Childhood adverse experiences associate with reduced brain CB1 endocannabinoid receptor availability in healthy controls and patients with first-episode psychosis

Background The brain endocannabinoid system (ECS) is dysregulated in first-episode psychosis (FEP) but understanding of the nature and origins of ECS dysregulation in FEP is limited. The imprinting of developmental adversity and stress into the adult ECS has not been previously studied in humans. We tested the hypothesis that childhood adverse events (ACE) associate with decreased brain type-1 endocannabinoid receptor (CB1R) availability in patients with FEP and healthy controls (HC). Methods CB1R availability was measured cross-sectionally in male and female patients with FEP (n=15), and healthy participants (n=20). Brain CB1R binding was measured with the selective CB1R radiotracer [18F]FMPEP-d2 using positron emission tomography (PET). Distribution volumes (VT) using metabolite corrected arterial input was a proxy of CB1R availability, which was measured in 13 functionally relevant regions of interest (ROI). ACE before the age of 16 were categorized as simple (0-1 events) or multiple (≥ 2 events) using a Finnish population survey questionnaire. Results An rmANOVA model of regional CB1R VT (ROI ~ sex + group + sex*group + ACE) indicated statistically significant associations of ACE (p<0.001), group (p=0.027) and sex*group interaction(p=0.018). The largest effect sizes of ACE on CB1R were seen in the amygdala (η2=.37), temporal cortex (η2=.35), hippocampus (η2=.33) and insula (η2=.31). Discussion Multiple childhood adverse effects were associated with lower availability of temporo-limbic CB1R in adulthood in healthy participants and in patients with first-episode psychosis. These results corroborate previous results from pre-clinical studies, and expand the literature in showing that early adversity can be imprinted into the function of human brain in adulthood. The results have implications for studies on resilience and adaptation to stress as well as studies on vulnerability to psychiatric disorders.