Intermediate cannabis dependence phenotypes and the FAAH C385A variant: an exploratory analysis

Cannabis dependence is a growing problem among individuals who use marijuana frequently, and genetic differences make some users more liable to progress to dependence. The identification of intermediate phenotypes of cannabis dependence may aid candidate genetic analysis. Promising intermediate phenotypes include craving for marijuana, withdrawal symptoms after abstinence, and sensitivity to its acute effects. A single nucleotide polymorphism (SNP) in the gene encoding for fatty acid amide hydrolase (FAAH) has demonstrated association with substance use disorder diagnoses, but has not been studied with respect to these narrower phenotypes. FAAH is an enzyme that inactivates anandamide, an endogenous agonist for CB1 receptors (to which Delta(9)-tetrahydrocannabinol binds). CB1 binding modulates mesocorticolimbic dopamine release, which underlies many facets of addiction. The SNP, FAAH C385A (rs324420), was examined to determine whether its variance was associated with changes in craving and withdrawal after marijuana abstinence, craving after cue exposure, or sensitivity to the acute effects of marijuana. Forty daily marijuana users abstained for 24 h, were presented with a cue-elicited craving paradigm and smoked a marijuana cigarette in the laboratory. C385A variance was significantly associated with changes in withdrawal after abstinence, and happiness after smoking marijuana in the predicted directions, was associated with changes in heart rate after smoking in the opposite of the predicted direction, and was not associated with changes in craving or other acute effects. These data lend support to some previous association studies of C385A, but suggest that further refinement of these intermediate phenotypes is necessary.