Randomized, double-blind, placebo-controlled, crossover study of the effects of repeated-dose caffeine on neurobehavioral performance during 48 h of total sleep deprivation

Psychopharmacology (Berl). 2019 Apr;236(4):1313-1322. doi: 10.1007/s00213-018-5140-0. Epub 2018 Dec 11.


Rationale: Caffeine is widely used as a countermeasure against neurobehavioral impairment during sleep deprivation. However, little is known about the pharmacodynamic profile of caffeine administered repeatedly during total sleep deprivation.

Objectives: To investigate the effects of repeated caffeine dosing on neurobehavioral performance during sleep deprivation, we conducted a laboratory-based, randomized, double-blind, placebo-controlled, crossover, multi-dose study of repeated caffeine administration during 48 h of sleep deprivation. Twelve healthy adults (mean age 27.4 years, six women) completed an 18-consecutive-day in-laboratory study consisting of three 48 h total sleep deprivation periods separated by 3-day recovery periods. During each sleep deprivation period, subjects were awakened at 07:00 and administered caffeine gum (0, 200, or 300 mg) at 6, 18, 30, and 42 h of wakefulness. The Psychomotor Vigilance Test and Karolinska Sleepiness Scale were administered every 2 h.

Results: The 200 and 300 mg doses of caffeine mitigated neurobehavioral impairment across the sleep deprivation period, approaching two-fold performance improvements relative to placebo immediately after the nighttime gum administrations. No substantive differences were noted between the 200 mg and 300 mg caffeine doses, and adverse effects were minimal.

Conclusions: The neurobehavioral effects of repeated caffeine dosing during sleep deprivation were most evident during the circadian alertness trough (i.e., at night). The difference between the 200 mg and 300 mg doses, in terms of the mitigation of performance impairment, was small. Neither caffeine dose fully restored performance to well-rested levels. These findings inform the development of biomathematical models that more accurately account for the time of day and sleep pressure-dependent effects of caffeine on neurobehavioral performance during sleep loss.

Keywords: Caffeine gum; Cognitive performance; Dose response; Sleep loss; Within-subject design.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Attention / drug effects
  • Attention / physiology
  • Caffeine / administration & dosage*
  • Chewing Gum
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Psychomotor Performance / drug effects*
  • Psychomotor Performance / physiology
  • Sleep / drug effects*
  • Sleep / physiology
  • Sleep Deprivation / drug therapy*
  • Sleep Deprivation / physiopathology
  • Sleep Deprivation / psychology*
  • Treatment Outcome
  • Wakefulness / drug effects*
  • Wakefulness / physiology
  • Young Adult


  • Chewing Gum
  • Caffeine