A runner’s high is a subjective sense of well-being some humans experience after prolonged exercise. For decades, it was hypothesized that exercise-induced endorphin release is solely responsible for a runner’s high, but recent evidence has suggested that endocannabinoids also may play a role. Here, we demonstrate that wheel running increases endocannabinoids and reduces both anxiety and sensation of pain in mice. Ablation of cannabinoid receptor 1 receptors on GABAergic neurons inhibits running-induced anxiolysis, and pharmacological blockage of central and peripheral cannabinoid receptors inhibits analgesia. We thus show for the first time to our knowledge that cannabinoid receptors are crucial for main aspects of a runner’s high. 
 
 Abstract 
 
 Exercise is rewarding, and long-distance runners have described a runner’s high as a sudden pleasant feeling of euphoria, anxiolysis, sedation, and analgesia. A popular belief has been that endogenous endorphins mediate these beneficial effects. However, running exercise increases blood levels of both β-endorphin (an opioid) and anandamide (an endocannabinoid). Using a combination of pharmacologic, molecular genetic, and behavioral studies in mice, we demonstrate that cannabinoid receptors mediate acute anxiolysis and analgesia after running. We show that anxiolysis depends on intact cannabinoid receptor 1 (CB1) receptors on forebrain GABAergic neurons and pain reduction on activation of peripheral CB1 and CB2 receptors. We thus demonstrate that the endocannabinoid system is crucial for two main aspects of a runner's high. Sedation, in contrast, was not influenced by cannabinoid or opioid receptor blockage, and euphoria cannot be studied in mouse models. 

 ALTANTA (CBS Atlanta)– The “high” you get after running may be linked to the same high you get from smoking weed, according to a new study. 
 
 Researchers found the post-exercise feeling of euphoria provides a similar effect as smoking marijuana due to the brain’s cannabinoid receptors that relieve pain, as reported by Daily Mail. 
 
 University of Hamburg and University of Heidelberg researchers studied cannabinoid receptors in mice after they ran. Previous research indicates that the pleasant feeling associated with a runner’s high is due to raised levels of beta-endorphins. 
 
 However, the new findings suggest that these endorphins are actually too large to get through the blood-brain barrier and that it’s more likely the feeling is associated with the cannabinoid receptors. These receptors can affect appetite, pain, mood, and memory. 
 
 “Running exercise increases blood levels of both beta-endorphin (an opioid) and anandamide (an endocannabinoid),” the researchers wrote. 
 
 Researchers tested the theory by conditioning a group of mice to run on a treadmill, they were then separated into two groups. One group ran on the treadmill for five hours while the other group stayed inactive. 
 
 Both groups were then evaluated for reduced anxiety by seeing how the mice behaved in the dark and by testing their tolerance for pain. 
 
 A second experiment used all the same factors, but also gave the mice endocannabinoid and endorphin antagonists that blocked the effects. This time the mice who ran showed no results of a runner’s high. 
 
 “[This shows] for the first time to our knowledge that cannabinoid receptors are crucial for main aspects of a runner’s high,” study authors note. 

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 Phys Ed Gretchen Reynolds on the science of fitness. 
 
 We’ve probably all heard someone exclaim, “Ah, my endorphins are kicking in!” at the end of a good run. Endorphins are famous for supposedly producing “runner’s high,” that fleeting sense of calm and euphoria that engulfs many of us after a satisfying workout. 
 
 But in fact, endorphins may be unfairly hogging the credit for making workouts enjoyable, according to an enlightening new experiment with animals. The findings suggest that endorphins have little to do with runner’s high. Instead, that euphoric feeling may be the product of a completely different but oddly familiar substance — the body’s own endocannabinoids, the chemicals that, like the cannabinoids in marijuana, lighten mood. 
 
 Endorphins first became a household word in the 1980s, when researchers found that blood levels increased after prolonged exercise. This finding made sense. Exercise can cause discomfort or pain, and endorphins are the body’s self-produced opiates, with pain-relieving properties much like morphine. 
 
 From that discovery, it was a short step to believing that endorphins must also produce the pleasurable mental sensations that many people feel after exercise. 
 
 But there is a substantial problem with that idea, and it involves the substantial-ness of endorphins. They are large molecules, too big to pass through the blood-brain barrier. They might staunch pain in the muscles, but they wouldn’t have effects directly inside the brain, where any high would originate. 
 
 So for the past decade or so, scientists have been looking for other substances that might be involved in making exercisers feel high, which led them, perhaps unsurprisingly, to endocannabinoids. 
 
 Endocannabinoids are, essentially, internally produced marijuana, or cannabis. Cannabis contains cannabinoid molecules, which are small enough to cross the blood-brain barrier and attach there to receptors, producing a floaty, hey-dude high. 
 
 In recent years, scientists have found that exercise raises the levels of endocannabinoids in the bloodstreams of people and animals, making these molecules good candidates to underlie the runner’s high. 
 
 But few studies have directly compared the effects of endorphins and endocannabinoids to determine which really makes exercise mildly intoxicating. 
 
 So for the new study, which was published this week in Proceedings of the National Academy of Sciences, researchers with the Central Institute of Mental Health at the University of Heidelberg medical school in Mannheim, Germany, rounded up healthy lab mice, tested their anxiety levels by putting them in cages with pockets of darkness and light (anxious animals stick to the shadows), and then gave them running wheels. 
 
 Mice generally like running, engaging in the activity even when they are not being pursued. That suggests, researchers believe, that they gain some kind of mental satisfaction or reward from it, experiencing the mouse version of a runner’s high. 
 
 That possibility was borne out in an early portion of the new experiment, when the scientists noted elevated levels of both endorphins and endocannabinoids in the animals’ bloodstreams after running. The scientists also found that the animals were more tranquil after running, spending longer periods of time in lighted areas within their cages — something that anxious, twitchy animals won’t do — and that they were more pain tolerant when exposed to slight physical discomfort. 
 
 In general, these post-running mice were more chill than before. 
 
 But when the researchers used drugs to block the workings of some of the animals’ endocannabinoid system, so that receptors in the animals’ brains couldn’t take up the molecules, their post-run cool disappeared. The animals proved to be as anxious then after running as they had been before and very sensitive to pain. 
 
 Without a working endocannabinoid system, they developed no runner’s high. 
 
 However, when the researchers similarly blocked the animals’ response to endorphins, while leaving their endocannabinoid system unchanged, the mice enjoyed all of the soothing effects of running. They were calmer in their cages afterward and seemed to experience less sensitivity to pain. 
 
 Even without the ability to respond to endorphins, in other words, they experienced the rodent version of a runner’s high, strongly suggesting that endorphins do not contribute to the high, but endocannabinoids do. 
 
 The practical implications of these results are somewhat limited, of course, because they involve mice, not people, and tell us only what goes into creating a runner’s high and not how to ensure that we will feel that same post-run serenity. 
 
 One possible if slightly disheartening lesson of the study could be, in fact, that we may need to cover considerable mileage in order to experience a runner’s high; the mice in the study, small as they are, averaged more than three miles every day on their wheels. 
 
 More broadly encouraging, though, the results should remind us that, like mice, we were built through evolution to be in motion. Our ancestors ran to avoid danger and hunt food. For them, “reduced sensations of pain and less anxiety through long-distance running would have been a benefit,” says Johannes Fuss, now a professor at the University of Hamburg, who led the new study. 
 
 To survive as a species, we seem to have needed to run, and nature obligingly found ways to make this strenuous movement pleasurable by providing us with a runner’s high. 
 
 So the subtle upshot of the new study may be that we should run. And if we don’t feel a high, perhaps try running more, until eventually a gentle euphoria may settle in and we can turn to our running companion and say, “Ah, my endocannabinoids are kicking in at last!” 
 
 Related:
– It's known that a runner's high isn't actually the result of endorphins, which are too large to cross the blood-brain barrier, but scientists have long sought the elusive cause of the much-talked-about sense of euphoria and calm that can accompany the end of a workout. Now researchers are reporting in the Proceedings of the National Academy of Sciences that endocannabinoids—chemicals that the New York Times describes as, "essentially, internally produced marijuana"—are behind the subtly intoxicating effects of exercise. To test this, researchers conditioned mice to run on a treadmill, then let one group run for five hours and forced the second to be inactive. All mice were then watched for signs of anxiety (i.e. preference for darkness, pain intolerance, etc.). Then, in a second experiment that looked nearly identical, the researchers added endocannabinoid and endorphin antagonists to block their effects. This time the mice who ran did not exhibit the reduced anxiety associated with a runner's high, reports CBS Atlanta. The results can't be directly translated to humans, but the fact that such tiny animals have to run three miles a day to produce a runner's high may suggest that humans have evolved to be in motion. "The subtle upshot of the new study may be that we should run," writes Gretchen Reynolds in the Times. "And if we don’t feel a high, perhaps try running more, until eventually a gentle euphoria may settle in and we can turn to our running companion and say, 'Ah, my endocannabinoids are kicking in at last!'" (Endocannabinoids are implicated in over-eating, too.)