It is now well established that the psychoactive effects ofCannabis sativa are primarily mediated through neuronal CB1 receptors, while its therapeutic immune properties are primarily mediated through CB2 receptors. Two endocannabinoids, arachidonoylethanolamide and 2-arachidonoylglycerol, have been identified, their action on CB1 and CB2 thoroughly characterized, and their production and inactivation elucidated. However, many significant exceptions to these rules exist. Here we review the evidence suggesting that cannabinoids can modulate synaptic transmission, the cardiovascular system, and the immune system through receptors distinct from CB1 and CB2, and that an additional “independent” endocannabinoid signaling system that involves palmitoylethanolamide may exist.
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