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).

"New" Class of Omega Fatty Acids Shows Promise in Cardiovascular Health

A class of fatty acids known as omegas have been studied since the 1970s.  In particular, the omega-3 fatty acids have become famous for their various health benefits.  

Recently a "new" class of omega fatty acids has emerged in the research as showing promise for cardiovascular health and potentially other health benefits.  A class of omegas known as omega-7s may be as good, and perhaps even better, than omega-3 fatty acids for certain aspects of health.  

It must be first be understood that omega-7 fatty acids have always been part of fish oil, just like omega-3s.  However, they have not been the focus of research until now, and, therefore, no one has bothered to concentrate them and provide them in supplement form until now.  It should also be understood that the research on omega-7 fatty acids is still preliminary.  Compared to the massive amount of data available on omega-3s, the research on omega-7s is still quite small.  Having said that, the research on omega-3s was once small as well.  So far, the available data on omega-7s is quite impressive.

An overview of the data on omega-7 fatty acids shows dramatic improvement on C-Reactive Proteins (CRP), a marker for inflammation.  One study showed a 50% drop in CRPs in 30 days among patients who observed no dietary changes.1  Another similar study showed a drop in CRPs by nearly 64% among patients who did undergo some lifestyle changes.2  Triglycerides, a fat in the bloodstream that is responsible for making the blood sludgy leading to clogging in the arteries, also shows impressive improvement with the addition of omega-7 fatty acids; up to 36% drop in triglycerides in 30 days.  All cholesterol numbers also improve with the administration of omega-7s.  

As data is mounting implicating inflammation as the biggest culprit in heart disease, the early research on omega-7 fatty acids is promising in preventing and perhaps treating certain aspects of cardiovascular disease.  

1. MartinezL.Purifiedomega-7inthereductionofhs-CRP:adouble-blinded,randomized, placebo-controlled study. Proprietary research report, 2013.

2. MartinezL.Lipidandhs-CRPreductionsobservedwiththeadministrationofpurified palmitoleic acid: an open label trial. Proprietary research report, 2013.

Inflammation Worse for Heart Than Cholesterol

Worse than cholesterol?

That might be difficult to believe, but the top health concern of millions of Americans is about to be trumped by what medical researchers say is an even bigger trigger of heart attacks.

The condition is low-grade inflammation, which may originate in a variety of unlikely places throughout the body, including excess fat. New federal recommendations are being written that will urge doctors to test middle-aged and older Americans for it. The discovery of its surprising ill effects is causing a top-to-bottom re-thinking of the origins and prevention of heart trouble.

Conventional doctors call it a revolutionary departure from viewing the world's top killer as largely a plumbing problem blamed on cholesterol-clogged arteries, which is the standard theoryin modern cardiology.

"The implications of this are enormous," says Dr. Paul Ridker of Boston's Brigham and Women's Hospital. "It means we have an entire other way of treating, targeting and preventing heart disease that was essentially missed because of our focus solely on cholesterol."

In the past few years the evidence has become overwhelming that inflammation hidden deep in the body is a common trigger of heart attacks, even when plaquing in the arteries is minimal. Inflammation can be measured with a generic $10 test that looks for high levels of a chemical called C-reactive protein (CRP), one of many that increase during inflammation.

While measuring cholesterol is still an important consideration, it is noteworthy that half of all heart attack victims have levels that are normal or even low. Clearly, something big has been missing from the equation, and that something appears to be inflammation.

Ridker estimates that between 25 million and 35 million seemingly healthy middle-aged Americans have normal cholesterol but above-average inflammation, putting them at unusual risk of heart attacks and strokes. A series of landmark studies by his team beginning in 1997 suggest that inflammation is a better predictor of heart attacks than cholesterol. They found those with high levels of CRP have double the risk of people with elevated cholesterol. High amounts of CRP also predict increased risk of heart attacks and strokes years before they occur, even when cholesterol levels are low.

Having both inflammation and high cholesterol together is especially ominous, resulting in a NINE-FOLD increase in risk.

Nearly everyone who reaches middle age has at least some degree of fatty buildup, known as plaque, in the arteries. The new evidence suggests it becomes threatening if weakened by inflammation, which makes it squishy and fragile. Even a small lump of plaque can burst, prompting the formation of a clot that in turn chokes off blood flow and causes a heart attack or stroke.

Many people with no outward signs of anything wrong have high levels of internal inflammation. It is exactly the same sort that causes swelling, heat, and redness during infections or allergic rashes.

Researchers believe the internal inflammation has many possible sources. Often, the plaque itself becomes inflamed as immune cells invade the area in a defense response. But inflammation that arises elsewhere apparently can be just as bad, because it bombards the plaque with damaging chemicals.

For example, fat cells churn out these inflammatory mediators, which is one of many reasons why being overweight is so bad for the heart. Fat cells, or adipocytes, are now being referred to as “endocrine organs” by researchers because of their ability to “talk” to the rest of body through inflammatory mediators, and the language they speak is one of alarm. Being overweight sets off an ongoing state of alarm throughout the body through the production of inflammatory chemicals, and they in turn can cause muscle tissue breakdown and a catabolic snowball process that leads to more inflammation, more production of fat cells, and an accelerated rate of aging and degeneration through increased oxidation.

Other possible triggers of CRP include high blood pressure, smoking and lingering low-level infections such as chronic gum disease.

Although many chemicals increase during inflammation, CRP is particularly easy to measure. Many doctors believe that CRP should measured in everyone over age 40, just like cholesterol, regardless of their other risk factors like cholesterol or high blood pressure.

"It begins to look like a standard risk factor that one would evaluate at least once in middle age in most people," says Dr. Wayne Alexander of Emory University. "This is a very important concept for the general public to be aware of and to think about for their own health."

"We believe the niche for C-reactive protein - and it is a large niche - is the healthy population who want to do what they can to lower their risk of cardiovascular disease," says Dr. Richard Cannon of the National Heart, Lung and Blood Institute.

Screening is important because inflammation can be readily lowered in several ways. One of the most powerful is losing weight. Exercise also helps, as does moderating alcohol intake, giving up smoking and lowering one’s blood pressure. Thus, doctors are likely to urge these habits for people with high CRP readings who until now would have seemed to be at no special risk of heart problems.

"In the last decade, people talked about their cholesterol levels," Dr. Cannon says. "In the next decade, the cocktail chatter will be, 'What's your C-reactive protein?' Everyone will need to know that."

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Stay tuned for my next post on powerful interventions that fight inflammation naturally.