Adolescent Cannabinoid Exposure Produced Schizophrenia-Like Behavior Across 359 Animal Experiments

Across 359 experiments from 108 articles, CB1 receptor agonists (both natural and synthetic cannabinoids) during adolescence impaired working memory (g=-0.56), novel object recognition (g=-0.66), novel object location recognition (g=-0.70), social novelty preference (g=-0.52), social motivation (g=-0.21), pre-pulse inhibition (g=-0.43), and sucrose preference (g=-0.87). Effects were similar across sexes and species. Locomotion effects were negligible.

Pre-registered systematic review and meta-analysis (CRD42022338761) searching four databases through May 2024. Included studies on schizophrenia-like behavior in rats and mice after repeated cannabinoid exposure during the peri-pubertal period (postnatal day 23-45). Risk of bias assessed using SYRCLE tool.

This is the first meta-analysis to comprehensively test whether epidemiological links between adolescent cannabis use and schizophrenia are supported by controlled animal experiments. The consistent findings across hundreds of experiments strengthen the biological plausibility of this association.

Epidemiological studies have long linked adolescent cannabis use to increased schizophrenia risk, but critics note that observational data cannot prove causation. This meta-analysis of controlled animal experiments provides the experimental evidence that was missing from the debate.

Animal models cannot fully replicate human schizophrenia. Substantial protocol variability and moderate-to-high heterogeneity across studies. Synthetic cannabinoids used in many studies may not reflect typical cannabis exposure. CBD may have different effects (limited data suggested enhanced fear memory recall).