Anandamide and 2-arachidonyl-glycerol (2-AG) which we isolated from porcine brain in 1992 and from canine gut in 1995 respectively are the major endogenous cannabinoids identified so far. We have strong indications based on chromatographic separations monitored by receptor binding studies that additional endocannabinoids are present in brain. We shall try to isolate and identify them. We have indications that 2-AG is released in brain on closed head injury and that 2-AG reduces edema and neurological consequences of the injury. We aim at solidifying the data which could show that endocannabinoids play a neuroprotective role. We have found that 2-AG reduces the formation of TNF-alpha, a multipotential cytokine. We plan to look at the activity of 2-AG with other cytokines. We plan to synthesize 2-AG-type compounds which will parallel 2-AG in its actions but will not be hydrolyzed in vivo and could thus serve as lead compounds for novel drugs with neuroprotective and anti-inflammatory activity. We have synthesized major cannabidiol (CBD) metabolites. As CBD is a potent anti-arthritic cannabinoid, with no psychotropic effects, we shall investigate the activities of these metabolites on the production of several cytokines as well as in models of multiple sclerosis and experimental colitis. We shall attempt to synthesize CB1 agonists which act outside the brain only. (Added, May 2001) 1. We have now isolated and identified a new endocannabinoid 2. We have shown that 2-AG reduces brain infarct volume and hippocampal cell death due to closed head injury. An antagonist blocks these 2-AG actions.