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Multi-ingredient, Caffeine-containing Dietary Supplements: History, Safety, and Efficacy

Published:September 25, 2014DOI:https://doi.org/10.1016/j.clinthera.2014.08.012

      Abstract

      Purpose

      Our objective was to review the history, safety, and efficacy of caffeine-containing dietary supplements in the United States and Canada.

      Methods

      PubMed and Web of Science databases (1980-2014) were searched for articles related to the pharmacology, toxicology, and efficacy of caffeine-containing dietary supplements with an emphasis on Ephedra-containing supplements, Ephedra-free supplements, and energy drinks or shots.

      Findings

      Among the first and most successful dietary supplements to be marketed in the United States were those containing Ephedra—combinations of ephedrine alkaloids, caffeine, and other phytochemicals. A decade after their inception, serious tolerability concerns prompted removal of Ephedra supplements from the US and Canadian markets. Ephedra-free products, however, quickly filled this void. Ephedra-free supplements typically contain multiple caffeine sources in conjunction with other botanical extracts whose purposes can often be puzzling and their pharmacologic properties difficult to predict. Ingestion of these products in the form of tablets, capsules, or other solid dosage forms as weight loss aids, exercise performance enhancers, or energy boosters have once again brought their tolerability and efficacy into question. In addition to Ephedra-free solid dosage forms, caffeine-containing energy drinks have gained a foothold in the world market along with concerns about their tolerability.

      Implications

      This review addresses some of the pharmacologic and pharmaceutical issues that distinguish caffeine-containing dietary supplement formulations from traditional caffeine-containing beverages. Such distinctions may account for the increasing tolerability concerns affiliated with these products.

      Key words

      Introduction

      Caffeine (1,3,7-trimethylxanthine) is one of the most heavily consumed and widely studied stimulants in history. Caffeine-containing beverages, primarily coffee (Coffea arabica) and tea (Camellia sinensis), have been a mainstay in both Eastern and Western society for >500 years.
      • Fredholm B.B.
      Notes on the history of caffeine use.
      The appearance of carbonated soft drinks or colas in the early 20th century often used kola nut (Cola acuminata) as a flavoring agent and caffeine source, whereas the recent emergence of energy drinks incorporate guarana (Paulina cupana), green tea (C sinensis), and Yerba maté (Ilex paraguariensis) as natural caffeine sources. Together, these beverages constitute the primary sources of caffeine in the modern diet. In fact, almost 90% of US adults consume caffeine in forms of coffee, tea, or other caffeinated food products.
      • Frary C.D.
      • Johnson R.K.
      • Wang M.Q.
      Food sources and intakes of caffeine in the diets of persons in the United States.
      The popularity of these beverages stems from the mild stimulatory effects (eg, increased wakefulness, improved cognition, and decreased fatigue) that caffeine has on the central nervous system (CNS) when ingested in moderate quantities (≤200 mg).
      • Ribeiro J.A.
      • Sebastião A.M.
      Caffeine and adenosine.
      Because of its CNS stimulant properties, purified caffeine (≤200 mg) can also be found in various nonprescription drug products (eg, NoDoz® [caffeine] and Excedrin® [acetaminophen, aspirin, and caffeine]).
      When consumed in moderation, caffeine-containing products have an excellent safety profile. Apart from CNS stimulation, moderate caffeine consumption can, in many instances, transiently increase blood pressure and reflexively lower heart rate.
      • Riksen N.P.
      • Smits P.
      • Rongen G.A.
      The cardiovascular effects of methylxanthines.
      Long-term ingestion of caffeine, however, can lead to pharmacologic tolerance of some CNS effects
      • Riksen N.P.
      • Smits P.
      • Rongen G.A.
      The cardiovascular effects of methylxanthines.
      but not necessarily its cardiovascular effects.
      • Riksen N.P.
      • Smits P.
      • Rongen G.A.
      The cardiovascular effects of methylxanthines.
      • James J.E.
      Critical review of dietary caffeine and blood pressure: a relationship that should be taken more seriously.
      Excessive amounts of caffeine (>2000 mg) can give rise to significant toxic effects, including nausea, vomiting, tachycardia, severe hypertension, arrhythmia, seizures, and even death; however, individuals sensitive to caffeine may exhibit adverse effects at lower doses.
      • Hoffman R.J.
      Methylxanthines and selective β2 agonists.
      The deleterious aspects of caffeine overconsumption were first recognized in 1833,
      • Cole J.
      One the deleterious effects produced by drinking tea and coffee in excessive quantities.
      and up until 1980, reports of the toxic effects of caffeine only occasionally appeared in the medical literature, often in the context of ingestions with other legal (eg, amphetamine) or illegal (eg, cocaine) stimulants.
      • Hoffman R.J.
      Methylxanthines and selective β2 agonists.
      Between 1980 and 2013, the number of publications in the medical literature that described adverse effects of caffeine or caffeine-containing products has increased by a factor of 8 (Figure 1). An uptick in reports beginning in the 1990s may have been bolstered by passage of the US Dietary Supplement Health and Education Act (DSHEA) in 1994.

      Dietary Supplement Health and Education Act (DSHEA), Public Law 103-417, 1994; Act 42 U.S.C. 287C-11.

      From the figure, it is clear that published accounts of caffeine-related toxic effects took another noticeable upswing in 2000-2001, a trend that has continued to the present, where the number of yearly reports has more than doubled during the 13-year period. This increase was likely in part due to the increased use of Ephedra-containing dietary supplements (almost all of which contained natural caffeine sources) during the period of 2000 until 2004, at which time the US Food and Drug Administration (FDA) banned these products because of tolerability concerns. Since 2005, a proliferation of aggressively promoted Ephedra-free dietary supplements and caffeine-containing energy drinks have inundated the world market and appear to underlie many of the tolerability concerns associated with caffeine. To appreciate why a seemingly innocuous dietary ingredient such as caffeine has suddenly become a cause célèbre for health concerns, it is necessary to understand the origin and development of caffeine-containing dietary supplements.
      Figure thumbnail gr1
      Figure 1Citation counts for articles about caffeine adverse effects in the PubMed® and Web of Science (WOS) databases by year.

      A Brief History of Caffeine-Containing Dietary Supplements

      Tolerability concerns related to caffeine-containing dietary supplements can be traced to caffeine’s ability to augment the various pharmacologic effects of sympathomimetic amines. This effect first caught the medical community’s attention in the late 1970s, when synthetic combinations of caffeine, phenylpropanolamine, and ephedrine—known as amphetamine look-alikes—gained notoriety as over-the-counter appetite suppressants and legal speed.
      • Lake C.R.
      • Quirk R.S.
      CNS stimulants and the look-alike drugs.
      Shortly after their appearance, amphetamine look-alikes were linked to an upsurge in serious adverse drug events, namely, myocardial infarctions, strokes, seizures, and psychoses, most of which occurred in young adults.
      • Lake C.R.
      • Quirk R.S.
      CNS stimulants and the look-alike drugs.
      In 1982, the FDA deemed look-alikes as unapproved new drugs that presented a potential health hazard.
      • Hayes A.H.
      New drug status of OTC combination drug products containing caffeine, phenylpropanolamine, and ephedrine.
      By 1988, the FDA disallowed the marketing of look-alikes as nonprescription medications.
      Cold, cough, allergy, bronchodilator, and anti-asthmatic drug products for over-the-counter human use; tentative final monograph for combination drug products.
      Outside the United States, however, some countries allowed combinations of purified caffeine and ephedrine to be sold as prescription weight loss aids as late as 2002.
      • Hallas J.
      • Bjerrum L.
      • Støvring H.
      • Andersen M.
      Use of a prescribed ephedrine/caffeine combination and the risk of serious cardiovascular events: a registry-based case-crossover study.
      In 1994, enactment of the DSHEA ushered in an entirely new source of caffeine-containing products, this time in the form of dietary supplements. Dietary supplements are defined as “any product (other than tobacco) added to the total diet that contains at least one of the following ingredients: a vitamin, mineral, herb or botanical, amino acid, metabolite, extract, or combination of any ingredient described previously.”

      Dietary Supplement Health and Education Act (DSHEA), Public Law 103-417, 1994; Act 42 U.S.C. 287C-11.

      Among the more popular dietary supplement categories to appear on the US market at this time were multi-ingredient, Ephedra-containing formulations. Marketed as weight loss aids, energy boosters, and exercise performance enhancers, these products incorporated extracts of natural caffeine sources (eg, guarana, green tea, and kola nut), Ephedra, and a host of other botanicals. The plant genus Ephedra is source to several ephedrine alkaloids, namely, ephedrine, pseudoephedrine, norephedrine (an enantiomer of racemic phenylpropanolamine), methylephedrine, and norpseudoephedrine. Ephedrine alkaloids are sympathomimetic amines that act as indirect α- and β-adrenergic agonists. When formulated with caffeine along with a host of other herbal extracts—whose phytochemicals also exhibited cardiovascular and CNS effects—Ephedra supplements were essentially natural amphetamine look-alikes. As a result of the DSHEA, the FDA rulings regarding synthetic combinations of caffeine, ephedrine, and phenylpropanolamine were essentially circumvented as long as botanical sources of the drugs were used. Many of these seemingly haphazard mixtures of botanical extracts were devised by supplement manufacturers who failed to seek the advice of scientists versed in pharmacognosy, pharmacology, or pharmaceutics. A simple review of the medical literature should have caused formulators to rethink their decision of combining natural sources of ephedrine alkaloids and caffeine, especially because the FDA had precluded the marketing of synthetic combinations of these drugs in 1982. Thus, a trickle of adverse event reports and case reports that began in 1995 linking Ephedra-containing supplements to adverse health effects turned into a veritable flood by 2003.
      • Anonymous
      Adverse events associated with ephedrine-containing products—Texas, December 1993-September 1995.
      • Pace S.
      Ma huang food supplement toxicity in two adolescents.
      • Zaacks S.M.
      • Klein L.
      • Tan C.D.
      • et al.
      Hypersensitivity myocarditis associated with ephedra use.
      • Zahn K.A.
      • Li R.L.
      • Purssell R.A.
      Cardiovascular toxicity after ingestion of “herbal ecstacy.”.
      • Haller C.A.
      • Benowitz N.L.
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      • Jacobs K.M.
      • Hirsch K.A.
      Psychiatric complications of ma-huang.
      • Vahedi K.
      • Domigo V.
      • Amarenco P.
      • Bousser M.-G.
      Ischemic stroke in a sportsman who consumed ma huang extract and creatine monohydrate for body building.
      • Kaberi-Otarod J.
      • Conetta R.
      • Farkash A.
      • Kundo K.
      Ischemic stroke in a user of Thermadrene: a case study in alternative medicine.
      • Favreau J.T.
      • Ryu M.L.
      • Braunstein G.
      • et al.
      Severe hepatoxicity associated with the supplement LipoKinetix.
      • Traub S.J.
      • Hoyek W.
      • Hoffman R.S.
      Dietary supplements containing ephedra alkaloids (Report of myocardial infarction after using ephedra).
      • Kockler D.R.
      • McCarthy M.W.
      • Lawson C.L.
      Seizure activity and unresponsiveness after Hydroxycut ingestion.
      • du Boisgueheneuc F.
      • Lannuzel A.
      • Caparros-Lefebvre D.
      • De Broucker T.
      Cerebral infarction in a patient consuming Ma Huang extract and guarana.
      • Samenuk D.
      • Link M.S.
      • Homoud M.K.
      • et al.
      Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine.
      • Wettach G.E.
      • Falvey S.G.
      A mysterious blood pressure increase in a drilling naval reservist.
      • Roberts D.
      • Setzer S.
      • Bangh S.
      • et al.
      The most unkindest cut of all: pontine hemorrhage associated with ephedrine.
      • Rezkalla S.H.
      • Mesa J.
      • Sharma P.
      • Kloner R.A.
      Myocardial infarction temporally related to ephedra—a possible role for the coronary microcirculation.
      • Verduin M.L.
      • Labbate L.A.
      Psychosis and delirium following Metabolife use.
      • Kaberi-Otarod J.
      • Conetta R.
      • Kundo K.K.
      • Farkash A.
      Ischemic stroke in a user of Thermadrene: a case study in alternative medicine.
      • Schweinfurth J.
      • Pribitkin E.
      Sudden hearing loss associated with ephedra use.
      • Boerth J.M.
      • Caley C.F.
      Possible case of mania associated with ma-huang.
      • Morgenstern L.B.
      • Viscoli C.M.
      • Kernan W.N.
      • et al.
      Use of Ephedra-containing products and risk for hemorrhagic stroke.
      • Estes J.D.
      • Stolpman D.
      • Olyaei A.
      • et al.
      High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure.
      • Miller S.C.
      • Waite C.
      Ephedrine-type alkaloid-containing dietary supplements and substance dependence.
      • Krome C.N.
      • Tucker A.M.
      Cardiac arrhythmia in a professional football player: was ephedra to blame?.
      • Walton R.
      • Manos G.H.
      Psychosis related to ephedra-containing herbal supplement use.
      • Miller S.C.
      Safety concerns regarding ephedrine-type alkaloid-containing dietary supplements.
      • Foxford R.J.
      • Sahlas D.J.
      • Wingfield K.A.
      Vasospasm-induced stroke in a varsity athlete secondary to ephedrine ingestion.
      • Naik S.D.
      • Freudenberger R.S.
      Ephedra-associated cardiomyopathy.
      • Enders J.M.
      • Dobesh P.P.
      • Ellison J.N.
      Acute myocardial infarction induced by ephedrine alkaloids.
      To many in the medical community, such findings came as no surprise because the Ephedra controversy’s pharmacologic underpinnings appeared linked to the combined CNS and cardiovascular stimulatory effects of caffeine and ephedrine alkaloids. Moreover, many of the adverse events occurred in the context of vigorous exercise, a finding compounded not only by the physiologic stress of exercise (especially in naive users) but also by the fact that product labels recommended they be taken in conjunction with exercise—a sometimes fatal combination.
      • Haller C.A.
      • Benowitz N.L.
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      • Samenuk D.
      • Link M.S.
      • Homoud M.K.
      • et al.
      Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine.
      • Krome C.N.
      • Tucker A.M.
      Cardiac arrhythmia in a professional football player: was ephedra to blame?.
      Unlike the over-the-counter amphetamine look-alikes, Ephedra-containing dietary supplements were not as easy for the FDA to act on. These products fell under the aegis of the DSHEA, which limited the FDA’s regulatory power with regard to removing dietary supplements from the market because of tolerability concerns. By 2004, however, the FDA had gathered sufficient evidence to deem Ephedra-containing dietary supplements as “adulterated under the Federal Food, Drug, and Cosmetic Act because they present an unreasonable risk of illness or injury under the conditions of use recommended or suggested in labeling,” thus precluding the further sale of these products.
      Final rule declaring dietary supplements containing ephedrine alkaloids Adulterated because they present an unreasonable risk.
      Shortly before the removal of Ephedra-containing dietary supplements from the market in 2004, Ephedra-free formulations made their appearance. Although Ephedra-free supplements purportedly contain no ephedrine alkaloids in their formulations, they often incorporate multiple sources of caffeine and other botanical extracts whose phytochemicals exhibit a wide range of pharmacologic activities (eg, p-synephrine, forskolin, and yohimbine). The caffeine content for most Ephedra-free dosage forms often well exceeds that present in beverages such as coffee, tea, and soft drinks. This issue is compounded by the fact that caffeine content is rarely indicated on product labels, thus subjecting many consumers to unanticipated adverse effects.
      • Kole J.
      • Barnhill A.
      Caffeine content labeling: a missed opportunity for promoting personal and public health.
      Also, like Ephedra, Ephedra-free supplements are marketed as weight loss aids, energy boosters, and exercise performance enhancers. The moniker Ephedra free thus implies trouble free, but an increasing number of case reports, adverse event reports, and calls to Poison Control Centers—eerily similar to their Ephedra-containing predecessors—seem to belie this connotation.
      • Nykamp D.L.
      • Fackih M.N.
      • Compton A.L.
      Possible association of acute lateral-wall myocardial infarction and bitter orange supplement.
      • Nasir J.M.
      • Durning S.J.
      • Ferguson M.
      • et al.
      Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine.
      • Bouchard N.C.
      • Howland M.A.
      • Greller H.A.
      • et al.
      Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine.
      • Gange C.A.
      • Madais C.
      • Felix-Getzik E.M.
      • et al.
      Variant angina associated with bitter orange in a dietary supplement.
      • Burke J.
      • Seda G.
      • Allen D.
      • Knee T.S.
      A case of severe exercise-induced rhabdomyolysis associated with a weight-loss dietary supplement.
      • Holmes R.O.
      • Tavee J.
      Vasospasm and stroke attributable to ephedra-free Xenadrine: case report.
      • Muller G.J.
      • Smedema J.P.
      Coronary spasm and thrombosis in a bodybuilder using a nutritional supplement containing synephrine, octopamine, tyramine and caffeine.
      • Thomas J.E.
      • Munir J.A.
      • McIntyre P.Z.
      • Ferguson M.A.
      STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement.
      • Ahmed I.
      Malignant hypertension and acute aortic dissection associated with caffeine-based ephedra-free dietary supplements: a case report.
      • Karth A.
      • Holoshitz N.
      • Kavinsky C.J.
      • et al.
      A case report of atrial fibrillation potentially induced by Hydroxycut: a multicomponent dietary weight loss supplement devoid of sympathomimetic amines.
      • Moaddeb J.
      • Tofade T.S.
      • Bevins M.B.
      Hypertensive urgency associated with Xenadrine EFX use.
      • Retamero C.
      • Rivera T.
      • Murphy K.
      “Ephedra-free” diet pill-induced psychosis.
      • Cvetanovich G.L.
      • Ramakrishnan P.
      • Klein J.P.
      • et al.
      Reversible cerebral vasoconstriction syndrome in a patient taking citalopram and Hydroxycut: a case report.
      • Young C.
      • Oladipo O.
      • Frasier S.
      • et al.
      Hemorrhagic stroke in young healthy male following use of sports supplement Jack3d.
      • Pendleton M.
      • Brown S.
      • Thomas C.M.
      • Odle B.
      Potential toxicity of caffeine when used as a dietary supplement for weight loss.
      Perhaps Ephedra was not the principal culprit.
      Simultaneous to the advent of Ephedra-free dietary supplements came the arrival of caffeine-containing energy drinks and energy shots. Beginning with Red Bull® in the early 1990s, energy drinks and shots have become the fastest growing dietary supplement category on the market in terms of number, variety of products, and sales revenue.
      • Heckman M.A.
      • Sherry K.
      • de Mejia E.G.
      Energy dinks: an assessment of their market size, consumer demographics, ingredient profile, functionality, and regulations in the United States.
      The boom in energy drink use, especially among adolescents and young adults, has also sparked an upsurge in caffeine-related adverse events among this population.
      • Worrall B.B.
      • Phillips D.
      • Henderson K.K.
      Herbal energy drinks, phenylpropanoid compounds, and cerebral vasculopathy.
      • Seifert S.M.
      • Schaechter J.L.
      • Hershorin E.R.
      • Lipshultz S.E.
      Health effects of energy drinks on children, adolescent, and young adults.

      Trabulo D, Marques S, Pedroso E. Caffeinated energy drink intoxication. BMJ Case Rep. http://dx.doi.org/10.1136/bcr.09.2010.3322.

      Gray B, Jipin DK, Semsarian C. Consumption of energy drinks: a new provocation test for primary arrhythmogenic diseases. Int J Cardiol. http://dx.doi.org/10.1016/j.ijcard.2012.05.121.

      • Wolk B.J.
      • Ganetsky M.
      • Babu K.M.
      Toxicity of energy drinks.
      • Nordt S.P.
      • Vilke G.M.
      • Calrk R.F.
      • et al.
      Energy drink use and adverse effects among emergency department patients.
      • Benjo A.M.
      • Pineda A.M.
      • Nascimento F.O.
      • et al.
      Left main coronary artery acute thrombosis related to energy drink intake.
      • Kaoukis A.
      • Panagopoulou V.
      • Mojibian H.R.
      • Jacoby D.
      Reverse Takotsubo cardiomyopathy associated with the consumption of an energy drink.
      • Rottlaender D.
      • Motloch L.J.
      • Reda S.
      • et al.
      Cardiac arrest due to long QT syndrome associated with excessive consumption of energy drinks.
      • Usman A.
      • Jawaid A.
      Hypertension in a young boy: an energy drink effect.
      • Dikici S.
      • Saritas A.
      • Besir F.H.
      • et al.
      Do energy drinks cause epileptic seizure and ischemic stroke.
      • Pomeranz J.L.
      • Munsell C.R.
      • Harris J.L.
      Energy drinks: an emerging public health hazard for youth.
      • Cotter B.V.
      • Jackson D.A.E.
      • Merchant R.C.
      • et al.
      Energy drink and other substance use among adolescent and young adult emergency department patients.
      • Seifert S.M.
      • Seifert S.A.
      • Schaechter J.L.
      • et al.
      An analysis of energy-drink toxicity in the National Poison Data System.
      • Sepkowitz K.A.
      Energy drinks and caffeine-related adverse effects.
      • Goldfarb M.
      • Tellier C.
      • Thanassoulis G.
      Review of published cases of adverse cardiovascular events after ingestion of energy drinks.
      Energy drinks and energy shots differ from conventional caffeinated soft drinks in that they are not as highly carbonated (making them easier to consume quickly), have higher caffeine content, and often contain vitamins, amino acids, l-carnitine, taurine, glucuronolactone, and botanical extracts, such as guarana, ginseng, Ginkgo biloba, and milk thistle, to name a few. Like Ephedra-free dietary supplements, ambiguity of energy drink label claims for caffeine content may contribute to the purported health risks linked to these beverages. For a while certain energy drinks were formulated with alcohol, but tolerability concerns regarding caffeine and alcohol combinations prompted the FDA to preclude sale of these products in 2011.
      • Arria A.M.
      • O’Brien M.C.
      The “high” risk of energy drinks.
      • Attwood A.S.
      Alcohol and caffeine: caffeinated alcohol beverages: a public health concern.
      Nevertheless, the combination of energy drinks and alcoholic beverages remains a cause for alarm for both health care professionals and law enforcement officials.
      • Arria A.M.
      • O’Brien M.C.
      The “high” risk of energy drinks.
      • Attwood A.S.
      Alcohol and caffeine: caffeinated alcohol beverages: a public health concern.
      • O’Brien M.C.
      • McCoy T.P.
      • Rhodes S.D.
      • et al.
      Caffeinated cocktails: energy drink consumption, high risk drinking, and alcohol-related consequences among college students.
      • Howland J.
      • Rohsenow D.J.
      Risks of energy drinks mixed with alcohol.
      Since 1994 the advent of caffeine-containing dietary supplements has certainly contributed to the caffeinated culture of the United States. Along with this increase in caffeine consumption come concerns regarding the tolerability and efficacy of these products. Although much research has been conducted on the pharmacology of caffeine when administered as a purified pharmaceutical ingredient or in the form of coffee or tea, relatively few studies have assessed the tolerability and efficacy of multi-ingredient, caffeine-containing dietary supplements or energy drinks. From the data currently available, it appears that the pharmacologic and toxicologic activities of caffeine can be markedly influenced by a host of other phytochemicals present in supplement formulations. In addition, when marketed as exercise performance enhancers, the combination of vigorous exercise and caffeine may be especially hazardous for some users of these products.

      TOLERABILITY of Caffeine-Containing Dietary Supplements

      Pharmacology of Caffeine

      Caffeine’s stimulant effects on the cardiovascular system and CNS stem from 4 principal mechanisms: nonselective antagonism of G-coupled adenosine A1 and A2A receptors, nonselective inhibition of phosphodiesterases with the subsequent accumulation of cyclic adenosine monophosphate (cAMP) and an intensification of the effects of catecholamines, mobilization of intracellular calcium via activation of ryanodine receptor channels, and inhibition of γ-aminobutyric acid neurotransmission.
      • Riksen N.P.
      • Smits P.
      • Rongen G.A.
      The cardiovascular effects of methylxanthines.
      • Benowitz N.L.
      Clinical pharmacology of caffeine.
      Only at higher serum concentrations (>25 µg/mL) do the later 3 mechanisms appear to contribute significantly to caffeine pharmacodynamics.
      • Riksen N.P.
      • Smits P.
      • Rongen G.A.
      The cardiovascular effects of methylxanthines.
      Caffeine’s dose-dependent CNS stimulant effects (eg, mood enhancement, wakefulness, insomnia, anxiety, tremors, and seizures) stem from antagonism of brain adenosine receptors, whereas antagonism of A1 and A2A receptors in the heart and vasculature account for its hemodynamic effects (eg, increased heart rate, coronary and peripheral vasoconstriction, and elevated blood pressure).
      • Riksen N.P.
      • Smits P.
      • Rongen G.A.
      The cardiovascular effects of methylxanthines.
      • Benowitz N.L.
      Clinical pharmacology of caffeine.
      As a result of adenosine antagonism, caffeine also stimulates the release of several neurotransmitters (eg, dopamine, norepinephrine, and serotonin), which also accounts for many of the drug’s indirect pharmacodynamic effects. (For an excellent review of the cardiovascular effects of caffeine, see the article by Riksen et al.
      • Riksen N.P.
      • Smits P.
      • Rongen G.A.
      The cardiovascular effects of methylxanthines.
      ) Caffeine can also reduce cerebral, hepatic, and mesenteric blood flow and produce mild diuresis via increased glomerular filtration and enhanced sodium and water excretion.
      • Benowitz N.L.
      Clinical pharmacology of caffeine.
      At higher doses, caffeine can also cause other pharmacodynamic effects, including bronchodilation, lipolysis, hyperglycemia, and hypokalemia.
      • Benowitz N.L.
      Clinical pharmacology of caffeine.
      Caffeine-induced hypokalemia could contribute to ventricular arrhythmias and sudden death.
      • Goldfarb M.
      • Tellier C.
      • Thanassoulis G.
      Review of published cases of adverse cardiovascular events after ingestion of energy drinks.
      Long-term consumption of caffeine, however, can lead to pharmacologic tolerance, which can occur within a few days.
      • Shi J.
      • Benowitz N.L.
      • Denaro C.P.
      • Sheiner L.B.
      Pharmacokinetic-pharmacodynamic modeling of caffeine: tolerance to pressor effects.
      Owing to the rapid development of tolerance, a person’s response to caffeine depends on dose, dosing regularity, and their pharmacokinetic profile.
      Individual sensitivity to the effects of caffeine is well recognized.
      • Nehlig A.
      • Daval J.L.
      • Debry G.
      Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects.
      Such sensitivities may be attributable, in part, to an individual’s genetic makeup.
      • Yang A.
      • Palmer A.A.
      • de Wit H.
      Genetics of caffeine consumption and responses to caffeine.
      Only recently has an appreciation developed for the effects that human receptor gene polymorphisms can have on the pharmacodynamics of caffeine. Adenosine A2A and α2-adrenergic receptor polymorphisms have been linked to caffeine-induced insomnia,
      • Rétey J.V.
      • Adam M.
      • Khatami R.
      • et al.
      A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep.
      • Byrne E.M.
      • Johnson J.
      • McRae A.F.
      • et al.
      A genome-wide study of caffeine-related sleep disturbance: confirmation of a role for a common variant in the adenosine receptor.
      anxiety,
      • Alsene K.
      • Deckert J.
      • Sand P.
      • de Wit H.
      Association between A2a receptor gene polymorphisms and caffeine-induced anxiety.
      • Childs E.
      • Hohoff C.
      • Deckert J.
      • et al.
      Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety.
      habitual coffee consumption,
      • Cornelis M.C.
      • El-Sohemy A.
      • Campos H.
      Genetic polymorphism of the adenosine A2A receptor is associated with habitual caffeine consumption.
      and blood pressure elevation,
      • Renda G.
      • Zimarino M.
      • Antonucci I.
      • et al.
      Genetic determinants of blood pressure responses to caffeine drinking.
      whereas animal studies hint that cardiac ryanodine receptor mutations may increase caffeine’s arrhythmogenic potential.
      • Jiang D.
      • Jones P.P.
      • Davis D.R.
      • et al.
      Characterization of a novel mutation in the cardiac ryanodine receptor that results in catecholamine polymorphic ventricular tachycardia.
      Another gene polymorphism associated with the adverse effects of caffeine is the enzyme catechol-O-methyltransferase (COMT). In the case of functional COMT polymorphisms, the sympathomimetic effects of endogenous catecholamines (eg, norepinephrine) are enhanced; after caffeine ingestion, such mutations have been linked to rapid heart beat,
      • Brathwaite J.M.
      • Da Costa L.A.
      • El-Sohemy A.
      Catechol-O-methyltransferase genotype is associated with self-reported increased heart rate following caffeine consumption.
      elevated blood pressure,
      • Miller R.J.
      • Jackson K.G.
      • Dadd T.
      • et al.
      The impact of the catechol-O-methyltransferase genotype on vascular function and blood pressure after acute green tea ingestion.
      and the incidence of acute coronary events.
      • Happonen P.
      • Voutilainen S.
      • Tuomainen T.-P.
      • Salonen J.T.
      Catechol-O-methyltransferase gene polymorphism modifies the effect of coffee intake on incidence of acute coronary events.
      Despite these emerging gene-caffeine associations, more work is required before the functional variants involved in the caffeine response can be delineated.
      Caffeine’s physicochemical and pharmacokinetic properties set it apart from most phytochemicals. Caffeine is one of the few phytochemicals whose oral bioavailability is almost complete.
      • Blanchard J.
      • Sawers S.J.
      The absolute bioavailability of caffeine in man.
      Peak blood concentrations of caffeine are usually achieved within an hour of ingestion.
      • Arnaud M.J.
      Pharmacokinetics and metabolism of natural methylxanthines in animal and man.
      On account of its excellent aqueous solubility and small molecular weight, caffeine readily enters the intracellular space and is widely distributed—its volume of distribution mimics that of total body water.
      • Arnaud M.J.
      Pharmacokinetics and metabolism of natural methylxanthines in animal and man.
      Accordingly, caffeine readily crosses the blood brain barrier and can be found in almost all body fluids and tissues.
      • Arnaud M.J.
      Pharmacokinetics and metabolism of natural methylxanthines in animal and man.
      The pharmacokinetic properties of caffeine are dose dependent, which likely contributes to toxic effects associated with many caffeine-containing dietary supplements.
      • Denaro C.P.
      • Brown C.R.
      • Wilson M.
      • et al.
      Dose-dependency of caffeine metabolism with repeated dosing.
      Caffeine biotransformation is mediated primarily via hepatic cytochrome P450 1A2 (CYP1A2), and saturation of this pathway can occur at doses as low as 5 mg/kg.
      • Arnaud M.J.
      Pharmacokinetics and metabolism of natural methylxanthines in animal and man.
      Caffeine’s principal CYP1A2-mediated metabolite in humans is paraxanthine, which exhibits pharmacologic effects similar to its parent compound,
      • Thorn C.F.
      • Aklillu E.
      • McDonagh E.M.
      • et al.
      PharmGKB summary: caffeine pathway.
      • Benowitz N.L.
      • Jacob P.
      • Mayan H.
      • Denaro C.
      Sympathomimetic effects of paraxanthine and caffeine in humans.
      whereas minor metabolites include theophylline and theobromine.
      • Thorn C.F.
      • Aklillu E.
      • McDonagh E.M.
      • et al.
      PharmGKB summary: caffeine pathway.
      Caffeine clearance is highly variable, and both genetic and environmental factors (eg, diet, smoking, and oral contraceptive use) are contributors to this variability.
      • Arnaud M.J.
      Pharmacokinetics and metabolism of natural methylxanthines in animal and man.
      • Carrillo J.A.
      • Benitez J.
      Clinically significant pharmacokinetic interactions between dietary caffeine and medications.
      • Gunes A.
      • Dahl M.-L.
      Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms.
      Like the receptor polymorphisms mentioned above, allelic variants in CYP1A2 can affect caffeine’s pharmacokinetic properties and pharmacologic response. Among caffeine users, both slow and rapid metabolizer phenotypes have been described, each corresponding to respective allelic variants that give rise to loss or gain of enzyme function. Habitual coffee use and higher consumption of coffee appear to correlate with rapid metabolizer phenotypes (homozygous CYP1A2*1A),
      • Josse A.r.
      • Da Costa L.A.
      • Campos H.
      • El-Sohemy A.
      Associations between polymorphisms in the AHR and CYP1A1-CYP1A2 gene regions and habitual caffeine consumption.
      whereas slow metabolizer phenotypes (heterozygous CYP1A2*1F) have been linked to higher risks of hypertension
      • Palatini P.
      • Ceolotto G.
      • Ragazzo F.
      • et al.
      CYP1A2 genotype modifies the association between coffee intake and the risk of hypertension.
      and nonfatal myocardial infarction.
      • Cornelis M.C.
      • El-Sohemy A.
      • Kabagambe E.K.
      • Coffee Campos H.
      CYP1A2 genotype, and the risk of myocardial infarction.
      CYP1A2 allelic variants aside, caffeine metabolism is also susceptible to a host of environmental influences. Smoking and diets rich in cruciferous vegetables induce CYP1A2 gene expression, presumably through activation of the aryl hydrocarbon nuclear receptor, resulting in enhanced caffeine clearance.
      • Arnaud M.J.
      Pharmacokinetics and metabolism of natural methylxanthines in animal and man.
      • Gunes A.
      • Dahl M.-L.
      Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms.
      Conversely, alcohol consumption, oral contraceptives, fluvoxamine, and quinolone antibiotics are known to inhibit CYP1A2 activity, lower caffeine clearance, and increase both area under the plasma concentration time curve and elimination half-life.
      • Carrillo J.A.
      • Benitez J.
      Clinically significant pharmacokinetic interactions between dietary caffeine and medications.
      Other phytochemicals thought to affect the pharmacokinetic properties of caffeine when consumed concomitantly include tanshinone,
      • Wang X.
      • Lee W.Y.
      • Or P.M.
      • Yeung J.H.
      Effects of major tanshinones isolated from Danshen (Salvia miltiorrhiza) on rat CYP1A2 expression and metabolism of model CYP1A2 probe substrates.
      quercetin,
      • Chen Y.
      • Xiao P.
      • Ou-Yang D.S.
      • et al.
      Simultaneous action of the flavonoid quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, N-acetyltransferase and xanthine oxidase activity in healthy volunteers.
      genistein,
      • Chen Y.
      • Xiao C.Q.
      • He Y.J.
      • et al.
      Genistein alters caffeine exposure in healthy female volunteers.
      curcumin,
      • Chen Y.
      • Liu W.H.
      • Chen B.L.
      • et al.
      Plant polyphenol curcumin significantly affects CYP1A2 and CYP2A6 activity in healthy, male Chinese volunteers.
      daidzein,
      • Peng W.X.
      • Li H.D.
      • Zhou H.H.
      Effect of daidzein on CYP1A2 activity and pharmacokinetics of theophylline in healthy volunteers.
      and naringenin.
      • Fuhr U.
      • Klittich K.
      • Staib A.H.
      Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man.
      Given the multiplicity of botanical extracts that constitute caffeine-containing dietary supplement formulations, it is difficult to predict how such complex phytochemical mixtures will affect caffeine pharmacokinetic and pharmacodynamic properties. What is well recognized, however, is that caffeine can potentiate the cardiovascular and CNS effects of other stimulants. Such stimulants include plant-derived α- and β-adrenergic agonists such as those found in Ephedra species (eg, ephedrine, pseudoephedrine, norephedrine, and methylephedrine)
      • Lake C.R.
      • Zaloga G.
      • Rosenberg D.
      • Chernow B.
      Transient hypertension after two phenylpropanolamine diet aids and the effects of caffeine: a placebo-controlled follow-up study.
      • Brown N.J.
      • Ryder D.
      • Branch R.A.
      A pharmacodynamic interaction between caffeine and phenylpropanolamine.
      • Haller C.A.
      • Jacob P.
      • Benowitz N.L.
      Enhanced stimulant and metabolic effects of combined ephedrine and caffeine.
      and α2-adrenergic antagonists from the African plant Pausinystalia yohimbe (eg, yohimbine and rauwolscine),
      • Waluga M.
      • Janusz M.
      • Karpel E.
      • et al.
      Cardiovascular effects of ephedrine, caffeine and yohimbine measured by thoracic electrical impedance in obese women.
      as well as synthetic stimulants such as amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, and cocaine.
      • Derlet R.W.
      • Tseng J.C.
      • Albertson T.E.
      Potentiation of cocaine and d-amphetamine toxicity with caffeine.
      • Vanattou-Saïfoudine N.
      • McNamara R.
      • Harkin A.
      Caffeine provokes adverse interactions with 3,4-methylenedioxy-methamphetamine (MDMA, ‘ecstasy’) and related psychostimulants: mechanisms and mediators.
      • Frau L.
      • Simola N.
      • Morelli M.
      Contribution of caffeine to the psychostimulant, neuroinflammatory and neurotoxic effects of amphetamine-related drugs.
      When combined with ephedrine alkaloids or amphetamines, especially in the context of vigorous exercise, caffeine may increase the likelihood of serious adverse health effects, such as arrhythmia,
      • Haller C.A.
      • Benowitz N.L.
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      myocardial infarction,
      • Haller C.A.
      • Benowitz N.L.
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      stroke
      • Haller C.A.
      • Benowitz N.L.
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      • Chen C.
      • Biller J.
      • Willing S.J.
      • Lopez A.M.
      Ischemic stroke after using the over the counter products containing ephedra.
      , seizure,
      • Haller C.A.
      • Benowitz N.L.
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      • Kockler D.R.
      • McCarthy M.W.
      • Lawson C.L.
      Seizure activity and unresponsiveness after Hydroxycut ingestion.
      hypertensive crisis,
      • Moawad F.J.
      • Hartzell J.D.
      • Biega T.J.
      • Lettieri C.J.
      Transient blindness due to posterior reversible encephalopathy syndrome following ephedra overdose.
      and exertional heat illness.
      • Oh R.C.
      • Henning J.S.
      Exertional heatstroke in an infantry officer taking ephedra-containing dietary supplements.
      • Stahl C.E.
      • Borlongan C.V.
      • Szerlip H.
      • Szerlip M.
      No pain, no gain—exercise-induced rhabdomyolysis associated with the performance enhancer herbal supplement ephedra.

      Rhidian R. Running a risk? Sport supplement toxicity with ephedrine in an amateur marathon runner, with subsequent rhabdomyolysis. BMJ Case Reports. http://dx.doi.org/10.1136/bcr.11.2011.5093.

      Because many caffeine-containing dietary supplements are marketed as exercise performance enhancers and weight loss aids, exercise and obesity have exhibited equivocal effects on caffeine pharmacokinetic properties.
      • Arnaud M.J.
      Pharmacokinetics and metabolism of natural methylxanthines in animal and man.
      Several studies suggest that caffeine disposition is not significantly altered during exercise,
      • McLean C.
      • Graham T.E.
      Effects of exercise and thermal stress on caffeine pharmacokinetics in men and eumenorrheic women.
      • Haller C.A.
      • Duan M.
      • Jacob P.
      • Benowitz N.
      Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions.
      while other studies indicate that peak caffeine plasma levels may be enhanced.
      • Collomp K.
      • Anselme F.
      • Audran M.
      • et al.
      Effects of moderate exercise on the pharmacokinetics of caffeine.
      Likewise, obesity’s effect on caffeine pharmacokinetic properties is also difficult to predict.
      • Kamimori G.H.
      • Somani S.M.
      • Knowlton R.G.
      • Perkins R.M.
      The effects of obesity and exercise on the pharmacokinetics of caffeine in lean and obese volunteers.
      • Caraco Y.
      • Zylber-Katz E.
      • Berry E.M.
      • Levy M.
      Caffeine pharmacokinetics in obesity and following significant weight reduction.

      Skinner TL, Jenkins DG, Leveritt MD, et al. Factors influencing serum caffeine concentrations following caffeine ingestion. J Sci Med Sport. http://dx.doi.org/10.1016/j.jsams.2013.07.006.

      Such ambiguities may contribute to the questionable tolerability and efficacy of caffeine-containing dietary supplements. What is less ambiguous is that vigorous exercise may exacerbate the pharmacodynamic effects of caffeine.
      • Daniels J.W.
      • Molé P.A.
      • Shaffrath J.D.
      • Stebbins C.L.
      Effects of caffeine on blood pressure, heart rate, and forearm blood flow during dynamic leg exercise.
      • Stebbins C.L.
      • Daniels J.W.
      • Lewis W.
      Effects of caffeine and high ambient temperature on haemodynamic and body temperature responses to dynamic exercise.
      • Astorino T.A.
      • Rohmann R.L.
      • Firth K.
      • Kelly S.
      Caffeine-induced changes in cardiovascular function during resistance training.
      • Woolf K.
      • Bidwell W.K.
      • Carlson A.G.
      The effect of caffeine as an ergogenic aid in anaerobic exercise.
      • Arciero P.J.
      • Ormsbee M.J.
      Relationship of blood pressure, behavioral mood state, and physical activity following caffeine ingestion in younger and older women.
      • Sung B.H.
      • Lovallo W.R.
      • Whitsett T.
      • Wilson M.F.
      Caffeine elevates blood pressure response to exercise in mild hypertensive men.
      Of particular concern is the recent finding that caffeine reduces myocardial blood flow during exercise.
      • Higgins J.P.
      • Babu K.M.
      Caffeine reduces myocardial blood flow during exercise.
      Such consequences could have significant health repercussions, especially in caffeine-naive, untrained athletes.
      • Sinclair C.J.D.
      • Geiger J.D.
      Caffeine use in sports: a pharmacological review.
      • Tunnicliffe J.M.
      • Erdman K.A.
      • Reimer R.A.
      • et al.
      Consumption of dietary caffeine and coffee in physically active populations: physiological interactions.
      Collectively, these genetic and environmental influences can have a significant bearing on the tolerability of caffeine-containing dietary supplements. In the following sections, we discuss how multi-ingredient dietary supplement formulations, with natural caffeine sources as a central ingredient, may pose significant health risks to susceptible individuals, particularly when taken in conjunction with vigorous exercise.

      Ephedra-Containing Dietary Supplements

      Throughout their 10-year tenure (1994–2004), Ephedra-containing dietary supplements were a source of controversy. Before their removal from the US market in 2004, thousands of adverse events were reported to manufacturers, the FDA, and state or regional poison control centers or described in the medical literature.
      • Haller C.A.
      • Benowitz N.L.
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      • Samenuk D.
      • Link M.S.
      • Homoud M.K.
      • et al.
      Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine.
      • Bent S.
      • Tiedt T.
      • Odden M.
      • Shlipak M.G.
      The relative safety of ephedra compared with other herbal products.
      • Woolf A.D.
      • Watson W.A.
      • Smolinske S.
      • Litovitz T.
      The severity of toxic reactions to ephedra: comparisons to other botanical products and national trends from 1993-2002.
      • Dennehy C.E.
      • Tsourounis C.
      • Horn A.J.
      Dietary supplement-related adverse events reported to the California Poison Control System.
      The more serious events included myocardial infarctions,
      • Zaacks S.M.
      • Klein L.
      • Tan C.D.
      • et al.
      Hypersensitivity myocarditis associated with ephedra use.
      • Haller C.A.
      • Benowitz N.L.
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      • Traub S.J.
      • Hoyek W.
      • Hoffman R.S.
      Dietary supplements containing ephedra alkaloids (Report of myocardial infarction after using ephedra).
      • Samenuk D.
      • Link M.S.
      • Homoud M.K.
      • et al.
      Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine.
      • Rezkalla S.H.
      • Mesa J.
      • Sharma P.
      • Kloner R.A.
      Myocardial infarction temporally related to ephedra—a possible role for the coronary microcirculation.
      • Naik S.D.
      • Freudenberger R.S.
      Ephedra-associated cardiomyopathy.
      strokes,
      • Haller C.A.
      • Benowitz N.L.
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      • Vahedi K.
      • Domigo V.
      • Amarenco P.
      • Bousser M.-G.
      Ischemic stroke in a sportsman who consumed ma huang extract and creatine monohydrate for body building.
      • Kaberi-Otarod J.
      • Conetta R.
      • Farkash A.
      • Kundo K.
      Ischemic stroke in a user of Thermadrene: a case study in alternative medicine.
      • du Boisgueheneuc F.
      • Lannuzel A.
      • Caparros-Lefebvre D.
      • De Broucker T.
      Cerebral infarction in a patient consuming Ma Huang extract and guarana.
      • Samenuk D.
      • Link M.S.
      • Homoud M.K.
      • et al.
      Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine.
      • Roberts D.
      • Setzer S.
      • Bangh S.
      • et al.
      The most unkindest cut of all: pontine hemorrhage associated with ephedrine.
      • Kaberi-Otarod J.
      • Conetta R.
      • Kundo K.K.
      • Farkash A.
      Ischemic stroke in a user of Thermadrene: a case study in alternative medicine.
      • Morgenstern L.B.
      • Viscoli C.M.
      • Kernan W.N.
      • et al.
      Use of Ephedra-containing products and risk for hemorrhagic stroke.
      • Foxford R.J.
      • Sahlas D.J.
      • Wingfield K.A.
      Vasospasm-induced stroke in a varsity athlete secondary to ephedrine ingestion.
      • Chen C.
      • Biller J.
      • Willing S.J.
      • Lopez A.M.
      Ischemic stroke after using the over the counter products containing ephedra.
      arrhythmias,
      • Haller C.A.
      • Benowitz N.L.
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      • Samenuk D.
      • Link M.S.
      • Homoud M.K.
      • et al.
      Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine.
      • Krome C.N.
      • Tucker A.M.
      Cardiac arrhythmia in a professional football player: was ephedra to blame?.
      seizures,
      • Haller C.A.
      • Benowitz N.L.
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      • Kockler D.R.
      • McCarthy M.W.
      • Lawson C.L.
      Seizure activity and unresponsiveness after Hydroxycut ingestion.
      • Haller C.A.
      • Meier K.H.
      • Olson K.R.
      Seizures reported in association with use of dietary supplements.
      psychoses,
      • Jacobs K.M.
      • Hirsch K.A.
      Psychiatric complications of ma-huang.
      • Verduin M.L.
      • Labbate L.A.
      Psychosis and delirium following Metabolife use.
      • Boerth J.M.
      • Caley C.F.
      Possible case of mania associated with ma-huang.
      • Walton R.
      • Manos G.H.
      Psychosis related to ephedra-containing herbal supplement use.
      and rhabdomyolysis.
      • Oh R.C.
      • Henning J.S.
      Exertional heatstroke in an infantry officer taking ephedra-containing dietary supplements.
      • Stahl C.E.
      • Borlongan C.V.
      • Szerlip H.
      • Szerlip M.
      No pain, no gain—exercise-induced rhabdomyolysis associated with the performance enhancer herbal supplement ephedra.

      Rhidian R. Running a risk? Sport supplement toxicity with ephedrine in an amateur marathon runner, with subsequent rhabdomyolysis. BMJ Case Reports. http://dx.doi.org/10.1136/bcr.11.2011.5093.

      The underpinnings of their tolerability concerns can be traced to the complexity of product formulations. Ephedra-containing dietary supplement formulations were a miscellany of botanical extracts that included Ephedra, natural caffeine sources, and other phytochemicals whose pharmacologic effects were more potent than Ephedra alone. (Examples of Ephedra-containing supplement formulations are given in Table I.) That combinations of caffeine and ephedrine alkaloids produced enhanced sympathomimetic effects was not unexpected given the problems amphetamine look-alikes posed more than a decade earlier. What appeared underappreciated, however, was the contribution other phytochemicals present in the formulations may have had.
      Table IExamples of Ephedra-containing dietary supplement formulations.
      Metabolife™Xenadrine RFA™Yellow Jacket™Ripped Fuel™
      Ephedra extractEphedra extractEphedra extractEphedra extract
      Guarana extractGuarana extractKola nut extractGuarana extract
      Bee pollenCitrus aurantiumCitrus aurantiuml-carnitine
      GinsengWhite willow barkCapsicumChromium
      GingerAcetyl l-carnitineGinseng
      Bovine complexl-tyrosineSida cordifolia
      DamianaGinger rootGinger root
      SarsaparillaVitamin B5
      Goldenseal
      Nettles
      Gotu kola
      Spirulina algae
      Royal jelly
      The imprudence of combining Ephedra with other natural stimulants was recognized by the Chinese thousands of years ago.
      • Mehendale S.R.
      • Bauer B.A.
      • Yuan C.S.
      Ephedra-containing dietary supplements in the US versus ephedra as a Chinese medicine.
      Unfortunately, supplement manufacturers in the United States did not heed the sagacity of the Chinese. In fact, how the plant was used in the United States during its 10-year stint as a dietary supplement ingredient was contradictory to its traditional use in China (Table II).
      • Mehendale S.R.
      • Bauer B.A.
      • Yuan C.S.
      Ephedra-containing dietary supplements in the US versus ephedra as a Chinese medicine.
      Why combinations of Ephedra and natural caffeine sources were potentially hazardous can be easily explained with a brief summary of ephedrine alkaloid pharmacology.
      Table IIEphedra: East versus West.
      ChinaUnited States
      5000-year history of useExtensive use from 1994 to 2004
      Treatment of asthma and nasal congestionDiet aid, energy booster, exercise performance enhancer
      Duration of use: 7–10 daysIndicated for long-term use
      Rarely combined with other stimulants, such as caffeineUsually combined with other stimulants (caffeine, synephrine, yohimbine)
      Administered as a decoction (Ephedra tea)Administered as concentrated extracts (tablets, capsules, sconcentrated liquid)
      Not indicated as a diet aid
      Ephedrine alkaloids are nonspecific indirect agonists for α1-, β1-, β2-adrenergic receptors.
      • Westfall T.C.
      • Westfall D.P.
      Adrenergic agonists and antagonists.
      Accordingly, these actions account for their use as vasopressors, nasal decongestants, bronchodilators, and appetite suppressants and their common adverse effects: tachyarrhythmia, hypertension, anxiety, and tremors.
      • Haller C.A.
      • Meier K.H.
      • Olson K.R.
      Seizures reported in association with use of dietary supplements.
      Like caffeine, the ephedrine alkaloids have excellent oral bioavailability, reach peak blood levels within 2 to 3 hours, and are widely distributed into well-perfused tissues, such as the heart and brain.
      • Gurley B.J.
      • Gardner S.F.
      • White L.M.
      • Wang P.
      Ephedrine pharmacokinetics following the ingestion of Ephedra sinica (ma huang) products.
      When ingested in combination, ephedrine and caffeine reach their peak plasma concentrations simultaneously, a biopharmaceutical factor that likely contributes to their mutually enhanced sympathomimetic activities.
      • Haller C.A.
      • Jacob P.
      • Benowitz N.L.
      Pharmacology of ephedra alkaloids and caffeine after single-dose dietary supplement use.
      Unlike caffeine, ephedrine alkaloids are excreted unchanged primarily via renal mechanisms. Sensitivity to ephedrine alkaloids can also be manifested through adrenergic receptor genetic polymorphisms.
      • Magalhães E.
      • Gomes M.D.
      • Barra G.B.
      • et al.
      Evaluation of the influence of the codon 16 polymorphism of the beta-2 adrenergic receptor gene on the incidence of arterial hypotension and ephedrine use in pregnant patients submitted to subarachnoid anesthesia.
      As an adenosine antagonist and phosphodiesterase inhibitor, caffeine is uniquely suited to enhance the pharmacodynamic properties of ephedrine. Ephedrine and caffeine combinations are recognized for their ability to increase blood pressure and heart rate, reduce cerebral blood flow,
      • Heiss W.D.
      • Podreka I.
      Assessment of pharmacological effects on cerebral blood flow.
      and lower seizure thresholds.
      • Vanattou-Saïfoudine N.
      • McNamara R.
      • Harkin A.
      Caffeine provokes adverse interactions with 3,4-methylenedioxy-methamphetamine (MDMA, ‘ecstasy’) and related psychostimulants: mechanisms and mediators.
      That caffeine and other phytochemicals can potentiate the cardiotoxic effects of Ephedra and ephedrine alkaloids was revealed in several rodent toxicity models.
      • Nyska A.
      • Murphy E.
      • Foley J.F.
      • et al.
      Acute hemorrhagic myocardial necrosis and sudden death of rats exposed to a combination of ephedrine and caffeine.
      • Howden R.
      • Hanlon P.R.
      • Petranka J.G.
      • et al.
      Ephedrine plus caffeine causes age-dependent cardiovascular responses in Fischer 344 rats.
      • Dunnick J.K.
      • Kissling G.
      • Gerken D.K.
      • et al.
      Cardiotoxicity of ma huang/caffeine or ephedrine/caffeine in a rodent model system.
      • Brown C.E.
      • Trauth S.E.
      • Grippo R.S.
      • et al.
      Combined effects of ephedrine-containing dietary supplements, caffeine, and nicotine on morphology and ultrastructure of rat hearts.
      When administered alone, Ephedra produced few cardiotoxic lesions, yet when caffeine was added to Ephedra, the occurrence and severity of lesions, as well as mortality, were significantly increased.
      • Dunnick J.K.
      • Kissling G.
      • Gerken D.K.
      • et al.
      Cardiotoxicity of ma huang/caffeine or ephedrine/caffeine in a rodent model system.
      • Brown C.E.
      • Trauth S.E.
      • Grippo R.S.
      • et al.
      Combined effects of ephedrine-containing dietary supplements, caffeine, and nicotine on morphology and ultrastructure of rat hearts.
      In addition, preparations of Metabolife™—a supplement that contains several botanical extracts in addition to Ephedra and guarana—produced a greater incidence of mortality than synthetic combinations of ephedrine and caffeine.
      • Brown C.E.
      • Trauth S.E.
      • Grippo R.S.
      • et al.
      Combined effects of ephedrine-containing dietary supplements, caffeine, and nicotine on morphology and ultrastructure of rat hearts.
      This effect is further highlighted in Table III, which summarizes the findings of a pilot Ephedra toxicity study conducted in mice. The results indicate that multi-ingredient Ephedra-containing dietary supplement formulations were more toxic despite delivering lower doses of ephedrine alkaloids. Clearly, caffeine and other phytochemicals present in the formulations contributed to this heightened effect.
      Table IIIInfluence of product complexity on Ephedra supplement toxicity.
      Once capsule of each supplement was extracted with 10 mL of water of which 0.4 mL was administered via oral gavage. EPH 833™ contained only Ephedra extract. Formulations for the other products are depicted in Table 1.
      SupplementMice, No.Volume, mLMortalityComposition, mg/mLDose, mg/kg
      PSEEPHMEPHTotal
      EPH 833™40.40/43.37.30.110.7357
      (AST Sports Science, Golden, CO)
      Metabolife™40.43/40.41.80.02.273
      (Metabolife International Inc., San Diego, CA)
      Ripped Fuel™40.43/40.90.40.61.963
      (Twin Laboratories, Ronkonkoma, NY)
      Xenadrine™40.44/40.82.30.03.1103
      (Cytodyne Technologies, Lakewood, NJ)
      EPH = ephedrine; MEPH = methylephedrine; PSE = pseudoephedrine.
      low asterisk Once capsule of each supplement was extracted with 10 mL of water of which 0.4 mL was administered via oral gavage. EPH 833™ contained only Ephedra extract. Formulations for the other products are depicted in Table 1.
      It is these other phytochemicals that are often overlooked. Botanical dietary supplement formulations often contain myriad phytochemicals—in a concentrated form—many of which had never been ingested in combination before the marketing of the product. (The DSHEA does not require that dietary supplements undergo premarket tolerability or efficacy studies before marketing.) When the pharmacologic activity of various phytochemicals present in Ephedra-containing dietary supplements is scrutinized, it is easily conceivable why these formulations were problematic. A few examples from the products listed in Table I readily illustrate this point.
      Guarana—common to many of the products listed in Table I and Table IV—is an Amazonian plant that is an excellent source of caffeine and also contains high concentrations of catechin polyphenols.
      • Carlson M.
      • Thompson R.D.
      Liquid chromatographic determination of methylxanthines and catechins in herbal preparations containing guarana.
      Catechin polyphenols include epigallocatechin-3-gallate (EGCG), epigallocatechin, epicatechin, among others. The catechins are readily absorbed from the gastrointestinal tract and undergo significant presystemic metabolism, primarily via methylation, glucuronidation, and sulfation.
      • Lambert J.D.
      • Sang S.
      • Yang C.S.
      Biotransformation of green tea polyphenols and the biological activities of those metabolites.
      • Clifford M.N.
      • van der Hooft J.J.
      • Crozier A.
      Human studies on the absorption, distribution, metabolism, and excretion of tea polyphenols.
      Catechins and their conjugated metabolites are widely distributed in tissues.
      • Lambert J.D.
      • Sang S.
      • Yang C.S.
      Biotransformation of green tea polyphenols and the biological activities of those metabolites.
      • Clifford M.N.
      • van der Hooft J.J.
      • Crozier A.
      Human studies on the absorption, distribution, metabolism, and excretion of tea polyphenols.
      Catechins and even their metabolites can inhibit COMT
      • Lambert J.D.
      • Sang S.
      • Yang C.S.
      Biotransformation of green tea polyphenols and the biological activities of those metabolites.
      • Lu H.
      • Meng X.
      • Yang C.S.
      Enzymology of methylation of tea catechins and inhibition of catechol-o-methyltransferase by (-)-epigallocatechin gallate.
      —an enzyme involved in the peripheral metabolism of catecholamine neurotransmitters—and by doing so exacerbate the pharmacologic effects of ephedrine and caffeine.
      • Dulloo A.G.
      • Seydoux J.
      • Girardier L.
      • et al.
      Green tea and thermogenesis: interactions between catechin-polyphenols, caffeine and sympathetic activity.
      Recent findings also indicate that catechins, particularly EGCG, can inhibit the human intestinal uptake transporter OATP1A2, thereby precluding absorption of drugs such as the antihypertensive nadolol, which are substrates for this protein.
      • Misaka S.
      • Yatabe J.
      • Müller F.
      • et al.
      Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects.
      Thus, catechins present in green tea or guarana may give rise to pharmacokinetic-based herb-drug interactions if taken concomitantly with OATP1A2 substrates. Moreover, certain catechins elicit their own inotropic effect on the heart,
      • Kubota Y.
      • Umegaki K.
      • Tanaka N.
      • et al.
      Safety of dietary supplements: chronotropic and inotropic effects on rat atria.
      which may have contributed to the adverse cardiovascular effects of Ephedra supplements.
      Table IVExamples of Ephedra-free dietary supplement formulations.
      Xenadrine EFXZantrex 3MeltdownMetaboliftHydroxycut Hardcore
      GuaranaGuaranaCaffeine anhydrousGuaranaCaffeine anhydrous
      Green teaGreen teaα-Methyltetradecylthioacetic acidGreen teaGreen coffee extract
      Yerba matéYerba matéYerba matéCitrus aurantiumColeus forskohlii (forskolin)
      Ginger rootCaffeine3’,5’-cyclic AMPGinger rootl-theanine
      Salvia sclarea extractKola nutMethyl-synephrine HClQuercetin dehydrateCocoa extract (theobromine)
      Calcium tribasicDamianaR-β-phenylethylamineCitrus bioflavonoid complexYohimbe extract
      dl-MethionineSchizonepetaN-methyl-β-phenylethylaminel-Phenylalanine(yohimbine, rauwolscine)
      l-theaninePiper nigrum11-Hydroxy yohimbineCayenne fruit
      Cocoa extractTibetan ginsengYohimbine HClSt. John’s Wort extract
      l-tyrosinePanax ginsengα-Yohimbine
      Acetyl-l-tyrosineMaca rootMethyl-hordenine HCl
      Grape seed extractCocoa nut
      Vitamin CThea sinensis
      Vitamin B6Niacin
      Pantothenic acid
      Magnesium
      Theobromine
      Phenylethylamine
      2-Dimethylaminoethanol
      Tetrahydroxyflavone
      Pentahydroxyflavone
      AMP = adenosine monophosphate.
      Citrus aurantium extract was also a common ingredient in many Ephedra supplements and is currently found in many Ephedra-free supplements (Table II and Table IV). C aurantium, or bitter orange, is a source of p-synephrine, a naturally occurring phenylethylamine with mild sympathomimetic properties.
      • Fugh-Berman A.
      • Myers A.
      Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical and basic research.
      By itself, p-synephrine is a fairly innocuous compound,
      • Stohs S.J.
      • Preuss H.G.
      • Shara M.
      A review of the human clinical studies involving Citrus aurantium (bitter orange) extract and its primary protoalkaloid p-synephrine.
      but when combined with other stimulants, such as ephedrine and caffeine, it can add to the cardiovascular stress of these products.
      • Haller C.A.
      • Duan M.
      • Jacob P.
      • Benowitz N.
      Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions.
      • Rossato L.G.
      • Costa V.M.
      • Limberger R.P.
      • et al.
      Synephrine: from trace concentrations to massive consumption in weight-loss.
      In a series of Ephedra products evaluated in a rodent toxicity model, those formulated with guarana and C aurantium exhibited some of the most toxic effects.

      Gurley BJ, Ali S. Toxicity of multi-component ephedra-containing dietary supplements. AAPS J. 2001 [abstract]. http://abstracts.aaps.org/SecureView/AAPSJournal/k998z12k0bcu2svbttqa.htm. Accessed April 20, 2014.

      Other botanicals listed in Table 1 that might have contributed to the pharmacologic effects of Ephedra supplements include goldenseal, capsicum, ginseng, and ginger root, whose unique phytochemicals (berberine,
      • Lau C.W.
      • Yao X.Q.
      • Chen Z.Y.
      • et al.
      Cardiovascular actions of berberine.
      capsaicin,
      • Cheng Y.P.
      • Wang Y.H.
      • Cheng L.P.
      • He R.R.
      Electrophysiological effects of capsaicin on pacemaker cells in sinoatrial nodes of rabbits.
      ginsenosides,
      • Wang Y.G.
      • Zima A.V.
      • Ji X.
      • et al.
      Ginsenoside Re suppresses electromechanical alternans in cat and human cardiomyocytes.
      and gingerol,
      • Kobayashi M.
      • Shoji N.
      • Ohizumi Y.
      Gingerol, a novel cardiotonic agent, activates the Ca2+-pumping ATPase in skeletal and cardiac sarcoplasmic reticulum.
      respectively) can potentially elicit diverse cardiovascular effects. In short, although each botanical may have beneficial effects of its own, certain combinations may have exacerbated the toxic potential of Ephedra and caffeine. An ongoing shortcoming of the dietary supplement industry still today is that little is known about the disposition and pharmacodynamics of unique phytochemicals present in many botanical formulations. The formulations listed in Table 1 represent only 4 examples of literally hundreds of Ephedra supplement formulations that were available at the time. Many others also contained unique phytochemicals with distinctive CNS or cardiovascular stimulant activities. With no prospective assessment of their tolerability, it would have been impossible to discern which formulations were more or less problematic.
      Not all of the blame, however, could be laid at the feet of Ephedra and caffeine. Other exogenous factors were likely contributors to many of the adverse events. Two relatively common features coincident to many Ephedra-related adverse events were smoking and vigorous exercise. Although smoking may reduce caffeine exposure, production of its principal active metabolite, paraxanthine, is increased.
      • Arnaud M.J.
      Pharmacokinetics and metabolism of natural methylxanthines in animal and man.
      Nicotine also appears to exacerbate the cardiovascular toxic effects of Ephedra-containing dietary supplements,
      • Brown C.E.
      • Trauth S.E.
      • Grippo R.S.
      • et al.
      Combined effects of ephedrine-containing dietary supplements, caffeine, and nicotine on morphology and ultrastructure of rat hearts.
      which may partially explain why many case reports of Ephedra-related myocardial infarction involved smokers.
      • Rezkalla S.H.
      • Mesa J.
      • Sharma P.
      • Kloner R.A.
      Myocardial infarction temporally related to ephedra—a possible role for the coronary microcirculation.
      • Naik S.D.
      • Freudenberger R.S.
      Ephedra-associated cardiomyopathy.
      • Enders J.M.
      • Dobesh P.P.
      • Ellison J.N.
      Acute myocardial infarction induced by ephedrine alkaloids.
      • Chen-Scarabelli C.
      • Hughes S.E.
      • Landon G.
      • et al.
      A case of fatal ephedra intake associated with lipofuscin accumulation, caspase activation and cleavage of myofibrillary proteins.

      Flanagan CM, Kaesberg JL, Mitchell ES, et al. Coronary artery aneurysm and thrombosis following chronic ephedra use. Int J Cardiol. http://dx.doi.org/10.1016/j.ijcard.2008.6.081.

      That vigorous exercise was often coincidental to Ephedra use is not unexpected because many of the products were marketed for use in conjunction with exercise. Vigorous exercise is a significant cardiovascular stimulant in its own right; however, the addition of Ephedra and caffeine may have stressed the hearts of many consumers to their limit.
      • Haller C.A.
      • Benowitz N.L.
      Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
      • Krome C.N.
      • Tucker A.M.
      Cardiac arrhythmia in a professional football player: was ephedra to blame?.
      • Stahl C.E.
      • Borlongan C.V.
      • Szerlip H.
      • Szerlip M.
      No pain, no gain—exercise-induced rhabdomyolysis associated with the performance enhancer herbal supplement ephedra.
      • Myers J.B.
      • Guskiewicz K.M.
      • Riemann B.L.
      Syncope and atypical chest pain in an intercollegiate wrestler: a case report.
      • Scoville S.L.
      • Gardner J.W.
      • Magill A.J.
      • et al.
      Nontraumatic deaths during U.S. armed forces basic training, 1977–2001.
      • Magkos F.
      • Kavouras S.A.
      Caffeine and ephedrine: physiological, metabolic and performance-enhancing effects.
      • Sachdeva R.
      • Sivasankaran S.
      • Fishman R.F.
      • et al.
      Coronary thrombosis related to use of Xenadrine RFA.
      • Forte R.Y.
      • Precoma-Neto
      • Neto N.C.
      • et al.
      Myocardial infarction associated with the use of a dietary supplement rich in ephedrine in a young athlete.
      Before their removal from the market, only one study assessed the effect of exercise on the cardiovascular effects of a caffeine-containing Ephedra supplement among nonathletes. Kleinjan
      • Kleinjan K.J.
      The cardiovascular effects of caffeine and ephedrine during exercise [master’s thesis].
      found that, when compared with placebo, a commercially available Ephedra supplement that contained 150 mg of caffeine and 20 mg of ephedrine alkaloids significantly elevated heart rate before, during, and after 60 minutes of exercise on a cycle ergometer at 60% maximal aerobic capacity. During the postrecovery period, mean arterial pressure and resting pulse pressure were significantly elevated, whereas stroke volume was markedly decreased. As with many Ephedra studies, Kleinjan
      • Kleinjan K.J.
      The cardiovascular effects of caffeine and ephedrine during exercise [master’s thesis].
      only investigated the effects of a one-time dose of the supplement. Whether multiple Ephedra doses would have exacerbated the cardiovascular stress of exercise remains to be determined.
      To Ephedra supplement manufacturers, such pharmacologic effects were not unexpected. This was evidenced by the warnings present on all Ephedra product labels. An example of a typical warning label is depicted in Figure 2. The statements “Exceeding recommended serving may cause serious adverse health effects including heart attack and stroke” and “Individuals who consume caffeine with this product may experience serious adverse health effects” were tacit admissions of the products’ toxic potential. Heeding such warnings was prudent because recommended servings were often difficult to follow because many products exhibited significant lot-to-lot variability in ephedrine alkaloid and caffeine content.
      • Gurley B.J.
      • Gardner S.F.
      • Hubbard M.A.
      Content versus label claims in ephedra-containing dietary supplements.
      Validity was added to these warnings from a series of prospective studies performed in healthy volunteers that documented significant cardiovascular effects when products were administered per label directions.
      • Gardner S.F.
      • Franks A.M.
      • Gurley B.J.
      • et al.
      Effect of a multicomponent, ephedra-containing dietary supplement (Metabolife 356) on Holter monitoring and hemostatic parameters in healthy volunteers.
      • McBride B.F.
      • Karapanos A.K.
      • Krudysz A.
      • et al.
      Electrocardiographic and hemodynamic effects of a multicomponent dietary supplement containing ephedra and caffeine: a randomized trial.
      • Haller C.A.
      • Jacob P.
      • Benowitz N.L.
      Short-term metabolic and hemodynamic effects of ephedra and guarana combinations.
      In addition, assessments of the Toxic Exposure Surveillance System of the American Association of Poison Control Centers revealed that Ephedra-containing supplements were more likely to result in severe medical outcomes than botanical products that did not incorporate Ephedra.
      • Bent S.
      • Tiedt T.
      • Odden M.
      • Shlipak M.G.
      The relative safety of ephedra compared with other herbal products.
      • Woolf A.D.
      • Watson W.A.
      • Smolinske S.
      • Litovitz T.
      The severity of toxic reactions to ephedra: comparisons to other botanical products and national trends from 1993-2002.
      A meta-analysis of published case reports, controlled trials, and adverse event reports regarding Ephedra supplement use found that the products were associated with an increased risk of psychiatric, autonomic, gastrointestinal, and cardiovascular symptoms.
      • Shekelle P.G.
      • Hardy M.L.
      • Morton S.C.
      • et al.
      Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis.
      Figure thumbnail gr2
      Figure 2Example of a typical warning label from an Ephedra-containing dietary supplement.
      By 2004, an ever-increasing number of adverse effects prompted the FDA to remove Ephedra-containing dietary supplements from the market.
      Final rule declaring dietary supplements containing ephedrine alkaloids Adulterated because they present an unreasonable risk.
      In retrospect, it appears that several factors contributed to the hazards of Ephedra supplements: an overly permissive piece of legislation (DSHEA); lack of foresight from supplement manufacturers regarding the additive pharmacologic effects of ephedrine, caffeine, and other phytochemicals; poorly conceived product formulations; ill-advised marketing practices; and lack of appreciation for their customers’ genetic diversity and individual susceptibility to sympathomimetic agents. In response to the ban, manufacturers simply removed Ephedra—sometimes replacing it with other natural stimulants—and developed Ephedra-free formulations, which were marketed in a similar manner to their same customer base.

      Ephedra-Free Dietary Supplements

      With the current widespread distribution and use of Ephedra-free supplements, the question that arises is whether these products are more tolerable than their Ephedra-containing predecessors. Once again, on account of the DSHEA, manufacturers are not obligated to conduct prospective studies on the tolerability of these new and improved products. This is especially disconcerting because the number and type of adverse event reports appearing in the medical literature and reported to the FDA and poison control centers is increasing, and they appear eerily similar to that of their problematic namesakes. Reports that link myocardial infarction,
      • Nykamp D.L.
      • Fackih M.N.
      • Compton A.L.
      Possible association of acute lateral-wall myocardial infarction and bitter orange supplement.
      • Gange C.A.
      • Madais C.
      • Felix-Getzik E.M.
      • et al.
      Variant angina associated with bitter orange in a dietary supplement.
      • Muller G.J.
      • Smedema J.P.
      Coronary spasm and thrombosis in a bodybuilder using a nutritional supplement containing synephrine, octopamine, tyramine and caffeine.
      • Thomas J.E.
      • Munir J.A.
      • McIntyre P.Z.
      • Ferguson M.A.
      STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement.
      • Karth A.
      • Holoshitz N.
      • Kavinsky C.J.
      • et al.
      A case report of atrial fibrillation potentially induced by Hydroxycut: a multicomponent dietary weight loss supplement devoid of sympathomimetic amines.
      strokes,
      • Bouchard N.C.
      • Howland M.A.
      • Greller H.A.
      • et al.
      Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine.
      • Holmes R.O.
      • Tavee J.
      Vasospasm and stroke attributable to ephedra-free Xenadrine: case report.
      • Cvetanovich G.L.
      • Ramakrishnan P.
      • Klein J.P.
      • et al.
      Reversible cerebral vasoconstriction syndrome in a patient taking citalopram and Hydroxycut: a case report.
      • Young C.
      • Oladipo O.
      • Frasier S.
      • et al.
      Hemorrhagic stroke in young healthy male following use of sports supplement Jack3d.
      seizures,
      • Pendleton M.
      • Brown S.
      • Thomas C.M.
      • Odle B.
      Potential toxicity of caffeine when used as a dietary supplement for weight loss.
      psychoses,
      • Retamero C.
      • Rivera T.
      • Murphy K.
      “Ephedra-free” diet pill-induced psychosis.
      rhabdomyolysis,
      • Burke J.
      • Seda G.
      • Allen D.
      • Knee T.S.
      A case of severe exercise-induced rhabdomyolysis associated with a weight-loss dietary supplement.
      • Haller C.A.
      • Jacob P.
      • Benowitz N.L.
      Short-term metabolic and hemodynamic effects of ephedra and guarana combinations.
      • Shekelle P.G.
      • Hardy M.L.
      • Morton S.C.
      • et al.
      Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis.
      • Donadio V.
      • Bonsi P.
      • Zele I.
      • et al.
      Myoglobinuria after ingestion of extracts of guarana, Ginkgo biloba and kava.
      • Mansi I.A.
      • Huang J.
      Rhabdomyolysis in response to weight-loss herbal medicine.
      • Dehoney S.
      • Wellein M.
      Rhabdomyolysis associated with the nutritional supplement Hydroxycut.
      • Elsayed R.K.
      • Glisson J.K.
      • Minor D.S.
      Rhabdomyolysis associated with the use of a mislabeled “acai berry” dietary supplement.
      and other sympathomimetic-associated injuries
      • Nasir J.M.
      • Durning S.J.
      • Ferguson M.
      • et al.
      Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine.
      • Ahmed I.
      Malignant hypertension and acute aortic dissection associated with caffeine-based ephedra-free dietary supplements: a case report.
      • Moaddeb J.
      • Tofade T.S.
      • Bevins M.B.
      Hypertensive urgency associated with Xenadrine EFX use.
      to Ephedra-free supplement use imply that ephedrine alkaloids were not the only contributors to the Ephedra problem.
      Many of the same problems associated with Ephedra-containing supplements currently plague Ephedra-free products. Such troubles include content inconsistency, labeling inadequacies, product adulteration and contamination, and ill-considered combinations of botanical extracts. Caffeine quantity can vary considerably among brands of Ephedra-free supplements.
      • Andrews K.W.
      • Schweitzer A.
      • Zhao C.
      • et al.
      The caffeine contents of dietary supplements commonly purchased in the US: analysis of 53 products with caffeine-containing ingredients.
      Moreover, few products provide an adequate indication of caffeine quantity on the product label.
      • Kole J.
      • Barnhill A.
      Caffeine content labeling: a missed opportunity for promoting personal and public health.
      • Foster L.
      • Allan M.C.
      • Khan A.
      • et al.
      Multiple dosing of ephedra-free dietary supplements: hemodynamic, electrocardiographic, and bacterial contamination effects.
      This can be especially troubling for individuals who are overly sensitive to caffeine or who may be taking prescription stimulants (eg, Adderal® [amphetamine, dextroamphetamine mixed salts] and Ritalin® [methylphenidate hydrochloride]) or antihypertensive medications. Multiple natural caffeine sources (eg, guarana, green tea, kola nut, and Yerba maté) are often formulated together or frequently combined with synthetic caffeine. Dietary supplements that contain added caffeine must list caffeine as an ingredient on the label but need not indicate the amount of caffeine. If caffeine is listed as part of a proprietary blend of botanical extracts, then the amount of the blend must be listed but not the amount of caffeine in the blend.
      • Kole J.
      • Barnhill A.
      Caffeine content labeling: a missed opportunity for promoting personal and public health.
      Recently, many Ephedra-free supplements have been haunted by the specter of adulteration. The purposeful addition of prescription stimulants, such as sibutramine,
      • Huang Z.
      • Xiao S.
      • Luo D.
      • et al.
      Simultaneous determination of sibutramine and N-di-desmethylsibutramine in dietary supplements for weight control by HPLC-ESI-MS.
      designer stimulants, such as dimethylamylamine,
      • Zhang Y.
      • Woods R.M.
      • Breitbach Z.S.
      • Armstrong D.W.
      1,3-dimethylamylamine (DMAA) in supplements and geranium products: natural or synthetic?.
      or methamphetamine analogs, such as N,α-diethyl-phenylethylamine,

      Cohen PA, Travis JC, Venhuis BJ. A methamphetamine analog (N,α-diethyl-phenylethylamine) identified in a mainstream dietary supplement. Drug Test Anal. http://dx.doi.org/10.1002/dta.1578.

      to product formulations poses significant health risks to susceptible consumers. Caffeine’s ability to augment the adrenergic effects of these agents renders such products akin to a supersympathomimetic supplement. Because many of these formulations are marketed as preworkout supplements, it is understandable why their use in conjunction with vigorous exercise has been linked to serious adverse events and even fatalities in young adults.
      • Young C.
      • Oladipo O.
      • Frasier S.
      • et al.
      Hemorrhagic stroke in young healthy male following use of sports supplement Jack3d.
      • Eliason M.J.
      • Eichner A.
      • Cancio A.
      • et al.
      Case reports: Death of active duty soldiers following ingestion of dietary supplement containing 1,3-diethylamylamine (DMAA).
      Although Ephedra is no longer an ingredient, the combination of botanical extracts found in these products may not be as innocuous as manufacturers assert. When it comes to the myriad components found in Ephedra-free formulas, the ability of phytochemicals to impart additive or synergistic pharmacologic effects to caffeine cannot be ignored. Table IV provides examples of 5 Ephedra-free supplement formulations and their botanical constituents. Although hundreds of unique formulations are commercially available, a few of the components listed in Table IV help illustrate the concept that the pharmacodynamic underpinnings of Ephedra-free supplements are not necessarily limited to caffeine. A comparison of Ephedra and Ephedra-free formulations (Table I vs Table IV) reveals that the latter tend to be more intricate and thus may give rise to more complex pharmacologic properties.
      A cursory examination of the medical literature reveals that many phytochemicals present in these botanical extracts may contribute, directly and indirectly, to the cardiovascular and CNS effects reported for these products. For example, Yohimbe extract is a natural source of the alkaloid yohimbine, a α2-adrenergic antagonist that increases efferent sympathetic outflow and elevates blood pressure.
      • Tam S.W.
      • Worcel M.
      • Wyllie M.
      Yohimbine: a clinical review.
      Yohimbine also has 2 active hydroxylated metabolites, each with pressor activity and longer elimination half-lives in humans.
      • Le Corre
      • Parmer R.J.
      • Kailasam M.T.
      • et al.
      Human sympathetic activation by α2-adrenergic blockade with yohimbine: bimodal, epistatic influence of cytochrome P450-mediated drug metabolism.
      The metabolism of yohimbine exhibits tremendous variability that depends on genetic variation in both CYP2D6 and CYP3A4 enzymes (perhaps the 2 most important drug metabolizing enzymes in humans), with nonmetabolizers exhibiting exaggerated norepinephrine release and pressor response.
      • Le Corre
      • Parmer R.J.
      • Kailasam M.T.
      • et al.
      Human sympathetic activation by α2-adrenergic blockade with yohimbine: bimodal, epistatic influence of cytochrome P450-mediated drug metabolism.
      When combined with caffeine and exercise, yohimbine has an additive effect on plasma norepinephrine concentrations, producing undesirable cardiovascular effects, especially in obese individuals.
      • Waluga M.
      • Janusz M.
      • Karpel E.
      • et al.
      Cardiovascular effects of ephedrine, caffeine and yohimbine measured by thoracic electrical impedance in obese women.
      Yohimbine also selectively attenuates baroreflex heart rate control in normotensive adults
      • Tank J.
      • Heusser K.
      • Diedrich A.
      • et al.
      Yohimbine attenuates baroreflex-mediated bradycardia in humans.
      and can prolong QTc intervals, which may lead to the development of serious arrhythmias.
      • Yeragani V.K.
      • Tancer M.
      • Uhde T.
      Heart rate and QT interval variability: abnormal alpha-2 adrenergic function in patients with panic disorder.
      Thus, given yohimbine’s propensity for producing untoward cardiovascular effects, it is not surprising that Yohimbe-containing herbal supplements were associated with a significantly greater proportion of severe outcomes reported during a 6-year period to the California Poison Control System.
      • Kearney T.
      • Tu N.
      • Haller C.
      Adverse drug events associated with yohimbine-containing products: a retrospective review of the California Poison Control System reported cases.
      Catechin polyphenol-mediated inhibition of human COMT was described in the previous section, and their contribution to the pharmacology of caffeine-containing, Ephedra-free supplements is equally applicable. This also holds true for the effects of C aurantium and its sympathomimetic amine p-synephrine, another common Ephedra substitute.
      • Bent S.
      • Padula A.
      • Neuhaus J.
      Safety and efficacy of Citrus aurantium for weight loss.
      Attendant to their effects on COMT, catechin polyphenols also appear capable of inhibiting cardiac ion channels,
      • Jin J.Y.
      • Park S.H.
      • Bae J.H.
      • et al.
      Uncoupling by (-)-epigallocatechin-3-gallate of ATP-sensitive potassium channels from phosphatidylinositol polyphosphates and ATP.
      • Kang J.
      • Cheng H.
      • Ji J.
      • et al.
      In vitro electrocardiographic and cardiac ion channel effects of (-)-epigallocatechin-3-gallate, the main catechin of green tea.
      in particular human hERG potassium channels at plasma concentrations achievable with some products.
      • Kelemen K.
      • Kiesecker C.
      • Zitron E.
      • et al.
      Green tea flavonoid epigallocatechin-3-gallate (EGCG) inhibits cardiac hERG potassium channels.
      Inhibition of cardiac ion channels may lead to electrocardiographic anomalies and possibly arrhythmias. A wide variety of flavonoids present in many formulations may also contribute to the sympathomimetic effects of caffeine either through inhibition of COMT, monoamine oxidase (MAO), or both.
      • Gugler R.
      • Dengler H.J.
      Inhibition of human liver catechol-O-methyltransferase by flavonoids.
      • Dixon Clarke S.E.
      • Ramsay R.R.
      Dietary inhibitors of monoamine oxidase A.
      • Carradori S.
      • D’Ascenzio M.
      • Chimenti P.
      • et al.
      Selective MAO-B inhibitors: a lesson from natural products.
      Consumption of sympathomimetics along with MAO inhibitors has long been recognized as a mechanism for hypertensive crises, and although many Ephedra-free supplement labels warn against taking the products with conventional MAO inhibitors (Figure 3), it seems ironic that flavonoids within the formula may act, to some degree, as natural MAO inhibitors. Like the catechins, certain citrus flavonoids commonly found in these supplements also appear capable of inhibiting hERG channels, which may lead to QTc prolongation in healthy volunteers.
      • Zitron E.
      • Scholz E.
      • Owen R.W.
      • et al.
      QTc prolongation by grapefruit juice and is potential pharmacological basis: hERG channel blockade by flavonoids.
      Figure thumbnail gr3
      Figure 3Example of a typical warning label from an Ephedra-free dietary supplement.
      Presystemic metabolism by intestinal and hepatic CYPs can impede phytochemical bioavailability
      • Gurley B.J.
      Pharmacokinetic herb-drug interactions (Part 1): origins, mechanisms, and the impact of botanical dietary supplements.
      ; therefore, as a means of enhancing absorption, supplement formulators sometimes add natural CYP inhibitors present in Piper nigrum, Piper longum, Schizandra chinensis, and Hydrastis canadensis extracts to product formulations.
      • Gurley B.J.
      • Fifer K.E.
      • Gardner Z.
      Pharmacokinetic herb-drug interactions (Part 2): drug interactions involving popular botanical dietary supplements and their clinical relevance.
      These particular extracts are host to a variety of phytochemicals with methylenedioxyphenyl functional groups (eg, piperamides, gomisins, schizandrins, berberine, and hydrastine) that act as noncompetitive inhibitors of human CYP3A4 and CYP2D6.
      • Gurley B.J.
      • Fifer K.E.
      • Gardner Z.
      Pharmacokinetic herb-drug interactions (Part 2): drug interactions involving popular botanical dietary supplements and their clinical relevance.
      Improved phytochemical bioavailability via CYP inhibition may augment not only product efficacy but also its toxicity.
      • Gurley B.J.
      Emerging technologies for improving phytochemical bioavailability: benefits and risks.
      Natural CYP inhibitors may also increase the risk of herb-drug interactions if these supplements are taken in conjunction with conventional medications that are also CYP substrates.
      • Gurley B.J.
      • Fifer K.E.
      • Gardner Z.
      Pharmacokinetic herb-drug interactions (Part 2): drug interactions involving popular botanical dietary supplements and their clinical relevance.
      Other common Ephedra-free supplement ingredients include cocoa extract and Coleus forskholii root extract (Table IV). Cocoa extract is a source of the methylxanthines theobromine and theophylline, which if consumed in excess with caffeine may produce untoward cardiovascular and CNS adverse effects.
      • Riksen N.P.
      • Smits P.
      • Rongen G.A.
      The cardiovascular effects of methylxanthines.
      Coleus forskohlii, a tropical perennial plant of the Lamiaceae family, is a source of forskolin, a natural activator of adenylate cyclase and promoter of cAMP production in cardiac myocytes.
      • Alasbahi R.H.
      • Melzig M.F.
      Forskolin and derivatives as tools for studying the role of cAMP.
      Forskolin’s amplification of intracellular cAMP accounts for its positive inotropy and its ability to intensify caffeine’s effect on adenosine receptors.
      • Bristow M.R.
      • Ginsburg R.
      • Strosberg A.
      • et al.
      Pharmacology and inotropic potential of forskolin in the human heart.
      However, potentiation of myocardial cAMP may have undesirable effects because this mechanism is thought to underlie forskolin’s ability to exacerbate the teratogenicity of methylxanthines in an embryonic heart model.
      • Nishikawa T.
      • Ishiyama S.
      • Takeda K.
      • Kasajima T.
      The effect of forskolin on the teratogenicity of methylxanthines in the chick embryo heart.
      In short, although each botanical component has its own unique pharmacologic activity, the contribution of the plethora of phytochemicals present in these multicomponent formulations is difficult—if not impossible—to predict, yet few of these products have been examined prospectively with regard to tolerability.
      To date, fewer than 10 small prospective studies have been conducted on the tolerability aspects of multicomponent, caffeine-containing Ephedra-free dietary supplements even though hundreds of distinct formulations are commercially available. All the studies have used healthy volunteers screened with a litany of exclusion criteria. Not unexpectedly, the results varied with regard to hemodynamic and/or electrocardiographic findings, and there was disagreement as to what potential health risks these entities might pose. Eight of the studies found no significant changes in blood pressure, heart rate,
      • Min B.
      • McBride B.F.
      • Kardas M.J.
      • et al.
      Hemodynamic impact of an ephedra-free multicomponent weight-loss supplement.
      • Sale C.
      • Harris R.C.
      • Delves S.
      • Corbett J.
      Metabolic and physiologic effects of ingesting extracts of bitter orange, green tea and guarana at rest and during treadmill walking in overweight males.
      • Seifert J.G.
      • Nelson A.
      • Devonish J.
      • et al.
      Effect of acute administration of an herbal preparation on blood pressure and heart rate in humans.
      or electrocardiographic findings
      • Min B.
      • McBride B.F.
      • Kardas M.J.
      • et al.
      Electrocardiographic effects of an ephedra-free, multicomponent weight-loss supplement in healthy volunteers.
      or only modest increases in systolic
      • Haller C.A.
      • Benowitz N.L.
      • Jacob P.
      Hemodynamic effects of ephedra-free weight-loss supplements in humans.
      • Bloomer R.J.
      • Canale R.E.
      • Blankenship M.M.
      • et al.
      Effect of the dietary supplement Meltdown on catecholamine secretion, markers of lipolysis, and metabolic rate in men and women: a randomized, placebo controlled, cross-over study.
      or diastolic blood pressure,
      • Haller C.A.
      • Duan M.
      • Jacob P.
      • Benowitz N.
      Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions.
      • Haller C.A.
      • Benowitz N.L.
      • Jacob P.
      Hemodynamic effects of ephedra-free weight-loss supplements in humans.
      • Bloomer R.J.
      • Canale R.E.
      • Blankenship M.M.
      • et al.
      Effect of the dietary supplement Meltdown on catecholamine secretion, markers of lipolysis, and metabolic rate in men and women: a randomized, placebo controlled, cross-over study.
      suggesting that these products may not be as problematic as Ephedra-containing supplements. These studies, however, investigated only a single, one-time dose
      • Haller C.A.
      • Duan M.
      • Jacob P.
      • Benowitz N.
      Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions.
      • Min B.
      • McBride B.F.
      • Kardas M.J.
      • et al.
      Hemodynamic impact of an ephedra-free multicomponent weight-loss supplement.
      • Sale C.
      • Harris R.C.
      • Delves S.
      • Corbett J.
      Metabolic and physiologic effects of ingesting extracts of bitter orange, green tea and guarana at rest and during treadmill walking in overweight males.
      • Bloomer R.J.
      • Canale R.E.
      • Blankenship M.M.
      • et al.
      Effect of the dietary supplement Meltdown on catecholamine secretion, markers of lipolysis, and metabolic rate in men and women: a randomized, placebo controlled, cross-over study.
      or doses that were only half the label recommendation.
      • Seifert J.G.
      • Nelson A.
      • Devonish J.
      • et al.
      Effect of acute administration of an herbal preparation on blood pressure and heart rate in humans.
      • Min B.
      • McBride B.F.
      • Kardas M.J.
      • et al.
      Electrocardiographic effects of an ephedra-free, multicomponent weight-loss supplement in healthy volunteers.
      Studies that used only single, acute doses or dosing regimens less than label recommendations may not be representative of typical consumer use and thus may provide misleading information about the cardiovascular effects of these supplements. The one study that examined multiple products for multiple days while following label-recommended dosing noted a variety of untoward sympathomimetic-related adverse effects and significant changes in hemodynamic and electrocardiographic parameters.
      • Foster L.
      • Allan M.C.
      • Khan A.
      • et al.
      Multiple dosing of ephedra-free dietary supplements: hemodynamic, electrocardiographic, and bacterial contamination effects.
      Owing to the variability among product formulations, the daily dose of caffeine administered in this study ranged from 540 to 1098 mg. (Variability in caffeine and catechin polyphenol content is not unexpected among caffeine-containing supplements.
      • Andrews K.W.
      • Schweitzer A.
      • Zhao C.
      • et al.
      The caffeine contents of dietary supplements commonly purchased in the US: analysis of 53 products with caffeine-containing ingredients.
      • Seeram N.P.
      • Henning S.M.
      • Niu Y.
      • et al.
      Catechin and caffeine content of green tea dietary supplements and correlation with antioxidant capacity.
      ) Only one study was conducted in the context of moderate exercise, and although 30 minutes on a cycle ergometer at 75% to 80% maximum heart rate had no affect on caffeine pharmacokinetic properties, postexercise blood pressures were higher during the active period when compared with placebo.
      • McLean C.
      • Graham T.E.
      Effects of exercise and thermal stress on caffeine pharmacokinetics in men and eumenorrheic women.
      From this small number of controlled prospective studies, it is difficult to infer causation in any of the case reports or adverse event reports that involve caffeine-containing Ephedra-free dietary supplements. This is not surprising because none of the studies mimicked many real-world conditions in which a typical consumer ingests these products. Nevertheless, it would appear that neither a single ingredient nor a phytochemical is the sole culprit in producing many of the adverse effects linked to these products; the entire milieu must be considered. The combined hemodynamic and electrocardiographic effects of complex mixtures of caffeine, catechins, flavonoids, alkaloids, and other phytochemicals remain to be determined, and even though millions of consumers are currently serving as innocent test subjects, it is probably safe to say that most will not experience any serious adverse effects from these supplements; however, it is important to remember that not all Ephedra-free supplements are created equally and neither are their consumers.

      Energy Drinks and Shots

      Surveys indicate that 30% to 50% of children and adolescents and as many as 80% of college students regularly consume energy drinks.
      • Seifert S.M.
      • Schaechter J.L.
      • Hershorin E.R.
      • Lipshultz S.E.
      Health effects of energy drinks on children, adolescent, and young adults.
      • Hoyte C.O.
      • Albert D.
      • Heard K.J.
      The use of energy drinks, dietary supplements, and prescription medications by United States college students to enhance athletic performance.
      Principal reasons for such high use include increased alertness, compensation for insufficient sleep, athletic performance enhancement,
      • Hoyte C.O.
      • Albert D.
      • Heard K.J.
      The use of energy drinks, dietary supplements, and prescription medications by United States college students to enhance athletic performance.
      or peer pressure.
      • Taddeo D.
      • Harvey J.
      • Boutin A.
      Health hazards related to energy drinks: are we looking for them?.
      Aggressive marketing campaigns by manufacturers drive energy drink sales but may also increase potential health risks. Paralleling the public’s support for energy drinks is a growing anxiety within the medical community.
      • Seifert S.M.
      • Schaechter J.L.
      • Hershorin E.R.
      • Lipshultz S.E.
      Health effects of energy drinks on children, adolescent, and young adults.

      Trabulo D, Marques S, Pedroso E. Caffeinated energy drink intoxication. BMJ Case Rep. http://dx.doi.org/10.1136/bcr.09.2010.3322.

      • Pomeranz J.L.
      • Munsell C.R.
      • Harris J.L.
      Energy drinks: an emerging public health hazard for youth.
      Many of the concerns expressed by health care professionals center around the increasing number of case reports, adverse event reports, calls to poison control centers, and emergency department visits that link caffeine-related toxic effects in young adults to energy drink consumption.
      • Sepkowitz K.A.
      Energy drinks and caffeine-related adverse effects.
      According to the Drug Abuse Warning Network, the number of emergency department visits that involved energy drinks doubled in the period 2007-2011.

      Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. (January 10, 2013). The DAWN Report: Update on emergency department visits involving energy drinks: a continuing public health concern. Rockville, MD.

      In fact, energy drinks are the subjects of many of the publications that constitute the recent 5-year upsurge in Figure 1.
      The spike in energy drink-related adverse events is likely a combination of several factors. First, they constitute the fastest growing segment of the US beverage market
      • Seifert S.M.
      • Schaechter J.L.
      • Hershorin E.R.
      • Lipshultz S.E.
      Health effects of energy drinks on children, adolescent, and young adults.
      and are especially popular among young adults and adolescents.
      • Pomeranz J.L.
      • Munsell C.R.
      • Harris J.L.
      Energy drinks: an emerging public health hazard for youth.
      Second, energy drinks and energy shots (a more concentrated form of energy drink) contain higher quantities of caffeine than conventional soft drinks and coffee products, yet their caffeine quantity, which can range from 9 to 250 mg/oz, is rarely indicated on product labels.
      • Kole J.
      • Barnhill A.
      Caffeine content labeling: a missed opportunity for promoting personal and public health.
      Third, because energy drinks and shots are less carbonated, or in many instances noncarbonated, they may be more easily and quickly imbibed than hot coffee or typical carbonated soft drinks. In addition, like Ephedra-free supplements, energy drinks are often formulated with a variety of botanical extracts, although the number of ingredients is far less. Besides purified caffeine, other typical components include guarana, Yerba maté, green tea, taurine (2-aminoethanesulfonic acid), glucuronolactone, Panax ginseng, yohimbe, and B vitamins.
      • Heckman M.A.
      • Sherry K.
      • de Mejia E.G.
      Energy dinks: an assessment of their market size, consumer demographics, ingredient profile, functionality, and regulations in the United States.
      • Higgins J.P.
      • Tuttle T.D.
      • Higgins C.L.
      Energy beverages: content and safety.
      Many energy drink phytochemicals are present in lower quantities than that found in Ephedra-free supplements, whereas components such as taurine and glucuronolactone are present at higher concentrations and may contribute to the purported benefits or suspected risks of energy drinks or shots.
      • McLellan T.M.
      • Lieberman H.R.
      Do energy drinks contain active components other than caffeine?.
      For example, an energy drink that contained taurine (1000 mg) and caffeine (80 mg) increased 24-hour and daytime blood pressures over that of a compounded solution that contained an equivalent dose of caffeine only.
      • Franks A.M.
      • Schmidt J.M.
      • McCain K.R.
      • Fraer M.
      Comparison of the effects of energy drink versus caffeine supplementation on indices of 24-hour ambulatory blood pressure.
      Consumption of a caffeine, taurine, and glucuronolactone formulation increased mean arterial blood pressure and platelet aggregation and decreased endothelial function in healthy young adults.
      • Worthley M.I.
      • Prabhu A.
      • De Sciscio P.
      • et al.
      Detrimental effects of energy drink consumption on platelet and endothelial function.
      Further evidence for taurine’s contribution to enhanced hemodynamic effects comes from an ex vivo preparation, in which taurine exhibited both a positive inotropic effect and potentiated caffeine-induced cardiac muscle contraction.
      • Steele D.S.
      • Smith G.L.
      • Miller D.J.
      The effects of taurine on Ca2+ uptake by the sarcoplasmic reticulum and Ca2+ sensitivity of chemically skinned rat heart.
      These additional elements aside, caffeine remains the principal psychoactive component of energy drinks and is responsible for most reported toxic effects.
      • Wolk B.J.
      • Ganetsky M.
      • Babu K.M.
      Toxicity of energy drinks.
      The final, and perhaps most controversial, contributor to the adversity surrounding energy drinks is their consumption with alcohol.
      • Wolk B.J.
      • Ganetsky M.
      • Babu K.M.
      Toxicity of energy drinks.
      • O’Brien M.C.
      • McCoy T.P.
      • Rhodes S.D.
      • et al.
      Caffeinated cocktails: energy drink consumption, high risk drinking, and alcohol-related consequences among college students.
      • Benowitz N.L.
      Clinical pharmacology of caffeine.
      For a brief period between 2009 and 2011, caffeinated alcoholic beverages were commercially available in the United States before the FDA forced their removal from the market, deeming them adulterated under the Federal Food Drug and Cosmetic Act.
      • Howland J.
      • Rohsenow D.J.
      Risks of energy drinks mixed with alcohol.
      Nevertheless, this practice has continued, with many consumers self-mixing energy drinks or shots with alcohol.
      • Howland J.
      • Rohsenow D.J.
      Risks of energy drinks mixed with alcohol.
      Although this custom appears to reduce the subjective sensation of alcohol intoxication, it does not reduce alcohol-induced motor coordination and/or visual perception deficits
      • Benowitz N.L.
      Clinical pharmacology of caffeine.
      • Ferreira S.E.
      • de Mello M.T.
      • Pompéia S.
      • de Souza-Formigoni M.L.O.
      Effects of energy drink ingestion on alcohol intoxication.
      ; therefore, individuals who combine energy drinks with alcohol may underestimate their true level of impairment.
      • Arria A.M.
      • O’Brien M.C.
      The “high” risk of energy drinks.
      In addition, the combination of energy drinks with alcohol has also been associated with greater risk-taking behaviors, such as driving under the influence of alcohol, binge drinking, or having unprotected sex.
      • O’Brien M.C.
      • McCoy T.P.
      • Rhodes S.D.
      • et al.
      Caffeinated cocktails: energy drink consumption, high risk drinking, and alcohol-related consequences among college students.
      • Benowitz N.L.
      Clinical pharmacology of caffeine.
      • O’Brien M.C.
      • McCoy T.P.
      • Egan K.L.
      • et al.
      Caffeinated alcohol, sensation seeking, and injury risk.
      • Berger L.
      • Fendrich M.
      • Fuhrmann D.
      Alcohol mixed with energy drinks: are there associated consequences beyond hazardous drinking in college students?.
      Such practices likely contribute to the increase in energy drink-related emergency department visits.
      • Nordt S.P.
      • Vilke G.M.
      • Calrk R.F.
      • et al.
      Energy drink use and adverse effects among emergency department patients.
      • Cotter B.V.
      • Jackson D.A.E.
      • Merchant R.C.
      • et al.
      Energy drink and other substance use among adolescent and young adult emergency department patients.

      Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. (January 10, 2013). The DAWN Report: Update on emergency department visits involving energy drinks: a continuing public health concern. Rockville, MD.

      When consumed sensibly and in moderation, energy drinks or shots rarely produce significant adverse health effects. From the few prospective clinical studies conducted to date, elevations in blood pressure and heart rate, as well as minor CNS effects (eg, insomnia), are commonplace.
      • Franks A.M.
      • Schmidt J.M.
      • McCain K.R.
      • Fraer M.
      Comparison of the effects of energy drink versus caffeine supplementation on indices of 24-hour ambulatory blood pressure.
      • Worthley M.I.
      • Prabhu A.
      • De Sciscio P.
      • et al.
      Detrimental effects of energy drink consumption on platelet and endothelial function.
      • Kurtz A.M.
      • Leong J.
      • Anand M.
      • et al.
      Effects of caffeinated versus decaffeinated energy shots on blood pressure and heart rate in healthy young volunteers.
      However, irresponsible overconsumption or coingestion of energy drinks or shots with other stimulants certainly contributes to caffeine-related toxic effects.
      • Seifert S.M.
      • Schaechter J.L.
      • Hershorin E.R.
      • Lipshultz S.E.
      Health effects of energy drinks on children, adolescent, and young adults.
      • Sepkowitz K.A.
      Energy drinks and caffeine-related adverse effects.

      Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. (January 10, 2013). The DAWN Report: Update on emergency department visits involving energy drinks: a continuing public health concern. Rockville, MD.

      Depending on the specific product and the number of units imbibed, ingested caffeine doses can easily exceed 1000 mg. In healthy adults, a caffeine intake of ≤400 mg/d is considered tolerable; acute clinical toxic effects begin at 1000 mg, and 5000 to 10,000 mg can be lethal.
      • Hoffman R.J.
      Methylxanthines and selective β2 agonists.
      • Seifert S.M.
      • Schaechter J.L.
      • Hershorin E.R.
      • Lipshultz S.E.
      Health effects of energy drinks on children, adolescent, and young adults.
      Although often difficult to assign specific causation, reports that link energy drinks to serious adverse health effects suggest that these products are vehicles for caffeine overdose. The increasing number of caffeine-related overdoses among adolescents and young adults presenting to emergency departments corroborates this assessment.
      • Nordt S.P.
      • Vilke G.M.
      • Calrk R.F.
      • et al.
      Energy drink use and adverse effects among emergency department patients.