Caffeine in Food and Dietary Supplements: Examining Safety: Workshop Summary (2014)

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8 Public Comments At the end of Day 1, workshop participants were invited to com- ment on any issue, with 3 minutes provided per participant. This chapter summarizes comments made, in alphabetical order by the last name of the participant. Note that the observations and opinions expressed here are those of individual workshop participants. RICHARD H. ADAMSON, Ph.D., TPN ASSOCIATES, LLC Both roasted and brewed coffees have more than one thousand com- pounds, Richard Adamson reiterated. Caffeine is not even the most abundant compound in coffee. Chlorogenic acid, trigonelline, total pep- tides, and total carbohydrates are all present in greater quantities. Energy drinks, on the other hand, generally have only four or five ingredients, usually caffeine, taurine or another amino acid, glucose or another car- bohydrate, sometimes glucuronolactone, and sometimes herbs. Caffeine is usually the only or central stimulant. There is very little evidence that any of those other ingredients have adverse effects. Adamson noted that both taurine and glucuronolactone have been examined several times by the European Food Safety Authority, which has established a no ob- served adverse effect level (NOAEL) of 1,000 mg per kg in animals and a safe level in humans of 100 mg per kg. 145 

146 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS BOB ARNOT, M.D., MEDICAL ADVISOR TO MONSTER BEVERAGE, INC. Bob Arnot found it particularly striking how little caffeine is con- sumed by adolescents and children. He clarified that the U.S. Food and Drug Administration (FDA) itself has recognized that several deaths rec- orded in the FDA Adverse Event Reporting System are not necessarily causally associated with caffeinated energy drinks. One of the two law- suits launched against Monster Energy involves a 14-year-old girl who had myocarditis. Arnot said it is important to note that no link has been found between caffeine or other stimulants and myocarditis. The second case is a 19-year-old boy who had cardiomyopathy. The boy’s lawyer alleged a causal effect resulting from 3 years of drinking energy drinks and consuming about 320 mg of caffeine per day. Again, in Arnot’s opinion, there is no link between caffeine or caffeinated energy drinks and cardiomyopathy. The boy had other risk factors for cardiomyopathy. JOEL GEERLING, M.D., Ph.D., HARVARD MEDICAL SCHOOL, BOSTON Joel Geerling remarked that he had been following for a number of years the controversies in the literature regarding caffeinated energy drinks, partly because his colleagues and patients have questions about it and partly because he himself consumes caffeinated energy drinks. He switched from coffee to caffeinated energy drinks a number of years ago because of personal preference and because he likes the moderate and consistent amount of caffeine in energy drink cans compared to cof- fee purchased from a coffee shop. He expressed disappointment with much of what he has read in the literature, even in what he considers good peer-reviewed clinical journals. He has seen what he considers ex- aggerations and, in some cases, misstatements that have passed peer re- view. As an example, he mentioned an article published in Pediatrics a couple of years ago in which the authors stated that some children are at increased risk for cardiac arrhythmias and sudden death from caffeine- containing products (Seifert et al., 2011). According to Geerling, the au- thors cited three articles that did not even contain the word “caffeine,” which Geerling found worrisome. He urged workshop participants to consider the content and quality of the evidence being discussed. One of the articles was about prenatal exposure to cocaine (Frassica et al., 

PUBLIC COMMENTS 147 1994), and the other was about the ethics of treating children with car- diomyopathies (Lipshultz, 2000). He noticed that during the work- shop discussion of behavioral survey data, no one mentioned what Geerling identified as the largest randomized controlled trial of caf- feine administration to infants and children. The trial included behav- ioral outcomes. Geerling also referred to the many other randomized controlled trials conducted with intravenous caffeine that have found no causal association between caffeine and seizures. JOHN P. HIGGINS, M.D., M.B.A., UNIVERSITY OF TEXAS MEDICAL SCHOOL, HOUSTON John Higgins observed that the physician code of ethics includes “First, do no harm.” He reiterated that caffeinated energy drinks are different from coffee. If coffee was dangerous, more issues would have emerged by now. Likewise with pure caffeine—it has a different effect. If physicians are to, first, do no harm, in Higgins’s opinion, one of the first questions that needs to be asked is: Who is vulnerable? Even if just a small percentage of children and adolescents are vulnerable, for whatever reason, then why not consider doing what others have done and protect, as a society, that small percentage? Some countries have banned such drinks altogether, and others have banned their sale to individuals under the age of 18. Also, his understanding was that the 14- year-old girl involved in one of the two lawsuits against Monster Energy was diagnosed with Ehlers-Danlos syndrome, not myocarditis. RICHARD KINGSTON, Pharm.D., SAFETYCALL INTERNATIONAL, BLOOMINGTON, MINNESOTA Richard Kingston expressed concern that the poison control adverse event data presented by Alvin Bronstein (see Chapter 3 for a summary of Bronstein’s presentation) excluded what Kingston considered two of the most important outcome categories: (1) nontoxic, no follow-up, asymptomatic outcomes, and (2) minor effect, no follow-up out- comes. The analysis presented by Bronstein was published in Clini- cal Toxicology (Bronstein et al., 2011), where all 1,480 nonalcoholic energy drink exposures are categorized into outcomes by age group. 

148 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS According to Kingston, if the excluded outcomes are included, chil- dren less than 6 years of age had the lowest incidence of adverse effects even though they had the highest exposure rate. In fact, ac- cording to Kingston, 85 percent of cases involving children less than 6 years of age were either nontoxic or resulted in minor adverse conse- quences. When including the 6- to 12-year-old population, still greater than 80 percent of cases were nontoxic, and serious outcomes were rare. Leaving out these two outcome groups distorts the denominator and exaggerates the overall relative percentage of adverse effects in all populations, Kingston explained. In his opinion, a more meaningful statistic would be to highlight the average age of all symptomatic exposure, which would likely demon- strate that older teenagers and adults should be the target populations for risk mitigation efforts. For the 13- to 20-year-old population, overall numbers of incidents were extremely low considering the ubiquitous avail- ability of products. Even for the 249 cases tabulated, serious outcomes ap- pear to be uncommon. In fact, for all populations, serious outcomes appear to be uncommon. In Kingston’s opinion, seven major effects is small. He found the analysis further disappointing in that seven cases contained virtually no incident details, such as an indication of which products may have been involved, formulation characteristics, doses of caffeine, and other factors potentially contributing to the reported adverse effects. In Kingston’s opinion, a positive and important message from Bronstein’s presentation is that more focused postmarket surveillance is needed to define which products and formulations give rise to ad- verse effects, especially in those populations routinely consuming such products. More focused postmarket surveillance would help to direct in- jury prevention methods to the appropriate populations. EMILIA C. LONARDO, Ph.D., GROCERY MANUFACTURERS ASSOCIATION, WASHINGTON, DC Caffeine has been part of the human diet for centuries, Emilia Lonardo remarked. It is a safe, naturally occurring substance found in leaves, seeds, or fruits of more than 60 plants, many of which are sta- ples in the human diet. In addition to its natural presence in commonly consumed foods, caffeine is used as a food ingredient. Caffeine safe- ty has been extensively studied, with more than 140 regulatory agencies 

PUBLIC COMMENTS 149 worldwide considering the appropriate use of caffeine in food to be safe. Lonardo expressed the Grocery Manufacturers Association’s willing- ness to work with the FDA on enhancing label information on caf- feinated products so that consumers are more aware of the caffeine content in the products they enjoy and to collaborate with the FDA on developing a guidance document that sets appropriate boundaries for the addition of caffeine to food products. Such boundaries should be based on sound scientific evidence and in the best interest of public health. REND AL-MONDHIRY, J.D., COUNCIL FOR RESPONSIBLE NUTRITION, WASHINGTON, DC The Council for Responsible Nutrition (CRN) encourages balanced robust discussions on caffeine, continued research on caffeine in all sources and its potential effect on vulnerable populations, and exami- nation of data gaps. Future policies and regulation should be based on sound science. The CRN believes that safety is paramount and, as such, supports the current regulatory framework, which helps to promote safe dietary supplement products, including those containing caffeine. The CRN also recognizes the role of industry in ensuring safe products and the importance of transparency so that consumers, particu- larly parents, can make good decisions. At the manufacturing level, good manufacturing practices help to ensure high-quality products. Manufacturers are also required by law to ensure that products are safe before they are sold and that products are labeled appropriately. Al-Mondhiry noted that the CRN-recommended labeling guidelines for caffeine-containing dietary supplements play an important role in in- forming consumers, particularly parents, about the amount of caffeine in a particular supplement and alerting those who are sensitive to caffeine about the presence of caffeine in a product. Finally, the CRN also supports mandatory adverse event report- ing, which the council views as an effective and important way to monitor safety postmarket. In closing, Al-Mondhiry expressed CRN’s support of the type of dialogue being fostered at this workshop and looks forward to working with the FDA on any future guidance documents for these products. 

150 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS J. PHILIP SAUL, M.D., UNIVERSITY OF SOUTH CAROLINA, MOUNT PLEASANT, AND CONSULTANT TO THE AMERICAN BEVERAGE ASSOCIATION As a pediatric cardiologist, Phil Saul divides his patients into three groups: (1) patients under the age of 12, for whom he does not recom- mend caffeine but does not restrict chocolate; (2) patients between the ages of 12 and 18, for whom he recommends no caffeine only if the pa- tient has an underlying cardiac condition (the three main conditions of concern being arrhythmias, syncope, and any kind of significant cardio- myopathy); and (3) other patients. Although evidence suggests that most arrhythmias are not exacerbated by caffeine, some are, and almost all physicians recommend that patients with arrhythmias avoid caffeinated beverages. Saul recommends slow withdrawal for patients with benign syncope, which is often exacerbated by caffeine. Saul usually queries his patients about the types of beverages they consume because most patients between the age of 12 and 18 are not aware of caffeine in the products they are consuming. He observed that energy drinks almost never come up. Although the data presented at this workshop suggest that energy drinks have been replacing other sources of caffeine over the past few years, he has not been observing that trend. Most of his patients drink sweet tea, Mountain Dew, and occasionally Pepsi. Saul generally recommends moderation, which he considers 3–5 mg per kg per day, so 2 to 3 servings of 1 to 1.5 mg per kg. With respect to the sudden deaths, Saul opined that almost all ado- lescents who die suddenly have an underlying cardiac condition. Not all conditions can be identified, but they include long QT syndrome, hyper- trophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, and catecholaminergic polymorphic ventricular tachycardia. Although one might expect individuals with any of these underlying conditions to be sensitive to caffeine, the evidence does not indicate such. JOHN R. WHITE, JR., Pharm.D., WASHINGTON STATE UNIVERSITY, SPOKANE John White commented on a suggestion made earlier during the workshop that the rapid intake of caffeine associated with energy drink consumption is problematic. In his opinion, however, based on the ki- 

PUBLIC COMMENTS 151 netics of caffeine, that is, time of absorption and half-life, intake time is of only nominal consequence with respect to peak concentrations. On the basis of some models that he has run, White observed that peak con- centrations are the same whether the input is immediate (intravenous), fast (5 minutes), or slow (45 minutes). White also commented on the association between caffeine and risky behavior and cautioned that there are not enough data to suggest a causal relationship between the con- sumption of caffeinated energy drinks and progression to the use of more-addictive drugs. REFERENCES Bronstein, A. C., D. A. Spyker, L. R. Cantilena, B. H. Rumack, and R. C. Dart. 2011. 2011 annual report of the American Association of Poison Control Centers’ National Poison Data Systems (NPDS): 29th annual re- port. Clinical Toxicology 50:911–1164. Frassica, J. J., E. J. Orav, E. P. Walsh, and S. E. Lipshultz. 1994. Arrhythmias in children prenatally exposed to cocaine. Archives of Pediatric and Adolescent Medicine 148(11):1163–1169. Lipshultz, S. E. 2000. Ventricular dysfunction clinical research in infants, children and adolescents. Progress in Pediatric Cardiology 12(1):1–28. Seifert, S. M., J. L. Schaechter, E. R. Hershorin, and S. E. Lipshultz. 2011. Health effects of energy drinks on children, adolescents, and youth. Pediat- rics 127(3):511–528.