the stable, bio-identical form of folate that circulates in blood.
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the stable, bio-identical form of folate that circulates in blood.
L-5-Methyltetrahydrofolate Calcium (L-5-MTHF-Ca)—the stable, bio-identical form of folate that circulates in blood.
Rapid effect in healthy adults. Eight weeks of 400 µg L-5-MTHF lowered serum total homocysteine (tHcy) by ≈25 % and out-performed an isocaloric folinic-acid arm. pubmed.ncbi.nlm.nih.gov
Low-dose efficacy confirmed. As little as 113 µg day⁻¹ of L-5-MTHF for 12 weeks reduced plasma tHcy to the same extent as 200 µg folic acid in a placebo-controlled crossover trial. pubmed.ncbi.nlm.nih.gov
Endothelial function. An acute intra-arterial dose (50 nmol min⁻¹) of L-5-MTHF restored flow-mediated dilation and decreased vascular superoxide in human radial arteries, implying improved eNOS coupling—an effect not seen with equimolar folic acid. pubmed.ncbi.nlm.nih.gov
Why it matters: Lowering tHcy and improving NO bioavailability translate into better vascular tone and may reduce long-term cardiovascular risk.
Up to 40 % of the global population carries the C677T or A1298C MTHFR variants that slow the conversion of folic acid to 5-MTHF. Supplementation with the ready-made form (Quatrefolic® or calcium salt) circumvents this “bottleneck,” producing higher red-cell folate and lower tHcy than folic-acid at equal doses. pmc.ncbi.nlm.nih.gov
Assisted reproductive technology (ART). In a 269-patient retrospective study, women given 400 µg day⁻¹ L-5-MTHF + B12 achieved higher clinical-pregnancy (52 % vs 34 %) and live-birth rates (45 % vs 30 %) than those on 400 µg folic acid alone. pubmed.ncbi.nlm.nih.gov
Neural-tube-defect (NTD) prevention & perinatal folate levels. Prospective data show L-5-MTHF raises maternal plasma folate more efficiently than folic acid and is considered particularly useful for women with MTHFR variants or impaired folate metabolism. pmc.ncbi.nlm.nih.gov
Treatment-resistant depression. Two sequential double-blind RCTs demonstrated that 15 mg day⁻¹ L-methylfolate added to SSRIs nearly doubled response rates compared with placebo augmentation (32 % vs 15 %). Meta-analytic reviews now list 15 mg L-MTHF as a provisionally recommended nutraceutical in MDD guidelines. pmc.ncbi.nlm.nih.gov
Monotherapy pilot. A classic 6-week head-to-head trial found 25 mg L-MTHF produced similar remission rates to 150 mg amitriptyline, with fewer adverse effects. pmc.ncbi.nlm.nih.gov
Mechanistic angle: L-MTHF crosses the blood-brain barrier, donates one-carbon units for monoamine synthesis, and may dampen neuro-inflammation and NMDA-driven excitotoxicity.
| Area | Key findings | Evidence grade* |
|---|---|---|
| Sub-fertile men & women | Case series show normalization of semen parameters and reduced miscarriage when couples with MTHFR variants switch from high-dose folic acid to ≤ 400 µg L-MTHF. | ⬤⬤◯◯ |
| Hypertensive disorders of pregnancy | Pre-clinical work indicates 5-MTHF improves placental endothelial function under oxidative stress. | ⬤◯◯◯ |
| Chronic kidney disease | Small crossover study: oral 5-MTHF lowered tHcy and restored endothelium-dependent vasodilation in uraemic patients. | ⬤⬤◯◯ |
*⬤⬤⬤⬤ = robust RCT/meta-analysis; ⬤⬤⬤◯ = ≥2 RCTs; ⬤⬤◯◯ = single RCT or good observational; ⬤◯◯◯ = pre-clinical or pilot.
| Purpose | Dose range (elemental L-MTHF) | Notes |
|---|---|---|
| General folate support / tHcy control | 200 – 400 µg day⁻¹ | Matches adult RDA; safe during pregnancy. |
| Fertility / ART support | 400 – 800 µg day⁻¹ (often with B12/B6) | Begin ≥ 8 weeks pre-conception. |
| Psychiatric adjunct (MDD) | 7.5 – 15 mg day⁻¹ | Use medical-food grade; monitor for hypomania in bipolar spectrum. |
L-5-MTHF is well-tolerated; unlike high-dose folic acid it does not mask B-12 deficiency or accumulate as unmetabolized folic acid. Mild GI discomfort and insomnia are uncommon (<2 %). Always pair with adequate B-12 (methyl- or hydroxo-cobalamin) to maintain one-carbon balance.
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