Note: Compiled content—for personal reference only. One day I’ll write a paper…

Folic Acid as L-5-MTHF

Despite what most people would assume, the body does not actually use folic acid. Folic acid must be converted to its active forms, like L-5-MTHF, to be used by the body. This is a multi-step biochemical process that occurs in the intestines and liver. In the presence of intestinal or liver dysfunction this conversion may not occur sufficiently enough to meet the body’s needs. Furthermore, up to one-third of the U.S. population may have a genetic enzyme defect that makes it difficult for them to convert folic acid (even folinic acid) into active 5-MTHF. For these individuals and many others, 5-MTHF supplementation may be a more effective method of folate repletion.

L-5 MTHF is involved in many processes in the body, including the reduction of homocysteine, the detoxification of many toxins, as well as the production of many neurotransmitters.  A healthy mood and proper cognitive function are connected to an adequate supply of L-5 MTHF.  L-5 MTHF’s most important role may be that it is involved every time we make new cells—which is all the time.  L-5 MTHF helps the body make exact replicas with exact DNA matches, reducing one of the key concerns in cancer—mutations. In concert with vitamin B12, 5-MTHF functions as a methyl-group donor involved in the conversion of the amino acid homocysteine to methionine. Methyl-group donation is vital to many biochemical conversion processes, including the synthesis of serotonin, melatonin, and DNA.

Therefore L-5-MTHF is a pre-cursor to self-confidence, a feeling of safety and security, healthy sleep patterns and appetite, as well as possibly avoiding cancers, heart disease, and dementia.


The problem with typical folic acid supplements is that many people (possibly 30% or more) have a genetic defect which limits their ability to convert folic acid into the activated form L-5 MTHF.  This defect is believed to be associated with an increases risk of certain cancers, depression, anxiety, bone density, and more.  Keep in mind that all these conditions are multi-factorial, so this genetic defect is considered just one of the many issues contributing to these conditions.   Supplemental L-5 MTHF is a perfect way to provide the activated form of folic acid, bypassing this very serious genetic defect.

400-800mcg per day of L-5 MTHF is recommended.


L-5-MTHF plays a role in DNA synthesis and repair. Inadequate levels of 5-MTHF is linked to childhood leukemia. Cancers of the colon and breast are also associated with suboptimal L-5-MTHF status, as is the precancerous condition called cervical dysplasia. In a study involving smokers, high doses of folic acid and vitamin B12 reversed precancerous cellular changes in the lungs.

Genetic Expression

L-5-MTHF is very important to genetic expression. Methyl groups are strategically placed on certain genes to inactivate them. Every cell in the human body has the genetic information to produce every other type of cell. The thing is that most of the genes are not active. Methyl groups (supplied indirectly by L-5-MTHF) silence the genes that should not be active in a given cell at a given time. This is obviously critical for good health. Some of the genes within our cells are tumor promoters. Proper methylation, which requires L-5-MTHF, keeps these genes silenced. When L-5-MTHF is lacking, these tumor promoter genes become active and trouble begins. Cancer cells have been found to be lacking in methylation.

Dopamine & Serotonin

The importance of L-5-MTHF involves more than its role in promoting proper genetic expression, DNA synthesis and repair. L-5-MTHF also plays a role in dopamine and serotonin metabolism. Not surprisingly, folic acid deficiency is a consistent finding in depression. L-5-MTHF transfers methyl groups to S-adenosylmethionine (SAM or SAMe), which is the compound that directly donates methyls to DNA and to serotonin and dopamine. Like L-5-MTHF, SAM is available in supplemental form. SAM is a popular remedy for depression and arthritis. It is likely that individuals who respond to SAM are actually in need of L-5-MTHF. It makes sense to try L-5-MTHF before SAM because it is much less expensive.


L-5-MTHF also plays an important role in detoxication of a variety of compounds, including environmental toxins (such as mercury, lead, arsenic and tin), medications, and some of the body’s own hormones. Estrogens are detoxified through methylation. Inadequate levels of L-5-MTHF cause potentially toxic build-up of estrogens in the body, which increases risk to breast, prostate and other cancers. Other conditions of estrogen excess, such as uterine fibroids and endometriosis, are also more likely to occur and be more severe. Histamine, epinephrine (adrenaline), and norepinephrine are also detoxified by methylation. Inadequate L-5-MTHF could therefore potentially worsen allergy and stress-related symptoms.


L-5-MTHF is critical for the detoxication of homocysteine, a metabolite of SAM. Like blood cholesterol, serum levels of homocysteine are directly associated with cardiovascular disease. In a recent study of people who had their atherosclerotic (clogged) coronary arteries treated by balloon angioplasty, homocysteine levels were measured. Half of the study participants were supplemented with folic acid and vitamin B12. At the end of the study, homocysteine levels and coronary artery clogging were again evaluated. The group that received folic acid and B12 had lower homocysteine levels and less blood vessel clogging. High homocysteine levels do more than damage arteries.

Conditions associated with elevated homocysteine levels include coronary artery disease, heart attack, stroke, deep vein thrombosis, peripheral vascular disease, miscarriage, birth defects, depression, sensorineural hearing loss, osteoporosis, cancer, arthritis, dementia, Alzheimer’s disease, Parkinson’s disease, and complications of diabetes. It is unfortunate that more people don’t know what their homocysteine levels are.

There is a new blood test that can identify individuals with impaired genetic ability to synthesize their own L-5-MTHF.


Esfahani ST, Cogger EA, Caudill MA. Heterogeneity in the prevalence of methylenetetrahydrofolate reductase gene polymorphisms in women of different ethnic groups. J Am Diet Assoc 2003;103(2):200-07

Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677CT polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002;288(16):2023-31

Sharp L, Little J, Schofield AC, et al. Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR). Cancer Lett 2002;181(1):65-71

Lytinski P, Loehrer F, Linder L, Todesco L, Fowler B. Effect of low doses of 5-methyltetrahydrofolate and folic acid on plasma homocysteine in healthy subjects with or without the 677CT polymorphism of methylenetetrahydrofolate reductase. Eur J Clin Invest 2002;32(9):662-68

Venn BJ, Green TJ, Moser R, Mann JI. Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am J Clin Nutr 2003;77(3):658-62


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