After finishing a grueling run and collapsing onto your living room floor, you’re often met not only with exhaustion, but also an immense sense of satisfaction and happiness. This surprising mood is a testament to the incredible benefits from exercise, and was often credited to an endorphin rush from running. But new research indicates that the positive mental effects of running are primarily hormonal, and like the runner’s high, are caused by the endocannabinoid system. But why was it originally credited to endorphins, and how are we certain the endocannabinoid system is the true cause?
The initial reason endorphins were credited with the improved mood was due to their role in pain reduction and increased presence during intense physical activities. The stress of running does trigger the pituitary gland to release beta-endorphins into the bloodstream. And while endorphins do reduce pain by binding to nerve receptors in muscles and tissues, the truth is endorphins in the bloodstream can’t access the brain due to the blood-brain barrier. In its unconjugated form, beta-endorphins are hydrophilic peptides, or large chains of amino acids that are attracted to water while the blood-brain barrier is made of cells with a lipid cell membrane and tight junctions, preventing the passage of large molecules and hormones. The contrasting characteristics of endorphins hinders its ability to transfer through the brain capillary wall. Additionally, enzymes called peptidases located near the brain capillaries quickly break down the endorphins to useable amino acids – so the few endorphins that near the blood-brain barrier end up getting deteriorated [1]. Since the mental benefits of running are due to neurobiological mechanisms within the brain, which endorphins aren’t able to access, what actually causes this increased mood?
The answer lies in the endocannabinoid system. Made from a lipid structure derived of omega-6 polyunsaturated fatty acids [2], endocannabinoids can pass through the blood-brain barrier and readily access the CB1 receptors which are heavily distributed throughout the brain, particularly in the striatum, prefrontal cortex and hippocampus [1] which control mood and feelings of reward and satisfaction. A 2019 study found that moderate intensity exercise led to significant elevations in the endocannabinoid anandamide among women with major depressive disorder [3]. A moderate inverse relationship was observed from changes of concentration of anandamide and negative mood, supporting the reasonable conclusion that the endocannabinoid system contributes to the increased euphoria after exercise.
In a 2015 study, researchers investigated the anxiolytic, or anxiety-reducing, benefits of long-distance running in mice. Mice were provided with continuous access to running wheels, emulating prolonged exercise. Their behavior was then assessed using a dark-light box test and compared to that of sedentary control mice. The running mice spent significantly more time in the illuminated part of the box, suggesting a reduction in anxiety. Scientists then experimented with mice who were given endocannabinoid blockers or had a genetic deletion of CB1 endocannaboid receptors and discovered that they did not display the reduction in anxiety after exercise. However, the mice that were given naloxone, an opioid antagonist which blocks the effects of endorphins, didn’t have a significant change in behavior. These results indicate that the endocannabinoid system is main effector for the benefits of running [4]. Ultimately, running is a powerful stress-reducing and mood booster due to the intricate endocannabinoid system. When life gets frustrating, remember that a pair of running shoes and an open trail may be the cure to your troubles.
[1]:
Pardridge, William M., Domingo Triguero, and Jody L. Buciak. “βEndorphin Chimeric Peptides: Transport through the Blood-Brain Barrier in Vivo and Cleavage of Bisulfide Linkage by Brain” Endocrinology, vol. 126, no. 2, 2 Aug. 2006, pp. 977–985, https://academic.oup.com/endo/article-abstract/126/2/977/2533012. Accessed 20 June 2025.
[2]:
Amatriain-Fernández, Sandra et al. “The Endocannabinoid System as Modulator of Exercise Benefits in Mental Health.” Current neuropharmacology vol. 19,8 (2021): 1304-1322. doi:10.2174/1570159X19666201218112748
[3]:
Meyer, Jacob D et al. “Serum Endocannabinoid and Mood Changes after Exercise in Major Depressive Disorder.” Medicine and science in sports and exercise vol. 51,9 (2019): 1909-1917. doi:10.1249/MSS.0000000000002006
[4]:
Fuss, Johannes et al. “A runner’s high depends on cannabinoid receptors in mice.” Proceedings of the National Academy of Sciences of the United States of America vol. 112,42 (2015): 13105-8. doi:10.1073/pnas.1514996112