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Levomefolate (L-methylfolate, 5-MTHF)

Active form of vitamin B9, ready for methylation reactions

ATC code: B03BB-METHYLFOLATE(Levomefolate calcium (L-methylfolate, 5-MTHF))

Brand names: Deplin, Metafolin

Updated · Methodology

Indications

A

Folate (vitamin B9) deficiency

First line

Levomefolate is first-line for confirmed folate deficiency in patients with malabsorption, coeliac disease, long-term methotrexate, phenytoin or trimethoprim therapy and in confirmed functional MTHFR deficiency. AEMPS registers Asanvit; for suspected deficiency 0.4–1 mg/day orally is usually sufficient. In most patients without MTHFR impairment, regular folic acid is equally effective and substantially cheaper.

Sources

  1. AEMPS: Ficha técnica de Asanvit (levomefolato cálcico) (2023)
  2. BSH: Guidelines for the diagnosis and treatment of cobalamin and folate disorders (2014)

ICD-10: E53.8 · ICD-11: 5B5E

A

Megaloblastic anaemia

First line

Levomefolate corrects folate-deficiency megaloblastic anaemia. 2014 recommends ruling out B12 deficiency before starting folate: correcting folate with undiagnosed B12 deficiency masks anaemia and allows neurological progression (subacute combined degeneration of the spinal cord). Dose 5 mg/day orally until haemoglobin recovers and MCV normalises. In most patients regular folic acid is equivalent.

Sources

  1. BSH: Guidelines for the diagnosis and treatment of cobalamin and folate disorders (2014)
  2. AEMPS: Ficha técnica de Asanvit (levomefolato cálcico) (2023)

ICD-10: D53.1 · ICD-11: 3A01

B

Neural tube defect prevention

Adjunct

Levomefolate is used to prevent fetal neural tube defects as an alternative to classical folic acid. SEGO 2020 recommends 0.4 mg folic acid daily 1–3 months before conception and throughout the first trimester for all women planning pregnancy, with 5 mg/day in high-risk groups (prior NTD, diabetes, obesity, antiepileptics). In women with confirmed homozygous MTHFR C677T, levomefolate is a reasonable alternative, but 2023 notes that NTD prevention efficacy is established for classical folic acid; data on 5-MTHF are limited.

Sources

  1. SEGO: Síndrome de ovario poliquístico: documento de consenso (2017)
  2. USPSTF: Folic acid supplementation to prevent neural tube defects: recommendation statement (2023)

ICD-10: Q05 · ICD-11: LA02

Marketing claims without evidence base

The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.

D

Major depressive disorder

Not recommended

Levomefolate is marketed as an «antidepressant adjunct» based on the hypothesis that MTHFR polymorphism impairs methylation, raises homocysteine and reduces monoamine synthesis. In the US, Deplin is registered as a medical food; in the EU it is not. Cochrane 2019 on folate for depression: adding folate to standard therapy in 13 RCTs produced no clinically meaningful improvement on depression scales. In patients with confirmed folate deficiency, correction is justified; in non-deficient patients it is not. If levomefolate was recommended «for depression» based on MTHFR testing without folate and B12 measurements, consider seeking a second opinion.

Sources

  1. Cochrane: Folate for depressive disorders (2019)

ICD-10: F32.9 · ICD-11: 6A70.Z

D

MTHFR polymorphism and methylation (supplement marketing)

Not recommended

Levomefolate (L-methylfolate, 5-MTHF) is an active form of folate. Supplement brands market it for people with the MTHFR gene polymorphism, claiming it supports "methylation" better than ordinary folic acid. There is no convincing evidence that methylfolate gives carriers of this polymorphism an advantage over folic acid on clinical outcomes. For documented folate deficiency and pregnancy planning, folate supplementation at recommended doses is what has proven value, and matching the "methyl form" to a genotype does not meaningfully change outcomes. The compound itself is safe in this use, but do not take it instead of therapy with proven benefit, since that risks missing the treatment you actually need.

Sources

  1. SEGO: Síndrome de ovario poliquístico: documento de consenso (2017)
How to read tiers A–F
  • AStrong evidence – first or second line in international guidelines
  • BRecommended in selected cases
  • CStudy data contradict each other
  • DBenefit not proven, no documented harm
  • FDocumented harm, or risk without benefit

Mechanism of action

Levomefolate (5-methyltetrahydrofolate, 5-MTHF) is the active folate form into which ordinary folic acid is converted by dihydrofolate reductase and MTHFR. 5-MTHF is the methyl-group donor in homocysteine remethylation to methionine, participates in purine and pyrimidine synthesis and supports erythropoiesis. Bioavailability is comparable to folic acid in people with normal MTHFR activity; in C677T polymorphism carriers 5-MTHF does not need enzymatic activation, but clinical trials do not confirm advantage in most indications.

Safety

Contraindications

  • Hypersensitivity to levomefolate
  • Undiagnosed vitamin B12 deficiency (risk of masking anaemia and neurological progression)
  • Folate-dependent malignancies (without oncologist agreement)

Serious adverse effects

  • Allergic reactions up to anaphylaxis (very rare)
  • Masking of neurological deficit with undiagnosed B12 deficiency

Common adverse effects

  • Nausea
  • Flatulence
  • Skin itching

Pregnancy: can you take Levomefolate (L-methylfolate, 5-MTHF)?

AEMPS allows levomefolate in pregnancy up to 5 mg/day. In women with confirmed homozygous MTHFR C677T it may serve as an alternative to classical folic acid.

Breastfeeding: can you take Levomefolate (L-methylfolate, 5-MTHF)?

Compatible (Hale L1). Levomefolate passes into milk at physiological folate concentrations. Daily intake during lactation 0.5 mg.

Calculate RID

Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.

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Frequently asked

What is Levomefolate (L-methylfolate, 5-MTHF) used for?

Levomefolate (L-methylfolate, 5-MTHF) is evaluated for the following indications with varying evidence strength: Megaloblastic anaemia (evidence tier A), Folate (vitamin B9) deficiency (evidence tier A), Neural tube defect prevention (evidence tier B). See the full indication matrix with dosing and citations above on this page.

What are the side effects of Levomefolate (L-methylfolate, 5-MTHF)?

Common side effects of Levomefolate (L-methylfolate, 5-MTHF) (≥ 1 in 100): Nausea, Flatulence, Skin itching. See the Safety section for uncommon and serious reactions.

Is Levomefolate (L-methylfolate, 5-MTHF) safe during pregnancy?

AEMPS allows levomefolate in pregnancy up to 5 mg/day. In women with confirmed homozygous MTHFR C677T it may serve as an alternative to classical folic acid.

Is Levomefolate (L-methylfolate, 5-MTHF) compatible with breastfeeding?

Compatible (Hale L1). Levomefolate passes into milk at physiological folate concentrations. Daily intake during lactation 0.5 mg.

Who should not take Levomefolate (L-methylfolate, 5-MTHF)?

Levomefolate (L-methylfolate, 5-MTHF) is contraindicated in: Hypersensitivity to levomefolate; Undiagnosed vitamin B12 deficiency (risk of masking anaemia and neurological progression); Folate-dependent malignancies (without oncologist agreement). Full list in the Safety section.

Other drugs in this group

Cyanocobalamin, Folic acid, Hydroxocobalamin, Iron oral (salts: sulfate, bisglycinate, fumarate, gluconate, polymaltose; heme iron polypeptide, lactoferrin), Methylcobalamin, Vitamin B12 (cobalamin)