B12: Homocysteine

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Vegan For Life by Jack Norris, RD & Ginny Messina, MPH, RD

Mild B12 Deficiency - Cardiovascular Disease & Homocysteine

Summary: Vegetarians who do not supplement their diet with vitamin B12 tend to have elevated homocysteine levels. Elevated homocysteine is associated with early mortality, heart disease, stroke, dementia, and birth defects. There is evidence that lowering homocysteine levels in otherwise healthy people can prevent death from stroke. A 2012 study found that vitamin B12 supplements improved cardiovascular function in vegetarians independently of lowering homocysteine levels. Vegetarians who follow B12 recommendations will minimize any elevated homocysteine problems due to a low B12 intake.

Contents
Introduction Background on Homocysteine Homocysteine in Vegans and Lacto-ovo Vegetarians Homocysteine and Disease Elevated Homocysteine is Associated with Increased Mortality Homocysteine's Association with Cardiovascular Disease Vitamin B12 Supplementation in Lacto-ovo Vegetarians and Cardiovascular Markers Lowering Homocysteine with Vitamins in Non-vegetarians Secondary Prevention of Cardiovascular Disease by Lowering Homocysteine Primary Prevention of Stroke But Aren't Vegans Protected From Cardiovascular Disease? B12, Homocysteine, and Dementia Homocysteine and Birth Defects What Level of B12 Should You Aim For? Should Vegans have their Homocysteine or B12 Levels Checked? References

Introduction
Most vegans are probably aware of the need to ensure a reliable source of vitamin B12 to prevent nerve damage in cases of severe depletion. Around 2000, research uncovered another dangerous condition that can result from less severe B12 depletion: elevated homocysteine.

Background on Homocysteine
Methionine is an essential amino acid obtained from protein in the diet. Some methionine is turned into homocysteine. The body turns much of this homocysteine back into methionine with the help of vitamin B12. If someone is B12-deficient, homocysteine levels will increase because this reaction cannot take place. Homocysteine appears to be a nerve and vessel toxin, promoting mortality, cardiovascular disease (CVD), stroke, and dementia. High homocysteine levels are also associated with birth defects. These will each be discussed below. Normal serum homocysteine levels are from 2.2 to 13.2 mol/l ( 2). Levels of homocysteine in typical Western populations are about 12 mol/l (3). Keeping homocysteine at levels associated with lower rates of disease requires both adequate B12 and folate (also known as folic acid) status. Low vitamin B6 status can also cause elevated homocysteine in some people.

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Contact | Copyright 2003-2013 VeganHealth.org

In most non-vegetarians with elevated homocysteine, folate is more of a problem than is B12. Since vegetarian diets are typically high in folate, elevated homocysteine levels in vegetarians are normally due to a low B12 intake (click here for a list of plant sources of folate).

Homocysteine in Vegans and Lacto-ovo Vegetarians

At least 14 studies have measured the homocysteine levels in vegetarians. Figure 1 shows the blood B12 levels of the participants of 13 of those studies (one did not report B12 levels ( 16)).
Figure 1: Serum B12 Levels in Homocysteine Studies on Vegetarians (pg/ml)

A - Most of these vegetarians did not supplement their diets with B12. USA '985, USA '99 (averaged 5.6 g B12/day)6, Australia '997, Chile '998, Chile '009, Slovak Republic '0010, India '0111, Germany '0112, Taiwan '0213, Italy '0214, Germany '0215, Taiwan '0317, Germany '0318, Germany '03 (took "B vitamins", amounts not reported)18

Normal B12 levels are from 200 to 900 pg/ml. Figure 1 shows that vegans had the lowest B12 levels, followed by lacto-ovo-vegetarians, and then non-vegetarians. Please note that the USA vegans had an average B12 intake, through fortified foods and supplements, of 5.6 g/day. Some of the vegetarians in the 2003 Germany study were probably supplementing with B12, but amounts were not given. The vegetarians in the other studies did not supplement their diets with B12. Figure 2 shows the blood homocysteine levels in the vegetarians who did not eat B12 fortified foods or take supplements.
Figure 2: Homocysteine Levels in Vegetarians (Mostly or All) Not Supplementing with B12 (mol/l)

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1998 USA5, 1999 Australia7, 1999 Chile8, 2000 Chile9, 2000 Slovak Republic10, 2001 India11, 2001 Germany12 2002 Taiwan11, 2002 Italy14, 2002 Germany15, 2002 United Kingdom16, 2003 Taiwan17, 2003 Germany18

The results in Figure 2 are the mirror opposite as those shown in Figure 1, with vegans having the highest homocysteine levels, lacto-ovo-vegetarians having the next highest, and non-vegetarians having the lowest. The consistency of this finding indicates that in vegetarians, B12 levels are inversely related to homocysteine levels. Figure 3 shows the homocysteine levels in vegetarians who either supplement with B12 or after a B12 injection (as indicated).
Figure 3: Homocysteine Levels in Vegetarians Receiving B12 (mol/l)

98 USA - 500 g/day for 2 months5; B12 levels increased to 553 pg/ml 99 USA - averaged 5.6 g B12/day6 00 CHILE - 1,000 g intramuscular injection9

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02 ITALY - B12 amount not reported14 03 GER - Germany; B12 amount not reported18

Neither the B12 levels nor the B12 intakes of the vegetarians in Italy were reported, and it is not clear why their homocysteine levels were so high. But the vegetarians in Chili, and the vegans in the USA, show very healthy homocysteine levels compared to those in Figure 2. Thus, vegans and vegetarians who supplement with B12 have homocysteine levels that are considered healthy, while vegans and vegetarians who do not supplement with B12 tend to have high homocysteine levels - higher than those in non-vegetarians.

Homocysteine and Disease

After reviewing the research on each of the following topics, Antoniades et al. (2009) write ( 52): It is now widely accepted that, at a cellular level, [homocysteine] exerts a detrimental effect on vascular wall and especially on endothelial cells, by decreasing [nitric oxide] bioavailability, increasing intracellular oxidative stress, and by triggering multiple pro-atherogenic mechanisms. In this context, epidemiological studies have clearly demonstrated that plasma [homocysteine] is an independent risk factor for atherosclerosis.

Elevated Homocysteine is Associated with Increased Mortality

A 1999 prospective study from the USA (19), a 1999 prospective study from Israel (20), and a 2001 prospective study from Norway (22) all found a statistically significant increase in mortality in people with homocysteine levels of about 14 to 15 mol/l. A 2001 prospective study from Norway found an increased risk of mortality but that was not statistically significant, although the analysis only tested for significance between people above and below 14 mol/l (21); had they tested against people with less than 10 mol/l, the finding would have been stronger. All of the studies adjusted their results for the blood pressure of the participants. The USA, Norway, and Netherlands studies also adjusted for cholesterol levels. These studies show a considerable risk in mortality associated with high homocysteine levels. If you average the two studies that calculated a risk of death per 5 mol/l, you get an increased risk of 33% per 5 mol/l increase in homocysteine.

Homocysteine's Association with Cardiovascular Disease

Cardiovascular disease (CVD) includes ischemic heart disease (IHD) (heart attack), coronary artery disease (CAD; plaque obstruction of the coronary arteries to the heart), and stroke. In 2002, two meta-analyses of prospective studies examining homocysteine and CVD were published. The Homocysteine Studies Collaboration (HSC) included 11 prospective studies of IHD and 8 of stroke (23). It compiled data from 9,025 people. HSC's analysis was geared mainly towards how much disease could be reduced through lowering homocysteine levels by 25% (about 3 mol/l). After adjusting for age, sex, smoking, systolic blood pressure, and total cholesterol levels, a 25% lower homocysteine level reduced the risk of IHD by 11%, and the risk of stroke by 19%. The second meta-analysis (24) examined 16 prospective studies of IHD. A 5 mol/l increase in homocysteine increased risk 23%. In 8 prospective studies on stroke, a 5 mol/l increase in homocysteine increased risk 42%. The results were adjusted for age, sex, smoking, cholesterol, and blood pressure (except for one study which adjusted only for age and sex). In 2008, Humphrey et al. (45) conducted a meta-analysis which included 24 cohort studies. They found that each increase of 5 mol/L in homocysteine level increases the risk of CHD events by approximately 20%, independent of traditional CHD risk factors.

Vitamin B12 Supplementation in Lacto-ovo Vegetarians and Cardiovascular Markers

A 2012 randomized, placebo-controlled, crossover clinical trial tested B12 supplementation's effects on flowmediated dilation (FMD) of the brachial artery and intima-media thickness (IMT) of the carotid artery, both of which are markers of cardiovascular disease (1). The study was done in Hong Kong and there were 50 vegetarians, two of whom were vegan. Twelve subjects (24%) had serum vitamin B-12 between 203-406 pg/ml and 35 subjects (70%) < 203 pg/ml. After 12-week periods of 500 g of B12 per day, average homocysteine levels went from 16.7 to 11.3 mol/l. Brachial artery FMD significantly increased and carotid IMT significantly decreased after vitamin B12 but not after placebo treatment. These positive effects appeared to be better correlated with the correction of vitamin B12 deficiency than with the lowering of homocysteine. The authors noted that the effects "on carotid intima-media thickness was quite subtle and of uncertain biological significance."

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Lowering Homocysteine with Vitamins in Non-vegetarians

It is clear that most people with slightly elevated (or higher) homocysteine levels can lower them through taking folate and vitamin B12. In 1998, the British Medical Journal published an analysis of 12 studies and concluded that folic acid in the range of 500-5,000 g/day reduced homocysteine by 25%, and that B12 supplements (average intake of 500 g/day) reduced it a further 7%. Vitamin B6 supplements (average of 16.5 mg/day) did not reduce homocysteine further. 500 g B12/day is a lot more than necessary. In one study reported in the BMJ, only 100 g B12/day (combined with folate and B6) was successful in reducing homocysteine from 7.2 to 5.8 mol/l ( 3). In another, only 20 g B12/day (combined with folate and B6) resulted in reducing homocysteine from 11.9 to 7.8 mol/l ( 3). Smaller amounts of B12 were not tested. People with kidney problems should not take large doses of cyanocobalamin, as they often cannot metabolize the cyanide efficiently. For more information, please see the Chronic Kidney Failure section of People Who Should Not Take the Cyanocobalamin Form of B12. In fact, there is evidence that cyanocobalamin is not effective at lowering homocyesteine in people with kidney disease (61 ).

Secondary Prevention of Cardiovascular Disease by Lowering Homocysteine

There have been a lot of clinical trials to see if lowering homocysteine through vitamin supplementation will decrease cardiovascular events in people already diagnosed with cardiovascular disease. Although most trials have shown no benefit (29, 49, 50, 53, 54, 55, 56 , 57, 37), some have shown benefit in preventing stroke (28, 58, 59, 60 ). In their 2009 review, Antoniades et al. (52) conclude: The existing data support that low-dose folate treatment (achieved by folate food fortification) may reduce cardiovascular risk, but any pharmacological treatment with folates on top of that is unlikely to achieve any additional benefit in subjects with plasma [homocysteine] within the 'normal range' [ < 15 mol/l].

Primary Prevention of Stroke

Although secondary prevention of cardiovascular disease by lowering homocysteine has not shown much promise, a more relevant question for vegan diets is whether lowering homocysteine in people without preexisting disease can prevent it in the future. There has been mainly one study shedding light on this question: A 2006 analysis (38) showed that a reduction in rates of death from stroke in both the USA and Canada paralleled the fortification of foods with folic acid. This study did not measure the folic acid intake of individuals and does not prove causality. However, it is still fairly impressive and suggests that a modest lowering of homocysteine in otherwise healthy people might prevent stroke.

But Aren't Vegans Protected From Cardiovascular Disease?

Studies show that vegans have lower cholesterol levels (31) and blood pressure (32) than non-vegetarians. These, and possibly other factors in the vegan diet, have led some to believe that vegans are so protected against cardiovascular disease that they do not need to worry about elevated homocysteine. However, as noted above, the studies on mortality and cardiovascular disease were adjusted for differences in cholesterol levels and blood pressure. The greater effect of elevated homocysteine on stroke compared to heart disease could explain why vegetarians have been shown to have lower rates of death from heart disease but not stroke (26). Since vitamin B12 succeeds in normalizing most vegans' homocysteine levels without any adverse effects, there is a simple solution and no reason to take any risk.

B12, Homocysteine, and Dementia

This sections has been moved to the page, Mild B12 Deficiency - Dementia & Depression.

Homocysteine and Birth Defects

Folic acid intake in the weeks before and after conception has been shown to decrease the number of neural tube defects (NTD), such as spina bifida, in at least four studies ( 39). While the focus has been primarily on folate deficiency, there has been increasing interest in B12's part, which would be important to vegans: Molloy et al. (44) (2009, Ireland) conducted three separate case-control studies and found that women with a serum B12 level of less than 300 pg/ml were significantly more likely to have a baby born with neural tube defects. Kirke et al. (41) (1993, Ireland) studied folate and B12 in 328 pregnant women. There was a statistically significant difference between B12 levels of women who had an infant with a NTD 243 pg/ml) and those who did not (296 pg/ml).

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Afman et al. (42) (2001, The Netherlands) found that low levels of a particular measure of B12 activity increased the risk of having a baby with a NTD by 5 times. Wald et al. (43) (1996, UK) studied 135 women, 27 of whom had a baby with a NTD. The women who had children with NTDs had B12 levels an average of 38 pg/ml lower in the first trimester than controls. However, after adjusting for folate levels, there was no independent association for B12 and NTDs. On the other hand, I am unaware of any reports of birth defects in babies born to vegan women with B12 deficiency, and it seems like this would have been reported in the scientific literature by now if it were a problem. To be safe, ensuring adequate B12 (and folic acid) intake in the weeks before and after conception may reduce the chances of NTDs.

What Level of B12 Should You Aim For?

Based on data from the National Health and Nutrition Examination Survey (NHANES) III, Selhub et al. (4) determined that 300 pmol/l (405 pg/ml) was the cutoff for keeping homocysteine at a healthy level. These levels can be accomplished by following the recommendations listed here.

Should Vegans have their Homocysteine or B12 Levels Checked?

Click here to see the Should I Get My B12 Status Tested?

References
1. Kwok T, Chook P, Qiao M, Tam L, Poon YK, Ahuja AT, Woo J, Celermajer DS, Woo KS. Vitamin B-12 supplementation improves arterial function in vegetarians with subnormal vitamin B-12 status. J Nutr Health Aging. 2012;16(6):569-73. | link 2. Loehrer FM, Schwab R, Angst CP, Haefeli WE, Fowler B. Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. J Pharmacol Exp Ther. 1997 Aug;282(2):845-50. 3. [No author.] Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ. 1998 Mar 21;316(7135):894-8. 4. Selhub J, Jacques PF, Dallal G, Choumenkovitch S, Rogers G. The use of blood concentrations of vitamins and their respective functional indicators to define folate and vitamin B12 status. Food Nutr Bull. 2008 Jun;29(2 Suppl):S67-73. Review. Link 5. Crane MG, Register UD, Lukens RH, Gregory R Cobalamin (CBL) studies on two total vegetarian (vegan) families. Vegetarian Nutrition. 1998; 2(3):87-92. 6. Haddad EH, Berk LS, Kettering JD, Hubbard RW, Peters WR. Dietary intake and biochemical, hematologic, and immune status of vegans compared with nonvegetarians. Am J Clin Nutr. 1999;70(suppl):586S-93S. 7. Mann NJ, Li D, Sinclair AJ, Dudman NP, Guo XW, Elsworth GR, Wilson AK, Kelly FD. The effect of diet on plasma homocysteine concentrations in healthy male subjects. Eur J Clin Nutr. 1999 Nov;53(11):895-9. 8. Mezzano D, Munoz X, Martinez C, Cuevas A, Panes O, Aranda E, Guasch V, Strobel P, Munoz B, Rodriguez S, Pereira J, Leighton F. Vegetarians and cardiovascular risk factors: hemostasis, inflammatory markers and plasma homocysteine. Thromb Haemost. 1999 Jun;81(6):913-7. 9. Mezzano D, Kosiel K, Martinez C, Cuevas A, Panes O, Aranda E, Strobel P, Perez DD, Pereira J, Rozowski J, Leighton F. Cardiovascular risk factors in vegetarians. Normalization of hyperhomocysteinemia with vitamin B(12) and reduction of platelet aggregation with n-3 fatty acids. Thromb Res. 2000 Nov 1;100(3):153-60. 10. Krajcovicova-Kudlackova M, Blazicek P, Kopcova J, Bederova A, Babinska K. Homocysteine levels in vegetarians versus omnivores. Ann Nutr Metab. 2000;44(3):135-8. 11. Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L, Guttormsen AB, Joglekar A, Sayyad MG, Ulvik A, Ueland PM. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr. 2001 Aug;74(2):233-41. 12. Herrmann W, Schorr H, Purschwitz K, Rassoul F, Richter V. Total homocysteine, vitamin b(12), and total antioxidant status in vegetarians. Clin Chem. 2001 Jun;47(6):1094-101. 13. Hung CJ, Huang PC, Lu SC, Li YH, Huang HB, Lin BF, Chang SJ, Chou HF. Plasma Homocysteine Levels in Taiwanese Vegetarians Are Higher than Those of Omnivores. J Nutr. 2002 Feb;132(2):152-158. 14. Bissoli L, Di Francesco V, Ballarin A, Mandragona R, Trespidi R, Brocco G, Caruso B, Bosello O, Zamboni M. Effect of vegetarian diet on homocysteine levels. Ann Nutr Metab. 2002;46(2):73-9. 15. Obeid R, Geisel J, Schorr H, Hubner U, Herrmann W. The impact of vegetarianism on some haematological parameters. Eur J Haematol. 2002 Nov;69(5-6):275-9. 16. Cappuccio FP, Bell R, Perry IJ, Gilg J, Ueland PM, Refsum H, Sagnella GA, Jeffery S, Cook DG. Homocysteine levels in men and women of different ethnic and cultural background living in England. Atherosclerosis. 2002 Sep;164(1):95-102. 17. Huang YC, Chang SJ, Chiu YT, Chang HH, Cheng CH. The status of plasma homocysteine and related B-vitamins in healthy young vegetarians and nonvegetarians. Eur J Nutr. 2003 Apr;42(2):84-90.

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18. Herrmann W, Schorr H, Obeid R, Geisel J. Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003 Jul;78(1):131-6. 19. Bostom AG, Silbershatz H, Rosenberg IH, Selhub J, D'Agostino RB, Wolf PA, Jacques PF, Wilson PW. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med. 1999 May 24;159(10):1077-80. 20. Kark JD, Selhub J, Adler B, Gofin J, Abramson JH, Friedman G, Rosenberg IH. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med. 1999 Sep 7;131(5):321-30. 21. Hoogeveen EK, Kostense PJ, Jakobs C, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD. Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes: 5-year follow-up of the Hoorn Study. Circulation. 2000 Apr 4;101(13):1506-11. 22. Vollset SE, Refsum H, Tverdal A, Nygard O, Nordrehaug JE, Tell GS, Ueland PM. Plasma total homocysteine and cardiovascular and non cardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr. 2001 Jul;74 (1):130-6. 23. No author listed. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002 Oct 2330;288(16):2015-22. 24. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002 Nov 23;325(7374):1202. 26. Key TJ, Fraser GE, Thorogood M, Appleby PN, Beral V, Reeves G, Burr ML, Chang-Claude J, Frentzel-Beyme R, Kuzma JW, Mann J, McPherson K. Mortality in vegetarians and nonvegetarians: detailed findings from a collaborative analysis of 5 prospective studies. Am J Clin Nutr. 1999 Sep;70(3 Suppl):516S-524S. 27. Robert A.J.M. van Dijk, Jan A. Rauwerda, Mieke Steyn, Jos W.R. Twisk, and Coen D.A. Stehouwer. Long-Term Homocysteine-Lowering Treatment With Folic Acid Plus Pyridoxine Is Associated With Decreased Blood Pressure but Not With Improved Brachial Artery Endothelium-Dependent Vasodilation or Carotid Artery Stiffness: A 2-Year, Randomized, Placebo-Controlled Trial. Arterioscler Thromb Vasc Biol. 2001 21: 2072-2079. 28. Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, Sun N, Liu L, Xu X. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet. 2007 Jun 2;369(9576):1876-82. 29. Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA. 2006 Dec 13;296(22):2720-6. (Abstract) 30. Hackam DG, Peterson JC, Spence JD. What level of plasma homocyst(e)ine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below 14 micromol/L. Am J Hypertens. 2000 Jan;13(1 Pt 1):105-10. 31. Appleby PN, Thorogood M, Mann JI, Key TJ. The Oxford Vegetarian Study: an overview. Am J Clin Nutr. 1999 Sep;70 (3 Suppl):525S-531S. 32. Appleby PN, Davey GK, Key TJ. Hypertension and blood pressure among meat eaters, fish eaters, vegetarians and vegans in EPIC-Oxford. Public Health Nutrition. 2002;5:645-654. 37. Loland KH, Bleie O, Blix AJ, Strand E, Ueland PM, Refsum H, Ebbing M, Nordrehaug JE, Nygard O. Effect of homocysteine-lowering B vitamin treatment on angiographic progression of coronary artery disease: a Western Norway B Vitamin Intervention Trial (WENBIT) substudy. Am J Cardiol. 2010 Jun 1;105(11):1577-84. Epub 2010 Apr 10. 38. Yang Q, Botto LD, Erickson JD, Berry RJ, Sambell C, Johansen H, Friedman JM. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation. 2006 Mar 14;113(10):1335-43. 39. Refsum H. Folate, vitamin B12 and homocysteine in relation to birth defects and pregnancy outcome. Br J Nutr. 2001 May;85 Suppl 2:S109-13. 41. Kirke PN, Molloy AM, Daly LE, Burke H, Weir DG, Scott JM. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Q J Med. 1993 Nov;86(11):703-8. 42. Afman LA, Van Der Put NM, Thomas CM, Trijbels JM, Blom HJ. Reduced vitamin B12 binding by transcobalamin II increases the risk of neural tube defects. QJM. 2001 Mar;94(3):159-66. 43. Wald NJ, Hackshaw AD, Stone R, Sourial NA. Blood folic acid and vitamin B12 in relation to neural tube defects. Br J Obstet Gynaecol. 1996 Apr;103(4):319-24. 44. Molloy AM, Kirke PN, Troendle JF, Burke H, Sutton M, Brody LC, Scott JM, Mills JL. Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic acid fortification. March 2, 2009. Pre-publication. 45. Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc. 2008 Nov;83(11):1203-12. 49. VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol. 2010 Sep;9(9):855-65. Epub 2010 Aug 3. 50. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Sleight P, Peto R, Collins R. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. 2010 Jun 23;303(24):2486-94. 51. See the section How Recommendations were Formulated of Vitamin B12: Are You Getting It?

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52. Antoniades C, Antonopoulos AS, Tousoulis D, Marinou K, Stefanadis C. Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials. Eur Heart J. 2009 Jan;30(1):6-15. Epub 2008 Nov 23. 53. Ebbing M, Bleie O, Ueland PM, Nordrehaug JE, Nilsen DW, Vollset SE, Refsum H, Pedersen EK, Nygard O. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA. 2008 Aug 20;300(7):795-804. 54. Khandanpour N, Loke YK, Meyer FJ, Jennings B, Armon MP. Homocysteine and peripheral arterial disease: systematic review and meta-analysis. Eur J Vasc Endovasc Surg. 2009 Sep;38(3):316-22. Epub 2009 Jun 27. Review. (Abstract) 55. Song Y, Cook NR, Albert CM, Van Denburgh M, Manson JE. Effect of homocysteine-lowering treatment with folic Acid and B vitamins on risk of type 2 diabetes in women: a randomized, controlled trial. Diabetes. 2009 Aug;58 (8):1921-8. Epub 2009 Jun 2. (Abstract) 56. Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K; NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006 Apr 13;354(15):1578-88. Epub 2006 Mar 12. (Abstract) 57. Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, Buring JE, Manson JE. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008 May 7;299(17):2027-36. 58. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J Jr; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006 Apr 13;354(15):1567-77. Epub 2006 Mar 12. 59. Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E; Heart Outcomes Prevention Evaluation 2 Investigators. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke. 2009 Apr;40(4):1365-72. Epub 2009 Feb 19. 60. Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis. Stroke. 2010 Jun;41(6):1205-12. Epub 2010 Apr 22. 61. Spence JD, Stampfer MJ. Understanding the complexity of homocysteine lowering with vitamins: the potential role of subgroup analyses. JAMA. 2011 Dec 21;306(23):2610-1. Link

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