Pathological Gambling and the Law NAADAC病理性賭博和法律naadac

NeurobiologyofAddictionJonE.Grant,JD,MD,MPHProfessor,UniversityofChicago

DisclosureInformationIhavethefollowingfinancialrelationshipstodisclose:MyresearchissupportedbyNIMHandtheNCRGGrant/Researchsupportfrom:ForestandRochePharmaceuticalsIwilldiscussthefollowingoff-labeluseand/orinvestigationaluseinmypresentation:Medicationsusedtotreataddictions.WhatisAddiction?Addict(verb)-“todevoteorgive(oneself)habituallyorcompulsively〞;fromLatinaddicere-boundtoorenslavedCoreComponentsofAddictionContinuedBehaviorDespiteAdverseConsequencesDiminishedorLostControl/CompulsiveEngagementCravingorUrgeStateComponentArbitraryDefinitionsStigmatizeaddictsandendorsearunner’shigh?Equivocateaboutcaffeineandalcoholandcondemncocaine?18thcentury–bookswereaddictive:womenwouldhavepassionsawakenedAnimalsandhumansselfmedicateAnimalsStudiesAnimalsconsumealcoholinthewildviafermentingfruitsandnectarAnimalsexhibitsignsofinebriationDarwindiscussedmonkeysgettingdrunk:“thefollowingmorningtheywereverycross,heldtheirheadswithbothhands,andturnedawayfrombeerindisgust〞AspectsofAddictionRewardSeekingPleasureImpulsivityLackofInhibitoryControlExpandingtheDefinition?Source:LookMagazine,March,1963RelationshipBetweenGamblingandSubstanceUseDisordersHighRatesofCo-Occurrence- PopulationandClinicalSamplesSimilarClinicalCourses- HighRatesinAdolescence,LowerRatesinOlderAdults- “Telescoping〞PatterninWomenSimilarClinicalCharacteristics- Tolerance,Withdrawal,RepeatedAttemptstoCutBackorQuit- AppetitiveUrgeorCravingStatesSimilarBiologies -GeneticContributions,NeuralCircuitsBehavioralAddictions?GamblingStealingSexualbehaviorShoppingFire-settingInternetuseOvereatingCommonCoreQualitiesofBehavioralAddictionsRepetitiveorcompulsiveengagementinabehaviordespiteadverseconsequencesDiminishedcontroloverproblematicbehaviorAnappetitiveurgeorcravingAhedonicqualityCommonCoreQualitiesofBehavioralAddictionsToleranceWithdrawalRepeatedunsuccessfulattemptstocutbackorstopImpairmentinmajorareasoflifefunctioningTelescopingDSM-IVSUBSTANCEABUSECRITERIAFailuretofulfillmajorroleobligationsatwork,school,orhomeRecurrentuseunderhazardousconditionsSubstance-relatedlegalproblemsContinuedusedespiteproblemsOneormoreproblemsoccurringwithinthesame12-monthperiodCRITERIAFORSUBSTANCEDEPENDENCEToleranceWithdrawalTakeninlargeramount/overlongertimeAttempts/desiretolimitorabstainfromuseOverinvolvementinuseInterferencewithresponsibilitiesUsedespiteknowledgeofproblems3ormoresymptomsoccurringwithinthesame12-monthperiodDSM-5TheroadtoDSM-5beganin1999,anditspublicationin2021istheculminationofalengthyandlabor-intensiveprocess.Thejourneyinvolvedtheeffortsofmanyexpertswhocarefullyreviewedtheliterature,collectednewdata,andperformedtargetedanalysesofexistingdata.TheDSM-5criteriahasbeen19yearsinthemaking.Notonlyhavethediagnosticcriteriabeenrevisedandupdated,butchapterplacementhaschanged.Substance-Relatedand

AddictiveDisordersInadditiontothesubstance-relateddisorders,thischapteralsoincludesgamblingdisorder,Reflectsevidencethatgamblingbehaviorsactivaterewardsystemssimilartothoseactivatedbydrugsofabuseandproducesomebehavioralsymptomsthatappearcomparabletothoseproducedbythesubstanceusedisorders.Groupsofrepetitivebehaviors,whichsometermbehavioraladdictions,withsuchsubcategoriesas“sexaddiction,〞“exerciseaddiction,〞“internetaddiction〞or“shoppingaddiction,〞arenotincludedAlcoholUseDisorderA.Aproblematicpatternofalcoholuseleadingtoclinicallysignificantimpairmentordistress,asmanifestedbyatleasttwoofthefollowing,occurringwithina12-monthperiod:1.Alcoholisoftentakeninlargeramountsoroveralongerperiodthanwasintended.2.Thereisapersistentdesireorunsuccessfuleffortstocutdownorcontrolalcoholuse.3.Agreatdealoftimeisspentinactivitiesnecessarytoobtainalcohol,usealcohol,orrecoverfromitseffects.4.Craving,orastrongdesireorurgetousealcohol.5.Recurrentalcoholuseresultinginafailuretofulfillmajorroleobligationsatwork,school,orhome.6.Continuedalcoholusedespitehavingpersistentorrecurrentsocialorinterpersonalproblemscausedorexacerbatedbytheeffectsofalcohol.7.Importantsocial,occupational,orrecreationalactivitiesaregivenuporreducedbecauseofalcoholuse.8.Recurrentalcoholuseinsituationsinwhichitisphysicallyhazardous.9.Alcoholuseiscontinueddespiteknowledgeofhavingapersistentorrecurrentphysicalorpsychologicalproblemthatislikelytohavebeencausedorexacerbated byalcohol.10.Tolerance,asdefinedbyeitherofthefollowing: a.Aneedformarkedlyincreasedamountsofalcoholtoachieveintoxicationordesiredeffect. b.Amarkedlydiminishedeffectwithcontinueduseofthesameamountofalcohol.11.Withdrawal,asmanifestedbyeitherofthefollowing: a.Thecharacteristicwithdrawalsyndromeforalcohol b.Alcohol(oracloselyrelatedsubstance,suchasabenzodiazepine)istakentorelieveoravoidwithdrawalsymptoms.Non-Substance-RelatedDisordersGamblingDisorderGamblingDisorderPersistentandrecurrentproblematicgamblingbehaviorleadingtoclinicallysignificantimpairmentordistress,asindicatedbytheindividualexhibitingfour(ormore)ofthefollowingina12-monthperiod:1.Needstogamblewithincreasingamountsofmoneyinordertoachievethedesiredexcitement.2.Isrestlessorirritablewhenattemptingtocutdownorstopgambling.3.Hasmaderepeatedunsuccessfuleffortstocontrol,cutback,orstopgambling.4.Isoftenpreoccupiedwithgambling(e.g.,havingpersistentthoughtsofrelivingpastgamblingexperiences,handicappingorplanningthenextventure,thinkingofwaystogetmoneywithwhichtogamble).GamblingDisorder5.Oftengambleswhenfeelingdistressed(e.g.,helpless,guilty,anxious,depressed).(former:gamblesasawayofescapingfromproblems…)6.Afterlosingmoneygambling,oftenreturnsanotherdaytogeteven(“chasing〞one’slosses).7.Liestoconcealtheextentofinvolvementwithgambling.8.Hasjeopardizedorlostasignificantrelationship,job,oreducationalorcareeropportunitybecauseofgambling.9.Reliesonotherstoprovidemoneytorelievedesperatefinancialsituationscausedbygambling.B.Thegamblingbehaviorisnotbetterexplainedbyamanicepisode.GamblingDisorderSpecifyif:Episodic:Meetingdiagnosticcriteriaatmorethanonetimepoint,withsymptomssubsidingbetweenperiodsofgamblingdisorderforatleastseveralmonths.Persistent:Experiencingcontinuoussymptoms,tomeetdiagnosticcriteriaformultipleyears.Specifyif:Inearlyremission:Afterfullcriteriaforgamblingdisorderwerepreviouslymet,noneofthecriteriaforgamblingdisorderhavebeenmetforatleast3monthsbutforlessthan12months.Insustainedremission:Afterfullcriteriaforgamblingdisorderwerepreviouslymet,noneofthecriteriaforgamblingdisorderhavebeenmetduringaperiodof12monthsorlonger.GamblingDisorderSpecifycurrentseverity:Mild:4–5criteriamet.Moderate:6–7criteriamet.Severe:8–9criteriamet.NESARC,2001-0212-monthprevalence(SE):Alcoholabuse 4.7%(0.18)Alcoholdependence 3.8%(0.14)Anyalcoholdisorder 8.5%(0.24)Drugabuse 1.4%(0.08)Drugdependence 0.6%(0.05)Anydrugdisorder 2.0%(0.10)NESARC,2001-02Lifetimeprevalence(SE):Alcoholabuse 17.8%(0.52)Alcoholdependence 12.5%(0.35)Anyalcoholdisorder 30.3%(0.77)Drugabuse 7.7%(0.2)Drugdependence 2.6%(0.1)Anydrugdisorder 10.3%(0.3)NationalComorbidityStudyPastYearRates(%)forAllAgesAnorexia0.1Schizophrenia/schizophreniform1.1PanicDisorder1.3Anti-socialPersonality1.5SocialPhobia1.7ObsessiveCompulsive2.1Dysthymia2.5DrugUseDisorder2.9CognitiveImpairment2.9Gamblingaddiction4.0MajorDepression5.8AlcoholUseDisorder7.3AnyPhobia11.0AnyAnxiety12.7AnyNCSdisorder28.0TheDrugProblemOnly12–30%of“problemdrugusers〞receivedsometypeoftreatment,whichimpliesthat11–34millionproblemdrugusers(70–88%)receivednotreatmentatallLessthan8%ofproblemgamblersseektreatmentLikelihoodofaSuicideAttemptRiskFactorCocaineuseMajorDepressionAlcoholuseIncreasedOddsOfAttemptingSuicide62timesmorelikely41timesmorelikely8timesmorelikelyAlcoholUseYouthalcoholuseoccursonacontinuumMostyouthhaveusedsomealcoholAlcoholUsebyYouth7millionteensbingedrinkatleastonceamonthTrendsinprevalenceofdrugsfor12thgraders:1994to2001

30-Day

Year

Alcohol%

1994 50.1 1995 51.3 1996 50.8 1997 52.7 1998 52.0 1999 51.0

2000 50.0 2001 49.8

Grade Alcohol% Marijuana% AnyIllicit%8 20 8 1010 35 18 21

12 49 22 25

SubstanceUsebyYouth-PriorMonth

SubstanceAbuse/Dependenceratesvary:3-15%EstimatesofProblemGambling-Lifetime

PercentageGroup RangeMedian

Adult <1-3%1.5%College 3

-11% 5%Adolescent

1-7% 2.9%EstimatesofProblemGambling-

PastYear

PercentageGroup RangeMedian

Adult <1-2%0.9%Adolescent

1

-9% 6%

Adolescent-DrugTx

9-13% 11%WhatCausesAddiction?Noevidencefor“addictivepersonality〞AlthoughanumberofpersonalitydisordersareassociatedwithelevatedriskforalcoholismMoralweakness?noevidenceUsingsubstancestodealwithunpleasantaffects:Maybe.Self-medicationSomepsychotropicmedicationsareavailablewithoutaprescriptionCaffeineAlcoholNicotineIllicitonesPeoplemakedecisionsaboutwhichonesandhowmuchWhatcanwelearnaboutourpatientsfromthesechoices?BiologicalFactors:Personalityfactors?(predisposingtoconcernaboutpotentialharm,socialdisapproval,attractiontonewexperiences)Metabolicfactors?(e.g.,increasedrisktoindividualswithdecreasedsubjectiveresponsetodrugsoralcohol)DevelopmentalBiologyAddictiongenerallystartsinyoungadulthood.Environmentalandgeneticinfluences-vulnerabilitytoandexpressionofaddictivedisordersChangesinbrainstructureandfunctionduringadolescencemightinfluencethemotivationtoengageinrisk-takingbehaviors.Duringlatechildhood,neuronsincreasetheirnumberofconnections.Butaround11–GIRLS;12?-BOYS:Someoftheseconnections areprunedoff.BrainDevelopmentWhenthepruningiscomplete,thebrainisfasterandmoreefficient.But…duringthepruningprocess,thebrainisnotfunctioningatfullcapacityDevelopmentMotivationEmotionJudgmentCerebellumAmygdalaNucleusAccumbensPrefrontalCortexPhysicalcoordinationNotice:Judgmentislasttodevelop!MotivationEmotionJudgment Age24Physicalcoordination,sensoryprocessing

BalancePFCamygdalaInthepresenceofstress…Ihateschool;IamgoingtoskipclassesandgetdrunkRoleofTraumaNeglectfulparentingstyleSubstanceusersmorelikelytoreporthistoriesofphysicalneglectemotionalabuseSexualabusePreferenceforphysicalactivityPoorplanningandjudgmentMorerisky,impulsivebehaviorsMinimalconsiderationofnegativeconsequencesAdolescentBehaviorUseBecomesMisuse/AbuseFirstuseto“FEELGOOD〞Somecontinuetocompulsivelyusebecauseofthereinforcingeffects(e.g.,to“FEELNORMAL〞)Changesoccurinthe“rewardsystem〞thatpromotecontinueduseDrugsHijacktheBrain’s

RewardCircuitryImmediateeffectofdruguseisanincreaseindopamineContinueduseofdrugsreducesthebrain’sdopamineproduction.Becausedopamineispartoftherewardsystem,thebrainis“fooled〞thatthedrughassurvivalvaluefortheorganism.Therewardsystemrespondswith“drugseekingbehaviors〞Cravingoccursand,eventually,dependence.rewardProblemBehaviorssmokingdelinquencymaledrugusegamblingsexualbehaviorYouthProblemBehaviorsAreadolescentsmoresusceptiblethanadultstoalcohol?

PercentagesofPastYearAlcoholUseDisorderAmongThosewithaRecentOnset(Prior2Years;n=4058)ofAlcoholUseAgeofPersoninYears%LowerRateswithOlderRecentUsersAdolescentratsarelesssensitivetothesedativeandmotorimpairmenteffectsofintoxication.moredrinkingbefore“signalstostop〞Adolescentratsaremoresensitivetothesocialdisinhibitioneffectsofalcohol.greatersocialcomfortfromintoxicationSurveyDataSuggestthatAdolescentsAreMoreSensitivetoAlcoholLong-TermEffectsCanAddictionbePreventedbyDelayingDrugUseOnset?Everyyearuseofasubstanceisdelayed,theriskofdevelopingasubstanceusedisorderisreduced.PercentagesofPastYearAlcoholDependenceorAbuseAmongAdultsAged21orOlder,byAgeofFirstUseAgeStartedDrinkingPercentAlcohol’sEffectsAdolescentswithahistoryofextensiveuse….

Hippocampusvolume(10%)brainactivityduringmemorytasksconvertsinformationtomemoryNotknownifrestorationorrecoverywilloccur.Long-Term,HeavyUseofAlcoholSignificantshrinkingofthebrain50%-75%showcognitiveimpairmentEffectsremainevenafterdetoxification&abstinenceAlcoholdementiais2nd-leadingcauseofadultdementia

Doesbraindevelopmentcontributetoadolescentsusceptibilitytogambling?1. >risktaking(particularlyingroups)(gambling?)>propensitytowardloweffort-highexcitementactivities(gambling?)<capacityforgoodjudgment&weighingconsequences(gambling?)>sensitivitytonovelstimuli(gambling?)ADHD:WhatRoleDoesItPlay?AreyouthwithADHDatheightenedrisk?

Theseyouthsufferfromproblemswithjudgmentandself-regulation,believedtobelinkedtopre-frontalcortexdeficits.

ADHD,asdefinedbyDSM-IV,isaconstellationofsymptomsrelatedtoInattentionHyperactivityPrevalence:about3%boys>girls

GrowingevidencethatADHD……….isadysfunctioninthebrain’sregulatorysystemsthatmanifestsasadeficitinbehavioraldysregulation,thisdysregulationismediatedbydeficitsinthepre-frontalcortex,andthesedeficitsinpre-frontalcortexcontributetoadisorderlikelyrelatedtoself-regulation-drugabuseLinkofADHDanddrugabuse

AmongchildrenwithADHD(somewithCDalso),comparedtocomparison...SUD

ElevatedalcoholuseElevatedmarijuanauseElevatedtobaccouse OR=1.8-3.2OR=2.2-4.6TheADHD-PGconnection:adultdata

PG non-PGRateofchildhoodADHD 15-36%4-8%ADHDandGamblingComorbidityCo-existenceof2(ormore)illnesseswithinthesameindividualCanbeconcurrentorlifetimePrimacyofonsetcaninfluencetreatmentanddiseaseclassificationStudyofcomorbiditycanbecomplicatedby“seculartrends〞inavailability(e.gProhibition)PrevalenceRatios(ECAStudy):BipolarDisorder:5.4Schizophrenia:3.4PanicDisorder:2.6MajorDepression:1.6AnyDiagnosis:2.0PrevalenceofPersonalityDisordersAmongThoseWithAlcoholUseDisordersAnyPD:28.6%Antisocial:12.3%Obsessive-Compulsive:12.1%Paranoid:10.2%

PrevalenceofAlcoholUseDisorders,GivenSpecificPersonalityDisorder:AnyPersonalityDisorder:16.4%Antisocial:28.7%Histrionic:29.1%Paranoid:19.5%Dependent:21.6%Grantetal,2004LinktoanxietyMedialprefrontalcortexPrelimbicregionandthedorsalanteriorcingulatepromotefearanddrugseekingDopamineviaD1receptorsStressGlutamateInputsgotonucleusaccumbenscoreInfralimbiccortexpromotesextinctionoffearanddrugseekingGlutamateInputstonucleusaccumbensshellPrefrontalcorticalpathologycanpredisposetobothaddictionsandanxietyDecreasedventromedialprefrontalcortexfunctionmayreflectanimpulsivehigh-riskphenotypeforaddictionsandanxietyMotivationalNeuralCircuitsMultiplebrainstructuresunderlyingmotivatedbehaviors.Motivatedbehaviorinvolvesintegratinginformationregardinginternalstate(e.g.,hunger,sexualdesire,pain),environmentalfactors(e.g.,resourceorreproductiveopportunities,thepresenceofdanger),andpersonalexperiences(e.g.,recollectionsofeventsdeemedsimilarinnature).

RolesforNeurotransmittersNeurotransmitter RoleinAddictionsNorepinephrine Arousal,ExcitementSerotonin Behavior Initiation/CessationDopamine Reward,ReinforcementOpioids Pleasure,UrgesSerotonin&ImpulseControlLowCSF5-HIAAAssociatedw/ImpairedImpulseControlAlteredBiochemicalandBehavioralResponsestom-CPP(5HT1Rand5HT2RPartialAgonist)GlutamateLevelsofglutamatewithinthenucleusaccumbensmediatereward-seekingbehaviorRestoringextracellularglutamateconcentrationinthenucleusaccumbensseemstodecreasecravings.RoleofDopamineDopaminereleaseintothenucleusaccumbens-translatesmotivateddriveintoaction-a“go〞signal

Dopaminereleaseassociatedwithrewardsandreinforcing

Dopaminerelease-maximalwhenrewardismostuncertain,suggestingitplaysacentralroleinguidingbehaviorduringrisk-takingsituations.Biochemistry–OpioidSystemTheendogenousopioidsysteminfluencestheexperiencingofpleasure.Opioidsmodulatemesolimbicdopaminepathwaysviadisinhibitionofγ-aminobutyricacidinputintheventraltegmentalarea.Addictionshavebeenassociatedwithelevatedbloodlevelsoftheendogenousopioidβ-endorphin.NeuralSystemsandAddictionMesocorticolimbicDopamineSystem(“OveractiveMotor〞)-VentralTegmentalArea,NucleusAccumbensFrontalSerotoninSystems(“BadBrakes〞)-Frontal/PrefrontalCorticalFunctionGABA,Glutamate,Opioids,...Neurochemistryof

ImpulsivityImpulsivityGLUTAMATEDOPAMINESEROTONINDopamineandImpulsiveBehaviorsinParkinson’sAlcohol,gambling,sex,spending-ReportedinAssociationwithParkinson’sDiseaseAssociationLinkedtoDopamineAgonistTreatmentPriorimpulsebehaviorandfamilyhistoryofaddictionMesocorticolimbicPathwayVentraltegmentalareaNucleusaccumbensAnteriorcingulatePrefrontalcortexNeurocognitioninAddictedIndividualsExecutivefunctiondeficits,includingplanning,cognitiveflexibility,andinhibitiongreatercomparedtocontrols.IndividualswithSUDsDiscountRewardsRapidlyOverTimeBehavioralMeasuresofRewardDiscountingAreAssociatedwithSUDTreatmentOutcomeHypofrontalityCommonadaptationtochronicaddictivebehaviorsishypofrontality–reducedbaselineactivityofprefrontalcortex,orbitofrontalcortex,anteriorcingulateProblemswithexecutivefunction,attention,behavioralinhibition,workingmemoryResultsinindividualsreporting“beingdrivenbyirresistibleinnerforces〞andhaving“noabilitytostop〞themselvesNeuroimagingVentromedialprefrontalcortex(vmPFC)-implicatedindecision-makingcircuitryinrisk-rewardassessmentDecreasedactivationinvmPFCinPGsubjectsduringgamblingcuesperformanceoftheStroopColor-WordInterferenceTaskandsimulatedgambling.ResponsivenessofthevmPFCtoserotonergicdrugchallenges(m-CPP,fenfluramine)-bluntedinimpulsiveaggressionandalcoholdependenceLeftvmPFCImplicatedDuringStroopPerformanceInGamblingDifference

Controls

Gamblers

DiffusionTensorImagingTrace-ameasureofthemagnitudeofwaterdiffusionineachimagevoxelFractionalanisotropy(FA)-ameasureoftheextenttowhichwaterdiffusionineachvoxelisdirectionallyrestricted.Regionsofcompromisedwhitematterintegrity-TracevaluesarehigherandFAvalueslowerthaninnormalwhitematterpresumablyowingtoaxonaldegenerationNearMissesNear-misseswereassociatedwithsignificantlygreatersignalintheventralstriatumandanteriorinsulaRecruitmentofwin-relatedregionsduringnear-missoutcomesunderliestheirabilitytopromotegamblingbehaviorGamblersarehypersensitivetopotentialgainsratherthaninsensitivetopotentiallosses.

GeneticsGeneticLiability-EtOH“Alcoholism〞isnotheritable—whatisheritableapparentlyarefactorswhichincreasethelikelihoodofdrinkinganddevelopingproblemsRisk