Methamphetamine (METH) exposure reportedly promotes microglial activation and pro-inflammatory cytokines secretion . Sustained inflammation in abusers of psychostimulant drugs further induces neural damage . Cholecystokinin-8 (CCK-8) is a gut-brain peptide which exerts a wide range of biological activities in the gastrointestinal tract and central nervous system . We previously found that pre-treatment with CCK-8 inhibited behavioural and histologic changes typically induced by repeated exposure to METH . Here, we aimed to estimate the effects of CCK-8 on METH-induced neuro-inflammation, which is markedly characterized by microglia activation and increased pro-inflammatory cytokines production in vivo and in vitro . Moreover, we assessed the subtypes of the CCK receptor mediating the regulatory effects of CCK-8, and the changes in the NF-κB signalling pathway . We found that CCK-8 inhibited METH-induced microglial activation and IL-6 and TNF-α generation in vivo and in vitro in a dose-dependent manner . Furthermore, co-treatment of CCK-8 with METH significantly attenuated the activation of the NF-κB signalling pathway by activating the CCK2 receptor subtype in N9 cells . In conclusion, our findings indicated the inhibitory effect of CCK-8 on METH-induced neuro-inflammation in vivo and in vitro, and suggested the underlying mechanism may involve the activation of the CCK2 receptor, which downregulated the NF-κB signalling pathway induced by METH stimulation.