New More Bioavailable Form Addresses A Common Nutrient Deficiency
By Chris D. Meletis, ND
The human body can generally convert basic forms of nutrients into their biological active forms, yet there are times where the process of conversion is either faulty or incapable of optimally performing this health-sustaining transformation. 5-MTHF, often abbreviated MTHF, is the most biologically active form of folate and is the molecule to which folic acid must be converted in the body to be utilized.
MTHF functions with methylcobalamin (vitamin B12), as a methyl-group donor involved in the conversion of the amino acid homocysteine to methionine. The importance of methyl (CH3) group donation cannot be over-emphasized, as it is involved in countless processes, including serotonin, melatonin, and DNA synthesis. In the case of 5-MTHF there are specific applications relative to sustaining wellness including controlling the level of homocysteine (an amino acid linked to heart disease), preventing neural tube defects, and improving vascular endothelial function. Endothelial cells are the cells that line the blood vessels. When there is damage to the endothelium—the blood vessel lining that contains these cells—it can obstruct blood flow, leading to heart attacks and strokes.
There is significant evidence that sufficient levels of folic acid, also known as folate, are involved in helping with not only the health aspects mentioned above but also countless number of other conditions (See Table 1).
|TABLE 1. Conditions Linked to Folic Acid Insufficiency|
The synthesis of the active forms of folic acid requires several enzymes, adequate liver and intestinal function, and adequate supplies of riboflavin (B2), niacin (B3), pyridoxine (B6), zinc, vitamin C, and serine. Even with the assumption that all these nutrients are present in sufficient amounts to allow for the conversion of dietary or supplemental folic acid to the bioactive form, there is still another confounding variable that can still compromise optimal MTHF generation within the body. These variables include enzyme defects, malabsorption, digestive system pathology, and liver disease.
Individuals with methylenetetrahydrofolate reductase (5-MTHFR enzyme) defects will have varying inability to convert folic acid to 5-MTHF.1-5
Folic Acid’s Most Active Form
There is evidence pointing to the benefits of using the biologically active form of folic acid, MTHF, as a preferred supplement form. Significantly greater red blood cell folate concentrations were observed after 24 weeks of supplementation with 5-MTHF compared to folic acid and placebo.6
A single, high-dose pharmacokinetic study of 5-MTHF or folic acid administration (5 mg) in patients with coronary artery disease demonstrated significantly higher bioavailability of 5-MTHF, which resulted in a 700-percent higher plasma folate concentration after 5-MTHF dosing compared to folic acid. This difference was irrespective of the patient’s enzymatic genotype.7
Folic Acid Deficiency and Symptoms
Folic acid deficiency is believed to be one of the most common nutritional deficiencies, which should not be surprising with statistics reporting that only 11 percent consume the daily recommendation of 5 to 7 servings of vegetables and fruit. Common presentations of insufficient folic acid can include macrocytic anemia (too large of red blood cells), fatigue, irritability, peripheral neuropathy, tendon hyper-reflexivity, restless legs syndrome, diarrhea, weight loss, insomnia, depression, dementia, and psychiatric conditions.8-13
While having ones annual blood work done, getting a CBC (Complete Blood Count with Differential) is very important. The MCV result on this test combined with total red blood cell count provides insight as to potential nutrient deficiencies. When red blood cells are enlarged, called macrocytic, the use of both folic acid with vitamin B12 is the most common treatment approach by nutritional minded healthcare providers. Depending on the patient’s nutritional status, the dose of folic acid or 5-MTHF required to reverse macrocytic anemia varies, but the therapeutic dose is usually 800-1,000 mcg (1 mg) daily.
Elevated plasma homocysteine is an independent risk factor for cardiovascular disease. Hyperhomocysteinemia has been connected to increased risk of neural tube defects, Alzheimer’s disease, cognitive decline, osteoporosis, rheumatoid arthritis, kidney failure, and cancer.14-15
MTHF is required for optimal homocysteine metabolism, since it acts as a methyl donor, thus providing a methyl group to vitamin B12. The methylated form of vitamin B12 (methylcobalamin) is the active form of B12 and can transfer its methyl group to homocysteine. Sufficient presence of methyl donors is absolutely essential for the re-transformation of homocysteine to methionine, resulting in homocysteine reduction.
MTHF can assist in lowering homocysteine and also enhance blood flow by increasing nitric oxide (NO) production in vascular endothelial cells. Impaired endothelial NO production arises as part of the pathological changes of cardiovascular disease, particularly atherosclerosis. The risk of atherosclerosis is amplified significantly as a result of the associated poor vasodilation due to insufficient nitric oxide production.
Homocysteine compromises the ability to generate sufficient amounts of NO that leads to injury of the endothelial lining and propagates further atherosclerosis. The pathophysiology that manifests includes increased “stickiness” of monocytes and platelets, increased smooth muscle proliferation, and clot formation. The evidence suggests that MTHF can improve NO synthesis by lowering homocysteine levels, while helping mitigate the impairment of dysfunctional endothelial NO production. MTHF also appears to reduce free radical generation and can substitute for tetrahydrobiopterin as a cofactor in the enzyme nitric oxide synthase, with an cumulative effect of improvement of blood flow.16-21
Inflammatory Bowel Disease
Individuals with inflammatory bowel disease (IBD) will often present with folic acid insufficiency arising from the increased demand of cellular healing, malabsorption and the use of medications such as Sulfasalazine, well known to inhibit folate absorption.22 A study of 99 UC patient records found folic acid supplementation was associated with a 62-percent decreased risk of neoplasia compared to patients not taking a folate supplement.23
Several studies have documented improvement in depression in some patients subsequent to oral supplementation with 5-MTHF at doses upwards of 15-50 mg daily.24-26 Folic acid has also been shown in some studies to significantly improve the antidepressant action of fluoxetine in subjects with major depression.27 Preliminary evidence suggests that supplemental folic acid might positively affect morbidity of some bipolar patients placed on lithium therapy.28
There is growing evidence that there is an association between folic acid sufficiency and cervical dysplasia.29-32 One study points to the possibility of folic acid supplementation at a dosage of 10 mg daily for three months may reverse cervical dysplasia in women taking oral contraceptives.33
It is important to note there are reports of women infected with certain strains of human papilloma virus who do not respond to folic acid therapy. This may be suggestive that without addressing the underlying viral infection and propagation of disease it negates some of the folic acid benefits. As reflected by the positive oral contraceptive study described above, folic acid sufficiency that can become reduced with oral contraceptive use may increase susceptibility to viral infection.
Folic acid sufficiency can improve gingival (gum) resistance to irritation and resultant inflammation and infection. A mouth rinse of folic acid used twice daily for four weeks, with a rinsing time of one minute, appears to be the most effective manner of application.34-36 Clinically, many patients will open up 2 to 5 capsules and mix the contents with about 1 to 2 ounces of water and make their own mouth rinse for each mouth rinsing session.
Folic acid is often added to vitiligo protocols. The scientific literature report varying degrees of effectiveness of re-pigmentation ranging from complete re-pigmentation in six subjects and 80-percent re-pigmentation in two subjects in eight individuals participating in a three year protocol with a dosage of 2 mg folic acid twice daily, 500 mg vitamin C twice daily, and intramuscular injections of vitamin B12 every two weeks.37 Another study that spanned two-years used a combination of folic acid, vitamin B12, and sun exposure for treatment of vitiligo reported positive results. One hundred patients with vitiligo were treated, with re-pigmentation occurring in 52 subjects. Total re-pigmentation was seen in six patients and the spread of vitiligo was halted in 64 percent of the patients.38
Individuals taking prescription medications should ask their pharmacist and physician about potential folic acid depletion. There are dozens of medications that can contribute to folic acid insufficiency. The list is far too lengthy for inclusion in this article. Yet, allow me to point out a couple important categories. Antacids and acid blockers can decrease the absorption of many nutrients including folic acid absorption.39 Sulfasalazine interferes with folic acid absorption and conversion to 5-MTHF.40 Long-term use of acetaminophen, aspirin, ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDS) can apparently increase the need for enhanced intake of folate to sustain sufficiency.41
New Active MTHF
The new supplement Active MTHF contains 800 mcg of MTHF, which is nearly 7 times more bioavailable than ordinary folic acid. Active MTHF requires no metabolic conversion before being absorbed or entering the cell. It readily crosses the blood-brain barrier and will not mask Vitamin B12 deficiency.
This brief review of the benefits of folic acid reflects the diverse biochemical importance of this often ignored B vitamin. Furthermore, a meaningful percentage of the populace is unable to sustain sufficient levels of folic acid, let alone the biologically active form, MTHF. Gastrointestinal, cervical, mental, red blood cell, DNA and cellular health are all dependent upon maintaining optimal levels.
1. Yates JR, Ferguson-Smith MA, Shenkin A, et al. Is disordered folate metabolism the basis for the genetic predisposition to neural tube defects? Clin Genet. 1987;31:279-287.
2. Lussier-Cacan S, Xhignesse M, Piolot A, et al. Plasma total homocysteine in healthy subjects: sex specific relation with biological traits. Am J Clin Nutr. 1996;64:587-593.
3. Kluijtmans LA, Van den Heuvel LP, Boers GH, et al. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;58:35-41.
4. Whitehead AS, Gallagher P, Mills JL, et al. A genetic defect in 5,10 methylenetetrahydrofolate reductase in neural tube defects. QJM. 1995;88:763-766.
5. Ulvik A, Evensen ET, Lien EA, et al. Smoking, folate and methylenetetrahydrofolate reductase status as interactive determinants of adenomatous and hyperplastic polyps of colorectum. Am J Med Genet. 2001;101:246-254.
6. 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.
7. Willems FF, Boers GH, Blom HJ, et al.Pharmacokinetic study on the utilisation of 5- methyltetrahydrofolate and folic acid in patientswith coronary artery disease. Br J Pharmacol. 2004;141:825-830.
8. Pentieva K, McNulty H, Reichert R, et al. The short-term bioavailabilities of [6S]-5-methyltetrahydrofolate and folic acid are equivalent in men. J Nutr. 2004;134:580-585.
9. Venn BJ, Green TJ, Moser R, et al. Increases in blood folate indices are similar in women of childbearing age supplemented with [6S]-5-methyltetrahydrofolate and folic acid. J Nutr. 2002;132:3353-3355.
10. Houghton LA, Sherwood KL, Pawlosky R, et al. [6S]-5-methyltetrahydrofolate is at least as effective as folic acid in preventing a decline in blood folate concentrations during lactation. Am J Clin Nutr. 2006;83:842-850.
11. Halsted CH. The intestinal absorption of dietary folates in health and disease. J Am Coll Nutr. 1989;8:650-658.
12. Revell P, O’Doherty MJ, Tang A, Savidge GF. Folic acid absorption in patients infected with the human immunodeficiency virus. J Intern Med. 1991;230:227-231.
13. Botez MI. Folate deficiency and neurological disorders in adults. Med Hypotheses. 1976;2:135-140.
14. Audebert M, Gendre JP, Le Quintrec Y. Folate and the nervous system (author’s transl). Sem Hop. 1979;55:1383-1387.
15. Young SN, Ghadirian AM. Folic acid and psychopathology. Prog Neuropsychopharmacol Biol Psychiatry. 1989;13:841-863.
16. Das UN. Folic acid says NO to vascular diseases. Nutrition. 2003;19:686-692.
17. Hyndman ME, Verma S, Rosenfeld RJ, et al. Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function. Am J Physiol Heart Circ Physiol. 2002;282:H2167-H2172.
18. Antoniades C, Shirodaria C, Warrick N, et al. 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation. 2006;114:1193-1201.
19. Stroes ES, van Faassen EE, Yo M, et al. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res. 2000;86:1129-1134.
20. Doshi SN, McDowell IF, Moat SJ, et al. Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide? Arterioscler Thromb Vasc Biol. 2001;21:1196-1202.
21. Verhaar MC, Wever RM, Kastelein JJ, et al. 5-methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation. 1998;97:237-241.
22. Lashner BA, Heidenreich PA, Su GL, et al. Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study. Gastroenterology. 1989;97:255- 259.
23. Lashner BA, Provencher KS, Seidner DL, et al. The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis. Gastroenterology. 1997;112:29-32.
24. Passeri M, Cucinotta D, Abate G, et al. Oral 5- methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging (Milano). 1993;5:63-71.
25. Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990;336:392-395.
26. Guaraldi GP, Fava M, Mazzi F, la Greca P. An open trial of methyltetrahydrofolate in elderly depressed patients. Ann Clin Psychiatry. 1993;5:101-105.
27. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000;60:121-130.
28. Coppen A, Chaudhry S, Swade C. Folic acid enhances lithium prophylaxis. J Affect Disord. 1986;10:9-13.
29. Botez MI, Peyronnard JM, Berube L, Labrecque R. Relapsing neuropathy, cerebral atrophy and folate deficiency. A close association. Appl Neurophysiol. 1979;42:171-183.
30. Liu T, Soong SJ, Wilson NP, et al. A case control study of nutritional factors and cervical dysplasia. Cancer Epidemiol Biomarkers Prev. 1993;2:525-530.
31. Grio R, Piacentino R, Marchino GL, Navone R. Antineoblastic activity of antioxidant vitamins:the role of folic acid in the prevention of cervical dysplasia. Panminerva Med. 1993;35:193-196.
32. Kwasniewska A, Tukendorf A, Semczuk M. Folate deficiency and cervical intraepithelial neoplasia. Eur J Gynaecol Oncol. 1997;18:526-530.
33. Butterworth CE Jr, Hatch KD, Gore H, et al. Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr. 1982;35:73-82.
34. Vogel RI, Fink RA, Schneider LC, et al. The effectof folic acid on gingival health. J Periodontol. 1976;47:667-668.
35. Thomson ME, Pack AR. Effects of extended systemic and topical folate supplementation on gingivitis of pregnancy. J Clin Periodontol. 1982;9:275-280.
36. Pack AR. Folate mouthwash: effects on established gingivitis in periodontal patients. J Clin Periodontol. 1984;11:619-628.
37. Montes LF, Diaz ML, Lajous J, Garcia NJ. Folic acid a
nd vitamin B12 in vitiligo: a nutritional approach. Cutis. 1992;50:39-42.
38. Juhlin L, Olsson MJ. Improvement of vitiligo after oral treatment with vitamin B12 and folic acid and the importance of sun exposure. Acta Derm Venereol. 1997;77:460-462.
39. Russell RM, Golner BB, Krasinski SD, et al. Effect of antacid and H2 receptor antagonists on the intestinal absorption of folic acid. J Lab Clin Med. 1988;112:458-463.
40. Lambie DG, Johnson RH. Drugs and folate metabolism. Drugs. 1985;30:145-155.
41. Pironi L, Cornia GL, Ursitti MA, et al. Evaluation of oral administration of folic and folinic acid to prevent folate deficiency in patients with inflammatory bowel disease treated with salicylazosulfapyridine. Int J Clin Pharmacol Res. 1988;8:143-148.
© 2008 Complementary Prescriptions 4610 Arrowhead Drive, Carson City, NV 89706
Used with Permission