Examining the longitudinal impact of circulating endocannabinoid levels on neurocognition, impulsivity, and early cannabis use patterns in youth enrolled in the ABCD Study - PROJECT SUMMARY The endogenous endocannabinoid (eCB) system includes cannabinoid receptor 1 (CB1R), CB2R, and two endogenous ligands (N-arachidonoylethanolamine, AEA and 2-arachidonoylglycerol, 2AG) and endocannabinoid lipid mediators (oleoylethanolamide, OEA, palmitoylethanolamide, PEA, and 2-oleoylglycerol, 2OG). Animal findings demonstrate that the eCB system undergoes dynamic changes during adolescence and suggest a significant role in neurodevelopment, especially in CB1R-dense prefrontal, parietal, striatal and limbic brain regions. Research in adults have found that eCB system signaling modulates executive functioning (i.e., impulsivity, behavioral approach), reward response, and affective processing. Thus, there is strong preclinical evidence that the eCB system plays a substantial role in neuronal activity and neurodevelopment and disruption of or reduced eCB signaling during adolescence may result in abnormal neurocognitive development, risk for psychopathology, and increased risk for substance use, especially cannabis (CAN) use. Despite this rich preclinical evidence, no study to date has examined the longitudinal role of the eCB system on neurocognition or early onset cannabis and other substance use ex vivo in human youth due to the inherent challenges in employing invasive techniques [i.e., PET studies]. However, there is now an available bioassay to measure circulating eCBs in serum collected from blood, that can be measured ex vivo in humans. Serum AEA and 2AG levels reflect both peripheral system synthesis and overflow from the brain and animal evidence has shown that circulating and brain eCB concentrations are robustly and significantly correlated. Further, adult studies have found significant associations between circulating serum eCBs and executive functioning, stress response, reward signaling, affective processing and regular CAN use. Notably, longitudinal studies relating serum eCB levels and neurocognitive and CAN use outcomes have not yet been conducted in youth- despite convincing preclinical evidence that the impact may be greater during these critical neurodevelopmental years. The proposed R01 project will expand upon our cross-sectional pilot R21 study and be the first to establish the longitudinal effects of circulating eCB levels and changes over time on neurocognitive, impulsivity/behavioral approach, and early CAN, alcohol and other substance use development in a subset of 2000 youth as they age from 13-20 years old who are already enrolled in the longitudinal Adolescent Brain Cognitive Development (ABCD) Study (8 research sites). We will also examine sex differences in these effects.
