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4 Safety of Caffeine Usage People around the world have been consuming caffeine for more than 1,000 years, but in the United States for at least the last 100 years its use has been surrounded by controversy related to potential negative health and behavioral effects, starting with federal seizure of a shipment of Coca-Cola syrup in Octo- ber 1909. Among the charges used to support the legality of this seizure was that caffeine was an "added" and "poisonous and deleterious substance". In 1959 caffeine was listed in the Code of Federal Regulations (21 CFR 182.1180formerly 21 CFR 121.101) as generally recognized as safe (GRAS) when used in cola-type beverages with a tolerance set at 0.02 percent. The toler- ance was based on industry practice at that time. The minor food use of caffeine in baked goods, frozen dairy desserts, and so forth is based on independent GRAS determinations. In 1978 the Select Committee on GRAS Substances of the Federation of American Societies for Experimental Biology completed an evaluation of the safety of caffeine. That comm~ttee's conclusions stated that "while no evidence in the available information on caffeine demonstrates a hazard to the public when it is used in cola-type beverages at levels that are now current and in the manner now practiced, uncertainties exist requiring that additional studies should be conducted". The major concern raised in that report was the potential behavioral effect of caffeine, especially in young children. In 1980 the Food and Drug Administration (FDA) proposed to delete the use of caffeine as an added food ingredient from the GRAS list, to declare that no prior sanction exists for the food use of caffeine, and to list caffeine as a food 47

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48 CAFFEINE FOR MENTAL TASK PERFORMANCE additive on an interim basis pending the conduct of additional safety studies. The agency identified several safety issues of concern with regard to caffeine, namely potentially fetotoxic and teratogenic properties, potential behavioral effects, and potential carcinogenicity (FDA, 1980b). In 1987 the FDA published a proposed rule on the use of caffeine in nonal- coholic carbonated beverages. Based on comments submitted to the agency in response to the proposal published in the Federal Register of October 1980, the FDA proposed to codify a prior sanction for the use of added caffeine in nonal- coholic carbonated beverages. Thus, the agency was proposing to use a provi- sion of the Food, Drug and Cosmetic Act that exempts from the definition of a food additive any substance used in accordance with an approval granted prior to the Food Additives Amendment of 1958. The FDA concluded that existing data did not demonstrate that a level of 0.02 percent caffeine added to nonalco- holic, carbonated beverages presented any risk to humans. The agency also received several comments regarding the use of caffeine in other foods, but because these comments did not assert that such uses were sanctioned previ- ously, these uses were not addressed in the proposal (FDA, 1987~. In 1992 FDA's Center for Food Safety and Applied Nutrition (CFSAN) car- ried out a review of scientific articles published from 1986 to 1991 that had bearing on the potential health effects of caffeine. The new information re- viewed included animal and clinical studies on developmental, reproductive, behavioral, carcinogenic, cardiovascular, and other effects. Based on this re- view, CFSAN found that there was no evidence to show a human health hazard arising from the consumption of caffeine through use of cola beverages at 100 mg/person/day or less. The exposures to caffeine from the intake of cola bever- ages at the ninetieth percentile for children (aged 3 to 5 years) and over a life- time are estimated by CFSAN to be 57 and 98 mg/person/day, respectively. These daily intakes are within the safe limit set by the prior sanction in 1959. Currently, caffeine is recognized by FDA as a substance that is a food additive with a provisional listing status. Despite this extensive scrutiny there continues to be controversy surround- ing the effects of caffeine on long-term health. The list of diseases in which caffeine has been implicated has changed over the years. Convincing research evidence has removed several diseases from consideration, including various cancers and benign breast disease. Extensive research also has evaluated the impact of caffeine consumption on the incidence of cardiovascular disease, reproduction and pregnancy outcomes, osteoporosis, and fluid homeostasis. With respect to the actions of caffeine on the central nervous system, it has been shown that ingestion of very high doses of caffeine can produce undesir- able effects on mental function such as fatigue, nervousness, and feelings of anger or depression. Additionally, caffeine use has been associated with physical dependence, which may be reflected in performance decrements during with- drawal under some circumstances.

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SAFETY OF CAFFEINE USA GE CAFFEINE AND CARDIOVASCULAR DISEASE RISK 49 For more than 30 years caffeine has been of interest in the etiology of heart disease particularly because it may be associated with alterations in blood lipids and blood pressure, arrhythmias, and other adverse cardiac functions. While earlier studies suggested an effect of caffeine on blood lipids, Sedor et al. (1991) found no influence of coffee on serum lipoproteins in women with normal cho- lesterol levels. These different results may be accounted for by the finding that the method of preparing coffee could influence the relationship between caffeine and blood lipids. Only one fraction of boiled coffee was found to significantly increase blood cholesterol and low-density cholesterol in a dose-dependent manner (Pirich et al., 1993~. In 1,074 adults studied in the United Kingdom, coffee consumption was not found to have a significant effect on total or high- density lipoprotein cholesterol (Lancaster et al., 1994~. Similarly, Lewis et al. (1993) found no consistent associations between caffeine-containing beverages and serum lipoproteins in 5,1 15 healthy black and white, men and women aged 18-30 years. In contrast, in a 17-month follow-up of 2,109 healthy nonsmokers, Wei et al. (1995) found that total serum cholesterol increased by about 2 mg/dL for each subsequent increase in cups of regular coffee per day. Furthermore, a dose-response in serum lipoproteins was found among those who increased consumption, continued the same dose, or decreased consumption of regular coffee. This association was not observed with the consumption of decaffeinated coffee, regular or decaffeinated tea, or caffeine-containing colas. However, in a double-blind, randomized trial of 69 young healthy subjects whose habitual coffee consumption was 5.9 cups (140 mL) of filtered regular coffee per day, abstinence from caffeine resulted in no effect on serum lipids (Bak and Grobbee, 1991~. Urgert and Katan (1997), in an extensive review, found effects of coffee brewing techniques on serum concentrations of total and low-density lipoprotein cholesterol. The compounds responsible for this effect are the diterpene lipids cafestol and kahweol, which make up about 1 percent (wt:wt) of coffee beans. These diterpenes are extracted by hot water but are retained by paper filters, thus explaining why filtered coffee has no effect on serum cholesterol, while boiled coffees such as Scandinavian cafetiere and Turkish coffees do. Several approaches have been utilized to investigate the possible relationship between caffeine intake and brood pressure. Results summarized in recent re- views by Myers (in press) and Green and Suls (1996) suggested that caffeine- naive individuals may experience a small increase in blood pressure after acute dosing with caffeine. During chronic administration of caffeine, tolerance appears to develop, and chronic long-lasting changes in blood pressure are usually not seen in individuals who routinely consume caffeine. Coffee consumption was shown to have no significant effects on blood pressure in the 1,074 adults studied by Lancaster et al. (1994~. Similarly, in the Coronary Artery Risk Development in Young Adults study of 5,115 black and white men and women aged 18-30

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so CAFFEINE FOR MENTAL TASK PERFORMANCE years, no consistent association was found between consumption of caffeine- containing beverages and blood pressure (Lewis et al., 1993~. The 6-year data from the Multiple Risk Factor Intervention Trial showed a significant, independ- ent, inverse relation between caffeine intake and both systolic and diastolic blood pressure (Stamler et al., 1997~. In contrast, a recent report of a meta-analysis of 11 controlled trials showed an independent, positive relationship between cups of coffee consumed (median dose = 5 cups/day) and subsequent change in systolic blood pressure (Jee et al., 1999~. Another recent review critically examined 30 years of controlled clinical and epidemiological studies on the blood pressure effects of coffee and caffeine (Nurnunen et al., 1999~. The authors concluded that the acute presser effects of caffeine are well documented, but that at present there is no clear epidemiological evidence that caffeine consumption is causally related to hypertension. They also concluded, however, that high caffeine intake may be an additional risk factor for hypertension at the individual level due to long- lasting stress or a genetic susceptibility to hypertension. In general, controlled clinical attempts to demonstrate the effects of caffeine on increasing heart rate or inducing arrhythmias have been unsuccessful (Myers, in press). Chelsky et al. (1990) reported that in patients with clinical ventricular arrhythmias, ingestion of 275 mg of caffeine did not significantly alter the in- ducibility or severity of arrhythmias. Newby et al. (1996) conducted a random- ized, double-blind, 6-week intervention trial using dietary caffeine restriction, caffeinated coffee, and decaffeinated coffee in 13 patients with symptomatic frequent idiopathic ventricular premature beats. Results showed no significant changes in palpitation scores of premature beat frequencies during the interven- tion weeks and no significant correlation between these variables and serum caffeine concentrations. A possible association between coffee and risk of coronary heart disease has been examined in case-controlled as well as longitudinal cohort studies. Case- control studies have produced variable results (Myers, in press). However, a meta-analysis of 11 prospective, longitudinal cohort studies showed no in- creased risk of coronary heart disease associated with consumption of up to 6 cups of coffee per day (Myers and Basinski, 1992~. Based on a meta-analysis of 8 case-control studies and 15 cohort studies, Kawachi et al. (1994) reported a pooled case-control odds ratio of 1.63 (95 percent confidence interval ICI], 1.50-1.78) for the effect on coronary heart disease of drinking 5 cups of coffee per day versus none. However, the odds ratio from the 15 cohort studies was not statistically significant. A study of 10,359 men and women in the Scottish Heart Health Study showed a significantly higher prevalence of coronary heart disease in subjects who were nonusers of coffee than in those who drank varying amounts of coffee (Brown et al., 1993~. A more recent follow-up of subjects in the Scottish Heart Health Study showed that for many conventional risk factors, coffee had a weak but beneficial gradient with increasing consumption (Wood- ward and Tunstall-Pedoe, 1999~. A 10-year follow-up of North American

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SAFETY OF CAFFEINE USAGE 51 women participating in a large prospective cohort study showed no evidence for any positive association between coffee consumption and risk of subsequent coronary heart disease (Willett et al., 1996~. For women initially drinking 6 cups or more of caffeine-containing coffee per day, the relative risk was 0.95 (95 percent CI, 0.73-1.26) compared to women who did not consume regular coffee. Despite numerous studies attempting to show a relationship between caf- feine and serum lipoproteins, blood pressure, cardiac arrhythmias, and risk of coronary heart disease, results have failed to show a consistent adverse effect of ingestion of moderate amounts of caffeine. Thus, increased risk of cardiovascu- lar problems resulting from the use of caffeine supplements by the military would, in most cases, not appear to be a major concern. One potential risk should be noted, however. A number of studies have dem- onstrated that caffeine consumption produces a transient elevation in blood pres- sure and that this occurs regardless of whether the individual is or is not a habit- ual user of caffeine (James, 1990; Lane et al., 1990, 1998~. Caffeine consumption has also been demonstrated to potentiate the effects of acute exercise and mental stress in increasing blood pressure (Hofer and Battig, 1993; Lane et al., 1990; Myers et al., 1989~. This effect of caffeine is more pronounced in those with high stress reactivity (i.e., high levels of anxiety) and those who are borderline hyper- tensive or are hypertensive (James, 1990; Lane et al., 1998; Lovallo et al., 1991; Sung et al., 1995~. Lovallo et al. (1996) demonstrated that in borderline hyperten- sive men, the use of caffeine in situations of behavioral stress may elevate blood pressure to a clinically meaningful degree and that these types of blood pressure rises in hypertensives would be large enough to transiently reduce the therapeutic effects of antihypertensive medication. However, earlier work by Greenberg and Shapiro (1987) compared two levels of caffeine in males with or without a family history of hypertension and found systolic blood pressure levels were signifi- cantly greater in individuals with a family history of hypertension across all con- ditions, but not specifically in response to caffeine. Wise et al. (1996) examined the effects of placebo or 6 mg of caffeine per kg lean body mass on calcium me- tabolism in no~motensive and hypertensive individuals. Urinary excretion of calcium over 72 hours following caffeine/placebo dosing was not different with respect to caffeine treatment, or between hypertensive and normotensive subjects. Both Eggertsen et al. (1993) and MacDonald et al. (1991) reported 24-hour am- bulatory blood pressures were not different between decaffeinated and caffein- ated coffee in treated hypertensives. Since military scenarios in which the use of caffeine supplements might be desirable would frequently occur when personnel are also under acute mental and/or physical stress, this could be a concern to those personnel with family histories of hypertension.

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52 CAFFEINE FOR MENTAL TASK PENANCE CAFFEINE EFFECTS ON REPRODUCTION Caffeine consumption has been suggested as the cause of numerous nega- tive reproductive outcomes, from shortened menstrual cycles to reduced con- ception, delayed implantation, spontaneous abortions, premature birth, low in- fant birthweight, and congenital malformations. As with most other aspects of caffeine consumption, there is a paucity of reliable data concerning the meta- bolic effects of caffeine on reproductive processes. As a general conclusion, no adverse effect on reproduction (e.g., conception, pregnancy, lactation) has been linked consistently to caffeine consumption (Christian and Brent, 2001; Leviton, 1998~. Similarly, the effects of small amounts of caffeine on infants and children seem to be modest and typically innocuous (Castellanos and Rapoport, in press). Nevertheless, physicians conventionally recommend that caffeine intake be limited in pregnant women and nursing mothers. This position is also taken by the FDA (Williams, 1999~. Such recommendations are in keeping with pharma- cological data showing that caffeine is distributed throughout body water, crosses the placenta to enter the fetus, and is secreted in milk. A number of reviews have examined the association between caffeine con- sumption and fertility, as well as its effects during pregnancy on risk of premature births, spontaneous abortions, and fetal problems including low birthweight and congenital malformations. In an epidemiological study of 403 healthy premeno- pausal women, heavy caffeine consumption (more than 300 mg of caffeine per day) was associated with a shortened menstrual cycle, but not with anovulation or short luteal or long follicular phase (Fenster et al., 1999~. The conflicting results and methodological inadequacies of some studies surveying the association in humans between caffeine intake and effects on fertility, birthweight, premature births, or congenital malformation (when malformations of all organs is used as the outcome measure) suggest that caffeine has no consistent effect on these out- comes in humans (Leviton, 1993, 1998) despite the findings in arrival studies. Extremely high doses of caffeine in pregnant rats (well outside the range of normal human consumption) are associated with teratogenicity and fetal and maternal loss (Christian and Brent, 2001; Leviton 1993, 1998; Purves and Sulli- van, 1993~. Similar teratogenic effects have not been confirmed in humans, and the relevance of the route of administration (intraperitoneally) in animal studies is dubious. More recent animal studies, using lower doses of caffeine, have indicated that preconceptual exposure of rats to caffeine reduced fertility due to effects on implantation rather than fertilization rate and was associated with lower birthweight and lower neonatal and prepubertal growth rates (Pollard et al., 1999~. Other studies by these same authors have indicated that in rats, caf- feine administration during pregnancy is also associated with increased fetal mortality, impaired sexual differentiation, and reduced maturation of neuronal mechanisms controlling respiration and parturition.

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SAFETY OF CAFFEINE USAGE 53 Recent reviews of human studies suggest that some of the initial reported associations between caffeine and reduced fertility, teratogenicity, and other fetal and maternal effects in humans may be explained by confounders such as associated cigarette smoking, reporting inaccuracies, and other methodological errors (Christian and Brent, 2001; Leviton, 1998~. A prospective study of 210 women consuming moderate and high levels of caffeine showed no association between birthweight of offspring and caffeine consumption (Caan et al., 1998~. In contrast, a population-based study of 7,855 live births showed a small but significant increase in the odds ratio for low birthweight and preterm delivery in mothers consuming both caffeinated and decaffeinated coffee, compared to those consuming neither (Eskenazi et al., 1999~. Cigarette smoking was con- trolled in this study; however the authors could not rule out reporting con- founders for caffeine consumption. This would seem to imply that some com- pound in coffee other than caffeine is the potential cause. A recent meta-analysis of studies encompassing 42,988 pregnancies indicated that there was a small but statistically significant increase in risk of spontaneous abortion and low- birthweight babies in pregnant women consuming more than 150 mg of caffeine per day; however, contributing factors such as maternal age, smoking, ethanol use, or other confounders could not be excluded (Fernandes et al., 1998~. A recent population-based, case-control study that controlled for confounders showed no effect of caffeine on low birthweight, preterm births, or intrauterine growth retardation (Santos et al., 19983. Early spontaneous abortions in caffeine-consuming women have been re- ported in some studies but not others (Dlugosz and Bracken, 1992~. Theoreti- cally, early spontaneous abortions could be related to a caffeine-induced de- pressed production of placental hormones and a vulnerable implantation. On the other hand, pregnancy slows caffeine metabolism and clearance, especially in the last trimester. One approach to obtaining an objective assessment of caffeine intake and exposure is to use biomarkers such as serum paraxanthine levels. A recent, well- controlled study of 487 women with spontaneous abortions and 2,087 normal controls, in which caffeine exposure was quantitated objectively by sent para- xanthine levels, showed that the mean serum paraxanthine concentration was significantly higher in women who had spontaneous abortions than in controls (752 versus 583 ng/mL). However, the odds ratio for spontaneous abortion was not significantly increased except in subjects with extremely high paraxanthine levels (> 1,845 ng/mL). The authors concluded that moderate consumption of caffeine was not likely to increase the risk of spontaneous abortion (Klebanoff et al., 1999~. Taken together, these studies suggest that the effects of caffeine on preg- nancy and fetal health vary according to the route of exposure and dosing schedule in animals, and according to caffeine dose and levels of exposure in both animals and humans. In humans, confounders that may account for many of

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54 CAFFEINE FOR MENTAL TASKPE~O~ANCE the observed effects of caffeine in pregnancy include concurrent cigarette smoking, maternal age, ethanol consumption, and inaccuracies in reporting of caffeine consumption. Early reports of delayed conception in women who chronically consume as little as 100 mg of caffeine per day have been confirmed in some but not all subsequent studies. However, this relationship is often confounded by coexisting cigarette smoking, which does lead to subLecundity. Based on the available evidence, some physicians recommend that caffeine consumption be avoided entirely by women who wish to become pregnant (Jensen et al., 1998; Stanton and Gray, 1995~. In the 1970s caffeine consumption was linked to benign lumps and fibro- cystic disease of the breasts. However, extensive subsequent research has failed to establish a causal relationship between caffeine use and either benign or ma- lignant diseases of the breasts. Wolfrom and Welsh (1990) concluded that the scientific literature to that point demonstrated no consistent role of methylxan- thines in the etiology of fibrocystic breast disease and no consistent beneficial effect on the disease of reducing or eliminating methylxanthine consumption. Possible effects on caffeine metabolism that are caused by hormonal changes during the menstrual cycle are unclear and poorly studied. Elimination of caffeine from the diet has been reco~ended to lessen premenstrual symptomology (Ros- signol, 1985), but the evidence for such an effect remains inconclusive. CAFFEINE EFFECTS ON BONE MINERAL DENSITY Caffeine consumption has been proposed as a risk factor for osteoporosis. One of the first papers indicating a deleterious effect of caffeine came from the laboratory of Heaney and Recker (1982~. Metabolic studies conducted in a large number of middle-aged women showed that caffeine intake contributed to a negative calcium balance. However, the overall loss amounted to less than 5 mg of calcium per cup of coffee. This original observation stimulated several obser- vational studies that examined the possible relationship between caffeine con- sumption, calcium intake, and various indices of bone health. In the large num- ber of studies that have since been conducted, there appears to be no consistent trend linking caffeine consumption and negative effects on bone mineral density or incidence of fracture. A moderate increase in hip fracture risk was seen in subjects in the Framingham Study who consumed more than 2 cups of coffee or 4 cups of tea per day (Kiel et al., 1990~. In a prospective study of a large number of women aged 34-59 years, a positive relation was observed between caffeine intake and risk of hip but not forearm fracture (Hernandez-Avila et al., 1991~. In contrast to these findings, more recent studies have failed to show a detrimental effect of caffeine on total bone mineral gain in three groups of teenage women with mean daily intakes of caffeine ranging from 14 to 77 mg (Lloyd et al., 1998), or in college-age women with a mean caffeine intake of 103 mg/day

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SAFER OF CAFFEINE USAGE 55 (Packard and Recker, 1996~. No effect of caffeine on hip fracture rates was found in women with coffee intakes of 5 cups or more per day (Tavani et al., 1995~. No effect was observed on bone loss in postmenopausal women whose habitual dietary caffeine intake ranged from 0 to 1,400 mg/day (Lloyd et al., 1997) or on bone mineral density in older men (Glynn et al., 1995~. Although early experimental studies also indicated a significant effect on acute calcium diuresis (Massey and Hollingbery, 1988; Massey et al., 1989), subsequent work indicated that this acute phase of excretion was compensated by a later decrease in excretion of calcium in the urine (Kynast-Gales and Massey, 1994~. Moreo- ver, in contrast to initial studies, later studies found either no significant effect of caffeine on calcium balance (Barger-Lux et al., 1990) or negative balance only in subjects consuming less than about 660 mg of calcium per day, or half of the currently recommended intake of calcium. After a comprehensive evaluation of currently available data, Heaney (in press) concluded that any deleterious effect of caffeine on calcium balance could be offset by only 1 or 2 tablespoons of milk added to coffee and that the real issue of concern is low calcium intake rather than high caffeine intake. CAFFEINE EFFECTS ON FLUID HOMEOSTASIS Wemple et al. (1997) found that the consumption of approximately 2,500 mL of a carbohydrate-electrolyte beverage containing caffeine led to a greater mean 3-hour urine output than the carbohydrate-electrolyte drink alone in a resting condition (1,843 mL with caffeine versus 1,411 mL without caffeine). During exercise, however, the difference between treatments was not significant (398 mL in 5.75 hours with caffeine and 490 mL in 5.75 hours without caffeine with 2,200 mL of fluid consumed during exercise). It should be noted that the caffeine dose in this experiment was extremely low (approximately 1 mg/kg) and was not sufficient to produce a positive effect on cycling performance. The fact that urine volume was affected by this dose could be of significance in military situations where significantly higher caffeine doses may be used. Caf- feine ingestion is of particular concern in situations where water balance is al- ready in jeopardy, such as in hot or high-altitude environments. Although moderate- to high-dose caffeine consumption (e.g., 600-900 ma) may increase fluid and electrolyte losses in urine, a normal diet will replace these losses in most military scenarios (Maughan and Leiper, 1994~. Nussberger et al. (1990) administered an oral dose of 250 mg of caffeine to eight healthy subjects and found an increase in diuresis, and increased sodium, potassium, and osmol excretion within 1 hour post-treatment. However, aldos- terone and vasopressin concentrations remained unchanged. Neuhauser-Berthold et al. (1997), in a controlled experiment with 12 healthy volunteers, adminis- tered enough coffee to provide 642 mg of caffeine in a single day, and moni- tored fluid homeostasis in comparison with a group with an equal amount of

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56 CAFFEINrE FOR MENTAL TASK PERFORMANCE fluid consumption from mineral water only. Subjects given the caffeine had a highly significant increase in 24-hour urine output of 753 + 532 ml, a corre- sponding negative fluid balance, and a corresponding decrease in body weight of 0.7 kg. Total body water as measured by bioelectrical impedance decreased by 2.7 percent, and sodium and potassium excretion increased by 66 and 28 per- cent, respectively. Caffeine use during prolonged operations in hot environments increases the risk of dehydration because such operations involve large sweat losses and/or inadequate fluid and electrolyte intake. The scientific literature indicates that a total body water deficit may (Gonzalez-Alonso et al., 1992; Maughan and Leiper, 1994; Neuhauser-Berthold et al., 1997) or may not (Brouns et al., 1998; Massey and Wise, 1984) occur. The deficit depends on the amount of caffeine consumed, the individual's history of acute and chronic caffeine use, and the total solute load of the beverage plus accompanying meals (Brouns et al., 1998; Wemple et al., 1997~. Finally, a recent study by Kiyohara et al. (1999), in an attempt to determine if serum uric acid concentration could be used as an indicator of increased uri- nation, examined 2,240 Japanese men. They found that men consuming less than 1 cup of coffee per day had a mean serum uric acid concentration of 60 mg/L, while those consuming 5 or more cups of coffee per day had a mean concentra- tion of 56 mg/L. DETRIMENTAL EFFECTS OF HIGH DOSES OF CAFFEINE High doses of caffeine can be acutely toxic. Ingestion of caffeine in doses up to 10 g has caused convulsions and vomiting with complete recovery in 6 hours (Dreisbach, 1974~. The fatal acute oral dose of caffeine in humans is esti- mated to be 10-14 g ~ 150-200 mg/kg) (Hodgman, 1998), but numerous factors can alter an individual's sensitivity to caffeine (e.g., smoking, age, prior caffeine status, pregnancy status, concurrent drug use) and thus alter the toxic dose. Doses of 1,000 mg (approximately 15 mg/kg body weight) have generated det- rimental side effects, with early symptoms being insomnia, restlessness, and agitation. These symptoms may progress to mild delirium, emesis, and convul- sions. Other symptoms can include tachycardia, asystole, and rapid respiration (Kamimori et al., 1999~. One potential risk of high doses of caffeine that needs further substantiation is dose-related decrements in mental functioning (Kaplan et al., 1997; Kuznicki and Turner, 1986; Lieberman, 1999~. A number of researchers have found that high doses of caffeine can adversely affect mental performance. Kaplan and colleagues (1997) reported that although a relatively low dose of caffeine (250 ma) produced favorable subjective effects (e.g., elation, pleasantness) and enhanced performance on cognitive tasks in healthy volunteers, higher doses (500 ma) led to less favor- able subjective reports (e.g., tension, nervousness, anxiety, restlessness) and less

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SAFER OF CAFFEINE USAGE 57 improvement in cognitive performance than placebo. Negative effects may be more pronounced in nonusers than in regular users of caffeine (Kuznicki and Turner, 1986~. Excessive intake of caffeine (caffeinism) may be mistaken for anxiety disorder (Benowitz, 1990~. Caffeine has been shown to produce anxiety or panic attacks in individuals with agoraphobia or panic disorders, but not in healthy controls (Boulenger et al., 1984; Charney et al., 1985~. Foreman et al. (1989) examined the effects of 0, 125, and 250 mg of caffeine on performance of a numerical version of the Stroop test, which requires sus- tained vigilance and intense cognitive effort as well as fast responses. Subjects receiving 250 mg of caffeine had significantly slower response times. Streufert et al. (1997) investigated the impact of 400 mg of caffeine in excess of normal consumption by persons who were already moderate to heavy caffeine consumers (400-1,000 mg/day) on performance of complex managerial tasks. Increased caffeine consumption in these individuals had mixed results. Speed of response to incoming information was faster with added caffeine; however, the managers' capacity to utilize opportunity decreased. The authors postulated that increased response speed in association with decreased effectiveness in immediate recall (Warburton, 1995) may have had unfavorable effects on a performance that re- quires bringing together events and actions that occur across a time dimension. Effects of Caffeine in the Context of Stress Among the preexisting variables that may contribute to variations in caf- feine sensitivity are baseline levels of stress exposure. Stress may include physi- cal stress (exercisesee Chapter 3), physiological stress (heat stress see Chapter 3, infection, sleep deprivation), or psychological stress. Stress expo- sures in the military may be acute or chronic (IOM, 1999~. After stress exposure, stress-responsive neurohormonal and neurotransmitter systems are activated, with associated release of the stress hormones corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol, and the adrenergic neurotransmitters (epinephrine, norepinephrine), which all interact with caffeine. Caffeine also alters the degree of responsiveness of these stress response systems to stressful stimuli (Iancu et al., 1996~. For example, caffeine has been shown to increase plasma norepinephrine, to potentiate epinephrine and cortisol stress reactivity to acute psychosocial stress (Lane et al., 1990), and to increase plasma cortisol levels in response to exam stress in medical students (Pincomb et al., 1987~. Caffeine also alters measures of autonomic nervous system function, including heart rate, skin conductance, and electrodermal activity (Zahn and Rapoport, 1987~. The degree of responsiveness in these studies varied according to previ- ous caffeine consumption (habitual users versus nonusers).

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58 CAFFEINE FOR MENTAL TASK PERFORMANCE Risks of Caffeine in Combination with Ephedrine and Other Stimulants The risks of additive effects of caffeine on cardiovascular function in the context of self-dosing with supplement preparations such as ephedrine or yo- himbine should be considered when evaluating additional dosing of caffeine. Waluga et al. (1998) found that administration of a combination of caffeine and ephedrine slightly increased systolic blood pressure during exercise, and addi- tion of yohimbine to this combination increased diastolic pressure and heart rate during rest and increased cardiac work load during exercise. Caffeine and ephedrine have also been found to significantly increase heart rate during exer- cise (Bell and Jacobs, 1999; Bell et al., 1999) and may also transiently increase metabolic heat production (Horton and Geissler, 1996~. A recent FDA-requested review related a number of reported adverse cardiovascular and central nervous system events to the use of ephedra-containing supplements (Hailer and Be- nowitz, 2000~. White (1999) recently reviewed interactions of caffeine with nicotine, benzodiazepines, and alcohol on behavior. Physical Dependence and Withdrawal The use of caffeine by humans is generally not associated with abuse or ad- diction (Dews et al., in press). Tolerance to some of the physiological effects of caffeine develops when caffeine-containing beverages are consumed regularly. Withdrawal symptoms often occur with the abrupt removal of caffeine from the diet. The frequency of occurrence of withdrawal, as reported in survey studies and clinical trials, varies anywhere from 4 to 100 percent (Goldstein et al., 1965; Griffiths and Woodson, 1988; Griffiths et al., 1986; Naismith et al., 1970; Rob- ertson et al., 1981; Weber et al., 1993~. The symptoms of cessation, when they do occur, are not long-lasting. The signs and symptoms of withdrawal vary widely and can range from mild to severe, following withdrawal from both low and high doses of caffeine (Sil- verman et al., 1992~. These include headaches, drowsiness, irritability, fatigue, low vigor, and flu-like symptoms including myalgia, nausea, and vomiting. Caffeine acts as a vasoconstrictor of the cerebral arteries, reducing regional blood flow (Cameron et al., 1990; Mathew et al., 1983), including blood flow velocity in the medullar-cerebral artery (Perod et al., 2000~. Caffeine with- drawal is associated with electroencephalogram changes (Reeves et al., 1995) and also causes changes in cerebral blood flow leading to vasodilation in high caffeine users that is thought to be associated with a throbbing, vascular-type headache, one of the most commonly observed caffeine withdrawal symptoms (Couturier et al., 1997; Lader, 1999; Mathew and Wilson, 1985~. This withdrawal phenomenon could lead to decrements in performance during military operations and thus should be avoided. Consuming low doses of

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SAFETY OF CAFFEINE USAGE 59 caffeine (25-50 ma) or slowly tapering the dose of caffeine can prevent with- drawal symptoms (Griff~ths and Mumford, 1995~. SUMMARY Caffeine is approved as a food additive with provisional status by the FDA, thus indicating that the agency concludes there is no evidence of a human health hazard arising from consumption of caffeine added to foods and cola beverages. However, controversy continues with respect to caffeine's role in cardiovascular disease, negative reproductive outcomes, physical dependency and withdrawal, and excessive intake. The preponderance of evidence indicates that the use of caffeine by the military would not place personnel at increased risk of cardio- vascular disease. Evidence on the risk of large doses of caffeine for individuals who are hypertensive or borderline hypertensive is inconclusive. For women there may be a small increase in risk of spontaneous abortion in the first trimes- ter of pregnancy. The effects of caffeine on calcium metabolism may be of some concern only for those with very low calcium intakes (less than 50 percent of the current recommended intake). Caffeine can significantly increase 24-hour urine output, and may or may not alter total body water. Therefore, if caffeine sup- plements are used, emphasis should be placed on adequate fluid consumption, particularly in hot or high-altitude environments. High doses of caffeine can have a negative effect on mood and cognitive performance, and thus the maximum content of caffeine in the delivery form of choice should not exceed 600 ma. In addition, caffeine potentiates the effects of physical, physiological, and psychological stress. Military personnel who are habitual caffeine consumers should not be denied access to caffeine in order to maximize effects of a caffeine supplement.

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