Outrage: Do Not Use Ephedra

This Is a Dangerous Substance and Should Be Taken off the Market

The following are excerpts from a letter sent in September to Health and Human Services (HHS) Secretary Tommy Thompson by Dr. Sidney Wolfe, Health Letter Editor.

The Public Citizen Health Research Group, representing 135,000 members, petitions the Food and Drug Administration (FDA) to ban the production and sale of dietary supplements containing ephedrine alkaloids. These dietary supplements include, but are not limited to, those containing ephedra, ephedra extract, and ma-huang. The grounds for FDA action are that these products present "a significant or unreasonable risk of illness or injury under conditions of use suggested or recommended in the labeling" or, if the label is not specific, "under ordinary conditions of use." Therefore, under 21 USC 331(a) and 342 (f) HHS must declare these products adulterated and issue an immediate ban on their sale and production.

You are known to be extremely concerned about food safety and these dangerous   "food supplements" pose a clear threat to the safety of the food supply in this country for those who use them. Among the frequent targets of these ephedrine-containing products are young people for whom they are being promoted as athletic performance enhancing.   Due to the gravity of the situation, the Canadian equivalent of the Department of Health and Human Services, Health Canada, recently issued a public advisory in June 2001 "warning consumers not to use products containing the herb Ephedra."  Health Canada based its decision to release the advisory, in part, on the United States' FDA adverse event reports. We urge you to immediately issue a similar advisory warning Americans not to use ephedra-containing dietary supplement products while you review our petition for the ban requested above.

We have obtained an internal FDA analysis of recent adverse event reports to FDA's own database that demonstrates that the ephedrine alkaloids are the most lethal and otherwise dangerous dietary supplements. We also obtained an FDA analysis of data collected by the American Association of Poison Control Centers (AAPCC) which shows that there was a sharp increase from 1997 through 1999 in the number of adverse event reports for these highly pharmacologically active and dangerous drugs masquerading as "dietary supplements."

FDA Analysis of FDA Adverse Event Reports

The recently updated review of FDA's Center for Food Safety and Applied Nutrition's (CFSAN) Special Nutritionals Adverse Event Monitoring System (SN/AEMS),   including  data collected from January 1993 until February 2001, shows that ephedrine alkaloid dietary supplements are associated with  more reports of deaths, myocardial infarctions, cardiac arrhythmias, hypertension, stroke and seizure events than all other dietary supplements combined. According to the FDA analysis, during this interval there were:

• 3,308 adverse events for all dietary supplements, 1,398 of these (42 percent) for the ephedrine alkaloids (EA);
• 137 reports of death, 81 deaths (59 percent) associated with EA;
• 38 reports of myocardial infarction/heart attack, 32 reports (84 percent) associated with EA;
• 98 reports of cardiac arrhythmias, 62 (63 percent) associated with EA;
• 144 reports of hypertension, 91 (63 percent) associated with EA;
• 85 reports of stroke, 69   (81 percent) associated with EA; and
• 121 reports of seizure, 70 (58 percent) associated with EA.

Two earlier FDA-commissioned reviews of a much smaller number of adverse events reported to the FDA involving the use of ephedrine alkaloids (did not include data from 2000 and 2001) confirmed the cardiac toxicity of these chemicals. The first study found that 47 percent of cases involved the cardiovascular system (17 cases of hypertension, 13 with palpitations or fast heartbeat, 10 strokes). There were also 7 reports of seizures. The second study, by our co-petitioner Dr. Ray Woosley of the University of Arizona, found that of the 104 reports in which causation by ephedrine alkaloids was very likely, there were 10 cases of sudden death, 9 cardiac arrhythmias, another 23 possible arrhythmic events, 3 heart attacks, 10 cases of chest pain and 15 severe strokes.

FDA Analysis of AAPCC Data

The second source of data about ephedrine alkaloids is a recent FDA analysis of data collected by the American Association of Poison Control Centers (AAPCC), which clearly shows that the number of serious adverse events associated with ephedrine alkaloid dietary supplements is on the rise. The total number of adverse events related to EA increased from 211 in 1997 to 407 in 1999, an increase of 196 reports, almost a doubling from the number of reports in 1997.

Between 1997 and 1999, AAPCC reports of central nervous system adverse events with ephedrine alkaloid dietary supplements increased 19 fold from 11 to 211. Cardiovascular adverse events increased 2.4 fold from 85 to 204, while gastrointestinal adverse events doubled from 70 to 140.

Underreporting Flaws Result in Fewer Adverse Events

The seriousness of the under-reporting to the FDA database is demonstrated by the fact that there were a total of 1,398 adverse event reports with ephedrine alkaloid dietary supplements in the FDA database during an eight year period (1993-early 2001), but there were 876 ephedrine alkaloid dietary supplement adverse event reports to the AAPPC database in just three years.   Furthermore, the Texas Department of Health reported approximately 500 adverse events in the period between December 1993 and September 1995. The fact that in under two years a single state could collect over a third as many ephedra adverse event reports as SN/AEMS has gathered between January 1993 and February 2001 speaks to the pitiful inadequacy of the current FDA system. Furthermore, dietary supplement labeling does not include instructions on how to contact either the FDA or the AAPCC which increases the likelihood of underreporting of adverse events. When both of these limited monitoring systems indicate that a product is causing hundreds of adverse events, thousands of consumers are likely being affected.

Cardiovascular Complications of Ephedrine Alkaloids Use

Randy Sasich, M.D., the son of our colleague Larry Sasich, Pharm D., MPH, was in an internal medicine residency at Barnes-Jewish, the main teaching hospital of Washington University in St. Louis. Within just a seven-month period, he took care of two patients admitted to the coronary care unit because an ephedrine alkaloid dietary supplement (Metabolife) had induced life-threatening cardiac arrhythmias. He is aware of a third patient, also discussed below, who used Metabolife and experienced an arrhythmia but was not hospitalized:  

Case 1-April 1999. This patient, a female in her late 50s, presented at the emergency room with a dangerously rapid rate of contractions of one of the large chambers of the heart, or ventricles (ventricular tachycardia or V-tach), after using an ephedrine alkaloid dietary supplement for weight control.  She was admitted to the coronary care unit for observation.  She was subsequently discharged.

Case 2-April 1999. This patient, a female in her late 30s, suffered a heart attack (acute anterior myocardial infarct) and cardiac arrest while using an ephedrine alkaloid dietary supplement for weight control. She was a smoker but had no evidence of previous atherosclerotic disease of any significance. She suffered brain damage due to a lack of circulation. 

Case 3-October 1999. A female nurse, age unknown, experienced a rapid heart rate while using an ephedrine alkaloid dietary supplement. The rapid rate was documented by her colleagues using an electrocardiogram (ECG or EKG).  She was observed until her rapid rate resolved.           

These three cases of cardiac injury from ephedrine alkaloid dietary supplements in one hospital in only seven months are further indication that ephedrine alkaloid toxicity is a much more common problem than the FDA and AAPCC data   indicate.

The AAPCC data show 416 ephedrine alkaloid dietary supplement related cardiovascular adverse events reported between 1997 and 1999. According to the SN/AEMS data, the most common manifestations of injury were hypertension, stroke, arrhythmia, chest pain, and palpitations.

The chart on this page shows the close chemical structures of PPA, ephedrine and amphetamine. Notice that PPA is identical to ephedrine except for the absence of a methyl (CH3) group. In fact, the body metabolizes a small portion of ephedrine to PPA which is also called norephedrine (nor meaning no methyl group).

Central Nervous System Complications of Ephedrine Alkaloid Use

The AAPCC data report at least 364 neurologic adverse events associated with the use of ephedrine alkaloids in the period between 1997 and 1999. Compared to all other dietary supplements combined, ephedrine alkaloid dietary supplements were responsible for the majority of reports of seizures, personality disorders, sleep disturbances, and headaches in the FDA database (SN/AEMS). The literature also describes cases of agitation, hallucination, seizures, psychoses, and mania. As with the arrhythmia reports described above, all psychiatric manifestations resolved after the offending agent was removed.

Some women reported continued use of ephedra-containing products despite adverse effects due to withdrawal symptoms such as fatigue and weight gain. Furthermore, 7 out of   36 users described frank ephedrine dependence. The sale of ephedrine alkaloid dietary supplements for the indications of weight loss and energy boosting almost guarantees a pattern of abuse. Since many consumers of dietary supplements consider them to be natural, and hence safe, a certain element of informed consent is lost when users are not properly educated about the likelihood of developing chemical dependence. This possibility is of particular concern in light of the increased risk of cardiovascular and central nervous system injury described above.

Conclusions

The wide range of adverse events associated with the consumption of ephedrine alkaloids demonstrates a significant and unreasonable risk of illness and injury. Especially because these risks are not balanced by any long-term benefits, it is imperative that you act quickly and decisively to prevent future death and injury. This problem is exacerbated by the underreporting of ephedrine alkaloid dietary supplement use to physicians by patients, and by health care professionals to national data collection authorities. The April 2001 report of the Department of Health and Human Services Inspector General revealed that voluntary data collection methods currently available to the FDA are woefully inadequate, and fail to account for 99 percent of all adverse events associated with dietary supplements. The problem of underreporting is multifaceted and is beyond the scope of this petition. Even with the limited data available via the SN/AEMS, AAPCC, and the medical literature, it is clear that ephedrine alkaloid dietary supplements present an unreasonable risk of illness and injury to American consumers. It is your responsibility to act upon our recommendation to remove ephedrine alkaloid dietary supplements from the market. Failure to do so will surely result in increased death and injury due to an unsafe product that has no proven benefit to consumers. 

We expect a rapid response to this urgent petition. From the perspective of defending the public health, you must be willing to take on this drug (ephedra)-pushing part of the dietary supplement industry.

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Consumers can report adverse experiences with prescription drugs, non- prescription drugs, medical devices, and dietary supplements to the Food and Drug Administration's Office of Emergency Operations by telephone at 301-443-1240 or over the Internet at   www.fda.gov/medwatch/report/consumer/consumer.htm.