Prophylaxis of migraine with melatonin: a randomized controlled trial

Neurology. 2010 Oct 26;75(17):1527-32. doi: 10.1212/WNL.0b013e3181f9618c.


Background: A previous open-label study of melatonin, a key substance in the circadian system, has shown effects on migraine that warrant a placebo-controlled study.

Method: A randomized, double-blind, placebo-controlled crossover study was carried out in 2 centers. Men and women, aged 18-65 years, with migraine but otherwise healthy, experiencing 2-7 attacks per month, were recruited from the general population. After a 4-week run-in phase, 48 subjects were randomized to receive either placebo or extended-release melatonin (Circadin®, Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) at a dose of 2 mg 1 hour before bedtime for 8 weeks. After a 6-week washout treatment was switched. The primary outcome was migraine attack frequency (AF). A secondary endpoint was sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI).

Results: Forty-six subjects completed the study (96%). During the run-in phase, the average AF was 4.2 (±1.2) per month and during melatonin treatment the AF was 2.8 (±1.6). However, the reduction in AF during placebo was almost equal (p = 0.497). Absolute risk reduction was 3% (95% confidence interval -15 to 21, number needed to treat = 33). A highly significant time effect was found. The mean global PSQI score did not improve during treatment (p = 0.09).

Conclusion: This study provides Class I evidence that prolonged-release melatonin (2 mg 1 hour before bedtime) does not provide any significant effect over placebo as migraine prophylaxis.

Classification of evidence: This study provides Class I evidence that 2 mg of prolonged release melatonin given 1 hour before bedtime for a duration of 8 weeks did not result in a reduction in migraine frequency compared with placebo (p = 0.497).

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antioxidants / administration & dosage*
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Delivery Systems
  • Female
  • Humans
  • Male
  • Melatonin / administration & dosage*
  • Middle Aged
  • Migraine Disorders / prevention & control*
  • Severity of Illness Index
  • Time Factors
  • Treatment Outcome
  • Young Adult


  • Antioxidants
  • Melatonin