The Effects of Cannabinoids on Pro- and Anti-Inflammatory Cytokines: A Systematic Review of In Vivo Studies

Abstract

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.

FIG. 1.

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram showing data extraction process.

FIG. 2.

Risk of bias assessment for each study (rows) and each item (columns) of the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) risk of bias tool.

FIG. 3.

Change in inflammatory cytokine levels from included studies are summarized in the bubble plot together with the cannabinoids assessed. The bubble plot is depicted in four quadrants: decreasing levels of pro-inflammatory cytokines (top left), increasing levels of pro-inflammatory cytokines (top right), decreasing levels of anti-inflammatory cytokines (bottom left), and increasing levels of anti-inflammatory cytokines (bottom right). Percentages were calculated based on the number of studies showing the observed change in the specific cytokine levels for a particular cannabinoid, divided by the total number of studies for that specific cytokine (some studies may be calculated twice to reflect treatment with different cannabinoids used in a single study). *Differing results for the effects of CBD on TNF-α within a single study. CBD, cannabidiol; CBG, cannabigerol; IL, interleukin; THC, delta 9-tetrahydrocannabinol; TNF-α, tumor necrosis factor alpha.