Levomefolic acid (INN, also known asL-5-MTHF,L-methylfolate andL-5-methyltetrahydrofolate and(6S)-5-methyltetrahydrofolate, and(6S)-5-MTHF) is the primary biologically active form offolate used at the cellular level forDNA reproduction, thecysteine cycle and the regulation ofhomocysteine. It is also the form found in circulation and transported across membranes into tissues and across theblood–brain barrier. In the cell,L-methylfolate is used in themethylation ofhomocysteine to formmethionine andtetrahydrofolate (THF). THF is the immediate acceptor of one carbon unit for the synthesis ofthymidine-DNA,purines (RNA andDNA) andmethionine. The un-methylated form,folic acid (vitamin B9), is a synthetic form offolate, and must undergo enzymatic reduction bydihydrofolate reductase (DHFR) to become biologically active.[1] Systematic reviews suggest thatadjunctive L-methylfolate modestly improves symptoms inmajor depressive disorder.[2][3]
L-methylfolate is water-soluble and primarily excreted via the kidneys. In a study of 21 subjects with coronary artery disease, peak plasma levels were reached in one to three hours followingoral orparenteral administration. Peak concentrations were found to be more than seven times higher thanfolic acid (129ng/ml vs. 14.1 ng/ml).[5]
Patients at risk forvitamin B12 deficiency should consult with their medical provider prior to taking L-Methylfolate. The interrelationship between these two vitamins (L-Methylfolate and B12) is best explained by the methyl trap hypothesis.[6][7]
Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease[9] and advanced cancers such as breast andcolorectal cancers.[10] It bypasses several metabolic steps in the body and better bindsthymidylate synthase withFdUMP, a metabolite of the drugfluorouracil.
In March 2012,Merck & Cie ofSwitzerland,Pamlab LLC (maker ofMetanx andCerefolin, Neevo DHA, and Deplin), and South Alabama Medical Science Foundation (SAMSF) (the plaintiffs) filed a complaint in theUnited States District Court for the Eastern District of Texas against four defendants: Macoven Pharmaceuticals (owned by Pernix Therapeutics), Gnosis SpA of Italy, Gnosis U.S.A and Gnosis Bioresearch Switzerland. The plaintiffs alleged that the defendants infringed on several of the plaintiffs' patents.[11] The Macoven products named in the suit are: "Vitaciric-B", "ALZ-NAC", "PNV DHA", and l-methylfolate calcium (levomefolate calcium).[12]
In September 2012, the same three plaintiffs filed a complaint requesting that theInternational Trade Commission begin a19 U.S.C.§ 1337 investigation of the same four defendants. The complaint states that Gnosis' "Extrafolic-S" and products which are made from it, infringe upon three of their patents:US 5997915,US 6673381, andUS 7172778.[13]
^Pietrzik K, Bailey L, Shane B (August 2010). "Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics".Clinical Pharmacokinetics.49 (8):535–48.doi:10.2165/11532990-000000000-00000.PMID20608755.S2CID12876272.
^abMaruf, Abdullah Al; Poweleit, Ethan A.; Brown, Lisa C.; Strawn, Jeffrey R.; Bousman, Chad A. (2022). "Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders".Pharmacopsychiatry.55 (3):139–147.doi:10.1055/a-1681-2047.ISSN1439-0795.PMID34794190.
^Smulders, Y. M.; Smith, D. E.; Kok, R. M.; Teerlink, T.; Swinkels, D. W.; Stehouwer, C. D.; Jakobs, C. (2006). "Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap".British Journal of Haematology.132 (5):623–629.doi:10.1111/j.1365-2141.2005.05913.x.PMID16445837.
^Ströhle A, Wolters M, Hahn A (June 2005). "Folic acid and colorectal cancer prevention: molecular mechanisms and epidemiological evidence (Review)".International Journal of Oncology.26 (6):1449–64.doi:10.3892/ijo.26.6.1449.PMID15870856.
^"Metafolin".MilliporeSigma. Retrieved28 November 2022.Metafolin® is our manufactured calcium salt of L-5-methyltetrahydrofolic or L-methylfolate. ... The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the US and Canada.
^"DEPLIN®". For Healthcare Professionals. Retrieved28 November 2022.
Brockton NT (October 2006). "Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate?".Cancer Causes & Control.17 (8):1005–16.doi:10.1007/s10552-006-0051-5.PMID16933051.S2CID20394873.
Stahl SM (October 2007). "Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent".CNS Spectrums.12 (10):739–44.doi:10.1017/S1092852900015418.PMID17934378.S2CID27000937.
