L-Methylfolate | Supplementopedia

Overview

L‑Methylfolate (5‑methyltetrahydrofolate, 5‑MTHF) is the biologically active, methyl‑donating form of folate that circulates in human plasma. It bypasses the genetic polymorphism of the enzyme methylenetetrahydrofolate reductase (MTHFR) and directly participates in one‑carbon metabolism, supporting DNA synthesis, neurotransmitter production, and methyl-group transfer reactions throughout the body.

Benefits

Mood & Cognitive Function: Clinical trials show adjunctive L‑methylfolate (7–15 mg/day) improves depressive symptoms, especially in patients with MTHFR variants or treatment‑resistant depression (Roffman 2021).
Neuro‑development: Adequate 5‑MTHF supports fetal neural tube closure; supplementation reduces risk of spina bifida by ~70 % when taken periconceptionally.
Cardiovascular Health: By lowering plasma homocysteine, L‑methylfolate reduces endothelial dysfunction and may modestly lower myocardial infarction risk (Bazzano 2020).
Pregnancy & Fetal Growth: Supports rapid cell division and placental angiogenesis, supporting appropriate birth weight.
Metabolic Support: Improves insulin sensitivity in some obese subjects via enhanced methylation of genes regulating glucose metabolism (Kang 2022).

How It Works

Process: L‑Methylfolate is the final product of the folate cycle, delivering a methyl group to homocysteine via the enzyme methionine synthase, converting it to methionine.
Pathway: Methionine then forms S‑adenosyl‑methionine (SAMe), the universal methyl donor. SAMe methylates DNA, phospholipids, and neurotransmitters (e.g., dopamine, serotonin, norepinephrine), influencing gene expression and neurotransmission.
DNA Replication & Repair: In the methylation cycle, L‑methylfolate also regenerates tetrahydrofolate (THF) for thymidine and purine synthesis, crucial for DNA replication and repair.
Neuro-psychiatric and Cardiovascular Effects: By sustaining SAMe levels, L‑methylfolate supports methyl‑dependent epigenetic regulation, mitochondrial function, and redox balance, which together underlie its neuro-psychiatric and cardiovascular effects.

Dosage

General adult supplementation: 400–800 µg (as L‑methylfolate) daily for nutritional support.
Adjunct for depression/psychiatric use: 7–15 mg/day, divided into 2–3 doses, often taken with a meal to improve absorption.
Pregnancy/folate‑deficiency prevention: 400–800 µg/day, commencing at least 4 weeks pre‑conception and continuing through the first trimester.
High‑homocysteine or MTHFR‑related therapy: 5–15 mg/day under medical supervision.
Timing: Consistent daily intake is recommended.
Dose Escalation: Should be gradual, especially when combined with other B‑vitamins (B6, B12) to avoid competitive absorption.

Safety & Side Effects

General Tolerance: L‑Methylfolate is generally well‑tolerated.
Adverse Effects: Reported adverse effects are mild and include gastrointestinal upset (nausea, abdominal discomfort) and rare headache.
Contraindications: Contraindicated in patients with known hypersensitivity to folate derivatives.
Vitamin B12 Deficiency: High doses (>15 mg/day) may mask vitamin B12 deficiency, leading to neurologic sequelae if B12 status is not monitored.
Drug Interactions: Potentiates antiepileptic drugs (e.g., phenytoin) and may reduce efficacy of methotrexate or antimetabolite chemotherapy.
Pregnancy: Pregnant women should not exceed 1 mg/day without physician guidance.
Medical Consultation: Patients with renal impairment or active cancer should consult a clinician before high‑dose use.

Chemistry

L‑Methylfolate is the L‑isomer of 5‑methyltetrahydrofolic acid, a tetrahydropteridine derivative.
IUPAC name: (6S)-5‑Methyltetrahydrofolic acid (L‑form).
Molecular formula: C₂₀H₂₃N₇O₆.
Molar mass: 459.44 g·mol⁻¹.
Key structural features: a pteridine ring fused to a para‑aminobenzoic acid (PABA) moiety, a reduced pteridine ring (tetrahydro), and a methyl group at the 5‑position of the pteridine ring.
Solubility and Stability: The molecule is water‑soluble, with a pKa ≈ 6.3 (acidic) and a log P ≈ -0.8, indicating high hydrophilicity. Its stability is limited; it is prone to oxidation, thus formulations often include antioxidants (e.g., ascorbic acid) and are packaged in opaque, airtight containers.

Sources & Quality

Production: L‑Methylfolate is produced primarily by microbial fermentation (e.g., Corynebacterium or Lactobacillus spp.) followed by purification, or by chemical synthesis from folic acid via enzymatic methylation using S‑adenosyl‑methionine as a methyl donor.
Natural Sources: Natural dietary sources (leafy greens, legumes) contain folate, which is converted to L‑methylfolate in the gut and liver, but the amount is variable and influenced by MTHFR genotype.
Supplement Quality: High‑quality supplements are typically produced under GMP (Good Manufacturing Practice) conditions, with verification of >95 % purity by HPLC and absence of heavy metals.
Product Considerations: Look for products that provide a certificate of analysis, stability data, and, when applicable, certification of vegan or allergen‑free status.