AbstractThere is strong biochemical, pharmacological and genetic evidence for the involvement of the endocannabinoid system (ECS) in alcohol dependence. However, the majority of studies have been performed in animal models. The aim of the present study was to assess the state of theCB1receptor, the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and the extracellular signal‐regulated kinase (ERK) and cyclic‐AMPresponse element‐binding protein (CREB) in the post‐mortem prefrontal cortex of alcoholic subjects. Experiments were performed in samples from 44 subjects classified in four experimental groups: (1) non‐suicidal alcoholic subjects (n = 11); (2) suicidal alcoholic subjects (n = 11); (3) non‐alcoholic suicide victims (n = 11); and (4) control subjects (n = 11). We did not observe statistically significant differences inCB1mRNArelative expression among the four experimental groups. Conversely, our results showed an increase inCB1receptor protein expression in the prefrontal cortex of the suicidal alcoholic group (127.2 ± 7.3%), with no changes in functionality with regard to either G protein activation or the inhibition of adenylyl cyclase. In parallel, alcoholic subjects presented lower levels ofMAGLactivity, regardless of the cause of death. A significant decrease in the active form ofERKandCREBlevels was also observed in both alcoholic groups. Taken together, our data are consistent with a role for theECSin the neurobiological mechanisms underlying alcoholism. Moreover, the alterations reported here should be of great interest for the therapeutic treatment of this chronic psychiatric disease.