Low-dose ketamine shows promise for easing chronic fatigue

A single, low-dose intravenous infusion of ketamine reduced symptoms of chronic fatigue in patients suffering from various medical conditions, though the results were not statistically significant when compared to another sedative. The trial offers early evidence that ketamine and similar drugs might act quickly to relieve severe fatigue, paving the way for larger clinical trials in the future. The findings were published in Pharmacological Reports.

Fatigue is a common and debilitating symptom for up to 90 percent of people dealing with chronic illnesses. Unlike ordinary tiredness, this type of condition is relentless, unpredictable, and does not improve with rest. Relentless exhaustion can severely disrupt daily life, employment, and mental well-being. The underlying causes of this condition remain poorly understood, though research points toward disrupted nervous system activity and chronic inflammation.

Taichi Goto, a researcher at the National Institutes of Health, and a team of colleagues investigated alternative treatments for chronic fatigue. Their prior work found that fatigue in cancer patients who had undergone radiation therapy was linked to the stimulation of specific targets in the immune system. When certain glutamate receptors were active, they increased the production of inflammatory molecules. This systemic inflammation contributes heavily to feelings of deep exhaustion.

Ketamine is a synthetic drug historically used as an anesthetic, though it has gained attention for its ability to treat severe depression. The drug works by blocking certain glutamate receptors in the brain and nervous system. It also increases levels of a special protein that promotes the survival and growth of neurons. The researchers suspected that this mechanism might interrupt the biological pathways responsible for chronic fatigue.

An earlier analysis by the same research group hinted that ketamine could rapidly alleviate fatigue in people with bipolar disorder. In that study, the anti-fatigue effects began within forty minutes of the infusion and lasted for roughly two days. To test if this rapid relief translated to other illnesses, Goto and his team designed a new clinical trial targeting chronic fatigue across multiple medical conditions.

The researchers enrolled ten adults into the study. The participants included cancer survivors as well as individuals diagnosed with fibromyalgia, systemic lupus erythematosus, and a condition known as myalgic encephalomyelitis or chronic fatigue syndrome. All the patients had experienced severe fatigue for an extended period, totaling at least six months of exhaustion over the past year.

The study was designed as a randomized, double-blind crossover trial. Four of the participants received a low-dose infusion of ketamine during the first phase of the study, delivered intravenously over the course of forty minutes. After a two-week waiting period, these same participants returned to receive an infusion of midazolam. Midazolam is a fast-acting sedative often used in medical procedures to induce sleepiness and relieve anxiety.

The other six participants received the exact same drugs, but in the reverse order. The researchers chose midazolam as the comparison drug because it mimics some of ketamine’s behavioral side effects, such as sedation and mild disorientation. This similarity was intended to keep the participants and the medical staff from guessing which drug was being administered at any given time.

Patients rated their fatigue on a visual scale from zero to one hundred before the infusions and at several specific time points over the following week. The visual scale provided a real-time snapshot of the participants’ current level of exhaustion. The researchers primarily wanted to see if ketamine would reduce these fatigue scores by at least 20 percent by the third day after the infusion.

When the researchers began examining the data, they noticed an unexpected pattern between the two phases of the study. At the start of the second phase, before the second drug was given, the participants reported lower baseline fatigue scores than they had at the very beginning of the trial. This meant the effects of the first phase were carrying over into the second phase, regardless of which drug was administered first.

Because of this carryover effect, the researchers analyzed the two phases of the study separately. During the first phase, participants who received ketamine experienced a 21 percent decrease in their fatigue scores by the third day. The participants who received midazolam experienced a 17.7 percent decrease in their fatigue scores over the same period.

During the second phase of the trial, the ketamine group saw a 10.9 percent drop in fatigue scores. The midazolam group saw a 12.6 percent drop. When comparing the two drugs in either phase, the differences in fatigue reduction were not statistically significant. This means the researchers could not definitively prove that ketamine worked better than midazolam in this specific sample of patients.

Despite the lack of statistical dominance against the sedative, ketamine did meet the research team’s original benchmark for preliminary success in the first phase. The drug produced an overall reduction in fatigue that successfully exceeded the 20 percent goal at the three-day mark. The data showed that the most dramatic drop in exhaustion for the ketamine group happened one day after the infusion, with fatigue scores falling by 38.7 percent.

The researchers acknowledged several limitations in their study. The trial initially aimed to recruit nearly sixty participants over a period of three years. Pandemic restrictions and strict eligibility criteria limited the final enrollment to just ten people. This unusually small group size makes it difficult to draw broad conclusions and increases the risk that the trial failed to capture the full differences between the two interventions.

The crossover design of the study also complicated the results. The trial revealed that midazolam might not act as a neutral comparison drug for studying fatigue. While midazolam successfully mimicked the side effects of ketamine, it also appeared to reduce fatigue on its own. Midazolam interacts with a brain chemical called gamma-aminobutyric acid, which is known to be imbalanced in some chronic fatigue patients.

Emerging evidence also suggests that midazolam might have anti-inflammatory properties of its own. By lowering systemic inflammation, the sedative might inadvertently ease the physical symptoms of exhaustion. Both ketamine and midazolam appeared to have fatigue-reducing effects, which obscured any relative advantages ketamine might have held over a truly inactive placebo.

The blinding process in the study also appeared to be compromised. In surveys given after the trial, both the participants and the clinicians accurately guessed which drug was being administered most of the time. This awareness could have triggered a placebo effect, contributing to the unexpected improvements seen during the second phase of the study.

The varied medical conditions of the participants might also play a role in how the drugs interacted with their bodies. The biological roots of exhaustion in cancer survivors largely involve the hormonal stress response and systemic inflammation. Meanwhile, the causes of fatigue in autoimmune disorders are primarily tied to specific immune proteins. A deeper understanding of these underlying mechanisms could eventually impact how patients respond to different pharmaceutical interventions.

Future trials will likely need to abandon the crossover design to avoid lingering effects between drug administration periods. The researchers noted that scientists should identify a different control drug that does not actively reduce inflammation or interact with the central nervous system in ways that alleviate tiredness. They also suggested measuring the highest anti-fatigue effects one day after the infusion to better capture ketamine’s rapid action.

The study, “A preliminary proof-of-concept trial on the effects of ketamine on fatigue: a randomized crossover trial,” was authored by Taichi Goto, Joy D. Kreskow, Alexander L. R. Ross, Catherine L. Blumhorst, Justin J. Zhao, Andrew J. Mannes, Miroslav Bačkonja, Carlos A. Zarate Jr, and Leorey N. Saligan.