Systematic review and meta-analysis on the effects of chronic peri-adolescent cannabinoid exposure on schizophrenia-like behaviour in rodents

Abstract

Abstract Background The link between cannabis use and schizophrenia is well-established in epidemiological studies, especially among adolescents with early-onset use. However, this association in rodent models is less clear. This meta-analysis examined the effects of adolescent cannabinoid exposure on distinct schizophrenia-like behaviours in rodents and how experimental variations influence outcomes. Methods Following a pre-registered protocol (CRD42022338761), we searched PubMed, Ovid Medline, Embse and APA PsychInfo for English-language original studies until May 2024. We synthesised data from experiments on schizophrenia-like behaviour in rats and mice after repeated peri-pubertal (onset between P23-P45) cannabinoid exposure. Risk of bias was assessed using the SYRCLE’s tool. Results We included 359 experiments from 108 articles across 9 behavioural tests. We found meta-analytic evidence supporting that CB1R agonists, both natural and synthetic, elicited broad schizophrenia-like behavioural alterations, including impaired working memory [g  = −0.56; (CI: −0.93, −0.18)], novel object recognition [g = −0.66; (CI: −0.97, −0.35)], novel object location recognition [g = −0.70; (CI: −1.07, −0.33]), social novelty preference [g = −0.52; (CI: −0.93, −0.11)], social motivation [g = −0.21; (CI: −0.42, −0.00)], pre-pulse inhibition [g = −0.43; (CI: −0.76, −0.10)], and sucrose preference [g = −0.87; (CI: −1.46, −0.27)]. By contrast, effects on novelty-induced locomotion were negligible. Subgroup analyses revealed similar effects across sexes and species. Substantial variance in the protocols and moderate-to-high heterogeneity in behavioural outcomes were observed. We found CBD may enhance fear memory recall, but data was limited. Discussion This is the first meta-analysis to comprehensively assess the link between cannabinoids and schizophrenia-like behaviours in rodents. Our results support epidemiological links between early cannabis use and schizophrenia-like phenotypes, confirming the utility of animal models. Standardising protocols will optimise models to strengthen reproducibility and comparisons, our work provides a framework for refining rodent models to elucidate biological pathways linking cannabis and schizophrenia.