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

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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.

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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

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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.