*Systematic*  **A Review on the Bioactivity of Cannabinoids on Zebrafish Models: Emphasis on Neurodevelopment**

**Rosario Licitra 1, Maria Marchese 1,\*, Valentina Naef 1, Asahi Ogi 1, Marco Martinelli 2, Claudia Kiferle 2, Baldassare Fronte 3 and Filippo Maria Santorelli 1,\***


**Abstract:** For centuries, the cannabis plant has been used as a source of food, fiber, and medicine. Recently, scientific interest in cannabis has increased considerably, as its bioactive compounds have shown promising potential in the treatment of numerous musculoskeletal and neurological diseases in humans. However, the mechanisms that underlie its possible effects on neurodevelopment and nervous-system functioning remain poorly understood and need to be further investigated. Although the bulk of research on cannabis and cannabinoids is based on in vitro or rodent models, the zebrafish has now emerged as a powerful in vivo model for drug-screening studies and translational research. We here review the available literature on the use of cannabis/cannabinoids in zebrafish, and particularly in zebrafish models of neurological disorders. A critical analysis suggests that zebrafish could serve as an experimental tool for testing the bioactivity of cannabinoids, and they could thus provide important insights into the safety and efficacy of different cannabis-extractbased products. The review showed that zebrafish exhibit similar behaviors to rodents following cannabinoid exposure. The authors stress the importance of analyzing the full spectrum of naturally occurring cannabinoids, rather than just the main ones, THC and CBD, and they offer some pointers on performing behavioral analysis in zebrafish.

**Keywords:** zebrafish; cannabis; cannabinoids; phytocannabinoids; Δ9-tetrahydrocannabinol; THC; cannabidiol; CBD
