LC-MRM Tracks "Runner's High" Chemistry

The body's cannabis-like signaling system, known as endocannabinoid (eCB) signaling and is made up of natural compounds that work through the same pathways as marijuana, has been linked to the physical and emotional effects of endurance exercise, including the well-known "runner's high." However, even though people can run for hours at a time, most of what we know about this signaling system comes from studies looking at workouts under an hour long. That leaves a real gap in our understanding of how this system behaves during much longer runs, and how that might connect to the emotional ups and downs runners experience along the way.

To address this gap, a research team investigated eCB signaling during long-distance running and following a 45-minute break. Plasma concentrations of the cannabis-like compounds anandamide (AEA), 2-arachidonoylglycerol (2-AG), 1-AG, arachidonic acid (AA), and the related fatty acid palmitoylethanolamide (PEA) were quantified by a standardized liquid chromatography/multiple reaction monitoring assay. A paper based on this study was published in the journal BMC Medicine.¹

What is the "Runner's High," and Why Has the Traditional Endorphin Explanation for It Fallen Short?

The "runner's high" tends to show up most reliably during moderate-effort endurance exercise, the kind of pace where a person is working hard but not so hard that your body starts relying heavily on anaerobic energy production.²In earlier research, the biggest boosts in mood tended to show up after around 35 minutes of endurance exercise.³The idea of the "runner's high" first showed up back in the 1970s. Early researchers pinned it on the release of endorphins, the body's natural feel-good chemicals, and for a long time, that explanation was widely accepted.^4,5The problem with that explanation, however, is that endorphins are large molecules that do not dissolve well in fat, and they work by binding to specific receptors, the same ones targeted by opioid drugs. The issue is, there is no solid evidence that endorphins cross from the bloodstream into the brain in any meaningful amount. In addition, studies that simply measured endorphins in the blood have produced mixed, inconsistent results, so they have not given us much real insight into what is happening in the brain during the runner's high.^3,6,7

How Do Endocannabinoid Levels and Mood Change During Marathon vs. Ultramarathon Distances, and How Do Those Changes Compare to Walking?

The researchers ran two separate studies to dig into this question. In the first, 19 experienced runners each completed a full marathon as well as a walk of the same duration, giving the team a direct comparison between running and simply being on your feet for a similar stretch of time. Blood samples were taken every 14 kilometers during the marathon, plus once more after a 45-minute recovery period, to track how these compounds changed over the course of the race.¹

In the second study, a larger group of 36 ultramarathon runners took on much longer distances, racing either 100, 160, or 230 kilometers. This time, blood samples were only taken before and after the race, rather than at multiple points throughout. Across both studies, the researchers also asked participants to rate their feelings of euphoria, anxiety, and pain using simple rating scales, capturing the key emotional and physical experiences typically associated with the "runner's high."¹

One of the cannabis-like compounds, AEA, climbed steadily throughout the marathon and stayed elevated even 45 minutes after finishing, while walking barely moved the needle by comparison. The same pattern held true for the ultramarathon runners, too. No matter which distance they ran, their AEA levels were higher after the race than before it started.¹

A second compound, 2-AG, behaved differently, only rising meaningfully during the standard marathon, and even then, mainly in the later stretches of the race and into the early recovery period. Interestingly, this compound was also elevated after all three ultramarathon distances, but since blood was only drawn before and after those races, it suggests this rise likely happens more as part of the recovery process rather than during the run itself.¹

As for how the participants felt, marathon runners reported more euphoria and less anxiety compared to when they simply walked the same distance, though pain started creeping in after about the 28-kilometer mark. The ultramarathon runners had a different experience: no matter which distance they ran, pain went up and anxiety went down, but interestingly, they did not report a significant boost in euphoria after finishing.¹

“Together,” write the authors of this paper,¹ “these findings show robust, time-dependent changes in circulating eCB concentrations during and after prolonged endurance running, as well as gradual increases in AEA during walking. These eCB dynamics occurred alongside acute affective changes during sustained endurance exercise.”

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References

1. Siebers, M.; Huvermann, D.; Siebers, C. et al. Endocannabinoid Dynamics Across Marathon and Ultramarathon Running: Evidence from Two Field Studies. BMC Med. 2026, 24 (1), 469. DOI: 10.1186/s12916-026-05186-z
2. Raichlen, D. A.; Foster, A. D.; Seillier, A. et al. Exercise-induced Endocannabinoid Signaling Is Modulated by Intensity. Eur J Appl Physiol. 2013, 113 (4), 869-75. DOI: 10.1007/s00421-012-2495-5
3. Siebers, M.; Biedermann, S. V.; Fuss, J. Do Endocannabinoids Cause the Runner's High? Evidence and Open Questions. Neuroscientist 2023, 29 (3), 352-369. DOI: 10.1177/10738584211069981
4. Black, J.; Chesher, G. B.; Starmer, G. A. et al. The Painlessness of the Long Distance Runner. Med J Aust. 1979, 1 (11), 522-523. PMID: 470706.
5. Partin C. Runner's "High.” JAMA 1983 249 (1), 21. DOI: 10.1001/jama.249.1.21
6. Dietrich, A.; McDaniel, W. F. Endocannabinoids and Exercise. Br J Sports Med. 2004, 38 (5), 536-541. DOI: 10.1136/bjsm.2004.011718
7. Dishman, R. K.; O’Connor, P. J. Lessons in Exercise Neurobiology: The Case of Endorphins. Ment Health Phys Act. 2009, 2, 4–9. DOI: 10.1016/j.mhpa.2009.01.002.