Is the euphoria produced by exercise mediated by opioid receptors or cannabinoid receptors?
The endorphin rush
The endorphin rush is an expression widely used in popular culture that refers to feelings of euphoria, elation, endurance, and decreased anxiety and pain supposedly caused by the release of endorphins in the brain.
The endorphin rush has sunk deep roots in the popular culture. There are drinks and rock bands named after it.
It is considered responsible for increasing the performance of athletes, the pleasure of sex and even “sub space”—an altered state of consciousness produced by pain in masochists.
The runner’s high
But the most well-known example of an endorphin rush is the runner’s high.
A marathon runner is about to hit the wall. His energy is depleted, he is exhausted, and his legs are about to give up. But, all of a sudden, something magical happens. He feels full of energy and can complete the race, running even faster. All the anxiety is gone and, in fact, he feels totally happy.
What happened? Well, his brain resorted to a last-resort trick. It released a bunch of endorphins that relieved his fatigue and made him high.
That was the story that we have been told for a long time. But now it turns out that it may not be the endorphins after all, but some marihuana-like compounds called endocannabinoids.
This article looks at the evidence for both explanations. In the process, it will explain some interesting facts about the brain and the methods that scientists use to explore it.
Endorphins and opioid receptors
“Endorphins” is the name popularly given to endogenous opioids, a large family of peptides found in the brain and the blood that are able to activate the opioid receptors used by drugs like morphine, heroin, fentanyl and codeine.
There are three classic opioid receptors, designated by the Greek letters mu, delta and kappa. A fourth receptor and its corresponding peptide were discovered simultaneously by two groups, so it was given the two names that they used: the nociceptin/orphanin receptor. However, this receptor does not produce euphoria or analgesia, so I will leave it out of this discussion.
Endorphins are peptides encoded by three genes: proopiomelanocortin (POMC), proenkephalin and prodynorphin. If Nature was well-organized and rational, each of these genes would encode a peptide that would activate each of the three classic opioid receptors, and that would be that.
Alas! Nature is neither simple nor rational. In fact, it displays a perverse penchant to make things convoluted. And so each gene encode for a complex mixture of peptides: enkephalins, dynorphins and beta-endorphin.
To make things even more fun, the POMC gene also encodes for two peptides that have nothing to do with opioids and their receptors. One is alpha-melanocyte-stimulating hormone (alpha-MSH), which regulates appetite and sexual behavior. The other is adrenocorticotropic hormone (ACTH), which is part of the stress response of the hypothalamus-pituitary-adrenal (HPA) axis.
See? I told you Nature was devious. So, let’s try to keep things simple for this discussion. Enkephalins and beta-endorphin bind to mu and delta opioid receptors, that produce analgesia and euphoria. Dynorphin binds to kappa receptors that produce analgesia and dysphoria—the opposite of euphoria.
Measuring endorphins in the blood or the saliva is meaningless
Initial studies on the runner’s high measured endorphin in the blood or the saliva of runners, and found that running and other types of exercise increased them.
However, this is meaningless. Endorphins do not cross the blood-brain barrier, a wall in the capillaries of the brain that makes its chemical environment totally different from that of the blood. So endorphins in the blood cannot induce euphoria or analgesia, because these effects are produced by neurons in the brain.
On top of that, endorphins (mainly the beta-endorphin encoded by the POMC gene) are released into the blood from the pituitary gland at the same time as ACTH, which is also encoded by the POMC gene. Since ACTH release is part of the stress response, endorphin in the blood does not produce euphoria. In fact, when endorphins are released in some parts of the brain (the locus coeruleus), they turn off the stress response.
Hence, to determine if the runner’s high is mediated by endorphins, we need to measure them in the brain of the runners.
A study of endorphin release in the brain of runners
Measuring endorphins in the brain of humans while they are awake—in fact, shortly after they performed a strenuous exercise—may seem like an impossible task. However, it can be done by using a fancy technique called positron emission tomography (PET). PET uses drugs that incorporate unstable isotopes like fluor-18 (18F) or carbon-11 (11C). These drugs are called radiotracers. When the isotopes decay, they release a positron. It interacts with an electron, producing a gamma ray, which is detected by the PET machine. When the radiotracer drug is bound to a receptor, like the mu-opioid receptor, it stays longer in that brain region, which gives a brighter PET signal. However, if endorphins are released in that brain region, they displace the radiotracer from the receptor, so the PET signal decreases. This allows scientists to create images of the brain where endorphin release is color-coded and quantified.
The first study that investigated the runner’s high with PET (Boecker et al., 2008) used as radiotracer [18F]FDPN, an opioid drug that binds to all the classical opioid receptors.
The subjects were 10 male runners who had experienced the runner’s high before and trained for a minimum of 4 hours weekly for the last 2 years. These inclusion criteria were important because they ensured that the effects studied were really a runner’s high and not mere responses to exercise or fatigue.
Thirty minutes after a two-hour run, the subjects received an injection of the radiotracer and had their brains scanned with PET. As control, they had a PET scan after 24 hours without exercise. These two PET scans were separated by 4 weeks and their order was randomized. The results were shown as endorphin release after running compared with rest for each subject.
An increase in endorphins was found in the following brain regions:
orbitofrontal cortex—a region of the prefrontal cortex that assigns value to actions, evaluates contingencies and appraises emotions;
dorsolateral prefrontal cortex—involved in decision making, cognitive flexibility, working memory and planning;
insula—an area of the cortex buried inside the brain hemispheres that is involved in pain, pleasure, euphoria and other emotions;
anterior cingulate cortex—a region of the cortex between the hemispheres that controls motivation, detects errors and conflicts, and plans actions;
posterior cingulate cortex—involved in spatial memory, emotional saliency and learning;
sensory and motor cortex—involved in detecting sensations and directing muscle contraction, respectively.
The runners were also given a psychological test to evaluate their emotions after running. Two emotions increased after running: happiness and euphoria. This indicated the presence of the runner’s high. Other emotions didn’t change after the run, including confusion, anger, sadness, fatigue, fear, energy and tension.
Finally, the scientists analyzed both sets of data together to determine if there was a correlation between the feelings of euphoria and endorphin release in each brain area. A positive correlation between endorphin release and euphoria was found in the orbitofrontal cortex, dorsolateral prefrontal cortex, anterior and posterior cingulate cortex, insula, sensory cortex and motor cortex.
These results strongly support the idea that the runner’s high is a feeling of euphoria caused by endorphin release in brain areas that process emotions and direct actions.
Endorphin release in the brain during moderate and intense exercise
Ten years later, another study (Saanijoki et al., 2018) used PET scanning to find out if moderate and intense exercise are equally able to induce endorphin release.
Another difference with the previous PET study is that they used a radiotracer, [11C]carfentanil, that is a selective agonist of mu-opioid receptors. The previous study used [18F]FDPN, which could also bind to the kappa opioid receptors and therefore detect the release of dynorphins in addition to enkephalins and endorphins. Remember that dynorphins binding to kappa opioid receptors produce dysphoria, the opposite of what the endorphin high is supposed to be.
But perhaps the most relevant differences were the subjects and the type of exercise. The 22 subjects were also men, but there was no requirement of them to have previously experienced the runner’s high or to exercise regularly.
The exercise used in the experiments was not running, but indoor cycling. Moderate intensity exercise was defined as cycling for 1 hour “at workload in the middle between aerobic and anaerobic thresholds,” which were determined previously. High-intensity interval training (HIIT) consisted of five cycling sprints of 30 seconds at maximal load, separated by 4 minutes rests.
They found that HIIT, but not moderate intensity exercise, induced endorphin release in many brain areas. Some were the same areas identified in the previous study: dorsolateral prefrontal cortex, orbitofrontal cortex, anterior and posterior cingulate cortex, thalamus and insula. In addition, they found endorphin release in the ventral striatum, hippocampus, cerebellum, amygdala and periaqueductal gray (PAG).
The ventral striatum contains the ventral tegmental area (VTA) and the nucleus accumbens, which form the dopamine reward pathway that mediates motivation and drug addiction. The amygdala mediates fear and controls the stress response. The PAG is the beginning of a neuronal pathway that goes from the brainstem to the spinal cord and inhibits pain.
Again, psychological tests were used to determine if the subjects had a runner’s high. They were taken by 12 subjects that did both types of exercise. Surprisingly, euphoria, motivation and satisfaction were higher during moderate-intensity exercise than during HIIT. Conversely, negative feelings like exhaustion, tension and irritation were higher during HIIT than during moderate exercise. Pain increased with exercise and it was not different between HIIT and moderate exercise.
Even more unexpected was the finding that the negative feelings during HIIT correlated with endorphin release, particularly in the dorsal prefrontal cortex. Moreover, the euphoria produced by moderate exercise also correlated with endorphin release in the dorsal prefrontal cortex.
So, there is no endorphin rush?
This second study brought into question the idea of the endorphin rush.
On the one hand, yes, exercise releases endorphins in the brain. And intense exercise releases more endorphins than moderate exercise.
But, instead of being associated with euphoria and feelings of energy, which is the classic description of the runner’s high, endorphin release during intense exercise correlated with negative emotions like exhaustion and irritation. On top of that, moderate exercise produced euphoria and other positive feelings.
All of these contrasts with the common description of the runner’s high, which is only achieved after hitting a wall of exhaustion during extreme exercise.
So, endorphin release during intense exercise does not produce euphoria? There is no endorphin rush?
The answer may be a bit more complicated. Maybe what happens is that endorphins are released during exercise as a compensatory response to negative feelings like pain, anxiety, irritation and exhaustion. With moderate exercise, they are able to eliminate these feelings and even produce euphoria. But with intense exercise, the negative feelings are so strong that endorphins cannot drown them.
These negative feelings may be mediated by neuropeptides like dynorphins, corticotropin-releasing factor (CRF) and cholecystokinin (CCK). CRF drives the stress response of the HPA axis and the locus coeruleus. CCK induces anxiety and opposes the effects of endorphins.
Mice do not have an endorphin rush
Meanwhile, some scientists raised the possibility that the runner’s high was mediated by endocannabinoids instead of endorphins.
Endocannabinoids are to cannabinoid receptors what endorphins are to opioid receptors. They are substances produced in the body that activate the same receptors as the psychoactive compounds in cannabis. The two main endocannabinoids are anandamide and 2-arachydonoyl-glycerol (2-AG).
The high produced by marihuana is mediated by CB1 receptors, which are abundant in the brain. There are at least two other cannabinoid receptors, CB2 and GPR55, which do not mediate the psychotropic effects of cannabis but some of its other effects on the body.
A study in mice (Fuss et al., 2015) showed that, when mice exercise on a running wheel, they have less anxiety and pain. They also had elevated levels of endocannabinoids in their blood. The analgesia produced by exercise was eliminated by blocking CB1 and CB2 receptors with their antagonists, but not by blocking opioid receptors with naloxone. This indicated that the pain reduction was mediated by endocannabinoids and not by endorphins. Similarly, the decrease in anxiety produced by exercise was blocked by antagonists of CB1 receptors, but not by antagonists of CB2 receptors or by naloxone.
In a sophisticated experiment, the scientists selectively eliminated CB1 receptors in GABA-releasing neurons in the forebrain of mice using transgenic techniques. These mice ran less on the wheel than normal mice and lose the anxiolytic effect of running. This showed that the decrease in anxiety produced by wheel running in mice is mediated by CB1 receptors in forebrain neurons.
However, this study does not tell us much about the runner’s high because its main characteristic is euphoria, and euphoria cannot be studied in mice. What it shows is that exercise decreases pain and anxiety in mice, and that these effects are mediated by the action of endocannabinoids in the forebrain. However, the analgesic and anxiolytic effects of cannabinoids have been known for a while.
So, it’s not endorphins but the endocannabinoids?
To see if endocannabinoids are responsible for the euphoria of the runner’s high, the same group performed their next experiments in humans (Siebers et al., 2021).
The obvious experiment would be to repeat the first two studies with PET scanning, but with a radiotracer that binds to cannabinoid receptors instead of opioid receptors. Indeed, there are several radiotracers for CB1 receptors (Horti et al., 2006; Varlow et al., 2020; Hou et al., 2021). However, this study did not use them.
Instead, they did three experiments.
The first consisted of measuring endocannabinoids in the blood before and after exercise, which consisted of walking or running on a treadmill for 50 minutes.
The second experiment consisted of a battery of psychological test to measure euphoria before and after the exercise. The subjects were injected with naltrexone, a mu-opioid receptor antagonist. If naltrexone decreased the euphoria, then it was mediated by endorphins. A more complete design would have used also CB1 receptors antagonists, like in the experiments with mice. Unfortunately, CB1 antagonists have not been authorized to be used in humans. Rimonabant, an antagonist of CB1 and CB2 receptors, was used in humans for a while, but withdrawn (Sam et al., 2011).
The third experiment was a sophisticated way to measure anxiety, called the human elevated plus-maze. The subjects were made to walk on wooden planks forming a plus sign while wearing a virtual reality (VR) headset. In one direction (closed arm), the headset showed the planks surrounded by protective rock walls. In the other direction (open arm), the VR headset showed a 55 meter (180 feet) fall to either a river of icy water or a parking lot with cars. The time the subjects spent in the open arm was a measure of their anxiety levels.
Both walking and running increased endocannabinoids in the blood, but running produced a larger increase than waking.
Running, but not walking, produced euphoria. Naltrexone produced a small decrease in euphoria that was not statistically significant.
As for the fancy experiment with the VR headset to measure anxiety, the results were rather meager. After running, the subjects experienced marginally less anxiety than after walking (p = 0.024). Naltrexone did not change the anxiety levels in either condition.
This study was touted by the press as showing that the runner’s high is mediated by endocannabinoid and not by endorphins.
Sensational news! People had been fooled into believing in the endorphin rush all along.
My conclusion: it’s the endorphins, after all
However, I have my doubts.
The paper by Siebers et al. did not invalidate the two original studies using PET imaging to measure endorphin release in the brain. In fact, those two studies were of much higher quality than the one by Siebers et al.
The two PET studies demonstrated the endorphins are released by exercise in brains areas relevant for controlling pain, mediating emotions and inducing euphoria. They were done by different groups and, in these measures, they were consistent which each other.
The main thing in question is whether the endorphins released by exercise produce euphoria. In this, the two PET studies reached conflicting conclusions. The one by Boecker et al. showed that strenuous running produced euphoria. The one by Saanijoki et al. showed that only moderate exercise produced euphoria, which correlated with endorphin release. Intense exercise produced negative emotions, which also correlated with endorphin release.
As I pointed out before, these results can be reconciled if we assume that endorphin release is a compensatory response that can reverse the negative emotions produced by moderate exercise, but not by intense exercise.
But, what about the third study arguing that the euphoria is mediated by endocannabinoids?
The results of the anxiety tests by Siebers et al. were even less conclusive. The effect of running on anxiety was too small when compared to walking. A key control is missing: anxiety measures at rest. This should be compared with anxiety after walking. If we don’t have a clear decrease in anxiety produced by exercise, testing the effect of naltrexone on this small effect is meaningless.
Endocannabinoids are released in the blood by exercise, for sure. But, although they cross the blood-brain barrier, this is not the same as endocannabinoids being released in brain areas that mediate euphoria, which is what the two PET imaging studies showed for endorphins. If we don’t know in which brain areas the endocannabinoids are released, we cannot propose a mechanism by which they induce euphoria.
Besides, cannabinoids decrease anxiety, but they do not produce the high levels or euphoria induced by the opioid drugs and the endorphins.
I think that the main source of confusion is the assumption that any strenuous exercise is going to automatically induce a runner’s high. This is not the experience of runners. The runner’s high is an altered state of consciousness that is encountered only by a selected group of runners after extremely long runs. It is probably a learned response.
Only the first study (Boecker et al., 2008) selected runners who had already experienced the runner’s high and that said that they achieved that state during the experiment. The second study (Saanijoki et al., 2018) did not even select athletes who trained regularly. The third (Siebers et al., 2021) selected subjects who performed “endurance exercise more than twice a week,” but did not check if they experienced a runner’s high.
My conclusion is that exercise releases endorphins and endocannabinoids. It induces a variety of positive and negative emotional states, mediated by euphoric (endorphins, endocannabinoids) and dysphoric (dynorphins, CRF, CCK) neurotransmitters. However, only in some special situations endorphin release raises to the level to produce the high euphoria seen in the runner’s high.
The endorphin rush is not automatic. It seems to require entering some sort of trance state, or breaking through a neurophysiological barrier.
References
Boecker H, Sprenger T, Spilker ME, Henriksen G, Koppenhoefer M, Wagner KJ, Valet M, Berthele A, Tolle TR (2008) The Runner's High: Opioidergic Mechanisms in the Human Brain. Cerebral cortex (New York, NY : 1991).
Fuss J, Steinle J, Bindila L, Auer MK, Kirchherr H, Lutz B, Gass P (2015) A runner's high depends on cannabinoid receptors in mice. Proceedings of the National Academy of Sciences 112:13105-13108.
Horti AG, Fan H, Kuwabara H, Hilton J, Ravert HT, Holt DP, Alexander M, Kumar A, Rahmim A, Scheffel U, Wong DF, Dannals RF (2006) 11C-JHU75528: A Radiotracer for PET Imaging of CB1 Cannabinoid Receptors. Journal of Nuclear Medicine 47:1689-1696.
Hou L, Rong J, Haider A, Ogasawara D, Varlow C, Schafroth MA, Mu L, Gan J, Xu H, Fowler CJ, Zhang MR, Vasdev N, Ametamey S, Cravatt BF, Wang L, Liang SH (2021) Positron Emission Tomography Imaging of the Endocannabinoid System: Opportunities and Challenges in Radiotracer Development. J Med Chem 64:123-149.
Saanijoki T, Tuominen L, Tuulari JJ, Nummenmaa L, Arponen E, Kalliokoski K, Hirvonen J (2018) Opioid Release after High-Intensity Interval Training in Healthy Human Subjects. Neuropsychopharmacology 43:246-254.
Sam AH, Salem V, Ghatei MA (2011) Rimonabant: From RIO to Ban. Journal of Obesity 2011:432607.
Siebers M, Biedermann SV, Bindila L, Lutz B, Fuss J (2021) Exercise-induced euphoria and anxiolysis do not depend on endogenous opioids in humans. Psychoneuroendocrinology 126:105173.
Varlow C, Boileau I, Wey HY, Liang SH, Vasdev N (2020) Classics in Neuroimaging: Imaging the Endocannabinoid Pathway with PET. ACS Chem Neurosci 11:1855-1862.
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