AIMS: High-protein meals stimulate pancreatic hormone release, and high-protein diets improve glucose homeostasis and decrease energy intake. These effects are partly mediated by gastrointestinal sensing of the amino acid products of protein digestion, including L-phenylalanine. Animal models suggest the calcium-sensing receptor mediates the glycaemic and anorectic effects of L-phenylalanine. However, there is conflicting evidence regarding L-phenylalanine on appetite, and the specificity of its effects on hormone release. MATERIALS & METHODS: Dose-finding study: non-randomised, unblinded, crossover study conducted October 2017 to December 2017 at the NIHR Imperial Clinical Research Facility in 5 participants. Assessed the tolerability of escalating doses of oral L-phenylalanine (0g, 3g, 6g, 10g). Acute study: randomised, double-blind, placebo-controlled crossover study conducted from January to May 2018 at the NIHR Imperial Clinical Research Facility in 11 participants. Investigated the effects of oral 10g L-phenylalanine relative to D-phenylalanine and placebo on gastroenteropancreatic hormone (insulin, glucagon, GIP, PYY, GLP-1) and glucose concentrations, visual analogue scales for subjective appetite and energy intake at an ad libitum meal served 70 minutes post-ingestion. RESULTS: L-phenylalanine was well-tolerated and increased insulin and glucagon concentrations prior to meal ingestion at several timepoints relative to placebo and D-phenylalanine (P<0.05). L-phenylalanine also increased GIP concentrations relative to D-phenylalanine (P=0.0420) and placebo (P=0.0249) 70 minutes following ingestion. L-phenylalanine reduced postprandial glucose AUC70-150mins relative to placebo (P=0.0317) but did not affect subjective appetite or energy intake (P>0.05). D-phenylalanine increased postprandial PYY AUC70-150mins concentrations relative to placebo (P=0.0002). CONCLUSIONS: Ingestion of L-phenylalanine, but not D-phenylalanine, increases insulin, glucagon and GIP concentrations without appearing to have a large effect on appetite. This article is protected by copyright. All rights reserved.