Recrea&onal*drug*use:*does*drug*toxicity* explain*more*than*drug*reward?*

Transcription

1 Recrea&onaldruguse:doesdrugtoxicity explainmorethandrugreward? EdwardH.Hagen CaseyJ.Roule>e DepartmentofAnthropology WashingtonStateUniversity RogerJ.Sullivan DepartmentofAnthropology CaliforniaStateUniversitySacramento

2 Tobaccouseisresponsiblefor1in5deathsinhighincome countries,andmorethan1in10deathsglobally.

3 Themainstream reward model Recrea&onaldrugsincreasemesolimbicdopamine Drugs)=)sugar) Dopamine) Falsesignaloffitnessbenefit

4 Reasonstodoubtrewardmodel

5 Most drugs are plant defensive toxins Nico&neintobacco Cocaineincoca THCincannabis Caffeineincoffee Arecolineinbetelnut Theseevolvedtoharmplant consumers,notrewardthem

6 Nico&neasamodeldrug

7 Nico&neisextremelytoxic Toxin Recreational dose Lethal dose Hydrogen cyanide 50 mg Nicotine 1-4 mg mg Onecigare>econtains10S20mgnico&ne,enoughtokillachild Thisacutetoxicityplaysalmostnoroleinmainstreamdrugusetheory (Nico&neisnotacarcinogen)

8 Nico&neac&vatesvirtuallyallknowntoxin defensemechanisms Bi>ertastereceptors Gastrointes&nal taste receptors Nocicep&ve(pain)neurons Xenobio&cSsensingnuclearreceptors Xenobio&cmetabolizingenzymes AversioncircuitryintheCNS Condi&onedtasteavoidance Nausea Vomi&ng

9 Hypothesis Drugtoxicityexplains: Agedifferencesinuse Sexdifferencesinuse Use

10 Agedifferencesinsubstanceuse

11 Cumula&vedistribu&onofageatfirstuse (selfreport) Degenhardtetal.2008WHOWorldMentalHealthSurveys N=85,052

12 Co&ninevs.age (Co&nineisanico&nemetabolite) NHANES) ) N=18,382 Age3S10 N=5932 Smokerinhousehold:1111 Co&ninehalflife 18hours

13 Rewardmodelsoflowchilduse: Reducedrewardfunc&oninchildren?

14 Sugarconsump&onvs.age NHANES1999S2004,Wangetal.2008 NHANES2005S2008,Ervinetal.2012

15 Imbalance model Chambersetal.2003,Caseyetal.2008,Steinberg2008 Prodrugsignals An&drugsignals Mesolimbicdopaminesystem(MDS) Reward Reinforcement Prefrontalcortex(PFC) SelfSregula&on Abstractreasoning Delibera&on Responseinhibi&on Planningahead

16 Imbalance model Chambersetal.2003,Caseyetal.2008,Steinberg2008 Childhood MDSandPFC inbalance Adolescence MDSandPFC outofbalance Adulthood MDSandPFC backinbalance

17 Imbalancemodeloflowchilduse: Socialrestric&ons

18 UStobaccocontrolprograms$500million/year Massmediaan&Stobaccocampaigns Dissemina&onofhealthwarningsvia,e.g.,cigare>e packagesandadver&sing Enforcingbansontobaccomarke&ng Monitoringtobaccouse EnforcingsomesmokeSfreelegisla&on Providingsometobaccocessa&onhealthcareprograms. Tobaccotaxesalsodeteruse.

19 Caffeine Caffeineisabi>erStas&ngplanttoxin CaffeineincreasesdopamineintheMDS Fewformalcontrolsonchildcaffeineconsump&on Caffeineaddedtomanysogdrinksmarketedto children Socialcontrolmodel:childrenshould consumeasmuchcaffeineasadults.

20 Coffeeintakevs.age Pa>ernverysimilartotobaccouse

21 Toxicitymodeloflowchilduse Thecostsofneurotoxinconsump&onare highinchildhoodbutdecreasewithage

22 Brain development and acetylcholine Acetylcholine plays a critical role in brain maturation from early embryogenesis to adolescence. nachrs detectable before neuralation Acetylcholine promotes switch from replication to differentiation Acetylcholine modulates axonogenesis and synaptogenesis Acetylcholine promotes/prevents neuronal apoptosis Interference with cholinergic signaling disrupts final architectural assembly of brain regions with cholinergic target zones, such as those that control learning and memory. Slotkin 2004

23 Heightenedchildtoxindefensemechanisms Avoidance Detec&on Elimina&on Greaterneophobiaand pickiness. Higherdensityoftastebuds onthe&pofthetongue. Greaterbi>ertastesensi&vity Largerliver/bodyra&o Higherdrugclearancerates

24 USnonSfatalpoisoningratevs.age

25 Adolescentonset:Brainmatura&on LongitudinalfMRI(LenrootandGiedd2006)

26 Sexdifferencesinsubstanceuse

27 Femalevs.maleprevalenceoftobaccouse N=157countries

28 Nosexdifferenceinconsump&onofaddedsugar NHANES2005S2010

29 Sexdifferencesinreinforcementlearning? Manysexdifferencesinspa&aland aversivelearning(dallaandshors2009) Sexdifferencesinappe&&velearning?

30 Toxicitymodel Costsofneurotoxinconsump&onarehigherforwomen (pregnancyandfetalexposure) S> Lessfemaledruguse

31 Heightenedfemaletoxindefensemechanisms Avoidance Detec&on Elimina&on Foodaversionsinpregnancy Higherdensityoftastebuds onthe&pofthetongue. Greaterbi>ertastesensi&vity Largerliver/bodyra&o Higherdrugclearancerates, especiallyinpregnancy???

32 Xenobio&cmetabolismacceleratedduring pregnancy(mostly) S S + +/S +

33 USnonSfatalpoisoningratevs.age

34 Femalevs.maleprevalenceoftobaccouse N=157countries

35 Femalevs.maleprevalenceoftobaccouse N=157countries

36 Femalevs.maleprevalenceoftobaccouse N=157countries

37 Femalesmokingprevalencevs.TFR Generalizedlinearmixedmodel(GLMM)withspa&alcorrela&on Coefficients: Value SE DF t-value p-value (Intercept) WECO tfr Male prevalence

38 FemaleAkasmokerstatusbyage (selfsreport) Female smoker status ~ age + mother_smoker Coefficients: Estimate Std. Error z value Pr(> z ) (Intercept) age mother_smokeryes

39 Prevalencebyageandsex(US) NHANES1999S2010co&nineconc.>3ng/ml

40 Ra&oofsmokingprevalence45S64years/25S44years 13countriesinGlobalAdultTobaccoSurvey(WHO) WithformerSovietBlockcountries (N=13) WithoutformerSovietBlockcountries (N=10)

41 Aregulatorymodel Thebrainisregula&ng,notelimina&ng, exposuretoplantneurotoxins Butwhy?

42 Honestsignalofbrainmaturity

43 Honestsignalofbrainmaturity Costofsubstanceuseishighforindividualswith s&llsdevelopingbrainsvs.thosewithcompleted braindevelopment. Substanceuseishonestsignalofbrainmatura&on. Maturityimportantcriterionformatechoiceand socialpartnerchoice HunterSgathererstypicallydonotkeeptrackof chronologicalage Considerableindividualvaria&oninbrain matura&on(giedd2008) Ifyoungmenrangedwidelyinsearchofmates, youngwomenwouldhavetoassess maturity on thebasisoflimitedobserva&ons.

44 Ma&ngandsubstanceuse

45 Agestartedregularsmokingvs.firstsex Males Females NHANES1999S2010,Controllingforethnicityandcurrentageofpar&cipant

46 Maturity,ma&ngandsubstanceuse Smokingini&a&onissignificantlyinfluencedbyperceived benefits,suchaslookingcool,lookinggrownup,being popular(halpernsfelsheretal.2004;morrelletal.2010; Songetal.2009;Borrellietal.2010) Smokingassociatedwithearlysexualbehavior(Sussman 2005) Higherma&ngeffortassociatedwithhighersmoking (JonesandFigueredo2007),otherdruguse(Richardson etal.2012),andmorelenientaotudestowardsdruguse (Kurzbanetal.2010).

47 Parasitedefense

48 Plant neurotoxins (e.g., recreational drugs) evolved to harm plant parasites Arthropods Nematodes Did animals evolve to take advantage of 400+ million years of pharmacological R&D by plants?

49 SpeciesknowntoselfSmedicateagainstparasites (Zoopharmocognosy,Pharmacophagy) Primates Fruitflies Ants Moths Bu>erflies Honeybees Birds Sheep Goats

50 Pharmacophagyhypothesis Recrea&onaldruguseisan(unconscious)formof selfsmedica&onagainsthelminthsandother macroparasites

51 Chemoprophylaxis & Chemotherapy Chemoprophylaxis: recreational drug use deters infection by pathogens with nervous systems Chemotherapy: recreational drug use treats infection by pathogens with nervous systems = Psychoac&vedrugs

52 Efficacy of nicotine against helminths Many commercial anthelmintics (e.g., levamisole, pyrantel) attack same neuroreceptor system as nicotine (nachrs). Nicotine sulfate was widely used to de-worm livestock. Aqueous tobacco extracts still used in developing world to de-worm livestock. Tobacco widely reported as an anthelmintic in the ethnomedical literature.

53 Helminthburdenandimmuneresponsevs.age

54 Study population: Aka foragers of the Central African Republic Aka camp Study)site)ra<onale) Highlevelsofintes&nalparasites Heavytobaccoandcannabisuseamongmen (verylowuseamongwomen). Almostnoaccesstocommercialanthelmin&cs.

55 Predic&ons Chemotherapy Inversecorrela&onbetweensmokinglevelsandwormburden. Trea&nghelminthinfec&onswillreducesmokingrela&vetoplacebo controls. Slownico&nemetabolizerswillhavelowerwormburdens. Chemoprophylaxis AmongAkatreatedforhelminths,smokinglevelsinyear1willbe inverselycorrelatedwithreinfec&onbyyear2. Countrieswithhigherhelminthdiversitywillhavehighersmoking prevalence.

56 Aka males 3 neighboring populations of Aka Up to 9 saliva and stool samples per person Controls (age, region, wealth & acculturation) Experimental and observational designs 2 1 3

57 Smoking levels Salivary cotinine Nicotine metabolite Half life ~ 18 hrs (nicotine half life ~ 2 hrs) Indexes level of recent nicotine exposure Barry Hewlett and Casey Roulette interviewing Aka about tobacco use Saliva collection tube

58 Worm burden Appreciable levels of three types Hookworm Ancylostoma duodenale, Necator americanus Ascaris lumbricoides Whipworm Trichuris trichiura Egg counts measured with 3 techniques Direct examination Kato technique Concentration by sedimentation Semi-quantified on a 10 point scale for each species for each technique Worm burden score: sum all scores for all species for all techniques. Stool collection kit Formalin/PVA

59 Chemotherapy: Observational study Interview upon entrance to study 3 saliva and 3 stool samples per subject over ~ 6 days

60 Controls Material wealth Radio Flashlight Watch Sets of clothes Region Age 1: Near village 2, 3: ~20 Km W, SE Acculturation Prefer forest or village Schooling (y/n) Church attendance (y/n)

61 Chemotherapy: Observational study Wormburdenscore Wormburdenscore Age Squarerootofco&nineconcentra&on

62 Generalized additive model Family: Negative Binomial(1.904) Link function: log Formula: worm ~ village + acculturation + wealth + s(age) + s(cotinine) + offset(log(stool_count)) Parametric coefficients: Estimate Std. Error t value Pr(> t ) (Intercept) <2e-16 villagetrue acculturation wealth Signif. codes: Approximate significance of smooth terms: edf Ref.df F p-value s(age) s(cotinine) Signif. codes: R-sq.(adj) = Deviance explained = 13.7% UBRE score = Scale est. = 1 n = 176

63 Limitations Males only Observational study (worm score vs. cotinine) Correlation Causation Limited controls (age, wealth, acculturation) Negative correlation for heavier smokers only Unexplained flat or positive relationship at low cotinine levels

64 Testing the chemotherapy hypothesis with a randomized control trial

65 Predictions Infec&onwithhelminthsshouldincreasesmoking Elimina&onofhelminthsshoulddecreasesmoking

66 Randomize into treatment and placebo control groups (double-blind) 400 mg albendazole Placebo

67 Randomized control trial 3 saliva/stools 3 saliva/stools ~ 2 weeks Administer 400 mg albendazole or placebo (double-blind)

68 Prediction Albendazole treatment group will have reduced salivary cotinine relative to placebo control group

69 Manipulation check Worm burden t = , df = , p-value = 2.001e percent confidence interval: 7.78 Inf sample estimates: mean in group control mean in group treatment t

70 RCT results

71 Limita&ons Cause(s)oftreatmenteffectmightbeunrelatedtoselfS medica&on Istreatmenteffectduetochangesinsmokingbehavior orchangesinmetabolism? Whydoescontrolgroupco&nineincreasepreStopostS interven&onforthosewithhighbaselineworm burden? Biaseda>ri&on(butnosignificantdifferencein treatmentvs.controlgroup)

72 CYP2A6genotype CYP2A6metabolizesnico&netoco&nine Polymorphismsincrease/decreasemetabolism Cheekswabs(WhatmanFTAcards) Driedbloodspots Predictphenotype Fastmetabolizingalleles=1 Normalalleles(wildtype)=0 Slowalleles=S1 Sumtwoalleles

73 Genotypestudypredic&ons Slowphenotypeswillhavehigherco&ninelevels(reflec&ng highernico&neexposure)andlowerwormburden

74 Akametabolicphenotypevs.co&nine RobustF=3.03,p=.076

75 Akametabolicphenotypevs.wormburden Normalmetabolizers Slowmetabolizers

76 Limita&ons 1. Wetestedforcommonslowandfast2A6alleles,butitislikelythat the default 1A wildtype allele category comprises a mix of wildtypeanduniden&fiedslowandfastalleles. 2. We assume that the rela&onship between 2A6 phenotype and wormburdenwasmediatedbynico&neexposure,buttheakadiet mightcontainothersubstratesof2a6thatmightaccountforthis effect. 3. 2A6isinvolvedinthebiosynthesisandmetabolismofendogenous signalingmoleculesthatmightplayaroleinimmunitytohelminths (e.g., steroids). Allelic varia&on in 2A6 might thus have numerous influencesonvulnerabilitytohelminthinfec&oninaddi&onto,or otherthan,itseffectonnico&nemetabolism;oritmightsimplybe confoundedwithotherfactorsinfluencingwormburden. 4. Currently, Aka exposure to nico&ne is primarily from the New World tobacco plant (probably). It is not clear what substrate in thediet,ifany,influencedselec&onon2a6intheakaoranyother popula&on.

77 Chemoprophylaxis:reinfec&onstudy Predic&on:Amongtheuninfected,higher smokingreducesriskof(re)infec&on. Specifically,year1andyear2smokinglevels willbeinverselycorrelatedwithreinfec&onby year2.

78 Reinfec&onstudy

79 Reinfection study r = -0.42, p =.02

80 Reinfection study r = -0.47, p =.01

81 Limita&ons Eventhoughlongitudinal,s&llacorrela&on study(correla&on causa&on) Smallsamplesize Cannotcontrolforconfounds.

82 CrossSna&onaltestofchemotherapy Predic&on:Countrieswithhigherparasitediversity willhavehighersmokingprevalence

83 Cross national data: Males lm(formula = Percentage_smokers_male ~ LnGNP Latitude^2 + RicArthropode + RichVirus + RichParasites, data = bio) Coefficients: Estimate Std. Error t value Pr(> t ) (Intercept) e-11 LnGNP Latitude^ RicArthropode e-05 RichVirus RichParasites e-07 LnGNP:Latitude^ Signif. codes: Residual standard error: 9.9 on 110 degrees of freedom (106 observations deleted due to missingness) Multiple R-squared: 0.47, Adjusted R-squared: F-statistic: 16.3 on 6 and 110 DF, p-value: 2.39e-13

84 Cross national data: Females lm(formula = Percentage_smokers_female ~ LnGNP + Latitude^2 + RicArthropode + RichVirus + RichParasites, data = bio) Coefficients: Estimate Std. Error t value Pr(> t ) (Intercept) LnGNP Latitude^ RicArthropode RichVirus RichParasites Signif. codes: Residual standard error: 9.5 on 110 degrees of freedom (107 observations deleted due to missingness) Multiple R-squared: 0.374, Adjusted R-squared: F-statistic: 13.2 on 5 and 110 DF, p-value: 4.79e-10

85 Neurotoxinregula&onmodel Tobaccousers&tratenico&neintake SomedopamineneuronsintheMDSrespond toaversives&muli Inflammatorysignalsreinforceopiumand ethanolconsump&oninrodents(hutchinsonet al.2012,blednovetal.2011,2012) Infec&oninducesbroaddownSregula&onof CYPP450metabolism,increasingplasma concentra&onsofdrug(morganetal.2008). Amajordevelopmentindrugaddic&onresearchinrecentyearshasbeenthe discoverythatimmunesignalingwithinthecentralnervoussystemcontributes significantlytomesolimbicdopaminerewardsignalinginducedbydrugsofabuse,and henceisinvolvedinthepresenta&onofrewardbehaviors. HutchinsonandWatkins 2014.

86 Conclusions Largeageandsexdifferencesinsubstanceuse Fewageorsexdifferencesinrewardor reinforcementlearning Ageandsexdifferencesinsubstanceuseparallel ageandsexdifferencesinthecostsofneurotoxin consump&on Higherco&nineassociatedwithlowerwormburden andlessreinfec&on Trea&ngwormsreducesexposuretonico&ne Parasitebiodiversityposi&velycorrelatedwithmale smokingprevalence