18 SEPTEMBER 2015 • VOL 349 ISSUE 6254 1289SCIENCE sciencemag.org
By Hans Peter Landolt
Caffeine wakes people up but also dis-
rupts the quality of sleep. A new study
by Burke et al. ( 1) reveals that consum-
ing caffeine in the evening—the equiv-
alent of a double espresso—delays the
human endogenous circadian clock by
antagonizing receptors for the endogenous
sleep factor adenosine in the brain (see the
figure). Mistimed caffeine consumption may
contribute to the growing incidence of sleep
problems in society.
Many people worldwide consume caf-
feine daily. Normal dietary consumption
is sufficient to antagonize up to 50% of the
inhibitory A1 and the facilitatory A2A ad-
enosine receptors in the brain ( 2, 3). This
increases alertness and allays drowsiness
and fatigue, but may also induce restless-
ness and prolong the time to fall asleep,
enhance nighttime wakefulness, and reduce
the depth of sleep ( 4).
Adequate sleep is required for good health
and quality of life. The sleep-wake cycle is
regulated by the fine-tuned interplay be-
tween homeostatic and circadian processes
( 5). Homeostatic sleep need accumulates dur-
ing wakefulness and dissipates during sleep,
whereas the circadian clock determines
when sleep occurs. Slow-wave (or delta) neu-
ronal activity (~0.75 to 4.5 Hz) recorded with
an electroencephalogram (EEG) during deep
sleep provides the most reliable biomarker
of sleep need ( 5). Because caffeine attenuates
sleep delta activity and blocks adenosine re-
ceptors, a role for adenosine and its receptors
in sleep homeostasis has long been suggested
( 4). Burke et al. investigated whether caffeine
also affects the human circadian clock. This
is important because sleep and circadian
systems are intimately linked at genetic, mo-
lecular, and behavioral levels.
Burke et al. used a highly sensitive proto-
col under strictly controlled conditions over a
period of 49 days, and quantified the effects
of 200 mg of caffeine on the timing of melato-
nin production in people when taken 3 hours
before habitual bedtime in the evening. Mela-
tonin is a hormone that in humans, entrains
the circadian rhythm of many physiological
processes, such as the timing of sleep, and is
a reliable phase marker of the endogenous
circadian pacemaker ( 6). Indeed, caffeine
strongly and consistently delayed the mela-
tonin rhythm by about 40 min, nearly half of
the delay caused by bright light exposure at
bedtime, a strong time cue for the circadian
clock ( 7). But how does caffeine delay the cir-
cadian rhythm?
The complex signaling cascade that regu-
lates clock functions is expressed in nearly
every cell of the body ( 8). In vitro, caffeine
not only blocks adenosine receptors but also
inhibits phosphodiesterase activity and ac-
tivates ryanodine receptors. These actions
increase cyclic adenosine monophosphate
(cAMP)–dependent signaling and intracellu-
lar calcium release ( 2), both of which contrib-
ute to circadian timekeeping and resetting of
the clock ( 9, 10). Burke et al. measured cir-
cadian transcriptional rhythms in genetically
engineered human cells expressing more than
10,000 proteins, including adenosine recep-
tors, multiple phosphodiesterases, and ryano-
dine receptors. They confirmed that caffeine
lengthens the circadian period and increases
cAMP concentration. Although some open
questions remain, their convergent pharma-
cological, genetic, and immunochemical data
suggest an adenosine A1 receptor–mediated,
cAMP-dependent mechanism.
Caffeine-induced interference with the
circadian clock may contribute to the high
incidence of sleep problems in society and
have a negative impact on brain functions
that rely on undisturbed slow-wave sleep
( 11). Indeed, circadian rhythmicity modu-
lates important functional characteristics of
slow-wave sleep in humans ( 12). Yet, prop-
erly timed caffeine could alleviate jet lag
and help patients with circadian sleep-wake
disorders. Research on causal relationships
among caffeine, circadian timekeeping,
sleep, and health is warranted.
Apart from the circadian clock, cAMP
signaling also plays an important role in
sleep homeostasis and in the effects of caf-
feine on the consequences of sleep loss in
animals (13, 14). In humans, the physiological
study of wakefulness and sleep is laborious,
and the molecular mechanisms underlying
sleep-wake regulation are difficult to eluci-
date. Given that cultured cells can display
a sleep-like state (that is, neuronal firing
activity reminiscent of sleep) ( 15), fundamen-
tal questions related to electrophysiological,
genetic, and molecular features, as well as the
pharmacology of sleep, can now be studied in
human cells in vitro. Combined with physi-
ological approaches, this opens up exciting
new perspectives to examine the molecular
bases of human sleep and to develop evi-
dence-based therapeutic interventions for
disturbed sleep in health and disease. ■
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Caffeine, the circadian clock, and sleep
10.1126/science.aad2958
Why is caffeine intake at bedtime a sleep disrupter?
CIRCADIAN RHYTHMS
1Institute of Pharmacology and Toxicology, University of
Zürich, Zürich, Switzerland. 2Zürich Center of Interdisciplinary
Sleep Research, University of Zürich, Zürich, Switzerland.
E-mail: [email protected]
Cafeine
Adenosine receptors
cAMP signaling
Sleep homeostasis Circadian clock
Sleep pressure
Sleep propensity
Time Time
ILLUSTRATION: V. ALTOUNIAN/SCIENCE
Double espresso effect. By blocking cerebral
adenosine A1 and A2A receptors, caffeine increases
intracellular cAMP signaling, attenuates the buildup of
homeostatic sleep propensity during waking, and delays
the circadian clock in vitro and in vivo.
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