Folic Acid, More Complicated Than You Might Think

Folic Acid Awareness Week

I couldn’t get out today for National Service Day, so I decided to instead do a blogpost that I hope will be useful to some. I bit my lip (figuratively) during National Folic Acid Awareness Week, and didn’t say what I was thinking. In part, that because I was having a particularly bad bout of reactions to having been “glutened.” I am one of those with celiac, so gluten free diet is not optional, not part of a fad, not for weight loss, but profoundly essential to my health and well-being. One of the issues of going gluten-free is that most Americans receive substantial vitamin supplementation from foods made with enriched wheat flour. Cut out the wheat flour, and you’ve cut out the enrichment. That means you’ve also cut out most of the folic acid supplementation, at least until you get pregnant (assuming that’s possible) and are given a script for pregnancy vitamins. My first pregnancy was the first time in my life that I actually felt GOOD. At the time, I thought that was because of the hormones. Now, I think it was the folic acid in the vitamins. I’ve had reason to learn a LOT about folic acid recently. It’s complicated.

But this is all getting a bit ahead of the story. Let’s back up for a minute. I’m saying folic acid is complicated. Actually, EVERYTHING is complicated, especially in healthcare, especially if you really dig into it deeply. When on the patient side of matters, as a non-expert, it can be hard to see the myriad issues and factors that tie into making what appears on the surface as a simple decision. Actually, it isn’t that easy for doctors and clinical care providers, either. It is entirely possible to start digging into any medical or healthcare topic, and just keep digging and digging, because there is always more. All of us have to draw the line somewhere, but the line is usually in different places for nonprofessionals than it is for professionals. When doctors explain something to a patient there is a certain amount of necessary censorship going on. It isn’t censorship in the sense of “I don’t want you to know this,” but rather in the sense of, “I have fifteen minutes, not weeks or months to go through the portion of a medical education that would MOSTLY explain this.” Trying to explain anything fully is a process of years or lifetimes. What the doctor tells a patient is a process of providing the most important parts of the information for you to take action or change behavior, combined with trying to guess how much background you have and how much detail to use, what is needed to be persuasive to you. This is really HARD.

So, I’ve had issues that have inspired me to learn more about this one small area, folic acid and folate, and I thought perhaps explaining how and what I’ve learned about this might serve as an example for others, with their own health issues. It might also, perhaps, help people understand better why it is so hard for doctors and patients to talk the same language and understand each other. Now, let’s start by taking a look at folic acid, what it is for, why it’s important, and why it is put in our foods. Please note in advance that I am oversimplifying greatly. Also note, I am NOT a doctor, and don’t have all the science background that goes along with the training.

Folic Acid Space-filled Molecule
1) What is folic acid?

CDC: “Folic acid is a type of B vitamin. It is the man-made (synthetic) form of folate that is found in supplements and added to fortified foods.”

ME: Did you notice they said folic acid is synthetic folate? That turns out to be really important for some people, even though it isn’t a big deal for most. Basically, though, wherever authorities say “folic acid” is important or needed, it is probably slightly inaccurate, and what they really mean is that “folate” is important or needed, a specific type of folate (since there are a few), and folic acid is one way to get that type of folate into your body. That happens because when most people eat food with folic acid, their body will digest it and break it down into the type of folate we need to be healthy. Right there, we have a major source of confusion, by this inaccuracy in the preferred language used to discuss the topic.

ME 2: It isn’t just “folic acid” versus “folate” either. There are so many terms used to describe this that it makes my head dizzy. I can’t remember them all, so I have to write it down. This is important because when you go searching for information, you will find very different information depending on which terms you use. Here are some of the other names used for this (and they may not all mean exactly the same thing): Folacin, Folate, Pteroylglutamic acid, Vitamin B9, Vitamin Bc. Other names used in vitamins that have folate instead of folic acid: 5-MTHF, L-5-MTHF, L-methylfolate, bioactive folic acid, Levomefolic acid, metafolin, metafolate, methylfolin, optimized folate. And then there are the chemical names: (2S)-2-[(4-{[(2-amino-4-hydroxypteridin-6-yl)methyl]amino}phenyl)formamido]pentanedioic acid or N-​(4-​{[(2-​amino-​4-​oxo-​1,​4-​dihydropteridin-​6-​yl)​methyl]​amino}​benzoyl)-​L-​glutamic acid; pteroyl-L-glutamic acid. And names of related compounds that may or may not be what’s wanted, such as Folin and Folinic acid. I am not even going to talk about the other kinds of folates, which have their own names that sound a lot like the other names. Like I said, it’s enough to make your head hurt.

Baby! Baby! Baby sighting at the office
2) Why is folic acid (ahem, folate) important?

What folate does in the body is basically to repair damage as it appears. It makes proteins the body needs, it breaks down proteins the body doesn’t need. It helps make red blood cells to carry oxygen throughout the body. It helps make DNA, to tell your body what it should be doing. It can’t do it alone — folate works with vitamin B12 and vitamin C to do this, and doesn’t work right without them.

Too Little Folate =

Birth defects (if you’re pregnant while folate deficient)
Menstrual problems
Poor growth
Gray hair
Mouth sores or ulcers
Leg sores or ulcers
Swollen tongue (glossitis)
Peptic ulcer
Palpitations (irregular heartbeat)
Shortness of breath
Tingling and numbness in the fingers and toes
Sleep problems
Memory loss
Cancer (especially colorectal)

‘Nuff said? Folate! Good stuff!

Veins & Cell Structure
3) Where is folic acid or folate in our foods? Why is it added to some foods?

The big deal is the birth defects. Nobody plans to have a baby with a birth defect. Some birth defects aren’t preventable, but the ones that come from being folate deficient are 100% avoidable and unnecessary.

“World-wide, at least 22,000 fatal or disabling birth defects such as spina bifida are prevented annually. That’s 60 babies a day. Countries around the world report 30% to 70% declines in NTDs after fortification begins. Countries save millions of dollars in healthcare cost when spina bifida is prevented.” (CDC)

Young women of childbearing age often don’t make a lot of money, which may show up in their diets. They might not feel they can afford vitamins, or might think they don’t need them. With both diet and vitamins at risk, they may not be getting enough folate in their diet. At least, not enough to count on growing a healthy baby, if they find themselves pregnant unexpectedly. Docs were seeing babies with neural tube defects, too many babies. Public health folk wanted to do something to try to help the young women have healthier babies. Imagine the conversation.

A: “So, is there anything we can do to make sure young women get enough folate to have healthy babies?”
B: “We can give them vitamins when they get pregnant.”
A: “That’s too late. Sometimes they don’t even know they are pregnant for months! We need to get folate into them before they get pregnant.”
B: “They should eat more green leafy vegetables. And beans. And liver! Those are great sources of folate.”
A: “Most kids don’t eat green leafies. And liver? Are you kidding? Kids don’t eat liver! And we can’t make them do it.
B: “We could import Marmite from Australia. That’s high in all kinds of good stuff.”
A: [laughs] “Let’s look at what they DO eat. They eat lots of carbohydrates, though. Sandwiches, cakes, doughnuts, bread, things like that. Burgers. Fries. Chips.”
B: “Hunh. Well, what if we put folate in the flour? It won’t cover everything, but it will put some in most of their foods. Might be enough.”
A: “Not a bad idea. But we couldn’t use folate. Not stable enough, it wouldn’t last. Easily destroyed by cooking. Maybe use folic acid? When people digest it, their body will convert it into folate.”
B: “Sounds good to me. But, now, if we put folic acid in the food supply, then it will get to EVERYONE. Could that be a problem? What if someone gets too much folic acid?”
A: “Nah. It’s water soluble. If someone needs it, their body will grab it. If they have enough already, their body will just wash it out. No problem.”
B: “Alright then, if it can’t hurt and it might help, let’s give it a try.”

Anyway, that’s my brief and simplified understanding of the logic behind why we supplement our food with folic acid. Fortifying flour with folic acid has been going on for 15 years in the United States and is now happening in over 50 countries around the world. Flour is the main place you’ll find it, but sometimes also in rice. Think when you see the word “Enriched” next to flour or rice. That is probably the extra folic acid as well as some other vitamins and minerals.

What's working for me. So far.
4) Sounds like folic acid is really good! Or was it folate? Does it really make a difference?

This is where it gets really tricky. Frankly, we are learning a lot fast, but we really don’t know that much and aren’t putting the pieces together fast enough to answer the questions that are arising. Questions like:

Is the amount of folic acid in the flour the right amount? Do we need more?
Can too much folic acid cause cancer?
Can too much folic acid cause heart attack for people with heart problems?
What is too much, when it comes to folate and folic acid?
What about folk with MTHFR deficiency? Is folic acid safe for them in the same way as for other people?

These are all questions that have come up in recent years, where research suggests there might be a potential problem but we don’t really have enough research yet. For preventing birth defects, the experts would really like to see the amount of folic acid in flour doubled. The question of whether folic acid can cause cancer not just where there is too little but also when there is too much got a lot of press a couple years ago, but again there isn’t yet enough data to really say. Ditto with heart attacks. If you ask doctors, many will say there is no such thing as too much folic acid, and others will say, “Well, let’s be cautious.” The Dietary Reference Intakes from the Institute of Medicine recommend that the question needs more study. And MTHFR? Whoa! What the heck is that?

MTHFR stands for Methylenetetrahydrofolate reductase. The MTHFR gene encodes how the MTHFR enzyme works for that person, and that will say how well that individual can digest folate and folic acid, and how well their body can make use of these. MTHFR deficiency or MTHFR mutation both mean that a person has one or two defective genes, which means people with MTHFR deficiency have problems with folic acid and folate. There is a severe form of this that is extremely rare, but until recently no one really knew that there was a mild version. The current estimate is that roughly 10% of Caucasian people in the United States would have two copies of MTHFR mutation (and we only get two copies of the gene, so that means both have the defect). More for Hispanics and folk from the Mediterranean regions, less for African-Americans. Almost half of the people would have at least one copy of a mutated MTHFR gene. People with two copies of the defective gene would be not unlikely to have this mild version of the MTHFR deficiency. Until genetic tests and genomic scans became cheaper and more available, this was something that even doctors usually didn’t know about. Most people would live their entire life never knowing that they had this problem.

Now that it is possible to more easily identify this, more research is coming out on MTHFR. Today, a search in Pubmed for reviews on MTHFR pulls up articles on colorectal cancer, cardiovascular disease, migraine, Alzheimer’s prevention, autism, head and neck cancer, pregnancy loss, hearing loss, neuropathy, erectile dysfunction, and squamous cell carcinoma.

MTHFR Cites by Year

Citations from Pubmed for articles about MTHFR by Year

What this tells us is that there is something going on with folate metabolism that might have broader implications than previously thought, and that there is growing interest in this as a research area. However, research is still extremely sparse and we really don’t know much. What we know is that the research to date is raising many questions, with researchers interested in MTHFR suggesting tentatively that people with problems processing folic acid and problems getting folate into their body might need extra vitamins, might have different requirements for folate for health, and that we need to know more about folate metabolism in general. The other side of the question that has been raised is if they can’t properly digest folic acid, than are they more at risk for side effects from folic acid, or are they even able to clear the folic acid from their bodies at the same rate as people with normal folate processing genes. Some docs are recommending that folk with mild MTHFR deficiency take more folic acid, others recommend that they avoid folic acid and take the folate instead.

Because we are just started to be aware of these potential problems and don’t really know enough, the usual response is to not worry about it. But it really does make a difference if you are going to start putting folic acid into the food supply. For me, because the folic acid supplementation is in wheat flour, and I have celiac and can’t eat wheat flour, this is less of an issue. My issue is that without the fortification of the flour, am I getting enough folate at all? And as someone with two defective copies of the MTHFR gene, am I getting enough folate, and the right kind of folate? And because we don’t have a strong solid research base in this area yet, all we have a guesses and trials, and seeing what seems to make any particular person feel better. But that doesn’t help anyone else, does it? And it doesn’t tell us the longterm effects of taking what might be too much folate, and what are the risks associated with that. There is just so much that we don’t know.

Like I said, it’s complicated. The idea that folic acid is a uniform public good is absolutely undeniable. But whether it might also be a risk to certain subgroups is something we are still trying to find out. Anytime that a doc is talking over an issue with a patient, chances are that most of the issues are like this one — a work in progress, and more complicated than you think.


CDC: Facts about Folic Acid:

CDC: Folic Acid:

CDC: IMMPaCt – International Micronutrient Malnutrition Prevention and Control Program: Flour Fortification Initiative: Celebrating 15 Years of Healthier Children Due to Fortified Flour:

Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. 1998. Folate. pages 196-304.

Genetics Home Reference: MTHFR:

Koontz JL, et al. Comparison of total folate concentrations in foods determined by microbiological assay at several experienced U.S. commercial laboratories. J AOAC Intl 2005 88(3):805-813.

Lab Tests Online: Vitamin B12 and Folate Deficiency:

National Folic Acid Awareness Week:

MedlinePlus: Folate deficiency:

MedlinePlus: Folate-deficiency anemia:

MedlinePlus: Folic Acid:

MedlinePlus: Folic Acid in Diet:

Methylenetetrahydrofolate Reductase (MTHFR) Genetic Polymorphisms and Psychiatric Disorders: A HuGE Review:

MMWR. Trends in Wheat-Flour Fortification with Folic Acid and Iron — Worldwide, 2004 and 2007. January 11, 2008 / 57(01);8-10.

National Agricultural Library: Why Every Woman Needs Folic Acid:

NIH Office of Dietary Supplements: Dietary Supplement Fact Sheet: Folate (Health Professional):

Oakley GP. Folic acid and vitamin B12 fortification of flour: a global basic food security requirement. Public Health Reviews 2010;32:284-295. PDF:

PGEN Participant: What Works for Me. So Far. Right Now.

PubMed Health: Folate Deficiency:

Sanghavi DM. A Growing Debate Over Folic Acid in Flour. NY Times October 12, 2011.

University of Maryland Medical Center: Folate deficiency – Overview.

Women’s Health: Folic Acid Fact Sheet:


5 responses to “Folic Acid, More Complicated Than You Might Think

  1. Pingback: More on folate genes, plus exomes, genomes, cancer, and Jay Lake | PGen Participant

  2. This is the best article I’ve read about folic acid vs folate. Thanks for writing it! May I ask, what supplements do you take?


Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )


Connecting to %s