“The incidence of chronic inflammatory disorders and autoimmune diseases is rapidly growing. To date, the COVID-19 pandemic caused by SARS-CoV-2 has killed over 6,209,000 people globally, while no drug has been proven effective for the disease. Screening natural anti-inflammatory compounds for clinical application has drawn much attention.

In this study, we showed that high-CBD cannabis extracts #1, #5, #7, #169, and #317 suppressed the levels of expression of proinflammatory cyclooxygenase 2 (COX2) and increased the expression of the anti-inflammatory suppressor of cytokine signaling 3 (SOCS3) in human small intestinal epithelial cells (HSIEC) in TNFα/IFNγ-triggered inflammation.

We revealed that these extracts, with the exception of extract #169, also profoundly attenuated induction of proinflammatory cytokines interleukin-6 (IL-6) and/or IL-8 proteins through miR-760- and miR-302c-3p-mediated silencing. The prevalent components in extracts #1 and #7 influenced the levels of IL-8 both individually as well as in combination with each other. However, the high-dose cannabis extracts displayed an inhibitory effect in the growth of HSIEC cells.

These results show that our high-CBD cannabis extracts decrease the levels of proinflammatory molecules COX2, IL-6, and IL-8 via transcriptional suppression or miRNA-mediated silencing, highlighting their potential against COVID-19-associated cytokine storm syndrome.”

https://pubmed.ncbi.nlm.nih.gov/37664748/

“Growing evidence has demonstrated that cannabinoids can reduce the production of pro-inflammatory cytokines and inhibit tumor growth in humans and/or animal models.”

“Our findings reveal certain anti-inflammatory and anti-cytokine properties of the several studied cannabis extracts, confirming the anti-COVID-19 potential of these extracts.”

https://www.cell.com/heliyon/fulltext/S2405-8440(23)06025-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2405844023060255%3Fshowall%3Dtrue

“Cannabis is a general name for plants of the genus Cannabis. Used as fiber, medicine, drug, for religious, therapeutic, and hedonistic purposes along the millenia, it is mostly known for its psychoactive properties. One of its major constituents, cannabidiol (CBD), a non-psychoactive substance, among many other biological activities, has shown potential as an anti-SARS-CoV-2 drug. In this work, three derivatives and an analogue of CBD were synthesized, and cell viability and antiviral activities were evaluated. None of the compounds showed cytotoxicity up to a maximum concentration of 100 μM and, in contrast, displayed a significant antiviral activity, superior to remdesivir and nafamostat mesylate, with IC₅₀ values ranging from 9.4 to 1.9 μM. In order to search for a possible molecular target, the inhibitory activity of the compounds against ACE2 was investigated, with expressive results (IC₅₀ ranging from 3.96 μM to 0.01 μM).”

https://pubmed.ncbi.nlm.nih.gov/37657273/

“Although specific antiviral drugs are available, COVID-19 treatment worldwide has not adhered to such available interventions due mostly because of lack of accessibility and cost-effectivity. Therefore, it is essential to search for alternatives in terms of antiviral compounds that would be effective in controlling SARS-CoV-2. In this context, cannabidiol (CBD), a non-psychoactive major constituent of Cannabis spp. plants, may contribute positively against COVID-19 by interfering with the mechanism of entry of the virus into the cell.”

https://www.sciencedirect.com/science/article/abs/pii/S0223523423007274?via%3Dihub

“The COVID-19 pandemic provoked a global health crisis and highlighted the need for new therapeutic strategies. In this study, we explore the potential of the molecular consortia of cannabidiol (CBD) and non-steroidal anti-inflammatory drugs (NSAIDs) as novel antiviral dual-target agents against SARS-CoV-2/COVID-19. CBD is a natural compound with a wide range of therapeutic activities, including antiviral and anti-inflammatory properties, while NSAIDs are commonly used to mitigate the symptoms of viral infections. Chemical modifications of CBD with NSAIDs were performed to obtain dual-target agents with enhanced activity against SARS-CoV-2. The synthesised compounds were characterised using spectroscopic techniques. The biological activity of three molecular consortia (CBD-ibuprofen, CBD-ketoprofen, and CBD-naproxen) was evaluated in cell lines transduced with vesicular stomatitis virus-based pseudotypes bearing the SARS-CoV-1 or SARS-CoV-2 spike proteins or infected with influenza virus A/Puerto Rico/8/34. The results showed that some CBD-NSAID molecular consortia have superior antiviral activity against SARS-CoV-1 and SARS-CoV-2, but not against the influenza A virus. This may suggest a potential therapeutic role for these compounds in the treatment of emerging coronavirus infections. Further studies are needed to investigate the efficacy of these compounds in vivo, and their potential use in clinical settings. Our findings provide a promising new approach to combatting current and future viral emergencies.”

https://pubmed.ncbi.nlm.nih.gov/37513798/

https://www.mdpi.com/2076-0817/12/7/951

“In the present study, the antiviral activity of cannabinoids isolated from Cannabis sativa L. was assessed in vitro against a panel of SARS-CoV-2 variants, indicating cannabidiolic acid (CBDA) was the most active. To overcome the instability issue of CBDA, its methyl ester was synthesized and tested for the first time for its antiviral activity. CBDA methyl ester showed a neutralizing effect on all the SARS-CoV-2 variants tested with greater activity than the parent compound. Its stability in vitro was confirmed by ultra-high-performance liquid chromatography (UHPLC) analysis coupled with high-resolution mass spectrometry (HRMS). In addition, the capacity of both CBDA and its derivative to interact with the virus spike protein was assessed in silico. These results showed that CBDA methyl ester can be considered as a lead compound to be further developed as a new effective drug against COVID-19 infection.”

https://pubmed.ncbi.nlm.nih.gov/37402317/

https://pubs.acs.org/doi/10.1021/acs.jnatprod.3c00111?cookieSet=1

“Cannabidiol (CBD) has a number of biological effects by acting on the cannabinoid receptors CB₁ and CB₂. CBD may be involved in anti-inflammatory processes via CB₁ and CB₂ receptors, resulting in a decrease of pro-inflammatory cytokines. However, CBD’s poor aqueous solubility is a major issue in pharmaceutical applications. The aim of the present study was to develop and evaluate a CBD nasal spray solution. A water-soluble CBD was prepared by complexation with β-cyclodextrin (β-CD) at a stoichiometric ratio of 1:1 and forming polymeric micelles using poloxamer 407. The mixture was then lyophilized and characterized using FT-IR, DSC, and TGA. CBD-β-CD complex-polymeric micelles were formulated for nasal spray drug delivery. The physicochemical properties of the CBD-β-CD complex-polymeric micelle nasal spray solution (CBD-β-CDPM-NS) were assessed.

The results showed that the CBD content in the CBD-β-CD complex polymeric micelle powder was 102.1 ± 0.5%. The CBD-β-CDPM-NS was a clear colorless isotonic solution. The particle size, zeta potential, pH value, and viscosity were 111.9 ± 0.7 nm, 0.8 ± 0.1 mV, 6.02 ± 0.02, and 12.04 ± 2.64 cP, respectively. This formulation was stable over six months at ambient temperature. The CBD from CBD-β-CDPM-NS rapidly released to 100% within 1 min. Ex-vivo permeation studies of CBD-β-CDPM-NS through porcine nasal mucosa revealed a permeation rate of 4.8 μg/cm²/min, which indicated that CBD was effective in penetrating nasal epithelial cells. CBD-β-CDPM-NS was tested for its efficacy and safety in terms of cytokine production from nasal immune cells and toxicity to nasal epithelial cells. The CBD-β-CDPM-NS was not toxic to nasal epithelial at the concentration of CBD equivalent to 3.125-50 μg/mL.

When the formulation was subjected to bioactivity testing against monocyte-like macrophage cells, it proved that the CBD-β-CDPM-NS has the potential to inhibit inflammatory cytokines. CBD-β-CDPM-NS demonstrated the formulation’s ability to reduce the cytokine produced by S-RBD stimulation in ex vivo porcine nasal mucosa in both preventative and therapeutic modes.”

https://pubmed.ncbi.nlm.nih.gov/37182795/

“In vitro and ex vivo experiments were performed to evaluate the efficacy and safety of CBD.

•CBD-β-CD complexed in poloxamer micelles were 4,275 times water-soluble than CBD.

•CBD-β-CD complexed in poloxamer micelles was developed and evaluated as nasal spray solution.

•The developed nasal spray reduced SARS-CoV-2-induced pro-inflammatory cytokines.”

https://www.sciencedirect.com/science/article/pii/S0378517323004556?via%3Dihub

“To control the COVID-19 pandemic, antivirals that specifically target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently required. The 3-chymotrypsin-like protease (3CLpro) is a promising drug target since it functions as a catalytic dyad in hydrolyzing polyprotein during the viral life cycle. Bioactive peptides, especially food-derived peptides, have a variety of functional activities, including antiviral activity, and also have a potential therapeutic effect against COVID-19.

In this study, the hemp seed trypsinized peptidome was subjected to computer-aided screening against the 3CLpro of SARS-CoV-2. Using predictive trypsinized products of the five major proteins in hemp seed (i.e., edestin 1, edestin 2, edestin 3, albumin, and vicilin), the putative hydrolyzed peptidome was established and used as the input dataset.

To select the Cannabis sativa antiviral peptides (csAVPs), a predictive bioinformatic analysis was performed by three webserver screening programs: iAMPpred, AVPpred, and Meta-iAVP. The amino acid composition profile comparison was performed by COPid to screen for the non-toxic and non-allergenic candidates, ToxinPred and AllerTOP and AllergenFP, respectively. GalaxyPepDock and HPEPDOCK were employed to perform the molecular docking of all selected csAVPs to the 3CLpro of SARS-CoV-2. Only the top docking-scored candidate (csAVP4) was further analyzed by molecular dynamics simulation for 150 nanoseconds.

Molecular docking and molecular dynamics revealed the potential ability and stability of csAVP4 to inhibit the 3CLpro catalytic domain with hydrogen bond formation in domain 2 with short bonding distances. In addition, these top ten candidate bioactive peptides contained hydrophilic amino acid residues and exhibited a positive net charge.

We hope that our results may guide the future development of alternative therapeutics against COVID-19.”

https://pubmed.ncbi.nlm.nih.gov/36615263/

https://www.mdpi.com/1420-3049/28/1/50

“The emergence of a novel coronavirus that later on rendered a global pandemic, caused desperation within the communities and drove increased interest in exploring medicinal plant-based therapeutics to treat and prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infections.

Many medicinal plants have been reported to have antiviral, anti-inflammatory, and immunomodulatory effects that hinder, cure, or ease the symptoms of COVID-19 infection.

This exploratory study seeks to dock the active components of Cannabis sativa, a natural plant with several pharmacological and biological properties, with the angiotensin-converting enzyme II (ACE2) receptor. A total of 3 C. sativa active components have been found to bind to the ACE2 protein active site and could inhibit spike binding, although they do not compete directly with the receptor-binding domain (RBD) of SARS-CoV-2. 6-Prenylapigenin, cannabivarin (CBN-C3), and Δ8-tetrahydrocannabinolic acid-A (Δ8-THCA) have a greater affinity (-8.3, -8.3, and -8.0 kcal/mol, respectively) and satisfactory interaction with ACE2 than its inhibitor MLN-4760 (-7.1 kcal/mol).

These potential drugs with higher affinity for the ACE2 receptor and adequate absorption, distribution, metabolism, excretion, and toxicity (ADMET) values are candidates for treating or preventing SARS-CoV-2 infections. In vitro and in vivo investigations are needed to evaluate further the efficacy and toxicity of these hit compounds.”

https://pubmed.ncbi.nlm.nih.gov/36582392/

“Our research reveals that 6-prenylapigenin, CBN-C3, and 8-THCA are 3 compounds that have shown promising binding and drug-likeness outcomes, which should be evaluated further for pharmaceutical development research.”

https://journals.sagepub.com/doi/10.1177/11779322221145380