Why do people become addicted to drugs? Early explanations centered on pleasure and dependence: habitual drug users initially feel pleasure but then endure psychological and physiological withdrawal symptoms as the drug wears off. They feel anxious, insecure, or just plain sick without the drug, so they take it again to alleviate those symptoms. In this way, they get hooked on the drug.

Although this dependency hypothesis may account for part of drug-taking behavior, it has shortcomings as a general explanation. For example, an addict may abstain from a drug for months, long after any withdrawal symptoms have abated, yet still be drawn back to using it. In addition, some psychoactive drugs, such as the tricyclic antidepressants, produce withdrawal symptoms when discontinued, but these drugs are not abused.

To account for all the facts about drug abuse and addiction, Terry Robinson and Kent Berridge (2008) proposed the incentive sensitization theory, also called the wanting-and-liking theory because wanting and liking are produced by different brain systems. Their wanting is craving, whereas liking is the pleasure the drug produces. With repeated use, tolerance for liking develops, and the expression of liking (pleasure) decreases as a consequence (Figure 6-14). In contrast, the system that mediates wanting sensitizes, and craving increases.

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The first step on the proposed road to drug dependence is the initial experience, when the drug affects a neural system associated with pleasure. At this stage, the user may like the substance—including liking to take it within a given social context. With repeated use, liking the drug may decline from its initial level. At this stage, the user may also begin to show tolerance to the drug’s effects and so may begin to increase the dosage to increase liking.

With each use, the drug taker increasingly associates the cues related to drug use—be it a hypodermic needle, the room in which the drug is taken, or the people with whom the drug is taken—with the drug-taking experience. The user makes this association because the drug enhances classically conditioned cues associated with drug taking. Eventually, these cues come to possess incentive salience: they induce wanting, or craving, the drug-taking experience.

The neural basis of addiction is proposed to involve multiple brain systems. The decision to take a drug is made in the prefrontal cortex, an area that participates in most daily decisions. When a drug is taken, it activates opioid systems in the brainstem that are generally related to pleasurable experiences. And wanting drugs may spring from activity in the mesolimbic pathways of the dopaminergic activating system.

In these mesolimbic pathways, diagrammed in Figure 6-15, the axons of dopamine neurons in the midbrain project to structures in the basal ganglia, to the frontal cortex, and to the limbic system. When drug takers encounter cues associated with drug taking, the mesolimbic system becomes active, releasing dopamine. Dopamine release is the neural correlate of wanting.

Another brain system may be responsible for conditioning drug-related cues to drug taking. Barry Everitt (2014) proposes that the repeated pairing of drug-related cues to drug taking forms neural associations, or learning, in the dorsal striatum, a region in the basal ganglia consisting of the caudate nucleus and putamen. As the user repeatedly takes the drug, voluntary control gives way to unconscious processes—a habit. The result: drug users lose control of decisions related to drug taking, and the wanting—the voluntary control over drug taking—gives way to the craving of addiction.

Multiple findings align with the wanting-and-liking explanation of drug addiction. Ample evidence confirms that abused drugs and the context in which they are taken initially has a pleasurable effect and that habitual users continue using their drug of choice, even when taking it no longer produces any pleasure. Heroin addicts sometimes report that they are miserable: their lives are in ruins, and the drug is not even pleasurable anymore. But they still want it. What’s more, desire for the drug often is greatest just when the addicted person is maximally high, not during withdrawal. Finally, cues associated with drug taking—the social situation, the sight of the drug, and drug paraphernalia—strongly influence decisions to take, or continue taking, a drug.

Notwithstanding support for a dopamine basis for addiction, recent research suggests more than one type of addiction. Some rats become readily conditioned to cues associated with reinforcement, for example a bar that delivers a reward when pressed. Other animals ignore the bar’s incentive salience but are attracted to the location where they receive reinforcement. Animals that display the former behavior are termed sign trackers and the other group, goal trackers. Sign trackers exposed to addictive drugs appear to attribute incentive salience to drug-associated cues. Their drug wanting is dependent upon the brain’s dopamine systems. Goal trackers may also become addicted, possibly via different neural systems. Such findings imply at least two types of addiction (Yager et al., 2015).

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We can extend wanting-and-liking theory to many life situations. Cues related to sexual activity, food, and even sports can induce wanting, sometimes in the absence of liking. We frequently eat when prompted by the cue of other people eating, even though we may not be hungry and derive little pleasure from eating at that time. The similarities between exaggerating normal behaviors and drug addiction suggest that they depend on the same learning and brain mechanisms. For this reason, any addiction is extremely difficult to treat.

Observing that some people are more prone than others to drug abuse and dependence, scientists have investigated and found three lines of evidence suggesting a genetic contribution to differences in drug use. First, if one identical twin (same genotype) abuses alcohol, the other twin is more likely to abuse it than if the twins are fraternal (have only some genes in common). Second, people adopted shortly after birth are more likely to abuse alcohol if their biological parents were alcoholic, even though they have had almost no contact with those parents. Third, although most animals do not care for alcohol, selective breeding of mice, rats, and monkeys can produce strains that consume large quantities of it.

Each line of evidence presents problems, however. Perhaps identical twins show greater concordance rates (incidence of similar behavioral traits) for alcohol abuse because their environments are more similar than those of fraternal twins. And perhaps the link between alcoholism in adoptees and their biological parents has to do with nervous system changes due to prenatal exposure to the drug. Finally, the fact that animals can be selectively bred for alcohol consumption does not mean that all human alcoholics have a similar genetic makeup. The evidence for a genetic basis of alcohol abuse will become compelling only when a gene or set of genes related to alcoholism is found.

Epigenetics offers another explanation of susceptibility to addiction (Hillemacher et al., 2015). Addictive drugs may reduce the transcriptional ability of genes related to voluntary control and increase the transcriptional ability of other genes related to behaviors susceptible to addiction. Epigenetic changes in an individual’s gene expression may be relatively permanent and can be passed along, perhaps through the next few generations. For these reasons, epigenetics can account both for the enduring behaviors that support addiction and for the tendency of drug addiction to be inherited.

Figure 6-16 charts the relative incidence of drug use in the United States—people aged 12 and older who reported using at least one psychoactive drug during the year preceding in a national survey conducted by the U.S. Department of Health and Human Services in 2013. The two most-used drugs, alcohol and tobacco, are legal. The drugs that carry the harshest penalties, cocaine and heroin, are used by far fewer people. But criminalizing drugs clearly is not a solution to drug use or abuse, as illustrated by the widespread use of marijuana, the third most used drug on the chart. In response to its widespread use, several states have legalized marijuana to some degree, but it remains illegal under federal law.

Treating drug abuse is difficult in part because legal proscriptions are irrational. In the United States, the Harrison Narcotics Act of 1914 made heroin and a variety of other drugs illegal and made the treatment of addicted people by physicians in their private offices illegal. The Drug Addiction Treatment Act of 2000 partly reversed this prohibition, allowing the treatment of patients but with a number of restrictions. In addition, legal consequences attending drug use vary greatly with the drug and the jurisdiction.

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From a health standpoint, tobacco has much higher proven health risks than does marijuana. Moderate use of alcohol is likely benign. Moderate use of opioids is likely impossible. Social coercion is useful in reducing tobacco use: witness the marked decline in smoking as a result of prohibitions against smoking in public places. Medical intervention is necessary to provide methadone and other drug treatment of opioid abusers.

The numerous approaches to treating drug abuse vary, depending on the drug. Many online sites support self-help groups and professional groups that address the treatment of various drug addictions. Importantly, because addiction is influenced by unconscious conditioning to drug-related cues and by a variety of brain changes, relapse remains an enduring risk for people who have apparently kicked their habit.

Neuroscience research will continue to lead to a better understanding of the neural basis of drug use and to better treatment. The best approach to any drug treatment likely recognizes that addiction is a lifelong problem for most people. Thus, drug addiction must be treated in the same way as chronic behavioral addictions and medical problems—analogous to recognizing that controlling weight with appropriate diet and exercise is a lifelong struggle for many people.

Many natural substances can act as neurotoxins; Table 6-2 lists some of them. Ongoing investigations of the neurotoxicity of these substances and other drugs in animal models show that many cause brain damage. Whether drugs of abuse cause brain damage in humans—especially whether they can do so at the doses that humans take—is more difficult to determine. It is difficult to sort out other life experiences from drug taking. It is also difficult to obtain the brains of drug users for examination at autopsy. Nevertheless, there is evidence that the developing brain can be particularly sensitive to drug effects, especially in adolescence, a time when drug experimentation is common (Teixeira-Gomes, 2015).

In the late 1960s, many reports linked monosodium glutamate, MSG, a salty-tasting, flavor-enhancing food additive, to headaches in some people. In investigating this effect, scientists placed large doses of MSG on cultured neurons, which died. Subsequently, they injected MSG into the brains of experimental animals, where it also killed neurons.

This line of research led to the discovery that many glutamatelike substances, including domoic acid and kainic acid, both toxins in seaweed, and ibotenic acid, which is found in some poisonous mushrooms, similarly kill neurons (Figure 6-17). Some drugs, such as PCP and ketamine, also act as glutamate agonists, leaving open the possibility that at high doses they too can cause neuronal death.

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Glutamatelike drugs are toxic because they act on glutamate receptors. Glutamate receptor activation results in an influx of Ca²⁺ into the cell, which through second messengers activates a suicide gene leading to apoptosis (cell death). This discovery shows that a drug might be toxic not only because of its general effect on cell function but also as an agent that activates normal cell processes related to apoptosis.

We must add that there is no evidence that moderate consumption of MSG is harmful.

What about the many recreational drugs that affect the nervous system? Are any neurotoxic? Sorting out the effects of the drug itself from the effects of other factors related to taking the drug is a major problem. Chronic alcohol use, for instance, can be associated with damage to the thalamus and limbic system, producing severe memory disorders. Alcohol, however, does not directly cause this damage. Alcoholics typically obtain low amounts of thiamine (vitamin B₁) in their diet, and alcohol interferes with the intestine’s absorption of thiamine. Thiamine plays a vital role in maintaining cell membrane structure.

Similarly, among the many reports of people who have a severe psychiatric disorder subsequent to abusing certain recreational drugs, in most cases determining whether the drug initiated the condition or aggravated an existing problem is difficult. Exactly determining whether the drug itself or some contaminant in it caused a harmful outcome also is difficult. With the increasing sensitivity of brain imaging studies, however, evidence is increasing that many drugs used recreationally can cause brain damage and cognitive impairments.

The strongest evidence comes from the study of the synthetic amphetaminelike drug MDMA, also called Ecstasy, and in pure powdered form, Molly (Büttner, 2011). Although MDMA is structurally related to amphetamine, it produces hallucinogenic effects and is called a hallucinogenic amphetamine. Findings from animal studies show that doses of MDMA approximating those taken by human users result in the degeneration of very fine serotonergic nerve terminals. In monkeys, significant terminal loss may be permanent, as shown in Figure 6-18.

Memory impairments and damage in MDMA users revealed by brain imaging may be a result of similar neuronal damage (Cowan et al., 2008). MDMA may also contain a contaminant, paramethoxymethamphetamine (PMMA). This notoriously toxic amphetamine is often called Dr. Death because the difference between a dose that causes behavioral effects and a dose that causes death is minuscule (Vevelstad et al., 2012). Contamination by unknown compounds can occur in any drug purchased on the street.

The psychoactive properties of cocaine are similar to those of amphetamine, and so cocaine also is suspect with respect to brain damage. Cocaine use is related to the blockage of cerebral blood flow and other changes in blood circulation. Brain imaging studies suggest that cocaine use can be toxic to neurons, because several brain regions are reduced in size in cocaine users (Liu et al., 2011).

Chronic marijuana use has been associated with psychotic attacks. Clinical Focus 6-4, Drug-Induced Psychosis, describes one. The marijuana plant contains at least 400 chemicals, 60 or more of which are structurally related to its active ingredient, tetrahydrocannabinol. Determining whether a psychotic attack is related to THC or to some other chemical in marijuana is almost impossible.

Whether or not THC can cause psychosis, there is no evidence that the disease is a result of brain damage. Indeed, beyond the therapeutic applications of TCH cited in Section 6-2, recent studies suggest that THC may have neuroprotective properties. It can aid brain healing after traumatic brain injury and slow the progression of diseases associated with brain degeneration, including Alzheimer disease and Huntington disease (Nguyen et al., 2014).

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Explaining and Treating Drug Abuse

Before you continue, check your understanding.

Question 1

Question 2

Question 3

Question 4

Question 5

Answers appear in the Self Test section of the book.