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Background and Purpose: Psychotic disorders have been reported in long‐term users of synthetic cannabinoids. This study aims at investigating the long‐lasting effects of repeated JWH‐018 exposure. Experimental Approach: Male CD‐1 mice were injected with vehicle, JWH‐018 (6 mg·kg−1), the CB1‐antagonist NESS‐0327 (1 mg·kg−1) or co‐administration of NESS‐0327 and JWH‐018, every day for 7 days. After 15 or 16 days washout, we investigated the effects of JWH‐018 on motor function, memory, social dominance and prepulse inhibition (PPI). We also evaluated glutamate levels in dialysates from dorsal striatum, striatal dopamine content and striatal/hippocampal neuroplasticity focusing on the NMDA receptor complex and the neurotrophin BDNF. These measurements were accompanied by in vitro electrophysiological evaluations in hippocampal preparations. Finally, we investigated the density of CB1 receptors and levels of the endocannabinoid anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) and their main synthetic and degrading enzymes in the striatum and hippocampus. Key Results: The repeated treatment with JWH‐018 induced psychomotor agitation while reducing social dominance, recognition memory and PPI in mice. JWH‐018 disrupted hippocampal LTP and decreased BDNF expression, reduced the synaptic levels of NMDA receptor subunits and decreased the expression of PSD95. Repeated exposure to JWH‐018, reduced hippocampal CB1 receptor density and induced a long‐term alteration in AEA and 2‐AG levels and their degrading enzymes, FAAH and MAGL, in the striatum. Conclusion and Implications: Our findings suggest that repeated administration of a high dose of JWH‐018 leads to the manifestation of psychotic‐like symptoms accompanied by alterations in neuroplasticity and change in the endocannabinoid system. [ABSTRACT FROM AUTHOR]