# Metafolin (L-methylfolate)

**Canonical URL:** https://ingredients.hermeticasuperfoods.com/ingredients/metafolin
**Data Source:** Hermetica Superfoods Ingredient Encyclopedia
**Updated:** 2026-03-30
**Evidence Score:** 2 / 10
**Category:** Vitamin
**Also Known As:** L-methylfolate, (6S)-5-methyltetrahydrofolate, 5-MTHF, L-5-MTHF, Levomefolic acid, Calcium L-methylfolate, Active folate, Methylfolate, L-methylfolate calcium, 5-methyltetrahydrofolate

## Overview

Metafolin is the calcium salt form of L-methylfolate (5-MTHF), the biologically active form of folate that crosses the blood-brain barrier and participates directly in one-carbon [metabolism](/ingredients/condition/weight-management) without requiring enzymatic conversion. Unlike folic acid, it bypasses the MTHFR enzyme step, making it effective even in individuals with MTHFR gene variants that impair folate metabolism.

## Health Benefits

• Supports DNA synthesis and cell reproduction through its role as the active folate form (mechanism established, clinical evidence limited) • Helps regulate homocysteine levels by methylating homocysteine to methionine via methionine synthase (biochemical pathway established, specific clinical trials not detailed) • May support mood and depression management as noted in pharmaceutical applications like Deplin (general reference noted, specific RCTs not provided) • Does not mask vitamin B12 deficiency unlike folic acid, potentially safer for undiagnosed B12 deficiency (safety profile noted, clinical comparison studies not cited) • Provides direct bioactive folate for individuals with MTHFR genetic variations who cannot efficiently convert folic acid (mechanism established, specific genetic studies not detailed)

## Mechanism of Action

L-methylfolate donates its methyl group to cobalamin (vitamin B12), converting homocysteine to methionine via methionine synthase, which simultaneously regenerates tetrahydrofolate (THF) for nucleotide synthesis. As the primary folate species in cerebrospinal fluid, 5-MTHF also serves as a cofactor in the synthesis of monoamine [neurotransmitter](/ingredients/condition/cognitive)s—[serotonin](/ingredients/condition/mood), dopamine, and norepinephrine—by supporting tetrahydrobiopterin (BH4) regeneration, which is a required cofactor for tyrosine hydroxylase and tryptophan hydroxylase. Because it is already in its reduced, active form, it does not require reduction by dihydrofolate reductase (DHFR) or activation by MTHFR, making it bioavailable regardless of MTHFR polymorphism status.

## Clinical Summary

A randomized controlled trial (Papakostas et al., 2012, n=75) found that adjunctive L-methylfolate at 15 mg/day significantly improved response rates in SSRI-resistant major depressive disorder patients compared to placebo, with a response rate difference of approximately 32% versus 15%. Observational and intervention studies in pregnant women demonstrate that 400–800 mcg/day of L-methylfolate effectively reduces neural tube defect risk comparably to folic acid, with plasma folate levels rising more rapidly due to bypassing hepatic conversion. A meta-analysis of homocysteine-lowering trials shows folate supplementation (including methylfolate forms) reduces plasma homocysteine by approximately 20–25%, though whether this translates to reduced [cardiovascular](/ingredients/condition/heart-health) events remains debated. Evidence for methylfolate specifically over folic acid remains limited by small trial sizes, and most long-term outcome data still relies on folic acid research extrapolated to this active form.

## Nutritional Profile

Metafolin is the calcium salt of L-5-methyltetrahydrofolate (L-5-MTHF), the naturally occurring, biologically active form of folate (vitamin B9). It is a patented form developed by Merck KGaA. Key nutritional details: **Active compound:** L-5-methyltetrahydrofolate calcium (6S-5-MTHF-Ca), typically standardized at ~400–1000 µg dietary folate equivalents (DFE) per dose in supplement form. **Bioavailability:** Significantly higher than synthetic folic acid for individuals with MTHFR polymorphisms (particularly C677T and A1298C variants, affecting ~30–40% of the population). Unlike folic acid, Metafolin does not require enzymatic reduction by dihydrofolate reductase (DHFR) or methylenetetrahydrofolate reductase (MTHFR) to become metabolically active. It is directly utilized in one-carbon [metabolism](/ingredients/condition/weight-management). Bioavailability is comparable to or exceeds equimolar doses of folic acid in plasma folate response studies (AUC comparable at ~7 nmol/L per µg dose). **Micronutrient equivalence:** 1 µg of L-methylfolate ≈ 1 µg DFE (dietary folate equivalent); by comparison, 1 µg folic acid supplement = 1.7 µg DFE when taken with food. **Calcium content:** Trace amount from the calcium salt (~40 µg Ca per 400 µg L-methylfolate dose, nutritionally negligible). **No macronutrients:** Contains no significant protein, fat, carbohydrate, or fiber. **Cofactor interactions:** Requires adequate vitamin B12 (cobalamin) as a co-substrate for methionine synthase activity; also functionally interacts with vitamin B6, riboflavin (B2, cofactor for MTHFR), and SAMe (S-adenosylmethionine) in the methylation cycle. **Absorption:** Absorbed primarily in the proximal small intestine via proton-coupled folate transporter (PCFT); does not contribute to unmetabolized folic acid (UMFA) accumulation in serum, which has been a concern with high-dose synthetic folic acid supplementation. **Stability:** More sensitive to light, heat, and oxidation than synthetic folic acid; typically formulated with stabilizers in supplement and pharmaceutical preparations.

## Dosage & Preparation

No clinically studied dosage ranges for Metafolin specifically are detailed in the research. The product is available as a stable crystalline calcium salt with ~98-99% L-isomer purity, with studies on analogs suggesting equivalent dosing to free L-methylfolate (e.g., 1 mg raw form ≈ 0.78 mg free methylfolate). Consult a healthcare provider before starting any new supplement.

## Safety & Drug Interactions

L-methylfolate is generally well tolerated; the most commonly reported side effects at therapeutic doses (7.5–15 mg/day) include irritability, [insomnia](/ingredients/condition/sleep), and nausea, which may reflect increased monoamine synthesis in sensitive individuals. It can mask hematological signs of vitamin B12 deficiency while neurological damage progresses, so B12 status should be assessed before initiating high-dose supplementation. L-methylfolate may reduce the efficacy of methotrexate, a folate antagonist used in cancer and autoimmune therapy, and should not be co-administered without oncologist guidance. It is considered safe and recommended during pregnancy at standard doses (400–800 mcg), and is often preferred over folic acid for women with MTHFR C677T or A1298C polymorphisms.

## Scientific Research

The research dossier indicates limited specific clinical trial data for Metafolin, with no PubMed PMIDs provided. General references note its use in conditions like depression (as the pharmaceutical Deplin), but specific study designs, sample sizes, or clinical outcomes are not detailed in the available research. FDA pharmacology review mentions no significant secondary pharmacology findings in open literature.

## Historical & Cultural Context

No historical or traditional medicine use is documented for Metafolin or L-methylfolate in systems like Ayurveda or TCM. As the endogenous active form of folate produced naturally in the human body, it is not a plant-derived traditional remedy but rather a modern synthetic reproduction of the body's own folate [metabolism](/ingredients/condition/weight-management) end-product.

## Synergistic Combinations

Vitamin B12, Vitamin B6, SAMe, TMG (Trimethylglycine), Magnesium

## Frequently Asked Questions

### What is the difference between Metafolin and folic acid?

Metafolin is the calcium salt of L-5-methyltetrahydrofolate (5-MTHF), the end-product of folate metabolism that cells use directly, whereas folic acid is a synthetic oxidized form requiring conversion by DHFR and MTHFR enzymes before it becomes active. Individuals with MTHFR C677T polymorphisms—affecting roughly 10–15% of the population homozygously—convert folic acid poorly, making Metafolin a more reliable option for maintaining adequate folate status.

### What dose of L-methylfolate is used for depression?

Clinical trials investigating L-methylfolate as an adjunct to antidepressant therapy have used doses of 7.5 mg/day and 15 mg/day, with the 15 mg dose showing statistically significant improvements in SSRI-resistant depression in the Papakostas et al. 2012 RCT. Standard dietary supplement doses range from 400 mcg to 1 mg, while prescription medical food formulations (e.g., Deplin) deliver the higher 7.5–15 mg therapeutic range.

### Can L-methylfolate help with MTHFR gene mutations?

Yes—individuals carrying MTHFR C677T or A1298C variants have reduced enzyme activity (up to 70% reduction in homozygous C677T carriers), impairing conversion of dietary folate and folic acid into 5-MTHF. Supplementing directly with L-methylfolate bypasses this enzymatic bottleneck, raising plasma 5-MTHF levels and normalizing methylation capacity without relying on functional MTHFR activity.

### Is Metafolin safe during pregnancy?

L-methylfolate is considered safe during pregnancy and is recommended at 400–800 mcg/day to reduce neural tube defect risk, consistent with guidelines for folate supplementation in general. Some practitioners prefer it over folic acid for pregnant women with MTHFR polymorphisms, though current evidence does not definitively show superior neural tube defect prevention over folic acid at equivalent folate equivalency doses.

### Does L-methylfolate interact with any medications?

The most clinically significant interaction is with methotrexate, which works by inhibiting DHFR and depleting folate; supplementing with L-methylfolate can directly antagonize its mechanism and should only be done under medical supervision in oncology or rheumatology contexts. Additionally, antiepileptic drugs such as valproate and phenytoin can lower folate levels, and L-methylfolate may be used to counteract this effect, but dosing must be coordinated with a physician to avoid altering seizure threshold.

### How does Metafolin's bioavailability compare to other folate forms?

Metafolin (L-methylfolate) is the active form of folate that directly enters cells without requiring enzymatic conversion, making it bioavailable regardless of MTHFR enzyme function or genetic variations. This contrasts with folic acid, which must be converted through multiple enzymatic steps that may be inefficient in some individuals. Clinical evidence suggests L-methylfolate achieves higher circulating levels and cellular uptake compared to standard folate supplements.

### Who is most likely to benefit from L-methylfolate supplementation?

Individuals with MTHFR gene variations, those with elevated homocysteine levels, and people experiencing mood-related concerns may benefit most from L-methylfolate supplementation. Those with absorption issues or who don't respond well to standard folic acid supplementation often see better results with this active form. Additionally, individuals with certain genetic polymorphisms that impair folate metabolism may derive greater benefit from the pre-converted L-methylfolate form.

### What is the typical recommended dosage range for Metafolin in supplements?

Common supplemental doses of L-methylfolate range from 400 mcg to 2,000 mcg (2 mg) daily, depending on individual needs and health goals. Dosing varies based on whether the supplement is intended for general nutritional support, homocysteine management, or mood support—with mood-related applications sometimes using the higher end of this range. Consultation with a healthcare provider is recommended to determine the appropriate dose for your specific circumstances.

---

*Source: Hermetica Superfoods Ingredient Encyclopedia — https://ingredients.hermeticasuperfoods.com*
*License: CC BY-NC-SA 4.0 — Attribution required. Commercial use: admin@hermeticasuperfoods.com*