Methylfolate vs. Folic Acid vs. Folate: What’s the Difference?

Folate is an essential vitamin that is often replaced by folic acid in individuals who do not consume enough folate naturally. However, folic acid is not an ideal option for people with MTHFR. Here is an overview of the importance of folate and your options for replacing it if you are not getting enough.

Like folate and folic acid, folate and methylfolate are used to obtain similar end goals in slightly different ways. Methylfolate is a reduced form of folate that can be found in certain dietary supplements. This means it's the already-converted, most active form of folate the body can use. 

Like folic acid, methylfolate serves as a synthetic form replacement for natural folate, though it’s much more bioavailable and useful to the body.

It can be used as a superior active folate supplement in many situations, as well as as a treatment for anemia, depression, diabetes, dementia, and other disorders. Methylfolate is a particularly common substitute for folate in individuals with an MTHFR gene mutation, a type of gene variant that prohibits a person from converting and using natural folate correctly.

The body works to produce an enzyme that converts a portion of folate and folic acid into folinic acid supplementation. Folinic acid is then converted into the active folate form, methylfolate, via the MTHFR gene, which can then be used by cells to perform its functions. 

It is also said that Folic acid and folinic acid reduce side effects in patients receiving methotrexate for rheumatoid arthritis and it also appears to be protective against abnormal serum transaminase elevation caused by methotrexate.

Unlike other forms of folic acid, methylfolate can be very effective in the production of SAMe & BH4 (tetrahydrobiopterin) which generate neurotransmitters like serotonin. Similarly, methylfolate can be effectively absorbed, and bioavailability has been shown to be unaffected by metabolic or genetic defects (Scaglione and Panzanvolta, 2014). Jan 14, 2021.

Folic acid is a synthetic form of vitamin B9, technically known as pteroylmonoglutamic acid. It is widely utilized in dietary supplements and is routinely added to processed foods such as flour and breakfast cereals to help people get enough folic acid and prevent nutritional deficiencies. 

Folic acid is not directly usable by the body; instead, it must be converted into the biologically active form of vitamin B9, called 5-MTHF (5-methyltetrahydrofolate), within the body’s digestive system.

However, the conversion of folic acid to 5-MTHF does not occur entirely in the digestive system but rather primarily takes place in the liver and other tissues. This metabolic process can be slow and inefficient, particularly in some individuals, due to genetic or physiological factors.

The body's ability to convert enough folic acid to 5-MTHF varies, and even small doses, typically ranging from 200 to 400 micrograms per day, may not be fully metabolized by the time the next dose is consumed. This inefficiency may be compounded by the consumption of foods fortified with folic acid, leading to a build-up of unmetabolized folic acid (UMFA) in the bloodstream.

Detection of unmetabolized folic acid in the red blood cells, even in a fasted state, is a common finding and raises health concerns. Studies have linked elevated levels of unmetabolized folic acid to several health issues, highlighting the need for more efficient forms of this vitamin.

In contrast, methylfolate is the bioactive form of folate, already in the necessary enzymatic form that the body can immediately use for cellular functions and energy production. As the most effective form of folate, methylfolate bypasses the complex conversion processes required by folic acid. 

This characteristic makes methylfolate a superior choice, especially for individuals who have difficulty with nutrient conversion, often referred to as "poor methylators." Methylfolate's direct usability supports faster and more effective metabolic processes, enhancing cellular function and overall energy levels.

Choosing between folic acid supplementation and methylfolate often depends on individual health needs and genetic factors influencing folate or folic acid metabolism. For those with genetic variations that impair folate conversion or for individuals seeking optimized nutrient absorption and utilization, methylfolate offers a direct, effective solution compared to folic acid.

This choice can significantly impact one's health, particularly in areas related to cellular repair, DNA synthesis, neurotransmitter generation, preventing neural tube defects, improving cognition and cardiovascular health, as well as the regulation of homocysteine, an amino acid that, at high levels, is associated with health problems.

As a natural form of folate, Methylene Folate offers many advantages over natural Folic acid. Furthermore, the methyl folates are absorbed well, and their bioavailability does not suffer from metabolic defects or gene variants (Scaglione and Panzavolta et al. 2014). 15 June 2019.

Methylenetetrahydrofolate reductase (MTHFR Gene Mutation) is a type of gene mutation[4] that lowers the efficiency of the MTHFR enzyme. Individuals with this mutation cannot properly convert folate into methylfolate. By disrupting the natural metabolic pathway, MTHFR blocks usable methylfolate from reaching the cells & doing its important jobs.

Inadequate methylfolate levels can have a wide variety of negative effects on the body, particularly those that affect the cardiovascular and nervous systems. During pregnancy, a lack of methylfolate can also have serious impacts on healthy fetal development.

Fortunately, there are several folate replacements available that can largely make up for deficiencies that are caused by an MTHFR gene mutation. Folic acid and folate can be cheap, but methylfolate tends to be the most effective option when it comes to treating the unique needs of MTHFR gene mutation and giving the body an enzyme it can directly act upon.

L-methylfolate (chemically (6S)-5-methyltetrahydrofolate) is the purest active form of methylfolate you can buy. Methylfolate and folic acid can sometimes perform similarly in individuals without MTHFR gene mutation, but completely eliminating enough folic acid from the diet is recommended to allow methylfolate to obtain the most benefits in those with MTHFR gene mutation.

Because folic acid is synthetic and requires 4 conversions before it can be fully utilized in the human body, it can cause health complications for people with MTHFR gene variants and should be avoided. Methylfolate should be taken by these individuals instead.

There are several types of methylfolate supplements available, and the best methylfolate product for you largely depends on the specific benefits you would like to get from it.

Products with methylfolate only are available, which can be taken on their own or in combination with other supplements you are currently taking that do not contain folic acid. There are also several products that combine methylfolate with other vitamins and nutrients that were formulated to treat a specific condition.

Methyl-Life's® MTHFR Newbies guide provides an overview of as well as 6 helpful tips to treat your MTHFR variant. It suggests several of the most common types of L-methyl folate supplements on the market, many of which are only available with a prescription.

Depending on the specific amount of methylfolate you need, your supplements may come in the form of chewable tablets, capsules you swallow, or medical foods you might want a prescription for.

Some common prescription L-methylfolate supplements are used as treatments that target specific health problems. CerefolinNAC is a multi-nutrient product typically used to treat dementia, Alzheimer's, and other concerns related to brain health (5.6 mg of L-methylfolate), while Metanx is used for neuropathy and conditions related to the nervous system (3 mg of L-methylfolate). Deplin 7.5 and Deplin 15 (7.5 mg and 15 mg) are different strengths of L-methylfolate only, used to treat depression by increasing serotonin production within the human body (via boosting SAMe & BH4 levels).

Women with an MTHFR gene mutation must be especially cautious about taking the proper supplements during pregnancy[5] because the mutation can have a significant impact on the development of the baby or lead to miscarriage for some. 

Prenatal methylfolate supplements with 1 mg of L-methylfolate can be used to support healthy pregnancies, though if you have MTHFR, you may wish to explore taking a larger daily methylfolate dose. These vital nutrients can be taken on their own or in combination with certain other types of prenatal vitamins to boost both the baby's development as well as the mother's health during pregnancy.

Other methylfolate supplements are more general and are used to support and optimize health overall, much like other supplements and multivitamins. These products can be used to boost mood, brain health, and general health without requiring the presence of a specific health problem. 

These supplements can be purchased without a prescription, though it is always a good idea to consult your healthcare provider before adding supplements to your diet to make sure they will meet your needs.

In conclusion, the nuances between folate, folic acid, and methylfolate are essential for optimal health management, especially for those affected by the MTHFR gene mutation. Folate, the naturally occurring form of vitamin B9, is vital for numerous biological functions, including cellular repair and DNA synthesis.

However, folic acid, the synthetic variant, often requires conversion into its bioactive form within the human body—a process that can be inefficient in those with certain genetic predispositions. This inefficiency can lead to elevated levels of unmetabolized folic acid (UMFA), which have been associated with various health issues.

Methylfolate presents a superior alternative, particularly for individuals with the MTHFR gene mutation, because it is already in the bioactive form that the body can immediately utilize. This form of folate bypasses the metabolic complications inherent in converting folic acid to its usable state, providing a direct route for cellular uptake and utilization.

The use of methylfolate supports enhanced metabolic processes, improves cellular function, and boosts overall energy levels. It is particularly crucial in managing conditions related to folate deficiency and in scenarios where effective folate utilization is compromised by genetic factors.

Given these considerations, individuals, especially those with an MTHFR gene mutation, should prioritize methylfolate over folic acid to maximize the health benefits of vitamin B9 supplementation. Consulting with healthcare providers can ensure that the choice of folate supplementation is tailored to the individual’s specific health needs and genetic background.

Such personalized healthcare approaches are essential for preventing complications associated with folate metabolism and for promoting overall well-being in individuals at risk for or currently experiencing folate-related health issues.

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9380836/
2. https://www.healthline.com/nutrition/folic-acid-vs-folate#folic-acid
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250974/
4. https://genome.gov/about-genomics/fact-sheets/Chromosome-Abnormalities-Fact-Sheet
5. https://ncbi.nlm.nih.gov/pmc/articles/PMC3218540#__sec4tit1