Cannabis:tasteandflavor

JoelB.EpsteinDMD,MSD,FRCD(C),FDSRCS(E),Dipl.ABOMProfessorandDirectorCancerDen?stry,Cedars-SinaiHealthSystemandMedicalDirector,DentalOncology,CityofHopeNa?onalMedicalCenter

LosAngeles,CA

Inorelateddisclosures

Flavor: taste, smell, texture, temperature, vision Causes of Taste Change in Cancer Survivors: •  Cancer Therapy:

�  Surgery �  Radiation �  Chemotherapy �  Targeted therapies �  Immunotherapy

•  Supportive care/ analgesics/other medications •  Comorbidities •  Oral conditions Underreported; Understudied; Impactful

TasteChangeinCancerSurvivors

DoctorsvPa3entSymptomReportinBCChemotherapy

Physicianevalua3on(CTCAE) Pa3entReport

Bayo J, Prieto B, Rivers J. The Breast J 2015

A 10-item, CTCAE derived questionnaire was administered to 600 breast cancer pts in adj chemo. Comparison of physician and pt reports.

JAMA Oncology 2016

BurdenofTasteandSmellchanges

Oral hygiene Dental health Oral habits

TASTE CHANGE

immunosuppression

Malnourishment

food avoidance Diet change

↓perfomance status

ModifyCAtreatment

Cancer Cancer TX

Hyposalivation Mucositis

�  Limited studies (!) �  Most data in breast cancer (taste changes,

metallic dysgeusia, preference for sweet) � ↑ incidence with docetaxel (possible

symptom cluster with CIPN?) �  Impact on fatigue and quality of life! �  Persistance of the symptom after treatment

CHEMOTHERAPY-INDUCEDTASTE&SMELLChanges

TASTEANDSMELLAFTERHSCT

OkadaN,etal.SupCareCancer2016;24:3979-85

� Variableincidence:àima?nib13-40%àsorafenib15-30%àsuni?nib10-60%àeverolimus/temsirolimus10-20%àlapa?nib10%àvismodegib50-70%

TARGETEDTHERAPY:TASTEANDSMELLChanges

Tastefunc3onfollowingHNC:qualita3veresearch•  “Ea?ngismorethannutri?on…it’salsoaverypleasurable

experience….mydaughtersareboth,Iguessyouwouldcall“foodies”…itislikeanac?vityforusmorethanjustea?ngfoodfornutri?on,it’ssomethingthatwedoforfun.Weenjoyea?nggoodfoods.”(GS=1.54)

•  “Havinggonethroughacoupleofmonthsofonlydrinkingliquids…itmeansalot.Iliketoeat.”(GS=0.15)

•  “BeforecancerIatetolive,andnowIlivetoeat…IneverreallyappreciatedfoodinthewaythatIdonowthatIcaneatagain.It’sagijIappreciatealotmore.”(GS=0.21)

•  “Thetasteoffoodisofsignificantimportance…it’salmostuptherewithsexintermsofyouknow,whatitbringsfromalistofthingsyoucouldn’tlivewithout…”(GS=0.02)

•  GanzerH,etal.OralOncol2015

Taste

Evaluatecontentoffood&preventinges?onoftoxicsubstances•  Biner:detectssubmicromolarlevelsoftoxic/noxious

compounds•  Sour:warnsofnoxious/poisonousagents•  Sweet:iden?fiesenergy-richnutrients•  Salt:ensuresintakeforelectrolytebalance•  Umami:(savory/pleasure)

–  recognizesaminoacids(glutamate,aspartate);MSG

Chandrashekaretal,Nature2006444:288-94

Gusta3onSpecialisedepithelialcells:TongueSojpalatePharynxLarynxUpper1/3ofoesophagus

Eachtastebud:50-100taste-receptor

cells;lifespanof~10-14daysNosegrega?onoftastequali?esinthe

humantongueScon,CurrOpinNeurobiol200414:423-7Scon,Neuron200548:455-64Chandrashekaretal,Nature2006444:288-94

Gusta3on–sugar/aminoacidreceptorsSweetandaminoacids–determinedbyT1Rgenes(T1R1,T1R2&

T1R3)•  T1Rreceptorsfunc?onasdimers

•  T1R1+3–aminoacids(MSG&aspartate;“umami”)

•  T1R2+3–sugars(includingsaccharin)Func?onasGproteincoupledreceptors(GCPCR)Tunedtoindividualcompounds(siteofligandbindingdeterminesrecogni?onofquality)KnockoutofT1R2+T1R3causeslossofsweetSweetpreferencedeterminedbyT1R

Scon,CurrOpinNeurobiol200414:423-7Scon,Neuron200548:455-64Chandrashekaretal,Nature2006444:288-94

Gusta3on–biTerreceptors

BiTer–determinedbyT2Rgenes(~25)DifferentT2Rreceptorsrecognise

differentcompoundse.g.hT2R14–picrotoxininhT2R28–phenylthiocarbamideMostT2RsexpressedonthesameTCR-

thecellsarebroadlytunedhighaffinitybinerreceptorsonasinglecell

Scon,CurrOpinNeurobiol200414:423-7Scon,Neuron200548:455-64Chandrashekaretal,Nature2006444:288-94

Taste–saltandsourSalt: sodiumchannels?(receptorunknown)Sour: Acidsensingprotonchannels?

Calciumchannels? Chloridechannels? Potassiumchannels? PKD2L1(involved)

Vhandrashekaretal,Nature2006444:288-94

Umami

•  Savory,desirable,enjoyable,goodtaste•  intensifiesothertastesensa?ons•  Aminoacidrichfoods,freeglutamate•  Glutamatereceptors:

–  T1R1/T1R3;mGluR4,mGluR1

FreeFaTyAcidReceptors(FFAR)•  Fanytaste:roleenergyintake&taste/texturepreferences•  Role:energyintake&appe?teviasecre?onofinsulin&incre?n&

sympathe?cs?mula?on•  HaraT,KimuraIetal.RevPhysiolBiochemPharmacol2013;Apr30

•  FFAR:G-proteincoupledreceptors(GPCR)oralcavity&GIT•  Medium&longchainFFARGPR40(Ffar1)&GPR120;ontastebud

typeI,IIcells•  Animalstudy:FA:tes?nglinoleicacid&oleicacid•  FFAalsomodifybinertaste,butnotmediatedbyGPR40/120

•  CartoniCYasumatsuK,OhkuriTetal.JNeurosci2010;30:8376-82

SpicyTaste•  C-fibers/Aẟfibers/neuropathy

Tastesignaling&Neuropep3deSecre3on•  Sweet,biner,umami↑calciumhomeostasismodulator1

(CALHMI)ionchannel&↑ATPreleasefromtastebud•  TarunoA,VingtdeauV,OhmotoMetal.Nature2013;495;223-6

•  Tastes?mula?onyieldsdifferentreceptorcellsignaling•  Tastant-↑ATP&effectviaK+&Ca+channels•  Sweet/umami:↑GLP-1,NP-Y↓glucagon•  Sour/salty:↑NP-Y,no∆GLP-1,glucagon•  Biner:no∆NP-Y,GLP-1,glucagon•  *NPY:neuropep?de-Y,GLP-1:glucagon-likepep?de

•  GeraedisMC,MungerSD.JNeurosci2013;33:7559-64

Tastesignaling&Neuropep3deSecre3on•  Sweet,biner,umami↑calciumhomeostasismodulator

1(CALHMI)ionchannel&↑ATPreleasefromtastebud•  TarunoA,VingtdeauV,OhmotoMetal.Nature2013;495;223-6

•  Tastes?mula?onyieldsdifferentreceptorcellsignaling•  Tastant-↑ATP&effectviaK+&Ca+channels•  Sweet/umami:↑GLP-1,NP-Y↓glucagon•  Sour/salty:↑NP-Y,no∆GLP-1,glucagon•  Biner:no∆NP-Y,GLP-1,glucagon•  *NPY:neuropep?de-Y,GLP-1:glucagon-likepep?de

•  GeraedisMC,MungerSD.JNeurosci2013;33:7559-64

Gusta3on–organisa3onofreceptorsSpa?alsegrega?onofsensesnot

evidentinhumans,althoughsomenervesthatsynapsetoT1Rprojecttorostralaspectsofthesolitarytractnucleus(andT2Rtocaudal)

Possiblesegrega?oninmice,but

nothumansScon,Neuron200548:455-64

AlteredtasteOralandURTdisease(infec?on,malignancy)BurningmouthsyndromeHyposaliva?onIatrogenicDrugs:Many!

Chemotherapy Cyclophosphamide,Dacarbazine,Daunorubicin Doxorubicin,5FU,MTX,Pla?num,Vincaalkaloids

SystemicdiseaseCNS(temporallobetumors,epilepsy)GERDetcRenal–chronicfailureHepa?cfailureDeficiencystates(zinc)Psychiatric(includinghypochondriasis)

SymptomBurdeninHNC:oralenergy&proteinintake•  43HNCpts,cross-sec?onal,prospec?vestudy•  Medianage60;97.7%Caucasian,81%M;HNCStageIII28%,StageIV63%;

AllRTHNC,mean6862gy;CT93%,•  feedingtube86%;tobacco81%,alcohol46%•  VHNSS2.024hrdietdietaryrecall,protein,energyintakeusing

Mypyramid.com•  GanserH,Touger-DeckerR,ParronJ.JSCC2012;July24

AlteredtasteandheadandneckmalignancyCommon–upto100%-butmayarisebeforetreatment–duetotumor.

Reviewsuggestedupto89%ofpa?entspriortoRThavesometastedisturbance

RuoReddaandAllisCancTreatRev200632:541-7

Subjec?veassessmentpriortoRTsuggestedpar?allossofbiner(35%),salt(18%)and/orsweet(6%)

Maesetal,RadiotherOncol200263:195-201

Tastechangebegins~3weeksandinsomestudiesimprovesby8weeksofTX

YamashitaH,NakagawaKetalIntJRadiatOncolBiolPhys2006;66:1422-9YamashitaH,NakagawaK.Etal.2008

Secondmostcommoncomplaintinpa?entsajer3and6monthspost-RTHNC

MurphyBA,EpsteinJB2011

Radiotherapy-associatedtastechangeEffectsontastequalityvariable

LossofsweetfirstBinerandsalt>sweet4“conven?onal”quali?esequallyaffectedUmamiaffected

Mossmanetal,19795:521-8

Maesetal,RadiotherandOncol200263:195-2001Zhengetal,FukuokaIgakuZasski200293:64-76

Shietal,AurisNasusLarynx200431:401-6Yamashitaetal,HeadandNeck2006June508-16RuoReddaandAllisCancTreatRev200632:541-7

YamashitaH,NakagawaKetal.2008Possiblyreflec?ng:

MethodofassessmentRadiotherapydose&technique

Lossofumamimayhavethestrongestcorrela?onwithQoLShietal,AurisNasusLarynx200431:401-6

Alteredtaste:headandneckmalignancyRadiotherapytastechangeshighlyvariable:

“Soapy” “Burning” “Oily” “Powdery” “Chemical” “Awful”

Impactoftastechange: Reduceddietaryintake Weightloss ReducedQoL Poor(er)outcomes

Sandowetal,2006JDentRes200685:608-611

Radiotherapy-associatedtastechangeTemporaleffectsvariable

Maximumlossoftasteat2/12,returnedby24/12

Maesetal,RadiotherOncol200263:195-201Tastedisturbances?llreportedat7yearspost-RT

Mossmanetal,IntJRadiatOncolBiolPhys19828:991-7)Normaltasteby6/12

Zhengetal,FukuokaIgakuZasski200293:64-764tastecuesreducedby3/52,returnedtonormalby4-8/12

Yamashitaetal,HeadandNeck2006June508-5164tastecuesreducedwithin1/12,normalby6/12

Sandowetal,2006JDentRes200685:608-611Possiblyreflec?ng:

MethodofassessmentRadiotherapydosageRadiotherapytechniquePa?entnumbers

TasteChangeinBreastCancer•  25pts,TXdocetaxelorpaclitaxelorwithin6monthsofCT•  mostcommonPRO:tastechange(8/10docetaxel;3/15paclitaxel)•  Dysguesia:55%;badtaste27%,hypoguesia45,hyperguesia9%•  Tastechangeaffectoralintake,irregularea?ngschedule,↓interestmeal

prepara?on•  Behaviors:newrecipes,stronglyflavoredfoods,foodcravings,candybefore

meals,addinglemon,sweeteneddrinks,plas?cutensils,drinkwithstraw,brushteeth&tongue,bakingsoda/saltrinsing,an?bacterialmouthwash

•  Selfmanagement:↑caloricintake,poorea?ngbehaviors,↑weight&associa?onofobesitywithpooroutcomes

•  SpeckRM,DeMicheleA,FarrarJTetal.SupportCareCancer2013;21:549-55

Nutri3onalissues&bodyweightinallo-BMTlong-termsurvivors•  441BMTsurvivorsofBMT,NSWAustralia

Symptom <2yrsBMTn=58

2-5yrsBMTn=159 >5yrsBMTn=224

Nausea 8(13.8%) 21(13.2%) 21(9.4%)

Vomi?ng 3(5.2%) 10(6.3%) 6(2.7%)

Cons?pa?on 10(17.2%) 15(9.4%) 41(18.3%)

Diarrhea 11(19.0%) 29(18.2%) 43(19.%)

Tastechange 26(44.8%) 53(33.3%) 55(24.5%)

Smellchange 19(32.8%) 34(21.4%) 35(15.6%)

Poorappe?te 16(27.6%) 29(18.2) 40(17.9%)

Mouthulcers 21(36.2%) 46(28.9%) 77(34.4%)

Drymouth 26(44.8%) 65(40.9%) 93(41.1%)

Median#symptoms 2(0-9) 1(0-9) 1(0-7)Smith J, Poon C, Gilroy N et al. Support Care Cancer 2017;25:137-44

PrevalenceofCT-relatedproblems&HRQOL•  363(43%responserate);mixeddiagnoses,CTfor“cure”•  Mostprevalentc/o:fa?gue(90%);changeinsmell/taste(69%)

•  RelatedtoHRQOLsocial/emo?onaldomains•  WaglandR,RichardsonA,EwingsSetal.SupportCareCancer2016:24:4901-11

Rank Problem %affected Severe Moderate Mild

1 Fa?gue 90% 11% 37% 42%

2 Changeintaste/smell 69% 11% 24% 34%

4 Troublewithsleep 55% 9% 21% 29%

5 Lowmood 56% 4% 16% 30%

9 Lossappe?te/interestinfood 54% 5% 17% 32%

10 Concentra?on,forget,confused 52% 3% 11% 38%

12 Soremouth/tongue 46% 6% 12% 20%

13 Diarrhea 39% 4% 12% 28%

Oralcomplaints&dentalcareinSCT•  Survey:101SCTadultpts(37%allo)(95%responseofsurvivors[possible

bias]);•  88pa?entsden?sts(59%response)•  TimesinceSCTmean19mos(range:8-31)•  AlloSCT:Meanmaxmucosi?sscore6.6(sd=3.3)

Bos-denBraberJ,Po�ngCMJ,BronkhorstEMeta.JSCC2015;23;13-9

Complaints Acute Chronic

Drymouth 70% 56%

Tastechange 86% 33%

Mucosi?s 96% 11%

Trimsus 14% 7%

TasteandSmellinSCT

•  23pts(16atall?mepoints):baseline,Day30,Day80•  Taste:0.32MNaCl;0.0056&0.018Mcitricacid;0.3Msucrose;

Olfactory:NIHtoolboxOdorIden?fica?ontest;QOL•  ↓sensi?vityforNaCl,citricacidonD30•  ↑sensi?vitysucroseD30•  TastelargelyrecoveredbyD80•  OlfactoryscoresunchangedbaselinetoD30•  QOLimprovedbyD80,althoughsomeoralsymptomsremain

•  AbasaeedR,ColdwellSE,LloidME,etal.JSCC2018;Apr27

Oral health & QOL in cancer patients in hospice •  104terminally-illCApts(2.5-3wklifeexpectancy);medianage

66.0;M40.8%,F59.2%•  OralProblemsScale(OPS):xerostomia,oralpain,tastechange&

func?onal/socialimpactonQOL;oralexam•  Hyposaliva?on(98.1%),erythema(50%),ulcera?on(20.2%),fungal

infec?on(35.6%),otheroralproblems(44.2%).•  Xerostomia,tastechange&oralpainimpactQOL(p<0.001,<0.042

&p<0.001,respec?vely)•  Oralpainsignificantsocialimpact(p<0.001);ulcers↑pain•  Erythemaassociatedwithfungalinfec?on&ulcera?on(p<0.0001)

•  FischerDJ,EpsteinJB,YaoY,WilkieDJ.SuppCareCancer2013

Flavor•  combina?onofsensoryfunc?ons:

•  Taste,texture,temperature,smell,visual,memory•  Basicquali?es:Sweet,biner,salty,sour,umami•  Otherquali?es:fat,spicy,water•  Umami~good/desirableflavormayhavestrongestcorrela?onwithQOL•  Impact:

–  Interestinfood–  alteredfoodintakeleadingtodietarydeficienciesorweightloss/

weightgain–  Impairedqualityoflife

Chandrashekar J, Hoon MA, Ryba NJ. Nature. 2006 Yamashita H, Nakagawa K et al. Oral Oncol. 2008 Shi HB, Masuda M, et al. Auris Nasus Larynx 2004 Murphy BA, Epstein JB. Head Neck 2011

FaTyAcidTaste•  Fanytastethoughttomediateimportantenergy

intake•  Medium&longchainFAreceptorGPR40(Ffar1)&

GPR120;ontastebudtypeI,IIcells•  Animalstudy:FAtes?nglinoleicacid&oleicacid•  IHC,nerverecording,behavioraloutcomeaffected•  FAalsoshowntomodifybinertaste,butnot

mediatedbyGPR40/120•  CartoniCYasumatsuK,OhkuriTetal.JNeurosci2010;30:8376-82

DietaryAdapta3ons/Maladapta3ons•  ↓quan?tyoffood•  ↓highfiberfoods•  ↓vitamin,mineral,protein&energy•  ↑fatcontent•  ↑caffeine&sugar•  ↑cariesriskImpact:

–  ↓interestinfood–  alteredfoodintake–  dietarydeficiencies,weightloss

ImportanceofOralHealthOutcomes:•  Oralhealthcondi?onsresultin:

•  Alteredfunc?on•  ↑Symptomburden•  ↓qualityoflife•  ↑costs

•  Oralhealthinfluencesgeneralhealth:•  Pain,taste,dysphagia;nutri?onaldeficits•  Aspira?onmaycausepulmonarydisease•  Periodon??sassociatedwithCAD•  Psychosocialimpact:pain,esthe?cs,socialfunc?on

•  ChangingExpecta?ons:•  ↑HNCinyoungeradults•  Reten?on&esthe?csofden??onisimportant

TasteinChemotherapy•  Consecu?vebreastCAptsadjuvantCT

–  baseline,6thcycle,6&12months•  TastedisturbancescommonduringCTv.baseline&v.tonoCT•  DuringCT:dysgeusia(metallicordrugtaste,33%)+hypogeusia

(22%)•  6monthsF/U:tastechange(20%)•  12monthsF/U:mostreportedtastechange:hypogeusia(16%)•  PI/GI↑ duringCT;mucosi?s:~20%,ulcer16%•  Tastethemostdistressingoralsymptomin22%duringCT,andin

10%at12months•  JensenSBetal.OralSurg2008

TasteChangeinBreastCancer•  25ptsondocetaxelorpaclitaxelorwithin6mosofCT•  mostcommonPRO:tastechange(8/10docetaxel;3/15paclitaxel)•  Dysguesia:55%;badtaste27%,hypoguesia45,hyperguesia9%•  Tastechangeaffectoralintake,ea?ngschedule,↓interestmeal

prepara?on•  Behaviors:newrecipes,strongflavoredfoods,foodcravings,candybefore

meals,addinglemon,sweeteneddrinks,plas?cutensils,drinkwithstraw,brushteeth&tonguefrequently,bakingsoda/saltormouthrinsing

•  Pa?entadapta?ons:some+/-:↑calorieintake,poorea?ngbehaviors,↑weight

•  SpeckRM,DeMicheleA,FarrarJTetal.SupportCareCancer2013;21:549-55

Taste&SmellChangeinCT•  OutPt518CTsubjects,varioussolidCA,ques?onnaire•  TSC:75%,>♀ 79%v♂59%,youngerpts•  TSC>breastCA;CT:cyclophosphamide,5FU,epirubicin;

venorelbine•  Tastechange:salty41%,sweet36%,biner24%,sour21%,

other48%•  Smellchange:49%,greatestperfume,cookingsmells•  ImpactofTSCassociatedwith(OR):

nausea4.0,vomi?ng1.7,oralproblems4.0,appe?teloss3.2,depression1.8

BernhardsonB-M,TischelmanC,RutqvistLE.SupportCareCancer200816:275-83

Taste&Olfac3oninBCpa3ents•  69BCpa?ents,meanage52.4yrs,24post-

menopausal,post–sx62,pre-CT•  Symptoms,smell(“Snffin’S?ks”)&tastetes?ng

(tastestrips)•  Resultscomparabletonorma?vedata:•  Nodifferenceinodorthreshold,odordetec?on,↓sensi?vityforsour,nochangeforsalt,sweet,biner;↑Tsizeassociatedwith↓smell,butnottaste;correla?onwithbinertaste&Her2+

•  SteinbachS,HundtW,ZahnertTetal.SupportCareCancer2010;18:707-13

Tastechangeincancerpa3ents

Under-reportedInfluenceofxerostomia:Correla?onspossible

MossmanetalIntJRadiatOncolBiolPhys19828:991-7Inokuchietal,Prac?caOto-Rhino-Laryngologica200295:1091-6

Zhengetal,FukuokaIgakuZasski200293:64-76Tonguevolume:Correla?onssuggested

Fernandoetal,ClinOncol(RCollRadiol)19957:173-8Yamashitaetal,HeadandNeck2006June508-516

Variability:unusualreportoflongtermcompletelossdespite½

tonguebeingsparedSaitoetal,Radia?onMedicine200220:257-60

�  Avoid use of metallic utensils �  ↓ food with metallic or bitter taste (eg: red meat,

coffee, tea) �  ↑ high-protein, mildly flavored foods (chicken, fish,

dairy products, eggs) �  ↑seasoning & spices to enhance flavors �  Serve foods at cold temperature �  Practice good oral hygiene �  If dry mouth provide saliva stimulation

1)StrategiestoImproveTasteandOdorAbnormali3es

�  Aim: to spare radiation of salivary glands, and reduce high dose RT to oral tissues when possible

2)IMRT

TherapyDietarycounselling/modifica?on

Seasoning,avoidunpleasantfoods,extenddietarychoice(pleasingcolor,form,smell,texture) PeregrinJAmDietAssoc2006106:1536-40

Foodprepara?on:spice/flavoring,increaseumamiflavorManagexerostomiaManageoraldiseaseZincsulphate

Reducedseverity&dura?onoftastedysfunc?on(18pa?ents)Ripamon?etal,Cancer199882:1938-45

Butbenefit(NS)observedinlargerstudy(169pa?ents;lowerdose)Halyardetal,IntRadia?onOncologyBiolPhys200767:1318-22

Medica?ons:clonazepam,gabapen?n,megestrol,THC(Marinol),CBDThorneT,OlsonK,WismerW.JSCC2015;23:284

ManageOral/OPCpainandnauseaifpresent

SupplementsandTaste

•  Zincmaypromotetastebudprolifera?on•  Zinc(50mg/TID)mayaffecttasteindependentofserumzinclevels

•  HeckmannSM,HujoelP,HabigerS.JDentRes2005;84:35-8•  TakaokaT,SakukuraN,UedaC.AurisNasusLarynx2010;37:190-4

•  Alphalipoicacidmayaffectneuropathy•  Alphalipoicacid(200mg?d)fortastedisorders:91%improved,46%

resolved•  FemianoF,ScullyC,GomboF.IntJOMFSurg2002;31:625-8

�  Variable results in trials and non homogeneity

Study

Design Regimen Outcomes

Mossman,1978

Caseseriesn=7,postHNRT

25or100mg/dayzincfor2-6months

Improvementinobjec?vetaste

Silverman&Thompson,1984

Caseseriesn=30;postHNRT

100-150mg/dayzincforatleast1month

Improvementinsubjec?vetaste

Silvermanetal,1983

RCTn=19;preHNRT

18mgqdzincfordura?onofRT

Nodifferenceinobjec?vetasteEarlierrecoveryofsubjec?vetaste

Ripamon?etal,1998

RCTn=18;inHNRT

45mg/dzincun?l1monthpostRT

Lessobjec?vetastedisturbsduringRT.Earlierrecoveryofobjec?vetaste

Halyardetal,2007

RCTn=169;preHNRT

30mg/dzincDuringRTand1monthajer

Nodifferenceinsubjec?vetastedisturbanceNodifferenceinrecoveryoftaste

Lyckholmetal,2012

RCTn=58;duringchemo

220mgbidzincDuringchemo

Nodifferenceintastealtera?onsLonger?metorecoveryofsmellaltera?ons

�  Naturalsubstances:Synsepalumdulcificum(miraclefruit)àbindstotastereceptorstogenerateasweetsensa?on,thusmaskingsomeunpleasanttastesforashortdura?on

�  Chlorhexidinemayblockbinertastereceptor�  Marinol(THCcannabinoid)àenhancesfoodenjoymentviaendocannabinoidreceptorsthats?mulatetheorosensoryrewardpathway

�  Megace:20-40mgBID

4)OTHER:WHAT’SNEW?

ZincSulfateTrialinHNRT•  169ptsrandomizedtoZincSO445mg/dduringRT+1

monthajervplacebo•  TasteoutcomesassessedwithWickhamques?onnaire

(WickhamRSOncolNursForum1999;26:697-706)

•  73%onZincv84%reportedtastealtera?ons(p=0.16)•  Complextastechange:absence16%;biner8%;salt4%;

sweet5%;metallictaste10%;wrinencommentssoapy,oilyorburningtaste

•  HalyardMY,JatoiA,SloanJA,etal.IntJRadiatOncolBiolPhys2007;67:1318-22

•  Benefitsontastereported;tastetes?ng:tastethresholds•  Ripamon?C,ZeccaE,BrunelliCetal.Cancer1998;82:1938-45

Clonazepam

•  Gabanergicdrugsmodifytasteinanimalstudy•  Staros?kMR,RebelloMR,ConerKA.PLoSOne2010;5:e13639

•  Clonazpam:gabaAagonistaffecttastechangeassociatedwithBMS•  GrushkaM,EpseinJ,MonA.OralSurgOralMedOralPathol1998;86:557-61

THC&ChemosensoryDisorders•  46pts,advancedcancer;21completedstudy,11dronabinol

(Marinol)[THC],10placebo,RX18days•  2.5/5.0/10mgbid•  THCindicated:nausea,appe?te•  THCvplacebo:

–  ↑apprecia?onoffood73%v30%–  ↑taste55%v10%–  ↑appe?tep<0.05,↑sleepquality,–  nooverall∆QOL

•  BrisboisT.AnnOncol2011•  DeLucaMNeuropharmacol2012

Megestrol

•  RT+/-CTadvancedcaner;100pts,randomizedtrialmegestrol,PROs

•  46megestrolduringRT,4ajerRT;50placebox3mos•  nodifferenceacutetoxicityofRT;acutetoxicityassociated

withwghtlossplacebobutnotmegestrol•  megestrol↑appe?te,↑taste,↑wght(p=0.000);↑smell

(p=0.02);•  noSE

•  ErkurtE,ErkisiM,TunaliC.JExpClinCancerRes2000;19:431

•  Megace480mg/d•  ThorneT,OlsonK,WismerW.JSCC2015;23:284

Localmeasuresforblockingabnormaltaste

•  Foodprepara?on:–  herbs,spices,sweetener,acidtofood

•  Maskingagents:–  mouthwashes,candy,gum

•  Chela?ng/blockingagents:–  chlorhexidinemayblocksalt&binertaste

•  MiracleFruit(Synsepalumdulcificum):–  Glycoprotein“miraculin”,maymodifybinerandsourtosweettaste;blockbiner?

–  ThorneT,OlsonK,WismerW.SupportCareCancer2015;23:2843-51–  JomaI,RenkenRJ,TerHorstGJ.CancerTreatRev2015;41:179-86

–  SwamyKB,HadiSA,SekaranM.JMedFood2014;17:1165-9

Localmeasuresforblockingabnormaltaste•  Blockingbinertaste:TAS2R2receptorinhibitors;belowaffectsome

binerreceptors,butnotall–  4-(2,2,3-trimethyl-cyclopentyl)butanoicacid(GIV3727)–  gama-aminobutryicacid–  6-methoxyflavones–  probenecid–  MSG–  Na,Na-bis(carboxymethyl)-1-lysine(BCML)–  phospa?dicacid-tactoglbulin–  adnenosine5’-monophosphate

•  Blockingsweettaste:–  Lac?sole–  Gymnemicacid

•  Blockingsweetandbiner:Chlorhexidine•  Changingacidtosweet/blockingbiner:Miraclefruit?

MiracleFruit•  MiracleFruit(Synsepalumdulcificum):

–  Glycoprotein“miraculin”maymodifybinerandsourtosweettaste

–  BindstoT1R2-T1RXasantagonistatneutralpH&agonistatacidpH

–  JomaI,RenkenRJ,TerHorstGJ.CancerTreatRev2015;41:179-86–  SwamyKB,HadiSA,SekaranM.JMedFood2014;17:1165-9

–  KoizumiA,TsuchiyaA,NakajimaKetal.ProcNatlAcadSci2011;108:16819-24

–  Transduceacidictosweetsignal;maskunpleasanttaste,increasepalatabilityofsomefoods

–  TasteimprovementMiraculinvplacebox2wksin8CTptsonCTcrossoverstudywithimprovementonac?vearm

–  WilkenMK,Sa?roffBA.ClinJOncolNurs2012;16:E173-7

Preven3onandTreatmentofNeuropathy•  Noprovenprophylaxis•  Management:basedonpainmanagementofneuropathic

pain•  Centrallyac?ngmedica?ons:

–  clonazepam,gabapen?n,pregabalin,duloxetene,tricyclics•  Topicalagents:

–  receptorblocking/s?mula?ngagents–  centrallyac?ngmedica?ons,trial:baclofen,amitriptyline,ketamine

•  Nerves?mula?on

Evidence-BasedStrategiesforOralComplica3onofCancerTreatment

knowledgeoftheburdenofillness,preven?onandtreatmentoforalcomplica?onsassociatedwithcancertherapiesisnecessarysystema?creviewsofthemostcommonoralcomplica?onswerecompletedbytheOralCareStudyGroupofMASCC/ISOO.Managementrecommenda?onandguidelineclassifica?onwasbasedoncriteriaoftheASCOra?ngthelevelofevidenceandgradeofrecommenda?on

Resources:•  MASCC.com•  NCI-PDQ:oralcare,mucosi?s•  EpsteinJB,BaraschA.Tastedisordersincancerpa?ents:

Pathogenesis,andapproachtoassessmentandmanagement.OralOncol2010;46(2):77-81.

•  EpsteinJB,MurphyBE.Oralhealthandsurvivorship:Lateeffectsofcancerandcancertherapy.In:TheMASCCTextbookofCancerSuppor?veCareandSurvivorship.OlverIN(Ed).Springer,NewYork,ISBN978-1-4419-1224-42010;pp399-406.

•  DaviesAN,EpsteinJB(Eds).OralComplica?onsofCanceranditsManagement.OxfordUniversityPressInc,GreatClarendonStreet,OxfordOX26DP;OxfordUniversityPressInc,NewYork,2010;ISBN978-0-19-954358-8.

Dysgeusia(5)Dysgeusia:anabnormalorimpairedsenseoftaste,anunpleasantaltera?onintaste,oradistor?onor

perversionoftasteMeanweightedprevalenceofdysgeusia:

Chemotherapyonly=56.3%Radiotherapyonly=66.5%CombinedRTandCT=76%

Management:Zincgluconate(LevelofevidenceII,recommenda?ongradeC)Sugges?ontoNOTusezincgluconatetopreventdysgeusiainHNCpa?ents,althoughthisisbeneficialinanon-

canceridiopathicdysgeusiacohortAmifos?ne(LevelofevidenceII,recommenda?ongradeB)RecommendNOTtouseamifos?nesolelyforthepreven?onofdysgeusiaHNCpa?entsDietarycounseling(LevelofevidenceII,recommenda?ongradeB)

OralFungalInfec3on(6)Oralcandidiasis:themajorityoforalfungalinfec?ons

presenta?on:pseudomembranouscandidiasis,erythematouscandidiasis,hyperplas?ccandidiasis,angularcheili?sWeightedprevalenceofclinicaloralfungalinfec?on(alloralcandidiasis)

pre-treatment=7.5%duringcancertreatment=39.1%ajertheendofcancertherapy=32.6%

Weightedprevalenceoforalcandidiasisbycancertreatmentduringheadandneckradia?ontherapy=37.4%duringchemotherapy=38%

Weightedprevalenceoforalcoloniza?onwithfungalorganisms

Beforecancertreatment=48.2%duringcancertreatment=72.2%ajercancertreatment=70.1%.

Weightedprevalenceoforalfungalcoloniza?onbycancertreatment

duringchemotherapy=72.8%duringradia?ontherapy=74.5%

OralfungalInfec3on(5)ManagementWeightedprevalenceofclinicaloralfungalinfec?onduringcancertherapybypreven?ve

treatmentregimenFluconazole=1.9%Amphotericin=2.3%Itraconazole=1.5%Nysta?nalone=6%Clotrimazoleandnysta?n=14.6%Amifos?ne=28.9%Placebo/Notreatment=20.3%

Topicalan?fungalagents(levelofevidenceII,recommenda?ongradeC)inconsistentefficacyoftopicalan?fungalagentsasprophylaxis.Norecommenda?onpossible.Systemican?fungalagents(levelofevidenceI,recommenda?ongradeA)Recommendfluconazoleforthepreven?onoforalcandidiasisincancertherapy.

OralViralInfec3on(7)PrevalenceofHSVoralandperioralinfec?on:Weightedprevalenceinpa?entstreatedwithchemotherapyforhematologicmalignanciesPa?entswithoralulcera?ons–samplingoralulcera?ons=49.8%Weightedprevalenceinpa?entstreatedwithradiotherapyPa?entswithradiotherapyonly-samplingoralulcera?ons*=0%Pa?entswithradiotherapy+CT-samplingoralulcera?ons=43.2%ManagementAcyclovir&valacyclovirrecommendedforthepreven?onofHSV(Gradeofrecommenda?onA,levelofevidenceI)Preven?on:acyclovir(800mg/day)orvalacyclovir(500-1000mg/day)valacyclovirmaybesuperiortoacyclovirintoxicity&cost(dependsontherouteofadministra?onofacyclovir—POor

IV)*-Simpleprevalenceispresentedasthisfindingisbasedonasinglereportintheliterature.

DentalDisases(8)•  Weightedprevalencefordentalcariesinpa?entstreatedwithcancertherapy•  Allstudies=28.1%•  Chemotherapyonly=37.3%•  Post-radiotherapy=24%•  Postchemotherapyandradiotherapy=21.4%•  •  Weightedprevalenceseveregingivi?sinpa?entsundergoingchemotherapy=20.3%•  •  Weightedprevalencedentalinfec?on/abscessinpa?entsundergoingchemotherapy=5.8%•  •  Management•  Recommendfluoridetopreventdentalcariesinpa?entswhoarepost-radiotherapy.Effec?veregardlessofthetypeofdeliverymethod.(LevelofEvidenceII,Gradeof

Recommenda?onB).•  •  Recommendchlorhexidinetoimproveoralhygiene,poten?alsideeffects:toothstaining,increasedcalculus,tastechanges(LevelofEvidence:II,Gradeof

Recommenda?on:B,)•  •  Suggesttheuseofresin-modifiedglassionomer,compositeresinoramalgamrestora?oninpa?entswhohavebeentreatedwithradiotherapy(LevelofEvidenceIII,Grade

ofRecommenda?onB).•  •  Noguidelinepossibleduetothelackofwelldesignedstudiesregardingthebenefitsoftoothpaste,pre-cancertherapydentalinterven?on,honey,andcheeseondental

health(LevelofEvidenceIII,Gradeofrecommenda?onC).• 

Osteoradionecrosis(ORN)(9)•  Weightedprevalenceinconven?onalRT=7.4%•  WeightedprevalenceinintensitymodulatedRT=5.2%•  WeightedprevalenceinRTandchemotherapy=6.8%•  Weightedprevalenceinbrachytherapy=5.3%•  •  Themajorityofcasesinvolvethemandible.•  •  Management•  •  Prac??onersshouldu?lizetheirclinicalexperienceandexper?seisdeterminingop?malmanagementfortheirpa?ents

rela?vetoORNofthemandibleorthemaxilla.•  •  Noguidelineispossibleregardingtheuseofprophylac?cHBOtherapyforthepreven?onofORNinpa?entsrequiringpost-

RTdentalextrac?ons•  (LevelofevidenceIII,recommenda?ongradeC)•  •  TheuseofsingletherapyHBOtherapyforthetreatmentofORNisNOTrecommended(LevelofevidenceII,

recommenda?ongradeB)•  •  Noguidelinespossibleforotherpreven?onandtreatmentstrategiesforORN• 

TreatmentforOralMalodor1•  Managementoflocaldentalpathosis

•  restora?ons,cariesorpulppathology;periodontaldisease;denturehygiene

•  Managementoforalsoj?ssuecondi?ons•  Diagnosis/ManagementofENTpathosis

•  sinusi?s,tonsoliths,postnasaldrip)

•  Dietarysugges?ons:•  Avoidodiferousfoods•  Avoidtobaccoandalcohol•  Reducetheconsump?onofredmeatanddairyproducts•  Avoidstayinghungry-healthysnacksbetweenmeals

•  Goodoralhygiene•  Homecareincludingbrushing,flossing,denturecare,tonguescraping•  Regularprofessionalcleaning

TreatmentforOralMalodor2•  Maintainmouthmoisture

–  hydra?on–  S?mula?on:sugarfreegum/candy–  Sialogogues

•  An?microbialmouthwashes–  Chlorinedioxide,cetylpyridinuimchloride,phenolicoil,zinc

chloride,triclosan,chlorohexidineetc•  Medicalevalua?onofsystemiccondi?ons

ManagementofOlfactoryDisorders Pharmacotherapy

•  Systemic&topicallyappliedcor?costeroidsformucosaledema/nasalpolyps

•  An?bio?cs,decongestants&an?histaminesforchemosensorylossduetosinusinfec?on&allergicrhini?s

•  Benzodiazepines,tricyclican?depressants,an?convulsantsmaybehelpful:–  clonazepam0.5-2mghs–  amitriptyline25-100mghs–  gabapen?n300-1,800mgperday

ManagementofOlfactoryDisordersSurgery•  Endoscopicnasal/sinussurgeryMiscellaneous•  counselingonsmoke&naturalgasdetec?on•  labelingoffoodtotrackspoilage•  Baseline&repeatchemosensorytes?ng*olfactoryfunc?onmaytakeyearsormaynever

recover,followingpost-viralinfec?onorheadtrauma

Conclusions:TasteandSmell

ImpactuponQoLKnownphysiologydoesnotmatchobserva?onsofpostRTtastedysfunc?on–

whyselec?veinquality?VolumeofRTmaycorrelatewithtastedysfunc?onSalivaryfunc?onseemsapartofthepresenta?on:(tastedysfunc?onresolves,

xerostomiadoesnotorxerostomiaresolvesandtastedoesnot)ZincsulphatehasuncertaineffectsMethodsthatlessen?ssuedamagemaybethewayforward(preven?on)

Summary:ReporttotheNa3ononStatusofCancer2013•  ↓Deathrates2000-2009:1.8%/yrM,1.4%/yrF;<14yrsage1.8%/

yr•  ↓ overalldeathsduetocancerforallbutmelanoma,liver,

pancreas&uterus•  2000-9↓incidenceoverallcancers0.7%/yrmen;stableinwomen,

↑0.6%children•  2000-9↑incidenceofHPVOPCwhitemen/women;vulvawhite&

blackwomen•  US:48.7%girls13-17HPVvaccinated,32%3doses;Canada

50-85%,UK/Australia70%•  Obesityrelatedto33%ofcancers

•  JemalA,SimardEP,DorellCetalJNCI2014;105

DietaryModifica3onsforCancerPa3ents

Diet TextureModifica3on

Regulardiet Allfoodsallowed

Dysphagiadiet,Advanced Soj-solidfoodsthatrequirechewing

Dysphagiadiet,mechanicallyaltered Cohesive,moist,semisolidfood,limitedchewingrequired

Dysphagiadiet,pureed Homogenous,cohesive,pudding-like

Liquiddiet Liquidsupplements

Epstein JB, Huhmann M. J Am Dent Assoc 2012;143:588-92

Na3onalDysphagiaDietDietConsistency Descrip3on

NDD-1(DysphagiaPureed) Soj,pudding-likeconsistency,smooth,nolumps

NDD-2(Dysphagiamechanicallyaltered)

Moist,soj,textured(eg:finelydicedmeats,soj-cookedvegetables,cannedfruit,moistcereals

NDD-3(Dysphagiaadvanced) Mostregularfoods,exceptveryhard,s?ckyorcrunchy

Liquidconsistencies

Spoonthick

thickenedtopuddingconsistency;remainonaspooninasojmass

Honey-like thickenedtoconsistencyofhoney,flowoffaspooninaribbon

Nectar-like consistencythatcoatsanddripsoffspoon

Thinliquids Allliquids

LiquidNutri3onalSupplementsType Descrip3on Examples

Readytodrinkliquidnutri?onal

Premixedliquid Ensure,Boost,Enlive,ResourceBreeze,IsopurePlus

Milk-based Poweraddedtomilk Carna?onInstantBreakfast(with/outsugar),Scndishake,proteinpowder

Disease-specificliquid Premixedliquid,diseasespecificingredients

Diabe?c:Glucerna,BoostGlucoseControlRenal:Nepro,Suplena,Renalcal

Modular Powderorliquidaddtofood(proteinorcaloricsupplement

Liquid:Benecalorie,Promod,Pro-statPowder:Beneprotein,UnjuryProtein

DietaryInterven3ons:Latecomplica3onsofHNCTherapyComplica3on DietaryInterven3on

LossofAppe?te Small,frequentmeals;limittonon-carbonatedbeveragesbetweenmeals,liquidsupplements

Tastechange Tartfood(citrusiftolerated),flavorfulseasoning,marinatemeats,chicken,fishinfruitjuice,soysauce,sweetwine,Italiandressing,addumamiflavors

Mucosi?s Avoidspicy,acidic,rough,saltyfoods

Hyposaliva?on Soj,moistfoodseasytoswallow(sakes,bananas,applesauce,noodles,icecream,yoghurt,eggs,gravy,broths,Chop,puree,blenderfoods;drinkliquidswithmealsAvoiddryfoods,simplesugars

Trismus/dysphagia Sojfoods,smallbites,blender,supplements

CariesRisk Avoidsugarsweeteneddrinks,gum,candy;fruitandjuicewithmeals,paircariogenicfoodswithcariosta?c(peanutbuner,cheese,milk,cereal,sweetsonlywithmeals,xylitolsweetnerBrushteethbeforemeals

Epstein JB, Huhmann M. J Am Dent Assoc 2012;143:588-92

EnteralFeedingRoute Indica3ons

GastricNasogastrictubePercutaneous(endoscopic)GastrostomyTube(PEG)Gastrostomytube

Shortterm,localirrita?onEndoscopicallyplacetube,leastinvasivepermanentfeedingtubeSurgicallyplacetube,placedduringSXorifendoscopicplacementnotpossible

SmallbowelPercutaneousendoscopicjejunostomytubeJejunostomytube

Endoscopicallyplacetube,usedifesophagusorgastricSXplannedSurgicallyplacedtube,placedduringSXorifendoscopicplacementnotpossible

Approachtomanagement:

•  Ifitworks,keepdoingit…•  Ifitdoesn’twork,stopdoingit….•  Ifyoudon’tknowwhattodo,don’tdoanything…

•  (Andofcoursedon’trefertoasurgeon![unlesssurgeryisneeded])

Cachexia/anorexiainCancerpa3ents•  upto90%ofadvancedcancer•  Lossofadipose?ssue/musclemass•  Cancerbiology,tumorgrowth•  Therapy:nausea,vomi?ng,flavor,appe?te•  Changeintaste,lackofhunger,lackoffoodenjoyment•  ↑inflammatorycytokinesassociatedwith:↓wght,fa?gue/

energy;physical/cogni?vedecline•  Mouthcondi?on(dentalstatus),mucosi?s,salivafunc?on•  Taste/smell/touch/temperature

•  ReuterSC,Mar?nJH.ClinPharmacokinet2016;55:807-12

Metabolismof2-AGandAnandamide

LiC,JonesPM.PharmacolToxicol2011;129:307-20

PathwaysofCannabinoidReceptorac3va3on

LiC,JonesPM.PharmacolToxicol2011;129:307-20

Blueline-inhibi?on;Redline-↑ac?va?on

LegendtoTableonSignalingPathwaysofCB1/2

CannabinoidsandTaste

CannabisinCancerCachexia-Anorexia•  Systema?creview:26papers•  Tetrahydrocannabinol(THC),cannabidiol(CBD)•  Routesofdelivery:inhala?on,oral,mucosalabsorp?on•  THClevels~thosebyinhala?onbyoral&GI;firstpassmetabolism<10%•  THClipophyllicfatuptake;half-life~22hr•  Distribu?oninfatvariable,affectedbycachexia?•  Hepa?cmetabolism:cytochromep450;urinaryclearance(range2hrs-20wks)•  GIabsorp?onaffectedbyGIfunc?on,mucosalabsorp?on•  ↑appe?te/wghtgain

•  NelsonK,WalshDJPalliatCare1994;10:39-97;•  PlasseTF,GorterRW.PahrmacolBiochemBehav1991;40:695-700.

•  Evidenceequivocalforuseincachexia-anorexiasyndrome•  ReuterSC,Mar?nJH.ClinPharmacokinet2016;55:807-12

Ac3onofCB1Receptor

LiC,JonesPM.PharmacolToxicol2011;129:307-20

GhrelinandCannabinoids(1)•  Ghrelin:circula?ngbrain&gutpep?de

–  ↑growthhormonesecre?on&appe?te,–  mediatedbygrowthhormonereceptors?mula?on&AMPK(AMPac?vatedkinase)

•  CBDs:orexin(hypocre?n)regulatesarousal&appe?te•  Ghrelin,Lep?n&CBDs

–  ↑AMPKhypothalamamus–  ↓AMPKinliver&adipose?ssue–  sugges?ngAMPKs?mulatesappe?te&↑peripheraleffectsofghrelin&CBDs

•  IntactghrelinsignalingneededforeffectsofCBDsonAMPK•  LimCT,KolaB,FeltrinDetal.MolecCellEndorcinol2013;365:303-8

•  KolaB,WinmanG,BodnarIetal.FASEBJ2013;27:5112-21

Lep3n/Grhelin:EnergyBalance

DNF:brainderivedneurogenicfactorCART:cocaine-amphetamineregulatedtranscriptCRH:cor?cotrophinreleasinghormoneGALP:galanin-likepep?deMCH:melaninconcentra?nghormoneNPY:neuropep?deYNT:neurotensinPOMC:pro-opiomelatoninOrexin:neuropep?de:alertness,appe?te

CannabinoidsandTaste•  Ratstudy:sweet/biner,THC&CB1antagonist(AM251)

–  THC↑sucrosehedonicresponse–  ↓rejec?onofquinine–  ↑palatability&intakeofallfoods

•  AM251reversedresponsetoTHCsuppor?ngac?onviaCB1receptor JarrenMMetal.PhysiolBehavior2007;90:425-30

•  BlockingCB1↓mo?va?ontoobtainfood•  Highlypalatablefoods?mulatesdopamine(DA)innucleus

accumbens(NAc)•  effectonDAintasterxtosucrosevaversive–quinine&NaCl•  THC↑sucroseeffect&↑DAinNAc•  CB1↑hedonictaste(sweet)butnoeffectonaversivetaste

•  DrosteSM,SalandSk,SchlinerEK.PharmacolBiochemBehav2010;95:443-8•  DeLucaMA,SolinasM,BimpisidisZ,etal.Neuropharmacology2012;63:161-8

B-caryophyllene(BCP):Dietaryphytocannabinoid•  BCPac?vatePPAR-a&-yreceptors&inhibittoll-like

receptors•  ↓immune/inflammatoryprocesses;synergywithµ-opioid

receptor,antagonistnico?nic-acetylcholinereceptors,noeffectserotonergic/GAGAergicreceptors

•  Effects:cardio-,nephro-protec?ve,an?oxidant,an?-inflammatory,an?microbial,immune-modulator;nausea/vomi?ng;neuropathicpain

•  Poten?aleffect:neurologicfunc?on,neurodegenera?vedisease;taste;nausea/vomi?ng

•  Oralbioavailability,lipophyllic•  SharmaC,AlKaabiJM,NurulainSM,etal.CurrPharmDes2016;22:3237-64

PPARreceptors

NeuraleffectsTetrahydrocannabivarin:Foodreward/aversion

•  Tetrahydrocannabivarin:CB1antagonist•  20volunteers,fMRI,responsetovisual&tastes?muli(visual/

tastechocolate&aversiveresponsepictureofmoldystrawberriesorstrawberrytaste)

•  Nodifferenceinsubjec?vera?ngsoftaste(CB1vplacebo)•  fMRI↑responsetochocolate&↑responsetoaversive

s?muli•  CB1antagonist↑neuralresponseto+&-s?muli;poten?al

forweightgainandweightloss•  TudgeL,WilliamsC,CowenPJetal.IntJNeuropsycholpharmacol2014;18(6)

•  TudgeL,WilliamsC,cowenPJ,McCabeC.IntJNeuropsychopharmacol2015;

THC-inducedtasteavoidanceinratmodel

•  THCaversivetastenotmediatedbyκ-opioidreceptor•  Noeffectonaversivetasteseeninadults,minor

inconsistenteffectinadolescentrats•  FlaxSM,WakefordAG,ChengKetal.Psychopharmacology2015;232:3193-201

THC&Cannabidiolicacid(CBDA):Acutean3cipatorynausea•  Ratmodel;nausea&tasteavoidancetest•  THC↓condi?onedtasteavoidance,effect↓byCBDA•  Nausea↓byTHC/CBDAindependently&together;centrally

mediatedatthevisceralinsularcortex•  Suggestedvalueasan?-nausea

•  RockEM,LimebeerCL,ParkerLA.Psychopharmacology2015;232:4445-54

•  Noeffectonaversivetasteinadults,inconsistenteffectinadolescentrats

•  THCaversivetastenotmediatedbyκ-opioidreceptor

•  FlaxSM,WakefordAG,ChengKetal.Psychopharmacology2015;232:3193-201

Cannabinoidsandhedonictasteresponse•  BlockingCB1↓mo?va?ontoobtainfood•  Highlypalatablefoods?mulatesdopamine(DA)in

nucleusaccumbens(NAc)•  AssessedTHCeffectonDAontastereac?vitytosucrose

vaversive–quinine&NaClinrats•  THC↑sucroseeffect&↑NAcDA•  CB1↑hedonictaste(sweet)butnoeffectonaversive

taste•  DrosteSM,SalandSk,SchlinerEK.PharmacolBiochemBehav2010;95:443-8

•  DeLucaMA,SolinasM,BimpisidisZ,etal.Neuropharmacology2012;63:161-8

CannabinoidsandTaste•  57adults,acutedosetrial(3days)•  Salivaflowrate:–vecorrela?onwithplasmadruglevelin

singledosearm•  Tastetes?ng:noeffect•  But+selfreportof↑tasteresponse&↑hedonics

•  ManesRD,ShawLM,EndelmanK.ChemSenses1994;19:125-40

THCpalliateschemosensorychangeincancerpa3ents

•  Pilotstudy:THC(2.5-10mgvplaceboBID)x18days(n=24/22);21completedstudy

•  Taste/smellsurvey,3dayfoodrecord,appe?te,macronutrientpreference,QOLques?onnaire

•  ↑chemosensorypercep?on(p=0.026)•  foodtastedbener(p=0.04)•  ↑appe?te(p=0.05)•  ↑caloriesasprotein(p=0.008)•  ↑qualityofsleep&relaxa?on(p<0.05)•  ↑QOL&totalcalorieintakeTHC&placebo

•  BrisboisTE,deKockIH,WatanageSMetal.AnnOncol2011;22:2086-93

CannabinoidsEnhanceSweetTaste

•  Cannabinoidsact@CB1receptorsinhypothlamus/limbicforebraininduceappe?te&s?mulatefoodintake

•  Endocannabinoidsinplasmainversetolep?n•  Tasteperipheraltargetoflep?n&cannabinoids•  CB1&T1r3receptorsontastecells•  Lep?n↓sweettasteinmice•  Cannabinoids↑sweettaste,noeffectonsalt,sour,biner,umami

•  YoshidaR,OhkuriT,JyotakiM,etal.ProcNatlAcadSciUSA2010;107:935-9

Alteredtasteduetosmokingsubstance•  1250opportunis?callyrecruited(study1)•  76recruitedabstainers,cannabis(recrea?onalanddaily

users)•  Tasteassessed:Sweet,salt,sour,biner,spicy•  Mul?pledrugusers&cannabisusers↑preferenceforsalt/

sour•  Dailycannabis&tobaccousers↑preferenceforsweet,spicy•  Pastusersofcannabismayhavedifferentresponsesto

cannabinoidsthanpriornonusers

•  DoveyTM,BoylandEJ,TraynerPetal.Appe?te2016;107:1-8

CannabinoidsandTaste•  Dronabinol(2.5mgBID)aloneorcombinedwithmegestrol

(800mg/d)vmegestrolalone•  469ptswithcancerrelatedcachexia•  49%reported↑appe?tewithdronabinol•  Noeffectseendronabinolorcombina?onvmegestrol

•  JatoiA,WindschitlHE,LoprinziCLetal.JCO2002;20:567-73

•  DbleblindstudyTHC(2.5mg)with/withoutCBDBIDvplacebofoundnodifferences

•  Noeffectduetodosing?;individual?tra?onmaybeneeded•  StrasserF,LujnerD,PossingerKetal.JCO2006;24:3394-400

THCandtaste•  46pts,advancedcancer;21completedstudy,11dronabinol

(Marinol)[THC],10placebo,RX18days•  2.5/5.0/10mgbid•  THCindicated:nausea,appe?te•  THCvplacebo:

– ↑apprecia?onoffood73%v30%– ↑taste55%v10%– ↑appe?tep<0.05,↑sleepquality,–  nooverall∆QOL

•  BrisboisT.AnnOncol2011•  DeLucaMNeuropharmacol2012

CannabisforAppe3teS3mula3on

•  Survey204pallia?vecare/cancerpa?ents;13%medicinalcannabis(n=26)

•  Ofpriorusers:givenforpain(n=9),appe?teloss(n=9);psychologicalproblems(n=5);insomnia(n=5),nausea(n=2)

•  Tablets/capsulespreferred71%,mouthspray42%,vaporiser41%

•  LuckenT,PhillipsJ,LintzerisN,etal.InternMedJ2016;46:1269-75

Macro-osmia

CannabinoidsandOlfac3on•  THCapprovedinEUforAIDS-associatedanorexia•  Addic?onpoten?al,incompleteunderstandingof

mechanismsofac?vity•  Hunger↑sensorypercep?on~↑foodintake•  THC/CBD↑odordetec?on,↑foodintakeinmice•  CB1receptorsoncor?calglutamanergicneuronsproject

totheolfactorybulbinmice(roleinhumansunknown)•  Soria-GomezE,BellocchioL.NatNeurosci2014;17:407-15

OlfactoryBulb

Olfactorybulb:MCL-mitralcelllayer;GCL-granularcelllayerOSN-olfactorysensoryneuron;MC-mitralcellsPCG(inhibitory)periglomerularcells;GC-(inhibitory)granularcell Saria-GomezE.MolecCellEndocrinol2014

Hormone/nutrientmodula3onofolfac3on

GLT-glucosetransporter;Kv1.3-voltagegatedKchannel;MOB-Mainolfactorybulb;AOC-anteriorolfactorycortex;PVN-paraventricularhypothalamus;LH-lateralhypothalamus;VMH-ventromedialhypothalamus;Arc-arcuatenucleusSaria-GomezE.MolecCellEndocrinol2014

Endocannabinoids*andOlfac3on

S?mula?onofolfactorypercep?on&foodintake.Presysnap?cCB1receptors.CB1s?mula?on↓glutaminergicreceptors↓inhibi?onofolfac?on

Saria-GomezE.MolecCellEndocrinol2014

*

ImpactofAnalgesicsonOlfactoryFunc3on•  100chronicpainpts;95healthycontrolswithno

analgesics•  Olfactorytes?ng(CNI)“Sniffins?cks”test,odor

threshold&iden?fica?on;intensity(VAS);CNVintranasals?mula?on

•  Chronicpainopioid&nonopioid(ajercontrolforneuropathy/chronicpainmedica?on)significantlyaffectCNI,Vsensoryfunc?on

•  Mechanism:viaopioidreceptorsinCNVganglionorCNI/Vinterac?on

•  MizeraL,GossrauG,HummelT.EurJPain2017;21:92-100

TherapyDietarycounselling/modifica?on

Seasoning,avoidunpleasantfoods,extenddietarychoice(pleasingcolor,form,smell,texture) PeregrinJAmDietAssoc2006106:1536-40

Foodprepara?on:spice/flavoring,increaseumamiflavorManagexerostomiaManageoraldiseaseZincsulphate

Reducedseverity&dura?onoftastedysfunc?on(18pa?ents)Ripamon?etal,Cancer199882:1938-45

Butbenefit(NS)observedinlargerstudy(169pa?ents;lowerdose)Halyardetal,IntRadia?onOncologyBiolPhys200767:1318-22

Medica?ons:clonazepam,gabapen?n,megestrol,THC(Marinol),CBDThorneT,OlsonK,WismerW.JSCC2015;23:284

ManageOral/OPCpainandnauseaifpresent

TasteFunc3oninOncology•  Themouthisapartofthebody•  Cri?calroleindiet/nutri?on/sustenanceandQOL

•  Controlledtreatment&prophylac?cstudiesindicatedwithpharmaceu?calproduct

•  Whilereceptorsandmechanismofac?onarebecomingbenerunderstood,manymoreques?onsthananswers

CannabinoidsandTaste/flavor

•  Themouthisapartofthebody•  Cri?calroleindiet/nutri?on/sustenanceandQOL•  Receptors&mechanismofac?onarebecomingbenerunderstood,

but,manymoreques?onsthananswers•  Controlledtreatment&prophylac?cstudiesindicatedwith

pharmaceu?calproduct•  Improvedcontrolofpa?entvariablesneeded•  Delivery,dose,route,scheduleofcannabinoidstobedetermined•  Validatedtoolsfororalcondi?on,oralhygiene,drymouth,taste,

smell,PROsneeded