Folate (as Quatrefolic Calcium Folinate and Methylfolate)
Also known as: (6S)-5-methyltetrahydrofolate (5-MTHF), calcium-L-methylfolate (CaLMF), Quatrefolic (glucosamine salt of (6S)-5-methyltetrahydrofolate), L-methylfolate, Metafolin, Quatrefolic, calcium folinate, Methylfolate
Overview
Methylfolate, also known as 5-MTHF, is the biologically active form of folate, a water-soluble B-vitamin crucial for DNA synthesis, repair, and methylation. Unlike folic acid, methylfolate doesn't require enzymatic conversion, making it particularly beneficial for individuals with MTHFR polymorphisms. Natural sources of folate include leafy greens, legumes, and liver, but supplementation with methylfolate ensures optimal absorption and utilization. Quatrefolic and calcium-L-methylfolate are stable and bioavailable forms. It is used to treat folate deficiency, support cognitive health, and as adjunctive therapy in depression and dementia. Research maturity is moderate to high for depression and folate deficiency, and emerging for cognitive decline.
Benefits
Methylfolate has shown promise in several key areas. In patients with major depressive disorder (MDD) unresponsive to antidepressants, adjunctive L-methylfolate (7.5–15 mg/day) has improved response rates, demonstrating a moderate effect size. Systematic reviews suggest potential benefits in slowing cognitive decline, although effect sizes are generally modest. Methylfolate is particularly effective in normalizing folate status in individuals with MTHFR polymorphisms, where it outperforms folic acid in raising folate levels. Benefits in depression may be observed within 4–8 weeks, while cognitive benefits, if present, are likely gradual and require longer-term use. The evidence for depression is stronger, supported by multiple RCTs, while evidence for cognitive decline is still emerging.
How it works
Methylfolate functions primarily as a cofactor in methylation reactions, which are essential for neurotransmitter synthesis, including serotonin and dopamine. It also supports the regeneration of tetrahydrobiopterin (BH4), another crucial cofactor for neurotransmitter production. Methylfolate crosses the blood-brain barrier, directly supporting brain health. Additionally, it reduces homocysteine levels, a known risk factor for cardiovascular disease. By bypassing the MTHFR enzyme, methylfolate ensures efficient folate utilization, especially in individuals with MTHFR polymorphisms. Its enhanced bioavailability, particularly at doses of 400 μg/day and above, contributes to its effectiveness.
Side effects
Methylfolate is generally well-tolerated at recommended doses. Common side effects, occurring in more than 5% of users, include mild gastrointestinal symptoms 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, encompass allergic reactions and mood changes. Methylfolate may interact with antiepileptic drugs, potentially reducing their efficacy, and may interfere with folate antagonists like methotrexate. It is contraindicated in individuals with known hypersensitivity to folate or its derivatives. Pregnant women can safely use methylfolate at recommended doses, and it is preferred over folic acid for individuals with MTHFR mutations.
Dosage
For general health, a minimum effective dose of 400 μg/day of methylfolate is recommended. Optimal dosage ranges from 400–1000 μg/day for general health, while 7.5–15 mg/day may be used for depression under medical supervision. The upper limit for general health is 1000 μg/day, although higher doses may be appropriate for specific indications under medical supervision. Methylfolate can be taken with or without food. Quatrefolic and calcium-L-methylfolate are preferred due to their enhanced bioavailability and stability. Absorption is not significantly affected by food. Adequate vitamin B12 is required for proper folate metabolism. It is important to adhere to recommended dosage guidelines to minimize the risk of side effects.
FAQs
Who should use methylfolate?
Individuals with MTHFR polymorphisms, treatment-resistant depression, or folate deficiency may benefit most from methylfolate supplementation due to its enhanced bioavailability and direct utilization.
Is methylfolate better than folic acid?
For those with MTHFR mutations or absorption issues, methylfolate is generally superior to folic acid because it bypasses the need for enzymatic conversion, ensuring better folate utilization.
Is methylfolate safe long-term?
Yes, methylfolate is considered safe for long-term use when taken at recommended doses. However, it's always best to consult with a healthcare provider for personalized advice.
When should I take methylfolate?
Methylfolate can be taken at any time of day, with or without food, as its absorption is not significantly affected by food intake. Consistency is key for optimal results.
What results can I expect from taking methylfolate?
Some individuals with depression may experience symptom improvement within 4–8 weeks. In cognitive decline, methylfolate might slow the progression, but the evidence is limited and results vary.
Research Sources
- https://www.mdpi.com/2077-0383/12/9/3075 – This systematic review examined the effects of methylfolate on cognitive decline and dementia, focusing on older adults with cognitive impairment. The review found limited but promising evidence that methylfolate may slow cognitive decline, although the effect sizes were modest and not always statistically significant. The authors noted heterogeneity in study designs and populations as a limitation.
- https://www.cambridge.org/core/journals/cns-spectrums/article/good-better-best-clinical-scenarios-for-the-use-of-lmethylfolate-in-patients-with-mdd/732A84D8B7A05A6F2B26E23BF4487C57 – This clinical review assessed the use of L-methylfolate in major depressive disorder (MDD), referencing multiple RCTs involving patients with treatment-resistant depression. The review indicated that adjunctive L-methylfolate (7.5–15 mg/day) improved depressive symptoms in patients unresponsive to antidepressants, with moderate effect sizes. The authors noted that not all studies showed consistent benefit and some lacked placebo controls.
- https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2022.7452 – This systematic assessment of bioavailability compared 5-MTHF to folic acid in healthy adults. The assessment found that 5-MTHF is more bioavailable than folic acid at 400 μg/day and above, proposing a conversion factor of 2 for higher intakes. The study was limited to bioavailability and did not assess clinical outcomes.
- https://quatrefolic.com/quatrefolic-vs-folic-acid/ – This resource compares Quatrefolic to folic acid, highlighting Quatrefolic's enhanced bioavailability and stability as a form of methylfolate. It emphasizes that Quatrefolic bypasses the need for enzymatic conversion, making it a more efficient option for individuals with MTHFR polymorphisms.
Recommended Articles
23andMe Genetics & Supplements: A Guide
Your 23andMe genetics report can guide personalized supplement choices based on nutrient absorption and health predispositions.
Active B-Complex Vitamins: A Complete Guide
Active forms of B-complex vitamins are more bioavailable, making them crucial for optimal health and absorption.
Affordable Methylfolate for MTHFR: A Buyer's Guide
Methylfolate is essential for individuals with MTHFR variants, and finding affordable, quality sources is crucial.
Unlocking Personalized Nutrition: The Role of 23andMe
23andMe results can significantly tailor supplement recommendations through genetic-based insights, enhancing personalized nutrition.