Dr Clare Craig
In the previous article I explained how the body only needs 100 micrograms of folate to replace daily losses. The claimed recommended daily allowance of 400 micrograms a day only came about once industry was involved in setting the allowance. This higher level is not achievable on any diet and makes the case for supplementation with folic acid for everyone. But it is not evidence based.
Almost everyone believes that folic acid is simply another form of folate. One occurs in food, the other is manufactured, both end up in the same biochemical pathways — so why should it matter which one enters the body?
Folates found in spinach, lentils, liver, eggs or breast milk are chemically reduced molecules that the body can put to use straight away. The molecule being added to British flour is not. Folic acid is the oxidised, chemically stable version, built to survive storage and baking. In order to convert it into the reduced form the body can use, it must pass through an enzyme, dihydrofolate reductase, which is very inefficient and creates a bottle neck. The consequence is that the unnatural folic acid chemical circulates in the blood in its unmetabolized state for many hours.
The human bottleneck
In 2009, Bailey and Ayling published a careful study in the Proceedings of the National Academy of Sciences, using fresh human liver obtained at surgery or from organ donors. Human DHFR (dihydrofolate reductase) turned out to be extraordinarily slow. It processed synthetic folic acid 1,300 times more slowly than the natural folate it evolved to handle – roughly 0.08 per cent of its normal efficiency.
The comparison with the laboratory rat is worth dwelling on, because the rat is the species on which most folic acid safety testing has been done. The human enzyme was on average 56 times slower than the rat’s at processing folic acid, with a range across individuals of 34 to 164 times slower. Different people’s livers varied fivefold in the rate at which the enzyme worked which means an identical dose can have very different consequences in two different people.
Once the enzyme reaches full capacity or saturates, the backlog of unmetabolized folic acid (UMFA) starts to build. Bailey and Ayling calculated that a normal adult liver begins to saturate at around 330 micrograms of folic acid. A single 400-microgram tablet, or a single serving of fortified cereal, pushes it past that point in one go.
The molecule that shouldn’t be there
A nationally representative US study by Pfeiffer and colleagues, drawing on the National Health and Nutrition Examination Survey, found detectable UMFA in 38 to 42 per cent of American adults even after a fast of ten hours or more. Close to half the adult population carries synthetic folic acid around in the bloodstream between meals.
The original rationale for fortification assumed that folic acid would promptly become folate. Instead a great deal of it lingers, unconverted, and the lingering interferes directly with getting real folate to the place that needs it most.
A receptor built for folate
The brain needs a steady supply of folate, and it gets it through a specialised transporter, folate receptor alpha, which concentrates folate against a gradient so that the cerebrospinal fluid normally holds two to three times more than the blood. The difficulty is that folic acid binds this receptor too — more tightly than natural folate does — and then it does not let go.
So when blood folic acid rises, after a supplement or a bowl of fortified cereal or a sandwich made with fortified flour, the receptor becomes effectively blocked by UMFA , and the active transport of real folate into the brain stops. Cerebrospinal fluid folate falls and stays low until the liver has slowly worked through the backlog and cleared the receptor.
The irony is hard to miss. By forcing synthetic folic acid into the circulation, fortification may be producing windows of cerebral folate insufficiency in exactly the people it is meant to protec: pregnant women, developing babies, young children, during the hours when folate most needs to be reaching the developing brain. This is the most likely explanation for the awkward finding in the first article: that as folic acid use rose through the 1990s, the fall in neural tube defects slowed rather than quickened.
The arithmetic of pregnancy
Given the emphasis on pregnancy as a time when folate is important, it is worth us pausing to ask the most important question – how much extra folate does a pregnancy actually require? There are three aspects to consider: the folate built into the growing baby; into the placenta; and into the extra blood, uterus and breasts of the mother. Using published estimates of fetal, placental and maternal folate accumulation, the total physically incorporated into new tissue across the whole of pregnancy is of the order of a few milligrams. That works out at less than 20 micrograms per day of pregnancy.
A woman having a normal diet plus a single 400 microgram folic acid supplement each day for three months before pregnancy and until the baby is born would be taking in around 146 milligrams of synthetic folic acid. The difference is stark. Add the exposure from fortified flour on top and it becomes more extreme still. The developing baby’s folate receptors will be flooded with a molecule that binds tightly to receptors and blocks them.
Pregnancy is not the only risk babies face. Formula-fed infants receive two to five times their daily folate requirement at every feed, because infant formula is fortified with synthetic folic acid far above the natural folate content of breast milk, which sits at around 80 to 85 micrograms per litre, almost all of it as natural methylfolate. A randomised trial that swapped natural L-methylfolate for synthetic folic acid in infant formula found markedly lower circulating UMFA and better folate status in the infants who received the natural form, with no difference in growth.
Why synthetic, and not folate?
Food is all that is needed for adequate folate including in pregnancy.
Where breast feeding is not possible, formula does need folate. Natural L-methylfolate, the reduced, methylated form the body actually uses, the form found in orange juice and lentils and spinach. It can be added to tablets, to formula, to cereal, to flour. It needs no slow enzyme step. Why doesn’t everyone use that instead?
The answer is partly shelf life. Folic acid is cheap and almost indestructible; methylfolate is less stable, needs more care in formulation, and costs a little more. Because it is less stable there is less certainty about what dose is being given. The other difference is cost. Fortifying a loaf with the synthetic molecule costs a few pence less than fortifying it with the natural one. The difference for a tin of infant formula is the same order of magnitude.
The growing market in methylfolate supplements is itself a quiet admission of the problem. Clinicians increasingly recommend the reduced form precisely because it bypasses the bottleneck. It matters most for the large minority least able to handle the synthetic kind. In the UK and Europe, around four in ten people carry one copy of a common variant in a gene called MTHFR leaving the enzyme that makes the body’s active, methylated folate working at reduced capacity. For them above all, being handed a synthetic precursor that must be converted before it can be used – rather than the active vitamin itself – is a poor bargain.
Back to 1875
You might think it is unlawful to add a synthetic product to organic flour. On 13 December it becomes compulsory despite the fact that on the present evidence, nine babies are lost for every neural tube defect prevented.
The body did not evolve to handle 400 micrograms of oxidised synthetic folic acid per serving. The enzyme that converts it cannot keep up at the doses being delivered. The receptor that carries folate to the brain is blocked by the surplus. Infants are being fed several times their requirement at every feed. And the NHS warns that whole categories of people must avoid folic acid altogether: those on methotrexate, those with undiagnosed B12 deficiency, those with certain cancers and kidney conditions.
In 1875 Parliament made it a criminal offence to put anything into bread that was injurious to health. That principle has never been repealed. It has simply been ignored.
Please sign this petition to stop the addition of folic acid to UK flour: https://petition.parliament.uk/petitions/769589
To find out more about folic acid:
Read this website:
https://fauxlate.org/
or listen to these interviews:
https://substack.com/@liamweavers/note/c-313188568?r=32qrer
Based on this, should a supplement like AG1 Pro that includes 680mcg DFE of 5-MTHF be avoided? Or is this form considered safe?