Introduction: The study was planned to investigate memory-enhancing, anti-inflammatory, and antiaging potential of cannabidiol (CBD) on vitamin D3 deficient diet (VDD)-induced rats.

Materials and Methods: Cytochrome P-450 enzymes were analyzed by RT-PCR method and others biomarkers by enzyme-linked immunosorbent assay.

Results:CYP2R1 and CYP27B1-mRNA were significantly increased by 39.29 and 38.37%, respectively, while; CYP24A1-mRNA was significantly reduced by 21.39% compared to VDD. Vitamin D3 receptor protein expression was significantly increased by 148.3%, 60.48%, and 142.03% in liver, kidney, and brain, respectively, compared to VDD group. Vitamin D3 metabolites and serotonin were significantly increased more than 60% and 100%, respectively, compared to VDD. Spatial memory (in terms of total distance, escape latency) and pain score were improved compared to VDD. Cytokines were significantly reduced than VDD. Besides, levels of superoxide dismutase (49.61%), glutathione peroxidase (178.87%), acetylcholine (25.40%), and klotho (145.57%) were significantly increased than VDD.

Conclusions: Study findings supported that CBD interacts with CYP2R1, CYP27B1, CYP24A1, and vitamin D receptors, resulting in increased vitamin D3 metabolites, which improved memory, pain tolerance, reduced inflammation, and aging through modulating antioxidative enzymes, cytokines, and neurotransmitters in VDD-induced rats.