Safety And Health Freedom -- Can We Have Both?
by Wyn Snow, Managing Editor
one is served by the continuing controversy over ephedra. The botanical
industry claims it is safe for millions to take on an extended basis
as a diet aid and performance enhancer -- and has some evidence
to support this claim. The US Food and Drug Administration (FDA)
claims ephedra is dangerous and has caused strokes, heart attacks,
and death among healthy adults who were not taking excessive dosages
-- and also has some evidence to support this claim.
rely on the media to provide accurate information about safety risks
of botanicals. Yet all too often, stories about herbal supplements
are sensational in flavor, intended to attract an audience rather
reporting lacks depth, context, and followup
news about health risks of various herbal supplements is sadly lacking
in understanding of the issues or in followup.
coverage of kava said it was linked to roughly 30 cases of severe
liver damage, a few of them fatal. Several countries including Canada
and the UK have banned all sale of kava products. However, most
of these patients were also either taking pharmaceutical drugs known
to cause liver damage or consuming high levels of alcohol.
Upton, Executive Director of the American Herbal Pharmacopoeia,
has examined the medical evidence on these cases, and says, "There
are only about four cases, maybe six, of liver toxicity that were
definitively related to kava alone. These cases are clearly idiosyncratic
reactions to kava that probably could not have been predicted."
Upton also points out that there are roughly one million daily prescribed
doses of kava in Europe -- and asks, "How many side effect injuries
will occur if all those million doses are changed to barbiturates,
or to other approved anti-anxiety drugs that may have a host of
over ephedra ignores equivalent OTC drugs
is equally lacking in the debate on ephedra. Both the media and
the government say nothing about widely used over-the-counter (OTC)
drugs that contain substances similar to those in ephedra. Ephedra
contains two main bioactive alkaloids: ephedrine and pseudoephedrine,
both of which are known to cause side effects, plus small amounts
of a third alkaloid: phenylpropanolamine.
versions of ephedra's two main alkaloids are the active ingredients
in widely used OTC drugs. Primatene® tablets contain ephedrine
hydrochloride, a brochodilator that until recent years was commonly
used for asthma and chronic bronchitis (most asthma products now
contain drugs that have fewer adverse effects). Sudafed® and
virtually all cold/allergy medications contain pseudoephedrine hydrochloride,
which acts as a decongestant.
phenylpropanolamine, the FDA asked OTC manufacturers to stop making
products with phenylpropanolamine because of a study in 2000 by
Yale University School of Medicine that showed an increased risk
of hemorrhagic stroke (bleeding of the brain). The FDA warning says,
"Although the risk of hemorrhagic stroke is very low, FDA has significant
concerns because of the seriousness of a stroke and the inability
to predict who is at risk."
medicines no longer contain phenylpropanolamine. This drug, which
was approved by the FDA in 1939 and taken by countless millions
of people, was an ingredient in Alka-Seltzer®, many cough medicines
such as Dimetapp®, Robitussin® and Triaminic®, as well
as weight-loss aids such as Acutrim® and Dexatrim®.
ephedra riskier than FDA-approved OTC drugs?
of side effects and drug interactions for Primatene®, Sudafed®
and similar OTC drugs are essentially the same as those for ephedra
comparison of OTC and
botanical ephedra] -- yet millions of people use these OTC
drugs safely. It is likely that every single American has taken
a product containing one of these alkaloids at least once in his
or her life.
most herbal supplements with ephedra contain a lower amount of these
alkaloids than their OTC cousins. For Primatene® tablets, normal
dosage is 25 mg each 4 hours, not to exceed 150 mg per day. For
Sudafed® and OTC cold/allergy drugs, normal dosage is 60 mg
each 4-6 hours, not to exceed 240 mg per day. Guidelines developed
by the herbal industry trade associations say, "Products are not
to contain in excess of 25 mg of total ephedrine alkaloids per serving;
usage instructions should limit daily consumption to 100 mg of total
ephedrine alkaloids." Responsible manufacturers comply with these
maximum (total not to exceed)
herbal industry has been active since 1994 in establishing guidelines
for ephedra. The American Herbal Products Association (AHPA) established
its first ephedra policy in 1994, and has refined it since. In subsequent
years, other supplement trade organizations have joined AHPA in
endorsing ephedra guidelines and in testifying before Congress.
In October 2000, AHPA filed a citizen's petition with the FDA formally
requesting them to adopt the industry guidelines as an official,
seeking to ban ephedra supplements rather than improve labeling
or endorse a reasonable dosage restriction for all manufacturers,
the FDA is clearly applying a double standard: one for OTC drugs
and another for supplements.
do we define safety?
double standard goes further. The Institute of Medicine (I0M), which
is part of the National Academies of Science, recently developed
a Proposed Framework for Evaluating the Safety of Dietary Supplements,
framework focuses on how to consider the safety of dietary
supplement ingredients rather than offering guidance on how to
consider their benefits and role in health. This was a
key point of the request to the Institute of Medicine from the
FDA, as is appropriate since dietary supplements are regulated
as foods that are assumed to be safe, rather than as drugs requiring
a risk-benefit analysis."
rationale for evaluating supplement safety differently from the
method used for drugs was repeated twice in the document.
Albert Leung, a pharmacognosist who is especially knowledgable about
Traditional Chinese Medicine, finds it odd that the FDA wants to
exclude benefits from a risk assessment of supplements. He says,
"other organizations or committees set up to evaluate ephedra always
include benefits as well as adverse effects. Why would they want
to exclude benefits?"
does excluding analysis of benefits mean on a practical basis? According
to Roy Upton, "The prognosis will be poor for ephedra and many other
botanicals. If you don't include an assessment of benefits, it's
a waste of time because everyone knows ephedra has side effects."
of foods and supplements
argument that the safety of supplements should be assessed "like
foods rather than drugs" implies that the FDA views supplement safety
the same way it does food safety, but a double standard reigns here
ground meat is contaminated with E. coli and causes illnesses
in thousands of people, including some deaths, the FDA does not
ban the marketing and sale of ground meat. Instead, insofar as is
possible, the contaminated product is recalled and measures are
taken to minimize any repeat occurrence. Yet when a single source
of tryptophan (which is an amino acid or protein) was contaminated
and caused an outbreak of eosinophilia myalgia syndrome that affected
thousands of people in 1989, the FDA banned tryptophan as dangerous
-- despite continuing its approval for use in infant formula.
do we establish safety?
legislation has established two pathways for dealing with safety.
are presumed to be safe unless proven otherwise (in which case
the FDA has the authority to remove them from the market).
are presumed to be risky unless proven to be sufficiently safe
to make their benefit-to-risk ratio an acceptable one. Thus,
companies that want to market a drug must submit their evidence
of both safety and effectiveness to the FDA for evaluation before
they can offer the drug to the public, either through prescriptions
question of whether vitamins, minerals, botanicals and other supplements
should be regulated as foods or as drugs was unclear until the 1994
Dietary Supplement Health and Education Act (DSHEA) both defined
supplements and established a food model of regulation (presumed
safe unless proven otherwise).
nothing in DSHEA indicated what sorts of criteria should be used
in determining whether a supplement was not safe -- and appropriately
so. Legislation should establish broad goals and outlines, enabling
enforcement to be flexible as scientific knowledge and public policy
assessment is inherently difficult
risk assessment is fraught with uncertainties because it is based
on assumptions and extrapolated from epidemiological or animal studies.
There are no solid rules about how to proceed. One cannot simply
take 10,000 babies or elderly people or even healthy adults and
subject them to a substance that may be toxic in order to see how
many injuries or deaths occur. Nor would one want to in a humane
most risk assessment deals with acute, short-term events. Analysis
of long-term, chronic effects is rarely done because they are very
difficult to assess.
assessment of botanicals is especially challenging because of the
complexity of both the herb itself and the formulations of botanical
products. Dr. Leung explains, "Most reported adverse effects have
very ambiguous origins. The effects can very rarely be proven as
being due to a particular herb or natural product." And on the subject
of ephedra, "There are so many kinds of products and formulas of
ingredients, how would you determine which ingredient or combination
was the cause? Is it ephedra itself or spiked with ephedrine? How
can anybody prove which is the case?"
in Traditional Chinese Medicine
has been safely used as a medicine in Traditional Chinese Medicine
(TCM) for thousands of years -- using an approach very different
from current ephedra products for weight loss or energy enhancement.
Dr. Leung points out that TCM is structured in a way that leads
to blended medicinal formulas: A strong herb like ephedra is balanced
with other herbs that have a moderating effect. Also, TCM formulas
(especially those with ephedra) are generally not designed to be
taken for weeks and months on end, even in the case of asthma. Dr.
Leung believes the problem is one of perception and outlook:
tend to overuse things. If it's good, take a double and triple
dose. But ephedra is basically a drug, not a supplement like One-A-Day
vitamins. A lot of botanicals are really good drugs that don't
need to go through the FDA screening of new drugs, but they need
another name than dietary supplements. If we called it
herbal medicine, people would know it's medicine and they
would be less likely to abuse it. If we call it a supplement,
people think in terms of foods, that you can take it daily with
question of how to educate Americans that botanicals should be treated
with the same respect as OTC drugs is a thorny one that flows from
the same essential concern: How do we best protect public health?
safe do we need to be?
1938, the FDA has been charged with the responsibility for ensuring
that food, cosmetics, drugs and medical devices are safe. But safety
is always relative, never absolute. The safety-assessment framework
proposed by the Institute of Medicine (IoM) has pinpointed four
types of evidence to be considered in investigating whether a particular
supplement is safe:
activity of [similar] substances
proposed categories are certainly thorough, but do we truly need
all four? Would similar kinds of inquiries be proposed for assessing
the safety of foods? Michael McGuffin, Executive Director of the
American Herbal Products Association, points out that carrots, mushrooms
and potatoes contain known toxins. Does that mean people should
stop eating them? Do we need to do a risk assessment on the safety
of these foods?
says, "If this risk-assessment process is well designed and does
what it is supposed to do, it should confirm any current assumption
of safety or danger that is well-substantiated by science -- but
it should also contradict or disprove any current assumption of
safety or danger that is based on faulty science. We need to throw
them an example of something that current thinking believes is unsafe,
but where scientific scrutiny that is done in a meaningful way would
chaparral, for example, McGuffin says, "They believe current scientific
data supports the notion that this herb is unsafe, and believe their
process will say See, we told you. But AHPA's position is
that chaparral can be safely used by a properly informed consumer."
supplements chosen for prototype monographs
is one of six supplements the IoM has chosen for prototype investigation:
because of concerns about liver toxicity; used in an herbal tea.
picolinate, because of reports of kidney toxicity and effects
on insulin regulation in diabetics; promoted to reduce body fat.
because of concerns about its use by diabetics; sold as an arthritis
because of reports of complications; used to treat insomnia and
palmetto, because of reports of heart problems; sold as a prostate
cartilage, because of a report of hepatitis following ingestion;
promoted as a treatment for cancer and other health conditions.
is extensive and reasonably solid scientific research documenting
health benefits of at least three of these supplements. Yet the
FDA and IoM are refusing to consider either these benefits or the
impact on millions of Americans if they are forced to switch to
other approaches that may be less effective (glucosamine/chondroitin
can stop the progression of osteoarthritis; nothing else has been
shown to do this), more prone to side effects (drugs for benign
prostatic hyperplasia), and quite likely more expensive.
if a supplement is risky for a portion of the population, such as
diabetics or people taking HIV drugs or birth control pills, warning
information can be placed on the label. There is no need to prevent
millions of other Americans from benefiting from its use.
on public health
debate concerning regulatory removal of a supplement from the marketplace
has the responsibility to investigate the full consequences of such
an action. It needs to consider the impact on public health of the
relative risks of alternative substances. Consumers who are motivated
to do something about their health are likely to take some action.
Thus, analysis of risk should take into account how many of these
consumers are likely to (a) do nothing, (b) take a less risky substance,
or (c) take a more risky substance -- if the supplement in question
is removed from the marketplace.
comments about kava are important here: How many kava users will
turn to barbiturates or other approved anti-anxiety drugs that may
have a host of side effects? Or in the case of ephedra: How many
dieters will do nothing about their weight, thereby continuing to
carry a heightened risk of heart disease and diabetes? How many
of those dieters will turn to OTC ephedrine and pseudoephedrine,
and are those substances more or less risky than botanical ephedra
risk assessment that does not consider the full social context is
limited in usefulness, and cannot protect the public from the law
of unintended consequences.
will gather and evaluate the evidence?
IoM's proposed risk-assessment framework is essentially a review
of existing literature -- the development of a monograph analyzing
scientific evidence for safety of the particular supplement being
investigated. It does not call for new research. But who will gather
and evaluate this evidence?
IoM recommends creation of a standing external advisory committee
composed of expert scientists. And, even while the IoM says it seeks
to "ensure that the critical evaluation of the monograph and related
information be as free of conflict of interest and as objective
as possible," they also state,
advisory committee members should be selected based on their disciplinary
expertise rather than as representatives of stakeholder viewpoints.
Advisory committee members should not have a financial stake in
the outcome of the process or otherwise have a real or perceived
conflict of interest. The external advisory committee should explicitly
exclude representatives of the dietary supplement industry and
its trade organizations. It is assumed that the organization assembling
the external advisory committee will use standard practices to
identify and avoid other types of conflict of interest as well."
this sounds like a reasonable method of eliminating conflict of
interest, in fact it accomplishes the opposite. It eliminates all
experts from the supplement industry and trade organizations from
having any voice in evaluating the evidence. It also eliminates
the voice of consumers and health practitioners, and ensures that
government (ie, lobbyist) interests alone will choose who sits on
this committee and will both choose and evaluate the evidence.
the FDA's agenda has been to push supplements into the pre-market
regulatory scheme that governs drugs. Since the new-drug-approval
process costs on average in excess of $500 million, this would effectively
remove supplements from the marketplace. Since supplements cannot
be patented, it is difficult for manufacturers to recoup this expense.
Also, a manufacturer who does such research gives a financial advantage
to its competitors -- who can use the results of the research without
having to pay the cost.
are few indications that the FDA's agenda has changed. If the FDA
appoints the members of an advisory committee that investigates
safety without also considering benefits of supplements or risks
of alternative products, it will be a slam dunk for finding risks.
Two other agencies within the National Institutes of Health are
mandated to carry out scientific investigation of supplements and
dissemination of information -- the Office of Dietary Supplements
and the National Center for Complementary and Alternative Medicine
-- but are not even mentioned in the IoM guidelines.
research is key to investigating safety
IoM approach has another flaw as well: A review of existing literature,
no matter how thorough, cannot tell us anything new. It only shines
a spotlight on what is already known and hotly debated.
health demands a rigorous process of scientific investigation to
settle questions of safety. Ideally, any study investigating the
safety of a dietary supplement should meet at least two criteria.
study must be sufficiently large in scope to discover rare but
significant problems, to control for confounding variables that
could cause adverse reactions to be unusually high or low, and
to determine whether problems are occuring at a higher rate than
among the population as a whole. A few hundred subjects is usually
not enough to accomplish these goals, especially for substances
used by many thousands or even millions of people.
thousands of people engage in an activity -- such as drinking
water or taking a supplement, be it ephedra, kava, glucosamine,
melatonin, saw palmetto or vitamin C -- some will suffer health
problems. In order to determine whether that activity caused
the health problem, one has to compare two reasonably large
groups who are similar in all other respects (such as age, activity
level and health status), where one group engages in the activity
and the other does not.
crucial, those who interact with the research subjects must
not be biased in their expections about what the study will find.
However, the design of the study itself must also be unbiased.
bias is known to skew results. When a doctor knows he is giving
a placebo, the patient somehow gets the message that these pills
won't work. The double-blind research design was invented to ensure
that both the people who interact with patients and the patients
themselves do not know who is getting "the real thing" or a placebo.
double-blind studies do not go far enough in ensuring neutrality
in research design. Sociological research has demonstrated that
even a double-blinded study can be influenced by bias. Imagine
one study where the people interacting with patients believe that
side effects will be minimal, and another where the researchers
expect to find serious problems. Imagine another where investigators
fail to ask crucial questions or collect key physiological data
because they don't believe these things are important.
bias cannot be completely eliminated from scientific research, how
can we minimize its influence? Basically, by creating a process
for reviewing study design that includes a wide range of stakeholders
and points of view.
needed is a scientifically-based standing committee that includes
relevant stakeholders from industry, health practitioners and consumers
to review the research design process and minimize bias. Until all
parties can agree that a research study is well designed, each side
of the controversy will continue to criticize the other's evidence
as inadequate and flawed.
a research-design committee through a non-governmental standards
organization (such as NSF International) assures the greatest flexibility
of response to changing scientific knowledge and minimization of
such a large scale and minimally biased study has been designed
and funded and yields its results, who then decides if the supplement's
benefits outweigh its risks?
issue of health freedom
debate on the safety of supplements and how they should be regulated
goes back decades. In the 1970s, the FDA tried to implement tighter
regulation of vitamins and minerals, but Congress rejected these
actions with the 1976 Vitamins and Minerals Amendments. When the
FDA once again tried to toughen regulation of supplements in the
1990s, Congress passed the Dietary Supplement Health and Education
Act in 1994.
fundamental question is: Who is responsible for an individual citizen's
health? The government -- or that citizen? The FDA sees itself as
a zealous guardian of public health. But Congress finds the FDA's
watchdog mentality to be excessive, and the courts find its actions
on limiting publicity of truthful health claims to be unconstitutional.
about acceptable levels of risk are fundamentally social and political
rather than scientific in nature. One cannot apply an equation or
a law of nature; one can only guess that if 10,000 patients
with high blood pressure take substance A, then 7,241 will live
longer with lowered blood pressure, but 26 will die of stroke and
17 will die of allergic reactions, while the remaining 2,719 are
not affected one way or the other -- and of the 7,241 who are helped,
986 will suffer headaches and 1,248 will suffer tremors and 159
will become insomniacs.
even if estimates of this nature are reasonably accurate and based
on large-scale epidemiological data, one is still faced with a trade
off: 7,241 people who live longer versus 43 who died earlier. This
point lies at the heart of all debates on ephedra and supplement
safety. Anyone who reads the warnings of potential side effects
cannot doubt that ephedra can be dangerous for some people. So one
question becomes: Do the benefits of weight loss for millions of
people -- and the corresponding gain in health and longevity --
outweigh the likelihood that some people will suffer injuries or
even death? An equally vital question is: Who decides?
decides if the benefits outweigh the risks?
core of the debate lies here: Who is responsible for protecting
a citizen's health? To what degree should the government decide
which supplements a citizen can purchase and swallow?
substances like dietary supplements, most of which have fewer side
effects than drugs and are less vulnerable to contamination and
spoilage than food, we believe the choice belongs in the hands of
a well-informed consumer. We believe with the US
Court of Appeals that when information is lacking or misleading,
the preferred solution is to provide more information to the consumer,
rather than to remove choices altogether.
also believe that the best way of minimizing bias is to have all
stakeholders and points of view represented in any decision-making
body. That is the fundamental tenet of democracy, that each citizen
can speak up, cast his or her vote, and be heard.
of Medicine, Oxford University Press.
of Medicine. Proposed Framework for Evaluating the Safety of Dietary
Supplements. National Academy Press, 2002. (See link in box above.)
Y. Leung, PhD, private communication, 26 August 2002. Dr. Leung
is an internationally renowned pharmacognosist (see
McGuffin, private communication, 20 August 2002. McGuffin is Executive
Director of the American Herbal Products Association (AHPA)
in Silver Springs MD.
Scarmoutzos, PhD, private communication, 27 August 2002. Dr. Scarmoutzos
is President of MVS Solutions, Inc. in Melrose MA (see
Upton, private communication, 20 August 2002. Upton is an herbalist
and Executive Director of the American Herbal Pharmacopoeia (AHP)
in Scotts Valley CA.
Food and Drug Administration. "Phenylpropanolamine (PPA) Information
Page." FDA website, www.fda.gov/cder/drug/infopage/ppa/default.htm.