PROJECT SUMMARY
The endogenous endocannabinoid (eCB) system includes cannabinoid receptor 1 (CB1R), CB2R, and two
endogenous ligands (N-arachidonoylethanolamine;; AEA and 2-arachidonoylglycerol, 2AG). 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, reward response,
and stress 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 evidence, no study to date has examined the
role of the eCB system on neurocognition, mood, or early onset cannabis use and early cannabis subjective
effects ex vivo in human youth due to the inherent challenges in employing invasive techniques [i.e., PET
studies or collecting CSF]. However, there is now an available bioassay to measure circulating AEA and 2AG
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, mood and anxiety symptoms and regular CAN use. Notably, studies relating
serum eCB levels and neurocognitive, psychopathology, 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. Thus, this R21 project will be the first to establish the link between circulating eCB
levels and neurocognitive, psychopathology, and early CAN use outcomes in a subset of 2000 youth aged 11-
14 who are already enrolled in the longitudinal Adolescent Brain Cognitive Development (ABCD) Study (at 8
geographically-diverse research sites). We will also examine sex differences in these effects. Ultimately, this
project will inform policy and health campaigns regarding the role of the eCB system in adolescent
development and provide mechanistic information regarding the long-term impact of CAN exposure in youth.
