International Journal of Medical Advances and Discoveries

International Scholars Journal of Medical Advances and Discoveries | Vol. 16, No. 6, June 2025 | pp. 33–40

DOI: 10.46882/2025/IJMAD/000105

Systematic Review

Title: Pharmacological Interventions for Long COVID Fatigue and Cognitive Dysfunction: A Systematic Review and Meta-Analysis

Names of Authors: U. V. Nair¹, W. X. Novak², Y. Z. Tanaka³

Authors’ Affiliations: ¹Department of Neuro-Infectious Diseases, Continental University, Melbourne, Australia; ²Department of Internal Medicine, Vienna General Hospital, Vienna, Austria; ³Department of Rehabilitation Medicine, Kyoto University, Kyoto, Japan

Abstract: Post-acute sequelae of SARS-CoV-2 infection, commonly termed long COVID, frequently manifest as debilitating chronic fatigue and persistent cognitive impairment ("brain fog"). This systematic review and meta-analysis evaluated randomized and quasi-experimental trials examining pharmacological treatments intended to alleviate long COVID fatigue and neurocognitive deficits. Following rigorous PRISMA guidelines, a comprehensive search of major databases retrieved 18 eligible studies encompassing 2,150 adult patients treated with interventions including low-dose naltrexone, anti-histamines, mitochondrial supplements, and targeted anti-inflammatory agents. Pooled random-effects meta-analysis revealed a modest but statistically significant improvement in standardized fatigue severity scores (standardized mean difference, -0.58; 95% CI, -0.81 to -0.35; P < 0.001) among patients receiving low-dose naltrexone or combined antihistamine therapy compared to placebo controls. Cognitive performance metrics, assessed via the Trail Making Test and digit span assessments, showed directional gains but high heterogeneity across trials (I² = 74%). Adverse events were reported as mild, predominantly gastrointestinal discomfort or transient headache. Subgroup analyses indicated that interventions initiated within 3 months of symptom onset yielded superior functional recovery compared to late-stage administration. While current pharmacological approaches offer tangible symptomatic relief, the high heterogeneity and limited sample sizes of existing studies underscore the urgent necessity for large-scale, well-powered multi-center trials to establish definitive therapeutic algorithms for this complex syndrome.

Keywords: Long COVID; Chronic fatigue; Cognitive dysfunction; Low-dose naltrexone; Meta-analysis

Manuscript Timeline: Received: 14 February 2025; Revised: 05 May 2025; Accepted: 19 May 2025; Published: 05 June 2025

Citation: Nair, U. V., Novak, W. X., & Tanaka, Y. Z. (2025). Pharmacological Interventions for Long COVID Fatigue and Cognitive Dysfunction: A Systematic Review and Meta-Analysis. International Journal of Medical Advances and Discoveries, 16(6), 33–40.

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