The statement, “WOW! I feel fantastic!” is not a phrase many would associate with endurance running. In fact, most people tend to exhibit feelings of dread when they grudgingly decide to lace up their shoes and go for a jog. Although some may believe that running-induced euphoria is an anomaly, it is actually a well-documented subjective occurrence. Those who have experienced a “runner’s high” describe it as a state in which they feel inner harmony, boundless energy, pure happiness, and a reduced sensation to pain. While it is generally accepted that this altered state of mind and body can occur both during and following a good run, we do not fully understand how this phenomenon occurs.
Traditionally, exercise-induced euphoria was thought to be a result of the release of endorphins, our body’s “natural opioids.” In the brain and spinal cord, these molecules target and activate our body’s opioid receptors (primarily the mu opioid receptor), which enables them to curb pain and elevate mood, similar to painkillers such as morphine or oxycodone. These molecules are not as potent as clinically prescribed opioids, but they do pack their own punch. When the biochemical mechanism of the runner’s high was first being explored, researchers found that strenuous endurance activities elevate plasma endorphin levels in both humans and mice. This finding became the foundation that the “endorphin hypothesis” for runner’s high was built on. Although the release of endorphins during and following exercise was a seemingly sound explanation for the reduced pain and elevated mood one would experience during and after a run, there are a few flaws associated with the “endorphin hypothesis.”
Endorphins, specifically 𝛃 endorphins, preferentially bind to the nervous system’s mu opioid receptors, which enables them to elicit analgesic and euphoric properties. Interestingly, minimal activation of mu opioid receptors can also result in respiratory depression, constipation, and contraction of the pupils. Now, if endorphins were the sole molecular player for runner’s high, one would think there would be more reports of seeing or experiencing these physical effects for runners and endurance athletes; however, this is not the case.
Another flaw associated with the “endorphin hypothesis” is the foundation of the hypothesis itself, which is solely based on observing elevated endorphins in circulating blood following endurance exercise. Endorphins are large, hydrophilic (i.e., “water-loving”) compounds, which makes it incredibly difficult for them to enter the brain. Because endorphins are restricted to the periphery (i.e., areas of the body outside of the brain), elevated blood endorphin levels cannot be responsible for the effects of mu opioid receptor activation on euphoria. This could explain why various studies have failed to show that peripheral release of endorphins correlates with enhanced mood following endurance exercise.
So if endorphins are not the sole cause of runner’s high, then what else could be going on? Well, in the last 15 years or so, researchers have turned their attention to the endocannabinoid system and the roles that the endogenous cannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) could potentially play. For a quick crash course on cannabinoids and their role within the endocannabinoid system, check out the recent ScIU post “Cannaba-what!?: Cannabinoids in their various forms — mainstream and uncommon.”
These two cannabinoids target our body’s cannabinoid type 1 and 2 receptors (CB1 and CB2, respectively), enabling them to produce analgesic and euphoric effects that are similar to those induced by the constituents of the Cannabis plant. Following the discovery that AEA and 2-AG blood plasma levels spike after moderate endurance exercise, the possibility that the endocannabinoid system could be involved in runner’s high has slowly gained traction.
Further bolstering the potential for their involvement in runner’s high, endocannabinoids, unlike endorphins, are small enough to enter the brain; therefore, peripheral increases in these lipid molecules could enable them to mediate central (i.e., brain) effects. Corroborating the latter statement, a handful of studies have found that elevated peripheral endocannabinoids correlate with elevated mood following moderate endurance activities.
Despite the lack of a correlation between enhanced mood and endorphins, that does not mean that endorphins are not involved in runner’s high. Recent brain scans using positron emission tomography (PET) suggest that there is indeed a role for endorphins in regulating exercise-induced euphoria. By using a radioactive drug (tracer) to measure metabolic activity in the brain, PET scans show that increased binding of endorphins to mu opioid receptors is associated with euphoria following endurance activities in humans.
These results could suggest that endorphins and endocannabinoids work together to elicit the subjective feeling of euphoria during a runner’s high. Further evidence of this cooperation can be seen when the effect of exercise-induced analgesia (i.e., pain relief) is investigated. It has been well-documented that both peripheral and central endorphin release following endurance exercise correlates with hypoalgesia, or a reduced sensitivity to pain. However, when opioid receptors are blocked by certain drugs like naltrexone (a mu opioid receptor antagonist), exercise-induced reductions in pain sensitivity are still evident. Further investigations found that hypoalgesia is mediated by CB1 and CB2 receptors. These findings suggest that our body’s opioid and endocannabinoid signaling pathways work together not only when producing exercise-induced euphoria, but also when reducing sensitivity to pain following endurance exercise.
Because runner’s high is a private experience and we only know of its existence through verbal reports, there are few rigorous, in-depth scientific investigations into this phenomenon and there is still much to learn. Given the evidence, however, it is time to recognize the role of endocannabinoids in this experience and the possibility that they work closely with endorphins to keep endurance athletes chasing the high that comes with a great workout.
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