BUY WEIGHT LOSS PILLS ONLINE WITHOUT PRESCRIPTION

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Weight Loss Nutritional Supplements

Chapter · January 2008

DOI: 10.1007/978-1-59745-231-1_8

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Joan Eckerson Creighton University

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Douglas Kalman

Nova Southeastern University

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WeightLossNutritional Supplements JoanM.Eckerson

Abstract

Obesityhasreachedwhatmaybeconsideredepidemicproportionsinthe UnitedStates,notonlyforadultsbutforchildren.Becauseofthemedical implicationsandhealthcarecostsassociatedwithobesity,aswellasthenegative socialandpsychologicalimpacts,manyindividualsturntononprescription nutritionalweightlosssupplementshopingforaquickfix,andtheweightloss industryhasrespondedbyofferingavarietyofproductsthatgeneratesbillionsof dollarseachyearinsales.Mostnutritionalweightlosssupplementsarepurported toworkbyincreasingenergyexpenditure,modulatingcarbohydrateorfatmetabolism,increasingsatiety,inducingdiuresis,orblockingfatabsorption.To reviewtheliterallyhundredsofnutritionalweightlosssupplementsavailableon themarkettodayiswellbeyondthescopeofthischapter.Therefore,severalofthe mostcommonlyusedsupplementswereselectedforcriticalreview,andpractical recommendationsareprovidedbasedonthefindingsofwellcontrolled,randomizedclinicaltrialsthatexaminedtheirefficacy.Inmostcases,thenutritional supplementsreviewedeitherelicitednomeaningfuleffectorresultedinchangesin bodyweightandcompositionthataresimilartowhatoccursthrougharestricted dietandexerciseprogram.Althoughthereissomeevidencetosuggestthatherbal formsofephedrine,suchasmahuang,combinedwithcaffeineorcaffeineand aspirin(i.e.,ECAstack)iseffectiveforinducingmoderateweightlossinoverweightadults,becauseoftherecentban onephedramanufacturersmustnowuse ephedra-freeingredients,suchasbitterorange,whichdonotappeartobeas effective.Thedietaryfiber,glucomannan,alsoappearstoholdsomepromiseasa possibletreatmentforweightloss,butotherrelatedformsofdietaryfiber, includingguargumandpsyllium,areineffective.

Keywords

Dietarysupplements Ephedra Obesity Overweight Complementary medicine Alternativemedicine Herbalmedicine Chromium Calcium

Chitosan Pyruvate Garcinia Psyllium Citrusaurantium Bitterorange

Guarana Herbalcaffeine Conjugatedlinoleicacid

From: NutritionalSupplementsinSportsandExercise

Editedby:M.Greenwood,D.Kalman,J.Antonio, DOI:10.1007/978-1-59745-231-1_8, HumanaPressInc.,Totowa,NJ

ObesityhasreachedepidemicproportionsintheUnitedStates, notonlyforadultsbutforadolescentsandchildren,aswell.Accordingtodatafromthe2001–2004NationalHealthandNutrition ExaminationSurveyreleasedbytheCentersforDiseaseControl, 32%ofadultsintheUnitedStateswereobese[bodymassindex (BMI) 30kg m2],and66%wereconsideredoverweight(BMI 25kg m2).Incomparison,theincidencesofoverweightandobese adultsin1974were47.7%and14.6%,respectively.Althoughthe numberofoverweightadultshasdramaticallyincreasedduringthe last30years,theincreaseinthenumberofoverweightchildrenand adolescentsisevenmorealarming.In1970,theincidenceofoverweightchildrenwas4.2%comparedto17.5%in2004,whichrepresentsanincreaseofmorethan400%.Becauseofthemedical implicationsandhealthcarecostsassociatedwithobesity,aswell asthenegativesocialandpsychologicalimpacts,manyindividuals turntononprescriptionnutritionalweightlosssupplementshoping foraquickfixorananswertotheirunsuccessfulattemptsatdieting andexercisetoloseweight.Infact,ithasbeensuggestedthatmany individualspreferdietarysupplementsandprescriptionweightloss drugstomakinghealthierlifestylechanges (1)

Theweightlossindustryhasrespondedtotherisingratesof obesityand,asaresult,generatesbillionsofdollarseachyear throughthesaleofavarietyofproductsandcommercialweight lossbusinesses.In2001,Americansspentmorethan$36billionon videos,books,low-caloriefoodsanddrinks,sugarsubstitutes,medicaltreatments,commercialweightlosschains,over-the-counter (OTC)drugs,andofcoursenutritionalsupplementstoassistin their‘‘battleofthebulge’’ (2).Infact,retailsalesofOTCnutritional weightlosssupplementsalonewereestimatedtobemorethan$1.3 billionin2001 (3).

Weightlosssupplementsarenotjustusedbyoverweightindividuals.Resultsofamultistatesurveyconductedin1998byBlancket al. (4) indicatedthat7%ofadultsatthattimeusedOTCweightloss supplementsandthatthegreatestconsumerswereobeseyoung women(28.4%).Interestingly,however,7.9%ofnormalweight womenalsoreportedusingdietarysupplementsforweightloss. Giventhatobesityrateswilllikelycontinuetoclimboverthenext

severalyearsand,correspondingly,theuseofOTCnutritional weightlosssupplementsbyobeseandoverweightindividualswill alsocontinuetoincrease,itisimportantforhealthprofessionalsto understandthephysiologicalmechanismsbywhichtheseproducts arepurportedtoresultinweightloss,aswellastheirsafetyand efficacy.MostOTCweightlosssupplementsarepurportedtowork byincreasingenergyexpenditure,modulatingcarbohydrateor fatmetabolism,increasingsatiety(feelingoffullness),inducing diuresis,orblockingfatabsorption.

2.NUTRITIONALSUPPLEMENTSTHATINCREASE ENERGYEXPENDITURE

2.1.EphedraAlkaloidsandHerbalCaffeine

Ephedra,alsoknownas mahuang,isprobablyoneofthemost widelyrecognizednutritionalsupplementsusedforweightloss. Becauseofseveralsafetyconcerns—hypertension,arrhythmias, heartattack,stroke,andevendeath—theU.S.FoodandDrug Administration(FDA)removedephedraproductsfromtheU.S. marketin2004becausetheriskofitsusewasdeemedgreaterthanits benefitsforweightloss.

EphedraisderivedfromashrubthatisnativetoChina(Ephedra sinica)andhasbeenusedformorethan5000yearsasanatural treatmentforasthmaandotherconditions (5).Theephedrine alkaloidspresentintheplantcontainsympathomimeticcompounds [i.e.,centralnervoussystem(CNS)stimulants]andareasourceof ephedrineandpseudophedrine,whichareusedinmanydecongestantsandcoldmedicines.Thehistoryofephedrineasaweightloss supplementgoesbackto1972whenaDanishphysicianinElsinore, Denmarkwhowastreatinghisasthmaticpatientswithacompound thatcontainedephedrineandcaffeinenoticedthattheywereexperiencingunintentionalweightloss.Hiscompoundbecameknownas theElsinorepill,andby1977itwasbeingusedbymorethan70,000 patients (6).Beforetheyweretakenoffthemarketin2004,dietary supplementsthatcontainedephedrinealkaloidswereregulated undertheDietarySupplementsHealthandEducationAct (DSHEA),butephedrineandpseudoephedrineareregulatedby thegovernmentasdrugs.

Ephedrineandnorephedrineareanalogsofmethamphetamine andamphetamine,respectively,andthereforearepotentCNSstimulantsthatactasboth a-and b-adrenergicagonists,releasing epinephrinefromsympatheticneurons (7).Theactionofephedra onadrenergicreceptorsincreasesthermogenesisandsuppresses hunger,whichinturnpromotesweightloss (5).Inanimalstudies, ithasbeenshownthatephedrinestimulatesthermogenesisinbrown adiposetissueviatheactivationof b-receptors;however,because humanshavelittlebrownadiposetissue,itisbelievedthatthermogenesisprimarilyoccursintheskeletalmuscle (6).

Arecentmeta-analysisbyShekelleetal. (8) thatexaminedthe efficacyandsafetyofephedraandephedrine-containingproducts foundthattheyhavemodestshort-termbenefits(upto6months) andareassociatedwithanincreasedriskofexperiencinganadverse event.Intheirstudy (8),ephedraresultedinweightlossthatwasonly 0.9kg( 2lb)morepermonththanwasachievedwithaplacebo,but ledtoa2.2-to3.6-foldincreaseintheoddsofexperiencingpsychiatric, autonomic,orgastrointestinalproblemsandarrhythmiasoftheheart.

Inanefforttomaximizefatburning,ephedrinehasbeenusedin combinationwithcaffeineandaspirin,whichisoftenreferredtoas anECAstack.Itisbelievedthatwhenthesethreecompoundsare takentogether(recommendedratio:60mgephedrine/200mgcaffeine/300mgaspirin),itresultsinanevengreaterthermogeniceffect thanthatofephedraaloneandmaybemoreeffectiveforinducing weightloss (9,10).Herbalequivalentsthatareoftenusedasa substituteforcaffeineinnutritionalweightlosssupplementsinclude guarana,kolanut,yerbamate,greentea,andyohimbe.Similarly, willowbarkisoftenusedinplaceofaspirin.HydroxycutTM isjust oneexampleofawellknownOTCproductthatcontainedanECA stack(mahaung,guarana,andwillowbark)beforetheFDAban in2004.

Thereissomeevidencetosuggestthatthecombinationofephedra withcaffeineand/oraspirin(ortheirherbalconstituents)mayindeed bemoreeffectiveforinducingweightlossthanephedraalone.Inan extensivereview,Greenway (6) examinedthesafetyandefficacyof ephedrinepluscaffeine(EC)andreportedthatthecombinationwas aseffectiveassomeprescriptionweightlossdrugsandwasassociated withfewersideeffects.InthestudiesreviewedbyGreenway (6),the acutesideeffectsforECwereconsideredmildandtransient,and

aftercontinuoustreatmentfor4to12weeksthereportedsideeffects werenotsignificantlydifferentfromthoseofaplacebo.Asaresult, Greenway (6) suggestedthatthebenefitsofECoutweightheassociatedrisksandpointedoutthatmanyoftheseriousadverseevents thathavebeenreportedintheliteraturearevoluntarycasereports thathavenoplaceboorcontrolgroupsforcomparison.Therefore,in hisopinion (6),theargumentforremovingherbalproductscontainingephedrinewassomewhatunfounded.

Hutchins (11) alsoindicatedthatmanyoftheephedraalkaloidrelateddeathsreportedintheliteratureoccurredinindividualswith preexistingcardiovascularconditionsorrisksand,therefore,thedangersassociatedwithephedrauseinhealthyindividualsmaybewidely speculative.Inaddition,Dulloo (12) suggestedthatmixturesofephedrineandcaffeinemayofferaviable,cost-effectiveapproachtothe treatmentofobesityandhasrecommendedthatmorelarge-scaleclinicaltrialsbeconductedtogainabetterunderstandingoftherisksand benefitsassociatedwiththecombinationofephedrineandcaffeine.

Intwoseparatestudies,Boozeretal. (5,13) alsoreportedthatma huang(herbalephedra)combinedwitheitherguarana (5) orkola nuts (13) wasmoreeffectiveforweightlossinoverweightmenand womenthanplaceboandresultedinnoadverseeventsandminimal sideeffects.Inthestudythatexaminedtheeffectsofmahuangand guarana (5),thetreatmentwasacommercialherbalmixturecalled Metabolife-3561,whichcontainedanequivalentof72mgofephedrineand240mgofcaffeine.Following8weeksofsupplementation,thetreatmentgrouplostsignificantlymorebodyweight(4.0 –3.4kg)andpercentbodyfat(2.1% – 3.0%fat)versustheplacebo group(0.8 – 2.4kgand0.2% – 2.3%fat,respectively).Intheother studybyBoozeretal. (13) thatexaminedtheeffectsofmahuang andkolanutonweightloss,theherbalpreparationwasequivalent to90mgofephedrineand192mgofcaffeine;whencomparedto placebo,itresultedinsignificantdecreasesinbodyweight(5.3 – 5.0 vs.2.6 – 3.2kg)andfatweight(4.3 – 3.3vs.2.7 – 2.8kg).Inboth studies (5,13),theherbalpreparationsalsoresultedinsignificant improvementsinthebloodlipidprofilesofthesubjects.Kalmanand Minsch (14) alsoshowedthatsupplementationofanECAstack (20mgephedrine þ 200mgcaffeine þ 325mgaspirin)for6weeksin overweightmenresultedinweightlossthatwassignificantlygreater whencomparedtoplacebo(4.17vs.0.68kg,respectively).In

agreement,Dalyetal. (15) alsoreportedthatanECAcombination (75–150mgephedrine þ 150mgcaffeine þ 330mg)resultedinmodestsustainedweightloss(2.2–5.2kg)in24obeseindividualscomparedtoplaceboandreportedthatthedoseswerewelltoleratedand hadnomeaningfuleffectsonheartrate,bloodpressure,insulinand glucoseconcentrations,orcholesterollevels.

Insomewhatcontrasttothestudiesdescribedabove,Vukovich etal. (16) reportedthatacuteadministration(3hours)ofherbal ephedrineandcaffeineatdosesof20mgand150mg,respectively, significantlyincreasedheartrate(22.7% – 5.5%),systolicblood pressure(9.1% – 2.2%),andrestingenergyexpenditure(REE) (8.5% – 2.0%)comparedtobaselinevalues.Althoughtheauthors (16) didnotdirectlyexaminetheeffectsoftheherbalmixtureon bodyweight,theysuggestedthattheincreaseinREEwouldbe negligibleintermsofweightloss.

Basedonmostofthefindingsintheliterature,itappearsthat herbalephedrinecombinedwithcaffeineorwithcaffeineandaspirin iseffectiveforinducingmoderateweightlossinoverweightadults whoareotherwisehealthyandhavenopreexistingcardiovascularor cerebrovascularconditions.Becauseofsafetyconcerns,andconsideringthatmanyindividualsmightbeunawareofunderlyingconditionsthatmaypredisposethemtoanincreasedriskfromherbal preparationsthatmimicbothcaffeineandephedra,consultation withaphysicianpriortotheirusemaybewarrantedasaprecaution.

2.2.BitterOrange (CitrusAurantium)

ThebanofephedrabytheFDAin2004hasledtotheproliferationofanumberof‘‘ephedra-free’’dietarysupplements.Manyof theseproductscontainbitterorange,whichisalsoknownas Citrus aurantium,zhishi,Sevilleorange,orsourorangeandreferstoa smallcitrustree(C.aurantium)anditspeelandfruit (17).Theactive componentsinbitterorangearesynephrineandoctopamine,which arestructurallysimilartoepinephrineandnorepinephrine,respectively.Therefore,thesecompoundsarealsochemicallyrelatedto ephedrineandarebelievedtoaffect a-receptorsand b3 receptors, butnot b1 or b2 receptors.Becausesynephrinedoesnotaffect b1 or b2 receptors,itisreportedlylessactiveintheCNSthanephedrine andistheorizedtohavefeweradverseeffects (17)

Thereissomeconfusionintheliterature,however,regardingthe actionofsynephrine.Forexample,Fugh-BermanandMyers (17) havereportedthatsynephrine(andoctopamine)activate b3 adrenoreceptorsbutnot b1 or b2 receptors,whichacttostimulatetheheart(b1 and b2)andresultinsystemicvasodilation(b2).However,Bentetal. (18) andPenzaketal. (19) reportedthattheextractscontainedin bitterorangeprimarilystimulate a1-adrenergicreceptorsbecausethey resemblephenylephrine(aselective a receptoragonistcommonlyused asanasaldecongestantthatisalsoknownasNeo-Synephrine)and wouldresultinvasoconstrictionandincreasedbloodpressure.

Itappearsthatmuchoftheconfusionliesinthefactthatthereare severalisomersofsynephrineincludingpara(p)-synephrine,meta (m)-synephrine,andortho(o)-synephrine,andthatitisnotexactly knownwhichoftheseisomersorcombinationofisomersarepresent innutritionalweightlosssupplementsproducts.Inaddition,thereis someconfusionastowhichsynephrinealkaloidsareactuallypresent inbitterorangeitself (20).Thisinformationiscritical,asthese variousisoformsexhibitdifferentpharmacologicalproperties.The differencesinthestudies (17–19) mentionedaboveregardingthe exactmechanismofactionofbitterorangearerelatedtothedifferent synephrineisoformsthateachauthorsuggestsiscontainedinthe extract.Forexample,Penzaketal. (19) andBentetal. (18) stated thatitcontains m-synephrine(i.e.,phenylephrine),whereasFughBermanandMyers (17) specificallystatedthat m-synephrine(phenylephrine)is not presentin C.aurantium andthatitsmostactive componentis p-synephrine.Blumenthal (21) hasalsostatedthatthe typeofsynephrineinbitterorangepeelis p-synephrineandthatithas beenincorrectlycharacterizedas m-synephrinebyvariousauthors. However,intheirtechnicalreportoftheconstituentsofbitterorange, Allisonetal. (20) statedthattheywereunabletofindanyconvincing datathatbitterorangesolelycontains m-synephrineor p-synephrine. Consideringforamomentthatbitterorangecontainsonly p-synephrineandthereforeselectivelyactivates b3 receptors,it seemsreasonabletosuggestthatthisisoformwouldbeableto induceweightlosswithfewersideeffectsthanotherCNSstimulants,including m-synephrine.However,becauseoftheirselective activationof b3 receptors,thesecompoundsmaybeineffectivein humans.Animalstudiesusingfatcellsfromrats,hamsters,anddogs haveshownthat b3 agonists,suchassynephrineandoctopamine,

havepotentlipolyticeffects;however,theyareweakstimulatorsin humanfatcells (17).Humanadipocytesrespondtoactivationof b1 or b2 receptorsandhavelittleexpressionfor b3 receptors.Therefore, itrequireshighconcentrationsofsynephrine(0.1–1.0mM)to stimulatefatcellsinhumans (22).

AsindicatedbyAllisonetal. (20),itislikelythatmostweightloss productscontainingbitterorangecontainboth p-and m-synephrine. Intheirtechnicalreport,Allisonetal. (20) analyzedaweightloss supplementcalledUltimateThermogenicFuelTM,whichstatedon thelabelthatitcontained m-synephrinefrombitterorange.The authorsdidindeedfindthattheproductcontainedboththe p-and m-isoforms.Therefore,ifbitterorangecontainsonly p-synephrine, themanufacturersoftheseweightlossproductsareeitheradding synthetic m-synephrineorareincludingotherCNSstimulants(e.g., guarana,caffeine,mahuang,yohimbe) (20).Asevidenceofthis,one needsonlytoreadthelabelonseveralothercommonlyusedOTC weightlosssupplementstoseethatmostdo,infact,includeseveral CNSstimulantsasaproprietaryblendtoboostthethermogenic effect.Forexample,inadditiontobitterorange,XenadrineEFXTM (CytodyneLLC)alsoincludestyrosine,greentea,yerbamate,and guarana.Similarly,CortiSlimTM (WindowRockHealthLaboratory) containsbitterorange,chromium,andgreentea,whichareall believedtohaveaneffectonweightloss.

Giventhatthesenewlyreformulatedweightlosssupplements containbitterorange,aswellasseveralotherbotanicalsthatalso havesympathomimeticactivity,thereissomeconcernthattheypose thesamerisksasephedra.Tohelpclarifythispoint,Halleretal. (23) examinedthepharmokineticsandcardiovasculareffectsoftwo oraldietaryweightlosssupplementscontainingbitterorangein10 healthyadultswhorangedinagefrom18to49years.Thesubjects weregivenasingledoseofAdvantraZTM (46.9mgsynephrine), Xenadrine-EFX(5.5mgsynephrine,5.7mgoctopamine,239.2mg caffeine),oraplaceboonthreeoccasionsthatwereseparatedbya 1-weekwashoutperiod.Theresultsshowedthat,comparedtothe placebo,Xenadrine-EFXincreasedsystolicbloodpressure(SBP) (9.6 – 6.2mMHg)anddiastolicbloodpressure(DBP)(9.1 – 7.8mM Hg),withpeakincreasesoccurring 2hoursafteringestion.AdvantraZ,however,hadnomeaningfuleffectsonbloodpressure. Heartrate(HR)wassignificantlyelevated6hoursafterdosing

withbothXenadrine-EFX(16.7 – 12.4b min –1)andAdvantra Z(11.4 – 10.8b min–1)comparedtoplacebo.Thepharmokinetics weresimilarforthetwosupplementsandshowedthatboth synephrineandoctopaminearepoorlyabsorbedand/orrapidly metabolizedwhentakenorally.Thetimetopeakplasmaconcentrationwas1to2hours,andthehalf-lifewasapproximately3hours forbothtreatments.

ThefindingthatAdvantraZ,whichcontainedeighttimesthe amountofsynephrineasXenadrine-EFX,hadnoeffectonblood pressuresuggeststhatithasminimalpharmacologicalactivity (23). However,whenbitterorangeiscombinedwithotheractiveherbal ingredients,aswasthecasewithXenadrine-EFX,thebloodpressureincreasedsignificantly.Thefindingthatbothsupplements resultedinashort-termincreaseinHRalsosuggeststhatbitter orangemayhavesome b1-adrenergicactivity (23).

Inastudythatexaminedthecardiovasculareffectsofbitter orange—intheformofsourorangejuice(SOJ)—Penzaketal. (19) reportedfindingssimilartothoseofHalleretal. (23).The specificpurposeoftheirstudy (19) wastoquantifythecontentof bothsynephrineandoctopamineinSOJanddetermineitseffectson SBP,DBP,meanarterialpressure(MAP),andHRin12normotensive(SBP/DBP 140/90mmHg)youngadults(agerange20–27 years).Eachsubjectservedashisorherowncontrolandconsumed either8ozoffreshlysqueezedSOJ( 14mgsynephrine)followedby repeatingestion8hourslater,or8ozofwaterusingthesame protocol,witha1-weekwashoutbetweenthetwotrials.

TheresultsshowedthatSOJhadnosignificant(p > 0.05)effect onanyoftheparametersmeasured(SBP,DBP,MAP,HR)when comparedtowatereventhoughtheSOJcontainedwhattheauthors (19) representedas 28mgof m-synephrine(andnooctopamine), whichisanamountcomparabletothatincludedincommonlyused decongestantmedicationscontainingphenylephrine.Theauthors (19) alsotestedregularorangejuicefromfrozenconcentrateand foundnotracesofsynephrineoroctopamine,whichindicatesthat thesecompoundsarederivedonlyfromthefruitof C.aurantium.

Penzaketal. (19) suggestedthattheirlackofsignificantfindings couldhavebeenduetothepoorbioavailabilityofsynephrine, whichwouldagreewiththefindingsofHalleretal. (23),asthey alsoreportedthatsynephrinewaspoorlyabsorbed.Interestingly,

however,Penzaketal. (19) didnotquantifytheisomers(i.e., p-and m-)ofthesynephrinecontainedintheSOJeventhoughtheyimplied thatitcontainedthe m-form.Therefore,inthisauthor’sopinion,it maybethatSOJprimarilycontains p-synephrine,whichwould explaininpartwhytherewerenosignificantcardiovasculareffects, asitwouldnotactivate b1 or b2 receptors.

BaseduponthefindingsofHalleretal. (23) andPenzaketal. (19),itappearsthatbitterorange alone maybeconsideredsafer thanephedra.However,whenitiscombinedwithothersympathomimeticssuchasguarana,caffeine,greentea,ortyrosine,itmay resultintransientincreasesinbloodpressureandHR.

Inoneofthefirstclinicalstudiestoinvestigatetheeffectofbitter orangeonweightloss,Colkeretal. (24) examinedtheeffectofan herbalmixturethatcontained975mgof C.aurantium extract(6% synephrinealkaloid),900mgofSt.John’swort(3%hypericum),and 528mgofcaffeineonbodyfatin20overweight(BMI > 25kg/m2),but otherwise,healthyadults.Thesubjectswererandomlyplacedina controlgroup(n =4),aplacebogroupthatingestedmaltodextrin (n =7),ortheactivetreatmentgroup(n =9);ifapplicable,thesubjectsingestedtheirrespectivesupplementoncedailyfor6weeks.All subjectsparticipatedinacircuittrainingexerciseprogramthreetimesa weekfor45minutespersessionandreceivedindividualcounseling fromaregistereddietitian tocomplywithan1800kcal d–1 dietrecommendedbytheAmerican HeartAssociation.

Thechangeinbodyweightfrombaselineto6weeksforthegroup takingthe C.aurantium was1.4kgcomparedto0.9kgintheplacebo group,and0.4kginthecontrolgroup.Thechangeinbodyfatand percentfat[viabioelectricalimpedanceanalysis(BIA)]foreachofthe threegroupswas–3.1kg/–2.9%,–0.63kg/0.8%,and–1.8kg/–2.2%, respectively.Thelossinbodyfatandpercentfatwassignificantly greaterinthe C.aurantium groupthanineithertheplaceboorthe controlgroup;however,therewereno significantdifferencesbetween thegroupsinregardtobodyweight,basalmetabolicrate,blood pressure,HR,orelectrocardiographicmeasurements.

Basedonthesefindings,theauthors (24) suggestedthatthe combinationof C.aurantium withSt.John’swortandcaffeinewas safeandeffectivewhencombinedwithadietandexerciseprogram forinducingweightlossandfatlossinhealthy,overweightadults. Theseresultsshouldbeinterpretedwithcaution,however,because

thechangeinpercentbodyfat(–2.9%)overthe6-weeksupplementationperiodwaslessthantheerrorthatistypicallyassociatedwith BIA( 3%–5%),andthistechniqueisnottypicallyregardedasa criterionmeasureofbodycomposition (25)

Morerecently,Saleetal. (26) examinedtheacuteeffectsof Xenadrine-EFXonmetabolismandsubstrateutilizationduringrest andduringtreadmillwalkingin10overweightmales(> 20%fat).To gatherrestingdata,thesubjectsingestedthesupplementandlaid supinefor7hours.Baselinemeasurementsweretakenduringthe firsthour;andexpiredgases,bloodpressure,andHRweremeasured andavenousbloodsampleobtainedevery30minutesfortheremaining6hours.Duringtheexercisearmofthestudy (26) thesubjects ingestedthesupplementoraplacebo,andat1hourafteringestionthey exercisedonatreadmillfor1hourat60%oftheirestimatedHR reserve.Venousbloodwasanalyzedfornonesterfiedfattyacids (NEFAs),glycerol,glucose,andlactate;andexpiredgaseswereused tocalculateenergy(ATP)productionandsubstrateutilizationfrom carbohydrateandNEFAsforboththerestingandexerciseconditions.

Theresultsshowedthattherewasnosignificanteffectofthe supplementontotalATPutilizationduringthe6hoursofrestor duringthe60minutesoftreadmillwalking.However,therewasa shiftinATPproductionandsubstrateutilizationduringbothphases ofthestudy,whichdemonstratedanincreaseinATPproduction fromcarbohydrateandadecreaseinNEFAs,aswellasanincreasein carbohydrateoxidation.Infact,theincreaseincarbohydrateoxidationatrestwasshowntobeashighas30%.Weightlosssupplements aretypicallypromotedtoincreasefatutilization;however,these findingsindicatethatXenadrine-EFXstimulatescarbohydrateuse andactually decreases ATPproductionfromfat.

Basedonthesefindings,itappearsthatthisproductwouldnot haveanyfavorableeffectsonbodyweight.However,morelong-termstudiesdesignedtoexamineitseffectonweightloss,bothwith andwithoutexercise,arewarrantedtoverifythisstatement.One positivefindingfromthestudy (26) wasthatXenadrine-EFXhad noeffectonrestingHRorbloodpressure(eitherSBPorDBP), whichisincontrasttothefindingsofHalleretal. (23).Zenketal.

(27) alsoreportedthatacommercialweightlossproductcalledThe LeanSystem7(iSatoryGlobalTechnologies),whichcontainsbitter orange,guarana,dehydroepiandrosterone(DHEA),andyerba

mateamongitsseveningredients,hadnoeffectonHRorblood pressure(SBPorDBP)following8weeksofsupplementationin47 overweightadultswhowerealsofollowingalow-caloriedietandan exerciseprogram.Perhapsmoreimportantly,however,Zenketal. (27) reportedthatthisproducthadnoeffectonBMI,bodyweight, fatweight,orfat-freeweightcomparedtoplacebo,eventhoughthe restingmetabolicratewassignificantly(p =0.03)increasedinthe treatmentgroup(7.2 – 1.6kcal d–1).

Basedontheavailableresearch,itdoesnotappearthatbitter orangeiseffectiveforweightloss.Moreover,becausesafetyinformationislimited,individualswithpreexistingcardiacproblemsand/or hypertensionshouldproceedwithcautionbeforeusingweightloss supplementscontainingbitterorangebecauseitismostcommonly usedinherbalmixturesthatcontainseveralotherCNSstimulants.In addition,futurestudiesarewarrantedtogainabetterunderstanding oftheexactisomerscontainedinvariousformsofbitterorange,asthe potencyvarieswidelybetweenthedifferentstereo(–)andpositional (m-and p-)isomers.Inshort,itappearstobe‘‘buyerbeware’’atthe presentmomentwithregardtothedifferenttypesofsynephrinethat manufacturersmaybeincludingintheirweightlossproducts,particularlyastheydonotnecessarilyneedtoregisterwiththeFDAorget FDAapprovalbeforeproducingorsellingtheseproducts.

2.3.Pyruvate

Pyruvate(PYR),athree-carboncompoundsynthesizedinthe bodyviaglycolysis,hasbeenstudiedforitseffectsonweightloss sincethelate1970swhenStankoetal. (28) foundthatPYRanda relatedthree-carboncompoundknownasdihydroxyacetone (DHA)reducedthedevelopmentoffattyliversinratsfedethanol. Follow-upstudiesperformedbythesameresearchgroup (29,30) usingratandpigmodelsalsoshowedthatPYRandDHAsupplementationresultedinincreasedenergyexpenditureandfatreduction,possiblythroughtheresultsofincreasedthermogenesis. Stankoetal. (31,32) havealsoreportedsignificanteffectsofPYR andDHAonweightlossinhumans.Inonestudy (32) thatexaminedtheeffectofPYR(19g d–1)andDHA(12g d–1)supplementationfor3weeksin21obesewomeningestingalow-caloriediet,it wasfoundthatthecombinationofPYR-DHAresultedinsignificantlygreaterlossesinbodyweight(6.5kg)andfatweight(4.3kg)

comparedtoplacebo(5.6kgand3.5kg,respectively),whichrepresentedadifferenceof 2lbbetweengroups.Inarelatedstudy, Stankoetal. (31) alsofoundthatwhenobesewomenwhofirst lostweightonalow-caloriedietweresubsequentlyplacedonahighcaloriedietwithPYR,theyregainedweightatasignificantly (p < 0.05)slowerratecomparedtoahigh-caloriedietwithout PYR.Basedonthesefindings,itwasconcludedthatPYRand PYR-DHAwhencombinedwithalow-caloriedietresultsingreater weightlossversuscalorierestrictionalone (32) andattenuates weightgainduringhypercaloricconditions (31).

AlthoughmanyofthestudiesconductedbyStankoandcolleagues (31

34) resultedinpositivefindings,itisimportanttonote thatheownsseveralpatents (29) forPYR-DHA;andalthough manyresearchersusepatentsasameanstoprotecttheirintellectual property,itisconsideredbysometorepresentaconflictofinterest. Inaddition,thedosagesrecommendedforthepatientswerelarge (i.e.,22–44g d–1),representingupto20%ofdailyenergyintake, andwereingestedconcurrentlywithalow-caloriediet (31,33).

TogainabetterunderstandingoftheefficacyofPYRonweight losswithoutcaloricrestriction,Kalmanetal. (35) determinedthe effectoflow-dosePYRonbodycompositionin51overweight(BMI > 25kg m2)menandwomenconsuminga2000kcal d–1 diet.In theirstudy (35),thesubjectsrandomlyreceivedaweightlossproductthatcontainedPYR(6g d–1)andDHA(50mg d–1)(n =18) oraplacebo(maltodextrin6g d–1; n =18)for6weeks,andanother 15subjectsservedasacontrolgroup.SubjectsinthePYRandPL groupsmetwitharegistereddietitianevery2weeksandreceived counselingtofollowa2000kcal d–1 diet(50%carbohydrate,20% protein,30%fat),andallsubjectscompletedacircuittraining protocolthreetimesaweekfor 45minutesat60%oftheirpredictedmaximalHR.Bodycompositionwastestedatbaselineand every2weeksthereafterusingBIA.Therewerenosignificantdifferencesbetweenthethreegroupsatbaseline;andattheendofthe6weekperiod,theresultsshowedthatnoneofthegroupsexperienced asignificantchangeinbodyweight.However,PYRresultedina significantdecreaseinfatweight(–2.1kg)andpercentfat(–2.6%), aswellasasignificantincreaseinfat-freeweight(1.5kg).Therewere nosignificantdifferencesinfatweightandfat-freeweightfrom baselineto6weeksfortheplaceboandcontrolgroups.Itis

unknownifanyofthedifferencesinbodycompositionweresignificantlydifferentbetweengroupsbccauseitdoesnotappearthat theauthors (35) performedastatisticalanalysistodetermine between-groupdifferencesafterbaseline.Theauthors (35) stated thatPYRsupplementationof6g d–1 for6weeksresultsinmodest decreasesinfatweightandaconcomitantincreaseinfat-freeweight whenperformedinconjunctionwithexercise.Theseresultsshould beinterpretedwithcaution,however,asthebodycompositionwas notassessedusingacriterionmethod,anditappearsthatincompletestatisticalanalyseswereperformed.

Kalmanetal. (36) performedasimilarstudythatwaspublished 1yearlatertoexaminetheeffectsofexercise(45–60minutesthree timesaweek)andPYR6g d–1 for6weeksonbodycompositionin 26overweightmenandwomencomparedtoplacebo.Theresultsof thisstudy (36) showedthatPYRresultedinastatisticallysignificant(p < 0.001)decreaseinbodyweight(1.2kg),fatweight (–2.5kg),andpercentfat(–3.0%),whereastheplacebogroup experiencednochangesoverthe6weeksofsupplementationand training.

IncontrasttothefindingsofKalmanetal. (35,36),amorerecent study (37) thatexaminedtheeffectofPYRduringtrainingonbody compositionreportednosignificanteffectscomparedtoplacebo.In thisstudybyKoh-Banerjeeetal. (37),23untrainedwomenwere assignedtoreceiveeitherPYR(10g d–1)oraplacebofor30days whileparticipatinginasupervisedexerciseprogram.Priortoand followingsupplementation,bodyweight,fatweight,andpercentfat wereassessedusingunderwaterweighing,whichisacommonly acceptedcriterionmethodforassessingbodycomposition. AlthoughthePYRgroupgainedlessweight(PYR0.3 – 0.3kgvs. placebo1.2 – 0.3kg),lostmorefatweight(PYR–0.4 – 0.5kgvs. placebo1.1 – 0.5kg),andlostagreaterpercentageofbodyfat(PYR –0.65% – 0.6%vs.placebo0.1% – 0.5%),theresultswerenot statisticallysignificant(p =0.16)whencomparedtoplacebo. Thesefindings (37) areinagreementwiththoseofStoneetal. (38),whoalsoreportedthatPYRsupplementation( 9g d–1)for 5weekshadnosignificanteffectonbodycompositionortraining adaptationsincollegefootballplayers.

AlthoughseveralstudieshaveshownthatPYR,bothwithand withoutDHA,resultsinpositiveeffectsonbodyweightandbody

composition (31 –36),mostofthesestudieswereperformedinthe samelaboratory,andsupplementationoccurredinconjunction withextremelylowcaloriediets (30 –33) .Incontrast,theresultsof othermorerecentwellcontrolledstudiesinwhichsubjectsmaintainedtheirnormaldiet (37 ,38) showednoeffectofPYRwhen comparedtoplacebo.Inaddition ,consideringthatthesubjects usedinmostofthestudiesthatshowedpositiveresultswereoverweightorobese,theweightlossinducedbyPYR( 2–3lb)waswhat maybeconsideredmodestatbest.Therefore,futurestudiesconductedbyseveralindependentlaboratoriesarenecessarytogaina betterunderstandingoftheefficacyPYRonbodycomposition beforeitcanberecommendedwithconfidenceasatreatmentfor weightloss.

3.SUPPLEMENTSTHATMODIFYCARBOHYDRATE ANDFATMETABOLISM

3.1.ChromiumPicolinate

Chromiumisapopularweightlosssupplementthathasbeenon themarketforanumberofyears.From1996through2003,salesof chromiumintheUnitedStatesincreasedfrom$65millionto$106 million (39).Chromiumisanessentialtracemineralthatenhances insulinactivityand,therefore,isinvolvedincarbohydrate,protein, andfatmetabolism.Mostdietaryweightlosssupplements(80%of allchromiumsales)containchromiumpicolinate(CrP),anorganic compoundoftrivalentchromiumandpicolinate,whichisaderivativeoftryptophan (39,40).BecauseCrPfacilitatestheactionof insulin,itisbelievedtodecreasebodyfat,increaseleanmass,and increasebasalmetabolism (39,40).However,moststudiesthathave examinedtheeffectofCrPonbodyweightandleanmassusing humanshavenotshownmanypositiveeffects.

Pittleretal. (40) conductedameta-analysisof10randomized clinicaltrialsthatexaminedtheeffectofCrPonbodyweightreduction.Theresultsshowedthatbodyweightdecreased1.1to1.2kg (0.08–0.2kg wk–1)comparedtoplaceboduringanintervention periodrangingfrom6to14weeks,withdailydosagesranging from188to924 mg.Inaddition,noadverseeventswerereported

inthestudiesthatalsoexaminedthepotentialadversesideeffectsof chromiumsupplementation (18,41)

Morerecently,Lukaskietal. (39) examinedtheeffectofCrPon bodyweightandbodycomposition(fatweightandfat-freeweight) viadual-energyx-rayabsorptiometry(DEXA)in83women(age range19–50years)withaBMIrangeof18–30kg m2.Thesubjects inthetreatmentgroup(n =27)ingestedanequivalentof200 mgof CrPfor12weeks,andtheothersubjectseitherrandomlyreceived 1720 mgpicolinicacid(n =27)oraplacebo(n =29).Allsubjects werecounseledbyaregistereddietitianandmaintaineda2000kcal diet(51%carbohydrate,18%protein,31%fat)tocontrolfor chromiumintakeduringthe12-weekstudy.

Theresultsshowedthatbodyweight[–1.0kg(placebo)to–1.3kg (CrP))andfat-weight(–1.1kg(CrP)to–1.4kg(placebo)]significantlydecreasedoverthe12-weekintervention.However,there werenosignificantdifferencesamongthethreegroups,whichindicatesthatthecalorierestriction,notCrP,wasresponsibleforthe weightloss.Therewerenosignificanteffectsacrosstimeforanyof thegroupsforfat-freeweightorbonemineraldensitydetermined fromDEXA.ThesefindingssupportthoseofPittleretal.(40) andsuggestthatCrPisasafe,butineffectivedietaryweightloss supplement.

3.2.Chitosan

Chitosan,apositivelychargedpolysaccharidethatisapolymer ofglucosamine,isderivedfromtheshellsofcrustaceans(i.e.,crabs, shrimp,lobster) (3,42).Itispurportedtoblockfatabsorption;and althoughtherearesomedataonanimalstosuggestthatitmightbe aneffectiveweightlosssupplement,thereislittlesupportforitsuse inhumans.Inonestudy (43),itwasfoundthatchitosanprevented anincreaseinweightinmicethatwerefedahigh-fatdietfor9weeks, andanotherstudyusinghamsters (44) reportedthatchitosan decreasedfoodintakeandbodyweight.

However,intheirreviewarticle,PittlerandErnst (42) performed ameta-analysisonfiverandomizedclinicaltrialsthatexaminedthe effectofchitosanonbodyweightinobeseandoverweightindividualsandreportedthat,inthreeofthefivestudies,chitosanhadno significanteffectonbodyweightcomparedtoaplacebo.The

dosagesusedinthestudiesrangedfrom0.48to3.1g d–1 andwere4 to12weeksinduration.However,inthestudythatusedthelowest dose,chitosanwascombinedwith Garciniacambogia (1.1g d–1), whichisalsocommonlyusedinmanydietaryweightlosssupplements.Whenexaminingtheotherfourstudiesthatusedchitosan alone,threeresultedinnosignificantfindings.Allfivestudiesused inthemeta-analysisreportedminoradversegastrointestinaleffects followingchitosansupplementation,includingconstipation,flatulence,bloating,nausea,andheartburn (42).

Aspreviouslymentioned,chitosanisapositivelychargedpolymer thatisbelievedtoblock,or‘‘trap,’’theabsorptionoffatbybinding withnegativelychargedfatmoleculesinthelumenoftheintestine (3).Ifmalabsorptionoffatdoesresultfromproductscontaining chitosan,itwouldbeexpectedthattherewouldbeanincreasein fecalfatexcretion.Totestthishypothesis,GadesandStern (45) quantifiedthefecalfatcontentinsubjectswhosupplementedwith anOTCproductcalledAbsorbitol(Natrol,Chatsworth,CA,USA).

Fifteenmales(age26.3 – 5.9years;BMI25.6 – 2.3kg m2)consumed fivemealsperdaycontaining15gfat(total75g d–1)for12days.

Thefirst4daysservedasacontrolperiod,followedbya4-day supplementationperiodinwhichthesubjectsreceivedchitosan 4.5g d–1.Thesubjectswerethenplacedbackonthecontroldiet foranother4days.Allfecalmatterondays2to12wascollectedto beanalyzedforfatcontent.

Theresultsshowedthatchitosansupplementationsignificantly (p =0.02)increasedfecalfatexcretionby1.1 – 1.8g d–1 (from6.1 –1.2to7.2 – 1.8g d–1),whichtheauthors (45) consideredclinically negligible.Theystatedthattheproductwouldhavenomeaningful effectonenergybalanceorweightloss.Basedonthesefindings (45) andthoseofPittlerandErnst (42),chitosandoesnotappeartobe effectiveforreducingbodyweightinhumansandisassociatedwith gastrointestinaldiscomfort,includingconstipation,flatulence,and bloating.

3.3. Garciniacambogia (HydroxycitricAcid)

Garciniacambogia,alsoknownasbrindelberry,isatropicaltree nativetoIndiathatbearsyellowish,pumpkin-shapedfruit.Both thenaturalfruitandrindcontainhydroxycitricacid(HCA),which hasbeenshowntodecreasefatsynthesis(lipogenesis),spare

carbohydrate,suppressfoodintake,andattenuatebodyweightgain (46).Theextractof G.cambogia isacomponentofmanydietary supplements(i.e.,CitrimaxTM,CitrileanTM),includingabottled drinkingwatercalled‘‘SkinnyWater1.’’Mostoftheseproducts claimthatwheningested30minutespriortoameal,theysuppress appetiteandblockcarbohydrateabsorption.

Ingeneral,theresultsforHCAasadietaryweightlosssupplementforhumansarenotpromising.Inanarticlethatexaminedthe effectofHCAasapotentialantiobesityagent,Heymsfieldetal. (46) reviewedsevenotherstudiesthathadexaminedtheeffectof HCAaloneorincombinationwithotheringredientsonbodyweight andfatweightinoverweighthumans,includingtwopeer-reviewed articles,fourabstracts,andoneopen-labelstudyfromanindustrial publication.Ofthesevenstudiesreviewed,fivereportedsignificant (p < 0.05)effectsofHCAaloneorincombinationwithanother weightlossagentonweightlossandfatloss;onestudythatfailed toincludestatisticsreportedthatsubjectswhoingestedHCA þ chromiumfor8weekslost 7poundsmorethansubjectsona placebo(HCA11.14lbvs.placebo4.20lb).However,Heymsfield etal. (46) notedthatinfiveofthestudiesHCAwastakenin combinationwithotheractiveingredientsthatcouldalsopotentiallyresultinweightloss(i.e.,CrP, L-carnitine,chitosan,herbal formsofcaffeine);therefore,thestudiesofferedlittleinsightintothe specificweightlosseffectsofHCA.Otherlimitationsincludedalack ofaplacebogroupordoubleblindinginonestudyandtheuseof near-infraredinteractancetoassessbodycompositioninanother, whichisconsideredbymanytobeaninvalidmethodformeasuring bodycomposition (46).

TogainabetterunderstandingoftheeffectofHCAaloneonbody composition,aswellasovercomesomeofthelimitationspreviously reportedintheliterature,Heymsfieldetal. (46) conductedtheir own12-weekdouble-blindplacebo-controlledstudyusingoverweight subjects(ages18–65years;BMI > 27–38kg m2)whowereeither randomizedtoreceive1500mg d–1 HCA(3 500mg d–1 30minutes priortomeals)(n =42)oraplacebo(n =42).Bodyweightandfat weight(viaDEXA)wereassessedatbaselineandat12weeks. Allsubjectswereprovidedwith5040kJ/daydietplan(i.e., 1200kcal)with50%,30%,and20%ascarbohydrate,protein,and fat,respectively.

Theresultsshowedthatsubjectsinbothgroupslostasignificantamountofweightoverthe12weeks;however,therewasno significantdifferencebetweenthetwogroups(placebo4.1 – 3.9kg vs.HCA3.2 – 3.3kg; p =0.14).Inaddition,therewasnosignificantdifferenceinpercentbodyfatlostbetweentheHCAand placebogroups(2.16% – 2.06%vs.1.44% – 2.15%,respectively). Basedontheseresults,HCAwasdeemednomoreeffectivethan placeboforreducingbodyweightandfatweightinoverweight individuals.

Kovacsetal. (47) alsofoundthatsupplementationwith 500mg d –1 HCAaloneorincombinationwithmedium-chaintriglyceridesfor2weeksdidnotresultinincreasedsatiety,fatoxidation,24-hourREE,orbodyweightloss(–1.0kgforplacebovs. –1.5kgforHCAalone)comparedtoplaceboin11overweight malesubjects(BMI27.4 – 8.2kg m 2 ).However,inafollow-up studythatwasalso2weeksindurationbutusedalargerdose, investigatorsfromthissamelaboratory (48) reportedthat 900mg d –1 HCAreducedenergyintakeby15%to30%,butdid notresultinanysignificantchangesinsatietyorbodyweight.The authors (48) suggestedthatHCAmaynotprimarilyserveasa weightlossagent,butcouldbeeffectiveforpreventingweight regaininoverweightindividuals,sinceitresultedinreducedenergy intake.

Inanotherrelatedstudy,Kriketosetal. (49) examinedtheeffect ofHCAonfatoxidationandthemetabolicratein10sedentarymen (ages22–38years;BMI22.4–37 6kg m2)usingadouble-blind, crossoverdesign.ThesubjectsvisitedthelaboratoryonfouroccasionstoexaminetheeffectsofHCA3.0g d–1 for3daysanda placeboonmetabolicparametersbothwithandwithoutmoderately intenseexercise(30minutesat40%VO2maxfollowedby15minutes at60%VO2max).TheresultsshowedthatHCAhadnoeffecton therespiratoryexchangeratioorenergyexpenditureatrestor duringexercise,indicatingthatithadnoeffectonfatoxidation. AlthoughtheirstudydidnotdirectlyexaminetheeffectofHCA onbodyweightloss,theauthors (49) commentedthatthelack ofmetabolicchangessuggestthatHCAwouldbeineffectivefor inducingweightlossinindividualsconsumingatypicalmixeddiet. Inagreement,vanLoonetal. (50) alsoreportedthatacuteHCA supplementation(18g d–1)hadnosignificanteffectsontotal

carbohydrateorfatoxidationin10trainedcyclistsatrestorduring submaximalexercise.

AlthoughtheresultsofseveralearlystudiesreviewedbyHeymsfieldetal. (46) suggestedthatHCAincombinationwithother ingredients,includingCrPandherbalcaffeine,enhancedweight loss,morerigorouswellcontrolledstudiesthatusedHCAalone suggestthatitisnotaneffectivedietaryweightlosssupplement comparedtoplacebo.Interestingly,however,arecentstudy (51) usingratssuggeststhattheredefinitelyisadifferenceinefficacy betweenproductsandthatthedosagesusedinhumanstudiesmight betoolowtoresultinsignificantfindings.

Intheirstudy,Louter-vandeHaaretal. (51) comparedthe effectsofthreeHCA-containingproductsonWistarrats(RegulatorTM,CitrinKTM,CitriMax)atdosescorrespondingto150and 200mg kg–1 onfoodintakeandbodyweightafterbothsingledose andrepeateddose(4days)administration.RegulatorandCitrinK significantlyreducedfoodintakefollowingbothsingleand repeateddoseadministration,whereassimilardosesofCitriMax showedlittleeffectonfoodintake.Repeatedadministrationof RegulatorandCitrinKalsoreducedbodyweight.Basedupthe results,theauthors (51) suggestedthatbecauseCitrimaxhaslow efficacy,humanstudiesthatusedCitriMax (47,48,50) likelyfound noresultsbecausethedosewastoolow.Evenwiththesefindings, however,itisimportanttokeepinmindthattheresultsofstudies usinganimalmodelsthathaveshownpositiveeffectsofHCAon foodintake,fatoxidation,andbodyweightlosshavenotnecessarilybeenreflectedinhumanstudies.Althoughmoreresearchthat examinestheeffectofHCAonweightlossandbodycomposition usinghigherdosesandforlongerperiodsoftimeiswarranted, mostofthecurrentresearchsuggeststhatitisanineffectivedietary weightlosssupplementwheningestedalone.

3.4.ConjugatedLinoleicAcid

Conjugatedlinoleicacid(CLA)isacollectivetermusedto describeagroupofpositionalandgeometricallyconjugated(i.e., alternatingsingleanddoublebonds)isomersoflinoleicacid[afatty acid(FA)]thatarenaturallyfoundinanimalfat,dairy,andpartially hydrogenatedvegetableoils (52,53).CLAisalsosoldcommercially asadietaryweightlosssupplement.MostCLAproductssoldOTC

havea40%:40%contentof cis-9,trans-11(c9t11)FAand trans-10, cis-12(t10c12)FA;theremaining20%istypicallycomposedof otherconjugatedFA( 1%–4%)andothernonconjugatedFA ( 15%–19%).Thec9t11CLAisomeraccountsfor85%to90% ofthetotalnaturalCLAcontentinthediet,whereasdietaryintake ofthet10c12isomerisnegligible (54).WhenthesetwoCLAisomers arecombinedinapproximatelyequalamounts,severalanimalstudieshaveshownstrongevidencethatCLAhasanticarcinogenicand antiatherogeniceffects,aswellaspositiveeffectsonbodycompositionandbloodlipidprofiles (41,52,53,55).Themechanismsof actionthatmayexplainhowCLApromotesweightlossarenot wellunderstood,butithasbeentheorizedthatitmayelicitpositive effectsonbodycompositionby:1)inhibitinghormone-sensitive lipoproteinlipasewhich,inturn,inhibitslipogenesis(fatsynthesis);

2)promotingadipocyteapoptosis(programmedcelldeath);3)preventingtriglcyceride(TG)accumulationinadipocytes;4)downregulatingtheexpressionofleptin;and5)modulatingglucose andfatmetabolismtoincreaseenergyexpenditure (56).Itiswell documentedthatCLAelicitsfavorableeffectsonbodycomposition andlipidprofilesinanimals;however,studiesontheeffectofCLA onbodyweightandbodycompositioninhumanshaveproduced conflictingfindings.

TriconandYaqoob (53) reviewed18studiesthatexaminedthe effectofbodyweightandbodycompositionusinghumansubjects andfoundthattheresultsweremuchlesspromisingthanthose foundforanimalstudiesusingmiceandpigs.Theamountusedin thestudiesreviewedrangedfrom0.7to6.8g d–1,mostofwhich containeda1:1mixtureofc9t11andt10c12CLAisomers.Ofthe 18studies,4demonstratedmodestreductionsinfatweight,2studies weredeemedinconsistentbecauseadose-responserelationwasnot found,andtheremaining12studiesshowednoeffectofCLAon bodycomposition (53).AlthoughfourstudiesreviewedbyTricon andYaqoob (53) didshowpositiveresultsforCLAonbody composition,uponcloserexaminationsomeofthefindingsare lessthandramatic.Forexample,Riserusetal. (57) examined theeffectofCLA4.2g d –1 for4weeksonabdominalfatand cardiovascularriskfactorsin25obesemenwithsyndromeXtype symptoms(i.e.,abdominalobesity ,hypertension,dyslipidemia, impairedfastingglucose)andreportedasignificant( p =0.04)

decreaseinsagittalabdominaldiametercomparedtoplacebo. However,thechangewas < 1cm(–0.57cm),andtherewerenosignificant differencesbetweengroupsforbodyweight,waistcircumference,waistto-hipratio,orbloodlipidconcentrations[cholesterol,highdensity lipoprotein(HDL),lowdensitylipopotein(LDL),TG]following supplementation.

Inanotherstudyshowingpositiveresults,Gaullieretal. (56) reportedthatsupplementationwithtwoisomersofCLAfor1year reducedbodyfatinoverweight(BMI25–30kg m2),butotherwise healthyadultmenandwomen(n =180).Intheirstudy (18),60subjectsingestedTG-CLA4.5g d–1 (n =60),FA-CLA4.5g d–1 (n =61),oraplacebo(oliveoil4.5g d–1)(n =59).After1yearof supplementation,bothCLAgroupsdemonstratedsignificant decreasesinbodyweight( FA-CLA,–1.1 – 3.7kg; TG-CLA, –1.8 – 3.4kg)comparedtoplacebo( 0.2 – 3.0kg),whichrepresents anapproximateweightlossofonly2.4to4.0lbovertheentireyear (0.20–0.33lbpermonth).Thefactthatthestandarddeviationis greaterthanthemeanchangevalueforeachgroupalsosuggeststhat theremayhavebeenconsiderablevariationinbodyweightexhibited bythesubjectsduringthe1-yearperiod,withsomesubjectslikely demonstratingnotableincreases.

Incontrast,Triconetal. (55) usedacrossoverdesigntoexamine theeffectofthreedosesofhigh-gradec9t11(0.59,1.19,or2.38g d–1) andt10c12CLA(0.63,1.26,or2.52g d–1)forthreeconsecutive 8-weekperiodsseparatedbya6-weekwashoutperiod.Theresults showedthattherewasnosignificanteffectofeitherisomeronbody weight,BMI,orbodycomposition(viaskinfoldmeasurements andBIA)atanydose.Inagreement,Malpuech-Brugereetal. (52) alsoreportednoeffectofhighgradec9t11ort10c12CLAsupplementationatdosagesof1.5or3.0g d–1 administeredinadairydrink for18weeksonbodyweightorbodycomposition(viaDEXA)in81 overweightmen.

Althoughanimalstudieshaveprovidedstrongevidencetoindicate thatCLAhaspositiveeffectsonbodycomposition,itspotentialasan antiobesitytreatmentforhumansismuchlesspromising.Brownand McIntosh (41) suggestedthattheconflictingfindingsinhuman researchmaybedue,inpart,tothefactthatthemechanismofaction ofCLAisisomer-specificandthatthedosagesusedinhumantrials aremuchlessthanthoseusedinanimalstudies.Researchfromtheir

ownlaboratory (41) hasshownthatthet10c12CLAisomer decreaseshumanadipocyteTGcontentanddifferentiation,whereas thec9t11isomerincreasesTGaccumulationandadipocyte-specific geneexpressioninhumanfatcells.Inarelatedstudy,Triconetal. (55) showedthatthesesametwoCLAisomersalsohadopposing effectsonbloodlipidprofilesinhealthyadults,witht10c12resulting inincreasesintheLDL:HDLcholesterolandtotalHDLcholesterol ratios,whereasc9t11resultedinadecreaseintheseratios.Giventhat thec9t11andt10c12CLAisomersappeartohaveoppositeeffectson adiposity,BrownandMcIntosh (41) speculatedthattheinconclusive findingsinhumanstudiescouldbeduetotheuseofmixedisomersfor supplementation,whichmaynegateeachotherand,thus,resultinno significantchangeinbodyfat.Althoughfuturestudiesarewarranted toexaminetheeffectofisomer-specificdosesofCLAonbodycomposition,thereisnoconclusiveevidence,todate,tosuggestthat supplementationwitheitheramixtureofCLAisomersorsingle CLAisomersresultsinanymeaningfuleffectsonbodycomposition inhumans.

3.5.Calcium

Calciumistypicallyknownforitsroleinmaintainingbone densityandbonemineralhomeostasis.However,evidencenow suggeststhatcalciummayalsoplayaroleinadipocytelipid kineticstohelpdecreasebodyfat.Thepotentialofcalciumto induceweightlosswasfirstreportedduringthelate1980swhen Metzetal. (58) demonstratedareductioninfatweightinhypertensiveratsthatwereingestinghighamountsofcalciumand sodium;andBurseyetal. (59) foundthatincreasingdietary calciumfrom0.1%to2.0%resultedinlessweightgaininboth leanandobeseZuckerrats.Interestingly,itwasnotuntil1999 withthepublicationoftwoabstracts (60,61) thatmoreresearch begantofocusonthisunexpectedrelationshipbetweencalcium andbodyfat.

Theexactmechanismofactionbywhichcalciumexertsitseffecton bodyweightisnotentirelyclear,however,Zemeletal. (62) proposed thatlowdietarycalciumintakestimulatesdihydroxyvitaminDand parathyroidhormone(PTH)which,inturn,simulatetheuptakeof calciumintoadipocytes.Thisinflux ofintracellularcalciumresults inincreasedlipogenesis(i.e.,fatsynthesis)anddecreasedlipolysis

(i.e.,fatbreakdown),withthenetresultbeinganincreaseinbodyfat. Incontrast,highdietaryintakeof calciumhastheoppositeeffectand inhibitsvitaminDandPTH,whichdecreasestheuptakeofcalcium intotheadipocytesand,inturn,increaseslipolysisanddecreases lipogenesis,resultinginweightloss (62).

Thediscoveryofanapparentinverserelationshipbetweendietary calciumintakeandbodyweighthasledtoseveraloriginalinvestigationsandthereevaluationofpreviouslypublisheddatatoexamine theefficacyofbothdietaryandsupplementalcalciumonbody composition.Forexample,Daviesetal. (63) reanalyzedfiveclinical trialsthatincluded780womenbetweentheirthirdandeighthdecades oflifeandfoundthatineachofthefivestudiesthecalcium/protein rationegativelypredictedBMIand/orchangeinbodyweight.In contrast,Shapsesetal. (64) combineddatafromthree25-week randomized,double-blindplacebo-controlledtrialstoreexamine theeffectofcalciumsupplementation(1000mg d–1,calciumcitrate) onbodyweightandfatweightinpre-andpostmenopausalwomen (N =100).Theyfoundnosignificantdifferencesforcalciumversus placeboandnosignificantactionofcalciumsupplementationon menopausalstatus.Theresultsfromseveraloriginalinvestigations (65

69) designedspecificallytoexaminetheeffectofcalciumon bodycompositionhavealsoresultedinconflictingfindings.

Zemeletal. (69) placed32obesesubjects(ages18–60years;BMI 30.0–39.9kg m2)onacalorie-restricteddiet(500kcal d–1 deficit) for24weeksandrandomizedthemtoastandarddiet(400–500mg dietarycalciumperdaysupplementedwithplacebo),ahigh-calcium diet(standarddietwithcalciumcarbonate800mg d–1),orahigh dairydiet(dietarycalcium1200–1300mg d–1 intheformofdairy productssupplementedwithplacebo).Theresultsshowedthatall subjectslostbodyweightasaresultofcaloricrestriction;however, thoseassignedtothehighcalcium(supplemental)andhighdairy dietlost8.58 – 1.1kgand11.07 – 1.63kgofbodyweight,respectively,whichwasgreaterthanthelossdemonstratedbythesubjects onthestandarddiet(6.60 – 2.58kg).Asimilartrendalsooccurred forfatweight,withthehighcalciumandhighdairygroupsexperiencinggreaterlosses(5.61 – 0.98kgand7.16 – 1.22kg,respectively) comparedtothoseonthestandarddiet(4.81 – 1.22kg),witha significantportionofthefatlossineachgroupoccurringinthe trunkregion.AlthoughthesamplesizeinthestudybyZemeletal.

(69) wasrelativelysmall,theirfindingsindicatethatcalciumsignificantlyaugmentsweightlosssecondarytocalorierestrictionand thatdairyproductshaveagreatereffectthansupplementalformsof calcium.Basedontheseresults,aswellastheirfindingthatcalcium regulateslipogenesisandlipolysisintheadipocyte (62),Zemeland colleaguessubmittedapatentfortreatingobesitywithcalcium (70).

IncontrasttothefindingsofZemel etal.(69),severalstudieswitha largernumberofsubjects (65–68) havefailedtofindasignificant relationshipbetweencalciumintakeandbodycomposition.Gunther etal. (67) determinedtheeffectoflong-term(1year)supplementation withdairycalciumon135healthy,normalweightwomen(ages18–30 years).Theyfoundnosignificantchangesinbodyweightorfatweight betweengroupsthatconsumedacontroldiet(< 800mg d–1),amoderate dairydiet(1000–1100mg d–1),orahighdairydiet(1300–1400mg d–1).

Inagreement,Haubetal. (68) showedthatacalcium-fortifiedbeverage (1125mg d–1)supplementedover1yearhadnoeffectonbodyweight,fat weight,orabdominalfatin37postmenopausalwomen(ages48–75 years)eventhoughsupplementationmorethandoubledthecalcium/ proteinratio.Barretal. (65) alsoshowedthatthreeservingsofmilkper dayhadnoeffectonweightlossorothermetabolicriskfactorsinolder adults;andina1-yearstudyusing178preschoolchildren(ages3–5 years),DeJonghetal. (66) reportedthattherewerenosignificant correlationsbetweenpercentbodyfatandfatmasschangesand dietarycalciumintake,andnosignificantdifferencesbetweencalciumsupplementedgroups(1000mg d–1)versusplacebo.

Thereisanoverwhelmingamountofevidencethatcalciumhas beneficialeffectsonbonehealthandmetabolism.However,itsroleas aweightlosssupplementhasnotbeenfirmlyestablished,asretrospectivestudiesandoriginalinvestigationshaveresultedinconflicting findings.Therefore,morelarge-scaleclinicaltrialsarenecessaryto helpgainabetterunderstandingoftheroleofcalciumonadiposity usingawiderangeofsubjectpopulations.Althoughmanyindividuals whoareattemptingtoloseweighttendtoeliminatedairyproducts, noneofthestudiesreviewedhereinreportedasignificantincreasein bodyweightfollowingincreasedcalciumintake.Therefore,solongas energyintakeislessthanenergyexpenditure,itdoesnotappearthat theadditionofcalcium-richdairysourcestothedietwouldleadto anysubstantialincreasesinbodyweightandmayhelpmanyindividualsmeettheirdailycalciumrequirements.

4.SUPPLEMENTSTHATINCREASESATIETY

4.1.Glucommannan,GuarGum,andPsyllium

Anumberofdietaryweightlosssupplementscontainwatersolublefiber,whichistheorizedtoabsorbwaterinthegut,thereby decreasingfeelingsofhungerand,inturn,reducingfoodintake, whichultimatelyleadstoweightloss.Examplesofsomeofthemost commonsourcesoffiberintheseproductsareglucomannan,psyllium,andguargum.

Glucomannan(Amorphophalluskonjac)isahighlyviscousdietaryfibernativetoAsiathatisderivedfromthekonjacroot(also knownaselephantyam);itiscomposedofapolysaccharidechainof glucoseandmannose(42).AnearlystudybyWalshetal. (71) that examinedtheeffectofglucomannan(3g d–1 8weekstakenbefore meals)onobesepatients( 20%ofidealbodyweight)foundthatit wasmoreeffectivethanplaceboforinducingweightloss,resulting inameanlossof2.49kg( 5.5lb).AmorerecentreviewbyKeithly andSwanson (72) alsoreportedthatatdosesof2to4g d–1 glucomannanresultedinsignificantweightlossinoverweightindividuals byincreasingsatiety.Moreover,itappearstobewelltolerated.

Thedietaryfiberguargum,derivedfromtheIndianclusterbean Cyamposistetragonolobus,isfoundinanumberofnaturalweight losspreparations.Todetermineitseffectivenessforreducingbody weight,PittlerandErnst (73) conductedameta-analysisof11 randomizedcontrolledtrialsthatrangedfrom3weeksto6months. Theyfoundthattherewasnosignificantdifferenceinoverweight subjectswhoreceivedguargum(7.5–21.0g d–1)comparedtothose whoreceivedplacebo(meandifferencebetweenguargumandplacebowas–0.04kg).Ofthe11studiesreviewed,7alsoreported severaladversegastrointestinaleffectsfromguargum,including flatulence,diarrhea,gastricpain,andnausea (73).Becauseofthe relatedadverseeventsandthefactthatitresultedinminimalweight losscomparedtoplacebo,PittlerandErnst (73) didnotrecommend guargumasadietarytreatmentforweightloss.

TheresultsofastudybyBirketvedtetal. (74) thatexaminedthe effectofthreedietaryfibersupplementscontainingglucomannan and/orguargumonweightlosswereconsistentwiththefindingsof thestudiesdescribedabove.Intheirstudy (74),176menandwomen randomlyreceivedoneofthreedietaryfibersupplementsoraplacebo

for5weekswhileconsumingabalanceddietof1200kcal d–1.Thefiber supplementsallcontainedglucomannanandincludedChrombalance1 (glucomannan),Appe-Trim1 (glucomannanandguargum),andGlucosahl1 (glucomannan,guargum,andalgninate).Theresultsshowed thatallthreefibersupplementsinconjunctionwiththedietresulted insignificantlymoreweightlossthandidtheplaceboanddietalone; however,therewerenosignificantdifferencesbetweenthethree treatments(3.8 – 0.9,4.4 – 2.0,and4.1 – 0.6kgforChrombalance, Appe-Trim,andGlucosahl,respectively),whichresultedinanaverageweightlossofapproximately0.8kg wk–1.Thesefindingssuggestthatglucomannaniseffectiveforinducingbodyweightlossand thatguargumandalginatehavenoaddedeffect (74)

Psyllium,derivedfromthehusksofripeseedsfromtheplant Plantagoovata or Plantagopsyllium(26,42),istheactiveingredient inmanynonprescriptionlaxativesandfibersupplementsincluding thewellknownbrandMetamucil1.Althoughpsylliumhasbeen showntobeeffectiveforloweringtotalcholesterolandLDL cholesterol,itdoesnotappeartobeaseffectiveasotherfibertypes forreducingbodyweightandisassociatedwithgastrointestinal disturbances,includingbloatingandflatulence (75)

Dietaryfiberiswellknownforitsbenefitsoncolonhealthandis commonlyusedforthetreatmentofhighcholesterollevels (75) Although,thereissomeevidencetosuggestthatfibersupplements maybeusefulforincreasingsatietyandinducingweightloss,there appearstobeadifferenceintheefficacyofthevariousdietary fibersupplements,withglucomannanshowingthemostpromising effects.Therefore,furtherstudiesarewarrantedtoexaminethe safetyandefficacyofglucomannanasanadjuvanttreatmentfor weightlosstohelpdecreasethehighprevalenceofoverweightand obesityintheUnitedStates.

5.OTHERDIETARYSUPPLEMENTS

Otherdietarysupplementsthathavebeenpurportedtoinduceweight lossaseithertheirprimaryorsecondaryactionincludeherbalpreparationssuchasdandelion,bladderwrack,sunflower,germander,and St.John’swort;theprohormoneDHEA;ß-hydroxy-ß-methylbutyrate,

whichisametaboliteoftheaminoacidleucine;andyerbamate,which wouldhaveactionssimilartothoseofmahaung,citrusaurantium,and guarana (3,9).Stillothersincludelicorice,vitaminB5,medium-chain triglycerides,and L-carnitine (3).Researchregardingtheefficacyof thesesupplementsforweightlosshasprimarilyresultedinnonsignificant findingsand,insomecases,supplementationhasresultedinserious adverseeffects (3,9).Therefore,theuseofthesedietarysupplements asatreatmentforobesityappearstobelargelyunwarranted.

6.CONCLUSION

Althoughtheuseofdietarysupplementsforweightlossiswidespread,theevidencefortheirefficacyandsafetyisnotoverwhelmingly convincing.Inmostcases,theseproductseitherelicitnomeaningful effectdespitethemanufacturer’s claims,orresultinchangesinbody weightandcompositionthatarecomparabletothosethatoccur througharestricteddietandexerciseprogram,whichcanresultin weightlossofupto1.5to2.5kg wk–1 (76).Thereissomeevidenceto suggestthatherbalformsofephedrine,suchasmahuang,combined withcaffeineorasanECAstackiseffectiveforinducingmoderate weightlossinoverweightadults.However,becauseoftherecentban onephedra,manufacturersmustnowuse‘‘ephedra-free’’ingredients, suchasbitterorange,whichdonotappeartobeaseffectiveandmay stillpossessthepotentialforadverse effects,particularlyinindividuals withpreexistingcardiovascularorcerebrovascularconditions.The dietaryfiberglucomannanalsoappearstoholdsomepromiseasa possibletreatmentforweightloss;however,moreresearchiswarrantedtoexamineitsefficacy,particularlywhenconsumedalone,to confirmthefindingsofpreliminaryresearch.

Itisimportanttorememberthatdietarysupplementsarenot regulatedlikedrugs,whichmustundergorigorousclinicaltesting usingbothanimalandhumanmodelsbeforeenteringthemarket. Therefore,themanufacturersofdietaryweightlosssupplements canmakeclaimsregardingtheeffectivenessoftheirproducts withoutnecessarilyconductingclinicalresearchtrialsfirst.Infact, inJanuary2007,theFederalTradeCommissionreceiveda$25 millionsettlementfromthemanufacturersoffourwell-known dietaryweightlosssupplementsfordeceptiveadvertising:Xenadrine

EFX,CortiSlim,TrimSpaTM,andOne-A-DayWeightSmartTM.

Whenmakingthedecisiontousedietarysupplements,itistherefore criticaltorelyonevidence-basedresearchand/ordieteticprofessionalsversusinfomercialsandadvertisementsfromfitnessand bodybuildingmagazines.

Thefutureofdietarysupplementsforweightlossdependsonwell designed,largescaleclinicalstudiesandmorestringentregulation ofthedietarysupplementindustry.Currently,however,thereare fewdietarysupplementsdesignedforweightlossthatcanberecommendedwithmuchconfidence.

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