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Endocannabinoids and CB1-type cannabinoid receptors are a key driver behind the to voluntarily seek aerobic exercise in the form of running, according to a new study (Muguruza et al., 2019) on mice published March 7 in the journal JCI Insight. This paper, “The Motivation for Exercise Over Palatable Food Is Dictated by Cannabinoid Type-1 Receptors,” also found that the endocannabinoid system in certain mice was so robust that these rodents preferred wheel running to eating chocolate.

According to the researchers, some mice love to run, but (much like humans) the majority of mice really like to eat chocolate. In order to measure the role that CB1 receptors play in a mouse’s motivation to seek running over eating palatable food, they “knocked out” the cannabinoid receptors in one cohort of mice.

Then, the researchers devised a laboratory model for testing the degree of effort each mouse was willing to put into gaining access to voluntary wheel running versus eating a morsel of chocolate. In order to unlock the treadmill-like wheel and run freely, mice had to push their snouts against a mechanism that gradually required more and more effort.

Like a junkie trying to get a fix, mice with robust CB1 receptors were willing to put a lot of effort into getting a runner’s high. On the flip side, mice without CB1 receptors exerted about 80 percent less effort via nose pokes required to unlock the running wheel. Without a well-functioning endocannabinoid system, these “knockout” mice displayed very little interest in running—but still put effort into getting a chocolate treat.

According to a statement by the researchers, “This finding indicates that the CB1 receptors play a major role in controlling motivation for exercise.” Although this research was conducted on mice, there's growing evidence that CB1 receptors also play a central role in humans’ motivation to seek aerobic exercise.

The latest findings on the endocannabinoid system also help to explain why some people find “runner’s high” so elusive and are less intrinsically motivated to exercise on a regular basis. The authors sum up their findings in a press release statement:

“In addition to these findings indicating that the cannabinoid receptor is essential for the motivation for exercise, this study opens up avenues for researching the neurobiological mechanisms behind pathological increases in this motivation. One illustration is provided by which often combines the decreased motivation to eat with an increased motivation to exercise.”

Although this research was conducted on mice, the latest findings on the role of cannabinoids on motivation to exercise have human implications. For example, pinpointing the role of CB1 receptors in seeking exercise might explain why some of us are "born to run" while others (who may not have enough cannabinoid receptors to experience a so-called "runner's high") find running to be a very disagreeable experience.

A Brief History of Runner's High, Endocannabinoids, and the Endorphin Neuromyth

Source: Random House/Fair Use

In the late 1970s, Jim Fixx’s pioneering exercise manifesto, The Complete Book of Running, spent countless months atop the New York Times' bestseller list and helped make "jogging" a nationwide fad for the first time in American history.

In the late-20th century, most people (including Fixx) assumed “runner’s high” was caused by endorphins. The word endorphin comes from the Greek root “endo” meaning “from within” combined with “ .” Endorphins bind with opiate receptors and are colloquially known as “your body’s own morphine.”

Coincidentally, in 1977, when the running phenomenon was really gaining steam, my late father, Richard Bergland (who was a neurosurgeon and ), took a six-month sabbatical from performing brain surgery to conduct some brain experiments on sheep in Melbourne, Australia.

Dad's research at The Florey Institute of Neuroscience and Mental Health was designed to explore how daily activities (e. ., eating, , trotting on a treadmill, having , etc.) changed the balance of various neurochemicals in the brains of Australian sheep in his laboratory. My father was especially curious to figure out if “self-produced" endogenous opioid neuropeptides and like endorphin could cross the blood-brain barrier (BBB).

Unfortunately, my father’s six-month research project didn’t yield any earth-shattering revelations. That said, in 1978, a landmark paper, “Blood-Brain Barrier Restriction of Peptides and the Low Uptake of Enkephalins,” by Cornford et al. reported that opioid-like molecules produced in the body were probably too big to cross the BBB.

Throughout the 1980s, the possible link between runner’s high and endorphins took center stage in many research labs around the globe and the exercise-endorphin link became part of every layperson's vernacular.

From a neuroscience perspective, in a landmark paper from the mid-1980s “Endorphins and Exercise,” (Harber & Sutton, 1984) the authors write, “Elevated serum beta-endorphin concentrations induced by exercise have been linked to several psychological and physiological changes, including mood state changes and 'exercise-induced euphoria.’”

Through the lens of pop culture, Annette Bening's ditzy character in Postcards from the Edge has a funny endorphin-related exchange while speaking to Meryl Streep's character on an L.A. movie set. Bening exclaims, "I'm in it for the 'endolphin' rush!" Streep corrects her by stressing each syllable: "It's 'en-dor-phin.'" Bening responds dismissively, "Whatever." Streep references the "endolphin vs. endorphin" discrepancy later in the movie when describing this incident to Dennis Quaid's character.

From a 21st-century neurobiology perspective, most experts now agree that because endorphin molecules are relatively large, they're restricted by the BBB. Therefore, contrary to popular belief, endorpins are most likely not the root cause of the psychological motivation/reward to seek exercise and the euphoria associated with runner’s high. (See, "The Neurochemicals of Happiness" and "Is Runner's High Our Evolutionary Antidote for Staying Put?")

Because neuromyths tend to be long-lasting and fade from collective consciousness slowly, I have a hunch that most general readers still think endorphins are the main reason that aerobic exercise makes runners feel blissful and euphoric. Hopefully, this post helps to debunk the "endorphin causes runner's high" neuromyth.

Over the past few years, mountains of evidence have accumulated showing that endocannabinoids (i.e., "self-produced ") are the prime driving force that motivates humans (and mice) who exercise regularly to stick with a workout regimen. For example, a few years ago researchers (Fuss et al., 2015) from the University of Hamburg and the University of Heidelberg in Germany studied the endocannabinoid system in mice who loved to run and reaffirmed that runner’s high is strongly associated with CB1 receptors in the brain. This paper, "A Runner’s High Depends on Cannabinoid Receptors in Mice," was published in Proceedings of the National Academy of Sciences.

Back in the 1980s, when the running craze was still in its early days, people began to notice that running was like a drug that appeared to be getting joggers "hooked" in ways that made them behave like so-called “exercise addicts." Tragically, Jim Fixx, whom many considered a running guru, died in 1984 at age 52 of a heart attack while he was out for a long jog in the Vermont woods near his home.

A poignant article, “The Jim Fixx Neurosis: Running Yourself to Death,” was published in the Washington Post a few weeks after his death. Long before neuroscientists understood the power of endocannabinoids and CB1 receptors (Muguruza et al., 2019), this article in the Post unwittingly touches on the potent ability of the endocannabinoid system to turn everyday runners and casual joggers into exercise fanatics in ways that resemble an .

This 1984 article in the Washington Post profiles the work of Alayne Yates and colleagues at the University of Arizona Health Sciences Center, who first identified what they called "obligatory runners" as: “Those for whom running is a compulsive drive that preempts fulfillment in other life areas or who run to the point of inflicting physical damage on their bodies.”

In 1983, Yates and colleagues published a seminal paper, “Running — An Analogue of Anorexia?" in the New England Journal of Medicine. In this paper, Yates and co-authors write:

“We have explored the apparent similarity between patients with anorexia nervosa and a subgroup of male athletes designated as "obligatory runners." Case examples are provided from interviews with more than 60 marathon and trail runners. Obligatory runners resemble women in terms of family background; socioeconomic class; and such characteristics as inhibition of , extraordinarily high self-expectations, tolerance of physical discomfort, denial of potentially serious debility, and a tendency toward ."

Yates and her co-authors also observed, “When the obligatory runners in our sample were unable to run, they experienced depression and about physical deterioration. Not surprisingly, they continued to run in spite of illness, which was often denied, or contraindications, such as arrhythmias, atherosclerotic heart disease or fractures. Such unreasonable dedication has resulted in permanent disability or even death."

Looking at the potential link between running and anorexia-like behaviors through the lens of the latest research (Muguruza et al., 2019) on CB1 receptors and motivation for exercise offers a fresh perspective on the neurobiology behind compulsive exercise that may exacerbate . Clearly, more research is needed to fully understand the role that CB1 receptors might play in the motivation to exercise excessively without eating enough food.

Full disclosure: I am a former obligatory runner, ultra-endurance junkie, and obsessive Ironman triathlete in recovery. Anecdotally, I know firsthand about the pros and cons of having a robust endocannabinoid system, the power of CB1 receptors to motivate someone to seek exercise, and the addictive potential of "runner's high" to fuel an uncontrollable and unhealthy urge to run extreme distances.

Although I still love jogging at a "tonic level" (e.g., a distance and degree of intensity that feels good without overdoing it) most days of the week, I retired from extreme distance competitions because my insatiable motivation to run, bike, and swim non-stop without taking sleep breaks almost killed me.

For example, my endocannabinoid system, CB1 receptors, and desire to go "ever higher" drove me to do insane things like running six back-to-back marathons on a treadmill in 24 hours. Although this feat of endurance garnered a Guinness World Record, it also shut down my kidneys and temporarily damaged my heart. During this record-breaking run, I refused to get off the treadmill or slow down despite very urgent warning signs to STOP! (e.g., My urine turned into ketchup-like sludge about five marathons into the 24-hour run but I continued to run for another 26 miles which landed me in the ICU for almost a week.)

Despite these harrowing experiences, jogging at moderate levels never fails to make me feel really good. To this day, I'm still highly motivated to run (albeit slooowly) in a way that isn't compulsive or self-destructive. I firmly believe that by educating ourselves about how CB1 receptors may drive the neurobiology of exercise fanaticism, each of us can become cognizant about fine-tuning a dose-response of self-produced cannabinoids that elicit blissful feelings via exercise without becoming obligatory runners or exercise fanatics.

For more on this topic see, "Better Brain Health Is Possible Without Exercise Fanaticism," "High Levels of Exercise May Be OK for Middle-Aged Hearts," "This Is Your 'Little Brain' on Cannabis" and "The Dark Side of Mythic Quests and the Spirit of Adventure."