The largest body of work in humans looking at the effect of exercise on tryptophan availability to the brain is concerned with the hypothesis that fatigue during exercise is associated with elevated brain tryptophan and serotonin synthesis. A large body of evidence supports the idea that exercise, including exercise to fatigue, is associated with an increase in plasma tryptophan and a decrease in the plasma level of the branched chain amino acids (BCAAs) leucine, isoleucine and valine (see64,65 for reviews). The BCAAs inhibit tryptophan transport into the brain.66 Because of the increase in plasma tryptophan and decrease in BCAA, there is a substantial increase in tryptophan availability to the brain. Tryptophan is an effective mild hypnotic,67 a fact that stimulated the hypothesis that it may be involved in fatigue. A full discussion of this topic is not within the scope of this editorial; however, it is notable that several clinical trials of BCAA investigated whether it was possible to counter fatigue by lowering brain tryptophan, with results that provided little support for the hypothesis. Further, exercise results in an increase in the plasma ratio of tryptophan to the BCAAs before the onset of fatigue.64,65 - www.ncbi.nlm.nih.gov