Vitamin B9 (Folate/5-MTHF)

1. Introduction – What is the product, chemical/botanical basics, mechanism of action

Vitamin B9, commonly referred to as Folate, is a water-soluble B vitamin essential for numerous metabolic processes in the human body. The term “folate” is a generic descriptor for a group of compounds with similar nutritional activity, including the naturally occurring food folates (tetrahydrofolate polyglutamates), the synthetic form Folic Acid (FA), and the biologically active form 5-Methyltetrahydrofolate (5-MTHF) [1].

Folic acid is the most common form used in fortified foods and most conventional supplements. However, it is biologically inactive and must be converted by the liver into the active form, 5-MTHF, through a multi-step process involving the enzyme Methylenetetrahydrofolate Reductase (MTHFR). For a significant portion of the population (up to 40% globally), a common genetic polymorphism in the MTHFR gene can impair the efficiency of this conversion process [2]. Supplementation with 5-MTHF bypasses this metabolic step, making the active form immediately available for biological use [3].

Mechanism of Action

Folate functions as a coenzyme in single-carbon transfer reactions, which are critical for the synthesis of nucleic acids (DNA and RNA) and the metabolism of amino acids. Its primary role is in the one-carbon metabolism cycle, where it facilitates the conversion of the potentially harmful amino acid homocysteine into the beneficial amino acid methionine [1]. Methionine is then used to synthesize S-adenosylmethionine (SAMe), a universal methyl donor crucial for methylation reactions, which are vital for gene expression, protein function, and neurotransmitter synthesis [2].

A key folate-dependent reaction is the methylation of deoxyuridylate to thymidylate, which is necessary for DNA synthesis and proper cell division. Impairment of this reaction due to folate deficiency leads to the characteristic large, immature red blood cells seen in megaloblastic anemia [1].

2. Chemical Composition/Key Bioactive Roles

The key bioactive form of Vitamin B9 is 5-Methyltetrahydrofolate (5-MTHF). This is the form that circulates in the blood and is directly utilized by cells.

Compound Name	Chemical Classification	Key Bioactive Role
5-Methyltetrahydrofolate (5-MTHF)	Active Folate (Methylfolate)	Coenzyme in one-carbon metabolism; methyl donor for DNA synthesis and homocysteine conversion to methionine.
Folic Acid (FA)	Synthetic Folate	Inactive precursor; requires enzymatic conversion (via MTHFR) in the liver to become 5-MTHF.
Tetrahydrofolate (THF)	Natural Folate	Central intermediate in the folate cycle, derived from food folates and a precursor to 5-MTHF.
Homocysteine	Amino Acid	Substrate for 5-MTHF; high levels are a risk factor for cardiovascular disease. Folate lowers these levels.

3. Health Benefits – Detailed health benefits with scientific evidence

Folate is integral to human health, with scientific evidence supporting its role in several major areas:

A. Prevention of Neural Tube Defects (NTDs)

The most established and critical role of folate is in preventing severe birth defects of the brain and spine, known as Neural Tube Defects (NTDs), such as spina bifida and anencephaly.

• Scientific Evidence: Extensive research, including randomized controlled trials and large-scale public health initiatives, has demonstrated that periconceptional (before and during early pregnancy) supplementation with folic acid significantly reduces the risk of NTDs by 50-70% [4]. This led to mandatory folic acid fortification of grain products in many countries.
• Dosage for Prevention: The U.S. Public Health Service recommends that all women capable of becoming pregnant consume 400 mcg DFE of folic acid daily to prevent NTDs [4].

B. Reduction of Homocysteine Levels and Cardiovascular Health

Folate, specifically 5-MTHF, is a critical cofactor in the conversion of homocysteine to methionine. Elevated plasma homocysteine levels are an independent risk factor for cardiovascular disease, stroke, and peripheral vascular disease.

• Scientific Evidence: Meta-analyses of randomized controlled trials have shown that folic acid supplementation effectively lowers plasma homocysteine concentrations [5]. Furthermore, some studies suggest that folic acid supplementation may reduce the risk of stroke, particularly in populations with low baseline folate status [6].

C. Treatment and Prevention of Megaloblastic Anemia

Folate is essential for the synthesis of DNA, which is necessary for the production of healthy red blood cells. Deficiency leads to megaloblastic anemia, characterized by abnormally large, immature red blood cells.

• Scientific Evidence: Folic acid is FDA-approved for the treatment of megaloblastic and macrocytic anemias due to folate deficiency [1]. Supplementation rapidly corrects the hematological abnormalities associated with this condition.

D. Support for Individuals with MTHFR Polymorphisms

For individuals with genetic variants of the MTHFR enzyme, the conversion of folic acid to 5-MTHF is compromised. Supplementation with 5-MTHF offers a direct-acting solution.

• Scientific Evidence: Studies suggest that 5-MTHF is a more effective strategy for increasing circulating folate levels in individuals with MTHFR polymorphisms compared to folic acid, as it bypasses the need for the compromised MTHFR enzyme [2, 3].

4. Dosage and Usage – Recommended dosages, food sources if applicable

Recommended Dietary Allowance (RDA)

Folate intake is measured in Dietary Folate Equivalents (DFEs) to account for the difference in bioavailability between food folate and synthetic folic acid.

Life Stage	RDA (mcg DFE/day)	Upper Limit (UL) for Folic Acid (mcg/day)
Adults (19+ years)	400	1,000
Pregnant Women	600	1,000
Lactating Women	500	1,000

• Conversion: 1 mcg DFE = 1 mcg food folate = 0.6 mcg folic acid from fortified foods or supplements taken with food = 0.5 mcg folic acid from supplements taken on an empty stomach [1].
• Therapeutic Doses: Doses for treating folate deficiency or high homocysteine can range from 1,000 mcg (1 mg) to 5,000 mcg (5 mg) daily, and should be taken under medical supervision.

Food Sources

Folate is naturally abundant in a variety of foods:

• Dark Green Leafy Vegetables: Spinach, kale, collard greens.
• Legumes: Lentils, beans, peas.
• Fruits: Oranges, bananas, melons.
• Fortified Grains: Enriched breads, cereals, pasta, and rice (contain Folic Acid).
• Organ Meats: Liver.

5. Safety and Precautions – Side effects, contraindications, drug interactions, warnings

Folate is generally considered safe when consumed at recommended levels. However, precautions must be taken, particularly regarding the synthetic form, Folic Acid.

Serious Safety Warning: Masking of Vitamin B12 Deficiency

The most significant safety concern is that high doses of Folic Acid can mask the hematological symptoms (megaloblastic anemia) of an underlying Vitamin B12 deficiency. While the anemia is corrected, the progressive neurological damage caused by the B12 deficiency continues, potentially leading to irreversible nerve damage [1]. This is the primary reason the Upper Limit (UL) for synthetic folic acid is set at 1,000 mcg (1 mg) for adults.

Side Effects

Side effects are rare at standard doses. Very high doses of folic acid have been associated with:

• Gastrointestinal issues (nausea, loss of appetite).
• Sleep disturbances.
• Skin reactions.

Contraindications and Drug Interactions

• Anticonvulsants: Folate supplementation may reduce the blood levels of certain antiepileptic drugs (e.g., phenytoin, carbamazepine, valproate), potentially increasing seizure frequency.
• Methotrexate: Folate is often given to patients taking methotrexate (a folate antagonist used for cancer and autoimmune diseases) to reduce side effects, but it must be carefully timed and dosed to avoid reducing the drug’s efficacy.
• Pyrimethamine: Folate may decrease the effectiveness of this antiparasitic drug.

Unmetabolized Folic Acid (UMFA)

Consumption of high doses of synthetic folic acid can lead to the presence of Unmetabolized Folic Acid (UMFA) in the bloodstream, especially in individuals with low MTHFR activity. The long-term health effects of UMFA are still under investigation, but some studies have suggested potential links to reduced natural killer cell activity and possible immune effects [1]. Using 5-MTHF avoids the accumulation of UMFA.

6. References

The following scientific sources were used to compile this information:

[1] Office of Dietary Supplements (ODS), National Institutes of Health (NIH). Folate – Health Professional Fact Sheet. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/[2] Carboni, L. (2022). Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health. Integrative Medicine: A Clinician’s Journal, 21(3), 36-41. https://pmc.ncbi.nlm.nih.gov/articles/PMC9380836/[3] Ferrazzi, E., Tiso, G., & Di Martino, D. (2020). Folic acid versus 5- methyl tetrahydrofolate supplementation in pregnancy. European Journal of Obstetrics & Gynecology and Reproductive Biology, 253, 312-319. https://doi.org/10.1016/j.ejogrb.2020.06.012[4] Centers for Disease Control and Prevention (CDC). Folic Acid: Facts for Clinicians. https://www.cdc.gov/folic-acid/hcp/clinical-overview/index.html[5] Wang, X., Qin, X., Chen, L., et al. (2007). The effects of folic acid supplementation on the concentrations of plasma homocysteine: a meta-analysis of randomized controlled trials. European Journal of Clinical Nutrition, 61(12), 1332-1338. https://doi.org/10.1038/sj.ejcn.1602686[6] Li, Y., Huang, T., Zheng, Y., et al. (2010). Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. Journal of the American Heart Association, 3(3), e000573. https://doi.org/10.1161/JAHA.114.000573