Influence of Caffeine Consumption on the Human Circadian System

NCT05409339 | Completed

• 1 other identifier: CChronobiology
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Caffeine; Caffeine Withdrawal; Sleep; Circadian Rhythm

Keywords

Caffeine; Withdrawal; Sleep; Circadian rhythm

Outcome Measures

Primary Outcomes (10)

• Sleep polysomnography in normal baseline sleep

  Electrophysiological activities were measured by electroencephalography during sleep. Spectral analysis was performed using a Fast-Fourier transformation to quantify delta (0.75 - 4.5 Hz), theta (4.5 - 8 Hz), alpha (8 - 12 Hz), and sigma (12 - 16 Hz), and beta (16 - 32 Hz) power density . Sleep stages, i.e., non-rapid eye-movement (NREM) stage 1, NREM2, NREM3, NREM4, and REM sleep were determined by visual scoring per 30-second epoch in accordance with the guideline of American Academy of Sleep Medicine (AASM).Sleep stages were reported relative to total sleep time. Duration of sleep latencies was also reported.

  First 8-hour nighttime sleep on the laboratory evening (Day 9)

• Sleep polysomnography in an evening nap

  Electrophysiological activities were measured by electroencephalography during the sleep. Spectral analysis was performed using a Fast-Fourier transformation to quantify delta (0.75 - 4.5 Hz), theta (4.5 - 8 Hz), alpha (8 - 12 Hz), and sigma (12 - 16 Hz), and beta (16 - 32 Hz) power density . Sleep stages, i.e., non-rapid eye-movement (NREM) stage 1, NREM2, NREM3, NREM4, and REM sleep were determined by visual scoring per 30-second epoch in accordance with the guideline of American Academy of Sleep Medicine (AASM).Sleep stages were reported relative to total sleep time. Duration of sleep latencies was also reported.

  approx. 13.5-hour after wake-up time on the laboratory day (Day 10)

• Sleep polysomnography in a recovery sleep

  Electrophysiological activities were measured by electroencephalography during the sleep. A Fast-Fourier Transformation was used to quantify slow wave activities (0.75 - 4.5 Hz), theta (4.5 - 8 Hz), alpha (8 - 12 Hz), and beta (12 - 16 Hz), and sleep stages, i.e., non-rapid eye-movement (NREM) stage 1, NREM2, NREM3, NREM4, and REM sleep were determined by visual scoring through each 30-second epoch in accordance with the guideline of American Academy of Sleep Medicine (AASM).

  Second 8-hour nighttime sleep following 20-hour wakefulness on the laboratory day (Day 10)

• Wake-EEG

  Electrophysiological activities during wakefulness measured by electroencephalography during the sleep. A Fast-Fourier Transformation was used to quantify slow wave activities (0.75 - 4.5 Hz), theta (4.5 - 8 Hz), alpha (8 - 12 Hz), and beta (12 - 16 Hz).

  14 measurements: (Day 9) -130, -20 minutes to the bedtime. (Day 10) +20, +140, +260, +370, +490, +600, +725, +867, +945, +1065, +1180, +1250 minutes after awakening.

• Melatonin levels

  The oscillation of melatonin levels across 43-hour laboratory stay were measured from the 33 salivary samples. The dim-light melatonin onset (DLMO) and average secretion level were analyzed and compared among three conditions.

  33 samples: (Day 9) -310,-250,-190,-140,-110,-80,-50,-10 minutes to the bedtime. (Day 10) + 50,+110,+170,+230,+290,+350,+400,+460,+515,+580,+610,+670,+700,+735,+765,+935,+965,+995,+1055,+1075,+1115,+1145,+1170, +1190,+1250 after awakening.

• Subjective sleepiness

  Participants were asked to assess their perceived sleepiness by Karolinska Sleepiness Scale (KSS), where they answered 1 for very alert and 9 for very sleepy.

  33 samples: (Day 9) -310,-250,-190,-140,-110,-80,-50,-10 minutes to the bedtime. (Day 10) + 50,+110,+170,+230,+290,+350,+400,+460,+515,+580,+610,+670,+700,+735,+765,+935,+965,+995,+1055,+1075,+1115,+1145,+1170, +1190,+1250 after awakening.

• Vigilance

  Vigilance was assessed by psychomotor vigilance tasks (PVT). Participants were asked to respond to each stimulus showing on a screen as soon as they can by keying down. The reaction times and lapses were used to indicate the vigilance.

  7 measurements: (Day 9) -160 minutes to the bedtime. (Day 10) +95, +335, +560, +795, +1040, +1235 minutes after awakening.

• Vigilance-related blood oxygen level-dependent activities

  Regional brain activation is measured by echo-planar-imaging (EPI) sequence in a 3T fMRI scanner during a psychomotor vigilance task (PVT).

  +795 minutes after waking up on the laboratory day (Day 10)

• Working memory-related blood oxygen level-dependent activities

  Regional brain activation is measured by echo-planar-imaging (EPI) sequence in a 3T fMRI scanner during a working memory task (N-back).

  +775 after waking up on the laboratory day (Day 10)

• Blood oxygen level-dependent activities in resting state

  Functional connectivity is measured by echo-planar-imaging (EPI) sequence in a 3T fMRI scanner during an eye-open resting state.

  approx.13.7 hours after waking up on the laboratory day (Day 10)

Secondary Outcomes (5)

• Cerebral blood flow

  approx. 13.5 hours after waking up on the laboratory day (Day 10)

• Caffeine concentrations

  12 samples: (Day 9) -185 minutes to the bedtime. (Day 10) +15, +120, +240, +300, +480, +590, +735, +825, +975, +1085, +1195 minutes after awakening.

• Working memory

  7 measurements: (Day 9) -140 minutes to the bedtime. (Day 10) +75, +315, +540, +775, +1020, +1215 minutes after awakening.

• Sleep diary

  Upon wake-up and bedtime during the ambulatory parts (Day1 to Day8 and Day11 to Day17)

• Actimetry

  Constant recording from Day1 to Day17.

Study Arms (3)

Caffeine-Caffeine (Condition "Caffeine")

EXPERIMENTAL

Through the 9-day pre-ambulatory, 2-day laboratory, and 7-day post-ambulatory parts, participants received 150 mg caffeine x 3 times daily.

Drug: Caffeine

Caffeine-Placebo (Condition "Withdrawal")

EXPERIMENTAL

During the 9-day ambulatory part, participants received 150 mg caffeine x 3 times daily, followed by a switch to placebo (150 mg mannitol) from the 2nd intake of the 9th day onward, through the laboratory and the post-ambulatory parts.

Drug: Caffeine; Drug: Placebo

Placebo (Condition "Placebo")

PLACEBO COMPARATOR

Through the 9-day ambulatory and 2-day laboratory, and 7-day post-ambulatory parts, participants received 150 mg mannitol x 3 times daily.

Drug: Placebo

Interventions

Caffeine DRUG

150 mg caffeine, 3 times/day (wakeup + 45 min, +255 min, and +475 min)

Caffeine-Caffeine (Condition "Caffeine"); Caffeine-Placebo (Condition "Withdrawal")

Placebo DRUG

Mannitol, 3 times/day (wakeup + 45 min, +255 min, and +475 min)

Also known as: Mannitol

Caffeine-Placebo (Condition "Withdrawal"); Placebo (Condition "Placebo")

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Self-reported caffeine consumption: 300 mg - 600 mg daily
• years old
• Healthiness

You may not qualify if:

• 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.
• 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)
• 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

Sponsors & Collaborators

• Psychiatric Hospital of the University of Basel: lead
• Swiss National Science Foundation: collaborator

Study Sites (1)

UPK Basel

Basel, Canton of Basel-City, 4002, Switzerland

Location

Related Publications (5)

• Weibel J, Lin YS, Landolt HP, Garbazza C, Kolodyazhniy V, Kistler J, Rehm S, Rentsch K, Borgwardt S, Cajochen C, Reichert CF. Caffeine-dependent changes of sleep-wake regulation: Evidence for adaptation after repeated intake. Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 20;99:109851. doi: 10.1016/j.pnpbp.2019.109851. Epub 2019 Dec 19.

  PMID: 31866308 RESULT

• Weibel J, Lin YS, Landolt HP, Kistler J, Rehm S, Rentsch KM, Slawik H, Borgwardt S, Cajochen C, Reichert CF. The impact of daily caffeine intake on nighttime sleep in young adult men. Sci Rep. 2021 Feb 25;11(1):4668. doi: 10.1038/s41598-021-84088-x.

  PMID: 33633278 RESULT

• Weibel J, Lin YS, Landolt HP, Berthomier C, Brandewinder M, Kistler J, Rehm S, Rentsch KM, Meyer M, Borgwardt S, Cajochen C, Reichert CF. Regular Caffeine Intake Delays REM Sleep Promotion and Attenuates Sleep Quality in Healthy Men. J Biol Rhythms. 2021 Aug;36(4):384-394. doi: 10.1177/07487304211013995. Epub 2021 May 23.

  PMID: 34024173 RESULT

• Lin YS, Weibel J, Landolt HP, Santini F, Garbazza C, Kistler J, Rehm S, Rentsch K, Borgwardt S, Cajochen C, Reichert CF. Time to Recover From Daily Caffeine Intake. Front Nutr. 2022 Feb 2;8:787225. doi: 10.3389/fnut.2021.787225. eCollection 2021.

  PMID: 35187019 RESULT

• Lin YS, Weibel J, Landolt HP, Santini F, Meyer M, Brunmair J, Meier-Menches SM, Gerner C, Borgwardt S, Cajochen C, Reichert C. Daily Caffeine Intake Induces Concentration-Dependent Medial Temporal Plasticity in Humans: A Multimodal Double-Blind Randomized Controlled Trial. Cereb Cortex. 2021 May 10;31(6):3096-3106. doi: 10.1093/cercor/bhab005.

  PMID: 33585896 RESULT

MeSH Terms

Interventions

Caffeine; Mannitol

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Sugar Alcohols; Alcohols; Organic Chemicals; Carbohydrates

Study Officials

• Carolin Reichert, Dr.

  UPK Basel

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Model Details: The project adopted a double blind, placebo-controlled, randomized within-subjects design. Screenings took place at the Centre for Chronobiology at the Psychiatric University Hospital Basel (UPK, single center). Data collection took place at Clinical Trial Unit, Department of Clinical Research, University of Basel and University Hospital of Basel. Each participant went through three study sessions, i.e. caffeine, placebo, withdrawal. Each of the session consisted of 9 days of pre-ambulatory part, 2 days of laboratory visit, and 7 days of post-ambulatory part.

Study Record Dates

• First Submitted: May 25, 2022
• First Posted: June 8, 2022
• Study Start: May 9, 2016
• Primary Completion: October 8, 2017
• Study Completion: December 17, 2017
• Last Updated: June 8, 2022

Record last verified: 2022-06

Locations

CH (1)