How to get rid of unmetabolized folic acid?

How to get rid of unmetabolized folic acid?

Updated On:

March 27, 2025

Table of Contents

    Folate or folic acid is referred to as vitamin B9, a key cofactor in one-carbon metabolism. Folate is the common terminology used for a group of molecules including folic acid, folinic acid or 5-formyltetrahydrofolate (5-FTHF), 5-methyltetrahydrofolate (5-MTHF) or L-methylfolate, 10-formyl-tetrahydrofolate (10-formyl-THF), 5,10-methylene-THF and unsubstituted tetrahydrofolate (THF).


    Supplementation of folate is required to maintain adequate levels in mammals. Folic acid, folinic acid and 5-MTHF are different forms of folate that can be found in folate supplements1. The main differences between folate and folic acid is all about the forms in which they exist, folate is a reduced form while folic acid is an oxidized form. The reduced forms of vitamin B9 such as dihydrofolate and tetrahydrofolate are less stable biochemically, whereas the oxidized form, folic acid in supplements and fortified foods stays stable for a longer period of time2. Folic acid is a synthetic (man-made) water-soluble compound that does not exist in nature. It is comprised of a pteroyl group which is connected to a glutamic acid part and shows greater stability than the folates which are in reduced forms. In addition, folic acid depends upon 4 different conversion processes that need to happen within the body before it can become the 5-MTHF which your body can then directly absorb and use.


    In contrast, Folate is a naturally occurring and comprised of polyglutamines in their tails. As compared to folate, folinic acid is also a naturally occurring compound in food, however, it is readily converted to THF even in the absence of dihydrofolate reductase (DHFR). Consequently, the effects of folinic acid are not affected by the drug compounds, for instance, methotrexate, which inhibits DHFR.


    5-MTHF, naturally available, has metabolic advantages over folic acid and folinic acid. One advantage is that changes in the pH of the gastrointestinal tract do not affect the absorption of 5-MTHF. And the other is that the bioavailability of 5-MTHF is not interrupted by metabolic issues related to genetics or any metabolic-related diseases. So the supplementation of 5-MTHF rather than folic acid is advised to reduce the possibilities of masking hematological symptoms that occur with a deficiency of vitamin B12. Also, 5-MTHF is believed to reduce the probable adverse effects caused by unmetabolized folic acid in the human body. Several notions such as disruption in folate metabolism due to genetic shortcomings like methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms or any drug interactions, malabsorption syndromes such as celiac and Crohn’s disease, long-term medications (folate antagonists, antacids), alcoholism, poor absorption of ingested folate and low dietary intake, have been considered for folate deficiency in the human population. Folate deficiency has been treated by recommending folic acid supplements and fortified foods – even though this may be an inferior way to address the deficiency. Supplementing with the active form of folate, L-5-Methylfolate, is now preferred for obtaining optimal health benefits.


    Also Read: How would I know if I have an MTHFR mutation?

    The food sources of folate are green leafy vegetables, sprouts, brewer’s yeast, beans, peanuts, sunflower seeds, cruciferous vegetables, fruits, whole grains, liver, seafood, and eggs.. Folate is necessary for DNA and RNA synthesis, metabolism of amino acids, regulated cell division, activation of B12, reduction of homocysteine levels, supporting the production of s-adenosyl methionine (SAMe) and reducing the of risk of neural tube defects in the pregnant women. Besides these above-mentioned functions, folate is a key methyl donor and involved in the synthesis of neurotransmitters such as dopamine, serotonin, melatonin, epinephrine and norepinephrine. Cancer, cardiovascular disease, neural tube defects and cognitive impairment are the possible consequences of folate deficiency.

    As per the Food and Agriculture Organization of the United Nations and World Health Organization (FAO/WHO) Expert Consultation report made in 1988, three states of folate nutrition were defined:


    • folate adequacy
    • impending folate deficiency and
    • overt folate deficiency


    Improvement in folate status for folate adequacy is not required and an increase in folate intake would not have any benefits. On the contrary, increasing folate intake levels would be mandatory to the people with impending folate and overt folate deficiencies. In the FAO/WHO report, folate levels greater than 150 mg/L in a red blood cell and greater than 7.5 mg/L in the liver was recommended.


    The red blood cell folate levels has been considered to be the golden standard for folate status, whereas the folate levels in the liver was thought to be of less relevance to a person’s true folate status.


    Because of the remarkable fluctuation in the plasma folate levels, it is rarely used in the identification of folate status. Hematological pathogenesis indicators including mean corpuscular volume, hypersegmentation of neutrophils and early stages of anemia are important indicators for the reduced folate status. Furthermore, plasma homocysteine is a very sensitive biomarker of folate status. An estimated average requirement as well as an estimation of the recommended dietary allowance of folic acid was suggested by FAO/WHO consultation experts as shown in the table below.


    It’s worth noting that these recommendations were made long before the Human Genome Project came along which gave us new information on folate metabolism through genetic polymorphisms found in the body like MTHFR.


    Also Read: How to get rid of unmetabolized folic acid? 

    Folate acts as a catalyst in one-carbon metabolism, its notable biological reactions are:

    • synthesis of purine and pyrimidine bases of nucleic acids
    • production of methylating agents that are required for gene regulation and
    • metabolism of amino acids including methionine, serine, glycine and histidine.

    Dietary folates exist as polyglutamates that must be hydrolyzed to monoglutamates in the intestinal mucosa for their easy transport and absorption. Folic acid is reduced (or converted) to dihydrofolate and then becomes tetrahydrofolate, which is converted once again to glycine and 5,10-methylene-THF. L-5-methyl-THF, the principal folate form in the plasma, is then formed through a final conversion from 5,10-methylene-THF in the presence of the riboflavin-dependent enzyme MTHFR.


    The production of thymidylate and purines in addition to the synthesis of methionine from homocysteine are the two active metabolic cycles observed in intracellular folate metabolism. The catalytic reaction between 5-methyl-THF and the vitamin B12-dependent enzyme, methionine synthase, provides a methyl group for the remethylation process to homocysteine. Consequently, the production of THF ensues and is then converted to 10-formyl-THF. In the presence of tetrahydrofolate dehydrogenase, otherwise known as trifunctional enzyme, 10-formyl-THF is converted to 5, 10-methylene-THF. Notably, 10-formyl-THF plays as a one-carbon donor for purine synthesis (Figure 1).

    Folate conjugase enzymes, intestinal brush border pteroylpolyglutamate hydrolase and the intracellular hydrolase, support the conversion of the polyglutamate residues in dietary folate to become monoglutamate in the intestinal lumen. The resultant folate monoglutamate is absorbed, and as indicated earlier, the bioavailability of folates is significantly affected because of the removal of polyglutamate side chains which reduces the bioavailability by more than 50%.


    Absorption of folate in the intestine happens in passive and carrier-mediated mechanisms. Passive absorption of folate exclusively occurs at high doses of folate. Three pathways such as the reduced folate carrier, the folate receptors and the proton-coupled folate transporter lead carrier-mediated transport of folate that transports oxidized and reduced folates with equal capacity1. Long-term and short-term clinical trials were conducted to ascertain the bioavailability of the folate levels in the supplements. Investigation of folate status parameters such as plasma folate levels, the concentration of folate levels in red blood cells and plasma total homocysteine were performed in long-term trials whereas short-term trials emphasized the area under the serum response curve method to detect the availability of folate and its active metabolites.


    Also Read: Folic Acid Deficiency – Causes and Prevention

    The 5-MTHF form (methylfolate) and its preparations have plenty of advantages over folic acid. The advantages include getting appropriate plasma concentrations of folate and not being dependent on slow and easily saturable DHFR catalytic activity. In addition, a five-fold variation of DHFR reductive activity of folic acid to THF observed in human samples means 5-MTHF could be considered the ultimate magic bullet to attain adequate levels of folate in the plasma. The low rate of conversion of folic acid to THF implies that the use of high doses of folic acid will be restricted by the saturation of DHFR, this issue would be magnified further in the individuals possessing lower activity of DHFR. Not to mention the high prevalence of MTHFR polymorphisms which mean the active 5-MTHF form is never quite achieved. Therefore, a high dose > 1 mg of folic acid from supplements and fortified foods along with the low activity of DHFR in the human liver causes high levels of unmetabolized folic acid (UMFA) in the plasma and urine. In this case, 5-MTHF would be best, because of its higher bioavailability, which would reduce the problem of excessive UMFA in the plasma.


    Also Read: 7 ‘Beneficial Vitamins for You AND Your Baby

    Many research studies have reported the levels of UMFA in adults and its association with high doses of fortified foods and supplemental folate and risk of cancer. Generally, in the presence of dihydrofolate reductase, folic acid is converted to dihydrofolate while dihydrofolate is then altered to tetrahydrofolate. Conversely, high doses of folic acid affect the conventional synthetic mechanism of tetrahydrofolate from folic acid. As a result, the conversion of oxidized folic acid to reduced folate is circumvented, thereby an increase in the levels of UMFA in the plasma and urine. The research studies have reiterated that the dosage of more than 260 mg/d or consecutive doses of folic acid such as 100 mg within a day had reported the presence of UMFA in the serum. Women with folic acid supplementation were found to possess the plasma levels of UMFA from 65% to 100% after twelve weeks of supplementation. A study claims that a high affinity of UMFA with the folate receptors facilitates its transport across the cells and leads to the presence of UMFA in the plasma and urine. Another study reveals that folic acid can compete with 5-MTHF, followed by the inhibition of the transport of 5-MTHF across the blood-brain barrier. Thus, the accumulation of UMFA happens from the use of high dosage and alternative folic acid supplements.


    To overcome the presence of excess UMFA in the serum, the administration of L-methylfolate can be considered as the preferred therapeutic strategy. Synthetic folic acid and intermediate folate derivatives like DHF, THF and 5,10-methylene THF are metabolized to the final folate form, L-methylfolate or 5-MTHF. L-methylfolate is the only form of folic acid derivatives that can cross the Blood Brain Barrier (BBB) and is also a cofactor in the synthesis of monoamines, norepinephrine, dopamine and serotonin.

    L-methylfolate has several advantages over folic acid including:

    • this active form crosses the BBB easily
    • the requirement of a 4-step conversion process pathway from folic acid to the active form gets bypassed
    • less chance of masking a vitamin B12 deficiency
    • the bioavailability is 7 times better than folic acid11.

    Some studies have linked the adverse effects of UMFA to potentially harmful effects on vitamin B12 deficiency, disruption of the immune system, neurological disorders, development of cancer and epigenetic dysregulation.


    So if you plan to supplement for a folate deficiency, make sure you’re using a reliable source of the active L-5-MTHF (or L-Methylfolate). Check out Methyl-Life™ as they are selling the purest methylfolate on the planet in their products.


    Also Read: Folate Therapy Directly Linked to Positive CFD Outcomes

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    References

    1. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014, 44(5):480-8.

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    2. FAO/WHO expert consultation on human vitamin and mineral requirements. Vitamin B12. Chapter-5; 53-64

      http://www.fao.org/3/a-y2809e.pdf

    3. Bailey SW, Ayling JE. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proc Natl Acad Sci USA, 2009, 106:15424–9.

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    4. Bailey RL, Mills JL, Yetley EA, Gahche JJ, Pfeiffer CM, Dwyer JT, Dodd KW, Sempos CT, Betz JM, Picciano MF. Unmetabolized serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative sample of adults aged > or =60 y in the United States. Am J Clin Nutr. 2010, 92(2):383-9.

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    5. Kalmbach R, Paul L, Selhub J. Determination of unmetabolized folic acid in human plasma using affinity HPLC. Am J Clin Nutr. 2011, 94(1):343S-347S

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    6. Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 1997;65:1790–5.

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    7. Sweeney MR, McPartlin J, Weir DG, Daly L, Scott JM. Postprandial serum folic acid response to multiple doses of folic acid in fortified bread. Br J Nutr 2006;95:145–51.

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    8. Troen AM, Mitchell B, Sorensen B, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 2006;136:189–94.

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    9. Pfeiffer CM, Sternberg MR, Fazili Z, Yetley EA, Lacher DA, Bailey RL, Johnson CL. Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults. J Nutr. 2015, 145(3):520-31.

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    10. Tam C, O'Connor D, Koren G. Circulating unmetabolized folic Acid:relationship to folate status and effect of supplementation. Obstet Gynecol Int. 2012, 485179.

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    11. Hunter, T, S. L-methylfolate in the therapeutic management of major depressive disorder. J. Pharm. Practice. 2008, 21, 278-286.

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    12. Obeid R, Herrmann W. The emerging role of unmetabolized folic acid in human diseases: myth or reality? Curr Drug Metab. 2012, 13(8):1184-95

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