Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers

Hum Psychopharmacol. 2008 Dec;23(8):693-705. doi: 10.1002/hup.980.


Background: Melatonin is an important regulator of the sleep-wake cycle. A prolonged-release formulation of melatonin (PR-M) that essentially mimics the profile of the endogenous production of the hormone is effective in the treatment of insomnia in patients aged 55 years and older. Because hypnotics result in impairments of various cognitive skills, it is important to examine the cognitive effects associated with the use of PR-M.

Objectives and methods: The effects of therapeutic oral doses of PR-M (2 mg), zolpidem (10 mg) and their combination administered at bedtime on cognitive functions in healthy subjects aged 55 years and older (12 males + 4 females, age 59.4 +/- 3.2 years) were assessed in a randomized, double-blind, placebo-controlled, and four-way crossover study. Psychomotor functions, memory recall, and driving skills were assessed at 1 and 4 h following administration and the next morning.

Results: Compared to placebo, PR-M alone did not impaired performances on any cognitive tasks. Zolpidem significantly impaired psychomotor and driving performance 1 h and 4 h post-dosing, and early memory recall; these impairment were exacerbated with PR-M co-administration. No effects on next morning psychomotor or driving performance were observed except that the decline in memory recall after zolpidem was more pronounced in the next day. No pharmacokinetic interactions were found.

Conclusions: This study extends previous researches showing impairment of cognitive functions by zolpidem within 5 h post-administration. Further, PR-M use was not found associated with impairment of psychomotor functions, memory recall, and driving skills, and point to a pharmacodynamic interaction between melatonin and GABA-A modulators.

Publication types

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

MeSH terms

  • Aged
  • Attention / drug effects
  • Automobile Driving*
  • Cognition / drug effects
  • Cross-Over Studies
  • Delayed-Action Preparations
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Interactions
  • Drug Therapy, Combination
  • Female
  • Humans
  • Hypnotics and Sedatives / administration & dosage
  • Hypnotics and Sedatives / adverse effects
  • Hypnotics and Sedatives / pharmacology*
  • Male
  • Melatonin / administration & dosage
  • Melatonin / pharmacology*
  • Mental Recall / drug effects*
  • Middle Aged
  • Psychomotor Performance / drug effects*
  • Pyridines / administration & dosage
  • Pyridines / adverse effects
  • Pyridines / pharmacology*
  • Zolpidem


  • Delayed-Action Preparations
  • Hypnotics and Sedatives
  • Pyridines
  • Zolpidem
  • Melatonin