Lower brain fatty acid amide hydrolase in treatment-seeking patients with alcohol use disorder: a positron emission tomography study with [C-11]CURB

Abstract

The endocannabinoid enzyme, fatty acid amide hydrolase (FAAH), has been proposed as a therapeutic target for alcohol use disorder (AUD) and co-morbid psychiatric illnesses. Investigating this target in the living human brain and its relationship to clinical outcome is a critical step of informed drug development. Our objective was to establish whether brain FAAH levels are low in individuals with AUD and related to drinking behavior. In this pilot study, treatment-seeking patients with AUD completed two PET scans with the FAAH radiotracer [C-11]CURB after 3-7 days (n = 14) and 2-4 weeks (n = 9) of monitored abstinence. Healthy controls (n = 25) completed one scan. FAAH genetic polymorphism (rs324420) and blood concentrations of anandamide and other N-acylethanolamines metabolized by FAAH were determined and AUD symptoms assessed. In AUD, brain FAAH levels were globally lower than controls during early abstinence (F(1,36) = 5.447; p = 0.025)) and FAAH substrates (anandamide, oleoylethanolamide, and N-docosahexaenoylethanolamide) were significantly elevated (30-67%). No significant differences in FAAH or FAAH substrates were noted after 2-4 weeks abstinence. FAAH levels negatively correlated with drinks per week (r = −0.57, p = 0.032) and plasma concentrations of the three FAAH substrates (r > 0.57; p < 0.04)). Our findings suggest that early abstinence from alcohol in AUD is associated with transiently low brain FAAH levels, which are inversely related to heavier alcohol use and elevated plasma levels of FAAH substrates. Whether low FAAH is an adaptive beneficial response to chronic alcohol is unknown. Therapeutic strategies focusing on FAAH inhibition should consider the possibility that low FAAH during early abstinence may be related to drinking.

Lower amygdala fatty acid amide hydrolase in violent offenders with antisocial personality disorder: an [11C]CURB positron emission tomography study

“…However, none of the other regions sampled had significantly lower [ 11 C]CURB λ k 3 values. Lower amygdala FAAH expression is consistent with decreased FAAH expression observed across the brain in other externalizing conditions, such as alcohol and substance use disorders 37 , 39 . Our study was likely underpowered to detect differences in all ROIs.…”

“…None of the participants screened positive for drugs of abuse, including cannabis. Healthy participants (e.g., no ASPD, no SCZ) and community participants with SCZ had previously participated in other PET experiments 36 , 37 . Groups did not differ in terms of age, ethnicity, body mass index, or number of participants with the C385A FAAH genotype.…”

Association of the Fatty Acid Amide Hydrolase C385A Polymorphism With Alcohol Use Severity and Coping Motives in Heavy‐Drinking Youth

“…Of note, a recent study in adult humans of Caucasian/European ancestry with AUD reported that individuals with the AC or AA genotype engaged in significantly more drinking days and heavy drinking episodes, and had greater self-reported alcohol use severity compared to CC homozygotes (Sloan et al, 2017). Consistent with this finding, low FAAH brain levels, as measured using positron emission tomography, were associated with increased alcohol consumption in a sample of treatment-seeking individuals with AUD (Best et al, 2020). Together, these findings suggest that low FAAH activity may be related to increased alcohol consumption and vulnerability for AUD, though the mechanism by which this might occur requires further investigation.…”

“…Participants were recruited from community and university settings in Toronto, Canada, for participation in 1 of 2 larger studies investigating the risk for AUD in youth (Best et al, 2020; Hendershot et al, 2017). To be eligible for inclusion in either of the 2 larger studies, participants were at least 18 years of age, reported at least 1 occurrence of HED in the previous 30 days, no current medication or medical condition contraindicating alcohol consumption and no current diagnosis or treatment of a psychiatric condition or substance use disorder, as assessed by the Structured Clinical Interview for DSM‐IV or the Mini International Neuropsychiatric Interview.…”

Endocannabinoid-Like Lipid Neuromodulators in the Regulation of Dopamine Signaling: Relevance for Drug Addiction

“…Recently, a PET scan study for a FAAH radiotracer was conducted in the brain of AUD patients during early abstinence. It showed transiently reduced FAAH levels, while its substrates AEA, OEA, and N- docosahexaenoyl ethanolamide (DEA) were elevated in the plasma (Best et al, 2020 ). Low FAAH levels are related to drinking behaviors and increased preference for alcohol, as demonstrated in several studies using animal models with genetic deletions (Basavarajappa et al, 2006 ; Blednov et al, 2006 ; Vinod et al, 2008 ; Pavón et al, 2018 ); or following pharmacological manipulation (Zhou et al, 2017 ).…”