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&K(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