It is well accepted that physical exercise is associated with health benefits and reduces risks of psychiatric illness, diabetes, cancer and cardiovascular disease. Previous studies also show that psychiatric disorders, such as depression is associated with changes in peripheral and central concentrations of kynurenine metabolites of tryptophan degradation. Animal experiments indicate that exercise protects against depression by increased expression of skeletal muscle kynurenic aminotransferase (KAT), hereby promoting synthesis of the neuroprotectant kynurenic acid (KYNA) over the neurotoxic quinolinic acid (QUIN). In a series of studies, we have investigated the effects of exercise on kynurenine metabolism in humans. We found that KAT gene and protein expression increased in the muscles of endurance-trained subjects compared with untrained subjects. Furthermore, one hour after cycling 150-km plasma KYNA was found to be substantially increased (+63%) while the ratio QUIN/KYNA was found to be decreased (27%). Both KYNA and the QUIN/KYNA ratio returned to baseline within 24 h. In another group of subjects, we analyzed kynurenines in the plasma before and after performing a half- marathon. In this group plasma KYNA increased (+125%) 30 min after the race. In contrast, plasma concentrations of KYNA and QUIN, did not change following eccentric exercise (consisting of a series of 100 drop jumps). We further investigated the effect of exercise on both peripheral and central concentrations of kynurenine pathway metabolites. Cerebrospinal fluid (CSF) concentrations of KYNA, 3-hydoxykynurenine and picolinic acid (PIC) increased after an acute exercise paradigm, while tryptophan and kynurenine remained unchanged. At the same time, plasma tryptophan and kynurenine levels decreased while KYNA, 3-HK, QUIN and PIC did not change. We further found that the most robust effect of exercise was detected in subjects performing acute bouts of exercise over four consecutive days, while changes induced by engaging in three times weekly training exercise over 4 weeks, led to very limited effects. We further observed that the correlation between plasma and CSF concentrations of most of the kynurenine metabolites was low, indicating limited equilibration through an intact blood brain barrier. The only exception was PIC, that correlated to a high degree between compartments both before and after the intervention   In summary, these results show that acute vigorous aerobic exercise intervention causes adaptations in kynurenine metabolism, while a training exercise protocol over a longer time frame may have more limited effects. Further studies are needed to address the durability of effects and also if other modalities of exercise, such as muscle strength training, may influence the results.