Ephedra-containing Dietary Supplements Research Articles

Intensity of heavy metal accumulation in plants of Silybum marianum L. in conditions of field rotation

Intensity of heavy metal accumulation in plants of Silybum marianum L. in conditions of field rotation

Steven B. Heymsfield, MD: Incoming President, The Obesity Society, 2018‐2019

Steven B. Heymsfield, MD: Incoming President, The Obesity Society, 2018‐2019

Physiological effects following administration of Citrus aurantium for 28 days in rats

BackgroundSince ephedra-containing dietary supplements were banned from the US market, manufacturers changed their formulations by eliminating ephedra and replacing with other botanicals, including Citrus aurantium, or bitter orange. Bitter orange contains, among other compounds, synephrine, a chemical that is chemically similar to ephedrine. Since ephedrine may have cardiovascular effects, the goal of this study was to investigate the cardiovascular effects of various doses of bitter orange extract and pure synephrine in rats. MethodFemale Sprague–Dawley rats were dosed daily by gavage for 28days with synephrine from two different extracts. One extract contained 6% synephrine, and the other extract contained 95% synephrine. Doses were 10 or 50mg synephrine/kg body weight from each extract. Additionally, caffeine was added to these doses, since many dietary supplements also contain caffeine. Telemetry was utilized to monitor heart rate, blood pressure, body temperature and QT interval in all rats. Results and conclusionSynephrine, either as the bitter orange extract or as pure synephrine, increased heart rate and blood pressure. Animals treated with 95% synephrine showed minimal effects on heart rate and blood pressure; more significant effects were observed with the bitter orange extract suggesting that other components in the botanical can alter these physiological parameters. The increases in heart rate and blood pressure were more pronounced when caffeine was added. None of the treatments affected uncorrected QT interval in the absence of caffeine.

“Ephedra-Free” Diet Pill-Induced Psychosis

The prevalence of obesity in the United States has increased from approximately 23% in 1990 to 33.8% in 2008. Multiple over-the-counter products claim to aid in weight loss under the pretense of being “natural” and “safe”. According to a national survey conducted in 2005 and 2006, 33.9% of respondents (who had made a serious weight-loss attempt) reported having used such a product. Following the FDA’s ban on ephedra-containing dietary supplements due to serious cardiovascular and neurological adverse reactions, manufacturers substituted ephedra with other substances, such as Citrus aurantium and marketed these products “ephedra-free”. We describe the development of severe psychosis in a middle aged woman after 2 weeks use of “ephedra-free” dietary supplements.

Determination of para-synephrine and meta-synephrine positional isomers in bitter orange-containing dietary supplements by LC/UV and LC/MS/MS

Dietary supplements that contain bitter orange ( Citrus aurantium) fruit as an integrated component have rapidly replaced ephedra-containing dietary supplements for use as weight loss products. However, the safety of bitter orange-containing supplements has been questioned because synephrine, an adrenergic alkaloid and a key component of bitter orange fruit, has potential adverse health effects. Conflicting reports have stated that synephrine exists as the para ( p) and/or meta ( m) positional isomers in some bitter orange-containing supplements and this is problematic because the p- and m-isomers have distinctly different pharmacological and metabolic activities. Two liquid chromatographic (LC) methods have been developed for the baseline separation and quantitation of p- and m-synephrine in bitter orange-containing supplements. An isocratic LC method that utilizes ultraviolet (UV) absorbance detection and a gradient LC method that utilizes tandem mass spectrometry (MS/MS) detection were optimized for separation of the isomers within a run time of 25 min. Terbutaline was utilized as an internal standard compound in both LC methods. The LC/UV and LC/MS/MS methods demonstrated limits of quantitation (LOQs) for synephrine of ≈30 ng (on-column) and ≈0.02 ng (on-column), respectively, and each method exhibited analytical linearity over three orders of magnitude. Both LC methods were used to evaluate the synephrine levels in a limited selection of commercially available bitter orange-containing supplements. Significantly, m-synephrine was not detected in any of the tested dietary supplements.

CrossRef Listing of Deleted DOIs

Ephedra has been used medicinally for thousands of years dating back to ancient Chinese medicine. Since its introduction to Western medicine in the 20th century, ephedra has been used for various ailments. The amphetamine-like activity of ephedra made it a popular supplement for promotion of weight loss and enhancement of athletic performance, despite limited supporting data. With the implementation of the Dietary Supplement Health and Education Act of 1994, the US Food and Drug Administration's (FDA) regulation of ephedra-containing supplements diminished. As these products became increasingly available, adverse effects associated with their use also increased. These adverse effects are mainly a result of ephedra's sympathomimetic activity and have been manifested by premature cardiovascular and central nervous system disease. With mounting evidence concerning the unsafe nature of these products, the FDA was able to ban the sale of ephedra-containing dietary supplements in April of 2004.

Rapid selective screening and determination of ephedrine alkaloids using GC‐MS footnote mark

Ephedra (ma huang) has been widely used as an herb or herbal extract in both traditional Chinese medicine and Western world dietary supplements. The effects of Ephedra have been attributed to a series of six ephedrine alkaloids including ephedrine and pseudoephedrine. A GC-MS method for the ephedrine alkaloids is described which couples ammoniacal chloroform as the extraction solvent with a two-stage derivatisation scheme. This scheme produces the O-trimethylsilyl, N-trifluoracetyl derivatives (O-TMS, N-TFA) for the primary and secondary amine alkaloids, and the O-TMS derivatives for the tertiary amine alkaloids. Relatively clean extracts are obtained from complex matrices, and the six ephedrine alkaloids are effectively separated and identified. This approach was also evaluated for quantitative analysis, and was shown to provide quantitative results for ephedrine and pseudoephedrine, and good estimates for the four minor alkaloids. Figures of merit are presented for linearity, detection limits, precision and accuracy. We have applied this approach to the rapid screening and profiling of the ephedrine alkaloids in whole Ephedra plants, liquid plant extracts, dried powder plant extracts and a variety of Ephedra-containing dietary supplements.

Analysis of Flavonoid Phytoestrogens in Botanical and Ephedra-Containing Dietary Supplements

Plant-derived botanical and dietary supplements are widely self-prescribed in the US and considered natural, safe, and beneficial. However, because they are not strictly regulated by the Food and Drug Administration (FDA), their ingredients are not always known and they may contain unexpected agents. Among the myriad plant-produced molecules are flavonoids, which reportedly have various human health effects, including anticancer, antioxidant, and estrogenic properties. Several flavonoids (eg, isoflavones) are known as phytoestrogens, based on their ability to mimic estrogen in mammals. Because botanical and dietary supplements are plant products and need not be processed or purified due to their FDA classification as foods, they may contain unexpected phytoestrogens, such as flavonoids. To analyze 8 botanical and 11 ephedra-containing dietary supplements for the presence and concentration of 5 flavonoids (biochanin A, daidzein, formononetin, genistein, quercetin), which may deliver unexpected estrogenic activity. Randomly selected tablets from single bottles of 19 botanical and dietary supplements purchased locally were pooled. Flavonoids were extracted into ethanolic solution and analyzed by high-performance liquid chromatography. Flavonoids were detected in all supplements tested, with the largest number (4) found in Kava Kava. Almost all supplements contained measurable amounts of genistein and/or daidzein, known estrogenic agents, at up to 22 mg/day of isoflavone, per recommended daily dosage of supplement. These results suggest that single-component botanical and multi-ingredient dietary supplements could contain unexpected estrogenic agents, which may impact the health of consumers.

Metal content of ephedra-containing dietary supplements and select botanicals

The metal content of dietary supplements, including 13 ephedra-containing supplements, was studied. Samples of botanicals (black cohosh, echinacea, goldenseal, kava kava, milk thistle, saw palmetto, Synephrine, and valerian root), ephedra-containing dietary supplements (Amp II, EPH 833, Ephedra, Ephedra 1000, Hydroxycut, Metabolife 356, Metabolift, Ripped Fuel, Ripped Fuel Extreme, Ripped Fuel [ma huang-free], Stacker 2 [two lots], Super Stinger, Virgin Earth, Xenadrine RFA-1 [two lots], Yellow Jacket), and nonprescription reference agents (NoDoz and Primatene) were digested in acid, reacidified, and then spiked with internal standards. Metals were quantified using Environmental Protection Agency quality assurance and quality-control standards 6020 and 200.8. Forty-seven metals were analyzed by inductively coupled plasma-mass spectrometry, with subpart-per-trillion detection limits. All metals detected were in concentrations below toxic levels or physiological limit levels for the daily doses specified by the products' labeling. Metals found in highest concentrations among all the supplements sampled were sodium, magnesium, calcium, potassium, aluminum, iron, titanium, mercury, strontium, lead, barium, and silver. Of the 27 supplements analyzed, those with the lowest metal concentrations were mostly single-ingredient botanical supplements, while multiple-component, ephedra-containing dietary supplements generally had higher metal concentrations. Significant lot-to-lot variations were found for two ephedra-containing dietary supplements. None of 47 metals was found in highly toxic amounts in 23 brands of dietary supplements and two nonprescription reference preparations.

OI-A-4Hemodynamic and electrocardiographic effects of an “ephedra-free” dietary supplement (Metabolife Ultra™)

BACKGROUND The 2004 FDA ban on ephedra-containing dietary supplements produced an upsurge of “ephedra-free” products onto the U.S. market. Despite their “ephedra-free” designation, many of these supplements contain botanical ingredients with sympathomimetic properties (e.g. synephrine, caffeine) that when taken together may produce untoward cardiovascular effects. The purpose of this study was to examine the cardiovascular and electrocardiographic effects of a 3-day course of an “ephedra-free” dietary supplement (Metabolife Ultra™). METHODS Baseline assessments of blood pressure were determined for 10 healthy male volunteers, and electrocardiographic data was collected for 24 hours via Holter monitoring. 24 hours later, subjects began a 3-day regimen of Metabolife Ultra™ (2 tablets, 3 times daily). On the third day of supplementation, blood pressure and Holter monitoring were performed again. After a two-week washout period, blood pressure and Holter monitoring were performed a third time. Group means for QTc, systolic and diastolic blood pressure, and heart rate were compared by nonparametric repeated measures ANOVA. RESULTS During supplementation, statistically significant increases were noted for QTc (+14 msec, p=0.04), systolic (+8 mm Hg, p=0.04), and diastolic blood pressure (+10 mm Hg, p<0.001). Two subjects exhibited prolongations in QTc intervals exceeding 40 milliseconds. CONCLUSIONS Metabolife Ultra™ may cause clinically significant changes in cardiac indices. Clinical Pharmacology & Therapeutics (2005) 79, P2–P2; doi: 10.1016/j.clpt.2005.12.005

Ischemic Stroke Associated With Use of an Ephedra-Free Dietary Supplement Containing Synephrine

In response to concerns regarding the safety of ephedra-containing dietary supplements, manufacturers have marketed "ephedra-free" products. Many of these contain synephrine, a sympathomimetic amine from the plant Citrus aurantium. Synephrine is structurally similar to ephedrine and has vasoconstrictor properties. We describe a 38-year-old patient with ischemic stroke associated with an ephedra-free dietary supplement containing synephrine and caffeine. The patient presented with memory loss and unsteady gait after taking 1 or 2 capsules per day of a dietary supplement (Stacker 2 Ephedra-Free) for 1 week. He had no notable medical history or major atherosclerotic risk factors and took no other medications. Physical examination showed a mildly ataxic gait and substantial Impairment of both concentration and memory. Computed tomography and magnetic resonance Imaging of the brain showed subacute infarctions in the left thalamus and left cerebellum in the distribution of the vertebrobasilar circulation. Other causes of ischemic stroke were evaluated, and findings were unremarkable; a vasospastic origin was considered most likely. The patient was discharged with nearly complete resolution of symptoms. Synephrine, a sympathomimetic amine related to ephedrine, may be associated with Ischemic stroke. Consumers and clinicians need to be Informed about the potential risks of ephedra-free products.

Ephedra-containing dietary supplements in the US versus ephedra as a Chinese medicine.

Ephedra has been commonly used in traditional Chinese medicine (TCM) without significant adverse effects. Ephedra-containing dietary supplements are widely used in the United States to promote weight reduction and energy enhancement. However, there are significant safety concerns regarding the use of ephedra-containing dietary supplements, especially when such use occurs by consumers without medical supervision. This article reviews and contrasts the usage of ephedra as a dietary supplement in the US against an herbal medication in TCM. The potential adverse effects of ephedra-containing dietary supplements are also reviewed.

US FDA to ban ephedra-containing dietary supplements

US FDA to ban ephedra-containing dietary supplements

US FDA to ban ephedra-containing dietary supplements

US FDA to ban ephedra-containing dietary supplements

Demographic, pathologic, and toxicological profiles of 127 decedents testing positive for ephedrine alkaloids

The relative toxicity of ephedra-containing dietary supplements is disputed. In order to ascertain the magnitude of the problem, we reviewed all autopsies in our 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 <0.49mg/l in 50% of the cases, range 0.07–11.73mg/l in trauma victims, and 0.02–12.35mg/l in non-trauma cases. Norephedrine (NE) was present in the blood of 22.8% (mean of 1.81mg/l, S.D.=3.14mg/l) and in the urine of 36.2% (mean of 15.6mg/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.

Effect of a multicomponent, ephedra-containing dietary supplement (Metabolife 356) on Holter monitoring and hemostatic parameters in healthy volunteers

Herbal products containing ephedra (a natural source of ephedrine alkaloids) in combination with other ingredients exhibiting sympathomimetic properties (kola nut, guarana, and green tea extract) are widely available under names such as Xenadrine RFA-1 (Cytodyne Technologies, Lakewood, New Jersey), Metabolife 356 (Metabolife International, San Diego, California), and Ripped Fuel (Twin Laboratories, Inc., Hauppauge, New York). These products are most often taken to promote weight loss and to enhance exercise performance. Metabolife 356 has become the nation’s best-selling weight loss supplement, capturing 45% of the weight loss supplement market. Metabolife 356 contains a variety of herbs, including ma huang, guarana, ginger, ginseng, and gotu kola, as well as various other vitamins and minerals. Only a few studies have evaluated the effectiveness of ephedra-containing products on weight loss, yet the safety aspects of these products remains equivocal. Ephedracontaining dietary supplements have been associated with serious adverse effects, including myocardial infarction, cardiac arrhythmia, hypertension, hepatitis, seizure, stroke, and death. 1– 8 This study was conducted to evaluate the short-term effects of Metabolife 356 on blood pressure, heart rate, 24-hour Holter monitoring, and hemostatic parameters in healthy subjects.  Healthy men aged 20 to 40 years were included in this study. Exclusion criteria were history of consumption of any ephedra-containing supplement, any known medical condition, smoking, and current use of any prescription or nonprescription medication. Subjects were required to refrain from caffeine and exercise throughout the study period. The protocol was approved by the institutional review board. All subjects provided written informed consent before any study-related procedures were initiated. After a 7-day, caffeine-free period, subjects underwent baseline venipuncture, cuff blood pressure measurement, heart rate, 12-lead electrocardiography, and physical examination. Casual cuff blood pressures were measured using an aneroid sphygmomanometer in the dominant arm after a minimum of 10 minutes of rest in a seated position. After confi rmation of a 12hour fast, venous blood samples were collected and the serum was separated and stored frozen at 70°C. The samples were shipped frozen to the clinical laboratories and were analyzed for tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) using enzyme-linked immunosorbent assay; ephedra was assessed using liquid chromatographic/ mass spectrophotometric techniques. A baseline chemistry panel and complete blood count were also obtained to rule out any abnormalities before supplementation. Subjects with normal fi ndings at the baseline visit

Exertional Heatstroke in an Infantry Soldier Taking Ephedra-Containing Dietary Supplements

This is a case report of a highly trained, heat-acclimatized infantry soldier who suffered from exertional heatstroke during a 12-mile road march shortly after taking an ephedra-based supplement. Heatstroke is associated with systemic complications and a high mortality rate if not recognized early. Control of risk factors is key to the prevention of heatstroke. Since there are no clear ergogenic benefits in using ephedra alone, clinicians and military commanders should strongly discourage the use of ephedra-containing substances in active duty soldiers undergoing strenuous exercise.

Medicine. Ephedra--scientific evidence versus money/politics.

Although clear evidence of the dangers of ephedra-containing dietary supplements exists, the U.S. Food and Drug Administration has failed to use its legal authority to ban them. This is in the face of bans from the U.S. Army and Air Force commissaries and U.S. sports organizations and a recall from the Canadian government. The [author][1] of this Policy Forum urges an FDA ban on ephedra products, which he says has been blocked by lobbying and campaign contributions from Metabolife and other dietary supplement makers. Recently, several companies have reformulated their products without ephedra as the main ingredient, an unsatisfactory regulatory alternative to an FDA ban. [1]: http://www.sciencemag.org/cgi/content/full/300/5618/437

Content versus label claims in ephedra-containing dietary supplements.

The content of ephedra alkaloids in herbal dietary supplements containing ephedra (ma huang) was studied. The ephedra alkaloid content of 20 ephedra-containing supplements was determined by high-performance liquid chromatography. Contents of (-)-ephedrine, (+)-pseudoephedrine, (-)-methylephedrine, (-)-norephedrine, and (+)-norpseudoephedrine were measured. Ephedra alkaloid content varied considerably among products. Total alkaloid content ranged from 0.0 to 18.5 mg per dosage unit. Ranges for (-)-ephedrine and (+)-pseudoephedrine were 1.1-15.3 mg and 0.2-9.5 mg, respectively. (+)-Norpseudoephedrine, a Schedule IV controlled substance, was often present. Significant lot-to-lot variations in alkaloid content were observed for four products. For one product, lot-to-lot variations in the content of (-)-ephedrine, (+)-pseudoephedrine, and (-)-methylephedrine exceeded 180%, 250%, and 1000%, respectively. Half of the products exhibited discrepancies between the label claim for ephedra alkaloid content and actual alkaloid content in excess of 20%. One product was devoid of ephedra alkaloids. Assay of 20 ephedra-containing dietary supplements showed that alkaloid content often differed markedly from label claims and was inconsistent between two lots of some products.