Review of B12 & Folate Research: May 2016

Reading Time: 8 minutes

1-s2.0-C20090377144-cov150hAntony Haynes, BA, RNT explores two key questions realted to supplementation with B12 and Folic acid. Want to listen to a pod cast? click me

  1. Should we fortify foods with folic acid to help reduce the risk of neural tube defects (NTDs)? &
  2. Are there really dangers of ingesting too much folic acid, particularly with regard to neurological conditions?

Some countries such as the United States, Canada, Chile, Costa Rica, South Africa and others have implemented fortification policies with a risk reduction of between 20 and 50%, on average about a third.

Other countries including the United Kingdom, Ireland and the EU have held back for a variety of cautious reasons, including uncertainties about the risks of folic acid fortification to ageing populations increasingly at risk of vitamin B12 deficiency.[1]

Dr Edward Reynolds from King’s College, London has researched this matter, reviewing the literature from the 1940’s. He maintains that the current upper limit of folate, which is 1 mg, is too high. It turns out that he has good reason for this opinion, which we will get to shortly.

Folate and vitamin B12 have fundamental roles in central nervous system function at all ages, especially in purine, thymidine, neucleotide, and DNA synthesis, genomic and nongenomic methylation and, therefore, in tissue growth, differentiation and repair.[2]

In fact, low folate and raised homocysteine levels are risk factors for dementia, including Alzheimer’s disease, and depression.[3] It’s not just low folate that has this association, but vitamin B12 too, which may be related to accelerated aging of the brain.

However, it has been long known that excess folic acid is harmful to the nervous system in the presence of a vitamin B12 deficiency. This would be particularly relevant in those with Pernicious Anaemia (PA), and the elderly whose absorption of B12 is more likely to be compromised. The bigger the dose of folic acid and the longer the duration the greater the frequency of neurological relapses.

Dr Reynolds identifies that the masking of the B12 deficiency has been the central reason behind expert committees’ reasoning behind warning against higher intakes of folic acid. As with many other nutrients within the human body, there is a balance to be had. However, the Institute of Medicine understood that folic acid could precipitate or aggravate the neurological manifestations of vitamin B12 deficiency.[4]

When those patients with PA were followed up over 5 to 10 years, it was discovered that those who remained well had at least some B12, and the addition of a liver extract rich in B12 prevented neurological relapse, as well as normalising haematological markers.

So, it appears that the ingestion of or treatment with folic acid increases the demand for B12, adding to a depletion of B12, and thus precipitating or aggravating the neurological deterioration. This has been confirmed in two short term studies of the administration of folic acid in patients with PA, without neurological complications in whom serum B12 levels fell in the great majority of patients. Furthermore, clinical studies show that PA patients who had neurological complications had the highest serum folate levels.

In epidemiological studies in the United States and Australia, the long-term exposure to food fortification of folate has been demonstrated in elderly folk to worsen neurological symptoms with incipient or definite vitamin B12 deficiency. The duration of the intake is important. What’s more is that patients with vitamin B12 deficiency associated with high folate levels have higher levels of homocysteine and methylmalonic acid than deficient subjects with normal folate levels.[5],[6]

Dr Reynolds concludes his paper with a very sensible and balanced comment, which may not come as any surprise to experienced nutritional therapists who have followed the evidence trail of their patients. Dr Reynolds asserts that the creation of a new upper limit for folate would not be needed; all that is required is to ensure that there is no vitamin B12 deficiency in the presence of the excess folic acid. In studies[7],[8] focused on homocysteine lowering cardiovascular disease prevention, the subjects were given small doses of vitamin B12 in addition to 2.5 mg of folic acid per day for 2 – 5 years without neurological complications, as they were protected from the risk to the nervous system associated with such an excess of folic acid.[9],[10]

There is a very strong case for suggesting that mandatory folic acid fortification policies should always be accompanied by vitamin B12 fortification. There is already evidence that vitamin B12 deficiency is also a risk factor for NTDs, and it has been suggested that the addition of vitamin B12 to folic acid would further reduce the risk of NTDs resulting from fortification policies.[11],[12],[13]

Summary Points

  1. Food fortification of folic acid has been adopted by some countries but not others, and has reduced the risk of NTDs by a third. However, there is still uncertainty about folate fortification which is why some countries including the UK and the EU have not adopted this practice.
  1. Historical research emphasises the importance of folic acid masking a B12 deficiency rather than focusing on the negative impact of folic acid at higher levels on neurological health.
  1. Higher levels of folic acid aggravate neurological symptoms if there is a lack of B12 compared to there being some vitamin B12 present, and the longer the duration of the intake of folic acid the greater the negative impact.
  1. Low levels of folate and B12 are also both related to accelerated brain aging. Elevated levels of homocysteine were found to be consistent with the low levels of these B vitamins.
  1. Even just a small amount of vitamin B12 can mitigate the negative impact of higher intakes of folate, and as such there is persuasive evidence to suggest that food fortification of vitamin B12 along with folic acid is warranted.

Observations & Comments

  1. The specific molecular mechanism that explains the aggravation of neurological symptoms when high levels of folic acid are consumed is not discussed nor elucidated.
  1. The specific molecular mechanism by which even small amounts of B12 protect against these neurological symptoms in the presence of higher levels of folate are not discussed.
  1. The specific amount of vitamin B12 is not discussed, and nor are suggestions made as to what food would provide this, nor what mcg supplement would suffice.
  1. The issue of what form of folate or B12 is most effective is not discussed.


[1] Committee on Medical Aspects of Food and Nutrition Policy (COMA). Folic Acid and the Prevention of Disease. The Stationery Office: London, UK, 2000.

[2] Reynolds EH. The neurology of folic acid deficiency. Handb Clin Neurol. 2014;120:927-43. doi: 10.1016/B978-0-7020-4087-0.00061-9. View Abstract

[3] Reynolds EH. What is the safe upper intake level of folic acid for the nervous system? Implications for folic acid fortification policies. Eur J Clin Nutr. 2016 May;70(5):537-40. doi: 10.1038/ejcn.2015.231. Epub 2016 Feb 10. View Abstract

[4] Reynolds EH. What is the safe upper intake level of folic acid for the nervous system? Implications for folic acid fortification policies. Eur J Clin Nutr. 2016 May;70(5):537-40. doi: 10.1038/ejcn.2015.231. Epub 2016 Feb 10. View Abstract

[5] Hooshmand B, Mangialasche F, Kalpouzos G, Solomon A, Kåreholt I, Smith D, Refsum H, Wang R, Mühlmann M, Ertl-Wagner B, Laukka EJ, Bäckman L, Fratiglioni L, Kivipelto M. Association of Vitamin B12, Folate, and Sulfur Amino Acids With Brain Magnetic Resonance Imaging Measures in Older Adults: A Longitudinal Population-Based Study. JAMA Psychiatry. 2016 Apr 27. doi: 10.1001/jamapsychiatry.2016.0274. [Epub ahead of print] View Abstract

[7] Morris MS, Selhub J, Jacques PF. Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the framingham heart study. J Am Geriatr Soc. 2012 Aug;60(8):1457-64. doi: 10.1111/j.1532-5415.2012.04076.x. Epub 2012 Jul 12. View Abstract

[8] Moore EM, Ames D, Mander AG, Carne RP, Brodaty H, Woodward MC, Boundy K, Ellis KA, Bush AI, Faux NG, Martins RN, Masters CL, Rowe CC, Szoeke C, Watters DA. Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: combined data from three cohorts. J Alzheimers Dis. 2014;39(3):661-8. doi: 10.3233/JAD-131265.

View Abstract

[9] Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, Sides EG, Wang CH, Stampfer M. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004 Feb 4;291(5):565-75. View Abstract

[10] 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. View Abstract

[11] Selhub J, Morris MS, Jacques PF. In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19995-20000. Epub 2007 Dec 4. View Abstract

[12] 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. Pediatrics. 2009 Mar;123(3):917-23. doi: 10.1542/peds.2008-1173. View Abstract

[13] Wang ZP, Shang XX, Zhao ZT. Low maternal vitamin B(12) is a risk factor for neural tube defects: a meta-analysis. J Matern Fetal Neonatal Med. 2012 Apr;25(4):389-94. doi: 10.3109/14767058.2011.580800. Epub 2011 Jun 1. View Abstract

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