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

Gary S. Richardson*, Phyllis C. Zee, Sherry Wang-Weigand, Laura Rodriguez, Xuejun Peng

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)456-461
Number of pages6
JournalJournal of Clinical Sleep Medicine
Issue number5
StatePublished - Oct 15 2008


  • Circadian rhythm
  • Dim-light melatonin offset
  • Melatonin receptor agonist
  • Phase advance

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Neurology
  • Clinical Neurology

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