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NationalInstituteonDrugAbuse(NIDA)

TheNeurobiologyofEcstasy

(MDMA)

LastUpdatedJanuary2007

https://www.drugabuse.gov

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TableofContents

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SectionI

Aneffectivewayofstartingapresentationistopresentsomething

interestingorprovocative.Thisfirstimageshowssectionstakenfrom

theneocortexofmonkeysthatweregivenecstasytwiceadayfor4

days(controlmonkeysweregivensaline).Thesectionontheleft,

takenfromthebrainofacontrolmonkey,showsthepresenceofalot

ofserotonin.Themiddlesectionshowsasectionfromamonkeytwo

weeksafterreceivingecstasy.Pointoutthatmostoftheserotoninis

gone.Thesectionontherightshowsasectionfromamonkeyseven

yearsafterreceivingecstasy.Pointoutthatalthoughtherehasbeen

somerecoveryofserotonin,thebrainstillhasnotreturnedtonormal.

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memory.

Ecstasyisaderivativeofamphetamine(showninpurpleonthe

image).Itschemicalnameis3,4-methylenedioxymethamphetamine

(MDMA)andithasasimilarstructuretomethamphetamine.ecstasy

hasavarietyofstreetnamesincluding,XTC,Adam,M&M,E,and

essence.Explaintostudentsthatecstasyisunlikeotherdrugsof

abuse,whichareoftenderivedfromplants(e.g.,cocaine,morphine,

nicotine).Incontrast,ecstasyissynthesizedinclandestine

laboratories--infact,thereareseveral"designerdrugs"thataremade

(inclandestinelaboratories)byalteringthestructureofthe

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Thechemicalstructureofecstasyallowsittoreachthebrainquickly

afteringestion.Usetheimagetoillustratetothestudentsthepathway

thatecstasyfollowsfromthemouthtothebrain.First,thepillis

ingestedanditdisintegratesquicklyinthestomachcontents.Once

dissolved,someecstasymoleculesareabsorbedfromthestomachinto

thebloodstream,butmostoftheecstasymoleculesmovefromthe

stomachintothesmallintestine.There,theyareabsorbedintothe

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ithasacharged(orpolar)character,whichmakesitdifficulttocrossa

absorbedfromthestomachintothebloodstream.Rather,theecstasy

moleculesgetemptiedfromthestomachintothesmallintestine.In

thesmallintestinethemorealkalineenvironmentcausesecstasyto

giveupitsH+,becomingmorenonpolar.Thelargesurfaceareaand

themorealkalineenvironmentenabletheecstasymoleculestodiffuse

acrossthemembraneintothebloodcapillariesveryquickly.

Ecstasymoleculesthathaveenteredthebloodstreamfromthe

stomachandsmallintestinesthentraveltotheliver(shownbythe

bottombluearrows).Intheliver,someoftheecstasyismetabolizedto

inactivecompoundsandtherestiscarriedthroughtheveinstothe

drugsfromenteringthebrain.However,ecstasyispredominantlyinits

nonpolarforminbloodandthereforeitcrossesthebarrierintothe

brainveryeasily.Itwilltakeabout15minutesforecstasytoreachthe

brainiftakenonanemptystomach.

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Inrecentyears,therehasbeenalotofresearchcarriedoutto

understandhowecstasyaffectsthebrain.Scientistshavemadealotof

progressinidentifyinghowecstasychangesmoodandbehavior.

Indicatetostudentsthatecstasyhasshort-termandlong-termeffects

onthebrain.Theshort-termeffectsofecstasyincludechangesinbrain

effectsareproduced.

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Bringuptheimportanceofanimalsinresearch.Researchinanimals

hasprovideduswithadetailedunderstandingabouttheactionsof

ecstasyinthebrain.Infact,manyoftheresearchfindingsobtained

fromanimals,suchasratsandmonkeys,havenowbeenreplicatedin

humans.Indicatetothestudentsthatanotherimportantaspectof

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Beforeexplaininghowecstasyworks,itmaybehelpfultopointoutthe

areasofthebrainthataresensitivetotheeffectsofecstasy.ecstasy

affectscognition(thinking),mood,andmemory.Italsocancause

anxietyandalteredperceptions(similartobutnotquitethesameas

hallucinations).Themostdesirableeffectofecstasyisitsabilityto

hippocampus(blue),basalganglia(purple),andhypothalamus(green),

whichisinvolvedinchangesinmood,emotions,andtheproductionof

anxiety(thehippocampusisalsoinvolvedinmemory).Scientistsdo

notknowyetwhichareaofthebrainisinvolvedintheabilityof

ecstasytogeneratefeelingsofempathy(youcouldaskstudentsto

suggestwheretheythinkecstasymightdothis-limbicareasarea

goodguess).

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effects.Theseincludeelevatedmoodandfeelingsofempathy.The

Studentsmightaskyouifecstasyisaddictive.Scientistsandhealth

professionalsdon'thaveadefinitiveansweryet.Fornowthereare

severalpiecesofevidencethatsuggestthatecstasyhasthepotential

tobeaddictive.Inonestudyofecstasyusers,43%ofrespondentsmet

criteriathatarecommonlyusedtodeterminedependenceforother

willnotself-administerdrugsthatarenotaddictive.Inaddition,thereis

emergingresearchtoshowthatecstasyhasactionsinaspecific

pathwaywithinthelimbicsystemcalledthe"rewardpathway",which

canexplainit'sreinforcingeffects.Infact,alladdictivedrugsactin

Manyofthepsychologicaleffectsofecstasyareduetoitsactions

withinthelimbicsystem(theamygdala,inred,andhippocampus,in

blue,especially).Theabilityofecstasytoproducemildstimulationis

duetoitsactionsinanotherpartofthelimbicsystem--thebasal

ganglia(inpurple).Itisherewhereecstasy'seffectsonthedopamine

systemmaybeimportant.Theheightenedperceptionsinvolvethe

actionsofecstasyintheneocotex(inyellow).ecstasycanalsoreduce

theappetite,becauseitactsinthehypothalamus(ingreen),which

controlsfeedingbehavior.

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Peoplewhotakeecstasydesireitspleasurableorreinforcingeffects

(justdescribedinthelastimage).However,fewdrugsareableto

producedesirableeffectswithoutalsoproducingsideeffects.ecstasy

isnoexception,andthereareseveralsideeffectsoradverseeffects

thatcanoccur,especiallyathighdoses.However,somepeoplewho

clenching)andhyperthermia.Inthelattercase,ecstasycandisruptthe

abilityofthebraintoregulatebodytemperature.Thisusuallyresultsin

hyperthermia,especiallywhentheuserisinahotenvironmentand/or

engaginginintensephysicalactivitysuchasfastdancingat"rave"

parties.Youcanprovidesomeexamplestoshowwhereecstasy

producesthesesideeffects.Forexample,thedevelopmentofthirst

andthehyperthermiaareduetoactionsofecstasyinthe

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temperature.Youmightpointoutthattheeffectofecstasyonthe

pathwaydescendsdownthespinalcord).Themotorneuronssend

Somepeopletakemultipledosesofecstasyinonenight("stacking").

Thismightbeduetothereinforcingeffectofthedrugwearingoffover

time.Often,ifsomethingfeelsgood,onewantstodoitagain!

Unfortunately,increaseddosesalsoincreasetheadverseeffects,and

someofthesecanbecomelife-threatening.Forexample,repeated

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hyperthermia,hypertension(highbloodpressure),cardiacarrhythmias

fluidretentionandkidneyfunctionand,ofcourse,bodytemperature.If

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SectionIII

Ecstasyisanunusualdrugbecauseithaseffectsonthebrainthat

developandpersistforashorttimeafterthedrugiseliminatedfrom

thebody.Theseoftenincludethedevelopmentofdepression-like

feelings,anxiety,restlessness,irritability,andsleepdisturbances.

These"aftereffects"occurbecauseofachemicalchangethattakes

placeattheserotoninsynapse.Toillustratehowthisoccurs,thisimage

showstheserotoninsynapseduringandaftertakingecstasy.Three

conditionsareillustrated:ontheleft,neuronsnormallyrelease

serotonininresponsetoelectricalimpulses(basicallythereleaseisin

"spurts").Thisresultsinthenormalactivationofserotoninreceptors,

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keel.So,forexample,wehaveanormalmoodandwearecalm.Inthe

replacethatwhichwaslost,soonceEcstasyisgonefromthebody(on

takingecstasyismemorydisruption.(Askstudentsiftheycanfigure

outwhichareaofthebrainisaffectedhere;theanswershouldinclude

thecerebralcortexandthehippocampus).Thisisanadverseeffect

thatmaypersistwithrepeatedorlong-termuseofecstasy.Indicateto

studentsthatthereissomeevidenceforthisobtainedfromhuman

studies.

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theterminalismetabolizedbyenzymes)arediminishedinthebrains

Thisisdescribedinthenextimage.

Averyimportantexperimentwasperformedinmonkeystodetermine

ifecstasycanactuallydamageneurons.Monkeysweregivenecstasy

twiceadayforfourdays(controlmonkeysweregivensaline).One

ImagecourtesyofDr.GARicaurte,JohnsHopkinsUniversitySchoolof

Medicine.

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groupofmonkeys'brainswereremovedtwoweekslaterforanalysis

themonkeywhodidnotreceiveanyecstasyhadalotofserotonin(in

destructionoftheserotonincellbodiesarisingbackinthebrainstem).

Pointtotheright-handpanelandshowstudentsthatthisdamage

appearedtobelong-termbecausesevenyearslatertherewassome

recovery,butitwasnotcomplete.Scientistsfoundsimilarchangesin

limbicareasofthebrainsuchasthehippocampusandamygdala.The

monkeyexperimentsareanimportantreminderthathumansmay

humans,becauseitrequiresremovingpiecesofthebraintolookfor

thelossoftheserotoninneurons.

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Thisimageillustratesthedegenerationofserotoninnerveterminals

afterlong-termorrepeateduseofecstasy(youcanreferbackto

image9tocomparethisdegeneratingterminaltoahealthyterminal).

Remindstudentsthatwehaveseveralpiecesofevidencethatsupport

thiseffectofecstasy.Experimentsinanimalsgivenecstasyindicate

abnormal.

Althoughscientistsdonotyetknowforcertainhowecstasydamages

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formation)foundintheterminalsmaycausetheterminalstobe

Itisnotpossibletolookdirectlyatdamagedserotoninterminalsin

livinghumans.Thebestevidencefordamagetoserotoninneurons

afterlong-termorrepeatedEcstasyuseinhumansistheassociation

betweentheneurochemicalandbehavioralchanges.Althoughmany

behavioralmeasureshavebeenassessedinEcstasyusers(thelistis

extensive),themostconsistentfindingsarethatsomechronicEcstasy

usershaveverbalandvisualmemoryimpairments.Researchis

ongoingtodetermineifthinkingabilityisdisruptedaswell.However,it

isimportanttokeepinmindthatmanyusersofEcstasymay

unknowinglybetakingotherdrugsthataresoldasEcstasy,and/or