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 January 22, 2026 DOI: 10.1007/s43440-025-00808-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| 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 |
| Topics | Esketamine Ketamine |
| Keywords | Active placebo Chronic illness Glutamate receptor Midazolam Pilot study |
| Key findings | 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.
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |
Citations in the library
Cites 10
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial American Journal of Psychiatry December 5, 2017
- Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review Therapeutic Advances in Chronic Disease April 13, 2015
- Efficacy and Safety of Ketamine vs Electroconvulsive Therapy Among Patients With Major Depressive Episode: A Systematic Review and Meta-analysis. JAMA Psychiatry October 19, 2022
and 5 more in the library