From Synaptic Plasticity to Neurotoxicity: Endocannabinoid Influence on Addiction and Neurodegeneration

The endocannabinoid system (eCBS) is a versatile neuromodulatory network that orchestrates synaptic plasticity, reward processing, and neuronal homeostasis. Increasing evidence implicates eCBS dysregulation in both addiction and neurodegenerative (ND) disorders, suggesting overlapping molecular and cellular mechanisms that underlie these conditions. This review synthesizes current advances in understanding how eCBS components—cannabinoid receptors (CB1 and CB2), endogenous ligands (anandamide and 2-arachidonoylglycerol), and their metabolic enzymes—modulate dopaminergic and glutamatergic signaling within reward and reinforcement circuits. Chronic exposure to drugs of abuse, including alcohol, cocaine, and methamphetamine, perturbs eCBS homeostasis, promoting oxidative stress, neuroinflammation, excitotoxicity, and protein aggregation—pathological features common to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Experimental studies demonstrate that pharmacological or genetic manipulation of eCBS components can mitigate neurotoxic outcomes, emphasizing their homeostatic and neuroprotective potential. Despite these advances, mechanistic gaps remain regarding how substance-induced eCBS alterations precipitate neurodegenerative cascades. Addressing these gaps will be critical for leveraging the eCBS as a therapeutic target to counteract addiction-driven neurotoxicity and age-related cognitive decline.