Ketosis elevates plasma concentrations of D-β-hydroxybutyryl-phenylalanine (BHB-Phe) in humans.
Level 2 - randomized trial
Analysis of blood samples from four clinical crossover trials
PubMed 42458538 · doi:10.1186/s12986-026-01172-7
What was done
Plasma D-β-hydroxybutyryl-phenylalanine (D-BHB-Phe) concentrations were measured in human blood samples collected across four clinical crossover trials: (1) 21 days on a ketogenic diet versus standard diet (n = 10); (2) acute oral ingestion of 30 g ketone salt (KS) and 30 g ketone ester (KE) versus placebo (n = 14); (3) oral KE dose-escalation at 10 g, 20 g, and 40 g (n = 10); and (4) oral versus iso-ketotic intravenous KS administration (n = 8).
What was found
A 21-day ketogenic diet increased plasma D-BHB-Phe from near-undetectable baseline levels (median 0 nmol/L; range 0–0.9) to a median of 2.1 nmol/L (range 0.9–19.9; p = 0.005). Oral KS and KE significantly elevated D-BHB-Phe relative to placebo (intervention × time, p < 0.001), showing a dose-dependent increase across 10 g, 20 g, and 40 g of KE (intervention × time, p < 0.001). Oral KS elicited a markedly higher peak D-BHB-Phe concentration (15.6 ± 6.4 nmol/L) than iso-ketotic intravenous KS infusion (1.5 ± 0.3 nmol/L; intervention × time, p < 0.001). Circulating D-BHB and D-BHB-Phe were positively correlated in pooled analysis, though this relationship was inconsistent within individual cohorts.
Why it matters
This study confirms that ketosis produces D-BHB-amino acid conjugates in humans and indicates that first-pass splanchnic metabolism is heavily involved in their formation.
Limits
All four crossover cohorts had very small sample sizes (8 to 14 participants per sub-study). The abstract reports no clinical or functional outcomes (such as appetite ratings, energy intake, or body weight changes) and leaves unclear whether these nanomolar circulating concentrations are physiologically active in humans.
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- context Conjugation of the ketone body beta-hydroxybutyrate with the amino acid phenylalanine mediates downstream appetite suppression and weight loss effects.