Appropriate amino acid mixtures for tryptophan depletion and tyrosine/phenylalanine depletion and the safety of long-term amino acid depletion in humans

Abstract

AbbreviationsATD Acute tryptophan depletionAPTD Acute tyrosine/phenylalanine depletionGMP GlycomacropeptideTrp TryptophanTyr TyrosinePhe PhenylalanineDOPA dihydroxyphenylalanineDear Editor,In a recent review in this journal, Badawy ( 2013) discussedthe appropriate composition of amino acid mixtures for acutetryptophan depletion (ATD) and acute phenylalanine/tyrosinedepletion(APTD)studiesandsuggestedthatglycomacropeptide(GMP), which contains no aromatic amino acids, may be asuitable protein to use in acute depletion studies and long-termATD and APTD treatments of patients with mania and schizo-phrenia. The review raises a number of interesting issues but hasaspects that are problematic.1. The review suggests that GMP may be an effective nutri-tionaltherapyformanicand psychoticdisorders.Howev-er,thereviewdoesnotraisetheissueofwhetheraproteinwill necessarily be free of adverse effects. GMP lacksaromatic amino acids and, if given chronically, wouldcause the intake of amino acids to be imbalanced. Aspointed out by Young (2008), the extensive animal liter-ature on the effects of imbalanced amino acid diets indi-cates adverse effects including reductions in food intake,growth retardation, and the development of fatty liver.Furthermore, tyrosine (Tyr) and tryptophan (Trp) areessentialaminoacids,anddepletingthemmayhavesubtleeffectsonproteinsynthesis.Thepossibleimplicationsforbrain function of long-term mild disturbances of proteinsynthesisarenotknown.Rulingoutanyadverseeffectsoflong-term ATD or APTD in humans would be difficult,andanylong-termdepletionstudyinhumans,usingeitheramino acid mixtures or a protein such as GMP, would behard to justify ethically.2. The review mentions that GMP is lacking in histidine.This means that GMP would be expected to depletehistidine levels, but the implications of this are not men-tioned. In rats, histidine levels influence brain histaminelevels more than Trp levels influence brain serotoninlevels, and acute histidine depletion in humans, using ahistidine-deficient amino acid mixture, has behavioral ef-fects (van Ruitenbeek et al. 2009). Therefore, if GMP isused for acute ATD or APTD studies, histidine should beaddedtotheGMPinbothdepletionandcontrolconditionsto avoid a study on the combined effects of low histamineand low serotonin or low histamine and low dopamine.3. The review suggests that GMP may be useful for treatingmania by depleting dopamine. This is based on the studyof Scarna et al. (2003) who found a therapeutic effect,relativeto placebo, of giving a mixture of branchedchainamino acids (BCAA) to manic patients everyday for7 days. The effect was attributed to lowered dopamine,as the BCAA will inhibit the uptake of phenylalanine(Phe) and Tyr into the brain. However, the BCAA willalso inhibit the uptake of Trp into the brain. Two studiessuggest that depletion of Trp may have played a moreimportant role than depletion of Phe and Tyr in the ther-apeutic effect of the BCAA. Firstly, the Tyr hydroxylaseinhibitor α-methylparatyrosine had no consistent effecton the symptoms of manic patients (Bunney et al. 1971).Secondly,ATDimprovedthesymptomsofmanicpatientsmore than treatment with a placebo (Applebaum et al.2007). Therefore, if GMP has an effect on manic