Biobehavioral Interactions between Endocannabinoid and Hypothalamic-pituitary-adrenal Systems in Psychosis: A Systematic Review

Background: The diathesis-stress paradigm and the cannabinoid-hypothesis have been proposed as possible pathophysiological models of schizophrenia. However, they have historically been studied independently of each other. Objective: This PRISMA 2020-compliant systematic review aimed at reappraising the interplay be- tween the hypothalamic-pituitary-adrenal (HPA) axis and the endocannabinoid (eCB) system in psy- chosis-spectrum disorder risk and outcome. Methods: All pathophysiological and outcome clinical studies, concomitantly evaluating the two sys- tems in psychosis-spectrum disorder risk and different stages of illness, were gathered from electronic databases (Pubmed, Web of Science, and Scopus), and discussed. Results: 41 eligible outputs were extracted, focusing on at least a biological measure (9 HPA-related studies: 4 eCB-interventional, 1 HPA-interventional, 1 both HPA-interventional and non-interventional, 3 non-interventional; 2 eCB-related studies: non-interventional), environmental measures only (29 studies: 1 eCB- interventional, 28 non-interventional), and genetic measures (1 study: non-interventional). In- dependent contributions of aberrancies in the two systems to the physiopathology and outcome of psy- chosis were confirmed. Also, concomitant alterations in the two systems, either genetically defined (e.g., CNR1 genetic variation), biologically determined (e.g., dysfunctional HPA axis or endocanna- binoid signaling), or behaviorally imputed (e.g., cannabis use, stress exposure, and response), were consistently reported in psychosis. Further, a complex biobehavioral perturbation was revealed not on- ly within each system (e.g., cannabis use affecting the eCB tone, stress exposure affecting the HPA ax- is), but also across the two systems (e.g., THC affecting the HPA axis, childhood trauma affecting the endocannabinoid signaling). Conclusion: There is a need to concomitantly study the two systems' mechanistic contribution to psychosis in order to establish more refined biological relevance.