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
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 Med1998;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.