Endocannabinoids

Endocannabinoids are endogenous lipid mediators that bind to cannabinoid receptors in the nervous system and other tissues. The best-characterized endocannabinoids are anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG). They are produced on demand from membrane phospholipid precursors in response to neuronal activity and are not stored in synaptic vesicles. Their signaling is typically short-lived because they are rapidly degraded by enzymes such as fatty acid amide hydrolase (FAAH) for AEA and monoacylglycerol lipase (MAGL) for 2-AG, with additional involvement from other hydrolases in some contexts.

Synthesis and signaling occur through several enzymatic steps. AEA is generated from N-acyl phosphatidylethanolamines via NAPE-PLD; 2-AG is produced from diacylglycerol by DAG lipase. Endocannabinoids signal mainly through the G-protein-coupled receptors CB1 and CB2. CB1 receptors are abundant in the central nervous system and modulate neurotransmitter release, while CB2 receptors are mainly found in immune cells and peripheral tissues. Endocannabinoids often operate via retrograde signaling: postsynaptic neurons release AEA or 2-AG that travel back across the synapse to activate presynaptic CB1 receptors, thereby reducing neurotransmitter release.

Physiological roles of the endocannabinoid system are diverse, including regulation of pain, appetite and energy balance, mood and stress responses, learning and memory, inflammation, and neuroprotection. The system participates in synaptic plasticity and helps maintain homeostasis across neural circuits. Dysregulation has been associated with conditions such as chronic pain, anxiety disorders, obesity, and neurodegenerative diseases. Pharmacological tools targeting FAAH, MAGL, or cannabinoid receptors have been explored for therapeutic potential, with varying clinical outcomes.