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 $8.8 billion in 1994, $15.7
billion in 2000, $17.8 billion in 2001. In 2009, Nutrition Business Journal, a
trade journal, estimated sales of $26.7 billlion.
·
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
·
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
the
·
In 1998, annual sales were
$151 million for ginkgo, $140 million for
Quantity (Consumer
Reports. 9/10/. 16-21)
·
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
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[5]. 8-9)
and by Rick Liva, ND, RPh (IMCJ.
2007. 6[5]. 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.
·
Lack of government
regulation (i.e. no requirement for companies to follow Good Manufacturing
Practices) 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.
·
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.
·
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.
·
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).
·
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 and that if taken as recommended by the manufacturer, each of these 14
products could result in heavy metal intakes above published regulatory
standards (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).
·
BEWARE of the following categories of dietary
supplements (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.
·
Heavy metals in dietary
supplements (IMCJ. 2007. 6[3].
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.
·
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.
Safety
·
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[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 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
·
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.
·
In the
·
In
·
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
·
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).
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:
·
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).
·
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 (
·
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 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.
·
Memorial Sloan
·
·
Clearinghouse 1-888-644-6226
·
Fact sheets
·
National
·
Personal Health Zone www.personalhealthzone.com
- Database of potential herb and supplement effects at http://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.
Companies listed 9/25/11 on USP Verified web
site
·
Banner Pharmacaps
·
IVC Nutrition
·
·
Natural Factors Nutritional
Products
·
NBTY Inc (
·
Perrigo Company – private
label brand supplements
·
Pharmavite LLC – Nature Made
and Nature’s Resource
·
Robinson Pharma
·
Schiff Nutrition – Schiff
brand supplements
·
Uni-Caps
Brand names listed 9/25/11 on the USP Verified
web site
·
Berkley & Jensen
·
Equaline
·
·
Nature Made
·
Nutri Plus
·
Safeway
·
Sunmark
·
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
·
Red Bull
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
·
Enzymadica
·
Fertility Sciences
·
Infinity 2 Health Sciences
·
Iovate Health Sciences
·
Kmart Corporation
·
Lalilab
·
Mannatech
·
Medical Research Institute
·
Medicine Shoppe
·
Meijer
·
Naturex
·
Nutritional Health Institute
Laboratories (NHIL)
·
Perrigo
·
Pharmanex
·
Pharmore Ingredients
·
Platinum Naturals
·
Polyphenolics
·
Publix
·
Sabinsa Corporation
·
Schiff Nutrition
·
Somalife International
·
The Coromega Company
·
Theralogix
·
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
·
Biholon
·
BIOSINT
·
CAPCO
·
Capsuleworks
·
Captek Softgel Intl
·
CC Pollen Company
·
Century Systems
·
Country Life
·
Creation’s Garden Natural
Products
·
Cyanotech Corporation
·
Cyvex Nutrition
·
Danisco
·
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
·
Metagenics
·
National Vitamin Company
·
Natrol
·
Nature’s Products
·
Nature’s Way
·
Nexgen
·
NHK Laboratories
·
Now Foods
·
NutraMed
·
Nutrition Now
·
Nutritional Engineering
·
Organic by Nature
·
Pacific Nutritionals
·
Paragon Laboratories
·
Pharmline
·
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
·
Solgar
·
Specialty Enzymes
·
STPCA DBA Sun Ten
Laboratories
·
Tishcon Corporation
·
Trace Minerals Research
·
Ultimate Nutrition
·
Valentine Enterprises
·
Vesta Pharmaceuticals
·
VitaCeutical Labs
·
Vitamer Labs
·
VitaRich Laboratories
·
VitaTech
·
Wellington Foods
·
WePackItAll
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.
_________________________________________________________________________________________________________________________
[Last Updated October 3, 2011] [Return to List of Topics]