5-MTHF: Methylfolate and How It Differs from Folic Acid

Folate is the point at which nutrition nomenclature becomes genuinely confusing, and the confusion is not accidental. Three different words are in circulation for three related but distinct things.

Getting them straight is most of the value of this page.

Folate, folic acid and 5-MTHF

Folate is the umbrella term for the whole family of B9 compounds, including the naturally occurring forms found in food

Folic acid is a synthetic, fully oxidised form. It does not occur in nature. It is used in supplements and in food fortification because it is stable and cheap

5-MTHF, L-5-methyltetrahydrofolate, is the predominant circulating form of folate in human blood, and the form that crosses into tissues

The relationship between them is a conversion sequence. Folic acid is not biologically active as ingested. It has to be reduced to dihydrofolate, then to tetrahydrofolate, then methylated, with the enzyme dihydrofolate reductase handling the early steps and methylenetetrahydrofolate reductase, MTHFR, handling the last.

5-MTHF is what sits at the end of that sequence. Supplying it directly means the conversion steps are not required.

What folate does

Folate's central role is one-carbon metabolism, the set of reactions that move single-carbon units around the cell. Two outputs matter most.

The first is nucleotide synthesis. Folate is required to make the purines and thymidylate used to build DNA, which is why folate demand rises wherever cells are dividing rapidly.

The second is the methylation cycle. Folate donates a methyl group in the conversion of homocysteine to methionine, a reaction that also requires vitamin B12. This is why folate, B12 and B6 are discussed together in the homocysteine literature, and why a folate product often appears alongside them.

The comparative research

The question of whether 5-MTHF offers anything over folic acid has been studied directly, and the findings are more nuanced than either camp's marketing suggests.

Pietrzik and colleagues reviewed the comparative pharmacokinetics and reported that 5-MTHF is at least as effective as folic acid at raising folate status, with a different absorption profile. Prinz-Langenohl and colleagues compared the two in women, including those carrying the common C677T variant, and found 5-MTHF effective at increasing plasma folate. Scaglione and Panzavolta published a widely cited review setting out why the three terms are not interchangeable.

There is a separate strand of research concerning unmetabolised folic acid in circulation, which appears when intake exceeds the capacity of dihydrofolate reductase. The clinical significance of this is an active area of discussion rather than a settled finding, and it should be reported that way rather than as a reason to avoid folic acid.

Delivery

This is a liquid liposomal formulation using Lipoid phospholipids, with 5-MTHF held in a phospholipid structure. The formulation also contains mixed tocopherols and citric acid, which is relevant because 5-MTHF is oxidation sensitive, and stability is a genuine formulation consideration for this molecule rather than an afterthought.

Ingredient Health Facts

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.

Dose and practical considerations

One millilitre provides 500 micrograms of folate as 5-MTHF, which is 250 percent of the Nutrient Reference Value.

The B12 point, which matters. High folate intake can mask the haematological signs of vitamin B12 deficiency while allowing the neurological consequences to progress undetected. This is the single most important safety consideration with any folate supplement and should appear on the PDP as well as here. Anyone supplementing folate at this level should ensure their B12 status is adequate, and anyone concerned should speak to their GP.

Anyone pregnant or planning a pregnancy should follow NHS guidance on folic acid and discuss supplementation with their midwife or GP rather than self-selecting a product.

Folate can interact with certain medications, including methotrexate and some anticonvulsants. Check with a pharmacist or GP.

Common questions

What is the difference between folate, folic acid and 5-MTHF? Folate is the umbrella term. Folic acid is a synthetic oxidised form requiring enzymatic conversion. 5-MTHF is the predominant circulating form in human blood.

Is methylfolate better than folic acid? Comparative studies have found 5-MTHF at least as effective at raising folate status. Folic acid has by far the larger evidence base, particularly in pregnancy, which is why public health guidance still specifies it.

What is MTHFR? An enzyme in the folate pathway. Common gene variants reduce its activity. This is a real genetic finding that is widely over-interpreted in supplement marketing.

Does folate need B12? The two work together in the homocysteine to methionine conversion. High folate intake can also mask signs of B12 deficiency, which is why B12 status matters when supplementing folate.

Should I take this if I am pregnant? Follow NHS guidance and speak to your midwife or GP. Do not self-select a folate product during pregnancy.

References

1. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014;44(5):480-488. doi:10.3109/00498254.2013.845705
2. Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clinical Pharmacokinetics. 2010;49(8):535-548.
3. Prinz-Langenohl R, Brämswig S, Tobolski O, et al. [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C→T polymorphism of MTHFR. British Journal of Pharmacology. 2009;158(8):2014-2021.
4. Bailey SW, Ayling JE. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. PNAS. 2009;106(36):15424-15429.
5. Obeid R, Holzgreve W, Pietrzik K. Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects? Journal of Perinatal Medicine. 2013;41(5):469-483.
6. Scientific Advisory Committee on Nutrition. Update on folic acid. UK Government, 2017.
7. NHS. Vitamins, supplements and nutrition in pregnancy. nhs.uk.
8. Great Britain Nutrition and Health Claims Register. Department of Health and Social Care, gov.uk.

Food supplements are not a substitute for a varied and balanced diet and a healthy lifestyle.