title: Dietary tryptophan depletion in humans using a simplified two amino acid formula - a pilot study.
abstract: 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 (ATDPHE/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 ATDPHE/LEUadministration relative to the ATD Moja-De protocol that has been established for use in children and adolescents.
  
  
  METHODS
  Seventy-two healthy adults (50% females) were randomized into four groups and administered ATD Moja-De, its TRP-balanced control condition (BAL), ATDPHE/LEU, or its respective control mixture (BALPHE/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 ATDPHE/LEUadministration 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 ATDPHE/LEUintake, 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 BALPHE/LEUadministration over a 6-h period was observed, and the large amount of PHE in the BALPHE/LEUmixture 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 ATDPHE/LEUprotocol. Future studies focusing on the effects of the ATDPHE/LEUprotocol 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.
authors.affiliation: Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.|JARA Translational Brain Medicine, Jülich Aachen Research Alliance, Jülich, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Linden
authors.affiliation: Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.|JARA Translational Brain Medicine, Jülich Aachen Research Alliance, Jülich, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Helmbold
authors.affiliation: Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.|JARA Translational Brain Medicine, Jülich Aachen Research Alliance, Jülich, Germany.|Faculty of Arts and Social Sciences, Maastricht University, Maastricht, The Netherlands.
authors.forename: Janina
authors.initials: J
authors.lastname: Kempf
authors.affiliation: Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.|JARA Translational Brain Medicine, Jülich Aachen Research Alliance, Jülich, Germany.|Faculty of Arts and Social Sciences, Maastricht University, Maastricht, The Netherlands.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Sippas
authors.affiliation: Section JARA-Brain, Jülich-Aachen Research Alliance (JARA), Jülich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Filss
authors.affiliation: Section JARA-Brain, Jülich-Aachen Research Alliance (JARA), Jülich, Germany.|Institute of Neuroscience and Medicine (INM-3, -4, -5), Research Centre Jülich, Jülich, Germany.|Department of Nuclear Medicine, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Karl-Josef
authors.initials: KJ
authors.lastname: Langen
authors.affiliation: Department of Pharmacy, RWTH Aachen University, Aachen, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Eisert
authors.affiliation: Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.|JARA Translational Brain Medicine, Jülich Aachen Research Alliance, Jülich, Germany.|Centre and Discipline of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, School of Psychiatry and Clinical Neurosciences & School of Paediatrics and Child Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, Australia.|Specialised Child and Adolescent Mental Health Services (CAMHS), Department of Health in Western Australia, Perth, Australia; florian.zepf@uwa.edu.au.
authors.forename: Florian Daniel
authors.initials: FD
authors.lastname: Zepf
keywords: Michaelis–Menten kinetics; amino acids; dietary tryptophan depletion; humans; influx rate; serotonin