A study of cannabinoid application in vitro showed that THC appears to accumulate primarily in neurons and that transformation to its metabolite, THC-COOH, depends on the presence of glia. The authors suggested that the adverse effects of cannabinoids on the brain may occur through a combination of pathways involving cannabinoid receptor activation, accumulation of cannabinoids and their metabolites and upregulation of neuroinflammatory cytokines. Findings of persistent alteration of brain function or cognitive impairment in human cannabis users support the notion that long-term cannabis use may result in morphological alterations of brain structures that subserve attention, learning, memory, executive functions and emotional processes. Since brain structural changes are evident in patients with schizophrenia, cannabis may exert greater adverse effects on brain morphology when the brain is already compromised. This chapter proposes that long-term heavy cannabis use leads to structural brain changes and associated deleterious functional sequelae that resemble aspects of schizophrenia.