by Jack Norris, RD • Last updated August 2013
- Background on Homocysteine
- Homocysteine in Vegetarians
- Cardiovascular Disease
- Birth Defects
- Bone Mineral Density
- What Level of B12 Should You Aim For?
- Should Vegans have their Homocysteine or B12 Levels Checked?
Vegans who don’t supplement their diet with vitamin B12 tend to have low vitamin B12 levels and elevated homocysteine. These conditions are especially linked with dementia and brain atrophy, but there is also evidence for birth defects, stroke, and low bone mineral density. Vegans who follow our B12 recommendations will minimize any such problems due to a low B12 intake.
Most vegans are probably aware of the need to ensure a reliable source of vitamin B12 to prevent nerve damage resulting from severe deficiency. There are also problems with mild vitamin B12 deficiency, especially dementia. Some of these problems are related to elevated homocysteine while others may not to be. Because low vitamin B12 status and elevated homocysteine normally go together, it is hard to separate one from the other.
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.
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.
Normal serum homocysteine levels are from 2.2 to 13.2 µmol/l (2). Levels of homocysteine in typical Western populations are about 12 µmol/l (3). It is not clear what the ideal level of homocysteine is, but 10 µmol/l or lower appears to pose little harm.
Homocysteine in Vegetarians
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.
|Plant Sources of Folate (74)|
|Black beans||cooked||1/2 cup||128|
|Romaine lettuce||shredded||1 1/2 cup||114|
|Orange juice||1 cup||109|
|Refried beans||canned||1/2 cup||106|
|Navy beans||cooked||1/2 cup||82|
|Sunflower seeds||1/4 cup||76|
|Pinto beans||cooked||1/2 cup||72|
|Kidney beans||cooked||1/2 cup||63|
At least 14 studies have measured the vitamin B12 and homocysteine levels in vegetarians. The findings have been consistent: When vegetarians do not supplement their diets with vitamin B12 through fortified foods or supplements, their B12 levels drop over time and their homocysteine becomes elevated higher than omnivores, inversely related to their vitamin B12 levels (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18). While this finding is stronger in vegans, it is also true of lacto-ovo vegetarians. In these studies, the average homocysteine levels of vegans were between 14 and 20 µmol/l compared to about 8 to 12 µmol/l for omnivores.
In contrast, a 1998 study of vegans receiving 500 µg/day of vitamin B12 for 2 months showed them to have homocysteine levels below 5 µmol/l (5). A 1999 study showed vegans who averaged 5.6 µg/day of B12 to have homocysteine levels of 7.9 µmol/l, slightly lower than the omnivores (6).
In other words, vegans who make sure they have a reliable intake of vitamin B12 should have ideal homocysteine levels, other things being equal such as enough folate in the diet and not having a genetic variant found in 5-25% of people which increases their need for folate (more info on this in The Linus Pauling Institute’s article, Folate: Genetic variation in folate requirements).
During the late 1990s and 2000s, homocysteine was suspected of causing damage to nerves and blood vessels.
A number of prospective studies found an association between homocysteine and early death. A 1999 study from the USA (19), a 1999 study from Israel (20), and a 2001 study from Norway (22) all found a statistically significant increase in mortality in people with homocysteine levels of about 14 to 15 µmol/l.
The early deaths associated with homocysteine had long been thought to be due mainly to an increase in cardiovascular disease, especially stroke. In 2002, two meta-analyses of prospective studies examining homocysteine and cardiovascular disease found an increased risk associated with elevated homocysteine (23, 24), as did a 2008 meta-analysis of 24 cohort studies (45). 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.
As recently as 2009, a group of researchers from the 1st Cardiology Department, Athens University Medical School in Greece wrote:
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. (52)
At the same time, clinical trials using folate, vitamin B12, and vitamin B6 to lower homocysteine levels in patients were mostly failing to provide any benefit for heart disease (29, 49, 50, 53, 54, 55, 56 , 57, 37), although a number of showed a benefit in preventing stroke (28, 58, 59, 60).
In 2010, Clarke et al. (62) published a meta-analysis of clinical trials of homocysteine-lowering therapy and after conducting many different analyses, concluded that there was no evidence, or even a hint, that lowering homocysteine reduces the risk of cardiovascular events, including stroke, even in the trials with large reductions in homocysteine over the course of five years.
In 2013, the Cochrane Collaboration performed a meta-analysis of 12 clinical trials (63). Homocysteine-lowering interventions did not significantly reduce heart disease, stroke, or mortality (though stroke was close to significant with a risk ratio of 0.91, 0.82-1.0). Regarding primary intervention (preventing events in people who had not previously had one), the researchers believed that no further trials were necessary to disprove a risk reduction of 20% or more.
A 2012 randomized, placebo-controlled, crossover clinical trial studied the impact of vitamin B12 supplements on cardiovascular markers in vegetarians (mostly lacto-ovo) (1). The study was done in Hong Kong and there were 50 vegetarians, two of whom were vegan. Twelve subjects (24%) had serum vitamin B12 between 203-406 pg/ml and 35 subjects (70%) < 203 pg/ml. After 12-week periods of 500 µg of B12 per day, blood flow improved after vitamin B12 treatment but not after placebo. These positive effects appeared to be better correlated with the correction of vitamin B12 deficiency than with the lowering of homocysteine.
In terms of cardiovascular disease, it is still possible that vitamin B12 could prevent long-term damage in vegans, with most of the benefit coming in the form of stroke prevention, though it is not as much of a concern as it once was.
Two literature reviews from 2000 (64, 65) note that people with Alzheimer’s disease have elevated homocysteine, elevated methylmalonic acid (a metabolite indicating low B12 status), low B12 levels, or low folate levels. A 2009 meta-analysis of prospective studies (67) showed elevated homocysteine to be associated with risk of Alzheimer’s disease. In some cases, B12-deficient dementia (which is a concern in itself) may be misdiagnosed as Alzheimer’s disease (68). However, the data is somewhat mixed (66).
A 2008 meta-analysis of B-vitamin supplementation and cognitive function found little benefit for people already diagnosed with dementia, but did improve cognition in elderly people with elevated homocysteine but who were not diagnosed with dementia (69). Another 2008 study found that B-vitamin supplementation did not slow cognitive decline in people with mild to moderate Alzheimer’s disease (70).
A 2011 study from Chicago Health and Aging Project (72), found that poor vitamin B12 status in older age is frequently missed by measuring serum vitamin B12 levels alone. Their findings suggested that methylmalonic acid (MMA) may affect cognition by reducing total brain volume, whereas the effect of elevated homocysteine on cognition may be caused by increasing white matter hyperintensity volume and strokes.
A 2013 study from University of Oxford found that B-vitamin treatment significantly reduced brain atrophy, in older subjects at risk for dementia with homocysteine levels above 11 µmol/l, over the course of 2 years (73). They believed that vitamin B12 supplementation (500 µg/day) was the main factor in preventing the atrophy. Some of the authors on this paper had a conflict of interest in that they hold patents to certain vitamin B therapies.
A 2002 report from the Oxford Vegetarian Study (71) showed that while overall mortality was the same between vegetarians and non-vegetarians, vegetarians had 2.2 times the death rate from mental and neurological diseases (the finding barely reached statistical significance). Given the research above, a low vitamin B12 intake seems like a possible explanation for this finding in vegetarians.
There is evidence that depression is often related to B12 deficiency. Some evidence suggests B12 deficiency can be confined to the brain. In such cases, massive doses of methylcobalamin might be necessary to replete B12 stores in the brain.
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).
- 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.
Bone Mineral Density
Taking vitamin B12 might also be important for bone mineral density. Two studies have linked low B12 status in vegetarians to poorer bone health.
For more information, see the Vitamin B12 and Bone Mineral Density.
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 minimum B12 level required to prevent elevated homocysteine. These levels can be achieved by following the B12 recommendations in Daily Needs.
Should Vegans have their Homocysteine or B12 Levels Checked?
Click here to see the article Should I Get My B12 Status Tested?
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.
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.
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.
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.
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.
17. 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.
18. Krivosikova Z, Krajcovicova-Kudlackova M, Spustova V, Stefikova K, Valachovicova M, Blazicek P, Nemcova T. The association between high plasma homocysteine levels and lower bone mineral density in Slovak women: the impact of vegetarian diet. Eur J Nutr. 2009 Oct 7.
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.
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.
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.
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)
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.
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.
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.
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.
62. Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, Bønaa KH, Spence JD, Nygård O, Jamison R, Gaziano JM, Guarino P, Bennett D, Mir F, Peto R, Collins R; B-Vitamin Treatment Trialists’ Collaboration. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med. 2010 Oct 11;170(18):1622-31.
63. Martí-Carvajal AJ, Solà I, Lathyris D, Karakitsiou DE, Simancas-Racines D. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2013 Jan 31;1:CD006612.
64. Nourhashemi F, Gillette-Guyonnet S, Andrieu S, Ghisolfi A, Ousset PJ, Grandjean H, Grand A, Pous J, Vellas B, Albarede JL Alzheimer disease: protective factors. Am J Clin Nutr. 2000 Feb;71(2):643S-649S.
70. Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ; Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled. JAMA. 2008 Oct 15;300(15):1774-83.
73. Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Smith AD. Preventing Alzheimer\’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9523-8. doi: 10.1073/pnas.1301816110. Epub 2013 May 20.