Robert W Malone, Philip Tisdall, Philip Fremont-Smith, Yongfeng Liu, Xi-Ping Huang, Kris M White, Lisa Miorin, Elena Moreno, Assaf Alon, Elise Delaforge, Christopher D Hennecker, Guanyu Wang, Joshua Pottel, Robert V Blair, Chad J Roy, Nora Smith, Julie M Hall, Kevin M Tomera, Gideon Shapiro, Anthony Mittermaier, Andrew C Kruse, Adolfo García-Sastre, Bryan L Roth, Jill Glasspool-Malone, Darrell O Ricke

PMID: 33833683 PMCID: PMC8021898 DOI: 10.3389/fphar.2021.633680


SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. SARS-CoV-2 infection is necessary but not sufficient for development of clinical COVID-19 disease. Currently, there are no approved pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We have investigated several plausible hypotheses for famotidine activity including antiviral and host-mediated mechanisms of action. We propose that the principal mechanism of action of famotidine for relieving COVID-19 symptoms involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release. Based on these findings and associated hypothesis, new COVID-19 multi-drug treatment strategies based on repurposing well-characterized drugs are being developed and clinically tested, and many of these drugs are available worldwide in inexpensive generic oral forms suitable for both outpatient and inpatient treatment of COVID-19 disease.

Keywords: Famotidine COVID-19; GPCR (G Protein Coupled Receptors), histamine (H2) receptor, mast cell activating disorder