Missing Pieces to the Endocannabinoid Puzzle

The most bioactive ingredient of cannabis (Cannabis sativaorindica) extracts,D9-tetrahydrocan-nabinol (THC), was identified in the 1960s as one of more than 110 phytocannabinoids. It acti-vates receptors of chemically different endogenous ligands (endocannabinoids) that, unlikeTHC, are metabolized by several enzymes of the endocannabinoid system. Here, the complexityof the plant-derived and endogenous cannabinoids (eCBs) is discussed, to better appreciate thechallenge of: (i) dissecting their mutual interactions; (ii) understanding their impact on humanpathophysiology; and (iii) exploiting them for human disease. To this aim, missing pieces tothe eCB puzzle must be urgently found, by solving the 3D structures of key components, andinterrogating noncanonical modes of regulation and trafficking of these lipid signals.