Abstract: Inflammopharmacology (2022) 30:477–486 https://doi.org/10.1007/s10787-022-00939-7 Inflammopharmacology ORIGINAL ARTICLE Advancing combination treatment with glycyrrhizin and boswellic acids for hospitalized patients with moderate COVID‑19 infection: a randomized clinical trial Adel A. Gomaa1 · Hamdy S. Mohamed4 · Rasha B. Abd‑ellatief1 · Mohamed A. Gomaa2 · Doaa S. Hammam3 Received: 4 February 2022 / Accepted: 8 February 2022 / Published online: 1 March 2022 © The Author(s) 2022 Abstract Recent evidence points to a potential therapeutic role for glycyrrhizin(GR) and boswellic acids (BA) in the treatment of COVID-19 but conclusive evidence is lacking. Our aim is to investigate the efficacy of GR + BA versus placebo for the treatment of hospitalized patients with moderate SARS-CoV-2 or COVID-19 variants infection. The current study is a randomized, double-blind, placebo-controlled, single-center trial. Patients with SARS-CoV-2 or COVID-19 variants diagnosed by PCR test who were admitted to Sohag University hospital were eligible if they were at least 18 years of age and had moderate symptoms. Patients were randomly assigned to receive oral GR capsule (60 mg) and BA (200 mg) twice daily for 14 days or a matching placebo. All patients also received treatment with the institutional protocol for COVID-19. The primary outcome was mortality and time to recovery. Secondary outcome was clinical status score, 14 days after receiving study drugs. Adverse events from use of study drugs have been evaluated for up to 14 days. The trial is registered at ClinicalTrials.gov (Identifier NCT04487964). During the 6-month enrollment period (June-November, 2021) only 50 patients (54% women; median age 60 years, IQR 54–65) met eligibility and were randomly assigned. Evaluation of the primary outcome at 14 days showed that there were five deaths in the placebo group and no deaths in the GR + BA group. With regard to recovery time, it was significantly shorter (p = 0.0001) in the group receiving GR + BA capsule compared to the placebo group (median 7.0; IQR 6.0–8.0 days vs. median 12.5; IQR 12–20 days). Clinical status on the ordinal score scale as a secondary outcome showed a significant difference between the GR + BA group (median (IQR) score, 2 [2–3]) and placebo groups (mean (IQR) score, 3 [3–5.5]). There was a significant decrease in CRB (p = 0.000041) in GR + BA compared with the placebo group. In conclusion, this safe, inexpensive, antiviral, immunomodulating and anti-inflammatory combination may be considered for use in mild to moderate infections of SARS-CoV-2 or COVID-19 variants. The study is limited by the small sample size; therefore, larger randomized trials are required. Keywords COVID-19 · Glycyrrhizin · Boswellic aids · Mortality rate · Time to recovery · Clinical status score Abbreviations BA Boswellic acids ACE2 Angiotensin-converting enzyme 2 * Adel A. Gomaa a.gomma@aun.edu.eg 1 Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt 2 Department of Plastic Surgery, Faculty of Medicine, Assiut University, Assiut, Egypt 3 Department of Pharmacology & Toxicology, Faculty of Pharmacy, Assiut University, Assiut, Egypt 4 Department of Internal Medicine, Faculty of Medicine, Sohag University, Sohag, Egypt COVID-19 Coronavirus disease 2019 CRB C-reactive protein GR Glycyrrhizin HMGB1 High-mobility group box 1 protein HsGAPDH Human GAPDH IQR Interquartile rang NLRP3 Nod-like receptor..