Methylfolate Calcium (Crystalline)
Also known as: Methylfolate calcium, L-methylfolate, 5-MTHF, levomefolate calcium, (6S)-5-Methyltetrahydrofolate calcium salt, 5-MTHF calcium, Metafolin, L-methylfolate calcium
Overview
L-methylfolate calcium is the calcium salt of L-5-methyltetrahydrofolate, the biologically active form of folate (vitamin B9). It is a highly bioavailable form of folate, bypassing metabolic defects associated with the MTHFR enzyme. Natural sources of folate include leafy greens, legumes, and liver, but L-methylfolate calcium is often used in supplement form to ensure optimal absorption and utilization. Its primary application is as an adjunctive treatment for major depressive disorder (MDD), particularly in individuals who have shown a partial response to traditional antidepressants. It acts as a methyl donor, supporting neurotransmitter synthesis and homocysteine metabolism. Research suggests a moderate level of evidence supporting its efficacy in MDD, with several RCTs and meta-analyses demonstrating benefits when used alongside antidepressants. The crystalline form is preferred for stability and bioavailability.
Benefits
The primary benefit of L-methylfolate calcium is its efficacy as an adjunctive treatment for major depressive disorder (MDD). Meta-analyses have shown that adding L-methylfolate to antidepressant therapy can improve response rates and reduce depressive symptoms. Specifically, one meta-analysis indicated a relative risk of 1.25 (95% CI: 1.08–1.46, p=0.004) for response compared to antidepressant monotherapy, and a standardized mean difference of -0.38 (95% CI: -0.59 to -0.17, p=0.0003) in depressive symptoms. These effects are typically observed within 4–12 weeks of adjunctive therapy. While some evidence suggests potential cognitive benefits in folate-deficient populations, the strongest evidence supports its use in adults with MDD who have not fully responded to antidepressants.
How it works
L-methylfolate calcium functions primarily as a methyl donor in the synthesis of key neurotransmitters, including serotonin, dopamine, and norepinephrine, which are crucial for mood regulation. It also supports homocysteine metabolism, converting it to methionine, and plays a role in DNA synthesis. By bypassing the MTHFR enzyme, L-methylfolate ensures that individuals with MTHFR polymorphisms can still effectively utilize folate. It is directly absorbed in the small intestine, making it highly bioavailable and independent of MTHFR enzyme activity. This direct action on neurotransmitter synthesis and homocysteine regulation contributes to its antidepressant effects.
Side effects
L-methylfolate calcium is generally considered safe and well-tolerated, particularly when used as an adjunctive therapy in adults with MDD. Common side effects, occurring in more than 5% of users, include mild gastrointestinal discomfort such as nausea and bloating. Uncommon side effects, affecting 1-5% of individuals, may include headache and sleep disturbances. Rare side effects, seen in less than 1% of users, can include allergic reactions and rash. No major drug interactions have been reported, although it may interact with antifolate medications like methotrexate. Contraindications include hypersensitivity to folate or calcium. While considered safe in adults, there is limited data on its use during pregnancy, lactation, and in children. It is important to monitor for any adverse reactions and consult with a healthcare provider if any concerns arise.
Dosage
The minimum effective dose of L-methylfolate calcium for adjunctive MDD treatment is typically between 7.5 and 15 mg per day. The most studied and effective dosage for MDD augmentation is 15 mg per day. Doses up to 15 mg/day are generally well-tolerated, with higher doses not being extensively studied. It can be taken once daily, with or without food. The crystalline form is preferred due to its stability and bioavailability. Absorption is not affected by MTHFR status, but concurrent supplementation with vitamin B12 is recommended to prevent masking of a B12 deficiency. While generally safe, it's advisable to stay within the recommended dosage range unless otherwise directed by a healthcare professional.
FAQs
Is L-methylfolate calcium a replacement for antidepressants?
No, L-methylfolate calcium is best used as an adjunctive therapy in MDD, not as a monotherapy. It enhances the effects of antidepressants.
What are the potential side effects of L-methylfolate calcium?
L-methylfolate calcium is generally well-tolerated. Monitor for rare allergic reactions. Common side effects include mild gastrointestinal discomfort.
How should I take L-methylfolate calcium?
Take it once daily, with or without food. Consistency is key for optimal results. Consult your healthcare provider for personalized advice.
How long does it take to see results with L-methylfolate calcium?
Expect to see modest improvements in depressive symptoms over 4–12 weeks of adjunctive therapy. Individual results may vary.
Can L-methylfolate calcium cure depression?
No, it is not a cure for depression. Benefits are adjunctive and modest, enhancing the effects of antidepressant medications.
Research Sources
- https://pubmed.ncbi.nlm.nih.gov/34794190/ – This systematic review and meta-analysis of 6,707 patients found that adjunctive L-methylfolate improved antidepressant response (RR 1.25, 95% CI 1.08–1.46) and reduced depressive symptoms (SMD -0.38, 95% CI -0.59 to -0.17). The study highlights the potential benefits of L-methylfolate as an add-on treatment for major depressive disorder, though it notes limitations such as heterogeneity in study designs and limited long-term data.
- https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1681-2047 – This study provides evidence on the efficacy of L-methylfolate in the treatment of depression. The research suggests that L-methylfolate can be a valuable addition to traditional antidepressant therapies, particularly for individuals who have not responded adequately to initial treatments.
- https://archive.hshsl.umaryland.edu/bitstreams/6689591e-8417-4d5b-bb5d-e58e6242e730/download – This resource provides information on the biochemical pathways and mechanisms of action of L-methylfolate. It details how L-methylfolate contributes to neurotransmitter synthesis and supports overall neurological function, which are key factors in its antidepressant effects.
- https://consensus.app/questions/lmethylfolate-safe/ – This source compiles expert opinions and research findings on the safety of L-methylfolate. It indicates that L-methylfolate is generally considered safe, with adverse event rates similar to placebo in controlled trials, supporting its use as a well-tolerated adjunctive treatment.
- https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.840116/full – This article explores the role of folate in mental health and the potential benefits of L-methylfolate supplementation. It discusses the mechanisms by which L-methylfolate can improve mood and cognitive function, particularly in individuals with folate deficiencies or genetic predispositions affecting folate metabolism.
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