The effects of exercise on circulating endocannabinoid levels—a protocol for a systematic review and meta-analysis
Authors: Bristot Viviane , Poletto Giorgio , Pereira Débora Maria Russiano , Hauck Melina , Schneider Ione Jayce Ceola , Aguiar Aderbal S. 
Published: May 2022

Abstract
Background
Increased circulating endocannabinoids levels are typically associated with aerobic exercise. This phenomenon is associated with a “runner’s high,” a state of euphoria and well-being experienced after a long exercise. We will provide in this review a transparent and standardized methodology following the PRISMA-P and Cochrane Handbook for Systematic Reviews of Interventions for conducting a systematic review and meta-analysis for synthesizing the available evidence about the effects of physical activity on the circulating levels of AEA and 2-AG endocannabinoids in healthy subjects.

Methods
A multi-disciplinary team with basic and clinical expertise in exercise science developed this protocol. PubMed, EMBASE, Web of Science, CINAHL, SPORTDiscus, and Scopus will be the databases. A health sciences librarian was consulted in the development of the research. Search strategies will combine MeSH terms and free text words, including “exercise,” “exercise, physical,” “exercise training,” “physical activity,” “endocannabinoids,” “2-arachidonoyl-glycerol,” “glyceryl 2-arachidonate,” “2-AG,” “anandamide,” “AEA,” “n-arachidonoylethanolamide,” “adult,” “young adult,” and “middle-aged.” We will select experimental or quasi-experimental studies published through December 2021. The selection of studies, data extraction, assessment of the risk of bias, and the quality of evidence will be carried out in a paired and independent manner, and the consistency will be assessed using the statistics of Cohen Kappa. Methodological quality will be assessed using the Revised Cochrane risk of bias tool for randomized trials (RoB 2) and the Risk Of Bias In Nonrandomized Studies of Interventions (ROBINS-I) risk tool. We will use the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of the evidence, χ2 and I2 tests for heterogeneity, funnel plots, and the Egger test for publication bias. A meta-analysis for each data comparison will be performed whenever possible to determine the effect of physical activity on endocannabinoids’ circulating levels.

Discussion
This systematic review and meta-analysis will provide an overview of the evidence about physical activity over AEA and 2-AG endocannabinoids, including comparability of variables between studies, critical interpretation of results, and use of accurate statistical techniques. The endocannabinoid is molecules by which muscles communicate with other tissues and organs, mediating the beneficial effects of exercise on health and performance, including increased glucose uptake, improved insulin action, and mitochondrial biogenesis. They are essential to exercise. Thus, this study will review the acute effect of physical exercise on circulating levels of endocannabinoids in healthy individuals. The results of this study will potentially be transferred to doctors, health professionals, and legislators to guide their decision making, as well as will improve future research.

Systematic review registration
PROSPERO CRD42020202886.