Home Ingredients Metafolin® (L-Methylfolate Calcium)

Metafolin® (L-Methylfolate Calcium)

Evidence Level
Limited
7 Clinical Trials
5 Documented Benefits
2/5 Evidence Score

Metafolin® is the crystalline calcium salt of L-5-methyltetrahydrofolate (L-5-MTHF), the main form of folate in the blood. It was first supplied for research by Merck Eprova of Switzerland, and Merck KGaA now holds the trademark. Unlike folic acid, it does not need to be converted by the body before use. In randomized trials that named Metafolin, doses from 113 mcg to 1.13 mg a day raised red blood cell and plasma folate and lowered homocysteine, a blood marker, compared with placebo. Against equal molar folic acid, an active comparator, blood folate rose more in some trials and about the same in others, including a trial in pregnancy. These trials measured blood markers, not birth outcomes or heart events, and folic acid is the form tested in the trials that lowered neural tube defects. EFSA found that 1 mg a day for adults raised no safety concern.

Studied Dose 113 mcg to 1.13 mg a day: 113 mcg for 24 weeks; 208 or 416 mcg for 24 weeks; 416 mcg for 16 weeks while breastfeeding; 625 mcg for 16 weeks in pregnancy; 1.13 mg for 12 weeks; and a single 416 mcg dose. EFSA found 1 mg a day for adults raised no safety concern.
Active Compound Calcium L-methylfolate, the calcium salt of (6S)-5-methyltetrahydrofolic acid (L-5-MTHF-Ca; CAS 151533-22-1). It is made by chemical synthesis from folic acid, and EFSA reports the unnatural D isomer at under 1 percent. Metafolin® is a registered trademark of Merck KGaA, Darmstadt, Germany; early trial material came from Merck Eprova AG of Schaffhausen, Switzerland, and later material from Merck & Cie, Schaffhausen.

Benefits

Red blood cell and plasma folate status

In trials of Metafolin against placebo, blood folate rose at every dose tested. Against equal molar folic acid, an active comparator, 416 mcg a day raised red blood cell folate more over 24 weeks in 136 women, and 1.13 mg a day gave higher levels at 12 weeks in Malaysian women (75 completed); at 113 mcg a day, and at 625 mcg a day in pregnancy, levels did not differ.

Supported by Trial 6, Trial 1

Homocysteine, a blood marker

Metafolin lowered plasma homocysteine compared with placebo in three trials. Against folic acid, the fall was similar at 208 or 416 mcg and at 1.13 mg a day, and larger at 113 mcg a day (14.6 versus 9.3 percent below placebo). Homocysteine is a marker: in pooled trials of homocysteine-lowering B vitamins, heart attacks and deaths did not fall, with a small drop in stroke.

Supported by Trial 3, Trial 6

Folate status in pregnancy

In 60 pregnant people given 625 mcg of Metafolin or an equal molar 600 mcg of folic acid a day for 16 weeks, red blood cell and serum folate did not differ between groups, while unmetabolized folic acid in plasma was about half as high on Metafolin, a difference the authors call of unclear relevance. The trial measured blood markers, not birth outcomes.

Supported by Trial 7, Trial 6

Folate status while breastfeeding

In 69 women assigned after delivery, 416 mcg of Metafolin a day for 16 weeks kept red blood cell folate higher than placebo and higher than a 400 mcg folic acid reference group, which was not randomized. The women had taken folic acid through pregnancy and ate fortified foods. The maker co-funded the trial.

Supported by Trial 4, Trial 1

Plasma folate response by MTHFR 677 genotype

In a single-dose crossover in 24 women with the MTHFR 677 TT or CC genotype, 416 mcg of Metafolin raised plasma folate more than 400 mcg of folic acid in both groups, about twice as much in TT women by area under the curve. A Merck company supplied and funded it, and a study of another maker's 5-MTHF found equal short-term absorption in men.

Supported by Trial 5, Trial 2

Mechanism of action

1

Active folate without the conversion steps

Folic acid must first be reduced by the enzyme dihydrofolate reductase and then converted, with the MTHFR enzyme making the final 5-MTHF form, the main folate in plasma. Metafolin supplies L-5-MTHF directly. In a single-dose study, plasma folate was mostly 5-MTHF after either form, while unmetabolized folic acid appeared regularly after folic acid and rarely after Metafolin.

2

Vitamin B12 dependent recycling and the masking question

5-MTHF passes its methyl group to homocysteine through methionine synthase, a vitamin B12 dependent enzyme, which regenerates tetrahydrofolate. Trial authors propose that, because of this step, 5-MTHF is less able than folic acid to correct the anemia of B12 deficiency and so less likely to mask it. None of the trials cited here tested this in people with B12 deficiency.

Clinical trials

1
Metafolin 416 mcg vs Folic Acid: Red Blood Cell Folate Over 24 Weeks
PubMed

Double-blind, randomized, placebo-controlled parallel trial; 416 or 208 mcg [6S]-5-MTHF calcium salt (Metafolin, Merck Eprova AG), 400 mcg folic acid as an equimolar active comparator, or placebo daily for 24 weeks; the earlier report from this trial states that Merck KGaA contributed financially and a Merck Eprova AG scientist was a co-author (Lamers et al. 2006, Am J Clin Nutr)

144 healthy women aged 19 to 33 in Bonn, Germany, with adequate vitamin B12; 136 analyzed.

Red blood cell folate rose more over time on 416 mcg Metafolin than on 400 mcg folic acid or 208 mcg Metafolin (P < 0.001), and more on folic acid than on 208 mcg. Plasma folate plateaued after 12 weeks; red cell folate had not plateaued by 24 weeks. Red cell folate is a marker of folate status, not a measured pregnancy outcome.

2
Metafolin 208 or 416 mcg vs Folic Acid: Homocysteine in the Same Trial
PubMed

Double-blind, randomized, placebo-controlled parallel trial (same 144 women as the red cell folate report); Metafolin from Merck Eprova AG named in the methods; funded in part by Merck KGaA, with a Merck Eprova AG co-author; 24 weeks (Lamers et al. 2004, Am J Clin Nutr)

144 healthy women in Bonn, Germany, recruited at ages 18 to 35 with adequate vitamin B12; 135 analyzed.

Plasma homocysteine fell on all three active supplements, and the fall did not differ between 400 mcg folic acid, 416 mcg and 208 mcg Metafolin. The plasma folate rise was smaller on 208 mcg than on folic acid or 416 mcg. No side effects were reported.

3
Low-Dose Metafolin 113 mcg vs Folic Acid: Homocysteine in Adults
PubMed

Double-blind, randomized, placebo-controlled 24 week trial; 113 mcg L-MTHF calcium salt (Metafolin, supplied by Eprova AG, whose chief scientific officer was a co-author) or an equimolar 100 mcg folic acid active comparator or placebo daily (Venn et al. 2003, Am J Clin Nutr)

167 healthy adults in New Zealand who did not take folic acid supplements and were not regular consumers of folic acid fortified foods (under 3 servings a week); 155 analyzed.

Compared with placebo, homocysteine was 14.6 percent lower on Metafolin and 9.3 percent lower on folic acid (P < 0.001 versus placebo; P = 0.045 between the active arms). Plasma folate and red cell folate rose on both, and the rises did not differ significantly between them. Homocysteine is a blood marker.

4
Metafolin 416 mcg During Breastfeeding: Maker-Funded Trial
PubMed

Sixteen week, double-blind trial: women randomized after delivery to 416 mcg [6S]-5-methylTHF a day or placebo, plus a nonrandomized 400 mcg folic acid reference group; the paper identifies the form as Metafolin and was supported by Merck Eprova AG and a Canadian research council (Houghton et al. 2006, Am J Clin Nutr)

69 healthy breastfeeding women in Toronto who had taken folic acid in pregnancy; 64 completed.

At 16 weeks, red blood cell folate after baseline adjustment was higher on [6S]-5-methylTHF (2178 nmol/L) than in the folic acid reference group (1967 nmol/L, P < 0.05) or on placebo (1390 nmol/L). Because the folic acid group was not randomized, that comparison is weaker than the placebo comparison.

5
Single Dose of Metafolin vs Folic Acid by MTHFR 677 Genotype
PubMed

Randomized crossover pharmacokinetic study; single oral 416 mcg [6S]-5-MTHF (Metafolin from Merck Selbstmedikation GmbH, which also funded the study) or an equimolar 400 mcg folic acid; plasma folate measured for 8 hours (Prinz-Langenohl et al. 2009, Br J Pharmacol)

24 healthy women: 16 with the MTHFR 677 TT genotype and 8 with CC.

Plasma folate area under the curve and peak were higher, and time to peak shorter, after Metafolin than after folic acid in both genotypes; in TT women the area under the curve was about twice as high. Unmetabolized folic acid appeared regularly after folic acid and rarely after Metafolin. No treatment-related adverse events occurred.

6
Metafolin 1.13 mg vs Folic Acid for 12 Weeks in Malaysian Women
PubMed

Double-blind, randomized, placebo-controlled trial; 1.13 mg L-5-MTHF calcium salt (Metafolin, Eprova) or an equimolar 1 mg folic acid active comparator or cellulose placebo daily; registered NCT01584050; high loss to follow-up (Henderson et al. 2018, J Nutr)

142 women aged 20 to 45 in Malaysia, where folic acid fortification is not mandatory; 108 attended baseline and 75 completed (20 on Metafolin).

At 12 weeks, red blood cell folate (1951 versus 1498 nmol/L, P = 0.003) and plasma folate were higher on Metafolin than on folic acid. Homocysteine was 15 percent (Metafolin) and 17 percent (folic acid) lower than placebo, with no difference between the two. Vitamin B12, methyl nutrients and LINE-1 methylation did not differ.

7
Metafolin 625 mcg vs Folic Acid in Pregnancy: Folate Status
PubMed

Double-blind randomized trial of 0.625 mg Metafolin (donated by Merck & Cie) or an equimolar 0.6 mg folic acid active comparator daily for 16 weeks with a folate-free prenatal vitamin; registered NCT04022135 (Cochrane et al. 2024, Br J Nutr)

60 pregnant people at 8 to 21 weeks' gestation in Vancouver, Canada; 54 analyzed.

Erythrocyte folate (1826 versus 1998 nmol/L) and serum folate did not differ between groups after adjustment. Plasma unmetabolized folic acid was 0.6 nmol/L higher on folic acid, roughly twice the level on Metafolin; the authors call the biological relevance unclear. Birth outcomes were not studied.

Side effects and drug interactions

Common Potential side effects

In a 24 week trial of 208 or 416 mcg a day in 144 women, no side effects were reported, and a single-dose study found no treatment-related adverse events.
In a 24 week trial in 167 adults, two people withdrew citing possible adverse reactions, one on placebo and one on folic acid; none were in the Metafolin group.
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 found 1 mg a day of calcium L-methylfolate for adults raised no safety concern.
In lab and rat studies by authors from Merck and DSM, calcium L-methylfolate was not genotoxic, caused no treatment-related effects at up to 400 mg/kg a day for 13 weeks, and did not harm embryos. These were animal and lab studies.

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 Metafolin itself are cited here. Tell your doctor or pharmacist about any supplement you take.

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Frequently asked questions about Metafolin® (L-Methylfolate Calcium)

What is Metafolin?

Metafolin is a branded calcium salt of L-5-methyltetrahydrofolate (L-methylfolate), the main form of folate in the blood. It was first supplied for research by Merck Eprova and is a trademark of Merck KGaA. It is used in supplements and prenatal vitamins in place of, or alongside, folic acid.

How is Metafolin different from folic acid?

Folic acid has to be converted by the body before use, while Metafolin is already in the active form. In trials against equal molar folic acid, blood folate rose more on Metafolin in some studies and about the same in others, and homocysteine fell about as much, or slightly more in one low-dose trial. Folic acid is the form tested in the trials that lowered neural tube defects.

How much Metafolin was used in studies?

Trials used 113 mcg to 1.13 mg a day for 12 to 24 weeks, most often 416 mcg, the molar equal of 400 mcg of folic acid. EFSA treats 5-MTHF taken at 400 mcg a day or more as worth 2.0 dietary folate equivalents per mcg. Follow the product label and ask a healthcare provider for personal advice.

Can Metafolin replace folic acid before or during pregnancy?

In a 16 week trial in pregnancy, Metafolin kept blood folate as high as folic acid, but it measured blood markers only. The protective effect against neural tube defects was shown with folic acid, and researchers consider a placebo-controlled trial of 5-MTHF for that outcome unethical, so blood folate is used as a stand-in. Discuss the choice with your clinician.

Is Metafolin safe?

In trials of up to 24 weeks, side effects were not reported more often than on placebo or folic acid, and EFSA found that 1 mg a day for adults raised no safety concern. 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 Metafolin used for?

NutraSmarts does not list Metafolin under a health category. What the research covers: In trials of Metafolin against placebo, blood folate rose at every dose tested. Against equal molar folic acid, an active comparator, 416 mcg a day raised red blood cell folate more over 24 weeks in 136 women, and 1.

Does Metafolin 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 Metafolin?

NutraSmarts rates the evidence for Metafolin as Limited (2 out of 5). It is backed by 7 study summaries and 16 cited references summarized on this page. A higher rating reflects more, larger, and better-designed human studies.

References(16 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. Lamers Y, Prinz-Langenohl R, Brämswig S, Pietrzik K. Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr. 2006;84(1):156-61. doi: 10.1093/ajcn/84.1.156.PubMedUsed to support: Double-blind randomized placebo-controlled trial in 144 healthy German women aged 19 to 33 (136 analyzed). Capsules held 416 or 208 mcg of [6S]-5-MTHF calcium salt named in the methods as Metafolin from Merck Eprova AG, 400 mcg folic acid, or placebo, daily for 24 weeks. The rise in red blood cell folate over time was greater on 416 mcg than on the equimolar 400 mcg folic acid active comparator or on 208 mcg (P < 0.001); plasma folate plateaued after 12 weeks, red cell folate did not plateau. The authors note that a placebo-controlled trial of 5-MTHF on neural tube defects would be unethical, so red cell folate serves as a surrogate marker; neural tube defect prevention was shown with folic acid. The authors declared no conflict of interest, but the earlier report from the same trial states that Merck KGaA contributed financially and Merck Eprova AG provided the Metafolin.
  2. 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: Earlier report from the same 24 week trial in 144 women, with Metafolin (Merck Eprova AG) named in the methods. Plasma total homocysteine fell over time on all three active supplements and the fall did not differ between 400 mcg folic acid, 416 mcg and 208 mcg [6S]-5-MTHF; the plasma folate rise was smaller on 208 mcg than on 400 mcg folic acid or 416 mcg [6S]-5-MTHF. The supplements were well tolerated and no side effects were reported. Merck KGaA contributed financially, Merck Eprova AG provided the Metafolin, and one author was from Merck Eprova AG.
  3. Venn BJ, Green TJ, Moser R, Mann JI. Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am J Clin Nutr. 2003;77(3):658-62. doi: 10.1093/ajcn/77.3.658.PubMedUsed to support: Double-blind randomized placebo-controlled 24 week trial in 167 healthy adults in New Zealand (155 analyzed): 100 mcg folic acid, an equimolar 113 mcg of L-MTHF calcium salt named in the methods as Metafolin (Eprova, Schaffhausen), or placebo daily. Versus placebo, homocysteine was 14.6 percent lower on L-MTHF and 9.3 percent lower on folic acid, a difference between the two active arms of P = 0.045; plasma and red cell folate rose on both, with no significant difference between them. Eprova AG provided the supplements, and its chief scientific officer was a co-author. Twelve people withdrew, two citing possible adverse reactions (one each on placebo and folic acid).
  4. Venn BJ, Green TJ, Moser R, McKenzie JE, Skeaff CM, Mann J. Increases in blood folate indices are similar in women of childbearing age supplemented with [6S]-5-methyltetrahydrofolate and folic acid. J Nutr. 2002;132(11):3353-5. doi: 10.1093/jn/132.11.3353.PubMedUsed to support: Report on the 104 women aged 18 to 49 within the same New Zealand trial (97 completed): 113 mcg of [6S]-5-MTHF calcium salt (Metafolin, Eprova) or 100 mcg folic acid or placebo daily for 24 weeks. The slopes of plasma folate and red cell folate increase did not differ between the two active forms (P = 0.48 and 0.70), and no steady state was reached by 24 weeks. Eprova AG, an affiliate of Merck KGaA, provided the supplements.
  5. Houghton LA, Sherwood KL, Pawlosky R, Ito S, O'Connor DL. [6S]-5-Methyltetrahydrofolate is at least as effective as folic acid in preventing a decline in blood folate concentrations during lactation. Am J Clin Nutr. 2006;83(4):842-50. doi: 10.1093/ajcn/83.4.842.PubMedUsed to support: Sixteen week trial in 69 Canadian women who had taken a folic acid prenatal supplement in pregnancy: after delivery they were randomly assigned to 416 mcg a day of [6S]-5-methylTHF or placebo, or assigned to a nonrandomized 400 mcg folic acid reference group; 64 completed. At 16 weeks of breastfeeding, red blood cell folate was higher on [6S]-5-methylTHF (2178 nmol/L) than on folic acid (1967 nmol/L, P < 0.05) or placebo (1390 nmol/L) after baseline adjustment. The paper introduces the supplemental form as Metafolin (Merck Eprova AG), and the study was supported by Merck Eprova AG and the Natural Sciences and Engineering Research Council of Canada.
  6. 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: Randomized crossover single-dose pharmacokinetic study in 24 healthy women (16 MTHFR 677 TT, 8 CC): 416 mcg [6S]-5-MTHF, named in the methods as Metafolin and obtained from Merck Selbstmedikation GmbH, or an equimolar 400 mcg folic acid. Plasma folate area under the curve and peak were higher and time to peak shorter after [6S]-5-MTHF in both genotypes; in the TT group the area under the curve was about twice that after folic acid. Unmetabolized folic acid appeared regularly after folic acid and rarely after [6S]-5-MTHF, and no treatment-related adverse events occurred. Financial support came from Merck Selbstmedikation GmbH.
  7. Henderson AM, Aleliunas RE, Loh SP, Khor GL, Harvey-Leeson S, Glier MB, Kitts DD, Green TJ, Devlin AM. l-5-Methyltetrahydrofolate Supplementation Increases Blood Folate Concentrations to a Greater Extent than Folic Acid Supplementation in Malaysian Women. J Nutr. 2018;148(6):885-890. doi: 10.1093/jn/nxy057.PubMedUsed to support: Double-blind randomized placebo-controlled 12 week trial in Malaysian women aged 20 to 45 (registered NCT01584050): 1 mg folic acid, an equimolar 1.13 mg L-5-MTHF calcium salt named in the methods as Metafolin (Eprova), or placebo. Of 142 randomized, 108 attended baseline and 75 completed (20 on L-5-MTHF). At 12 weeks the L-5-MTHF group had higher red blood cell folate (1951 versus 1498 nmol/L, P = 0.003) and plasma folate than the folic acid active comparator; homocysteine was 15 and 17 percent lower than placebo, with no difference between the two forms. Vitamin B12, methionine, betaine, choline and LINE-1 methylation did not differ. The authors declared no conflicts of interest.
  8. 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: Randomized trial in 60 pregnant people at 8 to 21 weeks' gestation in Canada (registered NCT04022135): 0.6 mg folic acid or an equimolar 0.625 mg of Metafolin (calcium salt of (6S)-5-MTHF) daily for 16 weeks, with a folate-free prenatal vitamin; 54 analyzed. Erythrocyte and serum folate did not differ between groups; plasma unmetabolized folic acid was 0.6 nmol/L higher on folic acid, about half as high on (6S)-5-MTHF, with uncertain biological relevance. Merck & Cie (Schaffhausen) donated the Metafolin; the authors declared no conflicts of interest. Blood markers only, not birth outcomes.
  9. 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 (not identified as Metafolin). 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, so short-term bioavailability was equivalent.
  10. Niederberger KE, Dahms I, Broschard TH, Boehni R, Moser R. Safety evaluation of calcium L-methylfolate. Toxicol Rep. 2019;6:1018-1030. doi: 10.1016/j.toxrep.2019.09.012.PubMedUsed to support: Laboratory and animal safety studies of calcium L-methylfolate by authors from Leveret GmbH, DSM Nutritional Products, Merck KGaA and Merck & Cie: not mutagenic or genotoxic in vitro or in vivo, no treatment-related effects in rats given up to 400 mg/kg body weight a day by gavage for 13 weeks (the no observed adverse effect level), and not teratogenic or embryotoxic. Animal and lab work, not a human study; the authors declare no conflict of interest.
  11. EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Turck D, Castenmiller J, De Henauw S, Hirsch-Ernst KI, Kearney J, Maciuk A, Mangelsdorf I, McArdle HJ, Naska A, Pelaez C, Pentieva K, Siani A, Thies F, Tsabouri S, Vinceti M, Cubadda F, Engel KH, Frenzel T, Heinonen M, Marchelli R, Neuhäuser-Berthold M, Poulsen M, Sanz Y, Schlatter JR, van Loveren H, Bernasconi G, Germini A, Knutsen HK. Calcium l-methylfolate as a source of folate added for nutritional purposes to infant and follow-on formula, baby food and processed cereal-based food. EFSA J. 2020;18(1):e05947. doi: 10.2903/j.efsa.2020.5947.PubMedUsed to support: EFSA nutrient source opinion. The source assessed is calcium L-methylfolate, commercialized by the applicant as Metafolin. It recounts that the 2004 EFSA opinion found use as a folate source in foods for particular nutritional uses, food supplements and general foods at 1 mg per adult per day not of safety concern, in line with the folic acid upper level, and that folic acid and calcium L-methylfolate have similar bioavailability at equimolar doses. It states that calcium L-methylfolate is authorized in the EU for food supplements and fortified foods, has GRAS status in the USA, where it is also listed as a new dietary ingredient for dietary supplements, and contains under 1 percent of the unnatural D isomer. It concluded the source is safe at the proposed uses in infant and follow-on formula and baby foods.
  12. 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 on converting calcium L-methylfolate and (6S)-5-MTHF glucosamine salt into dietary folate equivalents, based on a systematic review. Below 400 mcg a day, the same factor as folic acid (1.7) is proposed; at 400 mcg a day and above, 5-MTHF was found more bioavailable than folic acid and a factor of 2.0 is proposed. The cation is considered unlikely to change bioavailability beyond the margin of error.
  13. Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2017;8(8):CD006612. doi: 10.1002/14651858.CD006612.pub5.PubMedUsed to support: Cochrane review of 15 randomized trials (71,422 participants) of homocysteine-lowering B vitamins against placebo: no difference in myocardial infarction (RR 1.02, 95 percent CI 0.95 to 1.10) or death from any cause (RR 1.01), and a small reduction in stroke (RR 0.90, 95 percent CI 0.82 to 0.99). Supports treating homocysteine as a marker rather than a heart outcome; the trials did not test Metafolin.
  14. 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; adult RDA 400 mcg DFE, 600 mcg DFE in pregnancy; interactions with methotrexate, antiepileptic medicines and sulfasalazine.
  15. European Food Safety Authority (EFSA). Opinion of the Scientific Panel on food additives, flavourings, processing aids and materials in contact with food (AFC) related to Calcium L-Methylfolate. EFSA J. 2004;2(11):135. doi: 10.2903/j.efsa.2004.135. Not PubMed-indexed..SourceUsed to support: Not PubMed-indexed. EFSA AFC Panel opinion on calcium L-methylfolate (question EFSA-Q-2004-007), adopted 28 October 2004 and published 23 November 2004. Its conclusion is cited here as summarized in EFSA's 2020 opinion: use as a source of folate in foods for particular nutritional uses, food supplements and foods for the general population at 1 mg per adult per day raises no safety concern, in line with the upper level for folic acid.
  16. Merck KGaA. Metafolin® (L-5-methyltetrahydrofolic acid calcium (L-5-MTHF-Ca)), USP. Product CH2900019. Sigma-Aldrich (Merck KGaA) product page. 2026;Online product page, accessed October 2026. Not PubMed-indexed..SourceUsed to support: Not PubMed-indexed. Supplier page for Metafolin, L-5-methyltetrahydrofolic acid calcium (USP grade), sold under the SAFC line; it states that Metafolin is a registered trademark of Merck KGaA, Darmstadt, Germany, and lists dietary supplement use at 200 to 1000 mcg a day.