Cyclodextrins as a suitable carrier for the induction of feeding and analgesia by Delta-9 THC: a preclinical study in the female rat

Achieving consistent and effective oral delivery of Δ⁹-tetrahydrocannabinol (THC) remains challenging due to the compound’s low aqueous solubility, extensive first-pass metabolism, and variable pharmacokinetics. This research explores whether complexing THC with hydroxypropyl-β-cyclodextrin (HP-β-CD) can overcome these limitations and improve the drug’s therapeutic potential. Using female Wistar rats, we administered THC–HP-β-CD orally at multiple doses (0.3, 1, and 3 mg/kg) under acute (single-administration) and chronic (15-day) regimens. Behavioral assessments included tail-flick latency (analgesia), locomotor activity, and feeding behavior. Neurochemical analyses quantified dopamine (DA) levels in pain- and reward-related brain regions (periaqueductal gray, ventral tegmental area, nucleus accumbens, and prefrontal cortex). Additionally, hepatic concentrations of THC, its principal metabolites (11-OH-THC and 11-COOH-THC), and fatty acid metabolic markers were measured to evaluate bioavailability and metabolic effects. The results demonstrate that HP-β-CD formulation significantly enhanced THC’s oral pharmacological profile. Acute dosing with 3 mg/kg produced robust antinociceptive effects, evidenced by increased tail-flick latency, whereas chronic treatment revealed only mild tolerance, with analgesic efficacy sustained over 15 days. Regarding feeding behavior, low-dose (0.3 mg/kg) THC–HP-β-CD transiently stimulated food intake, while higher doses suppressed appetite over time and led to weight loss. Neurochemical data showed that chronic THC–HP-β-CD administration selectively increased DA levels in the ventral tegmental area, aligning with its role in reward and motivational pathways, whereas only the periaqueductal gray exhibited elevated DA following acute treatment—consistent with enhanced pain modulation. Metabolic profiling indicated improved THC absorption and biotransformation, marked by higher levels of THC metabolites in liver tissue, and dose-related shifts in endogenous fatty acids and endocannabinoid-related molecules. Overall, this thesis work substantiates the effectiveness of HP-β-CD as a carrier for oral THC, offering improved bioavailability and consistent therapeutic outcomes. The findings offer a strong foundation for future investigations into cyclodextrin-based cannabinoid formulations, with potential applications in pain management and appetite modulation.