Artificial sweeteners such as aspartame (NutraSweet®, Equal®), sucralose (Splenda®), and saccharin (Sweet’N Low®) are ubiquitous in processed foods and beverages; and are regularly consumed by 1/3 of all Americans in a variety of “diet” products.[i]  While designed to be low calorie alternatives to sugar, research has repeatedly shown that consumption of these artificial sweeteners is still linked to metabolic derangements such as weight gain, impaired glucose tolerance and increased incidence of type 2 diabetes.[ii],[iii] Now, research has discovered that while most of these synthetic sweeteners are excreted unchanged in either the urine or feces, they affect metabolism through alterations of the gut microbiota.

In an animal model, Suez et al. showed aspartame, sucralose and saccharin induced glucose intolerance over eight and eleven weeks; further study of saccharin demonstrated the effects were mediated through compositional and functional changes to the gut microbiota, with more than 40 operational taxonomic units altered in the saccharin-fed group.[iv]  Interestingly, Akkermansia muciniphila was underrepresented in the mice fed saccharin. Using antibiotics and transplanting fecal microbiota samples into germ-free mice, the group linked the impaired glucose tolerance to an altered microbiome.

The group then studied the effects of artificial sweeteners in a small-scale human intervention study. Seven subjects (who did not normally consume artificial sweeteners) consumed a regular diet supplemented with the upper limit of daily saccharin dose (5 mg/kg/day) for one week. Four of the seven volunteers showed an elevated glycemic response (responders), and the other three individuals showed no response. The researchers transplanted the four responders’ microbiota into germ-free mice and replicated the impaired glucose response, again linking the metabolic effects to the altered microbiota.  The responder/non-responder effect suggests that not all individuals are affected equally by artificial sweetener consumption, and the response may depend on an individual’s baseline microbiota.[v] Although this is one of the few human intervention trials available to show the effect of artificial sweeteners on the microbiome, other animal studies using these ingredients (at relevant dietary doses) suggests that this phenomena is an important link between artificial sweeteners and metabolic dysregulation.[vi],[vii]

Ironically, many “light” yogurt products include these artificial sweeteners as a key ingredient in the effort to retain palatability while reducing total sugars and calories. Consuming yogurt products in an effort to favorably modify the microbiome while consuming these “light” or “reduced calorie” additives may detrimentally undermine any beneficial changes to the microbiome the consumer anticipates.

 

[This is a short excerpt from the “Supporting the Microbial Ecosystem of the Gut” section of our newest Road map Functional Strategies for the Management of Gastrointestinal Disorders, which is now (finally) ready to be ordered.]

 

[i] Sylvetsky AC, Welsh JA, Brown RJ, Vos MB. Low-calorie sweetener consumption is increasing in the United States. Am J Clin Nutr. 2012 Sep;96(3):640-6.

[ii] Suez J, Korem T, Zilberman-Schapira G, et al. Non-caloric artificial sweeteners and the microbiome: findings and challenges. Gut Microbes. 2015;6(2):149-55.

[iii] Spencer M, Gupta A, Dam LV, et al. Artificial Sweeteners: A Systematic Review and Primer for Gastroenterologists. J Neurogastroenterol Motil. 2016 Apr 30;22(2):168-80.

[iv] Suez J, Korem T, Zeevi D, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014 Oct 9;514(7521):181-6.

[v] Nettleton JE, Reimer RA, Shearer J. Reshaping the gut microbiota: Impact of low calorie sweeteners and the link to insulin resistance? Physiol Behav. 2016 Apr 15. pii: S0031-9384(16)30164-0.

[vi] Palmnäs MS, Cowan TE, Bomhof MR, et al. Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat. PLoS One. 2014 Oct 14;9(10):e109841.

[vii] Abou-Donia MB1, El-Masry EM, Abdel-Rahman AA, et al. Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. J Toxicol Environ Health A. 2008;71(21):1415-29.

Re-assessing the Notion of “Pregnenolone Steal”

When clinicians measure salivary cortisol and DHEA (DHEA-S) to assess stress and HPA axis function, it is common to find DHEA levels below the reference range in a number of individuals. A common explanation for the depletion of DHEA and other hormones (e.g., progesterone, testosterone) due to chronic stress is the phenomenon known as “pregnenolone steal.” This notion basically states that since all steroid hormones use pregnenolone (derived from cholesterol) as a precursor, the elevated secretion of cortisol caused by acute or chronic stress will inevitably result in less available pregnenolone to serve as a precursor for the production of DHEA and other down-stream hormones. In other words, according to this theory, the need for cortisol synthesis “steals” pregnenolone away from other hormone pathways, reducing the potential synthesis and secretion of other necessary hormones, resulting in some of the pathophysiological changes related to stress.

While a rise in cortisol levels and a concomitant drop in DHEA is one of the clinical characteristics of early and mid-stage chronic stress progression, this phenomenon is not caused by diminished adrenal pregnenolone availability or “pregnenolone steal.” The most obvious reason is the fact that the conversion of cholesterol to pregnenolone occurs in the mitochondria of each respective adrenal cortex cell type that is responsible for producing these hormones. Simply put, there is no known adrenal pool of pregnenolone for one cell to steal away from another, and no known mechanism has been described that could facilitate the transfer of pregnenolone between the mitochondria of different cells (in this case, from the mitochondria of cells within the zona reticularis to those within the zona fasciculata). Unfortunately, the most common figures used to teach steroidogenesis show a common pathway and typically do not specify the differential regulation of available enzymes between different steroidogenic tissues. This leads many to incorrectly assume there is a single “pool” of pregnenolone available for all steroid hormone synthesis within the adrenal. A much better way to teach this is to show the different enzymes available to each cell within the adrenal cortex, showing that each is capable of converting cholesterol to pregnenolone; then to the various needed hormones. This is a figure from the new book- that shows a better way to teach this that avoids showing a single “pool” of pregnenolone for all down-stream hormones.

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In addition, the ACTH-driven adrenal synthesis of cortisol is orders of magnitude higher than that of DHEA, and fluctuates radically within a 24-hour period. If there were an adrenal “pregnenolone pool” that contained enough pregnenolone precursors for elevated cortisol production in the morning (or during stress), this “pool” would then also be available for the much smaller amount of needed DHEA production when cortisol synthesis drops even a little. Finally, as decades of steroidogenesis research has shown, the control of adrenal hormone output is regulated mostly by cell-specific enzyme concentrations and external signals coming from outside the adrenal gland (See our latest book for specifics).

What, then, does this mean in relation to cortisol and DHEA output which, when measured, appears to confirm this phenomenon? What about the role of oral pregnenolone therapy for supporting adrenal DHEA production? Well, it’s a bit complicated. While HPA axis stress and subsequent cortisol synthesis and secretion may be related to the acceleration of reduced DHEA production (i.e., a stress-induced down-regulation of DHEA), this relationship is facilitated by regulatory processes (e.g., feedback inhibitions, receptor signaling, genomic regulation of enzymes, etc.), not an intra-adrenal depletion of pregnenolone as a precursor to downstream hormones. For instance, experimentally-induced hyperglycemia and hyperinsulinemia has been shown to affect DHEA and androstenedione production in human subjects.[1],[2] In one study of poorly-controlled type 2 diabetic subjects with elevated cortisol and low DHEA levels, the enzyme necessary for DHEA formation in the zona reticularis (17,20 lyase) was shown to limit the production of DHEA. The enzyme activity was corrected (along with near normalization of cortisol, DHEA and DHEA-S levels) after six months of diet or pharmacotherapy to improve blood glucose control.[3] Additionally, cell-culture studies suggest that under inflammatory stress (IL-4 and other cytokines), the zona reticularis will down-regulate DHEA production when ACTH is present.[4],[5]These and many other factors (e.g., aging) are likely the driving influences affecting the dynamic relationship between cortisol (activated by the HPA axis) and measured DHEA and/or DHEA-S levels.

By re-assessing the specific mechanisms that drive the stress-related changes in adrenal hormone output, and moving away from older and incorrect explanations, we are able to seek (and perhaps address) the various signals that are actually responsible for modulating adrenal hormone secretion during the progression of chronic stress.

 

If you are interested in learning more about this subject and how oral pregnenolone and DHEA may improve outcomes in subjects with stress-related dysfunctions, please consider getting our newest book: The Role of Stress and the HPA Axis in Chronic Disease Management.

 

[1] Boudou P, Sobngwi E, Ibrahim F et al. Hyperglycaemia acutely decreases circulating dehydroepiandrosterone levels in healthy men. Clin Endocrinol (Oxf). 2006 Jan;64(1):46-52.

[2] Vásárhelyi B, Bencsik P, Treszl A, et al. The effect of physiologic hyperinsulinemia during an oral glucose tolerance test on the levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) in healthy young adults born with low and with normal birth weight. Endocr J. 2003 Dec;50(6):689-95.

[3] Ueshiba H, Shimizu Y, Hiroi N et al. Decreased steroidogenic enzyme 17,20-lyase and increased 17-hydroxylase activities in type 2 diabetes mellitus. Eur J Endocrinol. 2002 Mar;146(3):375-80.

[4] Woods AM, Judd AM. Interleukin-4 increases cortisol release and decreases adrenal androgen release from bovine adrenal cells. Domest Anim Endocrinol. 2008 May;34(4):372-82

[5] Woods AM, McIlmoil CJ, Rankin EN. Et al. Leukemia inhibitory factor protein and receptors are expressed in the bovine adrenal cortex and increase cortisol and decrease adrenal androgen release. Domest Anim Endocrinol. 2008 Aug;35(2):217-30

Is it “Adrenal Fatigue”?

Reassessing the Nomenclature of HPA Axis Dysfunction

 

Sometimes, when we endeavor to understand and describe complicated medical topics, there is a temptation to find a simple explanation to cut through the complexity. These explanations can help bridge the knowledge gap for a while, but as our knowledge grows, they lose some of their original usefulness (e.g., the notion of “good” and “bad” cholesterol). In some cases, those over-simplified explanations actually become a hindrance to helping clinicians and patients understand the important mechanisms and solutions related to chronic conditions. The use of terms like “adrenal fatigue” and “adrenal exhaustion” to summarize the complex dysfunctions related to the stress response is one such explanation. Though these terms have helped dispel the notion that only extreme issues related to adrenal function (Addison’s disease or Cushing’s disease) are of clinical importance, and have become surrogate descriptions for stress-related outcomes, they should now be replaced by more accurate and medically appropriate terms, like HPA axis dysfunction, adrenal insufficiency, or where applicable, hypocortisolism.

 

While it is true that the most common laboratory method to assess the function of the HPA axis is through the measurement of hormones secreted by the adrenal glands, primarily cortisol and DHEA(S), the mechanisms that control the level of these hormones resides mostly outside of the adrenal gland. Low cortisol and DHEA(S) levels may indeed be related to chronic stress, but as a result of HPA axis adaption (down-regulation) to protect tissues from excess cortisol, have little to do with the inherent capability of the adrenal gland to produce these hormones (see adrenal insufficiency below). While many clinicians (and laboratories) still refer to this as “testing the adrenals,” it is much more accurate to say that such testing is assessing the status of the HPA axis using adrenal hormone measurements as surrogate markers. So, why does this nomenclature reassessment matter?

 

First of all, using descriptive and accurate terms helps clinicians and patients better understanding the pathophysiology caused by stress and the stress response system. In most cases, issues related to perceived stress, glycemic control, circadian rhythm, cortisol feedback control (in the hypothalamus and/or pituitary), inflammatory signaling, or tissue-specific glucocorticoid effects will have much more to do with a treatment protocol than direct support of adrenal function. For instance, many adaptogenic herbs and nutrients that were once thought to function primarily by supporting adrenal function have been shown to have mechanism that modulate non-adrenal HPA axis or glucocorticoid signaling functions. Related to this is the ability of the clinician to interface appropriately with the vast amount of literature that describes patient outcomes related to stress and HPA axis function. The term “adrenal fatigue” is virtually absent from the peer-reviewed literature and has even caused the Endocrine Society to warn the public against the diagnostic “myth” of adrenal fatigue and to cast suspicion upon clinicians using such terms. While I generally agree with the Endocrine Society that the term “adrenal fatigue” is problematic, I do not agree with them that there is little evidence to connect chronic stress with adverse health outcomes, or that testing adrenal hormone output is of no value beyond diagnosing extreme adrenal disease conditions.

 

A

 

 

n increasing body of research links a variety of chronic dysfunctions with specific patterns of adrenal hormone output (basal or provoked). By avoiding the use of oversimplified (and incorrect) terminology to describe these relationships and instead choosing more appropriate descriptive terms, the clinician will enhance the credibility of this important phenomenon and be better equipped to incorporate therapies that address the complexity of the whole stress response system.

 

What are More Appropriate Terms?

HPA Axis Dysfunction (or Maladaption): This term is much more appropriate to describe the many consequences that link stress (allostasis) with the myriad of measurable negative outcomes related to the stress response. The majority of these outcomes can be linked in some manner to processes controlled by the HPA axis. Alternatively, some refer to these as “disorders of the stress system” or the “consequences of the maladaption to stress.”

 

Hypocortisolism: This is the most descriptive term to use when measured cortisol is well below the laboratory reference range. Still, it is a relative term and does not necessarily implicate dysfunction or “fatigue” of the adrenal gland. Extreme hypocortisolism is associated with Addison’s disease and other forms of primary and secondary adrenal insufficiency. Reduced HPA axis function resulting in low cortisol levels is common in PTSD, fibromyalgia, chronic fatigue syndrome, certain affective disorders, and individuals with high psychosocial “burnout”. Other specific terms for different stress-related HPA axis phenomena include hypercortisolism, loss of HPA circadian function, and low circulating DHEA(S).

 

Adrenal Insufficiency: This is a clinical manifestation that results in a deficient production or action of glucocorticoids, a condition that has potential life-threatening consequences. Primary adrenal insufficiency (i.e., Addison’s disease) describes diseases intrinsic to the adrenal cortex primarily caused by autoimmune adrenalitis. Secondary adrenal insufficiency relates to insufficient pituitary ACTH or intrinsic defects in the adrenal responsiveness to ACTH. Tertiary adrenal insufficiency results from impaired synthesis of hypothalamic CRH or AVP. The most common cause of tertiary adrenal insufficiency is the chronic use of exogenous glucocorticoids (pharmacotherapy), leading to the suppression of hypothalamic secretions of CRH. True adrenal insufficiency will almost always require hydrocortisone replacement therapy (often life-long). For a complete review of the etiology, pathophysiology, clinical presentation, diagnosis and treatment approaches to adrenal insufficiency, see Charmandari, et al.[i]

 

Dr. Guilliams’ new book entitled: The Role of Stress and the HPA Axis in Chronic Disease Management can be ordered now by following this link. This blog is a modified excerpt from this book.  

 

 

 

[i] Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014 Jun 21;383(9935):2152-67.

    According to the prevailing mantra, repeated in nearly every major media format, dietary supplements are completely (and shockingly) unregulated. We have been told that products can be made with no oversight, labels need not accurately disclose the contents of the product, and that outrageous claims of miracle cures are permitted without proof; furthermore, they claim that FDA has no power to do anything about it. The truth is, none of these characterizations are even remotely factual- no matter how often they are repeated.

    The latest and loudest critique of the dietary supplement world has come from HBO’s John Oliver, where he ridiculed Dr. Oz’s congressional testimony on his “Last Week Tonight” show, before “exposing” the unregulated dietary supplement industry and the lawmakers he deemed responsible for allowing its deregulation. Whether or not you believe Dr. Oz is good or bad for the supplement industry (or the medical world in general), the ignorance of dietary supplement regulations displayed by Oliver was simply shocking and should be defined as a form of  media malpractice. What Oliver has really exposed is a shockingly unregulated agenda-driven media industry; where humor, rather than truth, feeds the bottom line.

    Of course, HBO is not the only offender. Nearly every medical journal editor or medical writer for news outlets permits similar statements to be printed without qualification. Even positive stories about dietary supplements include such statements. When Time magazine did a piece on the use of herbal medicine in the Cleveland Clinic, they included this gem in passing: “The FDA doesn’t regulate herbs and supplements.” A statement obviously written by someone who has never endured a 3-week FDA inspection of a dietary supplement manufacturing facility or read any of the hundreds of warning letters sent by FDA to supplement company owners; or for that matter, has taken the time to peruse the hundreds of pages of guidelines outlining how FDA regulates the dietary supplement industry.

    But there appears to be something more insidious going on of late. For years we have had to deal with these unwarranted statements, usually tagged on to the latest adverse event report or “failed” vitamin study (see my blog on editorial bias in research media). However, over the past several years there seems to be an increasing emphasis in these statements targeting DSHEA (the Dietary Supplement Health Education Act) and those in congress who believe it to be a sufficient framework to protect the American people from harm while allow appropriate access to dietary supplements. Oliver went out of his way to point out that it was the massive amount of money used to lobby congress that has led to the shocking lack of regulation. Again, the unregulated staffers on Oliver’s HBO show must have been short on time to do some fact checking, so we will help them out.

    According to Opensecrets.org (the same source used by Oliver) the dietary supplement industry’s lobbying dollars reached their peak in 2013 at $3.6 million. How does this compare with the pharmaceutical industry? Well in 2013, the pharmaceutical industry spent over $140 million lobbying congress (the highest amount of all industry sectors). If lobbying dollars equates to deregulation, as Oliver clearly concludes, then he and HBO must have a mini-series in the works exposing Big Pharma. And these numbers pale in comparison to the promotional dollars used by pharmaceutical companies to lobby doctors, insurance companies and consumers. In 2012, nearly $15 billion dollars was spent detailing doctors, including another $5 billion in free samples. When you total all the promotional dollars, including over $3 billion in direct to consumer marketing, the pharmaceutical industry spent over $27 billion in 2012 (an amount equaling 85% of the total revenues of all dietary supplements that same year). Remember that the amount of money spent in advertising by pharmaceutical companies is mostly spent through the same medical journals and media outlets claiming dietary supplements are unregulated- a coincidence, perhaps.

    This is such an important topic that when putting together our last book (Supplementing Dietary Nutrients- A Guide for Healthcare Professionals), we specifically wanted to tackle this issue head-on. Not only is there a large chapter on the nuances of dietary supplement quality control and regulatory issues, we were able to reprint the HerbalGram article “Myths of an Unregulated Industry Dispelled” in its entirety (thanks American Botanical Council). This is a must-read for anyone who questions whether FDA has the ability or authority to properly regulate the dietary supplement industry or anybody recommending the use of dietary supplements to others.

    Like all regulated industries, the dietary supplement world has companies and rogue players at its margin. Nearly all of the issues related to dietary supplement safety have come from these groups- mostly in the form of products that contain illegal drugs masquerading as dietary supplements for weight loss, sexual enhancement or sports performance. The responsible majority of dietary supplement companies would like to see FDA use its authority to remove these players from the market, an authority given to them by congress through DSHEA. So the next time you read an article declaring that FDA has no ability to regulate herbs or dietary supplements, you ought to consider asking which is more regulated: the dietary supplement industry or the media declaring it unregulated.

Get our new book: Supplementing Dietary Nutrients- A Guide for Healthcare Professionals Today.

 

 

 

 

 

 


Available for Healthcare Professionals at
the Lifestyle Matrix Resource Center or directly from our site here.

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Those who have been following the trends over the past several years know that many functional medicine clinicians have been promoting the use of 5-methyltetrahydrofolate (5-MTHF) in place of folic acid; especially in patients with a known genetic predisposition for reduced folate methylation. It is quite common to hear speaker after speaker suggest that the use of 5-MTHF is necessary for clinical benefit and that the use of folic acid is useless or even harmful. But are these statements based on reliable evidence?

As it turns out, unlike the case with phosphorylated B6 and Riboflavin, where there is simply no advantage at all (See previous blog); the case of 5-MTHF is a bit more complex. This is how I put it in the conclusion of the folate/folic acid monograph in my most recent book (Supplementing Dietary Nutrients):

We recommend clinicians use 5-MTHF supplements, perhaps together in a B-complex product, in patients known to be homozygous (TT) for the MTHFR polymorphism. We also recommend supplementation of 5-MTHF, or 50:50 blends of folic:5-MTHF, for prenatal patients, those who are suspected of poor methylation and when using very-high-dose folate products. These suggestions should not be viewed as a recommendation to avoid folic acid in these subjects, as current data suggests neither lack of efficacy or harm when using folic acid in these subjects. There is, however, sufficient data and mechanisms to prefer 5-MTHF in these patient types. Folic acid is adequate for multivitamins intended for the average healthy population, especially where cost may hinder the use of necessary supplementation.  

Here I would like to address some of the questions I often get when I discuss this topic and the above recommendation with clinicians:

 

Why isn’t there a bigger difference in the clinical benefit between 5-MTHF and Folic acid in homozygous MTHFR TT individuals? This question stems from the fact that contrary to some expectations, the differences seen in clinical trials when using folic acid and 5-MTHF in these individuals is often, though not always, significant.

First of all, for those not up to speed on the MTHFR language- the methylenetetrahydrofolate reductase enzyme is necessary as the terminal step in producing 5-MTHF- the active form of folate. In sequencing the gene for this protein, researchers identified that some individuals had a cytosine (C) at base pair position 677 (this is the most common), and others had thymidine (T) at that position. This is often referred to as MTHFR C677T polymorphism, and causes an alanine-to-valine amino acid change at the 222 position of the protein. This small change in the protein results in less-efficient synthesis of active folate compounds—some estimates are 75% less efficient. About 45% of individuals in the U.S. are homozygous for the normal variant (677CC), but about 10% may be homozygous for the other variant (677TT) and others (~45%) heterozygous (677CT) with both gene variants. These heterozygous, and especially homozygous TT, individuals often have noticeably less-efficient methylation, accounting for higher risk for certain diseases and a higher need for folate supplementation.

One of the most comprehensive reviews comparing these two folate compounds concludes that “Studies comparing L-5-methyl-THF and folic acid have found that the two compounds have comparable physiological activity, bioavailability and absorption at equimolar doses. Bioavailability studies have provided strong evidence that L-5-methyl-THF is at least as effective as folic acid in improving folate status, as measured by blood concentrations of folate and by functional indicators of folate status, such as plasma homocysteine.”

Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2010 Aug;49(8):535-48

 

While there is documented clinical benefit to using 5-MTHF in patients with the TT polymorphism (this is now a common test available from many laboratories), I believe the main reason there is not always a measurable clinical difference between 5-MTHF and folic acid is that oral dosing of 5-MTHF only compensates for the initial methylation of that “dose” of folate- which is only a small portion of the total body folate pool. Meaning, that whatever benefit in the increased 5-MTHF levels is derived from consuming 5-MTHF directly (as opposed to consuming folic acid)- it is still a small proportion of the total amount of folate already in the body, most of which  would need to be re-methylated within the cells. While I still recommend the use of 5-MTHF in 677TT homozygous individuals or those suspected of poor methylation, the notion that folic acid does not work at all in these individuals is refuted by nearly every trial published. Even when the 5-MTHF is statistically better than the folic acid (as it often is)- both agents are significantly (statistically and clinically) better than placebo at raising RBC folate levels and reducing homocysteine levels. If they were the same cost to the user- we might choose 5-MTHF all the time, but there is a big difference in cost between these two (see below).

5-MTHF is natural and folic acid is synthetic- right?

Again, this is another common misunderstanding about folates. While it is true that natural dietary folates are often in the 5-methyltetrahydrofolate form- most of these dietary folates are also naturally polyglutamyl molecules. Folic acid, on the other hand, is a monoglutamate molecule that is fully oxidized (no hydrogens attached to the ring structures). Natural folates are usually partially or fully reduced (dihydro- or tetrahydrofolate, respectively), and are substituted at the 5 or 5,10 positions with methyl or other groups (see figure below) and have up to 7 or so glutamate molecules attached (polyglutamates).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Since only monoglutamate folates are transported into the body, all dietary polyglutamyl folates must by enzymatically deconjugated to their monoglutamyl form prior to absorption in humans. This deconjugation is performed by pteroylpolyglutamate hydrolase enzymes secreted from the brush border of the jejunum. Once inside the cell, further absorption is dependent upon the reduction and methylation steps needed to form 5-MTHF as seen in the figure below (some folic acid can passively absorb and can exist as “unmetabolized” folic acid- an issue that will be discussed below)

 

 

 

 

 

 

 

 

Due to various factors, especially the need to deconjugate polyglutamyl dietary folates, synthetic folic acid is usually considered to have approximately twice the bioavailability as dietary folates. When the Food and Nutrition Board set the Dietary Reference Intake (DRI) levels for folate (using dietary folate equivalents- DFEs) they determined that 1 mcg of folate from the diet is equal to 1 DFE, while 1 mcg of folic acid in supplements was equal to 2 DFE. When folic acid is added to foods via fortification, 1 mcg is equal to 1.7 DFE (this takes into account some anti-folate activities in foods).

What about 5-MTHF from supplements? The 5-MTHF used in medical foods and in dietary supplements (either the calcium or glucosamine salt forms) are not derived from “natural sources” and are not, as some describe them- true dietary folates. These compounds would be considered bio-equivalent (or bio-identical) synthetic analogs (5-MTHF, when naturally found in foods, is mostly in a polyglutamyl, not monoglutamyl form). Commercially available 5-MTHF is organically synthesized using folic acid as a starting material. After reduction to tetrahydrofolate and methylation- a racemic mixture (R,S) of a monoglutamyl 5-MTHF is formed. Crystallization and separation of the two stereoisomers allows for a purified S-form, which is then stabilized using calcium or glucosamine ions (the “S” describes the specific stereochemistry at the #6 carbon; this is often also called the “L” form due to the way this isomer reflects light). This process results in a raw material that is about 200 times more expensive than an equimolar amount of folic acid.


The arguments against folic acid- How strong is it?

Before getting into the details here, it is important to recall that purified 5-MTHF ingredients have only been available for about a decade or so (calcium salt) and only more widely available to use in a variety of formulas for about five years (when the glucosamine salt became available). This means that most of what we know about folates (positive and negative) have been performed using folic acid and the data using 5-MTHF alone or in comparison to folic acid is still being researched.

Even so, in addition to the need to convert folic acid to 5-MTHF already discussed above, there are other reasons often cited for avoiding the use of folic acid.

1. Folic acid can mask (not cause) a vitamin B12 deficiency. Large doses of folic acid, typically  more than 5 mg, given to an individual with an undiagnosed vitamin B12 deficiency could correct the symptoms of megaloblastic anemia without correcting the underlying vitamin B12 deficiency, leaving the individual at risk of developing irreversible neurologic damage. While definitive data is lacking, there appears to be some evidence that the use of 5-MTHF use is less likely to mask these B12 deficiency symptoms. However, since most functional medicine clinicians are aware of (and test for) vitamin B12 deficiency and most high dose folic acid and many 5-MTHF products are formulated with added vitamin B12- the issue of folate masking is rarely seen in the clinic using high dose folate therapies. We always suggest 500-2000 mcg of vitamin B12 should be included in any product containing 800 mcg or more of folic acid or 5-MTHF.

2. Un-metabolized folic acid. As we mentioned, while nearly all of the folic acid consumed orally will be converted to 5-MTHF prior to circulation, some folic acid does passively absorb prior to conversion. While it is now common for researchers to look for unmetabolized folic acid levels in the serum of folic acid-supplemented individuals, there is no clear evidence of a demonstrable negative consequence for these elevated levels or a proposed mechanism involving negative outcomes. The paper below covers most of the issues related to unmetabolized folic acid.

Obeid R, Herrmann W. The emerging role of unmetabolized folic acid in human diseases: myth or reality? Curr Drug Metab. 2012 Oct;13(8):1184-95.

So our position is that while the use of 5-MTHF may have some benefits over the use of folic acid, the much higher cost of pure 5-MTHF over folic acid requires that we reserve its use when it will be more likely to add value to the user. Since the data do not suggest folic acid to be harmful (compared to 5-MTHF) and clinically useful in most situations- the use of 5-MTHF should be considered mostly for those individuals with MTHFR polymorphisms that result in lower methylated folate. When using either folate compound above 800 mcg/day, additional vitamin B12 should be added to the regimen or formula.

If you find this information helpful, you may be interested in our new book- Supplementing Dietary Nutrients- A Guide for Healthcare Professionals.

If you want to know when Dr. Guilliams’ posts future blogs or when a new whitepaper is available, “Like” us on our Facebook page. 

To get Dr. Guilliams’ earlier book, The Original Prescription– you can purchase directly from the Point Institute or purchase on Amazon.

And don’t forget to sign up for our blog at the bottom of this page!

It has been a little while since I have been able to post a new message here on the Point Institute website; I have been busy editing and proofing our latest project, which, I am pleased to announce, is finally at the printer and will be available shortly.

 

Supplementing Dietary Nutrients: A Guide for Healthcare Professionals

This new guidebook was written as the first in our “Standard – Roadmap Series” (more to come later on this) focusing on the use of nutrient ingredients for dietary supplementation. Using the same sort of approach we have used in developing the Standard monographs since 1997, this guidebook can be used as a training manual or textbook and kept handy for its monograph information on over 30 nutrients. To see a bit more about the details of the book, go here.
As the book is slated to arrive in a few weeks, we are making it available first on our website, and will distribute it here for 20% off the cover price until May 15th (including free shipping in the US). If you want to get your copy, click the Buy Now button below:


They will be sent out as soon as they arrive.
A tremendous amount of work went into this guidebook and we have received great feedback from everyone who has seen the manuscript in progress. We are certain that anyone making supplemental nutrient recommendations within a healthcare setting will want to have this on their shelves.

Those familiar with our work know that we have spent quite a bit of time evaluating the therapeutic outcomes of marine-derived omega-3 fatty acids. Our recent review of the topic has been downloaded and widely circulated amongst healthcare providers and the general public, worldwide. In that review, we covered the types of fish used, how fish oil is made, sustainability issues, bioavailability differences, quality control concerns and much more; including the research comparing omega-3 fatty acid from fish oil and krill oil. You can get the article as a PDF file here.

Just a month after publishing our paper online, a few more studies comparing fish oil and krill oil were published that initially appeared to suggest that omega-3 fatty acids from krill oil may indeed have a slightly better bioavailability than those from fish oil and/or had triglyceride lowering effects similar to fish oil; but after only a month of scrutiny, these studies are exposed as epic failures of how marketing-driven research leads to bad science and confusing outcomes.

First- as a brief review for those who haven’t read our whitepaper. Our position was that the EPA and DHA in krill oil should function in much the same way as EPA and DHA from fish oil- assuming equal amounts of the fatty acid become bioavailable after consumption. The typical claims made by the marketers of krill oil is that, because krill oil omega-3s are delivered as phospholipids (PL, rather than triglycerides), they will have (or have been shown to have) higher bioavailability than fish oil omega-3s. Our whitepaper clearly shows that the studies used by marketers to “prove” such assertions are either not clinically or statistically significant; or are not appropriately designed to make such comparisons. However, the biggest issue is not their failure to prove better bioavailability, or the fact that krill oil appears to be nearly ¼ free fatty acids upon analysis (not all PL as claimed); but the fact that commercially available krill oil products are extremely low in EPA and DHA, while still costing much more than fish oil products (containing much more EPA and DHA). In fact, in the only trial comparing equivalent doses, researchers needed to use 14 krill oil capsules to get the same amount of EPA and DHA as 4 capsules of fish oil.

This is where the first of the new studies fits in. Published in December of 2013 in the open access Lipids in Health and Disease, this paper has such a hopeful title: Enhanced increase of omega-3 index in healthy individuals with response to 4-week n-3 fatty acid supplementation from krill versus fish oil [Free Download]. The cross-over designed trial appears to compare an equal amount of EPA and DHA from krill oil and fish oil (and a corn oil placebo); and indeed reports a higher increase in the omega-3 index (the percent of EPA and DHA within RBC phospholipids) during the time subjects were taking krill (compared to fish oil); although both fish and krill oil were better than placebo. They report that the various oils were provided in six- 500 mg capsules (3 with breakfast, 3 with dinner); describing the fish oil as a “TG 18/12” oil. Going one step further; they analyze and report the fatty acid composition of each of the three oil products; and this is where things get fishy.

They claim the fish oil to which they compared the krill oil was a TG 18/12, which is the usual designation for un-concentrated fish body oil providing 180 mg of EPA and 120 mg of DHA per 1000 mg of oil. However, their fatty acid composition lists a very unusual fatty acid profile for this fish oil: including 32% linoleic acid- an omega-6 fatty acid. Normally, fish oil contains about 2-3% omega-6 fatty acids; so what is going on with this oil? Well, we were not the only ones to wonder about this. In early January of 2014, a commentary of the above trial was also published in the same journal, asking about the strange fatty acid profile of this fish oil, along with a few other points of contention. You can find that Commentary Here.

Incredibly, the authors of the original paper explained it this way in their rebuttal [Found Here]: Our primary objective was to compare effects of consumption of same amount of n-3 fatty acids from krill or fish oil. When designing a double blinded placebo controlled randomised cross over trial, it was felt that the amounts of treatment products as well as the bioactives of interest be maintained consistent across different interventions. However, the n-3 PUFA content of the krill oil fell below that of fish oil. In order to match the concentrations of n-3 PUFA and volumes between krill and fish oil, the fish oil was diluted with the placebo, corn oil at a ratio of 1.3:1.0.[Emphasis added] Yes, you read that correctly. They used the lowest dose of fish oil they could find (one shown to have lower bioavailability than the concentrated TG forms) and still needed to dilute it with corn oil so they could reduce its omega-3 content for a head-to-head comparison to krill oil. The authors also admit: We agree that we could have included the information about dilution of fish oil in the original manuscript itself. While we will avoid the obvious question about motive usually entertained when a manufacturer of krill is involved in such a study; this begs the question of the type of expertise used in the peer-reviewing process that missed the obvious questions about the fatty acid profile of the fish oil.

This report, with the commentary and rebuttal, only solidifies our view that krill oil simply cannot deliver a cost-effective payload of EPA and DHA to be considered as a therapeutic alternative to fish oil. Krill oil products do not even have the amount of EPA and DHA found in the lowest concentrations of fish oil, while their cost is sometimes double or triple the same. From a therapeutic standpoint, concentrated TG forms can deliver 4-8 times more EPA and DHA per capsule, at an affordable price.

This brings us to the second paper, published in the February 2014 edition of Nutrition Research. Again, the title of this article (written by scientist employed by the manufacturer of the krill product used) was deceptively hopeful: Krill oil supplementation lowers serum triglycerides without increasing low-density lipoprotein cholesterol in adults with borderline high or high triglyceride levels. Unfortunately, the data proved to be anything but a straight-forward TG-lowering effect from krill oil- although their analysis is so flawed that it almost defies explanation.

The study was designed much like TG-lowering studies of fish oil. Three-hundred patients with high triglycerides were recruited and given placebo or 3 to 4 grams of krill oil providing 0, 100, 200, 400 or 800 mg of EPA/DHA over 12 weeks. Blood lipids and omega-3 index were measured at baseline, six weeks and 12-weeks after consuming the krill products. The data speaks for itself; after 12-weeks of krill oil consumption the change in TG levels in these individuals with a mean TG at baseline=231 was as follows: Placebo (+3.9%), 100 mg (-10%), 200 mg (-3.8%), 400 mg (-6.7%), 800 mg (+0.9%)- none of these reached statistical significance. The authors claim that the lack of efficacy and dose-response was due to the overwhelming intra-individual TG measurements and high standard deviation- making it impossible to measure fasting TG as an outcome. How then, with these numbers (even showing an increase in TG using 800 mg of EPA and DHA) were they able to declare a TG-lowering effect in the title?

The reviewers of the paper allowed these authors to circumvent the “limitations” of the study and use “an explorative data analysis approach to increase the statistical power of the study.” In essence what they did was to pool together all the doses, including the 6-week data points which happened to be better for nearly all the doses, and analyzed the data as if a theoretical average EPA/DHA content of 385 mg was given to all the subjects. The authors then boldly declare that “Relative to subjects in the placebo group, those administered krill oil had a statistically significant calculated reduction in serum TG levels of 10.2%.” Even if we accepted this flawed explorative data analysis, this data showed only a 6.3% reduction from baseline TG levels- a level that even if achieved in this study, represents a small clinical difference. In contrast, fish oil studies routinely see drops in TG (from baseline) of >25%, show clear dose-response and are maintained or even continue to improve between 6 and 12 weeks.

The fact that such a flawed study that failed to reach any statistical-significant reductions in TG based on the primary objective (12-weeks) and initial statistical plan was permitted to use statistical manipulation to imply a positive outcome is incomprehensible. Clinicians and patients would read the title and abstract of this paper thinking that krill oil was able to reduce TG levels in these subjects- when in fact, at the end of 12 weeks the data shows that it did not. This paper should be retracted, rewritten to describe it as a failure to meet its TG-lowering objective and republished.

While I am certain the marketing departments of krill manufacturers and distributors are eager to share with you their “latest success stories”- now you have the rest of story- revealing krill oil’s epic failure as a therapeutic contender in the omega-3 world.

[Dr. Guilliams discussed this and many more issues related to fish oil (from the whitepaper) in a discussion with Dr. Hoffman’s on his Intelligent Medicine podcast. Download and Listen Here.]

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   Over the past six months, I have been working on a big project (soon to be announced) evaluating a whole host of assumptions and presumptions concerning nutrients and their various forms. Natural vs. Synthetic, isolates vs. complexes, “activated” forms and chiral enantiomers. I hope to use a few separate blogs to help clinicians, researchers and interested nutrient aficionados understand when these differences appear to matter (at least in a way that can be measured). By the way, we will also try to make sense of all this d,l and R,S confusion that only seems to make sense to organic chemists.

   Some of the ones we will be covering over the next few blogs include: natural vitamin E (d-alpha) vs. synthetic vitamin E (d,l-alpha tocopherol); alpha vs. beta, gamma, delta tocopherols; vitamin K1 vs. K2; phosphorylated B6 and riboflavin forms, methylated folate and B12, R-lipoic acid vs R,S-Lipoic acid, Co-Q10 (ubiquinone) vs. ubiquinol and a few others that crop up now and again.

   Knowing that these topics can be a bit controversial, I want to start with one that is sure to stir the pot a little, but is fairly straightforward to explain: phosphorylated B-vitamins. It is quite common, especially here in the US, to hear well-regarded clinicians recommend the use of activated B-vitamins from the podium of prestigious integrative medicine conferences. Along with methyl-folate and B12, this list usually includes pyridoxal-5-phophate (P5P) and riboflavin-5-phosphate (R5P). But is there any evidence to suggest that either of these forms is better than their “inactive” counterparts? In fact, there is not; and the reason is shamefully obvious: both P5P and R5P must be de-phosphorylated prior to transport into the body.


   Food sources of vitamin B6 are found in all three forms (pyridoxine (PN), pyridoxamine (PM), pyridoxal (PL)), as well as each of their phosphorylated and glucoside-conjugated forms. All phosphorylated compounds are hydrolyzed into their respective un-phosphorylated form prior to absorption, after which in vivo conversion allows each to act as vitamin precursors. Phosphorylation of the coenzyme form occurs, as needed, in the liver. (See the figure from pg 176 of Present Knowledge in Nutrition-7th edition). Note that in each case the form of B6 is transported from one tissue to another, the phosphate portion is removed.

   The same phenomenon exists for riboflavin and riboflavin-5-phopshate. Riboflavin is naturally found in foods as either free riboflavin or one of its co-enzyme derivatives (FAD/FMN). The bioavailability of these compounds is similar since each form is hydrolyzed to free riboflavin prior to transport into the body. The similar pharmacokinetics of oral R5P (and its need for de-phosphorylation) compared to pyridoxine HCl have been known for over 45 years! So why is this so important? If they are the same, why bother with it all? Well first let’s also add to our discussion that the raw material cost (both in dollars and energy) is greater using these forms (about 3-times higher for R5P and about 7-times higher for P5P) and they are no more “natural” since each is chemically synthesized from either free riboflavin or pyridoxine HCl, respectively.

   Beyond the cost difference for the use of ingredient with no additional benefits, there are two other concerns that I would like to raise before closing. The first is that the blanket notion that consuming the “active” form of a vitamin will somehow improve the overall benefit of an oral supplement simply teaches the wrong view of vitamin physiology. All vitamins function in the body by a constant conversion between various active and inactive forms. In many cases, active vitamins are converted to their inactive forms (intentionally) by specific enzymes in order to transport vitamins from one part of the body to another. Inactivating the vitamin prevents it from inappropriately reacting prior to reaching the target tissue. Secondly, when such broad statements about “activated” vitamins are made, it makes it more difficult to explain the true differences between certain nutrients, when proven differences actually exists (many of which we will cover in future blogs).

   I am fairly certain that most clinicians, nutritionist, dieticians and even supplement manufacturers are unaware of this information (even though it is in all the textbooks); so no need to panic. In this case, these phosphorylated forms are not necessarily less clinically effective, they are just less cost effective ways to deliver the same nutrient.

• Vitamin B6 page- Linus Pauling Institute website: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB6/
• Office of Dietary Supplements- National Institutes of Health- Health Professional Information. http://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/
• Said HM. Intestinal absorption of water-soluble vitamins in health and disease. Biochem J. 2011 Aug 1;437(3):357-72
• Waldmann A, Dörr B, Koschizke JW, Leitzmann C, Hahn A. Dietary intake of vitamin B6 and concentration of vitamin B6 in blood samples of German vegans. Public Health Nutr. 2006 Sep;9(6):779-84.
• Gregory JF 3rd. Bioavailability of vitamin B-6. Eur J Clin Nutr. 1997 Jan;51 Suppl 1:S43-8.
• Riboflavin Page- Linus Pauling Website: http://lpi.oregonstate.edu/infocenter/vitamins/riboflavin/
• Bates CJ. Bioavailability of riboflavin. Eur J Clin Nutr. 1997 Jan;51 Suppl 1:S38-42.
• Jusko WJ, Levy G. Absorption, metabolism, and excretion of riboflavin-5′-phosphate in man. J Pharm Sci. 1967 Jan;56(1):58-62.

If you want to know when Dr. Guilliams posts future blogs or when a new whitepaper is available, “Like” us on our Facebook page. To get Dr. Guilliams’ book The Original Prescription– you can purchase directly from the Point Institute or purchase on Amazon.

 

Being involved with dietary supplement research for almost 18 years, I have witnessed my share of hype for, and against, the use of dietary supplements. Few, however have attempted such blatant finality to the subject as the recent editorial in the Annals of Internal Medicine– titled “Enough is Enough: Stop wasting money on vitamin and mineral supplements.The editorial, coupled with the publication of three papers in the same issue, declares in no uncertain terms that “..we believe the case is closed-supplementing the diet of well-nourished adults with (most) mineral or vitamin supplements has no clear benefit and might even be harmful. These vitamins should not be used for chronic disease prevention. Enough is enough.” The publication of the editorial was hyped by many news outlets who quickly found the usual supplement bashers, all too willing to add insult to injury by regurgitating decades-old sound-bites.

Anybody that has spent even a brief amount of time evaluating medical research, especially as it pertains to the use of vitamins and minerals, knows that such a conclusion (“the case is closed”) is as arrogant as it is absurd. In fact, the editorial doesn’t even do justice to the data presented in the three papers published within the same issue- let alone the broader evidence used to support the use of certain vitamins and minerals for the prevention of chronic disease. Let us briefly discuss the 3 papers published in this particular Annals issue- before moving on to the broader context that may expose the real issue behind this editorial. They included [1] the vitamin-only and placebo-only arms of the TACT (Trial to Assess Chelation Therapy), looking for reduced event rates after an initial myocardial infarction, [2] an attempt to see measurable cognitive changes when giving men a multivitamin- part of the Physicians Health Study II, and [3] a systematic review of a select group of studies using various vitamin preparations for primary prevention of cardiovascular disease and cancer- a review prepared for the U.S. preventative Services Task Force.

1.         We have previously discussed the initial data from the TACT trial [here]- which showed statistically lower events when patients were given EDTA chelation, compared to placebo.[1] Since this study was a 2×2 factorial trial- the two arms receiving no EDTA chelation (i.v. saline/placebo) given either placebo capsules or high-dose multivitamin capsules were compared in this study.

A high-dose vitamin supplement, similar to those sold by a number of physician-only product companies, was used for this study. Patients were at least 50 years old and all had sustained a previous myocardial infarction. The primary end-point was a composite of time to death from any cause, re-infarction, stroke, coronary revascularization or hospitalization for angina. A secondary end-point using just cardiovascular death, re-infarction and stroke was also assessed. According to the authors, the high-dose vitamins showed an 11% relative reduction in the primary end point compared to placebo, but this difference did not reach statistical significance (see the cumulative events recorded over 60 months in the primary (top) and secondary (bottom) outcomes in the adjacent figure). The authors make it clear to us that while the trial does not support the routine use of high-dose oral multivitamin regimen for all patients who have had an MI, the total number of events were smaller than the trial was originally powered to detect and thus -“ the reduced statistical power due to a small difference between groups, as well as the nonadherance to the study regimen, limits the conclusion of nonefficacy.” [emphasis added]. The number of people who stopped their vitamin or placebo therapy was staggeringly high at 46%.

Let us now review a few more things that might be of interest to you- but left out of the editorial. First is the fact that both the vitamin group and the placebo group were consuming a high number of pharmaceutical agents (as one might expect of a post-infarct cohort). Subjects were on aspirin (>82% of subjects), beta-blockers (70%), statins (70%), ACEi/ARB (60%), Clopidogrel (25%), and oral hypoglycemic (>20%). On top of this- nearly half the patients were taking other multivitamin supplements! So, in essence, this study was looking for a statistical difference between one group of subjects taking high-dose vitamins (46% of whom discontinued taking them) and another group of subjects (half of whom were consuming another multivitamin of unknown ingredients)- while both groups consumed high amount of pharmaceuticals which are known to reduce both the primary and secondary end-points measured.

Furthermore, there was one important cohort that realized a statistically significant reduction in the primary end-point when given the multivitamins; those individuals not on a statin drug (38% reduction in events p=0.012). So when we remove the effect of statins on these subjects- we see a strong benefit of the supplemental nutrients (these authors go on to tell to ignore these results, though they are both clinically and statistically significant, until more studies can be done). A very strong trend also existed in patients enrolled less than 5 years since their MI (p=0.046), suggesting that these nutrients are less effective the longer an individual has been pharmacologically-treated since their MI. Finally- while this study used a supplement containing much higher doses than nearly any other multivitamin trial to date- it is important to note that, unlike the widely repeated concerns of risk, this trial reported no difference in severe adverse events or incident cases of cancer. 

2. The second paper was a sub-study of the Physicians’ Health Study II (PHS2). Previous analysis of this data already showed that this multivitamin therapy statistically reduced the risk for cancer and cataracts.[2] In this analysis, cognitive function was measured using the Telephone Interview for Cognitive Status (TICS). Although the PHS2 involved 4 arms, the data presented here was between two group given either a multivitamin (Centrum Silver) or placebo. Subjects over 65 were recruited from within the PHS2 for this sub-study. They found, after 4 such telephone assessments over 12 years, that there was no statistical difference between the two groups in the mean level of cognition. They conclude that “in male physicians aged 65 years or older, long-term use of a daily [Centrum Silver] did not provide cognitive benefits.”

The limitations of this study are many. First, because this was a sub-study of the PHS2, the first (baseline) cognitive test began an average of 2.5 years after patients were randomized to their multivitamin or placebo. This means that the baseline could have been already influenced by years of the therapy. Even though their baseline data showed no statistical, between group differences, this fact alone would likely prevent anyone from drawing firm conclusions from this data. On top of this, subjects in the PHS2 were only prevented from taking other multivitamins if those products contained more than the USRDA of vitamin E, vitamin C, B-carotene or vitamin A. Which means they could be consuming high levels of B-vitamins- known to lower homocysteine (a metabolite associated in some studies with cognitive risk), or any of a number of other supplements known to affect cognition (Ginkgo biloba, phosphotidylserine, omega-3 fatty acids, vinpocetine, etc.) without the knowledge of the researchers (up to 1/3 of subjects were taking other multivitamins in the PHS2). These gross oversights are due to the simple fact that the PHS2 was obviously not designed to answer whether daily multivitamin use affects cognitive function in healthy older physicians in the first place.

Since few observational studies have examined the relationship between multivitamin use and cognition; and since the PHS2 was also not originally designed to ask this question; these data do not allow any broad conclusions about the benefits of all multivitamins (and doses) on potential cognitive benefits. While we don’t typically recommend products like Centrum Silver- it should have been obvious to these researchers that this product was not specifically designed to modulate cognitive function in healthy 65 year old male physicians; nor were there previous trials to suggest such an outcome. It is curious that a study (PHS2) not designed for this primary end-point, coupled with an intervention (Centrum Silver- one/day) not designed for this primary end-point can be evidence for anything- let alone for an argument that the “case is closed.” 

3. The last of the three published articles is a systematic review of the benefits and harms of vitamins and mineral supplements in community dwelling, nutrient-sufficient adults for the primary prevention of either cardiovascular disease or cancer. After weeding through thousands of potential articles, these reviewers selected 103 articles (representing only 26 studies) that fit their study selection criteria. As one would expect, these trials varied considerably in study design, recruitment criteria and primary end-points; and most importantly- differed dramatically in the multivitamins or mineral products used in each study. Not surprisingly, they “found no consistent evidence that the included supplements affected CVD, cancer, or all-cause mortality in healthy individuals without known nutritional deficiencies.”

Rather than attempt to parse the nuances of each selected study, a broader critique will be sufficient for this review. Blinded by their desire to debunk the use of “vitamins” and “minerals”- these reviewers ignore the fact that each nutrient has a completely different mechanism of action, therapeutic dose potential and historical data. Comparing studies where subjects consumed the hormone-like cholecalciferol, with studies using the water-soluble antioxidant ascorbic acid, merely because both are classified as “vitamins,” is absurd and unscientific. On top of that, they excluded from their analysis any studies that used doses higher than the upper tolerable limit set by the U.S. Food and Nutrition Board. This would exclude products with more than 4000IU vitamin D, 35 mg of niacin, 1 mg of folate, or 350 mg of magnesium- often exceeded in products known for their therapeutic benefit. Furthermore, since they excluded studies where subjects were nutrient deficient- this virtually eliminates the application of this data to “average” American- many of whom are deficient in more than one vital nutrient; which begs the question of this review’s intended application.

The authors do admit that this review study design is used “primarily to evaluate drug therapy. The design might not be ideally suited to evaluate nutrients.” They also acknowledge that since subjects in the placebo arm of each of these studies are healthy and not known to have any nutrient deficiencies- they are, in fact, comparing subjects with “adequate” nutrient intake (placebo) versus those with higher than adequate nutrient intake (supplemented treatment). In many cases, the “placebo” group is not even prevented from taking other supplements; or are consuming higher amounts of nutrients than the researchers originally anticipated (they note, for instance, that Women in the WHI control group had twice the average calcium intake than the study design anticipated).

In the end, this highly selected review of widely divergent low-dose studies (only a few which reflect “real-world” supplementation) adds little to the evaluation of the use of appropriately dosed nutrient supplements for reducing the risk of (i.e. preventing) chronic disease. 

A final perspective: I find it ironic that while the FDA demands that manufacturers of dietary supplements constantly reassure their customers that “these products are not intended to cure, treat or prevent any disease”- that this same statement (although almost certainly untrue) is somehow proof of no health benefit. What this statement, and these types of trials prove- is that, alas- nutrients are not drugs! Furthermore, the studies designed to “prove” drug efficacy are inadequate and inappropriate to evaluate the benefits of nutrients. What started out as “evidence-based medicine” has now morphed into “medicine-based evidence”- where drug companies set the rules and FDA gladly enforces them. And even though the $300 billion pharmaceutical industry is 10-times larger than the supplement industry (only ~40% of which is vitamins)- we are advised to “stop wasting our money” only on the latter. Thankfully, the American public knows better- even if they don’t have access to all the nuances uncovered here. For them, the case is also closed: and they are not going to wait for the paid researchers to finally figure it out. 

  1. Lamas GA et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013 Mar 27;309(12):1241-50.
  2. Gaziano JM, Sesso HD et al. Multivitamins in the prevention of cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012 Nov 14;308(18):1871-80.
  3. Rautiainen S, Wang L, Gaziano JM, Sesso HD. Who uses multivitamins? A cross-sectional study in the Physicians’ Health Study. Eur J Nutr. 2013 Oct 30

If you want to know when Dr. Guilliams posts future blogs or when a new whitepaper is available, “Like” us on our Facebook page. To get Dr. Guilliams’ book The Original Prescription– you can purchase directly from the Point Institute or purchase on Amazon.

 

With the recent discussion of water intake and health- here is an excerpt from The Original Prescription that discusses the principle of using water as our main source of hydration and a little bit about the origins of the 8 glasses per day “rule.”

This is just one of over 50 Lifestyle principles discussed in the Original Prescription.

Principle #6: Water should be your primary beverage; drink enough, and try to limit the number of liquid calories you consume.

Water is one of the quintessential nutrients of life and yet is often one of the most commonly neglected. Despite its great importance for nearly every bodily function, many of us are still at a loss when it comes to knowing how much we’re supposed to drink each day and which other beverages count toward our daily needs. All this confusion about water needs comes as no surprise considering that the first official recommendation for adequate intake (AI) of water was only established in 2004 by the Institute of Medicine, coinciding with an increase in popular awareness about water needs for preventing conditions such as cancer, heart disease, and weight gain (27). Prior to that, the RDA concluded that it was impossible to set a recommendation for water needs, and the National Research Council used a general rule of thumb of 1 ml/ kcal (that would be two liters of water per 2000 calories consumed, if you’re getting out your calculator) (28). Today’s recommendations for daily water requirements, however, are based on national averages from the NHANES III data, although individual needs vary greatly. It’s estimated that most of us need to get 80% of our daily hydration through beverages, mostly water, while about 20% of our hydration comes from the food we eat (less if you happen to avoid fresh fruits and vegetables) (28).

Throughout history, humans have relied on water as their primary source of hydration, struggling to ensure both an abundant and a clear source was available for their survival. Unfortunately, this struggle still exists in many locations around the world today. In the West, water abundance (at least for drinking) is rarely in jeopardy, and yet many choose other options. Countless individuals have replaced water with soft drinks to quench their thirst, and, as a result, sweetened beverages have become one of the major sources of calories in the American diet. Consumption of high fructose corn syrup, the major sweetener in commercial soft drinks, increased over 1000% between 1970 and 1990, and today, half of all Americans consume soft drinks every day. In fact, these beverages now constitute the leading source of added sugar in the average diet (29,30). To make matters worse, the calories provided by soft drinks often fail to satisfy hunger the way solid food does, nor do they quench our thirst in the way water can, making sugary beverages a key player in the obesity epidemic (30–33). If you want to maintain those good signals that your body is waiting for, limit the number of calories you consume through drinks. So how much water should you drink per day?  Well, that depends. How much you weigh (roughly 60% of that is water), how much water you lost recently to perspiration, and relative humidity will all affect the ultimate answer. The Institute of Medicine says that the adequate intake of total water per day is 3.7 liters for men and 2.7 liters for women.† The “8 by 8 rule” (8 glasses of 8 oz. each) equates to about 2 liters. Many rely on their thirst to tell them when to drink, and while it is true that most people’s thirst and hunger mechanisms can help manage their net water balance, in many people the thirst mechanism is blunted and mild dehydration can set in well before their body tells them to drink. Others try to rely on the color and darkness of their urine as a gauge of hydration, but this is not always a reliable indicator of the need for water (35)

So what’s the bottom line when it comes to hydration and water?

  • If you aren’t already doing it, drink mostly water to keep yourself hydrated.
  • Make sure your water source is clean and free of contaminants.
  • Tea and coffee are fine for most people (in moderation); if the caffeine causes you to urinate frequently, consider offsetting this loss with additional water.
  • Alcohol is dehydrating—plain and simple.
  • Remember to include water-based soups and stews, herbal teas, and low-sugar fruit juices.
  • Drink more water when you are physically active and when the weather turns hotter.

† The AIs provided are for total water in temperate climates. All sources (according to IOM) can contribute to total water needs: beverages (including tea, coffee, juices, sodas, and drinking water) and moisture found in foods. Moisture in food accounts for about 20% of total water intake.

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