A Randomized Controlled Trial of the Lowest Effective Dose of Acetazolamide for Acute Mountain Sickness Prevention

Am J Med. 2020 Dec;133(12):e706-e715. doi: 10.1016/j.amjmed.2020.05.003. Epub 2020 May 29.


Background: Acetazolamide is the most common medication used for acute mountain sickness prevention, with speculation that a reduced dose may be as efficacious as standard dosing with fewer side effects.

Methods: This double-blind, randomized, controlled noninferiority trial compared acetazolamide 62.5 mg twice daily to the standard dose acetazolamide 125 mg twice daily starting the evening prior to ascent from 1240 m (4100 ft) to 3810 m (12,570 ft) over 4 hours. The primary outcome was acute mountain sickness incidence (ie, headache, Lake Louise Questionnaire ≥3, and another symptom).

Results: A total of 106 participants were analyzed, with 51 (48%) randomized to 125 mg and 55 (52%) to 62.5 mg, with a combined acute mountain sickness incidence of 53 (50%) and mean severity of 3 (± 2.1). The 62.5-mg group failed to fall within the prespecified 26% noninferiority margin for acute mountain sickness incidence (62.5 mg = 30 [55%] vs 125 mg = 23 [45%], 95% confidence interval [CI] -11% to 30%). Participants in the 62.5-mg group had a higher risk of acute mountain sickness (odds ratio = 1.5, 95% CI 0.7-3.2) and moderate acute mountain sickness (odds ratio = 1.8, 95% CI 0.6-5.9), with a number needed to harm (NNH) of 9, with a number needed to treat (NNT) in the 125-mg group of 4.8. Increased acute mountain sickness incidence and symptom severity corresponded to lower weight-based and body mass index dosing, with similar side effects between groups.

Conclusion: Acetazolamide 62.5 mg twice daily failed to demonstrate equal effectiveness to 125 mg twice daily for prevention of acute mountain sickness. With increased risk and no demonstrable symptomatic or physiologic benefits, acetazolamide 62.5 mg twice daily should not be recommended for acute mountain sickness prevention.

Trial registration: ClinicalTrials.gov NCT03828474.

Keywords: Acetazolamide; Acute mountain sickness; High altitude; Prevention.

Publication types

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

MeSH terms

  • Acetazolamide / administration & dosage*
  • Acetazolamide / therapeutic use*
  • Altitude Sickness / pathology
  • Altitude Sickness / prevention & control*
  • Carbonic Anhydrase Inhibitors / administration & dosage*
  • Carbonic Anhydrase Inhibitors / therapeutic use*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Humans
  • Odds Ratio
  • Risk Factors
  • Severity of Illness Index
  • Surveys and Questionnaires


  • Carbonic Anhydrase Inhibitors
  • Acetazolamide

Associated data

  • ClinicalTrials.gov/NCT03828474