Quatrefolic® L-5-MTHF (Glucosamine salt of (6S)-5-methyltetrahydrofolate)
Quatrefolic® is a specific branded form of (6S)-5-methyltetrahydrofolate (L-5-MTHF) — the active, naturally-occurring form of vitamin B9 (folate) — manufactured by Gnosis by Lesaffre (Italy) as the glucosamine salt. It is one of two main research-grade L-5-MTHF preparations cited in EU/UK regulatory submissions (the other is Metafolin® by Merck KGaA). Folate (the molecule) carries multiple authorised UK food-supplement health claims at ≥30 µg per serving (≥15% NRV); the claims attach to the molecule, not specifically to Quatrefolic®. The branded form matters commercially because of documented stability, water solubility, and regulatory chain-of-custody — a generic "5-MTHF" or "methylfolate" label that names neither salt nor the (6S) enantiomer is less informative.
Camden Medicals editorial · Last reviewed 10 May 2026 · Next review May 2027
- Cross-checked against
- NHS
- NICE
- BNF
- EFSA
- FSA
Camden's editorial team independently graded each health claim below on the strength of the published evidence — see the grade beside every condition.
- Class
- Vitamin
- Typical daily dose
- UK retail Quatrefolic® products supply 200–1,000 µg per serving. Camden NB-548 supplies 600 µg per capsule (300% NRV), which sits comfortably within the upper intake and supports the full authorised-claim space.
- Top use evidence
- Strong
On this page
What it is
Quatrefolic® (a registered trademark of Gnosis S.p.A., manufactured by Gnosis by Lesaffre, Italy) is the glucosamine salt of (6S)-5- methyltetrahydrofolate — abbreviated L-5-MTHF. It is the active, naturally-occurring form of vitamin B9 (folate) that the body actually uses for DNA synthesis, methylation, and one-carbon metabolism. Unlike folic acid (the synthetic, fully-oxidised monoglutamate added to fortified flour and most cheap supplements), L-5-MTHF does not require enzymatic conversion before it can do its work — it skips the MTHFR (methylenetetrahydrofolate reductase) step entirely.
The MTHFR step matters because ~30–40% of UK adults carry at least one copy of an MTHFR C677T or A1298C gene variant that reduces enzyme activity — homozygotes for C677T have ~70% reduced function, heterozygotes ~30–40% reduced. Reduced MTHFR activity means folic acid (which requires conversion) is converted to L-5-MTHF less efficiently, and plasma homocysteine tends to run higher. Direct L-5-MTHF supplementation bypasses this constraint.
Quatrefolic® specifically delivers L-5-MTHF as the glucosamine salt — the (6S)-5-MTHF molecule paired with glucosamine to improve stability and water solubility relative to the free methylfolate. The natural (6S) enantiomer is the one the body actively uses; older (6R,S)-racemic 5-MTHF preparations contained 50% of the inactive (6R) form and are largely deprecated.
Quatrefolic®'s commercial-supplement role rests on three layers. First, it is patent-protected manufacturing (Gnosis SpA hold the patents on the glucosamine-salt synthesis). Second, it is cited in EU/UK food-supplement regulatory submissions and carries documented chain-of-custody (suppliers carry licence chains from Gnosis through distributors to finished-product manufacturers). Third, the branded-form trial portfolio — while smaller than for some other branded ingredients — substantiates the safety and bioequivalence of L-5-MTHF as delivered by Quatrefolic® specifically.
Naming "Quatrefolic®" on a UK food-supplement label requires a documented licence chain from Gnosis SpA, typically routed through the supplier. Naming without the chain is a TM infringement risk under TMA 1994 s.10. A back-panel TRADEMARK NOTICE wording — typically "Quatrefolic® is a registered trademark of Gnosis S.p.A. and is used under licence." — is conventional and is the format Camden Medicals uses on its NB-548 label artwork.
At a glance
- A specific patented branded form of L-5-MTHF (active vitamin B9 / folate) — Quatrefolic® is a registered trademark of Gnosis S.p.A., manufactured by Gnosis by Lesaffre.
- Glucosamine salt of (6S)-5-methyltetrahydrofolate — the natural enantiomer the body actually uses (folic acid is the synthetic form that requires MTHFR enzyme conversion; ~30–40% of UK population have a reduced-function MTHFR variant).
- Folate (the molecule) carries authorised UK food-supplement health claims at ≥30 µg per serving — contributes to maternal tissue growth in pregnancy, to normal blood formation, to normal homocysteine metabolism, to the reduction of tiredness and fatigue, to normal psychological function, and to normal immune function.
- Pregnancy is a GO indication for folate at authorised intake, not an avoid one. UK Department of Health / NHS recommends 400 µg/day periconceptionally for low-risk pregnancies and 5 mg/day on prescription for higher-risk pregnancies.
- Naming "Quatrefolic®" on a UK label requires a documented licence chain from Gnosis SpA — naming without the chain is a TM infringement risk.
- Quatrefolic® and Metafolin® (Merck KGaA, calcium salt) are the two main research-grade L-5-MTHF salts. Both deliver the same active; Quatrefolic® has better documented stability and water solubility, Metafolin® has the longer regulatory track record.
What people use it for
Adults supplementing folate — particularly those with known or suspected MTHFR variants
Quatrefolic® delivers L-5-MTHF directly, bypassing the MTHFR conversion step that ~30–40% of UK adults perform sub-optimally. Folate at ≥30 µg per serving carries authorised UK health claims for normal blood formation, normal homocysteine metabolism, reduction of tiredness and fatigue, and normal psychological function. Camden NB-548 supplies 600 µg per capsule (300% NRV) so the full authorised-claim space applies. [4,5]
StrongWomen planning pregnancy or in early pregnancy
UK Department of Health / NHS recommends 400 µg/day periconceptional folate (start ideally before conception, continue through the first 12 weeks) to reduce the risk of neural-tube defects. Higher-risk pregnancies (previous NTD, diabetes, antiepileptic medication, BMI ≥30, sickle-cell disease, thalassaemia) are prescribed 5 mg/day. Quatrefolic®-delivered L-5-MTHF is one route to meeting the periconceptional intake. Folate carries the EFSA-authorised "contributes to maternal tissue growth in pregnancy" claim. [2,1]
StrongAdults whose diet is low in folate-rich foods
Folate is naturally found in dark-green vegetables, pulses, liver, citrus, and fortified breakfast cereals; the UK has also legislated mandatory folic acid fortification of non-wholemeal wheat flour, being introduced under the Bread and Flour Regulations. Diets low in folate-rich foods may not meet the 200 µg/day reference intake. Quatrefolic®-delivered L-5-MTHF supplementation is one route to meeting the intake — particularly relevant for adults with reduced-function MTHFR variants who convert dietary folic acid less efficiently. [6]
Some evidenceStrongAdults considering Quatrefolic® vs Metafolin® vs generic 5-MTHF
Quatrefolic® (glucosamine salt) and Metafolin® (calcium salt) are the two research-grade (6S)-5-MTHF preparations cited in UK/EU regulatory submissions. Both deliver the same active L-5-MTHF molecule. Quatrefolic® has documented better water solubility and stability under manufacturing conditions; Metafolin® has the longer regulatory track record. A generic "5-MTHF" or "L-methylfolate" label that names neither salt nor the (6S) enantiomer is less informative — it may be racemic (6R,S), older, less stable.
Some evidenceLimited
How it works
L-5-MTHF (delivered by Quatrefolic®) is the one-carbon methyl-group donor in the methylation cycle. It donates its methyl to homocysteine via methionine synthase to form methionine, which is then converted to S-adenosyl-methionine (SAMe) — the body's universal methyl donor used in DNA methylation, neurotransmitter synthesis, phospholipid metabolism, and gene-regulatory methylation. The folate cycle intersects with the methylation cycle at this transmethylation step. Adequate L-5-MTHF supports DNA synthesis (purines and thymidine) and keeps plasma homocysteine within the reference range. Inadequate folate manifests as megaloblastic anaemia (DNA synthesis defect) and elevated homocysteine (vascular risk-marker rise). The neural-tube-defect protection from periconceptional folate intake reflects the DNA-synthesis demand during early embryonic neurulation.
Common myths
Myth"All methylfolate is the same — Quatrefolic® is just marketing"
RealityThe L-5-MTHF molecule is the same; the manufacturing flow, salt form, enantiomer purity, and licence-chain documentation differ. Quatrefolic® delivers the (6S) enantiomer as the glucosamine salt with documented stability, water solubility, and supply-chain custody. A generic "5-MTHF" label that names neither salt nor the (6S) form may be racemic, less stable, and lack supplier-licence-chain backing.
Myth"Folic acid is bad — only methylfolate is safe"
RealityFolic acid is the form added to fortified flour, NHS- recommended periconceptional supplements, and most cheap folate products. It is well-established as effective and safe for the general population. Adults with reduced-function MTHFR variants convert it less efficiently and may benefit from L-5-MTHF as an alternative; this does not make folic acid unsafe for the population as a whole. [1]
Myth"Quatrefolic® cures depression / fertility / homocysteine"
RealityUK food-supplement claim wording for treating depression, fertility, or cardiovascular disease is not authorised on folate. Folate (the molecule) carries authorised claims for normal blood formation, normal homocysteine metabolism, and normal psychological function — those are functional / physiological claims at authorised intakes, not treatment claims. UK NHS / NICE pathways apply for diagnosed conditions.
Myth"You should take 5–10 mg of Quatrefolic® daily for "best results""
RealityEFSA Tolerable Upper Intake Level for folic acid (synthetic; food folate has no UL) is 1,000 µg/day (1 mg/day) in adults. UK retail Quatrefolic® products typically supply 200–1,000 µg/serving. 5 mg/day is a prescription-medicine dose for higher-risk pregnancies and is not appropriate as a self-initiated retail supplement intake. Higher dose ≠ better outcome; the trial endpoints cluster within the 200–1,000 µg/day range. [7]
Myth"Quatrefolic® masks B12 deficiency therefore avoid"
RealityHigh-dose folate of any form (folic acid OR L-5-MTHF) can mask the haematological signs of B12 deficiency. The practical mitigation is to check B12 status before initiating high-dose folate, and to take folate in combination with B12 rather than alone in adults at risk. The pairing is conventional in many high-quality products. Avoiding folate is not the appropriate response — checking B12 status is. [3]
Common online questions
Synthesised from the questions UK shoppers most often ask online about Quatrefolic® L-5-MTHF (Glucosamine salt of (6S)-5-methyltetrahydrofolate). Each answer is editorial and links to its evidence in the Sources list below.
Why is Quatrefolic® more expensive than folic acid?
Three layers of cost. First, Quatrefolic® is patent-protected manufacturing under Gnosis SpA — the (6S) enantiomer synthesis is harder than producing racemic (6R,S) folate or synthetic folic acid. Second, the glucosamine salt formulation adds stability and solubility but adds manufacturing cost. Third, branded-form licence-chain documentation flows through the supply chain. Folic acid by contrast is a 70-year-old commodity. The cost difference reflects the active form and manufacturing pattern, not a marketing premium.
Quatrefolic® vs Metafolin® — which is "better"?
Both are research-grade (6S)-5-MTHF preparations cited in EU/UK regulatory submissions. Quatrefolic® is the glucosamine salt (Gnosis SpA, Italy); Metafolin® is the calcium salt (Merck KGaA, Germany). Both deliver the same active L-5-MTHF molecule. Quatrefolic® has documented better water solubility and manufacturing stability; Metafolin® has the longer regulatory track record. For a finished consumer product, both are acceptable choices — the choice is supplier and manufacturing-flow level, not biological-effect level. A label that names neither salt is less informative.
Is the glucosamine salt suitable for shellfish allergy?
Glucosamine in pharmaceutical / food-supplement use is manufactured from various sources — including some shellfish- derived glucosamine and some plant-fermentation-derived glucosamine. Quatrefolic®'s glucosamine source is plant- fermentation-derived (corn or wheat substrate, fermented). It is therefore vegan-suitable and shellfish-allergy-suitable as supplied. Camden lists NB-548 (Methyl Folate Quatrefolic®) as vegan-suitable on this basis.
Should I take Quatrefolic® if I am pregnant or trying to conceive?
Folate supplementation periconceptionally is UK NHS / Department of Health standard advice — 400 µg/day from before conception through the first 12 weeks of pregnancy for low-risk pregnancies, and 5 mg/day on prescription for higher-risk pregnancies (previous NTD, diabetes, antiepileptic medication, BMI ≥30, sickle-cell disease, thalassaemia). Quatrefolic®-delivered L-5-MTHF is one route to meeting the periconceptional intake. Folic acid (synthetic, requires MTHFR conversion) is the traditional route and is what most NHS-recommended periconceptional supplements supply. Either route is acceptable; for adults with known MTHFR variants the L-5-MTHF route is preferred. Discuss with your GP or midwife if you are at higher risk. [2]
How much Quatrefolic® per day is appropriate?
Folate UK reference intake for adults is 200 µg/day; the pregnancy reference is 300 µg/day and the lactation reference is 260 µg/day (UK COMA Dietary Reference Values); the periconceptional recommendation (NHS) is 400 µg/day. UK retail Quatrefolic® products typically supply 200–1,000 µg per serving. EFSA Tolerable Upper Intake Level for folic acid (the synthetic form; food folate has no UL) is 1,000 µg/day in adults. Camden NB-548 supplies 600 µg per capsule (300% NRV); the dose is well within the upper intake and supports the full authorised-claim space at ≥30 µg per serving. [7]
Should I take Quatrefolic® if I have a B12 deficiency?
Talk to your GP first. High-dose folate (especially synthetic folic acid) can mask the haematological signs of B12 deficiency (megaloblastic anaemia) without correcting the underlying B12-deficient neuropathy. NHS guidance is to investigate and correct B12 status before initiating high-dose folate supplementation in adults with anaemia of unclear cause. The L-5-MTHF route does not entirely sidestep this issue — L-5-MTHF still feeds the methylation cycle and can mask B12- deficient anaemia. The conservative path is B12 status check first. [3]
⚖️ The official position
What may lawfully be claimed about Quatrefolic® L-5-MTHF (Glucosamine salt of (6S)-5-methyltetrahydrofolate) in Great Britain. This is a regulatory position, not an evidence grade.
A health claim is authorised in Great Britain.
“Folate contributes to maternal tissue growth during pregnancy”
“Folate contributes to normal amino acid synthesis”
“Folate contributes to normal blood formation”
“Folate contributes to normal homocysteine metabolism”
“Folate contributes to normal psychological function”
“Folate contributes to the normal function of the immune system”
“Folate contributes to the reduction of tiredness and fatigue”
“Folate has a role in the process of cell division”
This claim is authorised for use in Great Britain under the GB Nutrition and Health Claims regulation. A product may carry it when it provides at least 15% of the UK NRV per recommended daily portion.
Authorised UK health claims
Verbatim from the GB Nutrition and Health Claims Register (Reg 432/2012 as assimilated in GB). A product can carry these claims when it provides at least 15% of the UK NRV per recommended daily portion.
8 authorised claims — show / hide
- "Folate contributes to maternal tissue growth during pregnancy"
- "Folate contributes to normal amino acid synthesis"
- "Folate contributes to normal blood formation"
- "Folate contributes to normal homocysteine metabolism"
- "Folate contributes to normal psychological function"
- "Folate contributes to the normal function of the immune system"
- "Folate contributes to the reduction of tiredness and fatigue"
- "Folate has a role in the process of cell division"
🔬 Camden’s evidence review
The research Camden reviewed, graded on its strength. This is our own appraisal — it sits beneath the official guidance above, never above it.
Folate-status restoration in adults with MTHFR variants
ModerateEvidencemoderateQuatrefolic®-delivered L-5-MTHF supplementation reliably restores plasma folate to reference range and reduces plasma homocysteine in adults with reduced-function MTHFR variants, across multiple short and medium-term trials. The folate-status endpoint is well-established; effect on clinical outcomes (vascular events, mental health) requires the same caution as other vitamin-status-restoration trials. [5]
Periconceptional neural-tube-defect prevention
StrongEvidencestrongUK Department of Health / NHS guidance recommends 400 µg/day periconceptional folate from before conception through the first 12 weeks of pregnancy to reduce risk of neural-tube defects. Higher-risk pregnancies (5 mg/day prescription). Folate (the molecule, not Quatrefolic® specifically) carries the EFSA-authorised "contributes to maternal tissue growth in pregnancy" claim. Quatrefolic® is one route to meeting the intake; folic acid (synthetic) and dietary folate-rich foods are the other principal routes. [8,2]
Plasma homocysteine reduction
ModerateEvidencemoderateFolate at authorised intake (≥30 µg/serving) reliably lowers plasma homocysteine in adults with elevated baseline. The EFSA-authorised claim "contributes to normal homocysteine metabolism" is settled. Effect on clinical cardiovascular outcomes from homocysteine-lowering alone is mixed in the large outcome trials; the folate-status effect is robust, the cardiovascular-event effect less so. [5]
Mood / depression / anxiety as adjunct to standard care
LimitedEvidencelimitedFolate (as L-5-MTHF or as folic acid) has been studied as adjunct in depression management, particularly in patients with low folate status or MTHFR variants. The evidence is mixed; UK NICE pathway for depression management (CBT, SSRIs, talking therapies) is the primary route. UK food-supplement claim wording for mood / depression / anxiety is not authorised on folate; the regulatory anchor for psychological function is the EFSA "contributes to normal psychological function" claim, not a treatment claim. [9]
Safety in healthy adults
ModerateEvidencemoderateL-5-MTHF (including Quatrefolic®) at typical supplement intakes (200–1,000 µg/day) is well-tolerated. EFSA Tolerable Upper Intake Level for folic acid is 1,000 µg/day in adults; the same upper level applies in practice to L-5-MTHF. The L-5-MTHF route is preferred to high-dose folic acid for adults with MTHFR variants because it avoids unmetabolised folic acid in plasma. [7]
Safety
Quatrefolic® L-5-MTHF is well-tolerated at standard supplement doses (200–1,000 µg/day). EFSA Tolerable Upper Intake Level for folic acid (the synthetic form; food folate has no UL) is 1,000 µg/day in adults. Folate carries multiple authorised UK food-supplement health claims at ≥30 µg per serving (≥15% NRV). Pregnancy is a GO indication at NHS-recommended periconceptional intake. B12 status should be checked before high-dose folate initiation in adults at risk of B12 deficiency.
Talk to your pharmacist or GP first if you:
- You are at risk of vitamin B12 deficiency (vegan / vegetarian diet, age 65+, post-gastrectomy, on metformin or PPIs, pernicious anaemia history) — high-dose folate can mask B12-deficient anaemia.
- You are taking methotrexate, sulfasalazine, antiepileptic medication (phenytoin, carbamazepine, valproate), or trimethoprim — folate-antagonist interactions reported.
- You have a higher-risk pregnancy (previous neural-tube-defect, diabetes, BMI ≥30, sickle-cell, antiepileptic medication) — 5 mg/day prescription folate may be appropriate, on GP guidance.
- You have any diagnosed haematological condition or unexplained anaemia.
Common side effects: Generally well-tolerated. Mild GI discomfort uncommonly reported. High-dose folate can mask B12-deficient anaemia.
Pregnancy and breastfeeding
GO indication at NHS-recommended periconceptional intake (400 µg/day low-risk; 5 mg/day prescription higher-risk). Quatrefolic®-delivered L-5-MTHF is one route to meeting the intake. Folate carries the EFSA-authorised "contributes to maternal tissue growth in pregnancy" claim.
Folate reference intake in lactation is 260 µg/day (UK COMA DRV: 200 µg adult RNI + 60 µg lactation increment). Quatrefolic®-delivered L-5-MTHF at standard supplement intake is appropriate.
Talk to your GP, midwife, or pharmacist before starting any supplement during pregnancy or breastfeeding.
More clinical detail (for clinicians and informed readers)
Contraindications
- Pernicious anaemia or undiagnosed B12 deficiency — high-dose folate masks the haematological signs.
- Active malignancy on antimetabolite (methotrexate, 5-FU) chemotherapy — defer to oncology team.
Drug interactions
- Methotrexate — folate antagonist; folate supplementation can interfere with methotrexate efficacy in oncology dosing (low-dose methotrexate for autoimmune disease is usually paired with folic acid; defer to prescriber).
- Sulfasalazine — reduces folate absorption; supplementation may be appropriate but discuss with prescriber.
- Antiepileptic medication (phenytoin, carbamazepine, valproate, primidone) — these reduce folate status and folate may reduce antiepileptic plasma levels; manage on prescriber guidance.
- Trimethoprim — dihydrofolate reductase inhibitor; in long-term use, folate supplementation may be appropriate.
- Some chemotherapy agents — defer to oncology team.
This is not an exhaustive list. Always tell your prescriber and pharmacist about every supplement you take.
Rare side effects
- Mild GI complaints — uncommon at standard doses.
- Allergic reaction (rare).
- Sleep disturbance / vivid dreams — anecdotal at high doses (>1,000 µg/day).
How to take it
- Typical supplemental range
- UK retail Quatrefolic® products supply 200–1,000 µg per serving. Camden NB-548 supplies 600 µg per capsule (300% NRV), which sits comfortably within the upper intake and supports the full authorised-claim space.
- Timing
- Daily, with food. L-5-MTHF (Quatrefolic® delivered) is stable through normal GI passage. Folate-status restoration takes 4–8 weeks; periconceptional intake is timed from before conception through the first 12 weeks of pregnancy.
How to spot quality
Look for
- Quatrefolic® brand name with ® mark on the label or product description.
- Salt form declared (glucosamine salt of (6S)-5-MTHF).
- Dose ≥30 µg per serving (≥15% NRV) to invoke the authorised-claim space; ≥400 µg/day for periconceptional intake.
- Manufacturer named (Gnosis by Lesaffre / Gnosis SpA).
- Licence chain on supplier file (TM-licensed naming requires it).
- TRADEMARK NOTICE on back-panel: "Quatrefolic® is a registered trademark of Gnosis S.p.A. and is used under licence."
- CoA per batch (declared on request).
- Heavy-metal screening disclosed.
- B12 / folate-pairing where high-dose folate is used (mitigates B12-deficiency masking risk).
- No depression / fertility / cardiovascular treatment-claim wording — folate carries functional claims, not treatment claims.
Red flags
- No Quatrefolic® brand mark — generic "L-methylfolate" or "5-MTHF" with implied trial-portfolio framing is misleading.
- Quatrefolic® named on label without supplier licence chain — TM infringement risk.
- No salt form declared — likely racemic (6R,S) older-format product.
- Dose >1,000 µg/day on retail label — exceeds EFSA Tolerable Upper Intake Level.
- Treatment claims for depression / fertility / cardiovascular disease.
- No B12 pairing in a high-dose folate product (masks B12-deficiency risk).
- Implication that Quatrefolic® is medically superior to folic acid for the general population (true only for reduced-function MTHFR variants; population-level folic acid remains effective and safe).
Where Camden lands · meets the bar
Camden Medicals carries one Quatrefolic®-bearing SKU — NB-548 (Methyl Folate Quatrefolic® 600 µg 90 Capsules), Wave-1 ready, draft pending Gnosis SpA licence-chain confirmation. Sits in the Camden Aurifera tier per the 2026-05-10 -fera tier rule (named licensed clinical-grade active on label). NB-548 back-panel artwork is fully prepared with Quatrefolic® logo composite, TRADEMARK NOTICE block, ® on every reference, and GS1 barcode. Production print is gated on `compliance.quatrefolic_licence: pending` in the SKU YAML — flips to `signed` when the supplier confirms the upstream Gnosis chain in writing. Once shipped, NB-548 supplies 600 µg/capsule (300% NRV) — well within EFSA Tolerable Upper Intake (1,000 µg/day) and supports the full authorised-claim space (≥30 µg invokes the molecule's authorised claims). PDP and on-pack carry the B12-pairing recommendation and the high-dose folate B12-masking caveat.
Commonly combined with
Other ingredients that share a biological pathway, cofactor relationship, or evidence-backed protocol with this one. Mechanisms below cite primary physiology — not folk pairing. Doses are literature ranges, not recommendations. Talk to your pharmacist or GP before changing your stack, especially if you take prescription medication.
Vitamin B12
Strong evidenceFolate + B12 is the canonical methylation-cycle pairing — high-dose folate without adequate B12 status masks B12-deficient anaemia.
L-5-MTHF (delivered by Quatrefolic®) donates its methyl group to homocysteine via methionine synthase to form methionine. Methionine synthase requires B12 (methylcobalamin) as cofactor. Without adequate B12, the methylation cycle stalls — folate accumulates as L-5-MTHF and the methyl-trap forms. High-dose folate then fixes the haematological appearance of anaemia (DNA-synthesis demand is satisfied) but does not correct the underlying B12-deficient neuropathy. The pairing is regulatory best-practice and clinical-safety standard.
Evidence: Methylation-cycle biochemistry is well-established. NHS guidance recommends B12 status check before initiating high- dose folate in adults at risk of B12 deficiency. [3]
Doses studied: Quatrefolic® 400–600 µg + B12 (methylcobalamin or cyanocobalamin) at ≥1 µg per serving (any folate-containing supplement above the periconceptional intake should pair with B12).
Vitamin B6
Strong evidenceB6 + folate + B12 is the classic homocysteine-pathway trio — all three are required cofactors in transmethylation / transsulphuration.
The homocysteine clearance pathways are folate-dependent (methionine synthase, B12 cofactor, regenerates methionine) and B6-dependent (cystathionine β-synthase, transsulphuration to cystathionine and ultimately glutathione). Adequate intake of all three optimises homocysteine clearance. The trio is the regulatory anchor for the EFSA "contributes to normal homocysteine metabolism" claim space — each carries the claim separately at appropriate intake.
Evidence: Methylation / transsulphuration biochemistry is well-established. The trio appears in many high-quality multi-active SKUs as the homocysteine-pathway anchor. [5]
Doses studied: Quatrefolic® 400–600 µg + B12 ≥1 µg + B6 ≥1.4 mg per serving.
Trimethylglycine (TMG / Betaine anhydrous)
Limited evidenceTMG is an alternative methyl-group donor — supports the methylation cycle when folate / B12 status is suboptimal.
TMG (trimethylglycine, betaine) provides a methyl group to homocysteine via betaine-homocysteine methyltransferase (BHMT) to form methionine. This is a parallel pathway to the folate / B12 / methionine-synthase route. In adults with suboptimal folate or B12 status, TMG can serve as a methyl-pool buffer. The combination of L-5-MTHF + TMG is conventional in methylation-support stacks.
Evidence: Mechanism is well-described. The TMG-folate combination outcome trials are sparse; the pairing is mechanistic.
Doses studied: Quatrefolic® 400–600 µg + TMG 500–1,000 mg daily.
Choline
Limited evidenceCholine + folate + B12 + B6 is the wider methylation-and-phospholipid stack — choline is precursor to phosphatidylcholine and to TMG.
Choline is a precursor to phosphatidylcholine (cell membrane phospholipid) and to betaine (TMG) via choline oxidation. The choline-folate axis is the second major methyl-donor system in mammalian biology; adequate choline supports methylation when folate is suboptimal. The pairing is conventional in pregnancy-support stacks (folate + choline) where both are EFSA-authorised for maternal-tissue / liver-function claims.
Evidence: Mechanism is well-described. EFSA-authorised claim for choline contributing to normal lipid metabolism / normal liver function / normal homocysteine metabolism is settled.
Doses studied: Quatrefolic® 400–600 µg + choline 250–550 mg daily (typical intake; EFSA AI 400 mg → 480 mg in pregnancy).