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Levomefolic

Also known as: L-methylfolate, 5-methyltetrahydrofolate, 5-MTHF, active folate, methylfolate, Levomefolic acid

Overview

Levomefolic acid is the biologically active, methylated form of folate (vitamin B9) naturally present in the body and certain foods. Unlike folic acid, it is the form that can directly cross the blood-brain barrier and is immediately utilized in one-carbon metabolism. It plays a crucial role in DNA synthesis, repair, and methylation, as well as in the production of neurotransmitters. Clinically, it is used to prevent and treat folate deficiency, particularly during pregnancy to reduce the risk of neural tube defects. It also serves as an important adjunct therapy in various psychiatric disorders and is being investigated for its cardiovascular and neurocognitive benefits. Its superior bioavailability, especially in individuals with MTHFR genetic polymorphisms, makes it a preferred form of folate supplementation.

Benefits

Levomefolic acid offers several evidence-based benefits. It is highly effective in preventing neural tube defects when supplemented during the periconceptional period, a critical public health intervention. In psychiatric care, systematic reviews and meta-analyses indicate that levomefolic acid significantly improves clinical outcomes in major depressive disorder (including postpartum and postmenopausal depression), schizophrenia, bipolar disorder, autism spectrum disorder, and ADHD, often when used as an adjunct to standard treatments. For cardiovascular health, meta-analyses demonstrate that folic acid supplementation, which includes levomefolic acid, reduces the risk of stroke and other cardiovascular events, primarily by lowering homocysteine levels. Furthermore, it has shown positive effects on birth weight and a reduced risk of adverse pregnancy outcomes. While evidence is less consistent, there is potential for modulating neurocognitive disorders and diabetes-related outcomes. The strength of evidence for these benefits is generally high, supported by numerous randomized controlled trials and comprehensive meta-analyses.

How it works

Levomefolic acid functions as a critical methyl donor in the one-carbon metabolism pathway. This pathway is essential for numerous biological processes, including DNA synthesis, repair, and methylation, which are vital for cell division and gene expression regulation. Unlike folic acid, levomefolic acid is the active form that can readily cross the blood-brain barrier, enabling it to directly participate in the synthesis of key neurotransmitters such as dopamine, serotonin, and norepinephrine. This direct involvement in neurotransmitter production explains its therapeutic role in neuropsychiatric disorders. It also contributes to the formation of red blood cells. Its direct bioavailability bypasses the need for metabolic conversion, which is particularly beneficial for individuals with genetic variations like MTHFR polymorphisms that impair folic acid metabolism.

Side effects

Levomefolic acid is generally well-tolerated and has a favorable safety profile, as observed in numerous clinical trials. Common side effects are rare and typically mild, primarily involving gastrointestinal discomfort. There are no major drug interactions reported, but caution is advised when co-administering with folate antagonists, which could counteract its effects. Contraindications include known hypersensitivity to the compound. Special caution is recommended in patients with undiagnosed malignancies, as folate's role in cell proliferation could theoretically promote tumor growth, although this is a complex area of ongoing research. While safe and recommended for use in pregnancy for neural tube defect prevention, its use in cancer patients should be carefully considered and managed by a healthcare professional. Overall, serious adverse events are uncommon, making it a safe supplement for most individuals when used appropriately.

Dosage

Typical oral dosages of levomefolic acid vary depending on the indication. For psychiatric adjunct therapy, doses commonly range from 7.5 mg/day to 15 mg/day. For the prevention of neural tube defects during pregnancy, a standard dose is 400–800 mcg/day, often included in prenatal vitamin formulations. The optimal dosage can be influenced by the specific condition being addressed and individual genetic factors, particularly in those with MTHFR polymorphisms who may require higher doses due to impaired folate metabolism. As levomefolic acid is the active form of folate, its absorption is highly efficient, bypassing the metabolic steps required for folic acid conversion. It can be taken with or without food. There are no established upper limits for levomefolic acid due to its low toxicity, but excessive intake is generally not recommended.

FAQs

Is levomefolic acid better than folic acid?

Yes, especially for individuals with MTHFR polymorphisms or psychiatric conditions, as it's the active form and can directly cross the blood-brain barrier.

Can it be taken with antidepressants?

Yes, levomefolic acid is often used as an adjunct therapy with antidepressants and is generally well-tolerated in such combinations.

How soon do effects appear?

Psychiatric improvements may be observed within weeks, while prevention of birth defects requires consistent preconception and early pregnancy supplementation.

Is it safe during pregnancy?

Yes, levomefolic acid is recommended during pregnancy to prevent neural tube defects and is considered safe for this purpose.

Research Sources

https://www.frontiersin.org/journals/public-health/articles/10.3389/fpubh.2020.550753/full – This umbrella review and meta-analysis synthesized findings from 108 meta-analyses of RCTs on folate supplementation. It found significant reductions in risk for birth outcomes, cardiovascular disease, and diabetes-related outcomes, and some neurocognitive benefits. The study highlighted the need for cautious use due to potential increased cancer risks with folate supplementation, based on large sample sizes and rigorous methodology.
https://pubmed.ncbi.nlm.nih.gov/34953391/ – This systematic review analyzed 23 randomized controlled trials on folate supplements, including levomefolic acid, for various psychiatric disorders. It found consistent evidence of clinical improvement and good tolerability across conditions like depression, schizophrenia, bipolar disorder, autism, and ADHD. The review included well-powered studies with control groups, supporting the statistical significance of the findings.
https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2024.1288417/full – This systematic review and meta-analysis investigated the effect of dietary folic acid and supplementation on primary stroke risk. It demonstrated a significant reduction in stroke incidence, utilizing dose-response analysis of both RCTs and observational studies. The robustness of the findings was confirmed through random-effects models and sensitivity analyses.
https://go.drugbank.com/drugs/DB11256 – This source provides detailed pharmacological information on Levomefolic acid, including its mechanism of action as the active form of folate that crosses the blood-brain barrier. It explains its role in neurotransmitter synthesis and its superior bioavailability compared to folic acid, particularly for individuals with MTHFR polymorphisms.
https://lpi.oregonstate.edu/mic/vitamins/folate – This resource from the Linus Pauling Institute offers comprehensive information on folate, including its various forms, metabolic pathways, and health implications. It details the importance of folate for DNA synthesis, red blood cell formation, and its role in preventing neural tube defects, providing a broad overview of folate's biological functions and health benefits.