Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses

LONG CHI NGUYEN, DONGBO YANG, VLAD NICOLAESCU,  THOMAS J. BEST, HALEY GULA, DIVYASHA SAXENA, JON D. GABBARD, SHAO-NONG CHEN, TAKASHI OHTSUKI, JOHN BRENT FRIESEN, NIR DRAYMAN, ADIL MOHAMED, CHRISTOPHER DANN, DIANE SILVA, LYDIA ROBINSON-MAILMAN, ANDREA VALDESPINOLETÍCIA STOCK, EVA SUÁREZ, KRYSTEN A. JONES, SAARA-ANNE AZIZI, JENNIFER K. DE MARCO, WILLIAM E. SEVERSON, CHARLES D. ANDERSON, JAMES MICHAEL MILLIS, BRYAN C. DICKINSON, SAVAŞ TAY, SCOTT A. OAKES, GUIDO F. PAULI, KENNETH E. PALMER, THE NATIONAL COVID COHORT COLLABORATIVE CONSORTIUM, DAVID O. MELTZER, GLENN RANDALL AND MARSHA RICH ROSNER 

SCIENCE ADVANCES • 20 Jan 2022 • First Release • DOI: 10.1126/sciadv.abi6110

Abstract

The spread of SARS-CoV-2 and ongoing COVID-19 pandemic underscores the need for new treatments. Here we report that cannabidiol (CBD) inhibits infection of SARS-CoV-2 in cells and mice. CBD and its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after viral entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD inhibits SARS-CoV-2 replication in part by up-regulating the host IRE1α RNase endoplasmic reticulum (ER) stress response and interferon signaling pathways. In matched groups of human patients from the National COVID Cohort Collaborative, CBD (100 mg/ml oral solution per medical records) had a significant negative association with positive SARS-CoV-2 tests. This study highlights CBD as a potential preventative agent for early-stage SARS-CoV-2 infection and merits future clinical trials. We caution against use of non-medical formulations including edibles, inhalants or topicals as a preventative or treatment therapy at the present time.

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