A large retrospective cohort study found that valproic acid use was associated with a decreased risk of testing positive for COVID-19; the fatty acid also reduced disease severity among those infected with the virus. Researchers at the University of Texas Health Science Center San Antonio analyzed data from over 3 million patients tested for COVID-19 between 2020 and 2021.
Key Findings
The study, published in PLOS ONE, showed valproic acid (VPA) use was associated with a 25% reduced risk of COVID-19 infection in exact-matched multivariate analysis.
Among COVID-19–positive patients, VPA use was associated with a:
- 12% to 15% reduction in emergency room visits
- 17% to 45% reduction in hospital admissions
- 33% to 39% reduction in mechanical ventilation use
- 14% to 16% reduction in intensive care unit admissions.
Researchers utilized data from the Optum electronic medical records dataset, which included 405,234 COVID-19–positive patients and 2,717,216 COVID-19–negative patients. The COVID-19–positive cohort had a mean age of 48.7 years; 42.6% of patients were male and 57.4% were female. Logistic regression models adjusted for demographics and comorbidities were used to calculate the odds ratios for COVID-19 positivity and clinical outcomes. Comorbidities among COVID-19–positive patients included cancer (8%), diabetes mellitus (21.7%), and chronic obstructive pulmonary disease (29.9%).
Rsearchers also explored VPA’s potential antiviral mechanisms through in vitro experiments. Although initial tests showed VPA’s antiviral activity at high concentrations, the IC50 for viral inhibition decreased significantly when cells were pre-incubated with VPA. Further experiments revealed that combining VPA with the omega-3 fatty acid docosahexaenoic acid (DHA) reduced the IC50 of VPA by nearly 10-fold—indicating a synergistic antiviral effect.
RNA sequencing revealed that VPA altered the expression of over 2,000 genes involved in viral replication and immune responses. The combination of VPA and DHA further enhanced the antiviral effects by modulating pathways such as Oxidative Phosphorylation and Sirtuin Signaling.
Despite the promising findings, the study’s observational nature limits the ability to establish causality. Furthermore, patient VPA serum levels were not available, preventing a detailed dose-response analysis. In a separate national dataset, the average serum VPA level was found to be 56.7 μg/mL, with less than 25% of patients achieving levels ≥80 μg/mL (~0.55 mM).
The study authors concluded, "These studies lay the groundwork for further clinical evaluation of VPA + DHA for treating coronaviruses in general, and provide the additional foundation for combination therapeutics of polyunsaturated fatty acids and histone deacetylase inhibitors."
The authors have declared that no competing interests exist.
