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5-MTHF -An utmost critical co-factor

Posted by Gerhard Fourie on

Written on the 14 March 2016 by The Compounding Team

To understand 5-MTHF a bit better, one needs to first describe Folic acid and Folates. Folic acid is actually an artificial B vitamin created, and then added to foods like baked goods, and also available in most multi-vitamins. Folates on the other hand, are naturally occurring in foods and occur in a few different forms, which is why we call them folates.
Folate, while it's an important and essential vitamin by itself, is unusable by the human body and has to be converted through a series of steps to the active, useable form of folate called 5-MTHF (5-methyltetrahydrofolate).
5-MTHF is a critically important co-factor in a variety of essential chemical reactions in the body, which means it makes those reactions actually take place.

5-MTHF -Why is it important?

  1. It's critical for the normal development of the nervous system when we are developing in our mother. This is why folic acid is added to foods, because it helps reduce spinal cord problems in babies.
  2. It is involved in the "detoxification" of homocysteine.  Homocysteine is a toxic product of the SAM reaction, (S-Adenosyl methionine), meaning that homocysteine is toxic and needs to be recycled back into nontoxic methionine or cystathione.
  3. If this does not happen, it can build up and damage our blood vessels, leading over years to the formation of plaques. (Clogged arteries which greatly increase the likelihood of heart attacks and strokes). It has also been linked to Alzheimers and dementia.
  4. It is important to make sure that homocysteine is effectively being recycled. 5-MTHF along with Vitamin B12 is critically important in this step.
  5. 5-MTHF is essential in the production of neurotransmitters, those brain chemicals which control our mood, our ability to think, generating movement, speaking, thinking, listening, regulating the systems of the body, and countless other functions. 5-MTHF also helps recycle another cofactor called BH4, (tetrahydrobiopterin), which is directly involved in the production of serotonin, dopamine, norepinephrine, epinephrine, and nitric oxide.
  6. This is why it is suggested that patients expressing certain psychiatric conditions, (depression, bipolar disorder, schizophrenia) or neurologic indications (including autism, ADD / ADHD) should request their physician to consider 5-MTHF treatment.
  7. Is also involved in the production of DNA.

5-MTHF -The Problem
We have two sets of genes, (one from mom, one from dad). If you have a mutation in one you are called heterozygous, if you have a mutation in both you are called homozygous. If you are heterozygous for the mutation your 5-MTHFR enzymes, (the enzyme that makes 5-MTHF), does not work well, meaning you produce less 5-MTHF than required, if you are homozygous your enzymes work very poorly indeed, meaning you make MUCH less 5-MTHF.
Folic acid / folate, as already said, is not usable by the body until it is converted into 5-MTHF. According to studies in US, Caucasians are around 50% heterozygous for the MTHFR mutations, and about 10% homozygous for MTHFR, and because this is a genetic issue, you will often see these concerns running strongly in families.
If a person has been struggling with depression her whole life and her siblings or parents or grandparents also expressed depression indicators, or other psychiatric or neurologic indicators, there's a good chance there may be links to 5-MTHFR mutations.
One of the reasons miscarriages occur may be 5-MTHFR mutations as per above. Testing and/or supplementing with 5-MTHF may be all that's required.
See an interesting 5-MTHF/Folic Acid comparison here.

5-MTHF -a Solution
A genetic test is available, and your physician can order it. Since it is a genetic test, it only needs to be done once in your life.
If tested positive for 5-MTHF deficiencies and MTHFR mutations, your physician can prescribe 5-MTHF treatment/supplementation. Your Solution Compounding Pharmacy can compound 5-MTHF to the correct strength and dosage, without colourants and fillers to which many patients are allergic.
Please note that certain side-effects of using 5-MTHF may indicate not just 5-MTHFR disorders, but significant additional methylation problems, and could require further and additional treatment. Your Solution Compounding Pharmacy regularly compound scripts for these patients as well.

5-MTHF -Conclusion
5-MTHF is necessary to produce all your neurotransmitters. For some people taking 5-MTHF really is magic. One doctor reports having treated more than 4 000 patients.
The solution though is to 'listen to your body'. If you have any problem with mood or behaviour, or with your nervous system, ask your doctor to test for 5-MTHF mutations. It may just make all the difference.

Please contact Your Solution Compounding Pharmacy for more information about 5-MTHF or visit us at 1/6 Pine Rivers Office Park, 205 Leitchs Rd. Brendale, QLD.

Other interesting references for further reading

Further reading
1. Roy M, Leclerc D, Wu Q, Gupta S, Kruger WD, Rozen R. Valproic acid increases expression of methylenetetrahydrofolate reductase (MTHFR) and induces lower teratogenicity in MTHFR deficiency. J Cell Biochem. 2008; 105(2): 467-76. PMID: 18615588
2. Wilcken B, Bamforth F, Li Z, Zhu H, et al. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J Med Genet. 2003; 40(8): 619-25. PMID: 12920077
3. Morales DR, Greenberg DM. Purification and properties of dihydrofolate reductase of sheep liver. Biochim Biophys Acta. 1964; 85: 360376. PMID: 14194852
4. Jarabak J, Bachur NR. A soluble dihydrofolate reductase from human placenta: Purification and properties. Arch Biochem Biophys. 1971; 142: 417425. PMID: 4396284
5. 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 U S A. 2009; 106(36): 15424-9. PMID: 19706381
6. Sweeney MR, McPartlin J, Scott J. Folic acid fortification and public health: report on threshold doses above which unmetabolised folic acid appear in serum. BMC Public Health. 2007; 7: 41. PMID: 17378936.
7. Norwich BioScience Institutes. Scientists Question Folic Acid Fortification. ScienceDaily. ScienceDaily, 2007 Nov 5.
8. Smith DA, Kim Y, Refsum H. Is folic acid good for everyone? Am J Clin Nutr. 2008; 87: 51733. PMID: 18326588
9. Sweeney MR, McPartlin J, Weir DG, Daly S, Pentieva K, Daly L, Scott JM. Evidence of unmetabolised folic acid in cord blood of newborn and serum of 4-day-old infants. Br J Nutr. 2005; 94(5): 727-30. PMID: 16277775
10. Sawaengsri H, Wang J, Desautels N, et al. Natural killer cell cytotoxicity is reduced in aged female mice fed a high folic acid diet. The FASEB Journal. 2013; 27: 643.21.
11. Troen AM, Mitchell B, Sorensen B, Wener MH, Johnston A, Wood B, Selhub J, McTiernan A, Yasui Y, Oral E, Potter JD, Ulrich CM. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr. 2006; 136(1): 189-94. PMID: 16365081

12. Xia W, Hilgenbrink AR, Matteson EL, Lockwood MB, Cheng JX, Low PS. A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophages. Blood. 2009; 113(2): 438-46. PMID: 18952896
13. Christensen KE, Mikael LG, Leung KY, Lévesque N, Deng L, Wu Q, Malysheva OV, Best A, Caudill MA, Greene ND, Rozen R. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. Am J Clin Nutr. 2015; 101(3): 646-58. PMID: 25733650
14. Farber S, Cutler EC, Hawkins JW, Harrison JH, Peirce EC 2nd, Lenz GG. The Action of Pteroylglutamic Conjugates on Man. Science. 1947; 106(2764): 619-21. PMID: 17831847
15. Kim YI. Folic acid supplementation and cancer risk: point. Cancer Epidemiol Biomarkers Prev. 2008; 17(9): 2220-5. PMID: 18768486
16.  Ebbing M, Bønaa KH, Nygård O, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Njølstad I, Refsum H, Nilsen DW, Tverdal A, Meyer K, Vollset SE. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. 2009; 302(19): 2119-26. PMID: 19920236
17. de Jong MM, Nolte IM, te Meerman GJ, et al. Low-penetrance genes and their involvement in colorectal cancer susceptibility. Cancer Epidemiol Biomarkers Prev. 2002; 11: 1332 52. PMID: 12433710
18. Houlston RS, Tomlinson IP. Polymorphisms and colorectal tumor risk. Gastroenterology. 2001; 121(2): 282-301. PMID: 11487538.
19. Sharp L, Little J. Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol. 2004; 159(5): 423-43. PMID: 14977639
20. Venn BJ, Green TJ, Moser R, Mann JI. Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am J Clin Nutr. 2003; 77(3): 658-62. PMID: 12600857
21. Lamers Y, Prinz-Langenohl R, Moser R, Pietrzik K. Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women. Am J Clin Nutr. 2004; 79(3): 473-8. PMID: 14985224
22. Prinz-Langenohl R, Brämswig S, Tobolski O, Smulders YM, Smith DE, Finglas PM, Pietrzik K. [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C>T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol. 2009; 158(8): 2014-21. PMID: 19917061
23. Wright AJ, King MJ, Wolfe CA, Powers HJ, Finglas PM. Comparison of (6 S)-5-methyltetrahydrofolic acid v. folic acid as the reference folate in longer-term human dietary intervention studies assessing the relative bioavailability of natural food folates: comparative changes in folate status following a 16-week placebo-controlled study in healthy adults. Br J Nutr. 2010; 103(5): 724-9. PMID: 19852872
24. Obeid R, Holzgreve W, Pietrzik K. Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects? J Perinat Med. 2013; 41(5): 469-83. PMID: 23482308
25. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014; 44(5): 480-8. PMID: 24494987
26. Patanwala I, King MJ, Barrett DA, Rose J, Jackson R, Hudson M, Philo M, Dainty JR, Wright AJ, Finglas PM, Jones DE. Folic acid handling by the human gut: implications for food fortification and supplementation. Am J Clin Nutr. 2014; 100(2): 593-9. PMID: 249440624

1. Bailey LB, Gregory JF (1999) Folate metabolism and requirements. J Nutr 129: 779-782. Cortese C, Motti C (2001) MTHFR gene polymorphism, homocysteine and cardiovascular disease. Public Health Nutr 4(2B): 493-7.
2. Cao, Y; Xu, J; Zhang, Z; Huang, X; Zhang, A; Wang, J; Zheng, Q; Fu, L; Du, J. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: A meta-analysis, Gene, Volume 514, Issue 2, 10 February 2013, Pages 105-111, ISSN 0378-1119,
3. Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007 Jan 1;165(1):1-13.
4. Ismaili, S (2010) Crossover comparative bioavailability study of 5-methyltetrahydrofolate glucosamine salt compared to the reference Metafolin® in healthy volunteers. IPSA-5MTHFA-583-09 Final Report.
5. Lamers Y, Prinz-Langenohl R, Bramswig S, Pietrzik K. Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr. 2006;84:156-161.
6. Marini NJ, et al. (2008) The prevalence of folate-remedial MTHFR enzyme variants in humans. PNAS 105: 8055-8060.
7. Miller, A. (2008). The methylation, neurotransmitter, and antioxidant connections between folate and depression. Alternative Medicine Review, 13(3), 216-226.
8. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338:131-137.
9. Natural Products Insider (2011). Gnosis' Quatrefolic® Wins NBT Award.
10. Selhub J (2002) Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Nutr Health Aging 6(1): 39-42.
11. Yigit, S., Karakus, N., & Inanir, A. (2013). Association of MTHFR gene C677T mutation with diabetic peripheral neuropathy and diabetic retinopathy. Molecular Vision, 19, 16261630.

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