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Toxicity Effects

CAS Registry Number: 299-42-3

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 2.

Names 1

  • Ephedrine
  • Ma Huang

Human Toxicity Excerpts

  • CASE REPORTS: The death of a 23-year-old body builder who consumed /a bodybuilder supplement that contains ma-huang, guarana, l-carnitine, and chromium picolinate/ "according to the stated directions" once or twice a day for >6 months. Autopsy revealed myocardial necrosis with healing of 1-2 weeks, mild fibrosis, and moderate myocyte hypertrophy and vascular congestion. /Ma-huang/[Theoharides TC; J Clin Psychopharmacol 17 (50): 437-9 (1997)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: /A case of/ generalized dermatitis due to oral ephedrine /is presented/.[Villas Martinez F et al; Contact Dermatitis 29 (4): 215-6 (1993)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: A case of acute myocardial infarction in a young athlete provoked by ephedrine abuse has been described in this study. An intracoronary thrombus found in the left anterior descending coronary artery at urgent angiography was successfully removed using the Pronto aspiration catheter. The intravascular ultrasound examination performed thereafter showed a nonobstructive atherosclerotic plaque in the culprit artery; there was no evidence whatsoever of possible plaque disruption. The result of percutaneous coronary intervention was satisfactory, and no stent implantation was needed. The patient experienced no adverse events until his outpatient visit 3 months later.[Kranjec I et al; Angiology 60 (2): 254-8 (2009)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: An ever increasing number of herbal remedies are recognized as potentially hepatotoxic. /The authors/ report a case of fulminant hepatic failure requiring liver transplantation associated with the use of ma-huang, a traditional Chinese remedy containing ephedrine-type alkaloids. ... /Ma-huang/[Skoulidis F et al; Eur J Gastroenterol Hepatol 17 (5): 581-4 (2005)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: Here, /the authors/ describe the case of a 45-year-old woman who died of cardiovascular collapse while taking ephedra. Tissue analysis revealed non-specific degenerative alterations in the myocardium (lipofuscin accumulation, basophilic degeneration and vacuolation of myocytes, as well as myofibrillary loss), associated with myocyte apoptosis, caspase activation, and extensive cleavage of miofibrillary proteins alpha-actin, alpha-actinin, and cardiac troponin T. ... /Ephedra/[Chen-Scarabelli C et al; Eur J Heart Fail 7 (5): 927-30 (2005)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: This is a case report of a reservist who presented for a physical examination with hypertension. It was discovered that the reservist was unknowingly taking large doses of Ephedra sinica, or ma huang, a Chinese herbal supplement, for body-building. One of the ingredients in ma huang is ephedrine, an active alpha- and beta-adrenergic stimulant that produces increases in heart rate, blood pressure, and cardiac output. Ma huang has been reported to cause hypertension, hepatitis, nephrolithiasis, and sudden death in healthy, normotensive people. Ma huang will produce a positive urinary drug screen for stimulants and can be a drug of abuse.[Wettach GE, Falvey SG; Mil Med 167 (6): 521-3 (2002)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: This is a case report on the neuropsychological deficits of anoxia in an otherwise previously healthy 36-year-old male pilot. The patient was taking an over-the-counter supplement that included an herb called Ma Huang on the day of his cardiac arrest. Ma Huang is reported to potentially present an increased risk of cardiac infarctions and central nervous system dysfunctions. Several instances of death have been linked to Ma Huang. The patient produced a neuropsychological profile that evidenced impairments in executive functioning, memory, language, attention, intellectual and academic functioning, as well as motor speed and coordination, all of which are consistent with diffuse brain damage. ...[Baggett MR et al; Mil Med 168 (9): 769-71 (2003)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: Three deaths from non-prescription diet aids or stimulants were reported; ephedrine concentrations in the blood were 3.5-20.5 mg/L; corresponding blood caffeine concentrations (130 to 344 mg/L) were sufficient to be lethal/[Garriott JC et al; J Anal Toxicol 9 (3): 141-3 (1985)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: Vasculitis and hypersensitivity myocarditis occurred in a 39-year-old man who ingested a ma-huang product (1-3 tablets twice daily for 3 months). /Ma-huang/[Zaacks SM et al; J Toxicol Clin Toxicol 37 (4): 485-9 (1999)] **PEER REVIEWED** PubMed Abstract
  • EPIDEMIOLOGY STUDIES: ... Long-term safety and efficacy for weight loss of an herbal Ma Huang and Kola nut supplement (90/192 mg/day ephedrine alkaloids/caffeine) /was examined/. /The study used a/ six-month randomized, double-blind placebo controlled trial. ... A total of 167 subjects (body mass index (BMI) 31.8+/-4.1 kg/m(2)) randomized to placebo (n=84) or herbal treatment (n=83) at two outpatient weight control research units. ... Primary outcome measurements were changes in blood pressure, heart function and body weight. Secondary variables included body composition and metabolic changes. ... By last observation carried forward analysis, herbal vs placebo treatment decreased body weight (-5.3+/-5.0 vs. -2.6+/-3.2 kg, P<0.001), body fat (-4.3+/-3.3 vs. -2.7+/-2.8 kg, P=0.020) and LDL-cholesterol (-8+/-20 vs. 0+/-17 mg/dL, P=0.013), and increased HDL-cholesterol (+2.7+/-5.7 vs. -0.3+/-6.7 mg/dL, P=0.004). Herbal treatment produced small changes in blood pressure variables (+3 to -5 mm Hg, P< or =0.05), and increased heart rate (4+/-9 vs. -3+/-9 bpm, P<0.001), but cardiac arrhythmias were not increased (P>0.05). By self-report, dry mouth (P<0.01), heartburn (P<0.05), and insomnia (P<0.01) were increased and diarrhea decreased (P<0.05). Irritability, nausea, chest pain and palpitations did not differ, nor did numbers of subjects who withdrew. ... In this 6-month placebo-controlled trial, herbal ephedra/caffeine (90/192 mg/day) promoted body weight and body fat reduction and improved blood lipids without significant adverse events.[Boozer CN et al; Int J Obes Relat Metab Disord 26 (5): 593-604 (2002)] **PEER REVIEWED** PubMed Abstract
  • EPIDEMIOLOGY STUDIES: ...To assess the efficacy and safety of ephedra and ephedrine used for weight loss and enhanced athletic performance /the authors/ searched 9 databases using the terms ephedra, ephedrine, adverse effect, side effect, efficacy, effective, and toxic. /They/ included unpublished trials and non-English-language documents. Adverse events reported to the US Food and Drug Administration MedWatch program were assessed. Eligible studies were controlled trials of ephedra or ephedrine used for weight loss or athletic performance and case reports of adverse events associated with such use. Eligible studies for weight loss were human studies with at least 8 weeks of follow-up; and for athletic performance, those having no minimum follow-up. Eligible case reports documented that ephedra or ephedrine was consumed within 24 hours prior to an adverse event or that ephedrine or an associated product was found in blood or urine, and that other potential causes had been excluded. Of the 530 articles screened, 52 controlled trials and 65 case reports were included in the adverse events analysis. Of more than 18,000 other case reports screened, 284 underwent detailed review. Two reviewers independently identified trials of efficacy and safety of ephedra and ephedrine on weight loss or athletic performance; disagreements were resolved by consensus. Case reports were reviewed with explicit and implicit methods. No weight loss trials assessed duration of treatment greater than 6 months. Pooled results for trials comparing placebo with ephedrine (n = 5), ephedrine and caffeine (n = 12), ephedra (n = 1), and ephedra and herbs containing caffeine (n = 4) yielded estimates of weight loss (more than placebo) of 0.6 (95% confidence interval, 0.2-1.0), 1.0 (0.7-1.3), 0.8 (0.4-1.2), and 1.0 (0.6-1.3) kg/mo, respectively. Sensitivity analyses did not substantially alter the latter 3 results. No trials of ephedra and athletic performance were found; 7 trials of ephedrine were too heterogeneous to synthesize. Safety data from 50 trials yielded estimates of 2.2- to 3.6-fold increases in odds of psychiatric, autonomic, or gastrointestinal symptoms, and heart palpitations. Data are insufficient to draw conclusions about adverse events occurring at a rate less than 1.0 per thousand. The majority of case reports are insufficiently documented to allow meaningful assessment. /The authors/ concluded that ephedrine and ephedra promote modest short-term weight loss (approximately 0.9 kg/mo more than placebo) in clinical trials. There are no data regarding long-term weight loss, and evidence to support use of ephedra for athletic performance is insufficient. Use of ephedra or ephedrine and caffeine is associated with increased risk of psychiatric, autonomic, or gastrointestinal symptoms, and heart palpitations.[Shekelle PG et al; JAMA 289 (12): 1537-45 (2003)] **PEER REVIEWED** PubMed Abstract
  • HUMAN EXPOSURE STUDIES: . . A randomized, double-blind cross-over study was performed evaluating the acute effects of caffeine (150 mg)/herbal ephedra (ma-huang; 20 mg ephedra alkaloids) versus a placebo. A total of eight healthy subjects (four males and four females) with a mean (+/-SD) age of 23.4+/-0.8 years (mean ages for males and females: 25.3+/-0.7 and 22.0+/-0.7 years, respectively) and 22.5+/-3.1% body fat (15.7+/-1.2 and 27.6+/-3.5% body fat for males and females, respectively) were recruited to the study. Participants were moderate caffeine users (approximately 150-300 mg/day). Subjects reported to the laboratory following a 12 hr fast and 48 hr of a caffeine-free diet. Resting energy expenditure (REE) was measured prior to supplementation and for 15 min every 30 min for 3 hr following supplementation. Heart rate (HR) and blood pressure (BP) were obtained every 15 min. Blood samples were obtained every 30 min following the measurement of REE and analyzed for caffeine, ephedrine, free fatty acids and glucose. By 3 hr, HR was 22.7+/-5.5% higher (P < 0.05) than baseline for the caffeine/ephedra trial compared with 8.9+/-2.2% higher for the placebo group. At 3 hr, systolic BP was 9.1+/-2.2% higher (P < 0.05) than baseline for the caffeine/ephedra trial compared with only 1.9+/-2.9% different from baseline for the placebo trial. There was no effect of the caffeine/ephedra combination on diastolic BP. Resting energy expenditure during the last 30 min was 4.5+/-2.5% higher in the placebo trial and 10.7+/-2.5% higher (P < 0.05) in the caffeine/ephedra trial; REE was 8.5 +/- 2.0% higher (P < 0.05) in the caffeine/ephedra trial compared with the placebo trial. Free fatty acids increased over time in the placebo and caffeine/ephedra trials (from 0.5+/-0.05 to 0.63+/-0.05 mEq/L and from 0.48+/-0.06 L to 0.8+/-0.05 mEq/L, respectively). Caffeine and herbal ephedra, at doses of 150 mg and 20 mg (ephedrine), respectively, result in a significant elevation in REE, HR and BP. Although significant, the increase in energy expenditure is negligible in terms of weight loss. /Ma-huang/[Vukovich MD et al; Clin Exp Pharmacol Physiol 32 (1-2): 47-53 (2005)] **PEER REVIEWED** PubMed Abstract
  • OTHER TOXICITY INFORMATION: According to the U.S. Food and Drug Administration (FDA), there is little evidence of ephedra's effectiveness, except for short-term weight loss. However, the increased risk of heart problems and stroke outweighs any benefits.[National Center for Complimentary and Alternative Medicine (NCCAM); Ephedra; Available from, as of January 28, 2014: http://nccam.nih.gov/health/ephedra] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Although ephedrine alkaloid-containing dietary supplements (frequently combined with caffeine) promoted for various uses (e.g., weight loss, body building, energy enhancement, increased mental concentration, increased sexual sensations, euphoria, alternative to illicit drugs) constitute less than 1% of all dietary supplement sales, these preparations account for 64% of adverse events associated with dietary supplements. /Ephedrine alkaloid supplements/[American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1352] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Based on the best available scientific data and the known pharmacology of ephedrine alkaloids and other sympathomimetics, dietary supplements containing ephedrine alkaloids pose short-term and long-term risks. This is clearest in long-term use, where increased blood pressure in any population will clearly increase the risk of serious adverse events, such as stroke, heart attack, and death. There is also evidence of increased risk of serious adverse events from shorter term use in patients with heart failure or underlying coronary artery disease. /Dietary supplements containing ephedrine alkaloids/[FDA; Dietary Supplements Containing Ephedrine Alkaloids Final Rule Summary. February 2004. Available from, as of March 12, 2007: http://www.fda.gov/oc/initiatives/ephedra/february2004/finalsummary.html] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Abuse of ephedrine has produced psychic dependence (characterized by compulsion, obsession, and preoccupation) and worsened mental disorders (e.g., depressive anxiety, thought disorders). Acute overdosage of the drug has been associated with tachycardia, difficulty in breathing, and death.[American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1351] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: An NCCAM-funded study that analyzed phone calls to poison control centers found a higher rate of side effects from ephedra, compared with other herbal products. Other studies and systematic reviews have found an increased risk of heart, psychiatric, and gastrointestinal problems, as well as high blood pressure and stroke, with ephedra use.[National Center for Complimentary and Alternative Medicine (NCCAM); Ephedra; Available from, as of January 28, 2014: http://nccam.nih.gov/health/ephedra] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Based on clinical data, the ephedrine alkaloids present in dietary supplements would be expected to have the same or similar effects as other sympathomimetics on heart rate and blood pressure. Controlled clinical trials using products containing ephedrine alkaloids confirm their typical sympathomimetic effects. These studies show a blood pressure effect from ephedrine itself, independent of any additional effect from caffeine. /Ephedrine alkaloids in dietary supplements/[FDA; Dietary Supplements Containing Ephedrine Alkaloids Final Rule Summary. February 2004. Available from, as of March 12, 2007: http://www.fda.gov/oc/initiatives/ephedra/february2004/finalsummary.html] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Between 1995 and 1997, the FDA received more than 900 reports of possible ephedra toxicity. Serious adverse events such as stroke, heart attack, and sudden death were reported in 37 cases.[National Center for Complimentary and Alternative Medicine (NCCAM); Ephedra; Available from, as of January 28, 2014: http://nccam.nih.gov/health/ephedra] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Common side effects /include/ headache, irritability, motor restlessness, nausea, sleeplessness, tachycardia, urinary disorders adn vomiting. Higher dosages may result in blood pressure and cardiac rhythm disorders. Dependence can develop with extended intake. Because of the danger of the development of tachyphylaxis and of dependence, /ma-huang/ should only be administered for short periods. /Ma-huang/[PDR for Herbal Medicines, 2nd ed. Ma Huang (Ephedra sinica). p. 488-9 (2000) Medical Economics Co., Montvale, NJ] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Ephedrine also may cause throbbing headache, respiratory difficulty, fever or a feeling of warmth, pallor, dryness of the nose and throat, precordial pain, sweating, mild epigastric distress, anorexia, nausea, or vomiting.[American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1352] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Ephedrine increases the irritability of the heart muscle and may alter the rhythmic function of the ventricles. Palpitation and tachycardia may result. Extrasystoles and potentially fatal arrhythmias including ventricular fibrillation may occur, especially in patients with organic heart disease or those receiving other drugs that sensitize the heart to arrhythmias including cardiac glycosides, cyclopropane, or halogenated hydrocarbon anesthetics.[American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1352] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Ephedrine may cause hypertension which may result in intracranial hemorrhage. Adverse reactions to ephedrine may be particularly likely to occur in hypertensive or hyperthyroid patients, and the drug must be administered with caution, if at all, to such patients. Ephedrine may induce anginal pain in patients with coronary insufficiency or ischemic heart disease. The drug also may induce potentially fatal arrhythmias in patients with organic cardiac disease or in those receiving drugs that sensitize the myocardium.[American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1353] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Ephedrine may deplete norepinephrine stores in sympathetic nerve endings and tachyphylaxis to the cardiac and pressor effects of the drug may develop. Administration of norepinephrine to replace tissue stores may be useful in restoring the pressor effects of ephedrine. In addition, after several doses of ephedrine are administered, hypotension more severe than that originally being treated may result from direct cardiac depression and vasodilation.[American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1352] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: In July 2003, GAO /US Government Accountability Office/ testified at a House Subcommittee hearing on issues relating to dietary supplements containing ephedrine alkaloids. ... The testimony ... /included/ an evaluation of Metabolife International's records of health-related calls from consumers of Metabolife 356 /a popular weight-loss supplement containing ma-huang, caffeine, and several other active ingredients./. GAO noted that the types of adverse events identified in the health-related call records from Metabolife International were consistent with the types of adverse events reported to /FDA/, as well as with the scientifically documented physiological effects of ephedrine alkaloids. GAO also noted that despite the limited information contained in most of the call records, 14,684 call records contained reports of at least one adverse event among consumers of Metabolife 356. The GAO testimony identified 92 serious events that included heart attacks, strokes, seizures, and deaths and emphasized that these findings were similar to other reviews of the call records, including those done by Metabolife International and its consultants. The GAO testimony noted that, in those call records where age was documented, many of the serious adverse events occurred in relatively young consumers, with more than one-third being under the age of 30. Furthermore, for those call records in which quantity of use and/or frequency and duration of use were noted, most of the serious adverse events occurred among Metabolife 356 users who used the product within the recommended guidelines, i.e., they did not take more of the product nor consume it for a longer period of time than the product label recommended. /Metabolife 356/[FDA; 21 CFR Part 119 Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk. Federal Register: February 11, 2004 (Volume 69, Number 28) Page 6787-6854] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: In considering whether dietary supplements containing ephedrine alkaloids present an unreasonable risk, FDA considered evidence from three principal sources: (1) The well-known, scientifically established pharmacology of ephedrine alkaloids; (2) peer-reviewed scientific literature on the effects of ephedrine alkaloids; and (3) the adverse events (including published case reports) reported to have occurred following consumption of dietary supplements containing ephedrine alkaloids. Based on the best available scientific data and the known pharmacology of ephedrine alkaloids and other sympathomimetics, dietary supplements containing ephedrine alkaloids pose short-term and long-term risks. This is clearest in long-term use, where increased blood pressure in any population will clearly increase the risk of serious adverse events, such as stroke, heart attack, and death. There is also evidence of increased risk of serious adverse events from shorter term use in patients with heart failure or underlying coronary artery disease. /Ephedrine alkaloid dietary supplements/[FDA; Dietary Supplements Containing Ephedrine Alkaloids Final Rule Summary. February 2004. Available from, as of March 12, 2007: http://www.fda.gov/oc/initiatives/ephedra/february2004/finalsummary.html] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: In patients receiving IV ephedrine for treatment of hypotension, prolonged therapy results in loss of the drug's vasopressor effects because of depletion of norepinephrine from nerve endings. Hypotension that is more serious than existed prior to initiation of ephedrine may develop. In the absence of norepinephrine depletion, excessive IV administration of ephedrine produces tachycardia, exaggerated rise in blood pressure, possible cerebrovascular bleeding, and adverse CNS effects.[American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1354] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Life-threatening poisonings are seen with very high dosages of /ma-huang/ (over 100 gm, lethal dosage with oral administration corresponding to approximately 1 to 2 g L-ephedrine). Symptoms of poisoning include severe outbreaks of sweating, enlarged pupils, spasms and elevated body temperature. Death following overdose is due to heart failure and asphyxiation. /Ma-huang/[PDR for Herbal Medicines, 2nd ed. Ma Huang (Ephedra sinica). p. 488-9 (2000) Medical Economics Co., Montvale, NJ] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Prolonged abuse of ephedrine injection may result in manifestations of paranoid schizophrenia, such as tachycardia, poor nutrition and hygiene, fever, cold sweat, and dilated pupils. ... refractoriness to ephedrine may develop with prolonged or excessive usage, addiction to the drug does not occur.[American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1352] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: The CNS-simulating effects of ephedrine may result in nervousness, anxiety, apprehension, fear, tension, agitation, excitation, restlessness, weakness, irritability, talkativeness, or insomnia. Dizziness, lightheadedness, and vertigo may occur, especially with large doses. Tremor or tremulousness, and hyperactive reflexes have also been reported. CNS disturbances may be prevented or overcome by administration of a sedative or tranquilizer. Large parenteral doses of ephedrine may cause confusion, delirium, hallucinations, or euphoria. Some asthmatic patients receiving continuous oral administration of the drug have taken extremely high doses in attempts to overcome refractoriness. Paranoid psychosis and visual auditory hallucinations occurred in some of these patients. Withdrawal of the drug produced rapid recovery.[American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1352] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: The evidence shows that there is an increase in blood pressure attributable to ephedrine alkaloids. A relative increase in blood pressure in any population, even individuals with "normal" blood pressure, will increase the risk of heart attack, stroke, and death in that population. Many individuals are unaware that they have coronary artery disease or early heart failure because these conditions may not cause prominent symptoms until later in the course of these conditions. Approximately one in four adults has high blood pressure. Of those with high blood pressure, 31 percent are unaware that they have it. The extremely high prevalence of diagnosed and undiagnosed hypertension in the United States population, and the likelihood that blood pressure in obese patients is already elevated, make the effects of great concern. /Dietary supplements of ephedrine alkaloids/[FDA; Dietary Supplements Containing Ephedrine Alkaloids Final Rule Summary. February 2004. Available from, as of March 12, 2007: http://www.fda.gov/oc/initiatives/ephedra/february2004/finalsummary.html] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: The principal manifestation of ephedrine overdosage is development of seizures. Acute overdosage of ephedrine also may result in nausea, vomiting, chills, cyanosis, irritability, nervousness, fever, suicidal behavior, tachycardia, dilated pupils, blurred vision, opisthotonos, spasms, pulmonary edema, gasping respirations, coma, and respiratory failure. Hypertension may develop initially, followed later by hypotension accompanied by anuria.[American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1354] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Use of ephedrine alkaloid-containing dietary supplements has been associated with a twofold to threefold increased risk of nausea, vomiting, adverse psychiatric effects (e.g., anxiety, mood changes), autonomic hyperactivity, and palpitations. Serious adverse effects (e.g., cardiovascular and nervous system effects) and deaths have been reported in individuals receiving ephedrine or ephedra-containing dietary supplements. Such adverse effects, including irregular heart rate, palpitations, increased blood pressure, chest pain, anxiety, nervousness, tremor, hyperactivity, headache, and insomnia, usually were associated with clinically serious conditions (e.g., myocardial infarction, stroke, psychoses, seizures, nephrolithiasis, death) and frequently were reported in young (i.e., 30 years of age or younger) to middle-aged adults (over 70% of whom were females) using the supplements, mainly for weight loss or energy enhancement. Many such adverse effects occurred within 2 weeks of first use, although they were reported on the first day of use in some cases. Most individuals who developed such adverse effects claim that they used the dietary supplements according to labeled instructions. /Ephedrine alkaloid dietary supplements/[American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1353] **PEER REVIEWED**
  • SURVEILLANCE: ... A report by the Southern California Evidenced Based Practice Center (the RAND report) /was/ commissioned by the National Institutes of Health (NIH)). RAND reviewed recent evidence on the risks and benefits of ephedra and ephedrine and found that dietary supplements containing ephedrine alkaloids are associated with higher risks of mild to moderate side effects such as heart palpitations, psychiatric effects, and upper gastrointestinal effects, and symptoms of autonomic hyperactivity such as tremor and insomnia, especially when they are taken with other stimulants. The RAND report identified 21 ``sentinel events'' among the adverse event reports it reviewed, including stroke, heart attack, and death. /Ephedrine alkaloids/[FDA; 21 CFR Part 119 Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk. Federal Register: February 11, 2004 (Volume 69, Number 28) Page 6787-6854] **PEER REVIEWED**
  • SURVEILLANCE: ... The aim of this systematic review was to assess all clinical evidence of adverse events of herbal food supplements for body weight reduction for which effectiveness data from rigorous clinical trials exist. /The authors/ assessed Ephedra sinica /and other supplements/. Literature searches were conducted on Medline, Embase, Amed and The Cochrane Library. Data were also requested from the spontaneous reporting scheme of the World Health Organization. /The authors/ hand-searched relevant medical journals and /their/ own files. There were no restrictions regarding the language of publication. The results show that adverse events including hepatic injury and death have been reported with the use of some herbal food supplements. For herbal ephedra and ephedrine-containing food supplements an increased risk of psychiatric, autonomic or gastrointestinal adverse events and heart palpitations has been reported. ... Although the quality of the data does not justify definitive attribution of causality in most cases, the reported risks are sufficient to shift the risk-benefit balance against the use of most of the reviewed herbal weight-loss supplements. ... /Ephedra-containing supplements/[Pittler MH et al; Obes Rev 6 (2): 93-111 (2005)] **PEER REVIEWED** PubMed Abstract
  • SURVEILLANCE: During December 1993-September 1995, the Bureau of Food and Drug Safety, Texas Department of Health (TDH), received approximately 500 reports of adverse events in persons who consumed dietary supplement products containing ephedrine and associated alkaloids (pseudoephedrine, norephedrine, and N-methyl ephedrine). This total included reports by individuals and reports identified by the Bureau of Epidemiology, TDH, in a review of records from the six centers of the Texas Poison Center Network. Reported adverse events ranged in severity from tremor and headache to death in eight ephedrine users and included reports of stroke, myocardial infarction, chest pain, seizures, insomnia, nausea and vomiting, fatigue, and dizziness. Seven of the eight reported fatalities were attributed to myocardial infarction or cerebrovascular accident. This report describes three patients in which the recommended dosage for the dietary supplements reportedly was not exceeded, summarizes results from ongoing investigations, and underscores the potential health risks associated with the use of products containing ephedrine. /Ephedrine alkaloid-containing supplement/[Morbidity Mortality Weekly Rep 45 (32): 689-93 (1996)] **PEER REVIEWED**
  • SURVEILLANCE: The relative toxicity of ephedra-containing dietary supplements is disputed. In order to ascertain the magnitude of the problem, /the authors/ reviewed all autopsies in /their/ Medical Examiner's jurisdiction, from 1994 to 2001, where ephedrine or any its isomers (E+) were detected. Toxicology testing results were tabulated and anatomic findings in E+ cases were compared to those in a control group of drug-free trauma victims. Of 127 E+ cases identified, 33 were due to trauma. Decedents were mostly male (80.3%) and mostly Caucasian (59%). Blood ephedrine concentrations were <0.49 mg/L in 50% of the cases, range 0.07-11.73 mg/L in trauma victims, and 0.02-12.35 mg/L in non-trauma cases. Norephedrine (NE) was present in the blood of 22.8% (mean of 1.81 mg/L, S.D.=3.14 mg/l) and in the urine of 36.2% (mean of 15.6 mg/L, S.D.=21.50mg/L). Pseudoephedrine (PE) was present in the blood of 6.3% (8/127). More than 88% (113/127) of the decedents also tested positive for other drugs, the most common being cocaine (or its metabolites) and morphine. The most frequent pathologic diagnoses were hepatic steatosis (27/127) and nephrosclerosis (22/127). Left ventricular hypertrophy was common, and coronary artery disease (CAD) detected in nearly one third of the cases. The most common findings in E+ deaths are those generally associated with chronic stimulant abuse, and abuse of other drugs was common in those with CAD. There were no cases of heat stroke or rhabdomyolysis. In most cases, norephedrine was not detected, suggesting it plays no role in ephedrine toxicity.[Blechman KM et al; Forensic Sci Int 139 (1): 61-9 (2004)] **PEER REVIEWED** PubMed Abstract

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Non-Human Toxicity Excerpts

  • GENOTOXICITY: Ephedra herba was screened for mutagenic activity by the rec-assay with Bacillus subtilis as well as the Ames reversion assay with S. typhimurium TA98 and TA100 with and without metabolic activation. The ephedra extract was not mutagenic at concentrations up to 100 mg/mL. /Ephedra extract/[Morimoto I et al; Mutat Res 97: 81-102 (1982)] **PEER REVIEWED** PubMed Abstract
  • GENOTOXICITY: Ephedrae sinica Staph extract was not mutagenic in Salmonella typhimurium TA98 or TA100 either in the absence or presence of S-9 at doses up to 40 mg/plate. The ephedra extract was also administered intraperitoneally to mice at doses described as equivalent to 1-40 times that used in traditional medicine. No changes in the ratio of polychromatic erythrocytes to total erythrocytes or in the frequency of micronucleated polychromatic erythrocytes in the bone marrow micronucleus assay were observed. /Ephedrae sinica Staph/[Xue-Jun Y et al; Mutat Res 260 (1): 73-82 (2001)] **PEER REVIEWED**
  • IMMUNOTOXICITY: This report investigated the ability of ephedrine to exacerbate processes associated with autoimmune disease in a lupus-prone mouse model. To mimic human supplementation, ephedrine was administered to NZM391 (lupus-prone) and BALB/c (nonlupus prone) mice orally twice a day for three months at a dose of 50 and 100 ug/day. Some ephedrine-treated NZM391 mice also were preadministered the beta-AR antagonist propranolol to investigate Beta-adrenergic receptor(beta-AR) involvement. Mice were bled monthly, and sera were assayed for a variety of lupus manifestations and immunological measurements. In NZM391 males and females, both doses of ephedrine significantly increased lupus manifestations, including IgG production and organ-directed autoantibody titers, and significantly lowered the ratio of IgG2a/IgG1 compared to controls. Ephedrine significantly decreased female lifespan and significantly increased circulating populations of plasma cells (CD38(hi) CD19(lo) cytoplasmic IgG+) and CD40+ B1a cells, while preventing an age-related decrease in the B1a cell population expressing a high level of CD5. While ephedrine induced gender-specific immunomodulation in BALB/c mice, increases in the lupus manifestations of anti-dsDNA titers and serum urea nitrogen were not detected. Preadministration of propranolol decreased lupus manifestations and serum levels of IgG and IgE in ephedrine-treated mice, but did not block the shift towards IgG1 production. These findings indicate that ephedrine via beta-AR can exacerbate lupus symptoms in NZM391 mice and that blockade of the beta-ARs on B cells, and not T cells, apparently was of greater importance as the inhibition of lupus symptoms corresponded to an inhibition of immunoglobulin levels, not a change of Th1/Th2 balance.[Hudson CA et al; Lupus 14 (4): 293-307 (2005)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Acute Exposure: ... Cardiac /effects are reported/ in 7- and 14-week-old male F344 rats exposed by gavage to ephedrine (25 mg/kg) and caffeine (30 mg/kg) administered in combination for one or two days. The ephedrine-caffeine dosage was approximately 12- and 1.4-fold, respectively, above average human exposure, based on a mg/m2 body surface-area comparison. Several (5/7) of the exposed 14-week-old rats died or were sacrificed in extremis 4-5 hr after the first dosing. In these hearts, changes were observed chiefly in the interventricular septum but also left and right ventricular walls. Massive interstitial hemorrhage, with degeneration of myofibers, occurred at the subendocardial myocardium of the left ventricle and interventricular septum. Immunostaining for cleaved caspase-3 and hyperphosphorylated H2A.X, a histone variant that becomes hyperphosphorylated during apoptosis, indicated multifocal generalized positive staining of degenerating myofibers and fragmenting nuclei, respectively. The Barbeito-Lopez trichrome stain revealed generalized patchy yellow myofibers consistent with degeneration and/or coagulative necrosis. In ephedrine-caffeine-treated animals terminated after the second dosing, foci of myocardial degeneration and necrosis were already infiltrated by mixed inflammatory cells. The myocardial necrosis may occur secondarily to intense diffuse vasoconstriction of the coronary arterial system with decreased myocardial perfusion. /This/ work shows the direct relationship between combined ephedrine and caffeine exposure and cardiac pathology.[Nyska A et al; Toxicol Sci 83 (2): 388-96 (2005)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Acute Exposure: ... The purpose of this study was to investigate the potential mechanisms associated with the cardiotoxicity of combined ephedrine and caffeine ingestion. Seven- and fourteen-week-old Fischer 344 rats treated with ephedrine in combination with caffeine exhibited increases in heart rate (HR), temperature, and corrected QT interval. Of the 14-wk-old rats treated with 25 mg/kg ephedrine plus 30 mg/kg caffeine, 57% died within 3-5 hr of treatment, whereas none of the similarly treated 7-wk-old rats nor any of the rats treated with vehicle died. One hour after treatment with this dose of ephedrine plus caffeine, 14-wk-old rats exhibited a larger increase in HR (as % increase over baseline) than 7-wk-old rats. Furthermore, the 14-wk-old rats that died had a higher HR and temperature than the 14-wk-old rats that lived. Histopathological studies suggested interstitial hemorrhage and myofiber necrosis in the 14-wk-old rats treated with the highest concentration of ephedrine and caffeine. This study showed enhanced susceptibility to ephedrine plus caffeine in 14-wk-old rats compared with 7-wk-old rats. The greater mortality in the 14-wk-old rats was associated with increases in body temperature, HR, and myocardial necrosis.[Howden R et al; Am J Physiol Heart Circ Physiol 288 (5): H2219-24 (2005)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The cardiovascular teratogenicity and embryotoxicity of ephedrine was studied in chick embryos treated after 2.5-6 days of incubation (Hamburger-Hamilton developmental stages 17-28). The embryos were examined on day 14. Cardiovascular malformations were observed in 29% (29/101) of treated embryos. Complicated anomalies, such as double-outlet right ventricle (DORV), truncus arteriosus communis (TAC) or overriding aorta with ventricular septal defect (VSD) were seen frequently in embryos exposed to the agent on day 3 of incubation. Malformations were induced by ephedrine at a dose as low as 1 umol/egg.[Nishikawa T et al; Toxicol Lett 29 (1): 59-63 (1985)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The cardiovascular teratogenicity of ephedrine was examined in pregnant Wistar-Imamichi rats injected ip on days 9,10, or 11 of gestation with single doses of 0.1, 1, 10, or 50 mg/kg of ephedrine. The frequency of cardiovascular abnormalities was dose dependent, ranging from 8.1 to 26.9%, although no significant differences were seen based on day of gestation dosed. All cardiovascular malformations were ventricular septal defects; no extracardiac malformations were observed.[Kanai T et al; Senten Ijo (Congen Anom) 26 (3): 246 (1986)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: Although ephedrine is a centrally active stimulant, its effect on midbrain dopamine neurons is not known. To study the effect of ephedrine on dopamine-containing cells, current-clamp microelectrode recordings were made from substantia nigra pars compacta (SNC) neurons in horizontal brain slice preparations. Ephedrine (100-1000 uM) slowed spontaneous firing and produced a modest concentration-dependent hyperpolarization of membrane potential (EC50 279 uM), with a concomitant net decrease in membrane resistance. These effects were blocked by the D2-like dopamine antagonist sulpiride (1 uM). Electrically evoked inhibitory synaptic potentials mediated by GABAB receptors were reduced 28% by ephedrine. However, ephedrine did not reduce fast synaptic potentials mediated by GABAA or ionotropic glutamate receptors. Inhibition of the GABAB response appeared to be mediated by a postsynaptic mechanism because ephedrine also reduced baclofen-induced hyperpolarization by 28%. Both ephedrine-induced hyperpolarization and inhibition of baclofen-induced hyperpolarization were abolished when slices were superfused with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). Despite perfusion with AMPT, the ability of ephedrine to cause hyperpolarization was restored after perfusing the slice with dopamine (30 uM). Taken together, these results suggest that ephedrine causes hyperpolarization and suppresses GABAB receptor-mediated effects by releasing endogenous dopamine. However, the high concentrations required to observe these effects in vitro suggest that biologically relevant central effects of ephedrine are more likely to be mediated either by non-dopamine systems, such as those involving noradrenaline, or by dopamine systems outside the SNC.[Munhall AC and Johnson SW; Brain Res 1069 (1): 96-103 (2006)] **PEER REVIEWED** PubMed Abstract
  • OTHER TOXICITY INFORMATION: ... Recent research suggests that nicotinic receptors (nAChRs) play a role in the development of locomotor sensitization to d-amphetamine and the goal of the present study was to determine if nAChRs similarly mediate the effects of ephedrine after acute and repeated drug injection. On 12 consecutive days, rats were pretreated with the nAChR antagonist mecamylamine (0.3-3.0 mg/kg) or saline followed by (-)-ephedrine (10-30 mg/kg) or saline injection and locomotor activity was measured. Ephedrine produced a dose-dependent increase in locomotor activity, and sensitization to ephedrine developed with repeated injection. Mecamylamine pretreatment attenuated the hyperactivity and sensitization produced by repeated, but not acute, ephedrine (10 mg/kg) injection. The inhibitory effect of mecamylamine was overcome at the higher ephedrine dose (30 mg/kg). The present results indicate that nAChRs play a mediating role in the development of locomotor sensitization to ephedrine.[Miller DK, Segert IL; Pharmacol Biochem Behav 81 (1): 165-9 (2005)] **PEER REVIEWED** PubMed Abstract
  • OTHER TOXICITY INFORMATION: Drug-induced weight loss in humans has been associated with undesirable side effects not present in weight loss from lifestyle interventions (caloric restriction or exercise). To investigate the mechanistic differences of weight loss by drug-induced and lifestyle interventions, we examined the gene expression (mRNA) in brown adipose tissue (BAT) and conducted histopathologic assessments in diet-induced obese (DIO) mice given ephedrine (18 mg/kg/day orally), treadmill exercise (10 m/min, 1-hr/day), and dietary restriction (DR: 26% dietary restriction) for 7 days. Exercise and DR mice lost more body weight than controls and both ephedrine and exercise reduced percent body fat. All treatments reduced BAT and liver lipid accumulation (i.e., cytoplasmic lipids in brown adipocytes and hepatocytes) and increased oxygen consumption (VO2 mL/kg/hr) compared with controls. Mitochondrial biogenesis/function-related genes (TFAM, NRF1 and GABPA) were up-regulated in the BAT of all groups. UCP-1 was up-regulated in exercise and ephedrine groups, whereas MFSD2A was up-regulated in ephedrine and DR groups. PGC-1alpha up-regulation was observed in exercise and DR groups but not in ephedrine group. In all experimental groups, except for ephedrine, fatty acid transport and metabolism genes were up-regulated, but the magnitude of change was higher in the DR group. PRKAA1 was up-regulated in all groups but not significantly in the ephedrine group. ADRBeta3 was slightly up-regulated in the DR group only, whereas ESRRA remained unchanged in all groups. Although our data suggest a common pathway of BAT activation elicited by ephedrine treatment, exercise or DR, mRNA changes were indicative of additional nutrient-sensing pathways in exercise and DR.[Slocum N et al; Exp Toxicol Pathol 65 (5): 549-57 (2013)] **PEER REVIEWED** PubMed Abstract
  • VETERINARY CASE REPORTS: Records from the American Society for the Prevention of Cruelty to Animals National Animal Poison Control Center pertaining to 47 incidents of accidental ingestion of herbal supplements containing mostly guarana and ma-huang in dogs were examined. Clinical signs of toxicity included tremors, seizures, vomiting, tachycardia, hyperthermia, and nonspecific behavioral changes. Doses of guarana and ma huang at which signs of intoxication were reported ranged between 4.4 and 296 mg/kg bw and 1.3 and 89 mg/kg bw, respectively. Clinical signs developed within 8 hours after ingestion in 80% of the dogs; duration ranged from 10 to 48 hours. /Ma-huang/[Ooms TG et al; J Am Vet Med Assoc 218 (2): 225-229 (2001)] **PEER REVIEWED** PubMed Abstract

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Mice ip 350 mg/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1573] **PEER REVIEWED**
  • LD50 Mice iv 74 mg/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1573] **PEER REVIEWED**
  • LD50 Mice oral 1,072 mg/kg (females) /Ephedrine sulfate/[Toxicology & Carcinogenesis Studies of Ephedrine Sulfate in F344/N Rats and B6C3F1 Mice Technical Report Series No. 307 (1986) NIH Publication No. 86-2563 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709] **PEER REVIEWED**
  • LD50 Mice oral 1250 mg/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1573] **PEER REVIEWED**
  • LD50 Mice oral 812 mg/kg (males) /Ephedrine sulfate/[Toxicology & Carcinogenesis Studies of Ephedrine Sulfate in F344/N Rats and B6C3F1 Mice Technical Report Series No. 307 (1986) NIH Publication No. 86-2563 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709] **PEER REVIEWED**
  • LD50 Mice parenteral 170 mg/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1573] **PEER REVIEWED**
  • LD50 Rat oral 600 mg/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1573] **PEER REVIEWED**
  • LD50 Rat sc 300 mg/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1573] **PEER REVIEWED**

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Absorption, Distribution And Excretion

  • ...This study aimed to develop a mechanistic model describing ephedrine, norephedrine, and caffeine pharmacokinetics and their interactions in healthy subjects. ... The treatments consisted of single-doses of pharmaceutical caffeine and ephedrine, given alone or together, and an herbal formulation containing both caffeine and ephedrine. /The authors/ used a mixed-effect statistical model and the program NONMEM to take account of intersubject variability. ... Three hundred and seventy-nine ephedrine, 352 norephedrine, 417 caffeine plasma concentrations and 40 ephedrine urine concentrations were obtained from 24 subjects. A one-compartment model with first-order absorption described the caffeine data. Caffeine clearance was 0.083 L/min (CV 38%) and decreased to 0.038 L/min in presence of oral contraceptive therapy, its volume of distribution was 38.6 L (CV 20%) and its absorption rate constant was 0.064 L/min (CV 50%). A four-compartment model described the pharmocokinetics of ephedrine and norephedrine. Ephedrine was eliminated mostly renally, with a clearance of 0.34 L/min (CV 11%), and a volume of distribution of 181 L (CV 19%). Nonlinearity in the conversion of ephedrine to norephedrine was observed. Different models showed that the simultaneous administration of caffeine, or the amount of caffeine in the absorption compartment, was associated with a slower rate of absorption of ephedrine. A 32% greater relative bioavailability of herbal compared with pharmaceutical ephedrine administration was observed. ... Concomitant ingestion of caffeine slowed the absorption rate of ephedrine, which is mainly related to the amount of the former in the absorption compartment. A saturable process appears to be involved in the metabolism of ephedrine to norephedrine.[Csajka C et al; Br J Clin Pharmacol 59 (3): 335-45 (2005)] **PEER REVIEWED** PubMed Abstract Full text: PMC1884794
  • Ephedrine is rapidly and completely absorbed after oral, intramuscular, or subcutaneous administration.[American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1573] **PEER REVIEWED**
  • Kakkon-to is one of the most common Traditional Chinese Medicine preparations for the attenuation of colds. Ephedrae Herba is one of the prescriptions of Kakkon-to. The major ingredients of Ephedrae Herba, ephedrines, are banned substances on the World Anti-Doping Agency (WADA) list. The purpose of this study was to investigate the elimination of urinary ephedrines after administering Kakkon-to and to determine the possibility of urinary positive ephedrine test results. Six healthy volunteers took one single dose of 2.5 g Kakkon-to extract granules. The concentrations of urinary ephedrines were analyzed by high-performance liquid chromatography. The result showed that ephedrine and norpseudoephedrine were excreted in the urine after taking one single dose of Kakkon-to. However, the highest amount of ephedrines in urine was ephedrine and the peak concentration was 4.35 +/- 1.82 ug/mL (mean +/- standard deviation), which was lower than the WADA permitted value (10 ug/mL). The estimated elimination half-lives of ephedrine, norephedrine, pseudoephedrine, and norpseudoephedrine following administration of this preparation were: 5.2 +/- 1.2, 4.2 +/- 1.3, 4.2 +/- 0.9, and 6.5 +/- 2.8 hr, respectively. This study concluded that the urine would not violate the rule of doping after administering a single dose of Kakkon-to. Nevertheless, a further study on administering the preparation for 3 times per day for 3 days showed a positive ephedrine result. Athletes should be careful when taking more than a single dose of Kakkon-to.[Chan KH et al; J Anal Toxicol 32 (9): 763-7 (2008)] **PEER REVIEWED** PubMed Abstract
  • Placental transfer of ephedrine occurs at 70% of the maternal blood levels. Ephedrine is also excreted in breast milk.[CANTOX: Safety Assessment and Determination of a Tolerable Upper Limit for Ephedra. Report prepared by CANTOX Health Sciences International, Ontario, for the Council for Responsible Nutrition, Washington, DC, p. 8 (2000).] **PEER REVIEWED**
  • Sho-seiryu-to is one of the most common Traditional Chinese Medicine preparations for the attenuation of colds. Ephedrae Herba is one of the prescriptions of Sho-seiryu-to. The major ingredients of Ephedrae Herba, ephedrines, are banned substances on the World Anti-Doping Agency (WADA) list. The purpose of this study was to investigate the elimination of urinary ephedrines after administering Sho-seiryu-to preparation and to determine the possibility of positive ephedrines test results in urine. Six healthy volunteers took a single 2.5-g dose of concentrated Sho-seiryu-to preparation. All urine was collected for 48 hr. The concentrations of urinary ephedrines were analyzed by high-performance liquid chromatography and the elimination half-life of the ephedrines was estimated. The results show that ephedrine and cathine (norpseudoephedrine), the prohibited substances of the WADA, were excreted in the urine after taking a single dose of Sho-seiryuto preparation. The peak concentration of ephedrine was 3.88 +/- 1.87 mg/mL (mean +/- SD), which was lower than the WADA permitted value (10 mg/mL). The estimated elimination half-lives of ephedrine, norephedrine, pseudoephedrine, and norpseudoephedrine following administration of this preparation were 5.3 +/- 1.2, 4.9 +/- 0.9, 4.4 +/- 1.0, and 5.4 +/- 1.8 hr, respectively. This study concluded that the urine would not violate the antidoping rules after administering a single dose of Sho-seiryu-to preparation. Nevertheless, an applied multiple-dose study upon administering the preparation for three times per day for three days showed a positive urine ephedrine result (13.7 mg/mL). Athletes should be careful when taking more than a single dose of Sho-seiryu-to preparation.[Chan KH et al; J Anal Toxicol 33 (3): 162-6 (2009)] **PEER REVIEWED** PubMed Abstract
  • This article describes a method for the detection and quantitation of cathine, pseudoephedrine, ephedrine, and methylephedrine in urine, using their deuterated analogues as internal standards and derivatization to form the corresponding trimethylsilyl derivatives after a simple liquid-liquid extraction. The study was designed to evaluate whether the urinary cutoff values set by the World Anti-Doping Agency for the banned ephedrines (cathine >5 ug/mL, ephedrine and methylephedrine >10 ug/mL) can be exceeded after the normal self-administration of common over-the-counter medicaments containing nonbanned ephedrines. The present method, after validation, has been applied on real urine samples obtained from 9 healthy volunteers taking different doses of over-the-counter preparations containing ephedrines. Results obtained from excretion studies show high interindividual differences in the urinary concentrations of both pseudoephedrine and cathine, not dependent on body weight or sex nor, in some instances, on the administered dose. The same typical therapeutic dose of pseudoephedrine (60 mg) produced a urinary concentration of more than 5 ug/mL for cathine and of more than 100 ug/mL for pseudoephedrine in 2 of 9 subjects only. When a dose of 120 mg was administered, cathine concentration exceeded 5 ug/mL in 4 of 7 subject, and also concentrations of pseudoephedrine above 100 ug/mL. After administration of 5 x 120 mg of pseudoephedrine (120 mg administered every 7 days for 5 weeks) to one of the subjects exceeding the urinary threshold values, the urinary concentration of cathine and pseudoephedrine exceeded 5 ug/mL (peak concentration 14.8 ug/mL) and 100 ug/mL (peak concentration 275 ug/mL), respectively. When the same subject took 180 mg of pseudoephedrine, the urinary concentration values were below 5 ug/mL for ephedrine and 100 ug/mL for pseudoephedrine. In the case of ephedrine administration in a sustained-release formulation containing 12 mg of ephedrine, 2 of 3 subjects exceeded the urinary cutoff value of 10 ug/mL. The high interindividual variability is still significant even if the urinary concentration values are adjusted by specific gravity and/or creatinine. These results confirm a high interindividual variability in the urinary concentration of ephedrines after the administration of the same therapeutic dose of a preparation.[Strano-Rossi S et al; Ther Drug Monit 31 (4): 520-6 (2009)] **PEER REVIEWED** PubMed Abstract
  • Up to 95% of an oral dose may be excreted in the urine within 24 hours. The urinary excretion of ephedrine is pH-dependent due to the presence of an ionizable group in the ephedrine molecule and is increased in acidic urine. In alkaline urine, excretion is reduced to 20 to 35% of the dose.[CANTOX: Safety Assessment and Determination of a Tolerable Upper Limit for Ephedra. Report prepared by CANTOX Health Sciences International, Ontario, for the Council for Responsible Nutrition, Washington, DC, p. 7 (2000)] **PEER REVIEWED**

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Metabolism/Metabolites

  • ... After /volunteers (n=3 for each drug) consumed a single clinical dose of ephedrine (EPH), pseudoephedrine (PEPH), phenylpropanolamine (PPA), methylephedrine (MEPH) or cathine/..., urine samples were subjected to tert-butyl-methyl-ether (TBME) extraction and trifluoroacetic acid (TFAA) derivatization before gas chromatography-mass spectrometry (GC-MS) analysis. Most ephedrines were excreted unchanged in urine, including EPH (40.9%), PEPH (72.2%), and PPA (59.3%). However, only a relatively small amount of MEPH (15.5%) was excreted unchanged in urine. In addition, a trace amount of PPA (1.6%) and cathine (0.7%) was found to be the metabolites of EPH and PEPH, respectively. Urinary EPH, PEPH, and PPA reached peaks at 2-6 hr and disappeared in urine at approximately 24-48 hr post-administration. For MEPH, the peaks of excretion extended from 4 to 12 hr post-administration and were undetectable at approximately 48 hr. A single clinical dose of EPH (25 mg) may exceed threshold level (10 ug/mL) in sport drug testing if the urine samples are tested within approximately 8 hr post-administration. However, a single dose of MEPH (20 mg) never reached the threshold value (10 ug/mL).[Tseng YL et al; Forensic Sci Int 157 (2-3): 149-55 (2006)] **PEER REVIEWED** PubMed Abstract
  • The metabolism of ephedrine in humans, dogs and several species of rodents proceeds primarily by three reactions; aromatic hydroxylation, N-demethylation, and oxidative deamination. The extent to which ephedrine is metabolized and the major metabolites vary quantitatively between species. The extent of aromatic hydroxylation is greatest in rats, followed by rabbits, guinea pigs, and dogs, with no aromatic hydroxylation observed in humans. N-demethylation of ephedrine is greatest in rabbits followed by dogs, guinea pigs, rats, and humans. Deamination is greatest in rabbits, followed by humans and rats. Ephedrine, 8-20%, is metabolized in humans by N-demethylation to /phenylpropanolamin/ PPA. A total of 4-13% of an oral dose of ephedrine undergoes oxidative deamination yielding 1-phenylpropan-1,2-diol and further side-chain oxidation to benzoic acid and hippuric acid.[CANTOX: Safety Assessment and Determination of a Tolerable Upper Limit for Ephedra. Report prepared by CANTOX Health Sciences International, Ontario, for the Council for Responsible Nutrition, Washington, DC, p. 7 (2000)] **PEER REVIEWED**
  • Yields L-norephedrine and phenylglycol in rabbits. /from table/[Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. E-2] **PEER REVIEWED**

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Tsca Test Submissions

  • None found

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Footnotes

1 Source: the NTP's CEBS database.

2 Source: the National Library of Medicine's Hazardous Substance Database, 02/28/2017.

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