Pilot randomized active-placebo-controlled trial of low-dose ketamine for the treatment of multiple sclerosis-related fatigue

Mult Scler. 2021 May;27(6):942-953. doi: 10.1177/1352458520936226. Epub 2020 Jul 7.


Background: Fatigue is the most common symptom of MS and has no effective pharmacotherapy.

Objective: To determine the tolerability, safety, and efficacy of low-dose ketamine infusion for MS-related fatigue.

Methods: In this double-blind, randomized, active-placebo-controlled trial, 18 subjects with multiple sclerosis (MS) and reported fatigue received a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.05 mg/kg). The primary outcome was change in Daily Fatigue Severity (DFS) for 7 days following the infusion. Secondary outcomes included Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS) measured up to day 28 post-infusion. We analyzed changes in all outcomes using mixed-effect models.

Results: In total, 18 participants were enrolled; 67% participants received ketamine. Side effects of ketamine were transient. No change in the DFS was observed after 7 days (-0.10 point; 95% confidence interval (CI): -0.32, 0.12; p = 0.40). We observed a trend in reduced FSS scores at 1 week (-5.2 points; 95% CI: -10.4, 0.14; p = 0.06) and a clinically and statistically significant reduction in MFIS score at day 28 (-13.5 point; 95% CI: -25.0, -1.98; p = 0.04).

Conclusions: Ketamine infusions were safe and well-tolerated. While no change in DFS after 7 days was observed, secondary analyses suggest a benefit of ketamine infusion for reduction of longer term fatigue severity in people with MS.

Keywords: Multiple sclerosis; fatigue; ketamine; midazolam; randomized controlled trial.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Double-Blind Method
  • Fatigue / drug therapy
  • Fatigue / etiology
  • Humans
  • Ketamine* / adverse effects
  • Multiple Sclerosis* / complications
  • Multiple Sclerosis* / drug therapy
  • Pilot Projects
  • Treatment Outcome


  • Ketamine