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After a nice long bout of aerobic exercise, some people experience what’s known as a “runner’s high”: a feeling of euphoria coupled with reduced anxiety and a lessened ability to feel pain. For decades, scientists have associated this phenomenon with an increased level in the blood of β-endorphins, opioid peptides thought to elevate mood.

Now, German researchers have shown the brain’s endocannabinoid system—the same one affected by marijuana’s Δ9-tetrahydrocannabinol (THC)—may also play a role in producing runner’s high, at least in mice (Proc. Natl. Acad. Sci. USA 2015, DOI: 10.1072/pnas.1514996112).

The researchers hit upon the endocannabinoid system as possibly being involved because they observed that endorphins can’t pass through the blood-brain barrier, says team member Johannes Fuss, who’s now at University Medical Center Hamburg-Eppendorf. On the other hand, a lipid-soluble endocannabinoid called anandamide—also found at high levels in people’s blood after running—can travel from the blood into the brain, where it can trigger a high. “Yet no one had investigated the effects of endocannabinoids on behavior after running,” Fuss says.

To explore how endocannabinoids are involved, the team familiarized a group of mice with running on an exercise wheel regularly. Then the researchers split the group into two sets of mice: one that would run for five hours and one that would remain sedentary. Soon after their five-hour run, the rodents in the first group displayed far less anxious behavior than the sedentary set when exposed to a so-called dark-light box test. In this test, a mouse’s anxiety is measured by the frequency with which the animal darts from well-lit areas into the dark to hide.

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Similarly, mice in the running group had a higher tolerance for pain than those in the sedentary group, as measured by their tendency to jump or lick their paws when placed on a hot plate.

Finally, the researchers performed these same experiments on mice that were given endocannabinoid and endorphin antagonists—molecules that block cannabinoid and opioid receptors in the brain, respectively. The endorphin antagonists did not significantly affect results, but mice treated with endocannabinoid antagonists and mice genetically engineered to lack endocannabinoid receptors were still anxious and sensitive to pain despite having run for hours.

The team’s findings suggest that endocannabinoids such as anandamide help cause runner’s high. “The authors have moved the field forward by providing such a complete view of how this key reward system is involved in allowing exercise to improve psychological state and pain sensitivity,” says David A. Raichlen, an expert in human brain evolution and exercise at the University of Arizona.