Ketamine shows early promise to relieve chronic fatigue in small clinical study

A proof-of-concept trial led by Rutgers Health and the National Institutes of Health has reported that a single low-dose infusion of ketamine reduced real-time fatigue scores in patients with chronic fatigue linked to cancer and autoimmune disease – although results did not significantly exceed those of an active comparator

Ketamine – a decades-old anaesthetic that has also served as a rapid-acting treatment for severe depression – has now shown early signs that it may relieve chronic fatigue in a small proof-of-concept clinical study led by Rutgers Health, New York, USA and the US National Institutes of Health.

Although the 10-participant trial found that ketamine only minimally outperformed an active comparator, researchers reported that a single low-dose infusion produced an energy increase sufficient to justify further investigation. In a field where therapeutic options remain limited and outcomes are often disappointing, even a modest signal has drawn therapeutic attention.

Chronic fatigue refers to a persistent and disabling exhaustion that does not resolve with rest. It affects the sufferer’s capacity to work, maintain family life and perform routine daily tasks. In the USA, the Centers for Disease Control and Prevention has estimated that 3.3 million adults live with chronic fatigue. The symptom occurs with particular frequency among people who receive cancer treatment and those who live with long-term conditions such as fibromyalgia or lupus. More than half of patients who complete primary cancer therapy develop sustained fatigue, which can persist for a year or more after treatment ends.

Despite its prevalence, chronic fatigue has resisted pharmacological interventions with the standard recommended treatment remaining structured exercise. While this approach has demonstrated benefit for some patients, many struggle to initiate or maintain a programme long enough to experience improvement.

The trial’s senior author, Dr. Leorey Saligan, professor at the Rutgers School of Nursing and member of the Cancer Prevention and Control Program at the Rutgers Cancer Institute, which serves as New York state’s only National Cancer Institute-designated Comprehensive Cancer Center, said that fatigue research had long faced conceptual and mechanistic challenges.

“Fatigue has always been ignored because it’s so difficult to understand what’s causing it,” said Saligan.

His interest in ketamine arose from earlier work that identified an association between chronic fatigue and blood concentrations of a glutamate receptor known as metabotropic glutamate receptor 5. Glutamate functions as a major excitatory neurotransmitter in the central nervous system. Ketamine acts in part to block glutamate receptors. This mechanistic link provided a rationale to test whether modulation of that pathway might reduce fatigue symptoms.

The investigators enrolled 10 participants who experienced chronic fatigue during cancer survivorship or in the context of fibromyalgia, chronic fatigue syndrome or lupus. Each participant received a single low-dose infusion of ketamine. Two weeks later, each received midazolam – a sedative – which served as an active comparator.

Before the trial began, the researchers defined a threshold to indicate a meaningful signal. They specified that a 20 per cent reduction in real-time fatigue scores three days after ketamine infusion would justify larger trials. Three days after infusion, real-time fatigue scores were on average 21 per cent lower than pre-injection values. The largest reduction occurred 24 hours after infusion, when fatigue scores fell by almost 39 per cent.

However, the difference between ketamine and midazolam did not reach statistical significance. Midazolam, although not recognised as a treatment for chronic fatigue, also produced reductions in reported fatigue. This findings for this comparator may have exerted its own therapeutic effect, or fatigue may just fluctuate naturally.

The study had aimed to enrol 59 participants but restrictions associated with the COVID-19 pandemic and strict eligibility criteria curtailed recruitment. Saligan has prepared a larger trial in breast cancer survivors to clarify whether the signal observed in this pilot study can replicate in a broader cohort.

“The idea is to prompt or reset the brain so people feel more motivated and able to take part in treatments that are proven to reduce fatigue,” said Saligan.

Even if ketamine demonstrates efficacy in larger trials, investigators do not propose long-term administration. Instead, they have considered its potential use as a short-term bridge. A temporary increase in energy may allow patients to engage with interventions such as structured exercise that offer more durable benefit.

Ketamine is off patent and has undergone extensive evaluation for other conditions, particularly severe depression. An intranasal formulation of esketamine, a stereoisomer of ketamine, has already received regulatory approval in several jurisdictions for treatment-resistant depression. Pharmaceutical companies have also pursued second-generation compounds that aim to retain antidepressant efficacy while reducing the dissociative and cardiovascular side effects.

Taken together, the pilot data have suggested that glutamatergic modulation merits further scrutiny as a strategy to address chronic fatigue. The results remain preliminary and require confirmation. Yet for a symptom that patients frequently describe as among the most debilitating and least acknowledged aspects of chronic illness, even cautious progress represents a development worth serious consideration.

For further reading please visit: 10.1007/s43440-025-00808-4