“Runner’s High” Depends on Endocannabinoids (Not Endorphins)

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Key Points:

• Endocannabinoids are better candidates than endorphins to explain "runner's high," a feeling of euphoria after aerobic exercise.
• Running and other forms of aerobic exercise stimulate the endocannabinoid system.
• Exercise-induced euphoria and post-workout anxiety reduction do not depend on endorphins binding to mu-opioid receptors, a new study finds.

For decades, scientists have suspected that endocannabinoids (not endorphins) are the key to experiencing the exercise-induced euphoria and anxiety reduction we colloquially refer to as "runners high."

In the mid-2000s, when I was writing The Athlete's Way, my book's subtitle, "sweat and the biology of bliss," was inspired by the newly discovered (Spalding et al., 2003; Dietrich & McDaniel, 2004) phenomenon of aerobic exercise stimulating the production of an endocannabinoid called anandamide or "the bliss molecule."

Over the years, I've continuously reported on a growing body of evidence-based research related to this topic. (See "Motivation to Run (or Not to Run) Is Linked to Cannabinoids" from March 2019.)

Alas, it often takes decades for seemingly esoteric neuroscientific research to trickle up into the mainstream and become part of public consciousness. Such is the case with the link between endocannabinoids and runner's high. Although endo- (self-produced from within) cannabinoids have been viewed as the key to exercise-induced euphoria and post-workout anxiolysis by experts in the field for years, most of the general population still equates runner's high with endorphins.

The good news: It's 2021, and the "endocannabinoid-runner's high connection" finally seems to be getting the general audience attention it deserves.

For example, on February 24, Runner's World published a highly informative article, "The Reason Behind the Runner's High Isn't What You Might Think," about a new peer-reviewed paper (Siebers et al., 2021) available online ahead of print in April's (Volume 126) Psychoneuroendocrinology journal.

This study found that "endorphins do not play a significant role in the underlying mechanism of a runner's high" and that the "core features of a runner's high depend on cannabinoid receptors but not opioid receptors."

First author Michael Siebers and coauthors acknowledge in their paper's abstract: "It has been a widespread belief that the release of endogenous opioids, such as endorphins, underlie a runner's high." They go on to explain that "exercise leads to the release of two classes of rewarding molecules, endocannabinoids (eCBs) and opioids."

"Previous research in mice [Fuss et al., 2015] found that beneficial effects of exercise don't depend on opioid receptors as assumed; instead, they rely heavily on the endocannabinoid system's receptors," senior author Johannes Fuss of the University Medical Center Hamburg-Eppendorf (UKE) in Germany told Runner's World.

"Those previous findings were based on a mixture of behavioral, pharmacological, and molecular genetics studies," Fuss added. "But obviously, we couldn't study the effects of euphoric feelings in mice. So, we repeated the experiment with humans."

In their recent double-blind, randomized, placebo-controlled human study, the German researchers recruited 63 healthy participants and had them run at "moderate-intensity" exertion levels on a laboratory treadmill for 45 minutes. During a separate treadmill session in an exercise lab, the same participants walked at a casual pace for 45 minutes.

On average, the researchers found that study participants "exhibited increased euphoria and decreased anxiety after 45 minutes of running on a treadmill in a moderate-intensity range compared to walking."

They also found that running vs. walking led to higher plasma levels of the endocannabinoids anandamide (AEA) and 2-arachidonoglycerol (2-AG). Because this study was designed to investigate if the two core features of a runner's high (euphoria and reduced anxiety levels) were dependent on opioid signaling, the researchers randomly used an opioid-receptor antagonist (naltrexone) to block these receptors.

Notably, runners who were given the opioid-receptor blocking naltrexone (which inhibits endorphins) still experienced exercise-induced euphoria and anxiolysis. "Opioid blockade did not prevent the development of euphoria and reduced anxiety as well as elevation of endocannabinoid levels following exercise," the authors wrote in the paper's abstract.

"This means endorphins don't seem to play a major role [in runner's high]," Fuss told Runner's World. "We found, instead, that running stimulates endocannabinoid release, and based on our present and earlier findings, we conclude that endocannabinoids are responsible for a 'runner's high.'"

"[Our] study indicates that the development of a runner's high does not depend on opioid signaling in humans, but makes endocannabinoids strong candidates in humans, as previously shown in mice," the authors conclude.