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Although considered as an illicit drug in most countries, <jats:italic>C. sativa<\/jats:italic> until recently started gaining attention for its medicinal application. This study sought to investigate the hepatoprotective effect of <jats:italic>C. sativa<\/jats:italic> on iron-mediated oxidative hepatic injury. Hepatic injury was induced <jats:italic>ex vivo<\/jats:italic> by incubating hepatic tissues with Fe<jats:sup>2+<\/jats:sup>, which led to depleted levels of reduced glutathione, superoxide dismutase, catalase and ENTPDase activities, triglyceride, and high-density lipoprotein\u2013cholesterol (HDL-C). Induction of hepatic injury also caused significant elevation of malondialdehyde, nitric oxide, cholesterol, and low-density lipoprotein\u2013cholesterol (LDL-C) levels while concomitantly elevating the activities of ATPase, glycogen phosphorylase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, amylase, and lipase. Treatment with the hexane, dichloromethane (DCM), and ethanol extracts of <jats:italic>C. sativa<\/jats:italic> leaves significantly (<jats:italic>p<\/jats:italic> &amp;lt; 0.05) reversed these levels and activities to almost near normal. However, there was no significant effect on the HDL-C level. The extracts also improved the utilization of glucose in Chang liver cells. High-performance liquid chromatography (HPLC) analysis showed the presence of phenolics in all extracts, with the ethanol extract having the highest constituents. Cannabidiol (CBD) was identified in all the extracts, while \u0394-9-tetrahydrocannabinol (\u0394-9-THC) was identified in the hexane and DCM extracts only. Molecular docking studies revealed strong interactions between CBD and \u0394-9-THC with the <jats:italic>\u03b2<\/jats:italic>2 adrenergic receptor of the adrenergic system. The results demonstrate the potential of <jats:italic>C. sativa<\/jats:italic> to protect against oxidative-mediated hepatic injury by stalling oxidative stress, gluconeogenesis, and hepatic lipid accumulation while modulating cholinergic and purinergic activities. These activities may be associated with the synergistic effect of the compounds identified and possible interactions with the adrenergic system.<\/jats:p>","DOI":"10.3389\/fphar.2021.705402","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T06:06:36Z","timestamp":1640066796000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Cannabis sativa L. 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