Reduction in Migraine and Headache Frequency and Intensity With Combined Antioxidant Prophylaxis (N-acetylcysteine, Vitamin E, and Vitamin C): A Randomized Sham-Controlled Pilot Study

Pain Pract. 2020 Sep;20(7):737-747. doi: 10.1111/papr.12902. Epub 2020 May 7.


Objective: To investigate the preventive effects of a combined antioxidant drug (N-acetylcysteine, vitamin E, and vitamin C [NEC]) on migraine outcomes. Migraine is characterized by increased oxidative stress and neurogenic inflammation in the brain; therefore, antioxidants may have a migraine preventive effect.

Design: Randomized, double-blind, sham-controlled pilot study.

Setting: Australian community.

Subjects: Adults reporting 2 to 8 migraines per month for at least a year.

Methods: After a 1-month baseline period, 35 subjects completed 3 months of treatment with NEC (n = 19) or sham (n = 16) capsules. The primary outcome was the difference in mean number of headaches per month between baseline and final month of the trial for NEC and sham groups; secondary outcomes are listed below.

Results: For NEC there was a significant decrease in mean number of headaches by 3.0 per month (P = 0.004) compared with 1.4 for sham (P = 0.073); there was no significant difference in these changes between the 2 groups (P = 0.052). Average monthly headache (P = 0.041) and migraine frequency (P = 0.018) were significantly less for NEC vs. sham. In NEC subjects, there was a significant decrease in average monthly migraine days (-3.1), moderate/severe headache days (-3.2), migraine duration, headache pain scores, and acute headache medication use.

Conclusions: This is the first randomized controlled trial to find that combined antioxidant therapy with NEC reduces headaches and migraines in adult migraineurs. Given the limitations of this pilot study, an adequately powered randomized controlled trial is planned to further investigate antioxidant prophylaxis in migraine.

Keywords: N-acetylcysteine; antioxidants; headache; migraine; vitamin C; vitamin E.

Publication types

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

MeSH terms

  • Acetylcysteine / therapeutic use*
  • Adult
  • Aged
  • Antioxidants / therapeutic use*
  • Ascorbic Acid / therapeutic use*
  • Australia
  • Double-Blind Method
  • Drug Therapy, Combination / methods
  • Female
  • Humans
  • Male
  • Middle Aged
  • Migraine Disorders / prevention & control*
  • Pilot Projects
  • Treatment Outcome
  • Vitamin E / therapeutic use*


  • Antioxidants
  • Vitamin E
  • Ascorbic Acid
  • Acetylcysteine