Addictions

AddictionsChemicals like caffeine, cocoa, nicotine, TCH, cocaine, and opiates are all plant poisons designed to kill herbivorous insects. Yet humans can crave all of these to the point of addiction. Why?

IntroductionDrug misuse refers to the use of a drug for purposes for which it was not attended or using a drug in excessive quantities.Drug addiction is a state of physical or psychological dependence on a drug.

IntroductionSocio-economic dataaffordability & availability lower class (poor)environment/communitySocial effects

Drug Use: Many drugs used for a long time; started using a long time agoAlcohol--made from whatever was availableMeade/gin/ale/winedepending on class Cocadomesticated in western Andesabout 7000 years agoWho uses drug the most?Alcohol of total adult population use alcoholMale more than femaleMost alcohol drunk by small minority of drinkersA lot of people have alcohol disorders (more male than female)Illicit drug useAgain, lot of people usingMany people who use them have drug disordersmale more than femaleEstimated 15.3 million people worldwide drug disorders Distribution of drug use: Cannabisused across all countries worldOpiateconcentrated in Asia and EuropeCocaineconcentrated America and a little in EuropeTobaccoSmokers--men low income smoke more then men high income (reverse is true of women)Smokers start mainly before the age of 25=childhood/adolescenceSocioeconomic effects on drug useOverall, low income more use and use more dangerouslyAlcoholPeople in lower socio-economic groups tend to have a more hazardous and harmful pattern of use than people in higher socio-economic groupsIllicit drug useUrban poverty=increase in illicit drug useTobaccoIn high-income countries, low-income people more cigarette useMarket forces and substance useDetermines drug use: affordability and availabilityAffordabilityrelates to both income and priceOverall, may drugs when increase price the amount of use goes downThe price of tobacco affects the prevalence and consumption of tobacco products Raise price of tobaccoLess people start usingIncrease cessationLess consumption from continuing usersYoung people really sensitive to priceSimilarly, increases in the price of alcohol reduce both the use and consumption of alcohol products.Cocaine and heroinhigh elasticity (a term to measure how much use changes when price changes)Differences in income also affect drug usePeople with high incomes are more likely to use alcohol than people with lower incomes, whereas income level has little relation to tobacco use.Demand for heroin is price-elastic because heroin users report adjusting their consumption levels to their daily incomeAvailabilityNatural experimentFirst World War: Danish government placed taxes on alcohol (due to shortages of food and other necessities) Price multiplieduse greatly decreasedDrop in alcohol use accompanied by drop in many other harm indicators such as:Alcoholism and other alcohol related moralityDrunkenness arrests Shortage of alcoholless useless alcohol related deaths Opening up trade markets for cigarettesincreased consumptionReduction heroine supplyless overdose deathsDid substitute for other drugs, but people didnt dieRisk and protective factors for substance useNumber of factors that place individuals, usually young people, at increased risk of substance use, dependence and the social and health consequencesRisk factors act cumulative wayCan be present early years or emerge later such as in adolescences Some risk factorsAdolescents that have difficult family life, someone use drugs, sole parent, etc. more likely use drug as wellConduct disorder or aggressionActs independently and is hanging out with peers who use drugsProtective factorsEasy temperament helps prevent useRelationships parents, school, teachersEmotionally and socially competent2 major aspects of familyincreases rates of drug use (illicit/licit) in young people in high-income countries1) Home environmentDisadvantagedNo supervisionPoor discipline2) Someone else drug use/alcoholTeenagersFamily, peers, and other adults influence choices make Relationships and experiences from childhood still matterSubstance use more likely inYoung kidswho didnt complete high school Earlier childhood developmentBehavior problemsSensation seekingAdventurous personality Different social settingsdifferent amounts of drug useHigher substance useAcademic failureAntisocial behaviorEarly use of tobacco and alcohol sign that later problems will ensueCorrelation between use of substance and environment (community)Not surprising that the risk of harmful substance use is heightened in a community where there are higher levels (perceived and/or actual) of substance use, community disadvantage and disorganization, ready availability of substances and positive media portrayals of substance use. Trends in substance useAlcohol consumption stay stable (exception)Drug overdose deathsseen increase Illicit drug use increase (in countries havent seen)Tobacco huge problem (huge increase eventually)Tobacco epidemic Low income/middle class countriesIncrease in substance use (alcohol, drugs) Socio-economic poormore affected ConventionsHaving some impact on rise of illicit drug use

Research Being Done: Paradox of Drug Reward Neurobiology: Reward Model interactions: drugs and nervous systemrewarding and reinforcinghedonic effects Evolutionary: Punishment Model interactions: plants and herbivoresneurotoxins evolved to deter consumptionParadox of drug rewardEvolutionary biologists studying plant-herbivore interactionsArgue: plant secondary metabolites, including alkaloids such as nicotine, morphine, and cocaine, are potent neurotoxins that evolved to deter consumption by herbivores--punishment modelNeurobiology--reward modelInteractions between drugs and nervous system as rewarding and reinforcing Usually through hedonic effectsPunishment and reward model are incompatible

Punishment and Reward Model IncompatibleHypothesis that can resolve paradox:Evolutionary perspective drug reward: fitness consequencesHypothesis assumes:Evolved in drug-free environmentInherently vulnerable to drugsDrugs of abuse are rewarding and that the feeling and perception rewards correlate with fitness consequencesResearch Being Done: Paradox of Drug Reward Hypothesis explaining paradox of drug reward Evolutionary perspective drug rewardfitness consequencesFitness consequences--behaviors beneficial to an animals reproductive success are rewarded and/or reinforced by positive emotions, while behaviors with fitness-impairing consequences are discouraged with negative emotions DrugsAffect/unsettle/destabilize the natural reward circuitsCreate signal in brain that falsely indicates the arrival of a huge fitness benefit (positive reinforcement)Block painful feelings or affect states which block the adaptive functions of negative emotionsFor this hypothesis to work assumeBrain and its reward system evolved in a drug-free environment Drug environment now is a noveltyArgument against:Evolutionary evidenceindicates humans and other animals have been exposed to drugs throughout their evolutionAnalysis of evolution of hepatic enzymes (liver enzymesP450) metabolize environmental chemicalsBrain and its reward centers are inherently vulnerable to drugsIdea follows from mismatch assumptionBrain and reward centers evolved in drug free environment, so makes sense that it hasnt evolved defenses to protect it from psychoactive substancesIf the drug environment today were not novel than the brain and its center should have evolved ways to fight/deal with/resist the deleterious effectsArgument Against: Human evolution always exposed to plant neurotoxinsUnlikely, to be inherently vulnerable to drugsEvidence:Genetics of drug metabolismDrugs of abuse are rewarding and that the feeling and perception rewards correlate with fitness consequencesArgument Against: Drugs many times experienced as unpleasant by new usersToxic to the nervous systemBasically, drugs are non-rewarding Research Being Done: Paradox of Drug Reward Neurobiological PerspectiveInitial drug seeking and acute effectsMDS--mesolimbic dopamine systempleasure feeling Evolutionary PerspectiveAntagonistic relationshipEvolutionary arms race

Drug-reward--The neurobiological perspectiveDifferent stages of drug use: Initial use and acute effectsinitial seeking and using Long term use and long term effectsdrug tolerance and addictionInitial drug seeking and acute effectsNeurobiological model of acute drug reward and reinforcement is the mesolimbic dopamine system (MDS)MDS comprises dopaminergic neurons projecting from the ventral tegmental area (VTA) in midbrain to the nucleus accumbus (NAc) in the basal forebrain Degree of activity of the dopaminergic projections affects concentrations of extracellular dopamine in the NAcFunction of MDSHedonia hypothesisDopamine mediates the unconditional pleasure produced by food, sex, etc., as well as the conditional pleasure produced by secondary reinforces like drugsThe feeling of pleasureIncentive salience hypothesisManipulation of dopamine transmission has a powerful impact on motivation without changing hedonic reactions, and that wanting is neurologically, psychologically and conceptually distinct from liking.MDS mediates wanting not likingInitial and acute exposure to all drugs of abuse is thought to interfere with the normal functions of the MDS by increasing dopaminergic transmission to NAcEx) stimulants like cocaine increase dopaminergic transmission in the NAcNot entirely sure effects of increased levels of dopamine dowidely believed that increased levels reward and/or reinforce drug use Plant Chemical Punishment of Herbivores: the Evolutionary Biological PerspectiveAntagonistic relationship--plants and animals that eat themEvolutionary arms raceplants evolve ways not eaten; herbivores evolve ways to eat them; and cycle continuesSome plants and other autotrophsevolved chemical defenses so not eaten by herbivoresChemical attacksby manipulating signaling systems made up of molecules such as peptides, steroids, etc.Manipulate because have coevolved compounds that are either identical to or mimic these signaling moleculesSignaling system=vulnerable to manipulation by adversaries such as the autotrophs (plants that dont want to get eaten)Ex) one or more plant alkaloids (nitrogenous organic compound that has physiological actions on humans) identified that interfere with every step in neural signaling Paradoxproperties that explain why common drugs like caffeine, nicotine, and cocaine are toxicalso help explain why they are toxicThese and other addictive drugs appear to have evolved only because they successfully deterred, not rewarded or reinforced, pant consumptionEx) nicotiana attenuatedomesticated North American tobacco plant; 20 different herbivores attackAttacks cause different defense responsesincluding production of nicotineExperimentWhen produced low levels nicotineattacked more; more moralityWhen production increasedattack less; less moralityCost for defenses=production of nicotineAllocated chemical defenses strategicallymost valuable parts of plant: stem, young leaves, etc.Herbivores evolved countermeasuresEx) Enzymes that detoxify plant secondary compounds, mechanisms that extract benefits from defensive chemicals, etc.

Key Question:Novelty?Whether or not ancestors exposed to psychoactive neurotoxins?Research Being Done: Paradox of Drug Reward Key question: novel or mismatch?--Whether or not our ancestors were exposed to psychoactive neurotoxins If drugs are not evolutionarily novel than paradox has been unresolved.

Research Being Done: Paradox of Drug Reward Is drug exposure an evolutionary novelty?Detoxification enzymes evolvedcytochrome P450 (CYP)found mainly in LiverParadox of human drug useinherently vulnerable to drugsinitial drug use elicit hedonic rewards and false-positive signalsPotency

Is Drug exposure an evolutionary novelty?Neurobiologistsdrug seeking and use is intimately related to neural circuitry involved in reward and/or reinforcementEvolutionary biologistsplant neurotoxins evolved to punish, not reward, plant consumers, and it is beneficial to both plant and consumer that consumer is averse to plant toxins Evolutionary ecology perspectiveplants should not have evolved defensive chemicals that easily trigger reward in consumersConsumers should not have evolved neural circuitry that readily but inadvertently rewards or reinforces consumption of numerous neurotoxinsArgument: MDS evolved to reinforce behaviors that successfully resulted in food acquisition, mating and other fitness enhancing outcomes, and is maladaptively triggered by evolutionary novel exposure to psychoactive plant toxins If this is trueexposure to plant toxins is novelthan humans should exhibit little evidence of evolved countermeasuresA) Detoxification enzymes: a coevolved countermeasure in humans and other animalsPrincipal heterotroph detoxification enzymescytochrome P450 (CYP)Found in bacteria and EukaryaAncestral CYP evolved approximately 3.5 years agoOriginal function/still central functionmetabolism of steroids and fatty acidsRise of terrestrial lifemajor function of CYP expanded to include detoxification of dietary phytochemicals via a co-evolutionary process involving dozens of gene duplication eventsFound in tissues of humans and many mammalsconcentrated in LIVERIn mammalsCYP oxidize 90% drugsCYA familiessome highly conserved across species while others variable Most of drug metabolizing enzymes=variableSuggest species specific adaptations to frequently encountered plant toxins and other environmental chemicalsEmergence of xenobiotic-metabolizing CYP in animals at about same time as evolution of terrestrial plants Localization of cross-species variation in CYP genes within the xenobiotic-metabolizing subsetLarge species differences in drug metabolismB) Evolution in human xenobiotic-metabolizing cytochrome P450Mammalianlong evolutionary history of exposure to plant toxins Humans are mammals so have phylogentecically inherited the cycochrome P450 system for detoxification of environmental chemicals Enough to disapprove novelty of drugsArgue that humans able to separate nervous systems in a niche that excluded plant toxins So gene inherited from mammalian ancestors not used/neededArguediet included less plant toxins FireMeat dietThe paradox of human drug useA) Are we inherently vulnerable to drugs? Inherently vulnerable to drugs implicit in neurobiological models of mammalian MDSCurrent assumption is that MDS is easily triggered by a broad range of neurotoxins because it was not exposed to such toxins during its evolutionContradicted by: coevolution of xenobiotic metabolizing CYP familiesdemonstrates that heterotroph signaling systems have successfully endured a relentless chemical assault by autotrophs for hundreds of million of yearsLong exposure to plant neurotoxinsCYP dataB) Does initial drug use elicit hedonic rewards and false-positive signals? Positive and negative affective experiences and sensations related to fitness consequencesDrugs interfere with effectively mediated fitness signalsProblem with this view:1) Commonly used drugs have multiple nervous system targets and may activate physiological responses that are unpleasant or physiological systems that do not mediate affective experiencesMany drugs have or cause unpleasant feelings/sensations/experiencesEx) betel nutcan induce tremors, face flushing, sweating, etc.Most commonly used plant drugs are correctly and unsurprisingly recognized as toxins by most new users, both physiologically and affectively, and the physical and affective responses are accurate warnings of fitness costs, rather than a false positive signal of a fitness benefit2) Modern euphoric drugs, like heroin, might represent a genuine evolutionary mismatchdrugs that are vastly more pleasurable than any neurotoxins occurring naturally in ancestral environmentsSmall populationuse Euphoric drugsProbably used this to support idea that people take drugs for reward purposesLarger populationuse non-Euphoric drugsNew experiments or modelsShould use non-Euphoric populationC) Potency Have argued that drugs used today are more potent and not likely to have been used by ancestorsMost commonly used drugs in the ancestral past are still most commonly used today, e.g. tobacco, coffee, tea, canabis, belel nut, khat, cocoa and cola nutConcentrations of alkaloids like nicotine in the wild (or partially domesticated) species encountered by ancestors is generally higher than in the domesticated species currently used in the manufacture of commercial brands Potency and DomesticationD) Routes of delivery Pretty much hasnt changed over the yearsThe basic waysEx) mouthE) Animal data of drug rewardSome of strongest evidence supporting drug reinforcement models emerged from decades of research using laboratory animalsEvidence for coevolution of neurotoxins and mammalian CYP shows that exposure to high concentrations of plant alkaloids is no more an evolutionary novelty for rats or rabbits than it is for humansHence, drug reward is as much as a paradox for laboratory animals as it is for humans

Research Being Done: Evolutionary explanations for substance misuse and addictionsEnvironmental mismatchTentative hypothesis: trade-offsDarwinian fitness

Research Being Done: Environmental mismatchFrom human culture development, phytochemicals are now not scarced.New possibilities offered by technological advancement Pharmacophagy

Research Being Done: Tentative hypothesis, trade-offsAdvantages of substance use must outweigh risks

Research Being Done: Darwinian FitnessTraits that are beneficial towards survival undergo strong selective pressurePrimary emotional systems Drug abuse may use to diminish unpleasant effects

Research can be done:Why people continue to use?Adverse effects Drug-specific mechanismsToxin-exploiting mechanismsHow or why people differ in their susceptibility to substance abuse and addiction?

Novel directions for future researchTrying to figure outwhy people continue to use?Averse/harmful effects when use drugs such as alcohol, tobacco, and other recreational drugsnauseaWhy dont aversion mechanisms overcome drug reward and reinforcement?Figuring out drug-specific mechanisms?Could drug seeking by humans be mediated by presently unknown toxin-exploiting mechanisms similar to those found in other organismsSome recreational drugs attack human pathogens Maybe seek out drugs because even though bad for humans worse for pathogens Could be tested in lab Animals infected with disease and see if drug helps.

Ethical QuestionsTesting on animals and humans?Drugs or food?

Withdrawal: Presence and severity of characteristic withdrawal symptoms.Reinforcement: A measure of the substance's ability, in human and animal tests, to get usersto take it again and again, and in preference to other substances.Tolerance: How much of the substance is needed to satisfy increasing cravings for it, and the level of stable need that is eventually reached.Dependence: How difficult it is for the user to quit, the relapse rate, the percentage of people who eventually become dependent, the rating users give their own need for the substanceand the degree to which the substance will be used in the face of evidence that it causes harm.Intoxication: Though not usually counted as a measure of addiction in itself, the level of intoxication is associated with addiction and increases the personal and social damage a substance may do.http://www.drugwarfacts.org/cms/Addictive_Properties#sthash.C971cRyK.dpbsWhat should be done?

Who benefits?