home/ephedrine alkaloids report	Your Account | View Cart | Order History

Ephedrine Alkaloids Report

FOR FURTHER INFORMATION CONTACT: Margaret C. Binzer, Center for Food Safety and Applied Nutrition (HFS-456), Food and Drug Administration, 200 C St. SW., Washington, DC 20204, 202-401-9859, FAX 202-260-8957, or E-mail M2B@FDACF.SSW.DHHS.GOV. SUPPLEMENTARY INFORMATION I. Background A. Characteristics of Ephedrine Alkaloids Dietary supplements containing ephedrine alkaloids are widely sold in the United States (Refs. 1 through 3). The ingredient sources of the ephedrine alkaloids include raw botanicals and extracts from botanical sources. Ma huang, Ephedra, Chinese Ephedra, and epitonin are several names used for botanical products, primarily from Ephedra sinica Stapf, E. equistestina Bunge, E. intermedia var. tibetica Stapf and E. distachya L. (the Ephedras), that are sources of ephedrine alkaloids. These alkaloids, ephedrine, pseudoephedrine, norpseudoephedrine, norephedrine, methylephedrine, methylpseudoephedrine, and related alkaloids, are naturally occurring chemical stimulants (Refs. 4 through 8). Although the proportions of the various ephedrine alkaloids in botanical species vary from one species to another, in most species used commercially, ephedrine is the most predominant alkaloid. The ephedrine and related alkaloids are amphetamine-like compounds. They exhibit some common types of effects but vary in the relative intensity of these effects (Table 1) (Refs. 5, 6, and 9 through 15). For example, ephedrine is a cardiovascular system (CVS) and nervous system (NS) stimulant. Pseudoephedrine has some CVS and NS stimulatory effects but is less potent than ephedrine. Norephedrine (also called phenylpropanolamine) is similar to ephedrine in its NS stimulant effects but has fewer CVS stimulant effects than ephedrine (Refs. 12 and 16 through 18). Although norephedrine is often a minor ephedrine alkaloid constituent, in humans it can be produced from ingested ephedrine through normal metabolic processes (Refs. 9, 19, and 20). Thus, its presence in body tissues and fluids may be detected, and its physiological effects can occur, even if norephedrine is not contained in meaningful amounts in the original supplement product. Data on the other ephedrine alkaloids and related alkaloids are limited, and thus their physiological and pharmacological effects are largely unknown (Ref. 15). Table 1.--Patterns of Signs and Symptoms Associated With Dietary Supplements Containing Ephedrine Alkaloids Organ/system involved Clinical significance Signs and symptoms Cardiovascular system Serious Dysrhythmias, severe hypertension, cardiac arrest, angina, myocardial infarction, and stroke \1\ Less clinically significant Tachycardia, mild hypertension, palpitations. Nervous system Serious Psychosis, suicidal, altered or loss of consciousness (including disorientation or confusion), and seizures. Less clinically significant Anxiety, nervousness, tremor, hyperactivity, insomnia, altered behavior, memory changes. Gastrointestinal (GI) Serious Altered serum enzymes, hepatitis. Less clinically significant GI distress (nausea, vomiting, diarrhea, constipation). Dermatologic Serious Exfoliative dermatitis. Less clinically significant Nonspecific rashes. General manifestations, Numbness, tingling, dizziness, fatigue, lethargy, weakness. \1\ For the purposes of this document, strokes (i.e., cerebrovascular accidents) are considered to be related to the cardiovascular system, because predisposing or inciting factors include hypertension, dysrhythmias and ischemia, although it is recognized that the consequences affect the central nervous system. C. Adverse Events Associated With Ephedrine Alkaloids Since 1993, FDA has received more than 800 reports of illnesses and injuries (AER's) associated with the use of more than 100 different dietary supplement products that contained, or were suspected to contain, ephedrine alkaloids. These adverse events tended to involve CVS effects and NS effects. FDA evaluated the AER's showing CVS and NS effects and found that the single most common element was that the products contained, or were thought to contain, a source of ephedrine alkaloids. Approximately 50 to 60 percent of the AER's associated with use of dietary supplements were for such products. The AER's associated with the ephedrine alkaloid-containing products included consistent patterns of signs and symptoms among both otherwise healthy individuals and those with underlying diseases or conditions. These signs and symptoms included rapid and irregular heart rhythms, increased blood pressure, chest pain, anxiety, nervousness, tremor, hyperactivity, and insomnia (i.e., inability or difficulty in sleeping) and were associated with clinically significant conditions, including heart attack, stroke, psychoses, seizure, and, in a few cases, death. Many of these signs and symptoms occurred in young adults who generally would not have been expected to be at high risk for such conditions (e.g., heart attack and stroke). Many adverse events were reported to occur with the first use or within the first 2 weeks of use. Although the majority occurred in women, men also reported experiencing adverse events. The nature and patterns of these AER's are consistent with the known physiological and pharmacological effects of ephedrine alkaloids as described in: (1) Pharmacology texts for single ephedrine alkaloid products, (2) case reports of adverse effects from the scientific literature related to the pharmaceutical use of ephedrine alkaloids, (3) adverse events reported in controlled clinical trials using ephedrine in the treatment of obesity, and (4) known safety concerns with traditional medical uses of botanicals that contain ephedrine alkaloids. As a result, FDA focused its investigation on ephedrine alkaloids as a likely factor in the rapidly increasing number of serious AER's associated with the use of dietary supplement products. Adverse events appear to reflect different inherent types of individual sensitivities relative to dose levels, frequency or duration of use, and subsequent results of sympathomimetic stimulation. In some cases, particular events appear to occur as the result of increased individual susceptibility to the effects of sympathetic stimulation (Refs. 39 through 42). For example, in one report (ARMS No. 10862 in the Appendix to this document), three young adult males consumed similar amounts of a dietary supplement containing ephedrine alkaloids, yet only one male experienced serious adverse effects, which resulted in his death (see Police and Medical Examiner's Reports in ARMS No. 10862 in public docket number 95N-0304). This report is illustrative of numerous AER's suggesting an unpredictable pattern and severity of adverse events when consuming ephedrine alkaloid-containing dietary supplements, even when used according to package directions or under ordinary conditions of use. In other cases, some of the adverse events were associated with consumption of relatively low levels of ephedrine alkaloids (e.g., approximately 10 mg or less total ephedrine alkaloids per serving), some occurring shortly after onset of use. The foregoing discussion summarizes the AER's from a descriptive statistical perspective. Many of these reports are summarized in the Appendix to this document. An abbreviated description of all reports is in public docket number 95N-0304. A few examples of experiences of particular individuals are given below. ARMS No. 11134--A 23-year-old male college student used an ephedrine alkaloid-containing ergogenic product for approximately 2 years, along with several other dietary supplement products. He was previously healthy and was known to have a healthy life style. He was found dead by his sister in the apartment that they shared. The Medical Examiner's report stated that the cause of death was due to ``patchy myocardial necrosis associated with ephedrine toxicity from protein drink containing Ma huang extract.'' ARMS No. 9552--A 35-year-old female, who was on no medications and who had a negative past medical history, developed a non-Q wave myocardial infarction (heart attack) while using an ephedrine alkaloid- containing dietary supplement within the dosage recommended on the label. She used the product for approximately 30 days, stopped for 1 week while on vacation, and then reinitiated the use of the product. About 11 days after restarting the product, she developed acute throbbing, anterior chest pain at rest, with radiation to the left shoulder, numbness of the left arm and hand, diaphoresis (sweating), and shortness of breath. In the hospital, clinical evaluations (electrocardiogram and cardiac enzymes) indicated an acute non-Q wave myocardial infarction, thought to be secondary to coronary artery spasm. Cardiac catheterization showed normal coronary arteries. ARMS No. 10009--A 35-year-old male took an ephedrine alkaloid- containing dietary supplement (2 capsules at noon, 3 capsules at 4:30 pm). He worked out from 5:30 to 6:30 pm, developing chest pain at 7:30 pm. He was admitted to the hospital with an acute myocardial infarction (by electrocardiogram and cardiac enzymes) and was treated medically. Subsequent cardiac catheterization demonstrated normal coronary arteries. ARMS No. 11144--A 28-year-old man used an ephedrine alkaloid- containing product for 10 months (1 capsule per day) for energy. His father found him bloody and responding inappropriately. In the emergency department, his blood pressure was 168/90, with a pulse of 116. Results of extensive clinical and laboratory evaluations were all within normal limits. He was diagnosed with syncope and a closed head injury. His neurologist concluded that ``most likely he had a seizure secondary to ephedrine'' from the health food substance he was taking. He was advised to avoid the product and dispose of it. This man was on no other medications and had no significant past medical history. In particular, he never had problems with dizziness or passing out. Back to Safety Page