Endocannabinoids and Stress-Related Neurospsychiatric Disorders: A Systematic Review and Meta-Analysis of Basal Concentrations and Response to Acute Psychosocial Stress
Leah C Gowatch 1, Julia M Evanski 2, Samantha L Ely 1 3, Clara G Zundel 1, Amanpreet Bhogal 1, Carmen Carpenter 1, MacKenna M Shampine 1, Emilie O'Mara 1, Raegan Mazurka 4 5, Jeanne Barcelona 6, Leah M Mayo 7, Hilary A Marusak 1 3 8 9
- 1Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, Michigan, USA.
- 2Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, USA.
- 3Translational Neuroscience PhD Program, Wayne State University, Detroit, Michigan, USA.
- 4Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
- 5Nova Scotia Health, Halifax, Nova Scotia, Canada.
- 6Center for Health and Community Impact, College of Education, Wayne State University, Detroit, Michigan, USA.
- 7Hotchkiss Brain Institute and Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
- 8Department of Pharmacology, Wayne State University, Detroit, Michigan, USA.
- 9Merrill Palmer Skillman Institute for Child and Family Development, Wayne State University, Detroit, Michigan, USA.
Affiliationer
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.
Keywords: 2-AG; 2-arachidonoylglycerol; Maastricht Acute Stress Test; Trier Social Stress Task; anandamide; anxiety; depression; post-traumatic stress disorder.