Introduction: Some cannabinoids have been identified as anti-inflammatory agents; however, their potential therapeutic or prophylactic applications remain controversial. The aim of this systematic review was to provide a timely and comprehensive insight into cannabinoid-mediated pro- and anti-inflammatory cytokine responses in preclinical in vivo studies. Methods and Materials: A systematic search was conducted using PubMed, Web of Science, EMBASE, and Scopus. Eligible studies where cannabinoids had been evaluated for their effect on inflammation in animal models were included in the analysis. Data were extracted from 26 of 4247 eligible full text articles, and risk of bias was assessed using the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) tool. Studies examined cannabidiol (CBD; n=20); cannabigerol (CBG; n=1); delta 9-tetrahydrocannabinol (THC; n=2); THC and CBD separately (n=1); and THC and CBD in combination (n=2). Results: Tumor necrosis factor alpha, interleukin (IL)-1β, IL-6, and interferon gamma were the most commonly studied pro-inflammatory cytokines and their levels were consistently reduced after treatment with CBD, CBG, or CBD+THC, but not with THC alone. The association between cannabinoid-induced anti-inflammatory response and disease severity was examined. In 22 studies where CBD, CBG, or CBD in combination with THC were administered, a reduction in the levels of at least one inflammatory cytokine was observed, and in 24 studies, some improvements in disease or disability were apparent. THC alone did not reduce pro-inflammatory cytokine levels (n=3), but resulted in improvements in neuropathic pain in one study. Conclusions: This review shows that CBD, CBG, and CBD+THC combination exert a predominantly anti-inflammatory effect in vivo, whereas THC alone does not reduce pro-inflammatory or increase anti-inflammatory cytokines. It is anticipated that this information could be used to inform human clinical trials of cannabinoids, focusing on CBD and CBG to reduce inflammation across a range of pathophysiological processes.
Keywords: CBD; THC; anti-inflammatory; cannabinoids; cannabis; cytokines; inflammation; systematic review.
Single-cell suspension was prepared from lung tissues. In brief, tissue samples were sieved through a 100 μM cell strainer (BD Biosciences, San Diego, CA, USA), followed by centrifugation (252 g, 10 min) to prepare single-cell suspensions. All cells were then stained with fluorescent antibodies to quantify neutrophils, macrophages, lymphocytes, and cytokine expression.
3 Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
In patients with severe COVID-19, the transition to ARDS is mainly due to the occurrence of cytokine storm and excessive inflammatory responses, including massive production of proinflammatory cytokines such as interleukin (IL)-6 and IL-1β, IL-17, as well as infiltration of neutrophils and monocytes into the lung tissue. 3–5 Currently, other than supportive measures, there is no definitive cure for ARDS, 6,7 illustrating the urgent need for creative and effective therapeutic modalities to treat this complex condition.
Animal model and application of Poly(I:C) and CBD
7 Department of Neurology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
Acute respiratory distress syndrome (ARDS) is a serious inflammatory lung condition responsible for the highest rate of medical complications and mortality among critically ill patients. 1 In the case of viral respiratory infections, symptoms are usually mild, self-limiting, and confined to the upper airways. However, in more severe respiratory viral infections, such as the current COVID-19 pandemic, the infection can affect the bronchoalveolar units of lower respiratory tracks, causing ARDS. There is increased pulmonary vascular permeability, alveolar infiltrates, hypoxemia, abnormal coagulation and fibrinolysis, and endothelial and epithelial damages. 2,3
1 Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia, USA.
Wild-type C57BL/6 mice (male, 12 weeks old) were divided into three experimental groups of sham, control, and treatment (n=5). All animals were housed in pathogen-free conditions at the animal facility of the Augusta University, and all experiments were performed in accordance with the rules and regulations of the Augusta University Institutional Animal Care and Use Committee (IACUC). All mice were anesthetized with isoflurane. Sham group received phosphate-buffered saline (PBS) while control and treatment groups were administered Poly(I:C) (Sigma Aldrich, St. Louis, MO, USA) (100 μg in 50 μL sterile PBS) intranasally (I/N) three once-daily doses.
Numerous studies report that cannabinoids may function as immune modulators, limiting the adverse effects of inflammatory diseases. 8 Endocannabinoids are produced in the respiratory system and cannabinoids-induced bronchial dilation suggests a significant therapeutic potential for cannabinoids in the treatment of respiratory diseases, including ARDS in case of patients with severe form of COVID-19. 9 Importantly, several reports demonstrated that cannabidiol (CBD), a phytocannabinoid produced by the cannabis plant, can block IL-6 in several models of inflammatory diseases. 9 Therefore, it is very reasonable to investigate whether cannabinoids can be as therapeutic agents to treat severe viral respiratory infections including current COVID-19 and ARDS symptoms.