Since the 1990’s most of the developed world has been consuming synthetically manufactured folic acid in a bunch of foods that otherwise have no nutritional value: breads, cereals, fruit juices……..pretty much anything that’s grown out of a wheat plant and put into a box.

The US of A has been doing this since January 1, 1998.  Other countries have taken our lead, with Australia the most recent country to join the bandwagon.  (In fact, if you’re a vegemite fan like I am you can blissfully glow in the fact that you’re spreading 20% of your RDA of pteroyl-L-glutamic acid onto your favorite sandwich whenever you use it).

Dietary folates are typically found in greens.  People don’t eat those anymore.  (Except, it seems like, whenever they want to make a fashion statement about what they eat on their facebook wall…….so annoying!).

Folates are used for the synthesis of DNA from the bases purine and thymine and people who are deficient in folates have an unusually high chance of developing birth defects and certain forms of cancer.

That was the whole raison d’etre of folic acid fortification in the first place.  Cells have unusually high folate needs in the fetus and mothers who don’t have high circulating levels of plasma folate have an increased chance of having children with neural tube defects.  [footnote]That’s when your body’s cells don’t replicate correctly, leading to misshapen spinal cords and a lumbar system eerily reminiscent of Quasimodo. [/footnote]

And folic acid prevents these very well.  Neural tube defects went down 25% after the inclusion of folic acid into our cereal boxes.

And better yet…..folic acid is much cheaper and much more stable than the kind you get in spinach.  Dietary folates are extremely finicky and easily lose their potency the minute you pluck them out of the ground.  By the time that spinach and artichoke dip gets to your plate its folate content is CYANARA!

But folic acid can sit on the grocery store shelf for months.  Unlike dietary folate, folic acid is already oxidized which allows it way more exposure to mother nature’s elements without being damaged.  It’s absorbed better too.  Microgram for microgram, folic acid gives you about 25% more juice than what you’d get from food.

The Trouble in Paradise

Folate and folic acid are used as synonyms, but the two have important differences.  Folic acid is not found in nature.  Plants synthesize folate as (get ready for it…..) 7,8-dihydrofolate.   Your neighborhood sigma-aldrich chemist synthesizes folic acid from pyrimidinone and glutamic acid.

Folic acid was something of a hack.  It was first made in a lab in 1945, and it was later discovered that your body can use the same enzyme it uses to metabolize 7,8-DHF (the stuff plants make) to turn folic acid into 5-MTHF…..the form of folate that courses through your blood. [footnote]The entire name is 5-methylenetetrahydrofolate for those of you who are curious.[/footnote]

So what’s the problem?  

The big issue is with the enzyme that’s used to convert folic acid into other stuff.  It’s called DHFR, and like Al Gore would remind us, it has some inconvenient truths to it.

There are three elephants in the room when it comes to DHFR and what it means for folic acid intake:

• The leaky bucket.  It was first thought that DHFR acts on folic acid in the small intestine, meaning that when folic acid left your tummy it was already in its bioavailable form, ready to go to work.  It turns out that’s not really true.  80% of supplementary folic acid hits your bloodstream as……folic acid. [footnote]This study is hindered by a small sample size, but it has the advantage of using fresh human liver.  However, it shouldn’t be considered conclusive evidence.[/footnote]
• A squirt gun, not a bazooka.  It’s your liver, and not your gut, that does most of the heavy lifting for folic acid metabolism.  And unfortunately for you my friend, DHFR is something of a pipsqueak in the liver.  People have 5x variations in liver DHFR activity, and DHFR is 1300% less selective for folic acid than it is for 7,8-DHF (the kind you get from food).
• We’re not f#$*ing hamsters!  The majority of the studies used to determine appropriate folic acid levels for human consumption were performed on……….mice.  A bit ironic isn’t it?  There’s actually a lot of scenarios where this is okay, but in this case it looks like gerbil physiology led us astray.  Mice have 35x higher DHFR activity than humans…..no small potatoes.  And in addition to being turbocharged, their folate enzymes are much more effective: human DHFR is 2% as effective as mouse DHFR in reducing folic acid. [footnote]The reason for this difference is the combination of them being smaller, warm-blooded, and having shorter life spans than us[/footnote]

What all of this means is that, a lifetime of slurping down on fortified grains leaves most people with lots of unmodified folic acid coursing through their bodies.  Depending on who you ask, somewhere between 33%-78% of the citizenry have the unmodified form of the vitamin collecting dust in their tissues.  (Other study done here).

Is unmetabolized folic acid just like anthrax?  No, not really.  It still has some biological activity and shouldn’t count as a toxin.

However, there are some reasons to think circulating folic acid might not be ideal for human health.

Zombie Folate

Our evolutionary history leaves our body with little experience for dealing with folic acid in our tissues.  It was the chemist Bob Stokstad and not mother nature that allowed us to digest it.

What might high levels of circulating folic acid do in our bodies?

• Trick our bodies into thinking its real folate.  Folic acid can still bind to folate receptors within the body, blocking out the real stuff, thus reducing the impact of the dietary folate we do consume.
• Create a pseudo-folate deficiency within the body.  This one’s a little wacky.  DHFR, the enzyme that’s used to metabolize folic acid, down-regulates the rest of your body’s folate metabolizing-machinery once its been topped out.  For many people, this will mean their body’s will turn off their ability to produce 5-MTHF (the kind of folate circulating in plasma) despite having insufficient amounts from the folic acid that wasn’t digested.  Excess folic acid can actually cause an internal folate deficiency. [footnote]If you click through to the link you might notice that the rats are fed 10x their RDA for folate, which is way higher than most people consume.  However, the methods of feedback inhibition have been proven in humans as well, so the same effect still holds, albeit in weaker form.[/footnote]
• Prevent some cancers, possibly promote others.  It’s true that folate is critical for the healthy function of DNA.  But how much is too much?  It’s beginning to look like folate is beneficial for preventing tumor formation before the onset of cancer, but excess folate might actually accelerate the progression of other types once its already developed.  This appears to be especially true for colon and prostate cancer.  Correlation is not causation, but the incidence rates of colorectal cancer in the US and Canada showed a sudden reverse from a decades long decline after folic acid supplementation became mandatory.

Maybe it Works Too Well? 

The RDA for folate is 400 mcg/day.  The upper recommended limit is just a tad bit higher at 1000 mcg/day.  The folic acid mandate has worked better than expected.   When conceived it was intended to provide an additional 100 mcg/day of dietary folate.  It ended up providing double that amount.    The extra folic acid disproportionately goes to the people least capable of handling it:  kiddies and geezers.  Both have underdeveloped metabolic systems and are the most reliant on processed foods as part of their diets.

Supplementary Measures

There’s a very good rationale for certain people (the pregnant, elderly, anemic) to supplement with some sort of folate.  There’s an equally compelling reason for many others not to do it.  A little bit of folate goes a long way and even a *hint* of something that comes out of the earth will probably do the trick for you.

When you do go pill poppin’, it’s much better to take folate as 5-MTHF.  This is the form that circulates in your bloodstream and does not need the liver or small intestine to do any additional work to make it usable.  Some people lack an enzyme that allows them to convert folic acid into 5-MTHF, making it worthless.  While 80% of folic acid leaves your gut undigested, only 4% of supplementary 5-MTHF is in an unusable form.  The rest is ready to GET TO WORK BABY! WOOOO!

The branded versions of 5-MTHF are Metafolin (made by Merck) and Quatrefolic Acid (made by Gnosis).  I’m not sure if there’s a huge difference between the two, although I do know that Merck is a little more generous donating their molecule for scientific research, so there’s more literature surrounding its effectiveness.  The Wellness Mama has a nice write up on this explaining the differences even further.

The only caveat you should be aware of is that 5-MTHF can actually have side effects if used rampantly.  Dr. Ben Lynch has a very nice article explaining how this works.   (He also seems to be the internet’s self-anointed expert on all things 5-MTHF, so if any of you are looking for a good resource on the topic mosey on over to his site).   There’s also an interview with him on the topic here, and all its various health implications.  It’s really very interesting.

5-MTHF is more expensive, but if you really have a need for extra folate just JUST SUCK IT UP AND PAY THE EXTRA $2!

Even the most destitute of you readers should be able to find that in your glove compartment.

Okay everyone……..

References:

1).  Smith, David A, et. al. Is Folic acid good for everyone?

2).  Wright AJ, Dainty JR, Finglas PM (2007) Folic acid metabolism in human subjects revisited: Potential implications for proposed mandatory folic acid forti?cation in the UK. Br J Nutr 98:667–675

3). The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake Steven W. Bailey1 and June E. Ayling1

4).  Patanwala, I, et. al. Folic acid handling by the human gut: implications for food fortification and supplementation

5).  Melikian V, Paton A, Leeming RJ, Portman-Graham H (1971) Site of reduction and methylation of folic acid in man. Lancet 2:955–957.

6). Whitehead VM,CooperBA(1967) Absorption of unaltered folic acid from the gastrointestinal tract in man. Br J Haematol 13:679–686.

7).  Troen AM, Mitchell B, Sorensen B, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 2006;136:189–94.

8). Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999–2000

9).  Christensen, Karen E, et. al. High folic acid consumption leads to pseudo-MTHFR de?ciency, altered lipid metabolism, and liver injury in mice.

10).  Song J, MedlineA, MasonJB, GallingerS, KimYI. Effects of dietary folate on intestinal tumorigenesis in the apcMin mouse. Cancer Res 2000;60:5434–40.

11). Song J, Sohn KJ, Medline A , Ash C, Gallinger S, Kim YI. Chemopreventive effects of dietary folate on intestinal polypsin Apc/Msh2-/mice.

12).  Kim YI. Folate, colorectal carcinogenesis, and DNA methylation: lessons from animal studies. Environ Mol Mutagen 2004;44:10–25.

13).  Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007;297: 2351–9.

14).  Kim YI. Folate and colorectal cancer: an evidence-based critical review. Mol Nutr Food Res 2007;51:267–92.

15).  Mason JB, Dickstein A, Jacques PF, et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 2007;16:1325–9.