1. Understanding Terminology
Defining terminology, when it comes to folate is critical to understanding. The word “folate” is a generic name for the group of chemically related compounds that share a similar folic acid structure.
Folate, Vitamin B9, is thought of as one of the 13 essential vitamins needed by humans. Alone, it cannot be synthesized by the body and must be obtained from supplementation or diet. Dietary folate is a naturally occurring nutrient found in foods such as leafy greens, egg yolks, liver, citrus fruit, and legumes. Folic acid is a synthetic dietary supplement that is present in artificially enriched foods and pharmaceutical vitamins.
Neither naturally occurring dietary folate nor synthetic folic acid can be directly used in cellular metabolism, they must first be reduced (to L-methylfolate).
The process of folic acid metabolism goes as follows, first, it is converted to dihydrofolate (DHF) and then tetrahydrofolate (THF) through enzymatic reduction, a process catalyzed by the enzyme DHF reductase (DHFR). THF can be converted to the biologically active L-methylfolate by the enzyme methylenetetrahydrofolate reductase (MTHFR). This key conversion is necessary to provide L-methylfolate for the one-carbon transfer reactions needed for purine/pyrimidine synthesis during DNA and RNA assembly, for DNA methylation, and to regulate homocysteine metabolism
Homocysteine will come up frequently in this article, and it is important to note that it is a potentially toxic amino acid and cardiovascular risk factor. https://www.ncbi.nlm.nih.gov/pubmed/10720211/
“ SUMMARY: Folate is eventually metabolized into MTHFR which is the critical enzyme for almost all biological processes that involve the metabolism of folate and methionine. Think of it this way, if you put raw crude oil in your car as gasoline, it would not run for long, it must be refined first into a usable fuel.”
2. The Body’s Ability to reduce folic acid to L-methylfolate
https://rarediseases.info.nih.gov/diseases/10953/mthfr-gene-mutation#ref_13395
The human genome project shed light on many aspects of our DNA that were not previously known, one of the most well-studied variants (or “mutations) discovered was regarding the MTHFR gene. Because MTHFR is a gene, we all carry two copies, both of which are necessary for telling our body how to create an enzyme involved in breaking down the amino acid homocysteine. It’s estimated that at least 60% of the American population has a variation of MTHFR. There are two MTHFR gene variants, called C677T and A1298C, that have been an active area of study (although there are over 30 known variants). These variants are common. In America, about 25% of people who are Hispanic, and 10-15% of people who are Caucasian have two copies of C677T. Research shows that these genetic variations can double the risk of Neural Tube Defect in children born to mothers who carry the variant and increase the risk of blood clots in men.
https://rarediseases.info.nih.gov/diseases/10953/mthfr-gene-mutation#ref_13395
This mutation does not allow for the proper metabolization of folate taken into the body in conventional ways (dietary or supplementation.)
It’s estimated that at least 60% of the American population has a variation of the MTHFR gene, and as such the push for fortified foods with folic acid may be working against our better health.
“SUMMARY: Folic acid is the crude oil, MTHFR is the gasoline. People with MTHFR mutations do not have an efficient refinery built, and their body “engine” is not running properly.”
3. If you can’t break it down, what does the body do with unusable folic acid?
The use of synthetic folic acid may result in unmetabolized folic acid in the body, hence building unhealthy levels of . Unmanaged levels of homocysteine have been linked to increased risk of cancer, tumor growth, decreased cognition, and depression. In addition, increased folic acid can mask the symptoms of B12 deficiency.
https://www.semanticscholar.org/paper/Folate-supplementation%3A-is-it-safe-and-effective%3F-Frankenburg/b04429fb088dad3fa19ee5e2637ed0171da1284e
“SUMMARY: Just like our analogy, if you don’t use the proper fuel for your engine, it won’t run well, or at all for long. Build up of the unusable product becomes dangerous”
4. What do you take if you can’t take folic acid?
L-methylfolate (folate in its biologically active form) is available in supplement form. By bypassing the synthetic form of folate, and moving to the derivate L-methylfolate, the body is able to utilize the micronutrient more readily, and avoid heightened homocysteine levels and possible side effects of folic acid toxicity.
5. What are the health benefits of L-methylfolate?
Improvement of neuropathy symptoms
Studies have concluded that metabolic correctors, such as active B-Vitamins (L-methylfolate) can increase nitric oxide synthesis, increase blood flow to the peripheral nerves, improve cutaneous sensibility, improve pain.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682498/
L-Methylfolate Supplementation with Vitamin B12 and N-acetylcysteine Delays Brain Deterioration in Alzheimer’s Disease
A study on 67 patients with Alzheimer’s disease showed that L-methylfolate supplementation with vitamin B12 and N-acetylcysteine significantly slowed deterioration in the brain.
https://www.ncbi.nlm.nih.gov/pubmed/27567825
- L-methylfolate and pregnancy
L-methylfolate is crucial for pregnant women as it helps reduce the risk of developing different disorders that can occur in both the fetus and the mom. Because of the importance of supplementation, the U.S. government began mandating the addition of more folic acid into grain products (140µg/100g) in January 1998 (prior to major findings in the human genome project).
In a recent double-blind, randomized, placebo-controlled trial of 144 women of childbearing age, Lamers and colleagues demonstrated that supplementation with l-methylfolate was more effective than folic acid at increasing red blood cell folate concentrations.
Demands for folate increase during pregnancy because it is also required for the growth and development of the fetus. Folate deficiency has been associated with abnormalities in both mothers (anemia, peripheral neuropathy) and fetuses (congenital abnormalities).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218540/#B53
- L-methylfolate can help treat depression.
In a study (DB-RCT) of 123 patients with either depression or schizophrenia, a large portion of them had folate deficiencies.
https://www.ncbi.nlm.nih.gov/pubmed/1974941
Patients with folate deficiencies were given either methylfolate or placebo. The patients given methylfolate improved significantly compared to placebo both clinically and socially, especially in mood, and the difference in improvements increased with time.
https://www.ncbi.nlm.nih.gov/pubmed/1974941
In a study (DB-RCT) of 68 depression patients who did not respond to antidepressants (selective serotonin reuptake inhibitors, or SSRI), 15 mg/day of L-methylfolate was given for 12 months. Of the 68 patients, 26 had a full recovery from their depression and 35 experienced a reduction in the severity of their depression (remission)
https://www.ncbi.nlm.nih.gov/pubmed/27035404
- L-Methylfolate Can Help With Alzheimer’s Disease
People with Alzheimer’s disease are more likely to have reduced folate levels compared to healthy people. Therefore, L-methylfolate supplements can improve symptoms in those patients .
Alzheimer’s disease is also brought about by increased inflammation in the brain due to higher levels of tumor necrosis factor (TNF)-α, an inflammatory molecule, and amyloid beta plaques. In a study (SB-RCT) of 121 patients, L-methylfolate greatly reduced levels of TNF-α and amyloid beta
https://pdfs.semanticscholar.org/f716/2540053fd8e02ee4ffa2e8b6628935915e3b.pdf
In a recent clinical trial of 30 Alzheimer’s and dementia patients, L-methylfolate greatly reduced brain deterioration in the hippocampus and cortical areas of the brain.
https://www.ncbi.nlm.nih.gov/pubmed/27567825
The conversion of homocysteine slowed brain deterioration and improved cognitive functions such as learning and memory.
https://www.ncbi.nlm.nih.gov/pubmed/27567825
- New studies suggest L-methylfolate may improve Autism
In a recent study L-methylfolate decreased symptoms of aggressive and disruptive behavior in an autistic child with a MTHFR C667T mutation.
Further studies need to be done to validate these results, but various studies are showing promising results.
https://www.ncbi.nlm.nih.gov/pubmed/28272116
Vitamins are useful for migraine prevention, and riboflavin is reported to be an effective alternative prophylactic agent among pediatric and adult migraine patients by increasing the synthesis of FMN and FAD to generate phosphorylation potentials. Lowering homocysteine levels through vitamin supplementation, specifically with folic acid and vitamins B6 and B12, may reduce migraine disability in patients.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359851/
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