Effect of Lithium Therapy on Long COVID Symptoms

In this double-blind, placebo-controlled study, 50 patients with long COVID will be randomly assigned to either low-dose oral lithium or placebo therapy for three weeks. After the double-blind study phase, all patients will be provided with lithium therapy for two additional weeks. Study visits will occur at baseline and after the three-week double-blind study phase.

• Lithium (Drug): Lithium has multiple mechanisms of action including anti-inflammatory actions, which may be relevant for treating long COVID.
• Placebo (Drug): Inactive pill

Primary outcomes

• Fatigue Severity Scale [Change from baseline to day 21]: 7-item questionnaire assessing fatigue severity. Score range 1-49 with higher values signifying worse outcome
• Brain Fog Severity Scale [Change from baseline to day 21]: 7-item questionnaire assessing brain fog severity. Score range 1-49 with higher values signifying worse outcome

Secondary outcomes

• Patient Global Impression of Change (PGIC) [Day 21]: Change in symptoms on 7-point scale. Single-item scale. Score range 1-7 with higher values signifying better outcome
• Well-Being Scale [Change from baseline to day 21]: Sense of well-being over past week on 10-point scale. Score range 0-10 with higher values signifying better outcome.
• Short Form-12 Health Survey (1-week Modification) [Change from baseline to day 21]: Quality of life assessment over past week, PCS-subscale. 12-item quality of life scale. Score range 0-100 for both the Physical Component Score and the Mental Component Score with higher values signifying better outcomes.
• Desire to Continue Therapy [Day 21]: Single Yes/No question. Single-item scale. Score range 1-2 with higher value signifying better outcome. Reported as % of respondents recording "yes".
• Generalized Anxiety Disorder-2 Scale [Change from baseline to day 21]: 2-item questionnaire assessing anxiety frequency over the past week. 2-item scale. Score range 0-6 with higher values signifying worse outcome
• Headache and Body Pain Bother Scale [Change from baseline to day 21]: 2-item questionnaire assessing frequency of headaches and body pain over the past week, Headache score. 2-item scale. Score range 2-10 with higher values signifying worse outcome
• Insomnia Severity Index [Change from baseline to day 21]: 7-item questionnaire assessing insomnia severity over the past week. 7-item scale. Score range 0-28 with higher values signifying worse outcome.
• Sense of Smell and Taste Change Scale [Day 21]: Subjective change from baseline on a 7-point scale (score range: 1-7) with higher scores indicating better outcomes. Scores of 1 and 7 indicate sense of smell and taste were "very much worse" or "very much improved", respectively, since the start of study treatment.
• Digit Symbol Substitution Test [Change from baseline to day 21]: Validated cognitive test. Score range 0-100 with higher scores indicating a better outcome.
• Delayed Recall Test [Change from baseline to day 21]: Validated cognitive test. Score range 0-5 with higher scores indicating better outcomes.

Sex: All, ages: 18 Years to 80 Years

1. Documented or self-reported positive test for COVID-19 ≥4 weeks prior to enrollment.
2. No fever for ≥4 weeks prior to enrollment.
3. Reports fatigue and/or brain fog (i.e. concentration or memory impairment) for ≥4 weeks prior to enrollment on the PASC-Specific Symptom questionnaire beginning after infection with COVID-19.
4. Fatigue Severity Scale (FSS) score ≥28 or Brain Fog Severity Scale (BFSS) score ≥28 at baseline.
5. Beck Depression Inventory II score <24.
6. No change in any psychoactive or steroid medications for ≥30 days.
7. No plan to change any psychoactive, steroid or diuretic medication for ≥5 weeks and not planning on obtaining a COVID vaccine within the next 5 weeks.
8. Not using any long COVID therapies felt to be worsening the patient's symptoms or starting a long COVID therapy within the next 5 weeks.
9. No history of fibromyalgia, chronic fatigue syndrome or progressive cognitive disorder prior to COVID-19 infection.
10. No active medical, psychiatric or social problems that would interfere with completing the study procedures in the opinion of the investigator.
11. No use of tobacco or marijuana products for >6 months and no current alcohol abuse (≥4 drinks/day) or illicit drug use.
12. Not receiving or applying for disability payments or workman's compensation for long COVID.
13. Not pregnant or nursing or planning to get pregnant over the next two months.

Participant flow

Outcome results

• Fatigue Severity Scale (Primary), Mean, score on a scale: Lithium -11.3 +/- 12.6; Placebo -8.6 +/- 12.3 (p 0.46)
• Brain Fog Severity Scale (Primary), Mean, score on a scale: Lithium -9.0 +/- 13.8; Placebo -8.1 +/- 10.6 (p 0.79)
• Patient Global Impression of Change (PGIC) (Secondary), Mean, score on a scale: Lithium 4.7 +/- 1.1; Placebo 4.6 +/- 1.2 (p 0.68)
• Well-Being Scale (Secondary), Mean, score on a scale: Lithium 1.0 +/- 2.0; Placebo 0.9 +/- 2.1 (p 0.89)
• Short Form-12 Health Survey (1-week Modification) (Secondary), Mean, score on a scale: Lithium 5.1 +/- 8.5; Placebo 4.2 +/- 11.1 (p 0.75)
• Desire to Continue Therapy (Secondary), Count of participants, Participants: Lithium 12; Placebo 13 (p 1.0)
• Generalized Anxiety Disorder-2 Scale (Secondary), Mean, score on a scale: Lithium -0.8 +/- 1.7; Placebo -1.4 +/- 1.7 (p 0.28)
• Headache and Body Pain Bother Scale (Secondary), Mean, score on a scale: Lithium -0.6 +/- 0.7; Placebo -0.7 +/- 1.2 (p 0.58)
• Insomnia Severity Index (Secondary), Mean, score on a scale: Lithium -6.0 +/- 6.7; Placebo -4.4 +/- 4.8 (p 0.41)
• Sense of Smell and Taste Change Scale (Secondary), Mean, score on a scale: Lithium 4.1 +/- 0.3; Placebo 4.2 +/- 0.4 (p 0.50)
• Digit Symbol Substitution Test (Secondary), Mean, score on a scale: Lithium 4.3 +/- 5.9; Placebo 6.6 +/- 9.0 (p 0.29)
• Delayed Recall Test (Secondary), Mean, score on a scale: Lithium 0.46 +/- 1.02; Placebo 0.35 +/- 0.80 (p 0.35)

Adverse events

Time frame: 5-weeks

• Results publication: Guttuso T Jr, Zhu J, Wilding GE. Lithium Aspartate for Long COVID Fatigue and Cognitive Dysfunction: A Randomized Clinical Trial. JAMA Netw Open. 2024 Oct 1;7(10):e2436874. doi: 10.1001/jamanetworkopen.2024.36874. PMID 39356507

• Study Protocol and Statistical Analysis Plan (PDF, 2023-03-01)

• Thomas Guttuso, Jr., MD, Principal investigator, University at Buffalo

NIH grants: UL1TR001412