Patterns of BDNF Dysregulation Following Cannabinoid Supplementation in Male Wistar Rats

Abstract

Background: Brain-derived neurotrophic factor (BDNF) is a critical biomarker implicated in the pathophysiology of various neurological and psychiatric disorders. This study investigated the dose- and time-dependent effects of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration on serum and hippocampal BDNF levels in male Wistar rats. Methods: A total of 75 male Wistar rats (120-140g) were divided into 3 study phases: acute (14 days), sub-chronic (28 days), and chronic (56 days). In each phase, the animals were randomly assigned to five experimental groups (n=5 per group per phase): Group 1 (control, distilled water); Group 2 (THC 5mg/kg); Group 3 (THC 15mg/kg); Group 4 (CBD 20mg/kg); and Group 5 (CBD 60mg/kg). At the end of each phase, serum and hippocampal BDNF levels were quantified and compared across treatment groups and time points. Results: In serum, both THC and CBD produced significant (p<0.05) BDNF reductions compared to controls across all phases. THC-treated groups exhibited the most pronounced suppression, with levels significantly lower than those of CBD-treated groups. Notably, hippocampal BDNF displayed divergent, dose-dependent responses: while high-dose THC (15mg/kg) consistently reduced hippocampal BDNF, CBD at 20mg/kg maintained levels comparable to controls during acute and sub-chronic phases, with suppression only emerging after chronic administration. The higher CBD dose (60mg/kg) resulted in significant hippocampal BDNF reduction from the acute phase onward, mirroring THC effects. Conclusion: Chronic administration of both cannabinoids is associated with significant BDNF downregulation in a dose- and tissue-specific manner, with THC demonstrating consistently greater suppressive effects. These findings suggest that prolonged cannabinoid exposure, particularly at higher doses, may indicate altered neurotrophic regulation associated with prolonged cannabinoid exposure. Chronic high-dose THC and CBD exposure reduce BDNF in a dose‑ and tissue-specific manner, with CBD showing limited neuroprotective potential at moderate doses.