WSU 2014 Drug toxicity vs reward - Washington State...

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

Edward*H.*Hagen*Casey*J.*Roule>e*

*Department*of*Anthropology*Washington*State*University*

*

Roger*J.*Sullivan**

Department*of*Anthropology*California*State*University*Sacramento*

Tobacco*use*is*responsible*for*1*in*5*deaths*in*high*income*countries,*and*more*than*1*in*10*deaths*globally.*

The*mainstream*“reward”*model*Recrea&onal*drugs*increase*mesolimbic*dopamine*

Dopamine)False*signal*of*fitness*benefit*

Drugs)=)sugar)

Reasons*to*doubt*reward*model*

Most drugs are plant defensive toxins

Nico&ne*in*tobacco*Cocaine*in*coca*THC*in*cannabis*Caffeine*in*coffee*Arecoline*in*betel*nut*

These*evolved*to*harm*plant*consumers,*not*reward*them*

Nico&ne*as*a*model*drug*

Nico&ne*is*extremely*toxic*

Toxin Recreational dose Lethal dose

Hydrogen cyanide 50 mg Nicotine 1-4 mg 30-60 mg

*One*cigare>e*contains*10S20*mg*nico&ne,*enough*to*kill*a*child*

***

This*acute*toxicity*plays*almost*no*role*in*mainstream*drug*use*theory**

(Nico&ne*is*not*a*carcinogen)*

Nico&ne*ac&vates*virtually*all*known*toxin*defense*mechanisms*

Bi>er*taste*receptors*Gastrointes&nal*�taste��receptors*Nocicep&ve*(pain)*neurons*Xenobio&cSsensing*nuclear*receptors*Xenobio&c*metabolizing*enzymes*Aversion*circuitry*in*the*CNS*Condi&oned*taste*avoidance*Nausea*Vomi&ng*

Hypothesis*

Drug*toxicity*explains:**Age*differences*in*use*Sex*differences*in*use**Use*

Age*differences*in*substance*use*

Cumula&ve*distribu&on*of*age*at*first*use*(self*report)*

Degenhardt*et*al.*2008*WHO*World*Mental*Health*Surveys**N*=*85,052*

Co&nine*vs.*age*(Co&nine*is*a*nico&ne*metabolite)*

NHANES)199962010)*

N*=*18,382**

Age*3S10**

N*=*5932*Smoker*in*household:*1111*

Co&nine*half*life*�*18*hours*

Reward*models*of*low*child*use:**

Reduced*reward*func&on*in*children?*

Sugar*consump&on*vs.*age*

NHANES*1999S2004,*Wang*et*al.*2008* NHANES*2005S2008,*Ervin*et*al.*2012*

“Imbalance”*model*Chambers*et*al.*2003,*Casey*et*al.*2008,*Steinberg*2008*

Mesolimbic*dopamine*system*(MDS)**Reward*Reinforcement*

Prefrontal*cortex*(PFC)**SelfSregula&on*Abstract*reasoning*Delibera&on*Response*inhibi&on*Planning*ahead**

Pro*drug*signals* An&*drug*signals*

“Imbalance”*model*Chambers*et*al.*2003,*Casey*et*al.*2008,*Steinberg*2008*

Childhood*MDS*and*PFC**in*balance*

Adolescence*MDS*and*PFC**out*of*balance*

Adulthood*MDS*and*PFC**back*in*balance*

Imbalance*model*of*low*child*use:***

Social*restric&ons**

US*tobacco*control*programs*$500*million/year*

Mass*media*an&Stobacco*campaigns*Dissemina&on*of*health*warnings*via,*e.g.,*cigare>e*packages*and*adver&sing*Enforcing*bans*on*tobacco*marke&ng*Monitoring*tobacco*use*Enforcing*some*smokeSfree*legisla&on*Providing*some*tobacco*cessa&on*health*care*programs.**Tobacco*taxes*also*deter*use.*

Caffeine*

Caffeine*is*a*bi>erStas&ng*plant*toxin*Caffeine*increases*dopamine*in*the*MDS*Few*formal*controls*on*child*caffeine*consump&on*

Caffeine*added*to*many*sog*drinks*marketed*to*children*

Social*control*model:*children*should*consume*as*much*caffeine*as*adults.*

Coffee*intake*vs.*age*Pa>ern*very*similar*to*tobacco*use*

Toxicity*model*of*low*child*use**

*The*costs*of*neurotoxin*consump&on*are*high*in*childhood*but*decrease*with*age*

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

Heightened*child*toxin*defense*mechanisms*

Avoidance*******Detec&on*******Elimina&on*

Higher*density*of*taste*buds*on*the*&p*of*the*tongue.**Greater*bi>er*taste*sensi&vity*

Greater*neophobia*and*“pickiness.”*

Larger*liver/body*ra&o**Higher*drug*clearance*rates*

US*nonSfatal*poisoning*rate*vs.*age*

Adolescent*onset:*Brain*matura&on*

Longitudinal*fMRI*(Lenroot*and*Giedd*2006)*

Sex*differences*in*substance*use*

Female*vs.*male*prevalence*of*tobacco*use*N*=*157*countries*

No*sex*difference*in*consump&on*of*added*sugar*NHANES*2005S2010*

Sex*differences*in*reinforcement*learning?*

Many*sex*differences*in*spa&al*and*aversive*learning*(Dalla*and*Shors*2009)**Sex*differences*in*appe&&ve*learning?*

Toxicity*model***

Costs*of*neurotoxin*consump&on*are*higher*for*women*(pregnancy*and*fetal*exposure)*

S>*Less*female*drug*use*

Heightened*female*toxin*defense*mechanisms*

Avoidance*******Detec&on*******Elimina&on*

Higher*density*of*taste*buds*on*the*&p*of*the*tongue.**Greater*bi>er*taste*sensi&vity*

Food*aversions*in*pregnancy*

Larger*liver/body*ra&o**Higher*drug*clearance*rates,*especially*in*pregnancy*

?*******?*******?*

Xenobio&c*metabolism*accelerated*during*pregnancy*(mostly)*

+*++*+*S*S*+*+/S*+*

US*nonSfatal*poisoning*rate*vs.*age*

Female*vs.*male*prevalence*of*tobacco*use*N*=*157*countries*

Female*vs.*male*prevalence*of*tobacco*use*N*=*157*countries*

Female*vs.*male*prevalence*of*tobacco*use*N*=*157*countries*

Female*smoking*prevalence*vs.*TFR*

Generalized*linear*mixed*model*(GLMM)*with*spa&al*correla&on

Coefficients: Value SE DF t-value p-value

(Intercept) 4.58 3.90 139 1.17 0.243WECO 1.65 0.78 139 2.11 0.037tfr1975 -1.19 0.48 139 -2.48 0.014Male prevalence 0.31 0.06 139 5.48 0.000

Female*Aka*smoker*status*by*age*(selfSreport)*

Female smoker status ~ age + mother_smoker

*Coefficients: Estimate Std. Error z value Pr(>|z|) (Intercept) 4.52726 1.18191 3.830 0.000128 *** age -0.07406 0.02582 -2.869 0.004123 ** mother_smokeryes -2.59852 0.72489 -3.585 0.000337 ***

*

Prevalence*by*age*and*sex*(US)*NHANES*1999S2010*co&nine*conc.*>*3*ng/ml*

Ra&o*of*smoking*prevalence*45S64*years/25S44*years**13*countries*in*Global*Adult*Tobacco*Survey*(WHO)*

With*former*Soviet*Block*countries*(N=13)*

Without*former*Soviet*Block*countries*(N=10)*

A*regulatory*model*

The*brain*is*regula&ng,*not*elimina&ng,*exposure*to*plant*neurotoxins*

***

But*why?*

Honest*signal*of*brain*maturity*

Honest*signal*of*brain*maturity*

Cost*of*substance*use*is*high*for*individuals*with*s&llSdeveloping*brains*vs.*those*with*completed*brain*development.*

Substance*use*is*honest*signal*of*brain*matura&on.*

Maturity*important*criterion*for*mate*choice*and*social*partner*choice**

HunterSgatherers*typically*do*not*keep*track*of*chronological*age*Considerable*individual*varia&on*in*brain*matura&on*(Giedd*2008)*If*young*men*ranged*widely*in*search*of*mates,*young*women*would*have*to*assess*“maturity”*on*the*basis*of*limited*observa&ons.*

Ma&ng*and*substance*use*

Age*started*regular*smoking*vs.*first*sex*

Males* Females*

NHANES*1999S2010,*Controlling*for*ethnicity*and*current*age*of*par&cipant*

Maturity,*ma&ng*and*substance*use*

Smoking*ini&a&on*is*significantly*influenced*by*perceived*benefits,*such*as*looking*cool,*looking*grown*up,*being*popular*(HalpernSFelsher*et*al.*2004;*Morrell*et*al.*2010;*Song*et*al.*2009;*Borrelli*et*al.*2010)*

Smoking*associated*with*early*sexual*behavior*(Sussman*2005)*

Higher*ma&ng*effort*associated*with*higher*smoking*(Jones*and*Figueredo*2007),*other*drug*use*(Richardson*et*al.*2012),*and*more*lenient*aotudes*towards*drug*use*(Kurzban*et*al.*2010).*

*

Parasite*defense*

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?

Species*known*to*selfSmedicate*against*parasites*(Zoopharmocognosy,*Pharmacophagy)*

Primates*Fruit*flies*Ants*Moths*Bu>erflies*Honeybees*Birds*Sheep*Goats*

*Pharmacophagy*hypothesis*

*Recrea&onal*drug*use*is*an*(unconscious)*form*of*

selfSmedica&on*against*helminths*and*other*macroparasites*

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&ve*drugs*

=

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.

Helminth*burden*and*immune*response*vs.*age*

Study population: Aka foragers of the Central African Republic

Aka camp

Study)site)ra<onale)*High*levels*of*intes&nal*parasites**Heavy*tobacco*and*cannabis*use*among*men*(very*low*use*among*women).**Almost*no*access*to*commercial*anthelmin&cs.*

Predic&ons*

Chemotherapy*Inverse*correla&on*between*smoking*levels*and*worm*burden.**

Trea&ng*helminth*infec&ons*will*reduce*smoking*rela&ve*to*placebo*controls.*

Slow*nico&ne*metabolizers*will*have*lower*worm*burdens.*

Chemoprophylaxis*Among*Aka*treated*for*helminths,*smoking*levels*in*year*1*will*be*inversely*correlated*with*reinfec&on*by*year*2.*

Countries*with*higher*helminth*diversity*will*have*higher*smoking*prevalence.*

2010-2011

206 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

1 2 3

Smoking levels

Salivary cotinine –  Nicotine metabolite –  Half life ~ 18 hrs (nicotine half life ~ 2 hrs) –  Indexes level of recent nicotine exposure

Saliva collection tube

Barry Hewlett and Casey Roulette interviewing Aka about tobacco use

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

Chemotherapy: Observational study

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

Controls

Material wealth Radio Flashlight Watch Sets of clothes

Acculturation

Prefer forest or village Schooling (y/n) Church attendance (y/n)

Region 1: Near village 2, 3: ~20 Km W, SE

Age

Chemotherapy: Observational study

Worm*burde

n*score*

Worm*burde

n*score*

Age* Square*root*of*co&nine*concentra&on*

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) 2.78046 0.18384 15.124 <2e-16 ***villageTRUE 0.28057 0.12250 2.290 0.0232 * acculturation 0.09957 0.09683 1.028 0.3053 wealth -0.03064 0.04700 -0.652 0.5153 ---Signif. codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1

Approximate significance of smooth terms: edf Ref.df F p-value s(age) 2.464 3.116 2.483 0.04512 *s(cotinine) 2.549 3.200 4.719 0.00281 **---Signif. codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1

R-sq.(adj) = 0.146 Deviance explained = 13.7%UBRE score = 1.054 Scale est. = 1 n = 176

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

Testing the chemotherapy hypothesis with a randomized control trial

Predictions

Infec&on*with*helminths*should*increase*smoking**

Elimina&on*of*helminths*should*decrease*smoking*

Randomize into treatment and placebo control groups (double-blind)

400 mg albendazole Placebo

Randomized control trial

Administer 400 mg albendazole or placebo (double-blind)

~ 2 weeks

3 saliva/stools 3 saliva/stools

Prediction

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

Manipulation check

Worm burden

t = 7.0537, df = 86.781, p-value = 2.001e-1095 percent confidence interval: 7.78 Inf sample estimates: mean in group control mean in group treatment 13.66 3.47

t

RCT results

Limita&ons*

Cause(s)*of*treatment*effect*might*be*unrelated*to*selfSmedica&on*

Is*treatment*effect*due*to*changes*in*smoking*behavior*or*changes*in*metabolism?*

Why*does*control*group*co&nine*increase*preS*to*postSinterven&on*for*those*with*high*baseline*worm*burden?*

Biased*a>ri&on*(but*no*significant*difference*in*treatment*vs.*control*group)*

*

CYP2A6*genotype*

CYP2A6*metabolizes*nico&ne*to*co&nine*Polymorphisms*increase/decrease*metabolism*

Cheek*swabs*(Whatman*FTA*cards)*

Dried*blood*spots*

Predict*phenotype*Fast*metabolizing*alleles*=*1*

Normal*alleles*(wildtype)*=*0*

Slow*alleles*=*S1*

Sum*two*alleles*

Genotype*study*predic&ons*

Slow*phenotypes*will*have*higher*co&nine*levels*(reflec&ng*higher*nico&ne*exposure)*and*lower*worm*burden*

Aka*metabolic*phenotype*vs.*co&nine*

Robust*F*=*3.03,*p=.076**

Aka*metabolic*phenotype*vs.*worm*burden*

Normal*metabolizers*

Slow*metabolizers*

Limita&ons*

1.  We*tested*for*common*slow*and*fast*2A6*alleles,*but*it*is*likely*that*the* default* *1A* wildtype* allele* category* comprises* a* mix* of*wildtype*and*uniden&fied*slow*and*fast*alleles.*

2.  We* assume* that* the* rela&onship* between* 2A6* phenotype* and*worm*burden*was*mediated*by*nico&ne*exposure,*but*the*Aka*diet*might*contain*other*substrates*of*2A6*that*might*account*for*this*effect.**

3.  2A6*is*involved*in*the*biosynthesis*and*metabolism*of*endogenous*signaling*molecules*that*might*play*a*role*in*immunity*to*helminths*(e.g.,* steroids).*Allelic*varia&on* in*2A6*might* thus*have*numerous*influences*on*vulnerability*to*helminth* infec&on* in*addi&on*to,*or*other*than,*its*effect*on*nico&ne*metabolism;*or*it*might*simply*be*confounded*with*other*factors*influencing*worm*burden.*

4.  Currently,* Aka* exposure* to* nico&ne* is* primarily* from* the* New*World* tobacco* plant* (probably).* It* is* not* clear* what* substrate* in*the*diet,*if*any,*influenced*selec&on*on*2A6*in*the*Aka*or*any*other*popula&on.*

Chemoprophylaxis:*reinfec&on*study*

Predic&on:*Among*the*uninfected,*higher*smoking*reduces*risk*of*(re)infec&on.**Specifically,*year*1*and*year*2*smoking*levels*will*be*inversely*correlated*with*reinfec&on*by*year*2.*

Reinfec&on*study*

Reinfection study

r = -0.42, p = .02

Reinfection study

r = -0.47, p = .01

Limita&ons*

Even*though*longitudinal,*s&ll*a*correla&on*study*(correla&on*≠*causa&on)*

*

Small*sample*size*Cannot*control*for*confounds.*

CrossSna&onal*test*of*chemotherapy*

Predic&on:*Countries*with*higher*parasite*diversity*will*have*higher*smoking*prevalence*

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)         74.72263    9.96451    7.50  1.8e-11 ***LnGNP                0.57758    1.11946    0.52  0.60693Latitude^2        0.01395    0.00364    3.83  0.00021 ***RicArthropode       -7.07995    1.71151   -4.14  6.9e-05 ***RichVirus           -1.04143    0.28156   -3.70  0.00034 ***RichParasites        1.29529    0.23681    5.47  2.9e-07 ***LnGNP:Latitude^2 -0.00373    0.00108   -3.45  0.00081 ***---Signif. codes:  0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1

Residual standard error: 9.9 on 110 degrees of freedom (106 observations deleted due to missingness)Multiple R-squared: 0.47,    Adjusted R-squared: 0.442F-statistic: 16.3 on 6 and 110 DF,  p-value: 2.39e-13

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) 15.91894 8.88752 1.79 0.07602 .LnGNP 2.29394 0.94081 2.44 0.01636 *Latitude^2 0.00383 0.00110 3.47 0.00074 ***RicArthropode -2.07676 1.63166 -1.27 0.20577RichVirus 0.04887 0.26472 0.18 0.85387RichParasites -0.18692 0.22008 -0.85 0.39754---Signif. codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1

Residual standard error: 9.5 on 110 degrees of freedom (107 observations deleted due to missingness)Multiple R-squared: 0.374, Adjusted R-squared: 0.346F-statistic: 13.2 on 5 and 110 DF, p-value: 4.79e-10

Neurotoxin*regula&on*model*

Tobacco*users*&trate*nico&ne*intake**Some*dopamine*neurons*in*the*MDS*respond*to*aversive*s&muli**Inflammatory*signals*reinforce*opium*and*ethanol*consump&on*in*rodents*(Hutchinson*et*al.*2012,*Blednov*et*al.*2011,*2012)**Infec&on*induces*broad*downSregula&on*of*CYP*P450*metabolism,*increasing*plasma*concentra&ons*of*drug*(Morgan*et*al.*2008).*

“A*major*development*in*drug*addic&on*research*in*recent*years*has*been*the*discovery*that*immune*signaling*within*the*central*nervous*system*contributes*significantly*to*mesolimbic*dopamine*reward*signaling*induced*by*drugs*of*abuse,*and*hence*is*involved*in*the*presenta&on*of*reward*behaviors.”*Hutchinson*and*Watkins*2014.*

Conclusions*

Large*age*and*sex*differences*in*substance*use**Few*age*or*sex*differences*in*reward*or*reinforcement*learning**Age*and*sex*differences*in*substance*use*parallel*age*and*sex*differences*in*the*costs*of*neurotoxin*consump&on**Higher*co&nine*associated*with*lower*worm*burden*and*less*reinfec&on**Trea&ng*worms*reduces*exposure*to*nico&ne**Parasite*biodiversity*posi&vely*correlated*with*male*smoking*prevalence*