Homocysteine Update: This Time a Big One

Mild vitamin B12 deficiency causes homocysteine levels to rise. This has been a concern for vegans who do not supplement regularly with vitamin B12 because their homocysteine tends to be at a level that has been associated with cardiovascular disease and early death.

In the past few years, however, evidence has been mounting that homocysteine-reducing therapy is not effective in reducing cardiovascular disease. Two meta-analyses, from 2010 (1) and 2013 (2) indicate that there may be no benefit from lowering homocysteine levels for cardiovascular disease.

At the same time, evidence continues to mount that elevated homocysteine can cause dementia, with a 2013 study showing that homocysteine-lowering treatment can significantly reduce brain atrophy (3).

Because of these findings, I have drastically changed the VeganHealth.org article, Mild B12 Deficiency – Cardiovascular Disease | Dementia | Birth Defects | Bone Mineral Density. It is too much to reproduce here, but I hope you will check it out!

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1. 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. | link

2. 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. | link

3. 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. | link

11 Responses to “Homocysteine Update: This Time a Big One”

  1. Dan Says:

    The Douaud trial is interesting – thanks for bringing that to your readers’ attention. I wasn’t aware of it. My concern is that brain atrophy is still only a biomarker and not a disease state. I have seen many cognitively intact patients with severe cerebral atrophy (the brain normally shrinks with age, and in the very old, water-filled spaces particularly predominate). In other words, no one presents to their physician complaining of brain atrophy.

    A clinical correlation for these data would be essential.

    Having said that, I think it’s mandatory that vegans get enough B12, given the fact that clinical B12 deficiency remains a highly preventable disease (with sometimes irreversible consequences when advanced).

    Whether homocysteine represents a causative ‘bad actor’ or is just a marker/epiphenomenon remains unknown. The large-scale randomized trials would suggest the latter. Folic acid has enough concerns to mitigate against using it for widespread use in a B cocktail for homocysteine reduction (ie. prostate, colon and lung cancer), unless one has a really poor diet, is an alcoholic, has small bowel disease, or is planning to get pregnant. In fact, our lab has stopped routinely testing for folate levels, because deficiency has become so rare with widespread fortification of the grain supply. The government has removed the test from the requisition.

  2. Jack Norris RD Says:


    For what it’s worth, I don’t think they were looking so much at the cerebrum.

    The authors say, “Direct comparison between groups revealed a significant effect of treatment: subjects receiving B vitamins showed a significant reduction of atrophy compared with the placebo group in posterior brain regions in- cluding bilateral hippocampus and parahippocampal gyrus, ret- rosplenial precuneus, lingual and fusiform gyrus, as well as in the cerebellum (Table 2). These regions are among those most af- fected in AD, and also in MCI subjects who later convert to AD (14, 15, 22–24). In the regions showing significant treatment effect, the average loss of GM over 2 y was 3.7% (±3.7) in the placebo group compared with only 0.5% (±2.9) in the B-vitamin group (Fig. 2 and Fig. S1).”

  3. Dan Says:

    That’s very interesting. I am not a cognitive neurologist but I suppose that suggests some specificity to the effect. Hippocampus is critical in memory and cerebellum for balance/gait. Both are affected in dementia. I am wondering why the authors did not report any cognitive outcomes data – too small a study perhaps and therefore underpowered for cognitive battery tests?
    The dose of B12 was quite high – 800 micrograms per day – which is much higher than in the usual B-complex. Clinically I’ve used up to 1200 micrograms and some of my colleagues uses 2400 micrograms orally to treat B12 deficiency.

  4. Jack Norris RD Says:


    > why the authors did not report any cognitive outcomes data

    They said, “Unfortunately, such testing is subject to short-term fluctuations, practice effects and intra-/interrater variability. In contrast, structural neuroimaging provides a robust way of assessing changes of a longer-term nature, including the impact of the treatment.”

    Do you want me to send you the study?

  5. Andreas Says:

    What about stress, air pollution and other toxins that lower the quantity of those vitamins in the body?

  6. Dan Says:


    Sorry – I was just being lazy and read only the abstract. I will get the full PDF.

    In clinical medicine, one gets inundated with “surrogate marker” trials, and too frequently they do not pan out when tested against patient-important outcomes such as death or disability. However, I do recall that B12 improved cognitive function in elderly persons in a trial in The Lancet published a few years back. I think there is tremendous rationale already for vegans to take B12 irrespective of effect on brain shrinkage (I don’t know if these patients were vegans or not, but I’m sure they eliminated anyone with subclinical B12 deficiency at baseline).

    I will have a look at the study text. Thanks.

  7. Joel Marks Says:

    I am not sure I understand the logic that led to your final conclusion about Cardiovascular Disease, Jack. You write:

    “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.”

    Why is it “not as much of a concern as it once was”? Because there seems to be little evidence of significant benefit from interventions? My confusion is that this would still seem to leave open the possibility that inadequate B12 was the cause of the disease, even though it cannot cure the disease; and then it would indeed be a concern. So further clarification would be appreciated. Thanks.

  8. Jack Norris RD Says:


    > My confusion is that this would still seem to leave open the possibility that inadequate B12 was the cause of the disease, even though it cannot cure the disease; and then it would indeed be a concern.

    This possibility is still open. There were some primary prevention trials in the meta-analyses in which people did not yet have disease and they still concluded there was no basis to think homocysteine had an effect. I still think elevated homocysteine/mild vitamin B12 deficiency is important to avoid because of dementia, especially, and perhaps the symptoms of dementia have some interaction with the symptoms of stroke and are being conflated in some of these observational studies.

    But at this time, especially when it comes to heart disease, the preponderance of the evidence seems to be that homocysteine has very little, if any, effect.

  9. Dan Says:

    Unfortunately, there’s no hard evidence that B-vitamins for reducing homocysteine prevent dementia either. It hasn’t been tested to the best of my knowledge in vegans, however. The interventions which seem to prevent dementia are blood pressure lowering in people with hypertension; maintenance of a healthy body weight; smoking cessation in smokers; and regular physical activity. Not that all of these have been tested in randomized trials.

  10. Dan Says:

    Following abstract may be of interest:

    The projected effect of risk factor reduction on Alzheimer’s disease prevalence.
    Barnes DE, Yaffe K
    Lancet Neurol. 2011;10(9):819.

    At present, about 33·9 million people worldwide have Alzheimer’s disease (AD), and prevalence is expected to triple over the next 40 years. The aim of this Review was to summarise the evidence regarding seven potentially modifiable risk factors for AD: diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactivity. Additionally, we projected the effect of risk factor reduction on AD prevalence by calculating population attributable risks (the percent of cases attributable to a given factor) and the number of AD cases that might be prevented by risk factor reductions of 10% and 25% worldwide and in the USA. Together, up to half of AD cases worldwide (17·2 million) and in the USA (2·9 million) are potentially attributable to these factors. A 10-25% reduction in all seven risk factors could potentially prevent as many as 1·1-3·0 million AD cases worldwide and 184,000-492,000 cases in the USA.
    Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94121, USA. deborah.barnes@ucsf.edu

  11. Andreas Says:



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