Figure 1. Structures of three cannabinoids. Chemical structures of ⁹-tetrahydrocannabinol (⁹-THC) the chief psychoactive ingredient of marijuana and hashish; WIN-55212-2 a commonly used synthetic agonist for the cannabinoid CB1 receptor; 2-arachidonyl glycerol (2-AG), a putative endogenous cannabinoid. Note that although all cannabinoids are lipophilic, their structures can be quite different. ⁹-THC does not resemble putative endogenous cannabinoids 2-AG or anandamide.

Figure 2. Depolarization induced suppression of excitation (DSE). Schematic of pre- (top) and post-synaptic terminals. Standard action potential-induced neurotransmitter release (using glutamate as example) occurs via activation of calcium channels linked to transmitter-filled vesicles which fuse with the membrane to release their contents. Glutamate then acts on assorted post-synaptic glutamate receptors. In contrast, DSE involves depolarization-induced post-synaptic production of endocannabinoids (eCBs) (anandamide or 2-AG – the latter shown as example). A favoured mechanism involves activation of the enzyme DAG lipase, converting diacylglycerol (DAG) into 2-AG. Rather than being released from vesicles, lipophilic eCBs appear to cross the membrane via facilitated diffusion across a transporter. The mechanism of subsequent transport across the synapse is unknown but may involve chaperone proteins. Activation of pre-synaptic CB1 receptors inhibits action potential-induced transmitter release by inhibiting Ca²⁺ channels.