Nonendocannabinoid

Nonendocannabinoid is a term used to describe molecules that interact with the endocannabinoid system (ECS) without being conventional endocannabinoids such as anandamide (AEA) or 2-arachidonoylglycerol (2-AG). The ECS comprises the cannabinoid receptors CB1 and CB2, their endogenous ligands, and the enzymes that synthesize and degrade them. Nonendocannabinoids can modulate ECS signaling directly by binding to receptors or indirectly by affecting endocannabinoid levels, release, transport, or breakdown. They include endogenous lipid mediators that cross-talk with the ECS or influence its tone, as well as exogenous compounds that modulate ECS activity via other targets or by inhibiting metabolic enzymes.

These molecules can act through various mechanisms: some influence receptor activity as allosteric modulators or antagonists; others alter the synthesis or degradation of endocannabinoids by targeting enzymes such as FAAH or MAGL; and still others interact with receptors outside the classical cannabinoid system, such as TRPV1, GPR55, or PPAR-α, thereby shaping ECS signaling indirectly.

Examples and scope: Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are fatty acid ethanolamides that do not strongly activate CB receptors but can regulate metabolism, inflammation, and pain through PPAR-α and related pathways, thereby modulating endocannabinoid tone. Some synthetic or dietary lipids and other endogenous mediators are discussed in the literature as nonendocannabinoid or endocannabinoid-like mediators.

Terminology varies; the term nonendocannabinoid is not universally standardized and may be used interchangeably with “endocannabinoid-like” in some contexts.