Subchronic tolerance trials of graded oral supplementation with ornithine hydrochloride or citrulline in healthy adults

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Ornithine and citrulline are amino acids used in dietary supplements and nutritional products consumed by healthy consumers; however, the safe intake level of ornithine or citrulline supplementation is unknown. The objective of this study was to conduct two 4-week clinical trials to evaluate the safety and tolerability of graded dosages of oral ornithine (as hydrochloride) and citrulline. Healthy male adults (n = 60, age 41.4 ± 1.5 years) completed graded dosages of either ornithine hydrochloride (3.2, 6, 9.2 and 12 g/d) or citrulline (6, 12, 18 and 24 g/d) supplement for 4 weeks with 2-week wash-out periods in between. Primary outcomes included vitals, a broad spectrum of circulating biochemical analytes, body weight, sleep quality and mental self-assessment. In the ornithine hydrochloride supplementation group, minor changes in plasma aspartic acid, glutamic acid concentrations and increased its plasma concentration at highest intake dosages were observed. In the citrulline supplementation group minor changes in laboratory data of serum lactate dehydrogenase and plasma amino acid concentration of lysine, methionine, threonine, aspartic acid, glutamic acid, glutamine and ornithine, as well as arginine and citrulline itself were measured. No other changes in measured parameters were observed, and study subjects tolerated 4-week-long oral supplementation of ornithine hydrochloride or citrulline without treatment-related adverse events. A clinical, no-observed-adverse-effect-level (NOAEL) of ornithine hydrochloride and citrulline supplementation in healthy adult males was determined to be 12 g/day and 24 g/day (4weeks), respectively.