A new clinical trial reveals that low-dose lithium aspartate is ineffective for long COVID brain fog and fatigue, yet exploratory results suggest that higher doses could hold future potential for relief.
Study: Lithium Aspartate for Long COVID Fatigue and Cognitive Dysfunction. Image Credit: Yellow_man / Shutterstock
A recent study published in JAMA Network Open investigated the effects of lithium aspartate on neurologic symptoms of post-coronavirus disease 2019 (COVID-19) condition (PCC).
PCC or long COVID is the persistence of symptoms for at least four weeks after recovery from initial COVID-19. PCC symptoms last for over six months in about 10% of patients, with post-exertional malaise, cognitive dysfunction, and fatigue being the most common symptoms. Neuroimaging and autopsy data support chronic brain inflammation as the mechanistic contributor to neurologic PCC symptoms (cognitive dysfunction and fatigue).
Lithium exhibits a range of neuroprotective actions in addition to being a treatment for bipolar disorder. One such action is its ability to decrease neuroinflammation by suppressing the activation of astrocytes and microglia. Therefore, lithium has been proposed as a potential treatment for neurologic PCC symptoms.
About the study
In the present study, researchers investigated the effects of lithium aspartate on PCC cognitive dysfunction and fatigue. This randomized, placebo-controlled, double-blind, clinical trial was performed between November 28, 2022, and June 29, 2023, at the University at Buffalo. Eligible patients were those with a positive COVID-19 test and subsequent cognitive dysfunction and fatigue for over four weeks post-recovery.
At screening, patients were required to have a newly developed, unvalidated Brain Fog Severity Scale (BFSS) or Fatigue Severity Scale 7-item version (FSS) score ≥ 28, a negative urine pregnancy test for females, and a Beck Depression Inventory (BDI)-II score < 29, and no other medical or psychiatric conditions known to cause fatigue or cognitive dysfunction. The BFSS was developed for this study, using the same seven questions as the FSS-7 but substituting "fatigue" for "brain fog" due to the lack of a validated scale for brain fog. The primary outcome was the change in the sum of BFSS and FSS-7 scores, with higher scores indicating more severe symptoms. Secondary outcomes were changes in scores of additional questionnaires. Participants were randomized to receive lithium aspartate (5 mg elemental lithium per capsule, chosen for its prior anecdotal use and availability) or identically appearing placebo capsules.
Subjects took two capsules daily for the first 10 days. If PCC symptoms remained bothersome, three capsules were allowed daily for the last 11 days. At the follow-up visit (21 days post-baseline), baseline tests or questionnaires were repeated. Patients were provided with a two-week supply of open-label lithium aspartate and instructed to take two capsules per day for a week, and three capsules per day for another week if symptoms were still bothersome.
Following the trial, a dose-finding study was conducted to determine whether higher doses of lithium aspartate were associated with greater reductions in BFSS or FSS-7 scores. This was initiated because one participant reported a satisfactory benefit to cognitive dysfunction and fatigue after taking additional lithium over five weeks, gradually increasing the dosage to 40 mg/day. Placebo non-responders were defined as patients who did not achieve a clinically meaningful reduction in fatigue/cognitive dysfunction scores on placebo (≥18-point reduction in FSS-7 or ≥15-point reduction in BFSS).
In the dose-finding study, participants from the original trial who were not placebo responders initially received lithium aspartate, 5-mg capsules, taken twice daily (a total of 20 mg/day) for one week. The daily dosage was then increased by one 5 mg capsule each week thereafter, as tolerated, up to a maximum of 45 mg/day. Blood tests and questionnaires were assessed at the follow-up visit three weeks later.
Findings
The trial randomized 52 patients to placebo or lithium aspartate groups. Two participants were lost to follow-up. Overall, 50 subjects entered the open-label lithium phase, and 45 provided outcome data. Five placebo and two lithium aspartate recipients had treatment-emergent adverse events (TEAEs). None had TEAEs during the open-label phase. No serious adverse events related to lithium were reported, and there were no clinically significant changes in thyroid or kidney function.
The researchers found no significant inter-group differences for primary or secondary outcomes. Five patients were enrolled in the dose-finding study. Four patients continued lithium aspartate at 15 mg/day for 7–12 months after the trial, but only one patient had a satisfactory benefit on entering the dose-finding study, and this patient eventually discontinued lithium without recurrence of symptoms, suggesting possible spontaneous resolution.
One patient with a history of intermittent diarrhea withdrew from the study due to exacerbating diarrhea and no perceived improvements in cognitive dysfunction or fatigue. No patient had significant changes in estimated glomerular filtration rates (eGFRs) or thyroid-stimulating hormone (TSH) levels, indicating no evidence of renal or thyroid toxicity over the study period.
Among the three subjects who completed the dose-finding study, lithium aspartate at 40–45 mg/day was associated with numerically higher reductions in cognitive dysfunction and fatigue scores compared to the 15 mg/day dosage, particularly in two patients who achieved serum lithium concentrations of 0.18–0.49 mEq/L, levels similar to those associated with benefit in prior Alzheimer’s and Parkinson’s trials. Furthermore, one patient, who had reported benefit at a very low serum lithium level, discontinued lithium aspartate seven months after enrolling in the dose-finding study, without experiencing recurrent cognitive dysfunction or fatigue; the study notes that this patient's symptoms may have resolved irrespective of lithium therapy.
Conclusions
In sum, lithium aspartate at 10–15 mg/day was ineffective for treating PCC cognitive dysfunction and fatigue. The dose-finding study was pursued based on an anecdotal report of satisfactory reductions in symptoms with 40 mg/day of lithium. However, only five patients participated in the dose-finding study, and results suggested that serum lithium concentrations of 0.18–0.49 mEq/L may offer meaningful improvements in symptoms.
The authors note that the very small sample size and open-label design of the dose-finding study limit generalizability, and emphasize that larger randomized trials targeting higher lithium serum levels are needed. Further trials, potentially incorporating biomarker assessments as suggested by the authors, are required to evaluate the potential benefits of higher doses of lithium for neurologic PCC treatment.
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