Abstract
Cannabis abuse has been linked to acute psychotic symptoms as well as to the development of schizophrenia. Although the association has been well described, causation has not yet been investigated. Therefore, we investigated whether cannabis or cannabinoid use is causal for the development of schizophrenia, conducting a systematic literature review according to the PRISM guidelines. Epidemiological studies and randomized clinical trials investigating the links between cannabis and psychosis-like events (PLE) and schizophrenia were identified (according to PRISM guidelines), and relevant studies were included in a Forest plot analysis. Confounder analysis was performed using a funnel plot, and the Hill causality criteria were used to estimate causation. A total of 18 studies fulfilled the search criteria; 10 studies were included in a forest plot. All studies reported an increased risk for PLE or schizophrenia, and nine of the ten studies, a significant increase; the overall OR was calculated to be 2.88 (CI 2.24 to 3.70), with a twofold-higher risk calculated for cannabis use during adolescence. Confounder effects were indicated by a funnel plot. The Hill criteria indicated a high likelihood for the contribution of cannabis to schizophrenia development. Cannabinoids likely contribute to chronic psychotic events and schizophrenia, especially if taken during adolescence. This effect likely increases with a high cannabis THC concentration and increased frequency of cannabis use, and is stronger in males than in females. This points to the possibility of a selective cannabis toxicity on synaptic plasticity in adolescence, as compared to adult cannabis use. Cannabis use should be regulated and discouraged, and prevention efforts should be strengthened, especially with reference to adolescence.