Acido folico (5-MTHF)
Also known as: 5-MTHF, L-methylfolate, active folate, methylfolate, folinic acid, 5-Methyltetrahydrofolate
Overview
5-Methyltetrahydrofolate (5-MTHF) is the biologically active form of folate, also known as Vitamin B9. Unlike synthetic folic acid, 5-MTHF does not require enzymatic conversion in the body, making it directly usable for various metabolic processes. It is naturally found in foods like leafy greens, legumes, and liver, and is widely available as a dietary supplement, often in its calcium salt form (5-MTHF-Ca). The primary applications of 5-MTHF supplementation include improving overall folate status, reducing elevated homocysteine levels (a risk factor for cardiovascular disease), and preventing neural tube defects (NTDs) during pregnancy. A key advantage of 5-MTHF is its ability to bypass metabolic bottlenecks, particularly in individuals with genetic variations like MTHFR polymorphisms, which impair the body's ability to convert folic acid into its active form. This also means it does not lead to the accumulation of unmetabolized folic acid (UMFA) in the bloodstream, a concern associated with high-dose folic acid supplementation. While folic acid has a longer history of research, 5-MTHF is increasingly recognized for its superior bioavailability and direct metabolic utility, with a growing body of clinical evidence supporting its efficacy and safety.
Benefits
5-MTHF offers several evidence-based benefits, primarily due to its role as the active form of folate. It significantly improves folate status, demonstrating higher bioavailability and more effective blood folate level increases compared to folic acid, especially in individuals with MTHFR polymorphisms. This is supported by systematic reviews showing superior efficacy in biomarker improvement. 5-MTHF is also highly effective in reducing plasma homocysteine levels, a known cardiovascular risk factor. Some studies suggest it may also improve endothelial function, contributing to cardiovascular health. While folic acid is well-established for neural tube defect (NTD) prevention, 5-MTHF shows promising potential, with ongoing clinical trials aiming to confirm its equivalence or superiority. For individuals with MTHFR gene variants (e.g., C677T), 5-MTHF is particularly advantageous as it bypasses the impaired metabolic pathway. Preliminary research also suggests potential benefits in certain psychiatric conditions, such as bipolar depression, though more robust randomized controlled trials are needed to confirm these effects. Improvements in folate status and homocysteine reduction can typically be observed within weeks of consistent supplementation.
How it works
5-MTHF functions as a crucial methyl donor in one-carbon metabolism, a fundamental biochemical pathway essential for numerous cellular processes. Its primary mechanism involves donating a methyl group for the remethylation of homocysteine to methionine, a reaction catalyzed by the enzyme methionine synthase. This process is vital for maintaining healthy homocysteine levels and for the synthesis of S-adenosylmethionine (SAMe), a universal methyl donor involved in DNA synthesis, repair, gene expression, and neurotransmitter synthesis. Unlike folic acid, 5-MTHF is absorbed directly via reduced folate carrier (RFC) transporters and does not require enzymatic reduction by dihydrofolate reductase (DHFR) or methylation by MTHFR. This direct usability ensures efficient entry into the folate cycle and methylation pathways, bypassing potential metabolic bottlenecks. 5-MTHF also readily crosses the blood-brain barrier, supporting the central nervous system's folate requirements and contributing to neurological health.
Side effects
5-MTHF is generally considered safe and well-tolerated, with a favorable safety profile observed in clinical trials. No common side effects (occurring in more than 5% of users) have been consistently reported. Uncommon side effects (1-5%) are rare and typically mild, with some individuals reporting transient gastrointestinal discomfort. Serious adverse events directly attributable to 5-MTHF supplementation are extremely rare (less than 1%). Potential drug interactions exist with medications that affect folate metabolism or are antifolates, such as methotrexate, certain antiepileptic drugs (e.g., phenytoin, carbamazepine), and some antibiotics (e.g., trimethoprim). Caution is advised when co-administering 5-MTHF with these drugs, and medical consultation is recommended. A critical consideration is the interaction with vitamin B12 deficiency: while 5-MTHF is less likely to mask the neurological symptoms of B12 deficiency compared to high doses of folic acid, it is still crucial to rule out or address B12 deficiency before initiating folate supplementation, as high folate levels can potentially exacerbate neurological damage in undiagnosed B12 deficiency. Contraindications include known hypersensitivity to 5-MTHF or any of its components. 5-MTHF is particularly beneficial and safe for special populations such as pregnant women, individuals with MTHFR polymorphisms, and those with malabsorption syndromes, given its superior bioavailability.
Dosage
The recommended dosage of 5-MTHF varies depending on the individual's needs and specific health goals. For general folate status improvement, clinical studies often utilize doses ranging from 200 to 400 micrograms (mcg) per day. For individuals with MTHFR polymorphisms or those requiring more significant homocysteine reduction, optimal dosage ranges commonly fall between 400 and 1000 mcg per day. Higher doses, up to 5 milligrams (mg) per day, may be used in specific clinical contexts under medical supervision, such as for certain psychiatric conditions or severe folate deficiencies. There is no established upper limit specific to 5-MTHF, and it is generally considered safe at doses used in clinical trials. Daily dosing is typically recommended. For neural tube defect prevention, supplementation should ideally begin before conception and continue through the first trimester of pregnancy. The calcium salt form (5-MTHF-Ca) is a stable and highly bioavailable form commonly used in supplements. 5-MTHF is absorbed efficiently via reduced folate carrier (RFC) transporters, offering superior bioavailability compared to folic acid. Adequate vitamin B12 status is crucial for optimal folate metabolism and should be ensured when supplementing with 5-MTHF.
FAQs
Is 5-MTHF better than folic acid?
Evidence suggests 5-MTHF has higher bioavailability and is more effective in individuals with MTHFR polymorphisms. It also avoids the accumulation of unmetabolized folic acid, a concern with high-dose folic acid. However, large-scale clinical outcome data for NTD prevention are still emerging.
Can 5-MTHF cause masking of B12 deficiency?
Unlike folic acid, 5-MTHF is less likely to mask the neurological symptoms of vitamin B12 deficiency. However, it is still important to ensure adequate B12 status, as both nutrients are interdependent in metabolic pathways.
When should 5-MTHF supplementation start for pregnancy?
For neural tube defect prevention, 5-MTHF supplementation should ideally begin at least one month before conception and continue throughout the first trimester of pregnancy to ensure adequate folate levels during critical fetal development.
Are there risks of unmetabolized folic acid with 5-MTHF?
No, 5-MTHF does not lead to the accumulation of unmetabolized folic acid (UMFA) in the bloodstream. This is a significant advantage over synthetic folic acid, especially at higher doses, as UMFA's long-term effects are still under investigation.
Research Sources
- https://pmc.ncbi.nlm.nih.gov/articles/PMC10318921/ – This systematic review and meta-analysis demonstrated that unmetabolized folic acid is common with folic acid supplementation, a problem avoided by 5-MTHF. The study found 5-MTHF to have superior bioavailability and efficacy in improving folate status, particularly in individuals with MTHFR polymorphisms, and reported a favorable safety profile.
- https://pmc.ncbi.nlm.nih.gov/articles/PMC11435031/ – This narrative review compared folic acid and 5-MTHF, highlighting the biochemical and pharmacokinetic advantages of 5-MTHF. It concluded that while more randomized controlled trials are needed to establish definitive clinical efficacy in outcomes like NTD prevention, preliminary data are promising and support 5-MTHF's use.
- https://archive.hshsl.umaryland.edu/bitstreams/6689591e-8417-4d5b-bb5d-e58e6242e730/download – This randomized controlled trial involving hemodialysis patients compared intravenous 5-MTHF with oral folic acid. It found that 5-MTHF was associated with improved survival independent of homocysteine lowering, suggesting additional benefits beyond just homocysteine reduction, potentially related to cardiovascular and inflammatory pathways in high-risk populations.