Endocannabinoids and Stress-Related Neurospsychiatric Disorders: A Systematic Review and Meta-Analysis of Basal Concentrations and Response to Acute Psychosocial Stress.

Background: Dysregulation of the endocannabinoid (eCB) system is implicated in various stress-related neuropsychiatric disorders (SRDs), including anxiety, depression, and post-traumatic stress disorder (PTSD). In this systematic review and meta-analysis, our objectives were to characterize circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) concentrations at rest and in response to acute laboratory-based psychosocial stress in individuals with SRDs and without (controls). Our primary aims were to assess the effects of acute psychosocial stress on eCB concentrations in controls (Aim 1), compare baseline (prestress) eCB concentrations between individuals with SRDs and controls (Aim 2), and explore differential eCB responses to acute psychosocial stress in individuals with SRDs compared with controls (Aim 3). Methods: On June 8, 2023, a comprehensive review of the MEDLINE (PubMed) database was conducted to identify original articles meeting inclusion criteria. A total of 1072, 1341, and 400 articles were screened for inclusion in Aims 1, 2, and 3, respectively. Results: Aim 1, comprised of seven studies in controls, revealed that most studies reported stress-related increases in AEA (86%, with 43% reporting statistical significance) and 2-AG (83%, though none were statistically significant except for one study in saliva). However, meta-analyses did not support these patterns (p's>0.05). Aim 2, with 20 studies, revealed that most studies reported higher baseline concentrations of both AEA (63%, with 16% reporting statistical significance) and 2-AG (60%, with 10% reporting statistical significance) in individuals with SRDs compared with controls. Meta-analyses confirmed these findings (p's<0.05). Aim 3, which included three studies, had only one study that reported statistically different stress-related changes in 2-AG (but not AEA) between individuals with PTSD (decrease) and controls (increase), which was supported by the meta-analysis (p<0.001). Meta-analyses showed heterogeneity across studies and aims (I2=14-97%). Conclusion: Despite substantial heterogeneity in study characteristics, samples, and methodologies, consistent patterns emerged, including elevated baseline AEA and 2-AG in individuals with SRDs compared with controls, as well as smaller stress-related increases in 2-AG in individuals with SRDs compared with controls. To consider eCBs as reliable biomarkers and potential intervention targets for SRDs, standardized research approaches are needed to clarify the complex relationships between eCBs, SRDs, and psychosocial stress.

Genetic variation in endocannabinoid signaling: Anxiety, depression, and threat- and reward-related brain functioning during the transition into adolescence.

BACKGROUND: The endocannabinoid system modulates neural activity throughout the lifespan. In adults, neuroimaging studies link a common genetic variant in fatty acid amide hydrolase (FAAH C385A)-an enzyme that regulates endocannabinoid signaling-to reduced risk of anxiety and depression, and altered threat- and reward-related neural activity. However, limited research has investigated these associations during the transition into adolescence, a period of substantial neurodevelopment and increased psychopathology risk. METHODS: This study included FAAH genotype and longitudinal neuroimaging and neurobehavioral data from 4811 youth (46% female; 9-11 years at Baseline, 11-13 years at Year 2) from the Adolescent Brain Cognitive DevelopmentSM Study. Linear mixed models examined the effects of FAAH and the FAAH x time interaction on anxiety and depressive symptoms, amygdala reactivity to threatening faces, and nucleus accumbens (NAcc) response to happy faces during the emotional n-back task. RESULTS: A significant main effect of FAAH on depressive symptoms was observed, such that depressive symptoms were lower across both timepoints in those with the AA genotype compared to both AC and CC genotypes (p's<0.05). There were no significant FAAH x time interactions for anxiety, depression, or neural responses (p's>0.05). Additionally, there were no main effects of FAAH on anxiety or neural responses (p's>0.05). CONCLUSIONS: Our findings add to emerging evidence linking the FAAH C385A variant to lower risk of psychopathology, and extend these findings to a developmental sample. In particular, we found lower depressive symptoms in FAAH AA genotypes compared to AC and CC genotypes. Future research is needed to characterize the role of the FAAH variant and the eCB system more broadly in neurodevelopment and psychiatric risk.

Smaller Hippocampal Volume Is Associated With Reduced Posttraumatic Stress Symptoms in Children With Cancer and Survivors Following a Brief Novel Martial Arts-Based Intervention.

PURPOSE: Children with cancer and survivors frequently report posttraumatic stress symptoms (PTSS), which are associated with volumetric changes in stress-sensitive brain regions, including the hippocampus. METHODS: We examined the impact of a novel, 4-week martial-arts-based meditative intervention on cancer-related PTSS in 18 pediatric patients and survivors and whether baseline hippocampal volumes correlate with PTSS severity and/or PTSS changes over time. RESULTS: Overall, PTSS did not significantly change from baseline to post-intervention. Smaller hippocampal volume was correlated with more severe re-experiencing PTSS at baseline, and greater reductions in PTSS post-intervention. CONCLUSIONS: Together, hippocampal volume may be a biomarker of PTSS severity and intervention response. Identifying hippocampal volume as a potential biomarker for PTSS severity and intervention response may allow for more informed psychosocial treatments.

The First "Hit" to the Endocannabinoid System? Associations Between Prenatal Cannabis Exposure and Frontolimbic White Matter Pathways in Children.

Background: Cannabis is the most used federally illicit substance among pregnant people in the United States. However, emerging preclinical data show that a significant portion of cannabis constituents, such as Δ9-tetrahydrocannabinol and its bioactive metabolites, readily cross the placenta and accumulate in the fetal brain, disrupting neurodevelopment. Recent research using the Adolescent Brain Cognitive Development (ABCD) Study cohort has linked prenatal cannabis exposure (PCE) to greater neurobehavioral problems and lower total gray and white matter volume in children. Here, we examined the impact of PCE on frontolimbic white matter pathways that are critical for cognitive- and emotion-related functioning, show a high density of cannabinoid receptors, and are susceptible to cannabis exposure during other periods of rapid neurodevelopment (e.g., adolescence). Methods: This study included 11,530 children (mean ± SD age = 118.99 ± 7.49 months; 47% female) from the ABCD Study cohort. Linear mixed-effects models were used to examine the effects of caregiver-reported PCE on fractional anisotropy of 10 frontolimbic pathways (5 per hemisphere). Results: PCE was associated with lower fractional anisotropy of the right (ß = -0.005, p < .001) and left (ß = -0.003, p = .007) fornix, and these results remained significant after adjusting for a variety of covariates, multiple comparisons, fractional anisotropy of all fibers, and using a quality-control cohort only. Conclusions: In sum, we demonstrated small, yet reliable, effects of PCE on white matter integrity during childhood, particularly in the fornix, which plays a crucial role in emotion- and memory-related processes. Future studies are needed to understand the impacts of small changes in brain structure or function on neurodevelopment and risk of neurobehavioral problems.

Attention, attention! Posttraumatic stress disorder is associated with altered attention-related brain function.

Posttraumatic stress disorder (PTSD) is a debilitating condition characterized by altered arousal, mood, and cognition. Studies report attentional alterations such as threat bias in individuals with PTSD, though this work has largely been conducted within emotionally-charged contexts (e.g., threatening stimuli). Emerging behavioral evidence suggests that PTSD-related attention deficits exist even in the absence of threatening cues or anxiety triggers. However, the role and functioning of attention brain circuits as they relate to PTSD remains underexplored. In this mini review, we highlight recent work using non-emotional stimuli to investigate the neurobiology of attention and disruptions to attention-related brain function among individuals with PTSD. We then discuss gaps in the current literature, including questions pertaining to the neural circuitry of attentional alterations in PTSD, as well as the contributions that trauma exposure, PTSD symptoms, comorbidities, and pre-existing vulnerabilities may have in this relationship. Finally, we suggest future directions for this emerging area of research, which may further inform knowledge surrounding the neurobiological underpinnings of PTSD and potential treatments.