Biosynthesis, Degradation, and Receptor Binding of AEA and 2-AG.

AEA is synthesized from membrane phospholipids in the postsynaptic neuron by NAPE-PLD. It crosses the synapse “against the traffic” and activates CB₁R and TRPV1 on the presynaptic neuron. Following reuptake to the presynaptic neuron by the EMT, AEA activates nuclear receptors—PPARs—and is degraded by FAAH.

THC directly activates CB₁R; CBD inhibits FAAH and EMT (increasing AEA levels), the endogenous ligand of CB₁R. Like AEA, CBD activates PPARs and TRPV1.

2-AG, 2-arachidonoylglycerol (blue ellipses and related lines); AA, arachidonic acid (green ellipses); AEA, anandamide (purple ellipses and related lines); CB₁R, cannabinoid type 1 receptor; CBD, cannabidiol; DAGL, diacylglycerol lipase; EMT, endocannabinoid membrane transporter (green tubes); FAAH, fatty acid amide hydrolase; GPR55, G protein-coupled receptor 55; MAGL, monoacylglycerol lipase; NAPE-PLD, N-acylphosphatidylethanolamine-specific phospholipase D; PPARs, peroxisome proliferator-activated receptors; THC, Δ9-tetrahydrocannabinol; TRPV1, transient receptor potential channels of vanilloid type-1. Broken lines = inhibition; half ellipses ( ) = receptors; hexagons = enzymes; yellow mesh = cell membrane. Thicker lines and half ellipses are of greater importance than the thinner ones. Black lines, other pathways; red lines, phytocannabinoid pathways.