A 24-hour simulation of plasma amino acid concentrations, LAT1 transport competition at the blood-brain barrier, and downstream monoamine synthesis. Four conditions: full PAH function, untreated PKU, a low-protein diet with formula, and PKU on a natural diet with LNAA tablets in three doses with meals, the regimen of the published trials.
A stylized model: curve shapes are qualitative, drawn to show transport ratio dynamics rather than measured values. Square-root scale on the timeline so normal-range levels stay visible beside PKU-range phe. Brain-entry mechanics follow the LNAA MRS crossover study (PMID 17368065) and the Pah-enu2 LNAA diet studies (PMIDs 26624009, 27655443); phe carries the highest LAT1 affinity of the six competitors (PMID 19437129). The LNAA condition follows the regimen of the trials: a phenylalanine-free LNAA tablet mixture in three divided doses with meals at 0.4 to 0.5 g/kg/day (PMIDs 12809641, 14654668, 16988900). Blood phe is drawn unchanged from the untreated condition because it did not differ between LNAA and placebo in the melatonin trial (P = .74) and remained essentially unchanged in the 2003 series while brain phe fell; the separate double-blind multicenter trial of an unnamed product found a 39% mean fall (PMID 17334706). In the randomized, double-blind, placebo-controlled crossover trial of the mealtime regimen in 10 adults, serum melatonin, urine 6-sulfatoxymelatonin and urine dopamine were higher after the LNAA phase than after placebo (P = .0008, .0008, .0005), the tryptophan/LNAA and tyrosine/LNAA ratios rose (P = .016, P = .0003), and blood phe did not differ (P = .74) (Yano 2013; PMID 23164313). Adding tryptophan and tyrosine tablets to the LNAA tablets raised urine dopamine and plasma Tyr:LNAA but did not raise melatonin, and the authors placed the serotonin limit at tryptophan hydroxylase under high phe (Yano 2014; PMID 24857519). In Pah-enu2 mice six weeks of an LNAA-supplemented diet raised brain serotonin from 35 to 71 percent and norepinephrine from 57 to 86 percent of wild-type and did not change brain dopamine (p = 0.307) (van Vliet 2015; PMID 26624009); tyrosine and tryptophan had to be in the mixture for the monoamine effect, the tyrosine requirement was higher than the tryptophan requirement, and the relative effect of brain phe reduction was larger for serotonin than for dopamine (van Vliet 2016; PMID 27655443). Eight supplemented LNAAs restored brain monoamines in adult PKU mice as well as a severe phe-restricted diet did, with brain and plasma phe still markedly elevated (PMID 29175141). The model's serotonin gauge tracks tryptophan influx alone; the hydroxylase limit reported in 2014 is not drawn. The diet-plus-formula condition follows the 24-hour profiling and dose-timing literature: blood phe peaks after the overnight fast, free amino acid substitutes absorb and clear rapidly, and randomized comparison of dosing schedules shows that concentrating the same daily dose into daytime hours produces wide 24-hour variability while distributing it across 24 hours removes it (PMIDs 23672685, 12971419, 41928294).