Folate. It’s a hot topic for people who are concerned about MTHFR gene mutations. In particular, the relationship between MTHFR, folate and folic acid can be a bit confusing.
Facebook forums are full of people asking questions about it:
- ‘What form of folate should I take for MTHFR?’
- ‘Do I really have to avoid folic acid?’
- ‘Is folic acid bad for everyone, or only if you have the mutation?’
There is a lot of confusion out there. On some level it makes sense that if you have trouble making enough methylfolate with your mutated gene, then you should take more folic acid so that there’s plenty available.
But here’s the problem with that: folic acid is not the same thing as natural folate. Worse, taking folic acid can cause a LOT of problems.
Before we go on it would be helpful if you already understood a bit about the MTHFR gene and mutations. You can read my primer on that subject here if you need a refresher. Otherwise, let’s get into it!
In a Nutshell
…from a biochemistry perspective, eating folic acid makes NO SENSE
This can be a complicated topic. Here’s the short version:
- Your body needs methylfolate to function properly;
- Methylfolate is the end product of the folate cycle;
- Taking synthetic folic acid stops your body’s folate cycle working properly;
- That is bad for everybody, but especially for people with the MTHFR gene mutation.
Bad Advice about MTHFR and Folic Acid
Unfortunately the advice given to many patients with MTHFR gene mutations by medical doctors is “take extra folic acid”.
That advice demonstrates a lack of understanding about both MTHFR and folate.
The flawed reasoning goes like this:
- The patient has the MTHFR gene mutation;
- That means they have trouble making methylfolate from folic acid;
- Therefore we should give them LOTS of folic acid so that the enzyme has plenty to work with and we can force it to work harder.
This approach simply doesn’t work.
Methylfolate is our goal.
It’s the form of folate that can be used to make SAMe, a molecule that powers the work of methylation in your body.
For now, think of methylfolate as our finish line in the folate cycle. It’s the form of folate that we want to get into our cells. It’s also what MTHFR patients have trouble making, because it is made by the MTHFR enzyme.
The folate in foods like leafy greens and liver goes through a number of steps to be converted into methylfolate. When we eat some lovely lettuce, the folate in that lettuce is good stuff, but it’s not methylfolate. What the body wants to do is take that lettuce-derived folate and make methylfolate with it.
Perfect, because this is what we want, too!
The Folate Cycle
Lettuce folate, as we shall now call it, must go through a process much like a production line in a factory, called the folate cycle.
In a factory, different machines perform different functions along an assembly line to produce the end product. The products are transported from machine to machine along conveyor belts or through funnels and pipes.
Our folate cycle is like this. Instead of machines, we have enzymes. Instead of conveyor belts and pipes, our body has transporter proteins and carriers that get folate to the places it needs to be (i.e. into the cells).
Enzymes – The Machines in our Folate Factory
Each enzyme takes a molecule and changes its shape or chemical makeup, and then spits it out ready to move to the next enzyme. The next enzyme does its job, and the process is repeated.
In this fashion, our lettuce folate is transformed, step-by-step, into methylfolate.
The First Step – DHFR
The first enzyme that lettuce folate comes across in this human factory is called DHFR. DHFR stands for dihydrofolate reductase.
As the first step in the process, it’s kinda critical. Let’s face it, if step one in a factory goes wrong, who cares what happens in steps 2 through 10!!
And here’s the wrap: folic acid blocks the action of DHFR.
So if you take folic acid as a vitamin supplement or in a fortified breakfast cereal or bread, you are causing the folate factory in your body to grind to a halt.
Even if you eat a truckload of lettuce, your DHFR enzyme is so burdened down by the synthetic folic acid you’ve eaten, that the lettuce folate gets left outside to rot. That sounds pretty bad, right? Well, it is.
Next – MTHFD1
After DHFR we come across MTHFD1, which does three of the steps in the folate cycle – it’s a machine of many talents.
Once MTHFD1 has done its last job, your lettuce folate has become 5,10 MTHF.
This is sent to MTHFR to be turned into methylfolate (which is technically called 5-MTHF.)
The MTHFR Enzyme at Work
MTHFR is the last step in our folate factory.
What is supposed to happen is that MTHFD1 delivers its 5,10 MTHF to the MTHFR enzyme where it gets turned into methylfolate (5-MTHF) and sent on its way.
However, if you have a poorly functioning MTHFR enzyme as a result of an MTHFR gene mutation, it is going to do that job a little slowly. Up to 80% more slowly than someone without a mutation.
So the methylfolate that comes trickling out of the faulty MTHFR enzyme comes out too slowly for the body’s liking. Demand outstrips supply.
We can’t do too much about the speed of our MTHFR enzyme (there are some things we can do, but they’re beyond the scope of this post.)
What we CAN do, is make sure that plenty of 5,10 MTHF gets delivered to MTHFR, so that even though it’s slow, it’s got plenty to work with.
And here’s our problem: folic acid stops the DHFR machine from working, so it has stopped the flow of lettuce folate through our folate factory. Poor old MTHFR doesn’t have much material to work with!
Combine a slow MTHFR enzyme with not much folate to process in the first place, and you’re going to get deficient in methylfolate really quickly.
But wait, there’s more bad news about Folic Acid…
Remember how there are conveyor belts in factories that transport products from one place to another? In our folate factory we have folate transporters, and folate receptors.
These proteins carry folate in various forms into cells for use.
Synthetic folic acid uses the same receptors and transporters as lettuce folate.
And guess what? Folic acid is a bully.
He grabs the spaces on the transporters before lettuce folate even gets a chance. He bonds more strongly to the transporters and takes all their places. So, like on an over-booked United Airlines flight, the paying passengers, ahem, I mean real food folates, get left behind outside the cell.
So there is even less real folate available for MTHFR to work with. Are you beginning to see the problem?
Here’s the catch – folic acid is bad for everyone
Lots of people say that if you have the MTHFR mutation, you must avoid folic acid.
What I’m here to tell you is that EVERYONE should avoid folic acid.
Everyone has that DHFR enzyme. Everyone wants to make a nice little pile of methylfolate from their lettuce folate. We all need methylfolate – it’s critical!!
And folic acid blocks that DHFR enzyme in EVERYONE. It also hogs the transporters in everyone.
Research has shown that the DHFR enzyme can ‘handle’ a certain amount of folic acid per day – about 100-200 micrograms as an estimate.
Research also shows that many Americans consume significantly more folic acid than this on a daily basis, just from fortified foods. If they take a multivitamin too, that definitely puts them over the limit.
Most of the supplements on the market that contain B vitamins contain this cheaper, synthetic form of folate, so that adds up to a LOT of people with a problem.
And we Australians shouldn’t think we’re getting off lightly – our food has almost as much folic acid added as in the USA.
What this means, essentially, is that most of the population is consuming enough folic acid to impair their folate factories. Whether or not they have an MTHFR mutation, they are making less methylfolate than they should be. And, they are absorbing this harmful, DHFR-impairing folic acid at a faster rate than they can absorb folate from their food due to the transporter issue. This is not good!
You’d probably expect that if all this synthetic folic acid was really bad for everyone, there would be studies showing that consuming folic acid is bad for people, right? Well you’d be right.
This study shows that supplementing with synthetic folic acid increases the risk of colorectal cancer.
This one talks about how folic acid fortification of foods increases the risk of various cancers:
This study demonstrated that even in a country (Ireland) where addition of folic acid to breads was voluntary, not mandatory, 100% of the newborn babies tested had unmetabolised folic acid in their blood at birth. This stuff is building up in everyone, and we know that it has negative effects:
This one talks about a lot of the dangers of folic acid (though in places it erroneously refers to folic acid as folate. The two are not the same thing. Folic acid always should refer to the synthetic (i.e. dangerous) form, whereas folate should refer to natural food folate and methylfolate in the body. Sadly not everyone adheres to the correct terminology.):
That article makes mention of the fact that synthetic folic acid clearly has different effects from natural folates, and the two should not be considered equivalent.
It also notes that
“Unmetabolized folic acid was detected in 78% of fasting plasma samples from the participants. This is the first study reporting the presence of this compound in healthy individuals who are not subjected to pharmacologic doses of folic acid. The presence of unmetabolized folic acid was associated with decreased natural killer cytotoxicity, and a trend toward lower natural killer cytotoxicity with greater amounts of folic acid in plasma”
Translation: synthetic useless folic acid was running around in the blood of these women, even though they weren’t being given folic acid in high doses. We noticed that the more of this folic acid was in their blood, the weaker their natural killer cells were. Basically, their immune system was impaired.
Put all this together and you get that fact that newborns in a country with lower levels of folic acid in food than there is in the USA and Australia, probably have impaired immune systems due to the folic acid their mothers consumed during pregnancy.
Would you like a side of folic acid with your hamburger now?
What to do?
Hopefully you can see that from a biochemistry perspective, eating folic acid makes NO SENSE.
Folic acid is cheap, and it has been in use for a long time. Unfortunately, it has taken a long time for its negative effects to become apparent. That’s partly because many studies failed to distinguish between natural food folate and synthetic folic acid. For a long time, science didn’t realise that the two were not the same thing.
In addition, cancers and other similar conditions take a long time to develop – sometimes decades. It is hard to detect a link between folic acid consumed as a child and cancer presenting in an older adult. So these correlations with folic acid have gone unnoticed for a long time, though that tide is turning.
I would not, however, expect folic acid to be taken out of our food anytime soon. There is a lot of investment in folic acid.
Food fortification programs and supplement manufacturers across the world have relied on this cheap alternative to the more expensive natural forms of folate. It will likely be a long time before there is so much scientific evidence of the detriment of folic acid that even these vested interests will have to listen.
In the meantime, you need to make the decision about whether you will avoid folic acid for yourself and your family. I personally think that the evidence is strong enough that I can’t just ignore it. My family and I choose to purchase organic (unfortified) bread, avoid breakfast cereals and we make our own baked goods from scratch. Even if it weren’t for folic acid, this would still be a healthier diet choice, as avoiding processed foods is always a good idea. Once you’re used to it, it’s not that hard.
And your MTHFR will thank you for it, mutated or not.