The term was introduced by Vincenzo Di Marzo and colleagues to capture the limitations of treating the endocannabinoid system (ECS) as a tightly bounded set of two ligands (anandamide and 2-arachidonoylglycerol), two canonical receptors (CB1 and CB2), and their associated enzymes. The endocannabinoidome extends this framework to include N-acylethanolamines, monoacylglycerols, N-acyl amino acids, and related polyunsaturated lipid mediators that interact with a wider receptor family , among them TRPV1, TRPV4, GPR55, GPR18, GPR119, and PPARα/γ nuclear receptors.
Mechanistically, these mediators are typically synthesised on demand from membrane phospholipid precursors and act as retrograde or paracrine signals, with activity governed by enzymatic hydrolysis and oxidative metabolism. The precise physiological roles of many endocannabinoidome components remain an active area of research; their interactions are often tissue-specific and concentration-dependent, making the network considerably more complex than early ECS models acknowledged.
Some researchers have proposed the hypothesis that disruptions to endocannabinoidome tone , whether through altered enzyme activity, receptor expression, or mediator availability , may underlie certain physiological imbalances. These proposals are currently hypotheses; the available human evidence is preliminary and does not yet establish causal mechanisms with clinical certainty.
In regulatory and pharmacological contexts, the breadth of the endocannabinoidome is relevant to understanding why cannabinoid-adjacent compounds may produce off-target effects, and why classifying such compounds under the Poisons Standard (the document governing Australia's scheduling framework, administered by the TGA) requires consideration of receptor promiscuity beyond CB1/CB2 alone.
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