Abstract
2315
Introduction: Cannabis withdrawal is a poorly understood mental health condition, experienced by a high proportion of frequent cannabis users upon drug-use cessation. Fatty Acid Amide Hydrolase (FAAH), the enzyme responsible metabolizing the major endocannabinoid anandamide is believed to be involved in cannabis use disorder (CUD) and cannabis withdrawal based on evidence from preclinical and human genetic association studies, which suggests that greater anandamide hydrolysis is associated with more severe withdrawal. This enzyme is the target for therapeutics presently under development for CUD. The aim of our study is to characterize the status of FAAH in the brain of people with CUD during acute withdrawal (72 hours of abstinence) from cannabis.
Methods: FAAH levels were measured in whole-brain regions of interest (ROIs) using positron emission tomography (PET) imaging of the radioligand for FAAH [C11]CURB. An irreversible 2-tissue compartment model with arterial input function was used to fit the time activity curves and provide [C11]CURB lk3, the parameter of interest for FAAH levels. An MRI was obtained to delineate ROIs in the analysis of the PET data. Participantswith CUD (n=6; M/F:5/1) were scanned twice, once after early (overnight) abstinence and after 72 hour to 1 week abstinence. Abstinence was monitored by measurements of minor cannabinoids with short half-lives (i.e.: cannabigerol, CBG). Blood for genotyping of a major functional single nucleotide polymorphism (SNP) for FAAH (rs324420, C385A) which affects [C11]CURB lk3 was drawn during a scan.Subjective assessments of craving, mood and withdrawal were conducted.
Results: A repeated measures analysis of co-variance with FAAH C385A genotype was conducted on 11 brain ROIs. We found non- significant +7% elevation in [C11]CURB lk3 between overnight, and 72 hour - 1 week abstinence (F(1,9)= 0.231, p=0.642) (Figure 1). Two participants had [C11]CURB lk3 increases above noise in whole brain ROIs (+15%), while four showed no change (-3-+6%). Plasma levels of CBG were not fully available at analysis.
Conclusions: Our pilot data suggest that levels of FAAH may be variable during acute cannabis-use cessation in people with CUD. Investigating whether variability in FAAH is linked with clinical symptomatology or level of abstinence will provide a deeper understanding of the involvement of this enzyme --- proposed as a treatment target for CUD --- in cannabis withdrawal.
Funded by NIH R21(PI: Boileau)
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