Which form of folate is the most bioavailable? The definitive guide to B9

October 8, 2025 •

4 min read

The bioavailability of synthetic folic acid can reach almost 100% when taken as a supplement on an empty stomach, but that doesn't tell the whole story. Determining which form of folate is the most bioavailable requires understanding how the body uses different versions of this critical nutrient. Bioavailability isn't just about how much is absorbed, but also how efficiently it is used for metabolic functions.

Quick Summary

This article explains the differences in bioavailability between folate forms, including synthetic folic acid, the active form 5-MTHF, and natural food folate. It discusses how genetics, like the MTHFR variant, can affect metabolism and explores the pros and cons of each form for optimal health and dietary supplementation.

Key Points

Folic Acid vs. 5-MTHF: Folic acid is a synthetic, inactive form with high absorption that requires enzymatic conversion, while 5-MTHF is the biologically active form ready for immediate use.
MTHFR Gene Impact: Individuals with MTHFR gene variants may have impaired conversion of folic acid, making 5-MTHF a more reliable source of active folate.
Source Bioavailability Varies: Supplemental folic acid has the highest initial absorption rate, but natural food folate offers lower and more variable bioavailability.
Unmetabolized Folate Concerns: High doses of folic acid can lead to a buildup of unconverted folic acid in the bloodstream, a concern not associated with 5-MTHF.
Personalized Supplementation: The best folate choice depends on individual factors like genetics and health conditions, so consulting a doctor is recommended.
Purpose of Supplementation: For population-wide public health goals like preventing neural tube defects, folic acid fortification is highly effective, but personalized approaches may be needed for those with specific metabolic needs.

What is Bioavailability?

Bioavailability refers to the proportion of a nutrient that is absorbed and becomes available for use by the body's metabolic processes. For vitamin B9, the key players are natural food folate, synthetic folic acid found in fortified foods and supplements, and the active form, 5-methyltetrahydrofolate (5-MTHF). Each form follows a different path and has a unique rate of bioavailability, impacting its effectiveness.

Folic Acid: The Inactive, Yet Highly Absorbed, Synthetic Form

Folic acid is a synthetic, oxidized monoglutamate that is highly stable and used to fortify grains and create many supplements. When taken on an empty stomach, supplemental folic acid has a bioavailability of nearly 100%, and about 85% when taken with food. However, the story doesn't end there, as folic acid is biologically inactive and must be converted by the liver into the active form, 5-MTHF, through a series of enzymatic steps involving dihydrofolate reductase (DHFR) and methylenetetrahydrofolate reductase (MTHFR).

Metabolic Bottleneck: The DHFR enzyme has a limited capacity, especially when consuming high doses of folic acid. If intake exceeds the liver's ability to convert it, unmetabolized folic acid can build up in the bloodstream.
Potential Concerns: The presence of unmetabolized folic acid in circulation is a topic of ongoing research, with some concerns raised about its potential health effects, such as masking a vitamin B12 deficiency.

5-MTHF: The Active, Biologically Ready Form

5-MTHF is the active, methylated form of folate that circulates in the blood and is used directly by the body's cells. It is present in smaller amounts in some foods but is primarily available through supplements. Unlike folic acid, 5-MTHF is immediately bioavailable and does not require the enzymatic conversion steps in the liver.

Bypasses MTHFR Issues: This direct availability makes 5-MTHF particularly beneficial for individuals with a genetic polymorphism in the MTHFR gene, which impairs the conversion of folic acid to 5-MTHF.
Efficient and Effective: Studies have shown that 5-MTHF can increase blood folate concentrations more effectively than folic acid, especially in women with the MTHFR variant. It can also lower homocysteine levels effectively, a key marker for cardiovascular health.

Food Folate: Natural but Variable Bioavailability

Naturally occurring folate, found in foods like leafy greens, legumes, and citrus fruits, exists mostly in a polyglutamate form. Its bioavailability is generally lower and more variable than that of supplemental folic acid, with estimates ranging from 50% to 80% relative to folic acid.

Digestion Required: For the body to absorb food folate, the polyglutamate tail must be removed during digestion, a process that can be incomplete or inconsistent.
Instability: Natural food folate is also less stable and more susceptible to degradation from heat, light, and oxidation during cooking and processing.

Comparison of Folate Forms


Feature	Folic Acid	5-MTHF (Active Folate)	Food Folate (Natural)
Bioavailability	Very high (85-100%) but dependent on enzymatic conversion.	High (Comparable to or greater than folic acid).	Variable and lower (approx. 50-80% relative to folic acid).
Form	Synthetic, inactive, oxidized monoglutamate.	Biologically active, reduced, methylated form.	Reduced, labile, polyglutamated forms.
Metabolism	Requires multi-step conversion in the liver via DHFR and MTHFR enzymes.	Ready for immediate use by the body, bypassing the conversion process.	Requires enzymatic deconjugation during digestion for absorption.
MTHFR Relevance	Conversion can be impaired by common MTHFR genetic variants.	Bypasses MTHFR polymorphism, making it more effective for those with variants.	Bioavailability can be affected by genetics but still a necessary source.
Unmetabolized Folate	Can accumulate in the bloodstream, especially with high doses.	Does not lead to unmetabolized folate accumulation.	Does not cause unmetabolized folate to accumulate.
Stability	Highly stable and resistant to heat and light.	Less stable than folic acid, more susceptible to degradation.	Least stable and easily destroyed by cooking and storage.

The Role of Genetics in Folate Metabolism

Approximately 40% of the global population has at least one common genetic polymorphism in the MTHFR gene, most notably the C677T variant. This variant reduces the efficiency of the MTHFR enzyme, which is critical for converting inactive folic acid into active 5-MTHF. Individuals with this polymorphism may struggle to convert sufficient folic acid, even with standard supplementation, potentially leading to lower circulating folate levels and higher homocysteine concentrations. For these individuals, supplementation with 5-MTHF can be a more effective strategy to achieve optimal folate status. For others, standard folic acid works perfectly well, and population-wide fortification with folic acid has been highly successful in reducing neural tube defects.

Who Should Consider 5-MTHF?

While folic acid remains a highly effective and cost-efficient option, certain individuals might benefit from considering 5-MTHF supplementation. This is particularly relevant for:

Individuals with MTHFR gene variants: Bypassing the enzymatic conversion can lead to more efficient and reliable folate status improvement.
Pregnant or lactating women: Ensuring optimal folate levels is critical during this period, and 5-MTHF offers a direct, readily available form for both mother and fetus.
Those with drug interactions: Certain medications, such as methotrexate, can inhibit the DHFR enzyme needed for folic acid conversion. 5-MTHF is not affected by this inhibition.
People with gastrointestinal issues: Since 5-MTHF is immediately bioavailable, it can be beneficial for individuals with malabsorption disorders.

Conclusion

So, which form of folate is the most bioavailable? The answer depends on individual metabolism. While synthetic folic acid has a very high absorption rate, its ultimate biological availability is dependent on the body's ability to convert it to the active form, 5-MTHF. For the general population, both food folate and folic acid are viable options, especially with fortification programs in place. However, for individuals with MTHFR genetic variants or other metabolic challenges, the ready-to-use 5-MTHF offers a more direct and efficient route to supporting optimal folate status. A personalized approach, often guided by a healthcare professional, is the most effective way to ensure adequate folate intake.

Visit the National Institutes of Health website for more on folate.

Frequently Asked Questions

Folate is the general term for vitamin B9 and refers to the naturally occurring forms found in foods. Folic acid is the synthetic, oxidized form used in fortified foods and supplements.

5-MTHF is the active form of folate and does not require conversion by the MTHFR enzyme. This makes it more bioavailable and reliable for individuals with MTHFR genetic variations that impair their ability to metabolize folic acid efficiently.

While small amounts of methylfolate (the natural version of 5-MTHF) are present in food, especially leafy greens and legumes, supplementation is often needed to achieve therapeutic doses, particularly for those with impaired metabolism.

For most of the population, folic acid is safe and effective, and its use has significantly reduced neural tube defects. However, individuals with MTHFR variants or a history of B12 deficiency may need to consider 5-MTHF to avoid potential health risks associated with unmetabolized folic acid.

MTHFR gene variants, such as C677T, can decrease the activity of the MTHFR enzyme. This reduces the body's ability to convert folic acid into the active 5-MTHF form, potentially leading to lower circulating folate and higher homocysteine levels.

Yes, some medications, including methotrexate and certain anticonvulsants, can interfere with the metabolism of folic acid by inhibiting the DHFR enzyme. In these cases, 5-MTHF is a preferable alternative as it bypasses the inhibited pathway.

Good food sources of natural folate include leafy green vegetables (spinach, kale), legumes (lentils, chickpeas), asparagus, and citrus fruits. However, natural folate is sensitive to heat and can be lost during cooking.