Chronic fatigue affects millions of people living with serious medical conditions. For many of them, unfortunately, effective treatments remain frustratingly out of reach. But a dissociative anesthetic, already used in clinical settings to treat depression, is now showing early promise as a fast-acting intervention for chronic fatigue.
This article explains the current evidence, how ketamine may reduce chronic fatigue, and what patients should know before speaking with their doctors.
What is chronic fatigue?
Chronic fatigue is not the same as feeling tired. It’s a persistent, overwhelming exhaustion that isn’t relieved by rest and significantly disrupts daily life, affecting one’s ability to work, exercise, complete basic tasks, and even maintain relationships.
It’s most commonly associated with conditions such as cancer survivorship, fibromyalgia, lupus, chronic fatigue syndrome (CFS/ME), and post-viral illness. The scale of the problem is significant: In the U.S., alone, the CDC estimates that 3.3 million adults live with chronic fatigue syndrome.
Despite how debilitating chronic fatigue can be, treatment options are limited. While structured exercise is the most consistently evidence-based recommendation, starting and maintaining such a program is a challenge for people with chronic fatigue. Effective pharmacological options for chronic fatigue have historically been scarce, which is why emerging research into new treatment pathways is generating interest.
What is ketamine?
Ketamine is a dissociative anesthetic that has been used safely in medical settings for decades, first as a surgical anesthetic, and later for a wider range of applications in emergency and critical care medicine. Recently, ketamine has gained clinical attention as a rapid-acting treatment for treatment-resistant depression and acute suicidal ideation, both conditions that have historically been difficult to treat quickly with conventional medications.
Ketamine works differently from traditional antidepressants. Rather than targeting serotonin, it affects glutamate, one of the brain’s key chemical messengers. By acting on specific glutamate receptors, ketamine sets off a chain reaction that encourages brain cells to build and strengthen connections with each other. This may help the brain adapt more quickly and could explain ketamine’s rapid antidepressant effects.
Spravato®, an esketamine-based nasal spray, has been FDA-approved for treatment-resistant depression and is available here at Keta Medical Center. Ketamine infusions (administered intravenously) remain an off-label treatment for depression and are not yet approved for chronic fatigue.
What does the research say about ketamine for chronic fatigue?
Research into ketamine as a chronic fatigue treatment is still in its early stages, but the preliminary findings are meaningful enough to warrant attention.
The first significant signal came from a 2016 clinical study led by researchers at the National Institutes of Health (NIH). 36 patients with treatment-resistant bipolar depression were enrolled in the trial and given either a single low-dose ketamine infusion (0.5 mg/kg IV over 40 minutes) or a placebo saline solution.
Ketamine significantly reduced fatigue scores compared to the placebo, with effects beginning within 40 minutes of the infusion and peaking around day two. Notably, 65% of patients on ketamine experienced a greater-than-50% reduction in fatigue at some point during the trial, compared to just 10% on the placebo. The anti-fatigue effect persisted even after statistically controlling for ketamine’s antidepressant action, suggesting that fatigue and depression, while often co-occurring, may involve distinct biological pathways.
A decade later, a 2026 clinical trial led by researchers at the NIH and Rutgers University extended this investigation to people living with chronic fatigue tied to a range of conditions, including cancer survivorship, fibromyalgia, chronic fatigue syndrome and lupus. In this randomized, double-blind crossover trial, 10 participants received either a single low-dose ketamine infusion or midazolam, a sedative used as an active comparison treatment.
Three days after infusion, fatigue scores in the ketamine arm fell by 21%, crossing the 20% threshold the trial had set in advance as its primary measure of efficacy. The largest drop came at 24 hours, when fatigue scores fell by nearly 39%. Midazolam also reduced fatigue, but it was the ketamine arm alone that met the predefined 20% threshold. The difference between the two drugs was not statistically significant, which limits how strongly the results can be interpreted. The trial was also substantially underpowered. It was designed to enroll 59 participants but reached only 10 because of disruptions, and a larger follow-up trial involving breast cancer survivors is planned.
Despite the small sample sizes, there is a compelling biological rationale underlying both studies. Earlier research from the same NIH team connected fatigue to a glutamate receptor called mGluR5, finding that its signaling in immune cells helped predict which patients would develop fatigue after cancer treatment. Because ketamine acts directly on glutamate receptors, it offers a biologically plausible mechanism for addressing fatigue, one that is fundamentally different from the serotonin and norepinephrine-targeting pathways of most existing treatments.
This evidence is preliminary. No large-scale trials in a fatigue-specific population have been completed yet. While early evidence suggests ketamine may be an option for some patients, it’s not an established or approved fatigue treatment.
How might ketamine help with fatigue?
To understand why ketamine might reduce fatigue, it helps to understand what it does in the brain.
Ketamine primarily works by blocking NMDA receptors, a subtype of glutamate receptor involved in regulating neural signaling, inflammation, and synaptic plasticity. By temporarily blocking these receptors, ketamine may reduce neuroinflammation and interrupt the dysfunctional signaling patterns that researchers believe contribute to chronic fatigue.
This blockade also triggers downstream effects. It releases BDNF (brain-derived neurotrophic factor), a protein that supports neural health. It also activates AMPA receptors in a process that promotes synaptogenesis, the formation of new synaptic connections. These effects are thought to underpin ketamine’s rapid antidepressant action and may similarly explain its impact on fatigue-related neural pathways.
Dr. Leorey Saligan, the lead researcher on both the 2016 and 2026 studies and a faculty member at Rutgers School of Nursing, has proposed a bridge hypothesis: Ketamine may not be a long-term, standalone solution for chronic fatigue but rather a short-term, biological reset. The idea is that a single ketamine infusion could provide enough of an energy window for patients to engage with exercise, physical therapy, or other fatigue-reduction strategies proven to produce lasting benefit but difficult to initiate when fatigue is severe. If proven in larger trials, this could position ketamine as a catalyst for broader rehabilitation efforts rather than as an isolated treatment.
Who might be a candidate for ketamine therapy for fatigue?
Ketamine has not been specifically approved by the FDA for the treatment of chronic fatigue syndrome. However, physicians often use approved medications in areas where promising research and clinical experience suggest potential benefit. Early studies of ketamine in patients with chronic fatigue offer clues about who may respond best to treatment.
The 2026 Rutgers/NIH trial selected people living with persistent fatigue linked to cancer survivorship, fibromyalgia, CFS/ME, and lupus, particularly those who had not found meaningful relief from standard treatments. People also suffering from treatment-resistant depression may also be relevant candidates for ketamine therapy, given the overlap in the biological mechanisms that ketamine targets. Researchers hypothesize that people whose fatigue has a neuroinflammatory or glutamatergic component may be the most likely to respond to ketamine therapy.
Ketamine is not appropriate for everyone. It is generally not recommended for people with: certain cardiovascular conditions, a history of psychosis, active substance abuse disorder, or other contraindications that a physician would assess individually. A thorough clinical evaluation is necessary before any treatment decision.
If you are living with chronic fatigue and have not found relief from conventional approaches, speaking with a Keta Medical Center clinician can help you understand whether ketamine may be appropriate as part of your care plan.
What does a ketamine infusion look like at Keta Medical Center?
At Keta Medical Center, ketamine is administered in a private, spa-like room, supervised by experienced emergency medical physicians. A typical infusion session lasts approximately 45 minutes, during which patients are monitored for safety and comfort and typically stay in the room for about 90 minutes. With the Spravato (esketamine) nasal spray, available to patients also diagnosed with treatment-resistant depression, the dissociative effects last about 45 minutes and patients are required by the FDA to stay in the clinic for two hours.
During the treatment, ketamine produces a temporary dissociative state — a sense of altered perception or detachment from one’s surroundings. This is a known and expected effect of the medication at therapeutic doses, and our clinical team prepares patients in advance and provides support throughout the session. It’s a transient experience that resolves as the infusion ends. Side effects are generally mild and short-lived and may include temporary dizziness, or nausea.
Apart from offering physician-led ketamine treatment and other therapies, Keta Medical Center actively monitors the evolving research on ketamine and chronic fatigue. Our clinicians evaluate each patient individually and can discuss whether ketamine therapy may be an appropriate component of a broader, individual treatment plan for you.
If you are living with chronic fatigue and want to explore options, we encourage you to speak with our clinical team to learn more about ketamine therapy for chronic fatigue.
FAQ’s
Preliminary findings from the 2026 Rutgers/NIH proof-of-concept trial suggest the most significant reductions in fatigue scores occurred within 24 hours of a single infusion, with effects persisting for several days. That said, individual responses varied, and research for ketamine as a treatment for chronic fatigue is still in early stages. These findings should be understood as encouraging signals rather than definitive predictions of how individual patients will respond to ketamine.
Most conventional fatigue treatments (including stimulant medications and structured exercise programs) work via dopamine, norepinephrine or behavioral pathways, but ketamine targets the glutamate system, specifically NMDA and AMPA receptors. This difference is significant because it suggests ketamine may be effective for people whose fatigue has not responded to approaches that target other chemical messengers in the brain.
Ketamine can potentially be addictive when used recreationally at high doses. In a supervised clinical setting, the risk of dependency is considered extremely low. : Doses are carefully controlled, administration is monitored by medical staff, and treatment frequency is limited. Before recommending any ketamine-based treatment, Keta Medical Center conducts a thorough intake evaluation for every patient, including a review of substance use history.
Keta Medical Center offers ketamine therapy for a range of conditions, including treatment-resistant depression, PTSD, anxiety, bipolar depression, postpartum depression, and OCD. Each patient is evaluated individually, and patients are encouraged to share their complete medical history and prior treatment experience(s) to help our providers determine whether ketamine therapy may be appropriate.
Ketamine infusions for chronic fatigue are not covered by most insurance plans, as this is an off-label application. However, if a patient also has a diagnosis of treatment-resistant depression (TRD), coverage may be available. Patients can find out whether their treatment may be covered by insurance and explore financing and payment options during a consultation with us.
