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The Effects of Cannabinoids on Stress-Coping

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The Effects of Cannabinoids on Stress-Coping Utah State University DigitalCommons@USU All Graduate Theses and Dissertations Graduate Studies 5-2021 The Effects of Cannabinoids on Stress-Coping Behaviors and Neuroendocrinological Measures in Chronic Unpredtictable Stress: A Preclinical Systematic Review and Meta-Analysis Noa Reuveni Utah State University Follow this and additional works at: https://digitalcommons.usu.edu/etd Part of the Psychology Commons Recommended Citation Reuveni, Noa, "The Effects of Cannabinoids on Stress-Coping Behaviors and Neuroendocrinological Measures in Chronic Unpredtictable Stress: A Preclinical Systematic Review and Meta-Analysis" (2021). All Graduate Theses and Dissertations. 8098. https://digitalcommons.usu.edu/etd/8098 This Thesis is brought to you for free and open access by the Graduate Studies at DigitalCommons@USU. It has been accepted for inclusion in All Graduate Theses and Dissertations by an authorized administrator of DigitalCommons@USU. For more information, please contact [email protected]. THE EFFECTS OF CANNABINOIDS ON STRESS-COPING BEHAVIORS AND NEUROENDOCRINOLOGICAL MEASURES IN CHRONIC UNPREDTICTABLE STRESS: A PRECLINICAL SYSTEMATIC REVIEW AND META-ANALYSIS by Noa Reuveni A thesis submitted in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE in Psychology Approved: __________________ __________________ Sara Freeman, Ph.D. Scott Bates, Ph.D. Co-Major Professor Co-Major Professor __________________ __________________ Diana Meter, Ph.D. Sarah Schwartz, Ph.D. Committee Member Committee Member __________________ __________________ Tyler Renshaw, Ph.D. D. Richard Cutler, Ph.D. Committee Member Interim Vice Provost for Graduate Studies UTAH STATE UNIVERSITY Logan, Utah 2021 ii Copyright © Noa Reuveni 2021 All Rights Reserved iii ABSTRACT The Effects of Cannabinoids on Stress-Coping Behaviors and Neuroendocrinological Measures in Chronic Unpredictable Stress: A Preclinical Systematic Review and Meta-Analysis by Noa Reuveni, Master of Science Utah State University, 2021 Major Professors: Dr. Sara Freeman and Dr. Scott Bates Department: Psychology Preclinical neuroscience research presents contradictory evidence in support of both protective and destructive effects of cannabinoids in the context of chronic unpredictable stress. Cannabis, one of the most commonly abused drugs, affects the hypothalamic pituitary adrenal axis stress response, similarly to other drugs of abuse. Compared to other drugs of abuse, cannabis primarily interacts with the endogenous cannabinoid system. The endogenous cannabinoid system has been recently identified to facilitate both activation and termination of the hypothalamic pituitary adrenal axis stress response. This systematic review and meta-analysis summarizes the existing preclinical literature on the effects of cannabinoid administration in the chronic unpredictable stress model of depression. Scopus, Embase, Psychology & Behavioral Sciences Collection, APA PsychINFO, PubMed, CINAHL Complete, and ProQuest Dissertations & Theses iv Global were systematically searched for articles that met inclusion criteria and the standardized mean differences were calculated for each continuous behavioral measure between vehicle chronic unpredictable stress groups and cannabinoid-treated chronic unpredictable stress groups. The overall effect of cannabinoids on depressive-like behavior was evaluated using a multi-level mixed effects model with effect size weights nested within control groups to address dependency between measurements compared to same control group. A total of 26 preclinical articles were included. Overall, cannabinoid administration rescued the negative effects of chronic unpredictable stress on anhedonia, learned helplessness, novelty suppressed feeding, and exploration anxiety with a pooled standardized mean difference of 0.4456 (95% CI 0.0498 – 0.8415, p = 0.0274). Moderator analyses revealed that this effect significantly increased with an increasing number of cannabinoid administrations and doses. Furthermore, this effect was significantly greater in mice, with cannabinoids that enhances the endogenous cannabinoid system, with cannabinoid treatments that are not co-treatments, and when the cannabinoid is administered during chronic unpredictable stress. These findings suggest that cannabinoids may be a viable treatment for stress-related psychopathologies but further investigation is needed into the sample characteristics where cannabinoids are more efficacious in order to properly assess the benefits of cannabinoid-based pharmacotherapies. (96 Pages) v PUBLIC ABSTRACT The Effects of Cannabinoids on Stress-Coping Behaviors and Neuroendocrinological Measures in Chronic Unpredictable Stress: A Preclinical Systematic Review and Meta-Analysis Noa Reuveni It is unclear if cannabis helps individuals cope with life’s stressors or increases the likelihood of developing stress-related disorders such as depression. Chronic unpredictable stress is a validated model of depression that exposes rodents to a series of frequently-occurring, intermittent stressors over the course of a few weeks. This systematic review and meta-analysis summarizes existing research using rodents on the effects of cannabinoids on stress-coping behaviors and neuroendocrinological measurements in chronic unpredictable stress. Databases were systematically searched for articles that met inclusion criteria, and effect sizes between control chronic unpredictable stress groups and cannabinoid-treated chronic unpredictable stress groups were calculated. A meta-analysis of the 26 included articles indicated that cannabinoids prevent the negative effects of chronic unpredictable stress, suggesting that the development of cannabinoid-based drugs has the potential to treat stress-related disorders such as depression. vi ACKNOWLEDGMENTS I am eternally grateful for Sara’s unconditional support, words of encouragement, and for believing in my capabilities. I could not have asked for a more approachable and inspirational role model. Thank you for mentoring me with empathy, humility, and for reminding me that it is okay to focus on one thing at a time. I am especially thankful for Cole’s commitment to the completion of this project and for providing me with the opportunity to grow as a mentor. I would like to thank Scott for believing in my success, for genuinely listening to me, and for ensuring that my voice is heard. I would also like to acknowledge Diana and Tyler’s for providing their resources and meta-analysis expertise throughout this project. I am grateful of Diana’s consistent reminders regarding the realities of research and for validating my approach to this learning experience. I am especially thankful for Sarah, Tyson, Demi and Jake for their statistical expertise and technical assistance with REDCap. This work would have not been possible without Sarah’s reassurance and help with the analysis. I would also like to especially thank Sandra and Mary for their expertise in the database search, for teaching me how to effectively utilize these databases, and for providing me with access to the Embase database. Finally, I would like to thank Ben, my numerous friends, and my family for their unconditional love and support throughout this process. This thesis is dedicated to parents and my two brothers, Guy and Itai. Noa Reuveni vii CONTENTS Page ABSTRACT ...................................................................................................................... iii PUBLIC ABSTRACT ........................................................................................................ v ACKNOWLEDGMENTS ................................................................................................ vi LIST OF TABLES ............................................................................................................ ix LIST OF FIGURES ............................................................................................................ X LIST OF ABBREVIATIONS ........................................................................................... Xi CHAPTER I. INTRODUCTION ........................................................................................ 1 Importance .................................................................................................................. 1 Aims ............................................................................................................................ 2 CHAPTER II. LITERATURE REVIEW ........................................................................... 3 Stress and The Hypothalamic Pituitary Adrenal Axis ................................................ 3 The Endogenous Cannabinoid System and Cannabinoids .......................................... 7 Stress-Induced Endocannabinoid Mobilization ........................................................ 12 Statement of the Problem .......................................................................................... 13 CHAPTER III. MATERIALS AND METHODS ............................................................ 15 Overview ................................................................................................................... 15 Criteria ...................................................................................................................... 15 Search Strategy ......................................................................................................... 16 Data Collection ........................................................................................................
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