Abstract Background Sepsis, caused by a dysregulated response to infections, can lead to cardiac arrhythmias. However, the mechanisms underlying sepsis-induced inflammation, and how inflammation provokes cardiac arrhythmias, are not well understood. We hypothesized that cannabidiol (CBD) may ameliorate lipopolysaccharide (LPS)-induced cardiotoxicity, via Toll-like receptors (TLR4) and cardiac sodium channels (NaV1.5). Methods and results We incubated human immune cells (THP-1 macrophages) with LPS for 24 h, then extracted the THP-1 incubation media. ELISA assays showed that LPS (1 or 5 μg·ml−1), in a concentration-dependent manner, or MPLA (TLR4 agonist, 5 μg·ml−1) stimulated the THP-1 cells to release inflammatory cytokines (TNF-α and IL-6). Prior incubation (4 h) with CBD (5 μM)...