A randomized clinical trial (RCT) published today in JAMA Network Open concludes that study doses of lithium aspartate don't improve long-COVID fatigue or brain fog but doesn't rule out the potential effectiveness of higher doses of the drug.

"Due to the lack of effective treatments, PCC [post-COVID condition] continues to cause major disability and reduced quality of life in an estimated 65 million people worldwide," the authors noted. "PCC can also cause substantial financial consequences, with about 45% of patients requiring reduced working hours and about 22% of patients unable to be employed."

Lithium aspartate is not approved by the US Food and Drug Administration for any indication, although it is sometimes sold as a dietary supplement. Another form of the drug, lithium carbonate, is used to treat bipolar disorder and can reduce inflammation of the brain, the researchers said.

For the double-blind trial, University at Buffalo researchers evaluated the use of 10 to 15 milligrams per day (mg/d) of lithium aspartate in 52 patients treated at a neurology clinic from November 2022 to June 2023 and followed for 3 weeks. Half of the patients received lithium aspartate, and half received a placebo.

The effect of higher dosages needs to be assessed in another randomized clinical trial.

The participants were eligible for the trial if they reported new, bothersome fatigue or cognitive dysfunction lasting more than 4 weeks after a self-reported COVID-19 positive test and high scores on the Fatigue Severity Scale-7 (FSS-7) or Brain Fog Severity Scale (BFSS). The average patient age was 58.5 years, and 58% were men.

Patients were instructed to take two 5-milligram (mg) capsules a day for 10 days and then take three capsules a day for 11 days if their long-COVID symptoms were still bothersome. Then patients were told to take two capsules per day for 7 days and increase the dose to three capsules a day for 7 days if they still had symptoms.

Subsequently, the authors conducted an open-label dose-finding study with doses up to 45 mg/d for 6 weeks among four of the same patients in January 2024. Patients were instructed to take two 5-mg capsules twice daily for a week, and each week thereafter, increased the dose by one capsule a day up to four capsules every morning and five capsules every night as tolerated.

In the clinical trial, lithium aspartate didn't significantly improve fatigue or cognitive dysfunction related to long COVID. But the subsequent dose-finding study found that 40 to 45 mg/d of the drug was tied to numerically greater symptom relief, especially in two patients with serum lithium concentrations of 0.18 and 0.49 milliequivalents per liter (mEq/L), respectively, compared with one with a level of 0.10 mEq/L. No adverse events were attributed to lithium aspartate.

"With such a small, open-label study subject to selection bias, it is difficult to draw any reliable conclusions regarding the merits of future neurologic PCC lithium trials," the authors wrote. Overall, "the findings of this trial suggest that lithium aspartate, 10 to 15 mg/d, is ineffective for neurologic post-COVID-19 condition fatigue and cognitive dysfunction; the effect of higher dosages needs to be assessed in another randomized clinical trial."