FAAH Variant Pro129Thr Modulates Subjective Effects Produced by Cocaine Administration

Background and Objectives: The endogenous cannabinoid anandamide (AEA), an agonist at type-1 cannabinoid (CB1) receptors, is metabolized by fatty acid amide hydrolase (FAAH). The common variant rs324420 C->A within the FAAH gene on chromosome 1 codes for a missense substitution (Pro129Thr), resulting in decreased FAAH activity and increased endocannabinoid potentiation. This FAAH variant has been linked to alterations in mood and stress reactivity, as well as being independently linked to increased risk for addiction. We hypothesized that cocaine use disordered (CUD) participants with the FAAH Pro129 Thr variant would exhibit a distinct profile of cocaine-induced subjective effects in the laboratory. Methods: A total of 70 CUD participants received intravenous doses of saline (placebo, 0 mg) and cocaine (20, 40 mg) in a lab-controlled setting and rated 10 subjective effect measures prior to and following saline and cocaine administration, using a Visual Analog Scale (VAS). Results: The variant allele was associated with increased cocaine-induced subjective ratings for Drug Effect, High, and Depressed. The prevalence of the variant allele A and the AA genotypes were greater in our CUD group than in the general population (Aallele: 47% vs. 34%; AA genotype: 30% vs. 13%; p<.05). Finally, the reported amount and frequency of tobacco and cocaine use was higher in subjects with the AC/AA allele. Conclusions and Scientific Significance: These results add to existing evidence that this variant of the FAAH genotype may be over-represented among those who have CUD, and this over-representation may result from greater subjective responses to cocaine administration.