Abstract
PURPOSE: Glioblastoma (GBM) remains the most common and lethal primary central nervous system tumor, with a median survival of only 14.6 months under standard care. The tumor’s characteristic "Warburg effect"—a dependency on aerobic glycolysis for energy—creates a metabolic vulnerability. This review evaluates the efficacy and safety of the ketogenic diet (KD) as an adjunctive metabolic therapy aimed at exploiting this glucose dependency. METHODS: This PRISMA-compliant systematic review updates clinical evidence by synthesizing data from databases from 2000 to September 2025. We searched PubMed, Embase, Cochrane, and Web of science for human studies assessing the ketogenic diet (KD) in glioblastoma and high-grade gliomas. Primary outcomes included overall survival (OS), progression-free survival (PFS), feasibility, and adverse events. Study quality was assessed using Joanna Briggs Institute tools. Prospero registration: CRD420251232650. RESULTS: Forty-one studies were included, ranging from randomized trials to case series and abstracts, utilizing interventions such as the classic 4:1 ketogenic diet, Modified Atkins Diet, and calorie restriction. Adherence was high (> 75% maintained nutritional ketosis). Recent data indicate significant survival benefits; adherent cohorts achieved a median OS of 29.4 months vs 14.6 months in historical controls; with 66.7% 3-year survival rate. The diet was well-tolerated, with adverse events limited to mild gastrointestinal symptoms and fatigue. No Grade 3/4 diet-related toxicities reported. CONCLUSION: Current evidence supports the KD as a safe, feasible, and biologically rational adjunct to standard glioblastoma treatment. It demonstrates potential to prolong survival without severe toxicity, highlighting the need for standardized Phase III trials to establish clinical guidelines. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10072-026-09035-y.