Introduction and Aim: Medicinal plants have shown to be effective in treatment of different stages of addiction with lower side effects, including reducing the severity of withdrawal symptoms that occur when an opioid-dependent patient stops using opioids. The current study aimed to evaluate the effective role of Mentha piperita oil on alleviating the symptoms of oxycodone withdrawal, and to elucidate the mechanisms by which it does so. Materials and Methods: Twenty-five healthy male rabbits divided into 5 groups (G1-G5) consisting of 5 rabbits each. The groups were divided as follows: G1-Control Group: G2-Oxycodone: G3-Oxycodone withdrawal: G4-Oxycodone withdrawal + M. piperita: G5-Oxycodone withdrawal +M. piperita. Blood was drawn from each animal and the serum obtained was analyzed for physiological (cortisol, serotonin, dopamine, CRP and T, LH levels), antioxidant parameters (LDH, SOD, GSH and MDA) and sperm activity. Results: This study found statistically significant changes in most variables. G2 rabbits had higher serotonin and dopamine levels, higher body weight, and lower cortisol and CRP levels than the healthy control group G1. Sperm activity, efficacy, testosterone, luteinizing hormone, superoxide dismutase, glutathione, and malondialdehyde did not alter across generations (G2 and G1). Group 3 showed that oxycodone withdrawal negatively affected dopamine, testosterone, LH, SOD, GSH, and sperm activity with weight, compared to Groups 1 and 2. Without therapy, rabbits in G3 with fast withdrawal had considerably higher cortisol, CRP, LDH, and MDA than G2 and G1. Serotonin level decreased in G3 compared with G1 and G2. An improvement in most of the studied variables, stress factors and antioxidants, as well as fertility indicators in the G4 and G5 improved gradually depending on period of treatment with M. piperita. Conclusion: M. piperita being rich in antioxidants can be adopted as one of the natural plant-based compound in patients undergoing oxycodone addiction withdrawal.
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