Subchronic Tolerance Trials of Graded Oral Supplementation with Phenylalanine or Serine in Healthy Adults

Abstract

Phenylalanine and serine are amino acids used in dietary supplements and nutritional products consumed by healthy consumers; however, the safe level of phenylalanine or serine 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 phenylalanine and oral serine. Healthy male adults (n = 60, 38.2 ± 1.8y) completed graded dosages of either phenylalanine or serine supplement (3, 6, 9 and 12 g/d) 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. At low dosages, minor changes in serum electrolytes and plasma non-essential amino acids glutamine and aspartic acid concentrations were observed. Serine increased its plasma concentrations at high supplemental dosages (9 and 12 g/day), and phenylalanine increased plasma tyrosine concentrations at 12 g/day, but those changes were not considered toxicologically relevant. No other changes in measured parameters were observed, and study subjects tolerated 4-week-long oral supplementation of phenylalanine or serine without treatment-related adverse events. A clinical, no-observed-adverse-effect-level (NOAEL) of phenylalanine and serine supplementation in healthy adult males was determined to be 12 g/day.

Detection of impurities in dietary supplements containing l-tryptophan

“…Using Trp as a typical ingredient in supplements, this is a paradoxical regulatory approach since a controlled clinical safety study in healthy adults described a substantial safety margin for high-purity supplementary Trp equal to more than 5-times its intake from regular food sources (Hiratsuka et al 2013). The same applies to numerous other proteinogenic amino acids (e.g., Gheller et al 2020;Miura et al 2021).…”

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

“…Subjects received supplements for the whole 4-week test period and were instructed to consume them daily before 12:00 pm, consistent with the previous research (Gheller et al, 2020;Miura et al, 2021). At the end of each 4-week test period, the subjects visited the clinic for safety evaluation following overnight fasting at least 8 hours.…”

“…A dietary intake survey was conducted at the end of each 4-week period using the brief-type self-administered diet history questionnaire (BDHQ) food habit assessment (Miura et al, 2021), which was previously validated for Japanese subjects (Sasaki et al, 2003). No signi cant effects of either ornithine or citrulline supplementation on intake of total energy (kcal/day), protein (g/day), fat (g/day) and carbohydrates (g/day) were found (Table 5).…”

Tolerable amounts of amino acids for human supplementation: summary and lessons from published peer-reviewed studies

“…In humans, the RQ for aromatic amino acids (phenylalanine/tyrosine) is 27.0 mg/kg BW/day (Table 2 ), and the mean intake of phenylalanine from all sources is 3.40 g/day (FNB/IOM 2005 ), and thus corresponds to an UC equal to 48.57 mg/kg BW/day (Table 1 ). The NOAEL for phenylalanine is 169.3 mg/kg BW/day (Miura et al 2021 ). Thus, the NOAEL/UC ratio is 3.5, these ratios being close to the ratios determined in rats (Table 1 ).…”

“…In humans, the mean consumption of serine from dietary sources and supplements is 3.52 g/day (FNB/IOM 2005 ), thus representing an UC equal to 50.29 mg/kg BW/day. The NOAEL for serine supplementation is 169.3 mg/kg BW/day (Miura et al 2021 ). Then, the NOAEL/UC ratio for serine in volunteers is 3.4, a value close to the one found in rats.…”