Updated: Jul 31
It's not undebatable about folate's health benefits, including preventing neural tube defects (NTD), driving for the folic acid food fortification that became mandatory in the US in 1998. However, do you know there are two forms of folic acid in supplements: folic acid and folate? What's the difference between the two?
Nowadays, many multivitamins, prenatal multivitamins, and most commercial flour, bread, and cereal products contain or are fortified with this synthetic nutrient. Next time when you choose a bottle of a supplement and reach a loaf of bread at the store, check the ingredients, and you will know what I am talking about! I want to challenge this approach for the following reasons:
Folic acid hasn't been tested enough on humans. Moreover, specific DHFR variants could make it more problematic.
The metabolism of folic acid begins with the DHFR enzyme catalyzing the two-step reduction of folic acid by converting it to dihydrofolate (DHF) and then to the active coenzyme tetrahydrofolate (THF).
Next, serine hydroxymethyltransferase converts THF into 5,10-methylene-THF, which is then converted to the metabolically active 5-Methyl THF by MTHFR [1,2].
It's critical to acknowledge that folic acid provides no physiological benefit until it's converted into dihydrofolate. A DHFR 19-base pair insertion-deletion polymorphism with del/del genotype is highly prevalent, reaching 20% homozygosity in the US population. This genotype has been associated with increased un-metabolized folic acid in plasma at intake >500 mcg/day and decreased RBC folate at intake <250 mcg/day . Adding dietary folic acid on top of it can potentially shut down the folate pathway, making it challenging for the body to make methyl-folate, which could eventually result in functional folate deficiency and mask the symptoms of B12 deficiency [3,4].
The compelling evidence also shows that this polymorphism is associated with adverse health outcomes and can be worsened by folic acid supplementation, with the DHFR 19del allele being associated with greater breast cancer risk and del/del homozygous mothers at a higher risk of having a child with early childhood retinoblastoma .
These findings are clinically relevant, especially considering the wide use of folic acid and the prevalence of the DHFR 19-bp del/del genotype. Taking a deeper dive into this subject only reinforced my views: The use of folic acid supplementation and its food fortification should be seriously questioned or even banned.
The current data on the DHFR 19-bp polymorphism on NTD, carcinogenesis, and cognitive function are still conflicting, and I hope to get more clarification. I'd also like to see more emerging literature to conclude that 5-MTHF is an effective and safer form of folate for preventing NTD and lowering folate deficiency risks.
Jenny Noland, MS, CNS, CNGS, CKNS, LDN, MBA
Functional Nutritionist in Eugene, Oregon
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S. Askari B, Krajinovic M. Dihydrofolate Reductase Gene Variations in Susceptibility to Disease and Treatment Outcomes. Curr Genomics. Published online 2010. doi:10.2174/138920210793360925
Caterina RD, Martínez JA, Kohlmeier M. Folate and Vitamins B6 and B12. In: Principles of Nutrigenetics and Nutrigenomics: Fundamentals of Individualized Nutrition. London: Academic Press an imprint of Elsevier; 2020:298-301.
says: E, Joy-Dr. Ben Lynch Team Member says: October 12, Joy-Dr. Ben Lynch Team Member says: et al. Folic Acid Side Effects. Dr Lynch. https://www.drbenlynch.com/folic-acid-side-effects/. Published October 30, 2020. Accessed January 28, 2021.
Nazarian RS, Lamb AJ. Psoriatic flare after the concomitant administration of L-methylfolate and methotrexate. JAAD Case Reports. 2017;3(1):13-15. doi:10.1016/j.jdcr.2016.10.001