Controversy is no stranger to vitamins and herbs, albeit there are periods of more and of less attention. Popular news sources recently have been making much of a couple of issues: To start, there has been a regular drumbeat regarding the uselessness of vitamins, either alone or in combination, for either preserving or improving health. Multi-vitamin/mineral supplements are common targets, but so are vitamins such as vitamin D and a number of popular herbs. Next, we are warned routinely of possible interactions between various supplements, especially herbal extracts, and prescription drugs. In particular, blood-thinning medications and certain immuno-suppressants used to treat HIV have been emphasized as being incompatible with a number of popular plant products, including St. John's wort and Chinese ginseng. Both sets of issues are real, to be sure, and need to be considered for safety's sake. Nevertheless, the ensuing controversy over supplements is perhaps just as important for what it reveals about American dietary and other habits as for what it reveals about the safety of vitamins and herbs.

In point of fact, many common foods have as great or greater an impact upon numerous medical conditions as do the vitamins and herbs that have been singled out. Examples of this will be given shortly. In considering these examples, the reader should be aware they are not exhaustive. They are being offered as evidence for a number of points worth pondering. First, what is revealed by the current focus upon the medical interactions of popular supplements? Second, if quite a number of foods pose the threat of similar interactions, does a lack of focus on or concern with dietary factors suggest that the diet of the average American is highly restricted in terms of food choices? Third, is it the case that many conditions for which drugs are readily prescribed for chronic use in this culture might be better treated by simple changes in the diet and/or the use, as first choice, of vitamins, herbs and other supplements which have negligible side effects?

Vitamin D One More Time
TotalHealth magazine over the past few years has been vigilant in examining controversial attacks on vitamin supplements and it is disappointing to many of us that wrong-headed analyses continue to be picked up and presented uncritically by both professional journals and the popular press. USA Today (January 23, 2014) is a good example of this as it states unambiguously that studies and reviews of vitamin D have found no "significant benefits for heart health, cancer prevention or even bone health in healthy people." The journal article that prompted these comments, large meta-analysis just published in the British medical journal Lancet is blunt in its assessment of vitamin D:¹ "Available evidence does not lend support to vitamin D supplementation and it is very unlikely that the results of a future single randomized clinical trial will materially alter the results from current meta-analyses."

The response from a number of primary vitamin D researchers to this and other recent meta-analyses has been withering. This includes the remarks of Dr. Michael Hollick, the scientist responsible for identifying the major circulating form of vitamin D in serum —25-hydroxyvitamin D3—which is the form of vitamin D measured medically to assess vitamin D status. Dr. Hollick terms the recent papers flawed and "silly." Dr. Hollick's views are reported by Dr. Mercola at his website (http://articles.mercola.com/sites/articles/archive/2014/02/17/vitamin-d-supplements.aspx) which provides an elaborate critique of the recent vitamin D papers. Another researcher who roundly dismisses the recent studies is Dr. Cedric Garland of the University of California at San Diego Moores Cancer Center. His comments cover both the Lancet paper already mentioned and another recent meta-analysis:

This meta-analysis is nothing new and is already obsolete since it is mainly based on old papers that used too little vitamin D to expect any effect. A New Zealand study saying we should only supplement people with vitamin D deficiency and evidence of bone loss is equally wrong. Virtually everyone in New Zealand, and most adults in the U.S., are vitamin D deficient by modern criteria, being below 32 ng/ml.

The reality is that we now know that they are deficient with regard to extraskeletal effects of 25(OH)D if their serum level is below 40 ng/ml. These papers should be disregarded as obsolete work. We are moving into a new era of using vitamin D3 in doses no less that 4,000 IU/day for people aged 9 years and older... Studies using less than 4,000 IU/day are on the verge of obsolescence.

In other words, the studies culled and used as the basis of the recent meta-analyses of vitamin D were themselves inadequate because designed around totally inadequate vitamin D daily dosages. Moreover, one does not need to look far for at least one very major review that disagrees with the conclusions of the negative meta-analyses in the most fundamental way. A Cochrane review published just this year on vitamin D and mortality gives an answer that seems more than sufficient to warrant another look at vitamin D, at least in its D3 form:²

Vitamin D3 seemed to decrease mortality in elderly people living independently or in institutional care. Vitamin D2, alfacalcidol and calcitriol had no statistically significant beneficial effects on mortality.

Blood Thinning Drugs
Another point of current controversy involves both vitamins/ vitamin-like compounds and various herbs. Many aging individuals are treated with anti-coagulants or "blood thinners" to reduce the risks of stroke and blood clots. One popularly prescribed such drug is Coumadin (warfarin). Drug interactions with any of the anticoagulants are quite common, including with such everyday items as alcohol and aspirin. The usual side effects involve too free bleeding and show up as such things as easy bruising, frequent nosebleeds, dark urine and tarry stools. Needless to say, excessive bleeding can be life-threatening under certain conditions. Interactions with anticoagulants are so common that some pharmaceutical experts caution against taking any new drug, including overthe- counter items such as aspirin, without first speaking with a doctor or pharmacist.

Ginkgo biloba extracts, particular examples of which in a number of clinical trials currently are being reaffirmed for cognitive health (but only in the case of certain extracts)3, possibly present a problem for those taking anticoagulant drugs largely because these extracts perform many of the same tasks as those drugs and much more. Ginkgo extracts improve the blood flow through the artery which serves the heart, improve circulation in the brain and more generally throughout the body, increase the clearance of toxins from the system, and protect the body against what is known as platelet-activating factor (PAF). PAF was only discovered in 1972, and since that time scientists have come to realize that it is involved in disturbances ranging from internal blood clots (often leading to heart attacks and strokes) to allergic reactions and asthma.⁴

Problems with excessively "sticky" blood are much more common in the United States than they are in many other countries around the world, such as in Japan. Diet appears to be by far and away the most significant factor in this. A quite large number of foods "thin" the blood. Food sources of omega-3 fatty acids, which include many coldwater ocean fish as well as walnuts and a few other items, all tend to increase clotting time. All members of the onion and garlic families act as blood thinners, especially if eaten regularly and in quantity. The same is true of the mo-er (black tree fungus) and reishi mushrooms, both of which can be purchased in markets, which carry specialty mushroom and Asian vegetables. Another natural blood thinner is hawthorn. Hawthorne, which is found primarily as an extract in this country, is the basis for some popular beverages in Asia and often taken as a tea in Europe. Red wine, especially if it is high in the antioxidant resveratrol, may increase coagulation time. The quinine found in tonic water will increase or prolong the actions of Coumadin and may have its own blood thinning effects. Grapefruit is notorious for reducing the clearance of warfarin-like compounds and therefore increasing the risk of hemorrhage.^5,6

A great many herbs, spices and digestive aids can exercise significant anticoagulant effects. These include cayenne pepper, bromelain from eating pineapple fruit and stem, papain from papaya, and likely paprika and most chili peppers. Ginger root, which is eaten in quantity in Indian and Oriental cuisines, can strongly inhibit clotting. So can its relative, tumeric, which is used widely in curries and a source for purified curcumin. Vitamins and vitamin-like compounds, as mentioned above, can lead to similar problems. These compounds include vitamin E, tocotrienols, omega-3 fatty acids, lipoic acid and many more.

Both Chinese and Indian (Ayurvedic) medicine would greatly expand these lists of foods and herbs which can increase clotting time, but, even as things stand, it should be clear that diet likely is the predominant factor by far in determining the activity of several elements in the blood which control clotting time. Of course, there are at least as many dietary factors which can influence blood coagulation in opposition to Coumadin as those which are additive.

Changing the Rate of Drug Clearance
Many drugs (including some protease inhibitors, calcium channel blockers, and oral contraceptives) are metabolized by the cytochrome P450 3A4 (CYP3A4) metabolic pathway, which is active in the liver. Grapefruit has already been mentioned as influencing this pathway; it contains the compound naringenin, which is one of the most powerful of common compounds in affecting CYP3A4. The herbal supplements, which presently are the most strongly implicated are goldenseal (Hydrastis canadensis), St. John's wort (Hypericum perforatum), and cat's claw (Uncaria tomentosa).⁷ Black pepper extracts, similarly, influence cytochrome P450 and other elements involved in drug clearance.

The ability to zero-in on this enzyme system through special research techniques, unfortunately, in many ways is a bit misleading. How much difference does it make in practice whether the clearance of a drug is delayed as opposed to its absorption being greatly enhanced? Black pepper, cayenne pepper, ginger and long pepper all either strongly increase absorption of other compounds and/or influence cytochrome P450. Some sources of lecithin, such as eggs, may similarly increase the uptake of certain drugs. Alcohol typically enhances the effects of many drugs, whether by increasing absorption, producing its own additive effects, or delaying clearance.

Quite a remarkable number of items in the diet can interfere with many drugs. Some interfere directly with absorption, as do the tannins and fibers found in many fruits and vegetables. Others do so indirectly by activating overall metabolism, liver and/or kidney functions.

Why Look to Dietary Choices Last?
Herbs, of course, do have many powerful effects upon the body and should not be treated as if they are innocuous merely because they are "natural." However, also missing in American culture at large is an awareness that it is relatively easy to intervene in many common conditions without resorting to prescription drugs. In point of fact, other than a quite narrow range public health messages regarding primarily fats and fiber in the diet, we do not tend to think of diet as having much of an impact upon health at all. There is no reservoir of knowledge in everyday American culture regarding the health uses of foods and herbs, unlike the cultures of Asia and even Europe. Moreover, the U.S. heavily subsidizes the growth and production of many foodstuffs used in "fast foods" (corn, wheat, sugar beets, etc.) while doing nothing to reduce the cost to consumers for fresh fruit and vegetables, i.e., items that are healthful rather than being merely sources of calories.

Indeed, there are entire classes of medications sold extremely widely in the United States for which there appears to be no need in many other cultures. One class which immediately comes to mind is that of the acid reflux / heartburn /antacid medications, whether over-the-counter or prescription. The entire notion that there are health problems stemming from the production of excess stomach acid is surely an odd one given the fact that we typically have no such problems when we are young and produce plenty of stomach acid, yet such problems in this culture are common in middle age and later, i.e., at the point at which the ability to produce stomach acid has already begun to decline markedly. What has really happened is that the muscle that closes off the top of the stomach and prevents its contents from flowing back up the esophagus has weakened. Items that reduce the production of stomach acid at the same time prevent the complete digestion of proteins in the stomach, but, again, do nothing to strengthen the muscle that controls acid reflux. Interestingly enough, acid reflux is virtually unknown in much of Asia where ginger is commonly used as a part of meals. Ginger just happens to strengthen the esophageal sphincter.

This returns us to our starting point. Were the average American consuming a truly varied diet, the American medical profession likely would be more aware of the impact of foods upon health. Likewise, there is the curiously dichotomous thinking of many of those who are medically trained to the effect that herbs are either without any benefit, on the one hand, or likely to be a threat to prescribed pharmaceutical drugs, on the other hand. According to this way of thinking, items are either foods or drugs. Foods support the structure and functions of the body, whereas drugs intervene. As long as herbs could be seen as being without effect, they could be relegated largely to the foods category, i.e., at best innocuous and a waste of money in terms of health benefits. Once it is admitted that herbs might have benefits, they must be treated like drugs and viewed as possessing a host of powerful side effects and drug interactions.

The problem is that even everyday foods can have quite powerful effects upon the body. So why not make use of these food effects as a first line of treatment, herbs as a second line, and drugs only when all else fails?

References

1. Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet. 2014 Jan 11;383(9912):146-55.
2. Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2014 Jan 10;1:CD007470.
3. Lewis JE, Melillo AB, Tiozzo E, Chen L, Leonard S, Howell M, Diaz J, Gonzalez K, Woolger JM, Konefal J, Paterson E, Barnes D. A double-blind, randomized clinical trial of dietary supplementation on cognitive and immune functioning in healthy older adults. BMC Complement Altern Med. 2014 Feb 4;14(1):43.
4. Murray, Michael T. "The Healing Power of Herbs," 2nd edition (Prima Publishing, Rocklin, California: 1995.)
5. Brinker, Francis. "Herb Contraindications and Drug Interactions." Revised 2nd edition. (Eclectic Medical Publications, 1998.)
6. Mindell, Earl and Hopkins, Virginia. "Prescription Alternatives." (Keats Publishing, 1998.)
7. Budzinski JW, Foster BC, Vandenhoek S, Arnason JT. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine. 2000;7(4):273-82.
8. Yeshi Donden. "Health Through Balance." Snow Lion Publications, 1986.)

Taking Supplementation Seriously Part III

There is little debate that a balanced diet is the most desirable method for obtaining essential nutrients, but there are cases when the use of supplemental nutrients may be requisite for insuring adequate nutrient intake. When negotiating the vast number of choices in dietary supplements, one criteria for deciding upon a product is whether it contains natural versus synthetic vitamins and minerals.

Choosing a quality dietary supplement can be an exercise in abstraction. As a class of product nestled somewhere in between food and drug, they lack many of the obvious quality measurements inherent to these two other categories (such as the sensory properties one uses to select quality produce, or the strict quality control procedures inherent to the manufacture of a government-regulated pharmaceutical). Until recently, the only way to assess the quality of a supplement (short of spending a personal fortune on lab testing), was from the synthesis of subjective data (brand reputation, marketing claims, and personal experience).

The recent definition of the Good Manufacturing Practices (GMPs) for dietary supplement manufacturers by the Food and Drug Administration has significantly improved how supplement quality is viewed. The 1995 Dietary Supplement Health and Education Act (DSHEA), in addition to legally defining supplements and setting guidelines for their sale and marketing, also provided for a set of regulations governing their proper manufacture. It wasn’t until 2007, however, that these rules (the GMPs), were finally issued by the FDA. The GMPs are a set of requirements and expectations for the quality manufacturing, testing, and storage of dietary supplement products. They were phased in over a three year period; as of June 2010, all manufacturers are expected to be GMP-compliant. GMPs are a great benefit to consumers, and promise to dramatically improve confidence in their dietary supplement choices.

While generally viewed as a positive step, the implementation of the FDA GMPs is relatively new, and the regulations themselves still contain areas (such as testing requirements) that are not fully defined. It may also be some time before the FDA gets around to assessing the GMP compliance of every dietary supplement manufacturer, if they even choose to do so. Therefore it is useful to be familiar with other resources to determine the quality of a supplement product; this article outlines some of the most common.

What is Quality in a Dietary Supplement?
There are several ways to define quality for a supplement, but conventional assessments of supplement quality usually concentrate on two areas: adherence to label claims and freedom from adulteration.

It is fairly obvious that a quality supplement should contain the amounts of each ingredient (within an acceptable margin of error) stated in the Supplement Facts panel. Less commonly known, however, is that supplements are required to adhere to ANY claims made on the label. For example, if the label of a super-fruit supplement claims that it “contains pomegranate, an excellent source of potassium,” then the product is expected to contain potassium, even if it is not explicitly listed and quantified under in the Supplement Facts panel.

Although adulteration suggests some sort of malicious intentional contamination, in terms of GMP, it is officially used to describe any contamination of a dietary supplement product. This includes elevated levels of toxic metals (most commonly lead, mercury, cadmium, or arsenic), high levels of microbes (both benign organisms that can cause spoilage, and pathogenic ones that can cause illness), as well as toxins, either naturally-occurring or man-made (pesticides, herbicides, chemical wastes). A quality supplement product is one that can minimize or avoid the inclusion of any of these adulterants. Most often, adulteration occurs when a company misses key quality control procedures, although in some (rare) cases adulteration truly is an intentional act. The melamine contamination of wheat gluten and the “spiking” of some male enhancement supplements with generic sildenafil (Viagra) are two examples where manufacturers mingled legitimate supplements with other chemicals for a competitive advantage.

It is important to note that quality and efficacy are independent factors; what one considers to being a good or effective supplement product does not have to be one with the greatest quality (in the sildenafil example above, the supplement product was adulterated by a prescription drug, yet many consumers found it to work well). Similarly, there are many products in the marketplace that are made with quality ingredients under strict manufacturing guidelines, but contain amounts and combinations of ingredients that are less than the documented effective doses.

Usually, the company that designs, assembles, and packages a dietary supplement is distinct from the one(s) that manufacturers the individual ingredients that are contained in the supplement. Thus, ingredient quality and manufacturing quality can be treated as separate measures that must both be considered when choosing a quality supplement. A good manufacturer cannot make a quality supplement using poor quality ingredients, just as the best ingredient cannot add to the quality of a product if the manufacturer cannot reliably put the correct amount in the bottle. Many of the quality clues listed below, such as branded ingredients or manufacturing certification, only address one side of this quality equation.

Identifying Quality in a Supplement
There are several lines of evidence, both direct and indirect, that can be used to select a quality supplement. Some, such as third party product testing, directly demonstrate that the product adheres to label claims and represent the best affirmation of product quality. Unfortunately, only a fraction of the supplement market will ever get an independent test, so the savvy consumer must often look for other quality indicators when making a quality assessment.

Standardization can be an indirect measurement of ingredient quality. A standardized ingredient is one that contains a measurable amount of a particular compound. This is most often applied to extracts. An illustrative example would be for the herb milk thistle, a well-studied liver tonic and detoxicant. The milk thistle contains hundreds of different compounds; the most active for liver detoxification is the compound silymarin. There are any number of ways for preparing a milk thistle extract, however, only those that contain silymarin will be useful as liver supplements. Therefore, to guarantee the desired activity of milk thistle, manufacturers standardize their extract to silymarin; that is, they extract the seeds of the milk thistle in a way that preserves a consistent, measurable amount of silymarin. On a label, this might appear as “Milk thistle, standardized to 68 percent silymarin.”

When indicated on the label for a particular ingredient, standardization is one measure of ingredient quality because it can differentiate between ingredients that contain active fractions or are assumed to display an anticipated health benefit, and those that may not. Continuing the above example, compare a product containing milk thistle versus one containing milk thistle, 68 percent silymarin. The former could contain almost any mixture of milk thistle-derived chemicals, while the latter is enriched in liver-tonifying silymarin.

One of the most dramatic consequences of (the lack of) standardization is seen for red yeast rice, a potent cholesterol-lowering ingredient. Red yeast rice contains monacolins, which are chemically similar to the statin class of prescription drugs. Because of this similarity, federal regulations prevent red yeast rice products from bearing any standardization information. Not surprisingly, the unstandardized red yeast rice found in dietary supplements vary dramatically in their quality and efficacy. In a published analysis of commercial red yeast rice products, the amounts of monacolins differed between products by almost 100-fold.

Standardization, while a useful indicator, is not without its drawbacks; not all extracts are standardized (either due to limitations in laboratory analysis, or because researchers have not yet identified or agreed upon the correct standard), and understanding which standards to look for in each dietary extract requires a little research.

Branded ingredients are ingredients with their own branding, usually reflecting that the ingredient manufacturer has a specialized manufacturing technique, or has invested resources into validating the efficacy of their ingredient through animal or human clinical trials. Branded ingredients are often indicated as such on product labels. While not a direct quality measurement, branded ingredients are usually well tested (clinical trials require stricter analyses of potency and purity than those for inclusion in a supplement product), and many maintain their own websites where details of their quality and efficacy can be found.

strong>Adherence to pharmacopoeial monographs
Pharmacopoeiae are books of standards (called monographs) that are used to describe the manufacturing of a high quality pharmaceutical; many pharmacopoeia also contain monographs for dietary supplement ingredients. They are developed and maintained by independent organizations of scientists, and are available to manufacturers as guidelines for manufacturing quality. The most familiar (and most well-respected in the U.S.) is the United States Pharmacopoeia (USP); there are pharmacopoeial standards in other countries as well, as well as smaller, supplement-oriented collections (such as those by the Council for Responsible Nutrition (CRN)).

An ingredient that adheres to all of the standards set forth in a monograph (most of which involve measurements of potency, purity, and limits of contamination) is assumed to be a high quality ingredient. This is often indicated on the product label (for example, if a supplement contains the amino acid glutamine which meets all of the standards set out by the USP monograph, it can be labeled glutamine USP).

It is important to note that not all dietary supplements have monographs, so it is not always possible to assess standards by this method. Additionally, adherence to a monograph is voluntary and not independently verified. Most monographs in pharmacopoeia describe the quality standards for individual ingredients; there are standards for dietary supplement formulas, but these are rarely followed in commercial products (for example, the USP has a monograph for calcium plus vitamin D tablets that describes a product with a precise amount of calcium and vitamin D and no other nutrients; most supplement manufacturers would find this too limiting).

Separately from their pharmacopoeia monographs, the USP also maintains the USP Verified Dietary Supplement Ingredient Program, a voluntary program in which manufacturers can have individual ingredients verified for manufacturing consistency, meeting label claims for purity, potency, and quality, and acceptable limits of contamination. The USP website maintains a list of ingredients and manufacturers which have been verified under this program.

Manufacturing Certification. Although all dietary supplement manufacturers and distributors are required to adhere to the FDA GMPs, not all have been/will be audited by the FDA, so their compliance is not necessarily guaranteed. There are organizations, however, that perform independent audits of dietary supplement manufacturing facilities to certify that they are manufacturing using good practices. Both NSF International, a non-profit public health and safety organization, and the Natural Products Association (NPA), an industry trade group, offer certification of dietary supplement manufacturers for compliance to manufacturing standards that are consistent with, or exceed the requirements set out by the FDA. NSF also performs testing of individual products for adherence to label claims and adulterants. Both organizations maintain a list of their GMP certified companies on their respective websites; dietary supplement manufacturers certified by these groups may also include this information on their own websites.

Company reputationis the most subjective metric for assessing manufacturing quality, and one that should be weighted the most cautiously. Aside from the number of years a company has been in business (not always the best indicator of quality), one could look for more objective quality measurements, such how often the companies products pass third party testing, if it has had any product recalls, or whether it has received any FDA warning letters (the latter two are available from the FDA website).

As noted above, third party product testing of a supplement product, when available, is the strongest evident of individual product quality. Aside from the infrequent involuntary testing by the FDA, there are several organizations that provide independent testing of supplements. Some also audit the manufacturers directly, to evaluate manufacturing methods and quality control procedures.

The USP Dietary Supplement Verification Program is a voluntary product-testing program in which participating manufacturers volunteer their product for random, off-the-shelf testing by the USP. A product verified under this program bears the USP-Verified mark, which indicates that the product has met label claims, does not contain harmful levels of specified contaminants, will break down properly in the digestive system to release its ingredients, and has been manufactured according to the current FDA GMPs. Note that the USP does not have laboratory test for all dietary ingredients, so not all products can be verified under this program (herbal/botanical products, for example, are underrepresented amongst the list of USP verified supplements).

The TruLabel program of the Natural Products Association maintains a database of supplement labels from their participating member companies, and periodically selects products within the database for random testing to verify label claims. Some results can be found on their website.

Subscription services offer the most comprehensive collections of quality information for individual products; for a fee. ConsumerLab performs random, off-the-shelf testing (reviews) of individual supplement products, and also accepts voluntary product submissions from manufacturers for testing.

The monthly product reviews usually focus on a single product type, such as CoQ10 or enzyme products, for which testing results available to subscribers (non-subscribers can view a list of tested brands and a general summary of test results for free.) Products which pass testing can bear the CL Seal, and are added to the ConsumerLab Approved Products list. According to the group, they have reviews of over 2900 products from over 350 brands. Consumer Reports also maintains reviews of individual supplement products as well, and will indicate which ones have been USP verified.