Association Between Fatty Acid Amide Hydrolase and Alcohol Response Phenotypes: A Positron Emission Tomography Imaging Study With [11C]CURB in Heavy-Drinking Youth.

BACKGROUND: Reductions in fatty acid amide hydrolase (FAAH), the catabolic enzyme for the endocannabinoid anandamide, may play a role in drinking behavior and risk for alcohol use disorder. We tested the hypotheses that lower brain FAAH levels in heavy-drinking youth are related to increased alcohol intake, hazardous drinking, and differential response to alcohol. METHODS: FAAH levels in the striatum, prefrontal cortex, and whole brain were determined using positron emission tomography imaging of [11C]CURB in heavy-drinking youth (N = 31; 19-25 years of age). C385A FAAH genotype (rs324420) was determined. Behavioral (n = 29) and cardiovascular (n = 22) responses to alcohol were measured during a controlled intravenous alcohol infusion. RESULTS: Lower [11C]CURB binding was not significantly related to frequency of use but was positively associated with hazardous drinking and reduced sensitivity to the negative effects of alcohol. During alcohol infusion, lower [11C]CURB binding related to greater self-reported stimulation and urges and lower sedation (p < .05). Lower heart rate variability was related to both greater alcohol-induced stimulation and lower [11C]CURB binding (p < .05). Family history of alcohol use disorder (n = 14) did not relate to [11C]CURB binding. CONCLUSIONS: In line with preclinical studies, lower FAAH in the brain was related to a dampened response to the negative, impairing effects of alcohol, increased drinking urges, and alcohol-induced arousal. Lower FAAH might alter positive or negative effects of alcohol and increase urges to drink, thereby contributing to the addiction process. Determining whether FAAH influences motivation to drink through increased positive/arousing effects of alcohol or greater tolerance should be investigated.

Imaging oxidative stress in brains of chronic methamphetamine users: A combined 1H-magnetic resonance spectroscopy and peripheral blood biomarker study.

Introduction: Preclinical data suggest methamphetamine (MA), a widely used stimulant drug, can harm the brain by causing oxidative stress and inflammation, but only limited information is available in humans. We tested the hypothesis that levels of glutathione (GSH), a major antioxidant, would be lower in the brains of chronic human MA preferring polysubstance users. We also explored if concentrations of peripheral immunoinflammatory blood biomarkers were related with brain GSH concentrations. Methods: 20 healthy controls (HC) (33 years; 11 M) and 14 MA users (40 years; 9 M) completed a magnetic resonance spectroscopy (MRS) scan, with GSH spectra obtained by the interleaved J-difference editing MEGA-PRESS method in anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC). Peripheral blood samples were drawn for measurements of immunoinflammatory biomarkers. Independent samples t-tests evaluated MA vs. HC differences in GSH. Results: GSH levels did not differ between HC and MA users (ACC p = 0.30; DLPFC p = 0.85). A total of 17 of 25 immunoinflammatory biomarkers were significantly elevated in MA users and matrix metalloproteinase (MMP)-2 (r = 0.577, p = 0.039), myeloperoxidase (MPO) (r = -0.556, p = 0.049), and MMP-9 (r = 0.660, p = 0.038) were correlated with brain levels of GSH. Conclusion: Normal brain GSH in living brain of chronic MA users is consistent with our previous postmortem brain finding and suggests that any oxidative stress caused by MA, at the doses used by our participants, might not be sufficient to cause either a compensatory increase in, or substantial overutilization of, this antioxidant. Additionally, more research is required to understand how oxidative stress and inflammatory processes are related and potentially dysregulated in MA use.