The effects of Δ9-THC are mediated by agonist/partial agonist effects at CB1 receptors (CB1R) where it has modest affinity (Ki = 35–80 nmol) and low intrinsic activity [40, 173]. CB1Rs are mostly coupled to Gi/o proteins, through which they inhibit adenylate cyclases and stimulate mitogen-activated protein kinases [100]. CB1R also inhibits voltage-activated Ca2+ channels and stimulates inwardly rectifying K+ channels [148, 173]. CB1Rs are distributed with high density in the cerebellum and cerebral cortex, particularly frontal regions, basal ganglia, hippocampus, and anterior cingulate cortex, brain regions that have been implicated in the putative neural circuitry of psychosis. CB1Rs are receptors encoded by the CNR1 gene, which resides on chromosome 6q14–15. The two best-studied endocannabinoids are anandamide and 2-arachidonoylglycerol (2-AG). Anandamide is produced from phospholipid precursors by the enzyme n-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and 2-AG by α- and β-diacylglycerol lipases (DAGL) [176]. Levels of 2-AG are 50–1,000 times higher than those of anandamide. Its proposed role is as an autocrine messenger in axonal guidance [86] and as a retrograde messenger in the adult brain [134]. CB1Rs are predominantly presynaptic [61] and
