Chapter 2How Stimulants Affect the Brain and Behavior

Overthelastseveraldecades,researchonsubstancesofabusehasvastlyimprovedourunderstandingofhumanbehaviorandphysiology
andthenatureofsubstanceabuseanddependence.Basicneurobiologicalresearchhasenhancedourunderstandingofthebiologicaland
geneticcausesofaddiction.Thesediscoverieshavehelpedestablishaddictionasabiologicalbraindiseasethatischronicandrelapsingin
nature(Leshner,1997).Bymappingtheneuralpathwaysofpleasureandpainthroughthehumanbrain,investigatorsarebeginningto
understandhowabusedpsychoactivesubstances,includingstimulants,interactwithvariouscellsandchemicalsinthebrain.

Thisnewinformationhasalsoimprovedourunderstandingofappropriatetreatmentapproachesfordifferentsubstanceusedisorders.This
chapterdescribestheeffectsthatcocaineandmethamphetamine(MA)usehaveontheuser'sbrainandbehavior,whichinturnleadsto
thestimulantusers'uniqueneeds.Knowledgeoftheseeffectsprovidesthefoundationforstimulantspecifictreatmentapproaches.This
knowledgewillgivetreatmentprovidersgreaterinsightintostimulantusersandwhycertaintreatmentapproachesaremoreeffective.

Stimulant Abuse And the Brain

AccordingtoNationalInstituteonDrugAbuseDirectorAlanI.Leshner,Ph.D.,thefundamentalproblemindealingwithanysubstance
ofabuseistounderstand"thetarget"(i.e.,theuser).Therefore,tounderstandwhypeopletakedrugssuchascocaineandMAandwhy
somepeoplebecomeaddicted,wemustfirstunderstandwhatthesedrugsaredoingtotheirtargetthatis,howstimulantsaffecttheuser.

Discussionsofsubstanceabuseanddependenceofteninvolvesomediscussionoftherootcausesthesocietalandriskfactorsthatleadto
theseconditions.Todate,investigatorshaveidentifiedasmanyas72riskfactorsforsubstanceuseanddependence(Leshner,1998).
Amongthemarepoverty,racism,socialdysfunction,weakfamilies,pooreducation,poorupbringing,andsubstanceabusingpeergroups.
Theseriskfactorsaswellasotherenvironmentalandgeneticfactorsonlyinfluenceanindividual'sinitialdecisiontousesubstancesof
abuse.Butafterinitialuse,anindividualcontinuestouseasubstancebecauseshelikesitseffects:Usemodifiesmood,perception,and
emotionalstate.Alloftheseeffectsaremodulatedthroughthebraininordertounderstandthisphenomenon,itisimportanttounderstand
somebasicneuroscience.

Forsubstancesofabusetoexerttheireffects,theymustfirstgettothebrain.Thefourmostcommonroutesofadministeringpsychoactive
(moodchanging)substancesare(1)oralconsumption(i.e.,swallowing),(2)intranasalconsumption(i.e.,snorting),(3)inhalationintothe
lungs(generallybysmoking),and(4)intravenouslyviahypodermicsyringe.

Aswallowedsubstancegoestothestomachandontotheintestinaltract.Somesubstanceseasilypassthroughthedigestivetractintothe
bloodstream.Othersubstancesarebrokendownintotheirchemicalcomponents(i.e.,metabolized)inthedigestivesystem,thereby
destroyingthesubstance.

Substancesthatareinhaledintothelungsadheretotheliningofthenasalpassages(thenasalmucosa)throughwhichtheyenterdirectly
intothebloodstream.Inhaledsubstancesareusuallyfirstchangedintoagaseousformbyigniting(e.g.,marijuana)orvolatilizingby
intenseheat(e.g.,crackcocaine,theiceformofMA).Thelungsofferalargesurfaceareathroughwhichthegaseousformmayquickly
passdirectlyintothebloodstream.

Injectedsubstancesobviouslyenterthebloodstreamdirectly,althoughatasomewhatregulatedrate.Intheselastthreeroutesof
administration,substancesenterthebloodstreamintheirunmetabolizedform.

Onceasubstanceentersthebloodstream,itistransportedthroughoutthebodytovariousorgansandorgansystems,includingthebrain.
Substancesthatenterthelivermaybemetabolizedthere.Substancesthatenterthekidneymaybeexcreted.Ifafemalesubstanceuseris
pregnant,andthesubstanceisabletocrosstheplacenta,thenthesubstancewillenterthefetus'bloodstream.Nursingbabiesmayingest
somesubstancesfrombreastmilk.

Toenterthebrain,asubstance'smoleculesmustfirstgetthroughitschemicalprotectionsystem,whichconsistsmainlyofthebloodbrain
barrier.Tightcellwalljunctionsandalayerofcellsaroundthebloodvesselskeeplargeorelectricallychargedmoleculesfromentering
thebrain.However,smallneutralmoleculeslikethoseofcocaineandMAeasilypassthroughthebloodbrainbarrierandenterthebrain.
Onceinsidethebrain,substancesofabusebegintoexerttheirpsychoactiveeffects.
Fundamentals of the Nervous System
Thehumannervoussystemisanelaboratelywiredcommunicationsystem,andthebrainisthecontrolcenter.Thebrainprocessessensory
informationfromthroughoutthebody,guidesmusclemovementandlocomotion,regulatesamultitudeofbodilyfunctions,formsthoughts
andfeelings,modulatesperceptionandmoods,andessentiallycontrolsallbehavior.

Thebrainisorganizedintolobes,whichareresponsibleforspecializedfunctionslikecognitiveandsensoryprocessesandmotor
coordination.Theselobesaremadeupoffarmorecomplexunitscalledcircuits,whichinvolvedirectconnectionsamongthebillionsof
specializedcellsthatthevarioussubstancesofabusemayaffect.

Thefundamentalfunctionalunitofthebrain'scircuitsisaspecializedcellcalledaneuron,whichconveysinformationbothelectrically
andchemically.Thefunctionoftheneuronistotransmitinformation:Itreceivessignalsfromotherneurons,integratesandinterprets
thesesignals,andinturn,transmitssignalsontoother,adjacentneurons(Charness,1990).

Atypicalneuron(seeFigure21)consistsofamaincellbody(whichcontainsthenucleusandallofthecell'sgeneticinformation),a
largenumberofoffshootscalleddendrites(typically10,000ormoreperneuron),andonelongfiberknownastheaxon.Attheendofthe
axonareadditionaloffshootsthatformtheconnectionswithotherneurons.Withinneurons,thesignalsarecarriedintheformof
electricalimpulses.Butwhensignalsaresentfromoneneurontoanother,theymustcrossthegapatthepointofconnectionbetweenthe
twocommunicatingneurons.Thisgapiscalledasynapse.Atthesynapse,theelectricalsignalwithintheneuronisconvertedtoa
chemicalsignalandsentacrossthesynapsetothetarget(i.e.,receiving)neuron.Thechemicalsignalisconveyedviamessenger
moleculescalledneurotransmittersthatattachtospecialstructurescalledreceptorsontheoutersurfaceofthetargetneuron(Charness,
1990).Theattachmentoftheneurotransmitterstothereceptorsconsequentlytriggersanelectricalsignalwithinthetargetneuron.
Approximately50to100differentneurotransmittershavebeenidentifiedinthehumanbody(Snyder,1986).Figure22illustratesa
typicalsynapticconnectionanddepictsthechemicalcommunicationmechanism.Neurotransmittersmayhavedifferenteffectsdepending
onwhatreceptortheyactivate.Someincreaseareceivingneuron'sresponsivenesstoanincomingsignalanexcitatoryeffectwhereas
othersmaydiminishtheresponsivenessaninhibitoryeffect.Theresponsivenessofindividualneuronsaffectsthefunctioningofthe
brain'scircuits,aswellashowthebrainfunctionsasawhole(howitintegrates,interprets,andrespondstoinformation),whichinturn
affectsthefunctionofthebodyandthebehavioroftheindividual.Theaccuratefunctioningofallneurotransmittersystemsisessential
fornormalbrainactivities(NationalInstituteonAlcoholAbuseandAlcoholism[NIAAA],1994HillerSturmhfel,1995).

Figure
Figure21:TheTypicalNeuron.

Figure
Figure22:TypicalSynapticJunction.

The Limbic Reward System

Thebraincircuitthatisconsideredessentialtotheneurologicalreinforcementsystemiscalledthelimbicrewardsystem(alsocalledthe
dopaminerewardsystemorthebrainrewardsystem).Thisneuralcircuitspansbetweentheventraltegmentalarea(VTA)andthe
nucleusaccumbens(seeFigure23).Everysubstanceofabusealcohol,cocaine,MA,heroin,marijuana,nicotinehassomeeffecton
thelimbicrewardsystem.Substancesofabusealsoaffectthenucleusaccumbensbyincreasingthereleaseoftheneurotransmitter
dopamine,whichhelpstoregulatethefeelingsofpleasure(euphoriaandsatisfaction).Dopaminealsoplaysanimportantroleinthe
controlofmovement,cognition,motivation,andreward(Wise,1982Robbinsetal.,1989DiChiara,1995).Highlevelsoffreedopamine
inthebraingenerallyenhancemoodandincreasebodymovement(i.e.,motoractivity),buttoomuchdopaminemayproducenervousness,
irritability,aggressiveness,andparanoiathatapproximatesschizophrenia,aswellasthehallucinationsandbizarrethoughtsof
schizophrenia.ToolittledopamineincertainareasofthebrainresultsinthetremorsandparalysisofParkinson'sdisease.

Figure
Figure23:TheLimbicRewardSystem.

Naturalactivitiessuchaseating,drinking,andsexactivatethenucleusaccumbens,inducingconsiderablecommunicationamongthis
structure'sneurons.Thisinternalcommunicationleadstothereleaseofdopamine.Thereleaseddopamineproducesimmediate,but
ephemeral,feelingsofpleasureandelation.Asdopaminelevelssubside,sodothefeelingsofpleasure.Butiftheactivityisrepeated,
thendopamineisagainreleased,andmorefeelingsofpleasureandeuphoriaareproduced.Thereleaseofdopamineandtheresulting
pleasurablefeelingspositivelyreinforcesuchactivitiesinbothhumansandanimalsandmotivatetherepetitionoftheseactivities.

Dopamineisbelievedtoplayanimportantroleinthereinforcementofandmotivationforrepetitiveactions(DiChiara,1997Wise,
1982),andthereisanincreasingamountofscientificevidencesuggestingthatthelimbicrewardsystemandlevelsoffreedopamine
providethecommonlinkintheabuseandaddictionofallsubstances.Dopaminehasevenbeenlabeled"themastermoleculeofaddiction"
(Nash,1997).

Whenthenucleusaccumbensisfunctioningnormally,communicationamongitsneuronsoccursinaconsistentandpredictablemanner.
First,anelectricalsignalwithinastimulatedneuronreachesitspointofconnection(i.e.,thesynapse)withthetargetneuron.The
electricalsignalinthepresynapticneurontriggersthereleaseofdopamineintothesynapse.Thedopaminetravelsacrossthesynapticgap
untilitreachesthetargetneuron.Itthenbindstothepostsynapticneuron'sdopaminespecificreceptors,whichinturnhasanexcitatory
effectthatgeneratesaninternalelectricalsignalwithinthisneuron.However,notallofthereleaseddopaminebindstothetarget
neuron'sreceptors.Extradopaminemaybechemicallydeactivated,oritmaybequicklyreabsorbedbythereleasingneuronthrougha
systemcalledthedopaminereuptaketransporter(seeFigure24).Assoonastheextradopaminehasbeendeactivatedorreabsorbed,the
twocellsare"reset,"withthereleasingneuronpreparedtosendanotherchemicalsignalandthetargetneuronpreparedtoreceiveit.
Substancesofabuse,andespeciallystimulants,affectthenormalfunctioningofthedopamineneurotransmittersystem(Snyder,1986
Cooperetal.,1991).

Figure
Figure24:Dopamine'sNormalAction.

Neurological Reinforcement Systems

Psychologistshavelongrecognizedtheimportanceofpositiveandnegativereinforcementforlearningandsustainingparticularbehaviors
(KoobandLeMoal,1997).Beginninginthelate1950s,scientistsobservedinanimalsthatelectricallystimulatingcertainareasofthe
brainledtochangesinmentalalertnessandbehavior.Ratsandotherlaboratoryanimalscouldbetaughttoselfstimulatepleasurecircuits
inthebrainuntilexhaustion.Ifstimulantssuchascocaineoramphetaminewereadministered,forexample,sensitivitytopleasurable
responseswassoenhancedthattheanimalswouldchooseelectricalstimulationofthepleasurecentersintheirbrainsovereatingorother
normallyrewardingactivities.

Theprocessjustdescribedinwhichapleasureinducingactionbecomesrepetitiveiscalledpositivereinforcement.Conversely,abrupt
discontinuationofthepsychoactivesubstancesfollowingchronicusewasfoundtoresultindiscomfortandbehaviorsconsistentwith
craving.Themotivationtouseasubstanceinordertoavoiddiscomfortiscallednegativereinforcement.Positivereinforcementis
believedtobecontrolledbyvariousneurotransmittersystems,whereasnegativereinforcementisbelievedtobetheresultofadaptations
producedbychronicusewithinthesameneurotransmittersystems.

Experimentalevidencefrombothanimalandhumanstudiessupportsthetheorythatstimulantsandothercommonlyabusedsubstances
imitate,facilitate,orblocktheneurotransmittersinvolvedinbrainreinforcementsystems(NIAAA,1994).Infact,researchershave
positedacommonneuralbasisforthepowerfulrewardingeffectsofabusedsubstances(forareview,seeRestak,1988).Natural
reinforcerssuchasfood,drink,andsexalsoactivatereinforcementpathwaysinthebrain,andithasbeensuggestedthatstimulantsand
otherdrugsactaschemicalsurrogatesofthenaturalreinforcers.Akeydangerinthisrelationship,however,isthatthepleasureproduced
bysubstancesofabusecanbemorepowerfullyrewardingthanthatproducedbynaturalreinforcers(NIAAA,1996).

Stimulants' Mechanisms of Action

Onashorttermbasis,stimulantsexerttheireffectsbydisruptingormodifyingthenormalcommunicationthatoccursamongbrain
neuronsandbraincircuits.CocaineandMAhavebothbeenshowntospecificallydisruptthedopamineneurotransmittersystem.This
disruptionisaccomplishedbyoverstimulatingthereceptorsonthepostsynapticneuron,eitherbyincreasingtheamountofdopamineinthe
synapsethroughexcessivepresynapticreleaseorbyinhibitingdopamine'spatternofreuptakeorchemicalbreakdown(Cooperetal.,
1991).

TheuseofcocaineandMAincreasestheamountofavailabledopamineinthebrain,whichleadstomoodelevation(e.g.,feelingsof
elationoreuphoria)andincreasedmotoractivity.Withcocaine,theeffectsareshortlivedwithMAthedurationofeffectismuch
longer.Asthestimulantlevelinthebraindecreases,thedopaminelevelssubsidetonormal,andthepleasurablefeelingsdwindleaway.

Agrowingbodyofscientificresearchbasedonanimalresearchandbrainimagingstudiesinhumanssuggeststhatthechronicuseof
stimulantsaffectdopaminergicneuronsinlimbicrewardsystemstructures(e.g.,theVTA,nucleusaccumbens).Theseeffectsmay
underlieaddictiontostimulants.Althoughtheneurochemicalpathwaysofstimulantaddictionarenotdefinitivelyestablished,afew
researchershavefoundevidenceofchangesinthestructureandfunctionofbrainneuronsafterchronicstimulantuseinhumans.Some
researchersproposethatthechangesmaycomefromdopaminedepletion,changesinneurotransmitterreceptorsorotherstructures,or
changesinotherbrainmessengerpathwaysthatcouldcausethechangesinmood,behavior,andcognitivefunctionassociatedwithchronic
stimulantabuse(SelfandNestler,1995).

Animalstudieshavedemonstratedthathighdosesofstimulantscanhavepermanentneurotoxiceffectsbydamagingneuroncellendings
(e.g.,Selden,1991).Thequestionofwhetherstimulantscanproducesimilareffectsinhumansremainstobeanswered.Researchershope
thatrecentlydevelopedbrainimagingtechniqueswillhelpprovidetheanswer.Atthistime,thereisonlyspeculationthatsuchpermanent
damagemayunderliethelongtermcognitiveimpairmentsseeninsomechronicstimulantusers.Thecontinuingdevelopmentand
applicationofnewtechnologieswillhelpexpandourknowledgeoftheneurologicaleffectsofstimulantsinhumans.(Themedicalaspects
ofstimulantusedisordersarediscussedinChapter5.)

Abuse and Dependence

Addictionisacomplexphenomenonwithimportantpsychologicalandsocialcausesandconsequences.However,atitscore,itinvolvesa
biologicalprocess:theeffectsofrepeatedexposuretoabiologicalagent(asubstance)onabiologicalsubstrate(thebrain)overtime
(NestlerandAghajanian,1997).Ultimately,adaptationsthatsubstanceexposureelicitsinindividualneuronsalterthefunctioningofthose
neurons,whichinturnaltersthefunctioningoftheneuralcircuitsinwhichthoseneuronsoperate.Thiseventuallyleadstothecomplex
behaviors(e.g.,dependence,tolerance,sensitization,craving)thatcharacterizeaddiction(Koob,1992Kreek,1996Wise,1996Koob
andLeMoal,1997).

Ageneraldefinitionofsubstanceabuseisthehabitualuseofasubstancenotneededfortherapeuticpurposes,suchassolelytoalterone's
mood,affect,orstateofconsciousness.Thecontinuedabuseofthesubstancemayleadtoadversephysiological,behavioral,andsocial
consequences.Asubstancedependentindividualwillcontinuehisusedespitetheseadverseconsequences.Moderatechronicuseorsevere
shorttermuseofsubstancesmayleadtoabuse,whichmayeventuallyleadtoaddictioncomponents(Ellinwood,1974Halletal.,1988
Kramer,1969).

Chronicsubstanceabuseresultsinacomplexsetofphysiologicalandneurologicaladaptations.Theseadaptationsaresimplythebody's
attempttoadjusttoorcompensateforsubstanceinducedimpairments.Repeatedexposuretoasubstancecanalsoleadtoadaptationsin
therewardcircuitrythatopposesand/orneutralizesasubstance'seffects(i.e.,counteradaptation).Substanceaddiction(orsubstance
dependence)ismanifestedby(1)psychologicalcraving(seethefollowingsection)(2)tolerance(theneedforincreasingamountsofthe
substancetoreproducetheinitiallevelofresponse,orsometimestosimplystaveofftheunpleasanteffectsofwithdrawal)(3)
sensitization(discussedinthesectiononthemedicaleffectsofstimulants)and(4)symptomsofwithdrawaluponcessationofuse,
indicatingphysiologicaldependence.

Socialandbehavioralmanifestationsofdependenceincludethereducedabilitytofunctionatworkorhomeandmayincludedisplaysof
erratic,moody,oranxiousbehavior.

Similartoothersubstancesofabuse,moderatechronicuseorsevereshorttermuseofstimulantsinanyformmayleadtoabuseor
dependence(Ellinwood,1974Halletal.,1988Kramer,1969).ClinicalobservationsofabusepatternsforbothcocaineandMAhave
notedthat,ingeneral,thereisanestimated2to5yearlatencyperiodbetweenfirstuseandfullblownaddiction.However,clinical
experienceandanecdotalevidencesuggestthatthelatencyperiodmaybeshortenedtolessthan1yearbyrapidroutesofadministration
(e.g.,injection,smoking)andincreasedstimulantpurity(e.g.,ice,crack).Withincreasinguse,theusermaydeveloptolerancetothe
effectsofstimulantsandmayneedtokeepincreasingtheamounttakentoproducethedesiredpsychologicaleffects.Aschronicabuse
progresses,userspreferthestimulantoverenjoyableactivitiesandeventuallymaypreferitoverfoodandsex(Halletal.,1988).Atthat
point,theindividualwillusuallycontinueheruseevenwhenfacedwithcontinuingadverseconsequencesthehallmarkofsubstance
dependence.Abruptdiscontinuationofthepsychoactivesubstancefollowingchronicusegenerallyresultsindiscomfort,dysphoria,and
behaviorsconsistentwithcraving.Theuserisnowmotivatedtouseasubstanceinordertoavoiddiscomfortanddysphoria.Thisshift
fromsubstanceuseaspositivereinforcementtonegativereinforcementis,perhaps,oneoftheforemostcharacteristicsoflatestage
addiction.

Drug Craving and Memory

Thedegreetowhichlearningandmemorysustaintheaddictiveprocesshasonlyrecentlybeenaddressed.Researchersbelievethateach
timeaneurotransmitterlikedopaminefloodsacrossasynapse,circuitsthattriggerthoughtsandmemoriesandthatmotivateaction
becomehardwiredinthebrain.Theneurochemistrysupportingaddictionissopowerfulthatpeople,objects,andplacesassociatedwith
substanceusearealsoimprintedonthebrain.

Craving,acentralaspectofaddiction,isaverystronglearnedresponsewithpowerfulmotivationalpropertiesoftenassociatedwith
specificmemories(i.e.,conditionedcuesandtriggers).Cuesanystimuli(substanceusingfriends,locations,paraphernalia,moods)
repeatedlypairedwithsubstanceuseoverthecourseofaclient'saddictioncanbecomesostronglyassociatedwiththesubstance's
effectsthattheassociated(conditioned)stimulicanlatertriggerarousalandanintensedesireforthesubstanceandleadtorelapse.High
relapseratesarecommonincocaineaddictionevenafterphysicalwithdrawalandabstinencehavebeenachieved.

Brainimagingstudieshaveshownthatcueinduceddrugcravingmaybelinkedtodistinctbrainsystemsinvolvedinmemory(e.g.,London
etal.,1990Stapletonetal.,1995).Brainstructuresinvolvedinmemoryandlearning,includingthedorsolateralprefrontalcortex,
amygdala,andcerebellum,havebeenlinkedtocueinducedcraving(Grantetal.,1995).Anetworkofthesebrainregionsintegrates
emotionalandcognitiveaspectsofmemoryandtriggerscravingwhenitreactstocuesandmemories.Thesecuesandmemoriesalsoplay
animportantroleinreinforcingsubstanceuse(Grantetal.,1995).

Mostsubstancetreatmentprogramsrecognizethepowerofthesefactorsintriggeringrelapseandwarnclientstoavoideverything
previouslyassociatedwiththeirsubstanceuseatallorderforaclientinanurbanenvironmentsaturatedwiththesubstanceandits
associatedreminders.Treatmentapproachesthataddresstheselearningandmemoryissuesofaddictionmayproveeffective.For
example,Childressdevelopedtreatmentstrategiestohelpclientsreducecravingandarousalduringencounterswithsubstancerelated
stimuli(Childress,1994).Inthelaboratory,clientsaregivenrepeated,passiveexposuretosubstanceremindingcuesinasubstancefree
protectedenvironment.Theresearchfindsthatinitialarousalandstrongcravingproducedbythecueseventuallydecrease(Childress,
1994).Betterunderstandingoftherelationshipoflearningandmemorytotheaddictionprocessmayleadtonewtreatmentapproaches.

Role of New Technologies

Therecentdevelopmentofnoninvasivebrainimaginghascreatedapowerfulnewtoolfordemonstratingnotonlytheshorttermeffects
ofsubstanceuse,butalsothelongertermconsequencesofchronicsubstanceabuseandaddiction.Thesetoolshaveallowedresearchersto
boldlygowheretheypreviouslycouldnotliterallyintothedepthsofalivinghumanbrain.Suchnoninvasivetechniquescandepictnormal
andabnormalfunctioningofdifferentbrainareasbymeasuringmetabolicactivity(i.e.,glucoseutilization).Theycanidentifysubstance
inducedstructuralchangesandphysiologicaladaptations.Throughacombinationoftechniques,theycanobservethealtered"processing"
ofinformationinvariouscircuitsasthebrainrespondstosubstanceuse.

Usingthesetechniques,investigatorshavebeenabletoidentifybrainstructuresinvolvedincraving,maptheemotionsofsubstanceusers,
plottheneurobiologicalbasisofsubstanceinducedeuphoria,andmore.Forexample,researchershaveusedmagneticresonanceimaging
(MRI)andspectroscopytoseehowbrainstructureschangeassubstancesproducetheireffects.Othershaveusedafunctionalimaging
techniquecalledphosphorusmagneticresonancespectroscopy(31PMRS)toshowthatchronicsubstanceabuseisaccompaniedby
abnormalmetabolisminsomeareasofthebrainthatseemstoreturntonormalwhenpeoplestopusingsubstances(Christensenetal.,
1996).Positronemissiontomography(PET)hasrevealedsubtlealterationsinthedopaminereceptorsofstimulantusers'brains(Iyoetal.,
1993).MorerecentPETstudieshavedemonstratedlongtermvulnerabilitytochronicstimulantabuse(Melegaetal.,1997aVolkowet
al.,1996,1997b).AnotherPETstudyhasestablishedadoseresponserelationshipbetweencocaineandthedrug'ssubjectiveeffects:The
greatertheamountofcocainethatisadministered,thegreaterthehighexperiencedbytheuser(Volkowetal.,1997a).

Otherresearcherscombinedelectroencephalograms(EEGs)andMRItoproduceatopographicbrainmapshowingincreasedelectrical
activity(intheformofbetawaves)duringstimulantwithdrawal(Herningetal.,1997).MappingEEGactivityduringstimulantuseand
withdrawalmayallowresearcherstofurtherdocumentsubstanceinducedneuropsychologicalimpairments.

Althoughmuchisknownabouttheeffectsofstimulantsinanimals,thereislittlesuchknowledgeoftheseeffectsinhumans(CSAT,
1997).Thecontinuingdevelopmentandapplicationofnewtechnologiessuchasnoninvasivebrainimagingwillallowresearchersto
improvetheirunderstandingofhowstimulantsaffectthehumanbrain.Greaterunderstandingoftheunderlyingneuronalimpairmentsof
stimulantabusewillaidinthedevelopmentofnew,moreeffectivetreatmentapproaches.

General Effects Of Stimulants

Substancesofabuseandstimulantsinparticularappeartoincreasethebrain'slevelsoffreedopamineinadosedependentmannerthat
is,moredopamineisavailablewhenhigherdosesofthesubstanceareadministered(Nash,1997).Thehigherthesubstancedose,the
greaterthefeelingsofelation,euphoria,andsatisfaction,andasthedopaminelevelsandpleasurablefeelingsubside,thereisanintense
desiretoreplicatethefeelingsofpleasurebyadministeringanotherdoseofthesubstance.Thistendencytowardrepeatedadministration
ischaracteristicofstimulantabuseandunderliesmostoftheothereffectsofstimulants,aswellasmostotheraddictivesubstances.

Continueduseoftenleadstoadverseconsequences,whichmayincludeneuropsychologicalimpairmentanddiminishedphysicalhealth.
Workperformanceandsocialandfamilyrelationscanbeadverselyaffected,andtheriskofarrestandconvictionondrugrelatedcharges
increases.Evenafterastimulantuserdiscontinuesuse,impairmentsincognitionandfunctioningmaypersist,andtheremayevenbe
persistentpsychiatricsymptoms(WadaandFukui,1990).Cravingsforthestimulant'seffectstendtolinger,evenafterabstinencehas
beenachieved,andthepotentialforrelapseishigh.

Medical Effects

Acute effects

Thegeneralacuteeffectsofstimulantshavebeenwelldocumented.Amongarangeofphysiologicalresponses,stimulantsareknownto
raisebothsystolicanddiastolicbloodpressure,increaseheartrate,increaserespirationrate,increasebodytemperature,causepupillary
dilation,heightenalertness,andincreasemotoractivity(CSAT,1997).
Acuteeffectsfromexcessivedosesincludedangerouslyrapidanderraticheartbeat,cerebralhemorrhaging,seizures/convulsions,
respiratoryfailure,stroke,heartfailure,braindamage,coma,anddeath(CSAT,1997).

Stimulantsarealsoknowntocausesensitization(i.e.,theoppositeoftolerance),forwhichmultipledrugexposureseventuallyproduce
somenewadversereaction.Forexample,inanimals,seizuresdonottypicallyoccuraftersinglelowtomoderatedoses.Butwith
repeatedexposure,ananimalcanbecomesensitizedtothestimulantandmayhaveaseizureafterasingle,previouslyharmless,dose.

Chronic effects

Althoughtheeffectsofchronicstimulantabuseinhumanshasnotbeenwelldocumented,someofthechroniceffectsincludeorgan
toxicity,compromisedhealth(e.g.,underfed,malnourished,poorhygiene),dentalproblems,anddermatitis.(Foracompletediscussionof
themedicalaspectsofstimulantuse,seeChapter5.)

Psychological Effects
Theimmediatepsychologicaleffectsofstimulantadministrationincludeaheightenedsenseofwellbeing,euphoria,excitement,
heightenedalertness,andincreasesinmotoractivity.Stimulantsalsoreducefoodintake,reducesleeptime,andmayincrease
socializationactivities.Stimulantsmayalsoenhanceperformanceofcertaintypesofpsychomotortasks.

Highdosesmayresultinrestlessnessandagitation,andexcessivedosesmayproducestereotypicbehaviors(repetitiveandautomatic
acts).Chronicpsychologicaleffectsofstimulantuseincludevariouspsychiatricdisorderssuchaspsychosis,paranoia,andsuicidal
tendencies.

Theremayalsobeneurologicalimpairmentsandcognitivedeficits.Toleranceeventuallydevelopstomanyofthebehavioraleffectsof
stimulants,sothatincreasingdosesarerequiredtoachievethesameeffect.

Theadministrationofstimulantsparticularlyifsmokedorinjectedintravenouslycanhaveimmediateandoftenveryintenseeffectson
theuser.However,the"rush"andsubsequentfeelingsofeuphoriamayjustasquicklyfade.Theintenseeffectscanbefollowedbya
dysphoric"crash."Tostavethecrash,theuserwilladministeranotherdoseofthestimulant,whichagainproducesarushandsubsequent
crash.

Thiscyclewillgoonagainandagain.Thispatternoffrequentlyrepeateddosingknownasbingeingmaycontinueforupto3sleepless
days.Duringthisperiod,theusermaynoteatandmaylapseintoaseveredepression,followedbyworseningparanoia,belligerence,and
aggressionaperiodknownastweaking.

Bingeingeventuallyendswhentheuserdepleteshissupplyofstimulantsorsimplycollapsesfromsheerexhaustion.Thestimulantuser
maythensleepforseveraldays,onlytoawakenandbeginthecycleagain.

Thereisagreatamountofanecdotalevidenceontherelationshipofstimulantuseandvarioussexualbehaviors.Stimulantsmaybeused
duringsexualactivitiestointensifysexualacts,heightenpleasure,lengthenthedurationofintercourse,andlesseninhibitions.Theabuse
ofstimulantsisalsoknowntoleadtouncharacteristicallyaberrantordeviantsexualbehaviors,theuseofprostitutes,andHIVhighrisk
behaviors(Rawsonetal.,1998b).

Effects of Route of Administration

CocaineandMAcanbesmoked,snorted,injected,oringestedorally.Thesevariousroutesofadministrationdifferindosageandinthe
rapidityandintensityofeffect,whichmayaffectthecourseofabuseanddependence.Someevidencesuggeststhattheonsetof
dependencevariesaccordingtotherouteofadministration(DEA,1995).Therouteofadministrationaffectstheamount(i.e.,thedosage)
ofstimulantdeliveredtothebrain,thespeedatwhichitisdelivered,andtheresultingintensityofthestimulant'seffects.

Theintensityofthepsychologicaleffectsofstimulants,aswithmostpsychoactivedrugs,dependsonthedoseandrateofentrytothe
brain.Forexample,whensnorted,stimulantsgenerallyreachthebrainwithin3to5minutes,andtheresultingrushor"high"maynotbe
perceivedasimmediateintravenousadministrationproducesarushinabout15to30secondswhereassmokingproducesanalmost
immediateeffect(ONDCP,1998a).
Becauseoftherapidityofdeliveryandhigherdosages,thesmokingofstimulantsproducesahighthatissaidtobefarmoreintensethan
thoseproducedthroughotherroutesofadministration.

Routeofadministrationhasbeenshowntoaffecttheresultinglevelofstimulantinthebody.Inacomparisonoforalingestionversus
smoking,CookmeasuredplasmalevelsofMAafteroraladministrationandaftersmoking(seeFigure25)(Cook,1991).Fortheoral
doseof0.25mg/kg,plasmalevelsbegantorise30minutesafteringestionandreachedpeaklevels(approximately38ng/mL)atabout3
hoursafteringestion.Plateaulevelsweremaintaineduntilabouthour4andthenslowlydeclinedoverthenext4hours.Aftersmoking
(doseofabout21mg/subject),MAplasmalevelsapproximated80percentofpeaklevelswithinminutes,peaked(approximately42
ng/mL)atabout2hoursafteradministration,maintainedapeakplateauforanother2hours,andthenslowlydeclinedoverthenext4
hours.Bycomparison,plasmalevelsofsmokedcocaineandsmokedMAbothpeakedrapidly(Cook,1991).Plasmalevelsofsmoked
cocaine(doseof21to22mg/subject)peakedatapproximately240ng/mLatabout5to10minutesafteradministration.Cocaineplasma
levelsthendeclinedrapidly,droppingto50percentofmaximumlevel(halflife)within1hour.SmokedMA(doseof21to22mg/subject)
nearedpeaklevels(approximately50ng/mL)withinminutesandcontinuedtoclimbuntilabout2hoursafteradministrationbeforeslowly
taperingoff.However,halflifelevelswerenotreacheduntil11to12hoursafteradministration(seeFigure26).Thelongplateau
effectandthemuchlongerhalflifeofMAversuscocainesuggestsconsiderabledangersinrepeatedsmokingofMAbecauseremarkably
higherplasmaconcentrationscouldbeexpectedtooccurifthedoseisrepeated,evenatfairlylongintervals(Cook,1991).Because
stimulantsexerttheireffectsinadosedependentmanner,therouteofadministrationhasseriousneurological,medical,psychiatric,and
neurocognitiveimplicationsforthestimulantuserandthetreatmentprovider.Theintensehighsproducedbysmokingcrackcocaineorice
MAcanleadtoequallyintense"lows"duringwithdrawal(e.g.,dysphoria,depression,irritability,anxiety,paranoia,dramaticmood
swings).Thesubsequentcravingscanalsobeextremelyintense.Prolongedhighdosesofstimulants(e.g.,duringbingeing)maycause
greaterandlongerlastingneurologicaldamage,whichinturnmayleadtogreaterandlongerlastingcognitivedeficits.Theonsetof
stimulants'chroniceffectsvariesacrossindividuals,andalthoughtherearefewdatatopredicthowlongitwilltakeforanyusertobegin
sufferingfromthechroniceffectsofstimulantabuseanddependence,onsetisprobablyrelatedtothesizeofthedoses,thefrequencyof
dosing,andtherouteofadministration.However,ingeneral,thehigherthedosesandthemorefrequentlythedosesareadministered,the
morequicklythechroniceffectswillappear.Fromatreatmentprovider'sperspective,astimulantuser'spreferredrouteofadministration
affectstheextentanddepthofchroniceffectsand,therefore,hasimplicationsforchoosingthemostappropriatetreatmentapproach.(See
Chapter4forafulldiscussiononthepracticalapplicationsoftreatmentstrategies.Foradiscussiononrouteofadministrationeffectson
toxicityandadversereactions,seeChapter5.)

Figure
Figure25:ComparisonofPlasmaLevelsofMethamphetamineAfterOralAdministrationandSmoking.

Figure
Figure26:ComparisonofPlasmaLevelsofMethamphetamineAndCocaineAfterSmoking.

Cocaine

Acute Effects
Cocainehastwomainpharmacologicalactions.Itisbothalocalanestheticandacentralnervoussystem(CNS)stimulanttheonlydrug
knowntopossessbothoftheseproperties.Cocaineexertsitslocalanestheticactionsbyblockingtheconductionofsensoryimpulseswithin
nervecells.Thiseffectismostpronouncedwhencocaineisappliedtotheskinortomucousmembranes.Cocainehydrochloridehas
approvedmedicaluseasalocalanestheticinsurgeryofthenose,throat,andlarynx.

AsaCNSstimulant,cocaineaffectsanumberofneurotransmittersystems,butitisthroughitsinteractionwiththedopamineandthe
limbicrewardsystemthatcocaineproducessomeofitsmostimportanteffects,includingitspositivereinforcingeffects.Themajor
influenceofcocaineonthedopaminesystemisitsabilitytoblockthesynapticreuptakeofdopamine.AsshowninFigure27,cocaine
doesnotdirectly"stimulate"thedopaminesystemrather,itcausesthesystemtobestimulatedbypreventingdopaminefrombeing
removedfromtheintracellularspace.Cocaineblockadeofthedopaminereuptaketransporterextendstheavailabilityofdopamineinthe
synapticspacewhereitcontinuestooccupythedopaminereceptorandcausesthepostsynapticneuronstofireforalongerthannormal
period.Thisextendedfiringofthepostsynapticneuronsresultingfromprolongeddopaminereceptoractivityisinitiallyexperienced
subjectivelybythecocaineuserasapositivesensationinvolvingincreasedenergy,arousal,andstimulation.Arecentstudyhas
demonstratedarelationshipbetweentheintensityofcocaine'ssubjectiveeffectsandthedegreetowhichthedopaminereuptake
transporterisblocked(Volkowetal.,1997a).Theeffectsexperiencedbyusersofcocaineduringtheinitialperiodoftheiruseare
generallymoodalteringinapositivemanner(Washton,1989).Formostindividuals,thesubjectiveexperienceoftheacuteeffects
includesageneralizedstateofeuphoriaincombinationwithfeelingsofincreasedenergy,confidence,mentalalertness,andsexual
arousal.

Figure
Figure27:CocaineBlockadeoftheDopamineReuptakeTransporter.

Undertheproperenvironmentalcircumstances,individualsalsoreportthatcocaineheightenstheirabilitytoconcentrate,increasessexual
excitement,increasestheirsociability,anddecreasesanypreexistingshyness,tension,fatigue,depression,orboredom.Manypeoplefeel
moretalkative,moreintenselyinvolvedintheirinteractionswithothers,andmoreplayfulandspontaneouswhenhighoncocaine.Asthey
comedownfromtheircocainehigh,someusersexperiencetemporaryunpleasantreactionsandaftereffects,whichmayinclude
restlessness,anxiety,agitation,irritability,andinsomnia.Duringthis"rebound"period,suspiciousness,confusion,hyperarousal,andother
elementsofparanoidthinkingmayalsoappear.

Withcontinuedescalatinguseofcocaine,theuserbecomesprogressivelytoleranttothepositiveeffectswhilethenegativeeffects
steadilyintensify(Washton,1989).Usersreportthatthehighsarenotsohighanymoreandthereboundaftereffectsincreasinglyleadtoa
dysphoric,depressedstate.Thesenew"lows"mayreinitiatethedesireformorecocaineinafutileattemptatmoodnormalization.The
searchforthepreviouslyexperiencedhighwilleventuallyleavetheuserinthedepthsofdepressionanddespair.

Whensnorted,smoked,orinjectedintravenously,cocainequicklyproducesanintensehigh.Butbecauseitisrapidlymetabolizedinthe
body,thishighisshortlived.Effortstoreplicatetheinitialhighpromptuserstotakeitoftenandrepeatedly.Becauseofitsmechanismof
action,cocainemayproducestrongcravingandstrongconditioningofcuesassociatedwithitsuse.Theresultsofarecentbrainimaging
studyrevealedthatcocaine'sfastuptakeinthebrainhasamajorroleinitsrewardingeffectsandthatitsfastclearancefromthebrain
setsthestageforfrequentabuse,craving,andthebingepatternincocaineaddiction(Volkowetal.,1996).Theseresearcherspostulated
thatdopaminergicactivationofthelimbicrewardsystemisinvolvedintherewardingeffectsofcocaine(andperhapsmost,ifnotall,
substancesofabuse)andthatcontinuedactivationofthissystemmayleadtolongtermchangesintheassociatedneuralcircuitsthat
perpetuatethecompulsiveadministrationofthisdrug(seebelow).

Cocaineusealsohasacuteadversephysiologicaleffectsinvolvingtherespiratory,cardiovascular,andcentralnervoussystems.Systemic
toxicitytococaineischaracterizedbyprofoundsympatheticstimulationoftherespiratory,cardiovascular,andcentralnervoussystems,
producingacombinationofmedicalandpsychologicaleffectssometimesknownasthe"cocainereaction."(Foradditionaldetailsonthe
medicalaspectsofcocaineabuse,seeChapter5.)

Chronic Effects
Formanycocaineusers,theinitialexperimentalusebeginstogivewaytomorefrequentorregularuse.Withcontinued,intensifieduse,
the"casual"userwillprogresstotheabusestage,requiringlargerandlargerdosestoachievethedesiredeffects.Theabusermay
becomeobsessedwiththeritualsofcocaineadministrationandmayfindthatmanycommonitemsorsituationstriggercravingsforthe
drug.Forsome,abusewillleadtofullfledgedaddiction.Therewillbeoverwhelmingurgesandcravingsforcocaine,andtheremaybe
aninabilitytoselflimitorcontroluse.Thecocaineaddictwilldenythatshehasadruguseproblemandwillcontinueuseofcocaine
despitethenegativeconsequences.Atthisstage,theadverseconsequencesofcocaineaddictionhaveprobablyaffectedallaspectsofthe
user'slife.TheaddicthassuccumbedtowhatDr.SidneyCohencalledcocaine's"pharmacologicalimperative"(Washton,1989).Figure
28liststhecharacteristicsofthestagesofcocaineaddiction.

Box
Figure28:TheCourseofCocaineAddiction.EarlyStageBrainchemistryalteredAddictivethinkingbeginsObsessive
thoughtsCompulsiveurgesConditionedcravingsLifestylechangesWithdrawalfromnormalactivities(more...)

Thetimetablefortheonsetofthechroniceffectsofcocaineusevariesacrossindividualsandmaydependonthesizeofthedoses,the
frequencyofdosing,andtherouteofadministration.Therearenodatatobaseapredictiononhowlongitwilltakeforanyindividualto
begintosufferfromthechroniceffectsofcocaineuse.However,similartotheeffectsofMA,thehigherthedosesandthemore
frequentlythedosesareadministered,ingeneral,themorequicklythechroniceffectsofcocainewillappear.Inaddition,intranasal
administration(snorting)isassociatedwithsloweronsetofchroniceffectsthanifcocaineissmoked(freebaseorcrack)orinjected
intravenously.Clearly,therearetremendousindividualdifferencesinthistimetable,withsomeindividualsreportinganabilitytousefor
extendedperiodswithfewsignsofnegativeconsequencesandothersreportingaverydramaticonsetofseveredetrimentaleffectsassoon
asafewweeksormonthsafterinitiationofcocaineuse.

Physically,thecocaineaddictmayappearthinorevenemaciated.Personalhygieneandselfcaremaybeneglected,andmedicaland
dentalneedsmaygounmet.Becausecocainesuppressesappetite,theuserfailstoeatproperlyandmaysufferfromvitamindeficiencies.
Severeaddictsmayignorefood,clothing,shelter,andsexualneeds.

Psychologically,cocaine'schroniceffectsareexactlytheoppositeofthedesiredinitialeffects.Continuedcocaineuseincreasesparanoia
andconfusionandcausesaninabilitytoconcentrateandaninabilitytoperformsexually.Thesamesubstancethatacutelyproducedamild
sensationofarousalanddecreasedfatigue,onachronicbasisresultsinchestpain,insomnia,anorexia,episodicdepression,andextreme
fatigue.

Fromatreatmentperspective,thecuriousthingisthattheuseroftenaccuratelyperceivesandattributesthepleasurable,acuteeffectsto
theuseofcocaine.However,hefrequentlyisunableorunwillingtorecognizetherelationshipofthenegative,chroniceffectstotheuse
ofcocaine.Althoughitmaybedramaticallyapparenttofamilyandfriendsthattheeffectsofcocainearehighlydetrimentaland
destructivetotheuser,theusermayinsistthattheuseofcocaineisveryhelpfulandbeneficial.Theextensivehealthcompromising
effectsofcocaineabuseareapparentwhenexaminingthebehavioralandpsychologicalprofileofclientsastheyentersubstance
treatment.Generally,theseclientsexhibitapronounceddisruptioninhealthybehaviorsandanelevationindysphoricemotionsincluding
anxiety,depression,andparanoia(Castroetal.,1992).

Chronicabuseofcocainemaycauseneuropsychologicalimpairments(O'Malleyetal.,1992)aswellasneuropsychiatricsyndromes
(Herningetal.,1997).Cocaineinducedcognitivedeficitscanlastupto3monthsafterheavyusebeforebaselinefunctioningisrestored.
Intheirreview,WeinriebandO'Brienfoundastrongassociationbetweenthechronicuseofcocaineanddeficienciesinshortterm
auditoryrecall,memory,concentrationespeciallyfornonverbalabstractingandproblemsolvingandslowedreactiontime(Weinrieb
andO'Brien,1993).

Thephysical,psychological,andcognitiveeffectsofchroniccocaineusereflecttheunderlyingphysiologicaleffectsattheheartofthese
effectsiscocaine'simpactontheneurotransmitterdopamine.

Methamphetamine
Acute Effects
AlthoughresearcheffortscontinuetofocusontheeffectsofMA,therearelimiteddataonMA'seffectsonhumans(CSAT,1997).Much
oftheavailableinformationhasbeensurmisedfromtheliteratureoncocaine.However,thephysiologicaleffectsofMAaregenerally
similartothoseofcocaine:increasedheartrate,elevatedbloodpressure,elevatedbodytemperature,increasedrespiratoryrate,and
pupillarydilation.Otheracuteeffectsincluderapidheartrate,irregularheartrate,andirreversible,strokeproducingdamagetosmall
bloodvesselsinthebrain.

MA'spsychologicaleffects,likethoseofcocaine,includeaheightenedsenseofwellbeingoreuphoria,increasedalertness,increased
vigor,decreasedfoodintake,anddecreasedsleeptime.Acuteadministrationhasbeenshowntoincreasesocializationinhumans.High
dosesmayproducerepetitiveandautomaticactsinbothhumansandanimals,andinhumans,maycauseirritability,aggressivebehavior,
excitement,auditoryhallucinations,andparanoia(delusionsandpsychosis).Dangerouslyelevatedbodytemperatureandconvulsionsoccur
withMAoverdoses,andifnottreatedimmediately,canresultindeath.Withcontinueduse,tolerancedevelopstothebehavioraleffects,
andrepeatedexposuremayproducesensitization.MAuserstendtoengageinviolentbehavior.Moodchangesarecommon,withtheuser
rapidlychangingfromfriendlytohostile.

ThecourseofaddictiontoMAisbelievedtobesimilartothatofcocaine.EventheunderlyingneurologicaleffectsofMAaresimilarto
theeffectsproducedbycocaine:increasedlevelsoffreedopamineinthebrain'slimbicrewardsystem.TheMA"withdrawalsyndrome"
islikethatofcocaine,butduetothelongereffectsofMA,withdrawalmaybemoreintenseandprotracted.Severalhoursafterlastuse,
theMAuserexperiencesadrasticdropinmoodandenergylevels.Sleepwhichmaybepromotedbytheuseofsecondarysubstances
suchasalcohol,barbiturates,andbenzodiazepinesfinallybeginsandmaylastforseveraldays.Uponawakening,theusermay
experienceseveredepression,perhapslastingforseveralweeks.Whileinthisdepressedstate,theuserhasanincreasedriskofsuicide.
Butoncetheuserfeelsthatshe"hasrecovered"fromabingeingepisode,cravingssetin,andthecycleoftenbeginsagain.

TherearethreeessentialdifferencesbetweencocaineandMA.First,MAisthoughttoenhanceCNSneurotransmissionbyincreasingthe
presynapticreleaseofdopaminewithinthelimbicrewardsystem.Second,recentresearchhasdemonstratedMA'sneurotoxicological
effectsinanimalsandhasbeguntosupportthehypothesisthatMAisneurotoxicinhumans.Unlikecocaine,MAdoescrossneuronalcell
membranesandwillenterintothemicroscopicsacs(calledvesicles)whereneuronsstoredopamine.MAisbelievedtodamagethe
storagesacsandtheneurons'axonalendingssuchthatdopamineleaksuncontrollablyintothesynapse(seeFigure29).MAcanalsocause
neurotoxicityindirectlybymobilizingdopamineoutofthesafestoragevesicleswithintheneuronandintotheneuron'scytoplasm(i.e.,the
cell'sinternalmaterial)whereitisconvertedtotoxicandreactivechemicals.Third,cocaineisrapidlymetabolizedbyplasmaandtissue
enzymes,whereasMAismetabolizedatamuchslowerrate,whichresultsinalongerdurationofaction(Cook,1991ONCDP,1998b).
Althoughthehalflife(effectivedurationofaction)ofcocaineis1to2hours,asingledoseofMAmayproduceaneffectfor8to12
hours.ThefactthatMAismetabolizedataslowerratealsoallowsmoretimeforMAtoexertitsneurotoxicologicaleffects.

Figure
Figure29:Methamphetamine'sEffectsonSynapticandIntraneuronalDopamineLeakage.

ThesustainedhighplasmalevelssuggestconsiderabledangersinrepeatedsmokingofMAbecauseremarkablyhigherplasma
concentrationscouldbeexpectedtooccurifthedoseisrepeated,evenatfairlylongintervals(Cook,1991).

Chronic Effects
ChronicabuseofMAmayresultininflammationoftheheartliningand,amonguserswhoinjectthedrug,damagedbloodvesselsandskin
abscesses.Chronicusersmayalsohaveepisodesofviolentbehavior,paranoia,anxiety,confusion,andinsomnia.Heavyusersshow
progressivesocialandoccupationaldeterioration.Psychoticsymptomsmaysometimespersistformonthsoryearsafterusehasceased.
SomeofthemostfrighteningresearchfindingsaboutMAsuggestthatitsprolongedusenotonlymodifiesbehaviors,butliterallychanges
thebraininfundamentalandlonglastingways.AnimalstudieshaveshownthatchronicuseofMAcansignificantlyreducebrain
dopaminelevelsforupto6monthsafterlastuse,withlesssignificantreductionspersistingforupto4years.MAimpairsthefunctioning
ofboththedopaminesystemandtheserotoninsystem(serotoninisanotherimportantCNSneurotransmitter).MAinducedneuronal
toxicityisspecifictocertainbrainregions(primarilythelimbicrewardsystem),andthistoxicityisreflectedbothbiochemicallyand
anatomically.TheadverseeffectsproducedbyMAareoftenlonglasting,andthereissomespeculationthatsometypesofdamagemay
bepermanent.Finally,theseimpairmentsinbrainfunctioningmayunderliethecognitiveandemotionaldeficitsseeninmanyMAusers.
UnderstandingthechroniceffectsofMAuseisessentialfortreatmentproviderswhoservethispopulation.

AnimalstudieshaveshownthathighdoseregimensofMAsignificantlydepleteneurotransmitterlevels,particularlythoseofdopamine
(e.g.,Seidenetal.,1976).Subsequentstudiesreplicatedthesefindings(e.g.,Ricaurteetal.,1980)anddemonstratedthatthesedepletions
wereevidentupto4yearsaftercessationofMAadministration(Woolvertonetal.,1989).Amorerecentstudydemonstratedthatchronic
amphetamineexposureinmonkeyscouldproducelongtermeffectsonthebrain'sabilitytoproducedopamine(Melegaetal.,1997a).
Significantdepletionofdopaminepersisted6monthslaterevenafter1year,thebraindopaminelevelswereonlyat80percentoftheir
preexposurelevels.Inaradiotracerstudyofhumans,Iyoandcolleagues(Iyoetal.,1993)revealedreductionsindopaminereceptor
bindingavailabilityinbrainareassuchasthefrontalcortexandstriatuminMAusers.AlthoughthereislittlecurrentevidenceonMA's
chroniceffectsinhumans,animalresearchhasproventhatprolongedorheavyuseofMAdramaticallyreducesthebrain'sabilityto
producedopamine.

NumerousanimalstudieshavedemonstratedthatMAcandamagebothdopamineandserotoninsystems(e.g.,Peatetal.,1983Robinson
andBecker,1986Seidenetal.,1976TrulsonandTrulson,1982a,1982bWagneretal.,1979).MAtoxicityoccursafterrepeatedhigh
doseadministration,anditisselectiveforcertainneuronalsystems,particularlythoseinthelimbicrewardsystem(e.g.,striatum,
substantianigra,nucleusaccumbens).Withinthesebraincircuits,MAhasbeenshowntoreducethenumberofnervefibers,impair
normalphysiologicalfunctioning,anddestroybothaxonsandaxonterminals(i.e.,atsynapticjunctions).Thesestudieshavealsoshown
thatMAtoxicityishighlydependentondose,routeofadministration,andfrequencywithwhichthedrugisgiven.

ProlongedorheavyuseofMAdecreasesthebrain'sabilitytomanufacturedopamine.Thisimpairmentmaypersistforupto1yearafter
theuserhasstoppedtakingMA.Researchersnowbelievethatthosechangesindopamineandthedamagedonetodopamineandserotonin
neuronsareresponsibleforthechroniceffectsofMAusethataremuchmorepronouncedthantheacuteeffects.

IfMAdoesindeedcausedamagetodopamineandserotoninsystemsinhumans,thenthereareramificationstoconsider.Oneofthe
outcomesofchronicMAuseispsychosis.Psychoticindividualsareoftentreatedwithdrugstoreverseorreturntheirbrainfunctionsto
normal,andmostantipsychoticmedicationsworkbychangingtheactivitiesofthedopamineandserotoninneurons.Theunanswered
questionis:WillantipsychoticmedicationsbeabletoeffectivelytreatMAinducedpsychosesinindividualswhosedopamineandserotonin
systemshavebeenimpairedbychronicMAabuse?Todate,therehavebeenfew,ifany,studiesinvestigatingantipsychoticmedications
forthetreatmentofchronicMAabuseanddependence.

Insummary,althoughthereismuchevidenceofMA'sneurotoxicityinanimals,theissueofwhetherMAcausespermanentdamageto
dopamineandserotoninneuronsinhumansremainsverymuchanunansweredquestion.Becauseoftheinherentdangersassociatedwith
thistypeofresearch,theinformationwillhavetocomefrompostmortemstudies,advancedneuroimagingstudies,andthedevelopmentof
newstrategiesfordetectingneurotoxicitypossiblythroughtheuseofoperantbehavioralpharmacology.Finally,thedegreeof
neurotoxicitymustbeplacedinperspective,andthefunctionalconsequencesrequirefurtherscrutinytodeterminetheimpactofchronic
MAabuseonhumanbrainfunction.

Summary
RecentresearchhasshownhowstimulantssuchascocaineandMAexerttheireffectsontheuser'snervoussystemandchangetheuser's
feelings,emotions,andbehavior.Thereisnowagreaterunderstandingofneurologicalreinforcementsystems,howsubstanceusecan
leadtodependence,andtherolesthatcravingandmemoryplayinsustainingaddiction.Althoughthereiscurrentlyadearthofresearch
regardingtheneurologic,medical,psychiatric,andneurocognitiveeffectsofstimulantsinhumans(CSAT,1994b,1997),animalstudies
havedemonstratedcocaine'sandMA'sabilitytodisruptnormalbrainfunctionandcauselonglastingandperhapspermanentneurological
impairments.Withcontinuingresearchandthedevelopmentofnewimagingtechnologies,thefullextentofthesestimulants'effectson
humanswilleventuallyberevealed.Thisnewinformationshouldcontinuetoassistinthedevelopmentofnewandimprovedapproaches
fortreatingstimulantusedisorders.

Publication Details

Copyright
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Publisher
Substance Abuse and Mental Health Services Administration (US), Rockville (MD)

NLM Citation
Center for Substance Abuse Treatment. Treatment for Stimulant Use Disorders. Rockville (MD): Substance Abuse and Mental Health Services Administration (US);
1999. (Treatment Improvement Protocol (TIP) Series, No. 33.) Chapter 2How Stimulants Affect the Brain and Behavior.