Low-Dose Lithium Tested in Long COVID

Low doses of lithium aspartate did not successfully treat neurologic symptoms of long COVID, a randomized, double-blind, placebo-controlled trial showed.

In a study of 52 people with long COVID, lithium aspartate at 10 to 15 mg/day yielded no significant improvement in fatigue and cognitive dysfunction scores at 3 weeks compared with placebo, reported Thomas Guttuso Jr., MD, of the University at Buffalo in New York, and co-authors in JAMA Network Open.

The primary endpoint was the change in the sum of Fatigue Severity Scale-7 (FSS-7) and Brain Fog Severity Scale (BFSS) scores. Scores for each scale can range from 7 to 49, with higher scores indicating more severe symptoms.

There were no significant differences between the lithium and placebo groups on the primary outcome (-3.6 points, 95% CI -16.6 to 9.5, P=0.59) or any secondary outcomes.

However, a subsequent dose-finding study showed that open-label lithium aspartate at 40 to 45 mg/day was associated with numerically greater improvement in two patients with serum lithium levels of 0.18 and 0.49 mEq/L, compared with one patient with a level of 0.10 mEq/L.

“Although this finding is preliminary, I believe it provides some degree of hope for long COVID patients,” Guttuso said. “Another randomized controlled trial needs to be performed using higher dosages to determine if lithium may be effective for long COVID fatigue and brain fog,” he told MedPage Today.

Long COVID is a condition “for which we still lack established, evidence-based treatments,” observed Harlan Krumholz, MD, of Yale University in New Haven, Connecticut, who wasn’t involved with the trials. “Given that long COVID presents with a range of symptoms, many of which are neurologic, it is reasonable to explore lithium due to its neuroprotective properties,” he told MedPage Today.

“We must continue conducting well-designed trials to understand better the underlying mechanisms of long COVID, as well as rigorously assess potential therapeutic strategies,” Krumholz emphasized. “Currently, some approaches under investigation — though not enough trials, we need more — include immune modulators, antivirals, and treatments aimed at improving autonomic dysfunction, which may be relevant to conditions like POTS [postural orthostatic tachycardia syndrome] linked to long COVID.”

In the low-dose lithium aspartate trial, Guttuso and colleagues enrolled participants from an outpatient neurology clinic in Buffalo from November 2022 to June 2023. The subsequent open-label lithium dose-finding study involved the same participants.

Eligible patients had new, bothersome fatigue or cognitive dysfunction that persisted for more than 4 weeks after a positive COVID-19 test, an FSS-7 or BFSS score of 28 or greater, a Beck Depression Inventory-II score less than 29, and no history of a condition known to cause fatigue or cognitive dysfunction. All low-dose trial participants were eligible for the dose-finding study except those who responded to placebo.

In the low-dose trial, participants received lithium aspartate, 10 to 15 mg/day, or placebo for 3 weeks followed by open-label lithium aspartate, 10 to 15 mg/day, for 2 weeks. Of 52 participants enrolled, 58% were men. Mean age was about 59 years. Half the participants were randomized to low-dose lithium aspartate and half to placebo. No adverse events in the low-dose group were attributable to lithium therapy.

Five participants from the low-dose study enrolled in the subsequent study; four of them qualified for higher lithium doses. These participants received open-label lithium aspartate dosages up to 45 mg/day for 6 weeks. One experienced mild sedation at 45 mg/day, which resolved at 40 mg/day. No clinically significant changes in serum thyroid-stimulating hormone levels or estimated glomerular filtration rates emerged in any patient.

“The lithium dosages being studied for long COVID fatigue and brain fog are about half of those used to treat bipolar disorder, lithium’s only FDA-approved indication,” Guttuso pointed out. “Use of these lower lithium dosages are much less likely to cause side effects and were, in general, well tolerated in the long COVID patients involved in these studies.”

The trials were limited by their sample sizes and lack of biomarker data, Guttuso and co-authors acknowledged. The dose-finding study may have been subject to selection bias.

If future trials find that higher doses are effective, long COVID patients would need to speak with their healthcare providers before starting treatment, Guttuso noted. Individuals taking lithium aspartate at higher doses should have their blood lithium levels monitored, he added.

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