Endocannabinoid System Alterations in Opioid Use Disorder (OUD)

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ABSTRACT There are close interactions between the endogenous opioid system and endocannabinoid (eCB) system, which result in stronger reinforcing/rewarding effects of both opioids and cannabinoids. Targeting the eCB system has attracted great attention in the treatment of opioid use disorder (OUD), particularly given the urgent need to curb the current opioid crisis in the US. Increasing lines of evidence from animal studies demonstrate that chronic opioid use suppresses the eCB system. In particular, animal studies of chronic opioid administration reported decreased cannabinoid receptor type 1 (CB1R) in cortex. However, CB1R availability has not yet been investigated in humans with OUD. The availability of a PET ligand for CB1R makes it possible to study CB1R availability in individuals with OUD in vivo for the first time. The aim of this proposal is to use the CB1R-specific ligand [11C]OMAR and High Resolution Research Tomography (HRRT), a PET scanner with the highest sensitivity and resolution available for human brain imaging, to measure CB1R availability in vivo in individuals with OUD. As an exploratory aim, we will also measure peripheral levels of the eCBs anandamide (AEA) and 2-arachidonoylglycerol (2-AG) using liquid chromatography–mass spectrometry (LC-MS). Methods: Otherwise healthy individuals with opioid use disorder (on stable dose of maintenance methadone) and age-, gender-, race/ethnicity-matched healthy controls without recent use of any drugs (except nicotine, which will be matched between two groups) will undergo a single PET scan with [11C]OMAR and blood sampling to measure serum eCB levels (AEA and 2-AG). Hypotheses: Consistent with animal studies, relative to healthy controls, individuals with OUD will have lower availability of CB1R in cerebral cortex. Pilot data: Individuals with OUD (n=2) showed 12.76% lower cortical CB1R availability compared to matched historical controls from our repository of [11C]OMAR PET studies.