L-Methylfolate Calcium, also known as Calcium Levomefolate, is the biologically active form of folic acid (vitamin B₉) that doesn't require further conversion in the body to be utilized. It is essential for numerous biological processes, including DNA synthesis, cell repair, and amino acid metabolism. 

Main uses and benefits

Mental Health Support. L-Methylfolate Calcium has been studied for its role in supporting mental health (1) and treating conditions such as depression, contributing to the regulation of neurotransmitter levels.

Fetal Development. It is crucial for the prevention of neural tube defects in newborns, making it an important supplement during pregnancy to support proper fetal development.

Cardiovascular Health. It helps reduce blood homocysteine levels (2), a risk factor for cardiovascular diseases such as atherosclerosis.

Cognitive Function Support. L-Methylfolate Calcium can support cognitive function and brain health (3), helping to prevent age-related cognitive decline.

Optimized Absorption. Being the biologically active form of folic acid, it is more efficiently absorbed by the body, making it particularly useful for individuals with genetic variants such as the MTHFR mutation (4) that affect the conversion of folic acid.

Dietary Supplements. Often used in dietary supplements to ensure adequate folate intake, especially for pregnant women, people with folate deficiencies, or individuals with specific metabolic needs.

L-Methylfolate Calcium offers significant health benefits, providing direct support to multiple body processes without the need for enzymatic conversion, making it an effective option for folate supplementation.

Chemical Industrial Synthesis Process

Synthesis of L-Methylfolate. The production begins with the chemical or biotechnological synthesis of L-Methylfolate, starting from precursors such as folate or folic acid. This process may involve several reaction stages to introduce the methyl group into the folate molecule.

Conversion to Calcium Salt. The obtained L-Methylfolate is then converted into its calcium salt form to improve its stability and solubility. This is achieved by adding a calcium source to the L-Methylfolate solution and adjusting the pH to favor the formation of the salt.

Purification. The crude L-Methylfolate Calcium salt is purified to remove impurities and by-products of the synthesis. Purification may include techniques such as crystallization, chromatography, and filtration.

Quality Control. The purified product undergoes quality control checks to verify its purity, chemical composition, and absence of impurities. These tests can include spectroscopic analyses, chromatographic analyses, and identity tests.

Formulation. L-Methylfolate Calcium can be formulated into various forms for use in dietary supplements, such as tablets, capsules, or powders, depending on the needs of the final product.

It appears in the form of a white powder

Molecular Formula  C₂₀H₂₃CaN₇O₆

Molecular Weight  497.5 g/mol

CAS   151533-22-1

UNII    A9R10K3F2F

EC Number   691-636-3

Synonyms

• Levomefolate calcium
• Metafolin®
• Calcium levomefolate
• Levomefolinate calcium
• Bodyfolin

References_____________________________________________________________________

(1) Rainka M, Aladeen T, Westphal E, Meaney J, Gengo F, Greger J, Capote H. L-Methylfolate Calcium Supplementation in Adolescents and Children: A Retrospective Analysis. J Psychiatr Pract. 2019 Jul;25(4):258-267. doi: 10.1097/PRA.0000000000000400. PMID: 31291206.

Abstract. Previous studies have shown l-methylfolate to be a safe and beneficial therapy for neuropsychiatric conditions, including major depressive disorder and schizophrenia in adults. The purpose of this study was to assess safety and describe patient experience using l-methylfolate calcium in a real-world pediatric and adolescent population. A retrospective chart review of patients (7 to 20 y of age, mean age 16 y) prescribed l-methylfolate calcium at a psychiatry clinic in Amherst, NY, between January 1, 2010 and November 10, 2015 was conducted. Patients to whom l-methylfolate calcium 15 mg/d (n=139) or 7.5 mg/d (n=7) was administered were identified; 44 patients who were prescribed but to whom l-methylfolate calcium was not administered were included as a comparator population. Common neuropsychiatric diagnoses included anxiety disorders (68% in the treatment population vs. 50% in the comparator population) and mood disorders (57% in the treatment population vs. 52% in the comparator population). Antidepressants (69% vs. 55%) and mood stabilizers or antiepileptic drugs (63% vs. 57%) were frequently prescribed in combination with l-methylfolate calcium. Adverse events occurred less frequently in the treated population, possibly due to the addition of l-methylfolate calcium (10% vs. 25%, P=0.02). The most common adverse events in the treated population were impaired sleep (5 patients) and increased anxiety (3 patients). Rates of laboratory abnormalities did not differ significantly between the treated and comparator populations (P=0.13). Positive subjective treatment experiences were reported by 22.5% of treated patients and negative subjective treatment experiences were reported by 5.4% of treated patients. L-methylfolate calcium was well-tolerated in a pediatric/adolescent population and may provide benefits for patients with a range of neuropsychiatric conditions.

(2) Huang Y, Tan Y, Wang L, Lan L, Luo J, Wang J, Zeng H, Shu W. Consumption of very low-mineral water may threaten cardiovascular health by increasing homocysteine in children. Front Nutr. 2023 Mar 9;10:1133488. doi: 10.3389/fnut.2023.1133488. PMID: 36969809; 

Abstract. Introduction: Homocysteine (Hcy) is a critical factor for cardiovascular injury, and the elevation of Hcy in children will inevitably increase the risk of cardiovascular disease in adulthood. This study explored the effect of very low-mineral water on children's Hcy and cardiovascular health.....Conclusion: This study suggested that drinking very low-mineral water may increase Hcy level and oxidative stress, worsen lipid profile, and threaten the cardiovascular system in children. Reducing 1,25,(OH)2D3, and disordering of calcium metabolism might play important roles. This study first established an association between demineralized drinking water and cardiovascular health in children, suggesting a new environmental concern risk to cardiovascular health.

(3) Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013 Mar;18(3):369-81. doi: 10.1038/mp.2011.175. 

Abstract. Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg(-1) per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.

(4) Knowles L, Morris AA, Walter JH. Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency. JIMD Rep. 2016;29:103-107. doi: 10.1007/8904_2016_529. 

Abstract. S-adenosyl methionine, which is formed from methionine, is an essential methyl donor within the central nervous system. Methionine is formed by the enzyme methionine synthase for which 5-methyltetrahydrofolate (5-MTHF) and homocysteine are substrates. Patients with severe methylenetetrahydrofolate reductase (MTHFR) deficiency cannot make 5-MTHF and have extremely low levels in the CSF. As a consequence, methylation reactions in the CNS are compromised, and this is likely to play an important role in the neurological abnormalities that occur in MTHFR deficiency. Although treatment with oral betaine can remethylate homocysteine to methionine in the liver, betaine crosses the blood-brain barrier poorly, and CSF levels of methionine remain low. We report three patients with severe MTHFR deficiency (enzyme activity ≤1% of controls) who had undetectable levels of CSF 5-MTHF at diagnosis and while on treatment with either folic acid or calcium folinate. Only treatment with oral 5-MTHF given as calcium mefolinate at doses of 15-60 mg/kg/day resulted in an increase in CSF 5-MTHF.