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

Clinical Therapeutics/Volume ], Number ], 2014

Multi-ingredient, Caffeine-Containing Dietary Supplements: History, Safety, and Efficacy Bill J. Gurley, PhD1; Susan C. Steelman, MLIS2; and Sheila L. Thomas, MA(LS)2 1

Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, College of Pharmacy, Little Rock, Arkansas; and 2Education and Reference Services, University of Arkansas for Medical Sciences Library, Little Rock, Arkansas

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 caffeinecontaining 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. (Clin Ther. 2014;]:]]]–]]]) & 2014 Elsevier HS Journals, Inc. All rights reserved.

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Key words: caffeine, dietary supplements, Ephedra, Ephedra-free, energy drinks.

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 4500 years.1 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.2 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 (r200 mg).3 Because of its CNS stimulant properties, purified caffeine (r200 mg) can also be found in various nonprescription drug products (eg, NoDozs [caffeine] and Excedrins [acetaminophen, aspirin, and caffeine]). When consumed in moderation, caffeine-containing products have an excellent safety profile. Apart Accepted for publication August 23, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.08.012 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics from CNS stimulation, moderate caffeine consumption can, in many instances, transiently increase blood pressure and reflexively lower heart rate.4 Long-term ingestion of caffeine, however, can lead to pharmacologic tolerance of some CNS effects4 but not necessarily its cardiovascular effects.4,5 Excessive amounts of caffeine (42000 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.6 The deleterious aspects of caffeine overconsumption were first recognized in 1833,7 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.6 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 1994.8 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.

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 ap-

1800

Number of publications identified

1600 PubMed

WOS

1400 1200 1000 800 600 400 200

1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

0

Year

Figure 1. Citation counts for articles about caffeine adverse effects in the PubMeds and Web of Science (WOS)™ databases by year.

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B.J. Gurley et al. petite suppressants and legal speed.9 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.9 In 1982, the FDA deemed look-alikes as unapproved new drugs that presented a potential health hazard.10 By 1988, the FDA disallowed the marketing of lookalikes as nonprescription medications.11 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 2002.12 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.”8 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 βadrenergic 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

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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 2003.13–41 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.17,25,36 Unlike the over-the-counter amphetamine look-alikes, Ephedracontaining 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.42 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, psynephrine, 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.43 Also, like Ephedra, Ephedrafree 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,

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Clinical Therapeutics adverse event reports, and calls to Poison Control Centers—eerily similar to their Ephedra-containing predecessors—seem to belie this connotation.44–58 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 Bulls 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.59 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.60–75 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 2011.76,77 Nevertheless, the combination of energy drinks and alcoholic beverages remains a cause for alarm for both health care professionals and law enforcement officials.76–79 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, caffeinecontaining 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

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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 γaminobutyric acid neurotransmission.4,80 Only at higher serum concentrations (425 mg/mL) do the later 3 mechanisms appear to contribute significantly to caffeine pharmacodynamics.4 Caffeine’s dosedependent 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).4,80 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.4) Caffeine can also reduce cerebral, hepatic, and mesenteric blood flow and produce mild diuresis via increased glomerular filtration and enhanced sodium and water excretion.80 At higher doses, caffeine can also cause other pharmacodynamic effects, including bronchodilation, lipolysis, hyperglycemia, and hypokalemia.80 Caffeine-induced hypokalemia could contribute to ventricular arrhythmias and sudden death.75 Long-term consumption of caffeine, however, can lead to pharmacologic tolerance, which can occur within a few days.81 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.82 Such sensitivities may be attributable, in part, to an individual’s genetic makeup.83 Only

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B.J. Gurley et al. 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,84,85 anxiety,86,87 habitual coffee consumption,88 and blood pressure elevation,89 whereas animal studies hint that cardiac ryanodine receptor mutations may increase caffeine’s arrhythmogenic potential.90 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,91 elevated blood pressure,92 and the incidence of acute coronary events.93 Despite these emerging genecaffeine 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.94 Peak blood concentrations of caffeine are usually achieved within an hour of ingestion.95 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.95 Accordingly, caffeine readily crosses the blood brain barrier and can be found in almost all body fluids and tissues.95 The pharmacokinetic properties of caffeine are dose dependent, which likely contributes to toxic effects associated with many caffeine-containing dietary supplements.96 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.95 Caffeine’s principal CYP1A2-mediated metabolite in humans is paraxanthine, which exhibits pharmacologic effects similar to its parent compound,97,98 whereas minor metabolites include theophylline and theobromine.97 Caffeine clearance is highly variable, and both genetic and environmental factors (eg, diet, smoking, and oral contraceptive use) are contributors to this variability.95,99,100 Like the receptor polymorphisms mentioned above, allelic variants in CYP1A2 can affect caffeine’s pharmacokinetic properties and pharmacologic response. Among caffeine users, both

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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),101 whereas slow metabolizer phenotypes (heterozygous CYP1A2*1F) have been linked to higher risks of hypertension102 and nonfatal myocardial infarction.103 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.95,100 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.99 Other phytochemicals thought to affect the pharmacokinetic properties of caffeine when consumed concomitantly include tanshinone,104 quercetin,105 genistein,106 curcumin,107 daidzein,108 and naringenin.109 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)110–112 and α2adrenergic antagonists from the African plant Pausinystalia yohimbe (eg, yohimbine and rauwolscine),113 as well as synthetic stimulants such as amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, and cocaine.114–116 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,17 myocardial infarction,17 stroke17,117, seizure,17,23 hypertensive crisis,118 and exertional heat illness.119–121 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.95 Several studies suggest that caffeine

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Clinical Therapeutics disposition is not significantly altered during exercise,122,123 while other studies indicate that peak caffeine plasma levels may be enhanced.124 Likewise, obesity’s effect on caffeine pharmacokinetic properties is also difficult to predict.125–127 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.128–133 Of particular concern is the recent finding that caffeine reduces myocardial blood flow during exercise.134 Such consequences could have significant health repercussions, especially in caffeine-naive, untrained athletes.135,136 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.17,25,137–139 The more serious events included myocardial infarctions,15,17,22,25,28,40 17,19,20,24,25,27,30,33,39,117 strokes, arrhythmias,17,25,36 17,23,140 18,29,32,37 seizures, psychoses, and rhabdomyol119–121 ysis. 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. The imprudence of combining Ephedra with other natural stimulants was recognized by the Chinese thousands of years ago.141 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).141 Why combinations of Ephedra and natural caffeine

Table I. Examples of Ephedra-containing dietary supplement formulations. Metabolife™ Ephedra extract Guarana extract Bee pollen Ginseng Ginger Bovine complex Damiana Sarsaparilla Goldenseal Nettles Gotu kola Spirulina algae Royal jelly

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Xenadrine RFA™

Yellow Jacket™

Ripped Fuel™

Ephedra extract Guarana extract Citrus aurantium White willow bark Acetyl L-carnitine L-tyrosine Ginger root Vitamin B5

Ephedra extract Kola nut extract Citrus aurantium Capsicum Ginseng Sida cordifolia Ginger root

Ephedra extract Guarana extract L-carnitine Chromium

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Table II. Ephedra: East versus West. China 5000-year history of use Treatment of asthma and nasal congestion Duration of use: 7-10 days Rarely combined with other stimulants, such as caffeine Administered as a decoction (Ephedra tea)

United States Extensive use from 1994 to 2004 Diet aid, energy booster, exercise performance enhancer Indicated for long-term use Usually combined with other stimulants (caffeine, synephrine, yohimbine) Administered as concentrated extracts (tablets, capsules, sconcentrated liquid)

Not indicated as a diet aid

sources were potentially hazardous can be easily explained with a brief summary of ephedrine alkaloid pharmacology. Ephedrine alkaloids are nonspecific indirect agonists for α1-, β1-, β2-adrenergic receptors.142 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.140 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.143 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.144 Unlike caffeine, ephedrine alkaloids are excreted unchanged primarily via renal mechanisms. Sensitivity to ephedrine alkaloids can also be manifested through adrenergic receptor genetic polymorphisms.145 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,146 and lower seizure thresholds.115 That caffeine and other phytochemicals can potentiate the cardiotoxic effects of Ephedra and ephedrine alkaloids was revealed in several rodent toxicity models.147–150 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

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significantly increased.149,150 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.150 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. 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.151 Catechin polyphenols include epigallocatechin-3gallate (EGCG), epigallocatechin, epicatechin, among others. The catechins are readily absorbed from the gastrointestinal tract and undergo significant

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Clinical Therapeutics Table III. Influence of product complexity on Ephedra supplement toxicity.* Composition, mg/mL

Supplement EPH 833™ (AST Sports Science, Golden, CO) Metabolife™ (Metabolife International Inc., San Diego, CA) Ripped Fuel™ (Twin Laboratories, Ronkonkoma, NY) Xenadrine™ (Cytodyne Technologies, Lakewood, NJ)

Dose, Mice, No. Volume, mL Mortality PSE EPH MEPH Total mg/kg 4

0.4

0/4

3.3

7.3

0.1

10.7

357

4

0.4

3/4

0.4

1.8

0.0

2.2

73

4

0.4

3/4

0.9

0.4

0.6

1.9

63

4

0.4

4/4

0.8

2.3

0.0

3.1

103

EPH ¼ ephedrine; MEPH ¼ methylephedrine; PSE ¼ pseudoephedrine. * 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.

presystemic metabolism, primarily via methylation, glucuronidation, and sulfation.152,153 Catechins and their conjugated metabolites are widely distributed in tissues.152,153 Catechins and even their metabolites can inhibit COMT152,154—an enzyme involved in the peripheral metabolism of catecholamine neurotransmitters —and by doing so exacerbate the pharmacologic effects of ephedrine and caffeine.155 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.156 Thus, catechins present in green tea or guarana may give rise to pharmacokinetic-based herbdrug interactions if taken concomitantly with OATP1A2 substrates. Moreover, certain catechins elicit their own inotropic effect on the heart,157 which may have contributed to the adverse cardiovascular effects of Ephedra supplements. 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.158 By itself, p-synephrine is a fairly innocuous compound,159 but when combined with other stimulants, such as ephedrine and caffeine, it can add

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to the cardiovascular stress of these products.123,160 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.161 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,162 capsaicin,163 ginsenosides,164 and gingerol,165 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

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Table IV. Examples of Ephedra-free dietary supplement formulations. Xenadrine EFX™

Zantrex 3™

Meltdown™

Metabolift™

Guarana Green tea

Guarana Green tea

Yerba maté Ginger root Salvia sclarea extract

Yerba maté Caffeine Kola nut

Caffeine anhydrous α-Methyltetradecylthioacetic acid Yerba maté 3’,5’-cyclic AMP Methyl-synephrine HCl

Calcium tribasic

Damiana

R-β-phenylethylamine

DL-Methionine

Schizonepeta Piper nigrum Tibetan ginseng Panax ginseng Maca root Cocoa nut Thea sinensis Niacin

N-methyl-β-phenylethylamine 11-Hydroxy yohimbine Yohimbine HCl α-Yohimbine Methyl-hordenine HCl

L-theanine

Cocoa extract L-tyrosine Acetyl-L-tyrosine Grape seed extract Vitamin C Vitamin B6 Pantothenic acid Magnesium Theobromine Phenylethylamine 2-Dimethylaminoethanol Tetrahydroxyflavone Pentahydroxyflavone

Hydroxycut Hardcore™

Guarana Green tea

Caffeine anhydrous Green coffee extract

Citrus aurantium Ginger root Quercetin dehydrate

L-theanine

Citrus bioflavonoid complex L-Phenylalanine Cayenne fruit St. John’s Wort extract

Coleus forskohlii (forskolin) Cocoa extract (theobromine) Yohimbe extract (yohimbine, rauwolscine)

AMP ¼ adenosine monophosphate.

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.95 Nicotine also appears to exacerbate the cardiovascular toxic effects of Ephedra-containing dietary supplements,150 which may partially explain why many case reports of Ephedra-related myocardial infarction involved smokers.28,40,41,166,167 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.17,36,120,168–172 Before their removal from the market, only one study assessed the effect of exercise

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on the cardiovascular effects of a caffeine-containing Ephedra supplement among nonathletes. Kleinjan173 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, Kleinjan173 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

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Clinical Therapeutics 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 lotto-lot variability in ephedrine alkaloid and caffeine content.174 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.175–177 In addition, assessments of the Toxic Exposure Surveillance System of the American Association of Poison Control Centers revealed that Ephedracontaining supplements were more likely to result in severe medical outcomes than botanical products that did not incorporate Ephedra.137,138 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.178 By 2004, an ever-increasing number of adverse effects prompted the FDA to remove Ephedra-containing dietary supplements from the market.42 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,44,47,50,51,53 strokes,46,49,56,57 seizures,58 psychoses,55 rhabdomyolysis,48,177–182 and other sympathomimetic-associated injuries45,52,54 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.183 Moreover, few products provide an adequate indication of caffeine quantity on the product label.43,184 This can be especially troubling for individuals who are overly sensitive to

“Not for use by persons under age 18. Do not use if pregnant or nursing. Consult a physician or licensed qualified health care professional (“physician”) before product use if you have a family history of heart or thyroid disease, diabetes, high blood pressure, recurrent headaches, depression, any psychiatric condition, glaucoma, difficulty urinating, enlarged prostate, seizure disorder, if you are using a monoamine oxidase inhibitor (MAOI) or any other dietary supplement, or prescription drug, or over-the-counter drug containing ephedrine, pseudoephedrine, or phenylpropanolamine (ingredients found in certain allergy, asthma, cough/cold and weight control products) or if you intend on taking to reduce weight. Exceeding recommended serving may cause serious adverse health effects including heart attack and stroke. Discontinue use and call a physician immediately if you experience rapid heartbeat, dizziness, severe headache, shortness of breath, or other similar symptoms. Individuals who consume caffeine with this product may experience serious adverse health effects. Keep out of reach of children.”

Figure 2. Example of a typical warning label from an Ephedra-containing dietary supplement.

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B.J. Gurley et al. caffeine or who may be taking prescription stimulants (eg, Adderals [amphetamine, dextroamphetamine mixed salts] and Ritalins [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.43 Recently, many Ephedra-free supplements have been haunted by the specter of adulteration. The purposeful addition of prescription stimulants, such as sibutramine,185 designer stimulants, such as dimethylamylamine,186 or methamphetamine analogs, such as N,α-diethyl-phenylethylamine,187 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.57,188 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

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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.189 Yohimbine also has 2 active hydroxylated metabolites, each with pressor activity and longer elimination half-lives in humans.190 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.190 When combined with caffeine and exercise, yohimbine has an additive effect on plasma norepinephrine concentrations, producing undesirable cardiovascular effects, especially in obese individuals.113 Yohimbine also selectively attenuates baroreflex heart rate control in normotensive adults191 and can prolong QTc intervals, which may lead to the development of serious arrhythmias.192 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.193 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.194 Attendant to their effects on COMT, catechin polyphenols also appear capable of inhibiting cardiac ion channels,195,196 in particular human hERG potassium channels at plasma concentrations achievable with some products.197 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.198–200 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

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Clinical Therapeutics

DO NOT USE IN COMBINATION WITH CAFFEINE OR ANY STIMULANTS FROM OTHER SOURCES WHATSOEVER, INCLUDING BUT NOT LIMITED TO, COFFEE, TEA, SODA AND OTHER DIETARY SUPPLEMENTS OR MEDICATIONS. DO NOT USE UNDER EXTREME CONDITIONS OF HEAT, SLEEP DEPRIVATION, OR DEHYDRATION. DO NOT COMBINE WITH ALCOHOL. This product is only intended to be consumed by healthy adults 18 years of age or older. Before using this product consult with your physician if you are using any prescription or over the counter medication or if you have any pre-existing medical condition including but not limited to: high or low blood pressure, cardiac arrhythmia, stroke, heart, liver, kidney or thyroid disease, seizure disorder, psychiatric disease, diabetes, difficulty urinating due to prostate enlargement or if you are taking an MAOI (Monoamine Oxidase Inhibitor) or any other medication. This product contains caffeine and should not be taken by individuals wishing to eliminate this ingredient from their diet. Discontinue use 2 weeks prior to surgery. Discontinue use and consult your health care professional if you experience any adverse reaction to this product. Do not exceed recommended serving. Do not use if safety seal is broken or missing. Do not use for more than 5 out of 7 consecutive days. KEEP OUT OF REACH OF CHILDREN.

Figure 3. Example of a typical warning label from an Ephedra-free dietary supplement.

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.201 Presystemic metabolism by intestinal and hepatic CYPs can impede phytochemical bioavailability202; 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.203 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 CYP2D6.203 Improved phytochemical bioavailability via CYP inhibition may augment not only product efficacy but also its toxicity.204 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.203 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.4 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.205 Forskolin’s ampli-

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fication of intracellular cAMP accounts for its positive inotropy and its ability to intensify caffeine’s effect on adenosine receptors.206 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.207 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,208–210 or electrocardiographic findings211 or only modest increases in systolic212,213 or diastolic blood pressure,123,212,213 suggesting that these products may not be as problematic as Ephedra-containing supplements. These studies, however, investigated only a single, one-time dose123,208,209,213 or doses that were only half the label recommendation.210,211 Studies that used only single, acute doses or dosing regimens less than label recommendations may not be representative of typical

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B.J. Gurley et al. 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 labelrecommended dosing noted a variety of untoward sympathomimetic-related adverse effects and significant changes in hemodynamic and electrocardiographic parameters.184 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.183,214) 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.122 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.61,215 Principal reasons for such high use include increased alertness, compensation for insufficient sleep, athletic performance enhancement,215 or peer pressure.216 Aggressive marketing campaigns by manufacturers drive energy drink sales but may also increase potential health

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risks. Paralleling the public’s support for energy drinks is a growing anxiety within the medical community.61,62,71 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.74 According to the Drug Abuse Warning Network, the number of emergency department visits that involved energy drinks doubled in the period 2007-2011.217 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 market61 and are especially popular among young adults and adolescents.71 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.43 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.59,218 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.219 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.220 Consumption of a caffeine, taurine, and glucuronolactone formulation increased mean arterial blood pressure and platelet aggregation and decreased endothelial function in

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Clinical Therapeutics healthy young adults.221 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.222 These additional elements aside, caffeine remains the principal psychoactive component of energy drinks and is responsible for most reported toxic effects.64 The final, and perhaps most controversial, contributor to the adversity surrounding energy drinks is their consumption with alcohol.64,78,79 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.79 Nevertheless, this practice has continued, with many consumers selfmixing energy drinks or shots with alcohol.79 Although this custom appears to reduce the subjective sensation of alcohol intoxication, it does not reduce alcohol-induced motor coordination and/ or visual perception deficits79,223; therefore, individuals who combine energy drinks with alcohol may underestimate their true level of impairment.76 In addition, the combination of energy drinks with alcohol has also been associated with greater risktaking behaviors, such as driving under the influence of alcohol, binge drinking, or having unprotected sex.78,79,224,225 Such practices likely contribute to the increase in energy drink-related emergency department visits.65,72,217 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.220,221,226 However, irresponsible overconsumption or coingestion of energy drinks or shots with other stimulants certainly contributes to caffeine-related toxic effects.61,74,217 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 r400 mg/d is considered tolerable; acute clinical toxic effects begin at 1000 mg, and 5000 to 10,000 mg can be lethal.6,61 Although often difficult to assign specific causation, reports that link energy drinks to serious adverse health effects suggest that these

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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.65,72,73,217 Of course, as discussed in previous sections, certain environmental, genetic, and medical circumstances may predispose individuals to the effects of caffeine present in energy drinks or shots.

EFFICACY OF CAFFEINE-CONTAINING DIETARY SUPPLEMENTS Ephedra-Containing Dietary Supplements During their heyday, Ephedra-containing dietary supplements were touted as thermogenic weight loss aids, and it was through this marketing strategy that they achieved their widest distribution. The purported cornerstone of ephedrine-mediated thermogenesis was the activation of β3-adrenoreceptors.227 Ephedrine, however, has only weak partial agonist activity on β3-adrenoreceptors.228 Furthermore, ephedrine plasma concentrations necessary for β3-activation are 1000 times greater than that attainable after Ephedra administration.228 It is conceivable that ephedrinestimulated norepinephrine release could stimulate β3thermogenesis; however, human studies have failed to confirm this premise.229 It appears that β3-mediated lipolysis and thermogenesis are primarily restricted to rodents.230 Thus, mechanisms other than β3-receptor stimulation likely accounted for the observed increases in energy expenditure after ephedrine and caffeine administration. In the late 1980s and early 1990s, several prospective clinical studies in Denmark evaluated prescription ephedrine and /caffeine combinations for weight loss.178,231 Moderate weight loss and minimal adverse effects suggested that ephedrine and caffeine might provide an economical alternative to prescription anorectic agents. These pre-DSHEA findings fueled Ephedra sales in the United States, yet only a few small clinical trials attempted to evaluate their efficacy.231–237 As it turned out, the effectiveness of Ephedra was, at best, weak. Mean weight losses of 1 to 5 kg, occurring during 8 to 36 weeks, were characteristic of results obtained under medically supervised conditions.178 In addition, hemodynamic and CNS-related adverse effects were also common sequelae. When compared to the US experience with Ephedra supplements, a paucity of adverse effects among the medically supervised Danish studies led

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B.J. Gurley et al. to speculation that other ingredients besides ephedrine and caffeine were at work.238 Coincident with their promotion as diet aids, multiingredient Ephedra supplements were also marketed as exercise performance enhancers or ergogenic aids. Initial support for this indication came from a series of studies, generated by one research group, that evaluated purified ephedrine and caffeine combinations on various ergogenic end points among well-trained participants.239–244 Improvements in cycling time to exhaustion and running times, as well as lower ratings of perceived exertion, were attributed to CNS stimulation because no changes were noted for oxygen consumption, carbon dioxide production, or fat oxidation. Subsequent studies by other investigators, however, found that Ephedra-containing dietary supplements had no significant effect on muscle strength, muscle endurance, or peak anaerobic power when compared with placebo or caffeine alone.245 Because the toxic effects of sympathomimetic agents can be exacerbated by physical exercise, dehydration, and increased body temperature,246 serious adverse events that occurred during the unsupervised use of Ephedra supplements as ergogenic aids were not unexpected.17,36,121,169–173 As with the weight loss studies, multi-ingredient Ephedra-containing supplements appeared to pose greater risks to athletes than simple ephedrine and caffeine preparations. Thus, the admonition of a reviewer in 2001 that “the risks associated with the use of ma huang [Ephedra] far outweigh any possible ergogenic benefits” was quite prescient.247

Ephedra-Free Dietary Supplements To compensate for the absence of ephedrine alkaloids, Ephedra-free supplements typically incorporate a larger and more diverse assemblage of botanical extracts as evidenced by the formulations in Table IV. Integration of multiple natural caffeine sources (eg, green tea, guarana, kola nut, and Yerba maté) is a common feature of these products. Notwithstanding the disparate nature of Ephedra-free formulations, the preponderance of efficacy studies that have been conducted since the ban on Ephedra have used only green tea extract (GTE) preparations. GTEs (C sinensis) are complex mixtures of catechin polyphenols and caffeine. Catechins account for approximately 35% of the dry weight of C sinensis leaves, with EGCG being the most abundant; caffeine makes up

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approximately 2% to 5% of water extractable solids from the leaves.248 The phytochemical content of GTE can vary, depending on assorted growing, harvesting, drying, and processing methods. Consequently, clinical trial results often differ, depending on the particular GTE preparation administered. It has been hypothesized that the increase in energy expenditure and fat oxidation attributed to GTE stems from a synergy between caffeine and catechins, with the former stimulating norepinephrine release and the latter inhibiting norepinephrine metabolism via COMT inhibition. This may explain why caffeine-free GTE products are less effective as weight loss aids.248 To date, more than 50 clinical studies have examined the effectiveness of GTE as a weight loss or weight management aid. Recent meta-analyses of some of the better designed trials concur that prolonged administration (Z12 weeks) of caffeinecontaining GTE produce only modest reductions in anthropomorphic measures (eg, body mass index, weight, waist circumference, and waist-to-hip ratios). These reductions, however, although sometimes statistically significant, were deemed unlikely to be clinically relevant.249–251 In contrast, only 5 placebocontrolled studies with durations of Z8 weeks have evaluated multi-ingredient Ephedra-free formulations that incorporate either GTE or other natural caffeine sources (eg, guarana and kola nut) for their effectiveness in promoting weight loss.252,253 (Unfortunately, 2 of these studies remain unpublished.) All the studied formulations also included extracts of C aurantium, a source of the weak sympathomimetic agent p-synephrine, which serves as an Ephedra surrogate. Administered as part of a medically supervised diet and exercise regimen, the products—relative to placebo— generated reductions in body mass ranging from 0 to 3.1 kg with no serious adverse effects. As with GTE, the results of this small cadre of studies do not support the utility of these products as instruments for achieving clinically significant weight loss. Ephedra-free supplements are also touted as exercise performance enhancers, and a significant body of evidence supports the use of caffeine as an ergogenic aid. The consensus from several reviews of the available literature indicates that exercise performance benefits can be seen with moderate amounts (approximately 3 mg/kg) of caffeine and that these benefits are likely to occur across a range of sports, including endurance events and short-term, high intensity

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Clinical Therapeutics exercise.254–258 Alterations in perceived exertion, reaction time, cognition, and/or mood as a result of adenosine antagonism are the most probable mechanisms for caffeine ergogenesis,256,257 and it appears that elite athletes who do not regularly consume caffeine garner the most benefit.256 Furthermore, in controlled studies, anhydrous caffeine appears to impart a greater advantage over coffee, energy drinks, or dietary supplements.259 This may stem from the inconsistency of caffeine content among commercially available products. The small number of manufacturer-sponsored, placebo-controlled studies that have evaluated the ergogenic potential of multi-ingredient caffeine-containing dietary supplements have yielded results that appear dependent on the degree of athletic training. Among untrained or moderately trained volunteers, ingestion of these products r1 hour before exercise (approximately 200 mg of caffeine) produced no measureable benefit in aerobic or anaerobic exercise performance parameters.260–262 In resistance-trained athletes undergoing Wingate Anaerobic Tests, an acute increase in upperbody strength was noted 1 hour after supplementation (201 mg of caffeine); however, no improvements were observed among measures of lower-body strength, muscular endurance, anaerobic capabilities, or upperbody muscular endurance.263 When administered to endurance-trained men as part of a cycling time trial, a GTE supplement also had no measurable effect on athletic performance or energy metabolism.264 Taken together, these few studies do not support the ergogenic potential of Ephedra-free supplements. Although their ergogenic effects may be unconvincing, a plethora of multi-ingredient, caffeinecontaining preworkout supplements are currently marketed to athletes. From the number of case reports describing serious adverse events with such products, it would appear their risks outweigh any purported benefits, particularly in the context of vigorous exercise.50,51,57,179–182,188,265,266 A likely contributor to the toxicity of many of these products is their adulteration with synthetic stimulants. Recently, a rash of adverse events, including myocardial infarction and stroke, have been linked to dietary supplements that contain caffeine and 1,3-dimethylamylamine (DMAA) when ingested as preworkout supplements.57,188,265–267 Originally reported as a phytochemical present in geraniums, DMAA is a synthetic stimulant—initially developed in the

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1940s as a nasal decongestant but removed from the market in 1983—whose presence in dietary supplements is a consequence of purposeful adulteration.186 The combination of DMAA and caffeine has a dose-dependent effect on blood pressure, and although this effect appears innocuous in nonexercising individuals,268 it also has no adverse effects or ergogenic benefits when administered to exercisetrained individuals.269 What remains to be determined is a tolerability assessment of the marketed, multi-ingredient products that contain caffeine and DMAA in conjunction with exercise. Such an assessment, however, is not likely to occur because the manufacturer of the 2 most popular DMAA-containing products (Jack3d™ [proprietary blend of arginine alpha-ketoglutarate, creatine monohydrate, beta alanine, caffeine, 1,3-dimethylamylamine HCL, and Schisandra chinensis extract] and OxyElite Pro™ [proprietary blend of Bauhinia purpurea L. extract, Bacopa (Bacopa monnieri) extract, 1,3-dimethylamylamine HCL, Cirsium oligophyllum extract, and yohimbe (Pausinystalia yohimbe) bark extract and caffeine]) recently agreed to discontinue their production at the behest of the FDA.270 Nevertheless, a surfeit of case reports strongly suggests that exercise may exacerbate DMAA and caffeine toxic effects in susceptible individuals. Caffeine’s capacity to augment the toxic effects of other stimulants,110–116 coupled with its ability to increase cardiac workload133 and reduce myocardial blood flow during exercise,134 render Ephedra-free supplements as irrational ergogenic aids. Besides p-synephrine, yohimbine, and DMAA, other stimulants not listed on product labels (eg, oxilofrine, deterenol, and N,α-diethylphenylethylamine) have also been detected in multiingredient, preworkout supplements, and caffeine may bolster their toxic effects when administered together as an ergogenic supplement.187,271

Energy Drinks and Shots Improvements in mood and cognition are effects desired by just about every member of today’s fastpaced society. Reaction time, concentration, alertness, and subjective feelings of energy or vitality are important for athletes in many competitive sports. Strategies to enhance these attributes are often sought by nonathletes and athletes alike. During the last decade, several prospective studies have assessed the

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B.J. Gurley et al. effects energy drinks may have on these and other performance variables.272 Like coffee and other caffeine-containing beverages, energy drinks—when consumed sensibly—can improve and/or maintain mood and cognitive performance as determined by a variety of mood and cognition assessment instruments.272–275 Despite their varied ingredients, however, it appears that caffeine is the agent primarily responsible for the psychopharmacologic effects of energy drinks.273–275 The International Society of Sports Nutrition recently reviewed the ergogenic potential of energy drinks and came to the following conclusions. First, the primary ergogenic nutrients in energy drinks appear to be caffeine and/or carbohydrate. Second, the ergogenic contribution of other nutrients besides caffeine is minor. Third, consuming an energy drink r60 minutes before exercise can improve mental focus and alertness and may improve endurance performance in trained athletes. Fourth, ingestion of high-calorie energy drinks may promote weight gain. Fifth, children or adolescents should only consider using energy drinks with parental approval, and parents should be aware of potential adverse effects. Sixth, indiscriminate use may lead to adverse events and adverse effects. Seventh, individuals with diabetes or underlying cardiovascular, hepatorenal, or neurologic disease who are taking prescription medications or other stimulants should avoid energy drinks unless approved by their physician.272 Taken together, these cautionary aspects are equally applicable to any multi-ingredient, caffeine-containing dietary supplement. Energy shots, however, may be more problematic than energy drinks. A recent assessment of a single dose of 5-Hour Energys (niacin, vitamin B6, folic acid, vitamin B12, sodium, and an energy blend of taurine, glucuronic acid, malic acid, N-acetyl-L-tyrosine, L-phenylalanine, caffeine, and citicoline) on both subjective and objective measures found that participants reported increased ratings of vigor and decreased ratings of fatigue, although reaction times to a cued go/no-go task were not affected.276 Thus, although consumers may perceive improvements in subjective state, the benefits may not extend to objective performance. Coincident to participants’ perceptions of vigor and fatigue were significant increases in both systolic and diastolic blood pressure, lasting up to 6 hours after product

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ingestion. This finding prompted the authors to conclude that benefits of energy shots may be limited to improvements in subjective state and thus may not outweigh potential health risks, particularly for vulnerable individuals.

CONCLUSION Since their introduction in 1994, multi-ingredient, caffeine-containing dietary supplements have become one of the most widely used alternative medicines in the United States. What many consumers and health care professionals fail to realize is that these products are unlike coffee, tea, or other more conventional sources of caffeine. Such differences stem from the unpredictable pharmacologic consequences that can result when indiscriminate combinations of botanical extracts are formulated together and then consumed for the purposes of weight loss or exercise performance enhancement. It is clear that in this context caffeine may not be as innocuous as many consumers have come to believe. This popularity may ultimately lead to their ruin—like that of Ephedra—particularly for those consumers sensitive to caffeine. The marked increase in Ephedra-free supplement and energy drink use may aid in uncovering caffeine-sensitive individuals, which, in turn, might account for the proliferation of case reports and adverse event reports associated with these products. This finding illustrates a fundamental principle of prevention strategy put forth by the eminent British epidemiologist Geoffrey Rose: “A large number of people exposed to a low risk is likely to produce more cases than a small number of people exposed to a high risk.”277 Some caffeine-containing dietary supplements, however, appear more risky than others.

ACKNOWLEDGMENTS The concept and writing of the article was performed by Bill J. Gurley. Susan C. Steelman and Sheila L. Thomas performed the literature searches for the article, created Figure 1, and assisted in the writing of the manuscript.

CONFLICTS OF INTEREST Dr. Gurley has served as a paid expert witness in litigation involving manufacturers of dietary supplements and is a member of the US Pharmacopoeia’s Expert Panel on Dietary Supplements.

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Address correspondence to: Bill J. Gurley, PhD, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, College of Pharmacy, 4301 W Markham St, Mail Slot 5822, Little Rock, AR 72205. E-mail: [email protected]

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