The neuro-metabolic epidemic and the CB1R paradox

Obesity, metabolic syndrome, and neurodegenerative diseases are rising together, posing a public health issue. Alzheimer's disease, often referred to as "type-3 diabetes," shows how metabolic dysfunction can drive cognitive decline through disrupting brain insulin signaling, glucose metabolism, and causing inflammation. The endocannabinoid system, especially the CB1 receptor, plays a key role. While CB1R physiologically regulates energy homeostasis, chronic overnutrition leads to its pathological overactivation. Although CB1R antagonists showed strong efficacy in animal and early clinical studies, their development was halted due to neuropsychiatric side effects, underscoring an incomplete understanding of CB1R signaling across tissues and subcellular compartments. Incretin hormones, including GLP-1 and GIP, have emerged as key mediators linking metabolic control and brain health, exerting neuroprotective effects beyond glycemic regulation. Both the CB1R and incretin signaling converge on cyclic AMP pathways, suggesting that combined therapeutic strategies could improve metabolic and cognitive outcomes. Finding CB1R in mitochondria has changed our understanding, showing that cannabinoids can directly affect how cells produce energy by slowing complex I activity and interfering with how astrocytes and neurons share energy. This suggests that neuro-metabolic diseases are mainly problems with cell structures, not just with receptors. This review brings together what is known about the CB1R paradox - the observation that this receptor, essential for normal energy homeostasis, becomes a pathological driver in conditions of chronic metabolic excess. We explore how incretins protect the brain, the critical role of mitochondrial CB1R, and how cell-type-specific CB1R signaling across neural and peripheral tissues drives both metabolic and cognitive pathology.