L-Methylfolate calcium (Folate)

L-methylfolate is used in the methylation of homocysteine to form methionine and tetrahydrofolate (THF). THF is an immediate acceptor of one carbon unit for the syn-thesis of thymidine-DNA, purines (RNA and DNA) and methionine. The predominant active form of folate in the body is L-5-methyltetrahydrofolate (L-methylfolate) which is superior over synthetic folic acid which needs activation by enzymatic reduction steps, first (Pietrzik, Bailey, and Shane 2010). The maximum uptake of folic acid of 200 µg per day have been reported (Selhub and Rosenberg 2016). For higher intakes of folic acid unmetabolized folic acid have been reported (Page et al. 2017; Selhub and Rosenberg 2016). The consequences of unmetabolized folic acid are mainly unknown, yet (Prinz-Langenohl et al. 2009) but can result in inhibited reduction of folic acid by dihydrofolate reductase polymorphism (Selhub and Rosenberg 2016).

Interestingly, reduction of increased homocysteine has been reported with high intake of folic acid (2500 µg/d), vitamin B6 (50 mg/d) and vitamin B12 (1000 µg/d) in a randomized, placebo controlled study over 7 years with 5202 individuals with pre-existing cardiovascular diseases (CVD) while reducing the risk of AMD (Christen et al. 2009). A combination of L-methylfolate (3000 µg/d), vitamin B12 (2000 µg/d) and vitamin B6 (35 mg/d) reduced significantly homocysteine levels in a multicentre, randomized, double-blind, placebo-controlled trial including over 200 diabetic patients with neuropathy (Fonseca et al. 2013). 

L-methylfolate is the form of folate in the body circulation with the ability to be transported into peripheral tissue, including the blood retina barrier (BRB) and the blood brain barrier (BBB). L-methylfolate is used by the body in many biochemical pathways, most importantly in the recycling of homocysteine back into methionine. In a double-blind study treating hyperhomocysteinemia patients over 8 weeks 1000 µg L-5-methylfolate was more effective in reduced homocysteine than 1000 µg folic acid (Akoglu et al. 2008). In a 24-week, randomized, placebo-controlled study with healthy volunteers 113 µg L-methylfolate was more effective than 100 µg folic acid (equimo-lar to L-methylfolate) in reducing homocysteine (Venn et al. 2003). 

5-methyl-tetrahydrofolate (5-MTHF), the circulating metabolite of folic acid participating in homocysteine metabolism, has direct effects on vascular function. 5-MTHF and homocysteine on vascular redox and endothelial nitric oxide bioavailability in human vessels was investigated in 218 patients considering different methyl tetrahydrofolate reductase (MTHFR) gene polymorphisms (677C>T) (Antoniades et al. 2009). Vascular 5-MTHF, rather than plasma or vascular homocysteine, is a key regulator of endothelial nitric oxide synthase coupling and nitric oxide bioavailability in human vessels, suggesting that plasma homocysteine is an indirect marker of 5-MTHF rather than a primary regulator of endothelial function. Plasma or circulating 5-MTHF exert a direct effect on vascular tetrahydrobiopterin (BH4) levels, NO bioavailability and eNOS coupling in vessels in vivo thus improving endothelial function (Antoniades 2006). 

The association between folate intake and 10 year incidence for AMD indicated an intake of ≥ 473.3 µg dietary folate equivalents (Gopinath et al. 2013). High folat intake was associated with reduced risk of progression to geographic atrophy (B. M. Merle et al. 2016). Derived from model results with natural food folate intake of >450 µg dietary folate equivalents per day (DFE/day) (Marchetta et al. 2015), 900 µg L-methylfolate (2 x 450 µg folate) has been defined to maintain normal L-methylfolate levels with consequently normal homocysteine levels together with coenzymes outlined below. 

It has to be noted that 900 µg L-methylfolate intake is seen to be save due to clinical studies applying 3000 µg L-methylfolate over 24 weeks (Fonseca et al. 2013) or even higher doses 15,000 µg 5-Methylfolate over 3 weeks (Cagnacci, Cannoletta, and Volpe 2009) and over 3 months (Caruso et al. 2006) respectively.

Conclusion: The effective dosage for L-methylfolate of 900 µg maintains efficiently homocysteine levels. The level of L-methylfolate does not exceed the maximum level for the synthetic folic acid.