Potential role of CB2 receptors in Cannabis smokers with chronic hepatitis C
Authors: Robert F. Schwabe, Soeren V. Siegmund
Journal: Hepatology (2005)

We read with great interest the recent study by Hezode et al.1 on the effects of daily cannabis smoking on fibrogenesis in chronic hepatitis C, and we completely agree with the authors that patients with chronic hepatitis C should abstain from using cannabis based on the results of this study. In previous studies the authors have shown an upregulation of CB1 receptor expression in liver with fibrosis.2 Based on these results, Hezode et al. proposed that cannabis ingredients act through CB1 receptors to enhance hepatic fibrogenesis in patients with chronic hepatitis C, and they discussed CB1 receptor antagonists as potential treatment options for liver fibrosis. We suggest CB2-mediated immunomodulation as an alternative mechanism by which cannabis ingredients might enhance fibrogenesis in this specific set of patients. There is overwhelming evidence that Cannabis sativa, including the most active ingredient Δ-9-tetrahydrocannibol (THC) exerts powerful immunosuppressive effects.3, 4 In addition, we found an upregulation of hepatic CB2 receptor but not CB1 receptor expression in a mouse model of CCl4-induced hepatic fibrosis (Fig. 1). The immunosuppressive effects of THC are mediated through CB2 receptors, which are predominantly expressed on cells of the immune system.5 Cannabidiol and THC have been shown to reduce interferon γ and tumor necrosis factor α expression and have high therapeutic efficacy in mouse models of arthritis and artherosclerosis due to their anti-inflammatory properties.3, 6, 7 It is not unlikely that the immunomodulatory effects of cannabis ingredients affect disease progression and fibrogenesis in chronic hepatitis C by suppressing antiviral immunity. Suppressed cellular and humoral immunity are known to enhance disease progression in chronic hepatitis C infection, as seen in patients with hypogammaglobulinemia, HIV coinfection, or after pharmacological immunosuppression.8 Expression of CB1 and CB2 receptors in liver with fibrosis. C57/Bl6 mice underwent biweekly injection with CCl4 (n = 6, 0.5 μL/g body weight, dissolved in equal volume of mineral oil) or mineral oil (n = 4, 0.5 μL/g body weight) for 4 weeks. Hepatic mRNA levels of CB1 and CB2 receptor and collagen α1(I) were determined by quantitative real time PCR and normalized to 18S levels. We suggest an analysis of the influence of cannabis smoking in patients with other causes of hepatic fibrosis in future studies to determine whether cannabis has a direct influence on fibrogenesis independent of its potential effects on antiviral immunity. If the CB2-mediated immunomodulatory effects of cannabis ingredients predominate, hepatic fibrogenesis should be unchanged or even less severe in cannabis smokers with nonviral causes of hepatic fibrosis. Conversely, if effects of cannabis ingredients are not mediated by CB2-dependent immunomodulation, cannabis smokers with nonviral causes of hepatic fibrosis are also likely to have a more rapid progression of fibrosis. The dissection of mechanisms by which cannabis regulates hepatic inflammation, antiviral immunity, and fibrogenesis will not only help our understanding of lifestyle factors that promote hepatic fibrogenesis, but may also be useful for the development of novel antifibrogenic therapies that target the endocannabinoid system. Robert F. Schwabe M.D.*, Soeren V. Siegmund M.D.*, * Columbia University School of Medicine, New York, NY.