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

Abstract

BackgroundAcute 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.ObjectiveThis study investigated tryptophan (TRP) influx rates across the blood-brain barrier (BBB) after dietary ATDPHE/LEU administration relative to the ATD Moja-De protocol that has been established for use in children and adolescents.DesignSeventy-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.ResultsBoth 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/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 ATDPHE/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 BALPHE/LEU administration over a 6-h period was observed, and the large amount of PHE in the BALPHE/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.ConclusionsThis 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/LEU protocol. Future studies focusing on the effects of the ATDPHE/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.

Inflammation in cancer and depression: a starring role for the kynurenine pathway

“…Finally, the phenylalanine/tyrosine ratio, considered a measure of inflammation (Wannemacher et al 1976), was higher in the comorbid cancer and depression subgroup. Interestingly, an excess of phenylalanine could interfere with serotonin production by competing with tryptophan for the same active transport channel to cross the blood-brain barrier (Linden et al 2016). In a different study conducted in 61 breast cancer patients (Pertl et al 2013), the authors did not find an association between kynurenine pathway alterations and depressive symptoms, assessed here too with HADS score, before chemotherapy.…”

Effects of serotonin depletion and dopamine depletion on bimodal divided attention

“…As calculated with G*power ® a group size of at least 22 subjects would be necessary to reach a statistical power (1-β) of 0.8. No gender-related analysis was carried because of the preliminary and explorative nature of this study, in particular because a control for the menstrual phase would have been valuable and this has been done in some previous studies (see Helmbold et al 2016), but much ATD-related research has been done in males and the impact of the menstrual phase on ATD-research has often been neglected (Mendelsohn et al 2009). Serotonergic neurotransmission shows significant gender differences and is influenced by sex hormones which alternate throughout the menstrual cycle (Lasiuk and Hegadoren 2007).…”

“…The significance of the ensuing effects on central monoamine turnover has been documented both in animal and human studies (Booij et al 2003;Ruhé et al 2007;Mendelsohn et al 2009;Biskup CS et al 2012;Young 2013;Sanchez et al 2014). As demonstrated for the ATD protocol a significant reduction of the TRP influx occurs 90 minutes after ATD intake and reaches a nadir at 240 minutes, which is followed by a slow recuperation, whereas the TRP influx is still decreased at about 50% at 360 minutes after intake (Linden et al 2016), Dingerkus et al 2012).…”