Background: Nowadays, Alzheimer's Disease is the type of dementia with the highest incidence worldwide. NMDA receptor is one of the key players in this pathology, causing neurotoxicity and neuronal death after excessive stimulation. On the other hand, the cannabinoid receptor CB1 induces a neuroprotective role. In this research we aim to analyze the capacity of the CB1R to regulate and reduce NMDAR overstimulation in Alzheimer's pathology.Results: It has been demonstrated that CB1R and NMDAR colocalize and form heteromeric complexes in transfected HEK-293T cells. In the same cells, NMDAR activation blocks CB1R induced signalling and also CB1R activation blocks NMDAR induced calcium release and ERK1/2 phosphorylation. CB1R-NMDAR complexes have been detected in microglial and neuronal primary cultures where LPS and Aß pretreatments induce, respectively, an important increase in the number of heteromers. CB1R activation blocks NMDAR signaling in primary cultures of microglia and neuronal cells. CB1R-NMDAR complex expression increases in the APPSw/Ind mice model of Alzheimer’s disease.Conclussions: Cannabinoid receptors play a dual role in Alzheimer's disease. Inducing on the one hand, a neuroprotective effect and, on the other hand, decreasing the excitotoxicity caused by the activation of NMDAR.