A randomized, double-blind, placebo-controlled trial found that low-dose lithium aspartate was ineffective in treating fatigue and cognitive dysfunction associated with long COVID.

The study, published in JAMA Network Open, also included an open-label dose-finding component that explored higher lithium doses. Researchers at the University at Buffalo enrolled 52 participants with self-reported long COVID symptoms persisting for more than 4 weeks. The participants received either lithium aspartate 10 to 15 mg/d or placebo for 3 weeks. The primary outcome measure was the change in combined scores on the Fatigue Severity Scale-7 (FSS-7) and Brain Fog Severity Scale (BFSS).

The study involved 30 male and 22 female participants with a mean age of 58.5 years. Average symptom duration was 17.4 months in the lithium group and 17.5 months in the placebo group. Vaccination rates were similar between groups, with 83% of the lithium group and 96% of the placebo group having received COVID-19 vaccines.

No statistically significant differences were found between the lithium and placebo groups for the primary outcome (–3.6, 95% confidence interval [CI] = –16.6 to 9.5, P = .59) or for any secondary measures.

In the double-blind phase, the mean FSS-7 score changes were –11.3 for lithium vs –8.6 for placebo (P = .46), whereas the mean BFSS changes were –9.0 for lithium vs –8.1 for placebo (P = .79). Secondary outcome measures, including the Insomnia Severity Index, Generalized Anxiety Disorder Scale-2, and Beck Depression Inventory-II, also showed no statistically significant differences between the patient groups.

Following the double-blind phase, researchers conducted an open-label dose-finding study with 5 participants using lithium doses up to 45 mg/d over 6 weeks. Three patients completed this phase, with two patients achieving serum lithium levels of 0.18 to 0.49 mEq/L reporting greater symptomatic improvements compared with one patient with a level of 0.10 mEq/L. However, these findings are preliminary and require further investigation in a larger, controlled trial.

The participants were recruited from November 2022 to June 2023 and met eligibility criteria that included new fatigue or cognitive symptoms persisting more than 4 weeks after COVID-19. They had FSS-7 or BFSS scores ≥ 28 and Beck Depression Inventory-II scores < 24. They were randomized 1:1 to receive lithium aspartate 10 to 15 mg/d or placebo for 3 weeks. Overencapsulated lithium aspartate capsules, each containing 5 mg of elemental lithium, or identically appearing placebo capsules were administered.

The patients were instructed to take 2 capsules per day for the first 10 days, with an option to increase to 3 capsules per day if symptoms persisted.

In the main trial, 26 participants were randomized to lithium and 26 to placebo. Two lithium-receiving participants were lost to follow-up. No significant adverse events were attributed to lithium. The changes in primary outcome measures (sum of FSS-7 and BFSS) were –20.3 for lithium vs –16.7 for placebo (P = .59). Secondary outcome measures did not reveal any statistically significant differences.

In the dose-finding study, one participant withdrew as a result of worsening diarrhea at 40 mg/d, and another experienced mild sedation at 45 mg/d, which resolved when the dose was reduced to 40 mg/d. No clinically significant changes in thyroid-stimulating hormone levels or estimated glomerular filtration rates were observed.

The investigators acknowledged limitations, including the small sample size and lack of biomarker assessments, such as PET or MRI neuroimaging, which could provide further insights into neuroinflammatory changes in long COVID patients.

The lead author reported being president of e3 Pharmaceuticals. No other disclosures were reported.