Upload
others
View
1
Download
0
Embed Size (px)
Citation preview
Theevolutionarysignificanceofdrugtoxicityoverreward
EdwardH.HagenandRogerJ.Sullivan
ForthcomingintheRoutledgeHandbookofPhilosophyandScienceofAddiction,
S.AhmedandH.Pickard,eds.
Drugrewardisanevolutionaryconundrum.Itisnotsurprisingthatneuralcircuitry
evolvedtorewardorreinforcebehaviorsleadingtotheessentialsofsurvivaland
reproduction,likefood,water,andsex.Why,though,wouldthesesamecircuits
rewardandreinforcetheconsumptionofdrugsofabuse,whichisoftenharmful?
Herewebrieflyreviewthehistoryofreward-basedlearning,whichresultedina
widelyacceptedevolutionaryaccountofdrugrewardthatwetermthehijack
hypothesis.Wethencritiquetheevolutionarybasesofthehijackhypothesis.We
concludebysketchinganalternativeevolutionarymodelofhumandruguse
groundedindrugtoxicity.Specifically,avoidanceoftoxicdrugsisacompelling
hypothesisforthelowuseofdrugsbychildrenandwomenrelativetomen.In
addition,theregulatedingestionofsmallquantitiesoftoxinsmighthaveprovided
importantmedicinalandotherbenefitstohumansandnon-humananimalsoverthe
courseoftheirevolution.
Neurobiologicaltheoriesofdrugusearedeeplyintertwinedwiththoseofreward-
basedlearning.ThemainideawascapturedinThorndike’slawofeffect:“Ofseveral
responsesmadetothesamesituation,thosewhichareaccompaniedorclosely
followedbysatisfactiontotheanimalwill,otherthingsbeingequal,bemorefirmly
connectedwiththesituation,sothat,whenitrecurs,theywillbemorelikelyto
recur"(Thorndike1911).Therelatedconceptofreinforcementreferstotheability
ofcertainstimuli,suchasfood,tostrengthenlearnedstimulus-response
associations.Relieffromaversivestimulicouldsimilarly“negativelyreinforce"
stimulus-responseassociations.
Earlyanimalstudiesofdrugaddictionfoundevidenceforbothnegativeandpositive
reinforcement.Inanimalsaddictedto,e.g.,morphine,relieffromaversive
withdrawalsymptomsreinforcedstimuliassociatedwithobtainingthedrug,but
morphine’shedonicoreuphoriceffectsalsopositivelyreinforceddruguse(Spragg
1940;Beach1957).
Theneurobiologicalstoryofreward-basedlearningbeganwithOldsandMilner’s
observationthatratswillself-administeranelectricalcurrenttotheseptalregionof
thebrain.Theyconcludedthatsuchintracranialstimulationwaspossiblythemost
potentrewardeverusedinanimalexperimentationtothatdate(OldsandMilner
1954).Itsresemblancetodrugaddictionwasimmediatelyevident(Milner1991).
Morethantwodecadesofexperimentsensuedtoidentifythepreciseneuronsand
neurotransmittersmediatingthereinforcingeffectsofself-stimulation,in
conjunctionwithworkinvestedinunderstandingdrugrewardinitsownright.The
neuronscriticalforbothseptalself-stimulationandthereinforcingpropertiesofat
leastsomedrugsturnedouttobedopamineneuronsinthemidbrain,commonly
referredtoasthemesolimbicdopaminesystem(MDS).Thuswereborntwo
intimatelyintertwinedtheories,thedopaminetheoryofreinforcementlearningand
thedopaminetheoryofsubstanceuseandaddiction,eachdeeplyrootedinthe
stimulus-responseparadigmatthecoreofbehaviorism.
Thehijackhypothesis
Drugrewardrequiresanevolutionaryexplanation:unlikefood,sex,andother
naturalrewards,drugs,atfirstglance,donotmakeanobviouscontributiontoan
animal’ssurvivalorreproduction.Infact,chronicdruguseisoftenharmful.Hence,
itseemsthebrainshouldhaveevolvedcircuitstopreventdruguse,ratherthanto
reinforceit.Onepossibilityisthatdrugs,likewiresinthebrain,areevolutionarily
novelandtheirrewardingpropertiesareartificial.Indeed,neurobiologistscameto
viewdrugsinthesamewayasintracranialelectrodes,thatis,asevolutionarily
novellaboratoryinstrumentstoselectivelyactivateordeactivatespecificneural
circuits(Wise1996).Afternotingthat“intravenousdrugrewardsestablishand
maintainresponsehabitssimilartothoseestablishedandmaintainedbynatural
rewards"Wise(1996,320)goesontosaythat:“Thisshouldnotbesurprising;the
brainmechanismsthatmakeanimalssusceptibletobrainstimulationreward
evolvedlongbeforethehumaninventionsthatmadeintracranialself-stimulationor
drugaddictionpossible."Thesehumaninventionsinclude“e.g.theuseoffire,pipes,
andcigarettepapers;theuseofthehypodermicsyringeandneedle;agricultural
skillsfortheharvestingandcuringoftobacco;theabilitytosynthesizeorpurify
drugs;theabilitytoconcentrate,store,andtransportalcoholicbeverages”(Wise
1996,p.320).
Subsequenthighlycitedreviewarticlesontheneurobiologyofdruguseendorsed
thenotionthatbrainsaresusceptibletodrugsofabusebecausetheyare
evolutionarilynovelandareconsumedinanovelfashion.Naturalrewardssuchas
foodandsex“activate"therewardsystem,whereasdrugrewards“hijack,"“usurp,"
“co-opt,"orartificiallystimulateit(forreferences,seeHagen,Roulette,andSullivan
2013).KelleyandBerridge(2002,3306),forinstance,opentheirreviewwith:
Addictivedrugsactonbrainrewardsystems,althoughthebrainevolvedtorespondnottodrugsbutto
naturalrewards,suchasfoodandsex.Appropriateresponsestonaturalrewardswereevolutionarily
importantforsurvival,reproduction,andfitness.Inaquirkofevolutionaryfate,humansdiscoveredhow
tostimulatethissystemartificiallywithdrugs.
Inanotherexample,Hyman(2005,1414)leadsintoasectiontitled“AHijackingof
NeuralSystemsRelatedtothePursuitofRewards"with:
[A]ddictionrepresentsapathologicalusurpationoftheneuralmechanismsoflearningandmemorythat
undernormalcircumstancesservetoshapesurvivalbehaviorsrelatedtothepursuitofrewardsandthe
cuesthatpredictthem.
Accordingtothehijackhypothesis,then,drugsofabuse,likeintracranialelectrodes,
(1)areevolutionarilynovel,especiallyintheirpurityorconcentration,(2)are
consumedinanovelfashion,and(3)providednoevolutionaryfitnessbenefit.There
arereasonstobeskepticalofeachproposition.(Skepticismofthehijackhypothesis
isalsoincreasingwithinneurobiologybecausemostlaboratoryanimals,whengiven
achoicebetweenanintravenousdrugdoseandanon-drugreward,choosethenon-
drugreward;see,e.g.,Ahmedetal.2013).
Theevolutionofdrugsofabuseandotherpesticides
Alllivingorganisms,includingallhumans,arethelatestmembersofunbroken
lineagesoforganismsextendingbacktotheoriginoflife,over3billionyearsago.
Today,almostallorganismsacquiretheirenergydirectlyorindirectlyfrom
oxygenicphotosynthesis,whichusessunlighttoreducecarbondioxidetoorganic
carbon,andstoreschemicalenergyintheformofsugarsandothercarbohydrates.
Thesethenprovidethebuildingblocksandfuelforthegrowthandreproductionof
thephotosyntheticorganisms,termedautotrophs.Thefirstsingle-celledoxygenic
photosyntheticautotrophsevolvedabout2.4billionyearsago(Hohmann-Marriott
andBlankenship2011).
Unfortunatelyfortheseautotrophs,heterotrophsevolvedthatfeedonthem,
sparkinganevolutionaryarmsrace(DawkinsandKrebs1979)thatcontinuesto
thisday:heterotrophsevolvedtoexploitautotrophtissuesandenergystores;
autotrophs,inturn,evolvednumerousdefenses;heterotrophsthenco-evolved
countermeasures,andsoforth.1Keyeventsinthisarmsraceincludetheevolution
ofmarineanimalsmorethan600millionyearsago(KnollandCarroll1999),and
theevolutionofterrestrialplants∼400millionyearsago,alongwiththeterrestrial
1Autotrophsandheterotrophshavealsoundergonemutuallybeneficialcoevolution.SeediscussioninHagenetal.(2009).
bacterial,fungal,nematode,invertebrateandvertebrateherbivoresthatfeedon
them(HerreraandPellmyr2009).
Centraltoouraccountofhumandrugusearethechemicaldefensesthatevolvedin
marine,andlater,terrestrialautotrophs(plants).Somechemicaldefenses,suchas
tanninsandotherphenolics,haverelativelynon-specificeffectsonawiderangeof
moleculartargetsintheherbivore,forexamplebindingtoproteinsandchanging
theirconformation,therebyimpairingtheirfunction.Otherchemicaldefenses–
neurotoxins–evolvedtointerferespecificallywithsignalinginthecentralnervous
system(CNS)andperipheralnervoussystem.Variousplantneurotoxinsinterfere
withnearlyeverystepinneuronalsignaling,including(1)neurotransmitter
synthesis,storage,release,binding,andre-uptake(2)receptoractivationand
function;and(3)keyenzymesinvolvedinsignaltransduction.Plantneurotoxins
havetheseeffects,inmanycases,becausetheyhaveevolvedtoresemble
endogenousneurotransmitters.Disruptionofnervoussystemfunctionbysuch
toxinsservesasapotentdeterrenttoherbivores(Wink2011).
Becauseplantdrugs,almostbydefinition,interferewithsignalingintheCNSand
elsewhere,theyarewidelybelievedtohaveevolvedasplantdefenses(Wink2011).
Nevertheless,amongthepopularplantdrugs,onlynicotine,whichwediscussnext,
hasbeenconclusivelyshowntoserveplantdefense.
Nicotine
Inwhatfollowswewilloftenrelyonstudiesoftobaccoandnicotinebecause,forour
purposes,tobaccoisanidealmodeldrug.First,itisgloballypopularandhighly
addictive.Second,nicotine’sroleinplantdefenseiswelldocumented:numerous
studiesoftobaccodemonstratethatnicotinereducesleaflossandplantmortality
andincreasesproductionofviableseedbydeterring,harmingandkillingherbivores
(Baldwin2001;Steppuhnetal.2004).Third,wecandrawontheextensiveresearch
onthenervoussystemeffectsofnicotine.Fourth,althoughthetwodomesticated
tobaccospecieswereprobablyartificiallyselectedtoincreasetheirnicotinecontent,
severalofthemorethan60wildtobaccospecieshavenicotinecontentcomparable
toorexceedingthedomesticatedspecies(SissonandSeverson1990),andbothwild
anddomesticatedspecieswerewidelyusedbypre-ColumbianNativeAmericans
(TushinghamandEerkens2016).Thisindicatesthatconsumptionofnicotine-rich
tobaccoisnotsimplyamodernphenomenon.Finally,tobaccoisusuallyconsumed
bychewingorsmoking,anditisconceivablethathumanschewed,orevensmoked,
varioustoxicandpsychoactiveplantsformuchofourrecentevolution(Sullivanand
Hagen2002;Hardyetal.2012).
Nicotineisadangerousneurotoxin.Inhumans,oralingestionof4-8mgofnicotine
causesburningofthemouthandthroat,nausea,vomiting,anddiarrhea.Higher
dosesresultindizziness,weakness,andconfusion,progressingtoconvulsions,
hypertensionandcoma.Ingestionofconcentratednicotinepesticidescancause
deathwithin5minutes,usuallyfromrespiratoryfailure(Landoni1991).
Asinglecigarettetypicallycontains10–20mgofnicotine,enoughtoseriously
endangerayoungchildandcauseacutetoxicsymptomsinanadult.Whena
cigaretteissmoked,muchofitsnicotineisburned,however,andsmokersultimately
absorb0.5–2mgpercigarette.Tobaccochewersabsorbupto4.5mgper“wad”
(Hukkanen,Jacob,andBenowitz2005),adosethatisoftensufficienttocausesevere
acutetoxicityinnaiveusers.
Despiteitsacutetoxicity,nicotineisnotthoughttobedirectlyresponsibleforthe
chronicdiseasescausedbysmoking(butseeGrando2014).Thus,itstoxicity,which
explainswhyitispresentintobaccoleavesinthefirstplace,playslittlerolein
researchontobaccouseandaddiction.Intheframeworkwedevelophere,however,
drugtoxicityplaysacentralrole.
Althoughthedataarenotyetasconclusiveastheyarefornicotine,adefensiverole
willprobablybeestablishedformostotherplantdrugs,suchascocaine,morphine,
codeine,THC,andcaffeine(reviewedinHagenetal.2009).Likenicotine,mostplant
drugsareacutelytoxicforhumans,andthetypicalquantitiesconsumedbydrug
abusersareoftensurprisinglyclosetothelethaldose(Gable2004;Lachenmeier
andRehm2015).Forthesereasons,intheremainderofthechapterwewilloften
refertorecreationaldrugsasneurotoxicplantpesticides,whichbetterdescribes
theirevolvedfunction.
Wewillalsodrawontheextensiveresearchonpharmaceuticalsbecausetheseare
frequentlyderivedfromplanttoxins(e.g.,nicotine,whichhastherapeutic
applicationsandisalsowidelyusedasapesticide),chemicallyresembleplant
toxins,orhaveneurophysiologicaleffectsanalogoustothoseofplanttoxins.
Humantoxindefensemechanisms
Humancapabilitiestodetect,avoid,andneutralizeplanttoxinsevolvedoverthe
courseofourbillionyearevolutionaryarmsracewithautotrophdefenses.During
thefinalphaseofthisarmsrace,thehumanlineagewasalineageofprimates,which
divergedfromothermammalsroughly65millionyearsago,andwhichsubsist
mostlyonplantsandinsects(Fleagle2013).Asmanyinsectspeciessequesterplant
toxinstodeterpredators,bothelementsoftheprimatedietrequiredeffective
defensesagainstplanttoxins.Primatetoxindefensemechanisms,inheritedfrom
mammalianandvertebrateancestors,wouldthereforehavebeencontinuously
maintainedand‘tuned’bynaturalselection.Whenhumanandchimpanzee
ancestorsdiverged,probablymorethan6millionyearsago,thehumanlineage
inheritedarobustsuiteoftoxindefensemechanisms.Thereissubstantialevidence
thatthesedefensemechanismscorrectlyrecognizealldrugsofabuseastoxic
(Sullivan,Hagen,andHammerstein2008;Hagenetal.2009).
Tastereceptors
Basichumananatomyprioritizestoxindefense,andtastebudsareonthefrontlines.
Tasteisresponsibleforevaluatingthenutritiouscontentoffoodandpreventingthe
ingestionoftoxicsubstances.Thesweetandumamitastereceptors,whichidentify
twokeynutrients—sugarsandaminoacids—belongtoasmall,three-member
familyofgenes,theT1Rs,thatareexpressedintastereceptorcellsinthetongue
(Chandrashekaretal.2006).
Bittertaste,incontrast,mustpreventtheingestionoftensofthousandsof
structurallydiversetoxins.Notsurprisingly,bittertasteismediatedbyalarge
repertoireofabout25receptorgenes,theT2Rs(Chandrashekaretal.2006).All
commonrecreationalplantdrugstastebitter.Thus,thesereceptorsproperly
recognizecommonpsychoactiveplantdrugsastoxic.
Inadditiontotheirexpressionintongueandpalateepithelium,thesweet,umami,
andbittertastereceptorsarealsoexpressedinothertissuesexposedtonutrients
andtoxins,suchastherespiratorysystem,gastrointestinaltract,testes,andbrain
(BehrensandMeyerhof2010).
Barrierdefenses
Ifatoxicplantsubstanceisingesteditthenencountersa“barrierdefense."The
bodycanbeconceptualizedasasetofcompartments,suchastheintestinesand
lungs,thataretypicallyseparatedbytissuebarrierscomprisingepithelialor
endothelialcellslinkedtogetherwithspecialproteinsforming“tightjunctions."
Thesetissuebarriersincludeourskin,gastrointestinal(GI)tract,respiratorytract,
andthebloodbrainbarrier(BBB).Thebarriershaveseveralfunctions,suchas
allowinganinfluxofessentialchemicalslikesugarandoxygenintoacompartment,
andsimultaneouslypreventinganinfluxofmicroorganismsandtoxins(Mullinetal.
2005).Thebarriersachievetheseeffectsbylimitingorenhancingpassivediffusion
acrossthecellsandtightjunctions,andalsobyactivemechanismsthattransport
essentialchemicalsintoacompartment,andthatneutralizeandtransporttoxinsout
ofacompartment.
Figure1illustratesthebasicanatomicalandcellularcomponentsofthebarrier
defensesagainsttoxinsandotherxenobiotics.Aplanttoxin(representedasa
pharmaceutical)comesintocontactwithabarrier,suchastheskin,airways,lung,or
intestine.Ifthetoxinmanagestoenteracell,suchasanenterocyte,itthenactivates
acomplexnetworkofproteinsthatneutralizeandremoveitinafour-phaseprocess.
Figure1:Toxindefensemechanismsofthegut“barrier,"andfirstpasselimination.
Manytoxicsubstances(representedhereasapharmacueticaldrug)enteringthe
gastrointestinaltractarefirstmetabolizedbyenzymesinthegutwall,orare
transportedbackintotheintestine.Theremainingabsorbedfractionenterstheportal
veinandisimmediatelyroutedthroughtheliver,theprincipalorganofdetoxification,
beforeenteringsystemiccirculationwhereitencountersotherbarrierdefenses,such
astheblood-brainbarrier.FigurefromRodenandGeorgeJr(2002).
Phase0involvestransporters—specialproteinsthatspancellmembranesand
movechemicalsintoandoutofcellsusingpassiveandactivemechanisms.Efflux
transportersgenerallyremovetoxinsandwasteproductsfromthecell,andare
© 2001 Macmillan Magazines Ltd
ALLELES
Different versions of the samegene, one inherited from themother and one from the father.
NUCLEAR ORPHAN RECEPTOR
An analogue of a known nuclearreceptor (often for a hormone)with no putative ligand yetidentified.
38 | JANUARY 2002 | VOLUME 1 www.nature.com/reviews/drugdisc
R E V I EW S
spectrum are individuals with multiple functionalcopies of the gene, known as ‘hyper-extensive metabo-lizers’, who constitute up to 20% of some African popu-lations. Variability in the frequency and, indeed, thetypes of allelic variant among ethnic populations is acommon theme in contemporary genetics that couldwell underlie ethnic-specific beneficial and adverse drugresponses. This is one of the challenges in contemporarypharmacogenomic analyses, as discussed further below.
As a general principle, the problem of DNA variantscontributing to aberrant drug metabolism becomesmost evident for drugs that have only a narrow marginbetween the dosages that are required for efficacy, andthose that are associated with serious toxicity (such as isthe case with cardiovascular or oncology drugs), as wellas drugs that have only a single main pathway forelimination. Drugs whose biotransformation to inactivemetabolites is CYP2D6 dependent (for example, sometricyclic antidepressants or β-adrenergic blockers) causeside effects more often among poor metabolizers, andlack of efficacy among hyperextensive metabolizers.Conversely, drugs such as codeine, which undergoesCYP2D6-dependent biotransformation to form itsmore active metabolite (morphine), can have a lack ofefficacy in poor metabolizers, and exaggerated effectsamong hyperextensive metabolizers. A minority ofindividuals with ‘aberrant’ metabolism makes up thesubset that is generally identified in clinical investigation,and it is in this group that aberrant drug responses aremost commonly seen early during drug therapy. A sec-ond, increasingly recognized, problem in the dispositionof a drug that uses a single main pathway is the potentialfor drug–drug interactions. So, inhibition of CYP2D6 byco-administration of serotonin re-uptake inhibitors ortricyclic anti-depressant drugs29, or inhibition ofCYP3A4 by co-administration of erythromycin or keto-conazole30, can cause adverse drug effects, which occurduring chronic drug therapy and are therefore a risk inmost subjects that have ‘normal’ metabolism.
Although the concept of genetic variants in theproteins that accomplish drug metabolism is a relativelymature one, several new areas in drug disposition areemerging. One is the increasing recognition that druguptake into, and efflux from, intracellular sites is accom-plished by specific drug transport molecules, and thatthese also exhibit pharmacologically important allelicvariability31–34. For example, the integrity of theblood–brain barrier is now known to arise, not just fromtight junctions in the capillary endothelium in this region,but also from expression of the drug-efflux transporterP-glycoprotein on the luminal surface of these cells, whichthereby limits the access of drugs to the brain35.
Another area of active enquiry is the transcriptionalregulation of normal proteins, which can be highlyvariable because of allelic variants in regions of DNAthat regulate expression25,36. Variations in the functionor expression of genes encoding factors, such asNUCLEAR ORPHAN RECEPTORS, that control the transcriptionof the genes encoding drug-metabolizing enzymesand transporters37–41, could also contribute to variabledrug actions.
thiopurine methyltransferase24, glucuronosyltrans-ferases25 or sulphotransferases26; and cleavage bypseudocholinesterase27,28 (TABLE 1).
Although familial aggregation of unusual responsesto drugs has often been the first hint of the existence ofclinically important variants in drug-metabolizingenzymes, modern genetic approaches have found severalvariants in single genes21 (see link to the Human Cyto-chrome P450 (CYP) Allele Nomenclature Committee).For example, over 70 variants in the CYP2D6 gene havebeen described, some of which lead to loss of function.Homozygotes, which comprise 7% of Caucasian andAfrican-American populations, are rendered so-called‘poor metabolizers’ on this basis. Such loss-of-functionALLELES are very uncommon among Asian populations,in which, however, alleles causing reduction of functionhave been described. At the other end of the catalytic
Bile
Portal vein
Liver
Systemiccirculation
Kidney
Drug
Metabolite
Processes that decrease drug delivery to targets
Processes that enhance drug delivery to targets
Circulation–tissue interface (for example, blood–brain barrier)
Target tissue
Enterocyte
Small intestine
Figure 1 | Determinants of drug delivery to target sites. The processes of absorption,distribution into tissues, metabolism and elimination determine the amount of drug and metabolitesthat are delivered to target sites. In this figure, blue arrows indicate processes that enhance drugdelivery, whereas green ones show processes that decrease it. Although some of the processesshown here might occur passively, much of this drug handling is mediated by specific drug-uptakeor drug-efflux transporters, as well as by drug-metabolizing enzyme complexes. An ingested drugenters enterocytes, from where it can undergo metabolism, efflux into the portal circulation, or effluxback into the gut lumen. Similarly, a drug delivered to hepatocytes can be metabolized andexcreted into the bile, or returned to the systemic circulation, from where it can also be excreted,generally through biliary or renal routes. If the molecular target is not located within the circulation,further obstacles to a drug accessing its molecular targets might be encountered at plasma–tissuebarriers, which could limit drug access to certain cell populations, such as the brain or testes.Some drugs must access intracellular molecular targets, in which case uptake into, and efflux outof, the target cell might be key determinants of drug delivery and hence drug action.
typicallymembersoftheATPbindingcassette(ABC)superfamily.Humanshave48
ABCtransportergenes,about20ofwhichareeffluxtransporters.InPhase0,a
xenobioticentersthecell,andanABCtransporterpumpsitbackout.
InPhaseI,anyxenobioticremaininginthecellischemicallyalteredbyenzymesto
reducetoxicityandincreasewatersolubilitytofacilitateexcretion.Typically,this
involvesoxidationbyoneormorecytochromeP450(CYP)enzymes.Humanshave
57CYPgenes,about25ofwhichareinvolvedinxenobioticmetabolism(Sullivan,
Hagen,andHammerstein2008).
InPhaseII,diversefamiliesofenzymesconjugatechargedspecieswithxenobiotic
metabolites,furtherreducingtoxicity2andincreasingwatersolubility.PhaseIandII
xenobioticmetabolizingenzymesaremosthighlyexpressedintheliver,butarealso
expressedinmostothertissuebarriers,includingskin,intestine,lung,placenta,and
brain(Gundert-Remyetal.2014).Xenobioticscanalsobindtoxenosensingnuclear
receptorsthatthenup-regulateexpressionofmetabolicandtransportproteins,
acceleratingeliminationofthexenobiotic.
InPhaseIII,metabolitesarepumpedoutofthecellbyatransporterforrenalor
biliaryelimination.FordetailsonPhase0-III,seeTóthetal.(2015),andreferences
therein.
2Occasionally,PhaseIandPhaseIImetabolitesaremoretoxicthantheparentcompound.
Nausea,vomiting,andconditionedtasteaversion
Mostnutrients,toxins,andotherxenobioticsareprocessedinthegut,wheremany
toxinsarepartiallyorcompletelyneutralizedandeliminatedasjustdescribed.In
addition,thegutisrichlyinnervated,withlargequantitiesofinformationconveyed
fromtheGItracttotheCNSviatheafferentvagalnerve.Theareapostrema,in
particular,isachemosensitivepartofthebrainthatisoutsidetheBBB,and
thereforeisalsoexposedtochemicalsinsystemiccirculation.Together,these
circuitscanrespondtotoxinsinthegutandbloodwithnausea,vomiting,and
learnedaversionsandavoidances(BabicandBrowning2014).
Toxinsthatarenotexpelledfrom,ormetabolizedby,thegutenterthebloodstream
andarethenimmediatelyroutedthroughtheliver,theprincipaldetoxification
organ,whichfurthermetabolizesandeliminatesthem.Anyremainingtoxinenters
systemiccirculationwhereitencountersotherbarriertissues,suchastheBBB,and
furthermetabolism(Figure1).
Psychoactivedrugslikenicotineareneurotoxins,someportionsofwhichevadeall
suchdefenses,successfullyenteringthebrainandinterferingwithCNSfunction.
Evaluatingthehijackhypothesisinlightofevolvedxenobiotic
defenses
Themultiplelayersoftoxindefensesinvolvingscoresofreceptor,metabolicand
transportergenes,numerousdistincttissuebarriers,complexneuralcircuits,
organsliketheliverandkidneys,andthebasicorganizationofthecirculatory
system,alldemonstratethathumanancestorswereregularlyexposedtoalarge
varietyofdangerousxenobiotictoxinsthatenteredthebodyviatheskin,GItract,
andrespiratorytract.Thesetoxinsoftengainedaccesstosystemiccirculationand,
asevidencedbyanextremelyrobustBBBthatpreventsmostdrugsfromentering
thebrain(Pardridge2012),manyposedasubstantialthreattoCNSfunction,i.e.,
werepsychoactive.Exposuretopsychoactiveplantcompoundsisnotevolutionarily
novel.
Evolutionarilynovellevelsofdrugpuritydonotappeartobeageneralexplanation
fordruguseandaddictioneither.Purenicotineisnotabusedbyhumans,andmost
smokersdonotprefernicotinespraytoplacebo;nicotineandnicotinicreceptor
agonistsonlyslightlyimprovesmokingcessationrates;andotherconstituentsof
tobaccosmoke,suchasacetaldehyde,norharmanandharman(MAOinhibitors)
appeartopotentiatetheaddictivepropertiesofnicotine(Smalletal.2010).E-
cigarettes,whichdelivernicotineandflavorants,maybeasorlessaddictivethan
nicotinegums,whichthemselvesarenotveryaddictive(EtterandEissenberg
2015).
Evolutionarilynovelmethodsofadministrationarealsounlikelytoexplain
recreationaldruguseanddependence,aschewingtobaccoisaddictive(US
DepartmentofHealthandHumanServices,1986)butchewingplantsisnot
evolutionarilynovel.Inhalationoftoxicsmokewasalsoprobablycommonduring
humanevolution.Ourhominoidandhomininancestorsevolvedinforestand
savannahenvironmentsthatregularlyexperiencedwildfires,andourlineagemight
haveachievedcontroloffireby1millionyearsago(Parkeretal.2016).Itis
thereforelikelythathumanancestorswerefrequentlyexposedtovaporizedplant
toxins,whichprobablyhelpsexplainthepresenceofrobustxenobioticdefensesin
ourrespiratorytract.3Furthermore,indigenousdruguseoftenincorporatescultural
techniquesto“freebase”psychoactiveneurotoxinsandtoutilizephysiologyto
avoidfirst-passmetabolism.Forexample,bothbetelnut(SEAsia)andcoca
(AmericanAndes)iscommonlymixedwithabase(e.g.lime)andischewedinthe
buccalcavitywherethefreealkaloidscancrossdirectlyintothebloodstreamand
intotheCNS(SullivanandHagen2002).
Thus,psychoactivecompoundsarenotevolutionarilynovel;theycanbefoundin
plantsinconcentrationssimilartogloballypopulardrugs(e.g.,severalwildtobacco
species);evolutionarilynovelpuritydoesnotexplaintheiraddictiveness(atleast
fornicotine);andtheyregularlyenteredsystemiccirculationviaingestion,contact
withtheskin,andinhalation,justasrecreationaldrugsdotoday.Exposureto
psychoactivecompoundsisas‘natural’asexposuretosugarsandstarches.
Moreover,nicotineandotherpopularrecreationalplantdrugsactivatemostknown
toxindefensemechanisms,includingbittertaste(Wieneretal.2012),xenobiotic
3Evenhypodermicinjectionisnotanevolutionarilynovelmodeofexposuretopsychoactivetoxins.Althoughwehaveemphasizedplantneurotoxins,numerousvertebratesandinvertebratesproducepotentneurotoxinsthattheyinjectintopredatorsandpreywithstingersandfangs.Thereisincreasingevidencethathumanshaveaninnatefearofspidersandsnakes,probablybecausemanyofthesespeciesarevenomousandfrequentlyattackedhumanancestorswithfangs(ÖhmanandMineka,2001).Eventoday,snakebiteisamajorcauseofmorbidityandmortalityinmuchoftheworld(Gutiérrezetal.,2013).Thedangersofbitesandstingsmightalsoexplainanapparentinnatefearofneedles(Hamilton,1995).
nuclearreceptors(Lamba2004),xenobioticmetabolism(Sullivan,Hagen,and
Hammerstein2008),nauseaandvomiting(Wishartetal.2015),andconditioned
avoidancesandaversions(Lin,Arthurs,andReilly2016andreferencestherein).
Humanneurophysiologycorrectlyrecognizesdrugsofabuseasthetoxicpesticides
thattheyare.
Insummary,drugresearcherscorrectlyrealizedthattherewardingandreinforcing
propertiesoftoxicandharmfulsubstancesrequiredanevolutionaryexplanation,
but,onveryscantevidence,wronglyconcludedthatdrugsandtheirroutesof
administrationwereevolutionarilynovel,andthatthisprovidedanadequate
evolutionaryaccountofhumandruguse.Plantsareunderstrongselectiontoevolve
compoundsthat‘hijack’herbivorenervoussystems,butforpreciselytheopposite
effects:topunishanddeterplantconsumption,notrewardorreinforceit.
Withoutconsiderablefurtherevidence,itisnotpossibletoacceptthatneurotoxic
pesticideslikenicotineareableto‘hijack’rewardcircuitsbecausetheyare
evolutionarilynovel,orareconsumedinanovelfashion.Thehijackhypothesiscan
onlyberescuedwithmoreconvincingevolutionaryargumentsandmuchstronger
empiricalevidence.Asweexplainnext,thecorrectevolutionaryaccountofhuman
druguseisnotyetclear.
Theparadoxofdrugreward
Thewidespreadrecreationaluseof,andaddictionto,severalneurotoxicplant
pesticidesisextremelypuzzling,tosaytheleast.Thereigningneurobiological
paradigmofdruguse,groundedintherewardingorreinforcingeffectsofdrugsin
humansandotherlaboratoryanimals,isobviouslyinconflictwiththereigning
evolutionarybiologicalparadigmofdrugorigins,groundedinthepunishingeffects
ofnicotineandotherplant-baseddrugsonherbivores.Specifically,plantsshould
nothaveevolvedcompoundsthatrewardorreinforceplantconsumptionby
herbivores,norshouldherbivoreshaveevolvedneurologicalsystemsthatreward
orreinforceingestionofpotentplantneurotoxins.Thiscontradictionhasbeen
termedtheparadoxofdrugreward(Sullivan,Hagen,andHammerstein2008;Hagen
etal.2009;seealsoSullivanandHagen2002).
Drugresearchershavelongrecognizedthatdrugsaretoxinsandhaveaversive
effects,andthatdrugtoxicityandaversivenessisatoddswithdrugreward(for
review,seeVerendeevandRiley2012).Pavlovhimselfrelatedexperimentsinwhich
dogslearnedtoassociatethetoxiceffectsofmorphineinjectionswithstimuli.Inthe
moststrikingcases,vomitingandothersymptomscouldbecausedsimplybythe
dogseeingtheexperimenter(Pavlov1927).Unfortunately,drugaversionhashad
littleinfluenceondrugusetheory(VerendeevandRiley2012).
Intheremainderofthischapter,weproposethatdrugtoxicityexplainsdramatic
ageandsexdifferencesindruguse.Wealsoexplorepossibleresolutionsofthe
paradoxofdrugrewardthataregroundedintheneurotoxicpropertiesofcommon
recreationaldrugs.
Explainingthedramaticagedifferenceindruguse
Usersofpopularneurotoxicpesticidesreportlittle-to-nousepriortotheageof10
(Figure2).Thisisremarkable.Whyarechildrensoresistanttodruguse?Although
manyresearchersfocusontherapidadolescenttransitiontoneurotoxicpesticide
use,sofaraswecantellthereisessentiallynoinvestigationofthestrikinglackof
childneurotoxicpesticideuse.Perhapsdrugresearcherssimplyassumethat
parentalandsocietalrestrictionspreventchilduse.
Thisassumptionseemsreasonablefortobacco,astheUSspendsabout$500million
eachyearontobaccocontrolefforts(WHO2013).Itismuchlessreasonablefor
caffeine,abitter-tastingdefensiveneurotoxinthatisfoundin13ordersoftheplant
kingdom(AshiharaandSuzuki,2004),andthatshowspromiseasapesticideand
repellantforslugs,snails,birdsandinsects(e.g.,Hollingsworthetal.2002,Averyet
al.2005).Likenicotine,caffeineisarewardingpsychostimulantthatstrongly
interactswiththecentraldopaminergicsystems(Ferré2008).Unlikenicotine,
caffeinefacesfewsocialrestrictionsagainstuse—itislistedbytheUSFoodand
DrugAdministrationas“GRAS[generallyrecognizedassafe]foruseincola-type
beveragesatlevelsnottoexceed200partspermillion(ppm)(0.02%)”(Rosenfeld
etal.2014,p.26).Thislevelcorrespondsto71mgofcaffeineina12-ozserving
(althoughmostcolascontainabouthalfthatamount).Forcomparison,a1ozshot
ofespressocontainsabout64mgofcaffeine,an8ozcupofcoffeemightcontain145
mgofcaffeine,energydrinkstypicallycontain17-224mgofcaffeineperserving,
andchocolatecandycontains11-115mgcaffeineperoz(Rosenfeldetal.2014).
Despitethelightregulationofcaffeinecomparedtotobaccoandnicotine,andits
readyavailabilityincolas,chocolatecandies,andotherchildfoodproducts,child
consumptionofcaffeineislow(Figure3a,b,c),suggestingthatlowchilduseof
putatively“rewarding"neurotoxicpesticidesisnotexplainedsolelybyparentalor
societalcontrols.What,then,doesexplainthedramaticlackofchildneurotoxic
pesticideuse,andtheequallydramatic,‘switch-like’transitiontoneurotoxic
pesticideuseduringadolescence?
Figure2:Cumulativedistributionofself-reportedageoffirstuseofalcohol,tobacco,
cannabis,andcocaineinalarge(N=85,052)cross-nationalsampleofusersofthese
substances.Thesepatternssuggesttheexistenceofadevelopmental‘switch’todrug
useduringadolescence.FigurefromDegenhardtetal.(2016).
www.thelancet.com/psychiatry Vol 3 March 2016 253
Series
What is the extent of substance use in young people?When does substance use begin?Adolescence is the peak period during which substance use first occurs. This finding is consistently reported in surveys of drug use in young people and young adults. Levels and frequency of use begin to increase in mid-adolescence and peak in very early adulthood, as reported in long-running US cohorts.15
The age of onset in prospective cohorts is similar in high-income countries.16 Figure 1 shows the age-of-onset curves for use of substance use in people using specifi c substances in the World Mental Health Surveys (WMHS), cross-nationally.16 Among those who have used substances, the age-of-onset curves were strikingly similar across countries. For alcohol, median age of onset was 16–19 years for all countries, except South Africa (20 years), and the same age for tobacco in all countries,
Figure 1: Age of onset of substance use by people who had used each substance, by countryReproduced from Degenhardt and colleagues,16 by permission of Degenhardt and colleagues. If lines are not presented for an individual country, either no assessment was done for the age of onset of that substance, or fewer than 30 people reported having used the substance.
100Th
ose w
ho h
ad u
sed
(%)
80
60
40
20
0
90
70
50
30
10
100
Thos
e who
had
use
d (%
)
80
60
40
20
0
90
70
50
30
10
A Alcohol
C Cannabis
B Tobacco
D Cocaine
Age at first use (years)0 10 30 5020 40 60
Age at first use (years)0 10 30 5020 40 60
ColumbiaBelgiumItalyUkraineNigeriaJapanMexicoFranceNetherlandsIsraelSouth AfricaNew ZealandUSAGermanySpainLebanonChina
Figure3:Ageandsexvs.caffeineintakefromdietaryrecallandurinarycaffeine
metabolite5-acetylamino-6-amino-3-methyluracil(AAMU)inarepresentativesample
oftheUSpopulation(n=2466).FigurefromRybaketal.(2015).
Plantdefensivepesticidesareoftenteratogenic,disruptingdevelopmentand
permanentlyimpairingfunctionality.Nicotineisateratogenthatinterfereswith
acetylcholinesignaling,whichhasauniquetrophicroleinbraindevelopment.
Nicotineexposurecandisruptallphasesofbrainassembly(Dwyer,Broide,and
Leslie2008).
FIGURE 2 Comparison of 24-h caffeine intake from diet and supplements, spot urine AAMU concentrations, and urine AAMU excretion ratesin US persons aged $6 y, NHANES 2009–2010, stratified by demographic variables. Values are medians and 95% CI. (A) Caffeine intake, (B)AAMU concentration, and (C) AAMU excretion rate stratified by age. (D) Caffeine intake, (E) AAMU concentration, and (F) AAMU excretion ratestratified by sex. (G) Caffeine intake, (H) AAMU concentration, and (I) AAMU excretion rate stratified by race-ethnicity. Sample sizes (n) for spoturine concentration and excretion rate data appear in Supplemental Table 2. Intake data sample sizes for age were 6–11 y, n = 358; 12–19 y, n =381; 20–39 y, n = 575; 40–59 y, n = 589; $60 y, n = 505. Intake data sample sizes for sex were male, n = 1178; female, n = 1230. Intake datasample sizes for race-ethnicity were NHW, n = 1028; NHB, n = 447; all Hispanic, n = 807. AAMU, 5-acetylamino-6-amino-3-methyluracil; NHB,non-Hispanic black; NHW, non-Hispanic white.
772 Rybak et al.
at WASHING
TON STATE UNIVERSITY HO
LLAND LIBRARY on October 27, 2015
jn.nutrition.orgDownloaded from
Consistentwiththeriskthatplanttoxinsposetochilddevelopment,thereis
considerableevidenceforheightenedtoxindefensesduringinfancyandchildhood.
Althoughinfantsrecognizethatplantsaresourcesoffood,theyaremorereluctant
totouchnovelplantscomparedtoothertypesofnovelartifactsandnaturalobjects
ofsimilarappearance,whichmightreflectanevolvedpsychologicaldefenseagainst
planttoxins(WertzandWynn2014).Neophobicfoodrejectionoccursprimarilydue
tovisualcues.Foodsthatdonot‘lookright’–greenvegetablesforexample,orfoods
thatresembleknownbitterfoods–arerejectedwithoutbeingplacedinthemouth.
Foodneophobiapeaksbetween2and6,andthendecreaseswithage,becoming
relativelystableinadulthood,adevelopmentaltrajectorywidelyinterpretedto
reflectanevolveddefenseagainstplantteratogens.Childrenalsohaveahigher
densityoftastebudsonthetipofthetonguethanadultsandaremoresensitiveto
bittertastes.Highbittertastesensitivityleadstoreducedconsumptionofbitter
vegetables,especiallyinchildren.Forreview,seeHagen,Roulette,andSullivan
(2013).
Asastartingpointforfutureresearchonlowchilddruguse,weproposeamodel
withthreeelements.First,topreventingestionofteratogens,childrenareinnately
neophobic,picky,andhaveheightenedbittersensitivity.Consequently,theyfind
mostneurotoxicpesticidestobeespeciallyunpalatable.
Second,sociallearningplaysanespeciallyimportantroleintoxinavoidance.
Whereaslearningabouttoxicsubstancesviaindividualtrial-and-errorcomeswith
thepotentiallyhighcostofingestingatoxin,onecansociallylearntoavoidtoxic
substancesfromknowledgeableothers“forfree”(BoydandRicherson1985;Rogers
1988).Childrenshouldthereforebeparticularlyattentivetoinformationfrom
parentsandotheradultsthatcertainsubstancesaredangerous,poisonous,ordo
nottastegood,andassiduouslyavoidthosesubstances(Cashdan1994).Incontrast,
weexpectconsiderablechildresistancetoparents’effortstorestrictaccesstocandy
andothersugaryfoods,which,fromanevolutionaryperspective,arenearlypure
beneficialnutrients.
Third,inadolescencebrainandotherorgandevelopmentisnearingcompletion.We
proposethatadolescentonsetofneurotoxicpesticideuseispartlyrelatedtothe
reducedriskofdevelopmentaldisruptionandconsequentreducedaversiontoplant
toxins,whichalsoservestobroadendiet.SeeFigure4.
Figure4:Theoreticalmodelofageandsexdifferencesinuseoftobaccoandother
plantdrugs.TFR:Totalfertilityrate.FigurefromHagen,Garfield,andSullivan(2016).
Explainingthelargesexdifferenceindruguse
Moremenregularlyuseneurotoxicpesticides(andalcohol)thanwomen,thoughthe
extentofthemalebiasvariesbynation,substance,age,birthcohort,andother
factors.Maleprevalenceofsmokingisalmostalwaysgreaterthanfemale
prevalence,forinstance,albeitwithconsiderablevariationacrossnations(Fig.5).In
theUSthereisevenamalebiasincaffeineintake(Fig.3).
Theore%calmodeloftheeffectsofacutetobaccotoxicityonsmokingprevalencebyage,sex,andTFR
Childhood Adolescence Premenopause Postmenopause
Smokingprevalen
ce
MalesFemales,lowTFR
Females,highTFR
Highteratogenriskup-regulatestoxindefensesanddown-regulatesdrugconsump%on
Reducedteratogenrisk,increasedma%ngeffort,andincreasedparasiteloaddown-regulatetoxindefensesandup-regulatedrugconsump%on
Increasedriskoffetal/infantharmup-regulatesfemaletoxindefensesanddown-regulatesfemaledrugconsump%on,andrela%velymoresoinhighTFRpopula%ons
Decreasedriskoffetal/infantharmdown-regulatesfemaletoxindefensesandup-regulatesfemaledrugconsump%on,andrela%velymoresoinhighTFRpopula%ons
Figure5:Femalevs.malesmokingprevalenceacrossnations.Eachdotisonecountry.
Thesoliddiagonallinerepresentsequalprevalence.FigurefromHagen,Garfield,and
Sullivan(2016).
Theglobalmalebiasisnarrowerinyoungercohorts,especiallyforthelegaldrugs
tobaccoandalcohol,andinrecentyearsUSadolescentgirls(12-17)weremore
likelythanadolescentboystousealcoholandbenon-medicalusersof
psychotherapeuticdrugs.IntheUSpopulationasawhole,however,menweremore
likelythanwomentobeusersofallcategoriesofdrugs,includingpsychotherapeutic
drugsandalcohol.Forreview,seeHagen,Roulette,andSullivan(2013).
Overhumanevolution,ingestionofneurotoxicpesticideswouldprobablyhave
posedsimilarthreatstomenandwomen,butwomenofchildbearingagefacedthe
additionalriskofdisruptedfetalandinfantdevelopment.Ancestralwomenwere
pregnantorlactatingformuchoftheirlateteenstotheirlatethirties.Attheagethat
youngwomeninWesternsocietiesmightbeginregularuseofplantdrugs(and
●●
●
●
●
●●
●
●
●
●
●
●●
●
●
●
●
●
●
●
●●
●
●
●
●
●
●
●
●
●●●●●
●
●●
●
●
●
●
●
●
●
●
●
●
●●
●
●
●
●
●
●
●
●
●
●
● ● ●● ●
●
●
●●
●
●
●
●
●●
●
●
●
●●
●
●
●
●
●
●
● ●
●
●
●
●
●
● ●
●
● ●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●●●●
●
●
●●
●
●
●●●
●
●
●●
●
●
●
●
●
●
●●
●
●
● ●● ●
●
●
●
● ●
●
●●
●
●
●
●●
●
●●●● ●
●
●
●
●
●
●
●●
●
●
●
●●
●
●
●
●
●
●
●●
0
10
20
30
20 40 60
Male 2012 smoking prevalence (%)
Fem
ale
2012
sm
okin
g pr
eval
ence
(%)
Status●
●
DevelopedDeveloping
Total fertility rate●
●
●
246
regularuseofbirthcontrol),withtheirfirstpregnancyoftenyearsinthefuture,
mostwomeninancestralenvironmentswerebeginningabouttwodecadesof
pregnancyandlactation.Thiscouldhaveselectedforanincreasedabilitytodetect
andavoidplantteratogensthatwouldbeharmfultofetusesandnursinginfants,
resultinginlowerfemaleuseofneurotoxicpesticidesthatisevidenteventoday.
Thereisconsiderableevidenceforsexdifferencesintoxindetectionanddisposition.
Lesscleariswhetherthesedifferencesareaconsequenceofgreatertoxindefenses
inwomen,particularlypregnantwomen,orinsteadarebyproductsof,e.g.,sex
differencesinbodysizeandcomposition.
Womenhavemoretastebudsthanmenand,accordingtomoststudies,areableto
detectlowerconcentrationsofbittersubstances.Highbittersensitivity,inturn,
generallypredictsreducedvegetableintakeinbothwomenandmen.Moststudies
indicatethatwomenalsohavehighertoxinmetabolismrates.Duringpregnancy,
heightenedfoodaversionsappeartohelppreventingestionoftoxicplants,
includingcoffeeandtobacco,thatmightposearisktothedevelopingfetus,
especiallyduringorganogenesis.Womensmokers,forexample,commonlyreport
newolfactoryandgustatoryaversionstotobaccoduringpregnancy,andthe
olfactoryaversionsareassociatedwithwomensmokingless(Pletschetal.2008).
Nicotinemetabolismisacceleratedinpregnancy,andactivitiesofmanyxenobiotic-
metabolizingenzymesareincreasedseveral-fold.Forreferencesandfurther
discussion,seeHagen,Roulette,andSullivan(2013).
Incountrieswherewomenarepregnantandlactatingmoreoften(i.e.,thosewith
highertotalfertilityrates),therearefewerwomensmokers,evenafteraccounting
forgenderinequality(Hagen,Garfield,andSullivan2016).Thediminishingsex
differencesinuseofsomesubstancesinyoungercohortsmightthereforepartially
reflecttheglobalfertilitytransitionoverthelastseveraldecadesthatinvolves
increaseduseofbirthcontrol,laterageatmarriage,delayoffirstbirth,andlower
totalfertility,allofwhichwouldallowwomen,especiallyyoungerwomen,to
increasedrugintakewhilelimitingfetalandinfantexposure(Hagen,Roulette,and
Sullivan2013).Weproposethatsociallearningalsoplaysanimportantrolein
women’sdecisionstouseoravoidtoxicplantsubstances(PlacekandHagen2015;
underreview).Seefigure4.
Possibleexplanationsforregulatedneurotoxicpesticideintake:
anevolved‘taste’fordrugs?
Drugtoxicitywouldseemtopredictnousewhatsoeverbyindividualsofanyageor
sex,contrarytotheglobalpopularityofsmokingandotherdruguse.
Drugrewardmightbeanaccident.Over100,000plantdefensivecompoundshave
beenidentified(Wink2011),andperhapshumanssimplydiscoveredaveryfew
that,despitetheirtoxicitytoinsectsandotherherbivores,accidentallytrigger
rewardorreinforcementmechanisms(Hagenetal.2009).Thishypothesisfacesa
‘Goldilocks’problem,though:recreationalplantpesticidesmustbeaccidentally
rewardingorreinforcingenoughtoovercometheiraversiveproperties,yetbecause
theyareoftenhighlytoxic,theycannotbesorewardingorreinforcingformost
usersthattheyleadtoimmediateoverdosesanddeath.Theaccidentaleffectsof
thesecompoundsmustbe‘justright.’Hence,foreachdrug,theaccidenthypothesis
involvesnotjustonerareaccident,buttwo.
Alternatively,regulatedtoxinintakemighthaveproducedfitnessbenefitsincertain
circumstances.Becausewildplantfoodsareinfusedwithdefensivechemicals,plant
consumers,includinghumanancestors,shouldhaveevolvedsometypeof
regulatorymechanismthatbalancesintakeofnutrientsvs.toxinssoastoavoid
poisoning(TorregrossaandDearing2009).SeeFigure6.Butregulatedtoxinintake
occursevenintheabsenceofanutrientsignal.Laboratoryanimalsregulatetheir
self-administrationofdrugsatafairlyconstantandstablelevelregardlessofthe
doseperinjectionornumberofleverpressesrequires(YokelandWise1976).
Humancigarettesmokerssimilarlyaltertheirsmokingbehaviorinresponseto
changesinnicotinecontentsoastomaintainarelativelyconstantblood
concentrationofnicotine(SchererandLee2014).Thesearecluesthatspecial
mechanismsmighthaveevolvedtocarefullyregulateplanttoxinintake(Hagenetal.
2009;Hagen,Roulette,andSullivan2013).
Therearemanypossiblefitnessbenefitsofregulatedingestionofneurotoxicplant
pesticides,mostofwhichreconceptualizethesecompoundsasvaluablemedicines
ratherthanhijackers(SullivanandHagen2002;Sullivan,Hagen,andHammerstein
2008;Hagenetal.2009;Hagen,Roulette,andSullivan2013).Neurotoxicpesticides
achievetheireffectsbecausetheyevolvedtomanipulatecellularsignaling.Nicotine,
forinstance,mimicsacetylcholine,aneurotransmitterinvolvedinneuromuscular
communicationandmanyotherimportantfunctions.Inlargedoses,nicotinekills.In
small,highlyregulateddoses,though,suchasthe∼ 1mgdeliveredbysmokinga
cigarette,itmightprovideanumberofimmediatebenefits.(Thelong-termhealth
costsofsmokingareindisputable,however.)
Onepossiblebenefitisdefenseagainstparasites.Manyheterotrophicspecies
evolvedtoco-optplanttoxinsforprophylacticortherapeuticeffectsagainst
pathogens,i.e.,self-medication,alsoknownaspharmacophagyor
zoopharmacognosy.Allpopularrecreationaldrugsaretoxictoparasiticworms
(helminths).Itisnotoutofthequestionsthathumansandotheranimalsevolvedto
seekoutandingestsmallquantitiesofneurotoxicpesticidestohelpcombat
helminthsandotherparasites(Sullivan,Hagen,andHammerstein2008;Hagenetal.
2009;Hagen,Roulette,andSullivan2013;Rouletteetal.2014).Ifthe
pharmacophagyhypothesisiscorrect,thenthetoxicityofdrugstoparasites
providestheultimateexplanationfortheirusebyhumans.SeeFigure6.
Figure6:Theneurotoxinregulationmodeloftheevolutionof“recreational”druguse.
Benefitsareingreen;costsareinred.FiguremodifiedfromHagen,Garfield,and
Sullivan(2016).
Saltintakeprovidesausefulanalogy:therearecomplexneuronalandendocrine
mechanisms,includingspecialsaltytastereceptorsonthetongue,thatregulate
intakeofmilligramsofthisvaluableenvironmentalchemicaltomaintainsodium
homeostasis(GeerlingandLoewy2008),eventhoughthereisnoconscious
awarenessofitsbiologicalbenefits.Similarly,bittertastereceptorsandother
xenosensors,inconjunctionwithneuronal,immunological,andothermechanisms,
mightregulateintakeofmilligramsofneurotoxinsfortheirmedicinalorsocial
benefitswithoutanyconsciousawarenessofthesebenefits.
Selec%onpressuresforandagainstplantfoodconsump%on
Selec%onpressuresforandagainstplantdrugconsump%on
Macronutrients Micronutrients
TeratogenicityAcutetoxicity Fetal/infantharm
Time/resources
Possiblemedicinalbenefits
Preventortreatinfec%ons
Restoreorenhanceneurophysiologicalfunc%on
PossiblesocialbenefitsReinforcesocialbondsSignalmate/partnerquality
Evolu%onofmechanismstoregulateplantfoodintaketomaximizebenefitsandminimizecosts
Evolu%onofmechanismstoregulateplantdrugintaketomaximizebenefitsandminimizecosts
Xenosensors
BiGertastereceptors
Xenobio%cnuclearreceptors
Olfactoryreceptors
Specificdetec%onofneurotoxins?
Xenobio%cdefensiveproteins
Xenobio%ctransportproteins
Xenobio%cmetabolizingenzymes
Vomitreflex
Bloodbrainbarrier
Individuallearningoftoxic&teratogenicplantsubstances
Sociallearningoftoxic&teratogenicplantsubstances
Toxindefensemechanisms
Plantdrugseekingandintakemechanisms
Plantfoodseekingandintakemechanisms
Benefits
Costs
Macronutrientdetec%onandenergystores
Parasitedetec%onSocialfeedback
Inconclusion,popularrecreationaldrugsareneurotoxicpesticides,varietiesof
whichhaveinfusedthedietsofhumanancestorsforhundredsofmillionsofyears.
Theseandotherxenobioticsselectedforasophisticated,multilayeredtoxindefense
systemthatcorrectlyidentifiesalldrugsofabuseastoxins.Inthislight,itis
doubtfulthatrecreationaldrugsarebestcharacterizedasevolutionarilynovel
hijackersofrewardcircuitry.Althoughthecorrectevolutionaryaccountof
recreationaldruguseisnotyetclear,ourneurotoxinregulationhypothesis(Fig.6)
providesacompellinghypothesisfortheverylowuseofrecreationaldrugsby
children,thelowusebywomenofreproductiveagerelativetomen,andthecareful
titrationofdrugintakebyhumansandnon-humananimals.Theincreasingevidence
thatnon-humananimalsingestplanttoxinstohelpdefendagainstpathogensand
provideotherfitnessbenefitsshouldinspiresimilarhypothesesforhumandruguse.
References
Ashihara,H.andSuzuki,T.,2004.Distributionandbiosynthesisofcaffeineinplants.FrontBiosci,9(2):1864-76.
Avery,M.L.,Werner,S.J.,Cummings,J.L.,Humphrey,J.S.,Milleson,M.P.,Carlson,J.C.,Primus,T.M.andGoodall,M.J.,2005.Caffeineforreducingbirddamagetonewlyseededrice.CropProtection,24(7):651-657.
Babic,Tanja,andKirsteenN.Browning.2014.“TheRoleofVagalNeurocircuitsintheRegulationofNauseaandVomiting.”EuropeanJournalofPharmacology722:38–47.doi:10.1016/j.ejphar.2013.08.047.
Baldwin,I.T.2001.“AnEcologicallyMotivatedAnalysisofPlant-HerbivoreInteractionsinNativeTobacco.”PlantPhysiology127(4):1449–58.
Beach,HoraceD.1957.“MorphineAddictioninRats.”CanadianJournalofPsychology/RevueCanadiennedePsychologie11(2).UniversityofTorontoPress:104–12.
Behrens,M.,andW.Meyerhof.2010.“OralandExtraoralBitterTasteReceptors.”InSensoryandMetabolicControlofEnergyBalance,editedbyWolfgangMeyerhof,UlrikeBeisiegel,andHans-GeorgJoost,87–99.ResultsandProblemsinCellDifferentiation.Springer.
Robert,B.,&Richerson,P.J.1985.Cultureandtheevolutionaryprocess.UniversityofChicago,Chicago.
Cashdan,E.1994.Asensitiveperiodforlearningaboutfood.HumanNature,5(3),279-291.
Chandrashekar,J.,M.A.Hoon,N.J.P.Ryba,andC.S.Zuker.2006.“TheReceptorsandCellsforMammalianTaste.”Nature444(7117).NaturePublishingGroup:288–94.
Dawkins,Richard,andJohnRKrebs.1979.“ArmsRacesBetweenandWithinSpecies.”ProceedingsoftheRoyalSocietyofLondon.SeriesB.BiologicalSciences205(1161).TheRoyalSociety:489–511.
Degenhardt,Louisa,EmilyStockings,GeorgePatton,WayneDHall,andMichaelLynskey.2016.“TheIncreasingGlobalHealthPriorityofSubstanceUseinYoungPeople.”TheLancetPsychiatry3(3):251–64.
Dwyer,JenniferB.,RonS.Broide,andFrancesM.Leslie.2008.“NicotineandBrainDevelopment.”BirthDefectsResearchPartC:EmbryoToday:Reviews84(1):30–44.doi:10.1002/bdrc.20118.
Etter,J.F.,&Eissenberg,T.(2015).Dependencelevelsinusersofelectroniccigarettes,nicotinegumsandtobaccocigarettes.DrugandAlcoholDependence,147,68-75.
FerréS.Anupdateonthemechanismsofthepsychostimulanteffectsofcaffeine.JNeurochem(2008)105(4):1067–79.doi:10.1111/j.1471-4159.2007.05196.x
Fleagle,JohnG.2013.PrimateAdaptationandEvolution.AcademicPress.
Gable,R.S.2004.“ComparisonofAcuteLethalToxicityofCommonlyAbusedPsychoactiveSubstances.”Addiction99(6).BlackwellSynergy:686–96.
Geerling,JoelC.,andArthurD.Loewy.2008.“CentralRegulationofSodiumAppetite.”ExperimentalPhysiology93(2):177–209.
Grando,SergeiA.2014.“ConnectionsofNicotinetoCancer.”NatureReviewsCancer14(6).NaturePublishingGroup:419–29.
Gundert-Remy,Ursula,UlrikeBernauer,BrunhildeBlömeke,BarbaraDöring,EricFabian,CarstenGoebel,StefanieHessel,etal.2014.“ExtrahepaticMetabolismattheBody’sInternal–externalInterfaces.”DrugMetabolismReviews46(3).Taylor&Francis:291–324.
Gutiérrez,J.M.,Warrell,D.A.,Williams,D.J.,Jensen,S.,Brown,N.,Calvete,J.J.,Harrison,R.A.andGlobalSnakebiteInitiative,2013.Theneedforfullintegrationofsnakebiteenvenomingwithinaglobalstrategytocombattheneglectedtropicaldiseases:thewayforward.PLoSNeglTropDis,7(6),p.e2162.
Hagen,E.H.,R.J.Sullivan,R.Schmidt,GMorris,R.Kempter,andHammersteinP.2009.“EcologyandNeurobiologyofToxinAvoidanceandtheParadoxofDrugReward.”Neuroscience160:69–84.
Hagen,EdwardH,MelissaJ.Garfield,andRogerJSullivan.2016.“TheLowPrevalenceofFemaleSmokingintheDevelopingWorld:GenderInequalityorMaternalAdaptationsforFetalProtection?”Evolution,Medicine,andPublicHealth1.OxfordUniversityPress:195–211.doi:10.1093/emph/eow013.
Hagen,EdwardH,CaseyJRoulette,andRogerJSullivan.2013.“ExplainingHumanRecreationalUseof‘Pesticides’:TheNeurotoxinRegulationModelofSubstanceUseVs.theHijackModelandImplicationsforAgeandSexDifferencesinDrugConsumption.”FrontiersinPsychiatry4(142).doi:10.3389/fpsyt.2013.00142.
Hamilton,J.G.1995.Needlephobia:aneglecteddiagnosis.JournalofFamilyPractice,41(2),169-176.
Hardy,K.,Buckley,S.,Collins,M.J.,Estalrrich,A.,Brothwell,D.,Copeland,L.,...&Huguet,R.2012.Neanderthalmedics?Evidenceforfood,cooking,andmedicinalplantsentrappedindentalcalculus.Naturwissenschaften,99(8),617-626.
Herrera,CarlosM,andOllePellmyr.2009.Plant-AnimalInteractions:AnEvolutionaryApproach.JohnWiley&Sons.
Hohmann-Marriott,MartinF,andRobertEBlankenship.2011.“EvolutionofPhotosynthesis.”AnnualReviewofPlantBiology62:515–48.
Hollingsworth,R.G.,Armstrong,J.W.andCampbell,E.,2002.Pestcontrol:caffeineasarepellentforslugsandsnails.Nature,417(6892):915-916.
Hukkanen,J.,P.Jacob,andN.L.Benowitz.2005.“MetabolismandDispositionKineticsofNicotine.”PharmacologicalReviews57(1).ASPET:79–115.
Hyman,S.E.2005.“Addiction:ADiseaseofLearningandMemory.”AmericanJournalofPsychiatry162:1414–22.
Kelley,A.E,andK.CBerridge.2002.“TheNeuroscienceofNaturalRewards:RelevancetoAddictiveDrugs.”JournalofNeuroscience22(9):3306–11.
Knoll,AndrewH,andSeanBCarroll.1999.“EarlyAnimalEvolution:EmergingViewsfromComparativeBiologyandGeology.”Science284(5423).AmericanAssociationfortheAdvancementofScience:2129–37.
Lachenmeier,DirkW,andJürgenRehm.2015.“ComparativeRiskAssessmentofAlcohol,Tobacco,CannabisandOtherIllicitDrugsUsingtheMarginofExposureApproach.”ScientificReports5.doi:10.1038/srep08126.
Lamba,V.2004.“PXR(NR1I2):SpliceVariantsinHumanTissues,IncludingBrain,andIdentificationofNeurosteroidsandNicotineasPXRActivators.”ToxicologyandAppliedPharmacology199(3):251–65.doi:10.1016/j.taap.2003.12.027.
Landoni,JuliaHigade.1991.“Nicotine.”PoisonsInformationMonographs.InternationalProgrammeonChemicalSafety.http://www.inchem.org/documents/pims/chemical/nicotine.htm.
Lin,Jian-You,JoeArthurs,andSteveReilly.2016.“ConditionedTasteAversions:FromPoisonstoPaintoDrugsofAbuse.”PsychonomicBulletin&Review.Springer,1–17.
Milner,PeterM.1991.“Brain-StimulationReward:AReview.”CanadianJournalofPsychology/RevueCanadiennedePsychologie45(1):1–36.doi:http://dx.doi.org/10.1037/h0084275.
Mullin,JamesM,NicoleAgostino,ErikaRendon-Huerta,andJamesJThornton.2005.“KeynoteReview:EpithelialandEndothelialBarriersinHumanDisease.”DrugDiscoveryToday10(6).Elsevier:395–408.
Olds,James,andPeterMilner.1954.“PositiveReinforcementProducedbyElectricalStimulationofSeptalAreaandOtherRegionsofRatBrain.”JournalofComparativeandPhysiologicalPsychology47(6):419–27.
Öhman,A.andMineka,S.,2001.“Fears,phobias,andpreparedness:towardanevolvedmoduleoffearandfearlearning.”Psychologicalreview,108(3):483-522.
Pardridge,WilliamM.2012.“DrugTransportAcrosstheBlood–brainBarrier.”JournalofCerebralBloodFlow&Metabolism32(11):1959–72.doi:10.1038/jcbfm.2012.126.
Parker,C.H.,Keefe,E.R.,Herzog,N.M.,O'connell,J.F.andHawkes,K.,2016.“Thepyrophilicprimatehypothesis.”EvolutionaryAnthropology,25(2):54-63.
Pavlov,IvanPetrovich.1927.ConditionedReflexes:AnInvestigationofthePysiologicalActivityoftheCerebralCortex.OxfordUniversityPress.
Placek,C.D.,&Hagen,E.H.2015.FetalProtection:TheRolesofSocialLearningandInnateFoodAversionsinSouthIndia.HumanNature,26(3),255-276.
Placek,C.D.,&Hagen,E.H.Underreview.
PletschPK,PollakKI,PetersonBL,ParkJ,OnckenCA,SwamyGK,etal.Olfactoryandgustatorysensorychangestotobaccosmokeinpregnantsmokers.ResNursHealth(2008)31(1):31–41.
Roden,DanM,andAlfredLGeorgeJr.2002.“TheGeneticBasisofVariabilityinDrugResponses.”NatureReviewsDrugDiscovery1(1).NaturePublishingGroup:37–44.
Rogers,A.R.1988.Doesbiologyconstrainculture?.AmericanAnthropologist,90(4),819-831.
Roulette,CaseyJ,HayleyMann,BrianMKemp,MarkRemiker,JenniferWRoulette,BarrySHewlett,MirdadKazanji,etal.2014.“TobaccoUseVs.HelminthsinCongoBasinHunter-Gatherers:Self-MedicationinHumans?”EvolutionandHumanBehavior35(5).Elsevier:397–407.
Rybak,MichaelE,MayaRSternberg,Ching-IPao,NamanjeetAhluwalia,andChristineMPfeiffer.2015.“UrineExcretionofCaffeineandSelectCaffeineMetabolitesIsCommonintheUSPopulationandAssociatedwithCaffeineIntake.”TheJournalofNutrition145(4):766–74.
Scherer,Gerhard,andPeterN.Lee.2014.“SmokingBehaviourandCompensation:AReviewoftheLiteraturewithMeta-Analysis.”RegulatoryToxicologyandPharmacology70(3):615–28.doi:10.1016/j.yrtph.2014.09.008.
Sisson,V.A.,andR.F.Severson.1990.“AlkaloidCompositionoftheNicotianaSpecies.”BeiträgeZurTabakforschungInternational14:327–39.
Small,E.,Shah,H.P.,Davenport,J.J.,Geier,J.E.,Yavarovich,K.R.,Yamada,H.,...&Bruijnzeel,A.W.(2010).Tobaccosmokeexposureinducesnicotinedependenceinrats.Psychopharmacology,208(1),143-158.
Spragg,SidneyDurwardShirley.1940.“MorphineAddictioninChimpanzees.”ComparativePsychologyMonographs15.
Steppuhn,A.,K.Gase,B.Krock,R.Halitschke,andI.T.Baldwin.2004.“Nicotine’sDefensiveFunctioninNature.”PLoSBiology2:1074–80.
Sullivan,R.J.,andE.H.Hagen.2002.“PsychotropicSubstance-Seeking:EvolutionaryPathologyorAdaptation?”Addiction97:389–400.
Sullivan,R.J.,E.H.Hagen,andP.Hammerstein.2008.“RevealingtheParadoxofDrugRewardinHumanEvolution.”ProceedingsoftheRoyalSocietyB275:1231–41.
Thorndike,EdwardLee.1911.AnimalIntelligence:ExperimentalStudies.Macmillan.
Torregrossa,Ann-Marie,andM.DeniseDearing.2009.“NutritionalToxicologyofMammals:RegulatedIntakeofPlantSecondaryCompounds.”FunctionalEcology23(1):48–56.
Tóth,Attila,AnnaBrózik,GergelySzakács,BalázsSarkadi,andTamásHegedüs.2015.“ANovelMathematicalModelDescribingAdaptiveCellularDrugMetabolismandToxicityintheChemoimmuneSystem.”PLOSONE10(2).PublicLibraryofScience:e0115533.
Tushingham,Shannon,andJelmerWEerkens.2016.“Hunter-GathererTobaccoSmokinginAncientNorthAmerica:CurrentChemicalEvidenceandaFrameworkforFutureStudies.”InPerspectivesontheArchaeologyofPipes,TobaccoandOtherSmokePlantsintheAncientAmericas,editedbyElizabethAnneBollwerkandShannonTushingham,211–30.Springer.
USDepartmentofHealthandHumanServices.(1986).Thehealthconsequencesofusingsmokelesstobacco:areportoftheadvisorycommitteetotheSurgeonGeneral.
Verendeev,Andrey,andAnthonyL.Riley.2012.“ConditionedTasteAversionandDrugsofAbuse:HistoryandInterpretation.”Neuroscience&BiobehavioralReviews36(10):2193–2205.
Wertz,AnnieE.,andKarenWynn.2014.“ThymetoTouch:InfantsPossessStrategiesThatProtectThemfromDangersPosedbyPlants.”Cognition130(1):44–49.doi:10.1016/j.cognition.2013.09.002.
Wiener,Ayana,MarinaShudler,AnatLevit,andMashaY.Niv.2012.“BitterDB:ADatabaseofBitterCompounds.”NucleicAcidsRes40:D413–419.
Wink,Michael,ed.2011.AnnualPlantReviews,BiochemistryofPlantSecondaryMetabolism.Vol.40.JohnWiley&Sons.
Wise,RoyA.1996.“AddictiveDrugsandBrainStimulationReward.”AnnualReviewofNeuroscience19(1):319–40.
Wishart,David,DavidArndt,AllisonPon,TanvirSajed,AnChiGuo,YannickDjoumbou,CraigKnox,etal.2015.“T3DB:TheToxicExposomeDatabase.”NucleicAcidsResearch43(D1).OxfordUnivPress:D928–D934.
WorldHealthOrganization.WHOReportontheGlobalTobaccoEpidemic(2013).Availablefrom:http://www.who.int/tobacco/global_report/2013/en/
Yokel,RobertA.,andRoyA.Wise.1976.“AttenuationofIntravenousAmphetamineReinforcementbyCentralDopamineBlockadeinRats.”Psychopharmacology48(3):311–18.doi:10.1007/BF00496868.