Reference
Guttuso T Jr, Zhu J, Wilding GE. Lithium aspartate for long-Covid fatigue and cognitive dysfunction: a randomized clinical trial [published correction appears in JAMA Netw Open. 2024;7(10):e2444512]. JAMA Netw Open. 2024;7(10):e2436874.
Study Objective
To determine if lithium aspartate reduces fatigue and cognitive dysfunction associated with long-Covid
Key Take-Away
Thoughtful dosing of lithium aspartate is important and should be considered for patients suffering from fatigue and cognitive dysfunction caused by long-Covid.
Study Design
- Randomized, double-blind trial: a placebo-controlled, parallel-group trial
- Open-label, dose-finding study: Follow-up study to assess the potential effectiveness of higher doses of lithium aspartate
Participants
Patient recruitment occurred through the University at Buffalo Western New York Community-Based Long COVID Registry, local newspaper advertisements, and primary care offices. Eligible patients were enrolled if they reported a positive test for Covid-19 and experienced subsequent fatigue and cognitive-dysfunction symptoms for more than 4 weeks after recovering from the acute infection.
Exclusion criteria
- No tobacco or tetrahydrocannabinol use for more than 6 months
- No current lithium use or history of use
- Not pregnant or nursing
- No changes in psychoactive or steroid medications for 30 days or more
- No history of chronic conditions that cause fatigue or cognitive dysfunction (eg, fibromyalgia, chronic fatigue syndrome, rheumatoid arthritis)
A total of 251 patients were screened for enrollment from November 28, 2022, to June 29, 2023. Fifty-two eligible patients were enrolled (30 men and 22 women). The mean age was 58.54 years, and patients in the lithium and placebo groups were well-matched. Two patients in the lithium group were lost to follow-up, leaving 50 patients who completed the double-blind phase.
Five participants accepted an invitation for enrollment in the dose-finding study.
Interventions
- Double-blind phase
- Eligible patients were randomly assigned to receive lithium aspartate capsules (5 mg elemental lithium per capsule) or placebo capsules filled with microcrystalline cellulose.
- Patients were instructed to take 2 capsules per day for the initial 10 days. If their symptoms remained unchanged, they had the option to increase the dosage to 3 capsules per day for the final 11 days.
- Open-label, dose-finding study
- Lithium aspartate dosages of up to 45 mg/day were assessed. Patients took 2 capsules twice daily (5 mg each) for 1 week. The daily dosage was then increased weekly by 1 capsule per day, up to a maximum dosage of 4 capsules every morning and 5 capsules every night at bedtime (45 mg/day), as tolerated.
Study Parameters Assessed
The Fatigue Severity Scale 7-Item version (FSS-7) and the Brain Fog Severity Scale (BFSS) were used to measure the primary outcome of the study, comparing scores at baseline and at the end of the study.
Additional scales were included to determine changes from baseline:
- Headache and Body Pain Bother Scale
- Generalized Anxiety Disorder 2-item scale (GAD-2)
- Short Form-12 Health Survey (SF-12)
- Well-Being Scale (WBS)
- Insomnia Severity Index (ISI)
Patients invited to participate in the open-label, lithium-dose-finding study completed the:
- FSS-7
- BFSS
- Headache and Body Pain Bother Scale
- GAD-2
- SF-12
- WBS
- ISI
- Modified Fatigue Impact Scale (MFIS-39)
- Perceived Deficits Questionnaire (PDQ-5)
A venous blood sample was assessed for:
- Thyroid-stimulating hormone
- Lithium level
- Chemistry panel
Primary Outcome Measure
Change in sum of the Fatigue Severity Scale 7-Item version and Brain Fog Severity Scale scores
Key Findings
In the double-blind phase, results showed no significant intergroup differences for the primary outcome (−3.6; 95% CI: −16.6 to 9.5; P=0.59) or any of the secondary outcome measures.
There were no clinically significant changes in serum thyroid-stimulating hormone levels or estimated glomerular filtration rates in any patient.
Of the 43 patients invited to participate in the dose-finding study, 5 were enrolled.
Patient 1 reported continued satisfactory benefit from the original dosage on entering the dose-finding study and had not attempted to discontinue lithium therapy over the previous 12 months. At a higher dose, patient 3 experienced gastrointestinal symptoms, withdrew from the study, and reported no perceived improvement in fatigue or cognitive dysfunction at a dose of 40 mg/day. Patient 5 experienced sedation at 45 mg/day, which resolved at a reduced dose of 40 mg/day.
Among the 3 patients who completed the dose-finding study, 40 to 45 mg/day of lithium aspartate was associated with numerically greater reductions in fatigue and cognitive dysfunction scores compared with the 15 mg/day dosage. This was especially notable in 2 patients with serum lithium levels of 0.18 and 0.49 mEq/L, compared with 1 patient with a level of 0.10 mEq/L.
Seven months after enrolling in the dose-finding study, patient 1 reported discontinuing lithium aspartate therapy without any recurrence of subjective fatigue or cognitive dysfunction.
Transparency
Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001412 to the University at Buffalo.
The funding organization had no role in the design or conduct of the study; the collection, management, analysis, or interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.
Practice Implications & Limitations
According to the Centers for Disease Control and Prevention (CDC), long-Covid, also known as post-Covid conditions (PCC), is an infection-associated chronic condition that can occur after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects 1 or more organ systems.1
Over 200 long-Covid symptoms have been identified, including fatigue and cognitive dysfunction, often referred to as brain fog. Many symptoms, such as motor slowing, low motivation and energy, and short-term-memory impairment, may persist for months to years following infection.2 Unfortunately, there is a lack of effective treatment, with the CDC suggesting that Covid-19 vaccination is the best available tool to prevent long-Covid.¹
There is evidence that the neurological symptoms related to long-Covid are associated with brain inflammation rather than neuronal viral invasion.3 Neuroinflammation involving the brainstem has been observed in postmortem cases.4 Lithium, in addition to being an effective treatment for bipolar disorder, has a multitude of neuroprotective actions.5 Accumulating evidence suggests that inflammation plays a role in the pathogenesis of bipolar disorder and that lithium has anti-inflammatory effects that may contribute to its therapeutic efficacy.6 Some evidence suggests that lithium inhibits inflammatory-associated pathways such as glycogen synthase kinase-3β, nuclear factor-κB, and the transcription factor signal transducer and activator of transcription (STAT).6
In a pilot clinical trial in patients with Parkinson disease, lithium aspartate at a dosage of 45 mg/d was associated with reductions in a magnetic resonance imaging (MRI) neuroinflammation biomarker called free water in several brain sites, including the thalamus.5
In the study being reviewed here, patients were instructed to take 2 capsules (10 mg) per day for the initial 10 days. If their symptoms were still problematic, they could increase the dosage to 3 capsules per day (15 mg) for the last 11 days of the study. At the end of the 21-day period, results showed no significant differences in fatigue and cognitive dysfunction.
Over 200 long-Covid symptoms have been identified, including fatigue and cognitive dysfunction, often referred to as brain fog.
However, the open-label, lithium-dose-finding study found that 3 of 4 patients who completed the study reported reductions in fatigue and cognitive dysfunction after taking 40 to 45 mg of lithium aspartate per day. It is important to note that the 3 patients who experienced a positive response had higher serum lithium levels compared with the 1 patient who did not experience significant benefit, suggesting there is a threshold serum concentration to be effective.
Although the dose-finding study was small and preliminary, practitioners should consider advising lithium aspartate at doses greater than 15 mg/day to address fatigue and cognitive dysfunction associated with long-Covid while monitoring serum lithium levels. In addition, further clinical research is needed to better determine the effectiveness of higher dosages.
Conflict of Interest Disclosure
The author declares no conflict of interest.
