is generally considered to be safe even in high doses, but it may lead to convulsions in patients taking anticonvulsants and may precipitate neuropathy in pernicious anaemia. Some gastrointestinal disturbance and altered sleep pattern has been reported at doses of 15 mg daily. Allergic reactions (shortness of breath, wheezing, fever, erythema, skin rash, itching) have been reported rarely.
Anticonvulsants: requirements for folic acid may be increased, but concurrent use of folic acid may antagonise the effects of anticonvulsants; an increase in anticonvulsant dose may be necessary in patients who receive supplementary folic acid (monitoring required).
Antibiotics: may interfere with the microbiological assay for serum and erythrocyte folic acid (falsely low results).
Colestyramine: may reduce the absorption of folic acid; patients on prolonged colestyramine therapy should take a folic acid supplement 1 h before colestyramine administration.
Methotrexate: acts as a folic acid antagonist; risk significant with high dose and/or prolonged use.
Oestrogens (including oral contraceptives): may reduce blood levels of folic acid. Pyrimethamine: acts as a folic acid antagonist; risk significant with high dose and/or prolonged use; folic acid supplements should be given in pregnancy.
Sulfasalazine: may reduce the absorption of folic acid; requirements for folic acid may be increased.
Trimethoprim: acts as a folic acid antagonist; risk significant with high dose and/or prolonged use.
Adequate amounts of all B vitamins are required for optimal functioning; deficiency or excess of one B vitamin may lead to abnormalities in the metabolism of another.
Zinc: folic acid may reduce the absorption of zinc.
Folic acid is available in the form of tablets. For prevention of first occurrence of NTDs in women who are planning a pregnancy, oral, 400 µg daily before conception until 12th week of pregnancy.
For prevention of recurrence of NTDs, oral, 5 mg daily before conception until 12th week of pregnancy.
For prophylaxis during pregnancy (after 12th week), oral, 200–500 µg daily. A Cochrane review concluded that folate supplementation in pregnancy appears to improve haemoglobin status and folate status.76
In women with diabetes mellitus, oral, 5 mg daily before conception until the 12th week. This is because women with diabetes are at significantly increased risk of having a baby with NTDs. This dose has been recommended by Diabetes UK (2005), the British Medical Asso-ciation (2004) and the Society of Obstetricians and Gynaecologists (2003).77
As a dietary supplement, oral, 100–500 µg daily.
When co-prescribed with methotrexate, in patients who suffer mucosal or gastrointestinal side-effects with this drug, folic acid 5 mg each week may help to reduce the frequency of such side-effects. This dose has been recommended by ATTRACT, the British National Formulary and PRODIGY.78
Upper safety levels
The UK Expert Group on Vitamins and Minerals (EVM) has identified a likely safe total intake of folic acid for adults from supplements alone of 1000 µg daily.
There is good evidence that folic acid reduces the risk of neural tube defects, and supplementation is recommended pre-conceptually and during the first 12 weeks of pregnancy. There is increasing evidence that folic acid reduces elevated plasma homocysteine levels, a risk factor for CVD. However, it is still not clear whether folic acid, with or without other B vitamins, reduces the risk of CVD. This may be confused by the MTHFR gene, defects in which may influence the effect of folic acid. Epidemiological studies have shown an inverse relationship between serum folate levels and colon cancer. Poor folate status has also been demonstrated in some people with depression and a few RCTs have found supplementation helpful when added to conventional antidepressants. Depressed patients should be tested for folate and supplemented when folate is low. However, controlled trials are required to determine whether supplements reduce the risk of cancer.
- Laurence KM, James N, Miller MH, et al. Double-blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural tube defects. BMJ 1981; 282: 1509–1511.
- Smithells RW, Seller MJ, Harris R, et al. Further ex-perience of vitamin supplementation for prevention of neural tube defect recurrences. Lancet 1983; i: 1027–1031.
- Medical Research Council Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338: 131–137.
- Czeizel AE, Dudas I. Prevention of the first occurrence of neural tube defects by periconceptual vitamin supplementation. N Engl J Med 1992; 327: 1832–1835.
- Weller MM, Shapiro S, Mitchel AA, et al. Pericon-ceptual folic acid exposure and risk of occurrent neural tube defects. JAMA 1993; 269: 1257–1261.
- Molloy AM, Daly S, Mills JL, et al. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red cell folates: implications for folate intake recommendations. Lancet 1997; 349: 1591–1593.
- Nelen WLDM, Van der Molen EF, Blom HJ, et al. Recurrent early pregnancy loss and genetic related disturbances in folate and homocysteine metabolism. Br J Hosp Med 1997; 58: 511–513.
- Mills JL, McPartlin P, Kirke PM, et al. Homocysteine metabolism in pregnancies complicated by neural tube defects. Lancet 1995; 345: 149–151.
- Charles DH, Ness AR, Campbell D, et al. Folic acid supplements in pregnancy and birth outcome: re-analysis of a large randomised controlled trial and update of Cochrane review. Paediatr Perinat Epidemiol 2005; 19: 112–124.
- Czeizel AE, Vargha P. Preconceptual folic acid/multivitamin supplementation and twin pregnancy. Am J Obstet Gynecol 2004; 191: 790–794.
- Haggarty P, McCallum H, McBain H, et al. Effect of B vitamins and genetics on success of in-vitro fertilisation: prospective cohort study. Lancet 2006; 1513–1519.
- Alfthan G, Aro A, Gey KF. Plasma homocysteine and cardiovascular disease mortality. Lancet 1997; 397.
- Nygard O, Nordrehaug JE, Refsum H, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997; 337: 230–236.
- Wald NJ, Watt HC, Law MR, et al. Homocysteine and ischaemic heart disease: results of a prospective study with implications on prevention. Arch Intern Med 1998; 158: 862–867.
- Weir DG, Scott JM. Homocysteine as a risk factor for cardiovascular and related disease: nutritional implications. Nutr Res Rev 1998; 11: 311–338.
- Selhub J, Jacques PF, Wilson PWF, et al. Vitamin status and intake as primary determinants of homo-cysteinaemia in an elderly population. JAMA 1993;
- Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998; 279: 359–364.
- Hung J, Beilby JP, Knuiman MW, Divitini M. Folate and vitamin B-12 and risk of fatal cardiovascular disease: cohort study from Busselton, Western Aus-tralia. BMJ 2003; 326: 131–135.
- Brouwer IA, van Dusseldorp M, Thomas CMG, et al. Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomized trial. Am J Clin Nutr 1999; 69: 99–104.
- Malinow MR, Duell PB, Hess DL, et al. Reduction of plasma homocysteine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med 1998; 338: 1009–1015.
- Bronstrup A, Hages M, Prinz-Langenohl R, Pietrzik K. Effects of folic acid and combinations of folic acid and vitamin B-12 on plasma homocysteine concentrations in healthy young women. Am J Clin Nutr 1998; 68: 1104–1110.
- Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessmemt of plasma homocys-teine as a risk factor for vascular disease: probable benefits of increasing folic acid intake. JAMA 1995;
- Homocysteine Lowering Trialists’ Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 1998; 316: 894–898.
- Lee BJ, Huang MC, Chung LJ, et al. Folic acid and vitamin B12 are more effective than vitamin B6 in lowering fasting plasma homocysteine concentration in patients with coronary artery disease. Eur J Clin Nutr 2004; 58: 481–487.
- Stott DJ, MacIntosh G, Lowe GD, et al. Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease. Am J Clin Nutr 2005; 82: 1320–1326.
- Homocysteine Lowering Trialists’ Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 2005; 82: 806–812.
Flicker L, Vasikaran SD, Thomas J, et al. Efficacy of B vitamins in lowering homocysteine in older men. Stroke 2006; 37: 547.
Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002; 325: 1202–1204.
Lewis SJ, Ebrahim S, Davey Smith G. Meta-analysis of MTHFR 677CT polymorphism and coronary heart disease: does totality of evidence support a causal role for homocysteine and preventive poten-tial of folate? BMJ 2005; 331: 1053–1058.
Ho GYH, Eikelboom JW, Hankey GJ, et al. Methylenetetrahydrofolate reductase polymor-phisms and homocysteine-lowering effect of vitamin therapy in Singaporean stroke patients. Stroke 2006; 37: 456.
Toole JF, Malinow MR, Chambless LE, et al. Low-ering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Pre-vention (VISP) randomized controlled trial. JAMA 2004; 291: 565–575.
Peeters AC, van der Molen EF, Blom HJ, den Heijer M. The effect of homcysteine reduction by B-vitamin supplementation on markers of endothelial dysfunction. Thromb Haemost 2004; 92: 1086–1091.
Dusitanond P, Eikelboom JW, Hankey JG, et al. Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischaemic attack or stroke: a randomized substudy of the VITATOPS trial. Stroke 2005; 36: 144–146.
Durga J, van Tits LJ, Schouten EG, et al. Effect of lowering of homocysteine levels on inflammatory markers: a randomized controlled trial. Arch Intern Med 2005; 165: 1388–1394.
Mangoni AA, Arya R, Ford E, et al. Effects of folic acid supplementation on inflammatory and throm-bogenic markers in chronic smokers. A randomised controlled trial. Thromb Res 2003; 110: 13–17.
Setola A, Mont LD, Galluccio E, et al. Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocys-teine levels and hyperinsulinaemia. Eur J Endocrinol 2004; 151: 483–489.
Spoelstra-de MA, Brouwer CB, Terheggen F, et al. No effect of folic acid on markers of endothelial dysfunction or inflammation in patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia. Neth J Med 2004; 62: 246–253.
Mangoni AA, Sherwood RA, Asonganyi B, et al. Short-term oral folic acid supplementation enhances endothelial function in patients with type 2 diabetes. Am J Hypertens 2005; 18 (2 Pt 1): 220–226.
Lonn E, Yusuf S, Arnold MJ, on behalf of the Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354: 1567–1577. Epub 2006 March 12.
Bonaa KH, Njolstad I, Ueland PM, on behalf of the NORVIT Trial Investigators. Homocysteine lower-ing and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354: 1578–1588. Epub 2006 March 12.
Mason JB. Folate status: Effects on carcinogenesis. In: Bailey LB, ed. Folates in Health and Disease. New York: Marcel Dekker, 1995: 361–378.
Giovannucci E, Rimm EB, Ascherio A, et al. Alcohol, low methionine, low folate diets and risk of colon cancer in men. J Natl Cancer Inst 1995; 87: 265–273.
Glynn SA, Albanes D, Pietinen P, et al. Colorectal cancer and folate status: a nested case-control study among male smokers. Cancer Epidemiol Biomarkers Prev 1996; 5: 487–494.
Benito E, Stigglebout A, Bosch FX, et al. Nutritional factors in colorectal cancer risk: a case-control study in Majorca. Int J Cancer 1991; 49: 161–167.
Meyer F, White E. Alcohol and nutrients in relation to colon cancer in middle-aged adults. Am J Epi-demiol 1993; 138: 225–236.
Ferraroni M, La Vecchia C, D’Avanzo B, et al. Selected micronutrient intake and the role of colon cancer. Br J Cancer 1994; 70: 1150–1155.
Freudenheim JL, Graham S, Marshall JR, et al. Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol 1991; 20: 368–374.
Van Guelpen B, Hultdin J, Johansson I, et al. Low folate levels may protect against colorectal cancer. Gut 2006; 55: 1387–1389.
White E, Shannon JS, Patterson RE. Relationship between vitamin and calcium supplement use and colon cancer. Cancer Epidemiol Biomarkers Prev 1997; 6: 769–774.
Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate and colon cancer in women in the nurses’ health study. Ann Intern Med 1998; 129: 517–524.
Martinez ME, Henning SM, Alberts DS. Folate and colorectal neoplasia: relation between plasma and dietary markers of folate and adenoma recurrence. Am J Clin Nutr 2004; 79: 691–697.
Sanjoaquin MA, Allen N, Couto E, et al. Folate intake and colorectal cancer risk: a meta-analytical approach. Int J Cancer 2005; 113: 825–828.
Boyapati SM, Bostick RM, McGlynn KA, et al. Folate intake, MTHFR C677T polymorphism, alcohol consumption, and risk for sporadic colo-rectal adenoma (United States). Cancer Causes Control 2004; 15: 493–501.
Le Marchand L, Wilkens LR, Kolonel LN, Hen-derson BE. The MTHFR C677T polymorphism and colorectal cancer: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 2005; 14: 1198–1203.
Larrson SC, Giovannucci E, Wolk A. A prospective study of dietary folate intake and risk of colorectal cancer: modification by caffeine intake and cigarette smoking. Cancer Epidemiol Biomarkers Prev 2005; 740–743.
Larrson SC, Giovannucci E, Wolk A. Dietary folate intake and incidence of ovarian cancer: the Swedish Mammography Cohort. J Natl Cancer Inst 2004; 396–402.
- Zhang SM, Hankinson SE, Hunter DJ, et al. Folate intake and risk of breast cancer characterized by hor-mone receptor status. Cancer Epidemiol Biomarkers Prev 2005; 14: 2004–2008.
- Charles D, Ness AR, Campbell D, et al. Taking folate in pregnancy and risk of maternal breast cancer. BMJ 2004; 329: 1375–1376.
- Bottiglieri ET, Crellin RF, Reynolds EH. Folates and neuropsychiatry. In: Bailey L, ed. Folate in Health and Disease. New York: Marcel Dekker, 1995: 435–462.
- Joosten E, Lesaffre E, Riezler R, et al. Is metabolic evidence for vitamin B12 and folate deficiency more frequent in elderly patients with Alzheimer’s disease? J Gerontol A Biol Sci Med 1997; 52: M76–M79.
- Clarke R, Smith AD, Jobst KA, et al. Folate, vitamin B12 and serum homocysteine levels in confirmed Alzheimer’s disease. Arch Neurol 1998; 11: 1449–1455.
- Wang HX, Wahlin A, Basun H, et al. Vitamin B(12) and folate in relation to the development of Alzheimer’s disease. Neurology 2001; 56: 1188–1194.
- Luchsinger JA, Tang MX, Shea S, et al. Plasma homocysteine levels and risk of Alzheimer disease. Neurology 2004; 62: 1972–1976.
- Quadri P, Fragiacomo C, Pezzati R, et al. Homocys-teine, folate and vitamn B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr 2004; 80: 114–122.
- Ellinson M, Thomas J, Patterson A. A critical evaluation of the relationship between serum vitamin B, folate and total homocysteine with cognitive impairment in the elderly. J Hum Nutr Diet 2004; 371–383.
Kado DM, Karlamangla AS, Huang MH, et al. Homcysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am J Med 2005; 118: 161–167.
Ravaglia G, Forti P, Maioli F, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 2005; 82: 636–643.
Tucker KL, Qiao N, Scott T, et al. High homocys-teine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr 2005; 82: 627–635.
Malouf R, Grimley Evans J, Areosa Sastre A. Folic acid with or without vitamin B12 for cognition and dementia. Cochrane database, issue 4, 2003. London: Macmillan.
Papakostas GI, Petersen T, Lebowitz BD, et al. The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine. Int J Neuropsychopharmacol 2005; 8: 523–528.
Taylor MJ, Carney SM, Goodwin GM, Geddes JR. Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials. J Psychopharmacol 2004 18: 251–256.
Williams E, Stewart-Knox B, Bradbury I, et al. Effect of folic acid supplementation on mood and serotonin response in healthy males. Br J Nutr 2005; 94: 602–608.
Bryan J, Calvaresi E. Association between dietary intake of folate and vitamins B-12 and B-6 and self-reported psychological well-being in Australian men and women in midlife. J Nutr Health Aging 2004; 8: 226–232.
Lewis SJ, Lawlor DA, Davey Smith G, et al. The thermolabile variant of MTHFR is associated with depression in the British Women’s Heart and Health Study and a meta-analysis. Mol Psychiatry 2006; 11: 352–360 (Epub 2006 10 Jan).
Sato Y, Honda Y, Iwamoto J, et al. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA 2005; 293: 1082–1088.
Mahomed K. Folate supplementation in preg-nancy. Cochrane database, issue 3, 1997. London:
National Health Service. National Library for Health. http://www.clinicalanswers nhs.uk/ index.cfm?question=1473 (accessed 31 October 2006).
National Health Service. National Library for Health. http://www.clinicalanswers.nhs.uk/index. cfm?question=248 (accessed 31 October 2006).