COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms

Key Messages

This original research article investigates the various mechanisms of action proposed for famotidine as a COVID-19 treatment.

Based on their preclinical findings, the authors reject almost all of the previously proposed explanations.

The authors propose instead that abnormal mast cell activation and release of histamines occurs during SARS-CoV-2 infection. The ability of famotidine to block H2 receptors is stressed as a possible mechanism of action to explain its effectiveness for treating COVID-19.

Frontiers in Pharmacology

Publication Date: March 23, 2021
Peer Reviewed: Yes
Publication Type: Original | Clinical Prospective, Preclinical

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms

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


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.