Levomefolic acid (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway. Before the advent of motorized transportation, they also provided accomm ...

, also known as L-5-MTHF, L-methylfolate and L-5-methyltetrahydrofolate and (6''S'')-5-methyltetrahydrofolate, and (6''S'')-5-MTHF) is the primary biologically active form of

folate Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...

used at the cellular level for

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

reproduction, the

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

cycle and the regulation of

homocysteine Homocysteine (; symbol Hcy) is a non-proteinogenic α-amino acid. It is a homologous series, homologue of the amino acid cysteine, differing by an additional methylene bridge (). It is biosynthesized from methionine by the removal of its terminal ...

. It is also the form found in circulation and transported across membranes into tissues and across the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

. In the cell, L-methylfolate is used in the

methylation Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...

to form

methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other non-essential amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine play ...

and

tetrahydrofolate Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative. Metabolism In humans, tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate. It is convert ...

(

THF Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water-miscible organic liquid with low viscosity. It is ma ...

). THF is the immediate acceptor of one carbon unit for the synthesis of

thymidine Thymidine (nucleoside#List of nucleosides and corresponding nucleobases, symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine nucleoside, deoxynucleoside. Deoxythymidine is the DNA nuc ...

purine Purine is a heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted puri ...

s (

RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...

and

) and

. The un-methylated form,

folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...

(vitamin B₉), is a synthetic form of

, and must undergo enzymatic reduction by

dihydrofolate reductase Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in one-carbon transfer chemistry. ...

(

DHFR Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in one-carbon transfer chemistry. In ...

) to become biologically active. Systematic reviews suggest that

adjunctive In linguistics, an adjunct is an optional, or ''structurally dispensable'', part of a sentence, clause, or phrase that, if removed or discarded, will not structurally affect the remainder of the sentence. Example: In the sentence ''John helped Bill ...

L-methylfolate modestly improves symptoms in

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

. It is synthesized in the absorptive cells of the small intestine from polyglutamylated dietary

. It is a methylated derivative of

. Levomefolic acid is generated by

methylenetetrahydrofolate reductase Methylenetetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the ''MTHFR'' gene. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-Methylenetetrahydrofolate, 5,10-methylenet ...

(MTHFR) from

5,10-methylenetetrahydrofolate 5,10-Methylenetetrahydrofolate (N5,N10-Methylenetetrahydrofolate; 5,10-CH2-THF) is cofactor in several biochemical reactions. It exists in nature as the diastereoisomer R5,10-methylene-THF. As an intermediate in one-carbon metabolism, 5,10-CH ...

(MTHF) and used to recycle

back to

methionine synthase Methionine synthase (MS, MeSe, MTR) is primarily responsible for the regeneration of methionine from homocysteine in most individuals. In humans it is encoded by the ''MTR'' gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methio ...

(MS). 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 following

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

parenteral In pharmacology and toxicology, a route of administration is the way by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. ...

administration. Peak concentrations were found to be more than seven times higher than

(129 ng/ml vs. 14.1 ng/ml). Patients at risk for

vitamin B12 Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. One of eight B vitamins, it serves as a vital cofactor (biochemistry), cofactor in DNA synthesis and both fatty acid metabolism, fatty acid and amino a ...

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.

Metabolism

Medical uses

Major depressive disorder and other psychiatric conditions

Systematic reviews suggest that

L-methylfolate modestly improves symptoms in

and may benefit other psychiatric conditions with good tolerability. In patients with depression augmenting

SSRI Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by ...

/ SNRI treatment, L-methylfolate augmentation led to higher medication adherence and lower health care utilization and costs compared to augmentation with second-generation

atypical antipsychotics The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as tranquilizers and neuro ...

Cardiovascular disease and cancer

Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease and advanced cancers such as breast and

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...

s. It bypasses several metabolic steps in the body and better binds

thymidylate synthase Thymidylate synthase (TS) () is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleot ...

with

FdUMP Fluorodeoxyuridylate, also known as FdUMP, 5-fluoro-2'-deoxyuridylate, and 5-fluoro-2'-deoxyuridine 5'-monophosphate, is a molecule formed ''in vivo'' from 5-fluorouracil and 5-fluorodeoxyuridine. FdUMP acts as a suicide inhibitor of thymidylat ...

, a metabolite of the drug

fluorouracil Fluorouracil (5-FU, 5-fluorouracil), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stoma ...

Patent issues

In March 2012, Merck & Cie of

Switzerland Switzerland, officially the Swiss Confederation, is a landlocked country located in west-central Europe. It is bordered by Italy to the south, France to the west, Germany to the north, and Austria and Liechtenstein to the east. Switzerland ...

Pamlab Alfasigma USA, Inc. (''formerly'' Pamlab) is an American medical food company, and a division of Alfasigma Group, of Bologna, Italy. Alfasigma's base of operations is located in Bedminster, New Jersey. History The company entered the pharmace ...

LLC (maker of

Metanx Metanx is a prescription medical food made by Alfasigma that contains L-methylfolate (as Metafolin, a calcium salt of vitamin B9), methylcobalamin (vitamin B12) and pyridoxal 5'-phosphate (vitamin B6). It is a vitamin B supplement. Metanx is i ...

and

Cerefolin Cerefolin is a prescription medication made by Pamlab that contains 5.635 mg of folate as L-methylfolate, 1 mg of vitamin B12 as methylcobalamin, 50 mg of vitamin B2 as riboflavin, and 5 mg of vitamin B6 as pyridoxine. I ...

, Neevo DHA, and Deplin), and South Alabama Medical Science Foundation (SAMSF) (the plaintiffs) filed a complaint in the

United States District Court for the Eastern District of Texas The United States District Court for the Eastern District of Texas (in case citations, E.D. Tex.) is a federal court in the United States Court of Appeals for the Fifth Circuit, Fifth Circuit (except for patent claims and claims against the U.S. ...

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.The six patents named were , , , , and . The Macoven products named in the suit are: "Vitaciric-B", "ALZ-NAC", "PNV DHA", and l-methylfolate calcium (levomefolate calcium). In September 2012, the same three plaintiffs filed a complaint requesting that the

International Trade Commission The United States International Trade Commission (USITC or I.T.C.) is an agency of the United States federal government that advises the legislative and executive branches on matters of trade. It was created by Congress in 1916 as the U.S. Tari ...

begin a 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: , , and .

Formulations

* Levomefolate calcium, a calcium

salt In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...

of levomefolic acid is sold under the brand name Metafolin and incorporated in Deplin. * Levomefolate magnesium is a magnesium salt of levomefolic acid, manufactured as DeltaFolate, a primary ingredient in EnLyte. * Levomefolate calcium (a calcium

of levomefolic acid) is manufactured as ''Cerebrofolate''.Malik M, HUSSAIN A AND HASHMI A,

References

External links

Calcium L5-methyltetrahydrofolate (L-5-MTHF-Ca)
* * {{Vitamin Folates Coenzymes Medical food Patent case law