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Reference notes for each chapter

Throughout Life Over Cancer you will see superscripted numbers in the text.  These numbers correspond to the references for the book’s chapters.  Most of the chapters in Life Over Cancer have dozens of scientific references that back up the statements made in the text.  You will find these references on the Life Over Cancer website at the link to the chapter in which they appear.  The numbers appearing in bold on the website references correspond to the numbers in the text.  Please note that each number in the text may have two or more references associated with it, which will all be found on the Life Over Cancer website.

How to use PubMed to retrieve abstracts and articles

If you would like more information about specific references, you can start by looking them up in a resource provided by the U.S. National Library of Medicine called PubMed.  To use PubMed, go to www.pubmed.gov on the internet.  You will see a search form with a blank space to type search terms.  To find information on a particular paper, I’d suggest that you type in the last name and initials of the first author listed for the paper, and three or four important words in the title. Click the “Go” button and PubMed will return a list of article titles with similar content that match your search terms, with the most recent articles listed first –  it’s a type of  search engine for the medical literature. Search the list for the article you are looking for (or change your search terms if you can’t find it).  When you locate it, click on the title and PubMed will display an article abstract.  If you need to obtain the whole paper, look on the right side of the screen, where the publisher’s name is listed in a small box.  Sometimes this box will announce that the article can be obtained for free (the U.S. government requires that authors make free copies of papers arising from government grants available through PubMed after they are published in journals, and other arrangements for free articles are also made).  If there is no announcement of a free article, click on the publisher box to go to a website that will let you buy a copy of the full article.

Directory of Integrative Cancer Centers and Integrative Practitioners

Because the list of integrative cancer centers and practitioners is constantly changing, and because many areas do not have integrative cancer practitioners nearby, we have determined that displaying a list of practitioners on the internet at this time is not practical. 

As you begin looking for an integrative practitioner, there are some things you should know about the terms “integrative”, “complementary” and “alternative.”  They are, unfortunately, being used without clarity today.  Alternative medicine is usually felt to be treatments or medical practice that is outside what is taught in medical schools, and often works from quite different theoretical foundations than conventional treatment.  Alternative treatment may involve stopping use of conventional medical therapies even when they may still be useful to a patient. An example would be a breast cancer patient who is found to have a large tumor, which could be removed surgically and which also has aggressive characteristics, who decides not to have recommended surgery or adjuvant chemotherapy (which does improve survival) and instead only use, say, a diet or an herbal therapy that is advertised as a cancer cure. Some writers include in the term alternative medicine the use of a new drug or therapy that is overseen by a serious scientist or physician but is still under the earlier phases of research investigation, usually outside the United States.  I prefer to call these experimental therapies since they have a research focus and the approach includes routine medical monitoring.

Complementary medicine is the use of a variety of individual techniques to support elements of conventional treatment.  These treatments more typically use the same theoretical models as conventional treatment and are often used and researched as sole interventions in isolation from each other or from any unified model of practice.  Using music therapy to reduce stress for radiation patients would be a good idea and would be characterized as a complementary therapy, but unless it was part of a unified approach to managing the patient, I do not consider it integrative care.

While there are different models and definitions of integrative medicine, what I feel is truly integrative medicine is based on a systematic approach using conventional, complementary and sometimes alternative therapies.  Whenever possible, these should be applied under one roof, orchestrated by one or a few expert practitioners using a coherent model of practice, and with formalized and coordinated approaches for interaction among different practitioners.  Interventions should be applied with a central goal of addressing the major challenges a patient faces and with the intent of coupling conventional and complementary/alternative treatments to mitigate side effects, enhance treatment response, take advantage of favorable synergisms and avoid unfavorable interactions.  Assessments should be performed in order to objectively individualize various components of the integrative treatment. While the ultimate goal is to improve survival and the odds of lasting remission, a major focus would include interventions and attention toward improving each patient’s quality of life and reducing life threatening risks and complications.

As you start looking for an integrative clinic or practitioner, you will find several different options available. 

1. Full integrative clinic under one roof.  The Block Center for Integrative Cancer Treatment is a fully integrated medical clinic that has a chemotherapy unit in addition to a teaching kitchen, physical therapy and exercise teaching rooms, massage room, patient counseling rooms and other medical consultation spaces.  Practitioners are licensed or certified in their respective areas.  They are trained to work together for patients under the model presented in this book. The clinic’s cancer program addresses each of the main criteria encompassed in integrative cncer treatment, including but not limited to:  full medical work-ups, monitoring and treatment; comprehensive cancer treatment with a system for addressing all phases of clinical care,  including conventional treatment, containment, remission maintenance, rebuilding, overcoming resistance; and consulting and coordinating alternative and experimental options globally.
2. Hospital with a complementary clinic.  This is a common model. Integrative or complementary practitioners combine efforts within a conventional setting, although they mostly work independently. Many hospitals today have what are often termed integrative medicine clinics, but they are typically in separate buildings (or even towns) from the main medical building.  There may or may not be a close coordination of care between the physicians on the medical side and the therapists in the integrative clinic.  If you want to use such a clinic for your integrative services, be certain to observe and inquire into the degree of actual coordination and consultation that takes place between the physicians and complementary therapists.  In some countries, medical facilities are prohibited from having any complementary services, and you are likely to have to “integrate” your own care.
3. Complementary therapy clinic or office.  Many complementary therapists have their own offices or practices.  These specialize in treatments like massage therapy, nutrition, yoga teaching or other complementary methods and do not have physicians as part of their staff, though they may be quite willing to cooperate or consult with your doctors.  You may be able to find very useful services in these clinics, but you may have to arrange for the collaboration between your therapist and your doctor.
4. Free-standing complementary medicine clinic.  In this situation, a physician (usually) has developed a clinic on his or her own that refers patients to hospitals or other doctors for major procedures like chemotherapy but does not have them in-house.  These clinics often, however, have any of a variety of practitioners such as naturopaths, chiropractors, acupuncturists, massage therapists, yoga instructors, herbalists or biofeedback specialists.  In this case, you will need to discuss with the physician how he or she coordinates care with those who would be responsible for chemotherapy and other medical therapies.
5. Traditional medicine clinics or offices.  In this category I would place several types of well-established practitioners including traditional Chinese medicine (including acupuncture), herbalists, practitioners of Ayurveda (the traditional medicine of India), homeopaths and naturopaths (naturopaths practice using a broad range of natural therapies). Also in this group I would include a number of therapies that are more common in Europe than in the US, and that are implemented in natural health spas. All these groups have licensing and educational systems, and you should make sure that the therapist you use is appropriately licensed.  Such therapists are usually quite willing to cooperate with your physicians (some are themselves physicians) and often have established relationships with a number of doctors.  You can get some excellent services such as top-notch acupuncture at these clinics, but you may need to take the lead in establishing collaboration with your doctor.
6. Experimental clinics.  This is my term for cutting edge facilities that specialize in a specific single therapy or technique that is based on the scientific model but may not have reached the later stages of clinical research.  These clinics are run by a sophisticated scientist, provide careful disease monitoring, and do have a research orientation.  Such clinics are found around the world.
7. Alternative therapy clinics.  These are clinics that deliver a single or many types of therapies that are considered farther away from conventional medicine, and may actively discourage you from using interventions such as chemotherapy.  They may suggest that you avoid taking chemotherapy or radiation even if your physician has clearly explained why such treatments will be useful for you. They may specialize in any of a number of diets, herbal therapies, various energy therapies.  They may be practicing in a developing country, and their therapists might not be licensed.  While some alternative therapy clinics will collaborate with your physicians, others are reluctant to.
8. Other types of therapists and consultants.  There are several types of therapists and consultants who work with cancer patients.  Here is a list of the different types of practitioners who may work with cancer patients and what services they might be able to provide you:

n      Integrative physician consultants:  a small number of physicians consult with cancer patients and help them make decisions about conventional, integrative, experimental, complementary and alternative care.  They will help with coordination of care but do not themselves have clinics.

n      Non-physician consultants:  these individuals, some of whom are highly trained, often in programs that offer specific education for cancer consultants, also help cancer patients make decisions about conventional, integrative, experimental, complementary and alternative care.  While they are not physicians and cannot write prescriptions or administer other medical treatments, they may have good contacts with integrative physicians and other specialists.

n      Naturopaths:  naturopaths approach patient care holistically and specialize in application of a variety of natural therapies that promote the body’s healing capacities. Some maintain a special interest in cancer.  In some states, naturopaths are licensed to practice independently while in others they must practice with an M.D.  Naturopaths hold the degree Doctor of Naturopathy, N.D.

n      Chiropractors:  while chiropractors have traditionally focused on optimization of spinal health and relief of pain, a growing number are obtaining training in nutrition, and may counsel cancer patients in this area.  In rural areas around the U.S., chiropractors may act as primary care doctors and will thus help cancer patients coordinate their medical care.  Standard chiropractic treatment may be useful in relieving some types of pain associated with cancer, but they will not treat areas with bone metastases.  Chiropractors hold the degree Doctor of Chiropractic, D.C.

n      Traditional Oriental Medicine practitioners:  Several schools in the U.S. and in other countries offer training, including doctoral degrees, in traditional Oriental (Chinese) medicine.  This includes acupuncture, Chinese herbal medicine and related therapies.  These practitioners will provide you with a comprehensive treatment from this traditional viewpoint but are unlikely to offer conventional cancer treatment onsite. Acupuncture may be useful in relieving cancer pain as well as nausea and vomiting. Acupuncturists may be licensed by your state.  Traditional Oriental Medicine practitioners may hold the degree Doctor of Oriental Medicine, O.M.D.; some M.D.s are also trained in acupuncture and other traditional therapies.

Sources for herbal supplements discussed in Life Over Cancer

We do not provide referrals to brand names of supplements due to both legal restrictions and frequent changes in the supplement industry.  You should, however, read the following section to help you determine how to select high-quality supplements:

Tips on Selecting High-Quality Dietary Supplements

1. First talk to your integrative practitioner, doctor, pharmacist, dietitian or other health-care provider to make sure the type of herb or supplement you would like to take makes sense for your health.  Make sure you know the correct name of the herb or supplement, since names of supplements can overlap or be confusing..
2. Find information on the product from one of the reputable sources in the section “Reputable Sources for Credible Herb/Supplement Information” section below. Find out what part of the plant you should be using (root, leaf, seed etc)
3. Use the following 6 points to help you evaluate products.  When you have time, you should read the longer article below on “Assessing Supplement Quality”.

A.     Ingredient quality

a.       Make sure the herb or supplement in the bottle is the plant species or phytochemical that you are looking for, and that it includes the right plant part.

b.      It may be useful to get a product that is standardized to contain a specific amount of an active phytochemical

c.       Quality seals such as USP (U.S. Pharmacopeia) or NF (National Formulary) given by independent organizations are useful though not absolutely necessary indicators of quality.  No quality seals have yet been developed for products that contain multiple herbs or other ingredients, so you should not expect to see seals on these products.

d.      Look for the name and contact information of the manufacturer.  The company may have information on quality control procedures available by phone or internet.  If it is a company whose supplements you have used successfully in the past, this can be a good guide for making choices.

e.       Avoid supplements publicized as “miracle cures”, or ones that use testimonials rather than science to back up their use.

f.        Organically grown ingredients and wild herbs that give some indication (on packaging or website) of sustainable harvest practices are the best for the environment – and you!  You may also want to look for special information such as Kosher processing or vegetarian/vegan capsules.

g.       Avoid getting the cheapest supplement you can find.  Supplements that are priced much lower than similar products may be of lower quality or have much lower levels of active ingredients.

B.     Stability

a.       Look for a lot number or batch number on the packaging.  This enables the manufacturer to trace products back to their origin.  It does not ensure the product’s quality, but does indicate a responsible manufacturer.

b.      An expiration date may be useful, and can be used as an indication of freshness, although we do not actually know accurate ways to determine expiration for some types of supplements.

C.     Minimum safety information

a.       Make sure you understand the dose of the herb or supplement you will be taking, and the instructions for taking the supplement (i.e. should you take an entire dropperful or only a drop or two of a liquid supplement?  How many tablets per day and should they be taken with or without food?)

b.      Supplements should be tested for toxic substances such as pesticides, lead or mercury and this information should be available on the packaging or the manufacturer’s website. Look for hypoallergenic products if you have problems with food sensitivities.

D.    Expanded safety information

a.       Look for information about drug interactions or other safety considerations on the supplement package.  These would include possible side effects, use during pregnancy, use by children, whether the supplement should be taken with food, etc.

E.     Efficacy

a.       Clinical trials are the best indication of whether a supplement is efficacious for a particular condition.  The packaging may show data about a clinical trial; you may also be able to find information about whether a particular extract or phytochemical has been clinically tested on the manufacturer’s website

F.      Bioavailability

a.       One issue with some supplements is whether the tablet can dissolve in the body.  Supplements or websites may have information about dissolution or disintegration tests on a supplement.

Assessing Supplement Quality

Keith Block, M.D., Block Center for Integrative Cancer Treatment

Why Quality Counts--Understanding Purity and Potency

There are two fundamental issues when it comes to supplement quality: purity and potency.  Purity-related concerns have mainly to do with contamination and adulteration.  Herbal supplements in particular are prone to become contaminated by bacteria, heavy metals, and drug residues.  All three factors can be introduced at various points of the processing of supplements.  The health-related concerns are different for each type of
contamination:  bacteria might lead to infection, heavy metals to toxicity, and drug residues to untoward physiological effects. 

Most of the reported problems stem from the adulteration and contamination of herbal products.  For example, herbal producers in China are known to treat their raw materials with sulfur dioxide, which is presently not allowed here in the U.S.  Among the major contributors to heavy metal contamination are mercury fungicides, lead and arsenic insecticides, and industrial and automobile emissions.  Even many wild-crafted herbs (those harvested in the wild) frequently show a high concentration of heavy metals
such as lead, mercury, and cadmium.

Some herbal formulas from Asia contain toxic heavy metal salts, as these play a part in some traditional medicine systems.  Herbal producers in Asia will often add prescription and non-prescription drugs to their herbal preparations. Among the residues found in these herbs are acetaminophen, diazepam, hydrocortisone, indomethacin,
methyltestosterone, phenylbutazone, and prednisone.  In some countries combinations of what we consider prescription drugs with herbal medicine are in line with local regulations and therefore, including them in herbal supplements is common practice.  However, in the United States, supplements and drugs are clearly separated because of the potential harm in giving someone a prescription drug without their knowledge.  Obviously, you should be very cautious about using any imported formulas without knowing exactly what is in them and discussing their use with your integrative practitioner or physician.

Clearly not all supplements provide what they claim to provide, and some may be so contaminated that they may put your long-range health in jeopardy. Some of the contamination is a byproduct of the way these herbs are handled before they ever hit the marketplace.  For example, many of the machines, utensils and brewing containers that are used in processing the herbs may contribute to heavy metal contamination.  If the herbs have not undergone proper drying and storage, the crude plant material can become infested with microorganisms that are capable of producing mycotoxins.  Several of these
mycotoxins can in turn generate aflatoxins, which have been linked to various cancers.

     Given these facts, quality issues must not be overlooked when selecting supplements.  One of the ways supplement manufacturers can verify the potency, purity, and bioavailability of their supplement is to have the raw materials independently tested for both purity and potency.  Companies that care about their reputations will usually have this testing done ahead of time.  Of course, it's important to be sure that the laboratory used for the testing has no ongoing fiscal relationship with the supplement manufacturer or with the supplier of raw materials.  This kind of independent verification helps to prevent fraudulent misrepresentation by companies that simply want to promote their product.

Lastly, let's consider the issue of potency.  When I use the term potency, I'm referring to two things: (1) the strength and freshness of the supplement, and (2) the quantity or concentration of active ingredients.  These factors can vary immensely among supplements with ostensibly the same ingredients but different brand names.  Your first line of inquiry should be: Is the main ingredient(s) biologically active and thus likely to confer some benefit?  Since potency declines over time, supplement labels should carry
an expiration date-a basic measure of quality assurance.  They should also carry warnings regarding potential harmful interactions or side effects-ideally identifying those interactions that would be unique to cancer patients.  Unfortunately, most companies do not produce supplements designed specifically with the needs of cancer patients in mind.  It is even more reason that I believe physicians and nutrition experts must oversee, examine, and monitor the formulations they advise.

Perhaps the soundest way of ensuring a high-quality herbal supplement is to use high-quality ingredients – herbs that are grown under controlled conditions using seeds of a known species and variety of plant; harvested when their phytochemical contents are most advantageous; processed quickly, cleanly and efficiently; and maintained under clean conditions while they are being shipped and incorporated in the process of manufacturing a supplement.  Some companies specialize in obtaining and preparing herbs in this way, and then preparing extracts that simply concentrate the entire plant.  In many cases, whole plant extracts are the best products to use.  They include the full spectrum of phytochemicals in the plant.  If an herbal extract is made using water (or some other solvents), for instance, only the water-soluble components of the plant will be in the extract.  However, many herbs contain important non-water soluble components, and these would be missing.  You could, of course, simply take the entire unprocessed herb, but in many instances, you would need to take a large number of capsules to get as much herb as you need.  A process called “supercritical extraction” –  similar to the process used for decaffeinated coffee but without the use of problematic solvents – yields a whole plant extract that is highly concentrated.  Some excellent supplements are made through the combination of careful sourcing of the fresh herbal material and supercritical extraction.  In general, I advocate the use of whole plants in both herbs and foods, since these are the closest to the natural forms of plants that humans have been eating for millennia.  However, I also will use whole plant extracts that have specific compounds of known biological activity added to them for specific applications.

Standardized extracts are another way that manufacturers approach the problem of quality control.  Standardized extracts contain specified amounts of certain named phytochemicals based on what is scientifically thought to be the optimal concentration of the most effective array of phytochemicals. When a supplement is standardized, you can feel more confident that you’re getting what the label says. 

Standardization is achieved by several means: by making an extract containing only the phytochemicals that are thought to be effective (active) for a particular condition, by blending herbal extracts; by spiking with the active constituent or by standardizing to what is referred to as a “marker” compound.  The marker compound is a phytochemical that is unique to the species of plant that is present in the extract. 

By using standardized products, you know with some assurance how much of the
active ingredient is actually present in the supplement.  And for some ingredients, it is optimal to use products that are high in specific phytochemicals.  Let me give you
an example of how this plays out in my clinical practice.  My research team and I have formulated a decaffeinated green tea extract with a very high concentration-standardized to 70 percent of epigallocatechin gallate (EGCG). One gram of the EGCG supplement is equivalent to 35 grams of green tea. Since the typical bag of green tea contains 1.6 grams of tea, a daily dose of our supplement (8 tablets) contains the equivalent of more than fifty cups of green tea. Additionally, in taking this supplement, my patients are able to bypass the stimulating effect of caffeine, normally found in green tea.

If you think potency is not a serious concern for supplement users, think again.  Some manufacturers provide chemical analysis of their herbal products, which can give you some confidence in their products. Many supplements have inadequate levels of active ingredients or contain no active ingredients whatsoever.  In other cases, the active ingredients are either poorly defined or unknown-which of course takes the onus off the manufacturer. 

As a case in point, consider the findings from a study that sampled dozens of different ginseng products.  After pooling the results of numerous analyses, the investigators concluded six out of every ten products were deemed "worthless," while one in four contained no ginseng at all. Ginseng is among the herbal agents that have demonstrated anticancer as well as stress-reducing (adaptogenic) value.

The situation with St. John's wort, another widely used supplement, is similarly disturbing.  Hypericin is thought to be one of the active ingredients in St. John's wort, that helps to account for the herb's antidepressant impact (another compound, hyperforin, is likely even more important).  But a recent analysis found that seven of ten preparations did not meet the label's claims of hypericin content. What's worse, three of the ten products tested contained less than 50 percent of label's claims; and four of the ten had less than 90 percent of the labeled claims. 

Echinacea is perhaps the most popular of all herbal agents. Consumer Reports analyzed a dozen echinacea supplements for their phenolic content, since phenols are deemed to be the main active components.  The researchers found that the phenolic content varied by more than fivefold in the products they tested.  We know from previous studies that high-quality echinacea preparations show a phenolic content of at least four percent. Shockingly, of the echinacea products analyzed in this study, only 17 percent (fewer than one in five) actually met this key criterion for quality. 

The three supplements I've just mentioned-ginseng, St. John's wort, and echinacea-are among the more commonly used supplements on the market.  But they are just the tip of the supplement industry iceberg.  Many other agents have failed to meet the label claims for content. A fundamental problem is that the dosage of active ingredients for  effectiveness has not been determined for most supplements. Also important is the lack of governmental standards on quality as well as a lack of regulatory responsibility on the
part of the manufacturers.  Because the manufacture of non-pharmaceutical agents is mostly unregulated, many supplements may not provide what they claim to provide.

Herbs are not the only kind of material used for dietary supplements.  Vitamins, minerals and specific phytochemicals extracted from foods (such as beta-carotene) are also important supplement constituents. These phytochemicals can also be synthesized chemically instead of extracted from foods.  In general, I would tend to trust natural phytochemical supplements over synthetic supplements, because the latter may tend to have lower potency.  Many synthetic beta-carotene supplements, for example, are devoid of actual carotene content, according to my colleague Dr. Kedar Prasad, of the University of Colorado.  Synthetic vitamin E (DL alpha-tocopherol acetate) appears to have inferior antioxidant activity compared to the natural forms of vitamin E.  Although this principle certainly does not apply to all synthetic supplements, it is one I find worth heeding, at least in most cases.

There is hope on the horizon, though.  In 2007 the FDA published a set of rules for what are called “Good Manufacturing Practices” for U.S. supplement producers.  These rules are designed to get manufacturers to use procedures such as keeping records on individual batches of supplements, use good identification procedures, use appropriate equipment, protect supplements from becoming adulterated and establish quality control procedures.  These rules will be phased in over the next few years, and should reduce the number of problem supplements – at least for supplements manufactured in the U.S.  But these rules don’t address another issue that is a particular problem for cancer patients – formulation, or the process of deciding on the ingredients of supplement products and what type of product (e.g. pill, soft-gel, powder, liquid) is most suitable.  I address this problem in the next section.


The Importance of Formulation

An Example--Making Omega-3's Work for You Rather than Against You

When I formulate supplements for my patients, I combine multiple nutrients into a single formula to more effectively target specific mechanisms while making the program more practical.  When I first started out, patients found it difficult to take so many individual agents even if I provided them with the right forms and dosing.

Back in the late 1980s, my colleagues and I began to explore and do scientific research using dietary supplements as an integral facet of helping cancer patients maintain their overall health.  We began using advanced lab testing to evaluate the blood levels of
various nutrients and phytonutrients in our patients.  The results of this testing quickly alerted us to the fact that some supplements clearly were not performing as well as others. These are among the main reasons I started formulating my own supplements.  Additionally, the formulations were not designed for cancer patients nor the situations they were facing. We thus decided to seek out a manufacturing facility that meets the FDA standards for making pharmaceuticals.   Fish oil supplements are one example
of a quality concern that we had early on and have since addressed.  Here's what we learned along the way.

As most food scientists can tell you, the omega-3 fatty acids in fish oil tend to oxidize quite rapidly upon exposure to air or heat-and oxidized fish oil confers few if any health benefits.  Also, many of the fish oil products we looked at contained contaminants such as mercury and pesticides.  This led us to focus on formulating a fish oil supplement in accord with certain specifications. For example, while investigating the key quality issues, we learned that fish caught in the north Arctic Ocean had minimal contamination
with PCB's, heavy metals, and common pesticides.

We then opted to test each batch of fish oil with an independent laboratory to evaluate the levels of these contaminants. To further ensure that we met certain quality standards, we undertook careful processing of the fish oil using (1) low-temperature purification and encapsulation techniques, (2) nitrogen flushing to reduce the oxidation of omega-3 fatty acids, and (3) the inclusion of antioxidants to further minimize oxidation. We then elected to filter the fatty acids to develop a more pure omega-3 product.  Lastly, we decided to enterically coat the fish oil capsules.  This process renders them impervious to digestion in the stomach, thus helping avoid the "fishy-smelling burps" that consumers have complained about when taking fish oil and that can be particularly disturbing to cancer patients and others who may have gastrointestinal difficulties due to their disease or medications.  I feel confident that this last adjustment has improved the consistency with which our patients take fish oil, and that our healthy obsession with
quality has, in general, earned real dividends in terms of our ability to better serve our patients.

A 5-point System for Assessing Supplement Quality

Since there are currently few enforceable standards on the manufacturing of dietary supplements, assessing quality largely falls to the consumer.  Not surprisingly, the consumer is often ill-equipped to make such an assessment since a pharmaceutical and medical knowledge base is essential in assessing quality.  The consumer needs guidance from physicians, pharmacists and other healthcare professionals to help separate the quality supplemental products from the poor ones.  It is especially important now for physicians to guide their patients’ use of supplements because more people are using supplements than ever before.  According to one study, about 40% of the population takes vitamins or minerals and about 15% take an herbal or supplement.[1]  Another study from 1999 estimated the number of Americans using herbals at 35%.[2]  These numbers are up from about 2.5% of the US population who took an herbal or supplement in 1990.[3]  Additionally, many patients may not even discuss their supplement use with their physician.[4]  A 1993 study found that 72% of patients who used unconventional therapies did not inform their physician.  Once a patient’s supplement use has been established, there are several components to assess in determining a product’s quality.  One way to approach these elements is to rank them from the most basic to the most comprehensive element needed to determine quality.  A diagram of this type of quantification is shown in Figure 1.  As this diagram shows, these elements are:

·        1. Ingredient quality –includes GAP, GMP as well as adulteration issues

·        2. Stability – ensures proper storage and tracking of the product

·        3. Minimum safety information – provides basic dosing information

·        4. Expanded safety information – provides toxicology, purported mechanism of action, and possible side effects

·        5. Efficacy – shows clinical efficacy and measurable biologic response

1. Ingredient Quality

            As discussed earlier, there are currently no  Good Manufacturing Practice (GMP) standards for dietary supplements, although they are expected shortly.  Similarly, there are no Good Agricultural Practice (GAP – a similar set of standards for good practices in growing and havesting herbs) guidelines so the only way to tell if a product is made under a GAP/GMP standard is if the label states it.  The U.S. law mandates that active ingredients listed on the label be accurate in quality and quantity.  However, there is no indication in the law as to the degree of accuracy in identifying an herbal ingredient, nor as to the quantity of purported active components.   For instance, a ginseng product may be called Ginseng  which contains the species Panax quinquefolius (American ginseng).  Another Ginseng product may contain the species Panax ginseng (Asian ginseng). Technically speaking, both products close botanical relatives.  While they both are sometimes used as a tonic or adaptogen to relieve various stresses on the body, they each have different chemical, pharmacological and clinical profiles.[5]  For instance, Asian ginseng appears to have significant immunomodulating effects while American ginseng has been used in tradition Chinese medicine for its cooling effects and may have activity in reducing post-meal blood sugar levels in diabetics.[6]^,[7],[8]  Additionally, Korean ginseng has been extensively studied clinically with over 60 published clinical trials, while the data on American ginseng in still emerging.[9]  There are also products, like “Siberian ginseng” (Eleutherococcus senticosus) and “Brazilian ginseng” (Pfaffia paniculata) to name a few, that are completely different plants.  Siberian ginseng may also have adaptogenic and immunomodulating effects, but its biological activity probably relates to eleutherosides since it does not contain any ginsenosides, the active components of Asian ginseng.[10]  Brazilian ginseng has been studied very little and appears to have no adaptogenic effects.[11] 

The part of the plant used in the product needs to be labeled, according to federal regulations, but the physician must know how to interpret such information.  So for Korean ginseng, the roots contain most of the ginsenosides, the active component of ginseng, while the root hairs, the leaves and the stems have much less ginsenosides.  There thus can be considerable variability in the products.  One study looked at 25 different ginseng products in the US.[12]  While the plant products were all correctly identified by botanical plant species, there was wide variability in the concentration of ginsenosides, from less than 1% to over 13%.  Additionally, more than half of the products tested which listed the percent of ginsenosides on the label were inaccurate.  The variability found in ginsenosides in this study was probably due to the time at which the plant was harvested.[13]  Korean ginseng typically contains 1% ginsenosides after 1 year of growth and is not harvested until it is 5 years old.[14]  Generally, 2-3% ginsenosides are needed for therapeutic benefit. Because there may be inaccuracies in the labeling of products, the best way for a physician to assess the ingredient quality is to look for the use of GAP/GMP standards on the label.  The “USP Verified” stamp is one way to identify a quality product, at least in the case of products that contain only one herb or vitamin.  This stamp is related to the FDA GMP guidelines.  As these guidelines are phased in, there will likely be a number of manufacturers who submit specific products for USP approval.  Also important to many users of supplements is whether the ingredients are organically grown, sustainably harvested or processed in accordance with Kosher dietary laws.  You may find such information on the supplement label or on the manufacturer’s website.

2. Stability     

            Like pharmaceutical products, the efficacy of a supplement relies on its freshness.  Assuming GAP/GMP standards were followed, the next step in following the quality trail is to look for evidence of proper storage by the manufacturer, and a manufacturer tracking system so a specific batch can be identified if a problem with the product arises while on the market.  The presence of a lot number and formulation number indicate the manufacturer can trace a product back to its origin.  Specific recommendations on the label as to proper storage of the product as well as an expiration date for the product are indications the manufacturer is cognizant of freshness and stability issues with the product.  While the presence of these elements do not ensure the quality of the product, they do increase the likelihood that the product was responsibly made.

3. Minimum Safety

            Government regulation mandates that nutritional information and percent of the Recommended Daily Allowance (RDA) of all ingredients be listed on the product label.  While this information may be important for foods, vitamins and minerals, it is often inconsequential for herbals.  Many herbals with documented clinical efficacy, like ginseng or black cohosh, do not contain any elements relevant to nutritional guidelines.  Additionally, some supplements taken at mega-doses show efficacy not seen at the RDA levels.  Appropriate dose and duration of use are also particularly important both for achieving adequate effects as well as for limiting potential toxicities or adverse effects of an agent.  Because dosing and duration are dependent on clinical trial data (which is lacking for some supplements), the physician is essential in determining the proper usage for their patients.  Of particular interest to the physician is the dosage form of the supplement.  For instance, a standardized preparation of a supplement made from dried garlic powder, has a recommended dosage of 200-300mg 3 times daily for cardiovascular health.[15]  A preparation of aged garlic extract, however, has a recommended daily dosage of 300-800mg 3 times daily.[16]  Similarly a dry, normalized extract of saw palmetto [4:1 (w/w) containing 25% fatty acids] is indicated for prostate health at a dose of 400mg 2 times daily.[17]  A saw palmetto tea, however, is not suitable at all because the lipophilic active constituents are insoluble in water.[18]

Duration of use is important both for maximizing the potential helpfulness of an agent as well as minimizing the potential toxicities that may occur with the agent.  St. John’s Wort (SJW), for instance, must be taken regularly for 4-6 weeks to help maintain normal moods.[19]  To continue this effect, the dose of SJW should be continued for at least 6 months.  While the exact mechanism of action is still unknown for this agent, the dosing regimen is similar to most of the other pharmaceutical antidepressants on the market.  The use of licorice is a good example of an herbal whose use should be limited in duration due to the potential for adverse events.[20]  When licorice is taken at high doses for longer than 6 weeks, there is an increased risk of hypernatremia, hypokalemia, hypertension and edema. 

4. Expanded Safety

            As more information becomes known about an herbal or supplement through clinical trials, a physician can guide their patient’s use of such agents based on more classical parameters of pharmacologically relevant data.  As mechanisms of action are elucidated, and supplement-drug interactions become better-understood, the physician can identify potential adverse effects as well as toxicities and contraindications that may occur with that product.  Ephedra has been used for centuries in Asia as a therapeutic agent to treat asthma and congestion.[21]  In the 1980s and 1990s, it became exceedingly popular in the US as an agent to increase energy and promote weight loss.[22]  While ephedra was known to contain the alkaloids ephedrine and pseudoephedrine, its exact potency was unknown other than its ability to stimulate the sympathetic nervous system.[23]  A series of clinical trials were done in the 1990s which indicated that this activity could be quite potent both at levels usually taken as well as at increased doses of more than 300mg ephedra alkaloids daily.^27,[24]  Additionally, these herbal products sometimes contained caffeine which could increase the risk of cardiovascular adverse effects.  In February, 2004, the FDA concluded that there was sufficient evidence to conclude that ephedra was an unsafe herbal product, and it banned the sale of all products containing ephedrine alkaloids.[25] 

The use of Kava for anxiety is another example of how the physician is in a unique position to identify potential toxicities to their patients.  Kava has been used in the South Pacific for centuries and was considered to be relatively safe.[26]  While its mechanism is not completely understood, case reports of liver toxicity began to be reported in the medical literature in the US and Europe with the use of kava.²⁰  By 2002, there were over 30 case reports of such liver toxicity.  In March 2002, the FDA issued a consumer advisory that such a link may exist and that patients with liver dysfunction should consult their physician before beginning or continuing kava use.[27]  This type of emerging information about potential toxicities is best evaluated by the healthcare professional, especially since the average patient who may be using these products is often unaware these warnings exist.  The patient often misperceives that all products on the OTC shelf are safe, and that they can rely on the labeling information to guide their use of an supplement product.  As these  illustrations demonstrate, this approach is inadequate to protect the patient’s safety.  The patient must be educated as to the importance of discussing all of their herbal and supplement use with their physician.

Another element of significant importance to the physician is the potential for herb or supplement-drug interactions to occur.  These interactions can often be anticipated based on the mechanisms of action of each constituent.  St. John’s Wort is probably best known for interfering with other pharmaceutical agents.  Several recent studies have shown that SJW is a potent activator of a detoxification enzyme called CYP450 3A4.[28]^,[29]  CYP450 3A4 helps the body break down about 50% of all medications on the market today, a critical process in how our bodies handle drugs.³⁴  Because of this activity, SJW can significantly reduce the therapeutic blood levels of many antidepressants, oral contraceptives and anticoagulants.[30]^,[31]  Because more than 20 million Americans may be using herbal supplements unsupervised by a healthcare practictioner,⁸ your physician needs to take a more active role in trying to help their patients minimize the potential for these type of herbal-drug interactions.

5. Efficacy

            Efficacy of any agent is perhaps the most difficult to prove since it relies on well-designed, randomized, placebo-controlled, clinical studies with a sufficient number of patients to be able to generalize the results to the population at large with statistical certainty.  The FDA mandates these trials for pharmaceutical agents before they are brought to market.  The FDA does not require these trials, however, for herbals or supplements to be brought to market in the US.  Much of the information currently available comes from European studies where this type of data is required before a product can be distributed to the market.  NCCAM has helped increase the number of quality studies being done on herbals in the US, but for many compounds the data is still preliminary.  Fortunately, credible evidence for the use of some herbals is starting to emerge.  SJW has been examined in patients with mild to moderate depression to help maintain mood levels.[32]  Saw Palmetto has also been in trials with patients who have benign prostate disease to help maintain prostate health.[33]  The Cochrane Collaboration is an international nonprofit, independent organization that systematically reviews and performs meta-analyses on studies, including supplements, related to herbals.[34]  Their reviews can also validate some of the new data that is emerging on some supplements.

Of course, the ultimate measure of clinical efficacy is to correlate the clinical effects of an agent with a measurable level of the agent in the body.  Many of the studies about supplements, however, can show the clinical efficacy of a product but not the pharmacologic mechanism of the response.  These exact mechanisms remain elusive because many supplement products have multiple active components working synergistically or concurrently in the body.²³    This concept is quite different from most pharmaceutical agents which are single-entity products that work primarily at one particular target.  Consequently, one needs to approach standard drug metabolism parameters from a slightly different view.  For example, St. John’s Wort’s most active component is hyperforin.  However, the extract also contains hypericin, which sometimes is used to standardize the St. John’s Wort supplement.  This phytochemical can cause excessive light sensitivity in some patients but does not seem to be as active in combating depression as hyperforin.[35]  Measuring for specific markers, like hypericin, is a good way to ensure the agent is correctly identified, but it may not correlate to clinical effects.  Dissolution and disintegration studies of a particular product can show that the dosage form is appropriate for the herbal or supplement used.  These studies indicate whether a product’s active components are appropriately being made available to the body when in that dosage form.  When evaluating the evidence of an herbal or supplement, the presence of credible clinical indicates that the product and the specific brand are probably of high quality.

6.      Bioavailability

One problem with some supplements is that they do not dissolve in the stomach. Clearly if a tablet doesn’t even dissolve, it is unlikely that your body will adequately absorb the herbal ingredients.  Dissolution and disintegration studies of a particular product can show that the dosage form is appropriate for the herbal or supplement used.  These studies indicate whether a product’s active components are appropriately being made available to the body when in that dosage form.

There are other aspects to bioavailability.  Some phytochemicals (or medications) are simply not absorbed very well by gastrointestinal tract.  There are ways to get around these problems.  For instance, it is known that eating some kind of fat or oil wilth carotenoids (red or orange phytochemicals such as beta-carotene or lycopene) improves their absorption.  You may thus see instructions to take certain supplements with meals (although sometimes instructions to take supplements or medications with meals are simply to prevent stomach upset)  In some cases, manufacturers will put specific substances into supplements, such as bioperine, a pepper extract, to help optimize your ability to absorb them. 

Some new ways of formulating supplements also improve bioavailability, in particular the use of nano-technology or liposomes, which “package” supplements or phytochemicals in extremely tiny molecular “envelopes” that enter cells more easily.  Supercritical extracts (see above) provide highly concentrated herbal extracts that enable the user to take high doses of an herb in a small number of capsules.  One of the well-known strategies for regulating the availability of a supplement is the use of timed-release formulations. Familiar to many people from their use in medicines, these formulations are especially useful in cases where a supplement needs to be available to the body throughout a long portion of the day.  An example would be timed-release capsules of melatonin, a sleep aid.

Resources for Credible Herbal/Supplement Information

            As more alternative therapies are explored in clinical trials and used by patients, the physician is faced both with having to assess the validity of the evidence for that therapy as well as with recommending a product and protocol to the patient if the treatment appears credible.  There are several places one can look to find concise information about a botanical supplement.  This brief list of sources is evolving, and new credible sources are being compiled as more clinical evidence is validated.

            Books

·        The Complete German Commission E Monographs – Therapeutic Guide to Herbal Medicines  by Blumenthal M, Goldberg A, Busse WR, Gruenwald J, Hall T, Riggins CW, Rister RS (eds.)

This book is an English translation of the standard European reference for all herbals.

·        The ABC Clinical Guide to Herbs by Blumenthal M.

This book is unique in that it provides a list of all brand-name products used in various clinical trials.  This list is particularly useful since all products used in clinical trial must meet current GMP standards, and are thus more likely to be quality products.  The book includes concise monographs of about 40 commonly used herbal supplements.  It also briefly summarizes the current clinical evidence that supports or refutes the purported claims of the herbal. 

            Internet

·        www.naturaldatabase.org (Natural Medicines Comprehensive Database)  and www.naturalstandard.org. (Natural Standard) are subscription sites that provides a comprehensive list of both herbal and supplement monographs linked to primary literature that supports or refutes purported claims.  They are available by subscription.  Monographs developed by the Natural Standard staff are also available at www.medlineplus.gov under the “Drugs and Supplements” link.

·        www.mskcc.org/mskcc/html/11570.cfm - Operated by Sloan-Kettering Cancer Center, this site provides comprehensive monographs of herbs, botanicals and supplements free-of-charge.  The monographs summarize the clinical evidence with links to the primary literature. 

·        www.herbalgram.org – A site run by the American Botanical Council, a not-for-profit organization that provides a wide variety of types of information on herbal medicine.  The publication HerbalGram, available from the website, also provides interesting articles and research reviews on a variety of topics.

·        www.herbmed.org – A site operated by the Alternative Medicine Foundation, a not-for-profit organization that provides monographs of 20 herbs free-of-charge and a more comprehensive list with on a subscription or pay-per-access basis. The monographs summarize clinical data on an herbal and link to the primary literature.

Conclusion

            Dietary supplement use continues to increase⁸ at a time when the clinical efficacy of many agents are being validated.^36-38  Self-regulation and impending FDA legislation are producing many more quality supplement products.  It is time for the medical community to help guide their patients’ use of supplement products.  Healthcare professionals are in a unique position to evaluate both the quality and efficacy of supplement products so they can confidently advise on the rational use of such products.  When used properly, these products can be a powerful tool in increasing the health, benefit and quality-of-life of many patients.  Conversely, these products can cause significant harm when used inappropriately without supervision.  The physician can influence which extreme predominates.  The medical community can take back this responsibility and positively influence their patients’ lives.

Acknowledgements

Steven Silverstein, Pharm.D., is responsible for a preliminary draft of parts of this paper, written when he was an intern at the Block Center for Integrative Cancer Treatmen from the College of Pharmacy at the University of Illinois at Chicago.

References

[25] FDA website.  Final rule declaring dietary supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk.  Available from url:  http://www.cfsan.fda.gov/~lrd/fr040211.html.