Folic acid has been hailed as the big vitamin success story for over two decades. Many scientists cite folic acid’s role in preventing neural tube defects, like spina bifida and anencephalus, as one of the most firmly established pieces of evidence justifying supplementation or food fortification with the vitamin, at least in preconceptual and pregnant women. But as of the mid-naughties, the public became more nervous about folic acid’s use, especially in supplements, given emerging evidence suggesting that high doses may increase some types of cancer (e.g. breast, colorectal, prostate) in some people. It should be stressed that this occurred despite there having been a good clutch of other studies suggesting cancer protective effects of folic acid. Also, there has been an emerging view that any links between high total folic acid intake and cancer might be related more to the promotion of existing neoplasms and tumours, rather than the initiation of tumours.    

The inevitable now appears to be happening, at least in Ireland: neural tube defects are on the increase. Today, the Irish Times calls this a “scandal in the making”.  This is almost certainly the result of folate deficiency – and that means insufficient folate intake from all sources, whether it is naturally in the diet, from fortified foods or from supplements, or any combination thereof. You could say, we might be almost back to square one on the folate/NTD issue.

Looking at the latest data on NTD frequency in the EU, there is considerable variation between member states. There are too many factors involved to understand the relationships without much more research, but it’s nevertheless interesting that a country like France that has among the most restrictive regulations on dosages of vitamins has the highest rates, while the UK, with its highest rate of teen pregnancies, also has a high rate, which may be linked to reduced rates of supplementation or poor diets among preconceptual and pregnant young women.

Synthetic folic acid under the spotlight

While the folic acid success story is well known by many, it would be unfair to suggest that life-saving benefits were limited to folate. Let’s not forget that gross deficiencies in other vitamins are responsible for other diseases, such as vitamin D and rickets, B1 and beriberi, and niacin and pellagra. But even more relevant today is the science that’s suggesting that some people don’t absorb or metabolise essential vitamins properly because they have particular genetic polymorphisms (e.g. vitamin D receptor; folate metabolism, see below) or malabsorption issues.

As of around 2006, folic acid joined particular forms of vitamin E and beta-carotene that might be problematic if given in large amounts in their synthetic and isolated forms. A limited body of science suggests that the rates of certain types of cancer may increase in some with very high rates of folic acid supplementation in some, although, as mentioned before, this is more likely to do with the promotion of existing neoplasms and tumours rather than the initiation of new tumours.

Taking all of this into account, the media, not known for their expertise on folate, and many doctors and clinicians have been warning people to be wary of folic acid supplements, especially women.

US National Institutes of Health calls on more research

When in doubt, do more research. It’s a plausible notion, but will new science suddenly deliver clarity? The complexities around folic acid intake via fortified foods and supplements may never be resolved by consensus among scientists in our life times. In the meantime, how many will suffer? And not just from NTDs, but also from a rash of other issues relating to the gamut of other processes intimately linked to folate, such as impaired detoxification, cognitive decline, neurodegeneration and heart disease.

In this climate of confusing science and public health policy, including whether or not food fortification is a good thing, or may contribute to other downstream risks, the National Institutes of Health (NIH) in the US has just closed the door on a consultation over the science required to better assess folic acid’s complicated interactions with our health. ANH has weighed in on this via its US office, ANH-USA, with its submission being prepared by Rob Verkerk PhD, ANH-Intl’s founder and executive and director, also ANH-USA’s scientific director.

Among the key points we make in our consultation input are the following:

  1. There are no risks linked to food forms of folate (e.g. in leafy green vegetables, French beans, oranges) at any known dose rates. The risks are only associated with monoglutamatic, synthetic folic acid (known also as pterolymonoglutamic acid). There are two readily available forms of polyglutamic folate that are also free from any known risks, these being calcium and glucosamine salts of the bioactive form, 5’-methyltatrahydrofolate (5MTHF). These are referred to in Europe as calcium methylfolate and (6S)-5-methyltetrahydrofolic acid, glucosamine salt, respectively.
  2. It’s of critical importance to study how much unmetabolised folic acid (UMFA) persists in the bloodstream of those consuming high doses of synthetic folic acid, even after a fast. There is a suggestion that this might present one of the main risks in high intake groups, and a recent US study showed that up to about 40% of older Americans have significant levels of UMFA which persist after a fast.
  3. It is essential to look at the effects of multiple genetic polymorphisms that effect the conversion of folic acid to the bioactive form, 5’-methyltatrahydrofolate (5MTHF). These include polymorphisms in the following enzymes: reduced folate carrier 1 (RFC1) gene (A80G), methylenetetrahydrofolate reductase (MTHFR) (C677T, A1298C), methionine synthase reductase (MTRR) (A66G) and dihydrofolate reductase (DHFR) (C-1610G/T, C-680A, and A-317G). Consideration of these genetic sources of variation in need and uptake have so far been ignored in the NIH draft document.
  4. To investigate the paradoxical role of folic acid in cancer promotion and protection, it would be desirable to study the effect of folic acid supplementation on subjects guaranteed to be from premalignant lesions prior to initiation of folic acid supplementation. 

It would be a travesty of rates of NTDs increased because of knee-jerk reactions triggered by sensational media headlines and doctors and other clinicians who give advice to stop supplementation based on a hasty and incomplete survey of the current science.

Fresh green kale is a good source of natural folate, as are other leafy greens, broccoli, asparagus, citrus fruits, beans, peas, lentils, and more

How to save lives with folate

In our view, better education on folate is needed even more than new research. Recommending supplementation of polyglutamic folate (as the glucosamine or calcium salts, see point 1 above) at dose ranges between 1.5 g (1500 mcg) and 5 g (5000 mcg) daily, on top of a diet including plenty of high folate foods, is one step governments could take tomorrow – with no concerns about safety whatsoever. What’s stopping them?  

Folic acid fortification isn’t necessarily the best way forward given it’s difficult to regulate intakes and there are increasing numbers of people choosing to exclude cereal flour-based foods (e.g. bread, pasta) that are typically the targets of fortification programmes given issues with gluten sensitivity or intolerance. What’s more, those who choose to consume largely unprocessed foods, such as those following the ANH Food4Health plate guidelines, miss out on fortification. Supplements can be a much more flexible tool for these health-aware groups.

Much more emphasis also needs to be placed on encouraging people to eat naturally rich sources of folate. You can check out levels of folate in foods by consulting the USDA National Nutrient Database or the UK McCance and Widdowson’s Composition of Foods integrated dataset.

In a recent article in the American Journal of Clinical Nutrition, Prof Roy Pitkin at UCLA School of Medicine in Los Angeles stressed the need to identify high-risk subjects that need much higher levels of supplementation than others, adding that “If….the problem is some genetic aberration in metabolism, the approach would be different from if it was nutritional deficiency.”

Accordingly, when regulators choose to restrict vitamins, it’s essential they don’t also deny others levels that might be life saving, or at least significantly improve their quality of life. We will continue to watch how regulators move forward with policy on folate and folic acid very carefully, and will keep you informed, including when your input to the political process could make a real difference.


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