Objective This work was aimed at investigating the intervention effects of cannabidiol (CBD) on the monoamine neurotransmitter in a rat model of methamphetamine ( METH) dependence, and we revealed the potential mechanism underlying the therapeutic effects of CBD. Our research will benefit the treatment of drug dependence in humans. Methods We constructed an animal model based on METH ( 2 mg / kg) exposure and the conditioned place preference procedure. We dissected the nucleus accumbens (NAc), frontal cortex(FC), ventral tegmental area (VTA),caudate putamen(CPu), and hippocampus(Hip). The dopamine, 5-hydroxytryptamine, and norepinephrine contents were separated using high-performance liquid chromatography and quantified with mass spectrometry. Results Repeated METH (2 mg / kg) exposure significantly increased dopamine content and decreased 5-hydroxytryptamine content in the NAc, frontal cortex, VTA, caudate putamen, and hippocampus but increased norepinephrine content in the NAc and VTA of rats. Pretreatment of rats with CBD (10, 20, 40, 80 mg / kg) dose-dependently reduced the impact of METH on these monoamine neurotransmitters. Conclusions CBD may attenuate the reward effect of METH by maintaining the homeostasis of monoamine neurotransmitters in the reward-related brain regions of rats.