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Metafolin

Also known as: L-methylfolate, 5-methyltetrahydrofolate, 5-MTHF, Metafolin, L-methylfolate calcium salt

Overview

L-methylfolate, also known as 5-methyltetrahydrofolate (5-MTHF), is the biologically active form of folate (Vitamin B9). Unlike folic acid, it doesn't require enzymatic conversion to become bioactive, making it particularly beneficial for individuals with MTHFR polymorphisms or impaired folate metabolism. It is available as a calcium salt (Metafolin). Primary uses include improving folate status, adjunctive treatment in major depressive disorder (MDD), prevention of neural tube defects in pregnancy, and cardiovascular disease risk reduction. L-methylfolate acts as a methyl donor in one-carbon metabolism, crucial for DNA synthesis, repair, and methylation. Research indicates moderate to high evidence supporting its role in depression, pregnancy outcomes, and cardiovascular health, with good quality evidence from systematic reviews and meta-analyses of randomized controlled trials.

Benefits

L-methylfolate offers several evidence-based benefits. As an adjunctive treatment for depression, meta-analyses show modest efficacy in improving depressive symptoms in adults with MDD compared to placebo. Folate supplementation, including L-methylfolate, is associated with improved birth weight, placental weight, and length of gestation, reducing the risk of neural tube defects. Meta-analyses suggest folic acid supplementation reduces stroke risk by about 10% and overall cardiovascular disease risk by approximately 4%, likely through homocysteine lowering. Additionally, folic acid supplementation may reduce C-reactive protein (CRP) levels, a marker of systemic inflammation. These benefits are particularly pronounced in individuals with folate metabolism impairments, pregnant women, and those with depression or elevated cardiovascular risk. Effects are generally observed over weeks to months of supplementation.

How it works

L-methylfolate functions primarily as a methyl donor in one-carbon metabolism, which is critical for DNA synthesis, repair, and methylation processes. It converts homocysteine to methionine, thereby lowering homocysteine levels, a factor implicated in cardiovascular risk. This active form of folate supports central nervous system function through neurotransmitter synthesis and methylation, supports fetal development, and modulates inflammatory pathways. It interacts with enzymes in the folate cycle and methylation pathways, as well as homocysteine metabolism enzymes. Unlike folic acid, L-methylfolate is efficiently absorbed and directly utilized without the need for enzymatic conversion, enhancing its bioavailability.

Side effects

L-methylfolate is generally well-tolerated with a strong safety record. Common side effects, occurring in more than 5% of users, are generally insignificant, with occasional mild gastrointestinal discomfort reported. Uncommon side effects, affecting 1-5% of users, include rare allergic reactions or hypersensitivity. Serious adverse events are rare, occurring in less than 1% of users, and have not been consistently reported. L-methylfolate may interact with anticonvulsants and methotrexate, requiring caution in patients on these medications. Contraindications include hypersensitivity to folate derivatives and caution in patients with undiagnosed anemia. It is considered safe in pregnancy and lactation when used appropriately and is beneficial in individuals with MTHFR polymorphisms. Excessive folate intake can mask vitamin B12 deficiency, so monitoring is advised.

Dosage

The minimum effective dose of L-methylfolate is typically 7.5 mg/day when used as an adjunct therapy for depression. Lower doses, ranging from 400 to 800 mcg/day, are commonly used in pregnancy supplementation. For general supplementation, an optimal dosage range is between 400 and 800 mcg/day, while 7.5 mg/day is recommended for depression adjunct therapy. There is no established upper limit for L-methylfolate, and doses up to 15 mg/day have been used safely in clinical trials. Daily dosing is recommended, with benefits accruing over weeks to months. The calcium salt form (Metafolin) is preferred for stability and bioavailability. L-methylfolate is absorbed well regardless of MTHFR genotype, with bioavailability superior to folic acid in individuals with impaired metabolism. Vitamin B12 is an essential cofactor to support the methylation cycle and prevent masking B12 deficiency.

FAQs

Is Metafolin better than folic acid?

Yes, especially in individuals with MTHFR polymorphisms or impaired folate metabolism, as it bypasses enzymatic conversion steps required for folic acid to become bioactive.

Can Metafolin be used during pregnancy?

Yes, it is safe and effective for preventing neural tube defects and supporting fetal development when taken at recommended dosages.

How long before benefits appear?

For depression, benefits may be observed within several weeks. For cardiovascular and pregnancy outcomes, benefits depend on the duration and timing of supplementation.

Are there risks of overdose?

High doses are generally safe, but excessive folate can mask B12 deficiency. Monitoring is advised, especially with higher dosages.

Does it interact with medications?

Yes, particularly with methotrexate and some anticonvulsants. Consult healthcare providers before starting L-methylfolate if you are taking other medications.

Research Sources

https://pubmed.ncbi.nlm.nih.gov/34794190/ – This systematic review and meta-analysis of RCTs found that adjunctive L-methylfolate showed a modest but statistically significant improvement in depressive symptoms compared to placebo in adults with major depressive disorder on antidepressants. The study highlights the potential benefit of L-methylfolate as an adjunct treatment for depression, while noting the need for larger trials to confirm these findings.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3499376/ – This systematic review and meta-analysis on pregnancy outcomes indicated that folate supplementation, including L-methylfolate, significantly improved birth weight, placental weight, and gestation length, reducing adverse outcomes. The study supports the importance of folate supplementation during pregnancy to improve maternal and fetal health, although it acknowledges some heterogeneity in folate forms used across studies.
https://www.ahajournals.org/doi/10.1161/jaha.116.003768 – This meta-analysis of RCTs on cardiovascular disease risk demonstrated that folic acid supplementation reduced stroke risk by 10% and overall CVD risk by 4%, attributed to homocysteine lowering. The findings suggest that folic acid supplementation can play a role in reducing cardiovascular risk, particularly stroke, through its impact on homocysteine levels.
https://www.mdpi.com/2072-6643/13/7/2327 – This study investigates the effects of folic acid supplementation on inflammatory markers. Results suggest that folic acid may reduce C-reactive protein (CRP) levels, a marker of systemic inflammation, though effects on IL-6 and TNF-α were not significant. This indicates a potential anti-inflammatory role of folic acid, specifically in reducing CRP levels.
https://www.frontiersin.org/journals/public-health/articles/10.3389/fpubh.2020.550753/full – This umbrella review suggests that folate is associated with decreased all-cause mortality and reduced risk of various chronic diseases including diabetes and neurocognitive disorders. However, it also notes that some cancer risks may be increased. This highlights the complex relationship between folate and health outcomes, suggesting both potential benefits and risks depending on the specific condition.

Score: 68/100

Advanced B Complex

Cooper Complete

Score: 70/100