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.
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Funding and Disclosures
This study was supported in part by the National Institute of Health and National Institute of Drug Abuse (NIH/NIAAAR21 1R21AA022246-01A1 (IB)), the Ontario Mental Health Foundation (IB), Canadian Institutes of Health Research Project Grant (PG-389342 (IB)); a Canada Research Chairs program (the Canada Research Chair in Pharmacogenomics (RFT)), Canadian Institutes of Health Research (Foundation grant FDN-154294 (RFT)); CIHR TMH109787 (RFT); funding from the Canadian Institutes of Health Research (RPB), the Natural Sciences and Engineering Research Council of Canada (RPB), the Canada Research Chair in Brain Lipid Metabolism (RPB); the Canada Foundation for Innovation and the Ontario Ministry of Research and Innovation (SH); a Canadian Institutes of Health Research Doctoral Award—S Frederick Banting and Charles Best Canada Graduate Scholarships (CGS-D (LMB)), the Centre for Addiction and Mental Health and the CAMH Foundation. The authors disclose the following financial relationships: Laura M. Best is supported by a Canadian Institutes of Health Research Doctoral Award—S Frederick Banting and Charles Best Canada Graduate Scholarships (CGS-D); Belinda Williams discloses no biomedical financial interests or potential conflicts of interest. Dr Le Foll has/will received some in-kind donation of cannabis product from Canopy and Aurora, and medication donation from Pfizer and Bioprojet, and was provided a coil for TMS study from Brainsway. Dr Le Foll has/will perform research with industry funding obtained from Canopy (through research grants handled by CAMH or University of Toronto, Aphria (through research grants handled by CAMH or University of Toronto), Bioprojet, ACS, and Alkermes. Dr Le Foll has received in-kind donations of nabiximols from GW Pharma for past studies funded by CIHR and NIH. Esmaeil Mansouri discloses no biomedical financial interests or potential conflicts of interest. Dr Richard P Bazinet received funding from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, and is the Canada Research Chair in Brain Lipid Metabolism. RPB has received industrial grants, including those matched by the Canadian government, and/or travel support related to work on brain fatty acid uptake from Arctic Nutrition, Bunge Ltd., DSM, Fonterra, Mead Johnson, and Nestec, Inc. Moreover, RPB is on the executive of the International Society for the Study of Fatty Acids and Lipids, and held a meeting on behalf of Fatty Acids and Cell Signaling, both of which rely on corporate sponsorship. RPB has given expert testimony in relation to supplements and the brain. Dr Lin Lin discloses no biomedical financial interests or potential conflicts of interest. Dr Vincenzo De Luca discloses no biomedical financial interests or potential conflicts of interest. Dr Dina Lagzdins discloses no biomedical financial interests or potential conflicts of interest. Dr Pablo Rusjan discloses no biomedical financial interests or potential conflicts of interest. Dr Rachel F. Tyndale has undertaken this research, in part, thanks to funding from the Canada Research Chairs program (Dr Tyndale, the Canada Research Chair in Pharmacogenomics) a Canadian Institutes of Health Research (Foundation grant FDN-154294); the Centre for Addiction and Mental Health and the CAMH Foundation. RF Tyndale has consulted for Ethismos on unrelated topics. RF Tyndale has also received research grant support from a Global Research Awards for Nicotine Dependence (GRAND), an independently reviewed competitive grants program supported by Pfizer; Dr Alan A Wilson discloses no biomedical financial interests or potential conflicts of interest; Dr Christian Hendershot discloses no biomedical financial interests or potential conflicts of interest; Dr Markus Heilig discloses no biomedical financial interests or potential conflicts of interest; Dr Sylvain Houle discloses no biomedical financial interests or potential conflicts of interest. Dr Sylvain Houle has received funding from the Canada Foundation for Innovation and the Ontario Ministry of Research and Innovation; Dr Junchao Tong discloses no biomedical financial interests or potential conflicts of interest; Dr Stephen Kish receives a salary from the Centre for Addiction and Mental Health. During the past 36 months, he has been awarded as PI research grants from US NIH R21DA040066 and R21AA026680, and an investigator sponsored research grant from Jazz Pharmaceuticals aimed at understanding the possible involvement of dopamine in the actions of the drug Xyrem. He is co-investigator on a research grant entitled “Microglial activation in major depressive disorder: Relationship to comorbidity and loss of synaptic density” from the Canadian Institutes of Health Research; Dr Isabelle Boileau received funding from the National Institute of Health and National Institute of Drug Abuse (NIH/NIAAAR21 1R21AA022246-01A1 and the Ontario Mental Health Foundation to complete this research. Dr Isabelle Boileau has also received funding from the National Institute of Health (Co-I, R21AA026680; PI, 1R21DA04529), Canadian Institutes of Health Research (PI), the Caskey Francis Award (PI), and the Canadian Institute for Military and Veterans Health Research (PI) to complete other research projects.
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Best, L.M., Williams, B., Le Foll, B. et al. Lower brain fatty acid amide hydrolase in treatment-seeking patients with alcohol use disorder: a positron emission tomography study with [C-11]CURB. Neuropsychopharmacol. 45, 1289–1296 (2020). https://doi.org/10.1038/s41386-020-0606-2
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DOI: https://doi.org/10.1038/s41386-020-0606-2
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