Is 5-MTHF the Same as Folic Acid? Understanding the Key Differences in Nutrition

October 8, 2025 •

4 min read

As of early 2021, health authorities began measuring folate requirements in Dietary Folate Equivalents (DFEs) to better reflect the different bioavailability between forms. The critical question, is 5-MTHF the same as folic acid?, highlights a fundamental difference between the body's active folate and its synthetic counterpart.

Quick Summary

Folic acid is a synthetic, inactive form of vitamin B9 that the body must convert, whereas 5-MTHF is the biologically active form ready for immediate use. This conversion process can be slow or inefficient, especially for individuals with a specific gene variation.

Key Points

Not the Same: 5-MTHF is the biologically active form of folate, while folic acid is a synthetic and inactive version.
Requires Conversion: The body must convert inactive folic acid into active 5-MTHF through a multi-step enzymatic process primarily in the liver.
MTHFR Gene Impact: Individuals with certain MTHFR gene variations may have difficulty performing this conversion, making 5-MTHF a more direct and effective option.
Bioavailability and Efficacy: 5-MTHF is immediately usable and highly bioavailable, whereas folic acid conversion can be inefficient, leading to unmetabolized folic acid in the bloodstream.
B12 Interaction: High doses of folic acid can potentially mask a vitamin B12 deficiency, a risk not typically associated with 5-MTHF supplementation.
Personalized Approach: The best choice between 5-MTHF and folic acid depends on an individual's genetic profile, metabolic efficiency, and specific health needs, and should be discussed with a healthcare provider.

What is Folic Acid?

Folic acid is the synthetic, oxidized form of vitamin B9, and it is not found naturally in significant amounts in unprocessed foods. It is known for its stability and lower cost, making it the standard choice for fortifying processed foods like flour, pasta, and cereals and for inclusion in many dietary supplements. Its widespread use in food fortification has been one of the most successful public health initiatives, effectively reducing the incidence of neural tube defects (NTDs).

The Metabolic Challenge of Folic Acid

When consumed, folic acid is metabolically inactive and must undergo a multi-step process in the liver to become the active form the body can use. The conversion pathway involves several enzymes:

Reduction by Dihydrofolate Reductase (DHFR): Folic acid is first reduced to dihydrofolate and then to tetrahydrofolate (THF) by the enzyme DHFR. In humans, this enzyme has a slow catalytic rate and can be easily saturated, especially at higher doses of folic acid.
Conversion to 5-MTHF: THF is then converted to 5-MTHF with the help of the methylenetetrahydrofolate reductase (MTHFR) enzyme.

Due to this slow and potentially inefficient conversion process, unmetabolized folic acid (UMFA) can build up in the bloodstream, particularly with high-dose supplementation and regular consumption of fortified foods. The health implications of circulating UMFA are still under investigation, though some studies suggest it may interfere with immune function.

What is 5-MTHF?

5-MTHF, or 5-methyltetrahydrofolate, is the natural, active form of folate that is primarily found circulating in the blood and readily available for the body's metabolic processes. This form is found in naturally folate-rich foods such as green leafy vegetables, legumes, and eggs. Because it is already in its usable form, it is highly bioavailable and does not require conversion by the DHFR or MTHFR enzymes. This provides several advantages:

Rapid Availability: It enters the metabolic pathway directly, allowing for quicker and more effective elevation of folate levels.
Bypasses MTHFR Variations: Individuals with a variant of the MTHFR gene, which affects the ability to produce the MTHFR enzyme, may not efficiently convert folic acid. 5-MTHF bypasses this genetic barrier, ensuring adequate folate delivery.
Reduced Risk of Masking Vitamin B12 Deficiency: High-dose folic acid can correct the megaloblastic anemia associated with B12 deficiency, potentially masking the underlying neurological damage caused by the B12 shortage. Since 5-MTHF's metabolism requires B12, it is less likely to have this masking effect.

Comparison: 5-MTHF vs. Folic Acid


Feature	5-MTHF (Methylfolate)	Folic Acid (Synthetic Folate)
Source	Natural form, found in foods and some supplements.	Synthetic, man-made form, used in fortified foods and supplements.
Metabolic State	Biologically active and ready for immediate use.	Biologically inactive; requires conversion by enzymes in the liver.
Bioavailability	High and direct, not affected by metabolic defects.	Bioavailability can be affected by individual metabolism and saturable enzyme activity.
MTHFR Impact	Bypasses the MTHFR gene mutation, ensuring effective utilization.	Individuals with MTHFR mutations may have reduced ability to convert it.
Masking B12 Deficiency	Lower risk of masking the haematological symptoms of a B12 deficiency.	Higher doses can mask anemia symptoms associated with a B12 deficiency.
Plasma Levels	Does not accumulate as unmetabolized folate in the blood.	Can accumulate as unmetabolized folic acid in the bloodstream.
Cost	Generally more expensive due to complex processing.	Less expensive due to stability and simpler synthesis.
Stability	Less stable than folic acid, sensitive to oxygen and temperature.	Highly stable, making it ideal for food fortification.

Choosing Between 5-MTHF and Folic Acid

For most of the general population without known MTHFR variants, standard supplementation with folic acid and consumption of fortified foods is considered effective for maintaining adequate folate levels. The robust, long-term studies on neural tube defect prevention have primarily used folic acid, which is why it remains the recommended form by many health organizations.

However, for specific populations, 5-MTHF presents compelling advantages:

Individuals with MTHFR gene variants: Those with reduced MTHFR enzyme activity may benefit from 5-MTHF to ensure proper folate metabolism.
Addressing Potential Risks: For those concerned about potential risks associated with unmetabolized folic acid or masking a B12 deficiency, 5-MTHF offers a safer alternative, especially at higher doses.
Drug Interactions: Some medications, such as methotrexate, can inhibit the DHFR enzyme needed for folic acid conversion. In such cases, 5-MTHF can be a more effective option.

It is always best to consult with a healthcare provider to determine the most appropriate form and dosage of folate based on your individual health profile and needs. For more information on the distinctions, review the review of scientific literature at the National Institutes of Health.

Conclusion

In summary, 5-MTHF and folic acid are not the same, though both ultimately aim to increase the body's folate status. Folic acid is a synthetic, inactive compound that requires metabolic conversion, a process that can be inefficient for some individuals. 5-MTHF is the body's readily usable, active form of folate, offering better bioavailability and a direct pathway for individuals with genetic or metabolic challenges. While folic acid has a proven track record in public health, the availability of 5-MTHF provides a more personalized and potentially superior option for specific dietary and genetic considerations.

Frequently Asked Questions

The primary difference is metabolic state: folic acid is a synthetic, inactive form of vitamin B9, while 5-MTHF is the active, natural form that the body can use immediately.

Some people choose 5-MTHF because they may have a genetic variant (like MTHFR) that reduces their body's ability to convert folic acid into its active form efficiently. 5-MTHF bypasses this conversion process entirely.

Generally, both are considered safe when used appropriately. However, high doses of folic acid can potentially mask the symptoms of a vitamin B12 deficiency. Since 5-MTHF's metabolism requires B12, it has a lower risk of this masking effect.

Yes, 5-MTHF is the active form of folate found naturally in foods such as dark green leafy vegetables, legumes, and eggs.

Unmetabolized folic acid (UMFA) can appear in the bloodstream with high intake of fortified foods and supplements. While the long-term health implications are not fully understood, this accumulation does not occur with 5-MTHF.

Health organizations have long recommended folic acid due to its proven effectiveness in preventing neural tube defects. However, some recent research and complementary health approaches suggest 5-MTHF might be a beneficial alternative, especially for those with MTHFR mutations, but clinical evidence is still needed to establish its NTD prevention efficacy.

Genetic testing can reveal if you have an MTHFR variant. It may be beneficial to discuss this with a healthcare provider, especially if you have fertility issues, a history of recurrent fetal loss, or are concerned about your folate metabolism.