IFIC Review: Caffeine and Health Clarifying the Controversies Printed May 1993 Despite centuries of use of caffeine-containing foods and beverages, questions about the potential health effects associated with this ingredient persist. Caffeine is one of the most comprehensively studied ingredients in the food supply. Extensive research has not linked moderate caffeine consumption to any health risks, including cancer, cardiovascular disease or teratogenesis. This issue of IFIC Review provides background information on caffeine, and examines the research conducted on caffeine and health, summarizing the major findings. Sources of Caffeine Caffeine is a naturally occurring substance found in the leaves, seeds or fruits of over 63 plant species worldwide and is part of a group of compounds known as methylxanthines. The most commonly known sources of caffeine are coffee and cocoa beans, cola nuts and tea leaves (1, 2). The amount of caffeine in food products varies depending on the serving size, the type of product and preparation method. With teas and coffees, the plant variety also affects caffeine content (2, 3). A five-ounce cup of drip-brewed coffee typically has 115 mg. of caffeine; a five-ounce serving of brewed tea has 60 mg.; soft drinks which contain caffeine have an average of 18 mg. per six ounce serving; and an ounce of milk chocolate has just six mg. (1, 3). Caffeine Consumption The current per capita consumption level of caffeine for adults is approximately 200 mg. daily, showing a mean intake of 3 mg./kg. body weight (1, 4). For children and young adults, the primary source of caffeine is tea, while caffeine intake for adults 25 and older is mostly derived from coffee (4). Children consume significantly less caffeine than adults. The average daily intake of 5 to 18-year-old children is around 38 mg. This is equivalent to 1 mg./kg., which is substantially less than what adults normally consume (1, 4). Physiological Effects Caffeine is a pharmacologically active substance, and, depending on the dose, can be a mild central nervous system stimulant (2). Any pharmacological effects of caffeine are transient, usually passing within hours (5). Many other familiar foods also exert pharmacological effects. A glass of warm milk before bedtime is appreciated by some for the somnolent effects of tryptophan, and capsaicin in hot peppers is notorious for producing a burning sensation, that often evokes sweating. Caffeine does not accumulate in the body over the course of time and is normally excreted within several hours of consumption. The "half-life" of caffeine is the time it takes to eliminate one-half of consumed caffeine from the body. This varies among individuals, about three to four hours in healthy adults. Smoking increases the metabolism of caffeine, generally reducing the half-life to no more than three hours. Children also metabolize caffeine at a quicker rate (2). People differ greatly in their sensitivity to caffeine. When analyzing caffeine's effects on an individual, many factors must be weighed. The amount ingested and how often a person consumes caffeine are relative in evaluating caffeine's effects (5). With regular use, tolerance develops to many of the effects of caffeine. For example, a person who consumes caffeine on a regular basis may drink several cups of coffee in a few hours and notice little effect, whereas a person who isn't a regular coffee drinker may feel some stimulant effect after just one serving. Additionally, studies have shown that individuals who consume caffeine may increase memory and improve reasoning powers. Research indicated that those who consumed caffeine scored higher grades on motor skill tests, enhanced reaction times and improved auditory and visual vigilance (6, 7). Contrary to popular belief, children, including those diagnosed as hyperactive, are no more sensitive to the effects of caffeine than adults (5, 8). Plus, a 1984 study demonstrated that caffeine was not a cause of attention deficit hyperactivity disorder (9). Individuals tend to find their own acceptable level of daily caffeine consumption. Those people who feel unwanted effects tend to ease off their caffeine consumption; those who don't continue to consume caffeine at their own normal levels. In practice, the person who feels adverse effects such as sleeplessness learns not to consume caffeine before bedtime (9,10). Caffeine and Health Caffeine was placed on FDA's Generally Recognized As Safe (GRAS) list in 1958, and in 1978, the agency recommended additional research be conducted to resolve any uncertainties about the safety of caffeine (2,3). Since then, a great deal of research has been conducted on caffeine and its association with the development of various diseases and health concerns. Cancer Extensive research has shown no association between caffeine consumption and the incidence of cancer. In 1990, Rosenberg reviewed several epidemiologic and clinical studies that examined the link between bladder, rectal, colon and pancreatic cancers to coffee and tea consumption. The 13 studies reviewed, which included over 20,000 subjects, failed to establish a relationship between coffee or tea consumption and the incidence of bladder, rectal, colon or pancreatic cancers (11). One of the studies included in Rosenberg's review was a 1986 investigation of the relationship between coffee consumption and cancer incidence and mortality by Jacobsen, et al. The study evaluated 16,000 Norwegian men and women from 1967 though 1979. After controlling for smoking, diet and age, the researchers concluded that coffee did not significantly increase the incidence of any common cancer and that there was "no positive association between coffee drinking and any major cause of death" (12). A 1991 study by Jain et al, examined the association between coffee and alcohol with pancreatic cancer. The population-based study included 750 subjects and adjusted for smoking and caloric and fiber intake. After calculating lifetime tea and coffee consumption and the variety of coffee consumed, the researchers concluded that coffee consumption does not affect the development of pancreatic cancer (13). In 1990, Gordis published a review of studies on the relationship between caffeinated beverages (mainly coffee) and the incidence of pancreatic cancer. Gordis' review included a 1988 study of fatal pancreatic cancer in 34,000 Seventh-day Adventists. After controlling for cigarette smoking, the researchers found no significant increase in risk relative to coffee consumption. Upon final examination of all available data, Gordis further concluded that "current epidemiologic evidence does not suggest any significant increase in risk of pancreatic cancer with coffee consumption" (14). LaVecchia et al in 1988 further studied coffee consumption's relationship to digestive tract cancers. The case-control study included patients with confirmed cases of oral, rectal, stomach, liver and colon cancers, as well as patients who did not suffer any digestive tract disorders. The research confirmed no correlation between coffee consumption and the incidence of digestive tract cancer (15). In the case of breast cancer, a 1990 scientific review by Lubin and Ron examined all the data linking caffeine consumption and malignant breast tumors (16). Out of the 11 case-control studies reviewed, none established a significant link between caffeine intake and breast cancer incidence. Specifically, three separate studies performed in Israel, the United States and France, analyzed the relationship of coffee consumption to breast cancer development. Each study respectively controlled for dietary intake, medical and reproductive history and frequency of coffee intake. The results of each investigation, however, established no association between coffee consumption and breast cancer (16, 17). Overall, the universal scientific research does not support a relationship between caffeine consumption and cancer development. As a result, the American Cancer Society's Guidelines on Diet, Nutrition and Cancer state there is no indication that caffeine is a risk factor in human cancer and the National Academy of Sciences' National Research Council reports there is no convincing evidence relating caffeine to any type of cancer (17, 18). Cardiovascular Diseases Caffeine and cardiovascular disease (CVD) is another area that has been extensively examined, and no causal relationship between caffeine consumption and heart disease, hypertension or cardiac arrhythmias has been shown. Although a 1986 study cited a link between excessive coffee consumption and heart disease, the investigators failed to control for other significant risk factors such as diet and smoking (19). In 1989, researchers from the Framingham Heart Study issued a report stating that after examining all possible links between coffee intake and cardiovascular disease, no deleterious effect of coffee consumption was found. The researchers also concluded that there was no association between coffee intake and recurring heart attack episodes (20). The findings from the Framingham Study were substantiated in 1990 when a prospective study conducted by Harvard University researchers further concluded that caffeine consumption causes "no substantial increase in the risk of coronary heart disease or stroke." The study included 45,589 men between the ages of 40 to 75 years old and adjusted for major cardiovascular-risk indicators including dietary intake of fats and cholesterol and smoking (21). Additionally, a case-control study on the effect of filtered-coffee consumption on plasma lipid levels was published in 1992. The researchers concluded that coffee consumption led to a small increase in the level of high-density lipoprotein (HDL) cholesterol, thus would counter any risk for coronary heart disease (22). The effects of caffeine on blood pressure have been the subject of various hypotheses, many of which have been disproved. A number of studies have shown that any rise in blood pressure due to caffeine consumption is less than the elevation produced by normal, daily activities (23). Dr. Martin Myers, of the cardiology division at the Sunnybrook Centre in Toronto, reviewed the scientific literature of caffeine and blood pressure in 1988. In his review, Myers examined 17 scientific studies that investigated the effects of caffeine on blood pressure after long-term administration. Upon final examination, Myers concluded that "caffeine does not cause any persistent increase in blood pressure" (24). Furthermore, in 1991 researchers Bak and Grobbee conducted a double-blind randomized trial to examine caffeine's effects on serum lipids, as well as blood pressure. The study consisted of 69 healthy participants, and at the conclusion of the test period, the researchers determined that "caffeine has no adverse effect on cardiovascular risk by inducing unfavorable changes in blood pressure or serum lipids" (25). The effects of caffeine on cardiac arrhythmias also has been a topic of scientific investigation. The American Medical Association's (AMA) Council on Scientific Affairs concluded that abstaining from caffeine did not significantly influence the occurrence or frequency of arrhythmias (26). A clinical investigation published in 1991 examined the effect of caffeine on 22 patients with a history of ventricular arrhythmias. The investigators concluded that caffeine does not alter the inducibility or severity of ventricular arrhythmias (27). Likewise, a 1991 review by Myers of studies on caffeine and cardiac arrhythmias concluded that moderate caffeine consumption does not increase the frequency or severity of cardiac arrhythmias (28). Despite continued consumer questions on caffeine and heart disease, there is a significant amount of data that demonstrates there is no link between moderate caffeine consumption and cardiovascular disease. Caffeine and Women's Health Scientists worldwide have thoroughly investigated caffeine's effects on women's health. From reproduction to osteoporosis, scientific research addressing women's health has not shown that caffeine causes adverse effects. Fertility Scientists have recently studied the effects of caffeine on fertility. One small, but widely publicized, study in 1988 by Wilcox, Weinberg and Baird of the National Institutes of Health, suggested that the caffeine equivalent of 1- to 2-cups of coffee per day might decrease fertility in women (29). Subsequent larger, better-designed studies, however, have failed to support this finding. In 1990, researchers at the Centers for Disease Control and Harvard University examined the association between the length of time to conceive and consumption of caffeine-containing beverages in more than 2,800 women who had recently given birth and of 1,800 women with the medical diagnosis of primary infertility. Both groups were interviewed with the same questionnaire concerning caffeine consumption, medical history and lifestyle habits. Upon completion of the study, the researchers found that caffeine consumption had little or no effect on the reported time to conceive in those women who had given birth. Caffeine consumption also was not found to be a risk factor in the sample of women being treated for infertility (30). These findings were confirmed in an epidemiological study of more than 11,000 Danish women published in 1991. The study examined the relationship among number of months to conception, cigarette smoking and coffee and tea consumption. The study found no association between delayed conception and the consumption of caffeinated beverages among nonsmokers (31). Reproduction With increased attention to nutrition during pregnancy, many women wonder if it's safe to consume caffeine-containing foods or beverages. However, recent research has shown that moderate caffeine consumption during pregnancy causes no adverse health effects in the mother or offspring. Dr. Alan Leviton of Boston's Children's Hospital reviewed the results of 13 human studies conducted since 1981 on the effect of caffeine consumption on reproduction. Published in 1988, Leviton concluded that "no evidence has yet been offered that caffeine consumption at moderate levels by pregnant women has any discernible adverse effect on their fetuses" (32). A seven-year prospective study comprising over 1,500 women examined caffeine use during pregnancy and child outcome. Caffeine consumption, determined by self-reporting, averaged 193 mg. of caffeine daily during early pregnancy and decreased to 152 mg. per day by mid-term. The outcome of the study showed no relationship between caffeine intake and birthweight, birth length or head circumference. Follow-up examinations at ages eight months, four and seven years also revealed no effects of caffeine consumption on a child's motor development or intelligence (33). In 1993, researchers at the National Institutes of Health published the results of their investigation on the relationship between caffeine consumption during pregnancy and the occurrence of spontaneous abortion and low birth weight. The study consisted of 431 women who were within 21 days of conception and were monitored throughout pregnancy. After adjusting for risk factors such as smoking and alcohol intake, the researchers concluded that moderate caffeine consumption during pregnancy did not increase the risk of spontaneous abortion or abnormal fetal growth (34). Additionally, a series of reports in 1992 analyzed the effects of cigarettes, alcohol and coffee consumption on pregnancy outcome in more than 40,000 Canadian women. Although alcohol consumption and smoking tended to have negative effects on pregnancy outcome, moderate caffeine consumption was not associated with low birth weight and spontaneous abortion. The principal investigator, McDonald, concluded, "There's no evidence that moderate caffeine intake has adverse effects on pregnancy or pregnancy outcome" (35, 36). Furthermore, animal studies by the FDA found no adverse effects in offspring when rats were given high doses of caffeine in their drinking water. These results contradict agency findings in the early 1980s, which prompted an advisory to pregnant women to avoid caffeine. In the early study, rats were force-fed very high doses of caffeine through a stomach tube. Because the study was not representative of the way humans consume caffeine, FDA researchers carried out a subsequent study, but with caffeine consumed in drinking water. The adverse effects reported in the first study were not replicated (2, 3). FDA has since evaluated the scientific evidence and concluded that caffeine does not adversely affect reproduction in humans. The agency continues to advise pregnant women to consume caffeine in moderation (3). Benign Breast Disease Caffeine was first discussed in relation to breast disease in the late 1970s. One researcher published several studies suggesting that abstinence might alleviate the symptoms of fibrocystic breast disease, a condition of benign fibrous lumps in the breast. While caffeine subsequently was not linked to development of the disease, some subjects reported feeling less breast tenderness when they eliminated caffeine from their diets. However, problems with the designs of the studies, which were based on anecdotal reports from a small number of women, made the conclusions suspect. A larger case-control study conducted by the National Cancer Institute (NCI) involved more than 3,000 women. This 1986 study showed no evidence of an association between caffeine intake and benign tumors, fibrocystic breast disease or breast tenderness (35). Both the NCI and the AMA Council on Scientific Affairs have stated there is no association between caffeine intake and fibrocystic breast disease (37, 26). The original findings that suggested such a relationship have never been corroborated. Osteoporosis Given the recent awareness about the incidence of osteoporosis in post-menopausal women, the relationship between caffeine intake and bone health is a relatively new area of investigation. Because caffeine has been linked to calcium excretion, it has been suggested as a risk factor for osteoporosis. But, few studies have examined caffeine's effect on overall bone density, or the actual intake of caffeine or calcium by the subjects. Researchers at The Pennsylvania State University's College of Medicine examined the effects of caffeine consumption in vegetarian and nonvegetarian premenopausal women in 1991. The researchers found that although caffeine intake slightly increased urinary calcium excretion in both groups, there was no effect on overall bone density (38). At Creighton University School of Medicine, scientists investigated the effects of moderate caffeine intake, around 400 mg. per day, on the calcium status of 16 healthy premenopausal women. No significant effects of caffeine on calcium balance were observed in women who consumed at least 600 mg. of calcium per day, the amount found in two cups of milk. The researchers concluded that moderate caffeine intake was not a threat to bone health. (39) Scientists from the Mayo Clinic conducted a clinical study of 290 women to examine the influence of caffeine intake on bone mineral content. After adjusting for age, calcium intake, cigarette smoking and alcohol consumption the researchers concluded that caffeine was not an important risk factor for osteoporosis (40). Additionally, a 1992 population-based study of 619 septuagenarian men and women investigated the effects of daily coffee consumption on bone mineral content. After assessing for participants' calcium intake, exercise habits and tobacco smoking, the researchers concluded that although caffeine has an effect on calcium metabolism, the risk for loss of bone mass or fractures is negligible (41). Caffeine and Withdrawal Depending on the amount ingested, caffeine can be a mild stimulant to the central nervous system. Although sometimes colloquially referred to as "addictive," moderate caffeine consumption is safe and should not be classified with addictive drugs of abuse. In fact, the President's Office of National Drug Control Policy does not view caffeine as a "gateway drug." The Office states that linking caffeine to drugs of abuse in drug education programs undermines the effectiveness of a drug prevention program. Creating such an association may lead children to view cocaine and marijuana no more harmful than a soda, doing a disservice to the young people needed to be educated (42). When regular caffeine consumption is abruptly discontinued, some individuals may experience withdrawal symptoms, such as headaches, fatigue or drowsiness. These effects usually are temporary, lasting for a few days, and often can be avoided if caffeine cessation is gradual (10, 43, 44). Moreover, most caffeine consumers do not demonstrate dependent, compulsive behavior, characteristic of dependency to drugs of abuse (10). Although pharmacologically active, the behavioral effects of caffeine typically are minor. As further elaborated by the American Psychiatric Association, drugs of dependence cause occupational or recreational activities to be neglected in favor of drug-seeking activity (10). Clearly, this is not the case with caffeine. In Summary ... Caffeine is one of the most thoroughly investigated ingredients in the food supply. Because it is so widely used, the FDA has conducted extensive research and has carefully reviewed caffeine's safety. In 1987, FDA reaffirmed its position that scientific evidence does not indicate caffeine in carbonated beverages creates any adverse effects in humans (45). Furthermore, both the National Academy of Sciences National Research Council and the U.S. Surgeon General's office report that there has been no association established between moderate caffeine consumption and an increased risk to health (17, 23). It is apparent there is no shortage of research on the effects of caffeine on human health. The ingredient has been studied carefully for decades, with the preponderance of scientific evidence demonstrating that caffeine is safe when consumed in moderation. References (1) Barone, J.J., & Roberts, H. Human consumption of caffeine. In P.B. Dews (ed.), Caffeine. New York: Springer-Verlag, 1984. (2) Institute of Food Technologists (IFT) Expert Panel on Food Safety & Nutrition. Caffeine, A Scientific Status Summary, 1987. (3) Lecos, C. Caffeine jitters: some safety questions remain. FDA Consumer, 21:22-27, Dec. 1987/Jan. 1988. (4) Roberts, H. Caffeine Consumption. Paper presented at a meeting of the American Academy of Pediatrics Clinical Pharmacology Session, New Orleans, October 1991. (5) Dews, P.B. Caffeine Research: An International Overview. Paper presented at a meeting of the International Life Sciences Institute, Sidney, July 1986. (6) Lieberman, H.R., Wurtman, R.J., Emde, G.G. et al. The effects of low doses of caffeine on human performance and mood. Psychopharmacology, 92:308-312, 1987. (7) Jarvis, M. Does caffeine intake enhance absolute levels of cognitive performance? Psychopharmacology, 110:45-52, 1993. (8) Bergman, J. & Dews, P.B. Dietary caffeine and its toxicity. In J. Hathcock (ed.), Nutritional Toxicology. New York: Academic Press, 1987. (9) Rapoport, J.L., Berg, C.J., Ismond, D.R. et al. Behavioral effects of caffeine in children. Archives of General Psychology, 41:1073-1079, 1984. (10) Hughes, J.R., Higgins, S.T., Bickel, W.K. et al. Caffeine self-administration, withdrawal, and adverse effects among coffee drinkers. Archives of General Psychiatry, 48:611-617, 1988 (11) Rosenberg, L. Coffee and tea consumption in relation to the risk of large bowel cancer: A Review of Epidemiologic Studies. Cancer Letters, 52:163-171, 1990. (12) Jacobsen, B.K., Bjelke, E., Kvale, G. et al. Coffee Drinking, Mortality, and Cancer Incidence: Results From a Norwegian Prospective Study. Journal of The National Cancer Institute, 76:823-831, 1986. (13) Jain, M., Howe, G.R., St. Louis, P. et al. Coffee and alcohol as determinants of risk of pancreas cancer: a case-control study from Toronto. International Journal of Cancer, 47:384-389, 1991. (14) Gordis, L. Consumption of methylxanthine-containing beverages and risk of pancreatic cancer. Cancer Letters, 52:1-12, 1990. (15) La Vecchia, C., Monica, F., Negri, E. et al. Coffee consumption and digestive tract cancers. Cancer Research, 49:1049-1051, 1989. (16) Lubin, F. and Ron, E. Consumption of methylxanthine-containing beverages and the risk of breast cancer. Cancer Letters, 53:81-90, 1990. (17) National Research Council. Diet and Health: Implications for Reducing Chronic Disease Risk. Washington, D.C.: National Academy Press, 1989. (18) American Cancer Society's Medical and Scientific Committee. Guidelines on diet, nutrition, and cancer. CA-A Cancer Journal for Clinicians, 41(6):334-338, 1991. (19) LaCroix, A.Z., Mead, L.A., Lian, G. K.Y. et al. Coffee consumption and the incidence of coronary heart disease. The New England Journal of Medicine, 315:977-982, 1986. (20) Wilson, P.W.F., Garrison, R.J., Kannel, W.B. et al. Is coffee consumption a contributor to cardiovascular disease? Archives of Internal Medicine, 149:1169-1172, 1989. (21) Grobee, D.E., Rimm, E.B., Giovannucci, E. et al. Coffee, caffeine, and cardiovascular disease in men. New England Journal of Medicine, 323:1026-1032, 1990. (22) Fried, R.E., Levine, D.M., Kwiterovich, P.O. et al. The effect of filtered-coffee consumption on plasma lipid levels. Journal of The American Medical Association, 267:811-815, 1992. (23) U.S. Surgeon General's Report. Nutrition and Health, Washington, D.C.: U.S. Department of Health and Human Services, 1988. (24) Myers, M.G. Effects of caffeine on blood pressure. Archives of Internal Medicine, 148:1189-1193, 1988. (25) Bak, A.A.A. and Grobee, D.E. Caffeine, blood pressure, and serum lipids. American Journal of Clinical Nutrition, 53:971-975, 1991. (26) American Medical Association's Council on Scientific Affairs. Caffeine labeling, a report on the safety of dietary caffeine. Journal of the American Medical Association, 252(6):803-806, 1984. (27) Chelsky, L.B., Cutler, G.E., Griffith, K. et al. Caffeine and ventricular arrhythmias. Journal of the American Medical Association, 264:2236-2240, 1990. (28) Myers, M.G. Caffeine and cardiac arrhythmias. Annals of Internal Medicine, 114:147-150, 1991. (29) Wilcox, A., Weinberg, C. & Baird, D. Caffeinated beverages and decreased fertility. The Lancet, 2:1453-1455, 1988. (30) Joesoef, M.R., Beral, V., Rolfs, R.T. et al. Are caffeinated beverages risk factors for delayed conception? The Lancet, 335:136-137, 1990. (31) Olsen, Jorn. Cigarette smoking, tea and coffee drinking and subfecundity. American Journal of Epidemiology, 133(7):734-739, 1991. (32) Leviton, A. Caffeine consumption and the risk of reproductive hazards. Journal of Reproductive Medicine, 33(2):175-178, 1988. (33) Barr, H.M. & Streissguth, A.P. Caffeine use during pregnancy and child outcome: a 7-year prospective study. Neurotoxicology and Teratology, 13:441-448, 1991. (34) Mills, J.L., Holmes, L.B., Aarons, J.H. et al. Moderate caffeine use and the risk of spontaneous abortion and intrauterine growth retardation. Journal of the American Medical Association, 269: 593-597, 1993. (35) McDonald, A.D., Armstrong, B.G. & Sloan, M. Cigarette, alcohol, and coffee consumption and congenital defects. American Journal of Public Health, 82:91-93. (36) Armstrong, B.G., McDonald, A.D. & Sloan, M. Cigarette, Alcohol, and coffee consumption and spontaneous abortion. American Journal of Public Health, 82:85-90. (37) Schairer, C., Brinton, L., Hoover, R. Methylxanthines and benign breast disease. American Journal of Epidemiology, 124(4):603-611, 1986. (38) Lloyd, T., Schaeffer, J.M., Walker, M.A. et al. Urinary hormonal concentrations and spinal bone densities of premenopausal vegetarian and nonvegetarian women. American Journal of Clinical Nutrition, 54:001-006, 1991. (39) Barger-Lux, M.J., Heaney, R.H. & Stegman, M.R. Effects of moderate caffeine intake on the calcium economy of premenopausal women. American Journal of Clinical Nutrition, 52:722-725, 1990. (40) Cooper, C., Atkinson, E.J., Wahner, H.W. et al. Is caffeine consumption a risk factor for osteoporosis? Journal of Bone and Mineral Research, 7:465-471, 1992. (41) Johansson, C., Mellstrom, D., Lerner, U., et al. Coffee drinking: a minor risk factor for bone loss and fractures. Age and Aging, 21:20-26, 1992. (42) Correspondence with Donna Rigby, Office of National Drug Control Policy, Executive Office of the President, Washington, D.C., July 30, 1992. (43) Hughes, J.R., Oliveto, A.H., Helzer, J.E. et al. Should caffeine abuse, dependence, or withdrawal be added to DSM-IV and ICD-10? American Journal of Psychiatry, 149:33-40, 1992 (44) Silverman, K., Evans, S.M., Strain, E.C. et al. Withdrawal syndrome after the double-blind cessation of caffeine consumption. The New England Journal of Medicine, 327:1109-14, 1992. (45) U.S. Food and Drug Administration. Caffeine in nonalcoholic carbonated beverages. Federal Register, 52(97):18923-18926, May 27, 1987. Reprinted from the International Food Information Council Foundation, 1993

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