In the recent years increasing evidence of the advantages of reduced folate vs folic acid have been found. The rational use of reduced folate (particularly reduced and methylated such as Quatrefolic®) is derived from the inability of a part of world population to assimilate and metabolize folic acid from food or supplements (the most of folate assumption is coming from folic acid man-made version in supplements and added to foods).

Folic acid and also food folate are not biologically active and need to be converted to the metabolically active 5-methyltetrahydrofolate (5-MTHF) through a multi-steps process where the enzyme methylenetetrahydrofolate reductase (MTHFR) owns a key role. Some individuals, due to their unique genetic patterns and expression, have polymorphic forms of this enzyme and do not produce adequate or effective MTHFR [1, 2, 3].

Methylenetetrahydrofolate reductase (MTHFR) is one of the most important enzymes in human physiology, deficiencies in production or function of this enzyme have been associated with increased risk of different diseases [9, 1].

The inability of a part of world population to assimilate and metabolize folic acid from food or supplements may jeopardize their health and increase the risk of adverse health outcomes. The biological active form 5-Methylfolate such as Quatrefolic®, is kindly recommended because efficiently normalize the folate status of all potential subjects including who owns MTHFR polymorphism [10].

Population frequency of homozygosity by geographic area and ethnicity

These defects relate to MTHFR are very common, though they vary enormously between ethnic groups and regions [10, 11]. Emerging science of nutrigenomics indicates that MTHFR most often refers to a genetic mutation that inhibits the ability of the body to methylate (or convert folic acid from the food we eat into the metabolite we need, L-5-Methyltetrahydrofolate) so as some individuals cannot actually use folic acid [12].

Cutting edge scientific research is shed light how much the MTHFR polymorphism is implicated in chronic disease states and how folate nutrition may contribute to replace adequate methylation and overall health [9].

The other advantage is that Quatrefolic® passes the gastric barrier and is absorbed mainly in the small intestine by a carrier mediated mechanism. The carrier is not saturated and this enables Quatrefolic® to ensures a higher folate uptake [1, 4].

Quatrefolic® is the glucosamine salt of (6S)-5-methyltetrahydrofolate and is structurally analogous to the reduced and active form of folic acid so Quatrefolic® completely bypasses the "damaged" MTHFR conversion step and delivers a "finished" folate the body can immediately use without any kind of metabolization.


Several studies have reported an increase in serum of unmetabolized folic acid (UMFA) levels since the implementation of folic acid fortification, with possible concern about its potential 'overdosing' and adverse effects [5, 6, 7, 8].

Variability in the presence or persistence of UMFA in the population suggests that it may be accumulated in the blood as a consequence of different conditions described above, such as the impairment, and/or the slackness of the folic acid reduction pathway to the 5-methyltetrahydrofolate (genetic polymorphism), and the overdosing effect due to uncontrolled folic acid intake [13, 14, 15]

The threshold of ingestion of folic acid that leads to the direct appearance of UMFA in the plasma, results to be highest than 200-300 μg/daily intake. The consumption of highest dosage of synthetic folic acid results in absorption of unreduced folic acid, which may interfere with folate metabolism for a period of years [7, 8, 16, 17, 18, 19].

Quatrefolic® answers to all consumers' and physicians' concerns relating to potential harmful effects of folic acid administration. As Quatrefolic® provides the metabolic reduced folate form utilized and stored in the human body, the (6S)-5-methyltetrahydrofolate, it does not aid to the potential accumulation of UMFA in the blood, which has no biological function and whose effects are not yet known, also due to the potential uncontrolled assumption of folic acid by diet.


1. Patanwala I et al. Folic acid handling by the human gut: implications for food fortification and supplementation. Am J Clin Nutr. 2014

2. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014

3. Ulrich CM, Potter JD. Folate supplementation: too much of a good thing? Cancer Epidemiol Biomarkers Prev. 2006

4. Pietrzik K et al. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2010

5. Lawrence, Kripalani et al. "Profiling National Mandatory Folic Acid Fortification Policy Around the World." New York: Springer; 2012

6. Ulric et al. "Folate Supplementation: Too Much of a Good Thing?" Cancer Epidemiol Biomarkers Prev 2006;15:189-193

7. Strum et al. "Enzymatic reduction and methylation of folate following pH-dependant, carrier-mediated transport in rat jejunum." Biochim Biophys Acta 1979; 554, 249-257

8. Kelly et al. "Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements." Am J Clin Nutr 1997:65:1790-5

9. Jamil K. Clinical Implications of MTHFR Gene Polymorphism in Various Diseases. Biol Med. 2014

10. Wilcken B 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 worldwide. J Med Genet. 2003

11. Seremak-Mrozikiewicz A et al. The significance of 1793G>A polymorphism in MTHFR gene in women with first trimester recurrent miscarriages. Neuro Endocrinol Lett. 2010

12. Tsang BL et al. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: A systematic review and meta-analysis of trials and observational studies. Am. J. Clin. Nutr. 2015

13. Sweeney MR et al. Persistent circulating unmetabolized folic acid in a setting of liberal voluntary folic acid fortification. Implications for further mandatory fortification? BMC Public Health. 2009

14. Smith AD. Folic acid fortification: the good, the bad, and the puzzle of vitamin B-12. Am J Clin Nutr. 2007

15. Smith D. A. et al. Is folic acid good for everyone? Am J Clin Nutr. 2008

16. Colman, Green, Metz et al. "Prevention of folate deficiency by food fortification. Il. Absorption of folic acid from staple foods." Am J Clin Nutr I 975; 28:459-64

17. Shils et al. "Modern Nutrition in Health and Disease, 9th ed". Williams & Wilkins, Balt., 1999

18. http://www.efsa.europa.eu/it/home/publication/efsafolicacid.pdf

19. Morris MS et al. "Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors". Am J Clin Nutr. 2010

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