The endocannabinoid system

How the body builds, uses and breaks down its own cannabinoids — a look at anandamide and 2-AG metabolism, the enzymes involved, and why it all matters.

The nervous system runs on chemical signals. Here's how the endocannabinoid system fits into that picture — from retrograde signalling to receptor biology.

How do plant cannabinoids actually bind to receptors? A molecular look at CB1, CB2 and beyond — the chemistry, the hypotheses, and the limits of what we know.

The endocannabinoid system touches nearly every organ system in the human body. Here's what the receptor biology actually tells us — and where the science is still catching up.

The endocannabinoid system is one of the most studied yet least understood systems in the body. Here's why it keeps resisting easy answers.

2-Arachidonoylglycerol (2-AG) is an endogenous lipid mediator and full agonist at both CB1 and CB2 cannabinoid receptors, recognised as the most abundant endocannabinoid in the central nervous system.

Anandamide (AEA) is an endogenous lipid-derived neurotransmitter that acts as a partial agonist at cannabinoid receptors CB1 and CB2, and is one of the two principal endocannabinoids identified in the human body.

The cannabinoid type-1 receptor is a G protein-coupled receptor expressed primarily in the central nervous system that mediates most of the psychoactive and neuromodulatory effects of both endogenous cannabinoids and exogenous cannabinoids such as THC.

CB2 receptor (CB2R) is a G protein-coupled receptor encoded by the CNR2 gene, expressed predominantly on immune and haematopoietic cells, that binds endocannabinoids, phytocannabinoids and synthetic cannabinoids to modulate immune signalling and inflammatory responses.

Clinical Endocannabinoid Deficiency (CED) is a hypothesis proposing that insufficient endocannabinoid tone — whether through reduced synthesis, accelerated degradation, or receptor dysfunction — may underlie certain conditions characterised by overlapping physiological dysregulation.

The endocannabinoidome is the expanded network of lipid-derived mediators, their biosynthetic and degradative enzymes, and the receptors they act upon — encompassing the classical endocannabinoid system alongside a broader array of structurally related signalling molecules.

Endocannabinoid synthesis is the on-demand biosynthesis of lipid-based signalling molecules — principally anandamide (AEA) and 2-arachidonoylglycerol (2-AG) — from membrane phospholipid precursors within postsynaptic neurones and peripheral cells.

The endocannabinoid system is a widespread signalling network of receptors, naturally produced lipid molecules and enzymes that is involved in regulating numerous physiological processes.

Endocannabinoid tone refers to the baseline level of endocannabinoid system activity in a given tissue or organism, determined by the local concentrations of endocannabinoids, the expression density of their receptors, and the rate of their enzymatic synthesis and degradation.

Fatty Acid Amide Hydrolase (FAAH) is a membrane-bound serine hydrolase enzyme responsible for the primary intracellular degradation of anandamide (AEA) and related fatty acid amides in mammalian tissue.

GPR55 is an orphan G protein-coupled receptor that binds certain cannabinoids and lipid mediators, and whose classification as a canonical cannabinoid receptor remains under scientific debate.

Monoacylglycerol lipase (MAGL) is a serine hydrolase enzyme responsible for the primary degradation of 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid in the central nervous system.

N-acylethanolamines (NAEs) are a family of endogenous lipid signalling molecules formed by the conjugation of a fatty acid with ethanolamine, several of which interact with cannabinoid and related receptors as part of the broader endocannabinoid system.

Retrograde signalling is a form of synaptic communication in which a postsynaptic neuron releases chemical messengers that travel backwards across the synapse to modulate neurotransmitter release from the presynaptic terminal.

Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated, non-selective cation channel expressed widely in peripheral sensory neurones and certain central nervous system regions, activated by heat, low pH, and endogenous lipid mediators including anandamide.