Public Safety And Health Freedom -- Can We Have Both?
27 September 2002
by Wyn Snow, Managing Editor

No 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.

Consumers 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 than inform.

Media reporting lacks depth, context, and followup

Recent news about health risks of various herbal supplements is sadly lacking in understanding of the issues or in followup.

Recent 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.

Roy 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 side effects?"

Debate over ephedra ignores equivalent OTC drugs

Context 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.

Synthetic 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.

Concerning 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."

Cold 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®.

Is ephedra riskier than FDA-approved OTC drugs?

Warnings of side effects and drug interactions for Primatene®, Sudafed® and similar OTC drugs are essentially the same as those for ephedra [see 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.

Also, 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 guidelines.

The 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, enforceable regulation.

By 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.

How do we define safety?

This 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, which says,

"This 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."

This rationale for evaluating supplement safety differently from the method used for drugs was repeated twice in the document.

Dr. 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?"

What 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."

Safety of foods and supplements

The 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 as well.

When 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.

How do we establish safety?

Federal legislation has established two pathways for dealing with safety.

The 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).

However, 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 change.

Risk assessment is inherently difficult

All 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 society.

Also, 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.

Risk 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?"

Ephedra in Traditional Chinese Medicine

Ephedra 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:

"Americans 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 no problem."

The 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?

How safe do we need to be?

Since 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:

• human data
• animal data
• biological activity of [similar] substances
• in-vitro data

These 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?

McGuffin 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 question that."

On 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."

Six supplements chosen for prototype monographs

Chaparral is one of six supplements the IoM has chosen for prototype investigation:

There 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.

Certainly 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.

Impact on public health

Any 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.

Upton's 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 supplements?

A 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.

Who will gather and evaluate the evidence?

The 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?

The 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,

"External 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."

While 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.

Historically, 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.

There 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.

Scientific research is key to investigating safety

The 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.

Public 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.

Scope

The 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.

Whenever 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.

Bias

Equally 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.

Researcher 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.

However, 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.

Minimizing researcher bias

Since 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.

What's 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.

Convening 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 red tape.

Once 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?

The issue of health freedom

The 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.

The 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.

Decisions 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.

Indeed, 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?

Who decides if the benefits outweigh the risks?

The 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?

For 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.

We 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.

Sources

Dictionary of Medicine, Oxford University Press.

Institute of Medicine. Proposed Framework for Evaluating the Safety of Dietary Supplements. National Academy Press, 2002. (See link in box above.)

Albert Y. Leung, PhD, private communication, 26 August 2002. Dr. Leung is an internationally renowned pharmacognosist (see details).

Michael McGuffin, private communication, 20 August 2002. McGuffin is Executive Director of the American Herbal Products Association (AHPA) in Silver Springs MD.

Louis Scarmoutzos, PhD, private communication, 27 August 2002. Dr. Scarmoutzos is President of MVS Solutions, Inc. in Melrose MA (see details).

Roy Upton, private communication, 20 August 2002. Upton is an herbalist and Executive Director of the American Herbal Pharmacopoeia (AHP) in Scotts Valley CA.

US Food and Drug Administration. "Phenylpropanolamine (PPA) Information Page." FDA website, www.fda.gov/cder/drug/infopage/ppa/default.htm.