Folate is a water-soluble B vitamin, whose chief function in the body is DNA synthesis and therefore new cell formation. Deficiency symptoms include large-cell type anemia, a smooth red tongue, mental confusion, weakness, fatigue, irritability, headache, and elevated homocysteine levels. Folate is the form of this nutrient naturally occurring in foods, whereas folic acid is the form found in supplements and fortified foods.1
Although folates are widely distributed in foods, folate deficiencies may be more frequent than expected because their true availability may be impaired due to their instability under various food cooking and processing conditions. Folate deficiency is frequently observed in elderly people, smokers, alcoholics and oral contraceptive users. It is also associated with a mutation leading to methylenetetrahydrofolate reductase defects in which 10 percent of the population will have varying inability to convert folate/folic acid to its biologically active form 5-methyltetrahydrofolate (5- MTHF).2 Another problem relating to folate availability is autoantibodies against folate receptors on the choroid plexus3 (the area on the ventricles of the brain where cerebrospinal fluid is produced). In short, a folate deficiency can occur due to an inadequate dietary intake, malabsorption, altered hepatic and peripheral metabolism, or an increased elimination of folate.4
Consequently, supplementation with ordinary folic acid may not always address deficiency issues, particularly for those individuals who are unable to effectively convert this nutrient into its active 5-MTHF form. In these cases supplementation with 5-MTHF may be necessary. Furthermore, the bioavailability of 5-MTHF and other clinical data argue to make it the preferred form of folic acid for supplementation in general.
Bioavailability of 5-MTHF
In one study of 5-MTHF or folic acid administration in patients with coronary artery disease, 5-MTHF demonstrated significantly higher bioavailability. Irrespective of the patients’ enzymatic genotype, supplementation with 5-MTHF resulted in a 700 percent higher plasma folate concentration compared to supplementation with folic acid.5 Likewise, significantly greater red blood cell folate concentrations were observed after 24 weeks of supplementation with 5-MTHF compared to folic acid and placebo.6
5-MTHF Doesn’t Mask B12 Deficiency
A well established clinical issue is that supplementation with folic acid can mask an underlying vitamin B12 deficiency.7 A distinct advantage of 5-MTHF is that while it can treat a folic acid deficiency, it is unlikely to mask the hematologic indicators of vitamin B12 deficiency.8
5-MTHF & Homocysteine
5-MTHF is required for the remethylation of homocysteine to methionine. By inhibiting this remethylation pathway, folate deficiency induces homocysteine efflux into the circulation. This explains why many studies have shown that folate deficiency is a major cause of hyperhomocysteinemia.9
A 3-month study examined the effect of oral 5-MTHF treatment in 72 patients with hyperhomocysteinemia. The results were a very highly statistically significant reduction in homocysteine levels (P=0.002) to normal levels in both subjects with high and medium homocysteine levels. Furthermore, there was also a highly statistically significant reduction in the prooxidant cysteinylglycine. This suggests that 5-MTHF has an additive antioxidant action through increased nitric oxide production and superoxide radical scavenging, which may help to ameliorate endothelial dysfunction.10 This additional antioxidant action makes a good case for the use of 5-MTHF in place of folic acid for helping to promote healthy levels of homocysteine.
In addition, in a 24-week, randomized, placebo-controlled study 167 healthy patients were randomly assigned to receive a daily supplement containing folic acid, 5-MTHF or placebo. The results were that homocysteine levels were 14.6 percent lower in the 5-MTHF and 9.3 percent lower in the folic acid group compared to the placebo group. Clearly 5-MTHF was more effective than folic acid in lowering homocysteine levels.11
5-MTHF & Oropharyngeal Mucous Membranes
The oropharyngeal mucous membrane (the part of the pharynx between the soft palate and the epiglottis) can atrophy as a result of vitamin B12 and folic acid deficiencies. In a study12 of twenty-three patients' oropharyngeal mucous atrophies, treatment consisted of 5-MTHF for one month, and then vitamin B12 for another month. After the first month, 20 patients showed pink oral mucous membrane and reported the disappearance of caustic symptoms, and the laboratory tests showed values within normal limits. Furthermore, hypersensitive ulcers on the lips disappeared. The other three patients, who still had values under normal limits, were subjects who had undergone long-term chemotherapy. For these patients the therapy was continued for a further month, at which point the lingual mucous membrane appeared pink and re-epitheliated and patients reported disappearance of the painful oral symptoms. Also, laboratory tests were repeated again for all the patients and these confirmed values within normal limits for vitamin B12 and folic acid.
5-MTHF & Moodiness
Several studies have documented that 5-MTHF was able to promote improvement in patients experiencing moodiness. In one study,13 elderly patients being treated with standard psychotropic medication were additionally given 5-MTHF. Patients with borderline or definite folate deficiency experienced improvements in mood, and patients with normal levels of folate experienced significantly improvements in mood after three weeks of treatment. Similar beneficial results were seen with 5-MTHF supplementation in a doubleblind, placebo-controlled trial.14 The authors of this particular study also commented that their findings contributed to the evidence implicating disturbances of methylation in the nervous system in the biology of mood disturbances. A 6-week open-label trial15 using 5-MTHF noted that 81 percent of patients showed a markedly significant improvement in their moody symptoms at endpoint.
- Bruno Jr EJ, Zeigenfuss TM. Water-soluble Vitamins: Research Update. Current Sports Medicine Reports 2005; 4:207–213.
- Durand P, Prost M, Blache D. Folate deficiencies and cardiovascular pathologies. Clin Chem Lab Med 1998;36(7):419–29.
- Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med 2005;352(19):1985–91.
- Sikka PK, McMartin KE. Determination of folate transport pathways in cultured rat proximal tubule cells. Chemico-Biological Interact 114:15–31, 1998.
- Willems FF, Boers GH, Blom HJ, et al. Pharmacokinetic study on the utilisation of 5- methyltetrahydrofolate and folic acid in patients with coronary artery disease. Br J Pharmacol 2004;141:825–30.
- 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;84:156–61.
- Whitney EN, Cataldo CB, Rolfes SR: Understanding Normal and Clinical Nutrition. Belmont, CA: Wadsworth/Thompson Learning; 2002:322–8.
- 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;77:658–62.
- Durand P, et al. Clin Chem Lab Med 1998;36(7):419–29.
- Caruso R, Campolo J, Sedda V, De Chiara B, Dellanoce C, Baudo F, Tonini A, Parolini M, Cighetti G, Parodi O. Effect of homocysteine lowering by 5-methyltetrahydrofolate on redox status in hyperhomocysteinemia. J Cardiovasc Pharmacol 2006;47(4):549–55.
- Durand P, et. al. Clin Chem Lab Med 1998;36(7):419–29.
- Bottero A, Lauritano D, Spadari F, Zambellini Artini M, Salvato A. Atrophy of the oro-pharyngeal mucosa caused by vitamin B12 and folic acid deficiency. Etiopathologic aspects and clinico-therapeutic problems. Minerva Stomatol 1997;46(7-8):359–74.
- Passeri M, Cucinotta D, Abate G, Senin U, Ventura A, Stramba Badiale M, Diana R, La Greca P, Le Grazie C. Oral 5-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging (Milano) 1993;5:63–71.
- Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M, Chanarin I, Reynolds EH. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990;336:392–395.
- Guaraldi GP, Fava M, Mazzi F, la Greca P. An open trial of methyltetrahydrofolate in elderly depressed patients. Ann Clin Psychiatry 1993;5:101–5.
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Gene Bruno, MS, MHS
Gene Bruno is the Dean of Academics and Professor of Dietary Supplement Science for Huntington College of Health Sciences (a nationally accredited distance learning college offering diplomas and degrees in nutrition and other health science related subjects. Gene has two undergraduate Diplomas in Nutrition, a Bachelor’s in Nutrition, a Master’s in Nutrition, a Graduate Diploma in Herbal Medicine, and a Master’s in Herbal Medicine. As a 32 year veteran of the Dietary Supplement industry, Gene has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines, and peer-reviewed publications. Gene's latest book, A Guide to Complimentary Treatments for Diabetes, is available on Amazon.com, and other fine retailers.