I am a clinical cardiologist and scientist specializing in heart rhythm disturbances. The findings and opinions that follow are based upon my education, training and experience in medicine, cardiology, cardiovascular pharmacology, cardiac electrophysiology, and review of the medical literature.

Recent articles in the medical literature highlight the concern of medical practitioners with the overall quality, safety, and efficacy of some herbal products.1 In my opinion, the Dietary Supplement Health and Education Act (DSHE) passed in 1994 has not provided a satisfactory framework to protect the public health by allowing dietary supplements to be marketed without prior approval of efficacy or safety by the FDA. Though DSHE limits certain health claims for dietary supplements, these products are marketed in such a way that consumers believe they are effective to cure or treat many of the conditions that afflict the population, including obesity. Laboratory analysis of these products2 has disclosed that there is considerable variation in the composition of herbal supplements from one manufacturer to another and often from lot to lot from the same manufacturer. Most of these herbal products have not been tested rigorously, with the accepted norm of standardized, controlled, prospective, randomized trials that we use to test medical drugs and devices. In addition to lack of efficacy for the claimed use, some of these products produce important side effects either directly or by interactions between the herbal remedies and prescription drugs and over-the-counter (OTC) drugs. Due to limitations in the reporting system, it is estimated that less than one percent (1%) of the adverse effects caused by dietary supplements are reported to the FDA.3 The current regulatory framework requires that, if a safety concern arises, the burden of proof for safety lies not with the manufacturer but with the FDA to prove that the product is unsafe. In particular, dietary supplements containing ephedra and caffeine illustrate the health risks posed to consumers from the current system and will be the focus of this report.

II. Normal heart function

The heart and blood vessels provide oxygen and nourishment to every cell of the body and remove waste material by circulating blood throughout the body. The heart contracts, pumping about 5 quarts (4.7 liters) of blood every minute, or 1800 gallons (6768 liters) of blood every day. Oxygenated blood is pumped from the left ventricle to the body to provide oxygen and nutrients, while returning (de-oxygenated) blood is pumped through the lungs from the right ventricle to remove carbon dioxide and become re-oxygenated. This continuous cycle of synchronized contractions is driven by the heart's electrical system.

A healthy heart beats steadily and rhythmically at a rate of about 60 to 100 beats per minute when at rest (normal sinus rhythm). During strenuous exercise, the heart can increase the amount of blood it pumps fourfold. The normal heart beats approximately 38 million times per year, or about 3 billion times in a normal lifespan. The sinus node, a small group of specialized cells in the top right portion of the heart's upper chamber (atrium), serves as the pacemaker, initiating and orchestrating each heartbeat. Other tissues in the heart wait for the arrival of each sinus-generated beat, almost like electricity traveling over a wire, and fire in an orderly sequence, from the atria to the ventricles, to produce each heartbeat.

Multiple factors can influence the rate of discharge of the sinus node and can cause other tissues in the heart to fire prematurely and usurp control of the heartbeat. Among these factors, the autonomic nervous system is most prominent. 4 Predominantly two groups of nerves make up the autonomic nervous system: vagus nerves and sympathetic nerves. The vagus nerves exert an inhibitory effect on heart function by release of a substance called acetylcholine, slowing the heart rate, slowing conduction from the atria to bottom chambers (ventricles), lessening the strength of heart muscle contraction and dilating blood vessels. They oppose the action of sympathetic nerves. Sympathetic nerves are stimulatory by release of substances known collectively as catecholamines (adrenaline or epinephrine, and noradrenaline or norepinephrine), causing an increase in the heart rate, a quickening of conduction between the atria and ventricles, an increase in the strength of heart muscle contraction, and, for the most part, a constriction of the blood vessels. These actions result in an increase in blood pressure and also can provoke spontaneous discharge of the heartbeat from areas other than the sinus node. When heart tissue other than the sinus node initiates a heartbeat, this results in arrhythmias, or disorders of the heartbeat. The extent of the heartbeat disorder can range from a single premature beat, often felt as a "thump" in the chest or palpitation, to a lethal heart rhythm called ventricular fibrillation. The latter arrhythmia is the major cause of sudden cardiac death. It is a disorganized, rapid (400-600 times per minute) heart rhythm originating in the bottom chambers (ventricles) and preventing blood flow to the brain, which causes death in 3-5 minutes unless reversed. 5,6

III. Action of ephedra and caffeine on the heart and blood vessels

A. Ephedra/ephedrine

The ephedra products under discussion are marketed as dietary supplements for weight loss and to boost energy. These preparations stimulate both the heart and blood vessels, and the brain. They are chemically related to methamphetamine. 7 Most of these ephedra substances contain extracts of the ma huang plant, which is referred to as ephedra. Ephedra contains primarily ephedrine, which is a sympathomimetic amine. That means its actions mimic those actions produced by stimulation of the sympathetic nerves, noted above. Ephedra does this by both a direct effect on stimulating alpha and beta 1 and beta 2-adrenergic receptors, as the body's own catecholamines do, and indirectly by stimulating the release of the body's store of catecholamines and another compound called dopamine (20-30% increase). Ephedra can be chemically synthesized as ephedrine, rather than extracted from a plant, and has the same actions.

B. Caffeine

Most of these ephedra products also contain caffeine, typically extracts from guarana seed. Caffeine causes an anti-vagal effect by antagonizing the actions of adenosine, and can therefore promote vasoconstriction (blood pressure elevation) and increase the release of epinephrine, norepinephrine and dopamine.

Importantly, an exercising individual normally activates the autonomic nervous system to decrease vagal, and increase sympathetic, activity. These changes summate with the actions of ephedra and caffeine.

C. Physiologic effects

The result of the actions of ephedra and caffeine noted above is to:

1) Elevate the blood pressure

2) Elevate the heart rate

3) Put more stress on the heart (needs more oxygen)

4) Reduce the potassium level in the blood

These responses to ephedra/caffeine compounds can cause abnormal heart rhythms ranging from single premature beats to ventricular fibrillation and sudden death

IV. What evidence exists to show that ephedra compounds can cause cardiovascular harm?

Many animal and clinical studies have established the physiologic actions on the heart and blood vessels of the vagus and sympathetic nerves, catecholamines, and sympathomimetic amines like ephedra and ephedrine, as well as the actions of caffeine. No controversy exists about the physiologic actions of these drugs. The major issue under discussion is whether these ephedra/caffeine combinations have pathophysiologic actions, that is, can they cause bodily harm. Information to support the latter comes mostly from adverse event reports (AERs) and case reports, which are not as "robust" as clinical studies. Still, more than 1200 serious reactions related to ephedra have been reported to the FDA, and it is suspected that the actual number of events is undoubtedly far greater due to the under-reporting noted earlier. 7 These include strokes, arrhythmias, myocardial infarction, psychosis, and death. 8,9 Apparently, 13,000 complaints have been registered with the manufacturer of Metabolife 356, including several hundred patients who required hospitalization and 80 incidents of serious injury or death. 10

Canadian authorities have requested the voluntary recall of health products containing ephedra, noting its enhanced toxicity when combined with caffeine. 11

The reason for relying on AER and case report data is due to the relative infrequency of the adverse events. If a drug causes an adverse effect in only 1 of 1000 treated patients, then many patients have to be treated before a statistically significant result is noted. Such studies can be impossibly expensive to perform. And while information from AERs is less acceptable as proof of an effect, criteria can be applied to help establish validity. These include the following six criteria:

1) Temporal relation between taking the drug and the adverse response

2) Appropriate dose taken to have an effect

3) No other cause recognized to have produced the effect

4) Biologic plausibility, that is, the known action of the drug is consistent with the adverse response

5) De-and re-challenge, that is, stopping the drug eliminates further adverse responses, or re-starting the drug produces the same adverse response

6) Similar supportive data in published medical literature

Most of the reports on ephedra/caffeine compounds meet all six of these criteria. Some examples follow.

The report by Haller and Benowitz applied reasoning similar to the above 6 criteria in evaluating 140 AER reports submitted to the FDA between June 1997 and March 19998 and considered that 31% were definitely related to supplements containing ephedra and 31% possibly related. Ten events resulted in death and 13 produced a disability, representing 26% of the definite/probable and possible cases. Palpitations or tachycardia (rapid heart beat) occurred in 13.

Samenuk et al9 analyzed 37 patients from 926 cases of possible ma huang toxicity reported to the FDA between 1995 and 1997 and found that the compound was temporally related to stroke, heart attack, and sudden death at the normally taken doses in 36 of 37 people.

Gardner et al12 treated 10 healthy men with 2 Metabolife 356 caplets (12 ephedra and 40mg caffeine in each) 3 times daily for 2 weeks and found that at day 3, all subjects reported adverse effects, most commonly dry mouth, shakiness and insomnia. Two men reported chest pain, two had large numbers of premature atrial beats and one had a 3 beat run of ventricular tachycardia.

AERs were noted in an 8 week controlled prospective weight loss study of 72 mg/day ephedrine and 240 mg/day caffeine. 13 Boozer et al noted systolic pressure (4mm Hg) and heart rate (7 bpm) were higher in the ephedra group. One of thirty-five subjects left the study early due to elevated blood pressure and four due to palpitations with (1) or without (3) chest pain. Four additional subjects left the study after week 2 due to increased blood pressure, palpitations or extreme irritability. None left the study in the placebo group because of side effects. In a later 6-month study, Boozer14 found treated patients had increases in heart rate (4 bpm), blood pressure (3-5 mm Hg), dry mouth, insomnia, and heartburn.

An important recent review of the relative safety of ephedra products analyzed the number of adverse reactions adjudicated by poison control centers in the US in 2001 to be attributable to several commonly used herbal products. They found that products containing ephedra alone or combined with other herbs or substances accounted for 64% of all adverse reactions, yet these products represented only 0.82% of herbal sales. The relative risks for adverse reactions among ephedra users were 100-fold greater than the risk among users of other herbal products. 15

A comprehensive literature review of 59 articles that corresponded to 52 controlled clinical trials of ephedrine or herbal ephedra for weight loss or athletic performance found that short term use was associated with approximately 2 pounds weight loss per month compared with placebo. There was a modest effect on very short-term athletic performance. However, there was a two to three times increase in the risk of nausea, vomiting, psychiatric symptoms, autonomic hyperactivity, and palpitations. The number of individuals studied were insufficient to evaluate events with a risk of less than 1.0 per thousand. 16

V. Supporting information

Supporting information about the potential harm of catecholamines and sympathomimetic agents can be found in multiple sources. For example, plasma norepinephrine concentration is independently related to the subsequent risk of mortality. 17 Patients who have sustained ventricular arrhythmias have a selective increase in cardiac sympathetic activity. 18,19 In addition, use of sympathomimetic drugs leads to increased risk of hospitalization for arrhythmias in patients with congestive heart failure. 20 Plasma norepinephrine predicts survival and cardiovascular events in patients with end-stage renal disease. 21 Large stores of noradrenaline in the heart have been related to sudden death. 22

VI. What can account for the apparent unpredictable sporadic events?

The following can explain the above individual reactions to recommended doses of ephedra/caffeine compounds:

1) Variable absorption occurs, so that the amount of drug in the body can vary from one person to the next.

2) Variability in active drug content of botanical, as shown by Gurley et al. 2

3) Presence or absence of underlying disease or drugs. It is possible that patients with pre-existing conditions such as coronary disease or high blood pressure, or who are taking other drugs that may interact with the ephedra/caffeine compounds, are at increased risk for an adverse response.

4) Variability in electrolytes, particularly potassium that can predispose to the development of arrhythmias.

5) Herbal products may contain undeclared pharmaceuticals or heavy metals.

6) Genetic influences. There exist some patients with genetic changes in the autonomic nervous system that make them susceptible to large outpouring of catecholamines which could put them at risk of developing an arrhythmia, heart attack or stroke. 23,24 Also, some patients have inherited electrical abnormalities that do not become manifest until triggered by an external source like a drug. 25 This drug could have totally benign actions in all other individuals without the inherited abnormality.

VII. Ephedra/Caffeine and Exercise

Many ephedra products are marketed for sports nutrition or for weight loss. The directions for use suggest that they should be taken before exercise. During exercise, the oxygen requirements of the heart increase dramatically. If the oxygen supply falls behind the demands of the heart, such a response can trigger abnormal heart rhythms. Oxygen consumption of the heart is directly related to wall stress and heart rate, both of which increase during exercise. The effects of the ephedra/caffeine drugs exacerbate these responses. Serious arrhythmias can develop because of this constellation of events. As physicians, we know that humans are biologic organisms that are imperfect. Humans do not run with absolute precision like a Swiss watch. Slight variations in blood pressure, heart rate, and conduction of the heart's impulse can make a difference between having an arrhythmia that produces sudden death and not having one. These responses are often unpredictable. Numerous sport organizations, including the NCAA, NFL, and International Olympic Committee, prohibit the use of ephedra-containing products. 15

VIII. RECOMMENDATIONS:

Because of our inability to predict who might have an adverse response to these drugs, because of their minimal (if any) therapeutic effect and because of the potential for major adverse responses, I would recommend the following:

1) Recognize that ephedra and ephedrine are drugs, not dietary supplements

2) Recognize that they are capable of provoking harm, including ventricular fibrillation and sudden death

3) Eliminate over-the-counter use based on minor proven benefit and potential for major harm

4) Regulate their use by applying FDA criteria to distribution of ephedra/caffeine compounds as is done for all other drugs

Respectfully submitted,

Douglas P. Zipes, MD
Distinguished Professor of Medicine,
Pharmacology and Toxicology, Emeritus
Director of the Krannert Institute of Cardiology
And Division of Cardiology
Indiana University School of Medicine

References:

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3. Adverse Event Reporting for Dietary Supplements: An Inadequate Safety Valve. Washington, DC: Office of Inspector General, April 2001. (report #OEI-01-00-00-180).

4. Schwartz PJ, Zipes DP. Autonomic Modulation of Cardiac Arrhythmias. In: Cardiac Electrophysiology. From Cell to Bedside. Edition 3. Ed. Zipes DP, Jalife J, W.B. Saunders, Orlando. pp 300-314, 2000.

5. Zipes DP, Wellens HJJ. Sudden Cardiac Death. Circulation. 1998;98:2334-2351.

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