Dietary supplement adverse events: report of a one-year poison center surveillance project.

BACKGROUND: The safety and efficacy of dietary supplements is of growing concern to regulators, health-care providers and consumers. Few scientific data exist on clinical effects and potential toxicities of marketed products. Harmful supplements may not be identified for months or years with existing adverse event monitoring mechanisms. Retrospective review of poison center statistics to capture supplement-associated toxicity also has limitations. METHODS: We collaborated with the FDA Center for Food Safety and Nutrition (CFSAN) to conduct a 1-year prospective surveillance study of dietary supplement-related poison control center calls in 2006. Prompt follow-up of symptomatic cases, laboratory analysis of implicated dietary supplements, and causality assessment by a case review expert panel were performed. RESULTS: Of 275 dietary supplements calls, 41% involved symptomatic exposures; and two-thirds were rated as probably or possibly related to supplement use. Eight adverse events required hospital admission. Sympathomimetic toxicity was most common, with caffeine products accounting for 47%, and yohimbe products accounting for 18% of supplement-related symptomatic cases. Suspected drug-herb interactions occurred in 6 cases, including yohimbe co-ingested with buproprion (1) and methamphetamine (3), and additive anticoagulant/antiplatelet effects of NSAIDs taken with fish oils (1) and ginkgo (1). Laboratory analysis identified a pharmacologically active substance in 4 cases; supplement toxicity was ruled unlikely when analytical testing was negative in 5 cases. CONCLUSION: Most supplement-related adverse events were minor. Clinically significant toxic effects were most frequently reported with caffeine and yohimbe-containing products. Active surveillance of poison control center reports of dietary supplement adverse events enables rapid detection of potentially harmful products, which may facilitate regulatory oversight.

Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Performance-enhancing dietary supplements have not been clinically tested for safety or efficacy. In clinical trials performed under resting conditions, performance-enhancing supplements raise blood pressure and affect glucose homeostasis. The effect of exercise on the pharmacokinetics and pharmacodynamics of stimulant herbals is unknown. WHAT THIS STUDY ADDS: Supplement-induced effects on blood pressure and glucose levels are not ameliorated by exercise. Exercise does not affect the kinetics of stimulant ingredients, caffeine and synephrine. Performance-enhancing supplement use modestly improves exercise tolerance. AIMS Dietary supplements (DS) promoted to enhance athletic performance often contain herbal sympathomimetics such as Citrus aurantium (synephrine) and caffeine. We aimed to characterize the pharmacology of a performance-enhancing DS in the setting of exercise. METHODS: Ten healthy adults (three women) aged 20-31 years participated in a three-arm, double-blind, placebo-controlled, crossover study. Subjects ingested one dose of DS (Ripped Fuel Extreme Cut(R) with 21 mg synephrine and 304 mg caffeine by analysis) under resting conditions and 1 h prior to moderately intense exercise (30 min on cycle ergometer at 75-80% HR(max)), with a placebo (PLC)/exercise control. Plasma synephrine and caffeine concentrations were measured over 12 h, and vital signs, serum electrolytes, oxygen consumption and perceived exercise exertion were monitored. RESULTS: No significant adverse events occurred. Synephrine and caffeine pharmacokinetics were unaffected by exercise. Post-exercise diastolic blood pressure was higher after DS (peak mean 71.7 +/- 8.7 mmHg) than PLC (63.0 +/- 4.9 mmHg) (p = 0.007). There were no substantial treatment-related differences in post-exercise HR, systolic blood pressure, or temperature. Postprandial plasma glucose increased to 121.0 +/- 31.6 mg dl(-1) with DS and exercise vs. 103.7 +/- 25.5 mg dl(-1) with PLC and exercise (P = 0.004). No treatment differences in exercise-related oxygen consumption, serum lactate, or insulin were observed. Exercise was rated less difficult with DS than PLC (P = 0.001). CONCLUSIONS: Blood pressure and plasma glucose increased post-exercise with DS use, which could be detrimental in some people. Exercise was perceived as less strenuous after DS, presumably due to the stimulant effects of caffeine.

Hemodynamic effects of ephedra-free weight-loss supplements in humans.

PURPOSE: Ephedra-free weight loss dietary supplements containing bitter orange (Citrus aurantium), a botanical source of the adrenergic amines synephrine and octopamine, have quickly emerged on consumer markets to replace banned ephedra products. These supplements may have some of the health risks associated with ephedra, but studies in humans are lacking. Our aim was to characterize the pharmacokinetics and cardiovascular effects of C. aurantium dietary supplements. SUBJECTS AND METHODS: Ten healthy adult nonsmokers participated in a randomized, double-blind, placebo-controlled, three-arm crossover study. Single doses of C. aurantium (Advantra Z) containing 46.9 mg synephrine, Xenadrine EFX, a multi-component formulation containing 5.5 mg synephrine, and placebo were administered with a one-week washout. RESULTS: Compared with placebo, Xenadrine EFX but not Advantra Z increased systolic and diastolic blood pressure with peak changes from baseline at 2 hours of 9.6 +/- 6.2 mm Hg systolic (P = 0.047), and 9.1 +/- 7.8 mm Hg diastolic (P = 0.002). Heart rate was increased from baseline at 6 hours compared with placebo (16.7 beats per minute with Xenadrine EFX, P = 0.011; 11.4 beats per minute with Advantra Z, P = 0.031). Dose-adjusted synephrine pharmacokinetics were similar between treatments with t(max) = 90 min, t(1/2) = 3.0 hours, V/F = 16347 L, and CL/F = 88.9 L/min for Xenadrine EFX. CONCLUSION: Ephedra-free weight loss supplements have significant cardiovascular stimulant actions, similar to ephedra. These effects are not likely caused by C. aurantium alone, because an eightfold higher dose of synephrine (Advantra Z) had no effect on blood pressure, but may be attributable to caffeine and other stimulants in the multi-component formulation.

Short-term metabolic and hemodynamic effects of ephedra and guarana combinations.

OBJECTIVE: Serious adverse health events have been reported with the use of dietary supplements containing ephedra and guarana. We sought to determine whether repeated dosing and multi-ingredient formulations contribute to the adverse effects of these supplements. METHODS: In this study, 16 healthy adults (8 women) took 2 doses each of ephedra-guarana alone, Xenadrine RFA, a multicomponent dietary supplement containing 25 mg ephedra alkaloids and 200 mg caffeine, or placebo 5 hours apart in a randomized, double-blind, 3-arm crossover study. RESULTS: Peak plasma ephedrine levels averaged 130 to 140 ng/mL. Compared with placebo, Xenadrine and ephedra-guarana significantly increased heart rate (maximum increase, 9.4 +/- 8.6 beats/min; P = .002), blood pressure (maximum increase in systolic and diastolic pressure, 11.5 +/- 10.7 mm Hg and 7.3 +/- 7.4 mm Hg, respectively; P = .015), postprandial glucose concentration (maximum change, 41.0 +/- 18.8 mg/dL; P < .0001), and insulin concentration (maximum change, 41.2 +/- 47.8 microIU/mL; P = .005). Serum potassium concentrations were significantly decreased by both treatments. Hemodynamic and metabolic changes were observed after both the first and second doses. However, plasma free fatty acid concentrations increased after the first dose only. Xenadrine RFA produced higher increases in glucose concentration than ephedra-guarana, but no other pharmacodynamic differences between the treatments were found. CONCLUSIONS: Consumption of 2 doses of ephedra and guarana supplements, per supplement label recommendations, results in persistent increases in heart rate and blood pressure and unfavorable actions on glucose and potassium homeostasis. Such effects could be detrimental in persons with hypertension, atherosclerosis, or glucose intolerance, conditions that are strongly associated with obesity.

Seizures reported in association with use of dietary supplements.

BACKGROUND: Seizures in persons using dietary supplements (DS) have been reported through the Food and Drug Administration's (FDA) MedWatch system, but not formally reviewed. METHODS: Sixty-five cases of DS-associated seizures reported to MedWatch from 1993 to 1999 were obtained through the Freedom of Information Act and independently evaluated by three reviewers for probability of causation based on temporal relationship, biological plausibility, and underlying risk factors. Our aims in this review were 1) to assess the probability of causation in each case; 2) to characterize the patterns of use and types of supplements involved in cases of seizures; and 3) to identify trends that may explain potential risks factors for dietary supplement-related seizures. RESULTS: Twenty seizures were judged as probably related, 13 possibly related, and 10 as unrelated to DS use. Five cases were not seizures, and 17 cases contained insufficient information. In the 20 probably related cases, 19 involved ephedra, 14 involved herbal caffeine, and in one case, the supplement contained no herbal constituents but an array of elemental salts. Ephedra was also associated with 7 of the 13 possibly related cases, and caffeine was contained in 5 of these supplement products. Creatine, St. John's wort, and ginkgo biloba were other DS implicated in possibly related seizure events. Seizures were associated with hypoglycemia in 3 cases, and secondary to stroke in 2 cases and cardiac arrest in 2 cases. Weight loss (45%) and athletic performance enhancement (30%) were the most often cited reasons for supplement use. In most cases, DS use was within manufacturers' guidelines. CONCLUSION: Ephedra was implicated in 27 of 33 DS-associated seizures reported to the FDA over a 7-year period, further underscoring that significant health risks are associated with use of this herbal product.

Concentrations of ephedra alkaloids and caffeine in commercial dietary supplements.

Dietary supplements that contain Ma Huang (ephedra alkaloids) and guarana (caffeine) are widely marketed and used in the U.S. for weight loss and athletic performance enhancement, despite a lack of adequate research on the pharmacology of these botanical stimulants. We developed and applied a novel liquid chromatography-tandem mass spectrometry (LC-MS-MS) method to quantitate the various ephedra alkaloids found in dietary supplements that contain Ephedra species. The quantities of ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, methylephedine, methylpseudoephedrine, and caffeine were determined for 35 commercial dietary supplements and compared with the amounts listed on the product labels. The total ephedra alkaloid content ranged from 5.97 mg to 29.3 mg per serving. Two supplement brands did not list the quantity of ephedra alkaloids on the label, and four did not list the amount of caffeine per serving. Of the products tested, 31% contained > 110% of the total ephedra alkaloids listed on the label, and 6% of the supplements contained < 90% of the listed amount. For caffeine, 86% of the product lots that listed the caffeine amount contained less than 90% of the labeled quantity. No products contained > 110% of the declared caffeine content. The total ephedra alkaloid content varied significantly from lot to lot in 5 of 9 products. Three product brands contained proportions of alkaloids that exceeded amounts reported for E. sinica, including one that was 98% ephedrine, one that had 10% norpseudoephedrine, and one that contained an average of 13% methylephedrine. We conclude that product inconsistency is common among some commercially available dietary supplements that contain ephedra alkaloids and caffeine.

Determination of ephedra alkaloid and caffeine concentrations in dietary supplements and biological fluids.

Dietary supplements containing botanical forms of caffeine and ephedra alkaloids have been widely promoted and used in the U.S. for weight loss and athletic enhancement despite a lack of adequate research on the pharmacology of these botanical stimulants. In order to analyze dietary supplements and perform human pharmacokinetic studies, an analytical approach with good precision and accuracy was needed with sufficient sensitivity to detect very low levels of ephedra alkaloids. A liquid chromatography-atmospheric pressure chemical ionization (APCI) tandem mass spectrometry (LC-MS-MS) method was developed for quantitating the various ephedrine-group alkaloids found in dietary supplements that contain Ephedra species, and in plasma and urine of persons consuming these supplements. Using this method, low nanogram-per-milliliter concentrations of ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, methylephedrine, methylpseudoephedrine, and caffeine can be quantitated in a 12-min LC-MS-MS run.

Photosensitivity reaction in a woman using an herbal supplement containing ginseng, goldenseal, and bee pollen.

Photosensitivity, an abnormal skin reaction to light, is a rare adverse event associated with herbal medicine use. Case reports in the literature most commonly implicate St. John's wort. In this report, we describe the case of a 32-year-old woman who suffered a phototoxic reaction after taking a dietary supplement containing ginseng, goldenseal, bee pollen, and other ingredients. On presentation, she had a pruritic, erythematous rash, localized to the sun-exposed surfaces of her neck and extremities. She had no significant past medical history and was not taking any other medications. The skin rash slowly resolved after discontinuation of the supplement and with treatment including subcutaneous and topical corticosteroids. Although the individual ingredients in this dietary supplement have not been associated with cases of photosensitivity, it is possible that the combination of ingredients may have interacted to cause this toxic reaction. Therefore, we recommend caution in the combining of multiple herbs and supplements into new formulations.

Adverse events associated with dietary supplements: an observational study.

BACKGROUND: Adverse events associated with dietary supplements are difficult to monitor in the USA, because such products are not registered before sale, and there is little information about their content and safety. METHODS: In 1998, 11 poison control centres in the USA recorded details of 2332 telephone calls about 1466 ingestions of dietary supplements, in 784 of which patients had symptoms. We used a multitiered review process (kappa 0.42) to select 489 cases for whom we were at least 50% certain that their negative events were associated with dietary supplements. We aimed to assess the effects of multiple ingredients and long-term use, and collated data for patterns of use and information resources. FINDINGS: A third of events were of greater than mild severity. We noted both new and previously reported associations that included myocardial infarction, liver failure, bleeding, seizures, and death. Increased symptom severity was associated with use of several ingredients, long-term use, and age. Paediatric exposures were more often unintentional than were adult ingestions, and treatment of disease was the reason for supplement use in at least 28% of reports. Most products and ingredients were not identified in the information database (Poisindex) used by poison control centres, and specific adverse events were reported variably among five additional sources. INTERPRETATION: Dietary supplements are associated with adverse events that include all levels of severity, organ systems, and age groups. Associations between adverse events and ingredients are difficult to verify if a product has more than one ingredient, and because of incomplete information systems. Research into hazards and risks of dietary supplements should be a priority.

Pharmacologic agents for weight reduction.

Obesity is a major health problem in U.S. adults. Most successful weight loss programs have multiple components, including lifestyle modifications, reduced caloric intake, and exercise. Short-term use of medications for weight loss may be a part of such a plan. Currently, most medications are adrenergic stimulants and can produce adverse CNS and cardiovascular effects. Antiabsorptive agents appear to be safer but have significant GI side effects. An important finding is the potential for adverse life-threatening effects with over-the-counter products and dietary supplements that do not undergo evaluation similar to prescription drugs. The search continues for safe and effective pharmacologic agents to assist in weight loss.

An evaluation of selected herbal reference texts and comparison to published reports of adverse herbal events.

OBJECTIVE: There has been a recent proliferation of medical reference texts intended to guide practitioners whose patients use herbal therapies. We systematically assessed six herbal reference texts to evaluate the information they contain on herbal toxicity. METHODS: We selected six major herbal references published from 1996 to 2000 to evaluate the adequacy of their toxicological information in light of published adverse events. To identify herbs most relevant to toxicology, we reviewed herbal-related calls to our regional California Poison Control System, San Francisco division (CPCS-SF) in 1998 and identified the 12 herbs (defined as botanical dietary supplements) most frequently involved in these CPCS-SF referrals. We searched Medline (1966 to 2000) to identify published reports of adverse effects potentially related to these same 12 herbs. We scored each herbal reference text on the basis of information inclusiveness for the target 12 herbs, with a maximal overall score of 3. RESULTS: The herbs, identified on the basis of CPCS-SF call frequency were: St John's wort, ma huang, echinacea, guarana, ginkgo, ginseng, valerian, tea tree oil, goldenseal, arnica, yohimbe and kava kava. The overall herbal reference scores ranged from 2.2 to 0.4 (median 1.1). The Natural Medicines Comprehensive Database received the highest overall score and was the most complete and useful reference source. All of the references, however, lacked sufficient information on management of herbal medicine overdose, and several had incorrect overdose management guidelines that could negatively impact patient care. CONCLUSION: Current herbal reference texts do not contain sufficient information for the assessment and management of adverse health effects of botanical therapies.