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*
