LETTER TO EDITOR

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

Simon N. Young

Received: 12 July 2013 /Accepted: 28 July 2013 /Published online: 13 August 2013# Springer-Verlag Berlin Heidelberg 2013

AbbreviationsATD Acute tryptophan depletionAPTD Acute tyrosine/phenylalanine depletionGMP GlycomacropeptideTrp TryptophanTyr TyrosinePhe PhenylalanineDOPA dihydroxyphenylalanine

Dear Editor,In a recent review in this journal, Badawy (2013) discussed

the appropriate composition of amino acid mixtures for acutetryptophan depletion (ATD) and acute phenylalanine/tyrosinedepletion (APTD) studies and suggested that glycomacropeptide(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-tional therapy for manic and psychotic disorders. Howev-er, the review does not raise the issue of whether a proteinwill 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) are

essential amino acids, and depleting themmay have subtleeffects on protein synthesis. The possible implications forbrain function of long-term mild disturbances of proteinsynthesis are not known. Ruling out any adverse effects oflong-term ATD or APTD in humans would be difficult,and any long-term depletion study in humans, using eitheramino 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 beadded to the GMP in both depletion and control conditionsto 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,relative to placebo, of giving a mixture of branched chainamino 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, ATD improved the symptoms of manic patientsmore than treatment with a placebo (Applebaum et al.2007). Therefore, if GMP has an effect on manic

S. N. Young (*)Department of Psychiatry, McGill University, 1033 Pine AvenueWest, Montréal, Québec H3A 1A1, Canadae-mail: simon.young@mcgill.ca

Psychopharmacology (2013) 229:377–378DOI 10.1007/s00213-013-3237-z

symptoms, lowered serotonin probably contributes to theeffect.

4. The review states that the original 100 g ATD mixtureused by Young et al. (1985) has poor specificity due to itshigh content of the BCAA, which lowers the plasma ratioof (Tyr + Phe)/(BCAA + Trp). The large neutral aminoacids compete with each other for entry into the brain, andthe ratio of (Tyr + Phe)/(BCAA + Trp) is used as an indexof the availability in the brain of the dopamine precursorsTyr and Phe. The review suggests that the decline in thisratio indicates a decrease in dopamine synthesis. Thisshould not be a problem with GMP due to its lowerBCAA content. This issue was discussed in detail in arecent review (Young 2012). The ratio has Tyr plus Phe inthe numerator presumably because animal studies showthat Phe can be converted to Tyr and then to DOPA, byTyr hydroxylase. If Phe is an efficient substrate for humanbrain Tyr hydroxylase, then, untreated patients with phe-nylketonuria, who have high blood Phe and low bloodTyr, should have elevated brain catecholamine synthesis.In fact, in untreated phenylketonuria patients, there is alarge decrease in brain catecholamine synthesis, indicat-ing that the human brain uses primarily tyrosine in cate-cholamine synthesis. Thus, the appropriate ratio to use is(Tyr)/(BCAA + Phe + Trp). In studies where this ratio isreported, it is not lowered by ATD. Of course the ratio isonly an index of the relevant brain amino acid level. Anaccurate measure would take into account the affinities ofthe different amino acids for the system that transports thelarge neutral amino acids into the brain, but these are notknown. Ingestion of proteins or amino acids will alwayschange brain amino acids, somewhat, and such changesare unavoidable in ATD studies. The important issue forATD studies is that any change in Tyr levels in the brain isnot outside the normal physiological range associated withdiurnal changes and food intake. This is certainly true forthe original control mixture originally used by Young et al.(1985), as the amino acid composition is based on that ofhuman milk. Any differences in the changes in brain Tyrdue to the control and ATD mixtures will be negligible asTrp is the least abundant amino acid in protein, and

inhibition of Tyr uptake into the brain by Trp will be verysmall compared with inhibition by the other large neutralamino acids. Thus, GMP will have no advantage over theoriginal amino acid formulation in terms of specificity.

GMP may have an advantage over established amino acidmixtures in terms of reduced side effects, but the efficacy ofGMP in lowering serotonin or dopamine synthesis remains tobe established. On the other hand, the established amino acidmixtures have an advantage over GMP in that they have beenused extensively, and the decline in human brain serotoninsynthesis after ATD using amino acids has been demonstratedin several studies (Young 2012).

Conflict of interest I declare that I have no conflict of interest.

References

Applebaum J, Bersudsky Y, Klein E (2007) Rapid tryptophan depletionas a treatment for acute mania: a double-blind, pilot-controlledstudy. Bipolar Disord 9:884–887

Badawy A (2013) Novel nutritional treatment for manic and psychoticdisorders: a review of tryptophan and tyrosine depletion studies andthe potential of protein-based formulations using glycomacropeptide.Psychopharmacology (Berl). doi:10.1007/s00213-013-3191-9

Bunney WE, Brodie HKH, Murphy DL, Goodwin FK (1971) Studies ofalpha-methyl-para-tyrosine, L-dopa, and L-tryptophan in depressionand mania. Am J Psychiatry 127:48–57

Scarna A, Gijsman HJ, McTavish SF, Harmer CJ, Cowen PJ, GoodwinGM (2003) Effects of a branched-chain amino acid drink in mania.Br J Psychiatry 182:210–213

van Ruitenbeek P, Sambeth A, Vermeeren A, Young SN, Riedel WJ(2009) Effects of L-histidine depletion and L-tyrosine/L-phenylala-nine depletion on sensory andmotor processes in healthy volunteers.Br J Pharmacol 157:92–103

Young SN (2008) Rapid tryptophan depletion as a treatment for acutemania: safety and mechanism of the therapeutic effect. BipolarDisord 10:850–851

Young SN (2012) Acute tryptophan depletion in humans: a review oftheoretical, practical and ethical aspects. J Psychiatry Neurosci38(2):120209. http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-38/pdf/pg120209.pdf

Young SN, Smith SE, Pihl RO, Ervin FR (1985) Tryptophan depletioncauses a rapid lowering of mood in normal males. Psychopharma-cology (Berl) 87:173–177

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