A single low-dose intravenous infusion of ketamine reduced symptoms of chronic fatigue in patients suffering from a variety of medical conditions, but the results were not statistically significant when compared with other sedatives. This trial provides early evidence that ketamine and similar drugs can work quickly to reduce severe fatigue, paving the way for future large-scale clinical trials. This discovery was published in Pharmacological Reports.
Fatigue is a common and debilitating symptom for up to 90% of people with chronic illness. Unlike regular fatigue, this type of symptom is continuous, unpredictable, and does not improve with rest. Constant fatigue can have a serious impact on daily life, employment, and mental health. The underlying causes of this condition are still poorly understood, but research points to disruption of nervous system activity and chronic inflammation.
National Institutes of Health researcher Taichi Goto and a team of colleagues investigated alternative treatments for chronic fatigue. Their previous research found that fatigue in cancer patients who received radiation therapy was associated with stimulation of specific targets in the immune system. Activation of certain glutamate receptors increased the production of inflammatory molecules. This systemic inflammation greatly contributes to feelings of deep fatigue.
Ketamine is a synthetic drug that has historically been used as an anesthetic, but has gained attention for its ability to treat severe depression. This drug works by blocking certain glutamate receptors in the brain and nervous system. It also increases levels of special proteins that promote neuron survival and growth. The researchers suspected that this mechanism might block biological pathways that cause chronic fatigue.
Previous analysis by the same research group suggests that ketamine may rapidly reduce fatigue in patients with bipolar disorder. In that study, anti-fatigue effects began within 40 minutes after infusion and lasted approximately two days. To test whether this rapid relief also affects other diseases, Goto and his team designed a new clinical trial targeting chronic fatigue across multiple medical conditions.
Researchers enrolled 10 adults in the study. Participants included cancer survivors as well as people diagnosed with conditions known as fibromyalgia, systemic lupus erythematosus, myalgic encephalomyelitis and chronic fatigue syndrome. All patients had experienced severe fatigue for an extended period of time, with a total of at least 6 months of extreme fatigue over the past year.
This study was designed as a randomized, double-blind, crossover trial. Four of the participants received a low-dose intravenous ketamine infusion over 40 minutes during the first phase of the study. After a 2-week waiting period, these same participants returned to receive intravenous midazolam. Midazolam is a fast-acting sedative often used in medical procedures to induce drowsiness and relieve anxiety.
The other six participants received the exact same drugs, but in the reverse order. The researchers chose midazolam as a comparison drug because it mimics some of the behavioral side effects of ketamine, such as sedation and mild disorientation. This similarity was intended to prevent participants or medical staff from guessing which drug was being administered at any given time.
Patients rated their fatigue on a visual scale from 0 to 100 before the infusion and at several specific time points during the following week. The visual scale provided a real-time snapshot of participants’ current fatigue levels. The researchers primarily wanted to see if ketamine reduced these fatigue scores by at least 20% by day 3 after infusion.
When the researchers began examining the data, they noticed an unexpected pattern between the two phases of the study. At the beginning of the second phase, before the second drug was administered, participants reported lower baseline fatigue scores than at the start of the study. This meant that the effects of the first phase carried over to the second phase, regardless of which drug was given first.
Because of this carryover effect, the researchers analyzed the two phases of the study separately. Participants who received ketamine in the first phase had a 21 percent reduction in fatigue scores by day three. Participants who received midazolam had a 17.7% reduction in fatigue scores over the same period.
In the second phase of the trial, fatigue scores decreased by 10.9% in the ketamine group. The midazolam group decreased by 12.6%. The difference in fatigue relief was not statistically significant when comparing the two drugs at either stage. This means the researchers could not conclusively prove that ketamine was more effective than midazolam in this particular patient sample.
Despite lacking a statistical advantage over sedatives, ketamine met the research team’s initial criteria for preliminary success in the first phase. The drug resulted in an overall reduction in fatigue, and by day 3 I was well above my 20% goal. Data showed that the most dramatic reduction in fatigue in the ketamine group occurred on the first day after the infusion, with fatigue scores decreasing by 38.7%.
The researchers acknowledged that the study had some limitations. The trial originally aimed to recruit nearly 60 participants over three years. Pandemic restrictions and strict eligibility criteria limited final enrollment to just 10 participants. This unusually small group size makes it difficult to draw broad conclusions and increases the risk that the trial did not capture the full difference between the two interventions.
The crossover design of the study also complicated the results. This study revealed that midazolam may not serve as a neutral comparator for studying fatigue. Midazolam has been successful in mimicking the side effects of ketamine, but also appears to reduce fatigue on its own. Midazolam interacts with a brain chemical called gamma-aminobutyric acid, which is known to be out of balance in some patients with chronic fatigue.
Emerging evidence also suggests that midazolam may have anti-inflammatory properties of its own. By suppressing inflammation throughout the body, sedatives may unintentionally alleviate the physical symptoms of fatigue. Both ketamine and midazolam appear to have fatigue-reducing effects, but this has obscured any relative advantage that ketamine may have held over a truly inert placebo.
The study’s blinding process also appears to have been compromised. In post-trial surveys, both participants and clinicians correctly guessed which drug was being administered most of the time. This awareness may have triggered a placebo effect and contributed to the unexpected improvements seen in the second phase of the study.
A participant’s various medical conditions can also affect how the drug interacts with the participant’s body. The causes of biological fatigue in cancer survivors primarily involve hormonal stress responses and systemic inflammation. On the other hand, the causes of fatigue in autoimmune diseases are mainly related to specific immune proteins. A deeper understanding of these underlying mechanisms may ultimately influence patient response to various pharmaceutical interventions.
Future trials may need to abandon crossover designs to avoid persistence of effects between periods of drug administration. The researchers noted that scientists need to identify other control drugs that do not actively reduce inflammation or interact with the central nervous system in a way that reduces fatigue. They also proposed measuring the highest anti-fatigue effects one day after injection to better understand ketamine’s rapid effects.
The study, “A Preliminary Proof-of-Concept Study of the Effects of Ketamine on Fatigue: A Randomized Crossover Trial,” was authored by Taichi Goto, Joy D. Kleskov, Alexander L.R. Ross, Katherine L. Bloomhorst, Justin J. Zhao, Andrew J. Mannes, Miroslav Bakkonya, Carlos A. Zarate Jr., and Leorie N. Saligan.
