Ketamine May Fight Chronic Fatigue, Study Suggests

Ketamine, a decades-old anesthetic and fast-acting treatment for severe depression, may also offer some people rapid relief from chronic fatigue, according to a small proof-of-concept study led by researchers at Rutgers Health and the National Institutes of Health.

Ketamine's effects in the 10-participant clinical trial minimally outperformed an active placebo that unexpectedly exhibited its own antifatigue action. However, participants who received a single low-dose infusion of ketamine experienced a sufficient energy boost to justify further study.

For a symptom that has long resisted intervention, even a minor signal is noteworthy.

“Fatigue has always been ignored because it's so difficult to understand what's causing it,” said the study’s senior author, Leorey Saligan, a professor at the Rutgers School of Nursing who is also a member of the Cancer Prevention and Control Program at Rutgers Cancer Institute, the state’s only NCI-designated Comprehensive Cancer Center, together with RWJBarnabas Health.

Chronic fatigue is a persistent exhaustion that leaves victims without the energy needed for work, family life and basic function. No amount of extra rest fixes it.

The Centers for Disease Control and Prevention estimate that 3.3 million American adults suffer from chronic fatigue. This experience is more pronounced in individuals receiving cancer treatment and those with chronic illnesses. Most cancer patients who complete primary cancer therapy develop it, often lasting a year or more. The condition also afflicts individuals with fibromyalgia, lupus and chronic fatigue syndrome.

The standard approach to manage chronic fatigue is exercise, which works well for those patients who can motivate themselves to begin a program and stick with it for a few weeks. Most cannot.

Saligan began wondering if ketamine could help after his earlier research found that blood concentrations of a glutamate receptor called mGluR5 predicted chronic fatigue – or its absence – in cancer patients who completed cancer therapy. Ketamine blocks glutamate receptors, making it logical for testing whether that pathway might be a target for potential treatment.

The study enrolled 10 participants with chronic fatigue during cancer survivorship, those with fibromyalgia, chronic fatigue syndrome, or lupus. Each received one injection of ketamine and, two weeks later, an injection of a sedative called midazolam that served as an active comparator.

Before injections began, the investigators set a clear threshold for a “positive” result that would merit further trials: a 20% drop in real-time fatigue scores three days after ketamine infusion. Actual real-time fatigue scores were an average of 21% lower than preinjection levels three days after injection. The largest effect appeared at 24 hours after injection, when real-time fatigue decreased by nearly 39%.

Ketamine’s performance wasn’t significantly better than that of midazolam, which also produced reports of lower fatigue despite not being used as a treatment for the condition. This could indicate that the midazolam had a therapeutic effect or that fatigue levels naturally fluctuate.

The truth would likely be clearer if the study had achieved its initial goal of enrolling 59 participants. However, the COVID-19 pandemic and strict eligibility criteria limited recruitment, said Saligan, who is preparing a larger clinical trial in breast cancer survivors.

Even if ketamine proves effective, Saligan doesn’t envision it as a long-term medication. The most promising use, he said, might be as a bridge, a short energy boost that motivates patients to engage in other strategies that provide lasting relief, such as exercise.

"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.

Ketamine is off-patent and has already been studied for other health conditions, such as depression. A nasal spray version for depression, esketamine, is available, and drug companies are developing second-generation compounds with fewer side effects. Because of this, there are many promising opportunities to continue and expand this line of research.