A three pulse phase response curve to three milligrams of melatonin in humans

J Physiol. 2008 Jan 15;586(2):639-47. doi: 10.1113/jphysiol.2007.143180. Epub 2007 Nov 15.


Exogenous melatonin is increasingly used for its phase shifting and soporific effects. We generated a three pulse phase response curve (PRC) to exogenous melatonin (3 mg) by administering it to free-running subjects. Young healthy subjects (n = 27) participated in two 5 day laboratory sessions, each preceded by at least a week of habitual, but fixed sleep. Each 5 day laboratory session started and ended with a phase assessment to measure the circadian rhythm of endogenous melatonin in dim light using 30 min saliva samples. In between were three days in an ultradian dim light (< 150 lux)-dark cycle (LD 2.5 : 1.5) during which each subject took one pill per day at the same clock time (3 mg melatonin or placebo, double blind, counterbalanced). Each individual's phase shift to exogenous melatonin was corrected by subtracting their phase shift to placebo (a free-run). The resulting PRC has a phase advance portion peaking about 5 h before the dim light melatonin onset, in the afternoon. The phase delay portion peaks about 11 h after the dim light melatonin onset, shortly after the usual time of morning awakening. A dead zone of minimal phase shifts occurred around the first half of habitual sleep. The fitted maximum advance and delay shifts were 1.8 h and 1.3 h, respectively. This new PRC will aid in determining the optimal time to administer exogenous melatonin to achieve desired phase shifts and demonstrates that using exogenous melatonin as a sleep aid at night has minimal phase shifting effects.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Circadian Rhythm / physiology*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Humans
  • Male
  • Melatonin / administration & dosage*
  • Melatonin / metabolism
  • Melatonin / pharmacology*
  • Photoperiod
  • Saliva / metabolism
  • Sleep / drug effects*
  • Sleep / physiology*


  • Melatonin