On-demand lipid neurotransmitter system. Endogenous ligands synthesized from membrane phospholipids in postsynaptic neurons + immune cells: anandamide (N-arachidonoylethanolamine, AEA) via NAPE-PLD; 2-AG (2-arachidonoylglycerol) via DAGL. Retrograde signaling: endocannabinoids cross synapse to act on presynaptic CB1 (CNS) or peripheral CB2 (immune) — Gi/o-coupled → reduces neurotransmitter release. Degradation: AEA → FAAH (fatty acid amide hydrolase) → arachidonic acid + ethanolamine; 2-AG → MAGL (monoacylglycerol lipase) → AA + glycerol. Pharmacology: THC = partial CB1/CB2 agonist; CBD = weak CB receptor activity + multi-target (TRPV1, 5-HT1A, PPAR); rimonabant (withdrawn — psychiatric side effects) was a CB1 antagonist for obesity. FAAH inhibitors (BIA 10-2474 — fatal trial; others in development) raise endogenous AEA.
Organ Systems
nervous
immune-hematologic
digestive
Pathway Steps
postsynaptic-depolarization → endocannabinoid-release — via AEA (NAPE-PLD) + 2-AG (DAGL) synthesized on demand from membrane lipids. Endocannabinoids are made on demand: postsynaptic depolarization and Ca²⁺ entry trigger synthesis of lipid messengers (anandamide, 2-AG) from membrane precursors. Unlike classical transmitters they are not stored in vesicles — produced and released exactly when and where neuronal activity calls for them.
endocannabinoid-release → presynaptic-cb1 — via retrograde diffusion to CB1 (CNS) or CB2 (immune); Gi/o-coupled. Released endocannabinoids travel backward across the synapse (retrograde signaling) to activate presynaptic CB1 receptors, which suppress further neurotransmitter release. This retrograde, on-demand inhibition is the system’s signature — a feedback brake on synaptic activity, and the target of THC (a CB1 agonist).
anandamide → arachidonic-acid — via FAAH degradation; raises arachidonic pool. Anandamide is terminated by the enzyme FAAH, which hydrolyzes it to arachidonic acid and ethanolamine. Because FAAH controls anandamide tone, FAAH inhibitors have been pursued to raise endocannabinoid signaling for pain and anxiety (with cautious development after an early trial tragedy).
2-ag → arachidonic-acid-glycerol — via MAGL degradation. 2-AG, the more abundant endocannabinoid, is degraded mainly by monoacylglycerol lipase (MAGL) to arachidonic acid and glycerol. This links the endocannabinoid system to eicosanoids — MAGL-derived arachidonic acid feeds prostaglandin synthesis, so MAGL inhibition is both pro-cannabinoid and anti-inflammatory.