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

Folate absorption compared with calcium L-methylfolate

EFSA reviewed an unpublished single-dose crossover in 24 adults given 400 mcg of 5-MTHF as the glucosamine salt or as calcium L-methylfolate, each with 400 mcg of folic acid, and found no biologically relevant difference in serum folate. In a rat study by Gnosis authors, plasma 5-MTHF exposure was similar between the two salts.

Blood folate in pregnancy (HY-FOLIC glucosamine salt trial)

In 110 pregnant women randomized to 1,100 mcg a day of a 5-MTHF glucosamine salt product (HY-FOLIC) or an equal molar 600 mcg of folic acid for 12 weeks, red blood cell folate rose and homocysteine fell similarly in both groups (96 completed). The product's maker, Simex Pharmaceutical Indonesia, funded the trial; neither the paper's abstract nor its registry names Quatrefolic. Birth outcomes were not studied.

Blood folate and homocysteine (Metafolin evidence)

Quatrefolic was not tested in these trials. In a placebo-controlled trial of Metafolin, a competing calcium salt of L-5-MTHF, 208 or 416 mcg a day lowered homocysteine as much as 400 mcg of folic acid over 24 weeks, and a single Metafolin dose raised plasma folate more than folic acid in women. Both are blood markers.

Active folate without the MTHFR step

MTHFR variants slow the last step in making active folate, and L-5-MTHF supplies that end product directly. CDC says people with these variants can process all types of folate, including folic acid, and that blood folate in the 677 TT genotype is only about 16% lower than in CC at the same folic acid intake.

Folate before and during pregnancy

CDC advises 400 mcg of folic acid daily for anyone who could become pregnant, even with an MTHFR variant, because folic acid is the only form shown to help prevent neural tube defects. Trials of 5-MTHF salts in pregnancy measured blood folate, not birth outcomes.

Direct active folate provision

Quatrefolic provides L-5-MTHF directly in active form, so no MTHFR conversion step is needed. Common MTHFR variants slow that step, but CDC says people with them can process all types of folate, including folic acid, and that blood folate in the TT genotype is only about 16% lower on the same folic acid intake.

Salt form and absorption

Quatrefolic pairs 5-MTHF with glucosamine instead of calcium. EFSA considers the cation unlikely to change bioavailability much, although solubility may differ by cation. At 400 mcg a day or more, EFSA proposes counting 5-MTHF from either salt as 2.0 mcg of dietary folate equivalents per mcg.

Methylation cycle support

Once absorbed, L-5-MTHF gives its methyl group to homocysteine through the vitamin B12 dependent enzyme methionine synthase, forming methionine, which the body uses to make SAMe, a methyl donor. NIH uses plasma homocysteine as a functional marker of folate status for this reason.

Common Potential side effects

No adverse event data from a published human trial of Quatrefolic itself are available. In a 24 week trial of 208 or 416 mcg a day of Metafolin, a calcium salt from another maker, no side effects were reported.

As with any folate, large amounts can correct the anemia of vitamin B12 deficiency but not its nerve damage, and NIH notes concern that high folate intakes may worsen the anemia and cognitive symptoms of B12 deficiency. Keep B12 intake adequate and ask about testing if you are at risk.

NIH lists an upper limit of 1,000 mcg a day for the synthetic folate forms in supplements and fortified foods, which does not apply under medical supervision.

EFSA's 2013 assessment proposed the glucosamine salt for food supplements at up to 1.8 mg a day, equal to 1 mg of 5-MTHF.

Pregnancy or trying to conceive: CDC advises 400 mcg of folic acid daily, even with an MTHFR variant.

Important Drug interactions

Methotrexate: a folate antagonist. People taking it for cancer should ask their oncologist before using folate supplements; folate may reduce stomach side effects of low-dose methotrexate used for other conditions.

Antiepileptic medicines (phenytoin, carbamazepine, valproate): they can lower serum folate, and folate supplements might lower blood levels of these drugs; check with your prescriber.

Sulfasalazine: it reduces folate absorption and can cause folate deficiency; ask your doctor whether you need more folate.

No drug interaction studies of Quatrefolic itself are cited here. Tell your doctor or pharmacist about any supplement you take.

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

What is Quatrefolic?

Quatrefolic is a patented glucosamine salt of L-5-methyltetrahydrofolate (L-methylfolate), the main form of folate in the blood, made by Gnosis. It is used in supplements in place of, or alongside, folic acid. No published human trial naming Quatrefolic was found.

How is Quatrefolic different from Metafolin?

Both supply the same L-5-MTHF; Quatrefolic uses a glucosamine salt and Metafolin a calcium salt. EFSA found no biologically relevant difference in folate absorption between the two salts in an unpublished single-dose study and considers the cation unlikely to change bioavailability much. The published human trials of L-5-MTHF mostly used Metafolin.

Is Quatrefolic safe, and does it have side effects?

No human trial of Quatrefolic itself reports side effects. EFSA's 2013 assessment proposed the salt for food supplements at up to 1.8 mg a day. As with any folate, high intakes can hide or worsen problems from vitamin B12 deficiency, so keep B12 intake adequate, and check with your doctor if you take methotrexate, antiepileptic medicines or sulfasalazine.

What is Quatrefolic used for?

NutraSmarts does not list Quatrefolic under a health category. What the research covers: EFSA reviewed an unpublished single-dose crossover in 24 adults given 400 mcg of 5-MTHF as the glucosamine salt or as calcium L-methylfolate, each with 400 mcg of folic acid, and found no biologically relevant difference in serum folate.

What is the recommended dosage of Quatrefolic?

No published human trial has tested a dose of Quatrefolic itself. EFSA's 2013 assessment proposed up to 1.8 mg a day of the salt (1 mg of 5-MTHF) in food supplements. A pregnancy trial of a glucosamine salt product (HY-FOLIC) used 1,100 mcg a day. Always follow the product label and check with a healthcare provider for personal advice.

Does Quatrefolic interact with any medications?

Possible interactions include: Methotrexate: a folate antagonist. People taking it for cancer should ask their oncologist before using folate supplements; folate may reduce stomach side effects of low-dose methotrexate used for other conditions. 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 Preliminary (1 out of 5). It is backed by 10 cited references summarized on this page. A higher rating reflects more, larger, and better-designed human studies.

References(10 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.

Miraglia N, Agostinetto M, Bianchi D, Valoti E. Enhanced oral bioavailability of a novel folate salt: comparison with folic acid and a calcium folate salt in a pharmacokinetic study in rats. Minerva Ginecol. 2016;68(2):99-105..PubMedUsed to support: Rat study by Gnosis S.p.A. authors: single oral doses of Quatrefolic, (6S)-5-MTHF calcium salt or folic acid (6 rats each). Plasma 5-MTHF AUC over 8 hours was 1.12 times that of the calcium salt and 9.7 times that of folic acid, and peak concentration 1.8 times the calcium salt. Animal study by the maker; not evidence in people.
EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Turck D, Bohn T, Castenmiller J, De Henauw S, Hirsch-Ernst KI, Knutsen HK, Maciuk A, Mangelsdorf I, McArdle HJ, Naska A, Peláez C, Siani A, Thies F, Tsabouri S, Vinceti M, Cubadda F, Abrahantes JC, Dumas C, Ercolano V, Titz A, Pentieva K. Conversion of calcium-l-methylfolate and (6S)-5-methyltetrahydrofolic acid glucosamine salt into dietary folate equivalents. EFSA J. 2022;20(8):e07452. doi: 10.2903/j.efsa.2022.7452.PubMedUsed to support: EFSA opinion: Commission Regulation (EU) 2015/414 allows (6S)-5-MTHF glucosamine salt as a folate source in food supplements after EFSA's 2013 opinion, which proposed use up to 1.8 mg a day (1 mg 5-MTHF) and found bioavailability comparable to calcium L-methylfolate. An unpublished single-dose crossover in 24 adults (400 mcg 5-MTHF from each salt, with 400 mcg folic acid) showed no biologically relevant difference in serum folate. The cation is unlikely to greatly affect bioavailability; at 400 mcg a day or more, a DFE factor of 2.0 is proposed for 5-MTHF. Data were submitted by Gnosis by Lesaffre, among others.
Ernawati E, Akyuni Q, Gumilar E, Qonitatillah J, Damayanti DS, Dekker G. Comparative bioavailability of 5-methyltetrahydrofolate and folic acid in pregnant women: A randomized controlled trial. Clin Nutr ESPEN. 2026;76:105107. doi: 10.1016/j.clnesp.2026.105107.PubMedUsed to support: Double-blind randomized trial in 110 pregnant women at 9 to 14 weeks (96 completed): 1,100 mcg a day of a 5-MTHF glucosamine salt product, named in the trial registry (NCT06935630) as HY-FOLIC, or an equal molar 600 mcg folic acid for 12 weeks. Red blood cell folate rose (primary outcome, P = 0.714 between groups) and homocysteine fell with no significant difference between groups; the plasma 5-MTHF rise was larger on 5-MTHF only before baseline adjustment (adjusted P = 0.055). Funded by Simex Pharmaceutical Indonesia, described as the manufacturer of the 5-MTHF glucosamine salt product used; neither the abstract nor the registry names Quatrefolic or the source of the salt. Active comparator only, no placebo. Blood markers only.
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: Other product (Metafolin). 24-week double-blind randomized trial in 144 healthy women aged 18 to 35 (135 analyzed): 416 or 208 mcg [6S]-5-MTHF calcium salt, named in the methods as Metafolin from Merck Eprova AG, lowered plasma homocysteine as much as 400 mcg folic acid; plasma folate rose less on 208 mcg. This paper reports homocysteine and plasma folate only. Merck KGaA contributed financially, Merck Eprova AG provided the Metafolin, and one author was its chief scientific officer.
Prinz-Langenohl R, Brämswig S, Tobolski O, Smulders YM, Smith DE, Finglas PM, Pietrzik K. [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: Other product (Metafolin). Randomized crossover single-dose study in 24 healthy women (16 MTHFR 677 TT, 8 CC): 416 mcg [6S]-5-MTHF, named in the methods as Metafolin obtained from Merck Selbstmedikation GmbH, or 400 mcg folic acid. Plasma folate AUC and peak were higher and time to peak shorter after [6S]-5-MTHF in both genotypes; unmetabolized folic acid appeared regularly after folic acid and rarely after [6S]-5-MTHF. Financial support came from Merck Selbstmedikation GmbH.
Pentieva K, McNulty H, Reichert R, Ward M, Strain JJ, McKillop DJ, McPartlin JM, Connolly E, Molloy A, Krämer K, Scott JM. 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: Other product. Double-blind crossover in 13 men presaturated with folic acid: single 500 mcg doses of [6S]-5-MTHF calcium salt, folic acid or placebo, with capsules provided by BASF Aktiengesellschaft (one author was from BASF AG). Peak plasma folate (31.8 versus 33.4 nmol/L, P = 0.7) and the area under the curve did not differ between the two forms. Funded by an EU project and supported by Abbott GmbH.
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: Other product. In 10 wild-type and 10 MTHFR 677 TT healthy adults, 400 mcg a day of racemic [6RS] 5-MTHF (not the pure 6S form in Quatrefolic) or 400 mcg folic acid for 7 weeks lowered homocysteine comparably, with the larger absolute falls in TT subjects. No placebo group.
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: Other product (Metafolin). Randomized trial in 60 pregnant people: 0.6 mg a day folic acid or an equal molar 0.625 mg of Metafolin for 16 weeks; Merck & Cie (Schaffhausen) donated the Metafolin. Erythrocyte and serum folate did not differ between groups, while plasma unmetabolized folic acid was about half as high on Metafolin. Blood markers only, not birth outcomes.
Centers for Disease Control and Prevention. MTHFR Gene Variant and Folic Acid Facts. CDC. 2026;Online page dated July 16, 2026. Not PubMed-indexed..SourceUsed to support: Not PubMed-indexed. CDC states that people with an MTHFR gene variant can process all types of folate, including folic acid; that folic acid is the only type of folate shown to help prevent neural tube defects; that people with the 677 TT genotype have blood folate about 16% lower than CC at the same folic acid intake; and that anyone who could become pregnant should get 400 mcg of folic acid daily, even with an MTHFR variant.
Office of Dietary Supplements, National Institutes of Health. Folate: Fact Sheet for Health Professionals. NIH Office of Dietary Supplements. 2022;Updated November 30, 2022. Not PubMed-indexed..SourceUsed to support: Not PubMed-indexed. NIH fact sheet: some supplements contain 5-MTHF (L-methylfolate) instead of folic acid, and 5-MTHF is the main form of folate in plasma; large amounts of folate can correct the megaloblastic anemia but not the nerve damage of vitamin B12 deficiency, and concern has shifted to large amounts of folate worsening the anemia and cognitive symptoms of B12 deficiency; the upper limit of 1,000 mcg a day applies to the synthetic folate forms in supplements and fortified foods and not under medical supervision; the doses used in depression studies exceed it and should be taken only under medical supervision; adult RDA 400 mcg DFE, 600 mcg DFE in pregnancy; interactions with methotrexate, antiepileptic medicines and sulfasalazine.