DIETARY SUPPLEMENTS – POPULARITY, QUALITY, SAFETY, EFFICACY
Definitions (regulatory terms)
Dietary supplement – regulatory term. Includes vitamins, minerals, herbs, botanicals, fatty acids, and amino acids as long as they are prescribed in dosage forms, such as capsules, tablets, liquids, gels or powders.
Whole food supplements – whole foods with only the water and fiber removed (i.e. dried foods). They are processed below 112 degrees Fahrenheit, so the enzymes are alive and they thus have a limited shelf life.
Botanical – a plant or plant part that is used for its flavor, scent, and/or therapeutic properties.
Herb
Regulatory definition. Subset of botanicals. Products made from botanicals which are used to maintain or improve health.
Botanical definition - non-woody, seed-producing plants.
Culinary arts definition - vegetable products used to add flavor or aroma to food.
Medical definition - crude drugs of vegetable origin, used for treatment of disease.
Nutraceutical – includes dietary supplements and foods with therapeutic value
Medical food – the Orphan Drug Act of 1988 defines a medical food as "a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation."
Functional food – foods consumed as part of the normal diet, which contain biologically active components which can improve health or reduce the risk of disease.
Popularity
Sales of all dietary supplements, including vitamins, minerals, herbs, and a variety of other compounds defined in the U.S. as dietary supplements was estimated at $4 billion in 1994, $15.7 billion in 2000, $17.8 billion in 2001, $23.7 billion in 2008 (J Nutr. 2011. 141. 261-266).
In 2009, Nutrition Business Journal, a trade journal, estimated sales of $26.7 billion.
Sales estimated at $32 billion in 2012 (J Nutr. 2014. 144. 414-418).
Sales estimated at $46 billion in 2018, with sales specifically of botanicals estimated at $8.8 billion (Consumer Reports. December 2019. 28-35).
Annual retail sales of botanicals have risen from $200 million in 1988 to an estimated $5.1 billion in the U.S. in 1997. Sales then decreased to an estimated $4.2 billion in 2001. Estimated sales had increased slightly to $4.41 billion in 2005 (HerbalGram. 2006. 71. 64-66).
In 1998, annual sales were $151 million for ginkgo, $140 million for St. John's wort, $96 million for ginseng, $84 million or garlic, and $70 million for Echinacea.
The number of dietary supplements on the market in the US has risen from approximately 4000 in 1994 to approximately 75,000 in 2008.
WHO in 1985 estimated that 80% of the world population relies on herbs for primary health care needs.
Up to 30-40% of medical doctors in Germany and France rely on herbs as primary medications.
In the late 1980's, 36% of men and 48% of women used dietary supplements (Briefel RR and Johnson CL. Secular trends in dietary intake in the United States. Annu Rev Nutr. 2004. 24. 401-431).
A 1997 survey estimated that 12.1% of adults in the U.S. had used an herbal medicine in the past 12 months, as compared with 2.5% in a 1990 survey (JAMA. 1998. 280. 1569-1575).
NHANES data between 1999-2012 (n=37,958 adults, 74% response rate) shows that use of any dietary supplement within the preceding 30 days was stable from 1999-2000 2011-2012 at 52% (p for the trend =0.19) [JAMA. 2016. 316. 1464-1474].
According to a Gallop survey of 200 physicians, 94% recommend vitamins or minerals to some of their patients; 45% have recommended herbal supplements as well, and 7% sell product in their offices (cited in Consumer Reports. September 2016. Page 22).
In a Consumer Reports nationally representative survey of 2006 adults in 2019, 2/3 regularly take at least one supplement
Quantity (Consumer Reports. September 2010. 16-21 and September 2016. 20-33)
4000 dietary supplements prior to DSHEA legislation in 1994, and 90,000 dietary supplements in 2016 (Consumer Reports. September 2016. 20-33).
In 2010, more than 54,000 dietary supplement products in the Natural Medicine Comprehensive Database
Only 1/3 have some level of safety and effectiveness that is supported by scientific evidence
12% have been linked to safety concerns or problems with product quality
15,000 dietary supplement manufacturers whose products are sold in the US, according to a 2015 study in Drug Testing and Analysis, as cited in Consumer Reports. September 2016. Page 26. FDA inspects only approximately 400 of these manufacturers per year since 2010, according to data obtained by Consumer Reports through a freedom of information request.
Quality
The FDA on 6/22/07 announced a final rule establishing regulations to require current good manufacturing practices (cGMP) for dietary supplements.
The final rule itself, 814 pages, as published in the Federal Register, is posted here.
The establishment of cGMP for dietary supplements was required by DSHEA, passed by Congress in 1994. The FDA had issued a proposed rule 3/7/03, but the OMB in Congress was concerned about the impact of these regulations on small businesses, and spent much time studying this issue, further delaying the final rule until 6/22/07.
The rule is supposed to ensure that dietary supplements are produced in a quality manner, do not contain contaminants or impurities, and are accurately labeled.
The final cGMP and the interim final rule were to be effective August 24, 2007, but the comment period was extended twice, to 10/24/07.
To limit any disruption for dietary supplements produced by small businesses, the rule has a three-year phase-in for small businesses. Companies with more than 500 employees have until June 2008 to comply, companies with less than 500 employees have until June 2009 to comply, and companies with fewer than 20 employees have until June 2010 to comply with the regulations.
There are a number of shortcomings of this final rule – some are addressed by Joseph Pizzorno, ND (IMCJ. 2007. 6[5]. 8-9) and by Rick Liva, ND, RPh (IMCJ. 2007. 6[5]. 28-31).
The AHPA (American Herbal Products Association) in July 2007 recommended the following changes to the cGMP requirements
Clarification that a dietary ingredient manufacturer or supplier cannot be made subject to the final rule based on how its customers use its ingredients.
Removal of a potential loophole allowing companies to that package products made by someone else to avoid some parts of the rules on verifying product specification.
Define the terms manufacturing, packaging, labeling, and holding.
Allow master manufacturing records to include a range of batch sizes rather than specific batch sizes.
Remove language which would effectively prevent single-employee companies from the dietary supplement industry.
Allow personnel to conduct examinations for correct labels.
Require that the batch, lot, or control number appear on the finished products.
Quality really should start with Good Agricultural Practices (GAP’s).
Quality concerns with regard to laboratory testing (Integrative Medicine. 2006. 5 [1]. 34-37 and 5[2]. 38-41).
The Certificate of Analysis (COA) for raw material unfortunately is often just a certificate of content and may NOT accurately reflect the true content of the raw material.
Neither manufacturers’ in house labs nor contract labs are regulated.
Problems that exist with laboratory testing include dry labbing (lab reports a desirable result without ever performing the analysis), method rigging (lab alters the method of testing to produce a desirable result), and use of poor-quality reference standards (use of reagent grade chemicals rather than a primary or a secondary standard).
There are in 2006 very few fully validated laboratory methodologies for analytical testing of botanicals.
Quality issue - sub-potency or supra-potency of the active ingredient (i.e. discrepancy between the information on the label and the content in the bottle). Historically, from 1994 - 2009 this was attributable to lack of government regulation (i.e. no requirement for companies to follow Good Manufacturing Practices). Since 2009 it is attributable to lack of spot checks to enforce regulation, coupled with poor quality control of the manufacturing process by some manufacturers.
A Canadian study showed that no North American feverfew product analyzed contained the recommended minimal amount of 0.2% parthenolide believed to be required for effectiveness (Journal of Natural Products. 1991. 54. 1516-1521).
A study of ginseng products found tremendous variability, with as little as 12% and as much as 328% of the active ingredient in the bottle, compared to the information on the label (Am J Clin Nutr. 2001. 73. 1101-1106). A previous study of 54 ginseng products showed that 60% of those analyzed had very little ginseng, with no ginseng at all in 25% (Whole Foods. 1979. 2. 48-53).
A study of 59 Echinacea products from retail stores analyzed by thin layer chromotography showed that 6 contained no measurable Echinacea and only 9 of the 21 preparations labelled as standardized extracts actually contained in the sample the content listed on the label. Overall, the assay results were consistent with the labelled content in only 31 of the59 preparations (Arch Intern Med. 2003. 163. 699-704).
When the FDA announced in 2003 a proposed rule to establish good manufacturing practices for supplements, the FDA cited data that 5 of 18 soy and/or red clover supplements contained only 50-80% of the quantity of isoflavones stated on the label, and 8 of 25 probiotic products contained less than 1% of the live bacteria claimed on the label.
Vitamin D3 – 5 pills from each of 15 bottles of over-the-counter vitamin D3 (1000, 5000, and 10,000 IU) purchased at 5 stores in Portland OR showed wide variability in measured vitamin D content, with a range of 9% to 146%. Only half of the pills met USP standards, which require between 90% and 110% of the amount listed on the label (JAMA Intern Med. 2013. 173. 585-586).
Analysis of the monacolin K content of 28 brands of red yeast rice supplements purchased from mainstream US retailers showed no monacolin K in two brands and 60 fold variation in the other 26 brands, with content ranging from 0.09 - 5.48 mg per 1200 mg red yeast rice. Six brands provided more than 4 mg per day if the recommended dosage was consumed; the FDA has banned preparations containing more than 4 mg per day as an unapproved drug, since monacolin K is the active ingredient in prescription lovastatin (Eur J Prev Cardiol. 2017. 24. 1431-1434).
A 2017 study of 31 different over the counter melatonin preparations found that, when analyzed, the dosage of 71% of the products didn’t match what was stated on the label. Melatonin content varied from 17% to 478% of labeled melatonin, and 70% had a melatonin concentration that was less than 10% of what was claimed. Lot to lot variation of content as high as 465%, (J Clin Sleep Med. 2017; 13(2):163-1650).
A 2023 study of 25 melatonin gummy products found that 22 of 25 brands were mislabeled, meaning that the quantity of melatonin in the product varied from the quantity specified on the label; the actual quantity of melatonin ranged from 74% to 347% of the labeled quantity. In only 3 of the 25 products was the quantity of melatonin within ±10% of the declared quantity. One product labeled as melatonin did not contain detectable levels of melatonin but did contain 31.3 mg of CBD (Research Letter. JAMA. 2023; 329(16):1401-1402). NOTE for all gummies (independent of whether the active ingredient is melatonin versus a multivitamin versus an individual vitamin, the quantity of active ingredients tends to vary significantly from batch to batch and often the quantity in the gummy is different from the quantity specified on the labels (because, as per personal correspondence with Scott Berliner, RPh, “all gummies are made in molds using heat so there are changes from the heat and from the base itself“).
Additional quality issues include contamination of some herbs with other botanicals, micro-organisms, microbial toxins, fumigating agents, pesticides, heavy metals, or prescription or over the counter drugs.
Adulteration of imported Chinese dietary supplements sold in Japan is responsible for 622 cases of illness, 148 hospitalizations, and 3 deaths (Report of the Japanese Ministry of Health, Labor, and Welfare. September 20, 2002).
A 2002 Bastyr University study of 20 probiotic supplements found that 16 contained bacteria not listed on the label, 6 contained organisms that can make people sick, and 4 contained no live organisms.
In 1998 the California Department of Health reported in a letter published in the New England Journal of Medicine that 32% of Asian patent medicines sold in that state contained undeclared pharmaceuticals or heavy metals, including ephedrine ( a stimulant), chlorpheniramine (an antihistamine), methyltestosterone (an anabolic steroid), phenacetin (a pain killer), lead, mercury, and arsenic (N Engl J Med. 1998. 339. 847).
A study in which 500 Asian patent medicines were screened for the presence of heavy metals and 134 drugs found that 10% were contaminated (Bull Environ Contam Toxicol. 2000. 65. 112-119).
BEWARE of the following categories of dietary supplements, as supplements these categories have been identified on a number of occasions to contain prescription drugs (Consumer Reports. 9/10/. 16-21) – supplements for weight loss (manufacturers in 2008-2010 have voluntarily recalled more than 80 supplements that contained synthetic steroids or steroid-like substances), sexual enhancement (manufacturers in 2008-2010 have voluntarily recalled more than 50 supplements that contained sildenafil [Viagra] or other erectile dysfunction drugs), and bodybuilding (manufacturers in 2008-2010 have voluntarily recalled more than 40 supplements that contained sibutramine [Meridia] and other drugs).
PC-SPES was removed from the market in 2002 after it was determined that it was adulterated with the prescription blood thinner, warfarin .
In a study in which researchers tested 44 herbal products from 12 companies, they found that only two companies listed on the label all of the ingredients in the product. In some cases, it was a minor issue such as fillers not listed; in other instances contaminants with potentially serious side effects were not listed (BMC Medicine. 10/11/13).
Melatonin
Mass spectrometry identified 7 contaminants in 3 different commercial preparations including some contaminants found in L-tryptophan and associated with an epidemic of eosinophilia-myalgia syndrome in the US in 1989 (Chem Res Toxicol. 1998. 11. 234).
Analysis of 31 commercially available supplements showed melatonin adulterated with serotonin in 8 samples (Erland LAE et al. J Clin Sleep Med. 2017; 13(2):163-1650).
Toxic metals in dietary supplements (IMCJ. 2007. 6[3]. 36-38).
There are different methodologies of testing for heavy metals
USP Method #231 is outdated because it lumps all heavy metals together, and the limit of detection is 10 ppm
ICP-OES is better, with a limit of detection of 10-100 ppb, and the ability to screen for multiple elements, but still suboptimal.
ICP-MS can test for several metals at once, with a limit of detection of 10-20 ppb, and is a very good methodology.
California state law says a product cannot contain more than 0.5 micrograms of lead per daily serving. FDA says consumption of up to 75 micrograms/day of lead in a product is acceptable (this is 150 times more than the California upper limit).
USP says up to 10 ppm of lead (i.e. 10 microgram of lead per 1 gram of product) is acceptable – total quantity of lead in a given product involves a calculation, and will vary tremendously based on the daily dose of the dietary supplement. USP says up to 3 ppm of arsenic, cadmium, and mercury permissible in dietary supplements.
Case report of lead poisoning in a 41 year old male who had traveled to India and was treated with Ayurvedic medicine for oligospermia. He had a blood lead level of 78 microgram/dL; analysis of the dietary supplement he was taking revealed as much as 13,084 ppm of lead in one of the pills. It was estimated that this male had ingested 1.26 grams of lead over the course of treatment with this dietary supplement (J Toxicol Clin Toxicol. 2002. 40. 678).
A study in which all unique Ayurvedic herbal medicine products were purchased from all stores within 20 miles of Boston City Hall found that 14 of 70 products (20%) contained heavy metals. Of those with heavy metals, 13 contained lead at a median concentration of 40 ppm, 6 contained arsenic at a median concentration of 430 ppm, and 6 contained mercury at a median concentration of 20,225 ppm (JAMA. 2004. 292. 2868-2873).
A study in which 230 Ayurvedic medicines were randomly selected from 673 identified products based on internet searches found that “1/5 of both US-manufactured and Indian-manufactured Ayurvedic medicines purchased via the internet contain detectable lead, mercury, or arsenic” (JAMA. 2008. 300. 915-923).
A meta-analysis of 22 case reports, case series, and epidemiologic research concluded that “heavy metal (particularly lead) poisoning through traditional Chinese medicine use has been reported with some regularity” (Clin Pharmacol Ther. 2001. 70. 497-504).
Case report of arsenic toxicity in a 39 year old woman taking the dietary supplement Chitosin for weight loss (Clin Tox. 2002. 40. 644).
Standardized extracts
The analytic methods for identifying what and how much of an ingredient is in a product are very good. These include:
HPLC (high performance liquid chromatography)
HPTLC (high-pressure thin-layer chromatography)
DNA barcoding - newest technology, and most useful for analysis of whole plants. May not be useful for analyzing an extract, as most of the DNA is washed away with extraction
The HPLC pattern of a standardized extract should prevent the problem of adulteration due to misidentification of the herb in the field.
Standardized extracts adjust in part for genetic variability, variable growing conditions, differences in harvesting procedures and processing of herbs. HOWEVER, standardization refers only to reproducibility – it is possible to standardize a poor quality product.
U.S. law does not define standardization, AND due to lack of GMP standards, even "standardized extracts" in the U.S. sometimes do not have in the bottle what is on the label.
Whereas the ideal standardized extract is made by starting with the whole herb and standardizing it to a specific ingredient, some companies make a standardized extract by purchasing an isolated specific ingredient of the whole herb (i.e. synthetic hypericin) and adding this synthetic ingredient to the whole herb until an adequate peak is reached by HPLC. The latter is really more like a drug than a standardized herbal preparation.
A limitation of standardized extracts is that scientific knowledge of the active compounds in any given herb in terms of the mechanism of action is often incomplete. The extract can be standardized to a therapeutic active constituent, an active constituent, or a marker compound.
Quality issues - red yeast rice
Some brands are contaminated with citrinin, a mycotoxin which is nephrotoxic in animals. In a published study, 4 of 12 products tested had elevated levels of citrinin (Arch Intern Med. 2010. 170. 1722-1727).
Variability in total monacolins – these are the compounds which inhibit HMG-CoA reductase, and 14 distinct compounds are present in red yeast rice.
In a published study of 12 products, total monacolin content varied from 0.31 to 11.15 mg/600 mg capsule (Arch Intern Med. 2010. 170. 1722-1727).
A second published study of 28 commercial brands showed 60-fold variation in the quantity of monacolin K per 1200 mg (Eur J Prev Cardiol. 2017. 24. 1431-1434).
Quality from a chemical standpoint versus from a biological standpoint
Current industry GMP’s as well as the proposed FDA GMP’s address quality only from a chemical standpoint, not a biological standpoint (i.e. absorption, dissolution, bioavailability).
Bioavailability is often measured for one ingredient at a time rather than administering the whole product and then measuring the blood levels of each constituent component.
In a study presented at a 1999 Shaklee convention, 11 of 14 retail B complex brands did pass the industry standard for minimum folic acid dissolution.
The molecular form of a mineral may affect its bioavailability.
For minerals, some chelators may change the environment of the GI tract and thus alter bioavailability.
Disintegration is a measure of how quickly a tablet breaks apart into small particles within a specified period of time. Individual variations in digestion can affect disintegration times.
Dissolution is a measure of how quickly a supplement dissolves in liquid.
USP requires 75% of the assayed amount to dissolve within 60 minutes.
Slower dissolution may actually lead to higher bioavailability though.
Enteric coating can affect absorption, and the pH of the stomach can affect how quickly the enteric coating dissolves – a higher pH leads to more dissolution of the enteric coating in the stomach rather than the intestine.
Hardness – tablets tend to get harder with the passage of time, and this can interfere with the ability to chew them.
Excipients – inert substances used in the manufacturing process.
Flowing agents, including magnesium stearate, palmitic acid, stearic acid, dicalcium phosphate, and ascorbyl palmitate, facilitate the speed of the manufacturing process, BUT interfere with dissolution of the nutrients or phytochemicals in the supplement by coating each nutrient with a layer of saturated fat. Safer flowing agents and fillers include cellulose, magnesium citrate, silicon dioxide, and titanium dioxide.
Tablets contain many excipients, including flowing agents, lubricants, binders, fillers, and disintegrants. Many tablets also contain artificial coloring agents, and shellac coating, which may appear on the label as “pharmaceutical glaze.” Tablets using poor quality excipients may be compressed so tightly that they pass through the GI tract undigested.
Capsules generally have fewer excipients than tablets, but most capsules are manufactured using flowing agents and require fillers, and many capsules are made of gelatin, which is a beef byproduct.
Purity and the patient with food sensitivities
Often raw materials are not pure but have substances added to facilitate manufacturing – these substances may cause GI symptoms such as bloating, nausea, and diarrhea in sensitive patients.
Corn protein is often used to coat tablets, but may not be shown on the label as corn protein, but rather indicated on the label only as vegetable coating, natural protein coating, or maize.
Lactose is often used as a diluent.
Corn starch is sometimes used as a diluent.
Fillers may be allergenic. Magnesium citrate, aspartic acid, leucine, and silicon dioxide are probably the most hypoallergenic.
Artificial coloring used in many tablets may cause reactions.
Preparations of Herbs and Quality –generalizations as per Dr. Andrew Weil:
Tinctures, liquid extracts, and freeze dried extracts are probably best because they maintain their potency for a long time. However, note that tinctures and liquid extracts usually do contain a small amount of alcohol.
Teas, which are the traditional way to use herbs, are inexpensive, and may be especially useful for treating digestive ailments and urinary tract infections, but they are time consuming to prepare and often are not as potent as tinctures, liquid extracts, or freeze dried extracts.
Loose herbs sold in bulk and encapsulated, powdered herbs are probably best avoided because they lose their potency quickly, especially if exposed to heat, light, or oxygen (i.e. air).
Ways for the consumer to identify high quality brands of a given herb:
Look for USP designation on the label.
This is a third party certification. It is comprehensive and expensive.
Founded in 1820.
This web site includes a list of participating companies here and a list of verified brand names here. Clicking on any brand name here will provide information on the stores in which that brand name is available. The list of certified brand names and companies appears at the end of this outline.
Historically, products without FDA approved uses did not qualify for this designation, but the USP decided recently to apply its standards-setting expertise to a program to verify dietary supplements.
Historically, prior to the implementation of the USP dietary supplement verification program, a NF designation on the label meant that a product met USP standards but did not have an FDA approved use.
The USP Dietary Supplement Verification Program tests supplements and manufacturing practices against its own standards, and does include testing for dissolution.
USP standards are compiled in the National Formulary 22, which DSHEA recognizes as the nation’s official compendia for supplement standards.
Look for the NSF (National Sanitation Foundation) International designation on the label.
Third party certification, good only for 6 months, then re-certification required.
Founded in 1944 as an independent not-for-profit organization dedicated to the protection of public health safety, and the environment.
Web site is here.
Companies which are certified are available here and products which are certified can be identified by performing a ‘Search’ here. The list of certified companies and companies with certified products appears at the end of this outline. Those companies which are certified and also have certified products are listed in bold print.
Began in 1999 to work with industry experts to develop an American National Standard for Dietary Supplements, NSF/ANSI 173-03, in accordance with the American National Standards Institute (ANSI), a private, non-profit organization that administers and coordinates the U.S. voluntary standardization and conformity assessment system. This publication sometimes references USP monographs.
Be aware that NSF does not require testing for dissolution or measurement of bioavailability, but does include disintegration testing.
NOTE that if the company is certified but not the individual product, the NSF certification cannot appear on the label.
Look for the NPA GMP (Natural Products Association) designation on the label.
The Natural Products Association (NPA, previously known as NNFA) is an industry trade organization.
The NPA TruLabel Program has been in operation since 1990 – this is a certification for specific supplements, not manufacturing companies. In 2005 more than 17,000 product labels are registered as being in compliance with the program. Manufacturers may not label their products as being in compliance, but the brands of popular products which are in compliance with the TruLabel Program are available to the consumer for free here.
The NPA GMP is a third party certification of companies administered by NPA. This program is more recent than the TruLabel Program. A list of certified companies is available here and is reproduced at the end of this outline.
Be aware that NPA does not require measurement of bioavailability or testing for dissolution or disintegration.
Look for the TGA (Therapeutic Goods Administration of Australia) designation on the label. This is a third party certification. In 2007 Metagenics and Thorne have TGA certification.
Identify companies such as Mycology Research Labs which are a licensed pharmaceutical factory in the U.K. or Nordic Naturals which is licensed in Europe.
Be aware that Nature’s Way is now a subsidiary of a German Company, and the quality standards in Germany are excellent.
Be aware that Emerson Ecologics, a distributor for practitioners, health food stores, and pharmacies instituted the Emerson Quality ProgramSM (EQP) in January 2010 – this is a voluntary program which asks participating manufacturers to complete a questionnaire detailing their quality practices, including compliance with FDA Dietary Supplement cGMP, raw material and finished product testing. Verification of information includes on site audits. Information on this program is posted here. This web page includes links to EQP Gold Partners, EQP Silver Partners, and ‘EQP All Partners.’
Identify companies which meet the standards for third party certification for pharmaceutical products – Biotics, Integrative Therapeutics and Shaklee
Requires a manual of standard operating procedures, which proposed GMP’s do not require.
Requires dissolution testing, which proposed GMP’s do not require.
Requires shelf life dating, which proposed GMP’s do not require.
Requires disassembly and sanitization of all equipment after each production run, to avoid cross contamination, which proposed GMP’s do not require.
Be aware of deceptive claims such as “Exceeds GMP Standards” and “GMP Compliant” and “Food GMP.” These are self-declarations of conformity to quality standards which do not require any third party testing.
Go here for a listing of brands which have both passed and failed an independent chemical analysis.
This is a for-profit business founded in 1999 by Tod Cooperman MD.
Each product review notes which product fit in the kosher and also the gluten free categories, as well as providing a per-100 mg price guide so that the consumer can determine which product is cheapest.
The non-voluntary testing program historically served as an impetus for others (see above) to begin third party certification of dietary supplement companies.
This is called Products Review and ConsumerLab chooses which products to test and pays for the testing
The non-voluntary testing is a one-time certification.
The results are posted on a web site which is available to consumers for a small annual fee, currently $24/year.
Manufacturers may request voluntary testing of products and may request inspection of the manufacturing facility.
The manufacturer pays a fee for these services.
Results of these tests are posted on the free part of the ConsumerLab web site.
All products (both voluntary and non-voluntary program) to be tested are purchased on the open market through retail stores.
ConsumerLab does test for dissolution.
Website is packed with content
The results are also available in book format.
Go to Labdoor.com (Holistic Primary Care. Spring 2016. Page 7)
Founded in 2012, funded in 2014, and provides supplement analysis information free of charge, as supplements are also sold on the site.
When Labdoor completes a testing process for a category of supplement, via outsourced labs, it issues a press release and uses social media.
Sleek website design which emphasizes simplicity.
Go here for web-based information and purchase of dietary supplements from companies which meet stringent quality criteria.
Use the specific brand used in a study published in a peer reviewed journal. The American Botanical Council ABC Clinical Guide to Herbs provides this information.
Be aware that some pharmaceutical companies (American Home Products, Bayer, Pharmanex, and Warner-Lambert) now manufacture herbs too. Realize however that the manufacture of herbs is very different from the manufacture of pharmaceutical products, and may be done at entirely separate plants, so a pharmaceutical company as manufacturer is NOT a guarantee of quality.
Botanical Adulterants Prevention Program (BAPP) and Dietary Supplement Quality
BAPP was founded in 2010 by the American Botanical Council, American Herbal Pharmacopoeia and the University of Mississippi’s National Center for Proeducts Research.
Goal of BAPP is reducing the burden of contaminated and adulterated herbs in the global supply chain
Between 2010 and 2022, BAPP published 75 peer-reviewed documents detailing issues of adulteration of raw materials, extracts, and essential oils (adulteration may be intentional, unintentional, or economically motivated.
November, 2022 - BAPP issued “Standard Operating Procedures for Disposal/Destruction of Irreparably Defective Articles
The FDA provides clear definitions of what constitutes adulteration, but existing GMP do not delineate procedures for eliminating corrupted products from the supply chain
This November 2022 SOP document spells out a process for ethical companies to “burn it, don’t return it” because if returned, the raw material supplier may sell the adulterated product to a different manufacturer.
the BAPP document creates standardized terms of agreement between raw material suppliers and manufacturers such that if a contaminated or adulterated product is burned, the cost is absorbed by the raw material supplier and not the recipient manufacturing company.
Questions to ask of a company which markets dietary supplements to determine the quality of that companies products:
Do you manufacture the products you market?
If not, are the companies that manufacture the products certified by a third party?
If not, do you do independent testing on the finished products manufactured by a separate company?
Are you certified by a third party?
Confirm by asking company to mail a copy of certificate OR check the web site of the certifying organization and verify that the company is listed as certified.
If certified, consider asking the company to mail a copy of the most recent audit report.
If certified, be aware that NSF and NPA require for certification:
Skip lot testing of raw material and finished product
Microbiology testing
Identification for authenticity (i.e. no adulteration)
Potency assay
Stability testing program
If not certified, provide reasons for lack of certification.
If not certified, do you perform or have an independent laboratory perform:
Skip lot testing of raw materials
Skip lot testing of finished product
Microbiologic testing? Do you use USP limits (<3000 cfu/gm total aerobic bacterial count, <300 cfu/gm yeast and mold counts, no Salmonella species, no E. coli, no Staph aureus)
Identification for authenticity
Potency assay
Stability testing
If certified, do you go beyond the requirements of certification:
Do you have a manual of standard operating procedures - if yes, please mail Table of Contents and forms used
Do you have a functional QA/QC Unit in place
Do you use a questionnaire or an audit to assess qualifications of suppliers of raw materials
Do you use only suppliers who follow good agricultural practices - if yes, how do you know this
Do you use a questionnaire or an audit to assess qualifications of independent laboratories which perform analytical testing
Do you test every lot of raw material and finished product - if not, what protocol do you use for skip lot testing? Consider confirming by requesting a copy of a certificate of testing for raw material (supplier’s COA not acceptable) and a copy of a certificate of testing finished product
Do you perform genus and species testing for botanicals
Do you retest for potency and microbiologic contamination when raw material is stored for longer than a specified time
Do you perform ash content testing to detect herbal raw material ‘diluted’ by soil in the raw material
Do you perform floatation testing to detect contaminants such as insect fragments and rodent hairs
Do you perform alpha, beta, and gamma radiation testing, especially for herbs out of Eastern Europe
Do you test plant materials for aflatoxin (FDA limit is 20 ppb for total aflatoxins in feed and food)
Do you assay for toxic metals
If yes, do you assay raw materials and finished product
If yes, do you assay to ppb
Do you test for chemical solvent residues (metnanol, ethyl acetate, toluene, acetone, isopropyl alcohol, cyclohexane, and others)
Do you test for herbicide, pesticide, and fungicide residues (organo-chlorines, organo-phosphates, organo-nitrates, carbamates)
Do you test all oils for rancidity - if yes, do you test for both peroxide (WHO upper limit is 10 meq/kg) and anisidine (a downstream metabolite) levels
Do you test fish oils for
PCBs - if yes, do you test to ppt
Dioxins and furans (EU legal human consumption limit is 6 ppt, preferred limit is 1.5 ppt) - if yes, for how many different substances do you test (dioxin is a generic term used to describe a family of 210 compounds; 17 are most dangerous)
Do you perform hardness testing on the tablets
Do you perform dissolution testing on tablets
Do you sterilize all equipment between runs to avoid cross contamination
Do you test for stability at 12 and 24 months for the purpose of obtaining a scientifically valid expiration date
Do you perform literature searches on the safety of ingredients in your products
Do you perform human clinical evaluations on new products before marketing them? If yes, please send the results of the studies
Safety
Dietary supplements are marketed without prior FDA approval.
Recommendations by experts to improve safety without compromising consumer choice
Create a mandatory registry of supplements that includes the name of the product and contact information for the company, and this must be submitted prior to sale of a new supplement - this would facilitate FDA investigation into adverse events.
Require manufacturers and distributors to report to the CAERS database ALL adverse events, not just the ones deemed as serious.
There was no mandate in the 1994 DSHEA legislation requiring the manufacturers of supplements to record, investigate, or forward to the FDA reports of adverse effects they might receive (this changed 12/07 when 2006 legislation entitled the Dietary Supplement and Nonprescription Drug Consumer Protection Act went into effect).
Despite this lack of requirement, the FDA in 2001 received approximately 500 voluntary reports of adverse events, and poison control centers received 19,468 reports. Between 1/93 and 10/98, the FDA received 2621 reports of adverse events, including 101 deaths. In 2002, the FDA received 1214 voluntary reports of adverse events.
The FDA database for adverse events with supplements is named CAERS, for Center for Food Safety and Applied Nutrition Adverse Events
Clinicians and the public can report adverse events via the website - Nutritional Adverse Events Monitoring System.
The Office of the Inspector General estimates that only 1-2% of adverse events related to dietary supplements are reported to the FDA (compared to an estimated 10% of serious adverse effects associated with the use of prescription drugs, with a regulatory mandate to report adverse events).
Many reports can not be adequately investigated because the FDA cannot obtain the consumers identity or address, or because the ingredients in the supplement and the identity and address of the manufacturer are unknown - these details are all optional when a case is reported.
The web site is challenging to search.
Manufacturers are required by law (as of 2006) to report to CAERS any “serious” adverse events reported to the manufacturer - it is estimated that 3/4 of the reports in the CAERS database are submitted by supplement makers.
Based on nationally representative safety data from 63 emergency departments, it is estimated that 23,005 emergency department visits per year, and 2000 annual hospitalizations, were attributable to adverse effects dietary supplements, between 2004-2013. Many of these visits are due to cardiovascular effects of weight-loss or energy products among young adults, and swallowing problems among older adults (N Engl J Med. 2015. 373. 1531-1540). By comparison, these numbers are less than 5% of the numbers that have been reported for pharmaceuticals (JAMA. 2006. 296. 1858-186).
Contamination of some herbs with other botanicals, micro-organisms, microbial toxins, fumigating agents, pesticides, heavy metals, or prescription or over the counter drugs is a safety issue as well as a quality issue – see above in this outline for specifics.
Safety and Terminology
Adverse event – regulatory term, descriptively defined as harm in a patient administered a drug, but not necessarily caused by the drug. Defined by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use as “any untoward medical occurrence that may be present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this product.”
Adverse drug reaction – regulatory term, descriptively defined as harm directly caused by a drug at normal doses. Defined by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use as “a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or modification of physiologic function.”
Likelihood of a causal connection between a drug and an adverse event;
Certain: dechallenge and rechallenge information corroborates causation.
Probable: dechallenge information corroborates causation.
Possible: competing explanations are plausible.
Unlikely: timeline is improbable.
Adverse drug event – patient safety term, descriptively defined as harm from the use of a drug. Defined by the Institute of Medicine as “an injury resulting from a medical intervention related to a drug.” This includes harm from usual doses, harm from overdoses, harm from underdosing, and harm from a change in the dose or discontinuation.
There are multiple herb-drug interactions; our knowledge of these is still infinitesimal, and the published literature is tremendously variable in quality.
A summary of available data on herb-drug interactions can be found in Table 3 (N Engl J Med. 2002. 347. 2046-2056). This table provides a useful format for presenting this information, because it includes a column for comments.
A comprehensive summary of ‘In vivo clinical trials of herb-drug interactions can be found in Table 2 (Neustadt J. Herb-drug interactions: what clinicians need to know. Integrative Medicine. 2006. 5[1]. 16-26).
Two main mechanisms of herb-drug interactions
Induction or suppression of a specific cytochrome P450 enzyme.
Induction of p-glycoprotein, an intestinal membrane transport protein that pumps certain hydrophobic substances out of the intestinal epithelial cell and back into the intestine, interfering with absorption of the substance.
The data which supports herb-drug interactions is tremendously variable in scope and quality – many tables include interactions which are only theoretical or anecdotal side by side with those that are well documented.
For example, there is quite good data that interactions between garlic and aspirin or ginkgo and aspirin can be clinically significant, but currently limited data that the interactions between ginger and aspirin or ginseng and aspirin are clinically significant. In many tables, all four of these herbs are listed side by side in terms of risk if taken with aspirin.
See below in this outline for a list of the 12 Levels of Evidence with regard to herb-drug interactions. Note that in the same article “Keeping Your Patient With Heart Failure Safe: A Review of Potentially Dangerous Medications” (Arch Intern Med. 2004. 164. 709-720) in which these 12 levels of evidence were listed in Table 1, Table 3 “Herbs Associated with Adverse Cardiac Events” lists herbs in a highlighted table for which the evidence is often only Level 2, combined with a theoretic rationale.
In a search of Medline, Embase, and the Cochrane Library, 187 published cases of suspected herb-drug interactions were found, BUT 68.5% of these cases lacked so much information in the published report that they were labelled as ‘unable to be evaluated,’ and only 13% of the cases were ‘well-documented’ (Fugh-Berman A, Ernst E. Herb-drug interactions: review and assessment of report reliability. Br J Clin Pharmacol. 2001. 52. 587-595, with a published correction 2002. 53. 449).
Table 2 of a commentary in Integrative Medicine: A Clinicians Journal. 2006. 5(1). 16-26 provides an excellent summary of ‘in vivo clinical trials of herb-drug interactions.’
Theoretical vs. actual herb-drug interactions – in a survey of 804 patients, 122 (15%) used herbs, and 85 potential herb-drug interactions were identified in 49 patients (40% of the herbal medicine users). However, only 12 possible herb-drug interactions in 8 patients (7% of the herbal medicine users) were reported, and all were ranked as mild (Altern Ther Health Med. 2007. 13[2]. 30-35).
Limitations of the data on herb-drug interactions (Alt Med Alert. 2006. 9. 25-30 and 37-48).
Animal data is not valid since the expression of P450 isozymes varies widely within the animal kingdom.
In vitro data is often not valid, as tannins commonly found in herbs can alter P450 function in vivo.
There are tremendous individual differences in humans regarding expression of P450 isozymes.
For some drugs, the relationship between concentration and activity is not linear.
Varying outcomes with the same plant source can result from using different parts, preparations, doses, and durations.
In order to detect effects of an herb on induction of a cytochrome P450 enzyme or P glycoprotein, the herb must be dosed for at least 10 days prior to administering the drug.
Note that longstanding experience in traditional medicine is not a guarantee of safety, especially for infrequent adverse effects, teratogenic or carcinogenic effects, or adverse effects which develop only with prolonged use of a given supplement.
Furthermore, safety with traditional use does not assure safety when current use may involve administration via a different route or for a different indication or in a population with a different genetic makeup.
The L-tryptophan story - banned in 1989 as a dietary supplement based on association of this supplement with eosinophilia-myalgia syndrome (38 deaths and 1500 total cases). This syndrome was subsequently shown to be due to a contaminant traced to a single Japanese manufacturer, Showa Denko, and not the amino acid itself. The contamination was in part due to the use of a genetically engineered micro-organism in the production process.
The ephedra story - see the web page on "Regulation of Dietary Supplements" for extensive details
The skullcap story – listed in Consumer Reports 5/04 Cover Story of the ‘dirty dozen’ herbs which should not be available for commerce, based on a risk of liver damage. This conclusion is based on case reports, careful scrutiny of which shows that either no assay was done to confirm the identity of skullcap or that skullcap was consumed in combination with other herbs. There is published data on adulteration of skullcap with germander, an herb with known hepatotoxicity (Pharmaceut. J. 1984. 233. 80-82; Bus Herbs. 1996. May/June. 14-16; Pharmacol Res. 1993. 27. 15-16).
The St. John’s wort story:
Scientific knowledge of numerous and clinically important herb drug interactions came after the huge increase in popularity in the U.S. prompted by the media reports following the publication in 1996 in BMJ of a meta-analysis of 23 German studies documenting safety and efficacy.
The Medical Letter 6/26/00 summarized the data on herb-drug interactions, with multiple references.
A systematic review of clinical trials that examined the possible interactions of St. John’s wort with conventional drugs found that 7 of 22 did not even assay the herb to be sure that there was not adulteration of the product, and that 18 or 22 did not have a control group. Many of the trials were small, had few safeguards against bias, and failed to use methods consistent with “widely accepted standards of research practice” (BMJ. 2004. 329. 27-30).
The kava kava story: Herbalgram: The Journal of the American Botanical Council. 2002; 55:26-32. ; Alternative Medicine Alert. 2004; 7:85-95. ; JAMA (Commentary). 2010; 304:2174-2175
Long history (at least 1500 years) of traditional use (of a water extract) by indigenous populations in the South Pacific Islands, with no apparent safety concerns.
A systematic review of 7 RCT's including a total of 377 patients did not identify any safety issues (J Clin Psychopharmacol. 2000. 20. 84-89).
In 2001, the German Federal Drug Agency announced 24 cases of liver toxicity and one death.
Case reports of hepatotoxicity and hepatic failure appeared in the peer-reviewed medical literature in 2001(BMJ. 2001. 322. 139; Ann Intern Med. 2001. 135. 68-69).
Kava was banned in several European countries.
In the U.S. the FDA released a Consumer Advisory 3/25/02. The FDA advisory recommends suggest limiting the daily dose to 300 mg of total kavalactones and limiting daily use to a 4 week period.
In Australia, the TGA (Therapeutic Goods Administration) issued a Fact Sheet in April of 2005 (updated 9/20/10) which recommended a limit of 125 mg kavalactones per tablet or capsule, and a limit of 250 mg of kavalactones per day.
With regard to the case reports of hepatotoxicity, the British Medicines Control Agency concluded after careful review that in 12 of the 27 case reports, kava as the cause was either unlikely or unassessable. In 12 of the remaining 15 case reports, the individuals were taking conventional medication with hepatotoxic potential along with kava. In two of the remaining 3 case reports, there was high alcohol consumption in association with kava ingestion. Nonetheless, in these initial 27 case reports of hepatotoxicity, there were six positive dechallenges and two positive rechallenges.
In the United States, close inspection in 2001 of adverse event reports on file with the FDA showed that many of them were in association with a single instance of an adulterated product which actually contained no kava distributed at a New Year’s Eve rave in Los Angeles. An article in the New York Times 1/16/02 erroneously cited 60 kava-related adverse event reports by including the 29 “fX” cases in which there was actually no kava in the product distributed at the rave.
Subsequent analysis of the German report concluded that the death was due to alcoholic liver failure and not kava, that 4 of the 24 cases were listed twice, that 3 of the 24 cases had no connection to kava, that in 11 of the 24 cases other medications were involved, and that 10 other cases had uncertain connections to kava. Three of the 24 cases did appear related to kava, and 2 of the 3 appeared related to overdoses, leaving only one case in which kava monotherapy at recommended doses was associated with hepatotoxicity (Phytomedicine. 2003. 10. 440-446).
Subsequent investigation by the World Health Organization confirmed a rare risk of hepatotoxicity (WHO Document Production Services. 2007).
A clinical review confirmed the association of kava ingestion with hepatotoxicity on rare occasions – this review incorporated structured, quantitative, liver-specific causality assessment (Ann Hepatol. 2010. 9. 251-265).
Initially, as reports of toxicity surfaced in the early 2000’s, Swiss researchers linked the toxicity to an acetone-extraction manufacturing process which is widely used in German and Swiss products, and creates a highly concentrated final product. However, subsequent data shows that liver injury has been caused in some cases by the traditional water-based kava extracts (WHO Document Production Services. 2007; Liver Int. 2010. 30. 1270-1279). There is electron microscopy data suggesting that kavain has an adverse effect on hepatocytes (World J Gastroenterol. 2008. 14. 541-546). Preliminary data suggests that flavokavain B might be responsible for hepatotoxicity (Zhou P et al. FASEB J. epub 8/9/10). Nonetheless, the use of ethanol or acetone as solvents, as compared to a water extract, might increase the risk of hepatotoxicity.
Traditional use of kava involves an extract prepared from the peeled rhizome – some of the cases of hepatotoxicity might have arisen from use of aerial parts of the plant, as stems and leaves might contain a toxin, pipermethysticin (Phytochemistry. 2003. 63. 193-198).
Further investigation into kava hepatotoxicity revealed the existence of more than 200 varieties of this herb, referred to as cultivars. Traditional use involves consumption of kava from a group of 28 cultivars known as ‘noble,’ with Borugu as one of the preferred noble cultivars for traditional use.
Case reports of overdoses of kava not associated with hepatotoxicity suggest that hepatotoxicity is an idiosyncratic reaction and not a dose-dependent direct toxicity. A polymorphism of cytochrome P450 2D6, not detected in Pacific Islanders, but with a 10% prevalence in Europeans may cause poor detoxification of kavalactone metabolites, and thus accumulation (Ann Intern Med. 2001. 135. 68-69).
CONCLUDE in 2010 that safety is maximized by using only a water-based extract derived from peeled rhizomes of a noble cultivar such as Borogu, and at a maximum dose of 250 mg kavalactones per day.
Historically, based on an estimate of 250 million daily doses of ethanolic kava extract consumed in the previous decade, with only 2 causal cases of hepatotoxicity, one report quoted an incidence rate of 0.008 adverse effects per million doses of kava compared with 2.12 per million doses of diazepam (Duetsche Apotheker-Zeitung. 2002. 142. 58-63).
In a prospective study at 11 U.S. poison control centers which reported phone calls regarding dietary supplements, the supplements most commonly linked to adverse events were ephedra, guarana, ginseng, St. John's wort, chromium, melatonin, and zinc (Lancet. 2003. 361. 101-106).
Safety for a given herb may vary tremendously based on the part of the plant used, the type of extract used, the concentration of the extract used, and the duration of use, but many media reports and even published reports fail to address these nuances.
In one study, more than 70% of patients failed to disclose their herbal medicine use during routine preoperative assessment (J Clin Anesthesiology. 2000. 93. 148-151).
There is no requirement to put safety warnings on labels, BUT there is also no prohibition in terms of DSHEA legislation with regard to including extensive safety information on the label of a dietary supplement.
The American Botanical Society is piloting a Safety Labelling Program with Pharmavite, producer of Nature’s Resource brand herbs, in which all Nature’s Resource dietary supplements will have a peel-back label with extensive safety information.
ABC estimates that the cost to the manufacturing company of this program is $3000 per herb for which safety information sheets have been developed, $7000 per herb for which safety sheets have not been developed, and then an additional 8 cents per label on the bottle.
Additional cost per bottle of supplement is estimated by ABC at $1.00.
The University of Minnesota College of Pharmacy in 2005 established a Center for Dietary Supplement Safety to serve as a clearinghouse of information.
Dietary supplement containers lack childproof bottle caps.
There is an indirect risk that a dietary supplement without efficacy may replace a proven form of conventional treatment.
Consumer Reports (May 2004) and the “Dirty Dozen” unsafe herbs still readily available
“CONSUMER REPORTS has identified a dozen (supplements) that … are too dangerous to be on the market. Yet they are.” Introductory paragraph in red ink.
Factors contributing to unsafe supplements on the market.
“ ‘The standards for demonstrating a supplement is hazardous are so high that it can take the FDA years to build a case,’ said Bruce Silverglade, legal director of the Center for Science in the Public Interest, a Washington D.C., consumer advocacy group”(pg. 12).
“The FDA’s supplement division is understaffed and underfunded, with about 60 people and a budget of only 10 million “dollars)…” (pp. 12-13).
“…Overwhelming opposition from Congress and industry forced it to back down” when the FDA first tried to regulate ephedra in 1997 (pg. 13).
The public assumes a greater degree of government regulation than exists – in a 2002 Harris Poll of 1010 adults, 59% of respondents believed that supplements must be approved by a government agency before they can be sold to the public, 68% thought the government requires warning labels on supplements with regard to potential dangers, and 55% thought that supplement manufacturers could not make safety claims without solid scientific support.
Paraherbalism
Based on the incorrect notion that things of natural and organic origin are inherently superior to synthetic products.
There is in fact data on cardiotoxicity, hepatotoxicity, neurotoxicity, and renal toxicity of a variety of herbs (Table 2. N Engl J Med. 2002. 347. 2046-2056).
Efficacy
For herbs with a distinctive taste or smell, true blinding can be very difficult.
Methodologic quality of studies is often poor.
Publication bias may lead to an overestimation of treatment effect.
Botanical classification and chemical analysis of the herb of investigation is often lacking, even in published papers. ALL PUBLISHED STUDIES ON HERBS SHOULD INCLUDE THE HPLC (high performance liquid chromatography) IN THE METHODS SECTION OF THE STUDY.
It is possible that individual herbs in isolation may lack efficacy, but these same herbs in a combination product (as used traditionally) may have efficacy. An example is dong quai – shown to lack efficacy in treatment of hot flashes, but traditionally always used in combination with other herbs for this indication.
Excipients derived from dairy, wheat, corn, and yeast theoretically could be allergenic and interfere with the efficacy of the dietary supplement.
The ideal standard for herbs is efficacy based on at least one large randomized, double-blinded, placebo-controlled trial. However the cost to society of meeting this standard for each and every herb is impractical. From a practical standpoint, the herbs which should meet this gold standard include:
Those with significant adverse effects, so that one has the data necessary to weigh risks versus benefits.
Those indicated for serious health ailments, so that one does not delay potentially more effective treatment due to lack of data.
Those indicated for conditions for which a prescription treatment already exists, so that the risks/benefits/costs of the herbal remedy can be compared to the risks/benefits/costs of the prescription therapy in a meaningful way.
Herbs with evidence of efficacy based on RCT's and often meta-analyses and/or systematic analyses include Echinacea, feverfew, garlic, ginger, ginkgo, hawthorn, kava, saw palmetto, and St. John's wort. Evidence is inconclusive for ginseng, silymarin, and valerian.
Other herbs which have not been studied as extensively, but for which there is evidence of efficacy based on RCT's include black cohosh, butterbur, elderberry, fenugreek, horse chestnut seed extract, mistletoe, peppermint, psyllium, pygeum, stinging nettle, vitex, and willow bark.
Non-herbal dietary supplements for which there is RCT data on efficacy include fish oil supplements, glucosamine sulfate, chondroitin sulfate, SAMe, Coenzyme Q 10, and a few select probiotics.
NCCAM is sponsoring or cosponsoring in 2004 ongoing research on:
Yeast-fermented rice, to see if it can lower cholesterol levels in the blood.
Soy, to see if it slows growth of tumors.
Ginger and turmeric, to see if they can reduce inflammation associated with asthma and arthritis.
Chromium, to better understand its impact upon insulin in the body.
Green tea, to find out if it can treat heart disease.
Glucosamine hydrochloride and chondroitin sulfate, to see if they can relieve knee pain from osteoarthritis.
Black cohosh, to see if it reduces symptoms of menopause.
Garlic, to find out if it can lower moderately high cholesterol levels.
Ginger, to see if eases nausea and vomiting after chemotherapy.
Real world use of dietary supplements is often at doses and frequencies divergent from the suggested dose on the label, with individuals experimenting to tailor the dose to their bodies and needs. Furthermore, there is scepticism amongst the public with regard to interpretation of scientific information (Thompson JJ and Nichter M. The compliance paradox: what we need to know about “real-world” dietary supplement use in the United States. (Altern Ther Health Med. 2007. 13[2]. 48-55).
Levels of Evidence (Spilker B, ed. Guide to Clinical Trials. 1991. Pg 530. Lippincott, Williams & Wilkins)
Anecdotal observations or comments of investigators or patients
Case reports
Uncontrolled series of patients
Cases obtained from computer databases
Series of patients with literature controls
Series of patients with historical controls
Open-label trial
Randomized trial (single blind)
Randomized active medicine-controlled trial (double blind)
Randomized placebo controlled trial (double blind)
Randomized active medicine and placebo controlled trial (double blind)
Confirmatory trial of a trial listed under 10 or 11
LEVEL PLAYING FIELD (Arch Intern Med. 1998. 158. 2187-2191)
Uncritical acceptance of news of toxicity
High dose Vitamin C and kidney stones - review articles and book chapters cite abstracts, letters, and other review articles, but no articles in peer reviewed journals based upon a literature search.
Table 3 – Herbs Associated with Adverse Cardiac Events (Arch Intern Med. 2004. 164. 709-720).
Scornful, dismissive tone - Harrison's and multivitamins - words such as "massive, carelessness, useless, indiscriminate, false, indefensible, wasteful, unnecessary, deplored, poor medical practice."
Ignoring claims of efficacy - Vitamin E and intermittent claudication - four randomized, controlled trials (3 positive).
A meta-analysis of 39 prospective studies in U.S. hospitals found that in 1994, 2,216,000 hospitalized patients had an adverse drug reaction, and 106,000 had fatal adverse drug reactions (JAMA. 1998. 279. 1200-1205).
There are 16,000 deaths and 100,000 hospitalizations in the U.S. each year from NSAID's (New Engl J Med. 1999. 340. 1888-1899). It is estimated that only 1 in 5 individuals who GI bleed from a NSAID have any warning symptoms.
RCTs and systematic analyses of prescription drugs almost always focus on efficacy rather than adverse effects. The vast majority of adverse effect data on prescription drugs is qualitative rather than quantitative, and does not include data on the dose of drug administered or the likelihood that the adverse event was causal rather than coincidental. This makes clinical estimation of risk versus benefit impossible in most circumstances (BMJ [Editorial]. 2004. 329. 7-8).
Most published reports of drugs reported to interact with coumadin “are of poor quality and present potentially misleading conclusions…” (Arch Intern Med. 2005. 165. 1095-1106).
Published peer-reviewed literature often does NOT reflect the state of knowledge about a given pharmaceutical agent, due to publication bias and lack of submission of negative industry sponsored trials for publication. Furthermore, when negative industry sponsored trials are published, they are often written in a way that emphasizes the positive. In a study which compared the independent FDA medical reviews of the primary results of 74 trials of 12 antidepressant agents with the published literature on these 74 trials, the findings are as follows (N Engl J Med. 2008. 358. 252-260):
Of the 38 trials viewed as positive by the independent FDA analysis, 37 were published.
Of the 36 trials viewed as negative or questionable by the independent FDA analysis, only 14 were published (29%), and 11 or the 14 were published in a way that conveyed more positive findings than appeared in the FDA review.
It would appear from the published literature that 94% of the antidepressant trials were positive, whereas only 51% were positive from the standpoint of the of independent FDA medical reviews.
Resources
Natural Medicines Comprehensive Database – a book with this title is updated yearly and the website is updated daily. Each herb reviewed is rated as likely safe, possibly safe, possibly unsafe, or likely unsafe based on a thorough review of published data, which is referenced. Safety of each herb in pregnancy and lactation is also ranked. For each possible indication, each herb is rated as likely effective, possibly effective, possibly ineffective, likely ineffective, or insufficient reliable evidence to rate.
Natural Standard Research Collaboration at Massachusetts General Hospital – grades safety and efficacy of herbs (i.e A,B,C,D,F) for various conditions based on rigorously researched evidence-based information. Website (Internal Medicine News. 4/1/04. 15).
American Botanical Council: www.herbalgram.org
American Herbal Products Association: www.ahpa.org
Consumer Lab which independently tests products for quality and posts the results on www.consumerlab.com.
Healthyroads, a subsidiary of American Specialty Health, Inc. which provides web-based product retailing and consumer based web content. There are stringent criteria for quality for companies to whose products are available on this site: www.healthyroads.com
Memorial Sloan Kettering Cancer Center: www.mskcc.org/mskcc/html/11570.cfm
National Center for Complementary and Alternative Medicine: http://nccam.nih.gov/health
Clearinghouse 1-888-644-6226
Fact sheets
National Institute of Health Office of Dietary Supplements: http://ods.od.nih.gov
Database with scientific abstracts and citations (> 730,000 in 2004) ods.od.nih.gov/databases/ibids is the old web site address info.nih.gov/health_information/ibids.aspx is new site in 2004
Fact sheets: ods.od.nih.gov/factsheets
Personal Health Zone www.personalhealthzone.com - Database of potential herb and supplement effects at www.personalhealthzone.com/herbsafety.html.
USP Monographs
WHO Monographs
ESCOP Monographs
American Herbal Products Association (AHPA) Botanical Safety Handbook (BSH)
The Complete German Commission E Monographs. Mark Blumenthal (ed). 1998.
PDR for Herbal Medicines. Medical Economics Company. 1998.
PDR for Nutritional Supplements. Medical Economics Company. 2001.
ConsumerLab.com’s Guide to Buying Vitamins and Supplements: What’s really in the bottle. 2003.
References:
De Smet PAGM. Herbal remedies (Review Article). New Engl J Med. 2002. 347(25). 2046-2056.
Whybark MK. Third-party evaluation programs for the quality of dietary supplements. Herbalgram. 2004. 64. 30-33.
A Tattered Safety Net. Consumer Reports. September 2020. 30-37.
Page Updated May 16, 2023