Safety of dietary supplementation with arginine in adult humans

Abstract

Previous studies with animals and humans have shown beneficial effects of dietary supplementation with L-arginine (Arg) on reducing white fat and improving health. At present, a long-term safe level of Arg administration to adult humans is unknown. The objective of this study was to conduct a randomized, placebo-controlled, clinical trial to evaluate the safety and tolerability of oral Arg in overweight or obese but otherwise healthy adults with a body mass index of ≥ 25 kg/m. A total of 142 subjects completed a 7-day wash-in period using a 12 g Arg/day dose. All the remaining eligible 101 subjects who tolerated the wash-in dose (45 men and 56 women) were assigned randomly to ingest 0, 15 or 30 g Arg (as pharmaceutical-grade Arg-HCl) per day for 90 days. Arg was taken daily in at least two divided doses by mixing with a flavored beverage. At Days 0 and 90, blood pressures of study subjects were recorded, their physical examinations were performed, and their blood and 24-h urine samples were obtained to measure: (1) serum concentrations of amino acids, glucose, fatty acids, and related metabolites; and (2) renal, hepatic, endocrine and metabolic parameters. Our results indicate that the serum concentration of Arg in men or women increased (P < 0.05) progressively with increasing oral Arg doses from 0 to 30 g/day. Dietary supplementation with 30 g Arg/day reduced (P < 0.05) systolic blood pressure and serum glucose concentration in females, as well as serum concentrations of free fatty acids in both males and females. Based on physiological and biochemical variables, study subjects tolerated oral administration of 15 and 30 g Arg/day without adverse events. We conclude that a long-term safe level of dietary Arg supplementation is at least 30 g/day in adult humans.

Dynamic changes in circulating levels of metabolites in the portal‐drained viscera of finishing pigs receiving acute administration of l‐arginine

“…For example, Alvares, Conte‐Junior, Silva, and Paschoalin (2014) reported that l ‐arginine supplementation to humans for four weeks did not promote any beneficial changes in metabolic and hormonal parameters (Alvares et al, 2014), whereas Forbes and Bell (2011) observed no significant difference in GH and glucose following acute consumption of l ‐arginine (Forbes & Bell, 2011). Similarly, chronic oral administration of 15 or 30 g arginine/day to obese and overweight adults had no discernible effect on the plasma concentrations of GH or insulin (McNeal et al, 2018). It thus seems likely that the response of humans to arginine is dependent on their metabolic status.…”

“…Arginine may also affect multiple metabolic pathways involving amino acid degradation (Blachier, Davila, Benamouzig, & Tome, 2011), nutrient transport (Kim & Wu, 2009) and cellular redox state (Wu, 2009; Yin & Tan, 2010). Recent studies have shown that dietary supplementation with arginine can reduce plasma levels of glucose, fatty acids, homocysteine and asymmetric dimethylarginine (McNeal, Meininger, Wilborn, Tekwe, & Wu, 2018), while improving endothelium‐dependent relaxation in both type I and type II models of diabetes mellitus (Fu et al, 2005). Dietary arginine supplementation also alters amino acid concentrations in the plasma of swine, enhances protein synthesis in skeletal muscle and modulates intestinal microbial metabolites (He et al, 2009).…”

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

“…That observation was similar to findings from a single female patient with an inherited metabolic disorder [31] and from patients with non-alcoholic fatty liver disease [32], who were also characterized by a serine supplementation-induced drop in circulating branched-chain amino acids, which was not seen in the present trial. In parallel to previous phenylalanine and serine studies [30][31][32] and to clinical safety studies with other amino acids [15,33], plasma changes in tyrosine and serine were not considered pathological because they were transient, unaccompanied by imbalances of other amino acids and unconnected to any changes in the evaluated behavioral parameters. An increase in plasma tyrosine measured when phenylalanine was supplemented at 12 g/day might have hypothetically affected the brain catecholamines and thus reduced stress and mental fatigue [34].…”

Outcome of the public consultation on draft EFSA Statement on the derivation of Health‐Based Guidance Values (HBGVs) for regulated products that are also nutrients

“…RATIONALE: The risk assessment of regulated substances without history of use (e.g., high-intensity sweeteners) relies on in vitro and animal studies through established "classical toxicology" methodologies. Such approaches are not applicable to macronutrients with evolutionary food history, as illustrated in significant divergences in NOAELs derived from rodent and human sub-chronic evaluations of the amino acid methionine [14,15], leucine [16,17], and arginine [18,19].…”