Caffeine does not entrain the circadian clock but improves daytime alertness in blind patients with non-24-hour rhythms

Sleep Med. 2015 Jun;16(6):800-4. doi: 10.1016/j.sleep.2015.01.018. Epub 2015 Feb 11.


Objective/background: Totally blind individuals are highly likely to suffer from Non-24-Hour Sleep-Wake Disorder due to a failure of light to reset the circadian pacemaker in the suprachiasmatic nuclei. In this outpatient case series, we investigated whether daily caffeine administration could entrain the circadian pacemaker in non-entrained blind patients to alleviate symptoms of non-24-hour sleep-wake disorder.

Patients/methods: Three totally blind males (63.0 ± 7.5 years old) were studied at home over ~4 months. Urinary 6-sulphatoxymelatonin (aMT6s) rhythms were measured for 48 h every 1-2 weeks. Participants completed daily sleep-wake logs, and rated their alertness and mood using nine-point scales every ~2-4 h while awake on urine sampling days. Caffeine capsules (150 mg per os) were self-administered daily at 10 a.m. for approximately one circadian beat cycle based on each participant's endogenous circadian period τ and compared to placebo (n = 2) or no treatment (n = 1) in a single-masked manner.

Results: Non-24-h aMT6s rhythms were confirmed in all three participants (τ range = 24.32-24.57 h). Daily administration of 150 mg caffeine did not entrain the circadian clock. Caffeine treatment significantly improved daytime alertness at adverse circadian phases (p <0.0001) but did not decrease the occurrence of daytime naps compared with placebo.

Conclusions: Although caffeine was able to improve daytime alertness acutely and may therefore provide temporary symptomatic relief, the inability of caffeine to correct the underlying circadian disorder means that an entraining agent is required to treat Non-24-Hour Sleep-Wake Disorder in the blind appropriately.

Keywords: Alertness; Blindness; Caffeine; Circadian; Entrainment; Non-24-hour sleep–wake disorder.

Publication types

  • Controlled Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Affect / drug effects
  • Aged
  • Arousal / drug effects*
  • Blindness / psychology*
  • Blindness / urine
  • Caffeine / administration & dosage*
  • Circadian Clocks / drug effects*
  • Humans
  • Male
  • Melatonin / analogs & derivatives
  • Melatonin / urine
  • Middle Aged
  • Polysomnography
  • Sleep Disorders, Circadian Rhythm / drug therapy*
  • Sleep Disorders, Circadian Rhythm / urine


  • 6-sulfatoxymelatonin
  • Caffeine
  • Melatonin