A Systematic Review and Meta-Analysis on the Effects of Exercise on the Endocannabinoid System

Abstract

Introduction: The endocannabinoid (eCB) system plays a key role in maintaining homeostasis, including the regulation of metabolism and stress responses. Chronic stress may blunt eCB signaling, and disruptions in eCB signaling have been linked to stress-related psychiatric disorders and physical health conditions, including anxiety, depression, post-traumatic stress disorder (PTSD), diabetes, and obesity. Pharmacological and nonpharmacological behavioral interventions (e.g., exercise) that target the eCB system may be promising therapeutic approaches for the prevention and treatment of stress-related diseases. In this study, we perform a systematic review and the first meta-analysis to examine the impact of exercise on circulating eCB concentrations. Materials and Methods: We performed a review of the MEDLINE (PubMed) database for original articles examining the impact of exercise on eCBs in humans and animal models. A total of 262 articles were screened for initial inclusion. Results: Thirty-three articles (reporting on 57 samples) were included in the systematic review and 10 were included in the meta-analysis. The majority of samples that measured anandamide (AEA) showed a significant increase in AEA concentrations following acute exercise (74.4%), whereas effects on 2-arachidonoylglycerol (2-AG) were inconsistent. The meta-analysis, however, revealed a consistent increase in both AEA and 2-AG following acute exercise across modalities (e.g., running, cycling), species (e.g., humans, mice), and in those with and without pre-existing health conditions (e.g., PTSD, depression). There was substantial heterogeneity in the magnitude of the effect across studies, which may relate to exercise intensity, physical fitness, timing of measurement, and/or fasted state. Effects of chronic exercise were inconsistent. Conclusions: Potential interpretations and implications of exercise-induced mobilization of eCBs are discussed, including refilling of energy stores and mediating analgesic and mood elevating effects of exercise. We also offer recommendations for future work and discuss therapeutic implications for exercise in the prevention and treatment of stress-related psychopathology.

Keywords: anandamide; endocannabinoids; mental health; physical activity; running.

FIG. 1.

Flowchart of literature search strategy, and identification of articles for the systematic review and meta-analysis.

FIG. 2.

Forest plots for meta-analyses on effects of acute exercise on (a) AEA and (b) 2-AG concentrations (pmol/mL). Note: some articles reported effects in different samples separately (e.g., PTSD and healthy control groups); therefore, these articles are entered more than once in the meta-analysis and treated as separate subgroups. The total effects (bottom) are reported on a different scale than the study effects. Individual studies show mean difference scores and the pooled results show weighted mean differences and 95% confidence intervals. The size of the block indicates the weight assigned to that study in the meta-analysis and the horizontal line depicts the confidence interval. Thus, larger block sizes indicate studies with larger weight (typically with narrower confidence intervals), which contribute more to the calculation of the summary result. The summary result is presented as a diamond at the bottom. The total around that diamond is circled to draw attention to the total effect. 2-AG, 2-arachidonoylglycerol; AEA, anandamide; PTSD, post-traumatic stress disorder.

FIG. 3.

Proposed increase in AEA and 2-AG concentrations following moderate acute exercise.