Circadian phase-shifting effects of repeated ramelteon administration in healthy adults

J Clin Sleep Med. 2008 Oct 15;4(5):456-61.


Study objectives: To assess the ability of repeated daily oral ramelteon to facilitate re-entrainment of human circadian rhythms after an imposed phase advance of the sleep-wake cycle.

Methods: A total of 75 healthy adult volunteers aged 18-45 years remained in a sleep laboratory for 6 days and 5 nights; a 5-h phase advance in their sleep-wake cycle was imposed under dim-light conditions. Oral ramelteon (1,2, 4, or 8 mg once daily for 4 days) or placebo was administered 30 min before bedtime. The primary endpoint was the phase of the circadian rhythm as assessed by the time at which salivary melatonin concentrations declined below 3 pg/mL after morning awakening (dim-light melatonin offset [DLMoff]).

Results: After 4 days of once-daily treatment, participants receiving 1, 2, or 4 mg ramelteon exhibited statistically significant phase shifts in DLMoff of -88.0 (16.6), -80.5 (14.8), and -90.5 (15.2) minutes respectively, versus -7.1 (18.6) minutes for placebo (least-squares mean(SEM), p = 0.002, p = 0.003, p = 0.001, respectively). Change in DLMoff for the 8 mg dose of ramelteon, -27.9 (16.4) minutes, was not significantly different than that for placebo (p = 0.392).

Conclusions: Ramelteon (1, 2, or 4 mg per day) administered before bedtime significantly advanced the phase of the circadian rhythm after a 5-h phase advance in the sleep-wake cycle. These findings suggest that ramelteon has potential as a specific therapy for circadian rhythm sleep disorders.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Circadian Rhythm / drug effects*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Humans
  • Indenes / adverse effects
  • Indenes / pharmacology*
  • Male
  • Melatonin / blood
  • Polysomnography / drug effects
  • Sleep / drug effects*
  • Young Adult


  • Indenes
  • ramelteon
  • Melatonin