Needed every time a cell divides, and a partner to B12 in methylation.
Mechanisms, studies and evidence grades for each claim above.
Folate is the body's carrier for single carbon atoms. In its active form, tetrahydrofolate (THF), it picks up one-carbon units, mostly from serine as it converts to glycine, and hands them to reactions that need them. The most important of those reactions build DNA:
Without enough folate, dividing cells run short of thymidine. DNA polymerase then puts uracil into DNA where thymine should go. Repair enzymes cut it out, but they can't put thymine back, so the DNA keeps breaking. Cells stall partway through the division cycle. Tissues that divide constantly fail first: bone marrow, gut lining and a growing embryo. Methotrexate and several other cancer and antibiotic drugs work by blocking exactly this pathway.1
Folate also supports DNA methylation through its link with homocysteine (see below), the chemical tags that keep genes switched off where they should be. Deficiency therefore damages DNA in two ways: physical breaks and lost methylation. Both raise the chance of a cancer-starting mutation (see the folate paradox).
↑ back to summaryBone marrow makes about 2 million red cells every second, so it's the first place a folate shortage shows. Developing red cells keep growing and making hemoglobin, but they can't copy their DNA fast enough to divide on schedule. The result is fewer, oversized, fragile cells (megaloblastic anaemia). Blood tests show a high MCV and neutrophils with too many nuclear lobes. Many of the faulty cells are destroyed before they ever leave the marrow.1
Folate deficiency and B12 deficiency look identical under the microscope, because B12 is needed to release folate from its storage form (the "methyl-folate trap," see B12). That creates a real clinical trap. High-dose folic acid can get around the block and fix the anaemia of B12 deficiency while the nerve damage keeps getting worse. Before treating a large-cell anaemia with folate, check B12.1
↑ back to summaryFolate's carbon carrier ends up as 5-methyl-THF (also called L-methylfolate or 5-MTHF), after the enzyme MTHFR converts it. 5-MTHF has one job. It gives its methyl group to homocysteine, through B12-dependent methionine synthase, which turns homocysteine back into methionine and then into SAM, the body's general methyl donor (see Methionine). When folate is low, homocysteine builds up. That's why blood homocysteine is a sensitive functional marker of folate, B12, B6 and riboflavin status.
About 10% of people carry two copies of the MTHFR 677TT variant, an enzyme that loses its FAD cofactor easily. They tend to have higher homocysteine, especially when riboflavin or folate is low (see B2). Taking L-5-MTHF directly skips the MTHFR step.
Outcome trials. In people with vascular disease in countries that already fortify food with folic acid, homocysteine-lowering vitamins didn't prevent heart attacks (see B6). Stroke is different. In the China Stroke Primary Prevention Trial, 20,702 adults with high blood pressure, in a country without fortification, took enalapril with or without 0.8 mg of folic acid. The folic acid group had 21% fewer first strokes (2.7% vs 3.4%), and the benefit was concentrated in people who started with low folate.2 Correcting a real shortfall helps. Adding more on top of adequate status doesn't.
↑ back to summaryThe neural tube, which becomes the brain and spinal cord, folds and closes between days 21 and 28 after conception. That's often before a woman knows she is pregnant. It's a period of extremely fast cell division, and if the tube doesn't close fully, the result is spina bifida or anencephaly.
The Medical Research Council Vitamin Study settled the question in 1991. It randomised 1,817 women who had already had an affected pregnancy. Folic acid (4 mg/day) started before conception prevented 72% of repeat neural tube defects. A mix of other vitamins without folate had no effect.3 That led to the advice that every woman who could become pregnant should get 400 mcg/day, and to mandatory flour fortification in the US (1998) and many other countries. Neural tube defect rates then fell by roughly a quarter to a half.
↑ back to summaryFolate's link with cancer depends on the stage. That's how the same nutrient can seem to protect against cancer in one setting and speed it up in another.
Deficiency side. As described above, long-term deficiency puts uracil into DNA, breaks strands and strips methylation from gene promoters. All of that makes a cancer-starting mutation more likely. It was the original case for fortification.
Excess side. Once a pre-cancerous lesion exists, the picture flips. Fast-dividing cells, including adenoma (polyp) cells, need a lot of folate to keep copying their DNA, and extra folic acid can feed that growth. In a randomised trial of 1,021 people who had already had a colorectal adenoma removed, 1 mg/day of folic acid did not prevent new adenomas. At the second follow-up colonoscopy, advanced lesions were found in 11.6% on folic acid against 6.9% on placebo, a borderline-significant rise, and three or more adenomas were also more common.4
The fortification signal. Colorectal cancer rates in the US and Canada, which had been falling, rose briefly right after mandatory fortification began. Mason and colleagues suggested that fortification could have sped up existing hidden adenomas in an ageing population.5 Other things changed at the same time, including more screening, so the timing doesn't prove cause. But it fits the trial.
Form matters. The concern is specific to synthetic folic acid at supplement doses, not to folate in food. Food folate comes in forms the gut converts to 5-MTHF. Folic acid has to be reduced by the liver enzyme DHFR, which is slow in humans. Above roughly 200–400 mcg at once, unmetabolised folic acid shows up in the blood, a form that food never produces. In practice: get folate from food, and if you supplement, use L-5-MTHF and stay under 1,000 mcg/day of folic acid.
↑ back to summaryThe RDA is 400 mcg DFE/day for adults and 600 mcg in pregnancy. DFE (dietary folate equivalents) adjusts for the fact that folic acid is absorbed better than food folate. The upper limit applies only to synthetic folic acid and is 1,000 mcg/day. The word "folate" comes from Latin folium, leaf, and leafy greens and legumes are the richest food sources. Liver is far richer than any of them.
Large-cell anaemia, fatigue, a sore smooth red tongue, mouth ulcers, high homocysteine and, in pregnancy, neural tube defects. Deficiency is common with heavy drinking, malabsorption (coeliac disease), drugs that block folate use (methotrexate, trimethoprim, phenytoin) and diets without greens, legumes or liver. Nerve symptoms point to B12 deficiency rather than folate. That's worth working out, because the two are so often confused.1
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