High Dose Folate vs. Broad-Spectrum Nutrition for Methylation Support

The issue of high-dose folate has come up a lot lately, as a number of supplement companies offer folate in excess of 2,000 mcg and sometimes a lot more in products targeted for methylation and homocysteine metabolism. While some references are made to support this, the truth is that the literature is sparse on support of such high doses of folate for any application. Older data has not been validated at all on high-dose folate in certain women's reproductive health concerns, for example.  And, in fact, there appears to be diminishing returns on high-dose folate, as research published in the American Journal of Clinical Nutrition showed that doses of folate of 800 mcg and 2,000 mcg had precisely the same effect on reductions of homocysteine (see my previous post).  

"There are few intervention studies of folic acid or 5-MTHF as a stand-alone treatment." (Altern Med Rev. 2008 Sep;13(3):216-26) And there are no studies at all to my knowledge that show superior results in high dose folate vs. multiple nutrients.  (​If you know of any, please send them my way.)​
   

While the risk of toxicity of high dose folate is low, keep in mind that supplementation with folate can mask a B12 deficiency. 

In the supplement industry, a "more must be better" approach is often promoted among supplement companies and some practitioners, and this, of course, is the mindset of more ​conventional practitioners, as this is more consistent with the traditional medical model.  Providing mega-doses of any one substance is closer to a pharmacological approach rather than a holistic or complementary one.  ​But again, what does the preponderance of literature say?  As far as I can tell, there are no studies showing benefit of high dose folate vs. combining moderate ​folate amounts ​with other supportive nutrients.  

Truly holistic practitioners must resist the temptation to always believe that more is better.  An older study on vitamin E, for example, showed that mega-doses given to smokers actually seemed to increase the risk of lung cancer.  Why?  Because certain compounds given in mega doses in isolation of other supportive nutrients may turn out to be pro-oxidants rather than antioxidants.  

Thus, the most effective approach may be the one that addresses the potential folate deficiency, along with other deficiencies (B12, for example) while offering a comprehensive plan that takes into account a variety of supportive measures.​

Thus, methylation as a whole (and hence effective homocysteine metabolism)​ is less a situation of a singular nutrient and more a breadth of supportive accessory nutrients, such as zinc, B6, B12, betaine, molybdenum, N-acetylcysteine, and others. In other words, the more "natural" and effective approach is likely not high-dose folate but rational folate intake coupled with other methylation support nutrients. 

Folate and Homocysteine: Is There Diminishing Returns?

By now it is common knowledge that B-vitamins, particularly folate, B6, and B12, are extremely important to metabolize the amino acid, homocysteine, which is an intermediate in the metabolism of methionine and cysteine, and has been implicated in vascular disease.

Recently I had the opportunity to review a nutritional product that was touted as a supreme homocysteine support product.  It looked good, actually, but something stood out to me that is apparently not common knowledge among practitioners and supplement manufacturers.

The more-is-better idea is a common mindset among holistic pill poppers and those recommending them.  However, the idea that more is better does not apply to many things, and folate's role in homocysteine metabolism is one of them.

The supplement I reviewed has over 2,000 mcg of folate, which impresses many casual observers.  However, it must be noted that according to a study on homocysteine and folate published in The American Journal of Clinical Nutrition, even very low dose folate supplementation of 200 mcg lowers homocysteine significantly, and most notably, there was no difference in high dose folate supplementation and moderate dose supplementation in lowering homocysteine levels. (See chart below.)  Moderate dosing of 800 mcg lowers homocysteine by 23%, but pushing the dose up to 2,000 mcg did not show any additional benefit.  Even very high dosing at 5,000 mcg showed only minimal additional benefit of a mere two percentage points.  

What might make more sense in achieving the perfect formula for homocysteine metabolism is to keep the folate levels moderate in order to keep the cost down and make room for other important nutrients that aid in the methylation cycle and renal clearance of homocysteine -- nutrients such as molybdenum, N-acetylcysteine (NAC), manganese, betaine, etc.

NAC, in particular, is an important antioxidant that serves many roles in the body.  For example, it is an amazingly powerful antioxidant that supports liver detoxification and glutathione levels in the body, but it is also important for renal clearance of homocysteine.  Therefore, significant amounts of NAC (500 mg or more) should be considered to support those with elevated homocysteine or who have had a history of issues along these lines.

Consider supplementation that supports all four levels of homocysteine clearance (see below).

Studies Say Most Women Still Unaware of Importance of Folate Supplementation

Just the other day I saw something I had never seen before – a public service announcement on the side of a bus encouraging women to supplement their diets with folic acid. I was glad to see that the importance of supplementing with this vital nutrient is going mainstream.
Even so, studies show that the majority of U.S. women of childbearing age do not comply with government requirements to take a daily supplement of folic acid.

Folic acid and folate are two forms of vitamin B-9, and sufficient levels are required for the proper development of the fetal nervous system. Low maternal levels of folate can cause neural tube defects, including brain and spine abnormalities that can lead to disability or death.Because the neural tube develops within the first weeks of pregnancy - before women typically realize that they are pregnant - it is important that women of childbearing age maintain sufficient levels of folate at all times.Two studies published in the Journal Morbidity and Mortality Weekly Report highlight folic acid intake as a continuing maternal health issue.

In the first, researchers from the Centers for Disease Control and Prevention (CDC) analyzed the results of Gallup surveys conducted between 2003 and 2007 to determine women's awareness, knowledge and use of folic acid supplements. All women surveyed were between 18 and 45 years of age. Excluding those with confirmed pregnancy, no more than 48 percent of women in any one age group took a folic acid supplement daily. Rate of supplementation was lowest among women between 18 and 24, ranging between 25 and 31 percent. Women between 18 and 24 also had the lowest awareness and knowledge about the importance of folic acid for healthy pregnancy.

In the second study, researchers from the CDC and the Puerto Rico Department of Health compared folic acid knowledge and consumption with the occurrence of neural tube defects among Puerto Rican women between 18 and 44 years of age between 1996 and 2006. In 1997, only 22.4 percent of women surveyed were aware of the importance of folic acid, and only 20.4 percent used supplements. These numbers rose to 70.2 and 30.9 percent respectively by 2003, but had fallen to 56.5 and 24.8 percent by 2006. The occurrence of neural tube defects among Puerto Rican children fell between 1997 and 2003, and has remained steady since then.

Folic acid is important not only for prevention of neural tube defects, but also for prevention of various cancers. It is a major player in the prevention of heart disease, and deficiencies have been shown to be involved in depression and other neurological conditions. In light of the vital role that folate plays in our health, and in consideration of how many women (and men) still don’t understand its importance – at least not enough to actually begin taking it, it seems imperative that practitioners begin promoting its use among their patients.

The Right Form
Folate in the form of folic acid is effective in many people, but research has shown that there is a significant portion of the population that cannot metabolize folic acid in that form. Folic acid must be metabolized through five biochemical processes from an enzyme called, L-5-methylenetetrahydrofolate reductase (I must really be a nerd because I didn’t even have to look that up to spell it!) into the end metabolite called, 5-methyltetrahydrofolate (5-MTHF). Because of specific genetic mutations referred to as single-nucleotide polymorphisms, as much as 40% of the adult female population is missing the L-5-methylenetetrahydrofolate reductase enzyme, and therefore cannot metabolize folic acid. However, the enzymatic processes leading to conversion of folic acid can be bypassed entirely by supplementing with the end metabolite – 5-MTHF – instead of using folic acid.
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NOTE: Refer to the ingredient index in the back of your product catalog to find 5-MTHF-rich products.