Endocannabinoid system

The endocannabinoid system (ECS) is a regulatory signalling network present throughout the body, comprising three main components: cannabinoid receptors, endogenous ligands, and the enzymes that synthesise and degrade those ligands.

**Receptors** — CB1 receptors are concentrated in the central nervous system (cortex, limbic system, basal ganglia, hippocampus) and mediate most of the psychoactive and analgesic effects of cannabinoids. CB2 receptors are predominantly peripheral, on immune-system cells, and mediate inflammatory and immune-modulatory effects.

**Endogenous ligands** — anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) are the two best-characterised endocannabinoids that the body produces on demand to bind cannabinoid receptors.

**Regulating enzymes** — fatty acid amide hydrolase (FAAH) breaks down anandamide, and monoacylglycerol lipase (MAGL) breaks down 2-AG. CBD weakly inhibits FAAH, which is one mechanism through which it raises endogenous anandamide tone.

The ECS modulates pain perception, mood, sleep, appetite, memory, immune function, gut motility, and reproductive physiology. This breadth explains why cannabis-based medicines have such a wide potential indication space. Critically, individual variation in baseline ECS tone — partly genetic, partly state-dependent — accounts for why cannabinoid responses differ markedly between patients, and why dosing must be individualised rather than prescribed by formula.