am j clin nutr 1992 cangiano 863 7

8/3/2019 Am J Clin Nutr 1992 Cangiano 863 7

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in , j C /in N ior 1992 :56 :86 3-7 . P rin ted in U SA . 1992 A m erican Soc ie ty fo r C lin ica l N utritio n 86 3

Ea ting beha v io r and adhe re nce to d ie ta ry p rescr ip t ionsin obese adu lt sub je c ts trea ted w ith 5 -hyd roxy tryp tophan1 2Ca rlo C ang iano , F ab riz io C ec i, A n ton ia C asc ino , M aria D e l B en , A les sand ro La via no ,M aur izio M uscar ito li, F ab io la A n ton ucci, an d F ilip po R oss i-F ane lli

ABSTRACT Prev iou s observat ions h av e show n tha t o ra l ad -m in is tra tion o f 5 -hydroxy tryp to phan (5 -H TP) w itho u t d ie ta rypresc rip tions causes anorex ia , decreased fo od in take , and w eigh tlo ss in obese sub jec ts. T o co nfirm these da ta over a long er periodofobserva tion an d to verify w he th er adherence to d ie tary res tric -tion cou ld b e im p roved by 5-H TP , 20 obese p a tien ts w ere ran -dom ly assig ned to rece ive e ith er 5 -H TP (9 00 m g/d) o r a p laceb o .Th e s tudy w as doub le -b linded and w as fo r tw o consecu tive 6-w kperiod s. N o d ie t w as presc ribed during the f ir st pe riod , a 5040-kJ /d d ie t w as recom m ended fo r th e secon d . S ign ifican t w eigh tlo ss w as observed in 5-H TP-trea ted pa tien ts du ring bo th periods.A reduc tion in carbohydra te in take and a con sisten t p resen ce ofea rly sa tie ty w ere a lso found . T hese find ing s toge ther w ith thegood to le rance o bserv ed sugges t tha t 5 -H TP m ay be safe ly usedto trea t ob es ity . Am J C lin N u tr 1992;56:863-7.

K EY W O RD S Eating behav io r, anorex ia , 5 -hydro xy tryp-to phan , se ro to n in , o besity , adherence to d ie t, app e tite fo r car -bohyd ra tes , w eigh t loss

Introduction

Pharm aco log ica l, b iochem ica l, and behav io ra l ev idence hasaccum ulated in th e last tw o decad es , su gges ting tha t b ra in se -ro ton in h as an inh ib ito ry in fluence o n eating b ehav io r bo th inan im als and in h um ans ( I -4 ). R epo rted stud ies in favor o f apossib le ro le p layed by the se ro ton in erg ic sys tem in the pa tho -genesis o fano rex ia p resen t in d iffe ren t d iseases fu rthe r su pportth is idea (5 -7 ). C han ges in th e m etabo lism of bra in se ro ton inin an im als experienc ing d if fe ren t nu tr itiona l sta tes h av e beenreported (8 , 9 ). Fo od d ep riva tion prod uc in g a m ark ed increasein se ro ton in m etabo lism in the la teral hypo th a lam us m ay re flec tchanges in the av ailab ility o fb ra in tryp top han ; th is in tu rn con-stitu tes a po ten tia l m echan ism by w hich b eh av io ra l respon sesa re coord ina ted w ith nu tritio na l inpu ts (10) . A varie ty of d ifferen td irec t- an d in d irect-ac ting ago n ists a t cen tra l sero ton in syn ap sessuch as d ex fenflu ram ine and fluox e tine have been show n to causew eig h t loss as w ell as a m arked red uc tion in food in take in obesesub jec ts (1 1- 1 3). H ow ever, the adm in is tra tion of bo th drugscaused a h igh inc id en ce of s id e effec ts 1 2 , 13 ).

In a p rev ious short-te rm (5 w k ), doub le -b lind , c rosso ver stu dyw e observ ed tha t o ra l adm in is tra tion of the phy sio log ica l se ro -to n in precurso r 5 -hyd roxy try p tophan (5 -H TP ), w ithou t anyspec ific d ie ta ry prescr ip tion , w as fo llow ed by the on se t o f typ ica lan orex ia -re lated s igns , eg , decreased fo od in take and w eig h t loss

in obese sub jec ts (14). T he presen t s tudy a ttem pted to confirmth ese da ta ov er a longer p er io d of observa tion and to verifyw h ether ad herence to d ieta ry res tric tion cou ld b e im prov ed badm in iste ring 5-H TP to obese hyperp hag ic sub jec ts .

Sub je c ts and m eth odsSub jec ts

Tw enty -e igh t obese , hyperph ag ic adu lt fem ale su b jec ts (m eanage 43 .2 y I .7 : SE ) w ith b ody m ass indexes be tw een 30 and40 w ere s tud ied . H yperp hag ia w as defined as the excess o f da ilyenerg y in trodu ced w ith resp ec t to th e energy need ca lcu la tedaccord in g to sex , age , and phy sica l activ ity . S ub jec ts w ith g lu co sein to le ran ce, hyperlip idem ia , o r hy peru ricem ia w ere exc ludedfrom th e s tudy .S tudy d es ign

The resea rch pro toco l w as app roved by th e F acu lty E th icsC om m ittee ofthe U n iv ersity o f R om e, L a S ap ienza . A fte r g iv ingin fo rm ed con sen t, su b jec ts w ere ran dom ly ass igned to rece ivee ith er 5 -H TP (900 m g/d) o r a p lacebo com posed o fcorn s ta rch ,m ann ito l, an d m agnes ium stea ra te (b o th from S igm a-T au Indu strie s, Pom ez ia , I ta ly ). T he d rug , w hich w as in the fo rmcapsu les th a t do no t d isso lv e un til pH 8 .6 , w as taken th ree tim esper day , 30 m m before each m ea l. T he 1 2-w k-s tu dy period w assu bd iv ided fo r each gro up of sub jec ts in to tw o con secu tivew k periods . D uring the firs t pe riod there w ere no d ie tary restric -tions , w hereas a 5040-kJ/d d ie t w as recom m ended to sub jectsdu ring the secon d period o fobserva tio n . T he 5040 U w ere sub -d iv ided as fo llow s: 53% from carbohydra tes , 29% from lip ids,and 1 8% from p ro te in s. N o carb ohyd ra te -rich food s w ere allow edbe tw een m eals . Su b jec ts w ere exam ined every 2 w k to eva lua tefeed ing behav io r and body w eigh t. R ou tin e b lo od chem is trym easurem en ts w ere perfo rm ed for each sub jec t a t the beg in n ing

From the L aborato ry of C lin ica l N utritio n , 3 rd D ep ar tm en t o f In -te rna l M edic in e ; the D epartm en t o fH um an B iop ath o logy ; and Serv iz iod i D iete tica , Istitu to d i T erap ia M edica S istem atica , U nivers ity o f R om e,L a S ap ienza , R om e, Ita ly .

2 A ddress rep r in t requests to F Rossi-F an e lli. L aborato ry of C lin ica lN utritio n , 3 rd D epartm en t o f In te rn al M edic in e, V iale de lIU n iv ersit#{2 24}37 , 00185 Rom e, I ta ly .

R ece ived January 2 2 , 19 91 .A ccep ted fo r p ub lication M ay25 , 1992 .


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% of b a s a l w e ig h t

. --f-v ( ___

--

N O D IET

10 0

98

96

GA

_ f1-__ __ N S - - -D IET

.

0 2 4 6 8 10 12w e e k s

864 CA N G IA N O ET A LTA BLE IB ase line charac te ris tics o f su b jec ts5

B ody w eigh t T o ta l energ y Pro te ins C arbo hydra tes L ip id skg k/Id g /d g /d g/ d

Placebo 94.3 5.3 I I 398 1 020 104 1 1.3 331 29.1 120 12.35 -H TP 99 .7 5 .9 1 3 528 I 033 1 17 8.8 349 47.8 144 12.6

S SE : n = 10 fo r bo th gro ups .

and a t the end of each period of o bserva tion . T o test sub jec tscom p liance to trea tm en t, 24 -h urina ry excre tio n of 5 -hyd roxy-3 -ind o leace tic acid (5 -H IA A ) w as a lso de te rm ined every 2 w kby th e chrom atog raph ic -co lo rim etnc m ethod described byU denfriend et a l (1 5 ).

D a ily to ta l energy in take as w ell as s ing le m acronu trien t se -lec tion , w hich m ay d ef in e a sub jec ts ea tin g b eh av io r, w ere as-sessed ev ery 2 w k by us ing a 3-d d ie t d ia ry . Fo od d ia ries, in -c lud ing a ll beverages, w ere com piled by sub jects fo r 3 consecu tivew ork ing days . E ach sub jec t w as instru cted to care fu lly w eighfood b efo re m ea ls and then rew eigh any lef to vers. A ll reportsw ere va lida ted by a nex t o f k in s s ig na tu re . T o avo id reportedin ter fe rence due to prem ens trua l depression , foo d-in take m ea-su rem en ts w ere no t assign ed to th is tim e of the m on thI 6 ).

To inves tiga te anorex ia , pa tien ts w ere inv ited to repo rt thepresence of a series o f sym p tom s, nam ely m ea t avers io n , ta s teand sm ell a lteration , n ausea an d /o r vom iting , and early sa tie ty .A ll o f these sym ptom s in te rfe re w ith ea tin g an d are possib lyre la ted to a pa tho log ica l m odifica tion of the cen tra l-n e rvous-sys tem (CN S) regu la tio n offeed in g b eh av io r (5 , 6 ). Sub jec ts w ereinv ited to report a t the end ofeach p er io d o fstudy the presen ceo fside ef fects , inc lud ing w eakn ess, m ya lg ia , d row siness , ve rtigo ,d ia rrh ea, and s tip sis .Statistica l ana lysis

A ll d a ta w ere sub jec ted to standard sta tis tica l ana ly sis in clu d-ing m ean , standard erro r, and S tu den ts t te sts fo r bo th pa ired

and unpa ired da ta; m od ifica tions observed w ith in each treatm en tg rou p w ere com pared or p laceb o an d th e 5-H TP grou ps w erecom pared ( 1 7). T he Chi-square test w as used to com pare thp reva len ce o f b o th the anorex ia -re la ted sym ptom s and the s id eeffec ts ob se rved during p laceb o an d 5-H TP trea tm en ts. (17 ).T h e m in im um p robab ility leve l cons ide red fo r s ta tis tica l s ign if-icance w as P < 0 .05 .

Resu l tsTw enty ofthe 2 8 sub jec ts inc luded com p le ted the study . T h e

e igh t d ropo u ts (th ree in the s tu dy g roup and five in the con tro lg roup) d id n o t com ple te the study fo r the fo llow ing reason s:th ree had fam ily pro b lem s, tw o self-p resc ribed a low -energy d ie td uring th e firs t s tu dy period , tw o se lf-adm in iste red o ther ano -rec tic d ru gs, and one d id n o t com ple te the fo llow -up . Tw o group sof 10 su b jec ts each there fo re w ere stud ied . A s sh ow n in T ab le1, b ase lin e ch aracte ristic s w ere com parab le fo r the tw o g roupsof sub jec ts w ho d id n o t d iffe r in b ody w eigh t, da ily -to ta l-energyin take , and spec ific -m acro nu trien t se lec tio n .

C hang es in body w eigh t, exp ressed as percen tage ofb asa l va l-ues , are sh ow n in F igu re 1 . sub jec ts rece iv ing the p lacebo d idno t sh ow any s ign ifican t change in the ir body w eigh t duringe ithe r study period (94 .3 5 .6 vs 9 3 .2 5 .3 kg , I SE , basava lue v s en d-o f-s tudy va lu e) . In co n trast, sub jects rece iv ingH TP show ed a sign ifican t w eig h t loss a t the end ofthe firs t pe riod

FIG I. M ean body-w eigh t m odifica tio ns, expressed as percen tage of the basa l va lue , d uring bo th no-d ie t an d d ie tper iods o fobserva tio n . D , p laceb o : # { 1 4 9 } ,-hy droxy tryp tophan (S -H TP). 5S ign ifican tly d iffe ren t from beg inn ing of s tudy ,P < 0 .03 . 55S ig n ifican tly d ifferen t from valu e a t 6 w k for S -H TP grou p .< 0 .02 .


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E N E R G Y INTAKE P R O TE IN IN TAKE

B 6 12 B B 12 w e.k s B 6 12 B S l 2w s.k sP LAC E B O S - H IP P LA C E B O 5 - HIP

C AR B O HYDR ATE IN TAKE

35 0

L IP ID INTAKE

*0

B C 12 B 6 12w ..k sPL A C E B O S - HIP

FIG 2. M ean SE m odifications of total energy and single m acronutrient intakes during both no-diet0) and diet( periods of observation in the tw o groups of subjects. B ( basal records; PD ., prescribed diet.

B 6 12 B 6 12 w . . k sP LA C E B O S - HIP

5-H Y D R O X Y TR Y PTO PH A N TR EA TM EN T IN O B ESITY 865(99.7 5.9 vs 98.0 5.0 kg, < 0.03) follow ed by a greaterreduction of their body w eight at the end of the second periodofobservation (98.0 5.0 vs 94.7 5. 1,< 0.02). In the groupfinal w eight loss w as 5% of the basal body w eight.

A nalysis of the m ean total energy intake, as calculated fromsubjects reports, show ed no significant changes in the placebogroup during either period (Fig 2). The spontaneous reductionofdaily energy intake from 1 1399 1021 to 9778 907 kJ/dobserved at the end of the first study period w as not statisticallysignificant, nor w as the further negligible decrease to 8644 1 3 19 ki/d observed during the diet period. There w as a sig-nificant reduction of total energy intake in subjects receiving 5-H T P f r om 13528 1033 to 7892 773 kJ/d. In these subjects,total energy intake show ed a further significant reduction to 5326 647 kJ/d in the second study period.

A specific behavior w as observed in m acronutrient selections.The total protein intake rem ained unm odified in the controlgroup during the study period. In the 5-H TP group, proteinintake w as progressively reduced during the first period to valuesthat w ere not further m odified during the second half of thestudy (Fig 2). The carbohydrate intake, though reduced, w as notstatistically different from the basal value for the control group(Fig 2). C onversely, subjects receiving 5-H TP show ed a signifi-cant 50% reduction of their intake of carbohydrates at the endofthe first study period. This w as follow ed by a further significantreduction in the second study period during w hich the totalcarbohydrate intake w as even low er than the quantities includedin the dietary prescription. Finally, the lipid intake show edchanges sim ilar to those observed for carbohydrates although

the quantities consum ed during the second period in the 5-H TP-treated patients w ere alw ays higher than those included in thprescribed diet (Fig 2).

The evaluation of anorexia show ed different behavior in thetw o groups of subjects. A m ong the sym ptom s included inquestionnaire, early satiety w as reported by 100% and 90%subjects receiving 5-H TP during the first and second study penods, respectively. R eports of early satiety w ere alw ays signifi-cantly higher for subjects receiving 5-H TP than for the controlgroup. R eports of nausea, w hich w as episodically reported b80% of subjects on 5-H TP during theirst study period, w eresignificantly reduced during the last 6 w k ofobservation to 20% ,suggesting that this sym ptom m ay be considered a transitoryeffect of 5-H TP adm inistration. The other sym ptom s w ere notreported differently by the tw o groups of subjects (Fig 3).

The occurrence of side effects such as w eakness, m yalgia,drow siness, vertigo, diarrhea, and stipsis w ere investigated. A lof these sym ptom s w ere equally distributed in both groupspatients w ith no differences betw een the tw o periods of obser-vation (Fig 4). The total urinary 5-H IA A excretion show ed a50-fold difference betw een the tw o groups and provided evidencefor subject-com pliance w ith treatm ent (Fig 5) .

D iscussionThe role of am ino acids in the regulation of food intake has

been supported by experim ental data suggesting that changes iplasm a am ino acid concentrations m ay m odify food intake baffecting the brain availability of neurotransm itter am ino acid


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Ea r l y s a t i s t y

NO D IET20 40 60 80 10 0I I I I I_____________< . 0 0 5

Ns u s . /Vo m tt g p 04

T s s ts s l t# { 14 9 }r s tl o n

Sm . t t s t t s t l o n

M ss t a vi rs io n

W#{149 } skn# { 149 } ss

D t ows i s s s s

Dt s r t h o s s

Ii

NO D IET20 40 50 50 10 0I I t I I

11

B 2 4 6 8 10 1 2

P L A C E BO

B 2 4 6 81012 w e e k s5 - HT P

86 6 CANGIANO ET ALDIET

20 40 00 50 10 0____________ I I I I p < .0 I____ I.

FIG 3 . Prevalence o f the symptoms used to evaluate anorex ia in thetw o groups o f subjects during no -diet and die teriods o f o b se rv at io n.5 S ignificantly different from no die t fo r 5 -hy droxy tryptophan (5 -HTP)group, P < 0 .01 . 0, placebo : 0 , S -HTP.

precursors ( 1 8). O f the tw o majo r neuro transm itter sy stem s in-v o lved in the regulation o f feeding , the sero toninerg ic sy stemseems to play a spec if ic ro le (19 ). A pharmaco log ical study byLe ibow itz e t al (20 ), in fac t, prec isely charac terized the brains ite s and receptors invo lved as w e ll as the poss ible physio log icalro le o fendo genous sero tonin in co ntro lling natural patterns o feating and nutrient se lec tion. In particular, sero tonins ac tion isbelieved to inf luence bo th the energy balance and the c ircadianpatterns o f eating by ac tivating satie ty neurons localized in themedial hypo thalamus (19 ) . In this pro cess, s ero tonin seem s tointerac t antago nistically w ith norepinephrine and its 2 -no rad-renerg ic receptors (2 1. Pharmaco log ically induced variations inbrain sero tonin co ncentrations o r sero toninerg ic ac tiv ity in ex -penmental animals re sult in f luctuation o fappe tite (22 , 23 ). In198 1 , W urtman et al (4 ) and mo re recently Hill and B lunde ll(2 4 ) have show n that the sero toninerg ic sy s tem also play s animportant ro le in macronutrient se lec tio n espec ially in obesepeo ple consum ing large amounts o fcarbohydrate -rich food. Thesame authors have also demonstrated that such behav ior can becounterac ted by pharmaco log ically enhanc ing brain sero toninsynthes is . Pharmaco log ical manipulation o f brain sero toninconcentrations w ith sero toninerg ic -ac tiv e agents like dex fen-fluram ine and fluoxe tine has been reported to contro l fo od intakeand reduce body w eight in obese patients (12 , 1 3). N ev erthele s s,the inc idence o f s ide e ffec ts reported by subjec ts rece iv ing bo thdrugs w as higher than that reported in the contro l g roups(1 2 , 13 ).

In a prev ious s tudy w e observ ed that o ral adm inis tratio n o f5 -HTP to adult obese subjec ts w as fo llow ed by decreased foodintake and w e ight lo s s w ithout affec ting the subjec ts mood (14 ).The results o fthe present study seem to confirm those prev io uslyreported. In fac t, during the die t-free , 6 -w k period o f observation,subjec ts rece iv ing 5 -HTP at doses s im ilar to tho se prescribed inthe prev io us s tudy show ed a s ignificant reduc tion o f bo th bodyw e ight and daily carbohydrate intake . M oreo ver, w hen subjec tsw ere g iven a low -energy die t a further significant reduc tion o fbo th indice s w as observed. B ecause o f the meal-s truc ture char-ac tenstic o f the Italian die t (ie , pastairst, pro te in and breadsecond at lunch o r dinner), the early satie ty re ferred to duringthe die t- free f irst period o f the study may have altered the eval-uation o f to tal carbohydrate intake . How ever, a s ignificant re -duc tion in carbohydrate intake w as also o bserv ed during the

DIET20 40 60 50 10 0III1

IIFIG 4 . Prev alence o f the side e ffec ts inv es tigated in the tw o g roups o f

subjec ts during no -die t or die t periods o f observation. There w ere nos tatis tically s ig nificant differences be tw een groups o r s tudy periods . 0 ,placebo ; 0 , 5 -hydroxy try ptophan (5 -HTP).

low -energy die t period, w hen the meal structure w as subvertedas past and o ther carbohydrate -rich food w ere allow ed only insmall amounts . In additio n, the s ig nificant reduc tion in breadintake , w hich is usually eaten in combination w ith pro te ins ,argues in favo r o f a spec if ic ef fect o f carbohydrate s on appetite ,exerted by 5 -HTP. Thus, the o ptimal adherence to die tary prescriptio n observed in subjec ts rece iv ing 5 -HTP may have beenthe consequence o fa combination o fbo th early satie ty and low -carbohydrate intake .

The re lative ly high inc idence o f nausea during 5 -HTP adm inistration may raise the concern that it could, at leas t in part,have been respons ible for the 5 -HTP effec ts observed. How ever,no te that for most subjec ts, nausea w as reported episodically .N ausea w as significantly le s s frequent during the second 6 -w kperiod w hen the greater reduc tio n in food intake and w e ig htlo ss w as o bserved. Finally , w hen present, nausea w as o f lointensity and never caused a subjec t to dro p out o f the study .W e be lieve that the e ffec t o f nausea on w eig ht lo ss w as neg lig ible.The lack o f a s ignificant reduc tion o f bo dy w e ig ht observedthe contro l gro up during bo th study periods (ie, bo th w ithoutand w ith the low -energy diet) w as likely due to subjec ts non-compliance w ith die tary prescriptions as demonstrated by diereports.

In co nc lusion, the results o f this s tudy seem to confirm thspecific ro le played by the sero toninerg ic sy s tem in the regulatio n

mg / 2 4 h

500 L

4 0 0 L300

lot- i 1 HHHFIG 5 . M ean to tal 5 -hydroxy -3 -indo leace tic ac id (5 -1 -IIA A ) excre tion

during the l2 -w k study period in bo th g roups o f subjec ts .


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5-H Y D RO X Y TRY PTO PH A N TREA TM EN T IN O BES ITY 86 7of feed in g b eh av io r in hum ans . T he adm in is tration of 5 -H TPw as in fac t fo llow ed by a red uc tio n o f bo th da ily to ta l energ yan d carbohyd ra te in tak es fo llow ed by a sign ifican t loss o f b odyw eigh t. T he op tim al adh eren ce to d ie ta ry p resc rip tion as w ellas the g ood to le rance to 5-H TP trea tm en t observed sugges t tha tth is subs tan ce m ay be safe ly used in th e long -te rm trea tm en t o fobes i ty . B

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9 . P erez-C rue t I, T ag liam on te A , T ag liam onte P , G essa G L . C hangesin bra in se ro ton in m etab o lism assoc iated w ith fasting and sa tiationin rat s. Lif e Sci 1972;1 1:31- 9.

1 0 . W urtm an R I, W u rtm an II. N u trien ts , neuro transm itte r sy n thesis,and th e con tro l o ffoo d in take . In : S tun kart A i, S te lla r E , eds. E a tin gand its d iso rders . N ew Y ork : R aven , 1984 :7 7-86 .1 1. H utson PH , D onohoe TP , C urzo n G . In fusion of th e 5-hy droxy -tryp tam ine agon ists R U 24969 and TFM PP in to the paraven tricu la r

nuc leus of the hypo th alam us causes hy poph ag ia . P sych o l ForschI 9 8 8 ; 9 5: 5 5 0 -2 .

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