It is possible that shared physiological and biochemical mechanisms contribute to the comorbid abuse and substitution of ethanol and cannabis, but at first glance, these two substances seem remarkably different. On one hand, ethanol is a remarkably low affinity ligand for the many enzymes and receptors with which it interacts. Ethanol’s low affinity is evidenced by the fact that it must be consumed in quantities sufficient to produce blood concentrations in the millimolar range before substantial behavioral effects can be observed. In contrast, THC produces the majority of its effects through high-affinity interactions with a small number of molecular targets. Almost all of the centrally mediated, behavioral effects of THC intoxication result from activation of the cannabinoid 1 (CB1) receptor. CB1 is a G-protein coupled receptor (GPCR) and is the main receptor for the endogenous cannabinoid (endocannabinoid; EC) system in the brain. ECs are a class of lipid-derived neuromodulators that serve as retrograde transmitters in central synapses. Research within the past decade has made it clear that ethanol interacts with the EC system, and a growing body of evidence suggests
