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.
· 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.
· 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.
The number of dietary supplements
on the market in the
· WHO in 1985 estimated that 80% of the world population relies on herbs for primary health care needs.
Up to 30-40% of medical
A 1997 survey estimated that
12.1% of adults in the
Annual retail sales of
botanicals have risen from $200 million in 1988 to an estimated $5.1 billion in
In 1998, annual sales were
$151 million for ginkgo, $140 million for
Quantity (Consumer Reports. 9/10/. 16-21)
· 4000 dietary supplements prior to DSHEA; 29,000 dietary supplements in 2010, as per Dr Low Dog presentation at Scripps conference 10/28/12 (Clin Pharmacol Ther. 2010. 87. 147-149).
· In 2010, more than 54,000 dietary supplement products in the Natural Medicine Comprehensive Database
o Only 1/3 have some level of safety and effectiveness that is supported by scientific evidence
o 12% have been linked to safety concerns or problems with product quality
· The FDA finally 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 at http://www.fda.gov/OHRMS/DOCKETS/98fr/cf0441.pdf.
· 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. 8-9) and by Rick Liva, ND, RPh (IMCJ. 2007. 6. 28-31).
· The AHPA (American Herbal Products Association) in 7/07 recommended the following changes to the cGMP requirements
1. Clarification that a dietary ingredient manufacturer or supplier cannot be made subject to the final rule based on how its customers use its ingredients.
2. 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.
3. Define the terms manufacturing, packaging, labelling, and holding.
4. Allow master manufacturing records to include a range of batch sizes rather than specific batch sizes.
5. Remove language which would effectively prevent single-employee companies from the dietary supplement industry.
6. Allow personnel to conduct examinations for correct labels.
7. Require that the batch, lot, or control number appear on the finished products.
· Historically, lack of government regulation (i.e. no requirement for companies to follow Good Manufacturing Practices), and currently lack of spot checks to enforce regulation, coupled with poor quality control of the manufacturing process leads to a situation in which the amount of active ingredient in the bottle may be significantly different from the amount specified on the label.
· 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).
· 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. 1011/13).
· Quality really should start with Good Agricultural Practices (GAP’s).
· Quality concerns with regard to laboratory testing (Integrative Medicine. 2006. 5 . 34-37 and 5. 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.
· 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.
· Heavy metals in dietary supplements (IMCJ. 2007. 6. 36-38).
· 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.
· 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
· 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 from a chemical standpoint versus from a biological standpoint
· 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.
· 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
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.
· Web site www.usp.org includes a list of participating companies at http://www.usp.org/USPVerified/dietarySupplements/companies.html and a list of verified brand names at http://www.usp.org/USPVerified/dietarySupplements/supplements.html. Clicking on any brand name at http://www.usp.org/USPVerified/dietarySupplements/supplements.html 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 www.nsf.org.
· Companies which are certified are available at http://www.nsf.org/certified/gmp/Listings.asp?Program and products which are certified can be identified by performing a ‘Search’ at www.nsf.org/certified/dietary. 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
· 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.
· Web site is www.naturalproductsassoc.org.
· 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 at http://www.naturalproductsassoc.org/site/PageServer?pagename=ic_bg_trulabel.
· 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 at http://www.npainfo.org/index.php?submenu=GMPcert&src=gendocs&ref=CertifiedCompanies&category=QualityAssurance 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
Be aware that Nature’s Way
is now a subsidiary of a German Company, and the quality standards in
· 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 at http://www.emersonecologics.com/Quality/QualitySummaries.aspx. 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
· 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 to www.consumerlab.com 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.
· 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.
· The results are now also available in book format.
· Go to www.healthyroads.com 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.
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 NNFA 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 heavy 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 is1.5 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.
· Dietary supplements are marketed without prior FDA approval.
· 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 will change 12/07 when 2006 legislation entitled the Dietary Supplement and Nonprescription Drug Consumer Protection Act goes 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 Office of the Inspector
General estimates that less than 1% 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).
Clinicians can report adverse events via the web site http://vm.cfsan.fda.gov/~dms/supplmnt.html
which is maintained by the
· Many reports historically could 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.
· 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
· Certain: dechallenge and rechallenge information corroborates causation.
· Probable: dechallenge information corroborates causation.
· Possible: competing explanations are plausible.
· Unlikely: timeline is improbable.
· 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 (
· 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. 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. 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 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).
· 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
· 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.
· 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.
· 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.
· 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).
· 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:
· 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 hydorchloride 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
Levels of Evidence (Spilker B, ed. Guide to Clinical Trials. 1991. Pg 530. Lippincott
Williams & Wilkins)
1 Anecdotal observations or comments of investigators or patients
2 Case reports
3 Uncontrolled series of patients
4 Cases obtained from computer databases
5 Series of patients with literature controls
6 Series of patients with historical controls
7 Open-label trial
8 Randomized trial (single blind)
9 Randomized active medicine-controlled trial (double blind)
10 Randomized placebo controlled trial (double blind)
11 Randomized active medicine and placebo controlled trial (double blind)
12 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 -
· Ignoring claims of efficacy - Vitamin E and intermittent claudication - four randomized, controlled trials (3 positive).
A meta-analysis of 39
prospective studies in
There are 16,000 deaths and
100,000 hospitalizations in the
· 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).
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 (
· 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.
· Natural Medicines Comprehensive Database – a book with this title is updated yearly and the web site www.naturaldatabase.com 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. www.naturalstandard.com (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.
· Clearinghouse 1-888-644-6226
· Fact sheets
· 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.
Companies listed 9/25/11 on USP Verified web site
· Banner Pharmacaps
· IVC Nutrition
· Natural Factors Nutritional Products
· Perrigo Company – private label brand supplements
· Pharmavite LLC – Nature Made and Nature’s Resource
· Robinson Pharma
· Schiff Nutrition – Schiff brand supplements
Brand names listed 9/25/11 on the USP Verified web site
· Berkley & Jensen
· Nature Made
· Nutri Plus
· Tru Nature
· Your Life
Dietary supplement companies listed 9/25/11 on the NSF GMP web site
· A.M. Todd Botanical Therapeutics, Aaron Thomas Company, ABH Nature’s Products, Adam Nutrition, ADH Health Products, AIDP Inc. Albion Advanced Nutrition, Amazon Forest Inc, Ambix Laboratories, American Health Formulations, American Ingredients, American Nutritional Corp, Amerilab Technologies, AMT labs, Amway – see Nutrilite below, APN Labs, Arizona Co-Packing, Arizona Nutritional Supplements, Arizona Production and Packaging, Arnet Pharmaceutical Corp, Ashley-Martin Manufacturing, Atlantic Essential Products
· Bactolac Pharmaceutical, BASF Personal Care and Nutrition, Beehive Botanicals, Bellwyck Packaging Inc, Best Life Pharmaceuticals, Bio-Botanica, Bio-Nutraceuticals, BioCalth International, Biotanico Inc, BiProUSA, Blue California, Botanical Laboratories, Brand Packaging Group
· Capco Labs, Caps and Tabs, Inc, Capsugel Americas, Capsugel Div of Warner Lambert, Captek Softgel International, Cargill, Incorporated, Catalent Japan K K, Chick Cart, Inc, Chongqing Hechuan Xingxin Biochemical, Cognis Corporation, Columbia Nutritionals, Complementary Prescriptions, Contract Pharmacal Corp, Cornerstone Research and Development, Country Lane Sales, Country Life Vitamins, Custom Labelling & Bottling, Custom Nutrition Laboratories, Cytosport
Deerland Enzymes, Designs for Health,
· Eckhart, Emerson Ecologics, Enzyme Science, Enzymedica, ESM Technologies, Eurochem Asia, Everest Packaging
· Fenchem Biotek, FHG Corporation DBA Integrity, Formulation Technology, Fortress Systems International
Haiyang Sanfen Biochemical Co, Harmony Concepts, Health
Wright Products, Healthy Solutions, Herbally
Yours, Hill Pharmaceutical,
· IFP Innovative Food Processors, Inexa Industria Extractora, Innobio Limited, Innovative Flexpak, Innovative Labs
· Jarrow Industries, Javaplant
· Kaiser Pharmaceutical Co, Kelatron Corp, Kemin Health
· La Belle Associates, Leahy Orchards, Lief Organics, Liquadry, Liquid Health Inc, Lucerne Foods, Lyco Red Corp
· Main Street Ingredients, Marlyn Nutraceuticals, Martek Biosciences, Mason Vitamins, Matsun Nutrition, Maxcure Drugs and Pharmaceuticals, Medipro Pharmaceuticals, Membrell, MeriCal, Metagenics, Milk Specialties – Global, Mineral Resources International, Mission Vivacare Limited, Morishita Jintan Co, MTC Industries, Multipak Services
· Napro Pharma, National Enzyme Company, Natrol, Natural Alternatives International, Natural Organics, Natural Remedies Private Limited, Nature’s Answer and Natural Products Packaging , Nature’s Sunshine, Nature’s Value, Naturex, Nellson Nutriceutical, Nei-Nutritionals, New Chapter, Neways, NHK Laboratories, NHS Labs, Nigbo Liwah Plant Extraction Technology Limited, Nordic Naturals, Northwest Natural Products, Nutraceutix , Nutramax Laboratories, Nutramed, Nutri-Force, Nutribiotech Co, Nutricap Labs, Nutrilite Nutritional Supplements Exclusively from Amway, Nutrition Formulators, Nutrition Now, Nutrition Science Laboratories, Nutritional Laboratories, Nuvite Laboratories
· Optimum Nutrition, Orchid Health Care, Organic Food Bar
· Package All Corp, Palmer Natural Products, Paragon Laboratories, Perrigo Company of South Carolina, Perrigo Holland, PGP International, Pharmachem Laboratories, Pharmore, PJ Noyes Company, Pluspharma , PNP Pharmaceuticals, Premier Research Labs, Progressive Laboratories, ProTec, Prothera, Pt Deltomed Laboraties, Pure Encapsulations, PureTek Corporation, Purity Technology
· Quindao Yiquing Medicinal Capsules, Quality Packaging Specialists International
Randal Optimal Nutrients,
RBC Life Sciences, Red Bull
· Sabinsa Corporation, Sanmark Corp, Santa Cruz Nutritionals, Schiff Nutrition Interntational, Schwabe North America, Select Supplements, Sentry Manufacturing, Shaanxi Jiahe Phytochem, Soft gel Technologies, Supplement & Nutrition Technologies, Supplement Sciences, Swanson Health Products, Sweet Green Fields, Swisscaps USA, Synergy Worldwide
· The CorOmega Company, The FRS Company, Theralogix, Threshold Enterprises, Tianjin Jianfang Natural Products R&D, Tishcon Corp, Twinlab Corp
· Uckele Health & Nutritions, Ultimate Formulations, Uni-Caps, United Pharma, US Pharma lab, USANA Health Sciences, UST Corporation
· Valentine Enterprises, Verdure Sciences, Vidya Herbs, VitaCost, Vitaganic, Vitality Works, Vitarich Laboratories, Viva Pharmaceuticals, VMI Nutrition, VRP Manufacturing
· Wellable Group Marine Biological & Chemical Company
· Yantai Pengua Biochemical Products Company, Yessamin Health Co, Your Vitamins Inc
Functional food and beverage companies listed 2/24/09 on the NSF web site
· Bartech Manufacturing
· Nelson Nutraceutical
Additional companies with certified products listed 2/24/09 on the NSF Dietary web site
· All-Sports Endurance
· Amerifit Nutrition
· Appleboost Products
· Back Nine Nutrition
· Cardinal Distribution
· EAS (Experimental and Applied Science) by Ross
· Fertility Sciences
· Infinity 2 Health Sciences
· Iovate Health Sciences
· Kmart Corporation
· Medical Research Institute
· Medicine Shoppe
· Nutritional Health Institute Laboratories (NHIL)
· Pharmore Ingredients
· Platinum Naturals
· Sabinsa Corporation
· Schiff Nutrition
· Somalife International
· The Coromega Company
· Topco Associates
· Training Day
· Usana Health Sciences
· Vital Choice Seafood
· Wellable Group
· Yantai Kangde Biochemical Products Company
Companies listed 9/25/11 on the NPA GMP Certified web site
· AJES Pharmaceuticals
· Aloha Medicinals
· Anabolic Laboratories
· Archon Vitamin Corp
· Bactolac Pharmaceutical
· Captek Softgel Intl
· CC Pollen Company
· Century Systems
· Country Life
· Creation’s Garden Natural Products
· Cyanotech Corporation
· Cyvex Nutrition
· Earthrise Nutritionals
· FoodScience Corporation
· Fusion Formulations
GMP Laboratories of
· Hamida Pharma
· Herbal Authority
· J and D Laboratories
· J.R. Carlson Laboratories
· Life Sciences Laboratories
· M & L Pharmaceutical
· Metabolic Maintenance
· National Vitamin Company
· Nature’s Products
· Nature’s Way
· NHK Laboratories
· Now Foods
· Nutrition Now
· Nutritional Engineering
· Organic by Nature
· Pacific Nutritionals
· Paragon Laboratories
· Protech Nutraceuticals
· ProStar Manufacturing
· Pro-X Nutraceuticals
· Reliance Vitamin Company
· Robinson Pharma
· Shandong Yibau Biologics Co
· Shangong Zhongyuan Greentech Co
· SIRIO Pharma Co
· Soft Gel Technology
· Specialty Enzymes
· STPCA DBA Sun Ten Laboratories
· Tishcon Corporation
· Trace Minerals Research
· Ultimate Nutrition
· Valentine Enterprises
· Vesta Pharmaceuticals
· VitaCeutical Labs
· Vitamer Labs
· VitaRich Laboratories
· Wellington Foods
· 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.
[Last Updated January 12, 2014] [Return to List of Topics]