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Tolerance to the Effects of Caffeine
- Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

VII. Tolerance to the Effects of Caffeine

It is known that tolerance develops to some, but not to all effects of caffeine in humans and experimental animals (Robertson et al., 1981; Holtzman and Finn, 1988). The precise mechanism underlying these effects is not known. In animals, attempts to relate this to receptor changes were made. The number of adenosine A1 receptors is increased following long-term caffeine treatment (Fredholm, 1982). This effect appears to be due to the blockade of a down-regulation induced by the endogenous agonist adenosine but not to changes at the level of gene transcription (Johansson et al., 1993a). There are much smaller effects, if any, on A2A receptors. This agrees with the reports from in vitro experiments that A1 receptors are readily down-regulated, whereas A2A receptors are not. Responses to A2A receptors are decreased following changes in Gs-proteins or adenylyl cyclase but not by changes in receptor levels (Chern et al., 1993). It must be pointed out that a change in adenosine A1 receptors occurs when animals are fed or injected with higher doses of caffeine, but not when lower doses are given ( (Bona et al., 1995; Johansson et al., 1996a). The changes in the number of adenosine A1 receptors are not the cause of the tolerance (Holtzman et al., 1991), which may instead be due to other types of adaptive changes, perhaps at the level of gene transcription, as noted above.

A. Cardiovascular Effects

It is generally agreed that high coffee intake causes tachycardia, palpitations plus a rapid rise in blood pressure, and a small decrease in heart rate. However, the tolerance to the effects of caffeine on blood pressure and heart rate usually develops within a couple of days (Colton et al., 1968

It should be pointed out that caffeine could elevate catecholamines and renin both by peripheral and central actions. The release of noradrenaline from sympathetic nerves could be regulated by methylxanthines by a presynaptic mechanism at the sympathetic nerve terminal (Hedqvist and Fredholm, 1976; Hedqvist et al., 1978). It has, however, been shown that this action, which depends on the antagonism of adenosine acting at A1 receptors, does not appear to be physiologically important in comparison to the much more important autoreceptor control via noradrenaline acting on alpha2 adrenergic receptors (Sollevi et al., 1981; Fredholm, 1995). It is therefore likely that the most important mechanism underlying increases in catecholamines is a rise in the sympathetic outflow and that this is centrally regulated.

B. Effects on Sleep

As noted above, sleep seems to be one of the physiological functions most sensitive to the effects of caffeine in humans. It is well known that caffeine taken at bedtime affects sleep negatively (see Snel, 1993

The results of the few studies comparing sleep problems between heavy and light consumers are equivocal. In general, coffee abstainers who drink coffee experience a longer delay before the onset of sleep as well as more disturbances in the different sleep phases and a shortening of the total time of sleep (Curatolo and Robertson, 1983), while habitual coffee drinkers seem to be rather immune to the effects of coffee on sleep (Colton et al., 1968). Although caffeine use is higher in poor than in good sleepers, caffeine use in insomniacs is lower, perhaps because they tend to decrease their caffeine consumption to limit their poor sleep nights (Edelstein et al., 1984). In two studies, self-reported caffeine consumption was unrelated to sleep problems (Broughton and Roberts, 1985; Lack et al., 1988). In two other studies, consumption of caffeine was correlated inversely with total sleep time after controlling for age and cigarette smoking, even in drinkers of only two cups of coffee per day (Hicks et al., 1983; Levy and Zylber-Katz, 1983).

Likewise, the relation between the time of coffee drinking and sleep disturbances is not clear. After analysis of the relation between caffeine consumption and sleeping habits in 140 students separately for caffeine consumed during the last 4 h before bedtime and during the whole day, Pantelios et al. (1989) found that sleep onset was delayed in association with coffee before bedtime but not with total daily consumption. On the other hand, Landolt et al. (1995b) reported that in modest coffee drinkers (1.5 cups/day, n = 9) 200 mg of caffeine given in the morning reduced sleep efficiency for the subsequent night. Total sleep time was reduced by about 10 min, the latency to stage 2 sleep was prolonged by a similar interval, and sleep efficiency (time asleep/time in bed) was reduced by about 3%.

It is not clearly established yet whether the difference in the sensitivity to the effects of coffee on sleep could be attributable to tolerance. Some authors consider that the difference rather reflects interindividual variations in sensitivity to the effects of caffeine as well as variability in the subject's response from one night to the next (Goldstein et al., 1965; Lieberman et al., 1987), whereas other studies show the development of tolerance to the effects of caffeine on sleep (Colton et al., 1968; Curatolo and Robertson, 1983; Zwyghuizen-Doorenbos et al., 1990; Bonnet and Arand, 1992). Recently, two field studies were carried out controlling for sleep duration objectively with portable actometers. In the first study, sleep duration decreased and the latency to sleep onset increased after the intermittent caffeine days in a group given regular and decaffeinated coffee for alternating 2-day periods, whereas subjective sleep quality and nightly awakenings were unaffected by switching from regular to decaffeinated coffee. No significant differences were seen between the group with continued caffeine abstinence and the control group (Höfer and Bättig, 1994a). In a second study, an initial 3-day period of habitual coffee drinking was followed either by 3 days of consuming caffeine tablets (50 mg) or by consumption of decaffeinated instead of regular instant coffee. Saliva caffeine decreased by about 50% with the tablets and 90% with decaffeinated coffee, whereas sleep duration remained unaffected with the tablets but increased by about 30 min with decaffeinated instant (Höfer and Bättig, 1994b).

Taken together, the results suggest that habitual daily coffee drinking does not strongly modify caffeine effects on total sleep time, and the exact role of tolerance remains to be determined. Despite the fact that heavy consumers of caffeine tend to have smaller effects of caffeine on sleep (see Snel, 1993), tolerance is probably incomplete, particular regarding the effect of caffeine late during the day on the ease of falling asleep.

C. Effects on Mood

As discussed above (Section IVB), the reports on acute effects of caffeine on mood are somewhat equivocal. To the extent that positive changes were observed, they were described as feelings of being more active, awake, clearheaded, calm and attentive, and less fatigued. Negative changes obtained, particularly with higher doses or in nonusers, include having the jitters, nervousness, anxiety, tension, restlessness, and sleeplessness. Several different aspects have been proposed in the past to explain the differences in the findings, and habituation and tolerance might be decisive factors (Estler, 1982

Some attempts have been made to study tolerance with appropriate experimental protocols. Evans and Griffiths (1992) studied 32 subjects who had to abstain for the 32 days of the study from all dietary caffeine. During an initial choice phase of 3 days, the subjects were tested with the technique of color-cued capsules as to whether they preferred capsules containing caffeine (300 mg) or placebo. Around one third of the subjects chose caffeine, but this was not related to gender, age, smoking status, prestudy caffeine consumption, or years of coffee drinking. However, anxiety scores on the Spielberger State-Trait Inventory (STAI) index correlated with not choosing caffeine. This initial screening was followed by an 18-day treatment period for which the subjects were split into a placebo and a caffeine group, balanced for caffeine choosers and nonchoosers. Three capsules were given per day, the caffeine capsules containing increasing amounts of caffeine with 100 mg at the start and 300 mg at the end of the treatment phase. During this phase no subjective ratings differed between the caffeine and the placebo group. The study was then continued with a second choice period with the same procedure as the first one. In this period the placebo-caffeine differences of the subjective ratings varied considerably between the subjects who received placebo and those who received caffeine during the preceding chronic treatment phase. In the chronic placebo-pretreated group, caffeine produced in comparison to placebo strongly increased ratings of tension and anxiety, having the jitters, nervousness, and having shakes, a feeling of "different from normal" and stronger "drug action". On the other hand, no such placebo-caffeine differences appeared in the caffeine-pretreated group, although the choices of the subjects between placebo and caffeine were hardly different from the first choice period and were not affected by the nature of the previous treatment, placebo or caffeine. The caffeine choosers showed additional preference to caffeine, and a reduction of tension, anxiety, headache, confusion and bewilderment, and fatigue. In contrast, the nonchoosers revealed more tension and anxiety and more nervousness. During the final withdrawal period, the withdrawal effects, in particular headache, were limited to the subjects who were pretreated chronically with caffeine. However, the severity of withdrawal was not related to the caffeine chooser status.

This study provides good evidence that tolerance develops to some of the negative effects of caffeine on the subjective state, but it gives less information with respect to possible tolerance for the positive effects of the substance. In the two field studies by Höfer and Bättig (1994a,b) subjective wakefulness increased significantly and clearly above preabstinence baseline levels upon resumption of caffeine intake, suggesting that tolerance to this positive parameter develops. A recent experiment closely related to everyday conditions was carried out by Warburton (1995). He assessed mood ratings and performance data in subjects who were minimally deprived from caffeine by 1 h only. Under this condition, the low doses of 75 and 150 mg of caffeine still produced significant increases of clearheadedness, happiness, calmness, and decreases in tenseness. These data are interpreted as an argument against tolerance for the positive effects and also for the possibility that the habitual coffee drinking might do no more than reverse withdrawal.

Thus, it appears that some tolerance to the effects of coffee on mood probably develops, but also that more experimentation would be needed to delineate the phenomenon more quantitatively.

D. Other Central Effects

There is no difference in the effect of an acute dose of 10 mg/kg caffeine on deoxyglucose uptake, when caffeine is given to naive or chronically caffeine-exposed rats (Nehlig et al., 1986

Oral intake appears more efficacious than systemic injection in producing motor stimulation, judging by the relationship between plasma caffeine levels and forward locomotion (Lau and Falk, 1994), but both systemic and oral administration of caffeine can produce tolerance, albeit at slightly different rates (Lau and Falk, 1994). There was little evidence for any change in the amount of xanthine in plasma during daily i.p. injections, indicating that altered metabolism plays a minimal role in tolerance development in rats (Lau and Falk, 1994). Because brain caffeine levels do not completely match plasma levels especially following ingestion of the drug (Fredholm et al., 1983; but see Kaplan et al., 1990), this may represent differences in brain levels of caffeine and its behaviorally active metabolites. There is a cross-tolerance to the activity-stimulating effect of theophylline (Finn and Holtzman, 1987). Tolerance appears more marked to high doses than to low doses of caffeine (Lau and Falk, 1995). All these results suggest that part of the "tolerance" may be related to a sensitization to the aversive/motor depressant effects of caffeine and not only to a decrease in the stimulant effects. Nonetheless these animal results are in apparent contrast to the human data summarized above, which instead tended to suggest that there is tolerance to the negative effects of caffeine.

Caffeine disrupts operant responding in rats trained to press levers for food rewards, but tolerance develops to this effect: the dose-response curve was shifted to the right by a factor of 6 (Carney, 1982). This could indicate that the decrease in caloric intake noted above (Section IVF) might be an effect of acute rather than long-term caffeine use.

Caffeine's effects on psychomotor and cognitive performance have been investigated in innumerable studies. Hand steadiness, reaction times, and tapping rate have been altered mostly in the positive direction by caffeine insofar as any changes were observed at all (James, 1991). The situation is similar for tests of different types of cognitive performance, including mental arithmetic, learning, and information processing.

As discussed above, information processing has often been studied under the condition of maintaining vigilance. Koelega (1993), who recently reviewed such experiments, came to the conclusion that improvements do not depend on fatigue induced by protracted sessions and that they represent more than a mere recovery from a previously withdrawal-induced impairment. Systematic analysis of the different components of such tasks indicates that it is more likely that caffeine acts by facilitating the sensory input and motor output rather than the central processing functions (Lorist et al., 1994). In a study of reaction times, "users" and "nonusers" of coffee did not differ when tested without previous abstinence in the users (Rizzo et al., 1988). However, when the users had to abstain for 2 days, their reaction time performance was inferior to that of the nonusers. This result is not surprising, because withdrawal symptoms culminate on the second day of abstinence and are often accompanied by headache. However, as mentioned earlier, even a minimal abstinence duration of 1 hour affects mental performance, and a low dose of caffeine after this brief abstinence gives improvements in attention, problem solving, and delayed recall compared to the control condition (Warburton, 1995).

E. Differences between Acute and Long-Term Administration---Effect Inversion

The adaptive changes to long-term caffeine are very dramatic, being not only quantitatively different from but often opposite to the acute effects of caffeine in normal and pathological conditions. Thus, a long-term treatment with caffeine causes a decrease in locomotor activity (Nikodijeviç et al., 1993

In pathological conditions, the first example is the finding that long-term caffeine treatment leads to decreased susceptibility to ischemic brain damage (Rudolphi et al., 1989), whereas acute treatment with caffeine and other methylxanthines instead exacerbates the damage (Dux et al., 1990). One of the most dramatic effects is shown in very young animals. When pregnant and lactating rat dams are treated with caffeine in their drinking water (0.3 g/l), caffeine is absorbed by the fetuses and the pups through the placenta and maternal milk, respectively, leading to very low levels of caffeine in the serum of the pups (about 1 µM). Rat pups subjected to hypoxia-ischemia at 7 days suffered significantly less brain damage when previously treated with caffeine than the untreated controls (Bona et al., 1995). This protective effect of low doses of caffeine over a long period of time has been repeatedly confirmed and there is good evidence that it cannot be attributed to changes in adenosine receptor number (Jacobson et al., 1996).

Some of the most dramatic effects have been noted on seizures. It is known that high doses of caffeine can precipitate seizures in humans and animals. However, long-term treatment leads to decreased seizure susceptibility whether the seizures are induced by the glutamatergic agonist NMDA (Georgiev et al., 1993; Von Lubitz et al., 1993b) or by GABAA receptor antagonists such as bicuculline or pentylenetetrazol (Johansson et al., 1996a). These data indicate that the chronic caffeine effect is not related to any specific form of seizure but is more general and occurs in the complete absence of any change in the number of adenosine A1 receptors (Georgiev et al., 1993) or GABAA/benzodiazepine receptors (Johansson et al., 1996a). Furthermore, the effects were most marked during the ongoing treatment with caffeine, not after it, as would be expected had an increased transmission through adenosine receptors been the mechanism (Georgiev et al., 1993). Long-term treatment with the adenosine A1 receptor agonist cyclohexyladenosine actually increased susceptibility (Von Lubitz et al., 1993b), in complete contrast to the acute treatment with such agonists.

These results indicate that long-term treatment with caffeine, in doses similar to those habitually used by humans, can induce important adaptive changes in the brain (Jacobson et al., 1996). Furthermore, these adaptive changes may be beneficial rather than detrimental.

), whereas, as noted above, acute treatment stimulates locomotor behavior in rodents. Likewise, long-term treatment with caffeine leads to an improved capacity for spatial learning (Von Lubitz et al., 1993a), whereas acute treatment does not.). By contrast, animal studies on mice and rats demonstrate a marked tolerance to the behaviorally stimulant effect of caffeine. In the rotation model in rats, the stimulant effects of both caffeine and theophylline are virtually eliminated in animals that consumed 75 mg/kg/day of caffeine orally (Garrett and Holtzman, 1995). In mice that consumed oral caffeine (1 g/l in the drinking water) there was a marked increase in locomotion during the first day, but this subsided during continued treatment, and during the third week of treatment the animals actually showed a lower locomotion (Nikodijeviç et al., 1993). The response to injected caffeine was altered in that the depressant phase was shifted to lower doses. Possibly this is related to the sum of the effects of oral and injected caffeine. The effect of dopaminergic drugs was little altered (Nikodijeviç et al., 1993), suggesting that the tolerance is not nonselective. In another study, long-term infusion of caffeine tended to reduce the locomotor response to 20 mg/kg (Kaplan et al., 1993), but it is not certain if this represents tolerance or a shift of the entire inverted U-curve toward the left so that lower doses produce depressant effects. However, virtually complete tolerance to the increase of locomotor activity was observed in rats consuming approximately 40 mg/kg caffeine per day via their drinking water (Finn and Holtzman, 1986), and this was accompanied by a downward displacement and flattening of the dose-response curve.). The majority of 10 early studies revealed no significant effects (Estler, 1982), but a more recent review concludes that there is a clear deterioration of mood even after overnight caffeine deprivation (Rogers et al., 1995).). Generally, more than 200 mg of caffeine is needed to affect sleep significantly. The most prominent effects are shortened total sleep time, prolonged sleep latency, increases of the initial light sleep EEG stages, and decreases of the later deep sleep EEG stages, as well as increases of the number of shifts between sleep stages. Subjective sleep quality decreases in parallel to the lengthening of sleep latency, the duration and number of periods of wakefulness, and the shortening of total sleep time. REM sleep is hardly decreased in relation to total sleep time, but the latency to the first REM period is shortened. However, the practical importance of these findings is limited by the fact that most coffee is consumed in the morning and by the question as to what extent tolerance might develop to the sleep-disturbing effects, particularly in heavy consumers.; Robertson et al., 1981; Ammon, 1991; Denaro et al., 1991; Shi et al., 1993b). The tolerance to cardiovascular effects of caffeine is paralleled by a decrease in caffeine-induced increase in plasma adrenaline, noradrenaline, and renin levels (Robertson et al., 1981). Tolerance to caffeine pressor effects is lost after relatively brief periods of caffeine abstinence and depends on how much caffeine is consumed, the schedule of consumption, elimination half-life of caffeine, and possible saturation of caffeine metabolism (Denaro et al., 1991; Shi et al., 1993b). Furthermore, tolerance to the blood pressure-raising effects might not be complete (Höfer and Bättig, 1993). Whereas blood pressure at rest tends to be negatively correlated with self-reported coffee drinking, actual blood pressure readings within less than 3 h after the last coffee tend to be elevated. On the other hand, some field studies (van Dusseldorp et al., 1989; Höfer and Bättig, 1994a) reported increases of heart rate upon caffeine abstinence. It was, however, not examined whether this could be attributed to some of the more subjective changes discussed below.

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