Investigating Endocannabinoid Metabolism in Alcohol Use Disorder: a focus on fatty acid amide hydrolase (FAAH)

The endocannabinoid enzyme, fatty acid amide hydrolase (FAAH), has been proposed as a therapeutic target for Alcohol Use Disorder (AUD) and psychiatric illnesses. Studies suggest that FAAH regulates alcohol intake/preference, and its impairment increases risk for alcohol use disorder (AUD). This thesis’ main objective was to better characterize the status of FAAH in relation to AUD and AUD risk phenotypes. It was hypothesized that reduced FAAH (in brain or inherited via FAAH C385A polymorphism) is related to increased and more hazardous alcohol use, reduced negative and impairing effects of alcohol in heavy episodic drinking (HED) youth and clinical outcomes in AUD. FAAH levels in brain were quantified using positron emission tomography (PET) with [C-11]CURB in treatment-seeking individuals with AUD in early (3-7 days; n=14) and later (2-4 weeks; n=9) abstinence. FAAH in brain, striatum and PFC was measured in HED youth (n=31) and related to retrospective alcohol consumption and alcohol sensitivity during an intravenous alcohol challenge. FAAH C385A genotype was investigated in heavy-drinking youth (n=302) in relation to drinking motives and alcohol consumption patterns. Brain FAAH levels were reduced in AUD during early abstinence and related to increased alcohol consumption. Peripheral FAAH substrates were significantly elevated. Neither FAAH nor FAAH substrates differed in later abstinence. Lower brain FAAH levels in HED youth were related to increased alcohol-induced craving, reduced negative effects of alcohol and increased negative arousal. FAAH polymorphism was related to increased endorsement of coping motives for alcohol use, alcohol consumption and hazardous drinking. Mediation models in HED youth suggested that the FAAH minor A allele related to more hazardous alcohol consumption, which may be mediated by increased negative reinforcement. This thesis provides the first investigations of FAAH in living brain of humans in relation to hazardous alcohol use and AUD. Reduced FAAH and elevated endocannabinoid tone might be related to increased risk of negative consequences from alcohol including increased hazardous consumption, increased craving and AUD. While it is unclear whether reduced FAAH predates or is a consequence of chronic alcohol use, these findings should be considered if considering FAAH as a therapeutic target for AUD or co-morbid conditions.

Department dc:contributor.department

Medical Science

Year dc:date.issued

2022

Author dc:creator

• Best, Laura M

Advisor dc:contributor.advisor

• Boileau, Isabelle

• Alcohol Use Disorder
• anandamide
• endocannabinoid
• fatty acid amide hydrolase
• positron emission tomography

Statement dc:rights

• Attribution 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by/4.0/

Handle dc:identifier.uri

http://hdl.handle.net/1807/123339

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/123339