Effects of caffeine on the human circadian clock in vivo and in vitro.
Level 2 - randomized trial
Double-blind, placebo-controlled within-subject human trial combined with in vitro mechanistic assays
PubMed 26378246 · doi:10.1126/scitranslmed.aac5125
What was done
Investigators evaluated the effect of evening caffeine on human circadian timing using a double-blind, placebo-controlled, within-subject protocol lasting approximately 49 days. Participants consumed a caffeine dose equivalent to a double espresso 3 hours before habitual bedtime under controlled conditions. This was compared against placebo and against a positive control of 3 hours of evening bright light (~3000 lux, ~7 W/m2) starting at habitual bedtime. In parallel, human osteosarcoma (U2OS) clock gene luciferase reporter cells were used to measure cellular circadian period changes, cyclic AMP levels, and the signaling contributions of adenosine receptors, ryanodine receptors, and phosphodiesterases via pharmacological dissection and siRNA knockdown.
What was found
Consuming caffeine 3 hours before habitual bedtime induced a ~40-min phase delay of the circadian melatonin rhythm in humans. This magnitude was nearly half the magnitude of the phase-delaying response induced by 3 hours of evening bright light. In vitro, caffeine induced dose-dependent lengthening of the molecular circadian period and increased cyclic AMP levels. Pharmacological dissection and siRNA knockdown established that adenosine receptor signaling, rather than ryanodine receptor or phosphodiesterase activity, accounted for caffeine's effects on cellular timekeeping.
Why it matters
This study demonstrates that caffeine directly shifts the phase of the human circadian clock rather than simply masking sleepiness. It identifies an adenosine receptor- and cyclic AMP-dependent mechanism linking caffeine intake to human and cellular timekeeping.
Limits
The abstract does not disclose the sample size or demographic characteristics of the human participants. Mechanistic cellular experiments were conducted in an osteosarcoma cell line rather than human suprachiasmatic nucleus tissue. Effects of habitual caffeine intake levels and dose variations were not reported in the abstract.
Cited by
- supports Studies show that a cup of coffee affects the circadian clock equivalently to one to two hours of bright light exposure.