The fatty acid amide hydrolase C385A (P129T) missense variant in cannabis users: studies of drug use and dependence in Caucasians.
A genetic variation in fatty acid amide hydrolase (FAAH), C385A (P129T), has been previously associated with risk for problem street drug use. FAAH is a mammalian enzyme that inactivates neuromodulatory-signaling lipids including the endogenous cannabinoid 1 receptor agonist anandamide. We investigated in adult Caucasians (N = 749) whether this FAAH variant altered the risk for trying, regular use of or dependence on cannabis, alcohol or nicotine, traditional "gateway" drugs. Consistent with our knowledge that the A/A genotype results in reduced FAAH expression and activity in humans, subjects with the A/A genotype were less likely to be THC dependent than subjects with either a C/C or C/A genotype (11% vs. 26%, P < 0.05). No association was observed between the A/A genotype and risk for alcohol or tobacco regular use, or DSM IV dependence. Controlling for regular use of nicotine and sedatives, both identified as confounders, those with the A/A genotype were at significantly reduced risk for being THC dependent (OR 0.25, 95% CI: 0.07-0.88) as compared with those with the C/A or C/C genotype, supporting a link between alterations in the endocannabinoid system and THC dependence. Unexpectedly, we found an increased risk for regular use of sedatives among the A/A genotype group. The relationship between the FAAH A/A genotype and risk for drug dependence in this study was drug class specific, suggesting it is not part of a more general drug abuse effect. These results, particularly the observation of altered risk for sedative drug use, should be investigated further in multiple ethnic populations.
Tyndale
Rachel F
RF
Department of Pharmacology, Centre for Addiction and Mental Health, University of Toronto, Ontario, Canada.
Payne
Jennifer I
JI
Gerber
Alexandra L
AL
Sipe
Jack C
JC
D000328:Adult; D000428:Alcohol Drinking; D000581:Amidohydrolases / Q000235:genetics*; D002170:Canada; D002186:Cannabinoids; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008385:Marijuana Smoking / Q000235:genetics*; D020125:Mutation, Missense; D012907:Smoking; D019966:Substance-Related Disorders / Q000201:enzymology / Q000235:genetics*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D002186:Cannabinoids; D000099252:Fatty Acid Amide Hydrolases