Studies from preclinical animal models indicate that sustained activation of CB1 receptor signaling is a major contributing factor for the onset of cognitive deficits associated to chronic cannabis use, in particular within the working memory and decision-making domains. Yet, very few studies have been designed to directly assess the role of CB1 receptors in mediating the effects of cannabis on human brain function. This perspective review article provides an overview of current state of knowledge on possible neurobiological mechanisms accounting for the detrimental effects of chronic cannabis use on cognition and related changes in brain structure and functional connectivity. This article is part of the Special Issue entitled “A New Dawn in Cannabinoid Neurobiology”.