Esmaeil Imani-Almas
1,2,3, Maryam Azarfarin
4,2, Nayer Seyfizadeh
2, Hanieh Salehi-Pourmehr
5, Sara Salatin
5,2* 
, Samin Hamidi
1 Department of Neuroscience, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
2 Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
4 Resuscitation and Critical Care Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
5 Research Center for Evidence-Based Medicine, Iranian EBM Centre: A JBI Centre of Excellence, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
6 Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
Abstract
Purpose: Cannabinoids (CBs) have been shown to exert anti-inflammatory effects in Ischemic stroke (IS). This study aimed to systematically review preclinical studies exploring the anti-inflammatory capabilities of CBs in IS. Methods: A comprehensive literature search was conducted across major databases (PubMed, EMBASE, Web of Science, Scopus, Google Scholar) for studies published up to February 2025. The search strategy employed combinations of terms for IS ("stroke," "cerebrovascular accident," "cerebral ischemia"), inflammation ("inflammation," "inflammatory response," "cytokine"), and cannabinoids ("cannabinoid," "cannabidiol," "CB1," "CB2") using Boolean operators. Primary outcomes were changes in inflammatory marker expression; secondary outcomes included infarct volume, neurological function, and histopathological outcomes. The inclusion criteria focused on preclinical studies reporting the effects of CB compounds on inflammation in rodent models of IS. Results: The initial search identified 1326 studies. Following the removal of duplicates, 870 studies proceeded to the screening phase. Based on the title and abstract review, 826 studies were excluded. The full texts of 44 articles were then reviewed for eligibility, resulting in the exclusion of 16 studies for specific reasons. Ultimately, 28 studies met the inclusion criteria and were incorporated into the review. Available animal studies demonstrated anti-inflammatory action of CBs, often linked to the modulation of pro-inflammatory cytokines within the ischemic brain environment. Conclusion: While preclinical data support the anti-inflammatory potential of CBs in IS, their translation to clinical practice remains limited. Key challenges include concerns over potential psychoactive side effects and significant uncertainty regarding optimal dosing strategies. Further research, specifically well-controlled clinical trials, is essential to establish the safety, efficacy, and therapeutic windows of CB-based interventions for IS.