Associations of endocannabinoid serum concentrations with behavioral impulsivity and substance use in late childhood to early adolescence.

Abstract

Adolescence is characterized by rapid neurobehavioral development. The endocannabinoid (eCB) system modulates several co-developing neurotransmitter systems and is well-implicated in preclinical substance use (SU) models. Few studies, however, have investigated associations between the eCB system and SU in adolescence. The present study evaluated associations between circulating eCB lipids and SU, impulsivity, and behavioral approach endophenotypes. Concentrations of eCBs [2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)] and related small bioactive lipids were quantified in serum samples from a substudy of youth (n = 432) enrolled in the Adolescent Brain Cognitive Development Study using liquid chromatography-mass spectrometry. Youth completed the UPPS-P Impulsive Behavior and Behavioral Inhibition/Behavioral Approach System Scales, a SU interview, and questionnaire on factors that impact circulating eCBs. Generalized additive models assessed for associations and sex interactions between eCB concentrations and behaviors. 2-AG and 2-oleoylglycerol were broadly associated with behavioral approach and urgency, while AEA and other N-acylethanolamines were associated with higher-order functions like perseverance and planning, with several sex interactions observed. 2-AG and AEA were negatively associated with low-level substance use and full-unit substance use, respectively. Although relationships between serum eCBs and concentrations in brain are not known, the associations observed between peripheral eCB concentrations and substance use behaviors could reflect differences in eCB homeostasis in the brain. Observed sex differences may suggest hormonal or sex-specific eCB influences on brain development. Further work using direct measures of eCB concentrations in the brain are needed to validate these speculations. Future studies should investigate these mechanisms longitudinally.