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NEWSLETTER 7: EPHEDRA
Ephedra (Ma-Huang) Alternative Medicine/Dietary Supplement/Natural Remedy found Not to be GRAS (Generally Recognized as Safe) Warning: The FDA has ruled that ephedra poses an unreasonable health risk to consumers at large. Dietary supplements that contain ephedra and Ma huang are not allowed to be sold in the U.S. any longer as this dangerous "dietary supplement" has been finally exposed as the dangerous untested drug and thus loses its classification, "GRAS" or "Generally Recognized As Safe." The rule does not pertain to traditional Chinese herbal remedies or to herbal teas. Severe side effects and drug interactions (some life-threatening) have been reported with the use of ephedra (ma-huang). These effects and interactions are caused by ephedrine, the active ingredient in ephedra. Always check with a health care provider before taking any product containing ephedra (ma-huang). Most people are under the mistaken belief that a natural remedy is somehow proven to pure, safe and effective. This is not true. Other myths about alternative medicines that need to be broken include:
Herbal products are widely available, relatively inexpensive, and often make alluring but unsubstantiated claims. Herbal medicine appeals to consumers who believe that natural herbal products are preferable to synthetic pharmaceuticals. Exacerbating the problem, herbal remedies are often marketed on the Internet with misleading and unproved claims. Despite repeated warnings, consumers continue to equate “natural” with safe. As use becomes more prevalent and reports of adverse effects continue to mount, there is an increasing need for health care professionals to understand better the potential complications associated with these herbal remedies. There are numerous products currently on the market that have been associated with toxicity. On December 30, 2003, the FDA issued a consumer alert on the safety of dietary supplements containing ephedra. The alert advised consumers immediately to stop buying and using ephedra products. On April 12, 2004, a final rule went into effect prohibiting the sale of dietary supplements containing ephedra. On April 14, 2005, a Utah State Court judge overthrew the FDA control of ephedra. As of this writing, the legal status of ephedra sales in the United States is unclear, with products still finding their way to patients. What are other names for this remedy? Scientific and common names: Ephedra sinica, Ephedra gerardiana, Ephedra distachya, Ephedra equisetina, Ephedra shennungiana, Ephedra herba, Ephedra sinesis, ephedra, ma-huang, desert herb, herbal ecstasy, joint fir, popotillo, sea grape, teamster's tea, yellow astringent, yellow horse. Ephedra has been marketed as a safe and legal alternative to illicit street drugs. Street names for ephedra include “Herbal Ecstasy,” “Cloud 9,” and “Ultimate Xphoria.” The producers of Herbal Ecstasy have reportedly sold over 150 million pills over a 4-year time period. Ephedra can be found at drug paraphernalia shops, rock concerts, and rave parties with claims to have mood enhancing and aphrodisiac properties. The FDA has issued a public health warning to consumers not to purchase or ingest ephedrine-containing dietary supplements with labels that portray the products as alternatives to illegal street drugs. What is ephedra (ma-huang)? Ephedra is a shrub that grows mainly in Mongolia and the bordering regions of China. The dried young branches of the ephedra shrub are harvested for medicinal use in the fall. Ephedra has been an integral component of Chinese medicine throughout history with reports of its use dating back more than 5000 years. Ephedra was widely available in North America before the 2004 ban with preparations sold at neighborhood convenience stores, pharmacies, sports clubs, rock concerts, rave parties, and on the Internet. Approximately 1% of the United States population used ephedra-containing weight loss products per year, comprising 2.5 million persons. Ephedra is a botanical source of ephedrine alkaloids, typically containing 1% to 2% by weight. In 1887, ephedrine was isolated from ephedra by the Japanese chemist Nagai. It gained popular use in Western medicine when in 1930 Chen and Schmidt at Peking Union Medical College published a series of articles on its pharmacologic properties. Although ephedrine and pseudoephedrine are the most abundant constituents of ephedra, other sympathomimetic alkaloids are present and include methylephedrine, norephedrine, methylpseudoephedrine, and norpseudoephedrine. Most products containing ephedra are combined with other stimulants, such as caffeine. Products advertised to contain only pure herbal ephedra have also been found spiked with synthetic ephedrine alkaloids. What is it used for? The active ingredient in ephedra that is used in medicines is called ephedrine. The amount of ephedrine in each plant can vary so much that the same dosage of ephedra can produce very different effects. Ephedrine is a stimulant of the central nervous system. Ephedra has been suggested as a treatment for many conditions, but it is not considered safe. Ephedra can increase risk of stroke, seizure, and heart attack and may result in death. There is no safe use for ephedra. Be aware that uses for natural remedies are not approved by the US Food and Drug Administration (FDA). Natural remedies are classified as dietary supplements by the FDA. They are not subject to the same scrutiny and regulations as prescription medicines. Ephedra-containing products are relatively inexpensive and often attractively packaged to appeal to consumers of all ages. Its use has been purported to relieve such ailments as joint aches, low blood pressure, cold and flu symptoms, edema, enuresis, narcolepsy, asthma, and upper respiratory infections. It gained immense popularity because of its perceived thermogenic benefits in weight loss and as a drug of abuse with claims touting its ability to increase energy and enhance sexual sensation. Claims of efficacy of this agent remain largely unfounded. The German Commission E, the expert advisory panel for herbal medicinal agents, supports the use of ephedra for the treatment of respiratory tract diseases with mild bronchospasm in adults and children over 6 years of age. It is not advocated for other uses. The ephedrine alkaloids have both direct agonism at and ? adrenergic receptors and indirect agonism by augmenting release of norepinephrine from presynaptic neurons. Pharmacologic action results from the and ? adrenergic effects of the alkaloids, with corresponding smooth muscle relaxation in the bronchi and gastrointestinal tract in addition to arteriolar constriction and positive inotropic effects. Clinically, this can result in tachycardia, hypertension, diaphoresis, bronchodilation, agitation, and mydriasis with retained light reflex. These sympathomimetic effects provide rationale for the labeled and unlabeled uses of ephedra. Pharmacokinetic parameters for botanical ephedra are similar to those of synthetic ephedrine. How is it taken? Ephedra is taken as a tablet, capsule, or liquid. It can also be prepared as a tea to drink. Follow the directions printed on the product label or given by your health care provider. What should I watch out for? Do not take ephedra if you have:
Myocardial ischemia and infarction, dysrhythmias, and uncontrolled hypertension have been reported following consumption of ephedra. This may be caused by increased oxygen demand of the myocardium in persons with pre-existing arteriosclerotic heart disease who ingest this substance. Acute myocardial infarction secondary to coronary arterial vasospasm has been documented, however, in patients taking ephedra with normal coronary arteries and no cardiac risk factors. Theoharides described the death of a 23 year old secondary to chronic ephedrine toxicity from an ephedra-containing drink. The autopsy results in this case revealed pathologic features reminiscent of experimental and clinical aspects of sympathomimetic agent-induced myocyte toxicity. This report is consistent with other reports documenting cardiomyopathy induced by repeated doses or prolonged use of ephedrine-containing products. Rezkalla and coworkers published a report of a 25-year-old man with myocardial infarction after ingesting a diet pill containing ephedra whose coronary angiography revealed normal coronary arteries with slow flow suggestive of microcirculation abnormalities. Reports of cerebral vascular ischemia, intracranial hemorrhage, and central nervous system vasculitis have all been reported in association with the ingestion of ephedra. Seizures have also been associated with its use. Ephedra extracts have been shown to be toxic to specific neuronal cell lines. Acute psychosis has been linked with ephedra usage. Synthetic ephedrine itself was first associated with acute psychosis in 1968. Since that time, numerous reports have been published associating ephedrine use with induction of acute psychosis. Cases of ephedra-induced acute psychosis and mania have also been reported. The typical clinical picture is a paranoid psychosis with delusions and auditory hallucinations in the setting of clear consciousness. This psychosis typically has duration of days to weeks and is usually reversible with discontinuation of ephedra and supportive treatment. Numerous other adverse events have been reported including palpitations, anxiety, vomiting, syncope, erythroderma, insomnia, headache, and heat stroke. Ephedra-induced nephrolithiasis has been described. The substrate of these calculi has been documented to contain ephedrine, norephedrine, and pseudoephedrine. Ephedra is included in a growing list of herbal products that has been associated with hepatic injury. What are the possible side effects? Along with its desirable effects, this remedy may cause some unwanted side effects. Some side effects may be very serious. Some side effects may go away as your body adjusts to the remedy. Tell your health care provider if you have any side effects that continue or get worse. Serious (report these to your health care provider right away): Severe headache with no known cause; weakness, numbness, or tingling in the face, arm, or leg, especially on one side of the body; trouble walking, dizziness, loss of balance, or coordination; getting tired easily; nosebleeds; chest pain; shortness of breath; seizures, irregular heart beat, loss of consciousness. Other: Minor headache, irritability, confusion, restlessness, nausea or vomiting, sleeplessness, trouble urinating. Large doses may cause heart rhythm? problems or big increases in blood pressure. The 1994 Dietary Supplement Health and Education Act shifted the responsibility of product safety and content to those who manufacture the “dietary supplements” from the FDA. This has raised genuine concern for the consistency of these supplements between different products containing ephedra and among the same products with different lot numbers. Gurley and colleagues determined the amount of ephedrine alkaloids found in nine commercially available supplements. Ephedrine content varied from 1.08 to 13.54 mg per dose. One of the products exhibited lot-to-lot variations in ephedrine content of 137%. Another study conducted by Betz and associates analyzed the ephedrine alkaloid content of nine commercially available products using gas chromatography. Of the products in which measurable amounts could be detected, ephedrine content ranged from 0.3 to 56 mg/g. Flurer and colleagues used a cyclodextrin-modified capillary electrophoresis to determine ephedrine alkaloid content in three commercially available products. Ephedrine content in these samples ranged from 8.9 to 22.8 mg/g. The FDA has also conducted trials to determine ephedrine alkaloid content in products readily available to the consumer. Results of these trials have shown the level of ephedrine alkaloids to vary from undetectable to up to 110 mg per dose. Screening tests for drugs of abuse in persons consuming ephedra may be positive for amphetamines because of the similarity in structure between ma huang's ephedrine alkaloids and amphetamines. Ephedra has also caused false-positive results for opiates on certain drug screens. Verification by confirmatory tests, such as gas chromatography, subsequently helps to differentiate these. Currently, ephedra is a banned substance by numerous sporting associations, including the National Collegiate Athletic Association, the International Olympic Committee, and the National Football League. As a result, athletes who ingest herbal supplements that contain ephedra may be disqualified in drug-tested events. What products might interact with this remedy? When you take this remedy with prescription medicines, it can change the way this remedy or any of the medicines work. Nonprescription medicines, vitamins, other natural remedies, and certain foods may also interact. Using these products together might cause harmful side effects. Do NOT take ephedra if you are also taking:
Keep all natural remedies and medicines out of the reach of children. The Lessons of Ephedra What lessons can we learn from the ephedra fiasco? Products containing ephedra accounted for 64% of all reported adverse effects from herbs even though they represented less than 1% of total herbal product sales. The risk for an adverse effect from ephedra compared with other commonly used herbal products was very high. For example, relative risks for adverse effects from ephedra were 100 times greater than from kava and as much as 700 times greater than from Ginkgo biloba.The problems caused by Ephedra's widespread, unsupervised use are part of the general problem of alternative medicine and dietary supplements, which continue to be promoted and sold without evidence of purity, safety, efficacy or adequate standardization, and without reporting of adverse effects. The advertising is reminiscent of the snake oil salesmen with patent medicines a century ago, pushing concoctions consisting largely of alcohol; hawked as cures for serious diseases of all kinds. However, ephedra teaches a more specific lesson as well. Before it was "discovered" by the alternative medicine men of the 1990s, ephedra, and particularly its main alkaloid ephedrine, already had a long history, well documented in the pharmacological and medical literature. Calling ephedra an herb makes it sound benign. Actually, it is a dangerous potent botanical drug that was calling out to be regulated. Calling it a dietary supplement is even more misleading. Ephedra should have been removed from the market before avoidable deaths and injuries occurred. Why didn't the FDA ban Ephedra sooner? It’s not easy. Many people love ephedra and complained loudly about the threat of it leaving. The FDA does react to public opinion, even when it knows the public is wrong. The law that governs how FDA can regulate dietary supplements, the Dietary Supplement Health and Education Act (DSHEA), requires FDA to bear the burden in determining that a lawfully marketed dietary supplement presents a significant or unreasonable risk and should be removed from the market. In contrast to real drugs, which must be proven pure, safe and effective to be marketed, DSHEA requires FDA to develop evidence after the supplements are already on the market that a dietary supplement presents an "unreasonable risk of illness or injury." FDA has no authority to require any studies of safety or effectiveness for dietary supplements. This is reminiscent of the "patent medicines" of yesteryear that only required being "patented" to get on the market without any drug testing for purity, safety and efficacy. FDA first proposed regulating ephedra in 1997, but public outcry demanding ephedra stay along with other commenters including the U.S. General Accounting Office generally believed that FDA had not developed sufficient evidence for certain actions proposed. So, this dangerous drug was continued to be produced in a manner substandard to real drugs and provided without a prescription over the counter with the help of misleading advertising campaigns to a public that largely doesn’t have a clue how to use the drug safely and we wonder why people died. I still wonder why the alternative medicine industry isn't shut down for the snake oil salesman tactics they use to sell their untested products manufactured to sub-standard specifications with voluntary quality controls using deceptive advertising tricks to an unwitting nation. Since we are having trouble stopping the spread of these dangerous untested drugs masquerading as harmless safe dietary supplements, it is time to shut down this industry in their pocketbooks with lawsuits. And even though Ephedra is not Generally Recognized as Safe (GRAS) for foods and not approved for use as a food additive, some ephedra containing products will remain on the market, including: traditional Chinese herbal remedies; and, dietary supplements that are marketed as substitutes for dietary supplements containing ephedrine alkaloids. Hopefully, as many lawsuits for innocent people victimized from ephedra are settled for large amounts of money, this will minimize the number of people who will continue to be exposed to ephedra in the post ban era despite it being largely removed from the market. Sincerely: Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP Expert Medical Witness, ExpertMD PI (Principal Investigator), DSI (Drug Study Institute) Board Certified Internist, JPMC (Jupiter Preventive Medicine Center) DABIM (Diplomat American Board of Internal Medicine) FACP (Fellow American College of Physicians) CPI (Certified Physician Investigator) by the AAPP (American Academy of Pharmaceutical Physicians) CCTI (Certified Clinical Trial Investigator) by the ACRP (Association of Clinical Research Professionals) CCI (Certified Clinical Investigator) by the DIA (Drug Information Association) CCRC (Certified Clinical Research Coordinator) by the ACRP (Association of Clinical Research Professionals) CCRP (Certified Clinical Research Professional) by SoCRA (Society of Clinical Research Associates) Member, SIMPD (Society for Innovative Medical Practice Design) Member, ACPM (American College Preventive Medicine) Ethics Committee Member, Jupiter Medical Center IRB Member, Jupiter Medical Center Founder, CertifiedResearchers.com |