|CAS number||, (calcium salt)|
|PubChem||, (calcium salt)|
|Jmol-3D images||Image 1|
|Molar mass||459.46 g mol−1|
|oral, transdermal, subcutaneous|
|Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)|
Levomefolic acid (INN) (also known as 5-MTHF, l-methylfolate and 5-methyltetrahydrofolate) is the active form of folic acid used at the cellular level for DNA reproduction, the cysteine cycle and the regulation of homocysteine among other functions. The un-methylated form, folic acid (vitamin B9), is a form of folate found in a variety of foods and can be isolated or synthesized for use in nutritional supplements. Folic acid is metabolized in the body into levomefolic acid. Approximately 10% of Caucasian and Asian populations (homozygous TT) have 70% less activity in the enzymes needed to receive any benefit from folic acid.  Another 40% of the population (heterozygous CT) appear to convert only a limited amount of folic acid into levomefolic acid. They cannot fully process supplemental folic acid at RDA or higher dose levels. The remaining population do not have a known MTHFR polymorphism and can therefore metabolize folic acid more efficiently.
It is synthesized in the absorptive cells of the small intestine from polyglutamylated dietary folate. It is a methylated derivate of tetrahydrofolate (THF, H4F). Levomefolic acid is generated by methylenetetrahydrofolate reductase (MTHFR) from 5,10-methylenetetrahydrofolate (5,10-CH2-THF, MTHF) and used to recycle homocysteine back to methionine by 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) also known as methionine synthase (MS).
Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease and advanced cancers such as breast and colorectal cancers. It bypasses several metabolic steps in the body and better binds thymidylate synthase with fDump, a metabolite of the drug fluorouracil.
Commercial use of levomefolic acid in pharmaceutical products began in Europe in the early part of this decade[clarification needed] and have now[when?] appeared in the United States. Supplementation of folate/folic acid has potential to impact prenatal care, homocysteine management, and the treatment of depression, dementia and cardiovascular concerns.
- Prenatal care: low folate status has been linked to neural tube defects, recurrent pregnancy loss, low birth weight and a variety of age-related high risk complications of pregnancy.
- Homocysteine management: elevated homocysteine is frequently linked to the presence of the MTHFR polymorphism.
- Depression: folate status has been linked to the performance of SSRI drugs. Many patients have required folate supplementation in order to adequately respond to standard treatment protocol.
- Dementia: folate status has been linked to the efficacy of neural transmitters and cognitive performance. Only active, levomefolic acid can cross the blood brain barrier.
- Diabetic neuropathy: folate status has been shown to have a substantial impact upon wound care.
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5-MTHF is widely available as on over-the-counter nutritional supplement or as a pharmaceutical preparation.
The Italian company Gnosis SpA markets 3 levomefolic acid products:
- Extrafolate (Calcium-5-MTHF (racemic mixture))
- Extrafolate-S (levomefolate calcium)
- Quatrefolic (glucosamine salt of 5-MTHF)
Thorne Research, Inc of Dover, Idaho offers a 5-MTHF supplement with a 1mg dose of Extrafolate-S on license from Gnosis SpA 
Supplement company Neurobiologix markets 2 levomefolic acid products:
- Neuro-Immune Stabilizer Topical Cream (5-MTHF, Hydroxycobalamin, Methylcobalamin, P5P and Vitamin D)
- Methyl Folate Plus (Calcium-5-MTHF (5 mg), folinic acid (2 mg), and niacinamide (125 mg))
Supplement company Metabolic Maintenance manufactures 5 products with very high levels of L-methylfolate (Levomefolic acid):
- 5-MTHF 2.5 mg, 5 mg, 10 mg, and 15 mg (the same dosage as Deplin), and 5-MTHF Quatrefolic® 10 mg.
Pharmaceutical preparations include:
- Metafolin, a compound consisting of levomefolic acid as its calcium salt, levomefolate calcium, was developed in Germany and is marketed by Merck.
- Cerefolin NAC (5.6 mg) – Nutritional requirements of individuals under a physician's treatment for neurovascular oxidative stress or hyperhomocysteinemia, with particular emphasis for those individuals diagnosed with or at risk for mild to moderate cognitive impairment, vascular dementia, Alzheimer's disease, or recurrent ischemia.
- Deplin (7.5 mg or 15 mg) – Dietary management of suboptimal l-methylfolate levels in patients with major depressive disorder.
- Metanx (2.8 mg) – Dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy.
- Néevo and NeevoDHA (1 mg) – Dietary management of those women under a physician's treatment for vitamin deficiency throughout pregnancy, postnatal and the lactating periods. Néevo is specifically indicated for: patients with high risk pregnancies, older OB patients, and patients unable to fully metabolize folic acid.
- Zervalx (1 mg) – Dietary management of the following patient conditions: preconception hyperhomocysteinemia; intermediate to higher-risk pregnancies that require an increased dietary folate intake; hemolytic, megaloblastic or sickle cell anemia complicated by folate deficiency; and methotrexate induced plasma hyperhomocysteinemia.
In March 2012, Merck & Cie of Switzerland, Pamlab LLC (maker of Metanx and Cerefolin, 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 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 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 begin an 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 , and US 7172778 .
- 5,10-Methylenetetrahydrofolate (5,10-CH2-THF, MTHF)
- 5-Methyltetrahydrofolate-homocysteine methyltransferase (MTR)
- Methylenetetrahydrofolate reductase (MTHFR)
- S-Adenosylmethionine (SAMe)
- Pietrzik, Klaus; Lynn Bailey and Barry Shane (2010). "Folic Acid and L-5-Methyltetrahydrofolate Comparison of Clinical Pharmacokinetics and Pharmacodynamics". Clinical Pharmacokinetics: 535–548. PMID 20608755.
- "5-methyltetrahydrofolate - Compound Summary", PubChem (NCBI), retrieved 2012-09-25
- Willems, Frank F; Boers GHJ, Blom HJ, Aengevaeren WRM, Verheugt FWA (2004 March). "Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease". Br J Pharmacol (Nature Publishing Group) 145 (5): 825–830. doi:10.1038/sj.bjp.0705446. PMC 1574248. PMID 14769778. >
- Iris P Fohr, Reinhild Prinz-Langenohl, Anja Brönstrup, Anja M Bohlmann, Heinz Nau, Heiner K Berthold, and Klaus Pietrzik, IP; Prinz-Langenohl, R; Brönstrup, A; Bohlmann, AM; Nau, H; Berthold, HK; Pietrzik, K (2002). "5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women". Am J Clin Nutr (American Society for Clinical Nutrition) 75 (2): 275–282. PMID 11815318.
- Lakely, Susan. "RPH". L-Methylfolate. Retrieved 12 January 2012.
- Stahl, S. M. (2010). "Enhancing outcomes from major depression: Using antidepressant combination therapies with multifunctional pharmacologic mechanisms from the initiation of treatment". CNS spectrums 15 (2): 79–94. PMID 20414154.
- Gnosis website http://www.gnosis-bio.com/brands.php
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- "Folate / Folinic Acid", Neurobiologix website, retrieved 2012-09-25
- The six patents named were US 5997915 , US 6011040 , US 6254904 , US 6673381 , US 7674490 and US 7172778 .
- "Pernix Therapeutics’ Subsidiary Macoven Pharmaceuticals, LLC Named in Suit by Merck, Pamlab, L.L.C. and Others for Alleged". Bloomberg. 6 March 2012. Retrieved 1 October 2012.
- Schweibenz, Eric W. (2012-09-10). "SAMSF, Merck, and Pamlab File New 337 Complaint Regarding Certain Reduced Folate Nutraceutical Products and L-methylfolate Raw Ingredients Used Therein". Oblon, Spivak, McClelland, Maier & Neustadt, L.L.P. Archived from the original on 1 October 2012.
- CALCIUM L-5-METHYLTETRAHYDROFOLATE (L-5-MTHF-Ca)
- Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate?
- Stahl, SM (October 2007). "Novel Therapeutics for Depression: L-methylfolate as a Trimonoamine Modulator and Antidepressant-Augmenting Agent". CNS Spectrums 12 (10): 739–744. PMID 17934378.