If you've ever felt a surge of euphoria after going for a run, you're not alone. This phenomenon, known as 'the runner's high', is a natural response that can make people who don't even like to run feel invincible.
The search for the neurobiological causes of the runner’s high has fascinated scientists and laymen for the past decades. A runner’s high is defined as an emotional state during or after endurance training characterized by reduced pain sensitivity, sedation, euphoria, and eased anxiety. Some have also emphasized a lost sense of time and feelings of effortlessness.
Research has historically claimed that
the release of endorphins, a hydrophilic (i.e., mix with or dissolve in water) molecule binding to opioid receptors is responsible for the runner’s high.
Although this hypothesis was widely perpetrated by the media, it had little evidence to support it(1).
There were a couple lines of evidence that didn’t support this theory. First, peripheral endorphins do not have a major effect on the brain, as they cannot cross the blood-brain barrier due to their hydrophilic structure. Hence, a link between peripheral endorphin levels during endurance exercise and elevated mood could not be discovered(2).
Second, blockage of the opioid system did not affect the subjective experience during endurance exercise(3).
In the 1990s, two main endogenous endocannabinoids (arachidonoyl ethanolamide), which was termed “anandamide” (AEA) and 2-arachidonoyl glycerol (2-AG). Their discovery led to the endocannabinoid hypothesis of the runner’s high. Unlike the hydrophilic nature of endorphins, endocannabinoids are lipophilic (i.e., combine with or dissolve in lipids or fats) molecules and can penetrate the blood-brain barrier easily, making them better candidates to
explain the runner’s high(4).
The endocannabinoid system is a potent endogenous system involved in various physiological functions in the nervous system. Some involved physiological processes are synaptic transmission, mood, reward, anxiety, appetite, memory processing, neuroprotection, and neuroinflammation (see figure below).
Figure: The release of endocannabinoids is triggered by various stimuli (red arrows). Higher levels of endocannabinoids in turn were associated with a plethora of (neuro)biological consequences (blue arrows)(5).
In addition, they also play crucial roles during neural development, for example, neuronal proliferation, neuronal migration, and axonal growth.
Interestingly, it seems that not every human can experience a runner’s high.
For example, studies with endurance runners reported that only 69% to 77% of the participants experienced a runner’s high at least once in the past.
These findings may be complicated by a poor conceptualization of the runner’s high as a complete description of this phenomenon isn’t well communicated in research. Consequently, this complicates research into
the neurobiology of a runner’s high.
Despite the limited and inconsistent data in humans, animal research indicates that endocannabinoid signaling is essential for voluntary wheel running in mice and rats(6).
Another trait of the runner’s high, euphoria, is yet not possible to study in animal models. Therefore, in recent years, there have been increasing efforts to investigate the relationship between characteristics of runner’s high and endocannabinoids in humans.
This article will provide an overview of the relation between endurance exercise and endocannabinoids and address the four main features of the runner’s high:
Most of the evidence to date indicates a significant increase in endocannabinoids after acute exercise. Studies that didn’t demonstrate a significant increase in AEA used a low exercise intensity or a high latency until blood was sampled post-exercise. An increase in 2-AG was only found in about 40% of the studies which may be due to small sample sizes and not being able to detect 2-AG.
While
acute exercise enhances endocannabinoids and endocannabinoid-like lipids, the opposite was found for long-term endurance exercise programs, which regularly found a decrease in endocannabinoid levels. This finding must be interpreted with caution because only four studies were published on that topic and several potential biases must be considered.
Apart from a possible reporting bias, changes in body mass index and fat tissue following long-term exercise may have an impact on the endocannabinoid system.
Exercise consistently had an encouraging effect on mood.
For example, euphoria and feelings of happiness were reported after acute exercise(4).
Another study found a significant association between positive affect of AEA levels following acute exercise. While the self-reported positive effects of endurance exercise are a robust finding across studies, the possible role of endocannabinoids, and particularly AEA, has come into focus only recently.
The anxiolytic
(reduced anxiety) effect of exercise after a bout of exercise has been shown in 80% of the research. The anxiolytic effects of a bout of exercise were also detected in an anxiety-provoking virtual reality paradigm(4).
In exercising women suffering from major depression, a negative correlation between AEA levels and state anxiety after exercise was demonstrated. In a study where participants received predictable and unpredictable electric shocks in an Neutral-Predictable-Unpredictable threat task, a higher increase in endocannabinoids was associated with a higher decrease in anxiety and fear ratings(7).
Although a sedative effect of running is often assumed, none of the research indicates an effect of exercise on alertness.
Thus, there is still no evidence that the fourth criterion of
a runner’s high, namely, sedation, is indeed associated with the endocannabinoid system. Meanwhile, a study in mice suggests that sedation is an unspecific consequence of exercise that does not require endocannabinoid signaling(6).
Provoking a runner’s high might be challenged by several aspects. Lactate thresholds might differ between individuals. Moreover, a rise in lactate levels in the blood can affect metabolization in the brain which might influence endocannabinoid signaling(8).
Therefore, different exercise intensities and individual cardiorespiratory fitness levels may impact responses of the endocannabinoid system. Future research into endocannabinoid-mediated mechanisms should attend to these variations by measuring individual lactate changes or cardiorespiratory fitness.
These factors, as well as heterogeneities in how blood sampling and processing were performed, could explain the negative findings in some studies that investigated endocannabinoid after acute exercise. However, no correlation between AEA release and brain activity was detected. All research to date has focused on endocannabinoid ligands in blood.
There may be significant changes in endocannabinoid receptor expression and activity in the brain as demonstrated in animal research.
A research study with a positron emission tomography and an endocannabinoid ligand would be an important step toward the understanding of the brain structures involved with the positive effects of exercise-induced endocannabinoids in humans.
An ongoing and open question is where and how exercise-induced endocannabinoids may affect the brain. Using a functional magnetic resonance imaging (fMRI) task, increased activity in the caudate nucleus and hippocampus was found in a previous study also investigating endocannabinoids(9).
There needs to be more research regarding exercise-induced hypoalgesia, which is decreased sensitivity to painful stimuli.
While some evidence suggests that exercise-induced hypoalgesia may be explained through endocannabinoid release during
short-duration isometric exercise, studies included in this review that investigated acute endurance exercise were inconsistent.
No research has evaluated endocannabinoid levels after 60 minutes at 70% to 85% of age-predicted maximal heart rate. It might be that the endocannabinoid system is also affected when energy metabolization processes of the body change during longer exercise regimes. A trial with sampling blood during a marathon would be an elegant path to evaluate the endocannabinoid system over time.
Practically all the research to date has been performed inside a controlled laboratory. Surroundings during exercise might impact the endocannabinoid system and might help produce a runner’s high. Future research should focus on such contextual factors.
Acute aerobic exercise activates the endocannabinoid system. There were significant increases in AEA and less frequently in 2-AG after both preferred and prescribed exercise. Exercise-induced increases in endocannabinoids seem to be associated with features of a runner’s high, namely, decreased levels of anxiety and increased euphoria.
Some evidence indicates that endocannabinoids are associated with decreased perception of pain after exercise. Meanwhile, evidence for associations between endocannabinoids and sedation post-exercise is limited.
Chronic aerobic exercise, on the other hand, is associated with decreased levels of endocannabinoids and the neurobiological consequences of the supposed downregulation of the endocannabinoid system are not clear yet (see figure below)
Figure: The endocannabinoids anandamide and 2-AG are increased after acute exercise and the increase is associated with features of the runner’s high. In contrast, chronic exercise leads to a downregulation of the endocannabinoids and the neurobiological consequences of this downregulation are not yet clear(10).
After reviewing the current research to date, the following are suggestions on how to stimulate endocannabinoid release and produce a runner’s high:
Levagen+, an ingredient in Rested-AF, is one of two branded palmitoylethanolamides in the industry with gold-standard clinical studies.
Levagen+ is part of the extended endocannabinoid family which has been tested on various populations and clinically proven to:
- Reduce discomfort
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References:
1. Dietrich A, McDaniel WF: Endocannabinoids and exercise. Br J Sports Med 38:536-41, 2004
2. Kraemer RR, Blair S, Kraemer GR, et al: Effects of treadmill running on plasma beta-endorphin, corticotropin, and cortisol levels in male and female 10K runners. Eur J Appl Physiol Occup Physiol 58:845-51, 1989
3. Farrell PA, Gustafson AB, Garthwaite TL, et al: Influence of endogenous opioids on the response of selected hormones to exercise in humans. J Appl Physiol (1985) 61:1051-7, 1986
4. Siebers M, Biedermann SV, Bindila L, et al: Exercise-induced euphoria and anxiolysis do not depend on endogenous opioids in humans. Psychoneuroendocrinology 126:105173, 2021
5. Hillard CJ: Circulating Endocannabinoids: From Whence Do They Come and Where are They Going? Neuropsychopharmacology 43:155-172, 2018
6. Fuss J, Steinle J, Bindila L, et al: A runner's high depends on cannabinoid receptors in mice. Proc Natl Acad Sci U S A 112:13105-8, 2015
7. Crombie KM, Cisler JM, Hillard CJ, et al: Aerobic exercise reduces anxiety and fear ratings to threat and increases circulating endocannabinoids in women with and without PTSD. Ment Health Phys Act 20, 2021
8. Basso JC, Suzuki WA: The Effects of Acute Exercise on Mood, Cognition, Neurophysiology, and Neurochemical Pathways: A Review. Brain Plast 2:127-152, 2017
9. Marin Bosch B, Bringard A, Logrieco MG, et al: Effect of acute physical exercise on motor sequence memory. Sci Rep 10:15322, 2020
10. Siebers M, Biedermann SV, Fuss J: Do Endocannabinoids Cause the Runner's High? Evidence and Open Questions. Neuroscientist 29:352-369, 2023
11. Sparling PB, Giuffrida A, Piomelli D, et al: Exercise activates the endocannabinoid system. Neuroreport 14:2209-11, 2003
12. Petruzzello SJ, Landers DM, Hatfield BD, et al: A meta-analysis on the anxiety-reducing effects of acute and chronic exercise. Outcomes and mechanisms. Sports Med 11:143-82, 1991
13. Rice D, Nijs J, Kosek E, et al: Exercise-Induced Hypoalgesia in Pain-Free and Chronic Pain Populations: State of the Art and Future Directions. J Pain 20:1249-1266, 2019
14. Feuerecker M, Hauer D, Toth R, et al: Effects of exercise stress on the endocannabinoid system in humans under field conditions. Eur J Appl Physiol 112:2777-81, 2012
15. Stone NL, Millar SA, Herrod PJJ, et al: An Analysis of Endocannabinoid Concentrations and Mood Following Singing and Exercise in Healthy Volunteers. Front Behav Neurosci 12:269, 2018
16. Cedernaes J, Fanelli F, Fazzini A, et al: Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans. Psychoneuroendocrinology 74:258-268, 2016
