BACKGROUND AND PURPOSE Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non‐psychoactive constituent of Cannabis sativa with anti‐inflammatory properties that activates the 5‐hydroxytryptamine receptor 5‐HT_1A, on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide.

EXPERIMENTAL APPROACH Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5‐HT levels were measured 12 days after induction of hepatic failure.

KEY RESULTS Neurological and cognitive functions were severely impaired in thioacetamide‐treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide‐treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5‐HT levels in thioacetamide‐treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide‐treated mice was moderated after cannabidiol treatment.

CONCLUSIONS AND IMPLICATIONS Cannabidiol restores liver function, normalizes 5‐HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain.