Problem drug use and dependence are neurobehavioral disorders of complex origin. 
Although environmental factors contribute to drug abuse and addiction, genetic 
factors also play a significant role estimated at 40-60% of the total risk. 
Nonetheless, the precise identities of human genes that confer vulnerability to 
problem drug use remain mostly unknown. Here, we describe a natural single 
nucleotide polymorphism in the human gene that encodes the principal 
endocannabinoid-inactivating enzyme, fatty acid amide hydrolase (FAAH), that in 
homozygous form is strongly associated with both street drug use and problem 
drug/alcohol use. This single nucleotide polymorphism results in a missense 
mutation (385C-->A) that converts a conserved proline residue to threonine 
(Pro129-->Thr), producing a FAAH variant that displays normal catalytic 
properties but an enhanced sensitivity to proteolytic degradation. Collectively, 
these results suggest that genetic mutations in FAAH may constitute important 
risk factors for problem drug use and support a potential link between 
functional abnormalities in the endogenous cannabinoid system and drug abuse and 
dependence.