The use of cannabis for the management of a wide range of painful disorders has been well documented in case reports throughout history. However, clinical evaluations of cannabis and its psychoactive constituent THC have not led to a consensus regarding their analgesic effectiveness. On the other hand, THC and its synthetic derivatives have been shown to be effective in most animal models of pain. These antinociceptive effects are mediated through cannabinoid receptors in the brain that in turn appear to interact with noradrenergic and kappa opioid systems in the spinal cord to modulate the perception of painful stimuli. The endogenous ligand, anandamide, is also an effective antinociceptive agent. The extent to which the endogenous cannabinoid system is involved in the modulation of pain is currently unknown.