Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG

Psychopharmacology (Berl). 2003 Mar;166(2):127-38. doi: 10.1007/s00213-002-1315-8. Epub 2003 Jan 28.


Rationale: Modafinil is a wake-promoting agent that affects hypothalamic structures involved in the homeostatic and circadian regulation of vigilance. Administered during sleep deprivation, it reduces the need for prolonged recovery sleep and decreases the rebound in EEG slow-wave activity. These diachronic effects suggest an action of modafinil on a homeostatic sleep regulatory process.

Objectives: The aim of this study was to determine whether modafinil, in comparison to the d-amphetamine reference psychostimulant and to placebo, interferes with the vigilance regulatory processes reflected in the EEG during waking.

Methods: Thirty-three healthy subjects were investigated during 60 h of sustained wakefulness in a double-blind placebo-controlled parallel-design study. A 4-min maintenance-of-wakefulness test administered hourly allowed the concomitant assessment of alertness and waking EEG activity. The effects of equipotent psychostimulant dosages (modafinil 300 mg and d-amphetamine 20 mg) were evaluated at the beginning of the first sleep deprivation night, at the end of the second sleep deprivation night and in the afternoon preceding the first recovery night.

Results: One hour following ingestion, both psychostimulants increased alertness during 10-12 h, independently of the time of administration. At the level of the waking EEG, d-amphetamine attenuated the natural circadian rhythm of the different frequency bands and suppressed the sleep deprivation-related increase in low frequency (0.5-7 Hz) powers. In contrast, modafinil, which exhibited a transient amphetamine-like effect, had slight effect on circadian rhythms. Its selective action was characterized by maintenance of the alpha(1) (8.5-11.5 Hz) EEG power, which under placebo exhibited a homeostatic decrease paralleling that of alertness with a circadian trough at night.

Conclusions: These findings demonstrate that the alertness-promoting effects of modafinil and d-amphetamine involve distinct EEG activities and do not reside on the same vigilance regulatory processes. While d-amphetamine inhibits the expression of a sleep-related process, probably through a direct cortical activation masking EEG circadian rhythms, modafinil, through a synchronic effect, preferentially disrupts the homeostatic down-regulation of a waking drive.

Publication types

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

MeSH terms

  • Adolescent
  • Benzhydryl Compounds / pharmacology*
  • Central Nervous System Stimulants / pharmacology*
  • Child
  • Circadian Rhythm / drug effects*
  • Dextroamphetamine / pharmacology*
  • Double-Blind Method
  • Electroencephalography / drug effects*
  • Female
  • Homeostasis / drug effects
  • Humans
  • Male
  • Modafinil
  • Wakefulness / physiology*


  • Benzhydryl Compounds
  • Central Nervous System Stimulants
  • Modafinil
  • Dextroamphetamine