Folic acid is not the health-promoting vitamin you think it is, and researchers are uncovering risks
With the over-processing of foods has come the fortification of foods...but there's one vitamin in particular that no one is talking about that may actually pose a health concern: Vitamin B9, specifically, Folic acid.
What?! Folic acid? Don't women need to take it in pregnancy to prevent neural tube defects? How can it be a problem?
It's a problem because folic acid is synthetic, and the conversion that has to take place in the body to make it usable is very, very slow... so what this means, is there is unmetabolised, inactive folic acid floating around in the blood stream. Indeed, a 2015 research study found unmetabolised folic acid in nearly all serum samples from U.S. children, adolescents and adults, regardless of whether they took supplements or not.
Folic acid is not to be confused with the natural, biologically active forms of folate: methylfolate and folinic acid. These bioavailable forms are easily used by the body.
But first...Why is there so much folic acid in food anyway?
In the 1990's the U.S. Public Health Service recommended that all women of childbearing age consume 400 mcg of folic acid daily from fortified foods or supplements, or both, in addition to that obtained through a normal diet, in order to prevent neural tube defects. Since up to 50% of pregnancies are unplanned, and the neural tube closes within a month of conception (before women realize they're pregnant), a woman must supplement folic acid in advance of becoming pregnant.
The only way to get an entire population of women to align with these guidelines was to fortify foods (all types of flour, enriched pasta and cornmeal), and Canada followed suit to harmonize trade practices with the U.S.
On average, for every 100 grams of flour, there is 100-150 mcg of folic acid. To put this in context, a cup of Kellogg's Special K cereal has 676 mcg, a cup of Cherrios has 493 mcg, and a cup of enriched white wheat flour has 364 mcg.
The human body is very limited in how much folic acid it can convert, so a one-time dose that exceeds anywhere from 200-260 mcg, or consecutive small doses of 100 mcg, within a day have been shown to result in unmetabolized folic acid in the blood stream.
What does this unmetabolised folic acid do?
Researchers are in the early stages of uncovering the ways it may interact and influence body systems (which you'll see in a moment is also very complex just from an epigenetic perspective alone). Unmetabolised folic acid appears to prevent the "good" folate from doing what it needs to do and it does this by blocking folate transport proteins and folate receptors.
Other identified impacts are summarized well in this quote from the 2017 Weins and DeSoto paper:
"This raises concerns about detrimental effects of high serum synthetic folic acid. These include effects on the enzyme dihydrofolate reductase, regulation of folate uptake in renal and intestinal epithelia, reduced cytotoxicity of natural killer T cells in postmenopausal women, dysregulation of gene expression in lymphoblastoid cells, and cytotoxicity to neural tissues and mental health. In addition, evidence shows that high folic acid intake is associated with an increase in incidence of twin births, body fat mass and insulin resistance in offspring, increased risk of colorectal cancer, and other adverse outcomes."
Here is what "good" methylfolate does in the body:
prevents birth defects of the brain and spine
is required for proper cell division and growth
makes DNA and RNA
helps in the production of red blood cells
breaks down and recycles various amino acids in the body
appears to reduce the risk of some cancers
is required for neural development and neurological health
plays a role in reducing cardiovascular disease (particularly homocysteine)
donates methyl groups and plays an essential role in epigenetics
Epigenetics is a newer field of science that looks at how the environment impacts our genes -- essentially turning our genes "on" or "off". The way this happens is in large part through the process of DNA methylation. This is why a healthy lifestyle is so important -- even if someone has genes of "risk" for a certain condition, it is the environment that determines how that gene gets expressed.
Recently some researchers have shifted focus to the possibility that folic acid intake may lead to changes in epigenetic patterns. There is experimental animal and in vitro research documenting negative effects of excess or unmetabolized folic acid on genetic programming and neuronal development. Researchers indicate that there are countless, plausible ways that folic acid might affect any disease of interest, either positively or negatively, because of folate's role in epigenetics.
Animal models have shown it's possible to expose an animal to folic acid prenatally and thereby cause a specific DNA methylation change, which results in determining how the offspring looks, regardless of the parent's diet.
Researchers site concerns that unmetabolised folic acid may even have an influential role in the development of autism. Given the significantly elevated folic acid dosing many women take in pregnancy (often 1000 mcg/day), in addition to fortified food consumption, they are the demographic with the highest blood levels of unmetabolised folic acid. At least three studies have suggested that high levels of folic acid supplementation when taken throughout pregnancy may be associated with negative neurodevelopmental outcomes in offspring.
Armed with this knowledge, what are the best next steps?
First and foremost, avoid folic acid whenever possible, and thereby avoid processed foods. Folic acid is synthetic and its poor conversion leads to the accumulation of unmetabolised folic acid in the blood, which poses potential health risks.
Only ingest the natural folates found in the form of methylfolate or folinic acid. These are easily used by the body and found in liver, dark green leafy vegetables, beans, asparagus, brussel sprouts and various other food sources.
Be very cautious when purchasing supplements. The vast majority of the time they will contain cheap folic acid. Even if a label says "folate", unless they clearly describe what kind of folate it is, always assume it's just folic acid. The "good" forms of folate to look for include methylfolate, methyltetrahydrofolate or MTHF, or folinic acid or calcium folinate. High quality professional line products will use the active, bioavailable forms. The prescription form of folic acid you want to look for is Leucovorin (often used to decrease the toxic effects of methotrexate and pyrimethamine).
There's an important note to add to this discussion. There is a significant percentage of the population that is unable to properly metabolize folate due to defects in the MTHFR enzymes they carry (commonly referred to as "MTHFR mutations"). This means that for these people supplementing with methylfolate is essential, because it can enter the folate cycle directly, without the need for enzymatic modification.
Because folate needs can vary between individuals, and most people don't know their genetics when it comes to folate metabolism, you never want to run headlong into taking folate. I recommend working with a health professional who is informed on this and is able to create an individualized treatment plan.
Crider KS, Bailey LB, Berry RJ. Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients. 2011;3(3):370-384. doi:10.3390/nu3030370
Field MS, Stover, PJ. Safety of folic acid. Ann N Y Acad Sci. 2018 Feb; 1414(1): 59–71.
Gristan YD, Moosavi L. Folinic Acid. [Updated 2020 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK545232/ Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr. 1997 Jun;65(6):1790-5. doi: 10.1093/ajcn/65.6.1790. PMID: 9174474.
Koseki K, Maekawa Y, Bito T, Yabuta Y, Watanabe F. High-dose folic acid supplementation results in significant accumulation of unmetabolized homocysteine, leading to severe oxidative stress in Caenorhabditis elegans. Redox Biol. 2020;37:101724. doi:10.1016/j.redox.2020.101724
Pfeiffer CM, Sternberg MR, Fazili Z, Yetley EA, Lacher DA, Bailey RL, Johnson CL. Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults. J Nutr. 2015 Mar;145(3):520-31. doi: 10.3945/jn.114.201210. Epub 2014 Dec 10. PMID: 25733468; PMCID: PMC4336532.
Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2010 Aug;49(8):535-48. doi: 10.2165/11532990-000000000-00000. PMID: 20608755. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014 May;44(5):480-8. doi: 10.3109/00498254.2013.845705. Epub 2014 Feb 4. PMID: 24494987.
Tasnim Nathoo, Christina P. Holmes, Aleck Ostry, An analysis of the development of Canadian food fortification policies: the case of vitamin B, Health Promotion International, Volume 20, Issue 4, December 2005, Pages 375–382, https://doi.org/10.1093/heapro/dai015
Vidmar Golja, Maša et al. “Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate.” Journal of clinical medicine vol. 9,9 2836. 2 Sep. 2020, doi:10.3390/jcm9092836 Wiens D, DeSoto MC. Is High Folic Acid Intake a Risk Factor for Autism?-A Review. Brain Sci. 2017;7(11):149. Published 2017 Nov 10. doi:10.3390/brainsci7110149