cannabidiol and Liver-Diseases

Endocannabinoids are lipid mediators of the same cannabinoid (CB) receptors that mediate the effects of marijuana. The endocannabinoid system (ECS) consists of CB receptors, endocannabinoids, and the enzymes involved in their biosynthesis and degradation, and it is present in both brain and peripheral tissues, including the liver. The hepatic ECS is activated in various liver diseases and contributes to the underlying pathologies. In patients with cirrhosis of various etiologies, the activation of vascular and cardiac CB(1) receptors by macrophage-derived and platelet-derived endocannabinoids contributes to the vasodilated state and cardiomyopathy, which can be reversed by CB(1) blockade. In mouse models of liver fibrosis, the activation of CB(1) receptors on hepatic stellate cells is fibrogenic, and CB(1) blockade slows the progression of fibrosis. Fatty liver induced by a high-fat diet or chronic alcohol feeding depends on the activation of peripheral receptors, including hepatic CB(1) receptors, which also contribute to insulin resistance and dyslipidemias. Although the documented therapeutic potential of CB(1) blockade is limited by neuropsychiatric side effects, these may be mitigated by using novel, peripherally restricted CB(1) antagonists.

Topics: Animals; Cannabidiol; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Endocannabinoids; Fatty Liver; Fatty Liver, Alcoholic; Hepatic Encephalopathy; Hepatitis, Autoimmune; Humans; Liver Cirrhosis; Liver Diseases; Metabolic Syndrome; Mice; Receptor, Cannabinoid, CB1; Receptors, Cannabinoid; Reperfusion Injury

The pharmacokinetics and safety of a single oral dose of 200-mg plant-derived pharmaceutical formulation of highly purified cannabidiol (CBD) in oral solution (Epidiolex in the United States; 100 mg/mL) were assessed in subjects with mild to severe hepatic impairment (n =  8 each for mild and moderate, n = 6 for severe) relative to matched subjects with normal hepatic function (n = 8). Blood samples were collected until 48 hours after dosing and evaluated by liquid chromatography and tandem mass spectrometry. Pharmacokinetic parameters (primarily maximum measured plasma concentration, area under the plasma concentration-time curve from time zero to time t, area under the concentration-time curve from time zero to infinity, time to maximum plasma concentration, and terminal half-life) of CBD and its major metabolites were derived using non-compartmental analysis. CBD was rapidly absorbed in all groups independent of hepatic function (median time to maximum plasma concentration, 2-2.8 hours). Exposure (area under the concentration-time curve from time zero to infinity) to total CBD slightly increased in subjects with mild hepatic impairment (geometric mean ratio [GMR], 1.48; 90% confidence interval [CI], 0.90-2.41). However, there were clinically relevant increases in subjects with moderate (GMR, 2.45; 90%CI, 1.50-4.01) and severe (GMR, 5.15; 90%CI, 2.94-9.00) hepatic impairment, relative to subjects with normal hepatic function. Exposure to the CBD metabolites (6-hydroxy-CBD and 7-hydroxy-CBD) also increased in subjects with moderate and severe hepatic impairment, but to a lesser extent than the parent drug. The 7-carboxy-CBD metabolite exposure was lower in subjects with severe hepatic impairment when compared with subjects with normal liver function. These findings indicate that dose modification is necessary in patients with moderate and severe hepatic impairment, and a lower starting dose and slower titration are necessary based on benefit-risk. CBD was well tolerated, and there were no serious adverse events reported during the trial.

Topics: Adult; Aged; Cannabidiol; Female; Humans; Liver; Liver Diseases; Male; Middle Aged

The endocannabinoid system in mice plays a role in models of human cirrhosis and hepatic encephalopathy (HE), induced by a hepatotoxin. We report now the therapeutic effects of cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa, on HE caused by bile duct ligation (BDL), a model of chronic liver disease.. CBD (5mg/kg; i.p.) was administered over 4weeks to mice that had undergone BDL.. Cognitive function in the eight arm maze and the T-maze tests, as well as locomotor function in the open field test were impaired by the ligation and were improved by CBD. BDL raised hippocampal expression of the TNF-alpha-receptor 1 gene, which was reduced by CBD. However, BDL reduced expression of the brain-derived neurotrophic factor (BDNF) gene, which was increased by CBD. The effects of CBD on cognition, locomotion and on TNF-alpha receptor 1 expression were blocked by ZM241385, an A(2)A adenosine receptor antagonist. BDL lowers the expression of this receptor.. The effects of BDL apparently result in part from down-regulation of A(2)A adenosine receptor. CBD reverses these effects through activation of this receptor, leading to compensation of the ligation effect.

Topics: Adenosine A2 Receptor Antagonists; Animals; Bile Ducts; Brain-Derived Neurotrophic Factor; Cannabidiol; Chronic Disease; Cognition; Cognition Disorders; Cyclooxygenase 2; Disease Models, Animal; Female; Gait Disorders, Neurologic; Hepatic Encephalopathy; Ligation; Liver Diseases; Mice; Mice, Inbred Strains; Motor Activity; Receptor, Adenosine A2A; Receptors, Tumor Necrosis Factor, Type I; RNA, Messenger; Treatment Outcome; Triazines; Triazoles