https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987002/
o test the effect of CBD on SARS-CoV-2 replication, we pretreated A549 human lung carcinoma cells expressing exogenous human ACE-2 receptor (A549-ACE2) for 2 hours with 0โ10 ฮผM CBD prior to infection with SARS-CoV-2. After 48 hours, we monitored cells for expression of the viral spike protein (S). For comparison, we also treated cells over a similar dose range with an MLK inhibitor (URMC-099) previously implicated as an antiviral for HIV (12) and KPT-9274, a PAK4/NAMPT inhibitor (13) that our analysis suggested might reverse many changes in gene expression caused by SARS-CoV-2. All three inhibitors potently inhibited viral replication under non-toxic conditions with EC50s ranging from 0.2โ2.1 ฮผM (Fig. 1A). CBD inhibited SARS-CoV-2 replication in Vero E6 monkey kidney epithelial cells as well (fig. S1A). No toxicity was observed at the effective doses (fig. S1B). We also determined that CBD suppressed replication of a related beta-coronavirus, mouse hepatitis virus (MHV), under non-toxic conditions with an EC50 of ~5 ฮผM using A549 cells that express the MHV receptor (A549-MHVR), indicating the potential for more broader viral efficacy (fig. S1C,D).
When isolated from its source plant, natural non-synthetic CBD is typically extracted along with other cannabinoids, representing the unavoidable residual complexity of natural products. To verify that CBD is indeed responsible for the viral inhibition, we analyzed a CBD reference standard as well as CBD from three different sources for purity using 100% quantitative NMR (qNMR). These sources included two chemical vendors (Suppliers A and B) and one commercial vendor that used natural materials (Supplier C). The striking congruence between the experimental 1H NMR and the recently established quantum-mechanical HiFSA (1H Iterative Full Spin Analysis) profiles observed for all materials confirmed that 1) the compounds used were indeed CBD with purities of at least 97% (Fig. 1B) and 2) congeneric cannabinoids were not present at levels above 1.0% (11). Analysis of these different CBD preparations in the viral A549-ACE2 infection assay showed similar EC50s with a range from 0.6โ1.8 ฮผM likely reflecting the intrinsic biological variability of the assay (Fig. 1C). No toxicity was observed for any of the CBD preparations at the doses used to inhibit viral infection (fig. S1 EโG).
CBD is often consumed as part of a C. sativa extract, particularly in combination with psychoactive THC enriched in marijuana plants. We therefore determined whether congeneric cannabinoids, especially analogues with closely related structures and polarities produced by the hemp plant, are also capable of inhibiting SARS-CoV-2 infection. Remarkably, only CBD was a potent agent, while limited or no antiviral activity was exhibited by the structurally closely related congeners that share biosynthesis pathways and form the biogenetically determined residual complexity of CBD purified from C. sativa: THC, cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabichromene (CBC), or cannabigerol (CBG) (Fig. 2 AโB; see Methods). None of these compounds were toxic to the A549-ACE2 cells in the dose range of interest (fig. S2). Notably, combining CBD with THC (1:1) significantly suppressed CBD efficacy consistent with competitive inhibition by THC.
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