Ephedrine is a sympathomimetic that acts directly and indirectly on the sympathetic nerves. Its bronchodilating effects are the result of relaxation of bronchial smooth muscle through direct stimulation of adrenergic receptors. It is nasal decongestant, and has been used therapeutically for nocturnal enuresis, diabetic neuropathic edema, dysmenorrhea, narcolepsy, and myasthenia gravis. (5,6) Ephedrine in combination with caffeine has been shown to promote thermogenesis, fat loss, and muscle gain in several controlled trials. (7,8) Ephedrine is metabolized to norephedrine (phenylpropanolamine) which is responsible for the central nervous system stimulating effects of the drug. (5,6)
Therapeutic doses for bronchodilation range from 12.5 to 50 mg three times per day, with maximum daily doses between 120 and 150 mg. Because of its indirect effect on neurotransmitter stores, long-term use of ephedrine can lead to tachyphylaxis. Increasing dosage can induce toxic effects, including peripheral vasconstriction and cardiac stimulation, leading to increased blood pressure and increased heart rate; adverse effects on the central nervous system include nervousness, anxiety, tremor, weakness, irritability and insomnia. These effects increase with high doses, and overdose leads to nausea, vomiting, fever, palpitations, tachycardia, hypertension, paranoid psychosis, respiratory depression, convulsions and coma. (5,6)
Over-the-counter bronchodilators and cold medicines containing ephedrine are required to list the concentration in each dose, recommended dosage, potential adverse effects, and contraindications. (9) However products marketed as dietary supplements have not until recently been subject to similar regulation. Ephedrine products advertised as weight-loss aids, energy enhancers, and alternatives to illegal psychoactives have been sold for years without labeling indicating the pharmacologically active content of the products, let alone any potential adverse effects, contraindications, or dosage recommendations. In fact, much product marketing and packaging leads many consumers to believe that because an ephedrine product contains only the botanical source of the drug, it is safe. (10) Some products are directly mislabeled, and the actual content of many ephedrine products may far exceed that corresponding with legitimate therapeutic doses. One product that was analyzed by the Texas Department of Public Health indicated only wild Chinese ginseng on its label, yet laboratory analysis revealed a single tablet to contain 45 mg ephedrine and 20 mg caffeine. (11)
Over the years, the absence of labels warning of the potential for toxicity has combined with the misconception of safety, leading to increasing misuse and abuse of ephedrine-containing products. Reports in the literature indicate abuse and misuse of all ephedrine products -- not just those marketed as dietary supplements but also those marketed as over-the-counter bronchodilators and decongestants. The increased availability and marketing of botanically derived ephedrine products since the passage of the Dietary Supplement Health and Education Act of 1994 contributed to the increasing number of adverse effects. (10)
Adverse Effects Before 1994
Several reports of adverse effects in adults of ephedrine and pseudoephedrine appeared in the medical literature in and outside of the United States prior to 1982. These included hypertension, hypotension, drug interactions, cardiovascular disturbances, and psychosis. (12-17) The first report of fatal intracerebral hemorrhage due to ephedrine abuse appeared in a case report in the Annals of Neurology in 1983 which described the case of a 20 year old male with intracerebral hemorrhage and vasculitis. (18)
By 1984, the misuse and abuse of ephedrine-containing products was widely acknowledged. In a 1984 article in the Journal of the American Medical Association, Paul Pentel wrote "A particularly alarming development of the past few years is the mail-order advertising of OTC stimulants." (19) A year later, in 1985, another case report appeared of non fatal intracerebral hemorrhage following ingestion of a combination drug with ephedrine, phenylpropanolamine, and caffeine. (20)
Notwithstanding these reports, ephedrine preparations were included as generally recognized safe and effective for use as bronchodilators in the final monograph for OTC bronchodilator drug products on October 2, 1986. (21) Between 1986 and 1993, several additional case reports appeared in the literature, including another case of ephedrine-induced cerebral hemorrhage in 1990, (22) and three case reports of ephedrine consumption associated with stroke which appeared in the journal Neurology in 1993. (23)
The 1993 case reports were the result of an investigation initiated in 1991 after a 37 year old male presented with cerebral infarction at the Albuquerque Veterans Affairs Medical Center. The patient had ingested 10 "white-cross" ephedrine tablets daily for weight loss, a dose equivalent to approximately 150 mg/day. A review of records of the New Mexico office of the Medical Investigator 1981 to 1991 revealed a single case of fatal stroke in a 42 year old male who had hypertensive cerebral vasculopathy and a history of taking 10 - 20 white-cross tablets daily (150 - 300 mg/day) for 23 years. On autopsy, evidence of cerebral atherosclerosis, arteriolosclerosis and arteriolonephrosclerosis was found, with blood concentration of 2.7 g/ml ephedrine.
The New Mexico case review also revealed two other cases of fatal stroke involving ingestion of a combination of caffeine, phenylpropanolamine, and ephedrine. The third report in that case series was identified from an investigation of 17 fatal intracranial hemorrhages in Connecticut during the period April 1989 to April 1990; this case was an 84 year old female whose blood on autopsy was positive for the presence of ephedrine. (23)
The authors hypothesized that ephedrine-induced hypertension caused these three cases, but the disparity between them illustrates the uncertainty in identifying a causal chain, and sets the stage for the unbridled marketing of botanical ephedrine products that occurred after the Dietary Supplement Health and Education Act was passed in 1994. The first case had not significantly exceeded the normal daily therapeutic dose, although the duration is not mentioned. The second case appears to be one of significant long-term abuse; the high consumption of ephedrine over 23 years was a likely cause of the case's predisposition to stroke and the eventual fatality. The conditions surrounding the third case are much less clear; like the younger man in the second case, this patient had signs of cerebral atherosclerosis, atherosclerosis, and arteriolonephrosclerosis. But this was an 84 year old woman, and her history of medication was not evident. While it was possible that her stroke was precipitated by the vasoconstricting and hypertensive effect of ephedrine, it is difficult to determine with any confidence. Nonetheless, it was during the time this case series was being prepared that New Mexico became one of the first states to enact a regulation banning the sale of any OTC product containing ephedrine. (23)
The Dietary Supplement Health and Education Act
The passage of the Dietary Supplement Health and Education Act in October 1994 increased awareness among the U.S. population of the uses and restrictions surrounding dietary supplements. In lobbying for the passage of the act, manufacturers of supplements engaged in a highly publicized campaign to ensure that their products could remain readily available to consumers. With passage of the act, the burden of proof for adverse effects shifted from the manufacturer to the government. Although adverse effects of ephedrine products were clearly not absent from the literature, the uncertainty surrounding many cases provided an attractive loophole, opening the door for increased marketing, with advertisements for products soon appearing ubiquitously in magazines targeted at adolescents and college students.
The number of adverse events relating to ephedrine continued to escalate with the increasing availability and attractive advertising for "natural alternatives" to street drugs. The situation drew the attention of the media and some states scrambled to enact their own regulatory controls. Ohio had banned the sale of all ephedrine-containing products in 1994. (24) Texas enacted a ban on all ephedrine-containing products in 1994, but the ban was lifted by a court injunction three weeks later. (25-26) By July 1995, 14 states had placed some control or restriction on ephedrine, including some that banned over the counter sales. (27)
In October 1995, the FDA Food Advisory Committee released a statement reporting more than 330 adverse effects and 12 deaths due to ephedrine. (28) Reports of deaths were soon appearing as frequently in the popular press as in the medical literature. At the same time, the growth of the internet contributed to the flow of information and misinformation on ephedrine-containing products. Advertisements claimed "Ephedrine is the strongest safe stimulant known today. It will allow athletes to train longer and harder...." (29) One newsgroup targeted at recreational weight lifters and body-builders averaged approximately 100 out of 5500 messages per month about ephedrine and ephedrine-containing products such as "Ripped Fuel". (30)
The increased attention was leading to increased abuse, and the situation escalated in March 1996, when a 20 year old college student from Nassau County New York died while on vacation in Florida after consuming eight tablets of an ephedrine-containing product called "Ultimate Xphoria". His death was followed several weeks later by the death of a male graduate student who had died after consuming the Ripped Fuel product. (31)
On April 10, 1996, the FDA issued a warning that "consumers should not buy or consume ephedrine-containing dietary supplements whose labels portray them as apparent alternatives to illegal street drugs." (32) On April 12, the American Academy of Neurology released a press statement adding that consumption of ephedrine products may cause serious neurologic side effects. (33)
Then, in August 1996, the Texas Department of Health reported the results of a review of records for the period December 1993 to September 1995 from six centers of the Texas Poison Center Network. The review identified 500 adverse events, including eight deaths, associated with dietary supplements containing ephedrine, pseudoephedrine, norephedrine, or N-methylephedrine. (11) This report prompted the state to again propose a ban on ephedrine-containing products. (34)
As of March 1997, ephedrine products are banned or restricted in at least 20 states. Yet the potential for abuse and misuse remains. For example, the Nassau County New York regulation bans the sale of products promoted as alternative psychoactives, while still allowing those marketed as weight-loss or body-building supplements. Other states are more restrictive; Tennessee, Oklahoma, Florida, and Louisiana all have statutes making it unlawful to sell ephedrine products, and in some cases pseudoephedrine products, for "indication of stimulation, mental alertness, weight loss, appetite control, energy or other indications not approved pursuant to the pertinent federal over-the-counter drug final monograph..." (24, 35-38)
The popular press latched onto and highlighted the abuse of ephedrine through consumption of the products sold as alternative psychoactive stimulants, but ephedrine abuse occurs in a variety of scenarios. The increased occurrence of adverse events related to ephedrine consumption may be partly blamed on misleading marketing, poor labeling and the pervasive misconception of safety; but over-the-counter ephedrine products were abused prior to the introduction of the "natural psychoactive alternatives". The history of abuse and adverse effects predicts that as long as any ephedrine product, no matter how marketed or labeled, remain available, they will be subject to abuse and misuse.
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