Where does MTHFR fit?
If you look back at the folate pathway above, MTHFR occupies just one step within a much larger network.
MTHFR, or methylenetetrahydrofolate reductase, is the enzyme involved in converting 5,10-methylene-THF into 5-MTHF. This matters because 5-MTHF provides the folate-derived methyl group used when homocysteine is converted back into methionine, connecting the folate cycle with the methionine cycle and the production of S-adenosylmethionine (SAM), an important methyl donor within the body (Lyon et al., 2020).
The gene that provides the instructions for making this enzyme can vary slightly between people. These variations are known as single nucleotide polymorphisms, or SNPs: differences at a single position within our DNA. Two of the most frequently discussed MTHFR variants are C677T and A1298C.
Because we inherit one copy of the MTHFR gene from each parent, a person may carry one copy of a variant (heterozygous), two copies of the same variant (homozygous), or variants at both locations (compound heterozygous). These different combinations can influence MTHFR enzyme activity to varying degrees (Ledowsky et al., 2023; Lyon et al., 2020).
This does not mean that folate metabolism simply stops. MTHFR is one enzyme within an interconnected pathway involving different folate forms, enzymes and nutrient cofactors. Current Australian Pregnancy Care Guidelines state that women with an MTHFR variant can process all forms of folate, including folic acid, and note that folic acid intake has a greater influence on blood folate concentrations than MTHFR variant status (Living Evidence for Australian Pregnancy and Postnatal Care [LEAPP], 2026).
This distinction has become increasingly relevant as MTHFR testing has entered fertility and preconception care. Ledowsky et al. (2023) examined the prescribing practices of six Australian practitioners for 12 women with diagnosed infertility and identified MTHFR polymorphisms. All had been advised to remove supplemental folic acid and were prescribed either 5-MTHF or a combination of 5-MTHF and folinic acid. Eleven of the 12 women conceived during the treatment period, which averaged one year, and 10 were reported to have a live birth (Ledowsky et al., 2023).
These outcomes are interesting, but the study was a retrospective case series designed to document prescribing practices rather than determine whether changing the form of folate caused the pregnancies. There was no folic-acid comparison group, only 12 cases were included, and the clinical management of these women was not limited to changing folate form alone. The authors concluded that further research was needed to establish the clinical importance of these differences in folate prescribing and whether recommendations should differ according to MTHFR polymorphisms (Ledowsky et al., 2023).
The case series therefore raises a clinically interesting question, but it cannot establish whether changing folate form improves fertility or pregnancy outcomes. Answering that question requires prospective comparison of the different forms.
Folic acid or 5-MTHF: what does the evidence actually tell us?
There is a sound biochemical reason for being interested in 5-MTHF. As the pathway above shows, supplemental 5-MTHF enters folate metabolism downstream of the MTHFR-dependent conversion of 5,10-methylene-THF into 5-MTHF. Folic acid follows a different metabolic route before joining the reduced folate pool.
The more difficult question is whether these biochemical differences translate into meaningful differences in clinical outcomes.
This distinction is particularly important around conception. Current Australian Pregnancy Care Guidelines continue to recommend folic acid during the periconceptional period for the prevention of neural tube defects and specifically state that women with MTHFR variants can process folic acid (LEAPP, 2026).
Research showing that different supplemental folate forms produce different concentrations of serum folate, red-cell folate, 5-MTHF, homocysteine or unmetabolised folic acid can help us understand how those forms are handled by the body. Biochemical markers, however, are not the same as clinical outcomes. A difference in a folate biomarker does not by itself establish whether one form provides greater, equivalent or lesser protection against an outcome such as a neural tube defect. Clinical outcome evidence is required to answer that question (LEAPP, 2026; Ledowsky et al., 2026).
Ledowsky et al. (2026) took the next step by conducting a double-blind randomised feasibility trial comparing prenatal multivitamins containing 5-MTHF with those containing folic acid in 22 couples with recurrent pregnancy loss. The purpose was to determine whether a larger randomised controlled trial comparing the two forms could feasibly be conducted. The researchers examined feasibility, adherence and acceptability while also collecting preliminary efficacy data, including biochemical markers and pregnancy outcomes (Ledowsky et al., 2026).
The trial found high acceptability and supplement adherence in both groups. Unmetabolised folic acid decreased in the 5-MTHF group and increased in the folic-acid group, suggesting that the two supplemental forms were being handled differently. An important complication emerged when degradation of 5-MTHF was subsequently identified in retained samples of the study product, potentially affecting interpretation of the comparison (Ledowsky et al., 2026).
With only 22 couples, this was a feasibility study rather than a sufficiently sized efficacy trial, and the instability of the 5-MTHF formulation introduced an additional limitation. The study therefore cannot establish whether 5-MTHF is clinically superior, equivalent or inferior to folic acid. The authors concluded that conducting a fully online randomised trial was feasible, while identifying the need for future studies using stable formulations and larger sample sizes to evaluate clinical efficacy and more personalised approaches to folate supplementation (Ledowsky et al., 2026).
The research leaves an important question open. Different forms of folate are metabolised differently, and there are reasonable biological grounds for continuing to investigate whether those differences become clinically meaningful in particular people or reproductive circumstances. At present, however, the Australian recommendation for periconceptional neural tube defect prevention remains folic acid, while the clinical evidence surrounding alternative folate forms continues to develop (LEAPP, 2026; Ledowsky et al., 2026).
What does meeting your folate needs look like on the plate?
After all of that biochemistry, it is worth coming back to where we started: food.
Using food as medicine to supply at least a portion of our folate requirements is an option for most adults across the lifespan. Folate is present in a broad range of foods. When the diet regularly includes vegetables, legumes, leafy greens, avocado, fruits, nuts and seeds, these foods can collectively make a meaningful contribution to daily intake.
In Australia and New Zealand, folate requirements are expressed as dietary folate equivalents, or DFE. The terminology sounds more complicated than the concept. Naturally occurring food folates and folic acid differ in their bioavailability. DFE allows those differences to be considered when estimating how much folate we need (Australian Government Department of Health and Aged Care, 2025).
For most adults, the recommended dietary intake is 400 µg DFE each day. Requirements increase to 600 µg DFE during pregnancy and remain higher during lactation at 500 µg DFE per day (Australian Government Department of Health and Aged Care, 2025).
Four hundred micrograms can still be difficult to picture on a plate. Fortunately, it does not need to come from one particularly folate-rich food.
When someone is following a healthy and varied diet, folate is likely to be incorporated through a number of foods eaten across the day. Avocado or fortified bread might contribute at breakfast. Chickpeas, lentils or leafy greens might appear at lunch. Vegetables and legumes can contribute again at dinner. Fruit, nuts and seeds may add smaller amounts along the way. No individual food needs to carry the entire burden.
This is where dietary variety becomes particularly useful. A serving of lentils does not need to meet the day's folate requirement on its own. Neither does a handful of spinach simply because leafy greens have become almost synonymous with folate. When these foods are incorporated regularly into the diet, their individual contributions begin to accumulate.
There is, however, another layer to consider.
The folate measured in a lentil, asparagus spear or spinach leaf still has to make its way from the food into us. As we saw earlier, naturally occurring folates need to be released from the food matrix and prepared for absorption. Some folate can also be lost during storage, preparation and cooking. The structure of the food itself can influence how accessible its folate becomes during digestion (Liu et al., 2024).
This does not mean we need to calculate how much folate survives every saucepan or salad bowl. Food composition data gives us a useful way to estimate intake. It is still an estimate. Looking at the broader dietary pattern, including the variety and frequency of folate-rich foods, gives those numbers their clinical context.
When might food not be enough?
This brings us to an important clinical distinction.
There is a difference between asking whether food can provide enough folate to meet our nutritional requirements and asking whether there is a clinical reason for folate supplementation.
For most adults across the lifespan, a varied diet containing folate-rich foods can make a substantial contribution towards daily requirements. But our requirements are not static. They change with life stage and circumstance. Pregnancy and lactation increase folate requirements. Limited dietary variety can reduce intake. Gastrointestinal conditions that interfere with absorption can change what happens after folate has been eaten. Some medications can also influence folate status or metabolism (Australian Government Department of Health and Aged Care, 2025).
Preconception and early pregnancy provide one of the clearest and strongest examples of why the distinction between food and supplementation matters.
Someone preparing for pregnancy may already have an excellent dietary intake. Their meals might regularly include leafy greens, legumes, avocado, vegetables, fruit and fortified bread. That food foundation remains important. It does not, however, replace the specific recommendation for periconceptional folic acid.
The neural tube develops and closes very early in embryonic development. This can occur before a person knows they are pregnant. Australian Pregnancy Care Guidelines therefore recommend folic acid supplementation before conception and during early pregnancy to reduce the risk of neural tube defects (LEAPP, 2026).
In this situation, we are asking folic acid to do something quite specific.
The question is no longer simply whether dietary folate intake is adequate. Folic acid is being used for a preventive purpose supported by clinical outcome evidence. This becomes particularly relevant when we return to the discussion of folic acid and 5-MTHF.
There are genuine biochemical differences between these forms. There are also reasonable questions about whether those differences may prove clinically relevant in particular circumstances. At this stage, however, evidence showing differences in metabolism or biochemical markers cannot be considered interchangeable with the clinical evidence supporting folic acid for neural tube defect prevention (LEAPP, 2026; Ledowsky et al., 2026).
For some people, folate supplementation requires further individualisation. Australian guidance recommends higher-dose folic acid in certain circumstances where the risk of neural tube defects is increased (LEAPP, 2026). Identified folate deficiency, impaired absorption, medication use or other clinical circumstances may also change the conversation.
Food can therefore provide the nutritional foundation while supplementation has a more targeted role when the clinical circumstances require it.
So, can food meet your folate needs?
We began this article with a fairly simple question.
Can food provide enough folate?
For many adults across the lifespan, food can provide a substantial proportion of our folate requirements and, with a varied dietary intake, may provide enough to meet them. Folate-rich foods are widely available. Australia's mandatory fortification program also means that folic acid enters the diet through commonly consumed foods made with fortified wheat flour (Australian Government Department of Health and Aged Care, 2025; FSANZ, 2025).
But following folate from the plate through its intricate and complex journey through the human body shows us why the answer cannot rest on dietary intake alone.
Folate has to be released from food, prepared for absorption and transported into the body. Once there, it becomes part of the interconnected reactions of one-carbon metabolism. Different forms enter that pathway differently. Our requirements change across the lifespan. Sometimes the reason we need folate changes as well.
This is why reducing the conversation to natural folate versus folic acid, or deciding that one form must be better because its pathway appears more direct, misses much of the physiology sitting underneath it.
Food gives us our fundamental foundation.
Food first, wherever and whenever it is possible, because nature is not reductionist. A lentil does not give us folate alone. Leafy greens do not arrive carrying a single isolated nutrient. Alongside folate come fibre, minerals, antioxidants and other phytochemicals. Depending on the food, there may also be protein, non-haem iron, healthy fats and energy. These nutrients and compounds arrive together within a food matrix and ultimately within a broader dietary pattern.
A supplement is designed to do something different. It can provide a particular nutrient in a known amount and, when indicated, for a particular purpose.
And sometimes that is exactly what we need.
So perhaps the answer to our original question is that food should take us as far as it reasonably can. For many people, that may be enough to meet everyday folate requirements. At other times, requirements increase, absorption is compromised, deficiency is present, or folate is being used for a specific clinical purpose.
Food first, wherever and whenever possible, until diet alone is not enough. And that is where a nutritionist can step in, looking at your diet, life stage, health history and individual requirements, before deciding whether supplementation is needed, in what form, and how much.
References
Australian Government Department of Health and Aged Care. (2025). Folate. Nutrient Reference Values for Australia and New Zealand. Nutrient Reference Values – Folate
Food Standards Australia New Zealand. (2025). Australian Food Composition Database: Release 3. Australian Food Composition Database
Food Standards Australia New Zealand. (2025). Folic acid fortification. Folic acid fortification
Ledowsky, C. J., Schloss, J., & Steel, A. (2023). Variations in folate prescriptions for patients with the MTHFR genetic polymorphisms: A case series study. Exploratory Research in Clinical and Social Pharmacy, 10, 100277. https://doi.org/10.1016/j.rcsop.2023.100277
Ledowsky, C., Scarf, V., Rogers, K., & Steel, A. (2026). Feasibility of a randomized clinical trial comparing 5-methyltetrahydrofolate and folic acid prenatal multivitamins in couples with recurrent pregnancy loss. Nutrition Research, 146, 68–81. https://doi.org/10.1016/j.nutres.2025.12.008
Liu, F., Edelmann, M., Piironen, V., Li, Y., Liu, X., Yan, J.-K., Li, L., & Kariluoto, S. (2024). How food matrices modulate folate bioaccessibility: A comprehensive overview of recent advances and challenges. Comprehensive Reviews in Food Science and Food Safety, 23(3), e13328. https://doi.org/10.1111/1541-4337.13328
Living Evidence for Australian Pregnancy and Postnatal Care. (2026). Australian pregnancy care guidelines (Version 11.0). Australian Pregnancy Care Guidelines
Lyon, P., Strippoli, V., Fang, B., & Cimmino, L. (2020). B vitamins and one-carbon metabolism: Implications in human health and disease. Nutrients, 12(9), 2867. https://doi.org/10.3390/nu12092867
Patanwala, I., King, M. J., Barrett, D. A., Rose, J., Jackson, R., Hudson, M., Philo, M., Dainty, J. R., & Wright, A. J. A. (2014). Folic acid handling by the human gut: Implications for food fortification and supplementation. The American Journal of Clinical Nutrition, 100(2), 593–599. https://doi.org/10.3945/ajcn.113.080507
