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The effects of dietary neurotransmitterprecursors on human behavior1-3Ha"is R"Lieberman. PhD. Suzanne Corkin. PhD. Bonnie J Spring. PhD.Richard J ",urtman, MD. and John H Gro~wlon. MD

ABSTRACT The neurotransmitter JlRCUI'SOntryptophan and tyrosine a~ present in a varietlof foods. In order to document possible drects or tryptophan and tyrosine on human behavior.single oral doses of thc:sc substances and matc:hcd placebos ..'C~ administe~ to 20 men" in adouble-blind. crossover study. Various tests or mood state and performance we~ then administ~oTryptophan increased subjective fatigue and cIcc:reasedself-ratings or vigor and 'alenness.but didnot impair performance on any or the tests..Tyrosine produced no effects in our young populationcompared with placebo. but did decrease reaction time relative to tryptophan. It may be concludedthat tryptophan. has significant sedative-like propcnies. but unlike other sedath'CS ma)Onot impairperformance. m J C/in Nutr 1985:42:366-370.

KEY WORDS Tryptophan. tyrosine. DCUrotransmitterJlRCUrsors.mood. performance

Introduction

Consumption of certain foods and foodconstituents cah influence the rates at whichneurons synth~ize and release specificneu-rotransmitters ( I). Dietary substances canalter brain neurotransmission by changingthe central ne ous system(CNS) concentra-tion of the su tes used 'for the synthesisof neurotrans itters. Tryptophan and tyro-sine arc di amino acids and also neu-rotransmitter precursor:sknown to influencethe availability of their neurotransmitters.Ingestion of tryptophan increases the CNSconcentration of serotonin and its releasefrom brain neurons. Similarly, increased ty-rosine availability can enhance the releaseofcatecholamines when cells are firing fre-quently (1). Since ingestion of both of theseprecursors may influence the activity of spe-cific neural systems. it is possible that theconsumption of tryptophan and tyrosinemayalso modify the behavioral functions ass0-ciated with these neurotransmitter systems.For example. it has been reported that inges-tion of tryptophan induces drowsiness(2. 3)and decreasesthe time required for humansto fall asleep (4, 5). These findings are con-sistent with many animal studies demon-

stratingthat increasesin serotoninergicactiv-ity are involvedin the induction and mainte-nance of sleep (6). Less is known about thebehavioraleffectsof tyrosine, although whenadministered to mice it has been reported tohave stimulant-like effects (7). It has alsobeen reported that tyrosine may reduce thebehavioraleffectsof acute stress (8).

Althoughtryptophan and tyrosine are nat-urally occurring constituents of many foodsand have been shown to modify brain com-position in animals (I), there have been fewinvestigationsof their behavioral effects onwaking human subjects. We therefore ad-ministered single doses of tryptophan and

'From the ()q)anment or Psychology and ClinicalRescardl Center (HRL. SC), Massachusetts Institute ofTccbnolocY. Cambridge. MA, the Department or Psy-choIo&Y(815), Harvard Univcnity. Cambridge. MA. theDepartment or Nutrition and Food Science (RJW).Massachusetts Institute or Technology. Cambridge. MAand the Department of Ncurology (JHO). MassachusettsGeneral Hospital. Boston. MA.

2Supported b). NASA Grant NA02-132 and NIHGrants 000088-19 and EY02621.

) Address reprint requests to: Harris R Lieberman.PhD. Department or Psychology. EIO-IJOd. Massachu.setts Institute or Technology. Cambridge. MA 02139.

Receiwd February 19. 1985.Accepted for publication March 12. 1985.

366 Th~ Aml"rkan Journal ~rClinical Nutrition 42: AUGUST 1985. pp 366-370. Printed in USAC>1985 American Societ)Ofor Clinical Nutrition

NEUROTRANSMITTER PRECURSORS AND BEMA\'IOR

tyrosine to 20 men. and measured theirmood and sensorimotor performance underdrug and placebo conditions.

M~thods

SuhjC'd.,

T~nty heahhy male subjcm. qed 18 to 45 (mean. c 24). panicipated in the study.. They were m:ruitedIotall). by sign-up sheets and wonkf-mouth. The studywas appro~ by the institutional Committee on the Useof Humans as Experimental Subjects.

E.'pt'fimmlQI dnitn

Tryptophan (SOm8lkl) and tyrosine (100 ma!k&). inpill form. were each 8dministercd to all subjects. Adouble-blind. pIacebo.amtroUcd. CIOSSO~ design wasemployed. After one pr8CIicesession. each subject i~one of the t~'O amino acids or one of the two placebosfor each of the mnainina four sessions. The placebosearn were matched in appeara~ to one of the aminoacids. The order of substa~ inacstion for each subjectwas systematically varied by use of the Latin-squaredesign. The subject fasted for 12 h before each seaion. .and then. at 0700. inaested the substance designated forthat session. Tcstilll bcpn 2 h later.

Two self-rcpon mood questionnaires and four testsof pcrforma~ ~ 8dministercd.

Visual AlUllop~ Mood Sctl/~ WAMS). The VAMS isa self-rcpon mood questionnaire that yields three factor-analytically derived mood categories: Alert. S8d. andCalm (9). Each of 32 8djecti~ was rated by the subjectby moving a pointer alone a horizontal line presentedon a cathode ray tube (CRT). The absence of a particularmood was indicated by pIacinc the pointer on theextmnc left or the line. and the maximum by plac:inc iton the richt.

Pro/r/r of Mood SlQ,n (POMS). The POMS is a self-rcport mood questionnaire that yields 6 factors: Tension-Anxiety. Dcprcssion-Dcjcction. Anccr-Hosti1ity. ViIor-Activity. Fatiaue-Incnia. and Confusion-BcwiIdennent(10). The test consists of 6S 8djcctPes each of whictamust be rated on a S-point scale.

Simplr Audi,OI)' R«Iaion Timr. In this microc:om-puter-8dministercd tat, the subject responded. as rapidlyas possible. to the onset oIa 7S dB, 1900 Hz toile. After .6~ warmup trials. 12S 1CSttrials were presented. AYisual cue. presented on a CRT. indicated the stan of aarial.

T..y~Choicr Visual R«IaiOll Tim~. In this tat, thesubject was required to discriminate between two lli&hdydifferent letter-like symbols. which were pmented ta-chistoscopically on a CRT screen by a microcomputer.The stimulus duration was either 54 or 72 ms. Todecrasc the discriminability of the two stimuli andtherefore dillicuhy of the tat, a maskina stimulus ap-peared after each trial. The brief duration of the stimuli.

'Data from only 16 subjectsis reported for the RTtasks due to a proceduralerror multinc in the loss ofdata from the first four subjects.

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and their small size. required suslaincd viailantt b). thesubject.

Gr,lfwt'd PqtlttlOrd Tt'M For this tnI the subj«1 1Ira.\required to in5Cl1.as rapidl~ as possible. a series of 25pcp into randomly oriented holes on a board. Si~both the peas and board are 1fOCMd.each PCBmust beproperly oriented to be inscncd. Tk test is more difficultthan many other pqboard tests because the holes Ireslanted.

ThurstOll(, TQPpi"ll Tt'.u This in test of motor speedand coordination (II. 12). In the first pan of the test.the subject held a metal st~.lus in one hand and tapped.as rapidly as possible in a specific scquentt. the' seetonof a 13 em circle divided into 4 quadrants. In the SCC'OndItaIC' of the lest. the subject used both hands. simulta-ncousl)' tappina different patterns with each.

Results

The data from aU tests were analyzed bythe Latin-square analysis of variance (AN-OV A). The two within-subjccts main factorsin this analysis were substance and test sessionorder. The between-subjcct variable was orderof substance administration. A posterioricomparisons., when appropriate, were matJewith a two-tailed Neuman-Keuls statistic.

VAMS. The analysis of variance performedon the Alert scale of the VAMS detected asignificant main effect for both substance (p< 0.00 I) and test session order (p < 0.0 I).The substance effect was attributable to tryp-tophan, which on a posteriori testing wasfound to significantly decrease the Alertnessscale as compared to either placebo or tyro-sine (p < 0.01, Fig I). The other two VAMSscales. Calm and Sad. were not significantlyaltered by either substance.

POMS. The Fatigue-Inertia and Vigor-Activity subscales of the POMS were signifi- .

candy altered by substance administration.On a posteriori testing. tryptophan was foundto significantly increase the Fatigue-Inertiascale (p < 0.05), and decrease the Vigor-Ac-tivity scale (p < 0.0 I). when compared toeither its placebo or t)Tosine (Fig 2). Signifi-cant effects of test session order were alsodetected by these two subscales. The otherPOMS scales yielded no significant findings.

S;mp/~ Auditory R~aCl;on T;m~. This wasthe only performance test where a significanteffect attributable to substance was observed.Tryptophan significantl)' increased RT whencompared to tyrosine (p < 0.05 on the post-hoc test), but neither amino acid differed

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368

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UEBERMAN ET AL

The substances did not alter performance onthis task.

20

40

. TRYPTOPHANmTRYPTOPHAN PLACEBO. TYROSINEo TYROSINEPLACEBO

* P <0.01

10CALMALERT SAD

FIG I. The etrecu of tryptophan. tyrOSine. and theirrapective placebos on three rcaIes of VAMS Idf-reponmood questionnaire (mean :t SEM).

significantly from its respective placebo. Therewas also no significant difference between thetwo placebos; therefore, this performance dif-ference cannot be attributed to a placeboeffect.

TM-o-Choice Visual Reaction Time. Anal- .yses of variance were performed for each ofthe two stimulus durations presented. Neitheramino acid had any effect on two-choicereaction time.

Groo\'ed Pegboard Test. Separate analysesof variance were performed on time for com-pletion and number of pegs dropped. Therewere no significant effects of substance.

Thurston£' Tapping Test. Two analyses ofvariance were performed on the number oftaps per condition (unimanual or bimanual).

Disaassion

The observation of increased drowsinessresulting from tryptophan ingestion is con-sistent with other reports indicating that thisdietary constituent has hypnotic propenies(2, 4, 5). We have found that when trypto-phan is administered without the otherLNAA's present in protein that suppressitsuptake into the brain, it has considerablepsychopharmacologicalactivity with respectto human mood. Tyrosine, however,whengiven in a single oral dose, appears to be lesspotent. at least with regard to the limitednumber of behavioralparameters weassessed.This finding is not surprising since neuronscan become unresponsive to additional ty-rosine if their firing frequency slows(I).

The sedative-likeeffects of tryptophan onhuman mood are consistent with considerableneurochemical and behavioral evidencethatserotoninetgic neurons panicipate in the in-duction and regulation of sleep. Lesionsofserotoninetgic neurons reduce time spentsleeping.and various drugs that inhibit sero-toninergic neurotransmission also reducesleep (6).

The findingthat tryptophan increasedsim-ple RT compared to tyrosine may indicatethat these substances have antagonisticprop-enies. There are at least two possibleexpla-nations for this result. Ingestion of tyrosine.which competeSwith tryptophan for uptakeacross the blood-brain barrier. may decreasebrain tryptophan (I). Alternatively.tyrosineby acting on cated10laminergicneurons mayitselfimprove performance in a manner sim-ilar to the positive effectof L-dopaadminis-tration in patients with Parkinsonism. Tyro-sine has in fact been reponed to havebehav-ioral effects in animals similar to thoseresulting from administration of stimulantssuch as amphetamine and caffeine(7) andto reverse the effects of acute stress (8). Ithas also been reponed to be useful in thetreatment of human depression (13).

Becausetryptophan induces drowsinessbutdoes not impair performance, at least on thetests we administered, it is a good candidate

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CJ)::EoCL

4

2

NEUROTRANSMITTER PRECURSORS AND BEHAVIOR

* .TRYPTOPHAN

~ TRYPTOPHANPLACEBO.TYROSINEo TYROSINEPLACEBO

. P <005*.P < 001

FATIGUE-INERTIA

VIGOR- ANGER- CONFUSION-TENSION-DEPRESSION-ACTIVITY HOSTILITYBEWllDER- ANXIETY DEJECTION

MENT

FIG 2. The dl'ecu of tryptOphan.tyrosine. and their rcspcctiveplaceboson 1hcsi~ subscalesof 1hcPOMS self.report mood questionnai~ (mean %SEM).

for evaluation as a mild hypnotic. Mostprescription drugs currendy used as hypnot-ics, such as the benzodiazepinesand barbi-turates, impair performance not only imme-diately after administration but also the nextday (14). Further experimentation will berequired to confirm the sparing of perfor-mance noted after tryptophanadministration,especially since there is no consensus as towhich tests are most appropriate to use inassessing performance (14). Sincetryptophanhas been shown to reduce sleep latency inthe dose we-administered (4), it may bepreferable to such drugs, particularly if a lesspotent hypnotic would be sufficient.Regard-

less of the possible dinica1 application oftryptophan, this stud)' confirms that admin-istration of a normal dicJary constituent.tryptophan, can significantlymodify humanbeha~o~ D

Wc thank R BccdIcr. M DuKy. and C Wopn fortcchnicallUistallC'C .

References

I. WunmanRJ.HeftiF.MelamedE.Precursorcontrolof ncurotransmincrsynthesis.Pharmacol Rc,' 1981:32:31S-3S.

2. GrmIwood MH. Lader MH. Kanlamencni BD.Cunon G. The ICUtc cfl'ccts of oral (-Hryptophan

370 UEDERMAN £1 AL

in human subjects. Dr JOin Pharmarol 1975;2:165-72.

3. Hanmann E. Spin..'Cba Ct. Wa~ C L-tryplophan.L-Iucine and pIaccOO:Eft"«1Son subjective slcepines.\.Sleep Res 1976:5:~7.

.e. Hanmann E. Elion R. The insomnia or sleepingin a strange place. Psychophannarology 1977:53:131-3.

5. Hanmann E. SpinweberCL Sleep induced by L-tryptophan: effect or dosages within the normaldictary intake. J Nm- Mmt Dis 1979:167:497-9.

6. McGeer PL Eccles Jc. McGeer EG. Molecularneurobiolo&yor the mammalian brain. NA' York:Plenum Press. 1978.

7. Gibson CJ. Deikel SM. You", SN. Binik YM.Behavioral and biochemical eff«1Sor tryptophan.tyrosine. and phenylalanine in mice. Psychophar-macol08Y1982:76:118-21.

8. Lehnen H. Reinstein DK. StrowbridgeBW. Wun-man RJ. Neurochemical and behavioral conse-

quenc:n of 8CUte. uncontrollable stress: eff«1S ordictary tyrosine, Brain Res (in pens).

9. Spring B. Maller O. Wunman JJ. Digman L. ("Oozolino L. Ef«1S or protein and carbohydrate mc:al~on mood and per(ormanC't: Interactions with sc"and age. J P5>'tbiatr Res 1983:17:155-67.

10. McNair DM. Lon M. Droppleman LF. Profile ormood States manual. San Diqo. CA: Educationaland Industrial Testi", Servitt. 1971.

II. Thursaone LL A factorial stud>"or perception. Chi-cago. IL: Unhmity or Chicago Press. 1944.

12. ("orkin S. Acquisition or motor skills after bilateralmedial temporal-lobe excision. Neuropsychologia1968:6:255-65.

13. GelenberJ AJ. Wojcik JD. Growdon JH. Svcd AF.Wunman RJ. T>TOSinefor the treatment or depm-sion. Am J P5)'Chiatry 1980:137:622-3.

14. Johnson LC'. Chernik DA. Sedative-hypnotics andhuman performanC't. Psychopharmacology 1982:76:101-13.

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