Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults

J Pineal Res. 2012 May;52(4):437-45. doi: 10.1111/j.1600-079X.2011.00958.x. Epub 2012 Feb 21.


Melatonin is increasingly used for the treatment of sleep disorders. Surge-sustained formulations consisting of combined immediate release and controlled release dosing may mimic the endogenous melatonin physiologic profile. However, relatively little is known about the pharmacokinetic properties of low-dose (<0.5mg) and high-dose (>2mg) melatonin in a combined immediate release/controlled release dose, especially in older adults who may also exhibit altered melatonin disposition. To assess this, we conducted a randomized, double-blind, placebo-controlled study of low-dose (0.4mg) and high-dose (4.0mg) melatonin (25% immediate release+75% controlled release) in 27 older adults with insomnia complaints and low endogenous melatonin levels to determine whether melatonin pharmacokinetic properties differ between these two doses. The time to maximum level (1.3hrs versus 1.5hrs), elimination half-life (1.8hrs versus 2.1hrs), and apparent total clearance (379L/hr versus 478L/hr) did not differ significantly between the low- and high-dose arms, respectively. The maximum concentration was 405 ±93pg/mL for the low-dose arm and 3999±700pg/mL for the high-dose arm, both of which are substantially higher than physiologic melatonin levels for this age group. In addition, subjects in the high-dose arm maintained melatonin levels >50pg/mL for an average of 10hrs, which could result in elevated melatonin levels beyond the typical sleep period. Renal and liver function parameters remained stable after 6wks of treatment. The linear pharmacokinetic behavior of melatonin observed in the elderly can form the basis for future studies exploring a wider range of dosing scenarios to establish exposure-response relationships for melatonin-mediated sleep outcomes.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Aged
  • Aged, 80 and over
  • Alanine Transaminase / blood
  • Analysis of Variance
  • Area Under Curve
  • Aspartate Aminotransferases / blood
  • Creatinine / blood
  • Delayed-Action Preparations
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Humans
  • Kidney / metabolism
  • Liver / metabolism
  • Male
  • Melatonin / administration & dosage*
  • Melatonin / blood
  • Melatonin / pharmacokinetics*
  • Polysomnography
  • Sleep Initiation and Maintenance Disorders / drug therapy*
  • Sleep Initiation and Maintenance Disorders / metabolism*


  • Delayed-Action Preparations
  • Creatinine
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Melatonin