The non-psychoactive cannabinoid, cannabidiol (CBD), is FDA-approved for treatment of two drug-resistant epileptic disorders, and is seeing increased use among the general public, yet the mechanisms that underlie its therapeutic effects and side-effect profiles remain unclear. Here, we report a systems-level analysis of CBD action in human cell lines using temporal multi-omic profiling. FRET-based biosensor screening revealed that CBD elicits a sharp rise in cytosolic calcium, and activation of AMPK in human keratinocyte and neuroblastoma cell lines. CBD treatment leads to alterations in the abundance of metabolites, mRNA transcripts, and proteins associated with activation of cholesterol biosynthesis, transport and storage. We found that CBD rapidly incorporates into cellular membranes, alters cholesterol accessibility, and disrupts cholesterol-dependent membrane properties. Sustained treatment with high concentrations of CBD induces apoptosis in a dose-dependent manner. CBD-induced apoptosis is rescued by inhibition of cholesterol synthesis and potentiated by compounds that disrupt cholesterol trafficking and storage. Our data point to a pharmacological interaction of CBD with cholesterol homeostasis pathways, with potential implications in its therapeutic use.
Keywords: CBD, FRET biosensor, cannabidiol, cholesterol, high-content screening, lipidomics, metabolomics, multi-omics, phosphoproteomics, proteomics, systems pharmacology, transcriptomics
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of Interests XL, DC and WO are patent holders of PCT WO2019246632A1, and XL, DC, WO and EB are patent holders of PCT WO2019118837A1. Both patents are related to this work. Unrelated to the contents of this manuscript, AD and TN are founders of Omix Technologies Inc, D.C. is the founder of Bioloomics, Inc, and RS is the founder of Sievers Infinity LLC.