Cannabinoid binding sites exist throughout the central and peripheral nervous systems. The two most relevant receptors for cannabinoids are the CB and CB receptors, which are expressed predominantly in the brain and immune system respectively. Density of expression varies based on species and correlates with the efficacy that cannabinoids will have in modulating specific aspects of behavior related to the site of expression. For example, in rodents, the highest concentration of cannabinoid binding sites are in the basal ganglia and cerebellum, regions of the brain involved in the initiation and coordination of movement. In humans, cannabinoid receptors exist in much lower concentration in these regions, which helps explain why cannabinoids possess a greater efficacy in altering rodent motor movements than they do in humans.
A recent analysis of cannabinoid binding in CB and CB receptor knockout mice found cannabinoid responsiveness even when these receptors were not being expressed, indicating that an additional binding receptor may be present in the brain. Binding has been demonstrated by 2-arachidonoylglycerol (2-AG) on the TRPV1 receptor suggesting that this receptor may be a candidate for the established response.
In addition to CB1 and CB2, certain orphan receptors are known to bind endocannabinoids as well, including GPR18, GPR55 (a regulator of neuroimmune function), and GPR119.  CB1 has also been noted to form a functional human receptor heterodimer in orexin neurons with OX1, the CB1–OX1 receptor, which mediates feeding behavior and certain physical processes such as cannabinoid-induced pressor responses which are known to occur through signaling in the rostral ventrolateral medulla.