More Aroused, Less Fatigued: Fatty Acid Amide Hydrolase Gene Polymorphisms Influence Acute Response to Amphetamine

Abstract

Amphetamine is a stimulant drug that enhances attention and feelings of alertness. Amphetamine's effects are known to be modulated by endogenous cannabinoids, which are degraded by the enzyme fatty acid amide hydrolase (FAAH). In this study we investigated inter-individual differences in mood response to amphetamine in relation to four polymorphisms in the FAAH gene, including the FAAH missense variant rs324420C-A (Pro129Thr), which was previously found to be associated with street drug use and addictive traits. One hundred and fifty-nine healthy Caucasian volunteers participated in a three-session, double-blind crossover study receiving either placebo or oral d-amphetamine (10 and 20 mg). Associations between individual genotypes and levels of self-reported Arousal (Profile of Mood States) after d-amphetamine ingestion were investigated using two-way ANOVAs/ANCOVAs. Association analyses for haplotypes were performed using the adaptive permutation approach implemented in PLINK. Genotypes at rs3766246 and rs2295633 were significantly associated with increased ratings of Arousal (po0.05) and Fatigue (po0.01) after the 10-mg dose. Fatigue levels were also found to be associated with the haplotypes CCC and TAT formed from rs3766246, rs324420, and rs2295633 (po0.05). These data suggest that the endocannabinoid system influences variation in subjective response to amphetamine. This has important implications for understanding the role of endogenous cannabinoids in response to amphetamine, studies of poly-substance abuse, and understanding the genetic determinants of inter-individual differences in stimulant effects and risk of abuse.

Dose-dependent cannabis use, depressive symptoms, andFAAHgenotype predict sleep quality in emerging adults: a pilot study

“…Although we are not aware of other human studies investigating the relationship between endocannabinoid genes and sleep, one study reported a significantly greater decrease in fatigue for FAAH C/C genotypes after 10mg amphetamine administration compared to A carriers (75). This may be related to decreased somnolence with lower endocannabinoid activity.…”

“…This may be related to decreased somnolence with lower endocannabinoid activity. These researchers also examined three FAAH SNPs together as a haplotype block, finding that haplotype CCC was significantly associated with lower fatigue after 10mg administration, while haplotype TAT was associated with higher fatigue (75). Given these findings, future studies may consider more closely investigating the individual and group impact of other FAAH SNPs.…”

A review of pharmacogenetic studies of substance-related disorders

“…Investigators there assessed acute response to d-amphetamine in 398 individuals with no history of drug abuse. Interim pharmacogenetic analyses using 99–162 participants from this data set found associations between a number of gene variants and amphetamine response: ADORA2A (Hohoff et al, 2005), BDNF (Flanagin et al, 2006), CSNK1E (Veenstra-VanderWeele et al, 2006), COMT (Hamidovic et al, 2010a), DRD2 (Hamidovic et al, 2009), FAAH (Dlugos et al, 2010), OPRM1 (Dlugos et al, 2011), SLC6A3 (Hamidovic et al, 2010b; Lott et al, 2005), SLC6A4 (Lott et al, 2006), and SLC6A2 (Dlugos et al, 2007). The promising data from these publications were cited throughout the psychiatric genetics literature.…”

Interactions of Cannabis and Amphetamine-Type Stimulants

“…Allelic variants of the FAAH gene have been associated with the subjective response to AMPH [172], as well as a higher risk for substance abuse and dependence [173,174]. Similarly, genetic variants of the [AAT]n trinucleotide short-tandem repeat polymorphism of the CNR1 gene (encoding CB 1 receptors) have been associated with an increased risk for intravenous use of AMPH [175] as well as other drugs [176].…”