Research ArticleCircadian Rhythms

Effects of caffeine on the human circadian clock in vivo and in vitro

Science Translational Medicine  16 Sep 2015:
Vol. 7, Issue 305, pp. 305ra146
DOI: 10.1126/scitranslmed.aac5125

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Your daily drug resets your clock

Your morning cup of coffee may be shifting your circadian clock. Burke et al. show that caffeine—widely available, legal, and psychoactive—inserts a delay into the ~24-hour metabolic rhythm that keeps your body running in time with the world.

In a sensitive, within-subject experimental design, five people were kept under highly controlled conditions for 49 days. Before bedtime, they were given various treatments: either a double-espresso caffeine dose, exposure to bright or dim light, or a placebo. The caffeine delayed their internal clock by 40 min, a shift about half as long as bright light, a stimulus known to robustly lengthen the circadian phase.

The authors used cultured cells to determine that the drug acted directly on the adenosine receptor, which increases the intracellular messenger molecule cyclic AMP. The fact that cyclic AMP forms a key cog in the inner workings of the clock links caffeine’s biochemical effects to its delay of the circadian rhythm.

Not only do these results reinforce the common advice to avoid caffeine in the evening, but they also raise the intriguing possibility that caffeine may be useful for resetting the circadian clock to treat jet lag induced by international time zone travel.

Abstract

Caffeine’s wakefulness-promoting and sleep-disrupting effects are well established, yet whether caffeine affects human circadian timing is unknown. We show that evening caffeine consumption delays the human circadian melatonin rhythm in vivo and that chronic application of caffeine lengthens the circadian period of molecular oscillations in vitro, primarily with an adenosine receptor/cyclic adenosine monophosphate (AMP)–dependent mechanism. In a double-blind, placebo-controlled, ~49-day long, within-subject study, we found that consumption of a caffeine dose equivalent to that in a double espresso 3 hours before habitual bedtime induced a ~40-min phase delay of the circadian melatonin rhythm in humans. This magnitude of delay was nearly half of the magnitude of the phase-delaying response induced by exposure to 3 hours of evening bright light (~3000 lux, ~7 W/m2) that began at habitual bedtime. Furthermore, using human osteosarcoma U2OS cells expressing clock gene luciferase reporters, we found a dose-dependent lengthening of the circadian period by caffeine. By pharmacological dissection and small interfering RNA knockdown, we established that perturbation of adenosine receptor signaling, but not ryanodine receptor or phosphodiesterase activity, was sufficient to account for caffeine’s effects on cellular timekeeping. We also used a cyclic AMP biosensor to show that caffeine increased cyclic AMP levels, indicating that caffeine influenced a core component of the cellular circadian clock. Together, our findings demonstrate that caffeine influences human circadian timing, showing one way that the world’s most widely consumed psychoactive drug affects human physiology.

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