Folic Acid is the synthetic form of the naturally-occurring Folate (also called Vitamin B9), which is essential for creating and maintaining cells (such as red blood cells), creating and repairing DNA, preventing birth defects, regulating blood homocysteine levels (elevated homocysteine is a risk factor for heart disease), and other vital functions [1].
In fact, Folic Acid is so important that in 1998, the US rolled out a mandate that required cereal grain products to be fortified with Folic Acid [2]. According to the Food Fortification Initiative’s 2017 report [3], 87 countries have legislation for fortifying “wheat, flour, maize flour, and/or rice”.
As you can see, Folic Acid is a pretty big deal! That’s why at Rootine, we’re really pushing towards transparency around Folic Acid dosages - a number that heavily relies on genetic factors.
What happens when you take Folic Acid supplements?
To understand why Folic Acid dosages vary from person to person, we need to explore the MTHFR gene, probably the best-known nutritionally-relevant gene to date.
The MTHFR gene is deeply involved in how your body processes Folic Acid. Genetic variations in this gene can have serious consequences to your health if you’re not dosing your Folic Acid supplements correctly.
Let’s take a look at what happens when you take a Folic Acid supplement.
The process itself is pretty simple, and can be broken down into several steps:
1) Folic Acid supplements are in their “Inactive” form when you take them - meaning they aren’t converted into their naturally occurring form - Folate - just yet.
2) The DHFR gene is responsible for recognizing the Folic Acid you’re taking and converting it into its “Intermediate” form.
3) This form is then converted into the “Advanced” form.
4) This is where the MTHFR gene steps in, recognizes the Advanced form and converts it into the “Active” form [4], Folate, which goes on to do its magic (helping prevent heart disease, creating new cells, ensuring a healthy newborn, etc.)
Why the MTHFR gene determines your Folic Acid intake
The MTHFR gene is an essential step for the body to create the healthy and Active form of Folate, so anything that disrupts this step leads to an impaired ability to produce the essential Active form. “Anything” in this case being genetics.
Every person has two copies of the MTHFR gene - one from each parent. This means we have two of these genes that can carry out this important function in our body.
About 59% of the population are lucky, as they have two working copies of this gene and they can convert Folic Acid to its Active form very efficiently. About 32% of the population have just one functioning version of this gene, with the other not working well due to a variation in the gene’s genetic code. And 8% of the population have inherited two bad versions of this gene.
This means that people with two working copies create the Active form efficiently, people with only one working copy carry out this conversion about 65% as effectively, and people with two bad copies only have 30% of the conversion ability.
It is important to note that having two bad copies reduces the ability to convert Folic Acid to the Active form, but it doesn’t stop the process completely - a major misconception being perpetrated online. For more information, see the Rootine Science: Will having two bad MTHFR genes cause Folic Acid buildup? highlight box further down.
What if you have a MTHFR gene mutation?
People who have one or two copies of the inefficient version of the MTHFR gene are showing the same medical problems as people who don’t get enough Folate through their diet - in other words, they are deficient in bioactive (meaning, “having a biological effect”) Folate even if they are getting relatively normal amounts of Folic Acid. This can lead to serious health consequences.
This group is more prone to various cancers [5, 6] and has a higher chance of seeing birth defects [7], among other problems.
If you have one or two bad versions of the MTHFR gene, you may be eating Folate-rich foods that meet your daily Folic Acid requirements, but still be deficient in Folate. The only way to find out which segment of the population you fit into is to take a DNA test.
Steps to take if you have a MTHFR mutation
If you have one or two bad MTHFR genes, you have a few options to get your required daily Folate.
Option 1: Take the Active form directly
One way to tackle the problem is to actually go around the faulty gene(s) by directly taking the Active form as a supplement, which studies found works very well [8, 9].
Option 2: Adjust your dose of Folic Acid
The alternative is adjusting your Folic Acid dosage. The conversion from Folic Acid to the Advanced form actually occurs pretty quickly, and it’s at this stage when the MTHFR-gene converts it into to the Active form.
If you have one bad copy of the MTHFR gene, the conversion efficiency drops to 65% of the normal speed. This means your body can still produce the Active form, just a bit slower than usual. To sidestep this you can increase Folic Acid dosage.
Think of it this of it this way: if you take 10% of your daily required Folic Acid intake, the most that can be converted to Folate is 10%. If you double your daily dosage (200%), and your MTHFR gene is causing you to operate at 65% conversion efficiency, you’ll be able to reach your daily requirement.
Imagine a garden hose. If you have a relatively thin hose, it will take longer to, say, fill a bucket with water than with a regular-sized hose. To compensate, you might turn up the water pressure (aka increase the Folic Acid dosage) to ensure the bucket gets full in the same amount of time.
This is a generally acceptable approach for people with one bad copy of the gene. If you have two bad copies, where conversion rate drops to around 30%, this option reaches its limits. For more information about gene mutations that lower Folate conversion efficiency, see the Rootine Science box directly below.
Rootine Science: Alternative MTHFR gene mutations
To keep it simple, we’ve only been discussing the C677T mutation (or, “polymorphism”) within the MTHFR gene. It’s worth noting that other polymorphisms exist within this gene that can alter Folate conversion efficiency. One example is the A1298C polymorphism.
These two polymorphisms - C677T and A1298C - can be co-inherited, meaning that you could have one copy of the MTHFR gene with a C677T polymorphism, and the other with A1298C. The C677T polymorphism typically reduces conversion efficiency by around 35% per copy, and 1298C reduces conversion by around 20% per copy [10, 11, 12, 13].
When considering both polymorphisms and other lifestyle factors, a spectrum of Folate conversion efficiencies emerge from a population standpoint. At Rootine, we account for such mutations when we analyze your DNA test results, ensuring your nutrient packets contain the appropriate dosage of Folic Acid to account for polymorphisms like C677T and A1298C.
Are you taking too much Folic Acid?
If you have two bad MTHFR genes, and your body is converting Folic Acid to its Active form (Folate) at 30% efficiency, increasing the dosage isn't such a good idea - but not for the same reasons some researchers currently believe.
Rootine Science: Will having two bad MTHFR genes cause Folic Acid buildup?
There is a common misconception circulating online that originates from an incomplete understanding of the different types of Folate (the Active form we’re discussing is just one type of Folate, which is specifically converted from Folic Acid). Unfortunately this misconception has even reached articles that have a scientific background [14, 15].
The assumption is that if both MTHFR genes are bad - and recall that MTHFR is responsible for the last step in the conversion of Folic Acid (the Inactive form) to its Active form - Folic Acid accumulates to harmful levels.
The reality is that the MTHFR gene only carries out the last step of the conversion, so all that’s accumulated is the harmless Advanced form, not the Inactive form (which can indeed be harmful if enough is accumulated). What ends up being harmful is the resulting Folate deficiency!
When is taking too much Folic Acid harmful?
This isn’t the whole story. There is a case where a genetic variation may lead to harmful effects when taking standard Folic Acid, but it’s a different gene altogether.
If you look up at any of the illustrations above, you’ll see that the DHFR gene is responsible for the conversion of Folic Acid to Folate’s Intermediate form [16]. The only way Folic Acid (the Inactive form) can accumulate to harmful levels is if you supply more Folic Acid than the DHFR gene can handle. The exact overload dosage is controversial, and ranges from 500mcg to 1,000mcg. If you look at any vitamin isle you’ll see daily doses ranging from just under to just over this range.
If you happen to be one of the people with a common DHFR gene variation, the conversion from the Inactive to Intermediate form might be impaired [17]. According to the European Food Safety Authority, you can have a maximum daily intake of 1,000mcg of Folic Acid before the nutrient has adverse effects on your body [18]. But for those with the DHFR variation, the recommended upper intake level for Folic Acid is 500mcg.
That’s a 50% drop below the normal recommended Folic Acid dosage - not something you want to play guessing games with.
At Rootine, we stress the importance of understanding lifestyle factors, key genetic variations and blood levels in order to figure out the appropriate dosage for essential nutrients like Folic Acid.
Folic Acid Dosage Summary
Taking all of this into account, a clear picture emerges:
Folic Acid deficiency aspects
1) Having enough bioactive Folate is dependent on the MTHFR gene.
2) Based on your genetics, you may need more Folic Acid.
3) Alternatively, you may need the already active form of Folate.
Folic Acid toxicity aspects
1) Taking Folic Acid supplements is not harmful, even if you don’t have the good version of the MTHFR gene.
2) Taking Folic Acid supplements can be harmful if you don’t have the right version of the DHFR gene.
Depending on your genetic result, Rootine chooses the best strategy to supply the right form of Folate at the right dosage in your daily packet of microbeads.
A quick note about Vitamin B12 and Folic Acid
If you recall, Folate is also called Vitamin B9. The B vitamins play nice with one another, so it’s important to understand Vitamin B12’s role when discussing Folic Acid and Folate.
Vitamin B12 works alongside Folate to lower harmful homocysteine levels in the blood, reducing the risk of heart disease. This is why when talking about adequate Folate supply, Vitamin B12 is always part of the equation.
We recommend you explore our Vitamin B12 piece to fully understand how B9 and B12 ensure you have a healthy, long life.
Get personalized nutrients delivered to your door
Our personalized nutrient packets include Folic Acid and up to 17 other vital nutrients - all dosed according to DNA kit results and lifestyle assessment. To see what's included in your monthly subscription of Rootine vitamins and minerals, see the link below.
1. Harvard Health Publishing. “Ask the Doctor: Does Folic Acid Improve Immunity?” Harvard Health Blog, Harvard Health Publishing, Feb. 2011.
2. Crider, Krista S et al. “Folic acid food fortification-its history, effect, concerns, and future directions” Nutrients vol. 3,3 (2011): 370-84.
3. Food Fortification Initiative 2017 Annual Report.
5. He, Lilin and Yongxiang Shen. “MTHFR C677T polymorphism and breast, ovarian cancer risk: a meta-analysis of 19,260 patients and 26,364 controls” OncoTargets and therapy vol. 10 227-238. 6 Jan. 2017, doi:10.2147/OTT.S121472.
6. Ergül, Emel & Sazci, Ali & Utkan, Zafer & Canturk, Nuh Zafer. (2003). Polymorphisms in the MTHFR Gene Are Associated with Breast Cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 24. 286-90. 10.1159/000076460.
7. Williams, Jennifer et al. “Updated estimates of neural tube defects prevented by mandatory folic Acid fortification - United States, 1995-2011” MMWR. Morbidity and mortality weekly report vol. 64,1 (2015): 1-5.
8. Prinz-Langenohl, R et al. “[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->T polymorphism of methylenetetrahydrofolate reductase” British journal of pharmacology vol. 158,8 (2009): 2014-21.
9. Bernard J Venn, Timothy J Green, Rudolf Moser, Jim I Mann; Comparison of the effect of low-dose supplementation with l-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study, The American Journal of Clinical Nutrition, Volume 77, Issue 3, 1 March 2003, Pages 658–662.
10. Chango, A. et al. The effect of 677C—>T and 1298A—>C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects. Br J Nutr 83, 593-596 (2000).
11. Van der Put, N. M. et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62, 1044-1051, doi:10.1086/301825 (1998).
12. Weisberg, I., Tran, P., Christensen, B., Sibani, S. & Rozen, R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64, 169-172.
13. Lievers, K. J. et al. A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk. J Mol Med (Berl) 79, 522-528.
14. Leech, Joe. “MTHFR Mutation Guide For Non-Sciencey Types! Symptoms and Diet Explained.” Diet v.s. Disease.
15. Tafuri, Laura & Servy, Edouard & Menezo, Yves. (2018). The hazards of excessive folic acid intake in MTHFR gene mutation carriers: An obstetric and gynecological perspective. Clinical Obstetrics, Gynecology and Reproductive Medicine. 4. 10.15761/COGRM.1000215.
16. Kalmbach, Renee D et al. “A 19-base pair deletion polymorphism in dihydrofolate reductase is associated with increased unmetabolized folic acid in plasma and decreased red blood cell folate” Journal of nutrition vol. 138,12 (2008): 2323-7.
18. Tolerable Upper Intake Levels For Vitamins And Minerals. European Food Safety Authority, 2006.
