January 25

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Chasing a Runner’s High 

Posted by on January 25, 2024 in Behavioral Neuroscience, Emotions, Exercise, Hormones, Neuroscience, Neuroscience in pop culture | Leave a comment

5ks, 10ks, half marathons, full marathons, ultra marathons… These terms bring a smile to the face of people who enjoy running, but the same words may strike up a reasonable sense of dread in others. Distance running is a popular hobby for people all over the world hoping to maintain and improve their cardiac fitness, and avid runners everywhere continue to push the boundaries of what the human body is capable of. For someone who does not enjoy running, it may be hard to conceptualize why people enjoy an activity like endurance-focused distance running. Almost as common as the hobby itself is the phrase runner’s high. Runner’s high has no official definition, but it broadly refers to a euphoric state that occurs during and shortly after a run. Anecdotally, runners experiencing this “high” tend to experience a decrease in muscle pain, allowing them to persevere and complete their endurance workout without pain getting in the way [1]. Even more spectacular is that runners also report feeling euphoric, a phenomenon characterized by a decrease in anxiety and stress [1]. These positive effects are what make the experience so sought after and widely discussed. 

Shockingly, despite the prevalence of this phenomenon and a common social definition of what it entails, many people have only a surface-level understanding of the science underlying this “high.” Even more surprising may be the realization that the science most people believe leads to a runner’s high is based on antiquated theories – the pop culture definition is incomplete. Our ever-advancing understanding of how the body processes pain relief and pleasure has contributed to more recent work focused on how the runner’s high truly works. 

The Endorphin Hypothesis

In the 1980s, initial research focusing on understanding the molecular mechanisms of runner’s high describes the role of endorphins. Endorphins are hormones produced and circulated in the body. When one thinks about the positive benefits of exercise, something that often comes to mind is an increase in endorphins – they have become pop culture’s star explanation for why exercise makes us feel good. But how does this work, and is it responsible for both the physical and mental effects associated with runner’s high? 

Endorphins act on opioid receptors, which are located throughout the body [2]. Though they share the name of the class of drugs we know as opioids, these receptors are primarily targeted by endogenous opioids. These molecules are produced by the body, meaning they are naturally occurring, and they act upon opioid receptors to elicit pain relief and many other biological outcomes. Exogenous opioids, such as morphine, are structurally similar to the compounds our body naturally produces, which is why they are so crucial in clinical settings to reduce pain via opioid receptor activation [3]. 

Running has been shown to lead to an increase in endorphins circulating in the bloodstream [4]. This increase in endorphins also leads to an increase in activation of peripheral opioid receptors, likely underlying the decrease in muscle pain that is commonly associated with runner’s high.

It is likely true that endorphins play an important role in quieting muscle aches and other physical symptoms in endurance athletes during and shortly after exercise. However, it is no longer thought that endorphins circulating the periphery of one’s body are responsible for the mood-related effects of runner’s high [4]. Initial doubts of the endorphin hypothesis stemmed from the fact that endorphins circulating in the bloodstream are too large to cross the blood brain barrier (BBB) [2]. The BBB is a structure at the junction of the peripheral and central nervous systems that is selectively permeable to only specific molecules. Essentially, the BBB keeps the central nervous system, which includes your brain and spinal cord, isolated from rogue molecules that may circulate in the periphery [5]. It stands to reason that whatever the mechanism may be underlying psychological facets of the runner’s high, originates in the brain. Typically, measurements of endorphin concentrations in the body are obtained through blood testing, which is not representative of endorphin concentrations in the central nervous system. Thus, it is not possible to claim that an increase of endorphins is leading to mood changes or any other associated phenotypes. These complications and advances in the study of the opioid system led scientists to begin investigating the potential role of different molecules called endocannabinoids in runner’s high. 

The Endocannabinoid Hypothesis

Endocannabinoids are molecules produced within the body that act on specialized cannabinoid receptors. The prefix endo describes the cannabinoids’ endogenous, or internal origin, setting them apart from exogenous molecules with external origins, i.e. cannabis compounds [3]. Indeed, endocannabinoids act on some of the same receptors that are targeted by cannabis, which mimics the endogenous cannabinoid Anandamide (you can read more in this NeuWrite article about how the body processes cannabis). Cannabinoid receptors are divided into two subtypes, which are expressed in neurons (CB1 receptors, the receptors targeted by cannabis and Anandamide) and in immune cells (CB2 receptors) [6]. Upon activation, these receptors can lead to a myriad of physical and psychological outcomes, including reduction of pain and anxiety [7]. 

Importantly, it has been shown that humans display a significant increase in the endocannabinoid Anandamide levels following an hour of intense exercise – in one study’s case, focusing on endurance cardio – running on a treadmill or riding a workout bike [7]. Blood was analyzed immediately following exercise to quantify endocannabinoid levels, and each participant’s results were compared to their own baseline sample. This study indicated that exercise indeed increases endocannabinoid system activation in humans, specifically implicating the CB1 receptor in modulating behaviors relevant to runner’s high. However, further research needed to be carried out on a more mechanistic level to truly understand the reactions taking place, and this led researchers to animal behavior. 

To investigate the precise roles of CB1 and CB2 receptors in reducing anxiety and pain in the state of a runner’s high, researchers turned to lab mice. By utilizing mice as a model, researchers gain access to an exhaustive molecular-genetic toolkit. This not only allowed them to measure running-induced changes in endorphins and endocannabinoids, but also afforded the ability to block the function of specific opioid receptors to determine their precise role in the mechanism. Experimental mice were given running wheels in their cages for three days, where they ran an average of 5.4 kilometers each day. After habituating to the wheel, mice were broken into two groups – runners and controls – matched based on the average distance run. All mice were then blocked from their wheels for two days, before running groups were finally allowed to run for five hours on day 6. Then, behavioral testing began (Figure 1A) [8]. 

Figure 1. A) Running distance completed by control (black) and experimental (red, “RUN”) groups on days 1 through 6 of the experiment. B) Mice experiencing elevated levels of anxiety will remain in dark, safe, spaces, while less anxious mice will explore bright areas. In this assay, experimenters found that mice who ran before testing displayed decreased anxiety – they spent more time in the light area compared to controls. C) The hotplate assay is a measure of thermal pain response. Mice are placed on a warmed surface and experimenters measure the time it takes them to respond to the heat. Shorter latency is indicative of higher pain sensitivity. This experiment found that mice who ran before testing displayed longer latencies, indicating a decreased pain response. Adapted from Fuss et al, 2015.

Mice were tested on measures of anxiety and pain tolerance, two behaviors typically associated with runner’s high. It was found that mice in the running group displayed increased pain tolerance and decreased anxiety (Figure 1B, 1C). Interestingly, they also observed that when all mice were returned to their home cages with access to wheels, mice from the running group showed less activity than the control group – similar to another facet of runner’s high that has been previously reported – sedation [8]. While this is fascinating behavioral evidence, this team delved deeper into the mechanisms underlying these behaviors to learn more about the biology. The researchers decided to repeat these experiments with a pharmacological component; they administered several antagonists (blockers) of endocannabinoid receptors on day 6 before mice were allowed to run. They were able to determine that specifically when CB1 receptors were blocked, mice did not show decreased anxiety following running. This indicated that CB1 receptors are necessary for the runner’s high effect of decreased anxiety. Next, they also discovered that blocking either CB1 or CB2 receptors could prevent the increase in pain tolerance previously observed after running. Essentially, they found that different types of endocannabinoid receptors were necessary for two of the most highly reported runner’s high related phenotypes. This exciting work sheds light on the role of the endocannabinoid system in exercise, advancing our understanding of why running can make us feel good.

Chasing the High

Next time you complete an endurance workout, if you feel the rush of a runner’s high, you will know you have your endocannabinoid receptors to thank. Even so, if it eludes you, do not fret – not every run will bring you the benefits of this “high”. Additionally, not all types of exercise will bring one into the state of a runner’s high. Research has focused on endurance cardio, primarily running and stationary biking, but there is a myriad of other psychological and physical benefits to exercise that emerge when keeping one’s body active in other ways (for more information on exercise and brain state, check out this recent NeuWrite article discussing flow). Thus, even with our evolving understanding of the role endocannabinoids and endorphins both play in runner’s high, there is still a lot to uncover about how we access this state, as well as other flow-like brain states in exercise. For now, researchers will chase these advances in understanding like we chase that runner’s high.

Citations

  1. Siebers M, Biedermann SV, Fuss J. (2023). Do Endocannabinoids Cause the Runner’s High? Evidence and Open Questions. The Neuroscientist. 29(3), 352-369. doi:10.1177/10738584211069981
  2. Dietrich, A., & McDaniel, W. F. (2004). Endocannabinoids and exercise. British journal of sports medicine, 38(5), 536–541. https://doi.org/10.1136/bjsm.2004.011718
  3. Corder, G., Castro, D. C., Bruchas, M. R., & Scherrer, G. (2018). Endogenous and Exogenous Opioids in Pain. Annual review of neuroscience, 41, 453–473. https://doi.org/10.1146/annurev-neuro-080317-061522
  4. Linden, D. J. (2021). The truth behind “Runner’s high” and other mental benefits of running. Johns Hopkins Medicine. https://www.hopkinsmedicine.org/health/wellness-and-prevention/the-truth-behind-runners-high-and-other-mental-benefits-of-running
  5. Gawdi, R., Shumway, K. R., & Emmady, P. D. (2023). Physiology, blood brain barrier. NCBI bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK557721/
  6. Peter Grinspoon, M. (2021, August 11). The endocannabinoid system: Essential and mysterious. Harvard Health. https://www.health.harvard.edu/blog/the-endocannabinoid-system-essential-and-mysterious-202108112569
  7. Sparling, P. B., Giuffrida, A., Piomelli, D., Rosskopf, L., & Dietrich, A. (2003). Exercise activates the endocannabinoid system. Neuroreport, 14(17), 2209–2211. https://doi.org/10.1097/00001756-200312020-00015 
  8. Fuss, J., Steinle, J., Bindila, L., Auer, M. K., Kirchherr, H., Lutz, B., & Gass, P. (2015). A runner’s high depends on cannabinoid receptors in mice. Proceedings of the National Academy of Sciences, 112(42), 13105–13108. https://doi.org/10.1073/pnas.1514996112