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Introduction
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BACKGROUND AND WORKSHOP OBJECTIVES

Caffeine, a central nervous system stimulant, is arguably the most frequently ingested pharmacologically active substance in the world. Occurring naturally in more than 60 plants, including coffee beans, tea leaves, cola nuts, and cocoa pods, caffeine has been part of innumerable cultures for centuries. But the caffeine-in-food landscape is changing. From waffles to sunflower seeds, jelly beans to syrup, and even bottled water, the array of new caffeine-containing energy products, including energy drinks and supplements entering the marketplace, is, in the words of U.S. Food and Drug Administration (FDA) commissioner Margaret Hamburg, “truly mind boggling.” Years of scientific research have shown that moderate consumption by healthy adults of products containing naturally occurring caffeine is not associated with adverse health effects. But the changing caffeine landscape raises concerns about safety and whether any of these new products might be targeting populations not normally associated with caffeine consumption, namely, children and adolescents, and whether caffeine poses a greater health risk to those populations than it does to healthy adults.

At the request of the FDA, on August 5–6, 2013, the Institute of Medicine (IOM) convened a workshop in Washington, DC, to review the

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1The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants and are not necessarily endorsed or verified by the Institute of Medicine, and they should not be construed as reflecting any group consensus.



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1 Introduction1 BACKGROUND AND WORKSHOP OBJECTIVES Caffeine, a central nervous system stimulant, is arguably the most frequently ingested pharmacologically active substance in the world. Oc- curring naturally in more than 60 plants, including coffee beans, tea leaves, cola nuts, and cocoa pods, caffeine has been part of innumerable cultures for centuries. But the caffeine-in-food landscape is changing. From waffles to sunflower seeds, jelly beans to syrup, and even bottled water, the array of new caffeine-containing energy products, including energy drinks and supplements entering the marketplace, is, in the words of U.S. Food and Drug Administration (FDA) commissioner Margaret Hamburg, “truly mind boggling.” Years of scientific research have shown that moderate consumption by healthy adults of products contain- ing naturally occurring caffeine is not associated with adverse health ef- fects. But the changing caffeine landscape raises concerns about safety and whether any of these new products might be targeting populations not normally associated with caffeine consumption, namely, children and adolescents, and whether caffeine poses a greater health risk to those populations than it does to healthy adults. At the request of the FDA, on August 5–6, 2013, the Institute of Medicine (IOM) convened a workshop in Washington, DC, to review the 1 The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants and are not necessarily endorsed or verified by the Institute of Medicine, and they should not be construed as reflecting any group consensus. 1

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2 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS available science on safe levels of caffeine consumption in foods, bever- ages, and dietary supplements and to identify data gaps. See Box 1-1 for a detailed list of specific workshop objectives. Workshop participants included scientists with expertise in food safety, nutrition, pharmacology, psychology, toxicology, and related disciplines; medical professionals with pediatric and adult patient experience in cardiology, neurology, and psychiatry; public health professionals; food industry representatives; regulatory experts; and consumer advocates. The information presented in this workshop summary reflects only what was spoken or visually presented (on slides) during the workshop. Although this workshop summary covers a range of subject matter, it should not be construed as a comprehensive review of the subject matter. Nor should any of the information, opinions, or conclusions expressed here be construed as reflecting consensus on the part of the IOM, the Food and Nutrition Board, the Board on Health Sciences Policy, the workshop planning committee, or any group. The purpose of the work- shop was to engage in a dialogue about the safety of caffeine in food and dietary supplements, including, but not limited to, caffeinated beverage products, and to identify data gaps, not to reach consensus on any issue or to make recommendations. All the opinions, interpretations, and sug- gestions for future research summarized in this document reflect the opinions of individual workshop participants. Equally important, although much of the workshop discussion re- volved around the science of the safety of caffeine in energy drink bever- ages, the intended scope of the workshop discussion extended across all foods and beverages, as well as dietary supplements, and included coffee, tea, carbonated soft drinks, and numerous other types of products. Also, as the planning committee chair Lynn Goldman emphasized in her welcom- ing remarks, the workshop was intended to cover only the assessment of potential health risks associated with caffeine exposure (i.e., risk assess- ment), not the management of those risks (i.e., risk management). ABOUT THIS REPORT The organization of this report roughly parallels the workshop objec- tives and organization of the workshop itself. The major overarching themes of the workshop, reflected in the chapter summaries, are shown

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INTRODUCTION 3 BOX 1-1 Workshop Objectives  Evaluate the epidemiological, toxicological, clinical, and other relevant literature to describe important health hazards associated with caf- feine consumption.  Delineate vulnerable populations who may be at risk from caffeine ex- posure. Describe caffeine exposure and the risk of cardiovascular and other health effects on vulnerable populations, including additive effects with other ingredients and effects related to preexisting conditions.  Explore safe caffeine exposure levels for general and vulnerable pop- ulations. Identify data gaps on caffeine stimulant effects, including but not limited to cardiovascular, central nervous system, or other health outcomes. in Box 1-2. This first introductory chapter contains a summary of intro- ductory remarks made by Margaret A. Hamburg, commissioner of the FDA, and Michael R. Taylor, deputy commissioner for foods and veteri- nary medicine at the FDA, and it includes a list of major overarching themes of the workshop discussion, compiled by the rapporteurs. Chapter 2 summarizes the workshop presentations and discussion on methods being used to assess levels of caffeine exposure in the U.S. gen- eral population. Chapter 3 summarizes the presentations and discussion of the different types of surveillance in place for identifying safety sig- nals related to caffeine. Although the challenge of gaining a better scien- tific understanding of potentially vulnerable populations was addressed throughout the workshop in different contexts, Chapter 4 summarizes the one panel that focused specifically on vulnerable populations. Chapter 5 summarizes the presentations and discussion of the current state of the science on the risk of cardiovascular disease associated with caffeine exposure—in both general and vulnerable populations. Chapter 6 sum- marizes the several panels dedicated to exploring the effects of caffeine exposure on the central nervous system and behavior, again in both gen- eral and vulnerable populations. Chapter 7 summarizes the workshop presentations and discussion on the interactions between caffeine and other ingredients in caffeine-containing foods and dietary supplements. At the end of Day 1, workshop participants were invited to comment on any issue, with three minutes provided per participant. Chapter 8 summa- rizes those remarks. Finally, Chapter 9 summarizes the final session of the day, a panel on data gaps and ways to fill those gaps.

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4 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS THE PAST, PRESENT, AND FUTURE OF CAFFEINE REGULATION IN THE UNITED STATES Introductory Remarks Given by Margaret A. Hamburg, M.D., Commissioner of the FDA, and Michael R. Taylor, J.D., Deputy Commissioner for Foods and Veterinary Medicine at the FDA Caffeine in cola-type beverages has been listed as generally recog- nized as safe (GRAS) since 1959 (i.e., in cola up to 200 parts per million, or about 70 mg in a 12-ounce serving, in accordance with good manufac- turing practices). Nevertheless, even early on, according to FDA com- missioner Margaret Hamburg, there were concerns about the effects of caffeine consumption beyond moderate levels and in children, pregnant women, and other potentially vulnerable populations.2 In a 1978 report, the Select Committee on GRAS Substances raised questions about whether the chronic consumption of caffeine in cola-type beverages by children during a period of brain growth and development might affect behavior (FDA, 1989). The evidence was inconclusive. More recently, in response to the influx of caffeinated alcoholic beverages into the market- place, in 2010 the FDA sent four warning letters to manufacturers of those beverages. The beverages were subsequently removed from the BOX 1-2 Major Overarching Themes of Workshop Discussion  Although the health effects of caffeine have a long history of scientific study, caffeine is being marketed to consumers in novel products and in new ways, raising new questions about caffeine intake and the health consequences of caffeine exposure.  Many unanswered questions exist about actual exposure levels, es- pecially among children and adolescents, who have historically not consumed much caffeine but are increasingly consuming it in the form of caffeinated energy drinks and other food products, including ques- tions about physiologic responses to caffeine in naïve users. 2 For the purposes of this discussion, moderate intake of caffeine for the healthy adult population is defined as a dose level up to 400 mg/day (equivalent to 6 mg/kg body weight/day in a 65-kg person). Excessive intake of caffeine is considered to be greater than 500–600 mg/day (8.3–10 mg/kg) (4–7 cups of coffee or 7–9 cups of tea). Caffeine intake that is greater than 400 mg/day (6.7 mg/kg) “may increase the risk of detrusor instability (unstable bladder) development in women” (Nawrot et al., 2003).

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INTRODUCTION 5 BOX 1-2 Continued  Scientific evidence on cardiovascular effects associated with caffeine exposure is varied and incomplete. Scientists have examined several different end points, from arrhythmia to vasodilation, with mixed re- sults. There are many unanswered questions about individual and population variability (e.g., some individuals may be genetically sus- ceptible to cardiovascular effects associated with caffeine intake; some populations, particularly children and adolescents, may be more vulnerable than others), as well as the nature of the caffeine exposure (e.g., caffeine consumed in combination with one set of ingredients may have very different cardiovascular effects than caffeine con- sumed in combination with another set of ingredients).  As with cardiovascular effects, scientists have examined various cen- tral nervous system and behavioral effects of caffeine exposure. The evidence raises several questions about the safety of exposure in children and adolescents in particular. Little is known about the inter- actions between caffeine and other ingredients in caffeine-containing foods and dietary supplements and whether and how those interac- tions alter the health effects of caffeine exposure.  While most of the discussion of vulnerable populations focused on children, adolescents, and pregnant women, some participants ex- pressed concern that not enough scientific evidence has been col- lected to clearly identify vulnerability. Participants identified children with underlying heart medical conditions as a separate potentially vul- nerable population and identified individuals with certain genetic pre- dispositions as another.  There was some controversy over the urgency of the sudden cardiac death safety signal being observed in adolescents, with some work- shop participants expressing concern that the signal was being sensa- tionalized. Others emphasized that although not all clinicians may be seeing the signal, clearly some are, not just in the United States, but globally. Several calls were put forth to advance the discussion be- yond a debate over whether a safety signal exists and to consider ways that the signal can be scientifically investigated. Suggestions were put forth to improve and systematize the collection of exposure and both short-term and long-term health outcome data by populariz- ing the National Poison Control Center database, developing a na- tional registry, or conducting longitudinal cohort studies. market. As Hamburg explained, the FDA had not approved the use of caffeine in alcoholic beverages at any level and was concerned about their safety in light of published peer-reviewed studies suggesting that the consumption of beverages with added caffeine and alcohol is associ- ated with risk behaviors. Caffeine appears to mask some of the sensory cues individuals might otherwise rely on to determine their level of intoxication.

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6 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS Hamburg noted that although caffeinated beverages containing alco- hol are no longer on U.S. shelves, the energy drink marketplace has con- tinued to expand and is, today, a multi-billion-dollar business. The prod- ucts come in a range of sizes and are marketed as either conventional beverages or dietary supplements. Several contain other compounds that interact with the added caffeine or add yet another effect. Many of these products, just as with other products with added caffeine, appeal espe- cially or even particularly to a young audience. Hamburg identified three primary points she hoped workshop partic- ipants would focus on during the course of the next day and a half. First, she asked workshop participants to examine the health risks associated with the use of caffeine beyond moderate levels and for specific popula- tions. Some studies have suggested that heavier consumption or habitual use of caffeine increases these risks, particularly for vulnerable popula- tions, such as among pregnant women and children. For example, the literature suggests that there may be reproductive effects, such as re- duced fertility and decreased birth weight, even at lower intake levels (Fenster et al., 1991; Klebanoff et al., 1999). In addition, there is limited evidence of anxiety in children at low doses (Bernstein et al., 1994). By examining and evaluating the epidemiological, toxicological, clinical, and other literature, workshop participants will help the FDA to gain a better and more complete understanding of health risks for these various populations of concern. Second, Hamburg requested that workshop participants focus on is- sues surrounding the marketplace for these products, including expanded availability of caffeine and conditions under which these products are used. She noted that the American Academy of Pediatrics, as well as the report Nutrition Standards for Foods in Schools (IOM, 2007), have ex- pressed concern about making caffeine more readily accessible and attrac- tive to children and adolescents. The FDA needs to know what the re- search suggests about caffeine exposure, particularly the additive effects and the conditions under which it is used, including in energy drinks and similar sources, and whether the FDA should be more closely monitoring and regulating these products, especially in vulnerable populations. Third, the FDA intends to be as transparent as possible in its investi- gation and study of this area and these kinds of products. To that end, it has worked cooperatively with the food and beverage industries, who have shared their expertise and experience, and has reached out to public health and medical specialty groups as well as to consumers and con- sumer advocates. The agency has also conducted preliminary analyses of

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INTRODUCTION 7 available adverse-event databases. But, Hamburg said, now is the time to delve as deeply as possible and draw on all the expertise available. Hamburg remarked that she and her FDA colleagues are encouraged by how some in the industry have responded to concerns about the risk that children could be overexposed to caffeine, as demonstrated by Wrigley’s recent announcement not to market a chewing gum that it had developed with caffeine. Such voluntary restraint is helpful at this time when the FDA is still searching for information and considering how better to define the regulatory boundaries around caffeine. Hamburg said the agency looks forward to continuing to work with the different parts of industry. But despite the laudable restraint that the FDA has seen in some instances, Hamburg observed that it knows that some companies have been adding caffeine to their products on the basis of their opinion that such use is GRAS, and they have done so without engaging the FDA. As a result, those companies are raising numerous questions about the scope and rigor of their safety analyses. That approach threatens to implicate the credibility of the industry as a whole and potentially un- dermine the FDA’s carefully balanced regulatory oversight, which is de- signed to allow innovation while ensuring safety and public confidence. A goal for this workshop was to allow the FDA to take a close and thorough look at what is happening in the marketplace, how industry is proceeding, and what actions may be necessary. Hamburg opined that the workshop was occurring at a critical time and, as such, offered a critical opportunity to evaluate the data and to reach some informed conclusions. She said, “I really do believe that the deliberations that you will be un- dertaking over the next 2 days, the discussions that you will be having, the data presented, [and] the issues raised will all help to guide us as we consider the right steps forward to protect public health.” On the second day of the workshop, Mike Taylor, FDA Deputy Commissioner for Foods and Veterinary Medicine, emphasized the need to “get the science right” in determining whether there are safety con- cerns regarding the new uses of caffeine that warrant steps by the FDA. He elaborated on how the issues being addressed are not simple. Caffeine is not an ordinary food additive. It is a central nervous system stimulant, a drug with multiple effects in the human body. It is different from virtu- ally everything else that the FDA regulates as added ingredients in food because consumers seek it out for its pharmacologic effect. Taylor noted, as Hamburg had, that caffeine had been a part of human history for cen- turies, with the traditional uses of caffeine being apparently safe for healthy adults. Today, however, caffeine is available in a much wider

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8 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS variety of food products, as well as dietary supplement products, and is being consumed in a wider range of use conditions. Taylor underscored the importance of specifically addressing the new forms of caffeine and caffeine consumption scenarios that are attrac- tive or accessible to children and adolescents. Do these new use condi- tions raise new safety questions? How do we assess the intake resulting from these new exposure scenarios created by the wider availability of caffeine and by the fact that caffeine is, again, a sought-after ingredient for people wishing to experience its physiological effects? Are there spe- cial measures needed to address and possibly protect vulnerable popula- tions? Again, “getting the science right” is the first crucial step, Taylor said. This IOM workshop was intended to help the FDA to do that. Further complicating the issue for the FDA is the fact that these ques- tions must be addressed not in the abstract but in the context of the two regulatory frameworks provided by Congress to oversee ingredients in the food supply and in dietary supplements (see Box 1-3). The first regulatory framework, which addresses dietary supplement products, was established by the Dietary Supplement Health and Education Act in the 1990s. It is aimed at products designed to supplement the diet with ingredients that presumably provide beneficial effects to consumers. These products are permissible in the market unless there is significant or unreasonable risk of illness or injury under the labeled or ordinary conditions of use. For dietary ingredients that are not new, the burden is on the FDA to prove that the safety standard or risk standard has been exceeded. The second regulatory framework, the 1958 food additive law (Food Additives Amendment to the Food, Drug and Cosmetic Act), addresses the safety of ingredients that are added to conventional foods to provide traditional food functions such as nutrition, flavor, and hydration. Ac- cording to Taylor, it requires a higher standard of safety, that is, the “rea- sonable certainty of no harm” safety standard established by Congress for added ingredients in food. Under the food additive law, the burden is on industry to prove safety, and there is a prescribed pre-market approval process for food additives. The GRAS concept provides an alternative pathway to the marketplace, one that does not require FDA pre-market approval. The GRAS concept is an important feature of the framework. GRAS status determination must be based on the same quantity and quality of evidence required, as though the substance were being ap- proved by the FDA as a food additive, that is, with a reasonable certainty of no harm. In addition, there must be general recognition that the safety standard has been met based on publicly available data and information.

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INTRODUCTION 9 BOX 1-3 Dietary Supplements A “dietary supplement,” as defined by Congress in the Dietary Supple- ment and Education Act of 1994, is a product taken by mouth that contains a “dietary ingredient” intended to supplement the diet. Such ingredients may include “vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabo- lites.” Dietary supplements can also be “extracts or concentrates, and may be found in many forms such as tablets, capsules, softgels, gelcaps, liq- uids, or powders.” If a dietary supplement is in a bar, information on the label “must not represent the product as a conventional food or a sole item of a meal or diet.” SOURCE: U.S. Food and Drug Administration. Available at http://www.fda. gov/Food/DietarySupplements/QADietarySupplements/default.htm#what_is. Despite differences between the two regulatory frameworks, both provide similar options potentially available to the FDA. Taylor under- scored “potentially.” He remarked that the FDA had not made any deci- sions (about caffeine being added to new products) and had no precon- ceived notions of what the right steps are. If the science justifies doing so, under either framework the FDA can potentially restrict levels of caf- feine in products or conditions of use. The agency could also use labeling to inform consumers about the amount of caffeine in products or provide cautionary statements where appropriate. Taylor stressed that, regardless of which framework the FDA decides to operate under, the science is still the same with respect to how caffeine affects the body and whether there are effects that should be addressed in vulnerable populations. On behalf of the FDA, Taylor said, he appreciated the call put forth during the workshop by the Grocery Manufacturers Association to col- laborate with the FDA on defining boundaries around the use of caffeine (see Chapter 8). He also expressed gratitude for the restraint that many food companies have been exercising as the FDA works on what Taylor described as an “extraordinarily complex scientific puzzle, regulatory puzzle, [and] public health puzzle.”

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10 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS REFERENCES Bernstein, G. A., M. E. Carroll, R. D. Crosby, A. R. Perwien, F. S. Go, and N. L. Benowitz. 1994. Caffeine effects on learning, performance, and anxie- ty in normal school-age children. Journal of the American Academy of Child and Adolescent Psychiatry 33(3):407–415. FDA (Food and Drug Administration). 1989. Select Committee on GRAS Sub- stances (SCOGS) report no. 89: Caffeine. http://ww.accessdata.fda.gov/ scripts/fcn/fcnDetailNavigation.cfm?rpt=scogsListing&id=42 (accessed Janu- ary 13, 2014). Fenster, L., B. Eskenazi, G. C. Windham, and S. H. Swan. 1991. Caffeine con- sumption during pregnancy and spontaneous abortion. Epidemiology 2:168– 174. IOM (Institute of Medicine). 2007. Nutrition standards for foods in schools: Leading the way toward healthier youth. Washington, DC: The National Academies Press. Klebanoff, M. A., R. J. Levine, R. DerSimonian, J. D. Clemens, and D. G. Wilkins. 1999. Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion. New England Journal of Medicine 341:1639– 1644. Nawrot, P., S. Jordan, J. Eastwood, J. Rotstein, A. Hugenholtz, and M. Feeley. 2003. Effects of caffeine on human health. Food Additives and Contami- nants 20:1–30.