# L-Citrulline: A Non-Essential Amino Acid with Important Roles in Human Health
## 5 Ergogenic Effect of L-Citrulline Supplements
### Ergogenic Effect of Urea Cycle from L-Citrulline Supplements  
The urea cycle detoxifies the ammonia accumulated in skeletal muscles from high intensity exercise [61; 63]. Experimental studies in rats have proven that supplementation using a CIT/Arg/ornithine mix suppressed blood ammonia from accumulating following exercise and in a swimming activity it lengthened the time before becoming exhausted, by about 60% [63]. CIT supplementation, by buffering ammonia through the urea cycle, enhances the aerobic utilization of pyruvate and, therefore, decreases lactate production via the anaerobic pathway. Conversely, the central nervous system is instrumental in the development of exercise-induced fatigue [64]. The cerebral concentration of serotonin is increased during physical exercise, which can contribute to fatigue developing in the central nervous system [65]. The cerebral synthesis of serotonin requires tryptophan as a precursor, and it seems that tryptophan transportation through the blood-brain barrier is the factor limiting the speed of synthesis of cerebral serotonin [66]. BCAAs have been proposed as a means of alleviating central fatigue because of their capacity to compete with tryptophan, in traversing the blood-brain barrier using the same L-system transporter. However, studies in humans have not demonstrated the ergogenic effect of BCAA supplementation during physical exercise, due to excess hyperammonemia to the increased BCAA metabolism when exercising [67]. In humans, there is an increased brain absorption and accumulation of ammonia during prolonged exercise [68]; this seems to be able to induce central fatigue through alterations in cerebral energy metabolism and neurotransmission and signaling pathways within the neuron [69]. Thus, it appears that the lower plasma tryptophan/BCAA ratio following BCAA supplements could decrease the cerebral uptake of tryptophan and, consequently, serotonin synthesis, thereby preventing central fatigue during prolonged exercise [65].  
Combining BCAA and Arg supplements on the performance of intermittent sprints in simulated handball matches on two consecutive days in well-trained athletes showed a significantly lower plasma tryptophan/BCAA ratio following the activity on both days in the group that took the combined supplementation of BCAA + Arg, describing lower rates of perceived exertion (RPE), using [PERSON]'s 20-point scale, possibly by alleviating central fatigue [70]. Therefore, both Arg and CIT may decrease exercise-related build-ups of ammonia by increasing the urea cycle and NO biosynthesis [18]. [PERSON] et al. [71] studied how combining BCAA, Arg and CIT supplements affected central fatigue by monitoring three simulated matches in well-trained taekwondo athletes. Their results showed that supplementing BCAA and Arg and CIT achieved a significantly lower plasma free tryptophan/BCAA ratio and raised NO concentrations. Moreover, those supplements led to no additional ammonia accumulation, potentially with mediation of a raised NO production from Arg and CIT. The ergogenic effect may be potentially caused by mechanisms such as central fatigue alleviation (by means of inhibiting cerebral serotonin synthesis by BCAA) and preventing excess hyperammonemia, through increased urea genesis by Arg and CIT.