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MedicalHypotheses(2005)64,930–937
Endogenouspsychoactivetryptamines
reconsidered:ananxiolyticrole
fordimethyltryptamine
MichaelS.Jacob,DavidE.Presti
*
DepartmentofMolecularandCellBiology,UniversityofCalifornia,Berkeley,CA94720-3200,USA
Received15October2004;accepted4November2004
SummaryThepresenceofthepotenthallucinogenicpsychoactivechemical
N,N
-dimethyltryptamine(DMT)inthe
humanbodyhaspuzzledscientistsfordecades.EndogenousDMTwasinvestigatedinthe1960sand1970sanditwas
proposedthatDMTwasinvolvedinpsychosisandschizophrenia.Thishypothesisdevelopedfromcomparisonsofthe
bloodandurineofschizophrenicandcontrolsubjects.However,muchofthisresearchprovedinconclusiveand
conventionalthinkinghassinceheldthattracelevelsofDMT,andotherendogenouspsychoactivetryptamines,are
insignicantmetabolicbyproducts.TherecentdiscoveryofaG-protein-coupled,humantraceaminereceptorhas
triggeredareappraisaloftheroleofcompoundspresentinlimitedconcentrationsinbiologicalsystems.Interestingly
enough,DMTandotherpsychoactivetryptaminehallucinogenselicitarobustresponseatthetraceaminereceptor.
Whileitiscurrentlyacceptedthatserotonin5-HT
2A
receptorsplayapivotalroleintheactivityofhallucinogenic/
psychedeliccompounds,weproposethattheeffectsinducedbyexogenousDMTadministration,especiallyatlow
doses,aredueinparttoactivityatthetraceaminereceptor.Furthermore,wesuggestthatendogenousDMTinteracts
withtheTAreceptortoproduceacalmandrelaxedmentalstate,whichmaysuppress,ratherthanpromote,symptoms
ofpsychosis.ThishypothesismayhelpexplaintheinconsistencyintheearlyanalysisofendogenousDMTinhumans.
Finally,weproposethatamphetamineactionattheTAreceptormaycontributetothecalmingeffectsof
amphetamineandrelateddrugs,especiallyatlowdoses.
c
2004PublishedbyElsevierLtd.
Introduction
oftheAmazonianplant
Anadenantheraperegrina
[2–4]
.Thissnuff,variouslycalled
cohoba
and
yopo
,isusedbyAmazoniantribesinshamanicrit-
uals.
Epena
,anotherintoxicatingAmazoniansnuff
preparedfromthebarkresinofplantsofthegenus
Virola
andalsousedritualistically,wasshownin
the1960stocontainDMT
[2–4]
.DMThassince
beendescribedinhundredsoforganisms:fungi,
marinesponges,tunicates,frogs,legumes,and
grasses
[5]
.DMTisperhapsmostwellknownfor
itspresenceintheplant
Psychotriaviridis
,which
Scienticknowledgepertainingtothechemical
N,N
-dimethyltryptamine(DMT)beganinconspicu-
ouslywithitssynthesisbyManske
[1]
in1931.More
thantwodecadeslater,inthe1950s,DMTwas
identiedasoneoftheactivecompoundsinapo-
tentpsychoactivesnuffpreparedfromtheseeds
*
Correspondingauthor.Tel.:+15106432111.
E-mailaddress:
presti@socrates.berkeley.edu
(D.E.Presti).
c
2004PublishedbyElsevierLtd.
0306-9877/$-seefrontmatter
doi:10.1016/j.mehy.2004.11.005
 Endogenouspsychoactivetryptaminesreconsidered:ananxiolyticrolefordimethyltryptamine 931
isusedincombinationwiththevine
Banisteriopsis
caapi
,topreparethehallucinogenicbrew
ayahua-
sca
or
yage´
,usedbyindigenouspeoplesintheAma-
zonbasininshamanicceremonies
[6]
.Thepotent
hallucinogeniceffectsofpureDMTinhumanswere
rstreportedbySzara
[7]
in1956.Then,in1965,
DMT,tryptamineand5-hydroxy-
N,N
-dimethyltryp-
tamine(bufotenine)werereportedasnormalcon-
stituentsofhumanurineandblood
[8]
.
DespiteDMTsubiquitouspresencethroughout
theplantandanimalkingdoms,andeveninthehu-
manbody,itwasclassiedasaScheduleOnecon-
trolledsubstancewiththeimplementationofthe
USControlledSubstancesActin1970.ASchedule
OnecontrolledsubstanceisdenedbytheUSgov-
ernmentasasubstancethatdemonstratesahigh
potentialforabuse,hasnoacceptedmedicaluse,
andlacksacceptedsafetyforuse,evenundermed-
icalsupervision.TheplacementofDMTandother
hallucinogenic/psychedeliccompoundsinSchedule
Onehassignicantlyimpededscienticresearch
pertainingtotheseexceedinglyinteresting,neuro-
chemically-activemolecules
[9,10]
.DMTisessen-
tiallynon-toxictobodyorgansanddoesnotcause
physiologicaldependenceoraddictivebehaviors.
Thus,itsclassicationasadangerousdrugisbased
primarilyonsocio-politicalreasonsratherthan
clinical-scienticevidence.DMTisalsointerna-
tionallyclassiedasaScheduleOnesubstanceby
the1971UnitedNationsConventiononPsychotro-
picSubstances.
SoonafterthediscoveryofendogenousDMTin
humans,psychiatricresearchersbegantoreport
correlationsbetweenincreasedlevelsofDMTin
humanuidsandschizophrenia
[11–15]
.Itwas
suggestedthatexcessDMTbiosynthesismaypro-
motepsychoticsymptoms.Thisproposal(which
issometimesknownasthe‘‘transmethylation
hypothesis,’’becauseit involvesmethylated
amines)attractedinterestinthe1960sand
1970s.Inmorerecentyears,thetransmethylation
hypothesishasbeeneclipsedbythedopamine
hypothesisofschizophrenia,whereinpsychotic
symptomsarerelatedtoexcessiveactivityincer-
taindopaminergiccircuitsinthebrain.Recent
biochemicalandgeneticcharacterizationofa
newfamilyofreceptors,thetraceamine(TA)
receptors,foundinmammaliancentraland
peripheralnervoustissues,hasrenewedinterest
inapotentialrolefortraceaminesinpsychosis
[16]
.Itisbelievedthattryptamine,anecessary
metabolicprecursortoDMT,canactasaneuro-
transmitterattheTAreceptor
[16]
.AsDMTalso
showsactivityattheTAreceptor
[17]
,endoge-
nousDMTmayfunctionasaneurotransmitterin
theTAsystem.Tenyearsago,aseriesofdouble-
blind,placebo-controlledstudiesofDMTinhu-
mansincludedanalysisofbiologicalresponses
(neuroendocrine,autonomicandcardiovascular)
aswellasthesubjectiveeffects
[18,19]
.Inthese
studies,administrationofanon-hallucinogenic
doseofDMT(0.05mg/kg)producedarelaxed
andcomfortablementalstateinmanysubjects.
Weproposethatthemaineffectofendogenous
DMTmayresemblelow-dose,non-hallucinogenic
DMTadministration,providingahomeostatic
responseto
alleviate
,ratherthanpromote,
psychoticsymptoms.
EndogenoushumanDMTand
schizophrenia:theearlyresearch
ItwasoriginallysuggestedbyOsmondandSmy-
thies
[20]
in1952thatadisorderinmetabolism
mightproduceapsychotomimeticsubstanceand
promptschizophrenicsymptoms.AlthoughOsmond
andSmythiesproposedthatthemethylationof
nor-adrenelinemightproducesuchapsychotomi-
meticsubstance,Axelrod
[21]
demonstratedthat
mammaliantissuecouldproduceDMTandOsmond
andSmythies’theorywaslaterextendedbyBrune
andHimwich
[22]
toincludethepossibilityof
methylatedtryptaminesactingasanendogenous
triggerforpsychoses.Inashorthalf-pagereport
in
Nature
,FranzenandGross
[8]
reportedthepres-
enceof
N,N
-dimethyltryptamineinhumanblood
(8
·
10
9
g/mL)andurine(4
·
10
5
g/24h).
Subsequentresearchfoundtheselevelstobetoo
highandthattheaverageconcentrationsinnormal
subjectstendedtobearound5
·
10
10
g/mLin
blood
[12]
and4
·
10
7
g/24hinurine
[23]
.(It
shouldbenotedthatthethresholddosetoproduce
subjectiveeffectsinhumansisabout5
·
10
5
g/kg,whichleadstopeakbloodconcentrations
of1
·
10
8
g/mL
[18,24]
).AfterFranzenand
Gross’discovery,psychiatricresearchersreported
increasesintheurinaryexcretionofDMTinschizo-
phrenicpatients
[12–15]
.Murrayetal.
[11]
found
astatisticallysignicantincreaseinthelevelsof
DMTintheurineofschizophrenics(1
·
10
6
g/
24h),butfoundthatnotallschizophrenicpatients
excretedincreasedamountsofDMT.Theauthors
concludedthatDMTdidnotplayacausalrolein
schizophrenia,butcouldbeanintermediaryfac-
tor,exacerbatingcertainfeaturesofpsychosis.
Otherresearchprovedinconclusiveandresultsbe-
tweenstudieswereoftencontradictorywitheither
nocorrelationbetweenschizophreniaandex-
cretedDMT,ornostatisticallysignicantdiffer-
ence
[25–27]
.
932
JacobandPresti
DMTisnolongerconsideredtobealikelycause
ofschizophrenia,butitisstillrecognizedasplaying
apotentialroleinpsychoticsymptomatology.Are-
viewbyCiprian-OllivierandCetkovisch-Bakmas
[28]
summarizesthisupdatedhypothesis.Intheir
review,Ciprian-OllivierandCetkovisch-Bakmasre-
portresultsfromseveralstudiestheycompletedin
the1980swhereintheyfoundasignicantcorrela-
tionbetweenincreasedurinaryexcretionofDMT
andtheseverityofpsychoticsymptoms.The
authorsreadilyrecognizethecomplexityinvolved
inschizophrenia,suggestingacomplicatedinterac-
tionamongbiogenicamines,includingserotonin,
dopamine,andthe
N
-methylatedtryptamines.It
isinterestingtonotethatresearchersinFinlandre-
centlyfoundhigherlevelsofbufotenine(apsycho-
active
N
-methylderivativeofserotonin)inthe
urineofpsychiatricpatients(upto3
·
10
5
g/mL
[29]
).
Severalchallengeshavepreventedamorepre-
ciseexaminationoftheroleofendogenousDMTin
general:(1)thekeyenzymesthatproducemeth-
ylatedtryptamineshavenotbeenadequately
characterizedinvivo;(2)noneurochemicalsys-
temhasbeenlinkedwithendogenous,psycho-
activetryptaminesatlow,non-hallucinogenic
concentrations;(3)modernanalyticaltechniques
havenotbeenusedtoexaminethebloodandur-
ineconcentrationsofDMTanditsmetabolites.
Theremainderofthispaperwilladdressthese
issues,specicallythersttwo,inlightofrecent
discoveries.
abundantaminoacid,tryptophan.Thedecarboxyl-
ationoftryptophanbyaromaticaminoaciddecar-
boxylase(AADC),producesthetraceamine,
tryptamine(TYP).5-hydroxytryptohphanand
LL
-
DOPAarethemostwellknownsubstratesforAADC,
enroutetothesynthesisofserotonin(5-HT,5-
hydroxytryptamine)anddopamine,respectively.
Nonetheless,tryptophan(aswellasothertrace
amineprecursorssuchastyrosineandphenylala-
nine)canactasasubstrateforAADC,consistent
withtheobservationthatAADCistherate-limiting
enzymeinTYPformation
[31]
.Thediscoveryofthe
traceamine(TA)familyofreceptorshastriggereda
reconsiderationoftheroleofAADC.Infact,thehu-
manAADCgenecanundergoalternativesplicing,
fashioningtwodifferentisoforms
[32]
.Oneiso-
form,AADC
480
,catalyzesthedecarboxylationof
5-hydroxytryptohphanand
LL
-DOPA;theother,
AADC
442
,wasunabletodecarboxylateeither.It
wasnotedthatthesubstrateforAADC
442
isunclear,
butthatphenylalanine,tryptophan,andtyrosine
mayactassubstrates
[32]
.Nofurtherresearch
hasinvestigatedthepossibilityofauniqueAADC
isoformspecictothetraceaminepathway.
Thepathwayshownin
Fig.1
concludeswithtwo
successivemethylationreactions.First,TYPcan
actasasubstrateforindolethylamine-
N
-methyl-
transferase(INMT)andismethylatedtogive
N
-
methyltryptamine(NMT).Second,NMTcanactas
asubstrateforINMTaswell,thusformingDMT.
BiosynthesisofDMTisdependentupontheenzy-
maticefciencyandspecicityofINMT.Inprepa-
rationsofrabbitlungenzyme(themostwidely
studiedINMT),NMTshowsthelowest
K
m
(com-
monlyinterpretedashighbindingafnity)for
INMT,followedbyTYP
[33,34]
.5-hydroxytrypta-
mine(serotonin,5-HT)showsahigher
K
m
inrabbit
lung,suggestingalowerafnityofserotoninfor
theenzyme
[33]
.Thephysiologicalsignicanceof
thesevalueshasbeenrecentlybroughtunder
criticism.
DMTbiogenesis:newresearch
ThebiochemistryofDMTproductioninvitrowas
studiedsignicantlyinthe1970s
[30]
.
Fig.1
sum-
marizesthethreeshortstepsnecessaryforthe
completebiosynthesisofDMTfromthereadily
Figure1BiosynthesisofDMTfromtheaminoacidtryptophan:(1)aromaticaminoaciddecarboxylase(AADC)
catalyzestheformationoftryptaminefromtryptophan;(2)indolethylamine-
N
-methyltransferase(INMT)transfersa
methylgroupfromSAM(S-adenosylmethionine)totryptamine,yielding
N
-methyltryptamine(NMT).Arepeatofthis
reaction(2)withNMTasthesubstratetransfersanothermethylgroupandyieldsDMTandtwoequivalentsofSAH(S-
adenosylhomocysteine).
Endogenouspsychoactivetryptaminesreconsidered:ananxiolyticrolefordimethyltryptamine 933
Acontemporaryinvestigation,utilizingmodern
geneticandstructuraltechniques,hasprovideda
moredetailedanalysisofINMT,butdoesnotpro-
videacompletestory.Intwostudies,Thompson
etal.
[35,36]
,cloned,expressed,localized,and
characterizedtheactivitiesofrabbitandhuman
INMT.UsingNorthernblotanalysis,theyfoundrab-
bitINMTtranscriptsexpressedheavilyinthelung,
moderatelyintheliver,andweaklyinthebrain.Hu-
manINMTwasexpressedinthelung,thyroid,adre-
nalgland,heart,muscle,andspinalcord,butnotin
thebrain.Theauthorsobservehigh
K
m
values(an
orderofmagnitudehigherthaninpreviousstudies
[33,34]
)ofTYPforrecombinanthumanINMTand
anabsenceofINMTmRNAtranscriptsinthebrain.
Thus,Thompsonetal.concludethattheproduction
ofDMTinhumansisnotphysiologicallysignicant.
Theirconclusionplacesmuchweightonthesigni-
canceofobserved
K
m
valuesforrecombinanthu-
manINMTanddoesnottakeintoaccountseveral
additionalgeneticandenzymaticconcerns.
Despiteyearsofresearch,thereisnouniversally
acceptedunderstandingofthebiophysicsofen-
zymefunction
[37]
;thus,themeaningof
K
m
val-
ues,especiallyforinvivobiochemicalpathways,
isstillopentointerpretation.AlthoughThompson
etal.arguethathigh
K
m
valuessignifyan
enzyme–substratecombinationthatisnotbio-
logicallymeaningful,ameta-analysisofrecentre-
searchhasshownthathigh
K
m
valuesaresigni-
cantinbiologicalsystems
[38]
.Althoughenzyme–
substratecomplexeswithhigh
K
m
valuesshowless
bindingafnity,catalysisoftenproceedsatafaster
reactionrate.Infact,Ferhst
[38]
identiesmany
enzymesinglycolysisthatoperateat‘‘veryhigh’’
K
m
values–showingcatalyticefciencydespite
havingmMafnity.Ferhstarguesthatafnitybe-
comeslessimportantinintracellularsystems
wherehighconcentrationsofnecessarymetabo-
litesarepresentandsuggeststhatthespecicity
constant
k
cat
/
K
m
isthebestindicatorofenzyme–
substrateefciency.Thus,weadviseagainstthe
placementofundueemphasisonnumericalvalues
of
K
m
wheninterpretinginvitroactivity.Thestruc-
tureofhumanINMTneedstobedeterminedandits
invivokineticparametersmorethoroughlyas-
sessedbefore
N
-methylationoftryptaminescan
bewrittenoffasphysiologicallyirrelevant.There-
sultsofThompsonetal.shouldalsobetakenwith
cautionbecausetheirmeasurementsreectthe
activityofarecombinantenzyme,removedfrom
itsnaturalenvironmentwherecellularcompart-
mentalizationcouldsignicantlyalteritsactivity.
Geneticallyspeaking,theabsenceofconstitu-
tivelyproducedINMTtranscriptsinthebraindoes
notmeanthattheyare
never
produced;many
eventscouldpotentiallytriggerINMTtranscription
inthebrain.Abriefreportpublishedin1977
claimedthatINMTactivityincreasesunderstress
(electricshockandforcedswim)intherodent
brain
[39]
.Thus,astressresponsewhichproduces
largeamountsofTYPintissuescouldleadtosignif-
icantproductionofDMT.Inaddition,giventhe
presenceofINMTtranscriptsinperipheraltissues,
DMTproductioncouldoccuroutsidethebrainand
stillhaveactivityinthebrainbecauseDMTcan
readilycrossthebloodbrainbarrier.Thiswould
bedifferentfrommostneurotransmitters,which
donothavesignicantblood–brain-barrierperme-
abilityandthusmustbeproducedwithinthebrain.
DMT:physiologyandpsychological
effects
Adouble-blind,placebo-controlledstudyofDMTin
humanswasconductedbyStrassmanetal.
[18,19,40]
in1994.Uponintravenousadministration
ofDMTtohealthy,normalsubjects,increasesin
bloodpressure,heartrate,pupildiameter,andrec-
taltemperature,aswellasincreasedbloodconcen-
trationsof
B
-endorphin,corticotrophin,cortisol,
prolactin,andgrowthhormoneweremeasured.In
addition,usingaHallucinogenRatingScale(HRS)
developedforthestudy,Strassmanandcolleagues
reportedthesubjectiveeffectsofDMTonmental
state.Atintravenousdosesof0.2and0.4mg/kg,
therewasa‘‘nearlyinstantaneousonsetofvisual
hallucinatoryphenomena,bodilydissociation,and
extremeshiftsinmood,whichtotallyreplacedsub-
ject’spreviouslyongoingmentalexperiences.’’The
HRSincludesthefollowingsixcategories:Somaes-
thesia,Affect,Perception,Cognition,Volition,
andIntensity.Subjectsreportedstatisticallysignif-
icant,dose-dependentincreasesineachcategory
duringDMTadministration.
Strassman’sstudiesprovideanexcellentmeth-
odologyforfutureresearchwithpsychoactivetryp-
tamines.However,mostofthepsychedelicdoses
maybetoohightobeofrelevanceinunderstand-
ingendogenousDMTactivity.Nonetheless,itis
interestingthatStrassmanetal.
[19]
foundthat
theirHRSwasabletodistinguishbetweenplacebo
andalowdose(0.05mg/kg)ofDMTbetterthan
physiologicalmeasurementsofneuroendocrine,
cardiovascular,andautonomicvariables.Inother
words,subjectswereawareofsubjectivemental
statechangesevenwhenstatisticallysignicant
physiologicalchangeswerenotmeasurable.This
lowdosemaybemoreindicativeoftheeffectsof
endogenouslyproducedDMT,becauseitleadsto
934
JacobandPresti
bloodconcentrationsclosertosomelevelsob-
servedinhumansubjectsinthe1970s,although
stillhigherbyanorderofmagnitude.Aspectsof
Strassman’sworkthusprovidesavitalrststepin
characterizingtheroleDMTmightplayinvivo.
AnessentialcharacteristicofDMTpharmacology
alsoinvestigatedbyStrassmanthatdifferentiates
itfrommanyotherpsychedelicsubstancesisthat
DMTdoesnotappeartoleadtotoleranceinmam-
mals.Absenceoftolerancehasbeenshowninrats
[41]
,cats
[42]
andinhumans
[43]
.Thisprovides
additionalevidencethatendogenousDMTmayplay
aphysiologicalrole,especiallyifitsmechanismre-
quiresconsistentandrepeatedactivity.
researchersspeculatedontheexistenceofaDMT
receptor
[30]
.Itwasreportedatthattimethata
receptorwaspresentonratsynaptosomalmem-
braneswhichshowedsub-nanomolarafnity
(3.0
·
10
10
)forDMTandLSD,ledtotheproduc-
tionofcAMP
[48]
,andshowedmuchlessafnity
for5-HT
[50]
.Perhapstheseresearchershadinfact
discoveredthetraceaminereceptorovertwenty
yearsago.Additionalevidenceinsupportofaneu-
rotransmitterroleforDMTcomesfromresearch
suggestingthatDMTisactivelytransportedinto
ratnervecells,perhapsevidenceforareuptake
mechanism
[49]
.
DMTlikelyexertsmuchofitspotenthallucino-
genicresponseviathe5-HTsystem,butitseems
mostprobablethatendogenousDMTwouldinter-
actatTAreceptors,especiallygivenitpresence
atverylow(nanomolar)concentrations.Because
thereisaboutanorderofmagnitudedifference
intheresultingbloodconcentrationsbetween
thelow,non-hallucinogenicdoseofDMT(0.05
mg/kgIV)andthepeakhallucinogenicdose(0.4
mg/kgIV),weproposethatlowdoseadministra-
tionismorelikelytoprovideawindowintoDMT’s
roleduringendogenousproduction.Strassmanet
al.
[19]
suggestedthatthedifferenteffectsof
lowdose(0.05mg/kgIV)andhigherdose(0.2
mg/kgandgreaterIV)DMTadministeredtohishu-
mansubjectswasduetoagonismatboth5-HT
1A
and5-HT
2A
receptors.Itisreportedthatthe5-
HT
1A
and5-HT
2A
receptorsproduceopposingcel-
lularresponsesandareoftenexpressedonthe
samecell
[51]
.Inasubsequentstudy,Strassman
[24]
usedpindolol,a5-HT
1A
antagonist,incombi-
nationwithasub-hallucinogenicdoseofDMT(0.1
mg/kgIV)andfoundatwo-tothree-fold
enhancementofDMT’seffects(accordingtothe
HRS).Thus,itappearsthatthe5-HT
1A
issuppress-
ingDMTshallucinogenicactivity.Inhisreview,
Nichols
[45]
notesthatotherreceptorsystems
maymodifythepsychopharmacologicalresponse
ofhallucinogensandthat5-HT
2A
mediatedphos-
phoinositidehydrolysis(PI)cannotfullyaccount
fortheeffectsofhallucinogens.Forexample,
DMTshowsonlyabout20%maximumPIhydrolysis
atthe5-HT
2A
receptorwhencomparedto5-HT
[52]
.
Weproposethatthesubjectivesubtletiesoflow
dosesofDMTmaybeduetoagonismattraceamine
receptors,ratherthan,orinadditionto,effectson
the5-HTsystem.Thisstemsfromtheobservation
thatDMTelicitsastrongresponseattheTArecep-
toraswellaspossiblyshowingsub-nanomolarafn-
ity.SubjectsintheStrassmanetal.studyreported
thatlowdoses(0.05mg/kgIV)ofDMThadmildly
mood-elevatingproperties.Thesubjectiveactivity
DMT:aneurotransmitterinthetrace
aminepathway?
IfDMTplaysaphysiologicalrole,viawhatneuro-
chemicalpathwaydoesitoperate?Althoughsero-
tonin5-HT
2A
receptorsarethoughttoplaya
majorroleintheactivityofhallucinogenicdrugs,
thecomplexeffectsofthesechemicalsonmental
stateislargelynotunderstood
[44–46]
.Thedis-
coveryofreceptorsfortraceamines(tyramine,
phenethylamine,tryptamine)inthevertebrate
brainandperiphery
[47]
,withgreateractivation
byhallucinogenssuchasDMTandLSD(lysergicacid
diethylamide)thanbyserotonin
[17]
,addstothe
complexityofthesituation.Mightendogenous
DMTplayaneurochemicalrolehere?
Inadditiontodemonstratingsignicantactivity
attheTAreceptor,DMThasshownveryhighafn-
ityforsynaptosomalmembranes
[48]
andinvolve-
mentinactivetransportprocessesindicativeofa
reuptakemechanism
[49]
.ActivationoftheG-pro-
tein-coupledTAreceptorleadstotheproduction
ofcAMPandtheactivityofvarious‘‘exogenous’’
compoundsattheTAreceptorhasbeenmeasured
bycomparinglevelsofcAMPproductionrelative
totyramine
[17]
.Tyramine,whichexhibitsnano-
molarafnityfortheTA
1
receptor,istheproposed
endogenousligandforthisreceptor.Inastudycon-
ductedinvitrowith1micromolarconcentrations
ofligand,DMTactivityattheratTA
1
receptor
wasalmostequaltothatoftyramine
[17]
.Thehal-
lucinogenLSDtriggeredaslightlylowerproduction
ofcAMPandMDMA(methylenedioxymethamphet-
amine,streetname‘‘ecstasy’’)slightlylowerstill.
5-HTelicitedlessthan50%maximalcAMPproduc-
tionwhencomparedtotyramine
[17]
.Thus,the
TAreceptordemonstratesarobustresponseto
manyhallucinogens,andasubstantiallylesserre-
sponsetoserotonin.Inthelate1970s,several
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