Evidence-Based Nutrient Recommendations

Homocysteine and Mild B12 Deficiency in Vegans


More Information on Vitamin B12

Contents

Summary

Most vegans are probably aware of the need to ensure a reliable source of vitamin B12 to prevent nerve damage or anemia resulting from severe deficiency. Vitamin B12 is also needed to keep homocysteine levels from becoming elevated. Elevated homocysteine has been linked to cardiovascular disease, poor cognition, and low bone mineral density. Vegans who don’t supplement their diet with B12 tend to have low B12 levels and elevated homocysteine. Vegans who follow our B12 recommendations will minimize any such problems due to a low B12 intake.

Background on Homocysteine

Methionine is an essential amino acid obtained from protein in the diet. As a byproduct of metabolism, some methionine is converted to homocysteine. The body turns much of this homocysteine back into methionine with the help of vitamin B12, but if someone is B12-deficient, homocysteine levels will increase.

Normal serum homocysteine levels are from 2.2 to 13.2 µmol/l (Loehrer, 1997). Levels of homocysteine in typical Western populations are about 12 µmol/l (HLTC, 1998).

Treating disease with pharmacological doses of nutrients is normally beyond the scope of VeganHealth.org. Rather, our goal is to make sure vegans have the information they need to match any benefits non-vegans receive from their typical nutrition, and we try to base our recommendations on the nutrient guidelines set by the U.S. government.

The story about homocysteine continues to be a work in progress as research is conducted. The general pattern that has emerged, based on observational studies, is that it’s important to keep homocysteine levels <10 µmol/l in order to prevent or slow chronic disease. Meeting typical government recommendations for folate and vitamin B12 will keep most people in the safe range, though there’s an argument that the U.S. RDA for B12 of 2.4 µg might be a bit low.

Some people have a genetic variant in folate metabolism, the MTHFR polymorphism, that might require supplementation with 5-methyl-THF though research is currently inconclusive (see the National Institutes of Health article Folate for more information).

But because homocysteine has been a focus of B12 nutrition in vegan diets since the late 1990s, we’ve continued to periodically report on the general state of the evidence for homocysteine-lowering treatments. Many clinical trials have investigated the impact of pharmacological doses of B12, folic acid, and vitamin B6 in treating diseases associated with elevated homocysteine. To date, they have not shown much promise, with some exceptions noted below.

Homocysteine in Vegetarians

In most non-vegetarians with elevated homocysteine, folate is more of a problem than is B12. Vegetarians tend to have an advantage regarding folate as many plant foods are good sources. The RDA for adults is 400 µg.

Plant Sources of Folate
Food Preparation Serving µg
Lentils cooked 1/2 cup 179
Black beans cooked 1/2 cup 128
Romaine lettuce shredded 1 1/2 cup 114
Orange juice 1 cup 109
Spinach cooked 1/2 cup 103
Refried beans canned 1/2 cup 106
Garbanzo beans
(aka chickpeas)
cooked 1/2 cup 80
Navy beans cooked 1/2 cup 82
Broccoli cooked 1 cup 78
Sunflower seeds 1/4 cup 76
Pinto beans cooked 1/2 cup 72
Kidney beans cooked 1/2 cup 63
Taken from Wardlaw GM. Perspectives in Nutrition, 4th Ed. Boston, MA: McGraw-Hill; 1999.

Since vegetarian diets are typically high in folate, elevated homocysteine levels in vegetarians are normally due to a low B12 intake.

At least 14 studies have measured the vitamin B12 and homocysteine levels in vegetarians. The findings have been consistent—when vegetarians don’t supplement their diets with B12 their homocysteine levels rise to unhealthy levels (Bissoli, 2002; Crane, 1998; Haddad, 1999; Herrmann, 2001; Herrmann, 2003; Huang, 2003; Hung, 2002; Krajcovicova-Kudlackova, 2000; Krivosikova, 2009; Mann, 1999; Mezzano, 1999; Mezzano, 2000; Obeid, 2002; Refsum, 2001). While this finding is stronger in vegans, it’s also true of lacto-ovo vegetarians.

In the 14 studies above, the average homocysteine levels of vegans were 14 to 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 (Crane, 1998). 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 (Haddad, 1999).

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).

Mortality and Cardiovascular Disease

A number of prospective studies have found an association between elevated homocysteine and early death. Studies from the USA (Bostom, 1999), Israel (Kark, 1999), and Norway (Vollset, 2001) all found a statistically significant increase in mortality in people with homocysteine levels of about 14 to 15 µmol/l.

Two meta-analyses of prospective, observational studies found elevated homocysteine levels associated with an increased risk of cardiovascular disease (HSC, 2002; Wald, 2002), as did a 2008 meta-analysis of 24 cohort studies (Humphrey, 2008). A 2006 analysis showed that a reduction in rates of death from stroke in both the USA and Canada paralleled the fortification of foods with folic acid (Yang, 2006).

The Cochrane Database of Systematic Reviews conducted a meta-analysis of pharmacological doses of B-vitamins for lowering homocysteine and preventing cardiovascular disease in people with and without pre-existing cardiovascular disease. Their analysis included 15 high-quality, randomized controlled trials involving 71,422 participants lasting 1 to 7 years. They found a reduced risk of stroke (RR 0.90, CI 0.82–0.99), but no reduction in overall mortality or heart attacks (Martí-Carvajal, 2017). It’s not clear to what degree the participants in these trials had elevated homocysteine levels with some trials not reporting levels. A meta-analysis comparing the impact of lowering homocysteine only in people with levels above a particular threshold might find a stronger effect, but a closer examination is beyond the scope of general vegan nutrition and this article.

A 2012 randomized, placebo-controlled, crossover trial from Hong Kong studied the impact of B12 supplements on cardiovascular markers in 50 vegetarians, including 2 vegans. 35 subjects (70%) had B12 levels <150 pg/ml. After 12-week periods of 500 µg of B12 per day, blood flow improved with B12 supplementation. The positive effects more closely correlated to the correction of B12 deficiency than to lowering homocysteine (Kwok, 2012).

Adequate folate status might be more important than B12 for the primary prevention of cardiovascular events in the general population. For vegans, it’s important to follow B12 recommendations in order to maintain homocysteine levels below 10 µmol/l to minimize the risk of cardiovascular disease.

Cognition

Vitamin B12 is important for nerve function and people who become severely B12-deficient typically exhibit neurological and often cognitive problems. This has raised concerns that mild B12-deficiency over many years could contribute to cognitive impairment or dementia.

Observational Studies of Homocysteine and Cognition

Early reviews found associations between elevated homocysteine, low serum folate, low serum B12, and elevated methylmalonic acid (MMA) and risk of Alzheimer’s disease (Nourhashemi, 2000; Selhub, 2000; Van Dam, 2009). A 2017 prospective study found that higher homocysteine levels were associated with cognitive decline over the course of three years in middle-aged people (Walters, 2018).

A 2011 study from the Chicago Health and Aging Project cross-sectionally compared vitamin B12 metabolites with cognition scores in 121 older adults. An average of 4.6 years later, subjects were given an MRI. While serum B12 levels were not associated with outcomes, elevated MMA was associated with poor cognition at baseline and lower total brain volume as measured by the MRI (Tangney, 2011).

The Effects and Mechanism Investigation of Cholesterol and Oxysterol on Alzheimer’s disease (EMCOA) study from China included 2,533 people aged 50-70 years with normal cognitive functioning at baseline. After 2 years, the lowest quartile of B12 intake (0 to 1.3 µg/day) was associated with an accelerated cognitive decline across all domains, and the second quartile of B12 intake (1.3 to 2.1 µg/day) was associated with a decline in most cognitive domains, compared to the upper two quartiles (2.1 to 3.4 and 3.4 to 37 µg/day). In a subgroup case-control analysis, being diagnosed with Mild Cognitive Impairment (MCI) was not associated with B12 intake or B12 serum levels but rather with folate deficiency, disturbances of B-vitamin metabolism, and an imbalance of antioxidant-to-free radical ratio (An, 2019).

A cross-sectional study from Italy found a correlation between B12 levels and brain activity, and brain activity and cognitive scores, but no direct correlation between B12 levels and cognitive scores. It included 74 people, average age 74 years, of whom 56 had mild cognitive impairment. B12 levels averaged 297 ± 146 pmol/l (Cecchetti, 2019).

In a large observational study from South Korea, 2,991 older adults, average age 76.4, were divided into B12-insufficient (<259 pmol/l) and sufficient (≥259 pmol/l). Less than 2% of the subjects had a B12 level <148 pmol/l. There was no difference between the average MMSE scores between groups in the fully adjusted model (Soh, 2020).

In summary, it appears that B12-related cognitive impairment is limited to people who would traditionally be considered at least mildly B12-deficient or with marginal B12 intakes.

Clinical Trials of Homocysteine and Cognition

The Cochrane Database of Systematic Reviews is a leading journal and database for systematic reviews in healthcare. They conducted a review of randomized clinical trials using B vitamins to slow cognitive decline in people diagnosed with mild cognitive impairment but without overt vitamin deficiencies (McCleery, 2018). Five trials with 879 participants qualified, though one used only folic acid. They concluded that there was probably little or no effect of B vitamins taken for 6 to 24 months on episodic memory, executive function, speed of processing, or quality of life.

The Cochrane review included the VITACOG trial, using a daily dose of folic acid (0.8 mg), vitamin B12 (500 µg), and vitamin B6 (20 mg) for 2 years and found evidence for a slower rate of brain atrophy (Douaud, 2013). In their own meta-analysis, Smith and Refsum, two of the researchers from the VITACOG study, argue that B-vitamins are likely to provide benefit only to populations whose baseline homocysteine levels are greater than 10 to 11 µmol/l (Smith, 2016). Smith and Refsum hold patents to certain B-vitamin therapies (Douaud, 2013).

Vegetarians and Vegans

A 2002 report from the Oxford Vegetarian Study (Appleby, 2002) showed that while overall mortality was the same between vegetarians (including vegans) and non-vegetarians, vegetarians had about twice the death rate from mental and neurological diseases, though the finding barely reached statistical significance (RR 2.21, CI 1.02–4.78). A low vitamin B12 intake seems like a possible explanation for this finding.

At this time, it’s prudent for vegans to make sure they’re meeting B12 recommendations to prevent possible cognitive decline or dementia. A mild, long-term deficiency does not appear to be easily corrected by taking B12 once cognitive difficulties are discovered.

Bone Mineral Density

Vitamin B12 might also be important for bone mineral density, and two studies have linked low B12 status in vegetarians to poorer bone health. For more information, see the Vitamin B12 and Bone Mineral Density.

Bibliography

Last updated August 2020

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