A new pair of field studies, published in BMC Medicine, offers the most detailed real-world picture to date. A research team led by Michael Siebers and Johannes Fuss of the University of Duisburg-Essen, together with colleagues at the University Hospital Ulm, the German Sport University Cologne, the University Medical Center Mainz, and other institutions, tracked circulating endocannabinoid concentrations in trained runners during actual competitions, from a standard 42.2-kilometer marathon all the way up to 230-kilometer ultramarathons. Their results reveal a strikingly time-dependent chemical choreography, with one key messenger climbing steadily for hours while a second behaves in a surprisingly selective, distance-dependent manner.

The endocannabinoid system is built around lipid messengers that are synthesized on demand from membrane fats and act on two G-protein-coupled receptors, CB1 and CB2. CB1 receptors are densely expressed in brain regions governing mood, anxiety, and pain perception, which is precisely why the system has been a leading suspect in the runner’s high. The two most studied messengers are anandamide (AEA), an arachidonate-derived ethanolamide whose name derives from the Sanskrit word for bliss, and 2-arachidonoylglycerol (2-AG), which belongs to a different chemical family but activates the same receptors. Both are rapidly degraded by dedicated enzymes, fatty acid amide hydrolase for AEA and monoacylglycerol lipase for 2-AG, meaning their blood levels reflect a dynamic balance of production and clearance rather than a passive accumulation.

In the first study, 19 trained runners completed both a full marathon and a duration-matched walking session on separate occasions, an elegant design that held exercise duration constant while varying the intensity and the mode of locomotion. During the marathon, the researchers drew blood at every 14-kilometer checkpoint and again after a 45-minute recovery break, allowing them to chart the trajectory of five lipid signals: AEA, 2-AG, its structural isomer 1-AG, arachidonic acid, and palmitoylethanolamide, an anti-inflammatory lipid that does not bind CB1. Mood was captured with visual analog scales rating euphoria, anxiety, and pain, the three core psychological features of the runner’s high. All measurements were quantified with a standardized liquid chromatography and multiple reaction monitoring assay, the gold-standard technique for targeted lipidomics.

The headline finding concerns anandamide. AEA concentrations rose progressively throughout the marathon and, remarkably, remained elevated even after 45 minutes of rest, indicating that the signal is not a fleeting byproduct of exertion but a sustained shift in circulating lipid tone. By contrast, the duration-matched walking session produced only modest changes in AEA, suggesting that sustained moderate-to-vigorous intensity, not merely hours of movement, is what drives the messenger upward. The ultramarathon study reinforced this pattern: 36 runners competing over 100, 160, or 230 kilometers all finished with AEA levels above their own baselines, regardless of race distance. Whatever mechanism pushes anandamide into the bloodstream, it appears to engage early and keep working across an extraordinary range of exercise durations.

2-AG told a different and more nuanced story. In the marathon, 2-AG increased significantly only during the later stages of running and remained elevated into early recovery, a delayed profile that contrasts sharply with the steady climb of AEA. In the ultramarathon cohort, 2-AG was not elevated during the races themselves in the same way, but post-race concentrations were increased at all three distances, consistent with what the authors interpret as a delayed, recovery-related response rather than an acute exercise signal. This dissociation matters scientifically: it suggests that the two major endocannabinoids are regulated by partly independent mechanisms during prolonged endurance exercise, with AEA tracking the ongoing stress of running and 2-AG lagging behind, perhaps reflecting lipid remodeling or delayed enzymatic activity that continues after the finish line.

The psychological measurements added a crucial affective dimension. Marathon running was associated with significantly higher euphoria and lower anxiety than duration-matched walking, even though both activities lasted the same amount of time. Pain, however, told a more complicated tale: it increased after the 28-kilometer mark of the marathon, showing that the analgesic component of the runner’s high does not simply overwhelm accumulating musculoskeletal damage during very long efforts. In the ultramarathoners, post-race profiles showed increased pain, reduced anxiety, and no significant change in euphoria. Taken together, these patterns hint that different facets of the runner’s high may ride on different chemical rails, with the anxiolytic effect potentially linked to the sustained AEA rise and the euphoric peak perhaps requiring conditions, such as the intensity profile of a marathon, that ultramarathon pacing does not reproduce.

The field-based design is both the study’s greatest strength and its defining constraint. By sampling real competitors mid-race, the researchers captured physiological conditions that no laboratory protocol can faithfully simulate, including accumulated fatigue, dehydration, heat stress, and the psychological texture of competition. The trade-offs are equally real: field studies cannot control diet, pacing, sleep, or terrain with laboratory precision, and blood-based lipid measurements are an indirect window onto brain chemistry, since circulating endocannabinoids do not map one-to-one onto signaling within the central nervous system. The authors also note that the findings document robust correlations between eCB dynamics and affective states during prolonged running; establishing causation, for example by pharmacologically manipulating the system during exercise, remains a challenge for future work.

Even so, the implications are considerable. The endocannabinoid system is a validated target of both cannabis pharmacology and mainstream drug development, and exercise is increasingly recognized as a natural modulator of this network with potential relevance for mood disorders, chronic pain, and stress resilience. Demonstrating that hours of running produce sustained, intensity-dependent elevations of anandamide in real athletes provides an evolutionary and physiological scaffold for the idea that long-distance locomotion is intrinsically rewarding, a hypothesis sometimes framed as the endurance-exercise model of human origins, in which our ancestors’ capacity for persistence hunting and long-distance travel was reinforced by neurochemical rewards. The persistence of elevated AEA into recovery also raises practical questions about whether the mood benefits of a long run outlast the run itself, a possibility the marathon data directly support at the 45-minute mark.

What emerges from these two studies is a revised and richer picture of the runner’s high: not a single chemical switch flipped at some magical mileage, but a layered, time-dependent process in which anandamide builds steadily with sustained effort, 2-AG responds late and lingers into recovery, and the subjective experience, euphoria, calm, and pain, shifts in ways that only partially overlap with the lipid signals. For the millions of runners who chase that elusive feeling each weekend, the new work offers both validation and humility. The chemistry of bliss is real, measurable in a vial of blood taken at kilometer 28, and it follows rules that science is only now beginning to read, one marathon and one ultramarathon at a time.

Subject of Research: Endocannabinoid signaling dynamics during marathon and ultramarathon running and their relationship to acute mood and pain responses

Article Title: Endocannabinoid dynamics across marathon and ultramarathon running: evidence from two field studies

Article References: Siebers, M., Huvermann, D., Siebers, C., Canales-Romero, D., Florea-Ghile, A., Keite, L., John, L., Munk, M., Bizjak, R., Witzel, J., Schulz, S., Kirsten, J., Bindila, L., Hinney, A., Grau, M., Bizjak, D. A., Engler, H., & Fuss, J. (2026). Endocannabinoid dynamics across marathon and ultramarathon running: evidence from two field studies. BMC Medicine, 24(1), Article 469. https://doi.org/10.1186/s12916-026-05186-z

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05186-z

Keywords: endocannabinoids, anandamide, 2-arachidonoylglycerol, runner's high, marathon, ultramarathon, endurance exercise, CB1 receptor, lipidomics, euphoria, anxiety, pain perception