Biopsychology, Drug Use, Drug Addiction, 11th Ed - PDF

Chapter 15 Drug Use, Drug Addiction, and the Brain’s Reward Circuits Chemicals That Harm with Pleasure Phanie/Alamy Stock Photo Chapter Overview and Learning Objectives Basic Principles of Drug LO 15.1 Compare the various routes of drug a...

Chapter 15 Drug Use, Drug Addiction, and the Brain’s Reward Circuits Chemicals That Harm with Pleasure Phanie/Alamy Stock Photo Chapter Overview and Learning Objectives Basic Principles of Drug LO 15.1 Compare the various routes of drug administration. Action LO 15.2 Explain the ways in which drugs can influence the nervous system and how they are eliminated from the body. LO 15.3 Describe how the body becomes tolerant to drugs and the process of drug withdrawal. Explain what it means to be physically dependent on a drug. LO 15.4 Define drug addiction. Role of Learning in Drug LO 15.5 Explain contingent drug tolerance. Tolerance LO 15.6 Describe conditioned drug tolerance and conditioned compensatory responses. 404 M15_PINE1933_11_GE_C15.indd 404 22/01/2021 11:40  Drug Use, Drug Addiction, and the Brain’s Reward Circuits 405 Five Commonly Used LO 15.7 Describe the health hazards associated with nicotine Drugs consumption. LO 15.8 Describe the health hazards associated with alcohol consumption and the various stages of the full-blown alcohol withdrawal syndrome. LO 15.9 Explain the health effects of marijuana and the mechanism of action of THC. LO 15.10 Describe the health hazards associated with the consumption of cocaine and other stimulants. LO 15.11 Describe the health hazards associated with the consumption of opioids and the opioid withdrawal syndrome. Comparing the Health LO 15.12 Explain why it is difficult to determine causality in studies of Hazards of Commonly the health hazards of drugs. Used Drugs LO 15.13 Compare the direct health hazards of nicotine, alcohol, marijuana, cocaine, and heroin. Early Biopsychological LO 15.14 Explain the physical-dependence and positive-incentive Research on Addiction perspectives of addiction. LO 15.15 Describe the intracranial self-stimulation (ICSS) paradigm. LO 15.16 Describe two methods for measuring the rewarding effects of drugs. LO 15.17 Explain the role of the nucleus accumbens in drug addiction. Current Approaches to the LO 15.18 Describe the three stages in the development of a drug Mechanisms of Addiction addiction. LO 15.19 Describe two sets of findings that have challenged the relevance of drug self-administration studies. LO 15.20 Explain the significance of the case of Sigmund Freud. Drug addiction is a serious problem in most parts of the drugs) principles and concepts, compares the effects of five world. Globally, more than 1 billion people are addicted commonly used drugs, and reviews the research on the to nicotine; more than 100 million are addicted to alcohol; neural mechanisms of addiction. You likely already have more than 5 million are addicted to marijuana; more than strong views about drug addiction; thus, as you progress 28 million are addicted to illegal drugs; and tens of millions through this chapter, it is particularly important that you are addicted to prescription drugs (Degenhardt et al., 2018; do not let your thinking be clouded by preconceptions. In Sinha et al., 2018; Farrell et al., 2019). Pause for a moment particular, it is important that you do not fall into the trap and think about the sheer magnitude of the problem repre- of assuming that a drug’s legal status has much to say about sented by such figures—more than a billion addicted people its safety (see Nutt, King, & Nichols, 2013). You will be less worldwide. The incidence of drug addiction is so high that likely to assume that legal drugs are safe and illegal drugs it is almost certain that you or somebody dear to you will are dangerous if you remember that most laws governing be adversely affected by drugs. drug use in various parts of the world were enacted in the This chapter introduces you to some basic early part of the 20th century, long before there was any pharmacological (pertaining to the scientific study of scientific research on the topic. M15_PINE1933_11_GE_C15.indd 405 22/01/2021 11:40  406 Chapter 15 The two main advantages of the oral route of adminis- The Case of the Drugged High tration over other routes are its ease and relative safety. Its School Teachers main disadvantage is its unpredictability: Absorption from the digestive tract into the bloodstream can be greatly influ- People’s tendency to equate drug legality with drug safety was enced by such difficult-to-gauge factors as the amount and once conveyed to me (JP) in a particularly ironic fashion: I was type of food in the stomach. invited to address a convention of high school teachers on the topic of drug misuse. When I arrived at the convention center INJECTION. Drug injection is common in medical practice to give my talk, I was escorted to a special suite, where I was because the effects of injected drugs are strong, fast, and pre- encouraged to join the executive committee in a round of drug dictable. Drug injections are typically made subcutaneously taking—the drug being a special single-malt whiskey. Later, the (SC), into the fatty tissue just beneath the skin; intramuscularly irony of the situation had its full impact. As I stepped to the (IM), into the large muscles; or intravenously (IV), directly into podium under the influence of a psychoactive drug (the whis- veins at points where they run just beneath the skin. Many key), I looked out through the haze of cigarette smoke at an drug-addicted persons prefer the intravenous route because audience of educators who had invited me to speak to them the bloodstream delivers the drug directly to the brain. How- because they were concerned about the unhealthy impact of ever, the speed and directness of the intravenous route are drugs on their students. The welcoming applause gradually gave way to the melodic tinkling of ice cubes in liquor glasses, mixed blessings; after an intravenous injection, there is little and I began. They did not like what I had to say. or no opportunity to counteract the effects of an overdose, an impurity, or an allergic reaction. Furthermore, many drug users develop scar tissue, infections, and collapsed veins at the few sites on their bodies where there are large, accessible veins. Basic Principles of Drug INHALATION. Some drugs can be absorbed into the bloodstream through the rich network of capillaries in Action the lungs. Many anesthetics are typically administered by inhalation, as are tobacco and marijuana. The two main This module focuses on the basic principles of drug action, shortcomings of this route are that it is difficult to precisely with an emphasis on psychoactive drugs—drugs that influ- regulate the dose of inhaled drugs, and many substances ence subjective experience and behavior by acting on the damage the lungs if they are inhaled chronically. nervous system. ABSORPTION THROUGH MUCOUS MEMBRANES. Some drugs can be administered through the mucous Drug Administration, Absorption, membranes of the nose, mouth, and rectum. Cocaine, for and Penetration of the Central example, is commonly self-administered through the nasal Nervous System membranes (snorted)—but not without damaging them (see Walker, Joshi, & D’Souza, 2017). LO 15.1 Compare the various routes of drug administration. Drug Action, Metabolism, Drugs are usually administered in one of four ways: oral ingestion, injection, inhalation, or absorption through the and Elimination mucous membranes of the nose, mouth, or rectum. The LO 15.2 Explain the ways in which drugs can influence route of administration influences the rate at which and the nervous system and how they are the degree to which the drug reaches its sites of action in eliminated from the body. the body. DRUG PENETRATION OF THE CENTRAL NERVOUS ORAL INGESTION. The oral route is the preferred route SYSTEM. Once a drug enters the bloodstream, it is car- of administration for many drugs. Once they are swallowed, ried to the blood vessels of the central nervous system. drugs dissolve in the fluids of the stomach and are carried to Fortunately, a protective filter, the blood–brain barrier (see the intestine, where they are absorbed into the bloodstream. Chapter 3), makes it difficult for many potentially danger- However, some drugs readily pass through the stomach ous bloodborne-chemicals to pass from the blood vessels of wall (e.g., alcohol), and these take effect sooner because they the CNS into the extracellular space around CNS neurons do not have to reach the intestine to be absorbed. Drugs and glia (see Sweeney et al., 2019). that are not readily absorbed from the digestive tract or that are broken down into inactive metabolites (breakdown MECHANISMS OF DRUG ACTION. Psychoactive drugs products of the body’s chemical reactions) before they can influence the nervous system in many ways. Some drugs be absorbed must be taken by some other route. (e.g., alcohol and many of the general anesthetics) act M15_PINE1933_11_GE_C15.indd 406 22/01/2021 11:40  Drug Use, Drug Addiction, and the Brain’s Reward Circuits 407 diffusely on neural membranes throughout the CNS. Others There are three important points to remember about the act in a more specific way: by binding to particular synaptic specificity of drug tolerance: receptors; by influencing the synthesis, transport, release, or One drug can produce tolerance to other drugs that deactivation of particular neurotransmitters; or by influenc- act by the same mechanism; this is known as cross ing the chain of chemical reactions elicited in postsynaptic tolerance (e.g., Schiavi et al., 2019). neurons by the activation of their receptors (see Chapter 4). Drug tolerance often develops to some effects of a drug DRUG METABOLISM AND ELIMINATION. The actions but not to others (e.g., Castelló et al., 2014). Failure to of most drugs are terminated by enzymes synthesized by understand this second point can have tragic conse- the liver. These liver enzymes stimulate the conversion of quences for people who think that because they have active drugs to nonactive forms—a process referred to as become tolerant to some effects of a drug (e.g., to the drug metabolism. In many cases, drug metabolism elimi- nauseating effects of alcohol), they are tolerant to all nates a drug’s ability to pass through lipid membranes of of them. In fact, tolerance may develop to some effects cells so that it can no longer penetrate the blood–brain bar- of a drug while sensitivity to other effects of the same rier. In addition, small amounts of some psychoactive drugs drug increases. Increasing sensitivity to a drug is called are passed from the body in urine, sweat, feces, breath, and drug sensitization. mother’s milk. Drug tolerance is not a unitary phenomenon; that is, there is no single mechanism that underlies all exam- Drug Tolerance, Drug Withdrawal ples of it (Koshimizu et al., 2018; Siciliano et al., 2016). Effects, and Physical Dependence When a drug is administered at doses that affect ner- vous system function, many kinds of adaptive changes LO 15.3 Describe how the body becomes tolerant to can occur to reduce its effects. drugs and the process of drug withdrawal. Explain what it means to be physically Two categories of changes underlie drug tolerance: dependent on a drug. metabolic and functional. Drug tolerance that results from changes that reduce the amount of the drug getting to its DRUG TOLERANCE. Drug tolerance is a state of sites of action is called metabolic tolerance. Drug tolerance decreased sensitivity to a drug that develops as a result that results from changes that reduce the reactivity of the of exposure to it. Drug tolerance can be demonstrated in sites of action to the drug is called functional tolerance (see two ways: by showing that a given dose of the drug has Bespalov et al., 2016). less effect than it had before drug exposure or by showing Tolerance to psychoactive drugs is largely functional. that it takes more of the drug to produce the same effect. In Functional tolerance to psychoactive drugs can result from essence, what this means is that drug tolerance is a shift in several different types of adaptive neural changes (see the dose-response curve (a graph of the magnitude of the effect Martyn, Mao, & Bittner, 2019). For example, exposure to a of different doses of the drug) to the right (see Figure 15.1) psychoactive drug can reduce the number of receptors for (see Bespalov et al., 2016). it, decrease the efficiency with which it binds to existing receptors, or diminish the impact of receptor binding on the activity of Figure 15.1 Drug tolerance is a shift in the dose-response curve to the right as a the cell. At least some of these adap- result of exposure to the drug. tive neural changes are the result of epigenetic mechanisms (e.g., Ghezzi Drug tolerance is a shift in et al., 2013; Liang et al., 2013). Magnitude of Drug Effect the dose-response curve to the right. Therefore, DRUG WITHDRAWAL EFFECTS 2 1 In tolerant individuals, the same dose has less effect. 1 AND PHYSICAL DEPENDENCE. After significant amounts of a drug have been in the body for a 2 In tolerant individuals, a greater dose is required to produce the period of time (e.g., several days), its sudden elimination can trigger same effect. an adverse physiological reaction called a withdrawal syndrome. The Drug Dose effects of drug withdrawal are vir- Initial dose-response Dose-response curve after tually always opposite to the initial curve drug exposure effects of the drug. For example, the withdrawal of anticonvulsant drugs M15_PINE1933_11_GE_C15.indd 407 22/01/2021 11:40  408 Chapter 15 often triggers convulsions, and the withdrawal of sleeping drug to offset them—manifest themselves as withdrawal pills often produces insomnia. Individuals who suffer with- symptoms that are opposite to the initial effects of the drug. drawal reactions when they stop taking a drug are said to The severity of withdrawal symptoms depends on the be physically dependent on that drug. particular drug in question, on the duration and degree of the preceding drug exposure, and on the speed with which the drug is eliminated from the body. In general, longer Journal Prompt 15.1 exposure to greater doses followed by more rapid elimina- What do you think the withdrawal reaction might be tion produces greater withdrawal effects. when one suddenly stops taking an antidepressant medication after having taken it for many years? Drug Addiction: What Is It? The fact that withdrawal effects are frequently opposite LO 15.4 Define drug addiction. to the initial effects of the drug suggests that withdrawal Drug-addicted individuals are habitual drug users, but effects may be produced by the same neural changes that not all habitual drug users are drug-addicted individuals. produce drug tolerance (see Figure 15.2). According to this Drug-addicted individuals are those habitual drug users theory, exposure to a drug produces compensatory changes who continue to use a drug despite its adverse effects on in the nervous system that offset the drug’s effects and pro- their health and social life (see Heilig et al., 2016; Zakiniaeiz duce tolerance. Then, when the drug is eliminated from the & Potenza, 2018), and despite their repeated efforts to stop body, these compensatory neural changes—without the using it (see Keramati, Ahmed, & Gutkin, 2017). The greatest confusion about the nature of drug addiction concerns its relation to physical dependence. Many people equate Figure 15.2 The relation between drug tolerance and withdrawal effects. the two: They see addicted persons as people The same adaptive neurophysiological changes that develop in response to drug exposure and produce drug tolerance manifest themselves as withdrawal who are trapped on a merry-go-round effects once the drug is removed. As the neurophysiological changes develop, of drug taking, withdrawal symptoms, tolerance increases; as they subside, the severity of the withdrawal effects and further drug taking to combat the decreases. withdrawal symptoms. Although appealing in its simplicity, this conception of drug addiction is inconsistent with the evidence. Drug Exposure Addicted individuals sometimes take drugs Magnitude of Drug Effect to prevent or alleviate their withdrawal Adaptive Neural symptoms, but this is often not the major Changes motivating factor in their addiction. If it were, drug-addicted individuals could be easily cured by hospitalizing them for a few days, until their withdrawal symptoms Drug Withdrawal subsided. However, most addicted individuals renew their drug taking even BASELINE after months of enforced abstinence (see Magnitude of Initial Meye et al., 2017). This is an important issue, Withdrawal Effect and it will be revisited later in this chapter. Drugs are not the only substances to which humans become addicted. Indeed, people who risk their health by continually bingeing on high-calorie foods (see Majuri et al., 2017; Westwater, Fletcher, & Withdrawal Effect Ziauddeen, 2016) or risk their economic stability through compulsive gambling Drug exposure leads With no drug to clearly have an addiction (see Clark, 2014; to the development of counteract them, adaptive neural changes the neural adaptations Majuri et al., 2017; Robbins & Clark, 2015). that produce tolerance by produce withdrawal Although this chapter focuses on drug counteracting the drug effects opposite to the addiction, other addictions—such as food, effect. effects of the drug. gambling, and Internet addictions—may be based on similar neural mechanisms. M15_PINE1933_11_GE_C15.indd 408 22/01/2021 11:40  Drug Use, Drug Addiction, and the Brain’s Reward Circuits 409 received a test injection of alcohol, followed 1 hour later by Role of Learning in Drug a convulsive stimulation so that the amount of tolerance to the anticonvulsant effect of alcohol could be compared in the Tolerance two groups. As Figure 15.3 illustrates, the rats that received alcohol on each trial before a convulsive stimulation became An important line of psychopharmacologic research has almost completely tolerant to alcohol’s anticonvulsant effect, shown that learning plays a major role in drug tolerance. In whereas those that received the same injections and stimula- addition to contributing to our understanding of drug toler- tions in the reverse order developed no tolerance whatsoever ance, this research has established that efforts to understand to alcohol’s anticonvulsant effect. Contingent drug tolerance the effects of psychoactive drugs without considering the has been demonstrated to many other drug effects and in many experience and behavior of the subjects can provide only species, including humans (see Wolgin & Jakubow, 2003). partial answers. Research on the role of learning in drug tolerance has focused on two phenomena: contingent drug tolerance and Conditioned Drug Tolerance conditioned drug tolerance. These two phenomena are dis- LO 15.6 Describe conditioned drug tolerance and cussed in the following sections. conditioned compensatory responses. Whereas studies of contingent drug tolerance focus on what Contingent Drug Tolerance subjects do while they are under the influence of drugs, studies of conditioned drug tolerance focus on the situa- LO 15.5 Explain contingent drug tolerance. tions in which drugs are taken. Conditioned drug tolerance Contingent drug tolerance refers to demonstrations that refers to demonstrations that tolerance effects are maxi- tolerance develops only to drug effects that are actually mally expressed only when a drug is administered in the experienced. Most studies of contingent drug tolerance same situation in which it has previously been administered employ the before-and-after design. In before-and-after (see Castelló, Molina, & Arias, 2017; Siegel, 2011). experiments, two groups of subjects receive the same series In one demonstration of conditioned drug tolerance of drug injections and the same series of repeated tests, (Crowell, Hinson, & Siegel, 1981), two groups of rats received but the subjects in one group receive the drug before each test of the series and those in the other group receive the drug after each test of Figure 15.3 Contingent tolerance to the anticonvulsant effect of alcohol. The the series. At the end of the experiment, rats that received alcohol before each convulsive stimulation became tolerant to its anticonvulsant effect; those that received alcohol after each convulsive all subjects receive the same dose of the stimulation did not become tolerant. drug followed by a final test so that the degree to which the drug disrupts test performance in the two groups can be Baseline Treatment Trials Test Trial compared. convulsive convulsive alcohol before My colleagues and I (Pinel, Mana, stimulation; stimulation; plus convulsive & Kim, 1989) used the before-and-after no alcohol alcohol stimulation Mean Convulsion Duration design to study contingent tolerance to the anticonvulsant effect of alcohol. In 40 This group became one study, two groups of rats received tolerant exactly the same regimen of alcohol Alcohol after 30 convulsive injections: one injection every 2 days for stimulation the duration of the experiment. During the tolerance development phase, the 20 rats in one group received each alcohol Alcohol before convulsive This group injection 1 hour before a mild convulsive stimulation 10 did not amygdala stimulation so that the anti- become convulsant effect of the alcohol could tolerant be experienced on each trial. The rats in the other group received their injections Days 1 hour after each convulsive stimulation Before group After group so that the anticonvulsant effect of the alcohol could not be experienced. At the Based on Pinel, J. P. J., Mana, M. J., & Kim, C. K. (1989). Effect-dependent tolerance to ethanol’s end of the experiment, all of the subjects anticonvulsant effect on kindled seizures. M15_PINE1933_11_GE_C15.indd 409 22/01/2021 11:40  410 Chapter 15 20 alcohol and 20 saline injections in Figure 15.4 The situational specificity of tolerance to the hypothermic effects of an alternating sequence, one injection alcohol in rats. every other day. The only difference between the two groups was that the Normal rats in one group received all 20 alcohol 00.00 injections in a distinctive test room and Body Temperature –0.5 Tolerance to the the 20 saline injections in their colony Rats hypothermic room, while the rats in the other group received 20 effect of alcohol received the alcohol in the colony –1.0 injections of room and the saline in the distinctive alcohol and then –1.368 were tested in test room. At the end of the injection –1.5 Hypothermic the same period, the tolerance of all rats to the response to first environment hypothermic (temperature-reducing) injections of alcohol effects of alcohol was assessed in both environments. As Figure 15.4 Normal illustrates, tolerance was observed Rats received 20 only when the rats were injected in the Body Temperature –0.5 injections of environment that had previously been alcohol and then paired with alcohol administration. were tested in –1.0 an environment There have been dozens of other different from –1.318 demonstrations of the situational –1.368 the one in which specificity of drug tolerance: The effects –1.5 Hypothermic they had No tolerance to response to first received the 20 the hypothermic are large, reliable, and general. injections injections of alcohol effect of alcohol The situational specificity of drug tolerance led Siegel and his colleagues to propose that drug users may be Based on Crowell, C. R., Hinson, R. E., & Siegel, S. (1981). The role of conditional drug responses in t­olerance particularly susceptible to the lethal to the hypothermic effects of ethanol. Psychopharmacology, 73, 51–54. effects of a drug overdose when the drug is administered in a new context. Their hypothesis drug come to elicit greater and greater conditioned com- is that drug users become tolerant when they repeatedly pensatory responses; and those conditioned compensatory self-administer their drug in the same environment and, as responses increasingly counteract the unconditional effects a result, begin taking larger and larger doses to counter- of the drug and produce situationally specific tolerance (see act the diminution of drug effects. Then, if the drug user González et al., 2019). administers the usual massive dose in an unusual situation, Alert readers will have recognized the relation between tolerance effects are not present to counteract the effects of Siegel’s theory of drug tolerance and Woods’s theory of the drug, and there is a greater risk of death from overdose. mealtime hunger, which you learned about in Chapter 12. In support of this hypothesis, Siegel and colleagues (1982) Stimuli that predict the homeostasis-disrupting effects of found that many more heroin-tolerant rats died following meals trigger conditioned compensatory responses to mini- a high dose of heroin administered in a novel environment mize a meal’s disruptive effects in the same way that stimuli than died in the usual injection environment. (Heroin, as that predict the homeostasis-disrupting effects of a drug you will learn later in this chapter, kills by suppressing trigger conditioned compensatory responses to minimize respiration.) the drug’s disruptive effects. Siegel views each incidence of drug administration as a Pavlovian conditioning trial (see Chapter 5) in which vari- ous environmental stimuli (e.g., particular rooms, drug par- Journal Prompt 15.2 aphernalia, or other drug users) that regularly predict the What other external stimuli, besides the drug- administration environment, do you think might serve administration of the drug are conditional stimuli and the as effective conditional stimuli for the development of drug effects are unconditional stimuli. The central assump- conditioned drug tolerance? tion of the theory is that conditional stimuli that predict drug administration come to elicit conditional responses opposite to the unconditional effects of the drug. Siegel has Most demonstrations of conditioned drug tolerance termed these hypothetical opposing conditional responses have employed exteroceptive stimuli (external, public conditioned compensatory responses. The theory is that stimuli, such as the drug-administration environment) as conditional stimuli that repeatedly predict the effects of a the conditional stimuli. However, interoceptive stimuli M15_PINE1933_11_GE_C15.indd 410 22/01/2021 11:40  Drug Use, Drug Addiction, and the Brain’s Reward Circuits 411 (internal, private stimuli) are just as effective in this role. This change in perspective makes a big difference. For For example, both the thoughts and feelings produced by example, in the previously described alcohol tolerance the drug-taking ritual and the drug effects experienced experiment by Crowell and colleagues (1981), alcohol was soon after administration can, through conditioning, come designated as the unconditional stimulus and the resulting to reduce the full impact of a drug (Siegel, 2008). This point hypothermia as the unconditional response. Instead, about interoceptive stimuli is important because it indicates Ramsay and Woods would argue that the unconditional that just thinking about a drug can evoke conditioned stimulus was the hypothermia directly produced by the compensatory responses. exposure to alcohol, and the compensatory changes that Drug withdrawal effects and conditioned compensa- tended to counteract the reductions in body temperature tory responses are similar: They are both responses that were the unconditional responses. The important are opposite to the unconditioned effect of the drug. The point about all of this is that once one determines the difference is that drug withdrawal effects are produced by unconditional stimulus and unconditional response, it is elimination of the drug from the body, whereas conditioned easy to predict the direction of the conditional response compensatory responses are elicited by drug-predictive in any drug-conditioning experiment: The conditional cues in the absence of the drug. In complex, real-life situa- response is always similar to the unconditional response. tions, it is nearly impossible to tell them apart. Although tolerance develops to many drug effects, sometimes the opposite occurs, that is, drug sensitization. Drug sensitization, like drug tolerance, can be situationally specific (e.g., Carey, 2020; Singer et al., 2014). For example, Five Commonly Used Anagnostaras and Robinson (1996) demonstrated the situ- Drugs ational specificity of sensitization to the motor stimulant This module focuses on the health hazards associated with effects of amphetamine. They found that 10 amphetamine the chronic use of five commonly used drugs: nicotine, alco- injections, one every 3 or 4 days, greatly increased the abil- hol, marijuana, cocaine, and the opioids. ity of amphetamine to activate the motor activity of rats— but only when the rats were injected and tested in the same environment in which they had experienced the previous Nicotine amphetamine injections. LO 15.7 Describe the health hazards associated with nicotine consumption. THINKING ABOUT DRUG CONDITIONING. In any situation in which drugs are repeatedly administered, con- The drug nicotine—the major psychoactive ingredient of ditioned effects are inevitable. That is why it is particularly tobacco—is most commonly administered through inhalation, important to understand them. However, most theories of though other methods of administration are possible (e.g., drug conditioning have a serious problem: They have dif- orally, as in the case of nicotine gum). There are two common ficulty predicting the direction of the conditioned effects. methods of nicotine inhalation: (1) smoking—inhaling the For example, Siegel’s conditioned compensatory response smoke from the burning of tobacco (e.g., cigarettes, cigars) theory predicts that conditioned drug effects will always and (2) vaping—inhaling a vapor that contains nicotine be opposite to the unconditioned effects of the drug, but (e.g., e-cigarettes). Of the two, smoking is the most common there are many documented instances in which conditional method, although vaping is quickly catching up. stimuli elicit responses similar to those of the drug (e.g., conditioned drug sensitization). Ramsay and Woods (1997) contend that much of the con- fusion about conditioned drug effects stems from a misunder- standing of Pavlovian conditioning. In particular, they criticize the common assumption that the unconditional stimulus (i.e., the stimulus to which the subject reflexively reacts) in a drug- tolerance experiment is the drug and that the unconditional responses are whatever changes in physiology or behavior the experimenter happens to be recording. They argue instead that the unconditional stimulus is the disruption of neural func- tioning that has been directly produced by the drug and that the unconditional responses are the various neurally mediated compensatory reactions to the unconditional stimulus, which the experimenter may or may not be recording. Angela Hampton Picture Library/Alamy Stock Photo M15_PINE1933_11_GE_C15.indd 411 22/01/2021 11:40  412 Chapter 15 TOBACCO SMOKING. When a cigarette is smoked, nico- a teratogen (an agent that can disturb the normal develop- tine and some 4,000 other chemicals, collectively referred ment of the fetus; see Jung et al., 2016): Smoking during to as tar, are absorbed through the lungs. Nicotine acts on pregnancy increases the likelihood of miscarriage, stillbirth, nicotinic cholinergic receptors in the brain (see Nees, 2014; early death of the child, psychiatric disorders during ado- Pistillo et al., 2014). Tobacco is the leading cause of prevent- lescence (e.g., Hunter et al., 2020), and other health conse- able death and disease in developed nations (see Tuesta quences (e.g., Baskaran et al., 2019). et al., 2017). It contributes to more than 6.5 million deaths a Even the consumption of nicotine by the father can year across the globe—about 1 in every 10 deaths (Britton, affect their children. For example, there is evidence that the 2017; Reitsma et al., 2017). administration of nicotine to male rats can increase depres- Because considerable tolerance develops to some of sion and anxiety in their offspring animal models of those the immediate effects of tobacco, the effects of smoking a conditions (see Goldberg & Gould, 2019). This is an example cigarette on nonsmokers and smokers can be quite differ- of transgenerational epigenetics: the transmission of epigen- ent. Nonsmokers often respond to a few puffs of a cigarette etic changes to subsequent generations (see Chapter 2). with various combinations of nausea, vomiting, coughing, If you or a loved one is a cigarette smoker, we have sweating, abdominal cramps, dizziness, flushing, and diar- some good news and some bad news. First the bad news: rhea. In contrast, smokers are better able to tolerate nicotine, Treatments for nicotine addiction are only marginally effec- and they report that they are more relaxed, more alert, and tive (see Zwar, Mendelsohn, & Richmond, 2014). The good less hungry after a cigarette (see Tuesta et al., 2017). news: Many people do stop smoking, and they experience The consequences of long-term tobacco use are alarm- major health benefits. Indeed, even the replacement of ing. Smoker’s syndrome is characterized by chest pain, tobacco with another form of nicotine administration (e.g., labored breathing, wheezing, coughing, and a heightened nicotine gum, nicotine skin patch, nicotine mouth spray) susceptibility to infections of the respiratory tract. Chronic is likely to lead to major health benefits (see Fagerström & smokers are highly susceptible to a variety of potentially Bridgman, 2014; Kupferschmidt, 2014). lethal lung disorders, including pneumonia, bronchitis NICOTINE VAPING. In 2003, the pharmacist Hon Lik (chronic inflammation of the bronchioles of the lungs), presented the world with the first e-cigarette (see Löhler emphysema (loss of elasticity of the lung from chronic irrita- & Wallenberg, 2019). For over a decade it was marketed as tion), and lung cancer. Although the increased risk of lung a safer alternative to tobacco for consuming nicotine. Cur- cancer receives the greatest publicity, smoking also increases rent evidence supports the notion that e-cigarettes can help the risk of cancer of the larynx (voice box), mouth, esopha- people quit smoking (see Hajek et al., 2019; Liu et al., 2018). gus, kidneys, pancreas, bladder, and stomach. Smokers also At the same time, many who start using e-cigarettes will run a greater risk of developing a variety of cardiovascular have difficulty quitting (see Liu et al., 2018), and some will diseases, which may culminate in heart attack or stroke. move on to the smoking of tobacco (see Chapman, Bareham, Sufferers from Buerger’s disease provide a shocking & Maziak, 2019; Liu et al., 2018). illustration of the addictive power of nicotine. In Buerger’s Is vaping a safer alternative to smoking? In general, disease—which occurs in about 15 of 100,000 individuals, there haven’t been enough studies yet to answer that ques- mostly in male smokers—the blood vessels, especially those tion. However, there have been an increasing number of supplying the legs, become constricted. reports of respiratory ailments amongst heavy vapers. We If a patient with this condition continues to smoke, gan- know of no controlled studies that have looked at long- grene may eventually set in. First a few toes may have term health outcomes associated with e-cigarette use (see to be amputated, then the foot at the ankle, then the leg Pisinger, Godtfredsen, & Bender, 2019). at the knee, and ultimately at the hip. Somewhere along Particularly disturbing has been the rapid rise in their this gruesome progression gangrene may also attack the use by youth. For example, in 2016, 11% of American high other leg. Patients are strongly advised that if they will school students and 4% of American middle school students only stop smoking, it is virtually certain that the otherwise inexorable march of gangrene up the legs will be curbed. reporting using e-cigarettes in the past month (see Warner Yet surgeons report that it is not at all uncommon to find & Mendez, 2019). a patient with Buerger’s disease vigorously puffing away ADDICTION AND NICOTINE. There is no question that in his hospital bed following a second or third amputation heavy smokers and vapers are addicted in every sense of operation. (Brecher, 1972, pp. 215–216) the word. Can you think of any other psychoactive drug The adverse effects of tobacco smoke are unfortunately that is self-administered almost continually—even while not restricted to those who smoke. Individuals who live or the addicted person is walking along the street? The com- work with smokers are more likely to develop heart dis- pulsive drug craving (an affective state in which there is a ease and cancer than those who don’t. Even the unborn are strong desire for the drug), which is a major defining fea- vulnerable (see Abbott & Winzer-Serhan, 2012). Nicotine is ture of addiction, is readily apparent in any habitual smoker M15_PINE1933_11_GE_C15.indd 412 22/01/2021 11:40  Drug Use, Drug Addiction, and the Brain’s Reward Circuits 413 who has run out of cigarettes, or any habitual vaper, who variety of socially unacceptable actions. High doses result in is forced by circumstance to refrain from nicotine inhala- unconsciousness; and if blood levels reach 0.5 percent, there tion for several hours. Furthermore, habitual smokers and is a risk of death from respiratory depression. The telltale vapers who stop their nicotine inhalation experience a vari- red facial flush of alcohol intoxication is produced by the ety of withdrawal effects, such as depression, anxiety, rest- dilation of blood vessels in the skin; this dilation increases lessness, irritability, constipation, and difficulties in sleeping the amount of heat lost from the blood to the air and leads and concentrating. to a decrease in body temperature (hypothermia). Alcohol is About 68 percent of all people who experiment with also a diuretic; that is, it increases the production of urine smoking become addicted—this figure compares unfavor- by the kidneys. ably with 23 percent for alcohol and 9 percent for marijuana Alcohol, like many addictive drugs, produces both (see Curran et al., 2016). Moreover, nicotine addiction typi- tolerance and physical dependence. The livers of heavy cally develops quickly, within a few weeks, and only about drinkers metabolize alcohol more quickly than the livers of 20 percent of all attempts to stop smoking are successful for nondrinkers, but this increase in metabolic efficiency con- 2 years or more. tributes only slightly to overall alcohol tolerance; most alco- hol tolerance is functional. Withdrawal from alcohol, even after a single bout of drinking, can produce a withdrawal Alcohol syndrome of headache, nausea, vomiting, and tremors, which is euphemistically referred to as a hangover. LO 15.8 Describe the health hazards associated with Withdrawal from alcohol after a long bout of heavy alcohol consumption and the various stages of drinking produces a full-blown alcohol withdrawal the full-blown alcohol withdrawal syndrome. syndrome comprising four phases (see Perry, 2014). The This section discusses another commonly used drug: alco- first phase begins 6 to 8 hours after the cessation of alcohol hol. Alcohol is involved in more than 3 million deaths each consumption and is characterized by anxiety, tremor, nausea, year across the globe, including deaths from birth defects, and tachycardia (rapid heartbeat). The second phase begins ill health, accidents, and violence (see Degenhardt et al., 10 to 30 hours after cessation of drinking and is characterized 2108; Parrott & Eckhardt, 2018). Worldwide, approxi- by hyperactivity, insomnia, and hallucinations. The defining mately 100 million people are heavy users of alcohol. feature of the third phase, which typically occurs between Because alcohol molecules are small and soluble in both 12 and 48 hours after cessation of drinking, is convulsive fat and water, they invade all parts of the body. Alcohol activity. The fourth phase, which usually begins 3 to 5 days is classified as a depressant because at moderate-to-high after the cessation of drinking and lasts up to a week, is doses it depresses neural firing; however, at low doses, it called delirium tremens (DTs). The DTs are characterized by can stimulate neural firing (see Alasmari et al., 2018) and disturbing hallucinations, bizarre delusions, disorientation, facilitate social interaction. Alcohol addiction has a major agitation, confusion, hyperthermia (high body temperature), genetic component. and tachycardia. The convulsions and the DTs produced by With moderate doses, the alcohol drinker experiences alcohol withdrawal can be lethal. various degrees of cognitive, perceptual, verbal, and motor Alcohol attacks almost every tissue in the body impairment, as well as a loss of control that can lead to a (see González-Reimers et al., 2014). Chronic alcohol consumption produces extensive brain damage (see Zahr & Pfefferbaum, 2017). This damage is produced both directly (see Zahr, Kaufman, & Harper, 2011) and indirectly (see Weil, Corrigan, & Karelina, 2018). For example, you learned in Chapter 1 that alcohol indirectly causes Korsakoff’s syndrome (a neuropsychological disorder characterized by memory loss, sensory and motor dysfunction, and, in its advanced stages, severe dementia) by inducing and interacting with thiamine deficiency (see Moretti et al., 2017). But even heavy alcohol users without Korsakoff’s syndrome display changes in brain structures: The most common finding is a general loss of cortical white and gray matter (see Everitt & Robbins, 2016). Alcohol affects the brain function of drinkers in other ways as well. For example, it interferes with the function of second messengers inside neurons; it disrupts Marcos Mesa Sam Wordley/Shutterstock GABAergic and glutaminergic transmission; it leads to M15_PINE1933_11_GE_C15.indd 413 22/01/2021 11:40  414 Chapter 15 DNA methylation; and it triggers apoptosis (see ali Shah born with characteristics of FAS whose mothers did not et al., 2013; Berkel & Pandey, 2017)—it is a neurotoxin (see drink but whose fathers were alcoholics (see Vassoler, Henriques et al., 2018). Byrnes, & Pierce, 2014; Chastain & Sarkar, 2017). Chronic alcohol consumption also causes extensive One of the most widely publicized findings about scarring, or cirrhosis, of the liver, which is the major cause alcohol is that moderate drinking reduces the risk of of death among heavy alcohol users. Alcohol erodes the coronary heart disease. This conclusion is based on the muscles of the heart and thus increases the risk of heart attack. finding that the incidence of coronary heart disease is less It irritates the lining of the digestive tract and, in so doing, among moderate drinkers than among abstainers. You increases the risk of oral and liver cancer, stomach ulcers, learned in Chapter 1 about the difficulty in basing causal pancreatitis (inflammation of the pancreas), and gastritis interpretations on correlational data, and researchers (inflammation of the stomach). And not to be forgotten is worked diligently to identify and rule out factors other the carnage that alcohol produces from accidents on our than the alcohol that might protect moderate drinkers roads, in our homes, in our workplaces, and at recreational from coronary heart disease. They seemed to rule out sites—in the United States, more than 10,000 people die each every other possibility. However, a thoughtful analysis year in alcohol-related traffic accidents alone. led to a different conclusion. Let us explain. In a culture in Many people assume the adverse effects of alcohol which alcohol consumption is the norm, any large group occur only in people who drink a lot—they tend to define of abstainers will always include some people who have “a lot” as “much more than they themselves consume.” But stopped drinking because they are ill—perhaps this is they are wrong. Several large-scale studies have shown that why abstainers have more heart attacks than moderate even low-to-moderate regular drinking (a drink or two per drinkers (see Roerecke & Rehm, 2011). This hypothesis day) is associated with elevated levels of many cancers, was tested by including in a meta-analysis only those including breast, oral cavity, and colorectal cancer (Bagnardi studies that used an abstainers control group consisting et al., 2013; Castro & Castro, 2014; Huber & Tantiwongkosi, of individuals who had never consumed alcohol. This 2014; Stone et al., 2014). meta-analysis indicated that alcohol in moderate amounts The offspring of mothers who consume substantial does not prevent coronary heart disease; that is, moderate quantities of alcohol during pregnancy can develop drinkers did not suffer less coronary heart disease than fetal alcohol syndrome (FAS), which has a worldwide lifelong abstainers (Fillmore et al., 2006; Stockwell, 2012). prevalence of 0.7% (see Lange et al., 2017; Valenzuela et Likewise, a more recent meta-analysis found that moderate al., 2012). A child with FAS suffers from some or all of the alcohol consumption did not reduce the risk of mortality following symptoms: brain damage, intellectual disability, (see Stockwell et al., 2016). poor coordination, poor muscle tone, low birth weight, delayed growth, and/or physical deformity (see Landgraf et al., 2014; Subramoney et al., 2018). Because alcohol Journal Prompt 15.3 can disrupt brain development in so many ways (e.g., by Before reading this section, what were your views on the disrupting the production of cell-adhesion molecules or by effects of moderate drinking? Have your views changed disrupting normal patterns of apoptosis), there is no time at all now? Why or why not? during pregnancy when alcohol consumption is safe (see Paintner, Williams, & Burd, 2012). Moreover, there seems to be no safe amount (see Charness, Riley, & Sowell, 2016). Marijuana Although full-blown FAS is rarely seen in the babies of LO 15.9 Explain the health effects of marijuana and the mothers who never had more than one drink a day during mechanism of action of THC. pregnancy, children of mothers who drank only moderately while pregnant are sometimes found to have a variety of Marijuana is the name commonly given to the dried cognitive problems, even though they are not diagnosed flower buds of female Cannabis plants. Cannabis, the with FAS (see Hendricks et al., 2019; Koren et al., 2014). common hemp plant, has three species: Cannabis sativa, There is evidence that alcohol consumption might have Cannabis indica, and Cannabis ruderalis. The usual mode of effects on subsequent generations, even when consumed consumption is to smoke these flowers in a joint (a cigarette by the male parent; that is, alcohol consumption has been of marijuana) or a pipe, but marijuana is also effective when shown to produce transgenerational epigenetic effects (see ingested orally if first baked into an oil-rich substrate, such Chapter 2)—see Kippin (2014); Vassoler, Byrnes, and Pierce as a chocolate brownie, to promote absorption from the (2014). For example, the offspring of alcohol-consuming gastrointestinal tract. male rats display impairments on various cognitive tasks The psychoactive effects of marijuana are largely attrib- (see Goldberg & Gould, 2019; Vassoler, Byrnes, & Pierce, utable to a constituent called THC (delta-9-tetrahydro- 2014). Moreover, there have been reports of human children cannabinol). However, marijuana contains more than 80 M15_PINE1933_11_GE_C15.indd 414 22/01/2021 11:40  Drug Use, Drug Addiction, and the Brain’s Reward Circuits 415 cannabinoids (chemicals of the same chemical class as THC), Popularization of marijuana smoking among the mid- which may also be psychoactive. For example, one canna- dle and upper classes in the 1960s stimulated a massive binoid, THCV (delta-9-tetrahydrocannabivarin), has been program of research. One of the difficulties in studying the shown to have antipsychotic effects (see Chapter 18)—see effects of marijuana is that they are subtle, difficult to mea- Cascio et al. (2014). Most of the cannabinoids are found in sure, and greatly influenced by the social situation: a sticky resin covering the leaves and flowers of the plant; At low, usual “social” doses, the intoxicated individ- this resin can be extracted and dried to form a dark corklike ual may experience an increased sense of well-being: material called hashish. initial restlessness and hilarity followed by a dreamy, Findings from archeological sites suggests that Cannabis carefree state of relaxation; alteration of sensory per- Sativa was used for its psychological effects as early as ceptions including expansion of space and time; and a 11,000 years ago (see Bonini et al., 2018; Wei et al., 2017). more vivid sense of touch, sight, smell, taste, and sound; Written records of cannabis use go back 6,000 years in China, a feeling of hunger, especially a craving for sweets; and where its stems were used to make rope, its seeds were subtle changes in thought formation and expression. To used as a grain, and its leaves and flowers were used for an unknowing observer, an individual in this state of their psychoactive and medicinal effects (see Bonini et al., consciousness would not appear noticeably different. (National Commission on Marijuana and Drug Abuse, 2018). In the Middle Ages, cannabis cultivation spread into 1972, p. 68) Europe, where it was grown primarily for the manufacture of rope. During the period of European imperialism, rope Although the effects of typical social doses of marijuana was in high demand for sailing vessels, and the American are subtle, high doses do impair psychological functioning. colonies responded to this demand by growing cannabis At high doses, short-term memory is impaired, and the abil- as a cash crop. George Washington, the first president of ity to carry out tasks involving multiple steps to reach a the United States, was one of the more notable cannabis specific goal declines. Speech becomes slurred, and mean- growers. ingful conversation becomes difficult. A sense of unreality, The practice of smoking the flower buds of the canna- emotional intensification, sensory distortion, feelings of bis plant and the word marijuana itself seem to have been paranoia, and motor impairment are also common. Driving introduced to the southern United States in the early part under the influence of marijuana is obviously dangerous of the 20th century. In 1926, an article appeared in a New (see Neavyn et al., 2014). Orleans newspaper exposing the “menace of marijuana,” Some people do become addicted to marijuana, but its and soon similar stories were appearing in newspapers all addiction potential is low. About 9% of all marijuana users over the United States claiming that marijuana turns people become addicted—considerably less than for cocaine (21%), into violent, drug-crazed criminals. The misrepresentation alcohol (23%), and tobacco (68%) (see Curran et al., 2016). of the effects of marijuana by the news media led to the Most people who use marijuana do so only occasionally, rapid enactment of laws against the drug. In many states, with only about 10 percent of them using daily; moreover, marijuana was legally classified a narcotic (a legal term gen- most people who try marijuana do so in their teens and erally used to refer to opioids), and punishment for its use curtail their use by their 30s or 40s. Tolerance to marijuana was dealt out accordingly. Marijuana bears no resemblance develops during periods of sustained use, and obvious to opioid narcotics. withdrawal symptoms (e.g., irritability, nausea, nightmares, and other sleep disturbances) are present in about 50% of daily users who cease their marijuana use (see Curran et al., 2016). What are the health hazards of marijuana use? There are respiratory symptoms associated with heavy mari- juana smoking: bronchitis and coughing being the most common. There are also cardiovascular symptoms. For example, there is evidence of an increase in the like­lihood of a heart attack in individuals of all ages, with older individuals showing the most pronounced increases (see Singh et al., 2018). There is no evidence that marijuana use increases the likelihood of cancer (see Cohen, Weizmann, & Weinstein, 2019). You have likely heard that marijuana causes brain dam- age. This claim has been spread by governmental and social agencies attempting to discourage marijuana use. But what Stanimir G.Stoev/Shutterstock is the actual evidence? M15_PINE1933_11_GE_C15.indd 415 22/01/2021 11:40  416 Chapter 15 Surprisingly, no damage that can reasonably be attrib- CB2 (see Scherma et al., 2019). CB1 turned out to be one of uted to marijuana use has been found in the brains of living the most prevalent metabotropic receptors in the brain (see or deceased marijuana users (see Hall & Degenhardt, 2014). Chapter 4)—see Parsons and Hurd (2015), and it is present However, four lines of indirect correlational (see Chapter 1) in other parts of the body as well (e.g., Hedlund, 2014); CB2 evidence have a bearing on the question: is found throughout the CNS and in the cells of the immune system (see Mechoulam & Parker, 2013; Parsons & Hurd, Brain-imaging studies have found that hippocampal 2015; Wei et al., 2017). But why are there receptors for THC volumes tend to be slightly reduced in some heavy in the brain? They could hardly have evolved to mediate marijuana users (see Batalla et al., 2013; Cohen, the effects of marijuana smoking. This puzzle was quickly Weizmann, & Weinstein, 2019). However, such findings solved with the discovery of a class of endogenous cannabi- might be the result of preexisting differences between noid neurotransmitters: the endocannabinoids (see Lu et al., users and nonusers (e.g., Goldman, 2015; Pagliaccio 2019; McPartland et al., 2014; Yin, Wang, & Zhang, 2019). et al., 2015). The first endocannabinoid neurotransmitter to be isolated Functional brain-imaging studies have found reliable and characterized was named anandamide, from a word differences in marijuana users when they are asked that means “internal bliss” (see Piomelli, 2014; Scherma to perform any one of many different tasks while et al., 2019). undergoing functional brain imaging (e.g., fMRI; see THC has been shown to have several therapeutic effects Chapter 5). Yet, these studies provided no indication (see Katz-Talmor et al., 2018; Noonan, 2015). Since the early as to whether the observed changes are harmful or 1990s, it has been used to suppress nausea and vomiting beneficial (see Zehra et al., 2018). in cancer patients and to stimulate the appetite of patients Heavy marijuana users tend to have memory problems with AIDS (see Robson, 2014). THC has also been shown (see Crane et al., 2013; Hall & Degenhardt, 2014). to block seizures; to dilate the bronchioles of asthmatics; However, those memory deficits dissipate within about to decrease the severity of glaucoma (a disorder character- 72 hours after the cessation of marijuana use (see Scott ized by an increase in the pressure of the fluid inside the et al., 2018). Accordingly, it is not clear if the memory eye); and to reduce anxiety, some kinds of pain, and the problems are indicative of persistent brain damage (see symptoms of multiple sclerosis (see Koppel et al., 2014). In Mechoulam & Parker, 2013; Scott et al., 2018; but see 2010, Sativex, a mouth spray that contains THC and other Berliner, Collins, & Coker, 2018). cannabinoids, was introduced into several countries for the treatment of multiple sclerosis symptoms (see Cressey, 2015; Heavy marijuana users are slightly more likely to be Zlebnik & Cheer, 2016), for which it seems to be effective diagnosed with schizophrenia (see Chapter 18)— (see Chiurchiù et al., 2018). especially if they began using marijuana during There is evidence that marijuana consumption might adolescence (see Radhakrishnan et al., 2014; Cohen, have effects on subsequent generations, even when Weizmann, & Weinstein, 2019). Until the reasons for consumed by the father; that is, marijuana consumption has this correlation are sorted out (see Hill, 2015; Pasman been shown to produce transgenerational epigenetic effects et al., 2018; Renard et al., 2014), youths with a history (see Andaloussi, Taghzouti, & Abboussi, 2019; Meccariello of schizophrenia in their families should refrain from et al., 2020; Szutorisz & Hurd, 2018). For example, Andaloussi, marijuana use (see Burns, 2013). Taghzouti, & Abboussi (2019) found that the offspring of In short, regardless of what you have heard to the male rats who had been given a CB1-receptor agonist for contrary, there is no convincing evidence that marijuana 20 days displayed increased vulnerability to stress-induced causes brain damage. Complicating the situation further is anxiety. that marijuana may actually have neuroprotective effects. We cannot end this discussion of marijuana (e.g., For example, Nguyen and colleagues (2014) reviewed the Cannabis Sativa) without telling you the following story: data of adults who were treated for traumatic brain injury (see Chapter 10) and found that those individuals who You can imagine how surprised I (JP) was when my colleague went to his back door, opened it, and yelled, tested positive for marijuana use were 80 percent less “Sativa, here Sativa, dinner time.” likely to die from the brain injury than nonusers of mari- “What was that you called your dog?” I asked as he juana. Also suggestive is the finding that old mice display returned to his beer. improved performance in a variety of learning paradigms “Sativa,” he said. “The kids picked the name. I think after receiving a low dose of THC (see Bilkei-Gorzo they learned about it at school; a Greek goddess or some- et al., 2017). thing. Pretty, isn’t it? And catchy too: Every kid on the Research on THC changed irrevocably in the early street seems to remember her name.” 1990s with the discovery of two receptors for it: CB1 and “Yes,” I said. “Very pretty.” M15_PINE1933_11_GE_C15.indd 416 22/01/2021 11:40  Drug Use, Drug Addiction, and the Brain’s Reward Circuits 417 Cocaine and Other Stimulants in order to experience its psychological effects. Users report being swept by a wave of well-being; they feel self- LO 15.10 Describe the health hazards associated confident, alert, energetic, friendly, outgoing, fidgety, and with the consumption of cocaine and other talkative; and they have less than their usual desire for stimulants. food and sleep. Stimulants are drugs whose primary effect is to produce Individuals who are addicted to cocaine tend to go on general increases in neural and behavioral activity. Although so-called cocaine sprees, binges in which extremely high stimulants all have a similar profile of effects, they differ levels of intake are maintained for periods of a day or two. greatly in their potency. Coca-Cola is a mild commercial During a cocaine spree, users become increasingly tolerant stimulant preparation consumed by many people around to the euphoria-producing effects of cocaine. Accordingly, the world. Today, its stimulant action is attributable to larger and larger doses are often administered. The spree caffeine, but when it was first introduced, it packed a real usually ends when the cocaine is gone or when it begins wallop in the form of small amounts of cocaine. Cocaine to have serious toxic effects. The effects of cocaine sprees and its derivatives are the focus of this section; but we will include sleeplessness, tremors, nausea, hyperthermia, and, also be discussing other stimulants. in rare cases, psychotic symptoms, which is called cocaine Cocaine is prepared from the leaves of the coca shrub, psychosis and has sometimes been mistakenly diagnosed as which grows primarily in western South America. For schizophrenia (see Chapter 18). During cocaine sprees, there is a centuries, a crude extract called coca paste has been made risk of loss of consciousness, seizures, respiratory arrest, heart directly from the leaves and eaten. Today, it is more com- attack, or stroke (see Zimmerman, 2012; Stankowski, Kloner, mon to treat the coca paste and extract cocaine hydrochloride, & Rezkalla, 2014). Although tolerance develops to most effects the nefarious white powder that is referred to simply as of cocaine (e.g., to the euphoria), repeated cocaine exposure cocaine and typically consumed by snorting or by injec- sensitizes subjects (i.e., makes them even more responsive) tion. Cocaine hydrochloride may be converted to its base to its motor effects (see Li & Wolf, 2012). The withdrawal form by boiling it in a solution of baking soda until the effects triggered by abrupt termination of a cocaine spree water has evaporated. The impure residue of this pro- are relatively mild. Common cocaine withdrawal symptoms cess is crack, a potent, cheap, smokeable form of cocaine include a negative mood swing and insomnia. (see Fukushima et al., 2019). However, because crack is Although cocaine and its derivatives are widely mis- impure and consumed by smoking, it is difficult to study, used, amphetamine and its relatives are currently the most and most research on cocaine derivatives has thus focused widely misused stimulants (UN Global ATS Assessment, on pure cocaine hydrochloride. More than 18 million 2011). Amphetamine has been in wide use since the 1960s. people used cocaine in the past year across the globe It is usually consumed orally in the potent form called (Farrell et al., 2019). d-amphetamine (dextroamphetamine). Some of the effects Cocaine hydrochloride is an effective local anesthetic of d-amphetamine are comparable to those of cocaine; for and was once widely prescribed as such until it was example, it can also produce a syndrome of psychosis called supplanted by synthetic analogues such as procaine amphetamine psychosis. and lidocaine (see Farrell et al., 2019). It is not, however, In the 1990s, d-amphetamine was supplanted as the cocaine’s anesthetic actions that are of interest to users. favored amphetamine-like drug by several more potent People eat, smoke, snort, or inject cocaine or its derivatives relatives. One is methamphetamine, or “meth” (see Hsieh et al., 2014), which is commonly used in its even more potent, smokeable, crystalline form (crystal meth). Another potent relative of amphetamine is 3,4-methylenedioxy- methamphetamine (MDMA, or ecstasy), which is taken orally (see Cole, 2014). Besides being a stimulant, MDMA is also considered an empathogen. Empathogens are psychoactive drugs that produce feelings of empathy (see Bedi, Hyman, & de Wit, 2010; Bershad et al., 2016). The primary mechanism by which cocaine and its derivatives exert their effects is by altering the activity of dopamine transporters, molecules in the presynaptic mem- brane that normally remove dopamine from synapses and transfer it back into presynaptic neurons. Other stimulants increase the release of monoamines into synapses (see Sitte Jan Mika/model released people collection/Alamy & Freissmuth, 2015). M15_PINE1933_11_GE_C15.indd 417 22/01/2021 11:40  418 Chapter 15 Do stimulants have long-term adverse effects on Opioids have been used for their euphoric effects and to the health of habitual users? There is some evidence relieve pain for over 4000 years (Darcq & Kieffer, 2018). Three