Recent Advances in the Therapeutic Potential of Cannabinoids Against Gliomas: A Systematic Review (2022-2025)

Glioma is the most common and lethal primary brain tumor in adults, with glioblastoma (GBM) representing the most aggressive subtype, characterized by diffuse infiltration, resistance to therapy, and a poor prognosis. Despite standard treatments, survival remains only approximately 14 months. Cannabinoids have been increasingly investigated for their therapeutic potential in gliomas, particularly GBM. Although multiple reviews on this field of research have been published, most are current only up to 2022. This systematic review aims to provide an updated summary of studies published between 2022 and 2025, capturing recent developments in anti-glioma mechanisms, combinational strategies, immune modulation, and novel therapeutic platforms. Following PRISMA guidelines, PubMed, Scopus, ScienceDirect, and SpringerLink were searched for original English-language journal articles published between January 2022 and February 2025, using search terms related to cannabinoids and brain cancer. From 1031 records, 45 original research articles were included after removing duplicates, non-primary studies, and irrelevant topics. The studies were categorized into seven thematic domains based on content. Recent studies have elaborated on the anti-cancer mechanisms of cannabinoids beyond endocannabinoid signaling via the CB₁/CB₂ receptor, including ferroptosis induction, mitochondrial dysfunction, integrated stress response activation, and epigenetic modulation. Synthetic cannabinoids and their analogs demonstrated enhanced blood-brain barrier penetration and cytotoxicity in glioma models. Cannabinoids have been shown to modulate immune responses in glioma, influencing T cell infiltration, myeloid suppressor cell recruitment, and tumor-associated macrophage function. Novel formulation and delivery strategies have improved cannabinoid solubility, stability, and tumor targeting. Combination therapies, particularly cannabidiol with temozolomide or radiotherapy, exhibited additive or synergistic anti-tumor effects, although variability between glioma subtypes suggests the need for personalized approaches. Although cannabinoid-based glioma research has expanded our understanding of the mechanisms, discrepancies between preclinical findings and clinical data highlight the need for rigorous clinical trials and mechanistic research before cannabinoid-based treatments can be reliably integrated into standard glioma care.