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Effects of mental workload and caffeine on catecholamines and blood pressure compared to performance variations
Brain and Cognition 51 (2003) 143–154 www.elsevier.com/locate/b&c
Effects of mental workload and caffeine on catecholamines and blood pressure compared to performance variations Christos Papadelis,a,c Chrysoula Kourtidou-Papadeli,b,c,* Emmanouil Vlachogiannis,d Petros Skepastianos,c Panayiotis Bamidis,a,e Nikos Maglaveras,a and Kostantinos Pappasa a
b
Aristotle University of Thessaloniki, School of Medicine, Laboratory of Medical Informatics, University Campus, 54006 Thessaloniki, Greece Aristotle University of Thessaloniki, School of Medicine, Laboratory of Experimental Physiology, University Campus, 54006 Thessaloniki, Greece c Greek Aerospace Medical Association, Erythreas 2, Kalamaria, 55132 Thessaloniki, Greece d ‘‘Saint Paul’’ Hospital, Department of Internal Medicine, Ethnikis Antistasis 161, 55134 Thessaloniki, Greece e Department of Computer Science, City College, Thessaloniki, Greece Accepted 16 August 2002
Abstract Caffeine is characterised as a central nervous system stimulant, also affecting metabolic and cardiovascular functions. A number of studies have demonstrated an effect of caffeine on the excretion of catecholamines and their metabolites. Urinary epinephrine and norepinephrine have been shown to increase after caffeine administration. Similar trends were observed in our study in adrenaline (ADR) and noradrenaline (NORADR) levels and additionally a dose dependant effect of caffeine. The effect of caffeine on cognitive performance, blood pressure, and catecholamines was tested under resting conditions and under mental workload. Each subject performed the test after oral administration of 1 cup and then 3 cups of coffee. Root mean square error (RMSE) for the tracking task was continuously monitored. Blood pressure was also recorded before and after each stage of the experiment. Catecholamines were collected and measured for three different conditions as: at rest, after mental stress alone, after one dose of caffeine under stress, and after triple dose of caffeine under stress. Comparison of the performance of each stage with the resting conditions revealed statistically significant differences between group of smokers/coffee drinkers compared with the other two groups of non-coffee drinkers/non-smokers and non-smokers/coffee drinkers. There was no statistically significant difference between the last two groups. There was an increase of urine adrenaline with 1 cup of coffee and statistically significant increase of urine noradrenaline. Both catecholamines were significantly increased with triple dose of caffeine. Mental workload increased catecholamines. There was a dose dependant effect of caffeine on catecholamines. Ó 2003 Elsevier Science (USA). All rights reserved.
*
Corresponding author. Fax: +30310435331. E-mail address: [email protected] (C. Kourtidou-Papadeli).
0278-2626/03/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0278-2626(02)00530-4
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Keywords: Caffeine; Cognitive performance; Blood pressure; Catecholamines; Mental workload
1. Introduction A small but relatively constant fraction of the circulating levels of epinephrine (ADR) and norepinephrine (NORADR) in the blood is excreted into the urine (Frankenhaeuser, 1971; Levi, 1972). Consequently, assessment can be made in urine with the advantages that samples are relatively easy to collect, they do not interfere with subjectÕs normal habits and environment and they cause no harm or pain. Urinary epinephrine and norepinephrine (Atuk, Blaydes, Westervelt, & Wood, 1967; Bellet, Roman, DeCastro, Kim, & Kershbaum, 1969; Levi, 1967; Robertson, Frolich, Carr, & Watson, 1978) have been shown to increase after caffeine administration. However, whereas epinephrine is mainly produced by the adrenal medulla, the major part of the circulating norepinephrine is produced by sympathetic nerve endings. The sympathetic adrenal-medullar system (SAM) is activated when the individual is challenged in its control of the environment (Henry, 1992). Psychological stress stimulates the adrenal medulla to secrete the two catecholamines, epinephrine (adrenaline) and norepinephrine (noradrenaline) via hypothalamus and the sympathetic nervous system. The cardiovascular and neuroendocrine functions activated by the SAM system are aimed at mobilizing energy to the muscles and the heart and, at the same time, reduce blood flow to the internal organs and the gastro-intestinal system (Lundberg, 1984). Threats of a mental rather than a physical nature more often challenge the SAM system. CaffeineÕs stimulating activity on the central nervous system as well as other body organs results in certain physiological effects, which may be considered to be behaviour oriented. Caffeine causes a keener appreciation of sensory stimuli and reaction time is diminished. Motor activity is increased; typists, for example, work faster with fewer errors. Tasks requiring delicate muscular co-ordination and accurate timing may, however, be adversely affected. All of this occurs at doses of 150– 250 mg of caffeine (approximately 2 cups of coffee) according to Ritchie (Ritchie, 1975). Many studies have documented a dose effect of nicotine on cardiovascular function with changes in heart rate and blood pressure (Aronow, 1979; Tachmes, Fernandez, & Sackner, 1978). Such changes have been attributed to a stimulation of sympathetic ganglia by nicotine. This stimulation results in a rise of catecholamines, which in turn produces variable degrees of positive chronotropic and inotropic cardiac actions. Other effects include generalized peripheral vasoconstriction and transient systemic hypertension (Ball & Turner, 1974). Caffeine increases the amount of epinephrine and norepinephrine secreted by the adrenal medulla. Increases in catecholamines have multiple effects throughout the body. Caffeine also affects a number of performance variables, such as vigilance, accuracy, and reaction time (Bolton & Null, 1981). Even when not directly measured, these simple tasks are frequently part of more complex tasks in daily living. Caffeine also stimulates the adrenal medulla to secrete hormones which themselves are known to affect those variables and which are also closely associated with emotion, stress, and arousal. Caffeine can influence cardiovascular stress reactivity. Caffeine raises BP during stress by elevating the resting baseline from which the response is measured (Lane, Adcock, Williams, & Kuhn, 1990). Caffeine consumption may add to the blood pressure elevations seen in medical students, fluctuating their peak SBP into borderline hypertensive range (140–159) (Pincomb, Lovallo, Passey, Brackett, & Wilson,
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1987). Potentiation of stress reactivity is apparent in other variables also, e.g., stressrelated increases in forearm blood flow (Lane & Williams, 1985, 1987) and neuroendocrine reactivity. The observed interactions of caffeine and stress may be present even in individuals who habitually consume moderate amounts of caffeine (Lane et al., 1990). The significance of caffeine stress interactions in laboratory to cardiovascular and neuroendocrine reactivity in everyday psychosocial environment remains to be demonstrated; however, it might be reasonable to assume that it may raise BP during more natural stressors as well (Lane et al., 1990). Caffeine use might increase potential health consequences from prolonged exposure to occupational stress (Pincomb et al., 1987). The goal of this study was to clarify if the effects of caffeine in performance may or may not be independent of those of catecholamines it releases. They may interact to potentiate each other, or some of the properties attributed to caffeine may, in fact, be due to catecholamine activity.
2. Materials and methods Sixteen healthy volunteers (10 men with a mean body weight of 80 5 kg and 6 women with a mean body weight of 65 5 kg) of mean age 22 years old (SD: 3, range: 18–26) participated in this study, trained on an electronic multitask program for at least 3 weeks until they established their baseline (Fig. 1). They all signed a consent form and they were given a number, so that the investigator did not know anything about the subjectsÕ habits. They also responded to a questionnaire regarding their smoking and caffeine drinking habits, as well as their health status. All subjects abstained from caffeine drinks for at least 1 week before the study. During the study they performed the same tasks under the influence of a single and a triple dose of caffeine. Caffeine was weighted and the percentage of caffeine diluted in the cup was calculated. To select a dose of caffeine we used a predetermined quantity of instant coffee and diluted to 100 ml of water, which the subjects had to consume in 10 min. After caffeine was diluted, samples were sent to the General Chemistry Department of the Greek government and we received the exact amount of caffeine in each one of them. Subsequently, the caffeine concentration (1.4% caffeine or 62 mg caffeine/ 100 ml coffee) was analyzed and we established that for an 80 kg individual 1 coffee
Fig. 1. A young volunteer is training on the electronic multitask program during the experimental procedure.
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cup of 150 ml would be 1.5 mg/kg/day and 3 coffee cups (total 400–500 ml) would be 4.5 mg/kg/day. The coffee was always prepared in the same way and the volume consumed was based on the weight of the subject to provide the required caffeine dose. The multi-attribute task battery (MATB), which was used during the experimental procedure, was developed by Comstock and Arnegard (1992) at NASA Langley Research Center (Arnegard, 1991) and consists of a multitask electronic program, which simulates flight. MATB incorporates tasks analogous to activities that aircraft crew perform in flight, while providing a high degree of experimental control, performance data on each subtask and freedom to use non-pilot test subjects (Arnegard & Comstock, 1991). The main task of this program is the tracking task, which is located on the upper middle window of the monitor screen (Fig. 2). Using the joystick, the subjects keep the target at the centre of the window, while the monitoring tasks, located in the upper left window (Fig. 2) distract the subjects from their tracking task. The subject responds to the absence of the green light and the presence of the red light. We kept a medium difficulty mental workload, in order to trigger catecholamines activity. During the performance task, root mean square error (RMSE) for the tracking task was recorded in text files in order to perform the statistical measurements and the difference from the baseline (Test 0) was presented for each condition. RMSE is the deviation from the centre of the tracking target in pixel units given by the following formula: rffiffiffiffiffiffiffiffiffiffiffiffiffiffi x2 þ y 2 RMSE ¼ ; N where x and y are the spatial coordinates of the target and N is the root mean square data recording interval. The coordinates ð0; 0Þ correspond to the center of the target (Comstock & Arnegard, 1992).
Fig. 2. Multi-attribute task battery (MATB) screen shot.
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The subjects were divided into three groups according to their smoking and coffee drinking habits. Group A consisted of non-smokers and non-coffee drinkers; group B of smokers and coffee drinkers; and group C of non-smokers and coffee drinkers. Because of a very small number of subjects in the group of smokers/non-coffee drinkers, we did not include the fourth group in the study. The study was performed with administration of 1 cup of coffee corresponding to 1.5 mg/kg and 3 cups of coffee corresponding to 4.5 mg/kg on different days, after the subjects had abstained 1 week from caffeine. Performance was measured at rest (Test 0), after 30 min (Test 1), after 90 min (Test 2) and after 150 min (Test 3) of caffeine intake. The amount of urinary catecholamines, excreted after administration of 1 cup of coffee, 3 cups of coffee, after mental workload (stress) with no caffeine interference, and at rest was determined, from the concentration in the sample, multiplied by the total urine volume. We used the method of high performance chromatography with electrochemical detection (Hjemdahl et al., 1989; Lundberg, Holmberg, & Frankenhaeuser, 1988) to determine urine catecholamines.
3. Results In all conditions, statistically significant elevations were observed in adrenaline levels in all groups compared to those of resting levels. More specifically, in all conditions (stress, 1 cup of coffee + stress, 3 cups of coffee + stress) adrenaline levels of group A, group of non-coffee drinkers and non-smokers, compared to those of resting levels, revealed statistically significant differences (p < :05, p < :01, p < :005, respectively) with no statistically significant increase when caffeine was added to stress, in both doses. Comparing adrenaline levels of group B, group of coffee drinkers and smokers, in all conditions (stress, 1 cup of coffee + stress, 3 cups of coffee + stress) with resting levels, there was a statistically significant increase (p < :05). There was also a significant increase of adrenaline under stress (p < :01) with caffeine in both doses. Group C, group of coffee drinkers and non-smokers, increased adrenaline levels significantly (p < :01) in all conditions compared to resting levels. There was a statistically significant increase of adrenaline comparing stress with 1 cup of coffee and stress with 3 cups of coffee. The subjects of group C presented higher levels of adrenaline compared to those of group B. Comparing adrenaline levels between the groups in all conditions (Table 1), there was an increase for the group of coffee drinkers, but this was not statistically significant. Comparing performance scores with adrenaline levels at stress, linear regression and correlation statistics revealed no correlation between performance data and adrenaline levels for all three groups. Noradrenaline levels of group A, in all conditions compared with those of resting levels (Table 1), revealed a statistically significant increase (p < :005) for stress and stress with 1 cup of coffee, compared to resting levels, as well as stress with 3 cups of coffee compared to resting levels (p < :005). The asymmetry of the subject groups Table 1 Effects of stress and caffeine on catecholamine levels Group
A B C
At rest
Stress
Stress + 1 dose coffee (1.5 mg/kg/day)
Stress + 3 doses coffee (4.5 mg/kg/day)
ADR
NORADR
ADR
NORADR
ADR
NORADR
ADR
NORADR
5.70 7.75 7.86
41.33 42.07 54.40
23.90 23.23 32.40
143.70 151.50 160.80
29.05 27.60 32.80
184.50 181.50 199.40
32.03 34.50 44.60
200.70 207.25 232.60
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slightly influenced our results because the effects of smoking on catecholamines are minimal. Smoking habit is biochemically important as for the accelerated rate of caffeine metabolism. It is also found that there was a statistically significant difference between stress condition and stress with caffeine (p < :05). For groups B and C there was a statistically significant difference of noradrenaline levels in all conditions compared to resting levels, but there was no difference when caffeine was added to stress. Although noradrenaline levels increased with triple dose of caffeine, there was no statistically significant difference. Caffeine potentiated noradrenaline activity only for the group of non-coffee drinkers/non-smokers. There was a statistically significant increase of blood pressure in stress with the triple dose of caffeine for group A (p < :05) and no significant difference for the single dose of caffeine. Group B revealed a significant increase in blood pressure in stress in both doses of caffeine. Group C, coffee drinkers but non-smokers did not have any significant increase in both doses of caffeine. Comparing catecholamine levels with blood pressure (Tables 2–4), there was no correlation between them, although there was a relative increase of both parameters in all conditions. Root mean square error (RMSE) for tracking was calculated in all conditions and compared to baseline (Test 0) in order to clarify the effect of caffeine and catecholamines on performance data. Group A—Session 1: The results for the first study day with 1 cup of coffee revealed a statistically significant increase of cognitive performance 90 min after caffeine intake (p < :05) with maximum performance at 150 min (p < :007) (Fig. 3). In session 2, triple dose of caffeine (250 mg) enhanced performance with statistically significant differences (p < :05) (Fig. 4). In all cases the subjects performed well at the beginning of the task, but their endurance decreased significantly at the end of the task. Group B—Session 1: Performance was increased 90 min after 1 cup of coffee (p < :01) (Fig. 5) for the whole study period. There was a sudden decrease of performance during the 4th minute of the task, which was also accompanied with derangeTable 2 Comparison of blood pressure (mean values) with catecholamine levels in group A Group A
Blood pressure
Adrenaline
Noradrenaline
At rest Stress Stress + 1 dose caffeine (1.5 mg/kg/day) Stress + 3 doses caffeine (4.5 mg/kg/day)
118 122 127 124
5.70 23.90 29.05 32.03
41.33 143.70 184.50 200.70
Table 3 Comparison of blood pressure (mean values) with catecholamine levels in group B Group B
Blood pressure
Adrenaline
Noradrenaline
At rest Stress Stress + 1 dose caffeine (1.5 mg/kg/day) Stress + 3 doses caffeine (4.5 mg/kg/day)
120.25 125.75 133.25 139.75
7.75 23.23 27.60 34.50
42.07 151.50 181.50 207.25
Table 4 Comparison of blood pressure (mean values) with catecholamine levels in group C Group C
Blood pressure
Adrenaline
Noradrenaline
At rest Stress Stress + 1 dose caffeine (1.5 mg/kg/day) Stress + 3 doses caffeine (4.5 mg/kg/day)
125.6 128 131.6 132.4
7.86 32.40 32.80 44.60
54.40 160.80 199.40 232.60
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Fig. 3. Differences from baseline (Test 0) on root mean square error (RMSE) for Group A (non-coffee drinkers and non-smokers) during session 1 (1 cup of coffee).
Fig. 4. Differences from baseline (Test 0) on root mean square error (RMSE) for Group A (non-coffee drinkers and non-smokers) during session 2 (3 cups of coffee).
ment of the physiological measurements. In session 2, after triple dose of caffeine, performance improvement started right after caffeine intake (p < :005) and lasted for 90 min, starting gradually to decrease for the rest of the study (Fig. 6). A sudden decrease in performance at the 12th minute was probably due to tremor and eye–hand coordination decrements due to high dose of caffeine. Group C—Session 1: Performance revealed no improvement for the whole period of time with 1 cup of coffee. In session 2, after triple dose of caffeine performance improved in 90 min (p < :01) (Fig. 7) and remained in high levels for the whole study period.
4. Discussion In order to understand the real effects of caffeine, we tried to differentiate the effects of caffeine from those of noradrenaline and adrenaline and determine the
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Fig. 5. Differences from baseline (Test 0) on root mean square error (RMSE) for Group B (coffee drinkers and smokers) during session 1 (1 cup of coffee).
Fig. 6. Differences from baseline (Test 0) on root mean square error (RMSE) for Group B (coffee drinkers and smokers) during session 2 (3 cups of coffee).
manner in which they interact. One possible mechanism of interaction is put forward by Ritchie (1975). He noted that methylxanthines, such as caffeine, increase the concentration of cyclic AMP in many tissues, including the central nervous system through competitive inhibition of phosphodiesterase breakdown of cyclic AMP. The catecholamines also increase the concentration of cyclic AMP. They do this by stimulating cyclic AMP synthesis. Ritchie (1975) suggested that these two processes could go beyond a simple additive effect and result in a potentiation of the effects of the catecholamines. Comparing the adrenaline levels of group A in stress from resting condition, there was a significant increase of adrenaline levels. When caffeine was added to stress, a small increase, not statistically significant was observed in both doses (Table 1). It seems that once adrenaline reaches a certain level under the influence of one factor (mental stress in this case), another factor, as caffeine could no longer increase its
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Fig. 7. Differences from baseline (Test 0) on root mean square error (RMSE) for Group C (coffee drinkers and non-smokers) during session 2 (3 cups of coffee).
level significantly, especially for caffeine naive subjects. There was only a small increase of adrenaline levels, because of synergic effect of caffeine and stress. The subjects of group B (coffee drinkers/smokers) responded differently, by increasing further adrenaline levels after caffeine was added to stress condition (Table 1). That could be explained by the fact that coffee drinkers abstained from coffee for a whole week and when caffeine was added to stress they reacted fast by increasing significantly their adrenaline levels. Caffeine was the main trigger to increase adrenaline levels for the group of coffee drinkers. We observed a dose dependant effect of caffeine on adrenaline levels for the subjects of group B (non-coffee drinkers/nonsmokers). The subjects of group C presented higher adrenaline levels compared to those of group B, although they were all coffee drinkers (Table 1). The only difference between those two groups was the smoking habit of group B. The lower adrenaline levels of group B could be attributed to the fact that smoking increases caffeine clearance, affecting less smokers than non-smokers. There was no significant increase in blood pressure for group C subjects during the whole experiment with either dose of caffeine. This is probably due to caffeine tolerance of those subjects, as well as the fact that they did not smoke to aggravate their blood pressure. Blood pressure increased for the triple dose of caffeine in stress for the subjects of group A (caffeine na€ıve subjects and non-smokers). Alternatively caffeineÕs adenosine antagonistic actions (Fredholm, 1980) have been suggested (Von Borstel, Wurtman, & Conlay, 1983) to cause elevated systemic vascular resistance (Fredholm, 1985; Smits, Boekema, De Abreu, Thien, & VanÕt Laar, 1987, 1989). The vasodilator and the depressor effects of adenosine and the effect of increasing plasma norepinephrine can be blocked by relatively low dose of caffeine, in young healthy human subjects (Smits et al., 1989). Xanthines enhance the production of endogenous adenosine in the heart as well as antagonise the capacity of this to dilate coronary arteries. Vasodilating effects of adenosine seem to be mediated by a subclass of adenosinergic (A2-receptors), which are related to stimulation of cAMP formation (Fredholm & Sollevi, 1986). The response of blood pressure to caffeine is thought to depend on the balance between central vasomotor and myocardial stimulation, which tends to increase it, and central vagal stimulation and peripheral blood vessel dilation, which tends to decrease it (Ritchie, 1975). The subjects with caffeine drinking and smoking habits
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increased their blood pressure as soon as they had coffee either in single or triple dose. They were the most sensitive subjects and most aggravated. The statistical significant increase of noradrenaline levels of group A in all conditions shows that noradrenaline is more sensitive to stress and caffeine environment than adrenaline. According to Thomson norepinephrine is a neurotransmitter at peripheral autonomous synapses and increases activity at these sites. It is also found at high concentrations in brain structures influencing primarily the autonomic nervous system and some of those are involved in the motivational and emotional aspects of behavior (Thomson, 1975). The significant difference between noradrenaline levels in stress and stress with caffeine for both doses reveals probably a potentiation of noradrenaline levels with caffeine intake. This result appeared only for the group of caffeine na€ıve subjects. Numerous studies from laboratory experiments as well as from various natural settings illustrate the sensitivity of the SAM system to various psychosocial conditions, such as daily stress at work, at home, etc. (Levi, 1972; Mason, 1968). Catecholamines and their concomitant effects on other physiological functions, such as blood pressure, may serve as objective indicators of stress that an individual is exposed to. However, these bodily effects are also assumed to link psychosocial stress to increased health risks (Rozanski et al., 1988). Humoral or sympathetically mediated vasoconstriction has been suggested (Robertson, Wade, Workman, & Woosley, 1981; Smits, Hoffmann, Thien, Houben, & VanÕt Laar, 1983) as the major effect of the dose of 250 mg. Increases in circulating epinephrine, NE levels have been documented after a 250 mg dose in normal subjects, at rest (Robertson et al., 1978). Some studies found a stronger relationship between caffeine and NE rather than caffeine and Epinephrine (Denaro, Brown, Wilson, Jacob, & Benowitz, 1990; Heseltine, Dakkak, Woodhouse, Macdonald, & Potter, 1991). Caffeine is absorbed into the blood and body tissue within 5 min. In about 30 min, caffeine concentration reaches its peak level in the blood with a half-life period of approximately 4 h. Caffeine as a mild stimulant affects the brain by increasing neural activity. It increases the performance of simple intellectual tasks and enhances rapid processing of information. Caffeine also increases alertness and the ability to concentrate, along with countering fatigue. Mitchell et al. showed that caffeine prevents attention lapses in a visual monitoring test, which simulated night driving. The effect persisted for the 2–3 h experiment (Stephenson, 1977). A 200-mg dose of caffeine resulted in decreased decision time scores and improved motor time scores in volunteers (Bolton & Null, 1981). Hand steadiness, however, was impaired. After a caffeine intake of 200 mg, introverts performed less well on a verbal ability test as compared to extroverts when time pressure was applied (Ritchie, 1975). The group of non-coffee drinkers revealed an increase of their performance with the administration of 1.5 mg/kg of caffeine with some signs of nervousness which increased enormously when caffeine dose increased to 4.5 mg/kg and their hand steadiness was impaired adversely affecting delicate muscular coordination and accurate tracking. Non-coffee drinkers achieved their peak performance after 30 min of caffeine intake, but in the higher dose of the higher dose of caffeine, although they performed better they revealed a statistically significant increase of their blood pressure. Coffee drinkers/smokers achieved their peak performance only after high doses of caffeine administration and did not last more than 1 h with significant decrement afterwards, having their blood pressure also increased. Everyday life stress is enough to increase catecholamines and keep vigilance and arousal in high levels. Task oriented performance, attention, and concentrations may be modified by caffeine. The results of the present study provide an initial view of the potentially harmful combined effects of caffeine and stress and more research especially in hypertensive
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subjects could lead to significant information in the prevention and treatment of cardiovascular disease.
Acknowledgments We thank Mr. Simon Guy for his support as well as the General Chemistry Department of the Greek government for the analysis of caffeine doses.
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Pincomb, G. A., Lovallo, W. R., Passey, R. B., Brackett, D., & Wilson, M. F. (1987). Caffeine enhances the physiological response to occupational stress in medical students. Health Psychology, 6, 101–112. Ritchie, J. M. (1975). Central nervous system stimulants, the xanthines. In L. S. Goodman, & A. Gilman (Eds.), The pharmacological basis of pharmaceutics. New York: Macmillan. Robertson, D., Frolich, J., Carr, K., & Watson, J. (1978). Effects of caffeine on plasma rennin activity, catecholamines and blood pressure. The New England Journal of Medicine, 298(4), 181–185. Robertson, D., Wade, D., Workman, R., & Woosley, R. L. (1981). Tolerance to the humoral and hemodynamic effects of caffeine in man. Journal of Clinical Investigation, 67(4), 1111–1117. Rozanski, A., Bairey, C. N., Krantz, D. S., Friedman, J., Resser, K. J., Morell, M., Hilton-Chalfen, S., Hestrin, L., Bietendorf, J., & Berman, D. S. (1988). Mental stress and the induction of silent myocardial ishaemia in patients with coronary artery disease. The New England Journal of Medicine, 318(16), 1005–1011. Smits, P., Boekema, P., De Abreu, R., Thien, T., & VanÕt Laar, A. (1987). Evidence for an antagonism between caffeine and adenosine in the human cardiovascular system. Journal of Cardiovascular Pharmacology, 10(2), 136–143. Smits, P., Hoffmann, H., Thien, T., Houben, H., & VanÕt Laar, A. (1983). Hemodynamic and humoral effects of coffee after 1-selective and nonselective-blockade. Clinical Pharmacology and Therapeutics, 34(2), 153–158. Smits, P., Schouten, J., & Thien, T. (1989). Cardiovascular effects of two xanthines and the relation to adenosine antagonism. Clinical Pharmacology and Therapeutics, 45(6), 593–599. Stephenson, P. E. (1977). Physiologic and psychotropic effects of caffeine on man. Journal of the American Dietetic Association, 71(3), 240–247. Tachmes, L., Fernandez, R. J., & Sackner, M. A. (1978). Hemodynamic effects of smoking cigarettes of high and low nicotine content. Chest, 74(3), 243–246. Thomson, R. F. (1975). Introduction to physiological psychology (pp. 167–168). New York: Harper & Row. Von Borstel, R. W., Wurtman, R. J., & Conlay, L. A. (1983). Chronic caffeine consumption potentiates the hypotensive action of circulating adenosine. Life Sciences, 32(10), 1151–1158.
Effects of mental workload and caffeine on catecholamines and blood pressure compared to performance variations Christos Papadelis,a,c Chrysoula Kourtidou-Papadeli,b,c,* Emmanouil Vlachogiannis,d Petros Skepastianos,c Panayiotis Bamidis,a,e Nikos Maglaveras,a and Kostantinos Pappasa a
b
Aristotle University of Thessaloniki, School of Medicine, Laboratory of Medical Informatics, University Campus, 54006 Thessaloniki, Greece Aristotle University of Thessaloniki, School of Medicine, Laboratory of Experimental Physiology, University Campus, 54006 Thessaloniki, Greece c Greek Aerospace Medical Association, Erythreas 2, Kalamaria, 55132 Thessaloniki, Greece d ‘‘Saint Paul’’ Hospital, Department of Internal Medicine, Ethnikis Antistasis 161, 55134 Thessaloniki, Greece e Department of Computer Science, City College, Thessaloniki, Greece Accepted 16 August 2002
Abstract Caffeine is characterised as a central nervous system stimulant, also affecting metabolic and cardiovascular functions. A number of studies have demonstrated an effect of caffeine on the excretion of catecholamines and their metabolites. Urinary epinephrine and norepinephrine have been shown to increase after caffeine administration. Similar trends were observed in our study in adrenaline (ADR) and noradrenaline (NORADR) levels and additionally a dose dependant effect of caffeine. The effect of caffeine on cognitive performance, blood pressure, and catecholamines was tested under resting conditions and under mental workload. Each subject performed the test after oral administration of 1 cup and then 3 cups of coffee. Root mean square error (RMSE) for the tracking task was continuously monitored. Blood pressure was also recorded before and after each stage of the experiment. Catecholamines were collected and measured for three different conditions as: at rest, after mental stress alone, after one dose of caffeine under stress, and after triple dose of caffeine under stress. Comparison of the performance of each stage with the resting conditions revealed statistically significant differences between group of smokers/coffee drinkers compared with the other two groups of non-coffee drinkers/non-smokers and non-smokers/coffee drinkers. There was no statistically significant difference between the last two groups. There was an increase of urine adrenaline with 1 cup of coffee and statistically significant increase of urine noradrenaline. Both catecholamines were significantly increased with triple dose of caffeine. Mental workload increased catecholamines. There was a dose dependant effect of caffeine on catecholamines. Ó 2003 Elsevier Science (USA). All rights reserved.
*
Corresponding author. Fax: +30310435331. E-mail address: [email protected] (C. Kourtidou-Papadeli).
0278-2626/03/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0278-2626(02)00530-4
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Keywords: Caffeine; Cognitive performance; Blood pressure; Catecholamines; Mental workload
1. Introduction A small but relatively constant fraction of the circulating levels of epinephrine (ADR) and norepinephrine (NORADR) in the blood is excreted into the urine (Frankenhaeuser, 1971; Levi, 1972). Consequently, assessment can be made in urine with the advantages that samples are relatively easy to collect, they do not interfere with subjectÕs normal habits and environment and they cause no harm or pain. Urinary epinephrine and norepinephrine (Atuk, Blaydes, Westervelt, & Wood, 1967; Bellet, Roman, DeCastro, Kim, & Kershbaum, 1969; Levi, 1967; Robertson, Frolich, Carr, & Watson, 1978) have been shown to increase after caffeine administration. However, whereas epinephrine is mainly produced by the adrenal medulla, the major part of the circulating norepinephrine is produced by sympathetic nerve endings. The sympathetic adrenal-medullar system (SAM) is activated when the individual is challenged in its control of the environment (Henry, 1992). Psychological stress stimulates the adrenal medulla to secrete the two catecholamines, epinephrine (adrenaline) and norepinephrine (noradrenaline) via hypothalamus and the sympathetic nervous system. The cardiovascular and neuroendocrine functions activated by the SAM system are aimed at mobilizing energy to the muscles and the heart and, at the same time, reduce blood flow to the internal organs and the gastro-intestinal system (Lundberg, 1984). Threats of a mental rather than a physical nature more often challenge the SAM system. CaffeineÕs stimulating activity on the central nervous system as well as other body organs results in certain physiological effects, which may be considered to be behaviour oriented. Caffeine causes a keener appreciation of sensory stimuli and reaction time is diminished. Motor activity is increased; typists, for example, work faster with fewer errors. Tasks requiring delicate muscular co-ordination and accurate timing may, however, be adversely affected. All of this occurs at doses of 150– 250 mg of caffeine (approximately 2 cups of coffee) according to Ritchie (Ritchie, 1975). Many studies have documented a dose effect of nicotine on cardiovascular function with changes in heart rate and blood pressure (Aronow, 1979; Tachmes, Fernandez, & Sackner, 1978). Such changes have been attributed to a stimulation of sympathetic ganglia by nicotine. This stimulation results in a rise of catecholamines, which in turn produces variable degrees of positive chronotropic and inotropic cardiac actions. Other effects include generalized peripheral vasoconstriction and transient systemic hypertension (Ball & Turner, 1974). Caffeine increases the amount of epinephrine and norepinephrine secreted by the adrenal medulla. Increases in catecholamines have multiple effects throughout the body. Caffeine also affects a number of performance variables, such as vigilance, accuracy, and reaction time (Bolton & Null, 1981). Even when not directly measured, these simple tasks are frequently part of more complex tasks in daily living. Caffeine also stimulates the adrenal medulla to secrete hormones which themselves are known to affect those variables and which are also closely associated with emotion, stress, and arousal. Caffeine can influence cardiovascular stress reactivity. Caffeine raises BP during stress by elevating the resting baseline from which the response is measured (Lane, Adcock, Williams, & Kuhn, 1990). Caffeine consumption may add to the blood pressure elevations seen in medical students, fluctuating their peak SBP into borderline hypertensive range (140–159) (Pincomb, Lovallo, Passey, Brackett, & Wilson,
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1987). Potentiation of stress reactivity is apparent in other variables also, e.g., stressrelated increases in forearm blood flow (Lane & Williams, 1985, 1987) and neuroendocrine reactivity. The observed interactions of caffeine and stress may be present even in individuals who habitually consume moderate amounts of caffeine (Lane et al., 1990). The significance of caffeine stress interactions in laboratory to cardiovascular and neuroendocrine reactivity in everyday psychosocial environment remains to be demonstrated; however, it might be reasonable to assume that it may raise BP during more natural stressors as well (Lane et al., 1990). Caffeine use might increase potential health consequences from prolonged exposure to occupational stress (Pincomb et al., 1987). The goal of this study was to clarify if the effects of caffeine in performance may or may not be independent of those of catecholamines it releases. They may interact to potentiate each other, or some of the properties attributed to caffeine may, in fact, be due to catecholamine activity.
2. Materials and methods Sixteen healthy volunteers (10 men with a mean body weight of 80 5 kg and 6 women with a mean body weight of 65 5 kg) of mean age 22 years old (SD: 3, range: 18–26) participated in this study, trained on an electronic multitask program for at least 3 weeks until they established their baseline (Fig. 1). They all signed a consent form and they were given a number, so that the investigator did not know anything about the subjectsÕ habits. They also responded to a questionnaire regarding their smoking and caffeine drinking habits, as well as their health status. All subjects abstained from caffeine drinks for at least 1 week before the study. During the study they performed the same tasks under the influence of a single and a triple dose of caffeine. Caffeine was weighted and the percentage of caffeine diluted in the cup was calculated. To select a dose of caffeine we used a predetermined quantity of instant coffee and diluted to 100 ml of water, which the subjects had to consume in 10 min. After caffeine was diluted, samples were sent to the General Chemistry Department of the Greek government and we received the exact amount of caffeine in each one of them. Subsequently, the caffeine concentration (1.4% caffeine or 62 mg caffeine/ 100 ml coffee) was analyzed and we established that for an 80 kg individual 1 coffee
Fig. 1. A young volunteer is training on the electronic multitask program during the experimental procedure.
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cup of 150 ml would be 1.5 mg/kg/day and 3 coffee cups (total 400–500 ml) would be 4.5 mg/kg/day. The coffee was always prepared in the same way and the volume consumed was based on the weight of the subject to provide the required caffeine dose. The multi-attribute task battery (MATB), which was used during the experimental procedure, was developed by Comstock and Arnegard (1992) at NASA Langley Research Center (Arnegard, 1991) and consists of a multitask electronic program, which simulates flight. MATB incorporates tasks analogous to activities that aircraft crew perform in flight, while providing a high degree of experimental control, performance data on each subtask and freedom to use non-pilot test subjects (Arnegard & Comstock, 1991). The main task of this program is the tracking task, which is located on the upper middle window of the monitor screen (Fig. 2). Using the joystick, the subjects keep the target at the centre of the window, while the monitoring tasks, located in the upper left window (Fig. 2) distract the subjects from their tracking task. The subject responds to the absence of the green light and the presence of the red light. We kept a medium difficulty mental workload, in order to trigger catecholamines activity. During the performance task, root mean square error (RMSE) for the tracking task was recorded in text files in order to perform the statistical measurements and the difference from the baseline (Test 0) was presented for each condition. RMSE is the deviation from the centre of the tracking target in pixel units given by the following formula: rffiffiffiffiffiffiffiffiffiffiffiffiffiffi x2 þ y 2 RMSE ¼ ; N where x and y are the spatial coordinates of the target and N is the root mean square data recording interval. The coordinates ð0; 0Þ correspond to the center of the target (Comstock & Arnegard, 1992).
Fig. 2. Multi-attribute task battery (MATB) screen shot.
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The subjects were divided into three groups according to their smoking and coffee drinking habits. Group A consisted of non-smokers and non-coffee drinkers; group B of smokers and coffee drinkers; and group C of non-smokers and coffee drinkers. Because of a very small number of subjects in the group of smokers/non-coffee drinkers, we did not include the fourth group in the study. The study was performed with administration of 1 cup of coffee corresponding to 1.5 mg/kg and 3 cups of coffee corresponding to 4.5 mg/kg on different days, after the subjects had abstained 1 week from caffeine. Performance was measured at rest (Test 0), after 30 min (Test 1), after 90 min (Test 2) and after 150 min (Test 3) of caffeine intake. The amount of urinary catecholamines, excreted after administration of 1 cup of coffee, 3 cups of coffee, after mental workload (stress) with no caffeine interference, and at rest was determined, from the concentration in the sample, multiplied by the total urine volume. We used the method of high performance chromatography with electrochemical detection (Hjemdahl et al., 1989; Lundberg, Holmberg, & Frankenhaeuser, 1988) to determine urine catecholamines.
3. Results In all conditions, statistically significant elevations were observed in adrenaline levels in all groups compared to those of resting levels. More specifically, in all conditions (stress, 1 cup of coffee + stress, 3 cups of coffee + stress) adrenaline levels of group A, group of non-coffee drinkers and non-smokers, compared to those of resting levels, revealed statistically significant differences (p < :05, p < :01, p < :005, respectively) with no statistically significant increase when caffeine was added to stress, in both doses. Comparing adrenaline levels of group B, group of coffee drinkers and smokers, in all conditions (stress, 1 cup of coffee + stress, 3 cups of coffee + stress) with resting levels, there was a statistically significant increase (p < :05). There was also a significant increase of adrenaline under stress (p < :01) with caffeine in both doses. Group C, group of coffee drinkers and non-smokers, increased adrenaline levels significantly (p < :01) in all conditions compared to resting levels. There was a statistically significant increase of adrenaline comparing stress with 1 cup of coffee and stress with 3 cups of coffee. The subjects of group C presented higher levels of adrenaline compared to those of group B. Comparing adrenaline levels between the groups in all conditions (Table 1), there was an increase for the group of coffee drinkers, but this was not statistically significant. Comparing performance scores with adrenaline levels at stress, linear regression and correlation statistics revealed no correlation between performance data and adrenaline levels for all three groups. Noradrenaline levels of group A, in all conditions compared with those of resting levels (Table 1), revealed a statistically significant increase (p < :005) for stress and stress with 1 cup of coffee, compared to resting levels, as well as stress with 3 cups of coffee compared to resting levels (p < :005). The asymmetry of the subject groups Table 1 Effects of stress and caffeine on catecholamine levels Group
A B C
At rest
Stress
Stress + 1 dose coffee (1.5 mg/kg/day)
Stress + 3 doses coffee (4.5 mg/kg/day)
ADR
NORADR
ADR
NORADR
ADR
NORADR
ADR
NORADR
5.70 7.75 7.86
41.33 42.07 54.40
23.90 23.23 32.40
143.70 151.50 160.80
29.05 27.60 32.80
184.50 181.50 199.40
32.03 34.50 44.60
200.70 207.25 232.60
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slightly influenced our results because the effects of smoking on catecholamines are minimal. Smoking habit is biochemically important as for the accelerated rate of caffeine metabolism. It is also found that there was a statistically significant difference between stress condition and stress with caffeine (p < :05). For groups B and C there was a statistically significant difference of noradrenaline levels in all conditions compared to resting levels, but there was no difference when caffeine was added to stress. Although noradrenaline levels increased with triple dose of caffeine, there was no statistically significant difference. Caffeine potentiated noradrenaline activity only for the group of non-coffee drinkers/non-smokers. There was a statistically significant increase of blood pressure in stress with the triple dose of caffeine for group A (p < :05) and no significant difference for the single dose of caffeine. Group B revealed a significant increase in blood pressure in stress in both doses of caffeine. Group C, coffee drinkers but non-smokers did not have any significant increase in both doses of caffeine. Comparing catecholamine levels with blood pressure (Tables 2–4), there was no correlation between them, although there was a relative increase of both parameters in all conditions. Root mean square error (RMSE) for tracking was calculated in all conditions and compared to baseline (Test 0) in order to clarify the effect of caffeine and catecholamines on performance data. Group A—Session 1: The results for the first study day with 1 cup of coffee revealed a statistically significant increase of cognitive performance 90 min after caffeine intake (p < :05) with maximum performance at 150 min (p < :007) (Fig. 3). In session 2, triple dose of caffeine (250 mg) enhanced performance with statistically significant differences (p < :05) (Fig. 4). In all cases the subjects performed well at the beginning of the task, but their endurance decreased significantly at the end of the task. Group B—Session 1: Performance was increased 90 min after 1 cup of coffee (p < :01) (Fig. 5) for the whole study period. There was a sudden decrease of performance during the 4th minute of the task, which was also accompanied with derangeTable 2 Comparison of blood pressure (mean values) with catecholamine levels in group A Group A
Blood pressure
Adrenaline
Noradrenaline
At rest Stress Stress + 1 dose caffeine (1.5 mg/kg/day) Stress + 3 doses caffeine (4.5 mg/kg/day)
118 122 127 124
5.70 23.90 29.05 32.03
41.33 143.70 184.50 200.70
Table 3 Comparison of blood pressure (mean values) with catecholamine levels in group B Group B
Blood pressure
Adrenaline
Noradrenaline
At rest Stress Stress + 1 dose caffeine (1.5 mg/kg/day) Stress + 3 doses caffeine (4.5 mg/kg/day)
120.25 125.75 133.25 139.75
7.75 23.23 27.60 34.50
42.07 151.50 181.50 207.25
Table 4 Comparison of blood pressure (mean values) with catecholamine levels in group C Group C
Blood pressure
Adrenaline
Noradrenaline
At rest Stress Stress + 1 dose caffeine (1.5 mg/kg/day) Stress + 3 doses caffeine (4.5 mg/kg/day)
125.6 128 131.6 132.4
7.86 32.40 32.80 44.60
54.40 160.80 199.40 232.60
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Fig. 3. Differences from baseline (Test 0) on root mean square error (RMSE) for Group A (non-coffee drinkers and non-smokers) during session 1 (1 cup of coffee).
Fig. 4. Differences from baseline (Test 0) on root mean square error (RMSE) for Group A (non-coffee drinkers and non-smokers) during session 2 (3 cups of coffee).
ment of the physiological measurements. In session 2, after triple dose of caffeine, performance improvement started right after caffeine intake (p < :005) and lasted for 90 min, starting gradually to decrease for the rest of the study (Fig. 6). A sudden decrease in performance at the 12th minute was probably due to tremor and eye–hand coordination decrements due to high dose of caffeine. Group C—Session 1: Performance revealed no improvement for the whole period of time with 1 cup of coffee. In session 2, after triple dose of caffeine performance improved in 90 min (p < :01) (Fig. 7) and remained in high levels for the whole study period.
4. Discussion In order to understand the real effects of caffeine, we tried to differentiate the effects of caffeine from those of noradrenaline and adrenaline and determine the
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Fig. 5. Differences from baseline (Test 0) on root mean square error (RMSE) for Group B (coffee drinkers and smokers) during session 1 (1 cup of coffee).
Fig. 6. Differences from baseline (Test 0) on root mean square error (RMSE) for Group B (coffee drinkers and smokers) during session 2 (3 cups of coffee).
manner in which they interact. One possible mechanism of interaction is put forward by Ritchie (1975). He noted that methylxanthines, such as caffeine, increase the concentration of cyclic AMP in many tissues, including the central nervous system through competitive inhibition of phosphodiesterase breakdown of cyclic AMP. The catecholamines also increase the concentration of cyclic AMP. They do this by stimulating cyclic AMP synthesis. Ritchie (1975) suggested that these two processes could go beyond a simple additive effect and result in a potentiation of the effects of the catecholamines. Comparing the adrenaline levels of group A in stress from resting condition, there was a significant increase of adrenaline levels. When caffeine was added to stress, a small increase, not statistically significant was observed in both doses (Table 1). It seems that once adrenaline reaches a certain level under the influence of one factor (mental stress in this case), another factor, as caffeine could no longer increase its
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Fig. 7. Differences from baseline (Test 0) on root mean square error (RMSE) for Group C (coffee drinkers and non-smokers) during session 2 (3 cups of coffee).
level significantly, especially for caffeine naive subjects. There was only a small increase of adrenaline levels, because of synergic effect of caffeine and stress. The subjects of group B (coffee drinkers/smokers) responded differently, by increasing further adrenaline levels after caffeine was added to stress condition (Table 1). That could be explained by the fact that coffee drinkers abstained from coffee for a whole week and when caffeine was added to stress they reacted fast by increasing significantly their adrenaline levels. Caffeine was the main trigger to increase adrenaline levels for the group of coffee drinkers. We observed a dose dependant effect of caffeine on adrenaline levels for the subjects of group B (non-coffee drinkers/nonsmokers). The subjects of group C presented higher adrenaline levels compared to those of group B, although they were all coffee drinkers (Table 1). The only difference between those two groups was the smoking habit of group B. The lower adrenaline levels of group B could be attributed to the fact that smoking increases caffeine clearance, affecting less smokers than non-smokers. There was no significant increase in blood pressure for group C subjects during the whole experiment with either dose of caffeine. This is probably due to caffeine tolerance of those subjects, as well as the fact that they did not smoke to aggravate their blood pressure. Blood pressure increased for the triple dose of caffeine in stress for the subjects of group A (caffeine na€ıve subjects and non-smokers). Alternatively caffeineÕs adenosine antagonistic actions (Fredholm, 1980) have been suggested (Von Borstel, Wurtman, & Conlay, 1983) to cause elevated systemic vascular resistance (Fredholm, 1985; Smits, Boekema, De Abreu, Thien, & VanÕt Laar, 1987, 1989). The vasodilator and the depressor effects of adenosine and the effect of increasing plasma norepinephrine can be blocked by relatively low dose of caffeine, in young healthy human subjects (Smits et al., 1989). Xanthines enhance the production of endogenous adenosine in the heart as well as antagonise the capacity of this to dilate coronary arteries. Vasodilating effects of adenosine seem to be mediated by a subclass of adenosinergic (A2-receptors), which are related to stimulation of cAMP formation (Fredholm & Sollevi, 1986). The response of blood pressure to caffeine is thought to depend on the balance between central vasomotor and myocardial stimulation, which tends to increase it, and central vagal stimulation and peripheral blood vessel dilation, which tends to decrease it (Ritchie, 1975). The subjects with caffeine drinking and smoking habits
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increased their blood pressure as soon as they had coffee either in single or triple dose. They were the most sensitive subjects and most aggravated. The statistical significant increase of noradrenaline levels of group A in all conditions shows that noradrenaline is more sensitive to stress and caffeine environment than adrenaline. According to Thomson norepinephrine is a neurotransmitter at peripheral autonomous synapses and increases activity at these sites. It is also found at high concentrations in brain structures influencing primarily the autonomic nervous system and some of those are involved in the motivational and emotional aspects of behavior (Thomson, 1975). The significant difference between noradrenaline levels in stress and stress with caffeine for both doses reveals probably a potentiation of noradrenaline levels with caffeine intake. This result appeared only for the group of caffeine na€ıve subjects. Numerous studies from laboratory experiments as well as from various natural settings illustrate the sensitivity of the SAM system to various psychosocial conditions, such as daily stress at work, at home, etc. (Levi, 1972; Mason, 1968). Catecholamines and their concomitant effects on other physiological functions, such as blood pressure, may serve as objective indicators of stress that an individual is exposed to. However, these bodily effects are also assumed to link psychosocial stress to increased health risks (Rozanski et al., 1988). Humoral or sympathetically mediated vasoconstriction has been suggested (Robertson, Wade, Workman, & Woosley, 1981; Smits, Hoffmann, Thien, Houben, & VanÕt Laar, 1983) as the major effect of the dose of 250 mg. Increases in circulating epinephrine, NE levels have been documented after a 250 mg dose in normal subjects, at rest (Robertson et al., 1978). Some studies found a stronger relationship between caffeine and NE rather than caffeine and Epinephrine (Denaro, Brown, Wilson, Jacob, & Benowitz, 1990; Heseltine, Dakkak, Woodhouse, Macdonald, & Potter, 1991). Caffeine is absorbed into the blood and body tissue within 5 min. In about 30 min, caffeine concentration reaches its peak level in the blood with a half-life period of approximately 4 h. Caffeine as a mild stimulant affects the brain by increasing neural activity. It increases the performance of simple intellectual tasks and enhances rapid processing of information. Caffeine also increases alertness and the ability to concentrate, along with countering fatigue. Mitchell et al. showed that caffeine prevents attention lapses in a visual monitoring test, which simulated night driving. The effect persisted for the 2–3 h experiment (Stephenson, 1977). A 200-mg dose of caffeine resulted in decreased decision time scores and improved motor time scores in volunteers (Bolton & Null, 1981). Hand steadiness, however, was impaired. After a caffeine intake of 200 mg, introverts performed less well on a verbal ability test as compared to extroverts when time pressure was applied (Ritchie, 1975). The group of non-coffee drinkers revealed an increase of their performance with the administration of 1.5 mg/kg of caffeine with some signs of nervousness which increased enormously when caffeine dose increased to 4.5 mg/kg and their hand steadiness was impaired adversely affecting delicate muscular coordination and accurate tracking. Non-coffee drinkers achieved their peak performance after 30 min of caffeine intake, but in the higher dose of the higher dose of caffeine, although they performed better they revealed a statistically significant increase of their blood pressure. Coffee drinkers/smokers achieved their peak performance only after high doses of caffeine administration and did not last more than 1 h with significant decrement afterwards, having their blood pressure also increased. Everyday life stress is enough to increase catecholamines and keep vigilance and arousal in high levels. Task oriented performance, attention, and concentrations may be modified by caffeine. The results of the present study provide an initial view of the potentially harmful combined effects of caffeine and stress and more research especially in hypertensive
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subjects could lead to significant information in the prevention and treatment of cardiovascular disease.
Acknowledgments We thank Mr. Simon Guy for his support as well as the General Chemistry Department of the Greek government for the analysis of caffeine doses.
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