<p>Brain glucose metabolism, as measured by ¹⁸F-FDG PET/CT, reflects regional brain function and activity. Substance addiction has been shown to disrupt this metabolic activity, even though the affected brain regions and extent of disruption vary by substance and stage of addiction. This systematic review and meta-analysis aimed to evaluate the effects of substance use and dependence on cerebral glucose metabolism rate (CMR_glc) measured by ¹⁸F-FDG PET/CT imaging, regardless of study design or subject conditions. A systematic search was conducted following PRISMA guidelines to identify eligible human studies that used ¹⁸F-FDG PET in individuals with substance dependence. Meta-analysis was performed using a random-effects model, reporting Hedges’ <i>g</i> with 95% confidence intervals (CIs). Out of 385 records, ten studies met the inclusion criteria, covering substances such as nicotine, morphine, ethanol, methamphetamine, cocaine, and marijuana, and seven were eligible for meta-analysis. Addiction was consistently associated with hypometabolism in the prefrontal cortex, anterior cingulate cortex, and thalamus, which are areas involved in reward, cognition and emotion regulation. Meta-analysis revealed a significant reduction in CMR_glc overall (<i>g</i> = 0.92; 95% CI: − 1.27 to -0.57). Heterogeneity was moderate to high (I² = 70.43%, <i>p</i> = 0.002). Addiction leads to glucose hypometabolism in brain regions across different stages, whether during active use, withdrawal, or prolonged abstinence, regardless of the substance involved. ¹⁸F-FDG PET serves as a valuable molecular imaging tool to detect these brain changes and has great potential for monitoring recovery progress, understanding the withdrawal process, and evaluating treatment response.</p>