 |
|
|
The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.
To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.
AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.
We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.
Carolyn M. Clancy, M.D.
Director
Agency for Healthcare Research and Quality
Jean Slutsky, P.A., M.S.P.H.
Acting Director, Center for Practice and Technology Assessment
Agency for Healthcare Research and Quality
The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service.
We would like to thank Dr. Lori Love and Ms. Constance J. Hardy of the Food and Drug Administration for providing us with adverse event reports related to ephedra. We thank Dr. Catherine MacLean, a rheumatologist, and Dr. Barbara Vickrey, a neurologist, for providing advice on cases related to their fields. We thank Drs. Karen Miotto, a psychiatrist, and Martin Iguchi, a psychologist, for review of psychiatric case reports. We thank Ms. Birgit Danila, MA, for translation of Danish studies.
Objectives. To assess the efficacy of herbal ephedra-containing dietary supplements and ephedrine on weight loss and athletic performance, through comprehensive literature review and synthesis of evidence. We also assessed safety of these products through review of adverse events reported in clinical trials, published case reports of adverse events, reports on file with the U.S. Food and Drug Administration (FDA), and a file of reports kept by a manufacturer of ephedra products, Metabolife.
Search Strategy. We searched for studies of herbal ephedra and ephedrine using the following electronic databases: Medline, EmBase, BIOSIS, Allied & Complementary Medicine Database (AMED), MANTIS, the Cochrane Controlled Clinical Trials Register Database, International Pharmaceutical Abstracts, Pascal, and SciSearch. We were able to obtain unpublished studies by posting notices in relevant journals and through contacts on our Technical Expert Panel. The FDA provided us with copies of over 1,000 adverse event reports (AERs) related to herbal ephedra and 125 adverse event reports related to ephedrine. The Metabolife files contained 18,502 cases.
Selection Criteria. Only studies of weight loss that were controlled trials of human subjects with treatment of at least eight weeks duration were accepted to assess efficacy. For assessment of athletic performance, only controlled trials of human subjects were accepted, but no minimum follow-up was specified. Reports of adverse events from controlled trials were included regardless of treatment duration. We reviewed all available reports of death, myocardial infarction (heart attack), cerebral vascular accident (stroke), seizure, and serious psychiatric illness reported to the FDA prior to September 30, 2001 and contained in their ephedra or ephedrine files, and all case reports identified in our literature search.
Data Collection and Analysis. We found 59 articles that corresponded to 52 controlled clinical trials of ephedrine or herbal ephedra for weight loss or athletic performance. Forty-four were controlled trials assessing ephedra or ephedrine for weight loss. Of these, 18 were excluded from pooled analysis because they had treatment durations of less than eight weeks. Thirteen articles corresponding to six trials were excluded for a variety of reasons. For the outcome of weight loss the effects of ephedra/ephedrine were examined in six different types of comparisons: (1) ephedrine versus placebo; (2) ephedrine plus caffeine versus placebo; (3) ephedrine plus caffeine versus ephedrine; (4) ephedrine versus other active treatment; (5) ephedra versus placebo; and (6) ephedra plus herbs containing caffeine versus placebo. Only four placebo-controlled trials assessed the combination of ephedra plus herbs containing caffeine, and only one trial assessed ephedra without herbs containing caffeine. Because of their small number and heterogeneity, eight athletic performance trials were compared and contrasted using only a narrative review and were not synthesized statistically. We also conducted a pooled meta-analysis on those adverse event symptoms that occurred frequently in the controlled trials.
In reviewing the individual adverse event reports, we searched for documentation that an adverse event had occurred, documentation that the subject had consumed ephedra within 24 hours prior to the adverse event, or a toxicological examination revealing ephedrine or one of its associated products in the blood or urine. We also sought evidence that an adequate investigation had assessed and excluded other potential causes. Cases that met all these criteria were labeled “sentinel events.” Cases that met the first two criteria but had other possible causes of the event were labeled “possible sentinel events.” Classification as a sentinel event does not imply a proven cause and effect relationship. We used clinical judgment of expert clinicians to assess whether other causes had been adequately evaluated and excluded.
Main Results. Weight Loss. Short-term use of ephedrine, ephedrine plus caffeine, or dietary supplements containing ephedra with or without herbs containing caffeine is associated with a statistically significant increase in short-term weight loss (compared to placebo). The addition of caffeine to ephedrine is associated with a statistically significant modest increase in short-term weight loss. The observed effects on weight loss of ephedrine plus caffeine and ephedra-containing dietary supplements with or without herbs containing caffeine are approximately equivalent: a weight loss approximately two pounds per month greater than that with placebo, for up to four to six months. No studies have assessed the long-term effects of ephedrine or ephedra-containing dietary supplements on weight loss; the longest published treatment duration was six months.
Athletic Performance. The effect of herbal ephedra-containing dietary supplements on athletic performance has not been assessed. The few studies that assess the effect of ephedrine on athletic performance have included only small samples of fit individuals (young male military recruits) and have assessed its effect only on very short-term immediate performance. These data support a modest effect of ephedrine plus caffeine on very short-term athletic performance. One study reported the addition of caffeine to ephedrine is necessary to produce an effect on athletic performance. No studies have assessed the sustained use of ephedrine on performance over time.
Safety Issues. There is sufficient evidence from controlled trials to conclude that the use of ephedrine and/ or the use of ephedra-containing herbal supplements or ephedrine plus caffeine is associated with two to three times the risk of nausea, vomiting, psychiatric symptoms such as anxiety and change in mood, autonomic hyperactivity, and palpitations. The controlled trials studied relatively few people and in aggregate were insufficient to evaluate events with a risk of less than 1.0 per one thousand.
The majority of case reports are insufficiently documented to make an informed judgment about a relationship between the use of ephedrine or ephedra-containing dietary supplements and the adverse event in question. Prior ephedra consumption was associated with two deaths, three myocardial infarctions, nine cerebrovascular accidents, three seizures, and five psychiatric cases as sentinel events. Prior consumption of ephedrine was associated with three deaths, two myocardial infarctions, two cerebrovascular accidents, one seizure, and three psychiatric cases as sentinel events. We identified 43 additional cases as possible sentinel events with prior ephedra consumption and seven additional cases as possible sentinel events with prior ephedrine consumption. About half the sentinel events occurred in persons aged 30 years or younger.
Conclusions. Ephedrine, ephedrine plus caffeine, and ephedra-containing dietary supplements with or without herbs containing caffeine all promote modest amounts of weight loss over the short term. There are no data regarding long-term effects on weight loss. Single-dose ephedrine plus caffeine has a modest effect on athletic performance. The available trials do not provide any evidence about ephedrine or ephedra-containing dietary supplements, as they are used by the general population, to enhance athletic performance. Use of ephedra or ephedrine plus caffeine is associated with an increased risk of gastrointestinal, psychiatric, and autonomic symptoms. The adverse event reports contain a sufficient number of cases of death, myocardial infarction, cerebrovascular accident, seizure, or serious psychiatric illness in young adults to warrant a hypothesis-testing study, such as a case-control study, to support or refute the hypothesis that consumption of ephedra or ephedrine may be causally related to these serious adverse events.
At the direction of the funding agencies (National Institute of Health Office of Dietary Supplements (ODS), the National Center for Complementary and Alternative Medicine (NCCAM), and the Agency for Healthcare Research and Quality (AHRQ)), and in consultation with our Technical Expert Panel, we addressed research questions regarding the efficacy of herbal ephedra and ephedrine for weight loss and athletic performance through a comprehensive literature review and synthesis of evidence. We assessed the safety of these products through review of clinical trials. Meta-analysis was performed where appropriate. In addition, we reviewed herbal ephedra- and ephedrine-related adverse events reports on file with the U.S. Food and Drug Administration (FDA), published case reports, and reports to a manufacturer of ephedra-containing products. It is expected that the results of this review will be used to direct further research.
The following questions were provided to us by the funding agencies and guided this evidence report.
What is the evidence for efficacy of ephedra-containing dietary supplement products in weight loss, over a sustained period of time?
Can efficacy for weight loss be attributed to ephedra alone, or ephedra in combination with other ingredients (e.g., caffeine)?
Does ephedra have additive effects with other agents?
What dosage levels of ephedra are necessary to achieve weight loss?
What is the evidence for efficacy of ephedra-containing dietary supplement products in terms of energy enhancement and enhancement of athletic performance, over a sustained period of time?
Can efficacy for energy enhancement and enhancement of athletic performance be attributed to ephedra alone, or ephedra in combination with other ingredients (e.g., caffeine) that produce energy enhancement and/or enhancement of athletic performance?
Does ephedra have additive effects with other agents?
What dosage levels of ephedra are necessary to achieve energy enhancement and enhancement of athletic performance?
Does use of ephedra-containing dietary supplement products over a sustained period of time increase the risk of cardiovascular disease (CVD) or other serious and life-threatening events in specific populations?
What populations are at risk of CVD and other life-threatening events through use of ephedra over a sustained period of time?
Can the risk for adverse events in these populations be attributed to ephedra alone, or in combination with other ingredients (e.g., caffeine)?
Does ephedra have additive effects with other agents?
What dosage levels of ephedra produce risk of CVD or other life-threatening events?
Do ephedra-containing dietary supplement products alter physiologic markers of cardiovascular function?
What are the metabolic actions of ephedra, so as to explain its beneficial and adverse effects?
In addition to answering these 15 questions about ephedra-containing dietary supplement products, we were also asked to synthesize the available information on the same questions for the purified alkaloid, ephedrine.
After searching published reports, journal articles, conference presentations, and various sources of unpublished studies, we identified 52 controlled clinical trials of ephedrine or herbal ephedra for weight loss or athletic performance in humans. The Food and Drug Administration provided us with copies of over 1,000 adverse event reports (AERs) related to herbal ephedra and 125 AERs related to ephedrine. These reports often included interviews with patients and/ or family members, extensive medical records, and copies of product labels. We identified 65 case reports in the literature and received a disk of 15,951 reports containing 18,502 cases from Metabolife, a manufacturer of ephedra products.
Efficacy. Data for the efficacy analysis were abstracted from reports of controlled trials onto a specially designed form containing questions about the study design, the number of patients and comorbidities, dosage, adverse events, the types of outcome measures, and the time from intervention until outcome measurement. We selected the variables for abstraction with input from the project's technical experts. Two physicians, working independently, each extracted data from the same reports and resolved disagreements by consensus.
In selecting studies for the meta-analysis of weight loss efficacy, we considered only those trials of at least eight weeks treatment duration. Our technical expert panel judged that shorter treatment durations were insufficient to assess weight loss. In selecting studies on athletic performance, we found that these studies varied widely with respect to intervention. Because of this heterogeneity, we compared and contrasted these studies in a narrative review, rather than performing a statistical synthesis.
The effects of ephedra/ephedrine on weight loss were examined in six different types of comparisons: (1) ephedrine versus placebo; (2) ephedrine plus caffeine versus placebo; (3) ephedrine plus caffeine versus ephedrine; (4) ephedrine versus other active treatment; (5) ephedra versus placebo; and (6) ephedra plus herbs containing caffeine versus placebo. The last comparison subgroup contained only a single trial; thus, effect sizes were estimated only for the first five. The effect size was calculated by dividing the outcome of a study (e.g., difference in weight loss per month between the two groups) by its standard deviation, which produces a unitless measure that is useful when comparing studies that assess outcomes (such as weight) that are similar but are measured differently (e.g., weight loss in pounds versus change in body mass index). Effect sizes were pooled separately for each of the five comparison subgroups. In addition, we used meta-regression to conduct a cross-subgroup synthesis on the effect sizes of the subgroups with a placebo comparison: ephedrine versus placebo; ephedrine plus caffeine versus placebo; and ephedra plus herbs containing caffeine versus placebo.
Safety. We reviewed each report of a controlled trial (regardless of treatment duration) for data on adverse events. Adverse events were recorded onto a spreadsheet that identified each study arm, the description of the adverse event as listed in the original article, and the numbers of subjects and adverse events in each arm. We then compared event rates in the ephedra or ephedrine groups to those in the placebo groups. We conducted a meta-analysis on those adverse event symptoms for which appreciable numbers of events were noted in the controlled trials.
Adverse event reports compiled by the Food and Drug Administration (FDA) concerning ephedra or ephedrine were also reviewed by our physician reviewers. Within the time and resource constraints of this report, we reviewed all available reports of death, myocardial infarction (heart attack), cerebral vascular accident (stroke), seizure, and serious psychiatric illness filed prior to September 30, 2001. We also reviewed published case reports as well as event reports filed with Metabolife, a manufacturer of ephedra-containing products. After screening, all case reports were subjected to a review.
Based on input from our technical expert panel and the literature on methods to assess adverse event reports, we identified three important criteria for inclusion of such reports:
Documentation of an adverse event that met our selection criteria.
Documentation that the person having the adverse event took an ephedra-containing supplement or ephedrine within 24 hours prior to the event (for cases of death, myocardial infarction, stroke, or seizure).
Documentation that alternative explanations for the adverse event were investigated and were excluded with reasonable certainty.
We classified cases that met all three of these criteria as “sentinel events.” Cases in which the event might have had other possible causes but the pharmacology of ephedrine could have contributed were classified as “possible sentinel events.” Cases of death, myocardial infarction, cerebral vascular accident, and seizure were reviewed by internists, with additional review (as indicated) by a cardiologist, neurologist, or rheumatologist. Psychiatric cases were reviewed by a psychiatrist specializing in addictions and a psychologist with expertise in substance abuse. The criterion for use within 24 hours was not required for psychiatric cases.
Efficacy for Weight Loss. We identified 44 controlled trials that assessed use of ephedra or ephedrine used for weight loss. Of these, 18 were excluded from pooled analysis because they had a treatment duration of less than eight weeks. Six additional trials were excluded for a variety of other reasons. Of the remaining 20 trials included in the meta-analysis, only five tested herbal ephedra-containing products. Together, these 20 trials assessed 678 persons who consumed either ephedra or ephedrine. The majority of studies of both ephedra and ephedrine are plagued by methodological problems (particularly, high attrition rates) that might contribute to bias. These methodological limitations must be considered when interpreting any conclusions regarding the efficacy of these products. Nevertheless, the evidence we identified and assessed supports an association between short-term use of ephedrine, ephedrine plus caffeine, or dietary supplements that contain ephedra with or without herbs containing caffeine and a statistically significant increase in short-term weight loss (compared to placebo). Adding caffeine to ephedrine modestly increases the amount of weight loss. There is no evidence that the effect of ephedra-containing dietary supplements with herbs containing caffeine differs from that of ephedrine plus caffeine: Both result in weight loss that is approximately two pounds per month greater than that with placebo, for up to four to six months. No studies have assessed the long-term effects of ephedra-containing dietary supplements or ephedrine on weight loss; the longest duration of treatment in a published study was six months.
Efficacy for Physical Performance Enhancement. The effect of ephedrine on athletic performance was assessed in seven studies. No studies have assessed the effect of herbal ephedra-containing dietary supplements on athletic performance. The few studies that assessed the effect of ephedrine on athletic performance have, in general, included only small samples of fit individuals (young male military recruits) and have assessed the effects only on very short-term immediate performance. Thus, these studies did not assess ephedrine as it is used in the general population. The data support a modest effect of ephedrine plus caffeine on very short-term athletic performance. No studies have assessed the sustained use of ephedrine on performance over time. The only study that assessed the additive effects of these agents reported that ephedrine must be supplemented with caffeine to affect athletic performance.
Safety Issues. The data on adverse events were drawn from clinical trials and case reports published in the literature, submitted to the FDA, and reported to Metabolife, a manufacturer of ephedra-containing supplement products. The strongest evidence for causality should come from clinical trials; however, in most circumstances, such trials do not enroll sufficient numbers of patients to adequately assess the possibility of rare outcomes. Such was the case with our review of ephedrine and ephedra-containing dietary supplements. Even in aggregate, the clinical trials enrolled only enough patients to detect a serious adverse event rate of at least 1.0 per 1,000. For rare outcomes, we reviewed case reports, but a causal relationship between ephedra or ephedrine use and these events cannot be assumed or proven.
Evidence from controlled trials was sufficient to conclude that the use of ephedrine and/or the use of ephedra-containing dietary supplements or ephedrine plus caffeine is associated with two to three times the risk of nausea, vomiting, psychiatric symptoms such as anxiety and change in mood, autonomic hyperactivity, and palpitations.
The majority of case reports are insufficiently documented to make an informed judgment about a relationship between the use of ephedrine or ephedra-containing dietary supplements and the adverse event in question. For prior consumption of ephedra-containing products, we identified two deaths, three myocardial infarctions, nine cerebrovascular accidents, three seizures, and five psychiatric cases as sentinel events; for prior consumption of ephedrine, we identified three deaths, two myocardial infarctions, two cerebrovascular accidents, one seizure, and three psychiatric cases as sentinel events. We identified 43 additional cases as possible sentinel events with prior ephedra consumption and seven additional cases as possible sentinel events for prior ephedrine consumption. About half the sentinel events occurred in persons aged 30 years or younger. Classification as a sentinel event does not imply a proven cause and effect relationship.
We did not assess the plethora of additional symptoms that have been reported in the published literature and the FDA Medwatch file for ephedra-containing dietary supplements and ephedrine products.
Our analysis of the evidence reveals numerous gaps in the literature regarding the efficacy and safety of ephedra-containing dietary supplements. First, long-term assessments of the effectiveness of herbal ephedra or ephedrine for promoting weight loss are lacking. We identified no study with a treatment duration longer than 6 months. To improve health outcomes and reduce the risk of morbidities associated with being overweight, sufficient weight loss (5 to 10 percent of body weight) and long-term weight maintenance are necessary. Therefore, the benefit of ephedrine or herbal ephedra-containing dietary supplements for health outcomes is unknown.
Evidence regarding the effect of herbal ephedra or ephedrine on physical performance that reflects its use in the general population (repeated or long-term use by a representative sample) is also needed.
In order to assess a causal relationship between ephedra or ephedrine consumption and serious adverse events, a hypothesis-testing study is needed. Continued analysis of case reports cannot substitute for a properly designed study to assess causality. A case-control study would probably be the study design of choice.
This evidence report details the methodology, results, and conclusions of a comprehensive literature review and synthesis of evidence on the efficacy and safety of ephedra and ephedrine, either alone or in combination with other substances, to promote weight loss or to enhance athletic performance. Meta-analysis was performed where appropriate.
| Name | Expertise | Institution |
|---|---|---|
| Awang, Dennis V. (PhD) | Natural product chemist | MediPlant Consulting Services |
| Benowitz, Neal (MD) | Psychiatry, pharmacology | UCSF |
| Farnsworth, Norman (PhD) | Pharmacognosy | University of Illinois at Chicago |
| Fielding, Roger (PhD) | Exercise | Boston University |
| Goldberger, Jeffrey (MD) | Cardiology | Northwestern Univ. Medical School |
| Heber, David (MD, PhD) | Weight loss | UCLA School of Medicine |
| Ko, Richard (PharmD, PhD) | Food and drug scientist | California Department of Health Services |
| Leung, Albert (PhD) | Pharmacognosy | AYSL Inc. |
| Mills, Simon (FNIMN) | Herbalist | Center for Complementary Medicine, Exeter, UK |
| Nestmann, Earle (PhD) | Toxicology | CANTOX Health Sciences, Canada |
In searching for evidence of efficacy and safety, we were directed to assess studies using both the isolated alkaloid, ephedrine, and whole herb or extracts of the herb ephedra.
A 2000 survey by manufacturers of ephedra-containing supplement products estimated that three billion servings of these products were consumed in the prior year; these findings were revealed during testimony at a Public Meeting on the Safety of Dietary Supplements Containing Ephedrine Alkaloids held August 8, 2000. According to Michael McGuffin, an industry spokesperson, this figure represented a 65 percent increase in sales volume over the previous five years and would correspond to approximately $6.8 billion in total sales.1 Use of ephedrine alkaloid-containing products to promote weight loss or enhance athletic performance has garnered a great deal of media attention over the last year. This attention is due in part to a number of well-publicized adverse events reportedly associated with the use of ephedra or ephedrine alkaloid-containing products.2–7
Herbal ephedra has been used in China to treat respiratory conditions for over 5,000 years;8 however, the herb is not used for weight loss or physical performance enhancement in eastern medicine. Its active alkaloid, ephedrine, was first used in western medicine as an asthma treatment in the 1930s. Since then, ephedrine and other sympathomimetic alkaloids have been used in many over-the-counter (OTC) decongestants and cold medicines. It was not until the early 1990s that herbal ephedra and other products containing ephedrine began to be promoted as weight loss aids in the United States.
Federal regulation of dietary supplement products differs considerably from that of products that are deemed drugs. Dietary supplement products, including those that contain herbal ephedra (as distinct from the purified alkaloid ephedrine), are regulated by the Dietary Supplement Health and Education Act (DSHEA) of 1994. Under DSHEA, new products that contain only supplement ingredients that were sold in the United States before October 15, 1994 do not require FDA review before they are marketed, because they are presumed to be safe based on their history of use by humans. Manufacturers of a dietary supplement that contains a new ingredient not sold as a dietary supplement before 1994 must notify FDA of their intent to market that product and must demonstrate reasonable evidence for the safety of the product to humans. In turn, FDA can bar the new ingredient from the marketplace for safety reasons. However, manufacturers are not required to perform clinical or other studies to establish the safety of their products before marketing. Once a dietary supplement is marketed, FDA can restrict its use or order its removal from the marketplace only if it can prove that the product is not safe. In contrast to the rules for dietary supplements, before a drug product can be marketed, the manufacturer must obtain FDA approval by providing convincing evidence that it is both safe and effective.
On October 11, 1995, in response to a growing number of adverse event reports submitted to the FDA about ephedra-containing products (more than 300 at the time), the FDA convened an open meeting of the Special Working Group on Food Products Containing Ephedrine Alkaloids (a working group of the Food Advisory Committee) to assess the potential public health problems associated with dietary supplements and other food products that contained botanical sources of ephedrine alkaloids (that is, ephedra). The reported adverse events involved primarily the cardiovascular and central nervous systems. Most events occurred in young to middle-aged women, often those using the products for weight loss or to increase energy. Based on the reports and the evidence they heard, the working group found sufficient evidence to suggest that adverse effects were associated with the use of ephedrine alkaloids, that safe levels should be established and that warning labels should appear on products containing the ephedrine alkaloids, regardless of their source.
In August 1996, the FDA convened a meeting of its Food Advisory Committee to continue the discussion of the safety of ephedrine alkaloid-containing foods and supplements. By that time, the number of adverse events reported to the FDA had doubled from the year before to over 600. As a result of that meeting, some members recommended removal of dietary supplements containing ephedra from the market.9 Other members suggested that the FDA develop rules on use that would help reduce the risk of adverse events. In 1997, the FDA published a proposed rule on use of dietary supplements containing ephedrine alkaloids. It proposed a dose limit of 8 mg ephedrine alkaloid per serving, a daily limit of 24 mg, a duration limit of 7 days, and various label warnings. After the rule was published in the Federal Register, the FDA received a large number of comments from consumers, physicians, scientists, and supplement manufacturers. In response, the General Accounting Office (GAO) audited the methods used by the FDA to develop the proposed rules. In July 1999, the GAO reported that the FDA had insufficient evidence to support dosage and duration limits. As a result, in early 2000, the FDA withdrew a large part of the 1997 proposal.
However, the controversy over ephedra has continued. From 2000 to 2002, more than 100 people sued makers of ephedra products,7 and from 1992 through 2002, more than 1000 health problems were reported to FDA. These reports led a nonprofit consumer group, Public Citizen, to file a lengthy petition in 2001, asking the FDA to ban the production and sale of ephedra products. In the fall of 2001, the National Football League banned the substance following the deaths of several high school and college athletes after alleged use of ephedrine-containing products, and in January 2002, the Canadian government issued a warning against use of ephedra.
On June 14, 2002, the U.S. Department of Health and Human Services proposed an expanded scientific evaluation of ephedra. The agenda for that research will be based on the findings of the current report.
From 1999 through 2002, the prevalence of obesity in the United States increased by 1 percent per year, reaching a level of 19.8 percent among the adult population. This increase represents a 65 percent rise in the prevalence of obesity from 1991 to 2002 (from 12 percent to 19.8 percent), although a precise comparison is difficult because of changing definitions of obesity.10–12 Obesity is currently defined as a body mass index of 30 or greater: BMI is obtained by dividing body weight (in kilograms) by the height (in meters) squared. Overweight individuals are those whose BMI falls between 25 and 29.9. According to that definition, by the year 2000, the majority of Americans (56 percent) were overweight.10 Moreover, according to the 1999 National Health and Nutrition Examination Survey (NHANES), 13 percent of children and adolescents are currently seriously overweight and are displaying increasing rates of obesity-related chronic diseases such as Type II diabetes, not previously seen in children.13 Attempts to meet the body weight goal of the Healthy People 2000 Initiative14 (reducing the prevalence of overweight among adults to less than 20 percent of the population) have failed.
The United States is not alone is facing rising rates of obesity. In Canada, between 1985 and 1998, the overall prevalence of obesity increased in adults from 5.6 percent to 14.8 percent and from 1981 to 1996, it tripled in children.15, 16 The World Health Organization reports that there are more than 300 million obese people in the world, and the rising rate of obesity is no longer solely a problem of industrialized countries, but one that is rapidly appearing in developing countries.17, 18
In addition to Type 2 diabetes, other serious health risks are associated with obesity. Rates and severity of hypertension, dyslipidemia, insulin resistance (Syndrome X), coronary artery disease, stroke, sleep apnea, osteoarthritis, certain cancers, and other conditions increase with increasing weight.19, 20 Further, obesity increases the rate of mortality as well as morbidity, especially mortality associated with heart disease and diabetes.21 Using data from five large prospective cohorts, Allison and colleagues estimated that in 1991, 280,000 deaths were attributable to excess weight.22 Patients with a BMI greater than 30 accounted for more than 80 percent of the obesity-attributable deaths.
The costs of obesity to the health care system are large and growing with the increasing rates of obesity. In 1986, when only 34 million Americans were clinically obese, a conservative estimate of the economic costs related to obesity was $39.3 billion.23 By 1995, one study24 estimated direct cost for obesity at $70 billion, although another study estimated these costs at 25 percent lower.25 The costs of obesity are estimated to be higher than those for either smoking or excessive drinking.26
Intentional weight loss by obese persons leads to reductions in risk factors for disease. A minimum loss of 5 percent to 10 percent of body weight followed by long-term weight maintenance can improve health outcomes.27 Despite this finding, only 42 percent of obese people surveyed by Galuska and colleagues reported that their doctor recommended weight loss.28, 29 Still, much of the population reports that they are actively trying to lose weight: a 2000 survey showed that one third (38 percent) of subjects were actively trying to lose weight and another third (36 percent) were trying to maintain their weight.11 Furthermore, among those who were overweight, 45 percent of subjects were actively trying to lose weight, and 35 percent were trying to maintain their weight. Among those who were obese, 66 percent of subjects were actively trying to lose weight, and 21 percent were trying to maintain their weight.11 In a population-based study of 14,679 U.S. adults in 5 states using the 1998 BRFSS data, seven percent reported using nonprescription weight loss products; 2 percent reported using phenylpropanolamine and one percent reported using ephedra products from 1996 to 1998. More women used ephedra products than men; 1.6 percent of women and 0.4 percent of men reported using weight loss products containing ephedra. Extrapolated nationally, this study estimated that during 1996-1998, 2.5 million Americans used weight loss products containing ephedra. This study also has data to suggest that many individuals are not aware they are taking weight loss products that contain ephedra. Of the 183 respondents in Michigan who responded to the questions about using ephedra and reported that they took “other” nonprescription weight loss products, 33 percent reported using name-brand products that claim to contain both ephedra products and chromium picolinate.30
This estimate of use of ephedra-containing products may be low. Heber and Greenway state that the most widely used herbal products for weight loss contain ephedrine alkaloids.31 Among 230 (61 percent) of 376 adults in the St. Paul/Minneapolis area who reported using an herbal product during the past 12 months, 44 (19 percent) used ephedra. Of these 44, 20 (45 percent) used ephedra for weight loss. Therefore, 5.3 percent of these adults (20 of 376) reported using ephedra for weight loss.32
Stimulants have a long history of use in athletic performance, dating back to the early 1900s.33 Several serious accidents in the late 1960s, including the death of a cyclist using amphetamines, spurred the International Olympic Committee (IOC) to ban stimulants from use during competition. However, this ban was not fully enforceable until a reliable screening test became available in 1972.34 Use of OTC stimulants is regulated somewhat differently than that of stimulants available only by prescription, because OTC stimulants are widely available in products used to treat common conditions such as colds or congestion. Therefore, these compounds are not banned outright, but athletes whose use of these substances exceeds some reporting threshold are subject to censure.34
Use of dietary supplements by athletes is common and somewhat more frequent than that of the general public. In a review of 51 studies, Sobal and Marquart35 found that 56 percent of athletes used one or more supplements. Another study of college athletes reports a 42 percent prevalence of supplement use.36 Supplement use was higher among men than among women, and higher among elite athletes and in particular sports such as body building, weight lifting, and ultramarathon running.35 A survey among elite Australian swimmers supports this finding: 94 percent of them reported using dietary supplements. All participants reported using vitamins and/or minerals, and 61 percent reported using herbal preparations.37 Supplement use is prevalent even among younger athletes: 20 to 25 percent of adolescents are reportedly using supplements. For all athletes, performance enhancement is cited as a common reason for use, and multi-vitamins are the most frequently used dietary supplements.35
OTC stimulants, particularly ephedrine or its related alkaloids, are among the substances most frequently detected on drug screens or reported in surveys. In a series of 1,256 positive drug screens identified by IOC laboratories in 1989, 40 percent involved stimulants. Ephedrine alkaloids accounted for 75 percent of the stimulants reported.38 Evaluation of drug use by student athletes in the most recent National Collegiate Athletic Association (NCAA) survey (2001) showed that ephedrine and amphetamine use increased from 1997 to 2001, at a time when use of many other substances was declining.39 Ephedrine was used by 3.5 percent of responders in 1997, a figure that increased to 3.9 percent by 2001. In a survey of 511 subjects attending a gymnasium, self-reported use of ephedrine exceeded that of anabolic steroids (25 percent versus 18 percent for men; 13 percent versus 3 percent for women).40 The authors asserted that extrapolating these figures to the general public would suggest that 2.8 million people have used ephedrine-containing products to improve athletic performance within the last three years. Further, there may be a subset of committed users of ephedrine products who take high doses for extended periods of time. Gruber and Pope41 reported on a cohort of female weightlifters, 56 percent of whom were using doses of 120 mg ephedrine daily for over one year. Some individuals had been using such doses continuously for over five years, and the majority of these women continued to use ephedrine despite the presence of adverse symptoms.
Ephedra species have a long history of medicinal use, documented in medical treatises from China and India. Some experts have called it the oldest medicinal plant in continuous use:42 A species of ephedra was found in a Neanderthal grave and was presumably used medicinally.43 Use by Dioscorides, the famous Hellenistic herbalist, has been documented, as has use in Europe from the 15th to the 19th centuries.44 Use of ephedrine, the principal alkaloid in ephedra, gained notoriety during modern times when it was learned that the drug was given parenterally to Japanese kamikaze pilots during World War II.45 Over 40 species of ephedra are found throughout Asia, Europe, and the Mediterranean area, as well in North and South America.
Ephedra, or ma huang, is the common name for any one of three species grown medicinally in China and recognized in the Chinese Materia Medica: Ephedra sinica, Ephedra equisentina and Ephedra intermedia. 46
The branches of this small twiggy shrub have been used in the practice of traditional Chinese medicine to treat colds, fevers, and wheezing and as a diaphoretic and diuretic.47 Botanically related species have also been used in traditional Indian and Tibetan medicine for similar indications.48 In the modern discipline of phytomedicine, ephedra has been approved by the German Commission E to treat diseases of the respiratory tract with mild bronchospasm in patients over 6 years of age.49 In addition to the three species mentioned above, others, such as Ephedra distachya or Ephedra gerardiana may be used for preparation of commercial products.49 North American ephedra species, such as Ephedra nevadensis, commonly known as mormon tea, reportedly contain little or no ephedrine.50, 51
The active components of ephedra (about 1.32 percent by weight) are the phenylalanine-derived alkaloids such as (-)-ephedrine, (+)-pseudoephedrine, (-)-norephedrine, and (+)-norpseudoephedrine, which is also called cathine.45, 52 Alkaloid content and composition may vary based on species and growing conditions such as geographic location, altitude, and soil pH.53–56 Ephedra is harvested in the fall, when the alkaloid content is highest.57 Even though the total alkaloid content can vary from 0.5 percent to 2.3 percent, ephedrine accounts for the majority of the alkaloids (up to 90 percent of total), followed by pseudoephedrine (generally up to 27 percent of total).45, 58, 59 One species of ephedra, Ephedra intermedia, has been reported to have reversed ratios of ephedrine to pseudoephedrine, with approximately 30 percent ephedrine and up to 75 percent pseudoephedrine.57, 60 Norephedrine content is generally very low in commercial ephedra species.60 Ratios of the most common alkaloids vary in commercial preparations, but ephedrine and pseudoephedrine account for 90 to 100 percent of the alkaloids measured.61 The relative potency of the alkaloids is discussed below.
Although ephedrine was first isolated from ma huang in 1887, it was not until early in the twentieth century that the pharmacology of ephedrine and its related alkaloids was considered by Western medicine.44, 62–64 Ephedrine is defined as a mixed sympathomimetic agent, which acts indirectly by enhancing the release of norepinephrine from sympathetic neurons and directly by stimulating alpha and beta adrenergic receptors.65 The other, related, alkaloids have similar activities, although they are less potent than ephedrine.62 Thus, the pharmacologic activity of a given ephedra sample depends on its alkaloid composition.
In the cardiovascular system, ephedrine increases heart rate and therefore cardiac output.65, 66 Because of its peripheral vasoconstriction activity, ephedrine increases peripheral resistance and can lead to a sustained rise in blood pressure. As a result, parenteral ephedrine has been used to treat shock and hypotension associated with cesarean section. Elevations in blood pressure appear to be dose dependent in humans.67 However, there appears to be a threshold effect: doses under 50 mg do not necessarily result in increased blood pressure.
In the lung, ephedrine acts via the beta (2) adrenergic receptors to relax bronchial smooth muscle.65, 66 However, ephedrine's use as a bronchodilator (which began in 1924),63 has largely been supplanted by more selective agents for chronic use. Currently, ephedrine is used as a decongestant and for the temporary relief of shortness of breath due to bronchial asthma.
Because of its lipid solubility, ephedrine crosses the blood-brain barrier where it acts as a central nervous system stimulant.65, 66 Immediate effects are attributable to stimulation of dopamine release, but ephedrine also acts on central adrenergic receptors, which increases release of central norepinephrine. This combination of adrenergic and dopaminergic effects leads, in the short term, to improved mood and heightened alertness with decreased fatigue and desire for sleep. Physical activity also increases. Concern exists that because of its chemical similarity to amphetamines, ephedrine may have potential for abuse. Ephedrine has demonstrated reinforcing effects in humans that are similar to those of amphetamines but not as strong.68 At higher doses, the release of norepinephrine causes anxiety, restlessness, and insomnia.
Ephedrine and its alkaloids may promote weight loss via several mechanisms. First, ephedrine may exert an anorexic effect via central effects of norepinephrine on satiety centers in the hypothalamus.69 Second, stimulation of beta (3) receptors in brown fat, via release of catecholamines, leads to increased lipogenesis.70 Third, of the three principal alkaloids of ephedra (ephedrine, pseudoephedrine, and phenylpropanolamine), ephedrine is the most potent thermogenic agent (a substance that increases the portion of ingested calories that are dissipated as heat, at the expense of energy storage).
Ephedrine is readily absorbed from the gastrointestinal tract, with peak concentrations of an oral, immediate-release dose achieved at approximately two to three hours.71–73 It is distributed widely throughout the body, crossing the blood-brain barrier, as mentioned above, as well as the placenta. The half-life of ephedrine in the blood (the time required to reach half the peak concentration) is six hours.73 Metabolism does occur in the liver, but the majority of ephedrine (60–97 percent) is excreted unchanged via the urine.74, 75 The pharmacokinetics of pseudoephedrine and phenylpropanolamine (norephedrine) are similar.73
The disposition of a pharmaceutical preparation of ephedrine (25 mg) in ten healthy volunteers was compared with that of three botanical preparations that contained a roughly equivalent alkaloid dose.76 Among the four products tested, the time to achieve peak concentration ranged from 2.61 to 3.05 hours, and the elimination half-life (time that was required for half of the ingested product to be eliminated) varied from 4.85 to 6.47 hours. None of the botanical preparations tested was found to have statistically different pharmacokinetics from the purified ephedrine. These results are not completely confirmed by a second study, which compared purified ephedrine with a botanical preparation.77 This study found that the absorption of the botanical preparation was slower and took almost twice as long as the pharmaceutical preparation to reach maximal concentration (3.90 versus 1.69 hours). However, maximal concentration of ephedrine was actually higher for the botanical preparation. Elimination half-life was between five and six hours for both preparations.
| Common Name | Botanical Name |
|---|---|
| Cocoa | Theobroma cacao |
| Coffee | Coffea arabica |
| Guarana | Paullinia cupana |
| Kola nut | Cola acuminata |
| Cola vera | |
| Maté leaf | Ilex paraguayensis |
| Tea (black, green, oolong) | Camilla sinensis |
The topic of this report was nominated by the National Institutes of Health (NIH) Office of Dietary Supplements (ODS). The following questions were originally proposed:
What is the evidence for efficacy of ephedra-containing dietary supplement products for weight loss, over a sustained period of time?
Can efficacy for weight loss be attributed to ephedra alone, or ephedra in combination with other ingredients (e.g., caffeine)?
Does ephedra have additive effects with other agents?
What dosage levels of ephedra are necessary to achieve weight loss?
What is the evidence for efficacy of ephedra-containing dietary supplement products in terms of energy enhancement and enhancement of athletic performance, over a sustained period of time?
Can efficacy for energy enhancement and enhancement of athletic performance be attributed to ephedra alone, or ephedra in combination with other ingredients (e.g., caffeine) that produces energy enhancement and/or enhancement of athletic performance?
Does ephedra have additive effects with other agents?
What dosage levels of ephedra are necessary to achieve energy enhancement and enhancement of athletic performance?
Does use of ephedra-containing dietary supplement products over a sustained period of time increase the risk of cardiovascular disease (CVD) or other serious and life-threatening events in specific populations?
What populations are at risk of CVD and other life-threatening events through use of ephedra over a sustained period of time?
Can the risk for adverse events in these populations be attributed to ephedra alone, or in combination with other ingredients (e.g., caffeine)?
Does ephedra have additive effects with other agents?
What dosage levels of ephedra produce risk of CVD or other life-threatening events?
Do ephedra-containing dietary supplement products alter physiologic markers of cardiovascular function?
What are the metabolic actions of ephedra, so as to explain its beneficial and adverse effects?
In addition to the questions related to ephedra-containing dietary supplement products, the sponsor also requested a review of the scientific literature on ephedrine (the purified alkaloid) regarding its efficacy and safety. A brief review of the mechanism of action of ephedra was also requested.
We were also asked about the gaps in knowledge about the effects of ephedra, alone or in combination with other agents, on weight loss, energy enhancement, and enhancement of athletic performance. We were asked to focus on the following categories of potential consumers: children, adolescents, young athletes (male and female), and adults (male and female).
Our expert panel meeting was held at RAND's Arlington, Virginia, office on Wednesday, November 28, 2001. Margaret Coopey, the Task Order Officer, represented AHRQ. Dr. Paul Coates, head of the NIH ODS, also attended. At the meeting, we discussed the focus of the report. The TEP agreed that we should review articles that discuss either ephedra or ephedrine. Studies or case reports on pseudoephedrine were not to be reviewed, except in the context of ephedra/ephedrine. We agreed to include a brief description of the other alkaloids (pseudoephedrine, norephedrine, etc.) in the introduction to our report.
| Collection Item | Suggestions |
|---|---|
| Outcomes of interest when assessing efficacy | Weight = outcome for weight loss |
| Long-term weight loss = at least six months | |
| Long-term exercise = at least 12 weeks | |
| Change the term “exercise enhancement” to “exercise capacity” | |
| VO2 max, metabolism, heart rate = intermediate outcomes for exercise capacity | |
| Power, strength, endurance = primary outcomes for exercise capacity | |
| Subpopulations of interest | Age; gender; race; body composition/BMI; history of (Hx) hypertension; Hx asthma; Hx diabetes |
| Risk factors of interest in assessing possible harmful effects | Existing structural heart disease |
| Renal function | |
| Use of other drugs, tobacco | |
| Measure | Example |
|---|---|
| Temporal relationship | When the drug was consumed, dosage |
| De-challenge response | Do symptoms disappear when substance is removed? |
| Re-challenge response | Do symptoms appear again if substance is reintroduced? |
| Possibility of alternative explanation | Dehydration or consumption of other toxic substances |
| Prior reaction to same substance | |
| Dose response | |
| Objective evidence of adverse event | Witnesses or medical records |
| Previous conclusive reports | Has this same reaction happened when other persons consumed substance? |
| Definition of substance | |
Documentation (preferably medical) that the adverse event occurred.
Documentation that the patient took ephedra and that the dose and timing were consistent with the known pharmacology of ephedrine (for cases of death, myocardial infarction, stroke, or seizure). (The TEP later quantified this characteristic for acute events such as stroke or myocardial infarction to mean a dose preferably within six hours of the adverse event and in no cases greater than 24 hours before the adverse event.)
Performance of an evaluation sufficient to rule out other potential causes for the adverse event.
The TEP and EPC staff discussed extensively the types of information necessary to satisfy this last criterion. The TEP agreed that the absence of data could not be construed as a negative result. For example, the absence of information about prior cardiac disease could not be construed as an absence of cardiac disease. Furthermore, the TEP emphasized that verbal histories indicating no prior history of serious conditions were not sufficient to rule out alternative explanations for the most serious adverse events, since unrecognized preexisting cardiac disease, congenital abnormalities, berry aneurysms in the cerebral circulation, and other such conditions occur with some frequency and are known to cause death, myocardial infarction, or stroke without warning in otherwise “healthy” individuals. Realizing that it would be very difficult to attempt to define all of the possible evaluations and interpretation of results in the abstract, the TEP left it to EPC staff to resolve these issues, guided by the three characteristics listed above.
| SEARCH NUMBER | #1A |
| Database searched and time period covered | MEDLINE Via PubMed 1965-2001 |
| Search strategy | Ephedra AND (clinical trial OR clinical trials OR randomized controlled trials OR meta analysis OR meta-analysis OR review* OR Publication Type=Meta-Analysis OR Publication Type=Clinical Trial OR Publication Type=Review OR Publication Type=Randomized Controlled Trial) |
| Number of items retrieved | 8 |
| SEARCH NUMBER | #1B |
| Database searched and time period covered | EMBASE 1974-2001 |
| Search strategy | Ephedra AND (clinical trial* OR randomi* OR review* OR metaanalys* OR meta analys* OR Document Type=Review) |
| Number of items retrieved | 20 |
| SEARCH NUMBER | #1C |
| Database searched and time period covered | BIOSIS 1969-2001 |
| Search strategy | Ephedra AND (metaanal* OR meta anal* OR trial* OR review* in title or subject heading field OR Document Type=Review OR Document Type=Literature Review ) |
| Number of items retrieved | 15 |
| SEARCH NUMBER | #1D |
| Database searched and time period covered | Allied & Complementary Medicine 1984-2001 |
| MANTIS 1880-2000/Apr | |
| Cochrane Library - Controlled Clinical Trials Register Database (CCTR) | |
| Search strategy | ephedra |
| Number of items retrieved | 12 |
| SEARCH NUMBER | #2A (performed 4/5/01) |
| Database searched and time period covered | MEDLINE via PubMed 1965-2001 |
| Search strategy | ephedrine NOT ephedra AND (review OR meta analysis OR randomized controlled trials OR clinical trials OR Publication Type=Review OR Publication Type=Clinical Trial OR Publication Type=Randomized Controlled Trial OR Publication Type=Meta-Analysis) |
| Number of Items Retrieved | 704 |
| SEARCH NUMBER | #2B (performed 4/6/01) |
| Database searched and time period covered | EMBASE 1974-2001 |
| Search strategy | ephedrine NOT ephedra AND (review* OR meta analys* OR metaanalys* OR random* OR trial*) |
| Number of items retrieved | 1450 |
denotes truncated search term.
| SEARCH NUMBER | #1A (performed 6/25/01) |
| Database searched and time period covered | International Pharmaceutical Abstracts - 1970-2001/May |
| Pascal - 1973-2001/June Week 4 | |
| SciSearch (Archival File) - 1974-1989 | |
| SciSearch (Current File) - 1990-2001/June Week 4 | |
| Search strategy | ephedra OR ephedrine AND trial? OR review? OR rct? OR meta analys? OR metaanal? |
| Number of items retrieved | 167 |
| SEARCH NUMBER | #1B (performed 6/25/01) |
| Database searched and time period covered | International Pharmaceutical Abstracts - 1970-2001/May |
| Pascal - 1973-2001/June Week 4 | |
| SciSearch (Archival File) - 1974-1989 | |
| SciSearch (Current File) - 1990-2001/June Week 4 | |
| Search strategy | ephedra( IN TITLE OR SUBJECT HEADING FIELDS) OR ephedrine (IN TITLE OR SUBJECT HEADING FIELDS) AND adverse OR side effect? OR efficacy OR fail? OR succeed? OR success? OR effective? OR toxic? |
| AND | |
| adverse OR side effect? OR efficacy OR fail? OR succeed? OR success? OR effective? OR toxic? | |
| Number of items retrieved | 330 (NOTE - RESULTS FROM SEARCH 1A WERE “NOTTED OUT” OF THESE SEARCH RESULTS) |
Our TEP then suggested that we search three additional databases: the International Pharmaceutical Abstracts; Pascal (produced by the Institut de l'Information Scientifique et Technique (INIST) of the French National Research Council (CNRS), whose subject areas include physics, chemistry, biology, medicine, psychology, applied sciences, technology, earth sciences, and information sciences); and SciSearch. SciSearch contains all records published in Science Citation Index and additional records from about 1,000 journals whose table of contents pages are listed and indexed in the weekly Current Contents publications. Every subject area within the broad fields of science, technology, and biomedicine is included. Mary Hardy, MD, and Margaret Maglione, MPP, reviewed a total of 1,780 retrieved titles. Of those, 452 articles were deemed relevant to our undertaking and were ordered. Thirty-four additional articles were found through mining reference lists, and 64 were contributed by the TEP or AHRQ. We reviewed the reference list of every retrieved article for additional literature we might have missed and ordered any we found. Literature was tracked using ProCite and Access software.
We obtained the report “Safety Assessment and Determination of a Tolerable Upper Limit for Ephedra,” published in December 2000 by CANTOX Health Sciences and funded by the Council for Responsible Nutrition, an association of dietary supplement manufacturers. We ordered copies of all literature cited in this report. We also obtained transcripts of a public meeting, held in Washington, DC on August 8 and 9, 2000 and sponsored by the HHS Office on Women's Health, on the safety of dietary supplements containing ephedrine alkaloids. We contracted with physicians proficient in Japanese and Chinese to search for scientific literature in their native languages. These searches identified little on the use of ephedra for weight loss and exercise enhancement because ephedra is not used in that manner in Eastern cultures. In addition, we found nothing about ephedra on Phytonet, a European database. We also contacted Baptist University, Hong Kong, which has a database on herbal medicine, as well as the Taiwan Poison Control Center, but did not receive any data from either.
On January 31, 2002, we spoke to Dr. Phillip Waddington, Director of the Natural Health Products Directorate for Health Canada. He agreed to send us 60 adverse event reports regarding ephedra/ephedrine products. However, at the time of this report, we had not received anything.
In January 2002, we created an announcement regarding our project's need for any unpublished studies on the use of ephedra/ephedrine for weight loss or exercise enhancement. The announcement was submitted to both the journal Phytomedicine and the Herbalgram newsletter. The intent was to reach individuals who might know of small studies being done on ephedra or ephedrine of which the TEP were not aware. We receive no responses to this announcement.
In March 2002, we obtained a recent monograph on ephedra, written by Dennis McKenna, from the Institute for Natural Products Research, a nonprofit research and education foundation.
Finally, Wes Seigner, an attorney for the Ephedra Education Council in Washington, D.C., agreed to send us unpublished industry studies. We developed a confidentiality agreement, and Mr. Seigner sent us several reports on then-unpublished controlled trials conducted by members of the council.
We reviewed the articles retrieved from the various sources against our exclusion criteria to determine whether to include them in the evidence synthesis. A one-page screening review form (checklist) that contains a series of yes/no questions was created to track the articles (Figure 1
). After being evaluated against this checklist, each article was either accepted for further review or rejected. Two physicians and a policy analyst, each trained in the critical analysis of scientific literature, independently reviewed each study, abstracted data, and resolved disagreements by consensus. The principal investigator resolved any disagreements that remained unresolved after discussions among the reviewers. Project staff entered data from the checklists into an electronic database that was used to track all studies through the screening process.
To be accepted for analysis, studies had to be controlled clinical trials according to the following definitions:
Randomized controlled trial (RCT). A trial in which the participants (or other units) are definitely assigned prospectively to one of two (or more) alternative forms of health care, using a process of random allocation (e.g., random number generation, coin flips).
Controlled clinical trial (CCT). A trial in which participants (or other units) are either:
Definitely assigned prospectively to one of two (or more) alternative forms of health care using a quasi-random allocation method (e.g., alternation, date of birth, patient identifier)
OR
Possibly assigned prospectively to one of two (or more) alternative forms of health care using a process of random or quasi-random allocation.
We abstracted data from the articles that passed our screening criteria onto a specialized Quality Review Form (QRF—see Figure 2
). The form contains questions about the study design, the number of patients and comorbidities, dosage, adverse events, the types of outcome measures, and the time from intervention until outcome measurement. We selected the variables for abstraction with input from the project's TEP. Two physicians, working independently, each extracted data from the same articles and resolved disagreements by consensus. A senior physician resolved any disagreements not resolved by consensus.
To evaluate the quality of the studies, we collected information on the study design, withdrawal/dropout rate, method of random assignment (and blinding), and method for concealment of allocation (the attempt to prevent selection bias by concealing the assignment sequence prior to allocation). We also calculated the percentage of attrition by dividing the number of persons who dropped out of the trial (i.e., the number of people who entered the trial minus the number who completed the trial) by the number of persons entering the trial. The elements of design and execution (randomization, blinding, and withdrawals) have been aggregated into a summary score developed by Jadad.82 The Jadad score rates studies on a 0 to 5 scale, based on the answer to three questions:
Was the study randomized?
Was the study described as double-blind?
Was there a description of withdrawals and dropouts?
One point is awarded for each “yes” answer, and no points are given for a “no” answer. Additional points are awarded if the randomization method and method of blinding were described and were appropriate. A point is deducted if the method is described but is not appropriate. Empirical evidence has shown that studies scoring 2 or less show larger apparent differences between treatment groups than do studies scoring 3 or more.83
In selecting trials for the meta-analysis of weight loss, we considered all weight loss trials that included a treatment duration of at least eight weeks. Our TEP suggested that shorter treatment durations were insufficient to assess long-term weight loss. Trials on athletic performance encompassed a wide variety of interventions. Because of this heterogeneity, we compared and contrasted athletic performance studies in a narrative review and did not perform a meta-analysis. This section focuses on methods used for the meta-analysis of the weight-loss trials.
The available weight loss trials were judged to be sufficiently clinically homogeneous to support a pooled analysis. For some trials, several publications presented the same outcome data. In these cases, we picked the most informative of the duplicates; for example, if one publication was a conference abstract with preliminary data and the second was a full journal article, we chose the latter. The publications dropped for duplicate data do not appear in the evidence table but are noted in the text of Chapter 3 , Results. We note that multiple citations of the same article were removed at the title screening stage of the project.
Based on input from our TEP, we chose weight loss as the most clinically relevant outcome for the included trials. In order for a trial to be included in the analysis, the associated publication had to report on weight loss as an outcome, provide data prior to the crossover point if the trial was a crossover design, and contain sufficient statistical information for the calculation of an effect size. We calculated an effect size for every comparison of interest, e.g., ephedra versus placebo, at each relevant follow-up time-point, as described below. The effect size is calculated by dividing the difference between the weight loss in the treatment group and the weight loss in the placebo group by its standard deviation. The effect size is a unitless measure that is useful when comparing trials assessing outcomes that are similar (such as weight loss) but are measured in different ways (pounds versus body mass index). We synthesized effect sizes within comparison and follow-up subgroups. The percentage of weight lost, compared to pretreatment weight, is another clinically relevant outcome. However, we did not choose this outcome for our primary analysis for two reasons. First, pooling percentage of weight loss within a treatment group (e.g., an ephedra group) eliminates the placebo comparison from the trial and therefore does not make use of the strength of the randomized controlled design. Comparison of the treatment group to the placebo group within a trial utilizes the full strength of a randomized controlled trial, as patients who are similar in all aspects except treatment assignment are compared to each other. Thus, if one wanted to perform an analysis of weight loss percentage, we would advise pooling the difference in weight loss percentage between the treatment and placebo groups. The second, and more important, reason for not performing an analysis of weight loss percentage, regardless of whether the internal placebo comparison is made, is lack of data. The vast majority of trials did not report percentage of weight loss as an outcome. As a result, we would have had to make two assumptions in our calculations. First, to estimate mean percentage weight loss for a group in a trial, we took the ratio of mean weight loss between baseline and follow-up divided by mean baseline weight. The mean of a set of ratios does not equal the ratio of the means, but this would have been the best estimate we could obtain. Second, to estimate the standard deviation of our ratio, we would have had to use the delta method to approximate the standard deviation and furthermore would have had to estimate the correlation between the baseline and follow-up weights to be 0.5. We are unable to check either of these assumptions. In contrast, the vast majority of trials did report weight loss as an outcome, and also presented the standard deviation of this statistic. Hence, weight loss became our primary outcome for analysis.
The literature included 6 different types of comparisons: (1) ephedrine versus placebo; (2) ephedrine plus caffeine versus placebo; (3) ephedrine plus caffeine versus ephedrine; (4) ephedrine versus other active treatment; (5) ephedra versus placebo; and (6) ephedra plus herbs containing caffeine versus placebo. Only one trial compared the effect of ephedra alone versus placebo. If a trial had other treatment arms such as caffeine only, we dropped those arms from our analysis. Effect sizes were pooled separately within each comparison subgroup. In addition, a cross-subgroup synthesis using meta-regression was conducted on the ephedrine versus placebo; ephedrine plus caffeine versus placebo; and ephedra plus herbs containing caffeine versus placebo effect sizes as well as a direct within-study comparison for those few studies that presented data for more than one comparison, as described below.
For each trial, we calculated effect sizes for any of the six comparisons of interest for which the study provided data. The majority of trials included only one comparison—between a single treatment (e.g., ephedrine) arm and placebo. One trial84 included both an ephedrine plus caffeine plus aspirin arm and an ephedrine plus caffeine arm. However, we combined these arms into a single ephedrine plus caffeine arm, based on the clinical reasoning that aspirin has relatively little effect on weight loss.
Nevertheless, a small number of trials contained more than one relevant comparison between arms and thus contributed more than one effect size to be considered for analysis. Double-counting patients is a concern if a trial contributed more than one effect size to an analysis, and patients were included more than once in calculating those effect sizes. For example, if a trial had one placebo arm, an ephedrine arm, and an ephedrine plus caffeine arm, it contributed two effect sizes, both based on the same placebo patients. Fortunately we encountered relatively few instances of double-counting of patients within the analyses. One trial85 included two ephedrine doses and a placebo arm and thus contributed two ephedrine versus placebo effect sizes, that is, two effect sizes within a single comparison group.
Four trials84, 86–88 contributed effect sizes in more than one of the six comparison groups. Since we conducted the comparison group analyses separately, the four latter trials do not double-count patients within comparison group analysis. We discuss the possible influence of multiple effect sizes per study on the meta-regression analysis below.
For each trial, we extracted the means and standard deviations of weight loss between baseline and the relevant follow-up times for each arm, if available. For example, if a trial with placebo and ephedra arms reported follow-up data at two months, we extracted the means and standard deviations of weight loss at two months for the ephedra and placebo arms. If trials did not report a weight loss mean for any arm, or this mean could not be calculated from the given data, the trial was excluded from the meta-analysis.
We initially considered four separate treatment duration measurement times: two months, three months, four months, and six months. However, only one ephedra trial89 and two ephedrine plus caffeine trials89, 90 reported an outcome measure for a treatment duration of six months. These numbers are too small to perform a separate pooled analysis on six-month outcomes. Thus, we considered three treatment durations: The two-month duration of treatment included only outcomes for 8 weeks of treatment. However, for the analysis of three-month treatment durations, we included data collected anytime between 12 and 15 weeks, and for the four-month analysis, we included data collected between 18 and 24 weeks. We also analyzed the rate of monthly weight loss, as described below.
The large majority of included trials reported weight loss in kilograms; some trials reported weight loss in pounds. Since an effect size is unitless, data expressed in either unit of measure could be extracted for analysis. One trial91 reported weight loss only in terms of body mass index (BMI). Because this measure involves both height and weight, we first transformed the study data to kilograms by assuming an average height of 68 inches (within a range of reasonable values, the height that was chosen made little difference in the results).
As mentioned above, for each arm in each included trial, we also calculated the mean monthly weight loss by dividing by the number of months of treatment. Thus, using our previous example, we calculated the mean monthly weight loss for the placebo and ephedra arms respectively by dividing the associated two-month mean weight loss by two. For those trials that had more than one treatment duration time, we used the longest treatment duration time data to calculate the monthly weight loss. We extracted both weight loss at specific time points (e.g., two, three, and four months) and monthly weight loss to compare the results for both types of outcomes. This comparison allows us to check trends in weight loss, for example, whether weight loss is linear or dampens over time. Using meta-regression, we verified that weight loss was linear over the range of time for which data were available by comparing pooled monthly weight loss rates based on the two-month, three-month, and four-month data separately in each comparison group. Thus, our primary analysis focuses on monthly weight loss. We note that the included trials had relatively short-term follow-up; thus, our results address only short-term weight loss and should not be extrapolated beyond four months.
If a trial reported a standard deviation of weight loss at a relevant follow-up time, we extracted those data and used them to calculate the standard deviation of the monthly weight loss. Eight trials84, 87, 88, 92–96 failed to report a standard deviation for weight loss at a given follow-up time, or a standard deviation could not be calculated from the given data. For these trials, we imputed the standard deviation of the monthly weight loss by using those trials and arms that did report a standard deviation. We averaged the monthly weight loss standard deviations by weighting all arms equally in the imputed value calculation. For those trials missing standard deviations, we then used the imputed monthly weight loss standard deviation to calculate the standard deviation for weight loss at the relevant follow-up time.
For each pair of arms, an unbiased estimate97 of Hedges' g effect size98 and a 95 percent confidence interval were calculated. A negative effect size indicates that the treatment arm (ephedrine or ephedrine plus caffeine, or ephedra plus herbs containing caffeine) is associated with a larger weight loss at follow-up (or a larger monthly weight loss) than is the comparison arm, e.g., the placebo.
We estimated a pooled random-effects estimate99 by combining effect sizes for comparison subgroups that contained three or more effect sizes. We also report the chi-squared test of heterogeneity p-value.97
Forest plots were constructed for each comparison subgroup. Each individual trial effect size is shown with confidence intervals as a box whose area is inversely proportional to the estimated variance of the effect in that trial. The pooled estimate and its confidence interval are shown as a diamond at the bottom of the plot with a dotted vertical line indicating the pooled estimate value. A vertical solid line at zero indicates no treatment effect.
For each trial, we calculated the monthly weight loss percentage for each treatment group and the placebo group. Monthly weight loss percentage is defined as the mean monthly weight loss divided by the mean baseline weight in that group. Unfortunately, we were not able to calculate monthly weight loss percentage on an individual level. To determine the standard deviation of the monthly weight loss percentage, we used the delta method100 and assumed a correlation of 0.5 between the baseline and follow-up weights.101 For each comparison subgroup, we pooled monthly weight loss percentages in the treatment groups and placebo groups separately using a random effects model99 and produced associated 95% confidence intervals. We acknowledge that combining estimates within treatment groups only, or placebo groups only, does not take advantage of the randomization and pairing of treatment and control within a trial. This lack of pairing, and the fact that the monthly weight loss percentage in the treatment group must be compared to the associated monthly weight loss percentage in the placebo group, should be kept in mind when interpreting the results of this analysis.
When relevant, we conducted sensitivity analyses on subgroups of trials to determine the robustness of our conclusions. In order to assess the possible impact of attrition, we divided the trials into two groups: (1) those with less than 20 percent attrition in all arms and (2) all others. Twenty percent attrition is a commonly accepted threshold above which concerns about bias increase, due to loss to follow-up. For trials in which attrition was unknown, we assumed it was not less than 20 percent. We conducted the main analyses for the two attrition strata separately.
We also conducted further analyses on the attrition rates. To determine whether the attrition rate varied between treatment and placebo groups within a trial, we first collapsed all the treatment groups together within a trial and estimated a single attrition rate for treatment. We then conducted a paired t-test that assessed whether the difference between the treatment and placebo attrition rates within a trial was significantly different from zero. All studies were weighted equally in this analysis. We also categorized each trial as significant or not significant based on its effect size. Trials that had more than one effect size agreed in terms of significance (in other words, the trial reported consistent result with respect to significance at multiple time points). We then categorized each trial as to whether the attrition rate for the treatment group was higher than, lower than, or the same as that of the placebo group. We examined the bivariate distribution of studies into these six categories, (three relationships between group attrition rates categories, and whether each of these relationships was significant or nonsignificant), and conducted a chi-squared test of the association between significance and the relationship between group attrition rates.
When relevant, we also performed our calculations a second time, excluding the trial by Moheb and colleagues.84 This trial was presented only in abstract form and provided only the total sample size, not the sample sizes for each arm; thus, we had to assumed equal sample sizes across arms.
For the ephedrine plus caffeine versus placebo trials, we performed two sensitivity analyses. In the first, we dropped one trial102 that had synephrine in the ephedrine plus caffeine arm. In the second, we dropped one arm of one trial103 in which aspirin was combined with ephedrine plus caffeine; the sensitivity analysis was performed with the ephedrine plus caffeine arm alone.
A final sensitivity analysis concerned the choice of summary statistics to pool. Instead of pooling effect sizes or “standardized mean differences,” we applied a “weighted mean difference” approach. In the latter, we pooled the absolute differences in weight loss between the treatment and placebo groups, inversely weighted by the trial variances of the differences. That is, we did not first divide the differences by their standard deviations to produce effect sizes and then weight by the inverse variances of the effect sizes. If the variances are not homogeneous and/or the variances are not well estimated, these two methods may not produce the same results. The weighted mean difference approach has the appeal of being conducted entirely in the clinical units of interest—in this case, pounds.
We tested for a dose effect using a random-effects meta-regression model.104 A separate model was fitted within each comparison subgroup. We defined a low dose of ephedrine as 10–20 mg; a medium dose of ephedrine as 40–90 mg; and a high dose of ephedrine as 100–150 mg. We characterized each dose level as an indicator variable in a main-effects model and chose the medium-dose group as the level to exclude. The meta-regression approach allowed us to test directly the efficacy of low and high doses versus the excluded medium dose group, as well as to estimate the effect size for each dose level.
We assessed the possibility of publication bias by evaluating a funnel plot of effect sizes for asymmetry, which can result from the nonpublication of small trials with negative results. These funnel plots include a horizontal line at the fixed-effects pooled estimate and pseudo-95% confidence limits.105 If bias due to nonpublication exists, the distribution is asymmetric or skewed. Because graphical evaluation can be subjective, we also conducted an adjusted rank correlation test105 and a regression asymmetry test106 as formal statistical tests for publication bias. The correlation approach tests whether the correlation between the effect sizes and their variances is significant, and the regression approach tests whether the intercept of a regression of the effects sizes on their precision differs from zero; that is, both formally test for asymmetry in the funnel plot. We acknowledge that other factors, such as differences in trial quality or true study heterogeneity, could produce asymmetry in funnel plots.
As described above, in order to compare monthly weight loss effect sizes across comparisons, we conducted a random-effects meta-regression.104 The observations in this meta-regression were all monthly weight loss effect sizes across the ephedrine, ephedrine plus caffeine, and ephedra plus caffeine-containing herbs comparisons. The variables are indicator flags, one for each comparison. Only one trial85 had multiple effect sizes in the regression, and we did not account for the correlation between these two effect sizes in our model.
Three trials84, 86, 88 contained both ephedrine and ephedrine plus caffeine arms. For these trials, we were able to conduct a direct, or “head-to-head,” comparison of these treatments by pooling the effect sizes for each trial together. In the estimation of an effect size in this situation, the comparison group is that group of individuals who received ephedrine alone. Thus, a negative effect size means that ephedrine plus caffeine is associated with a larger monthly weight loss than is ephedrine alone. This direct comparison is more robust than the cross-group meta-regression described above, because the former compares groups only within a trial. However, due to the small number of trials that provided more than one treatment arm and the lack of any direct comparisons of ephedrine alone or ephedrine plus caffeine versus ephedra, we conducted both analyses.
To aid in interpreting our results, we back-transformed all pooled estimates to weight loss in pounds. In order to do this, we multiplied each pooled estimate by the average standard deviation across trials, and then further multiplied by 2.2 to transform kilograms to pounds. In this way, we were able to equate our unitless pooled effect size with weight loss in pounds. However, we note this back-transformation requires assuming a particular underlying standard deviation. Readers may wish to apply their own standard deviation, based on the particular patient population to which they wish to apply the results.
We conducted all analyses and drew all graphs using the statistical package Stata.107
Each trial that we identified was examined to determine whether it reported data on adverse events. Adverse events were recorded onto a spreadsheet that identified each study arm, the description of the adverse event as listed in the original article, the number of adverse events in each category, and the number of subjects in each arm.
The strongest level of evidence for attributing an adverse event to an exposure comes from placebo-controlled randomized trials of the exposure in question. In this evidence report, such evidence would come from placebo-controlled trials of ephedra or ephedrine. We therefore searched all such trials that we identified and extracted from each trial the adverse events that were reported associated with it, as described above. Because each event was counted as if it represented a unique individual, and because a single individual might have experienced more than one adverse event, this method may have overestimated the number of people having an adverse event. We then compared event rates in the people who received ephedra or ephedrine with those in people who received placebo. We performed a meta-analysis on those adverse events for which there was an appreciable number of reports in the randomized trials.
We collected data on adverse events for the randomized controlled trials. For each adverse event, e.g., vomiting, and for each treatment group and for the placebo group, we abstracted either the number of events or the number of people, depending on how the trial chose to report events. The majority of trials recorded the number of events, rather than the number of unique people who experienced the event. We treated all events as if they occurred in unique individuals, which, as we stated, may overestimate the number of people apparently affected in a particular event category.
We note that some trials recorded zero events in a particular event category, and these data were thus recorded. However, some trials recorded no data for a certain event category recorded no adverse events at all. These trials did not enter the adverse event meta-analysis, in that we did not assume zero observed events if a trial did not mention a particular type of event. By excluding these trials, we may have underestimated the number of patients for whom a particular adverse event was not observed. We note that, for the power calculation (described below) for serious adverse events (deaths, myocardial infarctions, strokes, seizures, and serious psychiatric symptoms), the sample sizes of all trials were taken into account, regardless of whether they mentioned these serious events. We assumed that such serious events would have been recorded had they been observed, so that a record of zero or no mention of a serious event could both be taken to mean that no such events were observed.
After abstracting the data, we identified mutually exclusive subgroups of similar events, based on clinical expertise. When we subgrouped events, we again treated all observed events as having occurred in unique individuals. For example, we considered nausea and vomiting as a single subgroup. For a trial that reported nausea events and vomiting events separately, we assumed the events that occurred in each category were unique and occurred in different individuals. The number of individuals who were at risk of being affected is the total number of patients in the trial's relevant group (placebo or treatment).
For each event subgroup, we report the number of trials that provided data for any event in the subgroup. We also report the total number of individuals in the placebo groups in the relevant trials who were observed to have experienced the event (calculated as described above) and the total number of patients in the placebo groups in those trials. We then report the analogous counts for all applicable treatment groups (ephedrine, ephedrine plus caffeine, ephedra) in the relevant trials. We specifically do not provide crude placebo and treatment rates (total number of affected patients divided by total number of patients at risk). Such crude rates do not weight trials appropriately.
Based on clinical importance and the availability of data, we chose a limited number of event subgroups for meta-analysis. For each chosen event subgroup, we estimated the pooled odds ratio across the trials that reported on any events in the subgroup, as well as a 95% confidence interval for the pooled odds ratio. Given that many of the events were rare, we utilized exact conditional inference to perform the pooling rather than applying the usual asymptotic methods that assume normality. Asymptotic methods require corrections if zero events are observed: Generally, half an event is added to all cells in the outcome by treatment two-by-two table in order to allow estimation, since these methods are based on assuming underlying continuity. Such corrections can have a major impact on the results when the outcome event is rare. Exact methods do not require such corrections. We conducted the meta-analysis using the statistical software package StatXact.108
We also conducted a power calculation to determine the lowest adverse-event rate that the clinical trials we identified had at least 80 percent power to detect. That is, we assumed a sample size equal to all the trials combined, and assuming a two-sided test of level 0.05, we determined the lowest detectable adverse-event rate. This calculation was performed to assess the statistical power we actually had available to detect adverse events if few or none were observed. Even if no adverse events are observed, we cannot necessarily conclude that the rate is zero, because the sample size available may have been too small to detect a rare event.
Because the clinical trial data had low statistical power to detect a rate of serious adverse events, we therefore assessed case reports of adverse events associated with ephedrine or ephedra-containing dietary supplement use in order to inform the sponsors regarding the Safety Assessment key questions concerning serious adverse events. We reviewed case reports from three sources: the FDA MedWatch file, published case reports, and a file kept by the ephedra supplement manufacturer, Metabolife. Published case reports were identified through our literature search process previously described.
In September 2001, the FDA's Office of Nutritional Products, Labeling, and Dietary Supplements produced an Excel spreadsheet with a master list of adverse-event report case numbers and summary information, in response to our request for all herbal ephedra-related adverse-event reports from their database. After several discussions and several months of work, the dataset construction algorithm was reproduced and limited to only herbal ephedra-related adverse-events reports, because some ephedrine adverse events had mistakenly been entered into the initial Excel file. We also received several sets of compact disks containing portable document format (PDF) files of events reported in the FDA Adverse Reaction Monitoring System (ARMS) for the dates specified. Documents retrieved included MedWatch Reports (FDA form 3500); Consumer Complaint Injury Reports (FDA Form 2516); Complaint/Injury Follow-up Forms (FDA Form 2516a); Adverse Reaction Questionnaires (Form A); letters from family members, health care professionals, or lawyers; affidavits collected from witnesses during FDA-held investigations; police reports; medical records, including physician notes (both inpatient and outpatient), emergency department reports, nurse notes, and laboratory reports; product labeling and related information; and product analysis results.
The second master list of only ephedra-related adverse-event reports was created at the product level, so that adverse-event report identification numbers (IDs) were repeated if multiple products appeared in one report. Because our analysis was at the adverse-event report level, where there were multiple products per single ID, we joined those into one record. We established a cutoff date of September 30, 2001, the production date for the CDs that contained actual reports. Our analysis does not include case reports filed after that cutoff date, since these files had not been redacted of identifying information.
| Event Type |
|---|
| Death |
| Stroke (CVA) |
| Myocardial infarction (heart attack) |
| Cardiovascular other than MI |
| Neurological other than stroke |
| Endocrine |
| Psychiatric |
| Pulmonary |
| Renal/urinary |
| Musculoskeletal |
| Gastrointestinal |
| Hepatic |
| Rheumatologic |
| Dermatological |
| Acid-base/electrolytic disturbances |
| Pain |
| Withdrawal symptoms |
| Gynecological/obstetrical |
| Hematological |
| Immunological/allergic reaction |
| Other rare events |
| Not described |
–3c). We developed these instruments to collect information from the corresponding PDF file or published case report on whether the report was actually on ephedra or ephedrine, whether the data were adequate to analyze the report, and whether or not the adverse event qualified as a “sentinel event” (see below). When a case report dealt with more than one individual, an AEA form was completed for each individual.
To understand the other potentially serious adverse events, we reviewed all case reports that had been grouped into the categories of “other serious cardiovascular,” “other serious neurological,” and “psychiatric” in our initial review of the master Excel file. For this review, we used a brief data abstraction form (Figure 4
). This brief form was developed to assess the evidence supporting the prior use of ephedra and to define the adverse event more precisely. Again, when a case report contained more than one subject, a brief form was completed for each subject. Then, the data collected in the brief review were used to justify including certain more-serious events into the more-detailed review described above. These more-serious adverse events included ventricular tachycardia/fibrillation, cardiac arrest, pulmonary arrest, transient ischemic attack, and brain hemorrhage. Select adverse-event reports were then reviewed a second or third time by project staff physicians to reach an implicit judgment about whether an adequate investigation of other potential causes had been performed. Internists performed the initial reviews of cases of death, myocardial infarction, stroke, and seizure, and were assisted (as appropriate) by a cardiologist, rheumatologist, or neurologist. Psychiatric events were reviewed by two experienced professionals: a psychiatrist specializing in addictions and a psychologist who leads RAND's Drug Policy Research Center. All cases were reviewed by two individuals, with differences resolved by consensus.
As part of additional work we were requested to perform, we received hard copies of MedWatch data on ephedrine, organized in the same manner as the data on ephedra. We first reviewed all these events with our short form to identify the serious adverse events. These events were then reviewed using the same methods we developed for the ephedra database. Two types of adverse events associated with ephedrine were not associated with ephedra. The first involved the intravenous use of ephedrine given during surgery; several such reports were filed by medical personnel. The second involved attempted suicide. We note these two types of case reports in our analysis.
During our literature search, we identified published case reports of adverse events associated with ephedra use. These published case reports were then reviewed using the same criteria used for the MedWatch events.
We received the following materials from the Food and Drug Administration (FDA), which had, in turn, received them from Metabolife:
A CD-ROM labeled “MIPER” (described in more detail below)
Photocopies of medical information pertaining to 43 cases (also described in more detail below).
A two-page Listing of Key Complaint for the Metabolife Medical Records Submitted, which is a listing of the key complaints for 46 cases, with photocopied medical information. (Note: we received medical information for only 43 cases.)
A two-page sheet entitled Index of Redacted Consumer Medical Records with Corresponding MIPER Numbers, which contained a listing of the 46 cases with additional medical record information and the file numbers for related information on the MIPER CD-ROM.
Three reviews of the Metabolife adverse-event file, which Metabolife commissioned. Note that to prevent their assessment from biasing our own, we did not read any of these reviews prior to our assessment, but did review them briefly when our assessment was completed.
A file entitled 77 ‘serious’ AE's as identified by Metabolife, which contains photocopies of reports of events that were selected by Metabolife as being the most serious in nature. Most, but not all, of these reports were contained on the MIPER CD-ROM. Again, in order to avoid bias, we did not examine this file until after our initial assessment was performed.
Several journal articles, all of which were already in our possession.
Later, we also received a report entitled Adverse Event Reports from Metabolife that had been prepared for Sen. Richard J. Durbin, Rep. Henry A. Waxman, and Rep. Susan A. Davis by the Minority Staff Report Special Investigations Division, Committee on Government Reform, U.S. House of Representatives, and which consisted of an analysis of the MIPER CD-ROM.
The MIPER CD-ROM contains several thousand files of adverse event reports organized in 20 folders. The adverse-event files are numbered from 15111 to 35069, and are continuous, except for three gaps—between 21121 and 22035; 25535 and 27472; and 30627 and 35047. Each file is a TIF picture file, generally of a single sheet of paper, on which is recorded information regarding the potential adverse event or events. This information was recorded in many different ways, including an email record of a telephone conversation between a company representative and the consumer; typed or handwritten letters from the consumer to the company; handwritten notes of telephone conversations with consumers, written on either a rudimentary form or on whatever piece of paper seems to have been handy at the moment; and a form developed by Metabolife for systematically collecting information about possible adverse events. Examples of all of these types of files are presented in Figure 5
. Personal identifiers had been redacted from the files we received.
Each consumer could experience one or more adverse events. We referred to a particular adverse event for a person as a “case,” and our analysis was conducted at the case level, rather than at the person level. Thus, a person could contribute more than one case to our analysis. We use this terminology throughout the remainder of the report. Practically speaking, in most instances of serious adverse events such as death, heart attack, or stroke, a person contributed only a single case in this manner.
In general, each file on the MIPER CD-ROM contained only a single sheet of paper. We did identify some files that were exactly the same as other files, and we excluded these files from our analysis. The information on a case might reside in a single file or in more than one file. For example, if a letter from a consumer concerning one of the adverse events experienced by that consumer was three pages long, each page resided in a separate file. If possible, we tried to identify all files that pertained to the same case (which we called “duplicate” files), so that we would not count a case more than once. Whether we identified all such instances is unknown, since information in each file was insufficient to allow us to check for duplicate files by matching on key variables such as age, gender, and the type of adverse event. No other mechanism for checking was possible within the time and resources available to the project. Therefore, while we did our best to identify and exclude or in some other way resolve duplicate files, we cannot be certain that all such files were identified. An example of the difficulty in identifying duplicates is given in Figure 6
. In this instance, Metabolife had identified in the 77 ‘serious’ AE's document that these two files belonged to the same case. We would not have been able to make this determination, because the files are separated by more than 7000 numbers on the MIPER CD-ROM (file 16897 and file 24209), and the notes in one file specify “seizure,” whereas the other file states “no history of seizure.”
, Example 5c). For this reason and because of duplicate files, the number of cases of possible adverse events does not equal the number of files.
In order to review this large CD-ROM dataset within the given time frame, we chose to have the initial data collected by a team of abstractors, each working on a portion of the MIPER CD-ROM. We retained six nurses, each with many years of experience in medical record abstraction. We developed a one-page data collection form to collect key variables related to age, gender, nature of the reported adverse event, and need for hospitalization, which is reproduced in Figure 7
. After undergoing training by the principal investigator, each nurse abstractor completed a sample of 135 records, each of which was reviewed in a group meeting with the principal investigator to identify areas of possible misinterpretation and vague language. Based on this experience, we revised the form and developed a “codesheet” to define how certain complaints were to be coded. Formal inter-rater reliability testing was performed on a 1 percent systematic sample of the MIPER files. This sample was stratified into two parts, the larger (N = 114) portion containing only a single adverse event in each file and the smaller portion (N = 16) containing more than one case per file. Inter-rater reliability was assessed using both absolute percentage agreement among abstractors and the kappa statistic, which adjusts for agreement due to chance. Kappa varies between 0 and 1.0, with values of 0.4 to 0.6 usually indicating moderate agreement beyond chance, 0.6 to 0.8 indicating substantial agreement beyond chance, and greater than 0.8 indicating almost perfect agreement.109 Inter-rater reliability testing demonstrated a kappa statistic of greater than 0.8 or absolute agreement of 95 percent or greater for all variables, indicating almost perfect agreement, for the “one case, one file” (N = 114) records. For the files with multiple cases, two produced disagreement over the number of multiple cases contained in the file. For the remaining 14 multiple-case files, this analysis showed levels of reliability similar to the “one case, one file analysis.” Based on these results, we concluded that the inter-rater reliability for the six nurse abstracters trained in this manner was acceptable for this project. Each nurse was then assigned approximately one-sixth of the MIPER file. Questions that arose during abstraction were posted by email or telephone to our EPC's lead physician abstracter (WAM), who answered their questions, reviewed files himself, and consulted with the principal investigator on decisions requiring nuanced judgment. He maintained the codesheet, keeping it up—to-date and redistributing it to the abstractors whenever changes or additions were made.
We reviewed the forty-three cases that included photocopies of medical information. Personal identifiers had been redacted. Some of these cases were related to cases contained on the MIPER CD-ROM. However, matching these cases was a challenge. As previously noted, we were sent a two-page Index of Redacted Consumer Medical Records with Corresponding MIPER Numbers, which indicated a number and the associated files on the MIPER CD-ROM. Unfortunately, the medical records we received were not numbered. Furthermore, a second table that we received entitled Listing of Key Complaint for the Metabolife Medical Records Submitted contained a list of main complaints, also numbered. However, the two numbering systems did not agree. We numbered the cases in the order in which we received them in the shipping box. Our numbering system and the two numbering systems we received start out in agreement, but discrepancies occur as we progress through and compare the three systems. We did our best to resolve them.
In our draft report, we assigned a likelihood of causality to selected cases, based on our modification of published methods. Many of the peer review comments received for this report pertained to our attempts to assign causality. These comments varied widely, ranging from critiques of our method for being too conservative (meaning, in the opinion of some reviewers, we had excluded or assigned too low a level of causality to certain cases) to critiques for being too liberal (meaning, in the opinion of some reviewers, we had assigned too high a level of causality to certain cases). Often, these conflicting comments concerned the same cases. We believe these peer review comments demonstrate that case report reviews involve considerably more subjective interpretation than do reviews of randomized trials. Because our goal in this evidence report is to report the evidence as objectively as possible, we ceased to assign assessments of causality to the case reports. Rather, we tried to identify those cases that would be classified medically as “idiopathic” in etiology, meaning the cause is not known. For such cases, given the known pharmacology of ephedrine, if use of ephedra or ephedrine was documented, a potential role for ephedra or ephedrine in causing the event must be considered. We classified such cases as “sentinel events.”
In order to be classified as a sentinel event, three criteria had to be met:
Documentation existed that an adverse event meeting our selection criteria occurred.
Documentation existed that the person having the adverse event took an ephedra-containing supplement within 24 hours prior to the event (for cases of death, myocardial infarction, stroke, or seizure).
Alternative explanations were investigated and excluded with reasonable certainty.
Within the time and resources available for this evidence report, we were able to do an in-depth review of FDA case reports only for those events classified as death, myocardial infarction (which included acute coronary syndromes), stroke (which included intracerebral hemorrhage), seizures, and severe psychiatric symptoms (see below). Cases that met all three criteria were classified as “sentinel events.” Cases where another condition by itself could have caused the adverse event, but for which the known pharmacology of ephedrine made it possible that ephedra or ephedrine may have helped precipitate the event, were classified as “possible sentinel events.” “Probably not related” was used for events that had other clear causes discovered on detailed investigation and to which the pharmacology of ephedrine was unlikely to have potentially contributed. We also classified many cases as having insufficient information because crucial information was missing, such as the presence of ephedrine or a metabolite in the blood or documentation that the patient took ephedra within 24 hours prior to the event (for cases of death, myocardial infarction, stroke, or seizure); or other possible causes were insufficiently investigated. (We also classified as “sentinel events” a few cases that, on detailed review, led us to question whether an event meeting our inclusion criteria had actually occurred.)
We translated the criteria for identifying sentinel events into the following set of procedures:
We required medical record documentation that an adverse event had occurred.
For adverse events described as seizure, cases described as generalized tonic-clonic seizures underwent further review.
For psychiatric symptoms, we reviewed cases described as psychosis, mania or severe agitation, severe depression, hallucinations, confusion or delusion, suicide attempt, paranoia, or violence.
We required (for all but psychiatric events) that there be documentation that the subject had consumed ephedra or ephedrine within 24 hours prior to the adverse event, or that a toxicological examination revealed ephedrine or one of its associated products in the blood or urine. Cases with no such documentation were not reviewed further. For the Metabolife cases, we assumed ephedra use to have been within the prior 24 hours for all but psychiatric events.
For psychiatric cases, we did not require documentation that the product was taken within 24 hours prior to the event. Ephedrine psychosis (as with amphetamine psychosis in general) is associated with prolonged use, which may lead to neurotoxicity, resulting in depletion of dopamine and other brain monoamines.110
To be eligible for detailed review to investigate other potential causes of death, a file required evidence that an autopsy had been performed, and the results had to be available.
To be eligible for detailed review to investigate other potential causes for cases of myocardial infarction, coronary angiography had to have been performed and the results had to be available.
All cases of stroke that met the criterion of having consumed ephedra or ephedrine within 24 hours were reviewed in more detail. To be classified as a “sentinel event,” reports of thrombotic stroke needed to have an assessment for a hypercoagulable state and vasculitis, reports of embolic stroke needed to have an embolic evaluation performed, whereas reports of hemorrhagic stroke required an examination to assess structural problems with the circulatory system of the brain.
Other potential causes of seizure were assessed by searching cases for the results of vital signs, brain imaging (CT or MRI), serum glucose and electrolytes, blood calcium and magnesium, an EEG, and prior history of a seizure disorder or substance abuse.
For cases with psychiatric symptoms, cases in which patients had a history of psychiatric or severe psychological problems were excluded from further review as reports of possible sentinel events. Cases where the patient reported use of or tested positive for other substances known to cause psychiatric symptoms were also excluded as possible sentinel events. For patients with a prior psychiatric history or use of other substances, these cases were classified as “inconclusive.”
One of the key questions we were asked to answer by the sponsoring agencies concerned the relationship between dose and the likelihood of serious adverse events. We do not believe such an analysis is justifiable based on the case report evidence presented here, for the following reasons. First, such an analysis assumes a cause-and-effect relationship that has not been proven by conventional standards of medical science. Second, it would rely to a great extent on patients' recall of dose after having suffered an adverse event, which increases the likelihood of recall bias. Third, and most important, for more than half the adverse-event cases, no dose data were available.
| Reviewer | Affiliation |
|---|---|
| Dr. David Allison | University of Alabama at Birmingham |
| Dr. Arne Astrup | The Research Department of Human Nutrition |
| The Royal Veterinary and Agricultural University, Denmark | |
| Dr. Dennis Awang | Mediplant Consulting Services |
| Dr. Neal Benowitz | University San Francisco, Dept. of Med., SFGH, Clin. Pharm Div. |
| Dr. Heidi Blanck | Centers for Disease Control and Prevention, Division of Nutrition and Physical Activity, Chronic Disease Nutrition Branch |
| Dr. George Bray | Pennington Biomedical Research Center |
| Hon Dan Burton | U.S. Representative |
| Mr. John Cardaro | Council for Responsible Nutrition |
| Ms. Beth Clay | U.S. House of Representatives, Hon Dan Burton's Office |
| Hon Dick Durbin | U.S. Senator |
| Dr. Norman Farnsworth | Univ. of Illinois Med. Center |
| Dr. Roger Fielding | Boston University Dept. of Health Services |
| Dr. Gary Franklin | University of Washington |
| Dr. Curt Furberg | Wake Forest University |
| Dr. Frank Greenway | Pennington Biomedical Research Center |
| Prof. Bill Gurley | University of Arkansas School for Med. Sciences, College of Pharmacy |
| Dr. Christine Haller | University California San Francisco, Div of Clinical Pharmacology |
| Dr. Robert Hart | National Institute of Neurological Disorders and Stroke |
| Dr. David Heber | UCLA Center for Human Nutrition, Obesity and Nutrition |
| Dr. Steve Heymsfield | St. Luke's/Roosevelt Hospital |
| Mr. Loren Israelsen | Utah Natural Products Alliance |
| Dr. Steven Karch | Assistant Medical Examiner, San Francisco |
| Dr. Steve Kimmell | Chair, Ephedra Education Council Expert Panel |
| Dr. Richard Ko | California Dept. of Health Services, Food and Drug Branch |
| Dr. Albert Leung | AYSL |
| Dr. Lori Love | Food and Drug Administration |
| Mr. Michael McGuffin | President, American Herbal Products Association |
| Dr. Simon Mills | Center for Complementary Health Studies, University of Exeter |
| Dr. Earle Nestman | CANTOX |
| Dr. Paul Pentel | Hennepin County Medical Center, Div. of Toxicology, Dept. of Medicine |
| Mr. Paul Rubin | Patton Boggs |
| Mr. David Seckman | National Nutritional Foods |
| Mr. Wes Seigner | Hyman, Phelps, & McNamara |
| Hon Henry Waxman | U.S. Representative |
| Dr. Raymond Woosley | University of Arizona Health Sciences Center |
| Ms. Susan Yanovski | Obesity and Eating Disorder Program |
| National Institute of Diabetes and Digestive and Kidney Diseases | |
| Organizations | |
| National Center for Complementary and Alternative Medicine | |
| National Institute of Diabetes and Digestive and Kidney Diseases | |
| National Heart, Lung and Blood Institute | |
| Office of Dietary Supplements | |
| Center for Science in the Public Interest | |
| Public Citizen Health Research Group | |
We considered each peer review comment (more than 100 pages in total) and detail our responses in Appendix 3. Service as a reviewer of this report should not in any way be construed as agreeing with or endorsing the content of the report.
Figure 8
displays the flow of the literature review. As a result of computerized library searches, reference mining, talking to experts, and searching government files (see Methods), we ordered 550 articles. Of those 550, we were unable to obtain 20 articles, mostly foreign or very old background articles, none of which appeared (from their titles and keywords) to be clinical trials of ephedrine or ephedra.
Of the 530 articles collected, 59 reported results from randomized clinical trials or controlled clinical trials that assessed the effects of either ephedrine or herbal ephedra on weight loss or athletic performance. The 59 articles, which corresponded to 52 unique controlled clinical trials, went on to further review and data abstraction. Articles that did not go on to initial data abstraction included 71 case reports or case series articles that reported adverse events. One hundred forty-nine articles were rejected from further review for “topic:” These articles did not discuss ephedra or ephedrine, although they may have discussed phenylpropanolamine, pseudoephedrine, or caffeine, or provided general background on herbal medicine, weight loss, or athletic performance enhancement. One hundred one other articles were rejected for “subject.” They discussed use of ephedra or ephedrine for other purposes, such as bronchial or cold medication. Sixty-eight more were rejected for “population.” Nearly all were animal studies. Another four articles were not actually articles but government documents or public testimony, and three other articles were duplicates of articles already on file. Seventy-five additional articles were rejected for design, including previous reviews of ephedra or ephedrine, descriptions of its chemical properties, editorials, commentaries, letters to journal editors that did not report new cases, and newspaper or trade journal stories.
The adverse events analysis includes 52 controlled trials and 65 of the 71 case reports/case series articles (six articles were rejected because they were duplicates of articles or reports already included in the analysis).
| Disposition of trials | Number of Trials |
|---|---|
| Total retained in meta-analysis | 20 |
| Total dropped from meta-analysis | 24 |
| Reasons for dropping trials from meta-analysis: | |
 Duration of treatment less than eight weeks | 18 |
| Ephedrine dose did not vary between study arms | 1 |
| Cross-over study without data available prior to the cross-over point | 1 |
| Insufficient statistics | 3 |
| Inappropriate outcome (weight gain) | 1 |
Ephedrine versus placebo
Ephedrine plus caffeine versus placebo
Ephedrine plus caffeine versus ephedrine alone
Ephedrine versus another active pharmaceutical for weight loss
Ephedra versus placebo
Ephedra plus herbs containing caffeine versus placebo
For the 16 trials that reported baseline sample sizes, the attrition rate in the treatment arms averaged 27 percent, whereas the attrition rate in the placebo arms averaged 29 percent. This difference was not statistically significant. Five trials reported more dropouts from the treatment than from the placebo group: Four of these trials reported a statistically significant benefit for the treatment, and one did not. Eight trials reported more dropouts from the placebo group than the treatment group. Five of these trials reported a statistically significant benefit for treatment, whereas three did not. Three trials reported an equivalent number of dropouts from the treatment and placebo groups. No significant association was found between the frequency of favorable results and the relative proportion of dropouts in the treatment and placebo groups.
| Trial | Total n | Effect Size | 95% CI |
|---|---|---|---|
| Jensen88 | 17 | -1.52 | (-2.75, -0.29) |
| Lumholtz94 | 32 | -1.03 | (-1.78, -0.29) |
| Moheb84 | 64 | -0.49 | (-0.98, 0.01) |
| Pasquali85 | 19 | 0.00 | (-0.93, 0.93) |
| Pasquali85 | 24 | -0.42 | (-1.23, 0.39) |
| Quaade86 | 70 | -0.17 | (-0.64, 0.30) |
| Pooled Random Effect Estimate | -0.501 | (-0.85, -0.15) | |
Chi-squared test of heterogeneity p-value = 0.185
). The pooled average percent weight loss in the ephedrine-treated patients, compared to pretreatment weight, was 11 percent at 4 months.
A sensitivity analysis on only those trials that scored three or higher on the Jadad scale yielded a pooled estimate of effect substantially lower than the main analysis (effect size = -0.20); this difference was statistically significant (p= 0.049). All of these trials had an attrition rate greater than 20 percent; therefore, no sensitivity analysis on attrition could be performed. A final sensitivity analysis, in which the trial by Moheb84 was dropped, did not materially change these results.
| Trials | Adjusted Rank Correlation Test p-value | Regression Asymmetry Test p-value |
|---|---|---|
| Ephedrine vs. placebo | 0.45 | 0.82 |
| Ephedrine + caffeine vs. placebo | 0.30 | 0.12 |
| Ephedrine + caffeine vs. ephedrine alone | N.C. | N.C. |
| Ephedrine vs. another weight loss therapy | N.C. | N.C. |
| Ephedra + herbs containing caffeine vs. placebo | 0.73 | 0.23 |
N. C. = not calculated due to the small number of trials available.
| Trial | Total n | Effect Size | 95% CI |
|---|---|---|---|
| Astrup111 | 12 | -0.72 | (-1.88, 0.45) |
| Buemann92 | 32 | -0.55 | (-1.26, 0.16) |
| Daly103 | 24 | -0.65 | (-1.47, 0.18) |
| Jensen88 | 18 | -1.84 | (-3.10, -0.57) |
| Kalman96 | 25 | -0.46 | (-1.25, 0.34) |
| Kettle90 | 77 | -0.40 | (-0.85, 0.05) |
| Malchow-Moll87 | 69 | -1.14 | (-1.65, -0.63) |
| Moheb84 | 96 | -0.76 | (-1.20, -0.32) |
| Molnar112 | 29 | -1.35 | (-2.16, -0.54) |
| Quaade86 | 70 | -0.50 | (-0.98, -0.03) |
| Roed95 | 94 | -1.38 | (-1.83, -0.92) |
| Van Mil91 | 32 | -1.00 | (-1.74, -0.27) |
| Pooled Random Effect Estimate | -0.851 | (-1.08, -0.61) | |
Chi-squared test of heterogeneity p-value = 0.073
).
We interpret these data to indicate that the use of ephedrine is associated with a statistically significant increase in weight loss (1.3 pounds of weight loss per month) compared with that of placebo for up to four months of use.
We identified 12 trials that assessed the effect of ephedrine plus caffeine versus placebo for weight loss.84, 86–88, 90–92, 95, 96, 103, 111, 112 Six trials 86, 87, 92, 95, 96, 112 had scores of three or greater on the Jadad scale, a threshold that in other settings has been associated with less bias.83 Seven were described as randomized, double blind, placebo-controlled trials. Four of the trials measured weight loss at two months, four trials measured it at three months, and five trials measured it at four months. The random effects pooled estimate of the rate of weight loss per month was an effect size of -0.85 (95% CI: -1.1, -0.61), which translates to a weight loss of 2.2 pounds per month above that with placebo (Table 11 and Figure 11
). The pooled average percent weight loss in the ephedrine plus caffeine treated patients, compared to pretreatment weight, was 11 percent at 4 months.
A sensitivity analysis on only those trials that scored three or greater on the Jadad score yielded a result similar to the main analysis. Another sensitivity analysis on only those trials that had less than 20 percent attrition yielded a similar pooled estimate effect size of -0.74 (95% CI: -1.2, -0.3). Two trials96, 112 in this category were randomized, double-blind, placebo-controlled trials with an attrition rate of less than 20 percent. The first112 reported an effect somewhat greater than the main analysis (effect size = -1.35; 95% CI: -2.2, 0.54). The second96 had a smaller effect (effect size = -0.46; 95% CI: -1.3, 0.34). A fourth sensitivity analysis in which the trial by Moheb84 was dropped did not change the result compared with the primary analysis, nor did sensitivity analyses that dropped trials that also included synephrine or aspirin.
In our dose analysis, there was a trend toward increased weight loss with higher doses (weight loss greater than placebo of 2.0, 2.2, and 2.6 pounds per month for low, medium, and high doses, respectively) but these differences were not statistically significant. Neither visual nor graphical tests revealed any evidence of publication bias (See Table 11 and Figure 12
).
We interpret these data to indicate that the use of the combination of ephedrine and caffeine is associated with a significantly greater (2.2 pound) weight loss per month than is associated with placebo, for up to four months duration.
). There were too few trials to perform any sensitivity analysis.
We interpret these data to indicate that addition of caffeine to ephedrine is associated with a statistically significant increase in weight loss per month of about 0.8 pounds, over that attributable to ephedrine alone.
| Trial | Total n | Effect Size | 95% CI |
|---|---|---|---|
| Donikyan114 | 154 | -0.69 | (-1.02, -0.37) |
). The pooled average percent weight loss in the ephedra-treated patients, compared to pretreatment weight, was 5.2 percent at four months. A sensitivity analysis for only those trials that scored three or more on the Jadad scale yielded a result similar to the main analysis. All studies assessed medium doses of ephedra; therefore no analysis of dose effect was possible. Neither visual nor graphical tests revealed any evidence of publication bias (Table 11 and Figure 15).
We interpret these data to indicate that the use of a combination of ephedra plus herbs containing caffeine is associated with a statistically significant increase in weight loss per month of 2.1 pounds compared with that of placebo, for up to four months duration.
| Comparison Versus Placebo | Pooled Monthly Weight Loss Versus Placebo (lbs) | 95% CI | p-value for Test Versus Ephedra + Herbs Containing Caffeine |
|---|---|---|---|
| Ephedrine | -1.3 | (-2.1, -0.43) | 0.17 |
| Ephedra + herbs containing caffeine | -2.1 | (-2.8, -1.3) | N.C. |
| Ephedrine + caffeine | -2.2 | (-2.8, -1.7) | 0.75 |
N.C. = Not calculated as this is the comparison group.
. The table shows the pooled monthly weight loss in pounds and its confidence interval for each comparison group versus placebo. All are significantly different from zero, indicating that all treatments are associated with an increased weight loss as compared to placebo. The last column, which compares ephedrine alone, ephedrine plus caffeine, and ephedra plus herbs containing caffeine, shows no significant differences among these treatments. Figure 16 lists the comparison groups in order of least effective versus placebo (left) to most effective (right). The individual effect sizes converted to pounds within each comparison are plotted vertically as circles, with the circle area inversely proportional to trial variance. We connect the pooled-effect sizes in pounds within each comparison group by line segments, showing the visible downward trend from left to right.
These data indicate that both ephedrine plus caffeine and ephedra plus herbs containing caffeine are somewhat more effective than ephedrine alone in promoting weight loss and that there is no difference in effect between ephedrine plus caffeine and ephedra plus herbs containing caffeine. To help put these data in context, we note that placebo-controlled trials of some FDA-approved weight loss pharmacotherapies have shown losses of 6–10 pounds more than placebo, over 6–12 months, for patients taking sibutramine117–120 or orlistat;121–125 or 16 pounds more than placebo, at 9 months, for patients taking phentermine.126
We found eight published controlled trials of the effects of synthetic ephedrine on athletic performance; most were crossover designs, and all but one also included caffeine. One trial,127 which assessed the effect of ephedrine and exercise training on basal metabolic rate but did not report athletic performance outcomes, is not described below. The remaining seven trials were not appropriate for pooled analysis because they included various types of exercise and outcome measures. Thus, they are discussed here individually. We found no trials of the effect of herbal ephedra on athletic performance.
| Reference | Compounds | Type of Exercise | Results |
|---|---|---|---|
| Bell, Jacobs & Zamecnik128 | Placebo | Cycle ergometer trials to exhaustion | E+C significantly increased time to exhaustion compared to placebo. Heart rate during exercise was significantly increased for E+C, caffeine arms. |
| 1 mg/kg Ephedrine | |||
| 5 mg/kg Caffeine | |||
| 1mg/kg Ephedrine + 5 mg/kg Caffeine (E+C) | |||
| Bell & Jacobs130 | Placebo | Canadian Forces Warrior Test - 3.2 km run wearing 11 kg equipment | E+C trial run times were significantly faster than control and placebo trials. |
| 75 mg Ephedrine + 375 mg Caffeine (E+C) | |||
| Bell, Jacobs, McLellan, Miyazakie, and Sabiston131 | Placebo | Treadmill walking at 50% VO2 peak, 40 degrees celsius climate, 30% relative humidity | E+C did not significantly change tolerance times when compared to placebo. E+C did not affect skin or rectal temperature, sweat rate, or sensation of thermal comfort. |
| 1 mg/kg Ephedrine + 5 mg/kg Caffeine (E+C) | |||
| Bell, Jacobs, McLellan & Zamecnik129 | Placebo | Cycle ergometer trials to exhaustion at 85% VO2 peak | A lower dose of E+C resulted in ergogenic effect similar in magnitude to those reported previously with a higher dose, with fewer side effects. |
| 5 mg/kg Caffeine + 0.8 mg/kg Ephedrine | |||
| 4 mg/kg Caffeine + 1 mg/kg Ephedrine | |||
| 4 mg/kg Caffeine + 0.8 mg/kg Ephedrine | |||
| Pasternak, Jacobs & Bell132 | Placebo | Three supersets of leg press & bench press, to exhaustion | Ephedrine, E+C increased muscular endurance, but only in the first set. Systolic blood pressure was increase with ephedrine, E+C. |
| 0.8 mg/kg Ephedrine | |||
| 4 mg/kg Caffeine | |||
| 0.8mg/kg Ephedrine + 4 mg/kg Caffeine (E+C) | |||
| Bell, Jacobs & Ellerington133 | Placebo | Two different cycle ergometer tests, one was to exhaustion at 125% VO2 peak | Ephedrine improved performance during Wingate test of anaerobic power. Caffeine increased time to exhaustion in second test. |
| 1 mg/kg Ephedrine | |||
| 5 mg/kg Caffeine | |||
| 1 mg/kg Ephedrine + 5 mg/kg Caffeine (E+C) | |||
A trial by Sidney134 assessed the effects of ephedrine versus placebo or no treatment (for baseline measures) on performance on a variety of physical function tests among 21 healthy young men. No statistical differences were seen among the groups on performance of any of the tests, including VO2, measures of endurance and power, reaction time, hand-eye coordination, speed, and self-perceived exertion. These results agree with the finding by Bell and colleagues that ephedrine alone did not demonstrate significant effects on athletic performance.
In conclusion, the effects of ephedrine on athletic performance have not been well studied. The populations studied have been small and exclusively male, and the method of administration of ephedrine does not replicate the patterns of use reported for the general public. Effects of ephedrine on exercise performance are most often studied acutely (e.g., one to two hours after a single dose) in contrast to assessing the effects of chronic use on conditioning and performance. The one trial that did assess the effect on strength training did not find a sustained benefit of ephedrine supplementation. In addition, to show even a short-term effect of ephedrine, combination with caffeine was required. We identified no trials that assessed the sustained effect of ephedrine on aerobic conditioning or strength training and no trials that tested the effects of herbal ephedra on athletic performance.
We initially considered all 52 clinical trials of ephedra and ephedrine for the safety assessment. Two trials were excluded from the odds ratio meta-analysis because they did not contain a placebo group.113, 138 Numerous symptoms were reported as adverse events. We grouped clinically similar symptoms as follows:
Psychiatric symptoms: those symptoms described in the original clinical trials as “euphoria,” “neurotic behavior,” “agitation,” “neuropsychiatric,” “depressed mood,” “giddiness,” “irritability,” and “anxiety;”
Autonomic hyperactivity: those symptoms described in the original clinical trials as “tremor,” “twitching,” “jitteriness,” “insomnia,” “difficulty sleeping,” “sweating,” “increased sweating,” and “increased perspiration;”
Nausea/ vomiting: those symptoms described in the original clinical trials as “nausea,” “vomiting,” “abdominal pain,” “upset stomach,” “heartburn,” and “gastroesophageal reflux;”
Palpitations: those symptoms described in the original clinical trials as “palpitations,” “irregular heartbeat,” “loud heartbeat,” “heart pounding,” and “increased or stronger heartbeat;”
Tachycardia: those symptoms described in the original clinical trials as “tachycardia” and “slightly elevated heart rate;”
Hypertension: those symptoms described in the original clinical trials as “hypertension,” “increased systolic blood pressure,” and “increased diastolic blood pressure;” and
Headache.
| Adverse Events | # of Trials | Placebo | Intervention Groups | Pooled OR 95% CI | ||
|---|---|---|---|---|---|---|
| # Adverse Events | Sample Size | # Adverse Events | Sample Size | |||
| Psychiatric symptoms | 8 | 16 | 273 | 59 | 351 | 3.64 (1.91, 7.31) |
| Autonomic hyperactivity | 13 | 39 | 365 | 138 | 587 | 3.37 (2.19, 5.31) |
| Palpitations | 11 | 18 | 386 | 51 | 563 | 2.29 (1.27, 4.32) |
| Hypertension | 5 | 3 | 257 | 7 | 305 | 2.19 (0.49,13.34) |
| Upper gastrointestinal symptoms | 10 | 46 | 432 | 88 | 568 | 2.15 (1.39, 3.38) |
| Headache | 5 | 8 | 123 | 16 | 185 | 1.64 (0.62, 4.68) |
| Tachycardia | 1 | 0 | 45 | 6 | 90 | N.R. |
N.R. = not reported.
| Other Adverse Events | # of Trials | Placebo | Intervention Groups | ||
|---|---|---|---|---|---|
| # Adverse Events | Sample Size | # Adverse Events | Sample Size | ||
| Bundle branch block | 1 | 0 | 33 | 0 | 49 |
| Concentration difficulties | 5 | 17 | 257 | 18 | 391 |
| Constipation | 5 | 8 | 139 | 15 | 215 |
| Diarrhea | 3 | 3 | 81 | 3 | 114 |
| Dry mouth | 5 | 4 | 111 | 22 | 174 |
| Fatigue, weakness | 2 | 4 | 49 | 6 | 64 |
| Postural hypotension | 1 | 1 | 45 | 4 | 90 |
| Syncope | 1 | 0 | 45 | 1 | 90 |
| Ventricular events | 1 | 3 | 84 | 3 | 83 |
No serious adverse events (e.g., death, myocardial infarction, stroke, etc.) were reported in the 52 clinical trials that reported sample sizes. Therefore, the rate for these adverse events is zero. Even in aggregate, these trials had sufficient statistical power only to detect a serious adverse event rate of 1.0 in 1000, given the small numbers of patients studied in these trials. For trials of ephedra, statistical power in aggregate was sufficient only to detect a rate of serious adverse events of 4.0 in 1000. A conventional definition of a “rare” adverse event is about 1 in 1000. We also note that these data come from patients enrolled in clinical trials: Data from the pharmaceutical literature support the contention that patients taking pharmaceuticals outside of clinical trials may have a greater risk of particular adverse events than do patients selected to participate in clinical trials.139 Therefore, in community practice, the rate for serious adverse events may be higher than that seen in clinical trials.
Because, even in aggregate, the numbers of subjects enrolled in clinical trials have been too small to assess the possibility of rare but serious side effects, we assessed case reports of serious events allegedly associated with ephedra use.
| Data type | Event | ||||
|---|---|---|---|---|---|
| Death | Stroke | MI | Other | Total | |
| Available data | 71 (5.3%)* | 54 (4.0%) | 33 (2.5%) | 1,186 (88.2%) | 1,344 (100%) |
| Data dated after Sept. 30, 2001 | 17 (12.4%) | 15 (10.9%) | 5 (3.7%) | 100 (73.0%) | 137 (100%) |
| Unavailable data | 4 (1.9%) | 18 (8.4%) | 9 (4.2%) | 183 (85.5%) | 214 (100%) |
| Total | 92 (5.4%) | 87 (5.1%) | 47 (2.8%) | 1,469 (86.7%) | 1,695 (100%) |
Number of events (row percent).
Chi-squared test of independence p-value < 0.001.
Note: summary data were available for AERs beyond Sept 30, 2001. Detailed, redacted records were only available for AERs up through Sept 30, 2001.
is a graphical representation of the case report evidence used in the safety assessment. The first master list produced by the FDA's Office of Nutritional Products, Labeling, and Dietary Supplements contained 1,848 adverse event reports. The second master list, from which events associated with ephedrine were removed, contained 1,783 reports. When we combined event reports of identical ID number but different products, we reduced the observations by 88 to 1,695 total observations but did not lose any data. In addition, we removed 137 reports listed in the master Excel file as having been filed after our September 30, 2001 cut-off date. The master Excel list also contained 214 reports (dated before September 30, 2001) for which no PDF data files existed on the CDs. Because documentation was essential for review of each report, these reports were removed from our analysis, which left 1,344 reports in our final dataset. In Table 21, we show the result of a chi-squared test of independence, which tests the association between the type of event distribution (death; stroke; myocardial infarction; other) and the type of data (available; after September 30, 2001; not available). This test rejected the null hypothesis of no association (p < 0.001), indicating that the distribution of events was different for the different data types. Thus, bias may exist, because the events we included were different in type than those we had to exclude. Since more cases of death were reported, as a percentage of total cases, in the data subsequent to September 2001, it is possible that our results would be different had we had the opportunity to include the cases filed after September 2001.
To the 1,344 unique and available reports that met the cut-off date (Batch 1), the FDA added another 125 reports (Batch 2) that consisted predominately of adverse events related to ephedrine. Together, 1,469 reports from the FDA MedWatch files were reviewed. Within the 1,344 reports from Batch 1, 158 cases reported on the most serious adverse events (death, stroke, and myocardial infarction), and 1,186 reported on other adverse events according to the master Excel spreadsheet. Of the 1,186 case reports, we found 944 reports that fit the categories of “other serious cardiovascular,” other serious neurological," and “psychiatric.” (We did not examine the remaining 242 adverse event reports because the descriptors in the master excel spreadsheet appeared to fall outside our focus of serious adverse events.) The 944 reports contained data on 975 subjects, of which 925 reported taking ephedra. From the brief review, we determined that 164 of these subjects reported events serious enough (ventricular tachycardia/fibrillation, cardiac arrest, pulmonary arrest, transient ischemic attack, brain hemorrhage, seizure, or psychiatric symptoms) to warrant including their file in the more detailed review. Within the 125 reports of Batch 2 (reporting on 130 subjects), we found 106 subjects reporting ephedra or ephedrine use. Thirty-three of those subjects reported events serious enough (ventricular tachycardia/fibrillation, cardiac arrest, pulmonary arrest, transient ischemic attack, brain hemorrhage, seizure, or psychiatric symptoms) to warrant including their file in the more detailed review.
Of the 530 articles retrieved from the medical literature for this report, 195 described adverse events. Of the 195, sixty-five were rejected from the adverse events analysis for the following reasons: 23 were descriptive; 20 were review articles; two were not controlled trials; 18 were RCTs or CCTs of ephedrine use in normal persons or patients with asthma or nasal congestion or its use in labor and delivery, measuring either acute mental or physical effects or pharmacokinetics; one was a study of pharmacokinetics and cardiovascular effects of ephedra in normal adults; and one was an RCT of intramuscular ephedrine during spinal anesthesia for caesarean section. Of the remaining 130 articles reporting adverse events, 59 articles reported on 52 RCTs or CCTs. These articles contributed to the adverse events analysis already discussed. Seventy-one were case report or case series articles reporting adverse events; however, six articles were found to be duplicates of articles already included in the analysis.
From all sources, 84 deaths, 26 myocardial infarctions, 56 cerebral vascular accidents (strokes or cerebral hemorrhage), 30 “other cardiac” events, eight “other neurological” events, 40 cases of seizure, and 91 cases of psychiatric events. We identified two deaths, three myocardial infarctions, nine cerebrovascular accidents, three seizures, and five psychiatric cases as sentinel events with prior ephedra consumption. Three deaths, two myocardial infarctions, two cerebrovascular accidents, one seizure, and three psychiatric cases were identified as sentinel events with prior ephedrine consumption. We identified an additional 43 cases as possible sentinel events with prior ephedra consumption and an additional seven cases as possible sentinel events with prior ephedrine consumption. About half of the sentinel events occurred in persons aged 30 years or younger. Classification as a sentinel event does not imply a proven cause and effect relationship.
| Event type | Product | Investigation for Etiology | RAND Classification |
|---|---|---|---|
| Report date | Dose* | ||
| Age, sex | Timing; Duration | ||
| Consituent | |||
| Source | |||
| (ID) | |||
| Death | Hydroxycut | Autopsy conducted: Yes | Sentinel event |
| 11/03/1999 | 10.0 mg | ||
| 21 yo Male | <6 hours; < 48 hours | ||
| Ephedra | Ripped Fuel | ||
| FDA Case | Unknown | ||
| (13914) | Not described; not described | ||
| Death | Slacker II | Autopsy conducted: Yes | Sentinel event |
| 09/26/2000 | Unknown | ||
| 22 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (14390) | |||
| Death | MiniTabs | Autopsy conducted: Yes | Sentinel event |
| 30 yo Female | 250.0 mg | ||
| Ephedrine | Not described; >60 days (chronic) | ||
| FDA Case | |||
| (3275432) | |||
| Death | Max Brand Two-Way | Autopsy conducted: Yes | Sentinel event |
| 33 yo Male | 150.0 mg | ||
| Ephedrine | Not described; Not described | ||
| FDA Case | |||
| (3289590) | |||
| Death | Insufficient information | Autopsy conducted: Yes | Sentinel event |
| 28 yo Male | Unknown | ||
| Ephedrine | <24 hours; >60 days (chronic) | ||
| Literature Case | |||
| (348) | |||
| Death | Nature's Nutrition-Formula One | Autopsy conducted: Yes | Possible sentinel event |
| 05/19/1994 | Unknown | ||
| 36 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (9508) | |||
| Death | Nature's Nutrition-Formula One | Autopsy conducted: Yes | Possible sentinel event |
| 03/09/1995 | Unknown | ||
| 32 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (10276) | |||
| Death | Ripped Fuel | Autopsy conducted: Yes | Possible sentinel event |
| 07/25/1997 | 43.2 mg | ||
| 38 yo Male | <6 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (12485) | |||
| Death | Thermogenics Plus | Autopsy conducted: Yes | Possible sentinel event |
| 12/19/1997 | 23.1 mg | ||
| 21 yo Male | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (12722) | |||
| Death | Ripped Fuel | Autopsy conducted: Yes | Possible sentinel event |
| 04/11/1998 | 40.0 mg | ||
| 15 yo Female | <6 hours; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (12843) | |||
| Death | Ripped Fuel | Autopsy conducted: Yes | Possible sentinel event |
| 08/03/1999 | Unknown | ||
| 26 yo Male | Not described; 2–13 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (13906) | |||
| Death | Diet Fuel | Autopsy conducted: Yes | Possible sentinel event |
| 02/16/2000 | 26.6 mg | ||
| 26 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (14019) | |||
| Death | Hydroxycut | Autopsy conducted: Yes | Possible sentinel event |
| 01/09/2001 | 20.0 mg | ||
| 35 yo Male | 6–24 hours; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (14638) | |||
| Death | Ripped Fuel | Autopsy conducted: Yes | Possible sentinel event |
| 23 yo Male | 50.0 mg | ||
| Ephedra | Not described; >60 days (chronic) | ||
| Literature Case | |||
| (258) | |||
| Death | Street drug (“speed”) | Autopsy conducted: Yes | Possible sentinel event |
| 42 yo Male | 306.0 mg | ||
| Ephedrine | Not described; >60 days (chronic) | ||
| Literature Case | |||
| (44) | |||
| Death | Unknown | Autopsy conducted: Yes | Possible sentinel event |
| 84 yo Female | Unknown | ||
| Ephedrine | Not described; Not described | ||
| Literature Case | |||
| (44) | |||
| Death | Insufficient information | Autopsy conducted: Yes | Possible sentinel event |
| Literature Case | Unknown | ||
| Ephedrine | <24 hours; 14–60 days (acute) | ||
| 44 yo Male | |||
| (224) | |||
| Death | Ephedrine | Autopsy conducted: No | Intraoperative ephedrine |
| 31 yo Female | Unknown | ||
| Ephedrine | <6 hours; <48 hours | ||
| FDA Case | |||
| (313104) | |||
| Death | Insufficient information | Autopsy conducted: Yes | Suicide |
| 30 yo Female | Unknown | ||
| Literature Case | Not described; Not described | ||
| (17) | |||
| Death | Insufficient information | Autopsy conducted: Yes | Suicide |
| 19 yo Female | Unknown | ||
| Literature Case | <6 hours; Not described | ||
| (96) | |||
| Death | Insufficient information | Autopsy conducted: Yes | Suicide |
| 21 yo Male | Unknown | ||
| Literature Case | <6 hours; Not described | ||
| (96) | |||
| Death | Ripped Fuel | Autopsy conducted: Yes | Probably not related |
| 06/11/1999 | Unknown | ||
| 24 yo Male | <6 hours; < 48 hours | ||
| Ephedra | |||
| FDA Case | |||
| (13672) | |||
| Death | Max Alert | Autopsy conducted: No | Probably not related |
| 40 yo Male | Not described | ||
| Ephedrine | Not described | ||
| FDA Case | |||
| (1859087) | |||
| Death | Unknown | Autopsy conducted: Yes | Probably not related |
| Not described | Not described | ||
| yo Male | Not described | ||
| Ephedrine | |||
| FDA Case | |||
| (1902493) | |||
| Death | Insufficient information | Autopsy conducted: Yes | Probably not related |
| 30 yo Male | Unknown | ||
| Ephedrine | Not described; Not described | ||
| FDA Case | |||
| (3491515) | |||
| Death | Insufficient information | Autopsy conducted: Yes | Probably not related |
| 29 yo Male | Unknown | ||
| Ephedrine | Not described; Not described | ||
| FDA Case | |||
| (3772362) | |||
| Death | Cybergenics Body Builder | Autopsy conducted: No | Insufficient information |
| 03/10/1994 | Unknown | ||
| 23 yo Male | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (9188) | |||
| Death | Asian Herbal High Energy | Autopsy conducted: No | Insufficient information |
| 06/09/1994 | Unknown | ||
| 44 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (9327) | |||
| Death | Nature's Nutrition-Formula One | Autopsy conducted: No | Insufficient information |
| 06/14/1994 | Unknown | ||
| 43 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | Nature Nutritional Complex 1 | ||
| FDA Case | Unknown | ||
| (9395) | Not described; Not described | ||
| Death | Nature's Nutrition-Formula One | Autopsy conducted: No | Insufficient information |
| 06/20/1994 | Unknown | ||
| 36 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (9473) | |||
| Death | Nature's Nutrition-Formula One | Autopsy conducted: No | Insufficient information |
| 05/24/1994 | Unknown | ||
| 43 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (9506) | |||
| Death | Nature's Nutrition-Formula One | Autopsy conducted: Yes | Insufficient information |
| 09/07/1994 | Unknown | ||
| 45 yo Male | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (9864) | |||
| Death | Natural Trim | Autopsy conducted: Yes | Insufficient information |
| 04/07/1995 | Unknown | ||
| 26 yo Male | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (10104) | |||
| Death | Omnitrition Herbal Tea | Autopsy conducted: Yes | Insufficient information |
| 01/12/1993 | 39.0 mg | ||
| 43 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (10251) | |||
| Death | New Image Plus | Autopsy conducted: No | Insufficient information |
| 06/14/1995 | Unknown | ||
| 61 yo Female | >24 hours; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (10296) | |||
| Death | Cybertrim | Autopsy conducted: Yes | Insufficient information |
| 12/19/1994 | Unknown | ||
| 20 yo Male | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (10448) | |||
| Death | Unknown E'ola Product | Autopsy conducted: No | Insufficient information |
| 03/15/1995 | Unknown | ||
| 17 yo Female | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (10849) | |||
| Death | The Equillizer- Part B | Autopsy conducted: No | Insufficient information |
| 03/14/1996 | Unknown | ||
| 20 yo Male | <6 hours; < 48 hours | ||
| Ephedra | |||
| FDA Case | |||
| (10862) | |||
| Death | Quickshot | Autopsy conducted: No | Insufficient information |
| 04/08/1996 | Unknown | ||
| 67 yo Male | Not described; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (10902) | |||
| Death | Omni-Trim (Omni-Trim Int'l) | Autopsy conducted: No | Insufficient information |
| 04/12/1996 | Unknown | ||
| 29 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (11018) | |||
| Death | Nature's Nutrition-Formula One | Autopsy conducted: No | Insufficient information |
| 02/16/1996 | Unknown | ||
| 64 yo Female | >24 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (11060) | |||
| Death | Ripped Fuel | Autopsy conducted: Yes | Insufficient information |
| 05/20/1996 | 60.0 mg | ||
| Not described | Not described; >60 days (chronic) | ||
| yo Male | |||
| Ephedra | |||
| FDA Case | |||
| (11134) | |||
| Death | Nature's Nutrition-Formula One 42.4 mg | Autopsy conducted: No | Insufficient information |
| 05/13/1996 | Not described; >60 days (chronic) | ||
| 37 yo Male | Equillizer Fast Start | ||
| Ephedra | Unknown | ||
| FDA Case | >24 hours; >60 days (chronic) | ||
| (11248) | Not described | ||
| Unknown | |||
| Not described; Not described | |||
| Death | Herbalife Original Green | Autopsy conducted: No | Insufficient information |
| 07/11/1996 | 26.4 mg | ||
| 59 yo Male | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (11307) | |||
| Death | Herbalife Original Green | Autopsy conducted: No | Insufficient information |
| 06/25/1996 | Unknown | ||
| 34 yo Female | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (11417) | |||
| Death | Ripped Fuel | Autopsy conducted: No | Insufficient information |
| 07/23/1996 | 51.4 mg | ||
| 27 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (11441) | |||
| Death | Cybergenic super anti-fatigue | Autopsy conducted: No | Insufficient information |
| 07/12/1996 | 3.3 mg | ||
| 24 yo Male | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (11444) | |||
| Death | Easy Trim | Autopsy conducted: No | Insufficient information |
| 10/07/1996 | Unknown | ||
| 56 yo Female | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (11721) | |||
| Death | Escalation | Autopsy conducted: Yes | Insufficient information |
| 08/25/1997 | Unknown | ||
| 32 yo Female | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (12506) | |||
| Death | Ripped Fuel | Autopsy conducted: No | Insufficient information |
| 10/06/1997 | 20.0 mg | ||
| 0 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (12594) | |||
| Death | Ripped Fuel | Autopsy conducted: Yes | Did not meet temporal relationship criterion |
| 12/19/1997 | Unknown | ||
| 22 yo Male | >24 hours; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (12720) | |||
| Death | Herbalife Original Green | Autopsy conducted: No | Insufficient information |
| 04/23/1998 | 42.0 mg | ||
| 34 yo Male | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (12859) | |||
| Death | Diet Fuel | Autopsy conducted: No | Insufficient information |
| 04/24/1998 | 20.1 mg | ||
| 46 yo Male | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (12871) | |||
| Death | Ripped Fuel | Autopsy conducted: No | Insufficient information |
| 07/11/1998 | 63.6 mg | ||
| 43 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (13021) | |||
| Death | Metabolife 356 | Autopsy conducted: Yes | Insufficient information |
| 09/16/1998 | Unknown | ||
| 37 yo Female | Not described; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (13096) | |||
| Death | Thin Tabs | Autopsy conducted: Yes | Insufficient information |
| 10/08/1998 | Unknown | ||
| 49 yo Female | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (13127) | |||
| Death | Ultimate Orange | Autopsy conducted: No | Insufficient information |
| 02/27/1999 | Unknown | ||
| 18 yo Male | <6 hours; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (13380) | |||
| Death | Metabolife 356 | Autopsy conducted: No | Insufficient information |
| 05/19/1999 | 60.0 mg | ||
| 49 yo Male | Not described; < 48 hours | ||
| Ephedra | |||
| FDA Case | |||
| (13634) | |||
| Death | Metabolife 356 | Autopsy conducted: Yes | Did not meet temporal relationship criterion |
| 06/04/1999 | 72.0 mg | ||
| 40 yo Female | >24 hours; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (13706) | |||
| Death | Thermadrene | Autopsy conducted: No | Insufficient information |
| 06/30/1999 | Unknown | ||
| 37 yo Female | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (13762) | |||
| Death | Metabolife 356 | Autopsy conducted: No | Insufficient information |
| 08/06/1999 | Unknown | ||
| 59 yo Female | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (13802) | |||
| Death | Metabolife 356 | Autopsy conducted: Yes | Insufficient information |
| 08/03/1999 | Unknown | ||
| 37 yo Male | <6 hours; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (13806) | |||
| Death | Herbalife Original Green | Autopsy conducted: Yes | Insufficient information |
| 10/06/1999 | Unknown | ||
| 42 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (13901) | |||
| Death | Metabolife 356 | Autopsy conducted: No | Insufficient information |
| 10/13/1999 | Unknown | ||
| 62 yo Female | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (13993) | |||
| Death | Metabolife 356 | Autopsy conducted: Yes | Did not meet temporal relationship criterion |
| 04/04/2000 | Unknown | ||
| 29 yo Female | >24 hours; >60 days (chronic) | ||
| Ephedra | Omnitrition Herbal Tea | ||
| FDA Case | Unknown | ||
| (14113) | Not described; 14–60 days (acute) | ||
| Not described | |||
| Unknown | |||
| Not described; Not described | |||
| Death | Metabolift | Autopsy conducted: Yes | Insufficient information |
| 08/10/2000 | 60.0 mg | ||
| 32 yo Female | Not described; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (14323) | |||
| Death | Metabomax | Autopsy conducted: No | Insufficient information |
| 08/31/2000 | 72.0 mg | ||
| 46 yo Female | Not described; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (14347) | |||
| Death | Metabolife 356 | Autopsy conducted: No | Insufficient information |
| 09/14/2000 | Unknown | ||
| 40 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (14370) | |||
| Death | Thermogen Plus Liquid | Autopsy conducted: Yes | Insufficient information |
| 03/28/2000 | 72.0 mg | ||
| 56 yo Male | Not described; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (14465) | |||
| Death | Up Your Gas | Autopsy conducted: Not described | Insufficient information |
| 10/16/2000 | 34.2 mg | ||
| 46 yo Female | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (14470) | |||
| Death | Xenadrine | Autopsy conducted: Yes | Insufficient information |
| 11/14/2000 | 40.0 mg | ||
| 39 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (14498) | |||
| Death | Metabolife 356 | Autopsy conducted: No | Insufficient information |
| 11/18/2000 | 24.0 mg | ||
| 45 yo Female | >24 hours; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (14509) | |||
| Death | Diet 2X | Autopsy conducted: No | Insufficient information |
| 12/06/2000 | Unknown | ||
| 49 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (14561) | |||
| Death | Metabolife 356 | Autopsy conducted: Yes | Insufficient information |
| 12/24/2000 | 72.0 mg | ||
| 40 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (14585) | |||
| Death | Mini Thin | Autopsy conducted: Yes | Insufficient information |
| 03/18/2001 | 75.0 mg | ||
| 28 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | Yellow Jacket | ||
| FDA Case | Unknown | ||
| (14747) | Not described; >60 days (chronic) | ||
| Death | Metabolife 356 | Autopsy conducted: Yes | Insufficient information |
| 03/29/2001 | Unknown | ||
| 31 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (14808) | |||
| Death | Ephedrine | Autopsy conducted: No | Insufficient information |
| 3 yo Male | Unknown | ||
| Ephedrine | <6 hours; < 48 hours | ||
| FDA Case | |||
| (1772115) | |||
| Death | Unknown | Autopsy conducted: Yes | Insufficient information |
| 99 yo Male | Not described | ||
| Ephedrine | Not described | ||
| FDA Case | |||
| (1874879) | |||
| Death | MiniTabs | Autopsy conducted: Yes | Insufficient information |
| 30 yo Female | Unknown | ||
| Ephedrine | Not described; Not described | ||
| FDA Case | |||
| (3135225) | |||
| Death | Mini 2 Way Action | Autopsy conducted: Yes | Insufficient information |
| 46 yo Male | Unknown | ||
| Ephedrine | Not described; >60 days (chronic) | ||
| FDA Case | |||
| (3173538) | |||
| Death | Metabolift | Autopsy conducted: N/A | Insufficient information |
| 32 yo Female | Unknown | ||
| Ephedrine | <6 hours; Not described | ||
| FDA Case | |||
| (3551127) | |||
| Death | Diet 2X | Autopsy conducted: No | Insufficient information |
| 99 yo Female | Unknown | ||
| Ephedrine | Not described; 14–60 days (acute) | ||
| FDA Case | |||
| (3623625) | |||
| Death | Unknown | Autopsy conducted: No | Insufficient information |
| 44 yo Female | Not described | ||
| Ephedrine | Not described; >60 days (chronic) | ||
| FDA Case | |||
| (3768335) | |||
| Death | Ultimate Xphoria | Autopsy conducted: Not described | Insufficient information |
| 20 yo Male | Unknown | ||
| Literature Case | <6 hours; < 48 Hours | ||
| (462) | |||
dose reported in total daily alkaloids
yo = year old
| Event type | Product | Investigation for Etiology | RAND Classification |
|---|---|---|---|
| Report date | Dose* | ||
| Age, sex | Timing; Duration | ||
| Consituent | |||
| Source | |||
| (ID) | |||
| MI | Nature's Nutrition-Formula One | Angiography: Yes | Sentinel event |
| 03/20/1995 | Unknown | ||
| 45 yo Male | <6 hours; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (10024) | |||
| MI | Midnight Ecstacy | Angiography: Yes | Sentinel event |
| 23 yo Female | Unknown | ||
| Ephedrine | <6 hours; < 48 hours | ||
| FDA Case | |||
| (3446357) | |||
| MI | Ma huang | Angiography: Yes | Sentinel event |
| 30 yo Male | Unknown | ||
| Ephedra | <24 hours; Not described | ||
| Literature Case | |||
| (244) | |||
| MI | Dymetradine Xtreme | Angiography: Yes | Sentinel event |
| 19 yo Male | 48.0 | ||
| Ephedra | <6 hours; Not described | ||
| Literature Case | |||
| (516) | |||
| MI | Product unknown | Angiography: Yes | Sentinel event |
| 35 yo Female | Unknown | ||
| Ephedrine | <24 hours; 14–60 days (acute) | ||
| Literature Case | |||
| (224) | |||
| MI | E'ola Amp II Pro Drops | Angiography: Yes | Possible sentinel event |
| 04/22/1994 | Unknown | Note that this product was removed from the market- it contained illegal doses of ephedrine. | |
| 37 yo Male | <6 hours; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (9372) | |||
| MI | Nature's Nutrition-Formula One | Angiography: Yes | Possible sentinel event |
| 05/23/1994 | Unknown | ||
| 54 yo Male | 6–24 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (9504) | |||
| MI | Metabolift | Angiography: Yes | Possible sentinel event |
| 03/01/1995 | 50.0 mg | ||
| 35 yo Male | <6 hours; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (10009) | |||
| MI | Herbalife Original Green | Angiography: Yes | Possible sentinel event |
| 06/15/1998 | 25.6 mg | ||
| 38 yo Female | <6 hours; < 48 hours | ||
| Ephedra | |||
| FDA Case | |||
| (13009) | |||
| MI | Metabolife 356 | Angiography: Yes | Possible sentinel event |
| 04/18/2000 | Unknown | ||
| 37 yo Female | <6 hours; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (14114) | |||
| MI | Metab-O-Lite | Angiography: Yes | Possible sentinel event |
| 11/08/2000 | 72.0 mg | ||
| 43 yo Female | <6 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (14530) | |||
| MI | Ephedrine | Angiography: No | Intravenous injection of ephedrine |
| 25 yo Male | Unknown | ||
| Literature Case | <6 hours; Not described | ||
| (64) | |||
| MI | E'ola Amp II Pro Drops | Angiography: Yes | Insufficient information |
| 04/22/1994 | Unknown | ||
| 34 yo Female | Not described; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (9373) | |||
| MI | The Edge | Angiography: No | Insufficient information |
| 06/17/1994 | Unknown | ||
| Not described yo Male | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (9381) | |||
| MI | Nature's Nutrition-Formula One | Angiography: No | Insufficient information |
| 05/24/1994 | Unknown | ||
| 56 yo Female | >24 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (9512) | |||
| MI | Nature's Nutrition-Formula One | Angiography: Yes | Insufficient information |
| 08/26/1994 | Unknown | ||
| 49 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (9572) | |||
| MI | Nature's Nutrition-Formula One | Angiography: Yes | Insufficient information |
| 03/16/1995 | Unknown | ||
| 67 yo Female | Not described; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (10065) | |||
| MI | Omnitrition Herbal Tea | Angiography: Yes | Insufficient information |
| 07/03/1997 | 60.0 mg | ||
| 59 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (12452) | |||
| MI | Metabolife 356 | Angiography: Yes | Insufficient information |
| 04/21/1999 | 24.0 mg | ||
| 39 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (13532) | |||
| MI | Metabolife 356 | Angiography: No | Insufficient information |
| 08/05/1999 | Unknown | ||
| 51 yo Male | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (13815) | |||
| MI | Metabolife 356 | Angiography: No | Insufficient information |
| 04/06/2000 | Unknown | ||
| 30 yo Female | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (14123) | |||
| MI | Natural Herbal Energizer | Angiography: Yes | Insufficient information |
| 04/15/2000 | Unknown | ||
| 53 yo Male | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (14222) | |||
| MI | Diet Fuel | Angiography: Yes | Insufficient information |
| 07/05/2000 | 60.0 mg | ||
| 39 yo Male | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (14259) | |||
| MI | Xenadrine | Angiography: Yes | Insufficient information |
| 11/15/2000 | Unknown | ||
| 45 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | Thermocut | ||
| FDA Case | Unknown | ||
| (14521) | Not described; >60 days (chronic) | ||
| MI | Metabolife 356 | Angiography: No | Insufficient information |
| 12/02/2000 | Unknown | ||
| Not described yo Not described | Not described; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (14555) | |||
| MI | Metabolife 356 | Angiography: Yes | Insufficient information |
| 01/07/2001 | Unknown | ||
| 50 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (14645) | |||
dose reported in total daily alkaloids
yo = year old
| Event type | Product | Investigation of Etiology | RAND Classification |
|---|---|---|---|
| Report date | Dose* | ||
| Age, Sex | Timing; Duration | ||
| Constituent | |||
| Source | |||
| (ID) | |||
| CVA | Thermo Slim | Implicit review | Sentinel event |
| 01/03/1996 | Unknown | ||
| 26 yo Female | <6 hours; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (10874) | |||
| CVA | Power Trim | Implicit review | Sentinel event |
| 04/12/1996 | Unknown | ||
| 42 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (11062) | |||
| CVA | Trim Easy | Implicit review | Sentinel event |
| 04/17/1996 | 72.0 mg | ||
| 31 yo Female | 6–24 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (11105) | |||
| CVA | Ripped Fuel | Implicit review | Sentinel event |
| 09/04/1996 | 63.6 mg | ||
| 28 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (11675) | |||
| CVA | Ultimate Orange | Implicit review | Sentinel event |
| 06/16/1998 | Unknown | ||
| 39 yo Male | <6 hours; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (12980) | |||
| CVA | Ultimate Orange | Implicit review | Sentinel event |
| 12/31/1998 | 62.1 mg | ||
| 29 yo Male | <6 hours; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (13418) | |||
| CVA | Slim Caps | Implicit review | Sentinel event |
| 09/12/2000 | 24.0 mg | ||
| 53 yo Female | 6–24 hours; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (14372) | |||
| CVA | Xenadrine | Implicit review | Sentinel event |
| 10/20/2000 | Unknown | ||
| 46 yo Female | <6 hours; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (14473) | |||
| CVA | Thermadrene | Implicit review | Sentinel event |
| 33 yo Male | Unknown | ||
| Ephedra | 6–24 hours; Not described | ||
| Literature Case | |||
| (552) | |||
| CVA | Ephedrine | Implicit review | Sentinel event |
| 19 yo Female | Unknown | ||
| Ephedrine | <6 hours; Not described | ||
| Literature Case | |||
| (184) | |||
| CVA | “Purported amphetamine look-alike” | Implicit review | Sentinel event |
| 20 yo Female | Unknown | ||
| Ephedrine | <6 hours; < 48 Hours | ||
| Literature Case | |||
| (514) | |||
| CVA | E'ola Amp II Pro Drops | Implicit review | Possible sentinel event |
| 04/17/1992 | 75.0 mg | Note that this product was removed from the market- it contained illegal doses of ephedrine. | |
| 30 yo Female | <6 hours; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (9296) | |||
| CVA | E'ola Amp II Pro Drops | Implicit review | Possible sentinel event |
| 04/22/1994 | Unknown | Note that this product was removed from the market- it contained illegal doses of ephedrine. | |
| 56 yo Female | 6–24 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (9335) | |||
| CVA | Super Fat Burners | Implicit review | Possible sentinel event |
| 03/15/1995 | Unknown | ||
| 24 yo Female | 6–24 hours; <48 hours | ||
| Ephedra | |||
| FDA Case | |||
| (10094) | |||
| CVA | FitAmerica Natural Weight ControlAid | Implicit review | Possible sentinel event |
| 01/09/1998 | 100.0 mg | ||
| 64 yo Female | <6 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (12713) | |||
| CVA | Purple Blast | Implicit review | Possible sentinel event |
| 12/23/1997 | Unknown | ||
| 47 yo Male | <6 hours; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (12733) | |||
| CVA | Diet Phen | Implicit review | Possible sentinel event |
| 04/27/1998 | 13.5 mg | ||
| 41 yo Female | 6–24 hours; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (12888) | |||
| CVA | Natural Trim | Implicit review | Possible sentinel event |
| 09/13/2000 | 44.0 mg | ||
| 25 yo Female | 6–24 hours; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (14378) | |||
| CVA | Slim 'N Up | Implicit review | Possible sentinel event |
| 10/12/2000 | Unknown | ||
| 42 yo Male | 6–24 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (14434) | |||
| CVA/Subarachnoid hemorrhage | Metabolife 356 | Implicit review | Possible sentinel event |
| 11/16/2000 | Unknown | ||
| 55 yo Female | 6–24 hours; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (14553) | |||
| CVA | Ma huang | Implicit review | Possible sentinel event |
| 33 yo Male | 40 mg | ||
| Ephedra | 6–24 hours; 14–60 days | ||
| Literature Case | |||
| (270) | |||
| CVA | “Street drug” | Implicit review | Possible sentinel event |
| 37 yo Male | 153.0 mg | ||
| Ephedrine | Not described; 14–60 days (acute) | ||
| Literature Case | |||
| (44) | |||
| CVA | “Speed” | Implicit review | Possible sentinel event |
| 20 yo Male | Unknown | ||
| Ephedrine | <6 hours; Not described | ||
| Literature Case | |||
| (438) | |||
| CVA | Ephedrine | Not relevant | Intraoperative ephedrine |
| 29 yo Female | Unknown | ||
| Ephedrine | <6 hours; < 48 hours | ||
| FDA Case | |||
| (3720184) | |||
| CVA | Ephedrine | Not relevant | Intraoperative ephedrine |
| 45 yo Female | Unknown | ||
| Literature Case | <6 hours; < 48 hours | ||
| (485) | |||
| CVA | Nature's Nutrition-Formula One | Implicit review | Insufficient information |
| 05/12/1994 | Unknown | ||
| 36 yo Female | <6 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (9521) | |||
| CVA | Nature's Nutrition-Formula One | Not reviewed | Insufficient information |
| 06/22/1994 | Unknown | ||
| 52 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (9545) | |||
| CVA | Equillizer Fast Start | Not reviewed | Did not meet the temporal relationship criterion |
| 10/26/1994 | Unknown | ||
| 40 yo Female | >24 hours; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (9749) | |||
| CVA | Nature's Nutrition-Formula One | Not reviewed | Insufficient information |
| 09/14/1994 | Unknown | ||
| 49 yo Male | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (9865) | |||
| CVA | Nature's Nutrition-Formula One | Not reviewed | Insufficient information |
| 05/12/1995 | Unknown | ||
| 53 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (10187) | |||
| CVA | TriChromolean | Not reviewed | Insufficient information |
| 10/19/1995 | Unknown | ||
| 31 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (10477) | |||
| CVA | Thermoburn | Not reviewed | Insufficient information |
| 10/12/1995 | Unknown | ||
| 19 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (10508) | |||
| CVA | Metabolift | Not reviewed | Insufficient information |
| 02/07/1996 | 60.0 mg | ||
| 30 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (10893) | |||
| CVA | E'ola Amp II Pro Drops | Not reviewed | Insufficient information |
| 04/13/1996 | Unknown | ||
| 34 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (10957) | |||
| CVA | Natural Trim | Not reviewed | Insufficient information |
| 07/11/1996 | Unknown | ||
| 55 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (11306) | |||
| CVA | Herbalife Original Green | Not reviewed | Insufficient information |
| 07/18/1996 | Unknown | ||
| 39 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (11442) | |||
| CVA | E'ola Amp II Pro Drops | Not reviewed | Did not meet the temporal relationship criterion |
| 06/18/1996 | 21.5 mg | ||
| 35 yo Female | >24 hours; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (11619) | |||
| CVA | Herbalife Original Green | Not reviewed | Insufficient information |
| 08/21/1996 | Unknown | ||
| 33 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | AP300 | ||
| FDA Case | Unknown | ||
| (11706) | Not described; >60 days (chronic) | ||
| CVA | E'ola Amp II Pro Drops | Not reviewed | Insufficient information |
| 10/21/1996 | 36.8 mg | ||
| 69 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (12340) | |||
| CVA | Shape Fast | Not reviewed | Insufficient information |
| 06/05/1997 | 30.0 mg | ||
| 64 yo Female | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (12460) | |||
| CVA | Shape Fast | Not reviewed | Insufficient information |
| 08/01/1997 | 36.0 mg | ||
| 34 yo Female | Not described; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (12483) | |||
| CVA | Metabolife 356 | Not reviewed | Insufficient information |
| 04/22/1998 | Unknown | ||
| 43 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (12861) | |||
| CVA | Total Control | Not reviewed | Did not meet the temporal relationship criterion |
| 02/11/1999 | 66.0 mg | ||
| 47 yo Female | >24 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (13336) | |||
| CVA | Metacut | Not reviewed | Insufficient information |
| 02/01/1999 | 12.3 mg | ||
| 48 yo Female | Not described; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (13341) | |||
| CVA | Hydroxycut (Muscle Tech R&D) | Not reviewed | Did not meet the temporal relationship criterion |
| 06/01/1999 | 160.0 mg | ||
| 16 yo Male | >24 hours; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (13661) | |||
| CVA | Metabolife 356 | Not reviewed | Insufficient information |
| 06/23/1999 | Unknown | ||
| 18 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (13779) | |||
| CVA | Metabolife 356 | Not reviewed | Insufficient information |
| 08/03/1999 | Unknown | ||
| 24 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (13797) | |||
| CVA | Metabolife 356 | Implicit review | Insufficient information |
| 08/04/1999 | 48.0 mg | ||
| 30 yo Female | <6 hours; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (13829) | |||
| CVA | Metabolife 356 | Not reviewed | Insufficient information |
| 07/01/1999 | Unknown | ||
| 26 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (13837) | |||
| CVA | Metabolife 356 | Implicit review | Insufficient information |
| 10/27/1999 | Unknown | ||
| 36 yo Female | <6 hours; >60 days(chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (13905) | |||
| CVA | Ripped Fuel | Not reviewed | Insufficient information |
| 10/08/1998 | Unknown | ||
| Not described yo Female | Not described; Not described | ||
| Ephedra | |||
| FDA Case | |||
| (14056) | |||
| CVA | Metabolife 356 | Not reviewed | Insufficient information |
| 06/13/2000 | Unknown | ||
| 46 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | Xenadrine | ||
| FDA Case | Unknown | ||
| (14231) | Not described; 14–60 days (acute) | ||
| CVA | Slacker II | Not reviewed | Insufficient information |
| 10/03/2000 | Unknown | ||
| 21 yo Female | Not described; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (14431) | |||
| CVA | LiquiFit Exercise Drops | Not reviewed | Insufficient information |
| 01/16/2001 | 75.0 mg | ||
| 48 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (14632) | |||
| CVA | Ephedrine (“Maxi Thins”) | Implicit review | Insufficient information |
| 32 yo Female | Unknown | ||
| Ephedrine | Not described; >60 days (chronic) | ||
| FDA Case | |||
| (1823550) | |||
| CVA | “Over-the-counter anti-asthma pill” | Implicit review | Insufficient information |
| 68 yo Male | 60.0 mg | ||
| Literature Case | <6 hours; >60 days (chronic) | ||
| (515 ) | |||
dose reported in total daily alkaloids
yo = year old
| Event type | Product | Investigation for Etiology | RAND Classification |
|---|---|---|---|
| Report date | Dose* | ||
| Age, sex | Timing; Duration | ||
| Consituent | |||
| Source | |||
| (ID) | |||
| Cardiac/Near sudden death | Ripped Force | Angiography: No | Possible sentinel event |
| 04/08/1998 | 20.4 mg | ||
| 22 yo Male | 6–24 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (12851) | |||
| Cardiac/Cardiomyopathy | Ephedrine | Angiography: Yes | Possible sentinel event |
| 28 yo Female | 2000.0 mg | ||
| Literature Case | Not described; >60 days (chronic) | ||
| (110 ) | |||
| Cardiac/Cardiomyopathy | Herbalife Original Green | Angiography: Yes | Possible sentinel event |
| 39 yo Male | Unknown | ||
| Literature Case | Not described; 14–60 days (acute) | ||
| (297) | |||
| Cardiac | Ephedrine | Not relevant | Intraoperative ephedrine |
| 59 yo Female | Unknown | ||
| Ephedrine | <6 hours; < 48 hours | ||
| FDA Case | |||
| (3359234) | |||
| Cardiac | Ephedrine | Not relevant | Intraoperative ephedrine |
| 99 yo Male | Unknown | ||
| Ephedrine | <6 hours; < 48 hours | ||
| FDA Case | |||
| (3537599) | |||
| Cardiac | Ephedrine | Not relevant | Intraoperative ephedrine |
| 42 yo Male | Unknown | ||
| Literature Case | <6 hours; < 48 hours | ||
| (174) | |||
| Cardiac | RJB | Not relevant | Suicide attempt |
| 14 yo Female | 450.0 mg | ||
| Literature Case | <6 hours; < 48 hours | ||
| (281) | |||
| Cardiac | Power Trim | Not reviewed | Insufficient information |
| 07/19/1994 | Unknown | ||
| 43 yo Male | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (9818) | |||
| Cardiac | Nature's Nutrition-Formula One | Not reviewed | Insufficient information |
| 06/02/1995 | Unknown | ||
| 63 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (10275) | |||
| Cardiac | Natural Trim | Not reviewed | Insufficient information |
| 05/07/1996 | Unknown | ||
| 47 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (11133) | |||
| Cardiac | E'ola Amp II Pro Drops | Not reviewed | Insufficient information |
| 05/15/1996 | Unknown | ||
| 66 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (11282) | |||
| Cardiac | Shape Fast | Not reviewed | Insufficient information |
| 06/24/1996 | 80.0 mg | ||
| 35 yo Female | Not described; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (11464) | |||
| Cardiac | Pro ripped | Not reviewed | Insufficient information |
| 01/21/1996 | Unknown | ||
| 48 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (11782) | |||
| Cardiac | Ripped Fuel | Not reviewed | Insufficient information |
| 01/22/1998 | Unknown | ||
| 31 yo Female | Not described; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (12740) | |||
| Cardiac/Near sudden death | Herbalife Original Green | Angiography: Unknown | Insufficient Information |
| 07/29/1998 | 43.2 mg | ||
| 28 yo Female | <6 hours; < 48 Hours | ||
| Ephedra | |||
| FDA Case | |||
| (13031) | |||
| Cardiac | Metabolife 356 | Not reviewed | Insufficient information |
| 04/19/1999 | Unknown | ||
| 57 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (13516) | |||
| Cardiac/Near sudden death | Natural Trim | Angiography: Unknown | Insufficient Information |
| 05/19/1999 | 88.0 mg | ||
| 32 yo Female | <6 hours; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (13643) | |||
| Cardiac/Cardiomyopathy | Thermolean | Not reviewed | Insufficient Information |
| 07/23/1999 | Unknown | ||
| 65 yo Female | <6 hours; >60 days (chronic) | ||
| Ephedra | Power Trim | ||
| FDA Case | 84.0 mg | ||
| (13793) | <6 hours; >60 Days (chronic) | ||
| Cardiac | Natural Trim | Not reviewed | Insufficient information |
| 07/23/1999 | Unknown | ||
| 39 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (13796) | |||
| Cardiac/Ventricular Tachycardia | Metabolife 356 | Not reviewed | Insufficient Information |
| 11/15/1999 | Unknown | ||
| 48 yo Female | <6 hours; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (13945) | |||
| Cardiac | Unknown | Not reviewed | Insufficient information |
| 12/24/1999 | 45.0 mg | ||
| 48 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (13992) | |||
| Cardiac | Metabolife 356 | Not reviewed | Insufficient information |
| 11/08/1999 | Unknown | ||
| 46 yo Male | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (14017) | |||
| Cardiac | Ripped Fuel | Not reviewed | Insufficient information |
| 03/08/2000 | Unknown | ||
| 26 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | Hydroxycut (Muscle Tech R&D) | ||
| FDA Case | Unknown | ||
| (14080) | Not described; >60 Days (chronic) | ||
| Cardiac | Herbalife Original Green | Not reviewed | Insufficient information |
| 03/23/2000 | Unknown | ||
| 47 yo Female | >24 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (14108) | |||
| Cardiac | Metabolife 356 | Not reviewed | Insufficient information |
| 04/19/2000 | 24.0 mg | ||
| 41 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (14143) | |||
| Cardiac | Metabolize | Not reviewed | Insufficient information |
| 04/11/2000 | Unknown | ||
| 43 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | Unknown | ||
| FDA Case | Unknown | ||
| (14242) | Not described; Not described | ||
| Cardiac | FitAmerica Int'l Weight ControlAid | Not reviewed | Insufficient information |
| 07/19/2000 | Unknown | ||
| 26 yo Female | >24 hours; 2–13 days | ||
| Ephedra | |||
| FDA Case | |||
| (14284) | |||
| Cardiac | Biolean | I Not reviewed | Insufficient information |
| 09/14/2000 | Unknown | ||
| 39 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (14383) | |||
| Cardiac/Cardiomyopathy | Ephedrine | Angiography: No | Insufficient information |
| 32 yo Female | 450.0 mg | ||
| Literature Case | Not described; >60 days (chronic) | ||
| (260) | |||
| Cardiac/Cardiomyopathy | Insufficient information | Angiography: No | Insufficient information |
| 35 yo Male | Unknown | ||
| Literature Case | <24 hours; >60 days (chronic) | ||
| (271) | |||
dose reported in total daily alkaloids
yo = year old
| Event type | Product | Investigation of Etiology | RAND classification |
|---|---|---|---|
| Report date | Dose* | ||
| Age, Sex | Timing; Duration | ||
| Constituent | |||
| Source | |||
| (ID) | |||
| Neurological/ TIA | Metabolife 356 | Implicit review | Possible sentinel event |
| 06/29/98 | 48.0 mg | ||
| 57 yo Female | 6–24 hours; < 48 hours | ||
| Ephedra | |||
| FDA Case | |||
| (13062) | |||
| Neurological | Thermogenic Fat Burner (Joe Weider) | Not reviewed | Insufficient information |
| 11/27/95 | 48.0 mg | ||
| 54 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (10573) | |||
| Neurological | Excel Energy | Not reviewed | Insufficient information |
| 08/12/96 | 24.0 mg | ||
| 39 yo Male | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (11900) | |||
| Neurological | Metabolife 356 | Implicit review | Did not meet temporal relationship criterion |
| 02/10/00 | 24.0 mg | ||
| 59 yo Female | >24 hours; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (14018) | |||
| Neurological | Ripped Fuel | Not reviewed | Insufficient information |
| 08/31/00 | Unknown | ||
| 31 yo Female | Not described; 14–60 days (acute) | ||
| Ephedra | |||
| FDA Case | |||
| (14352) | |||
| Neurological | Metab-O-Lite | Not reviewed | Insufficient information |
| 11/7/00 | 24.0 mg | ||
| 35 yo Female | Not described; >60 days (chronic) | ||
| Ephedra | |||
| FDA Case | |||
| (14495) | |||
| Neurological | Ephedrine | Implicit review | Insufficient information |
| 29 yo Male | Unknown | ||
| Ephedrine | Not described; Not described | ||
| FDA Case | |||
| (1535075) | |||
| Neurological/ TIA | E'ola | Implicit review | Insufficient information |
| 12 yo Female | Unknown | ||
| Literature Case | <6 hours; < 48 hours | ||
| (218) | |||
dose reported in total daily alkaloids
yo = year old
| Event type | Product | Investigation for Etiology | RAND Classification |
|---|---|---|---|
| Age, Sex | Dose* | ||
| Constituent | Timing; Duration | ||
| Source | |||
| (ID) | |||
| Seizure | Shape Fast/Rite | CT/MRI of Head: Yes | Sentinel event |
| 19 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; 14–60 days (acute) | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (10974) | Magnesium: No | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Ephedrine | CT/MRI of Head: No | Sentinel event |
| 38 YO Female | Not described | Serum Electrolytes: No | |
| Ephedrine | 6–24 hours; Duration Not described | Glucose: No | |
| Literature Case | Calcium: No | ||
| (224) | Magnesium: No | ||
| Temperature: No | |||
| EEG: No | |||
| Seizure | Nature's Nutrition-Formula One | CT/MRI of Head: Yes | Possible sentinel event |
| 47 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | 6–24 hours; 14–60 days (acute) | Glucose: Yes | |
| FDA Case | Calcium: No | ||
| (9534) | Magnesium: No | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Nature's Nutrition-Formula One | CT/MRI of Head: Yes | Possible sentinel event |
| 37 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; >60 days (chronic) | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (10221) | Magnesium: Yes | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Thermo Slim | CT/MRI of Head: Yes | Possible sentinel event |
| 62 YO Male | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; >60 days (chronic) | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (10432) | Magnesium: Yes | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Metabolife 356 | CT/MRI of Head: Yes | Possible sentinel event |
| 23 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; >60 days (chronic) | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (11649) | Magnesium: No | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Ripped Fuel | CT/MRI of Head: Yes | Possible sentinel event |
| 26 YO Male | Not described | Serum Electrolytes: Yes | |
| Ephedra | <6 hours; >60 days (chronic) | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (13408) | Magnesium: Yes | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Metab-O-Lite | CT/MRI of Head: Yes | Possible sentinel event |
| 30 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | 6–24 hours; >60 days (chronic) | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (14275) | Magnesium: No | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Thin Tabs | CT/MRI of Head: Yes | Possible sentinel event |
| 31 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | 6–24 hours; 14–60 days (acute) | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (14571) | Magnesium: No | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Nature's Nutrition-Formula One | CT/MRI of Head: Yes | Insufficient Information |
| 38 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; 14–60 days (acute) | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (9528) | Magnesium: No | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Nature's Nutrition-Formula One | CT/MRI of Head: Yes | Insufficient information |
| 47 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; 2–13 days | Glucose: No | |
| FDA Case | Calcium: Yes | ||
| (9547) | Magnesium: Yes | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Ripped Fuel | CT/MRI of Head: Yes | Insufficient information |
| 40 YO Female | 25 mg | Serum Electrolytes: Yes | |
| Ephedra | Not described; 2–13 days | Glucose: Yes | |
| FDA Case | Calcium: No | ||
| (9747) | Magnesium: No | ||
| Temperature: No | |||
| EEG: No | |||
| Seizure | E'ola Amp II Pro Drops | CT/MRI of Head: No | Insufficient information |
| Age Not described, Male | Not described | Serum Electrolytes: No | |
| Ephedra | Not described; 14–60 days (acute) | Glucose: No | |
| FDA Case | Calcium: No | ||
| (9799) | Magnesium: No | ||
| Temperature: No | |||
| EEG: Yes | |||
| Seizure | Thermogenics Plus | CT/MRI of Head: Yes | Insufficient information |
| 34 YO Female | Not described | Serum Electrolytes: No | |
| Ephedra | Not described; 14–60 days (acute) | Glucose: No | |
| FDA Case | Calcium: No | ||
| (10301) | Magnesium: No | ||
| Temperature: No | |||
| EEG: Yes | |||
| Seizure | Slim Now | CT/MRI of Head: Yes | Insufficient information |
| 32 YO Male | Not described | Serum Electrolytes: Yes | |
| Ephedra | <6 hours; >60 days (chronic) | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (10416) | Magnesium: No | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Herbalife Original Green | CT/MRI of Head: Yes | Insufficient information |
| 55 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | <6 hours; 2–13 days | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (10437) | Magnesium: No | ||
| Temperature: No | |||
| EEG: No | |||
| Seizure | Thermochrome 5000 | CT/MRI of Head: Yes | Insufficient information |
| 38 YO Female | 21 mg | Serum Electrolytes: Yes | |
| Ephedra | 6–24 hours; <48 hours | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (10570) | Magnesium: Yes | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Diet Max/Super Diet Max | CT/MRI of Head: No | Insufficient information |
| 29 YO Female | Not described | Serum Electrolytes: No | |
| Ephedra | Not described; >60 days (chronic) | Glucose: No | |
| FDA Case | Calcium: No | ||
| (10964) | Magnesium: No | ||
| Temperature: No | |||
| EEG: No | |||
| Seizure | Guarana Plus | CT/MRI of Head: No | Insufficient information |
| 41 YO Female | Not described | Serum Electrolytes: No | |
| Ephedra | Not described; >60 days (chronic) | Glucose: No | |
| FDA Case | Calcium: No | ||
| (11001) | Magnesium: No | ||
| Temperature: No | |||
| EEG: No | |||
| Seizure | Quick Start | CT/MRI of Head: Yes | Insufficient information |
| 36 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; Not described | Glucose: Yes | |
| FDA Case | Nature's Nutrition-Formula One | Calcium: No | |
| (11078) | Not described | Magnesium: Yes | |
| 6–24 hours; >60 days (chronic) | Temperature: Yes | ||
| EEG: Yes | |||
| Seizure | Ripped Fuel | CT/MRI of Head: Yes | Insufficient information |
| 19 YO Male | Not described | Serum Electrolytes: Yes | |
| Ephedra | 6–24 hours; 2–13 days | Glucose: Yes | |
| FDA Case | Calcium: No | ||
| (11181) | Magnesium: No | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Ripped Fuel | CT/MRI of Head: No | Insufficient information |
| 24 YO Male | Not described | Serum Electrolytes: No | |
| Ephedra | Not described; Not described | Glucose: No | |
| FDA Case | Ripped Force | Calcium: No | |
| (11215) | Not described | Magnesium: No | |
| >24 hours; >60 days (chronic) | Temperature: No | ||
| EEG: No | |||
| Seizure | Victory Turbo Pump | CT/MRI of Head: Yes | Insufficient information |
| 20 YO Male | Not described | Serum Electrolytes: No | |
| Ephedra | Not described; >60 days (chronic) | Glucose: Yes | |
| FDA Case | Calcium: No | ||
| (11249) | Magnesium: No | ||
| Temperature: No | |||
| EEG: Yes | |||
| Seizure | E'ola Amp Pro Drops | CT/MRI of Head: No | Insufficient information |
| 38 YO Female | Not described | Serum Electrolytes: No | |
| Ephedra | <6 hours; <48 hours | Glucose: No | |
| FDA Case | Calcium: No | ||
| (11304) | Magnesium: No | ||
| Temperature: No | |||
| EEG: No | |||
| Seizure | Nature's Nutrition-Formula One | CT/MRI of Head: Yes | Insufficient information |
| 37 YO Male | Not described | Serum Electrolytes: Yes | |
| Ephedra | 6–24 hours; 14–60 days (acute) | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (11316) | Magnesium: Yes | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Fit America Intnl Weight Control Aid | CT/MRI of Head: No | Insufficient information |
| 34 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; 2–13 days | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (11594) | Magnesium: Yes | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Up Your Gas | CT/MRI of Head: No | Insufficient information |
| 15 YO Male | Not described | Serum Electrolytes: No | |
| Ephedra | <6 hours; <48 hours | Glucose: No | |
| FDA Case | Calcium: No | ||
| (12477) | Magnesium: No | ||
| Temperature: No | |||
| EEG: No | |||
| Seizure | Escalation | CT/MRI of Head: No | Insufficient information |
| Age Not described, Female | Not described | Serum Electrolytes: No | |
| Ephedra | Not described; 2–13 days | Glucose: No | |
| FDA Case | Calcium: No | ||
| (12948) | Magnesium: No | ||
| Temperature: No | |||
| EEG: No | |||
| Seizure | E-Z Trim Tablets | CT/MRI of Head: Yes | Insufficient information |
| 42 YO Female | 24 mg | Serum Electrolytes: Yes | |
| Ephedra | Not described; 2–13 days | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (13110) | Magnesium: Yes | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Metabolift | CT/MRI of Head: No | Insufficient information |
| 53 YO Female | Not described | Serum Electrolytes: No | |
| Ephedra | <6 hours; 14–60 days (acute) | Glucose: No | |
| FDA Case | Calcium: No | ||
| (13514) | Magnesium: No | ||
| Temperature: No | |||
| EEG: No | |||
| Seizure | Metabolife 356 | CT/MRI of Head: No | Insufficient information |
| Age Not described, Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; Not described | Glucose: No | |
| FDA Case | Calcium: No | ||
| (13519) | Magnesium: No | ||
| Temperature: No | |||
| EEG: No | |||
| Seizure | Metabolife 356 | CT/MRI of Head: Yes | Insufficient information |
| 46 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; 14–60 days (acute) | Glucose: Yes | |
| FDA Case | Calcium: No | ||
| (13625) | Magnesium: No | ||
| Temperature: No | |||
| EEG: Yes | |||
| Seizure | Diet Fuel | CT/MRI of Head: Yes | Insufficient information |
| 25 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; Not described | Glucose: Yes | |
| FDA Case | Ripped Fuel | Calcium: No | |
| (13715) | Not described | Magnesium: No | |
| Not described; Not described | Temperature: No | ||
| Hydroxycut | EEG: Yes | ||
| Not described | |||
| <6 hours; >60 days (chronic) | |||
| Seizure | Metabolife 356 | CT/MRI of Head: Yes | Insufficient information |
| 51 YO Male | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; 14–60 days (acute) | Glucose: Yes | |
| FDA Case | Calcium: No | ||
| (13895) | Magnesium: No | ||
| Temperature: No | |||
| EEG: Yes | |||
| Seizure | Ripped Fuel | CT/MRI of Head: Yes | Insufficient information |
| 17 YO Male | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; Not described | Glucose: Yes | |
| FDA Case | Thermo-Tek | Calcium: No | |
| (13946) | Not described | Magnesium: No | |
| <6 hours; >60 days (chronic) | Temperature: Yes | ||
| EEG: Yes | |||
| Seizure | Metabolife 356 | CT/MRI of Head: Yes | Insufficient information |
| 58 YO Male | Not described | Serum Electrolytes: Yes | |
| Ephedra | Not described; >60 days (chronic) | Glucose: Yes | |
| FDA Case | Calcium: No | ||
| (13972) | Magnesium: No | ||
| Temperature: No | |||
| EEG: Yes | |||
| Seizure | Thermo-Gen | CT/MRI of Head: Yes | Insufficient information |
| 39 YO Female | Not described | Serum Electrolytes: Yes | |
| Ephedra | 6–24 hours; >60 days (chronic) | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (14116) | Magnesium: Yes | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Ripped Fuel | CT/MRI of Head: Yes | Insufficient information |
| 23 YO Male | Not described | Serum Electrolytes: Yes | |
| Ephedra | <6 hours; <48 hours | Glucose: Yes | |
| FDA Case | Calcium: Yes | ||
| (14258) | Magnesium: Yes | ||
| Temperature: Yes | |||
| EEG: Yes | |||
| Seizure | Natural Trim | CT/MRI of Head: Yes | Insufficient information |
| 42 YO Female | Not described | Serum Electrolytes: No | |
| Ephedra | 6–24 hours; <48 hours | Glucose: No | |
| FDA Case | Calcium: No | ||
| (14297) | Magnesium: No | ||
| Temperature: No | |||
| EEG: Yes | |||
| Seizure | Ephedrine Plus | CT/MRI of Head: No | Insufficient information |
| Age Not described, Female | Not described | Serum Electrolytes: No | |
| Ephedrine | <6 hours; 14–60 days (acute) | Glucose: No | |
| FDA Case | Calcium: No | ||
| (3549038) | Magnesium: No | ||
| Temperature: No | |||
| EEG: No | |||
dose reported in total daily alkaloids
yo = year old
| Event type | Product | Investigation for Etiology*** | RAND Classification |
|---|---|---|---|
| Age, Sex | Dose* | ||
| Constituent | Duration | ||
| Source | Addiction Data** | ||
| (ID) | |||
| Psychosis, Sleep disturbance, Palpitations, Dizzy | Nature's Nutrition-Formula One | Psychiatric History: No | Sentinel Event |
| 21 YO Male | Not described | Other Substances/Meds: No | |
| Ephedra | <48 hours | ||
| FDA Case | Addiction: No | ||
| (9509) | |||
| Psychosis, Hallucinations, Sleep disturbance | Diet Now | Psychiatric History: No | Sentinel Event |
| 39 YO Female | 12 mg | Other Substances/Meds: No | |
| Ephedra | Over 1 year | ||
| FDA Case | Addiction: No | ||
| (11678) | |||
| Mania or severe agitation, Suicidal ideation, Violent, Personality changes, Headache | Hydroxycut | Psychiatric History: No | Sentinel Event |
| 19 YO Female | Not described | Other Substances/Meds: No | |
| Ephedra | 2–13 days | ||
| FDA Case | Addiction: No | ||
| (13809) | |||
| Psychosis, Mania or severe agitation, Severe depression, Suicidal ideation, Sleep disturbance, Homicidal ideation | Xenadrine | Psychiatric History: No | Sentinel Event |
| 29 YO Male | Not described | Other Substances/Meds: No | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (14529) | |||
| Mania or severe agitation, Ventricular tachycardia / fibrillation, Insomnia, Violent | Max Alert | Psychiatric History: No | Sentinel Event |
| 16 YO Male | Mini Thin | Other Substances/Meds: No | |
| Ephedrine | Not described | ||
| FDA Case | 60 days to 1 year | ||
| (1855921) | Addiction: Yes | ||
| Mania or severe agitation, Sleep disturbance | Ma huang/Ephedra | Psychiatric History: No | Sentinel Event |
| 45 YO Male | Not described | Other Substances/Meds: No | |
| Ephedra | 14–60 days (acute) | ||
| Literature Case | Addiction: No | ||
| (48) | |||
| Psychosis, Paranoia | Tedral | Psychiatric History: No | Sentinel Event |
| 30 YO Female | 144 mg | Other Substances/Meds: No | |
| Ephedrine | Over 1 year | ||
| Literature Case | Addiction: Yes | ||
| (238) | |||
| Psychosis, Hallucinations, Confusion/Delusional | Bronchi Pax | Psychiatric History: No | Sentinel Event |
| 59 YO Male | 360 mg | Other Substances/Meds: No | |
| Ephedrine | Over 1 year | ||
| Literature Case | Addiction: No | ||
| (285) | |||
| Severe depression, Suicide attempt | Slim NRG+ | Psychiatric History: No | Possible Sentinel Event |
| 28 YO Female | Not described | Other Substances/Meds: No | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (9751) | |||
| Psychosis, Suicidal ideation, Palpitations, Increased hypertension, | Ripped Fuel | Psychiatric History: No | Possible Sentinel Event |
| 19 YO Male | Not described | Other Substances/Meds: No | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (11157) | |||
| Psychosis, Hallucinations, Memory Loss | Nature's Nutrition-Formula One | Psychiatric History: No | Possible Sentinel Event |
| 13 YO Female | Not described | Other Substances/Meds: No | |
| Ephedra | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (12372) | |||
| Mania or severe agitation, Sleep disturbance | Ripped Fuel | Psychiatric History: No | Possible Sentinel Event |
| 21 YO Male | Not described | Other Substances/Meds: No | |
| Ephedra | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (13005) | |||
| Psychosis, Hallucinations | Metab-O-Lite | Psychiatric History: No | Possible Sentinel Event |
| 52 YO Female | Not described | Other Substances/Meds: No | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (14436) | |||
| Psychosis, Suicide attempt, Insomnia, Ventricular tachycardia / fibrillation, Dizzy | Metab-O-Lite | Psychiatric History: No | Possible Sentinel Event |
| 28 YO Female | Not described | Other Substances/Meds: No | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (14528) | |||
| Psychosis, Addiction/Substance Abuse, Paranoia | Max Alert | Psychiatric History: No | Possible Sentinel Event |
| 31 YO Male | up to 1250 mg / day | Other Substances/Meds: No | |
| Ephedrine | Over 1 year | ||
| FDA Case | Addiction: Yes | ||
| (1661966) | |||
| Psychosis, Mania or severe agitation, Hallucinations, Paranoia | Unknown | Psychiatric History: No | Possible Sentinel Event |
| 34 YO Male | Not described | Other Substances/Meds: No | |
| Ephedra | 2–13 days | ||
| Literature Case | Addiction: No | ||
| (79) | |||
| Psychosis, Sleep disturbance, Headache | Do-Do Tablet or Herbal Balance | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 40 YO Female | 100 mg | Other Substances/Meds: No | |
| Ephedra | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (9060) | |||
| Severe depression Suicidal ideation, | Nature's Nutrition-Formula One | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 47 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedra | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (9727) | |||
| Severe depression, Suicidal ideation | Nature's Nutrition-Formula One | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 38 YO Female | Not described | Other Substances/Meds: Yes | |
| Ephedra | >60 days (chronic) | ||
| FDA Case | Addiction: No | ||
| (9727) | |||
| Severe depression, Suicidal ideation | Nature's Nutrition-Formula One | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 30 YO Female | Not described | Other Substances/Meds: | |
| Ephedra | >60 days (chronic) | Yes | |
| FDA Case | Addiction: No | ||
| (9727) | |||
| Psychosis, Insomnia | Therachrome | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 43 YO Female | Not described | Other Substances/Meds: No | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (9403) | |||
| Psychosis, Violent | Diet Gel | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 39 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedra | Not described | ||
| FDA Case | Addiction: No | ||
| (10042) | |||
| Psychosis, Mania or severe agitation, Sleep disturbance | Ripped Force | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 17 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (10078) | |||
| Psychosis, Severe depression, Suicide attempt, Addiction/Substance Abuse | Mini Thin | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 38 YO Female | 285 mg | Other Substances/Meds: No | |
| Ephedra/Ephedrine | 60 days to 1 year | ||
| FDA Case | Addiction: Yes | ||
| (11052) | |||
| Psychosis, Mania or severe agitation, Violent, Addiction/Substance Abuse | Up Your Gas | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 17 YO Male | Not described | Other Substances/Meds: No | |
| Ephedra | Not described | ||
| FDA Case | Addiction: Yes | ||
| (11096) | |||
| Severe depression, Anxiety, Headache | Nature's Nutrition-Formula One | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 31 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedra | >60 days (chronic) | ||
| FDA Case | Addiction: No | ||
| (11145) | |||
| Violent | Up Your Gas | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 35 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedra | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (11289) | |||
| Severe depression Addiction/Substance, Abuse, Sleep disturbance | Nature's Nutrition-Formula One | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 38 YO Female | Not described | Other Substances/Meds: Yes | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: Yes | ||
| (11651) | |||
| Psychosis | M-80 pills | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 34 YO Female | Not described | Other Substances/Meds: No | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (11717) | |||
| Severe depression, Suicidal ideation | Herbalife Original Green | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 57 YO Female | Not described | Other Substances/Meds: No | |
| Ephedra | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (11828) | |||
| Mania or severe agitation, Suicidal ideation, Cyclothymia | Caloslim | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 15 YO Female | Not described | Other Substances/Meds: No | |
| Ephedra | >60 days (chronic) | ||
| FDA Case | Addiction: No | ||
| (13072) | |||
| Psychosis, Mania or severe agitation, Hallucinations, Sleep disturbance, Migraine | Mini Thin | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 20 YO Male | 75 mg | Other Substances/Meds: No | |
| Ephedra/Ephedrine | Not described | ||
| FDA Case | Hydroxycut | ||
| (13099) | Not described | ||
| 60 days to 1 year | |||
| Addiction: No | |||
| Severe depression | Xenadrine | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 28 YO Female | Not described | Other Substances/Meds: No | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (14089) | |||
| Mania or severe agitation, Severe depression, Addiction/Substance Abuse | Up Your Gas | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 29 YO Female | Not described | Other Substances/Meds: No | |
| Ephedra | Over 1 year | ||
| FDA Case | Addiction: Yes | ||
| (14276) | |||
| Psychosis, Severe depression, Insomnia | Hydroxycut | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 17 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedra | 2–13 days | ||
| FDA Case | Addiction: No | ||
| (14294) | |||
| Psychosis, Severe depression, Motor vehicle accident, Paranoia, Confusion/Delusional | Fen-Chi | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 42 YO Female | Not described | Other Substances/Meds: Yes | |
| Ephedra | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (14394) | |||
| Psychosis, Suicide/Suicide attempt, Hallucinations, Anxiety, Paranoia | Herbalife Original Green | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 36 YO Female | Not described | Other Substances/Meds: Yes | |
| Ephedra | >60 days (chronic) | ||
| FDA Case | Addiction: No | ||
| (14493) | |||
| Mania or severe agitation, Hallucinations | Metabolife 356 | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 32 YO, Sex Not described | Not described | Other Substances/Meds: Yes | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (14541) | |||
| Psychosis, Severe depression, Suicidal ideation, Hallucinations, Insomnia | Metabolift | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 22 YO Female | Not described | Other Substances/Meds: Yes | |
| Ephedra | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (14543) | |||
| Psychosis, Mania or severe agitation | Metabolife 356 | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 20 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedra | >60 days (chronic) | ||
| Literature Case | Addiction: No | ||
| (136) | |||
| Severe depression, Suicidal ideation, Violent | Metabolife 356 | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 27 YO Male | Not described | Other Substances/Meds: No | |
| Ephedra | Over 1 year | ||
| Literature Case | Addiction: No | ||
| (136) | |||
| Mania or severe agitation, Severe depression | Product Not described | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 40 YO Female | Not described | Other Substances/Meds: Yes | |
| Ephedra | Over 1 year | ||
| Literature Case | Addiction: No | ||
| (519) | |||
| Psychosis, Suicidal ideation, Anxiety, Dizzy, Increased hypertension | Nature's Nutrition-Formula One | Psychiatric History: No | Inconclusive - Other meds / substances |
| 33 YO Female | Not described | Other Substances/Meds: Yes | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (9516) | |||
| Mania or severe agitation, Suicidal ideation, Sleep disturbance | Nature's Nutrition-Formula One | Psychiatric History: No | Inconclusive - Other meds / substances |
| 45 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedra | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (10233) | |||
| Psychosis, Catatonia | Nature's Super Cap | Psychiatric History: No | Inconclusive - Other meds / substances |
| 36 YO Male | 99mg | Other Substances/Meds: Yes | |
| Ephedra | Thermadrene | ||
| FDA Case | Just Be Natural | ||
| (12488) | Gorilla Nitro Plus | ||
| Mega Creatine Fuel | |||
| Bolt | |||
| Not described | |||
| Over 1 year | |||
| Addiction: No | |||
| Mania or severe agitation, Hallucinations, Headache, Sleep disturbance, Irregular heart rate | Metacuts | Psychiatric History: No | Inconclusive - Other meds / substances |
| 19 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedra/Ephedrine | >60 days (chronic) | ||
| FDA Case | Addiction: No | ||
| (13370) | |||
| Psychosis, Mania or severe agitation, Hallucinations, Motor vehicle accident, Sleep disturbance | Xenadrine | Psychiatric History: No | Inconclusive - Other meds / substances |
| 27 YO Female | 40 mg | Other Substances/Meds: Yes | |
| Ephedra | 2–13 days | ||
| FDA Case | Addiction: No | ||
| (13526) | |||
| Severe depression, Suicidal ideation, Sleep disturbance | Ripped Force | Psychiatric History: No | Inconclusive - Other meds / substances |
| 15 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (14082) | |||
| Psychosis, Suicide attempt | Thermogenics Plus | Psychiatric History: No | Inconclusive - Other meds / substances |
| Age Not described, Female | Not described | Other Substances/Meds: Yes | |
| Ephedra | Over 1 year | ||
| FDA Case | Addiction: No | ||
| (14213) | |||
| Mania or severe agitation, Severe depression, Aneurysm, ruptured cerebra, Encephalopathy | Diet Fuel | Psychiatric History: No | Inconclusive - Other meds / substances |
| Age Not described, Male | Not described | Other Substances/Meds: Yes | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (14287) | |||
| Psychosis, Hyperkalemia | Metabolife 356 | Psychiatric History: No | Inconclusive - Other meds / substances |
| 37 YO Female | Not described | Other Substances/Meds: Yes | |
| Ephedra | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (14300) | |||
| Psychosis, Sleep disturbance, Confusion/Delusional | Metabolife 356 | Psychiatric History: No | Inconclusive - Other meds / substances |
| 36 YO Female | Not described | Other Substances/Meds: Yes | |
| Ephedra | >60 days (chronic) | ||
| FDA Case | Addiction: No | ||
| (14546) | |||
| Psychosis | Up Your Gas | Psychiatric History: No | Inconclusive - Other meds / substances |
| 39 YO Female | Not described | Other Substances/Meds: Yes | |
| Ephedra | Over 1 year | ||
| FDA Case | Addiction: No | ||
| (14575) | |||
| Psychosis, Mania or severe agitation, Confusion/Delusional, Headache | Metabolife 356 | Psychiatric History: No | Inconclusive - Other meds / substances |
| 54 YO Female | Not described | Other Substances/Meds: Yes | |
| Ephedra | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (14582) | |||
| Psychosis, Hallucinations | Ripped Fuel | Psychiatric History: No | Insufficient Information |
| Age Not described, Female | Not described | Other Substances/Meds: No | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (10019) | |||
| Psychosis, Irregular heart rate, Insomnia, Dizzy, Gastrointestinal problems | Diet Max | Psychiatric History: No | Insufficient Information |
| 24 YO Female | Not described | Other Substances/Meds: No | |
| Ephedra | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (10614) | |||
| Hallucinations, Nausea, Dizzy, Headache | Herbal Ecstasy | Psychiatric History: No | Insufficient Information |
| 20 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedra | <48 hours | ||
| FDA Case | Addiction: No | ||
| (11131) | |||
| Anxiety, Palpitations | Ripped Fuel | Psychiatric History: No | Insufficient Information |
| 25 YO Male | Not described | Other Substances/Meds: No | |
| Ephedra | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (11354) | |||
| Hallucinations | Power Trim | Psychiatric History: No | Insufficient Information |
| Age Not described, Sex Not described | Not described | Other Substances/Meds: No | |
| Ephedra | Not described | ||
| FDA Case | Addiction: No | ||
| (12368) | |||
| Psychosis, Severe depression, Seizure | Metab-O-Lite | Psychiatric History: No | Insufficient Information |
| 32 YO Female | Other Substances/Meds: No | ||
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (14105) | |||
| Psychosis, Seizure, Transient ischemic attack | Metab-O-Lite | Psychiatric History: No | Insufficient Information |
| 37 YO Female | Not described | Other Substances/Meds: No | |
| Ephedra | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (14615) | |||
| Suicide attempt | Thermogenic Fat Burner | Psychiatric History: No | Product taken solely |
| 15 YO Female | Not described | Other Substances/Meds: No | as suicide attempt |
| Ephedra | <48 hours | ||
| FDA Case | Addiction: No | ||
| (10378) | |||
| Suicide attempt, Headache | Metabolife 356 | Psychiatric History: No | Product taken solely |
| 16 YO Male | Not described | Other Substances/Meds: No | as suicide attempt |
| Ephedra | <48 hours | ||
| FDA Case | Addiction: No | ||
| (13331) | |||
| Severe depression, Suicide attempt, Addiction/Substance Abuse | Ephedrine | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 25 YO Male | 2500 mg | Other Substances/Meds: Yes | |
| Ephedrine | Over 1 year | ||
| FDA Case | Addiction: Yes | ||
| (11103) | |||
| Mania or severe agitation | Ma Huang/Ephedra + Caffeine | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 50 YO Female | 5.6 mg | Other Substances/Meds: | |
| Ephedra | 14–60 days (acute) | Yes | |
| FDA Case | Addiction: No | ||
| (11780) | |||
| Mania or severe agitation, Violent, Addiction/Substance Abuse | Mini Thin | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 30 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedrine | Over 1 year | ||
| FDA Case | Addiction: Yes | ||
| (185564) | |||
| Mania or severe agitation, Encephalopathy, Rhabdomyolysis, Hyperthermia | Do-Do Tablet or Herbal Balance | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 28 YO Female | 18.31 mg | Other Substances/Meds: Yes | |
| Ephedrine | <48 hours | ||
| Literature Case | Addiction: No | ||
| (69) | |||
| Psychosis, Severe depression, Hallucinations | Ephedrine | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 54 YO Female | Not described | Other Substances/Meds: Yes | |
| Ephedrine | Over 1 year | ||
| Literature Case | Addiction: Yes | ||
| (120) | |||
| Mania or severe agitation, Confusion/Delusional, Insomnia, Palpitations | Black Beauty | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 21 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedrine | <48 hours | ||
| Literature Case | Addiction: No | ||
| (157) | |||
| Psychosis, Hallucinations, Confusion/Delusional, Violent | Ephedrine | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 26 YO Male | Not described | Other Substances/Meds: No | |
| Ephedrine | 2–13 days | ||
| Literature Case | Addiction: No | ||
| (238) | |||
| Psychosis, Mania or severe agitation, Hallucinations, Confusion/Delusional, Violent | Ephedrine | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 26 YO Male | 300 mg | Other Substances/Meds: No | |
| Ephedrine | 14–60 days (acute) | ||
| Literature Case | Addiction: No | ||
| (238) | |||
| Suicide attempt, Ventricular/ fibrillation | Product Not described | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 20 YO Female | tachycardia 22500 gm | Other Substances/Meds: No | |
| Ephedrine | <48 hours | ||
| Literature Case | Addiction: No | ||
| (250) | |||
| Psychosis, Hallucinations, Sleep disturbance, Confusion/Delusional | Vicks inhaler | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 61 YO Male | Not described | Other Substances/Meds: No | |
| Ephedrine | Over 1 year | ||
| Literature Case | Addiction: No | ||
| (488) | |||
| Addiction/Substance Abuse, Palpitations | Ephedrine | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 29 YO Female | 2500 mg | Other Substances/Meds: Yes | |
| Ephedrine | Over 1 year | ||
| Literature Case | Addiction: Yes | ||
| (493) | |||
| Addiction/Substance Abuse | Ephedrine | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 23 YO Male | 2500 mg | Other Substances/Meds: Yes | |
| Ephedrine | 60 days to 1 year | ||
| Literature Case | Addiction: Yes | ||
| (493) | |||
| Addiction/Substance Abuse, Sleep disturbance, Palpitations | Ephedrine | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 22 YO Male | 1500 mg | Other Substances/Meds: Yes | |
| Ephedrine | 60 days to 1 year | ||
| Literature Case | Addiction: Yes | ||
| (493) | |||
| Job Loss, Motor vehicle accident | Ephedrine | Psychiatric History: Yes | Inconclusive - Prior psychiatric history |
| 33 YO Male | 1000 mg | Other Substances/Meds: Yes | |
| Ephedrine | Over 1 year | ||
| Literature Case | Addiction: No | ||
| (493) | |||
| Psychosis, Addiction/Substance Abuse | Ephedrine | Psychiatric History: No | Inconclusive - Other substances involved |
| 35 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedrine | Not described | ||
| FDA Case | Addiction: Yes | ||
| (130741) | |||
| Psychosis, Mania or severe agitation | Marax | Psychiatric History: No | Inconclusive - Other meds / substances |
| 19 YO Male | 125 mg | Other Substances/Meds: Yes | |
| Ephedrine | 14–60 days (acute) | ||
| Literature Case | Addiction: No | ||
| (490) | |||
| Addiction/Substance Abuse | Ephedrine | Psychiatric History: No | Inconclusive - Other meds / substances |
| 33 YO Female | 1500 mg | Other Substances/Meds: Yes | |
| Ephedrine | Over 1 year | ||
| Literature Case | Addiction: Yes | ||
| (493) | |||
| Psychosis, Paranoia, Violent, Impotence | Ephedrine | Psychiatric History: No | Inconclusive - Other substances involved |
| 65 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedrine | Over 1 year | ||
| Literature Case | Addiction: Yes | ||
| (120) | |||
| Psychosis, Mania or severe agitation, Severe depression, Hallucinations | Thermolift | Psychiatric History: No | Not related - exacerbation of previously undiagnosed bipolar disorder |
| 27 YO Female | Not described | Other Substances/Meds: No | |
| Ephedrine | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (14542) | |||
| Psychosis, Suicide attempt, Paranoia, Confusion/Delusional | Mini Thin | Psychiatric History: No | Product taken solely as suicide attempt |
| 46 YO Male | Not described | Other Substances/Meds: No | |
| Ephedrine | 14–60 days (acute) | ||
| FDA Case | Addiction: Yes | ||
| (94799) | |||
| Suicide attempt | Max Alert | Psychiatric History: No | Product taken solely as suicide attempt |
| 19 YO Male | Not described | Other Substances/Meds: No | |
| Ephedrine | Not described | ||
| FDA Case | Addiction: No | ||
| (1454817) | |||
| Suicide attempt, Arrhythmia (NOS) | RJ8 | Psychiatric History: No | Product taken solely as suicide attempt |
| 14 YO Female | Not described | Other Substances/Meds: No | |
| Ephedrine | <48 hours | ||
| Literature Case | Addiction: No | ||
| (281) | |||
| Psychosis, Severe depression, Palpitations | Max Alert | Psychiatric History: No | Insufficient Information |
| 40 YO Male | Not described | Other Substances/Meds: No | |
| Ephedrine | 60 days to 1 year | ||
| FDA Case | Addiction: No | ||
| (1761109) | |||
| Psychosis, Severe depression, Hallucinations, Addiction/Substance Abuse | Mini Thin | Psychiatric History: No | Insufficient Information |
| 38 YO Female | Not described | Other Substances/Meds: No | |
| Ephedrine | Not described | ||
| FDA Case | Excel Energy | ||
| (1834206) | Not described | ||
| Not described | |||
| Addiction: Yes | |||
| Severe depression, Suicide/Suicide attempt | E'ola Amp Pro Drops | Psychiatric History: Yes | Product removed from market- Contained illegal doses of ephedrine |
| 43 YO Female | 38 mg | Other Substances/Meds: Yes | |
| Ephedra/Ephedrine | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (9568) | |||
| Mania or severe agitation, Confusion/Delusional, Jumped out of car, Cardiac Enlargement | LiquiThin | Psychiatric History: Yes | Product removed from market- Contained illegal doses of ephedrine |
| 47 YO Female | Not described | Other Substances/Meds: Yes | |
| Ephedra | Not described | ||
| FDA Case | E'ola Amp Pro Drops | ||
| (12486) | 97.2 mg | ||
| 2–13 days | |||
| Addiction: No | |||
| Psychosis, Hallucinations, Rhabdomyolysis | E'ola Amp Pro Drops | Psychiatric History: No | Product removed from market- Contained illegal doses of ephedrine |
| 54 YO Male | Not described | Other Substances/Meds: Yes | |
| Ephedra/Ephedrine | 14–60 days (acute) | ||
| FDA Case | Addiction: No | ||
| (10894) | |||
| Psychosis, Hallucinations, Paranoia, Confusion/Delusional | E'ola Amp Pro Drops | Psychiatric History: No | Product removed from market- Contained illegal doses of ephedrine |
| 54 YO Female | 28000 mg | Other Substances/Meds: | |
| Ephedra/Ephedrine | Over 1 year | Yes | |
| Literature Case | Addiction: No | ||
| (275) | |||
dose reported in total daily alkaloids
yo = year old
Addiction: Yes = diagnosis or self-reported addiction to the product
Psychiatric history: Yes = recorded psychiatric history
Other substances/meds: Yes = patient taking other substances or medications known to cause psychiatric symptoms
| Demographics | Type of Event | Death | MI | Other Cardiac | CVA / Stroke | Other Neurological | Seizure | Psychiatric Symptoms |
|---|---|---|---|---|---|---|---|---|
| Total Events | ||||||||
| Sentinel Events | 2 | 3 | 0 | 9 | 0 | 3 | 5 | |
| Possible Sentinel Events | 9 | 7 | 2 | 10 | 1 | 7 | 7 | |
| Events by Sex | ||||||||
| Female | ||||||||
| Sentinel Events | 1 | 0 | 0 | 5 | 0 | 3 | 2 | |
| Possible Sentinel Events | 3 | 4 | 0 | 7 | 1 | 5 | 4 | |
| Male | ||||||||
| Sentinel Events | 1 | 3 | 0 | 4 | 0 | 0 | 3 | |
| Possible Sentinel Events | 6 | 3 | 2 | 3 | 0 | 2 | 3 | |
| Events by Age | ||||||||
| 13–30 | ||||||||
| Sentinel Events | 2 | 2 | 0 | 3 | 0 | 2 | 3 | |
| Possible Sentinel Events | 5 | 0 | 1 | 2 | 0 | 3 | 5 | |
| 31–50 | ||||||||
| Sentinel Events | 0 | 1 | 0 | 5 | 0 | 1 | 2 | |
| Possible Sentinel Events | 4 | 6 | 1 | 5 | 0 | 3 | 1 | |
| 51–70 | ||||||||
| Sentinel Events | 0 | 0 | 0 | 1 | 0 | 0 | 0 | |
| Possible Sentinel Events | 0 | 1 | 0 | 3 | 1 | 1 | 1 | |
includes three events from Metabolife analysis.
| Demographics | Type of Event | Death | MI | Other Cardiac | CVA / Stroke | Other Neurological | Seizure | Psychiatric Symptoms |
|---|---|---|---|---|---|---|---|---|
| Total Events | ||||||||
| Sentinel Events | 3 | 2 | 0 | 2 | 0 | 1 | 3 | |
| Possible Sentinel Events | 3 | 0 | 1 | 2 | 0 | 0 | 1 | |
| Events by Sex | ||||||||
| Female | ||||||||
| Sentinel Events | 1 | 2 | 0 | 2 | 0 | 1 | 1 | |
| Possible Sentinel Events | 1 | 0 | 1 | 0 | 0 | 0 | 0 | |
| Male | ||||||||
| Sentinel Events | 2 | 0 | 0 | 0 | 0 | 0 | 2 | |
| Possible Sentinel Events | 1 | 0 | 1 | 2 | 0 | 0 | 1 | |
| Events by Age | ||||||||
| 13–30 | ||||||||
| Sentinel Events | 2 | 1 | 0 | 2 | 0 | 0 | 2 | |
| Possible Sentinel Events | 0 | 0 | 1 | 1 | 0 | 0 | 0 | |
| 31–50 | ||||||||
| Sentinel Events | 1 | 1 | 0 | 0 | 0 | 1 | 0 | |
| Possible Sentinel Events | 1 | 0 | 1 | 1 | 0 | 0 | 1 | |
| 51–70 | ||||||||
| Sentinel Events | 0 | 0 | 0 | 0 | 0 | 0 | 1 | |
| Possible Sentinel Events | 1 | 0 | 0 | 0 | 0 | 0 | 0 | |
A 21-year-old male collapsed and died during a physical agility run at school after taking Hydroxycut and Ripped Fuel one time to increase energy. At autopsy, ephedrine and caffeine were found in the blood at concentrations of 0.02 mg/l and 0.31 mg/l, respectively. Although the autopsy report itself was not included in the FDA documents we received, a detailed description of the autopsy was found in the police notes that were included in the FDA file. According to these notes, the autopsy report stated that the coronary arteries were normal and that the diagnosis was acute arrhythmia due to ephedrine. (13914).
A 22-year-old female who weighed 183 pounds collapsed and died while standing in line to purchase ice cream. She had a history of asthma that was characterized as “well-controlled.” She had congenital hydrocephalus with a shunt placed. She was taking Slacker II. Ephedrine was found in the blood. The autopsy report stated that the coronary arteries were free of atherosclerosis. There was no myocarditis. The brain was normal, except for the presence of the shunt. There was no other cause of death. The death certificate listed “cardiac arrhythmia due to ephedrine-containing diet medication.” (14390)
A 30-year-old female died suddenly. Her husband stated that she had been taking MiniTabs in order to lose weight. She was found unresponsive by her husband and was brought to the emergency department in full cardiac arrest. Blood toxicology screen showed an ephedrine level of 24 micrograms (μg) per milliliter (ml). Examination of the heart and brain did not reveal any evidence of cause of death. Final pathological diagnosis included “acute drug toxicity-ephedrine” with the opinion that “this autopsy illustrates an instance of death due to acute drug toxicity.” (3275432)
A 33-year-old male was found dead. He had been taking an over-the-counter preparation named “Max Brand Two-Way ephedrine tablets.” Autopsy did not reveal any obvious cause of death, particularly with respect to the brain and heart. However, the blood ephedrine level was 13.4 μg per ml. The final pathological diagnosis was drug intoxication, with the opinion that the person died as the result of “drug intoxication with ephedrine.” (3289590)
A 28-year-old male truck driver was, according to his family, taking up to 600 mg of ephedrine per day for six years. After having consumed 250 mg of ephedrine one day, he collapsed while baling hay. Autopsy did not reveal any pathologic process to account for his death. “Specifically, the coronary arteries, valves, and myocardium, including the conduction system, were normal.” Only ephedrine and guaifenesin were identified on toxicology screens. The conclusion was that death “was most likely due to a cardiac arrhythmia triggered by the combination of an excessive use of ephedrine and strenuous labor on a hot day.” (348)
A 36-year-old female began taking Nature's Nutrition-Formula One in August 1993. In December 1993, she was taken to the emergency department and found to have low potassium but signed out Against Medical Advice. In May 1994, she had severe stomach cramps and later that day was found unconscious by her daughter. She was taken to the hospital, where she died five days later without having recovered consciousness. According to her husband, she had no history of heart, thyroid, or blood pressure problems. The medical record documents a past history of bulimia and anorexia. There is a brief autopsy form consisting of a series of hand-written notes and check marks. Next to the word “cardiovascular” is a handwritten check mark, suggesting the heart had been examined and found normal, but no dictation describes the heart. There is an extensive description of the brain, which was normal. Elsewhere in the medical chart is a statement that the patient was thought to have had an acute myocardial infarction with adult respiratory distress syndrome and heart failure. Her creatine phosphokinase (CPK) isoenzymes and myoglobin (MB) fractions were both elevated. The emergency department record reported a toxicology screen positive for ephedrine, phentermine, and chlorpheniramine. A cardiology note and an echocardiogram reported severe global cardiac dysfunction and a left ventricular ejection fraction of 25 percent. We classified this case as no higher than a possible sentinel event because there was no evidence available to us of an adequate examination of the heart. It is possible that this woman could have had acute myocarditis, which led to global cardiac dysfunction. (9508)
A 32-year-old male truck driver was found dead in his truck by the police. In the truck were found Nature's Nutrition-Formula One, Nature's Nutrition-Formula Three, a bottle of Tylenol with codeine, Vicks Formula 44, Nyquil, Ibuprofen, and Rexall cold tablets. The FDA files do not contain a copy of the actual autopsy report, but notes state that the autopsy report said the heart was enlarged, the coronary arteries were normal, and there was a slight case of pneumonia. The cause of death was listed as myocarditis, bronchiolitis, and pneumonia. Toxicology screen was negative for ephedrine but did show pseudoephedrine and doxylamine. We classified this case as a possible sentinel event because the myocarditis could have contributed to his death and the etiology of the myocarditis is unknown. (10276)
A 38-year-old male collapsed and died after jogging. Prior to jogging, he had had a cup of coffee and Ripped Fuel supplements. At autopsy, he was found to have triple vessel coronary artery disease and cardiomegaly. Because of this preexisting condition, we classified this as a possible sentinel event. (12485)
A 21-year-old male on his college wrestling team was trying to lose weight, perhaps as much as 17 pounds in a few days, to achieve a weight limit for an upcoming meet. He had been taking Thermogenics Plus for an unknown length of time. He began to feel weak while sitting in the sauna. He left the sauna, went to get a drink, and collapsed. On autopsy, the cause of death was listed as sudden cardiovascular collapse with rhabdomyolysis and dehydration. The heart exam revealed normal coronary arteries. We classified this as a possible sentinel event since the intense effort to lose weight likely led to dehydration, which then led to cardiac collapse. (12722)
A 15-year-old female collapsed and died while playing soccer. She had been taking Ripped Fuel for an unknown length of time. At autopsy, she was found to have a congenital abnormality: an anomalous origin of the left coronary artery from the pulmonary circulation (the Bland-White-Garland Syndrome). This condition is not usually associated with life beyond infancy, if left uncorrected. Due to this preexisting condition, the case was classified as a possible sentinel event. (12843)
A 26-year-old male had been taking Ripped Fuel for two weeks prior to his death. There is no autopsy report in the FDA files, but detailed notes state that the autopsy revealed he died of acute aortic dissection. According to the file, he had been having back pain two weeks prior to his fatal event and went to the emergency department complaining of severe chest pains. He was diagnosed with esophagitis and sent home. Four days later, he returned to the emergency room again with severe chest pains and was told the source of his pain was the chest wall. The next day, he was found dead by his girlfriend. According to his family history, several relatives had also had an aortic dissection, including a niece who had had an aortic dissection at age 18. The notes state, “This appears to have been some form of genetic connective tissue abnormality.” There is also evidence of prior borderline hypertension. Toxicology screen for cocaine, ephedrine, and amphetamines was negative. Only caffeine and acetaminophen were found in the blood. This case was classified as a possible sentinel event, because it appears the patient was genetically predisposed to aortic dissection. (13906)
A 26-year-old female was found dead by her father. She had been taking a product called Diet Fuel for six months. The adverse event report stated, “Coroner felt this was a massive heart attack.” Autopsy concluded she suffered from tachycardia, high blood pressure, and restriction of the coronary artery. The death certificate stated that death was due to “dissection of the left anterior coronary artery.” Ephedrine and pseudoephedrine were found in the blood. This case was classified as a possible sentinel event. (14019)
A 35-year-old male, who had been taking Hydroxycut for seven days to increase energy, came home from work early because he was not feeling well, went to the bathroom, and was later found unresponsive. At autopsy, an 80 percent stenosis of the proximal left anterior descending coronary artery was found, along with “moderate” stenosis of the right and left circumflex coronary arteries. The cause of death was listed as atherosclerotic coronary vascular disease. Because of this preexisting condition, we classified this case as a possible sentinel event. (14638)
A 23-year-old man was found dead in his apartment by his sister. He had been using Ripped Fuel. Autopsy showed “no gross evidence of a pathologic process.” Microscopic examination of the heart reported “multifocal and confluent myocyte necrosis with healing of approximately 1 to 2 weeks; mild perivascular, focal endocardial, and focal epicardial fibrosis; and moderate myocyte hypertrophy and vascular congestion. There was no evidence of myocarditis.” Blood toxicology screen was negative, but urine toxicology screen showed ephedrine at 1.6 μg per ml. We classified this case as a possible sentinel event. (258)
A 42-year-old male was found dead at home. On autopsy, he was found to have had an intracranial hemorrhage and was also found to have hypertensive cerebral vasculopathy. He had been taking a street drug (“speed”) that contained ephedrine, and toxicology screen was positive for ephedrine at 2.7 μg per ml. We classified this case as a possible sentinel event due to the preexisting vasculopathy. (44)
An 84-year-old female was found in a coma and subsequently died. On clinical investigation, she was found on computerized tomography (CT) scan to have a subarachnoid hemorrhage and a right subdural hemorrhage. At autopsy, she was found to have a ruptured berry aneurysm along with cerebral atherosclerosis. She had been taking an unknown drug containing ephedrine, and her blood toxicology screen was positive for ephedrine. We classified this case as a possible sentinel event due to the preexisting berry aneurysm. (44)
A 44-year-old male was taking ephedrine as a replacement for daily coffee and cocoa. He had a sudden cardiorespiratory arrest and died. Autopsy revealed an acute thrombus in the left anterior descending coronary artery. The report states, “All other coronary lumina were patent, although calcified with focal narrowing to approximately 50 percent.” Due to the preexisting coronary artery disease, we classified this case as a possible sentinel event. (224)
A 24-year-old male collapsed and died during a training run. He had reportedly taken Ripped Fuel, although none was found in his personal possessions, nor were traces of amphetamines found on toxicology screen (which looked for ephedrine as well). At autopsy, he was found to have died of massive sickle-cell crisis. As a result, we classified this case to be probably not related to ephedra use. (13672)
A 40-year-old male was taking Max Alert to stay awake on the job. He had “odd symptoms that were not a recognizable illness,” described as “nausea, dizziness, sweats, irritability, dehydration, respiratory problems, etc.” The report then states that he was killed in a car accident while driving. We classified this case as probably not related to ephedrine use and note that it may be the same case as Case 1902493, which has a virtually identical description, both cases having been filed within one month of each other. (1859087)
A young male was killed in an automobile accident while driving home in the early morning from his night shift job at a hotel. The patient had been using Max Alert to stay awake. The cause of death at autopsy was laceration of the aorta. We classified this case as probably not related. (1902493)
A 30-year-old male was found dead. He had had chronic low back pain and a chronic pain disorder and was on numerous medications. Autopsy did not reveal any cause of death; however, the toxicology screen was positive for alcohol, fentanyl, phenylpropanolamine, ephedrine, pseudoephedrine, bupropion, nordiazepam, alprazolam, chlordiazepoxide, and nortriptyline. Cause of death was listed as mixed drug and alcohol intoxication. We classified this case as probably not related. (3491515)
A 29-year-old male died. Toxicology screens of blood and urine revealed that he was positive for morphine, hydrocodone, acetaminophen, diphenhydramine, hydromophone, promethazine, dihydrocodeine, codeine, pseudoephedrine, ephedrine, brompheniramine, phenothiazine, cannabinoids, and nicotine. We judged this case as probably not related. (3772362)
A 37-year-old male collapsed and died after taking Metabolife for weight loss and energy. At autopsy, ephedrine was found in the blood. In addition, one coronary artery was found to be 70 to 80 percent stenosed. These data were recorded on a single page of telephone conversation notes in the file. Because there was no other documentary evidence regarding this case, we classified it as having insufficient information to judge. (13806)
A 56-year-old male who had recently started taking Thermogen Plus Liquid fat complexor tablets was found slumped over in his bathtub after a barbecue. He had a history of hypertension and was on a calcium channel blocker as well as daily baby aspirin. Within the year prior to his death, he had had a normal treadmill test. He also had elevated cholesterol for at least four years prior to his death. Four days before his death he was noted to have heartburn. No autopsy report was in the FDA records. A report of a phone conversation stated that the death certificate listed “cardiac arrhythmia of unknown etiology” as the cause of death. We counted this case as having insufficient information, because no autopsy report was available to us, and he had preexisting hypertension and elevated cholesterol. Without the finding of the autopsy report that detailed the examination of the cardiovascular system, we can come to no other conclusion. (14465)
A 45-year-old male took two tablets of Nature's Nutrition-Formula One prior to suffering a myocardial infarction. The patient had also smoked for 30 years and had been a practicing alcoholic until one year prior to the event. At angiography, the coronary arteries were found to be normal. (10024)
A 23-year-old female took four Midnight Ecstasy tablets as a sexual stimulant. Shortly thereafter, she began developing symptoms of autonomic hyperactivity followed by palpitations, shortness of breath, and pink frothy sputum. She was taken to the emergency room, where she was found to be in pulmonary edema. Cardiac enzymes indicated acute myocardial injury. Urine toxicology screen was positive for marijuana and amphetamines. Ephedrine was not mentioned in the toxicology report. Coronary angiography did not reveal any sign of coronary artery disease. Her recovery was complicated by a presumed infection, but she was ultimately discharged from the hospital in good condition. (3446357)
A 30-year-old male body builder was taking ma huang “as instructed by the product label.” He presented to the emergency department complaining of chest pain. Vital signs revealed tachycardia and no hypertension. Electrocardiogram was consistent with acute inferior cardiac ischemia. Cardiac enzymes confirmed a myocardial infarction. Urine toxicology screen was negative for cocaine and amphetamines. Emergency cardiac catheterization demonstrated normal coronary arteries with mild global left ventricular hypokinesis and mild left ventricle hypertrophy. He recovered well. (244)
A 19-year-old male experienced chests pains 30 minutes after taking Dymetadrine Xtreme at the recommended dose. Vital signs revealed tachycardia and elevated respiratory rate of 22. The physical examination was described as unremarkable except for diaphoresis. Electrocardiogram was consistent with an inferolateral myocardial infarction, and myocardial necrosis was confirmed by cardiac enzymes. Toxicology test was negative for cocaine. Cardiac catheterization was reported as showing “only minimal intimal disease of the distal left anterior descending artery.” The patient was reported to have recovered well. (516)
A 35-year old woman was taking a dietary supplement containing ephedrine for weight loss. She had the acute onset of chest pain, diaphoresis (perspiration), and shortness of breath. She was admitted to the hospital, where an electrocardiogram and cardiac enzymes were consistent with acute myocardial infarction. Results of a cardiac catheterization were reported as “normal cardiac function and normal coronary arteries.” She was discharged with a diagnosis of acute myocardial infarction secondary to cardiac spasm. (224)
A 37-year-old male took E'ola Amp II Pro Drops for twelve days prior to suffering an inferior myocardial infarction. At coronary angiography, his mid-right coronary artery was found to be 95 percent stenosed. The patient received percutaneous transluminal coronary angioplasty. Due to the preexisting condition, we classified this case as a possible sentinel event and note the product was later reported to include illegal doses of ephedrine. (9372)
A 54-year old-male with a history of hypertension had been taking Nature's Nutrition-Formula One for approximately three to four months prior to suffering an inferior myocardial infarction. He also had a cardiac arrest from which he was successfully resuscitated. On angiography, he was found to have an 80 percent stenosis of the right coronary artery along with total occlusion of the obtuse marginal artery. He was treated with angioplasty. Because of the preexisting condition, we classified this case as a possible sentinel event. (9504)
A 35-year-old male took five capsules of Metabolift prior to a vigorous workout. He then had an acute inferior myocardial infarction, for which he received thrombolytic therapy. At angiography, his left anterior descending coronary artery had ectasia, which is indicative of coronary artery disease. Therefore, we classified this case as a possible sentinel event. (10009)
A 38-year-old female took Herbalife Original Green for one day. The next day, she suffered an inferior myocardial infarction, for which she received thrombolytic therapy. At catheterization, the posterior descending artery was found to be totally obstructed. The left coronary artery was found to be normal except for one area with a 70 percent lesion. The toxicology screen was negative for cocaine but positive for amphetamines. Ephedrine was not mentioned in the toxicology report. The diagnosis was “presumed right coronary spasm with Prinzmetal's Angina.” In the setting of coronary artery disease, we classified this case as a possible sentinel event. (13009)
A 37-year-old female with a family history of coronary artery disease was both overweight and a cigarette smoker. She was taking Metabolife 356 to lose weight. She suffered a myocardial infarction and was found on angiography to have total occlusion of the right coronary artery with diffuse disease in the left anterior descending coronary artery and the left circumflex artery. She received percutaneous transluminal coronary angioplasty with placement of a stent. Because of the preexisting condition, we classified this case as a possible sentinel event. (14114)
A 43-year-old female had a heart attack. Earlier that day, she had taken six tablets of Metab-O-Lite. She was a cigarette smoker and had a lipid disorder. At coronary catheterization, the left main coronary artery was found to be normal, the left anterior descending artery had 20–30 percent stenosis, the left circumflex artery had no disease, and the right coronary artery had 30 percent stenosis. Because of the preexisting coronary artery disease, we classified this case as a possible sentinel event. (14530)
A 26-year-old female began taking Thermo Slim and The Accelerator daily for weight loss. Three days later, her legs became weak, and she reported feeling like she was going to pass out. She was taken to the emergency room where she was found to have a probable basal ganglia hemorrhage on CT scan. She also had paranoid psychosis. She was a long-time intravenous drug abuser and alcohol abuser. She had also smoked cigarettes for ten years. She was not taking oral contraceptive pills. Blood pressure in the emergency room was 129/71. Toxicology screen was positive for acetone and for benzodiazapines. It was negative for cocaine, amphetamines, and a host of other substances, but ephedrine was not specifically examined. Ephedrine was not mentioned in the toxicology report. She signed out Against Medical Advice from that hospital and ended up in another hospital later that day in restraints. Another toxicology screen was positive for phenylpropanolamine and benzodiazepine. At this hospital, rheumatologic and embolic evaluation was negative. (10874)
A 42-year-old female who was taking Power Trim began having headaches. Approximately one week later, when she was scheduled to undergo a root canal procedure to treat a dental abscess, her daughter heard a “thump” on the floor and found her mother shaking, lying on the floor, unresponsive. She was taken by ambulance to the emergency room, where she was observed to have a focal seizure, which then generalized. She had no prior history of seizure. Toxicology screen was negative. Glucose was 93. CT scan revealed a possible small area of hemorrhage in the upper right parietal region. An MRI with contrast revealed a 1 by 1-1/2 centimeter area of acute hemorrhage without mass effect and without abnormal vascularity. Digital subtraction angiography did not reveal any evidence of arteriovenous malformation. The patient remained seizure-free on anticonvulsant therapy. (11062)
A 31-year-old female had been taking Trim Easy for weight loss for nine months. She occasionally took up to 6 caplets at a time and smoked 3–4 cigarettes a day. She was found in the bathroom unconscious and brought to an emergency room. Her blood pressure was 143/86. CT scan showed a large intracerebral hematoma. Cerebral angiography did not show any source of the hemorrhage, and MRI also was remarkable only for the bleed. Medical records documented improvement over a period of time, but she was left with substantial physical limitations. (11105)
A 28-year-old male who was described as a weight trainer took Ripped Fuel. He also smoked two packs of cigarettes per day. During sexual relations with his wife, he had a headache and became dizzy. He was taken to the emergency department where he was found to have a right middle cerebral artery infarction that was “suggestive of vasospastic phenomenon.” At the time of his admission, his blood pressure was 132/78. His toxicological examination was positive for benzodiazapines. Ephedrine was not mentioned in the toxicology report. Cerebral angiogram was negative. Rheumatologic and hypercoagulability evaluations were negative. There was a negative transesophageal echocardiogram. Urine screen showed ephedrine, pseudoephedrine, and caffeine, according to a discharge summary, which also described the illness as “cerebral infarction associated with ephedrine and caffeine use.” (11675)
A 39-year-old male Navy diver, who regularly took Ultimate Orange for energy, presented to the ship doctor with right hand and leg numbness. The symptoms had occurred 1½ hours after using the product, during a workout. He also reported taking omeprazole, creatine, and vitamins. CT scan and angiogram were negative except for an intracerebral hemorrhage. Blood pressure initially was 140/72. The patient made a good recovery and was able to go back to work but was prohibited from further diving. (12980)
A 29-year-old male in the Army, who was taking Ultimate Orange and had a history of migraine headaches, reported that he was running on a treadmill, when he experienced “the worst headache of his life.” He was taken to the emergency department, where he had some right-sided weakness, which improved over the next 12 hours. The CT scan and lumbar puncture were normal. The following morning, most of his symptoms had resolved, but then he suddenly developed total hemiplegia. He underwent an emergency MRI and angiogram, which showed a complete occlusion of the right middle cerebral artery. The patient had a very stormy course, ultimately resulting in a right hemispherectomy to control swelling. A full hypercoagulability workup was done and was normal. Echocardiogram did not reveal an embolic source. Microscopic examination of the brain tissue did not show any sign of vasculitis. (13418)
A 53-year-old female was taking Slim Caps. In June 2000, she presented with the clumsy hand syndrome on the right. At the time, her blood pressure was 204/128. She stated that in the past, her systolic blood pressure had been 135. CT scan at the time of the event showed a lacunar infarct in the right frontal parietal region. She made a good recovery. A hypercoagulability workup was negative. Echocardiogram was done and showed no evidence of clot. (14372)
A 46-year-old female took Xenadrine for 4 days. While at work, she stood up, had a seizure, and became unresponsive. She was taken to the emergency department. A CT scan showed a left-sided frontal cortex stroke. MRI showed occlusion of the left middle cerebral artery. Blood pressure in the emergency room was 102/69. MR angiography was negative. Transesophageal echocardiogram was negative. Hypercoagulability workup was negative. (14473)
A 33-year-old male presented to the emergency department with the sudden onset of left hemiparesis and slurred speech. He smoked one pack of cigarettes a day and took bupropion for smoking cessation. He consumed Thermadrene 8 hours prior to the onset of neurologic symptoms. There was no hypertension. A noncontrast CT scan did not show any abnormalities. There was no evidence of intracerebral hemorrhage. He was treated with tissue plasminogen activator. Normal tests included a sedimentation rate, clotting studies, urine toxicology screen, homocysteine, antinuclear antibodies, Factor V level, complete hypercoagulability evaluation, echocardiogram, VDRL, and carotid and vertebral duplex studies. He was given a diagnosis of new cerebrovascular accident in the right middle cerebral artery. He was left with a permanent disability. (552)
A 19-year-old female with a history of anorexia/bulimia and alcoholism presented after taking 15 to 18 tablets that contained ephedrine 25 mg (along with guaifenesin). She had previously been taking this product 3 to 10 tablets at a time to lose weight, and the case report was silent regarding whether or not this increased dose was a suicide attempt. Initial presentation was unremarkable, but while in the emergency department, she developed a severe headache and right-sided paralysis. Blood pressure was elevated at 136/98. A CT scan showed left parieto-frontal cerebral hemorrhage with extension into the left lateral ventricle. Angiography did not document a source of the bleed. She was treated with an emergency craniotomy and hematoma evacuation. No arteriovenous malformation was found. She survived but had a major residual neurologic deficit. We classified this case as a sentinel event, but also note this may have been an unrecognized suicide attempt. (184)
A 20-year-old woman took two capsules of a “purported amphetamine look-alike.” Two hours after consumption, she developed a severe headache, nausea, hemiparesis, and aphasia. Ten hours later, she sought admission to a hospital. On initial evaluation, her blood pressure was not elevated and she had a right homonymous hemianopsia and a dense right spastic hemiparesis. At that time, sedimentation rate, clotting studies, rheumatologic studies, and other tests evaluating both vasculitis and the hypercoagulable state were negative. CT scan showed a left external capsular hemorrhage with shift of the midline structures. Angiography showed alternating narrowing and dilation of several branches of the middle cerebral artery. She made a slow and incomplete recovery. Analysis of the capsules demonstrated the presence of ephedrine, phenylpropanolamine, and caffeine. (514)
A 32-year-old female who was taking E'ola Amp II Pro Drops for weight loss suffered a brain stem stroke. She had been to the emergency room twice earlier in the day prior to her stroke and both times was thought to be having an allergic reaction to peanut butter. She was taking oral contraceptive pills. Evaluation of the cause of her stroke included a transesophageal echocardiogram that was negative except for an atrial septal aneurysm, but this was not thought to be the cause of the stroke. Lumbar puncture was negative. Cerebral angiography showed the basal artery was occluded with embolus. Because no hypercoagulability workup was noted, we could not judge this case as more than a possible sentinel event, and also note this product was later reported to include illegal doses of ephedrine. (9296)
A 56-year-old female who was taking E'ola Amp II Pro Drops for three months suffered a lacunar infarct. She had preexisting hypertension, total cholesterol of 238, and triglycerides of 529. She also had a 60-pack-per-year history of smoking. CT scan was negative. The MRI revealed microvascular changes. Because of her preexisting conditions, we classified this case as a possible sentinel event, and also note this product was later reported to include illegal doses of ephedrine. (9335)
A 24-year-old female had a right internal capsule stroke after taking one dose of Super Fat Burners. She was not taking oral contraceptive pills or on any other medications. Carotid arteriogram was normal, echocardiogram was normal, and drug screen was negative. She had had two miscarriages in the past. While most of the hypercoagulability evaluation was normal, one test suggested the presence of the lupus anticoagulant. Because the antiphospholipid antibody syndrome was not effectively excluded, we classified this case as a possible sentinel event. (10094)
A 64-year-old female with a history of hypertension, paroxysmal atrial fibrillation, and two transient ischemic attacks was on propranolol, isradipine, and aspirin therapy, and had taken Fit America Natural Weight Control Aid. She was found unconscious in the bathroom by her husband and taken to the emergency room, where she was found to have had an embolic stroke. She was given heparin, which resulted in a small left temporal parietal intracerebral hemorrhage. She was found to be in atrial fibrillation. Carotid ultrasound was negative. Due to the preexisting condition of atrial fibrillation, we classified this case as a possible sentinel event. (12713)
A 47-year-old male, who had a long history of hypertension but had not taken medication in 20 years, suffered a right lentiform nucleus bleed that manifested itself as left-sided paralysis. The notes stated that just prior to the event, he took Purple Blast to lose weight; however, there was no drug or alcohol use. When he arrived in the emergency department, his blood pressure was 196/94, and it later fell to 187/107. Chest x-ray revealed cardiomegaly. CT scan showed “large acute intracranial hemorrhage in mid portion of right cerebral hemisphere.” His triglyceride levels were 364. Because of the history of long-standing untreated hypertension, we classified this case as a possible sentinel event. (12733)
A 41-year-old female with a history of hypertension who had been taking Diet Phen and had four stroke events over a two-month period. Blood pressure in the emergency department after one event was 170/108, and at another time, it was 158/99. She was put on coumadin and discharged home after her first stroke but then was readmitted three times in the next two months for recurrent stroke, all of which occurred while she was on anticoagulants. She suffered additional neurologic events consistent with brain stem infarction. She had numerous magnetic resonance angiograms, the first of which revealed an “irregularity of the basilar artery.” Subsequent studies showed the basilar artery totally occluded. The interpretation of these angiograms was the subject of considerable discussion, with the final interpretation in the notes being “basilar artery vasculitis.” Rheumatologic evaluation and hypercoagulability evaluation were negative. This case was difficult for us to assess since amphetamines have been linked to vasculitis, but her vasculitis could also have had other etiologies and therefore we classified this case as a possible sentinel event. (12888)
A 25-year-old female who was taking Natural Trim presented with slurred speech and right-sided weakness. She was not on oral contraceptives and was a nonsmoker for five months. Blood pressure recorded in the nurse's notes was 144/88. MRI revealed a lacunar stroke. Carotid duplex was negative. Echocardiogram showed a mitral valve prolapse with a patent foramen ovale with a right-to-left shunt that was described as minimal. No clot was seen. The patient had total resolution of symptoms. Hypercoagulable workup was normal, but incomplete. No tests of protein S or C (proteins involved in blood clotting) were reported in the FDA material. Therefore, we classified this case as a possible sentinel event. (14378)
A 42-year-old male who was taking Slim 'N Up awoke with paresthesia on the left and difficulty walking and talking. He was a nonsmoker for five years. The patient had a known diagnosis of hypertension, was on Diltiazem, and also had hypercholesterolemia. Emergency department blood pressure was 132/89. Lumbar puncture in the emergency room was traumatic, with 35 red blood cells in tube 1 and 0 red blood cells in tube 4. A transcranial Doppler study was negative, carotid duplex study was negative, echocardiogram was negative, and MRI showed left cerebella infarct. Subsequent admissions were for seizure control. We classified this case as a possible sentinel event due to the prior hypertension and hypercholesterolemia and the lack of complete hypercoagulability workup. (14434)
A 55-year-old female who had been taking Metabolife 356 for 60 days developed a headache, had a seizure, and became unconscious. She was taken to the emergency department, where she was found to have a large subarachnoid hemorrhage. An emergency angiogram showed a large right posterior communicating artery aneurysm, which was subsequently clipped. She had a stormy course complicated by meningitis, hydrocephalus, and placement of a ventricular peritoneal shunt. Because of the preexisting large aneurysm, we classified this case as a possible sentinel event. (14553)
A 33-year-old man who had been taking ma huang (40–60 mg per day of ephedra alkaloids) for energy and weight training awoke with a severe Wernicke's aphasia. He had not complained of prior headache or other symptoms. He had a slight right-sided facial and arm weakness and a right Babinski sign. His blood pressure was 140/60, and his pulse was 54 per minute. Brain CT showed signs of extensive left middle cerebral artery infarct. Cervical ultrasound duplex scanning and cerebral angiography were normal. Cerebral CSF examination was normal. The report contained no coagulopathy assessment other than D-dimers (cross-linked fibrin molecules that may be a diagnostic marker for venous thromboembolism), which were within the normal range. Creatinine was in the normal range. Transesophageal echocardiography and ECG were also normal except for a patent foramen ovale. We classified this case as a possible sentinel event, because there was no additional documentation about the details of the coagulopathy evaluation. (270)
A 37-year-old male who ingested 10 pills of a “street drug” containing ephedrine (15.3 mg per tablet, as identified by subsequent analysis), developed sudden right body numbness and, on evaluation, was found to have pure right body sensory loss with a left thalamic infarct on MRI. Laboratory studies included normal prothrombin time and partial thromboplastin times, sedimentation rate, electrocardiogram and transthoracic electrocardiogram. The patient refused arteriography. As a result, we classified this case as a possible sentinel event. (44)
A 20-year-old man was admitted with nausea, vomiting, and headache that began one hour after he took an unknown quantity of what he called “speed.” Urine drug screen on the day of admission revealed only ephedrine, in particular excluding amphetamine, phenylpropanolamine, caffeine, and other drugs. CT scan obtained on admission demonstrated blood in the subarachnoid space, which was confirmed by lumbar puncture. Angiography on the day of admission was normal, and rheumatologic evaluation was negative. A repeat angiogram seven days later showed features typical of vasculitis. We classified this case as a possible sentinel event. (438)
A 36-year-old female who was taking Nature's Nutrition-Formula One for weight loss developed a headache. Based on CT and MRI, she was diagnosed as having had a stroke. She was a nonsmoker and was not taking oral contraceptive pills. This information was obtained from notes of a conversation with the patient herself. The notes stated that medical records were requested; however, none appeared in the FDA file. Therefore, we classified this case as having insufficient information. (9521)
A 30-year-old female who took Metabolife 356 for one week developed a headache while eating and had a stroke. A friend drove her to the hospital; en route, they encountered a paramedic, who obtained a blood pressure reading of 249/131. She stated that she was on no medications, had no hypertension, didn't smoke, and didn't drink. Unfortunately, no additional information appeared in this record. Therefore, we classified this case as having insufficient information. (13829)
A 36-year-old female who took Metabolife 356 had “respiratory failure and a possible stroke.” The file contains a note stating that medical records were requested but were never received. Thus, we classified this case as having insufficient information. (13905)
A 32-year-old female who, according to case notes, was taking over 100 “Maxi Thins” per day for five years and was “addicted to product,” had three cerebral hemorrhages and two strokes and was hospitalized for two months. No additional information is available. Thus, we classified this case as having insufficient information and also note the extraordinary dose of ephedrine being consumed. (1823550)
A 68-year-old man who had been taking an “over-the-counter anti-asthma pill” containing 40–60 mg of ephedrine per day for 10 years had a left temporal-parietal hematoma with rupture into the lateral ventricle. Angiography showed changes consistent with vasculitis, and pathological examination from material obtained during surgical evacuation of his hematoma showed necrotizing angiitis of the small vessels. The patient improved with prednisone. We classified this case as having insufficient information. (515)
A 22-year-old male who regularly used Ripped Force along with a variety of other supplements collapsed while lifting weights and had a ventricular fibrillation cardiac arrest complicated by hypoxic encephalopathy. Although he had a history of asthma, this was not felt to be an asthmatic attack. Toxicological examination revealed ephedrine, pseudoephedrine, methyl ephedrine, and phenylpropanolamine. An echocardiogram ruled out asymmetric septal hypertrophy but did reveal a reduced left ventricular ejection fraction (35–40 percent) and an increased left ventricular end diastolic dimension. CT scan showed no brain tumor or bleed. A pulmonary consultant who saw him in the hospital stated that he “doubts” that this incident was related to asthma. He recovered to the point where he could feed himself but he does not remember his friends and has substantial mental disability. We classified this as a possible sentinel event since the echocardiogram results raise the possibility that this patient could have had a cardiomyopathy, which then could be the cause of the cardiac arrest. (12851)
A 28-year-old female who took Herbalife Original Green had a cardiac arrest later that same day while playing softball. According to the affidavit, she needed to be defibrillated four times and now has a permanently implanted defibrillator. Unfortunately, other than this affidavit, no information was available. Therefore, we classified this case as having insufficient information. (13031)
A 32-year-old female had been taking Natural Trim for two weeks. On one morning, after taking Natural Trim, she ate lunch, went outside her office building to smoke a cigarette, and had a witnessed cardiac arrest. A physician bystander initiated CPR, and she was taken to the Emergency Department with decorticate posturing. Although successfully resuscitated, she was left with permanent heart and brain damage. She also had a permanent intracardiac defibrillator implanted. Notes from the FDA investigator said that her hospital records showed she had chronic obstructive pulmonary disease, ventricular fibrillation, and “cardiomyopathy versus acute myocarditis” with “possible contributing factor of cardiotoxic diet pill.” She had a left ventricular ejection fraction of 35 percent with global left ventricular hypokinesia, and endomyocardial biopsy found mild focal hypertrophy and mild focal interstitial fibrosis. No medical records were available in the FDA files. Therefore, we classified this case as having insufficient information. (13643)
A 28-year-old female who had been taking ephedrine tablets (2000 mg per day) for eight years to lose weight presented with dilated cardiomyopathy. She denied any other chronic alcohol or drug use except tobacco. She reported that after abruptly reducing the dose of ephedrine to only 75 mg per day, she rapidly developed symptoms of dyspnea, fatigue, and orthopnea (difficulty breathing while lying flat). Exhaustive diagnostic evaluation, including cardiac catheterization and endomyocardial biopsy, revealed no specific diagnosis, and the patient's dilated cardiomyopathy was characterized as idiopathic. We classified this case as a possible sentinel event, but note the extraordinary level of ephedrine use. (110)
A 39-year-old male with a history of hypertension presented with dyspnea on exertion, orthopnea, and edema. He had been taking numerous Herbalife supplements (including Original Green) for three months, which provided a total of between 7 and 21 mg of ephedrine alkaloid daily. Exhaustive diagnostic evaluation, including endomyocardial biopsy, yielded a diagnosis of hypersensitivity or eosinophilic myocarditis. He was treated with azothioprine and prednisone, and Herbalife medications were discontinued. At six months follow-up, his heart function was normal. We classified this as a possible sentinel event. (297)
A 32-year-old housewife who was noted to be abusing ephedrine, taking up to 450 mg a day, presented with “congestive cardiac failure” and received a clinical diagnosis of congestive cardiomyopathy of unknown etiology. No coronary angiography or myocardial biopsy was performed, which may have been within the standard of practice at the time of the case (1980). We classified this case as having insufficient information and also note the high level of ephedrine intake. (260)
A 65-year-old female who had been taking the product Thermolean for two years was hospitalized with acute congestive heart failure. Evaluation revealed cardiomyopathy with a left ventricular ejection fraction estimated at 15 percent and atrial fibrillation. It was the treating physician's opinion that the cardiomyopathy was “probably secondary to ephedrine use.” There were no medical records available with this file. Therefore, we classified this case as having insufficient information. (13793)
A 48-year-old female was taking Metabolife 356 for approximately one month when she developed a rapid heartbeat that would not subside. She was taken to the emergency department and found to be in ventricular tachycardia. The file contained no information on diagnosis or treatment procedures, although the MedWatch form stated that the patient said she was taking beta-blockers. No medical records were available for this adverse event. Therefore, we classified this case as having insufficient information. (13945)
A 57-year-old female with prior history of hypothyroidism, gastroesophageal reflux disease, depression, degenerative joint disease, and fibromyalgia began having nausea and vomiting and became disoriented. She had been taking Synthroid, Oxycontin, Prozac, Trazodone, Prilosec, and one other medication whose name was illegible in the file notes. She also took Metabolife 356 for one day and a total of 48 mg of ephedrine prior to the adverse events. Her husband took her to the emergency department, where an examination was inconclusive. Laboratory values were essentially normal. A toxicology screen was positive for opiates but negative for amphetamines. A CT scan was negative. She was seen in consultation by a neurologist who told her that she had a vasospasm transient ischemic attack, possibly related to ephedrine use, and the discharge instructions were to stop using the Metabolife 356 supplement. We classified this case as a possible sentinel event, because the symptoms alone do not confirm that she had a transient ischemic attack. (13062)
A 19-year-old female who reported using Shape Rite/Shape Fast at half the recommended dose for three to four weeks had one witnessed episode in which her “arms and legs went stiff, noticeable drool appeared, eyes rolled, [and she] appeared to black out,” followed by a postictal period (period of confusion typically observed following a seizure). She had no prior history of seizures. Electrolytes were normal; complete blood work was normal; and pregnancy test was negative. She had a normal CT scan without contrast and a normal electroencephalogram. She was seen by a consultant neurologist, whose diagnosis was that she had a “single-tonic seizure, and none of the other factors which (sic) are normally associated with seizures, are present.” (10974)
A 38-year-old female with no prior seizure history experienced two “petit mal” seizures (the authors' description) after taking two tablets of over-the-counter ephedrine-containing dietary supplements in the morning and evening. The following day, she had a generalized tonic-clonic seizure, during which she required respiratory assistance. Over the next five days, she continued to have petit mal and generalized tonic-clonic seizures. She was diagnosed with new onset of tonic-clonic seizures with complex partial seizures. The report (in Morbidity and Mortality Weekly) stated, “Other possible causes of seizures were excluded.” After discontinuing the ephedrine-containing dietary supplement, she had no further seizures. (224)
A 47-year-old female who had been taking Nature's Nutrition-Formula One for three weeks to lose weight (one pill twice a day) had a tonic-clonic seizure in her sleep at 2 a.m. Her husband took her to the emergency department, where some evaluation was done, but she was treated and released on no therapy. Two months later, she had another seizure, which occurred at 5 a.m. At that time, she was transported by ambulance to the emergency department and was seen by a neurologist. A random glucose was 90, electrolytes were normal, sedimentation rate was 52, MRI was normal, and EEG was described as “mildly abnormal.” She had a remote history of hysterectomy and ear surgery two years prior to the event. Her only medication was Premarin, and she used alcohol only socially. It was the neurologist's opinion that the patient had new onset generalized tonic-clonic seizures, and “hypoglycemia” was suspected but could not be proved. The patient's subsequent course was complicated by rash, fever, mild pancytopenia, and increased liver function tests, which were thought due to her anticonvulsive therapy. We classified this case as a possible sentinel event, because other causes were considered and not effectively excluded. (9534)
A 37-year-old female who was taking Nature's Nutrition-Formula One was admitted to the hospital for symptoms of dizziness, shortness of breath, palpitations, and “passing out,” and “intermittent episodes of confusion,” with one episode of “shaking of limbs and saliva coming out of her mouth.” She had no prior history of seizures. She denied using alcohol. She was seen in consultation by a neurologist. Electrolytes were normal, complete blood count was normal, arterial blood gas was normal, glucose was 179, magnesium was normal, toxicology screen was negative, pregnancy test was negative, CT scan with and without contrast was read as a “0.8 by 0.6 centimeter calcification in the frontal region, which may represent dural calcification.” Subsequent MRI was normal and showed no evidence of calcification in the area seen on CT scan. Mild chronic right sinusitis was noted. EEG was interpreted as mildly abnormal due to “excessive intermittent bi-temporal slowing.” No epileptogenic activity was seen. The impression of the neurologist was “complex seizures with generalization.” We classified this case as a possible sentinel event. (10221)
A 62-year-old male who had been taking the product Thermo Slim for three to four months for weight loss began to have periods of memory loss, confusion, and agitation. He then had a generalized seizure with lateralizing features characterized by right sided tonic-clonic jerking and was admitted to the hospital. The patient had a prior history of heavy alcohol consumption until approximately four years before the event. In the emergency room, the patient was noted to be normotensive and had no fever. He was characterized to be in acute delirium. Although he had no prior history of diabetes mellitus, his blood sugar on admission was 488, and he was given the diagnosis of diabetes. Toxicology screen was positive for benzodiazepines. Arterial blood gases revealed adequate oxygenation. CT scan of the brain without contrast showed atrophy but was otherwise unremarkable. MRI showed generalized brain atrophy. Electroencephalogram showed “moderate to severe abnormality, with bilateral cerebral dysfunction;” however, no epileptiform activity was identified. He was given a diagnosis of organic brain syndrome with senile dementia and also the possibility of “left temporal lobe cerebral infarct with secondary seizure.” One consultant raised the possibility of acute encephalopathy of uncertain etiology. Because of the focal nature of the seizures and the multiple metabolic problems, we classified this case as a possible sentinel event. (10432)
A 23-year-old female was taking Metabolife 356, one pill two to four times a day for four months. While driving out of a parking lot, she had a generalized tonic-clonic seizure witnessed by her husband. Her husband controlled the car and prevented a crash. The seizure lasted for two minutes (during which it was noted that the patient bit her tongue) and was followed by a postictal period. She had had one seizure two years prior, which had been only partially evaluated (she had not received a CT scan at that time), and she was not treated. In addition, she had one sibling who had had a seizure at age 8, and the paternal grandparents were noted to have had seizures. She reported using alcohol only rarely. On evaluation, CT scan (non-contrast) was negative, oxygen saturation was 99 percent, toxicology screen was negative, pregnancy test was negative, and EEG was abnormal, “indicative of a potential underlying seizure disorder.” Because of the prior history of seizures, we classified this as a possible sentinel event. (11649)
A 26-year-old male who had been using the product Ripped Fuel for approximately three years developed a headache that lasted approximately three days and then began experiencing seizures and was taken to the emergency room. While in the emergency department, he had a witnessed generalized tonic-clonic seizure. He had taken Ripped Fuel on the day of the event. Arterial blood gas and glucose were within normal limits. Drug screen was negative. Electrolytes were normal except for potassium of 3.2 and bicarbonate of 15.8. He had no history of medical illness, alcoholism, or serious injury. The family had no history of seizures. He had no further seizures over a three-hour period and was discharged home with referral to neurology. Two days later, he had another seizure and returned to the emergency department, where he was admitted to the hospital. Neurological consultation considered this case to be a complex partial seizure with generalized tonic-clonic seizure of new onset and to have a recent history suggestive of migraine headaches. Despite being given therapeutic doses of anti-seizure medications, he continued to have seizures to the point where he was placed in a Phenobarbital coma, requiring mechanical ventilation. After several weeks of a drug-induced coma, he was weaned off the Phenobarbital, but remained on anti-seizure medication and was left with a metabolic encephalopathy. He was transferred to a rehabilitation center. We classified this case as a possible sentinel event, because the clinical cause was quite complicated and from the records we had available we could not reach a more definitive conclusion. (13408)
A 30-year-old female was found by her husband to be moaning and making noises. She became limp and subsequently very confused. Paramedics were called and a blood glucose measured in the home was normal. She had been taking Metab-O-Lite for two to three months for weight loss (the records are inconsistent on this point). She took one tablet before lunch and one tablet before dinner. Her last dose was on the day of the episode. She was on no medications, and had no personal or family history of seizures. She was seen in consultation by a neurologist. MRI with contrast was normal. An additional CT scan of the head, which was done without contrast, was interpreted as “negative.” Serum electrolytes were normal, glucose was recorded in a dictated note as 19, but this is not commented on anywhere else in the notes and our presumption is that this is a typographical error. Serum calcium was normal, as was the complete blood count. The neurologist ordered an EEG, which showed an abnormality due to the presence of “some sharp waves emerging from the left hemisphere, mainly the parietal region.” The neurologist's impression was that this was “most likely a seizure,” and the patient was started and maintained on Dilantin. No further seizures were noted as of a follow-up three months after the event. We classified this case as a possible sentinel event, because it was not clear that the event was a seizure. (14275)
A 31-year-old female who was taking Thin Tabs (one tablet three times a day for approximately one month) developed a headache over her left eye, which became more severe after she took aspirin. The headache was followed by visual blurring, nausea, and vomiting, but no scintillations. She became tremulous, incoherent, and lethargic. She was taken by ambulance to the emergency room, where she had a generalized tonic-clonic seizure. In the emergency room, blood pressure was 165/107, pulse was 101, and respiratory rate was 24. Blood glucose was recorded as slightly elevated, and serum chemistries were normal. Sedimentation rate was normal. Non-contrast CT scan of the head was normal. Lumbar puncture was unremarkable. Gram stain was negative. Urine drug screen revealed amphetamines. She had no prior history of seizure. Physician's notes stated that the patient says she was “abusing” her diet pills, an assertion that was later denied in the medical record. Her medical history was remarkable for depression, for which she was being treated with Depakote (a drug used to treat seizure disorders, bipolar disorder, and schizophrenia), Trazodone, and Paxil (two antidepressants). It is also stated that she had an MRI, but those results were not in the material available for review. She had an electroencephalogram, which was normal, but which did not “entirely rule out a seizure disorder, as no Stage II sleep was seen, and a short record can miss intermittent phenomenon.” Because of her EEG and in light of her taking other medications known to lower the seizure threshold, we classified this case as a possible sentinel event. (14571)
A 40-year-old female who had taken Ripped Fuel (two capsules, two times per day) for two days had a generalized tonic-clonic seizure (witnessed by her husband) while cooking dinner in her kitchen. She had no history of seizures. During the seizure, she fell, suffering a laceration to her head and was taken to the emergency department. At that time, glucose was 104, serum electrolytes were normal, and CT scan with and without contrast was normal. No report of an electroencephalogram was in the file. We classified this case as having insufficient information. (9747)
A 21-year-old male took five to seven Nature's Nutrition-Formula One capsules in one day to stay alert while studying for final exams. He became psychotic and did not sleep for five days. A friend said he ran around campus looking like a homeless crazy person. The patient had no history of psychiatric or medical problems. (9509)
A 39-year-old female took Diet Now (tested by the manufacturer and said to contain 6 mg ephedra alkaloids per capsule, 12 mg per dose) for approximately one year at recommended doses. Her mother reports that the daughter experienced insomnia, hallucinations, psychosis, and delusions with the onset approximately one year after product initiation. She required hospitalization in a psychiatric facility for 40 days, with ongoing problems including terror, panic, and forgetfulness. She has now returned at work. (11678)
A 19-year-old female was taking Hydroxycut 2 pills twice a day to aid muscle definition and to speed metabolism. She reported dizziness and nausea two hours after use and began having violent outbursts, nightmares, poor mood, hot flashes, and fatigue. After a few days, she developed increased anger and rage and fought with boyfriend, mother, father, and sisters. She also tried to kill her boyfriend's sister and herself. After eight days of use, she developed a migraine and went to the emergency room. She then went home and picked up a knife, with homicidal intent, but was convinced to return to the hospital voluntarily. She was admitted for 18 hours and was readmitted later that day for a 72-hour involuntary hospitalization. Symptoms abated four days after Hydroxycut was discontinued. (13809)
A 29-year-old male took Xenadrine (two tablets twice per day) as a diet supplement for over six months. After six months of use, he was hospitalized three times for hyper-religiosity, paranoia, delusions, insomnia, and lack of concentration, and displayed some indication of the onset of bipolar disorder, but had no known history of prior mental health problems. Symptoms recurred twice more following use. (14529)
A 16-year-old male took MaxAlert and Mini Thin for 11 months, often ingesting up to 40 tablets per day for weight loss and as a stimulant. The patient had episodes of aggressive behavior, irritability, tachycardia, insomnia, and violent and destructive behavior. When he visited a physician, it was noted that his symptoms coincided with an increase in dose of MaxAlert. No significant medical history and no history of other drug use were noted. We classified this as a sentinel event; however, we note the extraordinary use of product. (1855921)
A 45-year-old male who had taken an herbal dietary supplement labeled as ma huang daily for two months was brought to the emergency room by his wife when, after several weeks of using greater amounts, he began to display irritability, sleeplessness, and strange religious preoccupation. He had no medical or psychiatric history. His symptoms disappeared after brief treatment with Trazodone and discontinuation of ephedra. (48)
A 30-year-old female had taken Tedral (which contains ephedrine) for asthma for many years. She had no other medical problems and no history of psychiatric problems. Her mother had noticed a marked change in her behavior over the previous two years, which seemed to coincide with taking more Tedral than medically necessary. The patient became paranoid, illogical, and hallucinatory. A diagnosis of acute schizophrenic psychosis, either due to or aggravated by the abuse of ephedrine, was made. She was asked to stop taking Tedral but took it occasionally until persuaded by her family doctor to switch to cromoglycic acid. At two years follow-up, her symptoms had disappeared. (238)
A 59-year-old male who had taken ephedrine-containing products for over 25 years to treat asthma experienced auditory hallucinations, was delusional, and entered a woman's home, believing he was saving her from being tortured. At the time of the event, he had been taking ephedrine hydrochloride plus Bronchipax (ephedrine resinate 30mg; theophylline 40mg; salicylamide 250 mg) but had just doubled his daily ephedrine dose to 360 mg ephedrine plus Bronchipax. The patient had no history of psychiatric problems. The psychotic symptoms diminished 10–13 days after a reduction of the ephedrine dose. (285)
A 28-year-old female reportedly took one Slim NRG+ (ma huang) three times per day without incident for over 6 months and lost 30 pounds. After abruptly discontinuing use of the supplement, she was hospitalized for severe depression and a suicide attempt (gunshot wound to chest). She took no concomitant medications. Because no information regarding psychiatric or medical history was available, we classified this case as a possible sentinel event. (9751)
A 19-year-old man who took Ripped Fuel as directed (two capsules, three times per day) for three weeks was hospitalized with palpitations, increased blood pressure, and psychosis. He had no previous psychiatric problems or medical conditions. Because no information regarding psychiatric or medical history was available, we classified this case as a possible sentinel event. (11157)
A 13-year-old female took Nature's Nutrition-Formula One for approximately two weeks at recommended doses of approximately one tablet twice per day for weight loss. Her first symptoms were noted approximately one to two weeks after she began to use the product. She reported auditory hallucinations, disorientation to place, and withdrawal. Her symptoms endured for approximately two months. No information regarding medical or psychiatric history was included in the report, so we classified it as a possible sentinel event. (12372)
A 21-year-old male used Ripped Fuel as directed for two weeks. His parents reported personality changes such as nervousness, anger, and rage, and he went long periods without sleep. He had no previous psychiatric or medical problems. His parents reported he was sensitive to caffeine, which is included in the product. His symptoms stopped after the product was discontinued. (13005)
A 52-year-old female took Metab-O-Lite, two tablets three times per day for five months, for weight loss. She reported hallucinations, psychosis, delusions, and paranoia, which led to hospitalization in a state psychiatric facility. Her symptoms persisted for two to three days. She had a history of asthma and high blood pressure and no history of alcohol abuse. The report included a very confusing indication of a previous episode of hallucinations secondary to surgery or perhaps to Metab-O-Lite a few months earlier than the identified adverse event. (14436)
A 28-year-old female who took Metab-O-Lite (eight pills per day) for over six months for weight loss began to experience dizzy spells and headaches almost immediately after starting the supplement. She later began to experience chest tightness and a racing heart. Approximately one week after starting, she began to experience auditory hallucinations, delusions, and paranoia. Auditory hallucinations and delusions endured for over a year after discontinuing the product, thus we classified this as a possible sentinel event. (14528)
A 31-year-old man used Max Alert for over four years, gradually increasing the dose until he was consuming 1,250 mg of ephedrine per day. He began to display psychotic behavior, including paranoia. Over four years, he was hospitalized three times, and at the time of report, was in a residential rehabilitation center for substance abuse treatment. The report states he had never used illicit substances and had no significant medical history. We classified this case as a possible sentinel event, but note the extraordinary dose of ephedrine. (1661966)
A 34-year-old male was brought to the emergency room after jumping from a second story window because he believed he was being chased. While taking ma huang over the previous nine days, he had experienced paranoid delusions and visual hallucinations. He had no history of mental illness. Medical history was not contained in the report. The patient was hospitalized for a number of weeks. After discontinuing ephedra, he remained well. The ephedrine content of the product was not noted in this case report; investigators contacted the manufacturer; however, they were unable or unwilling to disclose the amount of ephedrine in each tablet. (79)
| Adverse Event | Number of Events Reported |
|---|---|
| Fainting/ loss of consciousness | 39 |
| Heart rate >120 or <50 | 45 |
| Hypertension, systolic >180 or diastolic >120 | 51 |
| Paralysis | 7 |
| Liver failure, ALT/AST >200 | 7 |
| Rhabdomyolysis, CPK >400 | 3 |
| Coma | 1 |
| Miscarriage | 1 |
| Age | N | % |
| ≤ 10 | 5 | < 1 |
| 11–20 | 340 | 2 |
| 21–30 | 2163 | 12 |
| 31–40 | 2369 | 13 |
| 41–50 | 1598 | 9 |
| 51–60 | 912 | 5 |
| >60 | 343 | 2 |
| No Data | 10627 | 57 |
| Average Age | 38 | |
| Gender | N | % |
| Male | 707 | 4 |
| Female | 6792 | 36* |
| No Data | 11032 | 30 |
| Adverse Event | N | % |
| No adverse event reported | 2019 | 11 |
| Death | 3 | < 1 |
| Cardiovascular: Heart rate, >120 or <50 | 23 | < 1 |
| Cardiovascular: Heart rate, 50–120, or not otherwise unspecified | 584 | 3 |
| Cardiovascular: Hypertension, Systolic>180 or Diastolic>105 | 45 | < 1 |
| Cardiovascular: Hypertension, Systolic<180 or Diastolic<105, not otherwise specified | 405 | 2 |
| Cardiovascular: Myocardial Infarction/ Heart Attack | 22 | < 1 |
| Cardiovascular: Cardiac Dysrythmia, Other/ Palpitations | 630 | 3 |
| Cardiovascular: Cardiac arrest | 3 | < 1 |
| Cardiovascular: Ventricular Tachycardia/ Fibrillation | 0 | 0 |
| Cardiovascular: Chest Pain, not specified as MI | 582 | 3 |
| Pulmonary: Respiratory arrest | 2 | < 1 |
| Neurological: Transient Ischemic Attack | 5 | < 1 |
| Neurological: CVA/ Stroke, not known to be hemorrhage | 29 | < 1 |
| Neurological: Brain Hemorrhage | 2 | < 1 |
| Neurological: Fainting / Loss of consciousness | 41 | < 1 |
| Neurological: Coma | 0 | 0 |
| Neurological: Seizure | 46 | < 1 |
| Psychiatric: Depression | 57 | < 1 |
| Psychiatric: Hallucinations | 2 | < 1 |
| Psychiatric: Mania or severe agitation | 1 | < 1 |
| Psychiatric: Psychosis | 3 | < 1 |
| Psychiatric: Suicide attempt | 0 | 0 |
| Autonomic Hyperactivity (Includes: Tremor, twitching, jitteriness, insomnia, increased sweating, agitation, nervousness, and irritability) | 2536 | 14 |
| Changes in glucose <40 or >400 | 56 | < 1 |
| Liver failure ALT/AST >200 | 5 | < 1 |
| Liver abnormality, not otherwise specified | 46 | < 1 |
| Rhabdomyolysis CPK >400 | 1 | < 1 |
| Rhabdomyolysis, not otherwise specified | 0 | 0 |
| Miscarriage | 6 | < 1 |
| Allergic Reaction | 614 | 3 |
| Anesthesia complication | 2 | < 1 |
| Fatigue/Fever/ Chills | 724 | 4 |
| Abnormal lab values, not otherwise specified | 216 | 1 |
| Ear, Eye, Nose, or Throat | 795 | 4 |
| Respiratory System | 374 | 2 |
| Cardiovascular System | 255 | 1 |
| Gastrointestinal System | 4680 | 26 |
| Hepatobiliary System | 25 | < 1 |
| Musculoskeletal System | 1136 | 6 |
| Genitourinary System | 395 | 2 |
| Gynecologic (includes breast and menstrual symptoms) | 1009 | 5 |
| Sexual Dysfunction | 115 | 1 |
| Neurological System (includes headache) | 2475 | 13 |
| Mental Health | 462 | 3 |
| Skin (Includes Pruritis) | 1385 | 7 |
| Hematologic System | 126 | 1 |
| Oncologic System | 4 | < 1 |
| Other symptoms not specified above | 396 | 2 |
91 percent of files with reported gender are female.
. Table 26 presents summary data regarding the key variables from our abstraction form on these cases. In 57 percent of cases, the consumer's age was not included. The majority of the remaining cases were reported by persons between the ages of 21 and 50, with a mean age of 38. In 66 percent of all cases, sex was not recorded. Of the remaining cases, 91 percent were female.
A tabulation of the symptoms showed that there were three deaths, 22 cases of myocardial infarction, three cases of cardiac arrest, 29 cases of stroke, two cases of brain hemorrhage, 46 cases of seizure, three cases of psychosis, and two cases of hallucinations. The files contained 111 cases of hospitalization in addition to those associated with the serious cases just listed. These hospitalizations were for a variety of reasons, but most were for cardiovascular-related symptoms.
The MIPER files for death, heart attack, cardiac arrest, stroke, seizure, and certain psychiatric events were all reexamined by the principal investigator and other physicians and are listed in Appendix 2 of this report. One case of death occurred as a result of “a brain hemorrhage,” according to the notes. Another case involving a death contained a handwritten note that said, “wanted refund (sister's husb died).” The third case stated “cousin was taking Metabolife last yr, had stroke, died.” No additional information for these cases is present. Two additional deaths, identified by Metabolife in a document entitled 77 ‘serious’ AE's as identified by Metabolife (see below), were not included in the MIPER CD-ROM we received. These additions bring the total number of Metabolife-related deaths to five. The cases of other serious events range in documentation from several sentences of clinical information related by the patient, letters from patients stating that they had a serious adverse event, to simply the words “heart attack” or something similar on a sheet of paper in the MIPER file. This level of documentation is insufficient to make judgments about the possible relation between ephedra use and the event. The largest proportions of case reports included symptoms of autonomic hyperactivity (14 percent of all cases) and gastrointestinal symptoms (26 percent of all cases). These data are compatible with the results of our meta-analysis of adverse events in placebo-controlled trials of ephedra and ephedrine, which demonstrated both autonomic hyperactivity and upper gastrointestinal symptoms to be causally related to use of ephedra or ephedrine.
As mentioned above, included with the material we received was a document (a sheaf of paper) entitled 77 ‘serious’ AE's as identified by Metabolife. This sheaf contained photocopies of the MIPER files judged by Metabolife to be the most serious in nature. These MIPER files included reports of three deaths. Two of these deaths had the MIPER number blacked out, were marked “privileged and confidential,” were not found on the MIPER CD-ROM by our abstractors, and were not found using a modified MIPER CD-ROM that allowed text word searching (prepared for us by FDA).
The documentation on both cases consisted, as did many of the Metabolife files, of a printed version of an email. The first death was of a 45- to 55-year-old female, who was apparently initially healthy and continued to take Metabolife 356 for three weeks, despite symptoms of palpitations and a rapid pulse rate, until she suffered sudden death. An autopsy found “no conclusive cause of death.” The email notes that toxicology studies are pending “to ascertain if ephedrine was present in her system at the time of death.” No additional clinical information is available. The second case was that of a 30- to 40-year-old female who was found dead. According to her father, the autopsy “stated that the cause of death was of a cardiac nature of an unknown origin.” Drug analysis found “only caffeine.” No other clinical information was available.
| RAND # | Metabolife # | Explanation |
|---|---|---|
| DEATH | ||
| No # | Not on our MIPER CD-ROM | |
| No # | Not on our MIPER CD-ROM | |
| 23695 | Only notation is “migraine HA, wanted refund (sister's husb died)”. Unclear if this death is the consumer or a relative | |
| 35062 | 35062 | |
| MYOCARDIAL INFARCTION/ HEART ATTACK | ||
| 16006 | 16006 | |
| 17002 | 17002 | |
| 20416 | 20416 | |
| 20918 | 20918 | |
| 21010 | “the man who was taking them [Metabolife 356] has now suffered a heart attack” | |
| 22492 | “28 yrs old had a heart attack” | |
| 22584 | “customer had a heart attack thinks it was Met” | |
| 22779 | “heart attack, gall bladder surgery, cholecystectomy” | |
| 23877 | “13 heart att, 3 strokes” | |
| 24166 | 24166 | |
| 24236 | 24236 | |
| 24383 | “cold sweat ht attack” | |
| 24448 | 24448 | |
| 24859 | 24859 | |
| 27941 | 27941 | |
| 28168 | 28168 | |
| 28488 | 28488 | |
| 28835 | 28835 | |
| 35532 | Not on our MIPER CD-ROM | |
| CARDIAC ARREST | ||
| 15409 | 15409 | |
| 27600 | 27600 | |
| 35063 | 35063 | |
| STROKE | ||
| 16593 | 16593 | |
| 17196 | “vision disturbance” | |
| 18199 | 18199 | |
| 19474 | “short of breath, tachycardia” | |
| 20763 | 20763 | |
| 22308 | “pain in chest, took NTG, stood up, ?stroke, ?side won't move, CAT scan negative” | |
| 22325 | “had ministroke…$50 refund…will see neurologist” | |
| 22479 | “‘legal’ customer that had 2 strokes - lawyer” | |
| 22496 | “BP and Premarin ‘caffeine’ → stroke” | |
| 23002 | 23002 | |
| 23663 | “stroke that cousin suffered” | |
| 23877 | “13 heart att, 3 strokes” | |
| 24825 | 24825 | |
| 24945 | 24945 | |
| 25011 | “stroke” written on note, but remainder of notes are about skin and gastrointestinal symptoms. | |
| 25147 | “client had a stroke” | |
| 25482 | 25482 | |
| 25495 | 25495 | |
| 25521 | 25521 | |
| 27791 | “wife 1997 - had stroke” | |
| 28156 | “mild stroke symptoms” | |
| 28157 | “facial numbness” | |
| 28201 | “muscle weakness” | |
| 28281 | 28281 | |
| 28321 | 28321 | |
| 29424 | 29424 | |
| 29469 | 29469 | |
| 30391 | 30391 | |
| 30407 | 30407 | |
| BRAIN HEMORRHAGE | ||
| 27754 | “brain bleeding?” | |
| 35062 | Recorded by Metabolife under death | |
| SEIZURE | ||
| 15281 | 15281 | |
| 15345 | 15345 | |
| 16461 | 16461 | |
| 16653 | 16653 | |
| 16703 | 16703 | |
| 16897 | 16897 | |
| 16970 | 16970 | |
| 17369 | 17369 | |
| 17752 | “[redacted] and her sister both take Met [redacted] reports [redacted] had a seizure recently” | |
| 18335 | 18335 | |
| 18962 | 18962 | |
| 19149 | 19149 | |
| 20812 | 20812 | |
| 20864 | 20864 | |
| 20979 | 20979 | |
| 22150 | Definitely a seizure, but contained in the section of the main file that has refund requests and we inferred these cases were also recorded elsewhere in the MIPER file | |
| 22238 | “black out while driving had hot flashes also had 2 screwdrivers” | |
| 22364 | “seizures like activity” | |
| 22539 | “friend of a friend had seizure” | |
| 22800 | 22800 | |
| 23029 | 23029 | |
| 23440 | “s/e's → dad” | |
| 23468 | “sister - grand mal seizure” | |
| 24172 | “seizure” | |
| 24209 | Same case as 16897 | |
| 24344 | 24344 | |
| 24482 | 24482 | |
| 24711 | 24711 | |
| 24839 | 24839 | |
| 24947 | “seizures” | |
| 25371 | 25371 | |
| 27487 | 27487 | |
| 27523 | 27523 | |
| 28183 | 28183 | |
| 28329 | 28329 | |
| 28442 | 28442 | |
| 29882 | “seizure” checked off on list of symptoms on standardized form | |
| 35568 | Not on our MIPER CD-ROM | |
| RAND Case # | Index Case # | Complaint Case # | MIPER#(s) | Notes |
|---|---|---|---|---|
| 1 | 1 | 1 | 20867 | This is a 42-year-old male who took two Metabolife pills for the first time and presented with chest pain, chest-tightness and shortness of breath. He ended up in the emergency department where he was found to have a blood pressure of 140/82 with a pulse of 111. The electrocardiogram showed him to be in atrial fibrillation. A discharge summary is not included among the records received. However, the patient's note to Metabolife said that he was discharged after one day and that his doctors were “convinced” that his heart was “back to normal.” Of note is that his laboratory values established that he did not have thyroid disease and did not have any evidence of a myocardial infarction. |
| 20868 | ||||
| 2 | 2 | 2 | 20871 | This is a 28-year-old female who had shortness of breath, dyspnea and wheezing. She was seen in the emergency department and was said to be having an “anaphylactoid reaction.” She was treated with epinephrine, steroids and Benadryl with a complete response. |
| 20872 | ||||
| 3 | 3 | 3 | 16287 | This is a 38-year-old female who was admitted to the hospital with acute pancreatitis. The hospital record notes that she is “quite obese.” The record also notes that she had a prior total abdominal hysterectomy with bilateral salpingo-oopherectomy and at that time was found to have ovarian cancer with involvement of the bowel. This resulted in partial colectomy with a diverting colostomy, and subsequently she had a renastomosis. She also had a prior cholycystectomy. It is noted that she did not drink alcohol. Her admission records note an elevated white blood cell count with a value of 14,000 but no elevation in amylase or lipase. A subsequent note states that these laboratory tests did become elevated and then returned to normal. She was discharged after recovery. Actual laboratory values are not included with the records. There is no mention of a measurement of serum triglycerides. |
| 20873–75 | ||||
| 21033 | ||||
| 24047 | ||||
| 24051 | ||||
| 4 | 4 | 4 | 20876–78 | This case consists of a handwritten note from the patient and a medical care bill for $34. The age and gender of the patient are unknown. The complaint is of headache, dizziness and tingling. |
| 5 | 5 | 5 | 17895 | This file consists of a single physician note of a female of unstated age who came in with the complaints of “pain over the joints, gums would bleed, veins seemed to be thrombosing, some itching, easy bruisability and pain in the back over her kidneys.” The physical examination was normal, clotting studies were normal, sedimentation rate was seven, chemistry panel was normal. The patient left in good condition. |
| 20879 | ||||
| 23365 | ||||
| 6 | 6 | 6 | 20880 | This is a 28-year-old female who presented with 2 weeks of stomach pain, mostly after eating food, along with explosive diarrhea. Her laboratory work-up was essentially normal with a normal white blood cell count, liver enzymes and amylase. She was diagnosed as having “acute gastritis.” She had both upper and lower endoscopy that did not reveal a clear diagnosis. Stool for ova and parasites was negative. Stool was positive for occult blood. Stool culture was negative, abdominal series was negative. |
| 20883–85 | ||||
| 7 | 7 | 7 | 15998 | This is a 53-year-old female who presented with emesis and diarrhea after eating a hamburger at a fast food restaurant. Her examination was essentially unremarkable. The diagnostic impression was acute gastroenteritis. She was treated with antibiotics and Kaopectate. |
| 20886 | ||||
| 8 | 8 | 8 | 16166 | This is a 61-year-old female with a history of asthma who presented with headaches. She was found to have a potassium of 3.3 and a sodium of 118. It was noted that she drinks eight glasses of water a day. The diagnosis given was headache, possibly due to low sodium, and a viral upper respiratory tract infection. |
| 20887 | ||||
| 24083–84 | ||||
| 9 | 9 | 9 | 20888–89 | This is a 53-year-old female who was seen for increased intraoccular pressure. She was under the care of an ophthalmologist for what she called the “iridocorneoendothelial syndrome.” It was treated by her ophthalmologist. |
| 10 | 10 | 10 | 20890 | This is a female of unstated age who presented with a headache. The records note that she had migraines eight years ago. She had photophobia and emesis. Her blood pressure was 153/73. She was treated with Imitrex with mild relief and she also received Demerol and Phenergan. |
| 11 | 11 | 11 | No MIPER located | This is a male of unstated age who presented with abdominal indigestion without vomiting. The records note the patient had a prior vagotomy and pyloroplasty with gastroenterostomy. He received an ultrasound, CT scan and endoscopy. There was no indication of his treatment or response. In addition, there is no mention of taking Metabolife anywhere in the medical records. |
| 12 | 12 | 13 | 16995 | This is a 53-year-old female. The complaint that is listed is hyponatremia. However there is no medical record documentation of this. All that is included is a single copy of lab tests showing normal thyroid function and normal complete blood count. Whether these data apply to this patient is unclear, as the patient age on the lab slip is listed as 33. A doctor's note in the MIPER file states she required hospitalization. |
| 20892 | ||||
| 25503 | ||||
| 13 | 13 | 14 | 15996 | This is a 61-year-old female who presented with supraventricular tachycardia which required cardioversion and subsequent treatment with atenolol. This is documented in a note, possibly from her doctor, however there are no medical records included with this case. |
| 20893–95 | ||||
| 23828 | ||||
| 21035–37 | ||||
| 14 | n/a | 12 | n/a | This is a 60-year-old female who presented with palpitations and was found to be in atrial flutter. According to the discharge summary, she was electrically cardioverted and then given Digoxin and Cardizem. Subsequent clinic notes showed her to continue to be in sinus rhythm. There is no indication or records that other diagnostic studies were done. |
| 15 | 14 | 15 | 16642 | This is a 21-year-old female. The complaint is a rash. The only documentation provided is the bill of an emergency department visit. There are no medical records. |
| 20897–99 | ||||
| 21034 | ||||
| 23859 | ||||
| 16 | 15 | n/a | 17569 | This is a 49-year-old female, noted to weigh 160 lbs., who presented with chest pain and had an overnight hospitalization to evaluate myocardial infarction. CPK was elevated but the MB fractions were negative. The patient was discharged with the diagnosis of chest wall pain. |
| 20900–01 | ||||
| n/a | 16 | n/a | 15351 | No medical record received |
| 23010 | ||||
| 17 | 17 | 16 | 17605 | This is a 36-year-old female who claims to be “only 20 lbs. overweight” who stated that she had elevations in blood pressure, now requiring treatment with Maxzide. However there are no medical records accompanying this complaint, only a copy of bills. |
| 20904 | ||||
| n/a | n/a | 17 | n/a | (Listing of Key Complaints states chest pain, shortness of breath) |
| n/a | n/a | 18 | n/a | (Listing of Key Complaints states elevated blood pressure/ racing pulse) |
| 18 | 18 | 19 (?) (Listing of Key Complaints states Fainting) | 16199 | This is a 73-year-old female who was evaluated for near syncope that occurred while eating in a restaurant. In the emergency department, blood pressure was noted to be 132/37 with a pulse of 64 and glucose was 90. The discharge diagnosis was “syncope related to hypoglycemia vs. Metabolife vs. vasovagal episode.” Exercise treadmill test performed later was normal but there was a submaximal heart rate achieved. Carotid ultrasound was normal. Many additional notes cover healthcare judged to be irrelevant to the use of ephedra, including a podiatry consult, breast biopsies, pap smear and an endometrial biopsy. |
| 19 | 19 | 20 | No MIPER located | This is a 24-year-old female who presented with blood in the urine for one day. The records consist of a urine culture which was negative, a urinalysis which showed 2+ blood and a hemoglobin and hematocrit of 18 and 50, respectively. |
| 20 | 20 | 21 | 20905–06 | This is a 47-year-old male who presented in atrial fibrillilation, was shown not to have had a myocardial infarction, and who had an echo and exercise treadmill test that were both normal. There was no evidence of thyroid disease. The patient converted to sinus rhythm with medication and was then treated with Digoxin. A followup doctor's note stated that the patient was in sinus rhythm and implied that he was off Digoxin. |
| 25529 | ||||
| 21 | 21 | 22 | 17028 | This is a 31-year-old female who is noted to weigh 261 lbs. She presented with heart palpitations, shortness of breath and heart “flutter.” She had a history of hypertension with pregnancy. A consultant's note reported T-wave inversions in V1 and V3 with an elevated CPK but the MB fraction was normal and the Troponin test was negative. It is unclear exactly what happened, but this apparently resolved. |
| 20907–08 | ||||
| 24154 | ||||
| 22 | 22 | 23 | 17277 | This is a 36-year-old female who presented with nausea, dizziness and vomiting, headache and abdominal pain. Blood pressure was noted to be 134/87 and the pulse was 85. Abdominal ultrasound was normal, pregnancy test was normal. Urinalysis showed moderate ketones. The discharge diagnosis was “abdominal pain of uncertain etiology.” |
| 20914–15 | ||||
| n/a | 23 | n/a | 22408 | No medical record received |
| 20916–17 | ||||
| n/a | n/a | 24 | n/a | (Listing of Key Complaints states difficulty breathing/ anxiety) |
| 23 | 24 | 25 | 20918–21 | This is a 38-year-old female who made three visits to the emergency room over four days for epigastric and chest pain, initially being diagnosed as having esophageal reflux, then gastritis and then finally being recognized as having coronary artery disease with an 80% left anterior descending stenosis. This was treated with a coronary stent. Her cardiologist notes that she had a “very positive family history” of coronary artery disease and that her mother had an “early heart attack.” There was no indication in the record that a cholesterol test was done. |
| 21032 | ||||
| 24 | 25 | 26 | 20950 | This file contains no medical records, only medical bills documenting prescriptions for hydrochlorothiazide and phenazopyridine, along with a urinalysis. The MIPER file indicates the patient said she was diagnosed with hemorrhagic cystitis, and later hypertension. |
| 20953–54 | ||||
| 20958–59 | ||||
| 20961 | ||||
| 25 | 26 | 27 | 20962–66 | There are no medical records in this file, only bills. On one of the bills is written “drug reaction.” |
| 21006–07 | ||||
| 26 | 27 | 28 | 18445 | This is a 39-year-old female. The complaint is an allergic reaction. There are no medical records in this file, only bills. |
| n/a | 28 | n/a | 16521 | No medical record received |
| 17536 | ||||
| 27 | 29 | 29 | 20967–68 | This is a 40-year-old female who developed transient elevations of liver enzymes with an ALT of 125. Albumin and bilirubin were normal. Multiple tests for possible etiologies of this were performed, all of which were negative. Metabolife was discontinued and the liver function abnormalities drifted down to normal over time; the last note said that she had recovered totally. |
| 28 | 30 | 30 | 20969 | There are no medical records in this file. The only thing that is listed is a complaint from the patient about a heart rate being 188 and the blood pressure being high, that the patient was treated in the emergency room and that there were “blood tests to assess heart damage.” The MIPER includes a long letter from the patient that relates much the same thing. |
| 20971–75 | ||||
| 20977–78 | ||||
| n/a | 32 | n/a | No MIPER located | No medical record received |
| n/a | 33 | n/a | No MIPER located | No medical record received |
| n/a | n/a | 32 | n/a | Listing of Key Complaints states nothing identified- just a bill |
| n/a | n/a | 33 | n/a | Listing of Key Complaints states nothing identified- list of medications |
| 29 | 35 | 35 | 16376 | This is a 54-year-old male with chest pain and a headache who also complained of high blood pressure and lightheadedness. There are minimal records associated with this report of August 11, 1999, other than that the patient was diagnosed with accelerated hypertension. Of note, however, is that there are numerous clinic visit notes dating back to 1997, documenting that the patient had a history of hypertension, diabetes and hyperlipidemia, with a blood pressure on one occasion 154/92. It is noted that this was taken with a large cuff. In addition, there are clinic visits with chest pain as far back as 1997. |
| 21030 | ||||
| 30 | 34 | 34 | 21027 | This is a male of unstated age, possibly 40 years old, who wrote a note saying that he had stomach problems, kidney stones, colon problems and anxiety problems. There are no medical records associated with this file, only bills. |
| 21029 | ||||
| 31 | 31 | 31 | 21000–01 | There are no medical records with this file, only some discharge instructions that say that the diagnosis was “acute nausea.” The MIPER file states the patient is a 37-year-old female and that “hypoglycemia was likely.” |
| 32 | 36 | 36 | 20979 | This is a 50-year-old female who had a witnessed grand mal seizure while driving. Later that day, after undergoing a CT scan in the emergency room, she had a 2nd witnessed seizure and, according to an attorney's letter, she then had a 3rd seizure at some point. An evaluation included a CT of the brain, which was normal, and an electroencephalogram, which was also normal. She had no history of alcoholism. Serum sodium was normal and glucose was normal. Pulse oximetry was 99%. Toxicology screen was positive for amphetamines. There was no prior history of seizure disorder or neurologic disease. |
| 24840 | ||||
| 25498 | ||||
| 25501 | ||||
| 33 | 37 | 37 | 19473 | This is a 21-year-old female who is noted to weigh 200 pounds and on whom the MIPER file will say shortness of breath and tachycardia. There are minimal records associated with this, only a discharge diagnosis of hyperventilation, with a notation saying that a friend died two days ago. There is a listing of medications and, by implication, these are being taken by the patient. These are Darvocet (which may have been discontinued), Flexeril, Reglan, Cytotec, Dicyclomine, Viokase, Sudafed, Lopid, Citracel, Pariodel, Benadryl, DDVAP, Zantac, Trilisat, Carafate. Of note, the MIPER may also say the complaint includes aphasia, paralysis, and shortness of breath. |
| 23970 | ||||
| 34 | n/a | 39 | n/a | There are no medical records in this file, only a bill. |
| 35 | 40 | n/a | 19350 | This is a 39-year-old female who had the complaint of abdominal pain. The medical records submitted with this consist of a clinic note which says that the patient has “classic gastrointestinal illness” with mild nausea and no diarrhea, progressing to diarrhea with no vomiting. |
| 36 | 38 | 38 | 20864–66 | This is a 29-year-old female who had a witnessed tonic clonic seizure. There is no history of alcoholism. The grandmother had a history of seizures but was also noted to be an alcoholic. Blood pressure was normal at 120/80. Brain MRI was normal. EEG was normal. Toxicology screen by report had “large amount ephedrine and pseudoephedrines.” |
| n/a | 39 | n/a | 24495 | No medical record received |
| n/a | n/a | 40 | n/a | (Listing of Key Complaints states lower back pain/GI) |
| 37 | n/a | 41 | n/a | This is a patient of unknown age and unknown gender who presented for an allergic reaction. There are no medical records and only bills and medications in this file. |
| n/a | 41 | n/a | No MIPER located | No medical record received |
| 38 | n/a | 42 | n/a | There are only bills which have a diagnostic code 780.2 which is “syncope and collapse,” along with indications that an echocardiogram and duplex sonography were done. There are no other medical records. |
| 39 | 42 | 43 | 19604 | This is a 29-year-old female, who is noted to weigh 230 lbs., who presented for menstrual irregularity, numbness and tingling. Evaluation was unremarkable and no diagnosis was given. |
| 40 | n/a | 44 (?) (Listing of Key Complaints states intracranial hemorrhage, which is mentioned in patient history) | n/a | This is a 36-year-old female who complained of menstrual irregularity. The records document that she recently had a right posterior parietal intracranial hemorrhage with extension into the ventricular system requiring neurosurgery with a drain. This was subsequently shown by angiography to be due to an arteriovenous malformation, which was then subsequently resected. After this neurosurgery she had not had resumption of her menstrual period. In the notes available there was no work up of this symptom. |
| 41 | n/a | 45 | n/a | This is a 26-year-old female, who is noted to weigh 155 lbs., who had chest pains after using Metabolife for two months. She also had asthma and a brother who died of myocardial infarction at age 33. Her discharge diagnoses were asthma and chest pain. |
| 42 | n/a | 46 | n/a | This is a 27-year-old female who presented with sudden abdominal pain which was found to be due to a rupture of a splenic artery aneurysm which required emergency laporatomy and resection. The records note she had a history of congenital multiple ureters which had been surgically repaired at age 7 and she was left with some renal insufficiency as a result. There is no mention of the use of Metabolife in the medical records that are provided. |
| 43 | n/a | n/a | n/a | This is a 49-year-old male who had symptoms of chest pressure and pain along with shortness of breath. He had been a cigarette smoker but the record notes he quit. He had an exercise treadmill test that showed a normal electrocardiogram response but he had scintigraphic evidence of ischemia. He underwent coronary angiography that revealed normal coronary arteries. Three months later he was continuing to have unexplained chest pressure and pain. |
| n/a | 43 | n/a | No MIPER located | No medical record received |
| n/a | 44 | n/a | No MIPER located | No medical record received |
| n/a | 45 | n/a | No MIPER located | No medical record received |
| n/a | 46 | n/a | No MIPER located | No medical record received. |
Index Case # taken from Index of Redacted Consumer Medical Records with Corresponding MIPER Numbers.
Complaint Case # taken from Listing of Key Complaint for the Metabolife Medical Records Submitted.
MIPER #(s) taken from Index of Redacted Consumer Medical Records with Corresponding MIPER Numbers.
No MIPER located: this is the text from the Index of Redacted Consumer Medical Records… as it pertains to the Index Case #.
n/a: not available, no match found.
There were 12 cases with primarily cardiopulmonary symptoms (RAND ID cases 1, 13, 14, 16, 17, 20, 21, 23, 28, 29, 33, 43), two cases with neurologic symptoms (RAND ID cases 18, 38), two cases of seizure (RAND ID cases 32, 36), four cases of allergic reaction (RAND ID cases 2, 25, 26, 37), and 23 cases of miscellaneous symptoms (RAND ID cases 3, 4, 5, 6, 8, 9, 10, 11, 12, 15, 19, 22, 24, 27, 30, 31, 34, 35, 39, 40, 41, 42). There were no deaths, one case of myocardial infarction, no strokes, and no severe psychiatric events. The case of myocardial infarction (RAND ID case 23) was classified as a possible sentinel event, due to the presence of existing coronary artery disease. The two cases of seizure (RAND ID cases 32 and 36) were classified as sentinel events. Comparing these cases to the FDA Medwatch data contained in our Evidence Report demonstrates that neither the case of myocardial infarction nor the two cases of seizure are reported as sentinel or possible sentinel events in our analysis of the Medwatch file; thus, we are not double-counting these events.
We address the limitations of each set of analyses separately: meta-analysis of the weight loss and descriptive synthesis of athletic performance randomized controlled trials; analysis of the adverse events from the randomized controlled trials; and analysis of the case reports of adverse events.
The systematic reviews of the weight loss and athletic performance randomized controlled trials have the following potential limitations:
Our search procedures for randomized controlled trials were extensive and included canvassing experts regarding studies we may have missed. In addition, we observed little to no evidence of publication bias via visual inspection or formal testing for the weight loss studies. However, we acknowledge that publication bias may still exist despite our best efforts to conduct a comprehensive search and the lack of statistical evidence of the existence of bias. Publication bias may occur for a variety of reasons, including investigators' loss of interest in the study if “negative” results are found or if results are obtained that are contrary to the interest of the sponsor or investigator.
An important limitation common to many systematic reviews, whether or not a formal meta-analysis is conducted, is the quality of the original studies. Many of the weight loss studies suffered from an attrition rate higher than is normally allowed by FDA when assessing studies of pharmaceutical products seeking approval. However, recent attempts to define elements of study design and execution that are related to bias have shown that in many cases, such efforts are not reproducible and do not distinguish studies based on their results. Therefore, the current state of the science is to document such methodological weaknesses and perform sensitivity analyses when possible, but not to reject studies or use quality criteria to adjust the pooled outcome. We performed a sensitivity analysis on the subset of studies that had the best quality, according to the only validated scale available. The results of the sensitivity analysis did not alter the majority of our findings.
In our meta-analysis of the weight loss studies, we did not observe significant evidence of heterogeneity. However, the chi-squared test of heterogeneity is underpowered. We did use a random effects approach to attempt to incorporate any heterogeneity and conducted sensitivity analyses to assess the robustness of our conclusions.
We were limited by the small number of trials that provided direct comparisons between treatments of interest in the weight loss meta-analysis. Our meta-regression in this setting was an attempt to compare treatments across trials, but we acknowledge this approach does not allow for controlling for confounders within study. Direct comparisons are needed to draw more definite conclusions. In other words, while our observed results suggest that the amount of weight loss is approximately the same for ephedrine with caffeine, herbal ephedra with herbs containing caffeine, and herbal ephedra alone, the available data do not prove equivalence.
The weight loss studies as a group had limited treatment duration; thus, we cannot draw conclusions about the association between ephedra or ephedrine and weight loss over longer and more clinically relevant intervals than about four months. Current knowledge of weight loss is that it generally ceases after six months, irrespective of treatment, and any weight loss is generally regained. Current recommendations for appropriate clinical trials in this area include a much longer treatment duration (at least one year) and an evaluation of what happens after the agent is withdrawn.
The heterogeneity among the athletic performance studies prevented us from conducting a formal meta-analysis, so we were restricted to a descriptive synthesis.
The results of the clinical trials are directly applicable only to the persons studied in those trials. In most cases, enrollment was highly selective to avoid certain comorbidities. Whether efficacy would be equivalent in a more representative population is unknown.
The results of the ephedra studies regarding efficacy cannot be generalized to all ephedra-containing dietary supplements, because these may vary in their constituents from the concoctions studied and reported on here.
The analysis of the adverse events from the randomized controlled trials have the following major potential limitations:
In this analysis, we focused only on studies that addressed weight loss or athletic performance. Although we observed no serious adverse events in these trials, we might have identified adverse events in trials that tested the efficacy of ephedra for other conditions, had we included those conditions in our search. However, we did include all controlled trials of ephedra or ephedrine for weight loss or athletic performance; therefore, our estimates are relevant to the populations taking those supplements for these reasons, which certainly constitute the majority of users of ephedrine and ephedra products in the United States.
As with efficacy, the results of the clinical trials with respect to safety are directly applicable only to the persons studied in those trials. In most cases, enrollment was highly selective to avoid certain comorbidities. Whether safety is equivalent in a more representative population is unknown.
As with efficacy, the results for the ephedra studies with respect to safety cannot be generalized to all ephedra-containing dietary supplements, because these may vary in their constituents from those concoctions studied and reported on here.
The analysis of the case reports of adverse events had the following major potential limitations:
We did not have access to all adverse event files.
Many authorities consider MedWatch case reports to underestimate the number of events, because patients need to suspect an association in order to report an event.
This report did not review in detail other lines of evidence, such as animal studies, basic neuroscience studies, and adverse event data concerning other sympathomimetic amines that some authorities consider important when trying to assess causation.
Many of the adverse event reports did not contain all the data that we needed to make assessments. Therefore, how the cases we classified as “insufficient evidence” might have influenced our findings had they contained appropriate documentation is unknown.
An important limitation is that we do not have an estimate of the number of people using ephedra or ephedrine; that is, we do not have a denominator with which to calculate an event rate. An additional complication, we believe, is that the use of ephedra and ephedrine is increasing over time, as is the probability that someone will report an adverse event due to publicity.
The most important limitation is that the study design (that is, an assessment of case reports) is insufficient for us to reach conclusions regarding causality.
The major potential limitations of the analysis of the Metabolife files can be classified into two categories: limitations of the source material and limitations of our methods.
The source material for this review differed in several important ways from source material used in other EPC projects:
Much of what we reviewed was handwritten. Therefore, when the handwriting was poor we may not have correctly interpreted what the writer meant to say.
The information was not recorded in an organized fashion, leaving it up to us to interpret its meaning. A good example of this was MIPER 23695 that we (but not Metabolife) classified as a “death.” This file consisted of handwritten notes that stated, “migraine HA, wants refund, sister's husb died.” Does this mean the customer is the sister's husband, who had a migraine headache and then died? Or did the customer have a migraine headache, perhaps in part because her sister's husband died? Without additional information it is impossible to tell.
Each file did not attempt to collect the same information, so a recording bias probably exists.
As already noted, we are not confident we could identify all files associated with a single case, so some double-counting may have occurred.
The methods we used to review the files also had important limitations:
We relied on single-person review to screen cases. In the eight weeks we were given to review the files, we could not do dual review (which is standard in all our other EPC work) of over 18,000 cases. Therefore, more coding errors may have occurred than in situations where we use dual review. Mitigating this limitation is that we did do formal inter-rater reliability testing and demonstrated excellent reliability among reviewers. Also, the principal investigator reviewed all cases that were identified as serious. Furthermore, we identified nearly all the serious events identified by Metabolife, plus many more that Metabolife did not identify. So, while we acknowledge that there may still be errors in the data, we do not think they are so numerous or egregious as to threaten our conclusions.
The Metabolife analysis did not undergo as extensive a review process as did the other sections of this report. The Metabolife analysis was reviewed by three experts and two federal agencies, in contrast to the much more extensive review process for the other sections of the report. Furthermore, because of the timeline necessary to produce the final report, the time available to the reviewers of the Metabolife analysis was shorter than we normally afford. How additional peer review may have affected our conclusions from the Metabolife analysis is unknown.
The efficacy of herbal ephedra-containing dietary supplements has not been extensively studied in randomized clinical trials. We identified no clinical trials of herbal ephedra-containing dietary supplements that assessed their effect on athletic performance and only five clinical trials that assessed their effect on weight loss. Many more studies assessed the effects of ephedrine on weight loss; however, studies of the effects of ephedrine on athletic performance are still relatively sparse. The majority of studies—of both ephedra and ephedrine—are plagued by methodological problems known to be associated with bias, particularly high attrition rates. All of the conclusions on efficacy need to be considered with these methodological limitations in mind.
Given the above considerations, the evidence we identified and assessed supports the following conclusions:
The short-term use of ephedrine, ephedrine plus caffeine, or the assessed dietary supplements containing ephedra and herbs with caffeine is associated with a statistically significant increase in short-term weight loss (compared to placebo).
There are no studies assessing the long-term effects of the use of ephedra-containing dietary supplements or ephedrine on weight loss or maintenance. In order to improve health outcomes and reduce the risk of morbidities associated with being overweight, long-term weight maintenance is necessary.
There are no data to indicate that the effects of ephedrine plus caffeine are different from the effects of ephedra-containing dietary supplements with caffeine-containing herbs.
The effect of either ephedra-containing dietary supplements with caffeine-containing herbs or ephedrine plus caffeine is a weight loss that is approximately two pounds per month greater than that of placebo, for up to four to six months in duration.
As a percentage of pretreatment weight, the weight losses in these studies average between 5 percent and 11 percent in the treatment groups.
The only two studies that compared ephedrine plus caffeine to prescription weight loss pharmaceutical products reported no differences in effectiveness between products, but these studies were statistically underpowered to detect differences of moderate size.
The addition of caffeine to ephedrine is associated with a statistically significant increase in short-term weight loss.
One study of ephedra without caffeine-containing herbs reported a statistically significant increase in short-term weight loss that was comparable to the effects reported by four studies of ephedra with caffeine-containing herbs.
The data suggest a dose-response relationship with respect to ephedrine and weight loss.
All published studies on herbal ephedra and weight loss have used a medium dose of ephedra per day; consequently, no dose-response analysis is possible.
There are no studies assessing the effect of herbal ephedra-containing dietary supplements on athletic performance.
The few studies that assessed the effect of ephedrine on athletic performance did so only in small samples of mostly fit individuals (young male military recruits) and only on very short-term immediate performance. This model does not reflect the use patterns in the general population. These data support a modest effect of ephedrine plus caffeine on very short-term athletic performance.
No studies assessed the effect of the sustained use of ephedrine on performance over time.
It is probable that ephedrine alone, without the addition of caffeine, has little or no effect on athletic performance.
In the data we reviewed, the smallest dose of ephedrine that produced a measurable effect on athletic performance was 0.8 mg per kg of body weight. However, the effect of smaller doses has not been assessed. Higher doses produced unacceptable gastrointestinal side effects.
The data we reviewed on adverse consequences came from both clinical trials and case reports submitted to the FDA. The strongest evidence of causality should come from clinical trials; however, in most circumstances, such trials do not enroll sufficient numbers of patients to adequately assess the possibility of rare outcomes. Such was the case with our review of ephedrine and ephedra-containing dietary supplements. For rare outcomes, we reviewed case reports. However, we could not determine definite causality from case reports.
With these considerations in mind, the evidence we identified supports the following conclusions:
There is sufficient evidence from short-term controlled trials to conclude that the use of ephedrine and/or the use of ephedra or ephedrine plus caffeine is associated with two to three times the risk of nausea, vomiting, psychiatric symptoms such as anxiety and change in mood, autonomic hyperactivity, and palpitations. It is not possible to separate out the contribution of caffeine to these events.
There were no reports of serious adverse events in the controlled trials of ephedrine or ephedra, but these studies are insufficient to assess adverse events that occurred at a rate of less than 1.0 per 1000.
A large number of adverse event reports regarding herbal ephedra-containing dietary supplements have been filed with FDA. The majority of FDA case reports are insufficiently documented to make an informed judgment about the relationship between the use of ephedra-containing dietary supplements and the adverse event in question.
A very large number of adverse events were reported to one manufacturer of ephedra-containing dietary supplements. Nearly all of the case reports were too poorly documented to permit us to make any judgments about the potential relationship between ephedra use and the event.
We identified two deaths, three myocardial infarctions, nine cerebrovascular accidents, three seizures, and five psychiatric cases as sentinel events with prior ephedra consumption; and three deaths, two myocardial infarctions, two cerebrovascular accidents, one seizure, and three psychiatric cases as sentinel events with prior ephedrine consumption. Classification as a sentinel event does not imply a proven cause and effect relationship.
We identified 43 additional cases as possible sentinel events with prior ephedra consumption and seven additional cases as possible sentinel events with prior ephedrine consumption.
About half of the sent
