The body’s own cannabinoids shift throughout extreme endurance exercise

Endocannabinoid (eCB) signaling has been implicated in the physiological and affective responses to endurance exercise, including phenomena such as the runner's high. However, although humans have the capacity to run for several hours and even days, evidence regarding eCB signaling is largely limited to exercise bouts shorter than 60 min. Consequently, the temporal dynamics of eCB signaling during prolonged running and the accompanying acute affective responses remain unclear. This study investigated eCB signaling during long-distance running and following a 45-minute break. Two studies were conducted: In Study 1, 19 trained runners completed both a marathon and a duration-matched walking session, with repeated blood sampling every 14 km during the marathon and after a 45-minute recovery. In Study 2, 36 ultramarathon runners completed races of 100 km, 160 km, or 230 km and provided blood samples before and after their respective races. Plasma concentrations of anandamide (AEA), 2-arachidonoylglycerol (2-AG), 1-AG, arachidonic acid (AA), and palmitoylethanolamide (PEA) were quantified by a standardized liquid chromatography/multiple reaction monitoring assay. Euphoria, anxiety, and pain were assessed as core features of the runner's high using visual analog scales. AEA increased progressively throughout the marathon and remained elevated after 45 min, whereas walking elicited only modest changes. In line, after all ultramarathon distances AEA levels were increased compared with baseline. By contrast, an increase in 2-AG during exercise was observed only in the regular marathon, where concentrations rose significantly during the later stages of running and into early recovery. Elevated post-race 2-AG levels were also observed following all ultramarathon distances, consistent with a delayed, recovery-related response. Marathon running was associated with higher euphoria and lower anxiety than walking, while pain increased after 28 km of running. Ultramarathon running increased pain, reduced anxiety, and did not significantly alter euphoria post-exercise. Together, 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.