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L-Methylfolate Info

How L-Methylfolate Can Help

L-Methylfolate helps the body produce healthy DNA, have healthy neurotransmitter production, and optimal cardiovascular, hormonal, cellular, liver and reproductive functions.

MethylPro capsules contain professional strength L-methylfolate, the active form of folate (one of the body's essential B vitamins). L-Methylfolate is essential for biological processes throughout the human system involving methylation or one-carbon transfer. Without it there can be a significant breakdown of the human body's ability to produce healthy DNA, have healthy neurotransmitter production, and optimal cardiovascular, hormonal, cellular, liver and reproductive functions.

Folate deficiency is tied to a host of conditions:

Because L-methylfolate is required for the synthesis of the neurotransmitters serotonin, dopamine, and norepinehrine, low levels make it less likely that people will respond well to products that support a healthy mood. L-Methylfolate is also the only form of folate able to cross the blood-brain barrier. A decline of folate levels in the cerebral spinal fluid has been associated with reduced cognitive function. L-Methylfolate is essential for the conversion of homocysteine to methionine, supporting cardio and vascular health by lowering homocysteine levels. Since L-methylfolate participates in DNA synthesis and cell division, requirements are increased during pregnancy and periods of rapid growth.

Folic Acid & Folate Metabolism

Although folate occurs in naturally in some foods, and folic acid is used to fortify others, approximately 60 percent of the population in the United States have genetic variations that make them unable to utilize these nutrients. These variations do not allow the MTHFR enzyme to function properly so methylation of folate does not occur. Without this activation step, folate cannot be used by the body, resulting in negative health side effects and the possible inability to maintain a healthy mood.

This deficiency usually occurs because folic acid, the most common form of folate in supplements and fortified foods, must be converted to its active forms to be used by the body. The enzyme needed to convert folate to its active form, methylfolate, is called methylenetetrahydrofolate reductase (MTHFR). The problem lies in the fact that almost half of all people have genetic variations that reduce the ability of the MTHFR enzyme to make this conversion. Folate deficiencies are tied to a host of conditions.

For people with MTHFR gene variations, supplementing with the already activated form of folate is far more effective in providing this form of folate than introducing the pre-converted form to the body through typical folate supplements. L-Methylfolate supplements provide the active form of folate naturally present in the body and available for biological action.

This image illustrates the folic acid activation cycle. The other forms of vitamin B9 are folic acid and folate. Folate is often called the natural form of vitamin B9, but it actually refers to a family of different compounds that occur naturally in some vegetables. Folic acid is the supplemental or "synthetic" form of vitamin B9 and is typically the first line of treatment for folate deficiency and related health conditions, such as high homocysteine and neural tube defects. Any folic acid we ingest must be metabolized (converted) into Dihydrofolate (DHF), Tetrahydrofolate (THF), and then finally into L-methylfolate to be used in the body. Once in this form it can be transported into cells, tissues and even across the blood-brain barrier. But issues can arise during metabolism for those with an enzyme issue, such as an MTHFR mutation.

Our Staff

Why does MethylPro ® offer different forms of L-methylfolate?

MethylPro's L-methylfolate forms are produced by the Italian biotechnology company Gnosis S.P.A., are self-affirmed as GRAS (Generally Recognized as Safe), and have been filed as a New Dietary Ingredient (NDI) to the FDA. Extrafolate-S ® is an amorphous calcium-salt based molecule and is a 99.9% pure 6(S) isomer only ingredient (non-racemic). Quatrefolic ® is a glucosamine-salt based molecule and is a 99.9% pure 6(S) isomer only ingredient (non-racemic).

What are some of the signs and symptoms of an MTHF Deficiency?


Low Brain Chemistry Production

L-Methylfolate is essential for maintaining healthy brain chemistry and is responsible for the normal production of the neurotransmitters serotonin, melatonin, dopamine, epinephrine, and norepinephrine. These neurotransmitters are involved in a number of functions including short-term memory, concentration, sleep, motor control, hormone control, mood stability, motivation, and appetite control. Low folate levels have been associated with mood disorders and supplemental folate might be recommended as first line therapy.



Genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) have been proven to be the common hereditary factors of high-level homocysteine. Supporting normal homocysteine levels already in a normal range is important to good health. L-Methylfolate supplements address elevated homocysteine levels in the blood and improve peripheral blood flow in the arteries by increasing nitric oxide production in the vascular endothelium. This mode of action supports heart health.


Peripheral Neuropathy

L-Methylfolate supplements can help promote healthy peripheral nerve function by supporting normal homocysteine levels and increasing nitric oxide production.


Uric Acid

Gout is a condition characterized by the deposition of monosodium urate crystals in the joints or soft tissue. Acute gout most commonly affects the first metatarsal joint of the foot, but other joints are also commonly involved. Supplementing with L-methylfolate s can aide in the normal metabolism of uric acid.


Neural Tube Defects

Women who consume healthful diets with adequate folate throughout their childbearing years may reduce their risk of having a child with a birth defect of the brain or spinal cord. Sources of folate include fruits, vegetables, whole grain products, fortified cereals, and dietary supplements. Supplementing with folate significantly reduces the occurrence of neural tube defects. However, a study involving a group of women of childbearing age showed that supplementing with L-methylfolate results in a higher red blood cell folate level than supplementing with folic acid.



As with any supplement or medication you take, it is recommended that you first speak with a health care professional to ensure you are taking the correct strength for you, and that there are no possible interactions with any your current medications.


The most common side effect associated with L-methylfolate is agitation or irritability caused by the body's overproduction of adrenaline. Many physicians address this by suggesting that their patients add methyl-B12 and magnesium to their supplement regimen.*


Some laboratories do testing for MTHFR gene status that may give your doctor a better idea about how to select a strength. Some options for these labs include Genova Diagnostics, LabCorp, and SpectraCell Laboratories.

How else can L-methylfolate be labeled?

Because there are so many different varieties and ways that companies label L-Methylfolate, it can be confusing to identify what product is right for you. Here are the different ways that you may see L-methylfolate labeled:

Calcium salt based:

L-MTHF, L-5-MTHF, MTHF, L-Methylfolate

  • 6(S) isomer only Methylfolate
    Metafolin ®: Merck, medical food (NeevoDHA, Metanx, Cerefolin and Deplin) Extrafolate-S ®: Gnosis, dietary supplement available over the counter
  • 6(S) & 6(R) isomers Methylfolate
    Generic/racemic formulas, dietary supplement available over the counter

Glucosamine salt based:

Quatrefolic ®: Gnosis, dietary supplement available over the counter

Changing the names of our products from 5-MTHF to L-methylfolate

In 2016, Metabolic Maintenance, manufacturer of MethylPro® Products, changed the names of our products from 5-MTHF to L-methylfolate. The wording in the Supplement Facts has changed from L-5-Methyltetrahydrofolate to L-5-methylfolate. Our products remain the same. We still use pure S isomer (L) methylfolate from Extrafolate S® and Quatrefolic® made by Gnosis Bio in Italy. We still label only the active amount of the compounds with total compound amount in parenthesis. For example: Folate 5mg (from 6.8 mg L-5- Methylfolate, calcium salt).

This name change reflects the current nomenclature in the marketplace. When we first offered these products, there were very few on the market, so we used the entire chemical name and abbreviation: L-5- Methyltetrahydrofolate, and 5-MTHF. Since then, knowledge of this form of folate has spread, and the number of offerings on the market has increased. The most common name is now L-methylfolate. This is the name searched for and inquired about, and our new product names reflect this.

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Cao, Y; Xu, J; Zhang, Z; Huang, X; Zhang, A; Wang, J; Zheng, Q; Fu, L; Du, J. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: A meta-analysis, Gene, Volume 514, Issue 2, 10 February 2013, Pages 105-111, ISSN 0378-1119, http://dx.doi.org/10.1016/j.gene.2012.10.091. http://www.sciencedirect.com/science/article/pii/S0378111912013960

Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007 Jan 1;165(1):1-13.

Ismaili, S (2010) Crossover comparative bioavailability study of 5-methyltetrahydrofolate glucosamine salt compared to the reference Metafolin® in healthy volunteers. IPSA-5MTHFA-583-09 Final Report.

"L-Methylfolate (5-MTHF) |." DIET vs DISEASE. N.p., 29 Nov. 2016. Web. 08 Feb. 2017

Lamers Y, Prinz-Langenohl R, Bramswig S, Pietrzik K. Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr. 2006;84:156-161.

Marini NJ, et al. (2008) The prevalence of folate-remedial MTHFR enzyme variants in humans. PNAS 105: 8055-8060.

Miller, A. (2008). The methylation, neurotransmitter, and antioxidant connections between folate and depression. Alternative Medicine Review, 13(3), 216-226.

MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338:131-137.

Natural Products Insider (2011). Gnosis’ Quatrefolic® Wins NBT Award. http://www.naturalproductsinsider.com/news/2011/05/gnosis-quatrefolic-wins-nbt-award.aspx

Selhub J (2002) Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Nutr Health Aging 6(1): 39-42.

Yigit, S., Karakus, N., & Inanir, A. (2013). Association of MTHFR gene C677T mutation with diabetic peripheral neuropathy and diabetic retinopathy. Molecular Vision, 19, 1626–1630.

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.