There is no time to rest! Modern day life is non-stop, with constant and increasing demands on our time. Where do we find the time to meet these demands? The number of hours in a day has not changed, but the number of hours we are sleeping has. In 1985, Americans slept an average of 7.40 hours; this figure had decreased to 7.18 hours by 2012.1 The decrease in average sleep time was accompanied by a 31% increase in the number of ‘short sleepers’ (people sleeping less than six hours).1 With our ever-increasing emphasis on “doing” and constant activity, sleep, which superficially appears passive, occupies a position of low priority on to-do lists. We routinely sacrifice sleep as we burn the candle at both ends, and we rely on caffeine to facilitate this behavior. A cup of coffee in the morning and additional cups to combat “slumps” throughout the day help us to tackle our seemingly never-ending catalog of tasks and responsibilities. We may pay a price for this reliance on caffeine. While consuming caffeine purposely fends off sleep, it can also lead to unintended sleep loss. How does caffeine’s prominent position in modern-day life affect our sleep, and of equal importance, impact our function when we are sleepy?

Caffeine consumption is ubiquitous, with over 80% of adults worldwide using caffeine habitually.2 The main motivation behind caffeine ingestion is the desire to stay awake and remain alert; people consume caffeine to ward off sleep and sleepiness. Thus, it comes as no surprise that sleep loss is a prominent effect of caffeine. Caffeine consumption creates a vicious cycle, wherein people ingest caffeine to stay awake or overcome feelings of drowsiness, consequently (and predictably) sleep less, and ultimately require more caffeine to manage increasing fatigue. Studies consistently conclude that caffeine has negative impacts on sleep.2

The mechanism of caffeine binding in the brain provides insight into caffeine’s impact on sleep and sleepiness. Caffeine acts as a competitive inhibitor at adenosine receptors in the brain, meaning that caffeine binds to the receptor and thereby prevents adenosine from binding at the active site.2 Adenosine is a neuromodulator that plays an integral role in regulating sleep pressure; animal studies demonstrate that extracellular cerebral adenosine concentration increases during prolonged wake times and declines during sleep, supporting the conclusion that adenosine concentration is directly linked to sleep.3 Adenosine is generated by breakdown of adenine nucleosides (adenine nucleosides are cleaved in processes of energy expenditure). Therefore, adenosine accumulates during the energy consumption associated with wakefulness, and this increased adenosine concentration acts on receptors in different parts of the brain to induce a state of sleepiness (and eventually, sleep). During sleep, adenosine concentrations fall.3 The adenosine receptor A2A plays a particularly important role in sleep-wake regulation: binding of adenosine at this receptor promotes sleep. One study in mice found that loss of this receptor’s function led to decreased sleep and diminished sleep rebound, indicating a key role for A2A in sleep/wake homeostasis.4 Caffeine binds to A2A receptors in the brain (thus blocking adenosine binding at these receptors and the induction of sleepiness), explaining the mechanism of caffeine’s effect on sleep and wake cycles.

Coupling studies of sleep deprivation with an understanding of the role of adenosine facilitates understanding of the impact of caffeine on cognitive function and behavior. Both chronic partial sleep deprivation and acute total sleep deprivation have been linked to decreased cognitive function, as measured by the psychomotor vigilance test (PVT) and a host of other neurobehavioral tests.4 Likewise, the accumulation of adenosine has been linked to diminished cognitive function. In one study, rats received adenosine infusions in their brains before performing a psychomotor vigilance test.5 Compared to the control group, these adenosine-infused rats showed longer response times and performance lapses that mirrored the performance of sleep-deprived rats.5,6 Both sleep deprivation—which is associated with increased cerebral adenosine levels—and exogenous administration of cerebral adenosine reduce indices of cognitive function and performance.3 Given that caffeine inhibits adenosine binding at receptors in the brain, it should follow that caffeine can improve neurobehavioral function in sleepy individuals.

Caffeine wards off sleep and sleepiness by acting as an adenosine receptor antagonist, but does caffeine diminish the neurobehavioral consequences that accompany sleep loss? Studies confirm that caffeine does counteract impaired attentiveness caused by sleep-deprivation.7 Even low doses of caffeine antagonize adenosine receptors, combating sleepiness and reducing lapses in vigilance.3 Wyatt and colleagues performed an elegant study demonstrating caffeine’s reversal of neurobehavioral deficits associated with sleepiness and sleep deprivation.8 The study employed a 29-day desynchrony paradigm, with 42.85 hour days that were divided into 28.57 hours of wakefulness and 14.28 hours of sleep. The design enabled extensive testing of subjects at times when they were experiencing the effects of sleep deprivation. Subjects were randomly assigned to receive either a low dose of caffeine (0.3 milligrams per kilogram per hour) or placebo. This caffeine dosing schedule was calculated to achieve a physiological caffeine concentration proportional to the expected accumulation of adenosine in the brains of subjects during the experiment’s scheduled prolonged wake time.8,9 In order to investigate cognitive function, researchers administered the PVT, a test which reliably measures alertness based upon the speed at which subjects respond to visual stimuli. Compared to those in the placebo group, the caffeinated subjects had less deterioration in their cognitive function. Specifically, the caffeine group had fewer lapses than the placebo group on the PVT, and had less impairment in the slowest 10% of their reaction times than did the placebo group.8 These findings support the common belief that caffeine reduces cognitive deficits arising from sleepiness.3 That cup of coffee before an exam may do some good after all.

Although caffeine generally leads to improved neurocognitive function in sleepy people, the degree to which caffeine enhances cognitive function varies between individuals.10 Recognizing that individuals exhibit different sensitivities to caffeine, scientists have designed experiments to elucidate the biological effects and causes of this variability in the context of sleep deprivation. Rétey and colleagues conducted an experiment to test the vulnerability to consequences of sleep loss in caffeine-sensitive and caffeine-insensitive individuals.11 In addition, they investigated the effects of caffeine on cognitive function in the two groups after a period of prolonged wakefulness.11 The researchers dichotomized caffeine responsiveness into two groups: they recruited twelve subjects who subjectively reported caffeine-sensitivity, and ten subjects who reported caffeine-insensitivity. They established a baseline for the subjects’ cognitive function (following eight hours of sleep) based on performance on the PVT. There were no differences between groups at baseline. Next, subjects were kept awake for forty hours, and given a capsule with either 200 milligrams of caffeine or placebo at the eleven and twenty-three hour marks. In the placebo group, prolonged wakefulness caused greater impairment in PVT performance in caffeine-sensitive individuals than in caffeine-insensitive subjects. In the caffeine group, individuals with the most cognitive impairment (the caffeine-sensitive group) benefited most from caffeine intake: they had a greater increase in neurocognitive function upon caffeine administration than did the caffeine-insensitive subjects.11 These results suggest a possible link between caffeine sensitivity and vulnerability to sleep deprivation. Further investigation into the cause of caffeine sensitivity/insensitivity has focused on two common alleles of the ADORA2A gene.3 A common C to T substitution at nucleotide 1976 of ADORA2A results in two alleles for the gene.12 Individuals with the C allele tend to have disturbed sleep after caffeine intake (caffeine-sensitive), whereas individuals with the T allele are less affected by caffeine (caffeine-insensitive).13 Thus, there is a genetic basis for the inter-individual differences in the impact of caffeine on sleepy individuals.

Despite the expected finding that caffeine enhances cerebral function in sleepy individuals (albeit by varied amounts based on inter-individual differences), the study by Wyatt also uncovered an unanticipated effect of caffeine on sleepiness: subjects in the caffeine group self-reported more impairment in alertness than did those in the placebo group.8 In other words, although the caffeine group had enhanced cognitive function in comparison to the placebo group, they felt that they were more cognitively impaired. This surprising result was identified through participants’ subjective sleepiness ratings on the Karolinska Sleepiness Scale (a 9-point scale ranging from extreme alertness to extreme sleepiness). A possible explanation for this puzzling finding in subjective sleepiness ratings is that caffeine boosted the ability of subjects to remain awake for extended periods of time and thereby inhibited periodic unplanned (but refreshing) sleep onsets that may have occurred more often in the placebo group.8 In addition, subjects in the caffeine group had reduced quantities of verified sleep during scheduled sleep episodes.8 Thus, while caffeine inhibits sleep and enables heightened cognition in sleepy individuals, caffeine does not eliminate a sense of sleepiness or fatigue as effectively as sleep does. Now we know: Sleep is the only true antidote to subjective sleepiness.

Caffeine’s relationship to sleep and sleepiness is complex: although caffeine can overcome cognitive deficits associated with loss of sleep or prolonged wakefulness, it simultaneously increases the perception of sleepiness. Thus, while routine and pervasive caffeine consumption enables us to be more alert and effective in times of prolonged wakefulness or shortened sleep, this reliance on caffeine may, ironically, make us feel sleepier. Sleep is the only real remedy to both the cognitive impairment caused by lack of sleep and the attendant, subjective feelings of sleepiness. Perhaps we would do ourselves a favor by skipping a few of those trips to the local Starbucks and taking a nap instead.


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