Influence of Caffeine Consumption on the Human Circadian System

Surveys indicate that 85% of the adult population consume caffeine on a daily basis. Caffeine acts on sleep homeostatic mechanisms by antagonizing the sleep factor adenosine. Whether and how caffeine also impacts on the circadian regulation of sleep and -wakefulness is fairly unexplored. This study quantifies the influence of regular caffeine intake and its cessation on circadian promotion of sleep and wakefulness, on circadian hormonal markers, well-being, neurobehavioral performance and associated cerebral mechanisms. The knowledge is expected to contribute important insights on recent societal changes in sleep-wake behavior (e.g., shorter sleep duration and delayed sleep phase) and the related increase in people suffering from sleep problems.

Surveys indicate that 85% of the adult population consume caffeine, often on a daily basis. Caffeine acts on sleep homeostatic mechanisms by antagonizing the sleep factor adenosine. Whether and how caffeine also impacts on the circadian regulation of sleep and -wakefulness is fairly unexplored. The circadian timing system promotes wakefulness at the end of the biological day ("wake maintenance zone") and promotes sleep after the onset of the endogenous melatonin secretion ("opening of sleep gate"). There is mounting evidence that circadian and sleep homeostatic mechanisms continuously interact at the neurobehavioral, hormonal and cerebral level. Furthermore, earlier evidence has shown that the strength of circadian wake-promotion and the timing of circadian rhythmicity differs according to a genetic predisposition in the adenosinergic system. Thus, it was assumed that the daily consumption of caffeine may substantially impact on both circadian and homeostatic sleep-wake processes at different systemic levels.

This study aimed at quantifying the influence of regular caffeine intake and its cessation on circadian promotion of sleep and wakefulness, on circadian hormonal markers, well-being, neurobehavioral performance and associated cerebral mechanisms. Specifically, the study investigated the effects of sleep-wake regulatory adaptations to regular caffeine consumption and acute caffeine cessation a) on night-time sleep structure and sleep intensity (electroencephalography, EEG), b) on circadian wake-promotion (nap sleep during the biological day) and circadian timing of hormonal rhythms, and c) on waking quality, as indexed by subjective ratings, objective measures of neurobehavioral performance, and cerebral mechanisms (EEG and functional magnetic resonance imaging \[MRI\]).

Twenty young healthy regular caffeine consumers were examined in a double-blind, placebo-controlled within-subjects design with three conditions: Regular caffeine intake, regular placebo intake, and cessation of regular caffeine intake. In the laboratory, circadian sleep-wake promotion was assessed by combining EEG and multimodal MRI techniques. Circadian timing was assessed by salivary melatonin and cortisol rhythms. Sleep and waking quality were quantified by continuous polysomnography (during sleep at night and during a nap in the evening), waking EEG, subjective ratings (sleepiness, mood, craving, withdrawal symptoms) and cognitive performance (vigilance and working memory). Each of the three laboratory parts lasted more than 40 h under strictly controlled conditions (i.e., dim light, constant ambient temperature etc.). Subsequent to each laboratory condition, actimetry and sleep diaries served to assess sleep- and waking patterns in the field under caffeine vs. placebo conditions.

The aim was to substantially advance the knowledge about the impact of the commonly encountered caffeine consumption on the sleep-wake regulatory system. Furthermore, the project was intended to substantially contribute to the understanding of complex interplay between sleep-wake regulatory mechanisms in response to acute or long-term changes in the adenosinergic system.

Eligibility Criteria:
Inclusion Criteria:

* Self-reported caffeine consumption: 300 mg - 600 mg daily
* 18-35 years old
* Healthiness

Exclusion criteria based on chronic or debilitating medical conditions:

Normal current health was established based on questionnaires, screenings of urine, and examination by the physician in charge. Given the wide range of illnesses encountered in medical practice, we only list those that were certainly reasons of exclusion:

* Diseases of somatic origin: Cardiovascular-, respiratory-, gastrointestinal-, hematopoietic- visual- and immune system diseases, kidney and urinary tract, endocrine and metabolic diseases, neurologic diseases, infectious diseases, allergies (e.g. skin allergies, acute hay fever), thrombocytopenia or other dysfunction of the blood platelets.
* Sleep disorders: Narcolepsy, sleep apnea (apnea index \>10), periodic limb movements (PLMS \>15), insomnia (polygraphically recorded sleep efficiency \<70 %), hypersomnia, usual time in bed not between 6-9 h (assessed by \[101\]).
* Chronobiologic disorders: Hypernychthemeral sleep/wake cycle, delayed sleep phase syndrome (waketime \>2 h later than desired, or habitually after 10 am), advanced sleep phase syndrome (waketime \>2 h earlier than desired or habitually before 5 am).
* Drug/alcohol use, except caffeine: Volunteers must be drug-free (including nicotine and alcohol) for the entire duration of the study, with no history of drug (excluding caffeine) or alcohol dependency.

Exclusion criteria based on to the study requirements:

* Self-reported caffeine consumption: \< 300 mg and \> 600 mg daily (as estimated from mean caffeine content per serving of caffeine containing beverages and food)
* Body Mass Index (BMI) range: \<18 and \>26
* Participation in other clinical trials \<3 months prior to study begin
* Shift work \<3 months prior to study begin
* Transmeridian travel (\>2 time zones) \<1 month prior to study begin
* Extreme chronotype (Morningness-Eveningness Questionnaire \<30 or \>70)
* Inability to follow procedures
* Insufficient knowledge of project language (German)

Exclusion criteria based on MRI safety:

* Metallic prosthesis or metallic implants or non-removable objects on the body (e.g. splinters, piercings)
* Tattoos with larger diameter than 10 cm
* Tattoos above the shoulder area
* Claustrophobia
* Contraceptive coil