Caffeine’s Effects on the Human Stress Axis
Caffeine is one of the world’s most widely used drugs. Surveys in the U.S. have shown that approximately 80% of adults regularly consume caffeine, averaging two to three cups of coffee a day (Bonham and Leaverton, 1979). Caffeine activates the central nervous system (CNS) (Rall, 1980; Nehlig et al., 1992), leading to behavioral, autonomic, and endocrine responses. Caffeine’s effects on peripheral functions are widespread and are mediated by direct tissue effects along with hormonal and autonomic outputs. Caffeine increases circulating catecholamines and free fatty acids (Robertson et al., 1978; Pincomb et al., 1988). It also increases blood pressure (BP), both at rest and during behavioral stress, and in the lab and the workplace (Lane and Williams, 1985; Sung et al., 1990; James, 1993). The combined BP effect of caffeine plus stress is usually additive (Lane and Williams, 1985; Lovallo et al., 1991; Shepard et al., 2000).
Limited evidence from animal models suggests that caffeine may have pathogenic effects when combined with stress (Henry and Stephens, 1980). Such evidence in humans is lacking, although evidence suggests that persons at risk for hypertension may have greater cardiovascular responses and stress endocrine changes when exposed to stress following ingestion of caffeine, both in the lab and in daily life (Shepard et al., 2000). Caffeine interacts with CNS functions, it elevates stress hormone secretion, and it has direct effects on the heart and blood vessels. These points of action suggest that caffeine may be capable of influencing stress responses. In this post, we review evidence of caffeine’s effects on adrenal and sympathetic functions during rest and in response to acute stressful challenges.
CAFFEINE ACTS BY BLOCKING ADENOSINE RECEPTORS
Normal dietary intake of caffeine ranges from approximately 50 to 1500 mg per day, corresponding to consumption of one caffeinated soft drink up to 15 cups of coffee per day. In the U.S., the average reported adult intake is 250 mg per day, or about two to three cups of coffee. At these levels of intake, caffeine’s physiological actions are due to competitive blockade of adenosine receptors (Fredholm, 1980, 1995; Smits et al., 1990; Fredholm et al., 1999). Adenosine is produced by all tissues as a function of the breakdown of adenosine triphosphate during cellular metabolism and neurotransmission (Hoyle, 1992; Takiyyuddin et al., 1994; Johnson et al., 2001), and all cells have receptors for adenosine. The widespread effects of adenosine therefore account for caffeine’s broad spectrum of effects. In the CNS, adenosine is a putative physiological sleep factor that mediates the somnogenic effects of prior wakefulness. The duration and depth of sleep after periods of wakefulness appear to be profoundly modulated by elevated concentrations of adenosine in areas responsible for generalized arousal, and its gradual disappearance may account for the restorative effects of sleep (Porkka-Heiskanen et al., 1997).
Two actions of adenosine underlie caffeine’s cardiovascular and endocrine effects in humans. First, adenosine acts on potassium channels to hyperpolarize cell membranes of neurons, vascular smooth muscle, and cardiac muscle (Belardinelli, et al., 1989, 1995; Suzuki et al., 2001). This membrane effect of adenosine causes reduced rates of neuronal transmission and lowered responses of the heart and blood vessels. Second, adenosine acts presynaptically to decrease rates of transmitter release in the central and autonomic nervous systems (Fredholm and Dunwiddie, 1988). This reduces sympathetic outflow to the heart, blood vessels, and adrenal medulla (Shinozuka et al., 2002) . These effects lead to the general conclusion that adenosine acts to modulate the rate of neuronal firing and activation of target tissues.
Caffeine’s competitive antagonism of adenosine is therefore responsible for its ability to increase activation of the central and autonomic nervous systems. This suggests that caffeine can have effects both at rest and during periods of stress. Indeed, caffeine is consumed in greater quantities by employees during times of increased work stress (Conway et al., 1979), raising the possibility that caffeine consumption often accompanies periods of mental stress in daily life. We know that persons vary in their responses to stress (al’Absi et al., 1997), and the possibility presents itself that caffeine has greater effects in some persons than in others.
Effects of Caffeine on the HPA Axis during Rest
Among the most important of caffeine’s acute effects is its ability to alter the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis. The HPA axis affects all tissues and participates in functions occurring at rest and during stress. The HPA cascade is initiated at the hypothalamic paraventricular nucleus (PVN), resulting in release of corticotropin-releasing hormone (CRH) by terminals at the median eminence. CRH enters the portal circulation to the anterior pituitary, where it stimulates cleavage of pro-opiomelanocortin (POMC), causing release of adrenocorticotropic hormone (ACTH) and beta-endorphin into the general circulation. Arginine vasopressin (AVP) is also secreted at the median eminence, especially during stress, and together with CRH markedly potentiates ACTH secretion. ACTH increases the synthesis and release of cortisol by the adrenal cortex. Cortisol in turn exerts negative feedback on the HPA at the level of the pituitary and hypothalamus (Lovallo and Thomas, 2000).
Cortisol exerts numerous central and peripheral effects, including liberation of glucose by the liver and increasing plasma volume by causing a shift of fluid from intracellular to extracellular compartments and aiding in nutrient transport (Wilson and Foster, 1992; Vander et al., 1994). Cortisol participates indirectly in sympathetic nervous system or SNS function by increasing rates of catecholamine synthesis and production of adrenergic receptors. Cortisol also crosses the blood-brain barrier to reach the CNS, where it exerts negative feedback effects on the HPA axis. It also acts at sites where CRH receptors are found, including the anterior cingulate gyrus, prefrontal cortex, hippocampus, and amygdala (Fink et al., 1988; Swanson and Simmons, 1989; Diorio et al., 1993).
Experiments in rats show that caffeine stimulates production of cortisol/corticosterone, ACTH, and beta-endorphin (Vernikos-Danellis and Harris, 1968; Arnold et al., 1982; Spindel et al., 1984). In humans, we and others have noted that caffeine may elevate cortisol and ACTH production at rest (Arnold et al., 1982; Lane et al., 1990; al’Absi et al., 1995; Lovallo et al., 1996). These results suggest that caffeine’s adrenocortical actions in humans originate at the CNS. The effects of caffeine on ACTH and cortisol during rest were found to be comparable to that produced by acute stress (Lovallo et al., 1996). This suggests that caffeine alone may evoke an adrenocortical stress response during rest and in the absence of explicit stressful challenge. Such effects may counteract the effects of medications that normally suppress pituitary secretion. For example, caffeine increases the rate of recovery of adrenocortical functions after the administration of prednisolone, which suppresses corticosterone secretion in rats (Marzouk et al., 1991). Similarly, human studies have shown that ACTH and cortisol changes following caffeine ingestion may produce a false positive response to the dexamethasone suppression test, leading to escape in about a third of healthy persons (Uhde et al., 1985).
Most studies that have examined effects of caffeine in humans have used a dose range from 150 to 500 mg of caffeine (e.g., Rall, 1980; Spindel et al., 1984; al’Absi et al., 1998; Lane et al., 1990; Lovallo et al., 1996), or approximately 2 to 8 mg/kg. Low doses of caffeine tend to produce less consistent adrenocortical effects (see Lane et al., 1990; al’Absi et al., 1995). Early studies have shown that an oral dose of 250 mg of caffeine increased serum and urinary cortisol metabolites (Bellet et al., 1969; Avogardo et al., 1973), but other studies failed to show an effect of this dose during rest (e.g., Daubresse et al., 1973; Oberman et al., 1975; al’Absi et al., 1995). Similarly, caffeine increased catecholamine levels in some studies (Levi, 1967; Bellet et al., 1969; Robertson et al., 1978), but not in others (Jung et al., 1981). These inconsistencies have been attributed to the possibility that a low dose of caffeine would not be potent enough to produce consistent adrenocortical effects.
It should be noted here that the dose required to increase adrenocortical changes in rats tended to be high (approximately 20 mg/kg). This dose roughly equates to a 70-kg man drinking 10 to 15 cups of coffee in one sitting. Studies in humans that have used doses greater than 250 mg have provoked more consistent results. Cortisol levels were increased following ingestion of 500 mg of caffeine, but not after 250 mg of caffeine (Spindel et al., 1984). A dose of 500 mg of caffeine also increased beta-endorphin within 60 min of injestion, but no change in beta-endorphin levels were found after 250 mg. The beta-endorphin change also indicates the activation of the anterior pituitary and the cosecretion of ACTH (Guillemin et al., 1977).
Mechanisms that mediate caffeine’s stimulatory effects on the HPA axis are not yet fully delineated. It has been suggested that these effects may be due to blockade of the adenosine receptor and to interference with cyclic adenosine monophosphate (AMP) phosphodiesterase at the hypothalamus (Rall, 1980; Nehlig et al., 1992), as discussed elsewhere in this post. Each of these can result in increased availability of cAMP, which stimulates expression of the corticotropin- releasing factor (CRF) gene (Snyder et al., 1981). Secretion of CRF at the median eminence of the hypothalamus in turn stimulates ACTH release by the pituitary, resulting in increased cortisol production by the adrenal cortex (Petrusz and Merchenthaler, 1992). Caffeine may therefore increase CRF, ACTH, and cortisol through cAMP accumulation in the median eminence or pituitary, as has been shown in rats (Marzouk et al., 1991). Caffeine may also contribute indirectly to increased ACTH release through stimulation of epinephrine secretion (Neville and O’Hare, 1984), which can enhance cAMP production in the pituitary.
CAFFEINE AND CATECHOLAMINES
The first reported study of caffeine’s catecholamine effects was on dogs following intravenous administration, with the result that total catecholamine secretion increased (Deschaepdryver, 1959). In a survey of 19 studies on humans receiving dietary doses of caffeine (Table 8.1), 17 reported increases in epinephrine, 4 of which also showed increased norepinephrine. One study showed increased norepinephrine alone, while one found no effect on either catecholamine. The increase in epinephrine has been observed under resting conditions, in the laboratory and at home, and in the workplace during periods of normal work demand. It is seen following different methods of administration, dosages, and specimen sampling. It therefore appears that caffeine’s predominant effect on catecholamine secretion is on epinephrine, while changes in norepinephrine appear to be less common and are perhaps related to specific circumstances.
It is noteworthy that the one study reporting no change in either norepinephrine or epinephrine (Onrot et al., 1985) was done on patients with autonomic failure. The lack of both neurosympathetic and sympathoadrenal responses in these autonomic failure patients suggests that caffeine was unable to cause a direct release of epinephrine at the adrenal medulla. It further suggests that when caffeine does act to increase catecholamine output, it depends on an intact sympathetic nervous system to do so. If the sympathetic nervous system is essential for caffeine’s effect on catecholamine release, its relative specificity for epinephrine, while not absolute, indicates either a greater sensitivity of adenosine-mediated release of epinephrine than of norepinephrine, or a relative sensitivity due to the prevailing low concentrations of circulating epinephrine under basal conditions (20 to 50 mg/ml) in relation to norepinephrine’s higher levels (450 mg/ml). In line with this possibility, a number of the studies reviewed showed some norepinephrine response to caffeine that did not meet usual criteria for statistical significance. The predominance of an epinephrine response also suggests that caffeine exerts a stresslike effect on catecholamine secretion, as it appears to do for cortisol secretion. Although caffeine exerts an acute effect on catecholamine secretion, its dietary effects are less well understood. Daily dosing of volunteers with 750 mg of caffeine was shown to produce at least partial tolerance to the acute effects of caffeine on catecholamine levels (Robertson et al., 1981). The degree of tolerance produced by daily caffeine intake and the doses necessary to produce either complete or partial caffeine tolerance remain unknown (James, 1991).
CAFFEINE’S CARDIOVASCULAR EFFECTS DURING REST
Caffeine’s actions on the cardiovascular system are mediated by its competitive blockade of adenosine receptors. At the blood vessel wall, adenosine reduces the contraction of the smooth muscle cell (Suzuki et al., 2001), it enhances release by vascular endothelium of the regional vasodilator, nitric oxide (Buus et al., 2001), and it reduces release of the neurotransmitter norepinephrine (Fredholm and Dunwiddie, 1988). Adenosine therefore reduces vasomotor tone and vascular resistance to blood flow, and caffeine may be expected to oppose these effects.
Caffeine’s Effects on Blood Pressure
Caffeine’s ability to raise BP is perhaps its most extensively documented physiological effect, with publications dating back to the 1860s. While earlier studies caused uncertainty as to caffeine’s actions due to a lack of placebo controls, established dosages, and the availability of reliable BP devices, the earliest reliable report of caffeine’s pressor effect is by Wood (1912), who found an increase in BP and a slight fall in heart rate. Horst et al. (1934) confirmed caffeine’s pressor effect and slight bradycardia, and these have since been reported by many other investigators (Robertson et al., 1978, 1981; Lane, 1983; Smits et al., 1983, 1985; Whitsett et al., 1980; Pincomb et al., 1985, 1987; James, 1990; Lane et al., 1990; Sung et al., 1990; Lovallo et al., 1991; Shepard et al., 2000), to cite only a few. In addition to studies in the laboratory, caffeine’s pressor effect has also been measured outside the laboratory (Pincomb, 1987; Green and Suls, 1996; Shepard et al., 2000).
The BP response to a single dose of caffeine lasts approximately 3 h and is dependent on maintenance of elevated blood levels, declining as caffeine is cleared from the bloodstream (Robertson et al., 1978; Whitsett et al., 1984). In a representative study, 250 mg of caffeine was administered to healthy, caffeine-naîve subjects at rest, leading to BP increases (+14/10 mmHg) at 1 h, while heart rate fell slightly (Robertson et al., 1978). The nonconsuming status of these subjects indicates this may represent the upper limit of the BP response to caffeine among healthy persons. Comparison of BP responses to differing doses of caffeine spanning the range of usual daily intakes (2.2, 4.4, and 8.8 mg/kg, equivalent to about one to six cups of coffee) showed relatively little variation across doses and no tendency for a larger BP response to the highest dose (Whitsett et al., 1980). This suggests that caffeine’s effect on BP has a relatively flat dose-response relationship. We have consistently failed to find a significant correlation between caffeine blood or saliva levels and BP responses to acute administration. These findings indicate that caffeine’s occupancy of adenosine receptors in regard to BP regulation is complete at somewhere around 2 to 3 mg/kg and that higher doses, and consequently higher blood levels, do not exert a greater effect.
Despite the general understanding that caffeine elevates BP, there was longstanding uncertainty as to the underlying mechanism. It had been proposed that caffeine raised BP by increasing cardiac output (e.g., Rall, 1980). However, there was not good evidence for this view. A drawback to earlier investigations had been the difficulty of making measurements of cardiac output, particularly using reliable, noninvasive approaches that were not stressful for the subject or otherwise obtrusive on the test situation. In our first study (Pincomb et al., 1985), we administered oral doses of placebo vs. caffeine (3.3 mg/kg) to 15 medical students in a randomized, double-blind, crossover study and tracked their responses over 40 min. Along with BP, we measured cardiac output using impedance cardiography (Wilson et al., 1989; Sherwood et al., 1990), which allowed the calculation of total peripheral resistance, and therefore an estimation of the contributions to BP of changed blood flow and vascular resistance at each time point. Compared to placebo values, caffeine showed an increase in peripheral resistance that was statistically significant at 10 min after caffeine intake and increased progressively over the 40-min observation period, with a peak difference of +12% relative to placebo. This change preceded the rise in systolic/diastolic BP (+5%/+9%) and a decline in heart rate (-4.5%). Cardiac output did not change relative to the placebo condition (Pincomb et al., 1985). For this reason, it has been our position that caffeine’s principal resting cardiovascular effect is an increase in vascular resistance, which is the cause of the rise in BP. This finding has been replicated using the same and other techniques to measure cardiac output (Pincomb et al., 1993) and by other investigators (Casiglia et al., 1990).
This interpretation is consistent with caffeine’s adenosine antagonism. Competitive blockade of adenosine Aj receptors in the peripheral vasculature could increase the responsiveness of vascular smooth muscle cells to the tonic norepinephrine release by prejunctional sympathetic terminals. Caffeine may also reduce local secretion of the smooth muscle cell relaxant nitric oxide, further contributing to an overall rise in vascular resistance (Freilich and Tepper, 1992). Consistent with this interpretation, adenosine infused into the forearm causes increased blood flow secondary to decreased vascular resistance (Smits et al., 1991a,b), and this effect is antagonized by caffeine (Smits et al., 1990). In our studies, the effect of caffeine on vascular resistance appears before any significant effect on BP or heart rate, suggesting a peripheral vascular effect. However, a 250-mg dose also lowers baroreflex sensitivity for up to 3 h (Mosqueda-Garcia et al., 1990), potentially contributing centrally to a rise in pressure.
Caffeine’s Effects on the Heart
At the heart, adenosine decreases the firing rate of the sinoatrial node (Belloni et al., 1989), reducing the rate of atrial contraction and lowering heart rate. At the atrioventricular node, caffeine lengthens conduction time to the Hiss bundle (Conti et al., 1995), with no net effect on heart rate. At the ventricular wall, adenosine reduces contractility (Belardinelli et al., 1989), especially in the presence of beta-adrenergic stimulation (Isenberg and Belardinelli, 1984), therefore moderating the effects of myocardial ischemia (Freilich and Tepper, 1992; Sato et al., 1992; Song et al., 2002). Finally, adenosine improves coronary blood flow through its vascular actions. In contrast to the blood vessel, where peripheral factors are at least as important as central sympathetic outflow in determining vascular tonus, the heart at rest is governed more directly by a predominant parasympathetic drive (Berntson et al., 1994), augmented by sympathetic outflow under conditions of fight or flight, accompanied by a substantial responsiveness to circulating epinephrine (Sung et al., 1988). This interplay of dual central inputs combined with peripheral contributions in determining heart rate makes interpreting the present evidence difficult. For example, if adenosine increases the resting interval in the sinoatrial node, caffeine’s opposing action would be expected to increase heart rate. For this reason, caffeine’s bradycardic effect may be central in origin. At the brain stem, adenosine would be expected to reduce both parasympathetic and sympathetic outflow to the heart, with a greater effect on the parasympathetic branch, due to its greater gain factor at the sinoatrial node (Berntson et al., 1994), resulting in an increase in heart rate. Caffeine blockade of the above effects would therefore cause a net reduction of heart rate under resting conditions. There are no direct tests of this speculative explanation of caffeine’s bradycardiac effects.
CAFFEINE AND HPA RESPONSES TO STRESS
Caffeine consumption often increases during times of stress (Conway et al., 1981; Ratliff-Crain and Kane, 1995). Previous experiments in mice have demonstrated pathogenic effects of caffeine when administered while mice were subjected to the chronic stress of living in a competitive social environment (Henry and Stephens, 1980). Caffeine added to drinking water, supplied over several months to rats living in crowded conditions, increased corticosterone, adrenal weight, plasma rennin activity, and BP, leading to significant increases in morbidity and mortality compared with control mice drinking water alone.
We and others have noted that caffeine elevates cortisol production during mental stress (Lane et al., 1990; al’Absi et al., 1995; Lovallo et al., 1996), suggesting important interactions between caffeine’s CNS stimulation and endocrine components of the stress response. In a recent study, we evaluated the role of ACTH in the cortisol response to caffeine and stress (al’Absi et al., 1998). We measured ACTH, cortisol, and moods at several time points during placebo vs. caffeine on two resting control days and on two days with a behavioral stressor. During stress, the subjects worked on a reaction time (RT) task in alternation with mental arithmetic (MA). This simulated alternating work on mentally challenging tasks that people may engage in during daily life and that may be accompanied by consumption of caffeine. We found that caffeine and behavioral stress had a combined effect on both ACTH and cortisol (al’Absi et al., 1998).
In the presence of caffeine, behavioral challenges produce significant ACTH and cortisol responses, as documented in studies from our and others’ laboratories measuring cortisol alone (Pincomb et al., 1988; Lane et al., 1990; al’Absi et al., 1995, 1998). In some studies neither caffeine nor the acute stress alone produced cortisol responses, although significant elevations occurred when confronting acute challenges in the presence of caffeine (Lane et al., 1990; al’Absi et al., 1995). Consistent with this, Lane et al. (1990) found that caffeine raised cortisol concentrations when combined with mental arithmetic, but not during rest. Other studies have shown that caffeine alone at a similar dose (250 mg) was capable of producing significant ACTH and cortisol rises in the total sample when measured over a longer period of time and when compared with a time- synchronized placebo during a resting control day (Lovallo et al., 1996).
In summary, caffeine enhances the adrenocortical response to behavioral stress in the laboratory and may potentiate cardiovascular responses during mental stress (Pincomb et al., 1988; al’Absi et al., 1995). Caffeine in dietary doses is therefore capable of producing a pattern of responses associated with mental stress and can enhance such responses when individuals confront acute challenge.
CAFFEINE’S EFFECTS ON CARDIOVASCULAR RESPONSES DURING STRESS
In an early animal study, Henry and Stephens (1980) exposed male mice to social crowding and provided caffeine (3.3 mg/kg/d) in their drinking water. These stressful living conditions increased BP, contributed to renal pathology, and increased death rates in the animals. These findings indicate
the potential health relevance of studies of caffeine’s influence on cardiovascular activity during states of stress in humans. In addressing this issue, three questions arise: Does caffeine act on stress responses in an additive or synergistic fashion? Does it interact differently based on the nature of the stressor? Does it act differentially in certain groups of persons? In the human literature, caffeine has been examined with regard to stressors that can broadly be classified as mental and cognitive, exercise and psychomotor, painful or aversive, and occupational.
MENTAL AND COGNITIVE STRESSORS
A common mental stressor in the psychological laboratory is mental arithmetic, calling for rapid accurate calculations, usually in the presence of an experimenter and often with corrections for errors. This involves significant cognitive effort, and it is a social stressor due to its evaluative nature (Lovallo, 1997) . Other cognitive stressors involve demanding tasks such as the Stroop Color-Word Test, which calls for reading a list of color words printed in ink colors that differ from the word itself. The subject is instructed to read the ink color, ignoring the word, leading to a reliable stress response.
In most studies that use mental arithmetic or related stressors, caffeine consumed before stress raised systolic BP, diastolic BP, or both, during the prestress period. During the stressor, the most common finding has been that caffeine’s pressure elevation persists, and it appears to be additive with the effects of the stressor. As a result, the BP increase to caffeine combined with the stressor is often nearly identical to their combined effects. Most of the studies in the literature have used placebo-controlled, crossover designs and caffeine doses of 130 to 500 mg, resulting in increased systolic and diastolic BP levels during stress along with decreases in heart rate (Lane, 1983; Goldstein and Shapiro, 1987; Ratliff-Crain et al., 1989; James, 1990; France and Ditto, 1992; Lane et al., 1990). Other studies report either increased diastolic BP alone (France and Ditto, 1988) or increased systolic BP, when diastolic BP was not measured (Greenberg and Shapiro, 1987; Myers et al., 1989).
Although these studies show a relatively uniform additive effect of caffeine on BP during stress, there are reports of nonadditive effects. One study found a smaller diastolic BP increase to mental arithmetic stress after caffeine relative to placebo (Lane and Williams, 1985). All other examples of nonadditive effects indicate a response enhancement by caffeine. MacDougall et al. (1988) found strongly enhanced effects of mental arithmetic and video game stress on heart rate and systolic, but not diastolic, BP following caffeine. France and Ditto (1992) also reported greater heart rate responses to MA after caffeine intake. In most studies of heart rate in relation to caffeine exposure, the effect of caffeine was to lower heart rate, and this effect was generally found to persist during stress. The studies reporting nonadditive effects of caffeine and stress have usually reported an enhanced heart rate response to stress during caffeine exposure, with occasional effects on systolic BP. One report that caffeine increased the response to stress during electric shock (Hasenfratz and Battig, 1992) suggests that aversive challenges may interact differentially with caffeine, particularly in relation to beta-adrenergic responses associated with anxiety or fear.
EXERCISE, PSYCHOMOTOR STRESS, AND COLD PRESSOR CHALLENGE
Exercise has different characteristics than mental stress. Dynamic exercise increases heart rate and cardiac output and it induces a degree of vasodilation in the exercising muscle (Lovallo, 1997). In a related fashion, psychomotor challenges, typically reaction time tasks, call for rapid and accurate motor responses and appear to engage a similar response pattern, probably through induction of exercise-related central command mechanisms (Hobbs, 1982). Although both forms of stress have some common central characteristics, in dynamic exercise, centrally induced changes and peripheral ones combine to produce the global hemodynamic response.
Studies of dynamic exercise have shown caffeine’s pressor effect and modest heart rate decrease to be largely additive with the effects of exercise, such that BP is higher and heart rate the same or lower during exercise after caffeine is consumed. When caffeine (3.3 mg/kg) was administered to healthy male volunteers 1 h before a supine maximal bicycle ergometer test, it led to additive increases in systolic/diastolic BP and peripheral resistance at rest and during ergometry (Sung et al., 1990). This caused some subjects, especially those with a family history of hypertension, to have exaggerated BP responses to the exercise (see also Pincomb et al., 1991). A higher dose of caffeine (6 mg/kg) increased systolic BP to an equal degree at rest and during bicycle ergometer exercise (65% VO2 max) (Daniels et al., 1998). Caffeine did not affect heart rate, although it attenuated the increase in forearm blood flow otherwise seen during placebo. Similar BP and heart rate effects were seen when caffeine (5 mg/kg) was consumed before very mild (30 W) bicycle exercise (Perkins et al., 1994) . Studies of isometric or static exercise have also shown predominantly additive effects with caffeine (France and Ditto, 1992). Performance of a simple manual reaction time task is also primarily additive with the effects of caffeine on systolic/diastolic BP (Pincomb et al., 1988), although during the reaction time task caffeine increased cardiac output, an effect not seen at rest.
Some authors have tested the effects of habitual or background caffeine consumption on BP during exercise and related challenges. Instructions to drink six cups of coffee per day vs. none for 8 weeks resulted in volunteers having higher systolic/diastolic BP during orthostatic challenge than under no coffee, with no difference in the magnitude of the change (van Dusseldorp et al., 1992). Women who had consumed coffee on the day of dynamic and static exercise testing had a modest increment in systolic BP relative to those who had not (Hofer and Battig, 1993). In a study of the effect of caffeine intake on the results of diagnostic adenosine perfusion scans, caffeine blood levels ranging from 0.1 to 8.8 mg/l (equal to recent intake of up to five cups of coffee) were considered to be indicators of the recency and quantity of dietary caffeine intake (Majd-Ardekani et al., 2000). Higher blood levels of caffeine (> 2.9 mg/l) were correlated with higher systolic/diastolic BP before and during adenosine perfusion.
The majority of the studies reviewed above indicate that caffeine’s effects on BP and heart rate are additive with the effects of a variety of challenges. A small number of studies indicate that in some persons and under certain conditions, nonadditive or synergistic effects may also occur. Several of these studies have used psychomotor challenge (a simple reaction time task), some have used dynamic exercise, one used aversive stimulation, and some of these have compared persons at differing risk for hypertension. Caffeine therefore appears to have additive effects with acute mental stress, and both may have synergistic effects as well.
WORKPLACE AND RELATED SETTINGS OUTSIDE THE LABORATORY
Workplace studies have also found caffeine to elevate BP. Systolic BP increased after caffeine during telemarketing work (France and Ditto, 1989), and ad libitum coffee intake increased ambulatory diastolic BP in university workers relative to ad libitum decaffeinated coffee intake (Jeong and Dimsdale, 1990). Similarly, Lane et al. (1998, 2002) found caffeine increased ambulatory BP and heart rate at work and at home relative to placebo. Caffeine was examined in relation to the effects of variations in occupational stress by comparing BPs on lecture vs. exam days in medical students exposed to placebo and caffeine at both times. Caffeine (3.3 mg/kg) increased systolic/diastolic BP on mornings of lecture days, and it further elevated BP on mornings of exams, showing an additive effect (Pincomb et al., 1987). This additive relationship was confirmed in a more extensive study using ambulatory monitoring during extended portions of lecture and exam days (Shepard et al., 2000).
Two studies of Italian employees monitored in the workplace reported an inverse relationship between BP and self-reported coffee intake (Periti et al., 1987; Salvaggio et al., 1990). However,
these studies explicitly requested all employees to refrain from coffee intake the mornings of BP screenings, raising the possibility of a rebound BP effect in the regular consumers. Several other studies have found a positive association between casual BPs and reported caffeine intake among students attending a college campus BP screening (McCubbin et al., 1991). In 2436 Canadians being surveyed, reported coffee intake had a significant positive association with diastolic BP, although the effect was small (Birkett and Logan, 1988). In Denmark, coffee intake was significantly related to BP in 3608 adults (Kirchoff et al., 1994). In France, systolic/diastolic BPs were higher in 5430 coffee drinkers than in 891 abstainers (Lang et al., 1983b). In Algeria, diastolic BP was positively associated with coffee consumption in 1491 women and men (Lang et al., 1983a).
The nonlaboratory studies are therefore generally in agreement with those in the laboratory; BP is elevated by caffeine intake, either explicitly administered or by self-reported intake in the diet, and these effects are additive with the effects of stress when stress was manipulated. In general, the effects on BP are larger after specific dosing and smaller in relation to self-reported intake, perhaps due to lower reliability of self-reports and varying intervals between consumption and BP measurements. Although no mechanistic studies have been done, the results are generally in agreement with laboratory studies suggesting caffeine’s effect on the constrictor status of the blood vessel wall.
INDIVIDUAL DIFFERENCES IN THE EFFECTS OF CAFFEINE
Caffeine’s effects on the stress axis are variable across individuals. One of the individual differences that has been found to influence effects of caffeine on adrenocortical and sympathetic responses is risk for hypertension. Previous research has documented that risk for hypertension is accompanied by increased activation of the autonomic nervous system (Anderson et al., 1989) and the cardiovascular control centers of the hypothalamus and medulla (Folkow, 1982; Julius et al., 1988). Persons at genetic risk for hypertension may show greater cardiovascular reactivity to psychological stress (Fredrikson and Matthews, 1990; Lovallo and Wilson, 1992; al’Absi et al., 1996). The genetic disposition combined with the relatively elevated BP and exaggerated reactivity in these individuals may put them at a higher risk of becoming hypertensive (Borghi et al., 1986; Fredrikson and Matthews, 1990). The HPA axis is activated by exposure to novel and stressful situations, resulting in the secretion of cortisol from the adrenal cortex (Mason, 1975; al’Absi and Lovallo, 1993; al’Absi and Arnett, 2001). This activation may be exaggerated in persons at risk for hypertension (al’Absi et al., 1994; al’Absi and Wittmers, 2003).
Persons at risk for hypertension may be especially sensitive to caffeine’s effects on the HPA axis. For example, cortisol responses to caffeine at rest and following behavioral stress are greater and more persistent in persons at high risk for hypertension than in low-risk normotensives (Lovallo et al., 1989; al’Absi et al., 1995). Our research with individuals at high risk for hypertension also shows that ACTH and cortisol values at rest after caffeine were as high as those shown by the low- risk group in response to caffeine plus the tasks (al’Absi et al., 1995; Lovallo et al., 1996).
This indicates that caffeine may produce stresslike responses in high-risk persons even in the absence of behavioral demands, consistent with the hypothesis that risk for hypertension may be associated with increased activation of the HPA axis (al’Absi and Lovallo, 1993). Persons at risk for hypertension have increased activation of the autonomic nervous system (Julius et al., 1988) and the cardiovascular control centers of the hypothalamus and medulla (Folkow, 1982; Wyss et al., 1990). This may be paralleled by enhanced responses of the HPA responses to stimulant agents, such as caffeine.
In light of caffeine’s pressor effect and cortisol’s effects in enhancing cardiovascular activation, this line of research argues for further attention to the effect of caffeine in individuals at high risk for hypertension. For example, when at rest in a novel experimental environment, borderline hypertensives show enhanced adrenocortical activation relative to low-risk controls (Fredrikson et al., 1991; al’Absi and Wittmers, 2003) and they have larger responses during work on mental arithmetic and psychomotor stress (al’Absi et al., 1994). These tendencies are exaggerated in the presence of caffeine. Compared to low-risk controls, caffeine can differentially increase cortisol secretion in normotensive men at high risk for hypertension during work on a demanding psychomotor task (Lovallo et al., 1989) and in response to a combination of mental arithmetic and reaction time tasks (al’Absi et al., 1995). This suggests that persons at risk of hypertension may be especially sensitive to caffeine’s pituitary-adrenocortical effects when under stressful conditions.
In relation to caffeine’s predominant pattern of increased BP and bradycardia, the effects of caffeine may show important individual differences. Our initial finding that caffeine elevated vascular resistance led us to target persons for study who were at elevated risk for hypertension. Hypertension development may be accompanied by early vascular remodeling, with progressive thickening of the blood vessel wall (Folkow, 1990), causing an increase in vascular resistance while BP is still within the normal range (Lovallo et al., 1991; Marrero et al., 1997; Lovallo and al’Absi, 1998) , and consequently a greater sensitivity to agents that might elevate vascular resistance. We have therefore observed caffeine’s hemodynamic effects in young adults at differing levels of risk for hypertension, ranging from low risk (negative parental history and resting systolic BP < 125) to high risk (positive parental history and systolic BP > 125) to borderline hypertensive (BP > 135/85 and periodic elevations > 140/90) and medicated hypertensive patients. Persons at successively higher levels of hypertension risk have greater BP responses to caffeine (Hartley et al., 2000). This is especially apparent in borderline hypertensives and medicated hypertensives who have both a greater and more prolonged BP response to caffeine along with larger vascular resistance increases compared to controls (Sung et al., 1994, 1995; Pincomb et al., 1996).
This same dose of caffeine in borderline hypertensives led to a slightly greater increase in BP to the combination of task plus caffeine than in normotensive controls (Lovallo et al., 1996). This greater pressor effect in the borderline hypertensives was persistent over a 1-h task period involving both unsignaled reaction time and alternations with mental arithmetic in the latter half of the stress period (Lovallo and Thomas, 2000). Lovallo et al. (1991) found that caffeine (3.3 mg/kg) caused consistent increases in systolic/diastolic BP at rest due to increased vascular resistance. During an unsignaled simple reaction time task, caffeine caused a rise in cardiac output larger than its response to the task alone, contributing to a superadditive increase in the systolic BP response to the task.
Sung et al. (1995) compared normotensive and unmedicated hypertensive men during caffeine exposure and bicycle ergometer exercise. Caffeine (3.3 mg/kg) had an additive effect on systolic/diastolic BP during exercise in both groups and caused an elevation in vascular resistance and a small but significant decline in heart rate. During caffeine exposure, the diastolic BP rise to exercise diminished after 15 min in controls but persisted until 30 min in hypertensives, indicating a greater sensitivity to caffeine’s pressor effects in the hypertensives. This led a greater number of hypertensive mens having an exaggerated BP response at some point during exercise (> 230/120 mmHg). The studies showing nonadditive effects of caffeine and stress fall into two groups. One has found predominantly enhanced cardiac function as a result of psychomotor tasks, exercise, or aversive challenge. The second group includes studies of hypertensives or persons at high risk for future hypertension in whom increases in vascular responsiveness combined with increased cardiac output appear to have induced relatively greater BP rises than those found in normotensive controls.
In summary, persons at high risk for hypertension had greater pituitary-adrenocortical respon- sivity than low-risk men to the task challenges in the absence of caffeine compared with time- synchronized resting placebo control values. Caffeine alone elevated ACTH and cortisol concentrations relative to placebo in both groups. Both groups showed significant ACTH and cortisol rises to the combined tasks in the presence of caffeine, and the high-risk group showed earlier and more persistent rises throughout the tasks and the highest ACTH and cortisol levels seen in the experiment.
OTHER INDIVIDUAL DIFFERENCES
Caffeine’s BP effects are larger in older persons (Izzo et al., 1983) and men (James, 1990) and are more prolonged in blacks (Myers et al., 1989). Because there are on the order of 100 studies of caffeine’s pressor effect, a detailed review would be excessively long for the present purposes. A good, brief review is provided by James (1991).
CONCLUDING REMARKS AND FUTURE DIRECTIONS
Although research has demonstrated significant adrenocortical and sympathetic nervous system changes in response to caffeine, most studies produced findings that are limited to the examination of the effects of a single dose in regular users of caffeine who had abstained overnight. The acute and chronic tolerance effects of caffeine on adrenocortical responses to caffeine use on and behavioral challenges remain to be tested (see Robertson et al., 1981; James, 1993). Research so far is also limited by the exclusive use of men in most studies. Future studies could profitably address sex differences and should examine changes in response to caffeine and stress as a function of age and previous caffeine use.
The research conducted by our group showing an enhanced influence of caffeine in samples of normotensive men at elevated risk for hypertension suggests that similar studies should be conducted on other groups at elevated risk for cardiovascular disease, including smokers, blacks, and postmenopausal women. In addition, the responsiveness of the HPA axis to caffeine indicates that caffeine may also elevate levels of beta-endorphin, a potent ligand for opioid receptors located in the amygdala and elsewhere. Beta-endorphin shares an identical mode of release with ACTH at the pituitary (Guillemin et al., 1977). Future research into the role of neuroendocrine factors mediating the possible reinforcing effects of caffeine use could benefit from the examination of the HPA axis and endogenous function as potential mechanisms. Related systems that have been implicated in the addictive liability in caffeine, such as the GABAergic and dopaminergic systems, may also need to be further probed in terms of how their effects interact with HPA responses to caffeine and stress. Caffeine’s habitual intake may be encouraged by a mild experience of reward due to activation of central GABAergic neurons and release of dopamine from parts of the meso- pontine reticular system (Daly and Fredholm, 1998; Nehlig, 1999). These effects may underlie a reported inverse relationship between caffeine use and suicide in women (Kawachi et al., 1996) and the inverse risk of Parkinson’s disease in caffeine consumers (Ross and Petrovich, 2001). Work to examine the minimum effective dose of caffeine on these systems is still needed. Furthermore, the clinical significance of these changes needs to be clarified within the several lines of research that have been reviewed in this post.
In conclusion, current research indicates that caffeine, when combined with behavioral stress, enhances the effects of stress on ACTH and cortisol concentrations in humans. Individual differences in the effects of caffeine have also been shown. Specifically, research on persons at risk for hypertension indicates that these individuals may have greater pituitary-adrenocortical and sympathetic responses to caffeine, alone and combined with behavioral stress. In light of previously reported greater cardiovascular responses to stress in hypertension-prone individuals, this set of findings indicates a potential for greater negative impacts of caffeine in this group.
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