Background/Objectives: Diabetes mellitus is a growing global health concern, driving the exploration of new therapies like cannabidiol (CBD), which shows potential in improving insulin sensitivity and glycemic control, though its effects on glucose metabolism remain unclear. This study evaluates CBD’s dose-dependent effects on glycemia, insulin, and hepatic carbohydrate metabolism in diabetic rats. Methods: The Oral Glucose Tolerance Test (OGTT) was performed in healthy rats to compare intragastric vs. intraperitoneal CBD (0.5, 5, 50 mg/kg). Diabetic rats were treated with intragastric CBD (25, 50, 100 mg/kg) or metformin (70 mg/kg) for 8 days. Blood glucose, insulin, lipid profiles, and key carbohydrate-metabolizing enzymes were analyzed. Results: In the OGTT, intragastric CBD reduced glycemic AUC, with 50 mg/kg showing the strongest effect, while intraperitoneal CBD had no impact. In diabetic rats, metformin and 25 mg/kg CBD lowered blood glucose, but only CBD increased insulin. The 50 mg/kg dose caused the greatest glucose reduction and moderate insulin rise, while 100 mg/kg had no effect. At 25 mg/kg, CBD inhibited glucose-6-phosphatase and increased glucose-6-phosphate. The 50 mg/kg dose further suppressed gluconeogenic enzymes, reduced glycogen phosphorylase and liver glucose, and enhanced glucose-6-phosphate, showing the strongest metabolic effects. The 100 mg/kg dose increased hexokinase but had weaker metabolic effects. Metformin improved glucose utilization and glycogen storage. CBD at 25 and 50 mg/kg reduced triacylglycerols and increased HDL, while 100 mg/kg had no effect. Conclusions: This study provides strong evidence of CBD’s antidiabetic potential, especially at 50 mg/kg, particularly through its modulation of glucose metabolism and tendency to regulate insulin levels.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid from Cannabis sativa, has emerged as an important compound of interest in biochemical and pharmaceutical research. Its molecular activity is closely linked to the endocannabinoid system (ECS), which plays a central role in the regulation of metabolic homeostasis. Dysregulation of the ECS has been associated with insulin resistance, lipid imbalance, obesity, and increased cardiovascular risk. This review summarizes the current biochemical evidence on the mechanisms by which CBD modulates metabolic pathways through interactions with cannabinoid receptors and related molecular targets. Special emphasis is placed on the antioxidant and anti-inflammatory properties of CBD, its capacity to influence mitochondrial function, and its impact on glucose and lipid metabolism. Furthermore, this review discusses the influence of physicochemical factors, such as bioavailability and route of administration, on the pharmacokinetic and pharmacodynamic behavior of CBD. Potential interactions with other biomolecules and therapeutic agents are also considered, highlighting the need for systematic biochemical and pharmacological evaluation. Overall, the synthesis of the available literature indicates that CBD is a promising candidate for further biochemical and preclinical studies aimed at elucidating its regulatory role in metabolic processes and its potential for the development of novel therapeutic strategies.