Dietary tryptophan depletion in humans using a simplified two amino acid formula – a pilot study

BACKGROUND: Acute tryptophan depletion (ATD) is a well-established dietary method in translational brain research used to briefly lower central nervous serotonin (5-hydroxytryptamine (5-HT)) synthesis. A simplified two amino acid ATD formula (ATD(PHE/LEU)) was developed while reducing the overall amount of amino acids (AAs), with the objective of administration especially in children and adolescents in future studies. OBJECTIVE: This study investigated tryptophan (TRP) influx rates across the blood-brain barrier (BBB) after dietary ATD(PHE/LEU) administration relative to the ATD Moja-De protocol that has been established for use in children and adolescents. DESIGN: Seventy-two healthy adults (50% females) were randomized into four groups and administered ATD Moja-De, its TRP-balanced control condition (BAL), ATD(PHE/LEU), or its respective control mixture (BAL(PHE/LEU)) in a counterbalanced, double-blind, between-subjects design. Blood samples were collected at baseline and at hourly intervals for 6 h after AA intake. Questionnaires about mood, taste, and challenge tolerance were completed at fixed time points. RESULTS: Both challenge mixtures significantly reduced central nervous TRP influx as calculated by Michaelis–Menten kinetics relative to baseline and the respective control conditions with only mild and comparable side effects. A greater decline in TRP influx over the BBB after ATD(PHE/LEU) administration when compared with ATD Moja-De was detected without group effects for taste, challenge tolerance, and mood. There was unintended initial short increase in plasma TRP concentrations observed after ATD(PHE/LEU) intake, and a possible redistribution between free and protein-bound TRP triggered by protein synthesis stimulated by the ingested AAs may account for this finding. Moreover, a decline in TRP influx after BAL(PHE/LEU) administration over a 6-h period was observed, and the large amount of PHE in the BAL(PHE/LEU) mixture may be a possible explanation for this particular phenomenon, which could have led to an unexpected increase in displacement of TRP at the BBB in this control condition. CONCLUSIONS: This pilot study provides preliminary evidence for the possibility of lowering TRP influx as calculated by Michaelis–Menten kinetics into the brain by using a simplified ATD protocol in humans. The simplified composition of only two AAs, the lower overall AA amount, and the appropriate tolerance are characteristics of the newly developed ATD(PHE/LEU) protocol. Future studies focusing on the effects of the ATD(PHE/LEU) protocol and its respective control condition on CSF 5-HIAA concentrations, as well as neurochemical studies in rodents, are needed to further validate this newly developed AA mixture before definite conclusions about its usability in ATD-related research in humans, its specificity, and additional effects can be made.