A preliminary proof-of-concept trial on the effects of ketamine on fatigue: a randomized crossover trial.
Taichi Goto, Joy D Kreskow, Alexander L R Ross, Catherine L Blumhorst, Justin J Zhao, Andrew J Mannes, Miroslav Bačkonja, Carlos A Zarate, Leorey N Saligan
Pharmacological reports : PR January 22, 2026 DOI: 10.1007/s43440-025-00808-4 via PubMed
Summary
AI-generated from the abstractA small pilot trial tested whether a single low dose of ketamine (0.5 mg/kg) can reduce fatigue in people with chronic illnesses such as cancer, fibromyalgia, chronic fatigue syndrome, or lupus. Ten participants received both ketamine and the active placebo midazolam in random order, with a washout period between treatments. Because fatigue levels differed between the two study periods, results were analyzed separately. In the first period, fatigue scores dropped 21.0% after ketamine and 17.7% after midazolam; in the second period, the drops were 10.9% and 12.6%, respectively. The differences were not statistically significant, but the ketamine group showed a peak 38.7% reduction one day after infusion. The authors suggest future studies avoid crossover designs and find a better active placebo.
Study at a glance
| Characteristics | Randomized controlled trial Double-blind Peer reviewed |
|---|---|
| Sample size | 10 |
| Population | Adults who are cancer survivors or have fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome, or systemic lupus erythematosus |
| Interventions | Ketamine Midazolam |
| Dose | 0.5 mg/kg ketamine, 0.045 mg/kg midazolam |
| Duration | Single infusion, 3-day post-infusion follow-up |
| Keywords | Active placebo Chronic illness Glutamate receptor Midazolam Pilot study |
| Key finding | Ketamine did not produce a statistically significant greater reduction in fatigue than midazolam, but a 38.7% peak reduction was observed one day after ketamine infusion. |
Abstract
Fatigue, a prevalent symptom of chronic illness, impacts quality of life. This proof-of-concept, randomized, double-blind, crossover trial assessed the anti-fatigue effects of ketamine (0.5 mg/kg) versus midazolam (0.045 mg/kg), the active comparator. Ten participants, who were cancer survivors, with fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome, or systemic lupus erythematosus, were randomized into Arm 1 (n = 4, Period 1: ketamine to Period 2: midazolam) or Arm 2 (n = 6, Period 1: midazolam to Period 2: ketamine). The two periods were separately analyzed because of carryover effects with baseline fatigue scores, assessed by the fatigue visual analog scale (VAS), between the study periods (p = 0.03). Looking at changes in fatigue VAS scores from baseline (pre-infusion) to 3 days post-infusion, the ketamine group had a 21.0% decrease in Period 1 and 10.9% in Period 2, while the midazolam group showed a 17.7% decrease in Period 1 and 12.6% in Period 2. We did not observe a statistically significant difference in both periods. The largest fatigue score reduction for the ketamine group was at 1 day post-infusion, at - 38.7% in Period 1. Despite no statistical significance, a reduction in real-time fatigue scores was observed, which exceeded the 20% efficacy threshold, the primary outcome, in the ketamine arm from pre-infusion to 3 days post-infusion. The carryover effects and the peak reduction in fatigue at 24 hours after ketamine administration suggest that future trials may need to consider a study design without cross-over and an optimal active placebo alternative.