The discovery of the endocannabinoid signalling system, that is, of cannabinoid receptors,
their endogenous ligands, known as endocannabinoids, and of endocannabinoid anabolic
and catabolic enzymes, raised several questions regarding the physiopathological role
of these mediators. Several of these questions were answered by investigating alterations
in the levels of the most studied endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol
(2-AG), in tissues of animal models of disorders, and in bioptic samples and biological
fluids (cerebrospinal fluid and blood) of human volunteers. Subsequently, the pharmacological
effects of synthetic compounds that selectively target the cannabinoid CB(1) and CB(2)
receptors, and endocannabinoid anabolic and catabolic enzymes, established cause-effect
relationships between pathological alterations in endocannabinoid levels and the symptoms
and progress of several disorders, including emesis, obesity, metabolic disorders,
hepatic diseases, pain, inflammation and neurological and neuropsychiatric disorders.
These new developments are discussed in this second review on the endocannabinoids,
together with the results of pre-clinical and clinical studies on the potential therapeutic
use of plant-derived cannabinoids and synthetic agents that manipulate pharmacologically
the action at cannabinoid receptors or the tissue levels of AEA and 2-AG.