Key Concepts

  • Public health initiative – synthetic folate (folic acid) fortification of processed foods – appears to decrease risk of neural tube defects in developing fetus
  • L-5-MTHF (natural folate) appears to be superior form of supplement over folic acid (synthetic)
  • Most supplements contain folic acid
  • Long-term use of folic acid supplementation may have health consequences
  • MTHFR (genetic polymorphism) affects many people – affects folate metabolism and can lead to deficiency
  • Supplementation of 5-MTHF appears to be readily absorbed and beneficial to those with MTHFR
  • Blood serum folate tests may not indicate functional deficiency – peripheral blood smears and homocysteine levels may help in folate deficiency diagnosis
  • Food sources – Green leafy vegetables, mushrooms, cruciferous vegetables, citrus, nuts, needs, legumes
  • B Complex – $0.34/day

Intro/Supplement Info

Folate is destroyed by heat, oxidation, and light. Fifty to 80% of folate in foods is lost when it is processed.

In terms of supplementation, folate is a really important vitamin to be attention to. Vitamin B9 (folate) is found in its natural form in foods and body tissues. There is also a synthetic form of vitamin B9 called folic acid. It is found in fortified foods and in supplements. If you have a run-of-the-mill multivitamin or B-vitmain complex, its probably got folic acid in it rather than folate.

The introduction of mandatory folic acid fortification in refined grain products in the United States began in 1998. Since 1998 the prevalence of neural tube defects (NTDs) has been reduced, marking the fortification of B9 as a success in that sense. Neural tube defects include anencephaly and spina bifida and are caused by an abnormal development of the neural tube, the structure which gives rise to the central nervous system. So, the reduction in prevalence of NTDs is indeed a great success.

Unfortunately, folic acid may inhibit the uptake of 5-methyltetrahydrofolate (5-MTHF), the natural and most metabolically active form of folate in the body. Folic acid is eventually converted to 5-MTHF but it is a lengthy process. There are not many studies in the literature addressing this as a major concern as there appear to be benefits of folic acid supplementation in addition to preventing NTDs. This includes lowering homocysteine levels – which can increase the risk of cardiovascular disease – although studies are still not conclusive in showing that folic acid supplementation actually reduces the risk of cardiovascular disease.

Folic acid supplementation can lead to unmetabolized folic acid circulating in the blood stream. This has been associated with hematologic abnormalities and poorer cognition in adults 60 years in age or older. There have not been enough studies done to make conclusions regarding the implications of unmetabolized folic acid circulating in the blood stream and potential health risks.


Additionally, a large majority of the population has a single nucleotide polymorphism (SNP), a genetic variation which hinders folate metabolism. 5,10 methylenetetrahydrofolate reductase (MTHFR) is the enzyme affected by this SNP. It is estimated that 20-53% of the population is heterozygous for MTHFR – this results in about a 30% reduction in enzyme activity. Three to 32% of the population may be homozygous for MTHFR causing about a 65% reduction in enzyme activity. That is a lot of people! This is important because it can potentially lead to lower folate status, diminished methylation capabilities, and increased homocysteine levels in affected individuals.


Natural folates are metabolized to THF in the mucosa of the small intestine. Folic acid undergoes initial reduction and methylation in the liver, where conversion to the THF form requires the dihydrofolate reductase enzyme. This enzyme has low activity in the liver and may not be able to convert all of the folic acid ingested in one sitting. This leads to unmetabolized folic acid entering the systemic circulation.

There is a lot of talk these days about anti-nutrients like phytic acid inhibiting the absorption of folate. Anti-nutrients indeed inhibit folate absorption and are found in legumes like beans, lentils, and peas. But, it does not appear that eating legumes induces a clinical deficiency of folate. In other words, just because you eat legumes does not mean you will become deficient in folate. In addition, levels of phytic acid can be significantly reduced via soaking, fermenting, and cooking.

Absorption is also inhibited by alcohol consumption.


Folate is key. Folate coenzymes transfer one-carbon units involved in nucleic acid and amino acid metabolism as well as methylation reactions. Methylation serves many functions, including: turning genes on and off, ensuring proper gene expression, detoxification, building neurotransmitters (norepinephrine–> epinephrine –> serotonin –> melatonin), neurotransmitter metabolism (dopamine, epinephrine), immune cell maturation (T cells, NK cells), DNA synthesis, energy production, myelin production, and in building and maintaining cell membranes. Folate is also key in methionine synthesis (from homocysteine), in the metabolism of histidine, glycine, and serine, and in red blood cell production.

Recommended Dietary Allowances (RDAs)

  • Adults – 400 mcg DFE (dietary folate equivalents)
  • Increases to 600 mcg DFE during pregnancy


Folate deficiency can result in increased homocysteine levels, megaloblastic anemia (fatigue, weakness, shortness of breath), neural tube defects during pregnancy, cognitive impairment (dementia – risk of Alzheimer’s Disease), and perisperhal neuropathy. Those at increased risk for folate deficiency are those not eating folate in their diet, alcoholics, pregnant women, those with cancer, and tobacco users.

Folate Clinical Testing

Blood serum folate tests can indicate how much folate is circulating in the blood, but it does not indicate how much folate is being absorbed in the blood and if the cells are actually using that which has been found on the blood test.

To test for a functional (intracellular) folate deficiency, a peripheral blood smear can be used to examine the morphology of red blood cells which can indicate megaloblastic anemia. High levels of plasma total homocysteine can also point toward a possible folate deficiency.


The tolerable upper level intake (UL) is set at 1,000 mcg. Cognitive decline and development of certain cancers are potential risk factors for daily folic acid supplementation. The potential for cognitive decline occurred with daily use of 400 mcg of folic acid.

Food Sources

  • Spinach, boiled, ½ cup – 33%
  • Black-eyed peas (cowpeas), boiled, ½ cup – 26%
  • Brussels sprouts, frozen, boiled, ½ cup – 20%
  • Avocado, raw, sliced, ½ cup – 15%
  • Spinach, raw, 1 cup – 15%
  • Peanuts, dry roasted, 1 ounce – 10%


Based on my reading of the literature and common sense, it appears that 5-MTHF is superior to folic acid in terms of supplementation. Independent studies have demonstrated that [6S]-5-MTHF displays higher bioavailability compared to folic acid, irrespective of the patient’s genotype. Because so many people may have a gene polymorphism affecting folate metabolism, this is a crucial piece of information. And the common sense part – why would you want to take a supplement that required so many steps to convert to the metabolically active form of folate when you can just take the metabolically active form (5-MTHF)? And knowing that folic acid may inhibit dietary uptake of natural folate, it makes sense to dump the fortified foods and folic acid supplements/multivitamins and switch to 5-MTHF as a supplement. Of course, more studies will need to be conducted before jumping to a conclusion about which supplement is superior to another. Folic acid looks great for preventing NTD, perhaps 5-MTHF will have the same effect, or perhaps they can be used synergistically. For now, I think a diet with adequate folate will do, a 5-MTHF supplement as insurance, and avoidance of folic acid.

This article provides a great resource which explains the difference between natural folate found in supplements.


  1. Folic Acid Impairs the Uptake of 5-Methyltetrahydrofolate in Human Umbilical Vascular Endothelial Cells.
  2. Folic Acid Food Fortification—Its History, Effect, Concerns, and Future Directions

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