Quatrefolic® (L-5-MTHF Methylfolate — Gnosis)

Evidence Level
Moderate
3 Clinical Trials
6 Documented Benefits
3/5 Evidence Score

Quatrefolic® is the branded crystal salt form of L-5-methyltetrahydrofolate (methylfolate) from Gnosis SpA (Italy/Lonza) — the most-studied bioactive folate form for supplementation. Patented crystal salt technology produces stable, bioavailable methylfolate suitable for clinical-grade applications. Generic L-5-MTHF crystals exist but stability and bioavailability vary; Quatrefolic® has documented stability and pharmacokinetic data supporting consistent clinical effects. Used in prescription medical foods, prenatal vitamins, and clinical-grade supplements where methylfolate quality matters. FDA Generally Recognized as Safe (GRAS) status. The honest framing: Quatrefolic® is the form most published clinical evidence validates; the brand premium reflects pharmaceutical-grade quality control rather than dramatically different methylfolate activity. For general supplementation, generic L-5-MTHF works at similar dose; for clinical applications (pregnancy, depression adjunct, documented MTHFR variants), Quatrefolic®'s quality assurance is worth the premium.

Studied Dose General: 400-1,000 mcg DFE/day. Pregnancy: 400-800 mcg DFE. MTHFR variants: 1,000 mcg DFE or higher. Clinician-supervised antidepressant add-on (L-methylfolate): 7.5-15 mg/day.
Active Compound Quatrefolic® L-5-methyltetrahydrofolate glucosamine salt (Gnosis SpA); patented stable crystal form.

Benefits

Shelf-stable crystal form

Quatrefolic®'s glucosamine salt crystal form is shelf-stable and easy to formulate. Head-to-head data showing it is more stable or better absorbed than other L-5-MTHF crystals are limited, so this is a manufacturing quality point, not a separate health benefit.

Raises blood folate when swallowed

Pharmacokinetic studies of oral [6S]-5-MTHF show it raises plasma folate. In a single-dose crossover in healthy men, its short-term bioavailability was equivalent to folic acid, not dramatically higher. The published pharmacokinetic work used generic [6S]-5-MTHF material, not Quatrefolic-branded product.

FDA GRAS status

Quatrefolic® has FDA Generally Recognized as Safe (GRAS) status — important for clinical-grade supplement formulations and prescription medical foods. Other active folate forms, such as Metafolin, also hold GRAS status, so this is a shared regulatory point, not a Quatrefolic advantage.

Pregnancy and prenatal applications

Active folate forms are widely used in prenatal vitamins for women who prefer them or who carry MTHFR variants. A randomised trial in pregnant women found (6S)-5-MTHF kept red-cell and serum folate as high as folic acid did. That trial measured maternal folate status, not neural-tube-defect or birth outcomes, and used generic (6S)-5-MTHF rather than the Quatrefolic brand.

Homocysteine reduction with documented effects

Quatrefolic® clinical trials document homocysteine reduction in adults with elevated baseline levels. In randomised trials, [6S]-5-MTHF lowered homocysteine to the same degree as folic acid, not more. Homocysteine is a blood marker, not a measured heart-disease outcome.

Quality control for clinical applications

Pharmaceutical-grade manufacturing is used in some medical foods and prescription products. This is a manufacturing-quality attribute, not a measured health benefit for the person taking it.

Mechanism of action

1

Direct active folate provision

Quatrefolic® provides L-5-MTHF directly in active form. Bypasses MTHFR enzyme conversion that's impaired in 40-50% of population with gene variants. Mechanism foundation for the MTHFR-bypass applications.

2

Stable crystal form for bioavailability

Patented glucosamine salt crystal provides stable methylfolate that survives stomach acid and intestinal processing. Head-to-head data showing that generic L-5-MTHF crystals degrade faster or deliver less folate are limited, so treat this as a formulation-quality point rather than a proven difference.

3

Methylation cycle support

Once absorbed, Quatrefolic® L-5-MTHF participates in the methylation cycle as a methyl donor for methionine synthesis. Supports DNA methylation, neurotransmitter synthesis, and homocysteine metabolism.

Clinical trials

1
Homocysteine reduction trials
PubMed

Quatrefolic® clinical trials document homocysteine reduction in adults with elevated baseline levels.

Clinical population described in trial publication.

Quatrefolic® clinical trials document homocysteine reduction in adults with elevated baseline levels. In these randomised trials [6S]-5-MTHF lowered homocysteine to the same extent as folic acid, not more. The studies used generic [6S]-5-MTHF material, not Quatrefolic-branded product, so they do not validate the brand specifically.

2
Pregnancy folate-status trial
PubMed

Clinical use in pregnancy formulations supports adequate folate intake during pregnancy and lactation.

Clinical population described in trial publication.

A randomised trial in 60 pregnant women found (6S)-5-MTHF maintained red-cell and serum folate as well as folic acid and lowered unmetabolised folic acid. It measured maternal folate status, a blood marker, not neural-tube-defect or birth outcomes, and used generic (6S)-5-MTHF rather than the Quatrefolic brand.

3
Bioavailability studies
PubMed

Pharmacokinetic studies document Quatrefolic® bioavailability and time-to-peak.

Clinical population described in trial publication.

Single-dose pharmacokinetic studies of [6S]-5-MTHF show it raises plasma folate, with short-term bioavailability equivalent to folic acid. These studies used generic [6S]-5-MTHF material, not Quatrefolic-branded product.

Side effects and drug interactions

Common Potential side effects

Generally well-tolerated at standard supplementation doses.
Mild GI discomfort possible at higher doses.
May cause sleep disturbance or anxiety in sensitive individuals at high doses (mostly relevant for 15 mg+ depression protocols).
Reassuring long-term safety profile through clinical trial use.
Pregnant and lactating women: safe and recommended at standard doses.

Important Drug interactions

Methotrexate — methylfolate may interfere with methotrexate's mechanism in cancer/RA treatment; consult oncology/rheumatology before combining.
Pyrimethamine and trimethoprim — possible interaction; consult prescribing physician.
Anticonvulsants — may reduce folate levels; supplementation can be beneficial but consult prescribing physician.
SSRIs — combining with L-methylfolate may enhance antidepressant response (basis for the medical food indication).
Generally minimal interactions; consult healthcare providers for specific medication combinations.

Frequently asked questions about Quatrefolic® (L-5-MTHF Methylfolate — Gnosis)

What is Quatrefolic?

Quatrefolic® is the branded crystal salt form of L-5-methyltetrahydrofolate (methylfolate) from Gnosis SpA (Italy/Lonza) — the most-studied bioactive folate form for supplementation. Patented crystal salt technology produces stable, bioavailable methylfolate suitable for clinical-grade applications.

What is Quatrefolic used for?

Quatrefolic is researched primarily for Cardiovascular and Women's Health. Quatrefolic®'s glucosamine salt crystal form is shelf-stable and easy to formulate. Head-to-head data showing it is more stable or better absorbed than other L-5-MTHF crystals are limited, so this is a manufacturing quality point, not a sep…

What is the recommended dosage of Quatrefolic?

The clinically studied dose is General: 400-1,000 mcg DFE/day. Pregnancy: 400-800 mcg DFE. MTHFR variants: 1,000 mcg DFE or higher. Clinician-supervised antidepressant add-on (L-methylfolate): 7.5-15 mg/day. Always follow the product label and check with a healthcare provider for personal advice.

Is Quatrefolic safe, and does it have side effects?

For most healthy adults, Quatrefolic is well tolerated at studied doses. Reported effects can include: Generally well-tolerated at standard supplementation doses. Mild GI discomfort possible at higher doses. It may also interact with some medications. Quatrefolic is not right for everyone, so check with a healthcare provider first if you are pregnant or breastfeeding, have a medical condition, or take prescription medication.

Does Quatrefolic interact with any medications?

Possible interactions include: Methotrexate — methylfolate may interfere with methotrexate's mechanism in cancer/RA treatment; consult oncology/rheumatology before combining. Pyrimethamine and trimethoprim — possible interaction; consult prescribing physician. If you take prescription medication, check with a pharmacist or doctor before using it.

How strong is the scientific evidence for Quatrefolic?

NutraSmarts rates the evidence for Quatrefolic as Moderate (3 out of 5). It is backed by 3 clinical trials and 5 cited references summarized on this page. A higher rating reflects more, larger, and better-designed human studies.

References(5 citations)

Evidence ratings on NutraSmarts are based on the totality of human clinical research, with emphasis on randomized controlled trials, meta-analyses, and systematic reviews. The references below directly support claims made throughout this page.

  1. Prinz-Langenohl R, Bramswig S, Tobolski O, Smulders YM, Smith DE, Finglas PM, et al. [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol. 2009;158(8):2014-21. doi: 10.1111/j.1476-5381.2009.00492.x.PubMedUsed to support: In women regardless of MTHFR 677C->T genotype, [6S]-5-MTHF (the active isomer in Quatrefolic) raised plasma folate more effectively than equimolar folic acid, supporting the bypass-MTHFR bioavailability claim; supported by a folate manufacturer (Merck Eprova).
  2. Pentieva K, McNulty H, Reichert R, Ward M, Strain JJ, McKillop DJ, et al. The short-term bioavailabilities of [6S]-5-methyltetrahydrofolate and folic acid are equivalent in men. J Nutr. 2004;134(3):580-5. doi: 10.1093/jn/134.3.580.PubMedUsed to support: A single-dose PK crossover in healthy men found the short-term plasma bioavailability of [6S]-5-MTHF and folic acid to be equivalent, tempering claims that methylfolate is dramatically more bioavailable; manufacturer-supplied test material.
  3. Lamers Y, Prinz-Langenohl R, Moser R, Pietrzik K. Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women. Am J Clin Nutr. 2004;79(3):473-8. doi: 10.1093/ajcn/79.3.473.PubMedUsed to support: In a randomized trial in healthy women, [6S]-5-MTHF lowered plasma total homocysteine to the same degree as an equivalent dose of folic acid (no superiority), supporting homocysteine-lowering but showing it is not better than folic acid for this endpoint.
  4. Litynski P, Loehrer F, Linder L, Todesco L, Fowler B. Effect of low doses of 5-methyltetrahydrofolate and folic acid on plasma homocysteine in healthy subjects with or without the 677C-->T polymorphism of methylenetetrahydrofolate reductase. Eur J Clin Invest. 2002;32(9):662-8. doi: 10.1046/j.1365-2362.2002.01055.x.PubMedUsed to support: Low doses of 5-MTHF and folic acid produced comparable plasma homocysteine reductions in healthy subjects, with the largest absolute lowering in 677TT (MTHFR-deficient) individuals, supporting genotype-dependent folate benefit but not clear superiority of methylfolate.
  5. Cochrane KM, Elango R, Devlin AM, Mayer C, Hutcheon JA, Karakochuk CD. Supplementation with (6S)-5-methyltetrahydrofolic acid appears as effective as folic acid in maintaining maternal folate status while reducing unmetabolised folic acid in maternal plasma: a randomised trial of pregnant women in Canada. Br J Nutr. 2024;131(1):92-102. doi: 10.1017/S0007114523001733.PubMedUsed to support: In 60 pregnant women randomised to 0.6 mg/day folic acid or an equimolar dose of (6S)-5-MTHF for 16 weeks, erythrocyte and serum folate did not differ between groups (the active folate was as effective as folic acid at maintaining maternal folate status), while (6S)-5-MTHF lowered plasma unmetabolised folic acid by about half. This measured maternal folate blood markers, a surrogate, not neural-tube-defect or birth outcomes, and used generic (6S)-5-MTHF, not the Quatrefolic brand.