Chapter 2 Preview

A substantial body of research has accumulated over several decades and transformed our understanding of substance use and its effects on the brain. This knowledge has opened the door to new ways of thinking about prevention and treatment of substance use disorders.

This chapter describes the neurobiological framework underlying substance use and why some people transition from using or misusing alcohol or drugs to a substance use disorder—including its most severe form, addiction. The chapter explains how these substances produce changes in brain structure and function that promote and sustain addiction and contribute to relapse. The chapter also addresses similarities and differences in how the various classes of addictive substances affect the brain and behavior and provides a brief overview of key factors that influence risk for substance use disorders.

Conducting Research on the Neurobiology of Substance Use, Misuse, and Addiction

Until recently, much of our knowledge about the neurobiology of substance use, misuse, and addiction came from the study of laboratory animals. Although no animal model fully reflects the human experience, animal studies let researchers investigate addiction under highly controlled conditions that may not be possible or ethical to replicate in humans. These types of studies have greatly helped to answer questions about how particular genes, developmental processes, and environmental factors, such as stressors, affect substance-taking behavior.

Neurobiology studies in animals have historically focused on what happens in the brain right after taking an addictive substance (this is called the acute impact), but research has shifted to the study of how ongoing, long-term (or chronic) substance use changes the brain. One of the main goals of this research is to understand at the most basic level the mechanisms through which substance use alters brain structure and function and drives the transition from occasional use to misuse, addiction, and relapse.¹⁰

A growing body of substance use research conducted with humans is complementing the work in animals. For example, human studies have benefited greatly from the use of brain-imaging technologies, such as magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. These technologies allow researchers to “see” inside the living human brain so that they can investigate and characterize the biochemical, functional, and structural changes in the brain that result from alcohol and drug use. The technologies also allow them to understand how differences in brain structure and function may contribute to substance use, misuse, and addiction.

Animal and human studies build on and inform each other, and in combination provide a more complete picture of the neurobiology of addiction. The rest of this chapter weaves together the most compelling data from both types of studies to describe a neurobiological framework for addiction.

A Basic Primer on the Human Brain

To understand how addictive substances affect the brain, it is important to first understand the basic biology of healthy brain function. The brain is an amazingly complex organ that is constantly at work. Within the brain, a mix of chemical and electrical processes controls the body's most basic functions, like breathing and digestion. These processes also control how people react to the multitudes of sounds, smells, and other sensory stimuli around them, and they organize and direct individuals' highest thinking and emotive powers so that they can interact with other people, carry out daily activities, and make complex decisions.

The brain is made of an estimated 86 billion nerve cells—called neurons—as well as other cell types. Each neuron has a cell body, an axon, and dendrites (Figure 2.1). The cell body and its nucleus control the neuron's activities. The axon extends out from the cell body and transmits messages to other neurons. Dendrites branch out from the cell body and receive messages from the axons of other neurons.

Neurons communicate with one another through chemical messengers called neurotransmitters. The neurotransmitters cross a tiny gap, or synapse, between neurons and attach to receptors on the receiving neuron. Some neurotransmitters are inhibitory—they make it less likely that the receiving neuron will carry out some action. Others are excitatory, meaning that they stimulate neuronal function, priming it to send signals to other neurons.

Neurons are organized in clusters that perform specific functions (described as networks or circuits). For example, some networks are involved with thinking, learning, emotions, and memory. Other networks communicate with muscles, stimulating them into action. Still others receive and interpret stimuli from the sensory organs, such as the eyes and ears, or the skin. The addiction cycle disrupts the normal functions of some of these neuronal networks.

Figure 2.1

A Neuron and its Parts.

The Primary Brain Regions Involved in Substance Use Disorders

The brain has many regions that are interconnected with one another, forming dynamic networks that are responsible for specific functions, such as attention, self-regulation, perception, language, reward, emotion, and movement, along with many other functions. This chapter focuses on three regions that are the key components of networks that are intimately involved in the development and persistence of substance use disorders: the basal ganglia, the extended amygdala, and the prefrontal cortex (Figure 2.2). The basal ganglia control the rewarding, or pleasurable, effects of substance use and are also responsible for the formation of habitual substance taking. The extended amygdala is involved in stress and the feelings of unease, anxiety, and irritability that typically accompany substance withdrawal. The prefrontal cortex is involved in executive function (i.e., the ability to organize thoughts and activities, prioritize tasks, manage time, and make decisions), including exerting control over substance taking.

Figure 2.2

Areas of the Human Brain that Are Especially Important in Addiction.

These brain areas and their associated networks are not solely involved in substance use disorders. Indeed, these systems are broadly integrated and serve many critical roles in helping humans and other animals survive. For example, when people engage in certain activities, such as consuming food or having sex, chemicals within the basal ganglia produce feelings of pleasure. This reward motivates individuals to continue to engage in these activities, thereby ensuring the survival of the species. Likewise, in the face of danger, activation of the brain's stress systems within the extended amygdala drives “fight or flight” responses. These responses, too, are critical for survival. As described in more detail below, these and other survival systems are “hijacked” by addictive substances.

The Addiction Cycle

Addiction can be described as a repeating cycle with three stages. Each stage is particularly associated with one of the brain regions described above—basal ganglia, extended amygdala, and prefrontal cortex (Figure 2.3).¹⁰ This three-stage model draws on decades of human and animal research and provides a useful way to understand the symptoms of addiction, how it can be prevented and treated, and how people can recover from it.¹⁴ The three stages of addiction are:

Figure 2.3

The Three Stages of the Addiction Cycle and the Brain Regions Associated with Them.

• Binge/Intoxication, the stage at which an individual consumes an intoxicating substance and experiences its rewarding or pleasurable effects;
• Withdrawal/Negative Affect, the stage at which an individual experiences a negative emotional state in the absence of the substance; and
• Preoccupation/Anticipation, the stage at which one seeks substances again after a period of abstinence.

The three stages are linked to and feed on each other, but they also involve different brain regions, circuits (or networks), and neurotransmitters and result in specific kinds of changes in the brain. A person may go through this three-stage cycle over the course of weeks or months or progress through it several times in a day. There may be variation in how people progress through the cycle and the intensity with which they experience each of the stages. Nonetheless, the addiction cycle tends to intensify over time, leading to greater physical and psychological harm.¹⁰

The following sections describe each of the stages in more detail. But first, it is necessary to explain four behaviors that are central to the addiction cycle: impulsivity, positive reinforcement, negative reinforcement, and compulsivity.

For many people, initial substance use involves an element of impulsivity, or acting without foresight or regard for the consequences. For example, an adolescent may impulsively take a first drink, smoke a cigarette, begin experimenting with marijuana, or succumb to peer pressure to try a party drug. If the experience is pleasurable, this feeling positively reinforces the substance use, making the person more likely to take the substance again.

Another person may take a substance to relieve negative feelings such as stress, anxiety, or depression. In this case, the temporary relief the substance brings from the negative feelings negatively reinforces substance use, increasing the likelihood that the person will use again. Importantly, positive and negative reinforcement need not be driven solely by the effects of the drugs. Many other environmental and social stimuli can reinforce a behavior. For example, the approval of peers positively reinforces substance use for some people. Likewise, if drinking or using drugs with others provides relief from social isolation, substance use behavior could be negatively reinforced.

The positively reinforcing effects of substances tend to diminish with repeated use. This is called tolerance and may lead to use of the substance in greater amounts and/or more frequently in an attempt to experience the initial level of reinforcement. Eventually, in the absence of the substance, a person may experience negative emotions such as stress, anxiety, or depression, or feel physically ill. This is called withdrawal, which often leads the person to use the substance again to relieve the withdrawal symptoms.

As use becomes an ingrained behavior, impulsivity shifts to compulsivity, and the primary drivers of repeated substance use shift from positive reinforcement (feeling pleasure) to negative reinforcement (feeling relief), as the person seeks to stop the negative feelings and physical illness that accompany withdrawal.¹⁵ Eventually, the person begins taking the substance not to get “high,” but rather to escape the “low” feelings to which, ironically, chronic drug use has contributed. Compulsive substance seeking is a key characteristic of addiction, as is the loss of control over use. Compulsivity helps to explain why many people with addiction experience relapses after attempting to abstain from or reduce use.

The following sections provide more detail about each of the three stages—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation—and the neurobiological processes underlying them.

Binge/Intoxication Stage: Basal Ganglia

The binge/intoxication stage of the addiction cycle is the stage at which an individual consumes the substance of choice. This stage heavily involves the basal ganglia (Figure 2.4) and its two key brain sub-regions, the nucleus accumbens and the dorsal striatum. In this stage, substances affect the brain in several ways.

Figure 2.4

The Binge/Intoxication Stage and the Basal Ganglia.

Addictive Substances “Hijack” Brain Reward Systems

All addictive substances produce feelings of pleasure. These “rewarding effects” positively reinforce their use and increase the likelihood of repeated use. The rewarding effects of substances involve activity in the nucleus accumbens, including activation of the brain's dopamine and opioid signaling system. Many studies have shown that neurons that release dopamine are activated, either directly or indirectly, by all addictive substances, but particularly by stimulants such as cocaine, amphetamines, and nicotine (Figure 2.5).¹⁶ In addition, the brain's opioid system, which includes naturally occurring opioid molecules (i.e., endorphins, enkephalins, and dynorphins) and three types of opioid receptors (i.e., mu, delta, and kappa), plays a key role in mediating the rewarding effects of other addictive substances, including opioids and alcohol. Activation of the opioid system by these substances stimulates the nucleus accumbens directly or indirectly through the dopamine system. Brain imaging studies in humans show activation of dopamine and opioid neurotransmitters during alcohol and other substance use (including nicotine).^10,17 Other studies show that antagonists, or inhibitors, of dopamine and opioid receptors can block drug and alcohol seeking in both animals and humans.^14,18,19

Figure 2.5

Actions of Addictive Substances on the Brain. Notes: Figure 2.5 is a simplified schematic of converging acute rewarding actions of addictive substances on the nucleus accumbens (NAc). Dopamine neurons that originate in the ventral tegmental area (VTA) (more...)

KEY TERMS

Antagonist. A chemical substance that binds to and blocks the activation of certain receptors on cells, preventing a biological response. Naloxone is an example of an opioid receptor antagonist.

Cannabinoids such as delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of marijuana, target the brain's internal or endogenous cannabinoid system. This system also contributes to reward by affecting the function of dopamine neurons and the release of dopamine in the nucleus accumbens.

Stimuli Associated with Addictive Substances Can Trigger Substance Use

Activation of the brain's reward system by alcohol and drugs not only generates the pleasurable feelings associated with those substances, it also ultimately triggers changes in the way a person responds to stimuli associated with the use of those substances. A person learns to associate the stimuli present while using a substance—including people, places, drug paraphernalia, and even internal states, such as mood—with the substance's rewarding effects. Over time, these stimuli can activate the dopamine system on their own and trigger powerful urges to take the substance. These “wanting” urges are called incentive salience and they can persist even after the rewarding effects of the substance have diminished. As a result, exposure to people, places, or things previously associated with substance use can serve as “triggers” or cues that promote substance seeking and taking, even in people who are in recovery.

Figure 2.6 shows the major neurotransmitter systems involved in the binge/intoxication stage of addiction. In this stage, the neurons in the basal ganglia contribute to the rewarding effects of addictive substances and to incentive salience through the release of dopamine and the brain's natural opioids.

Figure 2.6

Major Neurotransmitter Systems Implicated in the Neuroadaptations Associated with the Binge/Intoxication Stage of Addiction. Notes: Blue represents the basal ganglia involved in the Binge/Intoxication stage. Red represents the extended amygdala involved (more...)

Early studies in animals demonstrated how incentive salience works. For example, after researchers repeatedly gave an animal a stimulant drug (e.g., cocaine) along with a previously neutral stimulus, such as a light or a sound, they found that the neutral stimulus by itself caused the animal to engage in drug-seeking behavior, and it also resulted in dopamine release that had previously occurred only in response to the drug.²⁰ Even more compelling results were seen when scientists recorded the electrical activity of dopamine-transmitting neurons in animals that had been exposed multiple times to a neutral (non-drug) stimulus followed by a drug. At first, the neurons responded only when they were exposed to the drug. However, over time, the neurons stopped firing in response to the drug and instead fired when they were exposed to the neutral stimulus associated with it. This means that the animals associated the stimulus with the substance and, in anticipation of getting the substance, their brains began releasing dopamine, resulting in a strong motivation to seek the drug.^21,22 Imaging studies in humans have shown similar results. For example, dopamine is released in the brains of people addicted to cocaine when they are exposed to cues they have come to associate with cocaine.^23,24 This effect occurs even though cocaine itself causes less dopamine to be released in these individuals compared to those who are not addicted to cocaine (an effect also seen with other substances).²⁵

Together, these studies indicate that stimuli associated with addictive drugs can, by themselves, produce drug-like effects on the brain and trigger drug use. These findings help to explain why individuals with substance use disorders who are trying to maintain abstinence are at increased risk of relapse if they continue to have contact with the people they previously used drugs with or the places where they used drugs.

Withdrawal/Negative Affect Stage: Extended Amygdala

The withdrawal/negative affect stage of addiction follows the binge/intoxication stage, and, in turn, sets up future rounds of binge/intoxication. During this stage, a person who has been using alcohol or drugs experiences withdrawal symptoms, which include negative emotions and, sometimes, symptoms of physical illness, when they stop taking the substance. Symptoms of withdrawal may occur with all addictive substances, including marijuana, though they vary in intensity and duration depending on both the type of substance and the severity of use. The negative feelings associated with withdrawal are thought to come from two sources: diminished activation in the reward circuitry of the basal ganglia¹⁴ and activation of the brain's stress systems in the extended amygdala (Figure 2.7).

Figure 2.7

The Withdrawal/Negative Affect Stage and the Extended Amygdala.

When used over the long-term, all substances of abuse cause dysfunction in the brain's dopamine reward system.²⁷ For example, brain imaging studies in humans with addiction have consistently shown long-lasting decreases in a particular type of dopamine receptor, the D2 receptor, compared with non-addicted individuals (Figure 2.8).^25,28 Decreases in the activity of the dopamine system have been observed during withdrawal from stimulants, opioids, nicotine, and alcohol. Other studies also show that when an addicted person is given a stimulant, it causes a smaller release of dopamine than when the same dose is given to a person who is not addicted.

Figure 2.8

Time-Related Decrease in Dopamine Released in the Brain of a Cocaine User. Notes: These fMRI images compare the brain of an individual with a history of cocaine use disorder (middle and right) to the brain of an individual without a history of cocaine (more...)

These findings suggest that people addicted to substances experience an overall reduction in the sensitivity of the brain's reward system (especially the brain circuits involving dopamine), both to addictive substances and also to natural reinforcers, such as food and sex. This is because natural reinforcers also depend upon the same reward system and circuits. This impairment explains why those who develop a substance use disorder often do not derive the same level of satisfaction or pleasure from once-pleasurable activities. This general loss of reward sensitivity may also account for the compulsive escalation of substance use as addicted individuals attempt to regain the pleasurable feelings the reward system once provided.¹⁵

At the same time, a second process occurs during the withdrawal stage: activation of stress neurotransmitters in the extended amygdala. These stress neurotransmitters include corticotropin-releasing factor (CRF), norepinephrine, and dynorphin (Figure 2.9).³⁰

Figure 2.9

Major Neurotransmitter Systems Implicated in the Neuroadaptations Associated with the Withdrawal/Negative Affect Stage of Addiction. Notes: Not shown is the neurotransmitter norepinephrine which is also activated in the extended amygdala during withdrawal. (more...)

Studies suggest that these neurotransmitters play a key role in the negative feelings associated with withdrawal and in stress-triggered substance use. In animal and human studies, when researchers use special chemicals called antagonists to block activation of the stress neurotransmitter systems, it has the effect of reducing substance intake in response to withdrawal and stress. For example, blocking the activation of stress receptors in the brain reduced alcohol consumption in both alcohol-dependent rats and humans with an alcohol use disorder.³¹ Thus, it may be that an additional motivation for drug and alcohol seeking among individuals with substance use disorders is to suppress overactive brain stress systems that produce negative emotions or feelings. Recent research also suggests that neuroadaptations in the endogenous cannabinoid system within the extended amygdala contribute to increased stress reactivity and negative emotional states in addiction.³²

The desire to remove the negative feelings that accompany withdrawal can be a strong motivator of continued substance use. As noted previously, this motivation is strengthened through negative reinforcement, because taking the substance relieves the negative feelings associated with withdrawal, at least temporarily. Of course, this process is a vicious cycle: Taking drugs or alcohol to lessen the symptoms of withdrawal that occur during a period of abstinence actually causes those symptoms to be even worse the next time a person stops taking the substance, making it even harder to maintain abstinence.

Preoccupation/Anticipation Stage: Prefrontal Cortex

The preoccupation/anticipation stage of the addiction cycle is the stage in which a person may begin to seek substances again after a period of abstinence. In people with severe substance use disorders, that period of abstinence may be quite short (hours). In this stage, an addicted person becomes preoccupied with using substances again. This is commonly called “craving.” Craving has been difficult to measure in human studies and often does not directly link with relapse.

This stage of addiction involves the brain's prefrontal cortex (Figure 2.10) the region that controls executive function: the ability to organize thoughts and activities, prioritize tasks, manage time, make decisions, and regulate one's own actions, emotions, and impulses. Executive function is essential for a person to make appropriate choices about whether or not to use a substance and to override often strong urges to use, especially when the person experiences triggers, such as stimuli associated with that substance (e.g., being at a party where alcohol is served or where people are smoking) or stressful experiences.

Figure 2.10

The Preoccupation/Anticipation Stage and the Prefrontal Cortex.

To help explain how the prefrontal cortex is involved in addiction, some scientists divide the functions of this brain region into a “Go system” and an opposing “Stop system.”³³ The Go system helps people make decisions, particularly those that require significant attention and those involved with planning. People also engage the Go system when they begin behaviors that help them achieve goals. Indeed, research shows that when substance-seeking behavior is triggered by substance-associated environmental cues (incentive salience), activity in the Go circuits of the prefrontal cortex increases dramatically. This increased activity stimulates the nucleus accumbens to release glutamate, the main excitatory neurotransmitter in the brain. This release, in turn, promotes incentive salience, which creates a powerful urge to use the substance in the presence of drug-associated cues.

The Go system also engages habit-response systems in the dorsal striatum, and it contributes to the impulsivity associated with substance seeking. Habitual responding can occur automatically and subconsciously, meaning a person may not even be aware that they are engaging in such behaviors. The neurons in the Go circuits of the prefrontal cortex stimulate the habit systems of the dorsal striatum through connections that use glutamate (Figure 2.11).

Figure 2.11

Major Neurotransmitter Systems Implicated in the Neuroadaptations Associated with the Preoccupation/Anticipation Stage of Addiction. Abbreviations: PFC - prefrontal cortex, DS - dorsal striatum, NAc - nucleus accumbens, BNST - bed nucleus of the stria (more...)

The Stop system inhibits the activity of the Go system. Especially relevant to its role in addiction, this system controls the dorsal striatum and the nucleus accumbens, the areas of the basal ganglia that are involved in the binge/intoxication stage of addiction. Specifically, the Stop system controls habit responses driven by the dorsal striatum, and scientists think that it plays a role in reducing the ability of substance-associated stimuli to trigger relapse—in other words, it inhibits incentive salience.³⁴

The Stop system also controls the brain's stress and emotional systems, and plays an important role in relapse triggered by stressful life events or circumstances. Stress-induced relapse is driven by activation of neurotransmitters such as CRF, dynorphin, and norepinephrine in the extended amygdala. As described above, these neurotransmitters are activated during prolonged abstinence during the withdrawal/negative affect stage of addiction. More recent work in animals also implicates disruptions in the brain's cannabinoid system, which also regulates the stress systems in the extended amygdala, in relapse. Studies show that lower activity in the Stop component of the prefrontal cortex is associated with increased activity of stress circuitry involving the extended amygdala, and this increased activity drives substance-taking behavior and relapse.³⁷

Brain imaging studies in people with addiction show disruptions in the function of both the Go and Stop circuits.^35-37 For example, people with alcohol, cocaine, or opioid use disorders show impairments in executive function, including disruption of decision-making and behavioral inhibition. These executive function deficits parallel changes in the prefrontal cortex and suggest decreased activity in the Stop system and greater reactivity of the Go system in response to substance-related stimuli.

Indeed, a smaller volume of the prefrontal cortex in abstinent, previously addicted individuals predicts a shorter time to relapse.³⁸ Studies also show that diminished prefrontal cortex control over the extended amygdala is particularly prominent in humans with post-traumatic stress disorder (PTSD), a condition that is frequently accompanied by drug and alcohol use disorders.³⁹ These findings bolster support for the role of the prefrontal cortex-extended amygdala circuit in stress-induced relapse, and suggest that strengthening prefrontal cortex circuits could aid substance use disorder treatment.

To recap, addiction involves a three-stage cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation—that worsens over time and involves dramatic changes in the brain reward, stress, and executive function systems. Progression through this cycle involves three major regions of the brain: the basal ganglia, the extended amygdala, and the prefrontal cortex, as well as multiple neurotransmitter systems (Figure 2.12). The power of addictive substances to produce positive feelings and relieve negative feelings fuels the development of compulsive use of substances. The combination of increased incentive salience (binge/intoxication stage), decreased reward sensitivity and increased stress sensitivity (withdrawal/negative affect stage), and compromised executive function (preoccupation/anticipation stage) provides an often overwhelming drive for substance seeking that can be unrelenting.

Figure 2.12

The Primary Brain Regions and Neurotransmitter Systems Involved in Each of the Three Stages of the Addiction Cycle.

Different Classes of Substances Affect the Brain and Behavior in Different Ways

Although the three stages of addiction generally apply to all addictive substances, different substances affect the brain and behavior in different ways during each stage of the addiction cycle. Differences in the pharmacokinetics of various substances determine the duration of their effects on the body and partly account for the differences in their patterns of use. For example, nicotine has a short half-life, which means smokers need to smoke often to maintain the effect. In contrast, THC, the primary psychoactive compound in marijuana, has a much longer half-life. As a result, marijuana smokers do not typically smoke as frequently as tobacco smokers.⁴⁰ Typical patterns of use are described below for the major classes of addictive substances. However, people often use these substances in combination.⁴¹ Additional research is needed to understand how using more than one substance affects the brain and the development and progression of addiction, as well as how use of one substance affects the use of others.

Factors that Increase Risk for Substance Use, Misuse, and Addiction

Not all people use substances, and even among those who use them, not all are equally likely to become addicted. Many factors influence the development of substance use disorders, including developmental, environmental, social, and genetic factors, as well as co-occurring mental disorders. Other factors protect people from developing a substance use disorder or addiction. The relative influence of these risk and protective factors varies across individuals and the lifespan. The following sections discuss some of these factors.

Use of Multiple Substances and Co-occurring Mental Health Conditions

Many individuals with a substance use disorder also have a mental disorder,^57,58 and some have multiple substance use disorders. For example, according to the 2015 National Survey on Drug Use and Health (NSDUH), of the 20.8 million people aged 12 or older who had a substance use disorder during the past year, about 2.7 million (13 percent) had both an alcohol use and an illicit drug use disorder, and 41.2 percent also had a mental illness.⁵⁹ Particularly striking is the 3- to 4-fold higher rate of tobacco smoking among patients with schizophrenia and the high prevalence of co-existing alcohol use disorder in those meeting criteria for PTSD. It is estimated that 30-60 percent of patients seeking treatment for alcohol use disorder meet criteria for PTSD,^60,61 and approximately one third of individuals who have experienced PTSD have also experienced alcohol dependence at some point in their lives.⁶⁰

The reasons why substance use disorders and mental disorders often occur together are not clear, and establishing the relationships between these conditions is difficult. Still, three possible explanations deserve attention. One reason for the overlap may be that having a mental disorder increases vulnerability to substance use disorders because certain substances may, at least temporarily, be able to reduce mental disorder symptoms and thus are particularly negatively reinforcing in these individuals. Second, substance use disorders may increase vulnerability for mental disorders,^62-64 meaning that the use of certain substances might trigger a mental disorder that otherwise would have not occurred. For example, research suggests that alcohol use increases risk for PTSD by altering the brain's ability to recover from traumatic experiences.^65,66 Similarly, the use of marijuana, particularly marijuana with a high THC content, might contribute to schizophrenia in those who have specific genetic vulnerabilities.⁶⁷ Third, it is also possible that both substance use disorders and mental disorders are caused by shared, overlapping factors, such as particular genes, neurobiological deficits, and exposure to traumatic or stressful life experiences. As these possibilities are not mutually exclusive, the relationship between substance use disorders and mental disorders may result from a combination of these processes.

Regardless of which one might influence the development of the other, mental and substance use disorders have overlapping symptoms, making diagnosis and treatment planning particularly difficult. For example, people who use methamphetamine for a long time may experience paranoia, hallucinations, and delusions that may be mistaken for symptoms of schizophrenia. And, the psychological symptoms that accompany withdrawal, such as depression and anxiety, may be mistaken as simply part of withdrawal instead of an underlying mood disorder that requires independent treatment in its own right. Given the prevalence of co-occurring substance use and mental disorders, it is critical to continue to advance research on the genetic, neurobiological, and environmental factors that contribute to co-occurring disorders and to develop interventions to prevent and treat them.

Biological Factors Contributing to Population-based Differences in Substance Misuse and Substance Use Disorders

Recommendations for Research

Decades of research demonstrate that chronic substance misuse leads to profound disruptions of brain circuits involved in the experience of pleasure or reward, habit formation, stress, and decision-making. This work has paved the way for the development of a variety of therapies that effectively help people reduce or abstain from alcohol and drug misuse and regain control over their lives. In spite of this progress, our understanding of how substance use affects the brain and behavior is far from complete. Four research areas are specifically emphasized in the text below.

References

1.

Berlin GS, Hollander E. Compulsivity, impulsivity, and the DSM-5 process. CNS Spectrums. 2014;19(1):62–68. [PubMed: 24229702]

2.

Kalivas PW. The glutamate homeostasis hypothesis of addiction. Nature Reviews Neuroscience. 2009;10(8):561–572. [PubMed: 19571793]

3.

American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5). 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.

4.

McLellan AT, Lewis DC, O'Brien CP, Kleber HD. Drug dependence, a chronic medical illness: Implications for treatment, insurance, and outcomes evaluation. JAMA. 2000;284(13):1689–1695. [PubMed: 11015800]

5.

Volkow ND, Koob GF, McLellan AT. Neurobiologic advances from the brain disease model of addiction. New England Journal of Medicine. 2016;374(4):363–371. [PMC free article: PMC6135257] [PubMed: 26816013]

6.

Hubbard RL, Craddock SG, Anderson J. Overview of 5-year followup outcomes in the drug abuse treatment outcome studies (DATOS). Journal of Substance Abuse Treatment. 2003;25(3):125–134. [PubMed: 14670518]

7.

Hser Y-I, Hoffman V, Grella CE, Anglin MD. A 33-year follow-up of narcotics addicts. Archives of General Psychiatry. 2001;58(5):503–508. [PubMed: 11343531]

8.

Vaillant GE. The natural history of alcoholism revisited. Cambridge, MA: Harvard University Press; 1995.

9.

Stone AL, Becker LG, Huber AM, Catalano RF. Review of risk and protective factors of substance use and problem use in emerging adulthood. Addictive Behaviors. 2012;37(7):747–775. [PubMed: 22445418]

10.

Koob GF, Le Moal M. Drug abuse: Hedonic homeostatic dysregulation. Science. 1997;278(5335):52–58. [PubMed: 9311926]

11.

Kalivas PW, Volkow ND. The neural basis of addiction: A pathology of motivation and choice. The American Journal of Psychiatry. 2005;162(8):1403–1413. [PubMed: 16055761]

12.

Davis M, Walker DL, Miles L, Grillon C. Phasic vs sustained fear in rats and humans: Role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology. 2010;35(1):105–135. [PMC free article: PMC2795099] [PubMed: 19693004]

13.

Ball G, Stokes PR, Rhodes RA, Bose SK, Rezek I, Wink A-M, Turkheimer FE. Executive functions and prefrontal cortex: A matter of persistence? Frontiers in Systems Neuroscience. 2011;5(3):1–13. [PMC free article: PMC3031025] [PubMed: 21286223]

14.

Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;35(1):217–238. [PMC free article: PMC2805560] [PubMed: 19710631]

15.

Koob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology. 2001;24(2):97–129. [PubMed: 11120394]

16.

Nestler EJ. Is there a common molecular pathway for addiction? Nature Neuroscience. 2005;8(11):1445–1449. [PubMed: 16251986]

17.

Clapp P, Bhave SV, Hoffman PL. How adaptation of the brain to alcohol leads to dependence: A pharmacological perspective. Alcohol Research & Health. 2008;31(4):310–339. [PMC free article: PMC2923844] [PubMed: 20729980]

18.

Moreira FA, Dalley JW. Dopamine receptor partial agonists and addiction. European Journal of Pharmacology. 2015;752:112–115. [PubMed: 25724788]

19.

Swift RM, Aston ER. Pharmacotherapy for alcohol use disorder: Current and emerging therapies. Harvard Review of Psychiatry. 2015;23(2):122–133. [PMC free article: PMC4790835] [PubMed: 25747925]

20.

Uslaner JM, Acerbo MJ, Jones SA, Robinson TE. The attribution of incentive salience to a stimulus that signals an intravenous injection of cocaine. Behavioural Brain Research. 2006;169(2):320–324. [PubMed: 16527365]

21.

Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward. Science. 1997;275(5306):1593–1599. [PubMed: 9054347]

22.

Phillips PE, Stuber GD, Heien ML, Wightman RM, Carelli RM. Subsecond dopamine release promotes cocaine seeking. Nature. 2003;422(6932):614–618. [PubMed: 12687000]

23.

Volkow ND, Wang G-J, Telang F, Fowler JS, Logan J, Childress A-R, Wong C. Cocaine cues and dopamine in dorsal striatum: Mechanism of craving in cocaine addiction. The Journal of Neuroscience. 2006;26(24):6583–6588. [PMC free article: PMC6674019] [PubMed: 16775146]

24.

Wong DF, Kuwabara H, Schretlen DJ, Bonson KR, Zhou Y, Nandi A, Kumar A. Increased occupancy of dopamine receptors in human striatum during cue-elicited cocaine craving. Neuropsychopharmacology. 2006;31(12):2716–2727. [PubMed: 16971900]

25.

Volkow ND, Tomasi D, Wang GJ, Logan J, Alexoff DL, Jayne M, Du C. Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers. Molecular Psychiatry. 2014;19(9):1037–1043. [PMC free article: PMC4827430] [PubMed: 24912491]

26.

Belin D, Jonkman S, Dickinson A, Robbins TW, Everitt BJ. Parallel and interactive learning processes within the basal ganglia: Relevance for the understanding of addiction. Behavioural Brain Research. 2009;199(1):89–102. [PubMed: 18950658]

27.

Volkow ND, Morales M. The brain on drugs: From reward to addiction. Cell. 2015;162(4):712–725. [PubMed: 26276628]

28.

Volkow ND, Wang G-J, Fowler JS, Logan J, Gatley SJ, Hitzemann R, Pappas N. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature. 1997;386(6627):830–833. [PubMed: 9126741]

29.

Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ, Wolf AP. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse. 1993;14(2):169–177. [PubMed: 8101394]

30.

Koob GF, Le Moal M. Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction. Nature Neuroscience. 2005;8(11):1442–1444. [PubMed: 16251985]

31.

Vendruscolo LF, Estey D, Goodell V, Macshane LG, Logrip ML, Schlosburg JE, Hunt HJ. Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals. The Journal of Clinical Investigation. 2015;125(8):3193–3197. [PMC free article: PMC4563748] [PubMed: 26121746]

32.

Parsons LH, Hurd YL. Endocannabinoid signalling in reward and addiction. Nature Reviews Neuroscience. 2015;16(10):579–594. [PMC free article: PMC4652927] [PubMed: 26373473]

33.

Koob GF, Arends MA, Le Moal M. Drugs, addiction, and the brain. Waltham, MA: Academic Press; 2014.

34.

Goldstein RZ, Volkow ND. Dysfunction of the prefrontal cortex in addiction: Neuroimaging findings and clinical implications. Nature Reviews Neuroscience. 2011;12(11):652–669. [PMC free article: PMC3462342] [PubMed: 22011681]

35.

Crunelle CL, Kaag AM, van den Munkhof HE, Reneman L, Homberg JR, Sabbe B, van Wingen G. Dysfunctional amygdala activation and connectivity with the prefrontal cortex in current cocaine users. Human Brain Mapping. 2015;36(10):4222–4230. [PMC free article: PMC6869379] [PubMed: 26220024]

36.

Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: Neuroimaging evidence for the involvement of the frontal cortex. American Journal of Psychiatry. 2002;159(10):1642–1652. [PMC free article: PMC1201373] [PubMed: 12359667]

37.

Volkow ND, Wang G-J, Telang F, Fowler JS, Logan J, Jayne M, Wong C. Profound decreases in dopamine release in striatum in detoxified alcoholics: Possible orbitofrontal involvement. The Journal of Neuroscience. 2007;27(46):12700–12706. [PMC free article: PMC6673312] [PubMed: 18003850]

38.

Rando K, Hong K-I, Bhagwagar Z, Li C-SR, Bergquist K, Guarnaccia J, Sinha R. Association of frontal and posterior cortical gray matter volume with time to alcohol relapse: A prospective study. American Journal of Psychiatry. 2011;168(2):183–192. [PMC free article: PMC3668974] [PubMed: 21078704]

39.

Mahan AL, Ressler KJ. Fear conditioning, synaptic plasticity and the amygdala: Implications for posttraumatic stress disorder. Trends in Neurosciences. 2012;35(1):24–35. [PMC free article: PMC3206195] [PubMed: 21798604]

40.

Koob GF, Karde DB, Baler RD, Volkow ND. Pathopsychology of addiction. In: Tasman A, Kay J, Lieberman JA, First MB, Riba M, editors. Psychiatry. 4th ed. Vol. 1. New York, NY: Wiley-Blackwell; 2015.

41.

Connor JP, Gullo MJ, White A, Kelly AB. Polysubstance use: Diagnostic challenges, patterns of use and health. Current Opinion in Psychiatry. 2014;27(4):269–275. [PubMed: 24852056]

42.

Heishman SJ, Singleton EG, Liguori A. Marijuana craving questionnaire: Development and initial validation of a self-report instrument. Addiction. 2001;96(7):1023–1034. [PubMed: 11440613]

43.

Lundahl LH, Johanson CE. Cue-induced craving for marijuana in cannabis-dependent adults. Experimental and Clinical Psychopharmacology. 2011;19(3):224–230. [PMC free article: PMC5113719] [PubMed: 21480734]

44.

Buckner JD, Zvolensky MJ, Ecker AH, Jeffries ER. Cannabis craving in response to laboratory-induced social stress among racially diverse cannabis users: The impact of social anxiety disorder. Journal of Psychopharmacology. 2016;30(4):363–369. [PMC free article: PMC5147424] [PubMed: 26839322]

45.

Dube SR, Felitti VJ, Dong M, Chapman DP, Giles WH, Anda RF. Childhood abuse, neglect, and household dysfunction and the risk of illicit drug use: The adverse childhood experiences study. Pediatrics. 2003;111(3):564–572. [PubMed: 12612237]

46.

Najavits LM, Hyman SM, Ruglass LM, Hien DA, Read JP. Substance use disorder and trauma. In: Gold S, Cook J, Dalenberg C, editors. Handbook of trauma psychology. Washington, DC: American Psychological Association; (In press)

47.

Teicher MH, Samson JA. Childhood maltreatment and psychopathology: A case for ecophenotypic variants as clinically and neurobiologically distinct subtypes. American Journal of Psychiatry. 2013;170(10):1114–1133. [PMC free article: PMC3928064] [PubMed: 23982148]

48.

Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos A, Rapoport JL. Brain development during childhood and adolescence: A longitudinal MRI study. Nature Neuroscience. 1999;2(10):861–863. [PubMed: 10491603]

49.

Squeglia LM, Tapert SF, Sullivan EV, Jacobus J, Meloy MJ, Rolfng T, Pfefferbaum A. Brain development in heavy-drinking adolescents. American Journal of Psychiatry. 2015;172(6):532–542. [PMC free article: PMC4451385] [PubMed: 25982660]

50.

Substance Abuse and Mental Health Services Administration, & Center for Behavioral Health Statistics and Quality. The TEDS Report: Age of substance use initiation among treatment admissions aged 18 to 30. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2014. [PubMed: 27631064]

51.

Hanson KL, Medina KL, Padula CB, Tapert SF, Brown SA. Impact of adolescent alcohol and drug use on neuropsychological functioning in young adulthood: 10-year outcomes. Journal of Child and Adolescent Substance Abuse. 2011;20(2):135–154. [PMC free article: PMC3083020] [PubMed: 21532924]

52.

Prescott CA, Kendler KS. Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. American Journal of Psychiatry. 1999;156:34–40. [PubMed: 9892295]

53.

Schuckit MA, Edenberg HJ, Kalmijn J, Flury L, Smith TL, Reich T, Foroud T. A genome-wide search for genes that relate to a low level of response to alcohol. Alcoholism: Clinical and Experimental Research. 2001;25(3):323–329. [PubMed: 11290841]

54.

Dick DM, Agrawal A. The genetics of alcohol and other drug dependence. Alcohol Research & Health. 2008;31(2):111–119. [PMC free article: PMC3860452] [PubMed: 23584813]

55.

Drgonova J, Walther D, Singhal S, Johnson K, Kessler B, Troncoso J, Uhl GR. Altered CSMD1 expression alters cocaine-conditioned place preference: Mutual support for a complex locus from human and mouse models. PLOS ONE. 2015;10(7) [PMC free article: PMC4501703] [PubMed: 26171607]

56.

Zhong X, Drgonova J, Li CY, Uhl GR. Human cell adhesion molecules: Annotated functional subtypes and overrepresentation of addiction-associated genes. Annals of the New York Academy of Sciences. 2015;1349(1):83–95. [PMC free article: PMC4564344] [PubMed: 25988664]

57.

Grant BF, Stinson FS, Dawson DA, Chou SP, Dufour MC, Compton W, Kaplan K. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions. Archives of General Psychiatry. 2004;61(8):807–816. [PubMed: 15289279]

58.

Grant BF, Stinson FS, Dawson DA, Chou SP, Ruan WJ, Pickering RP. Co-occurrence of 12-month alcohol and drug use disorders and personality disorders in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions. Archives of General Psychiatry. 2004;61(4):361–368. [PubMed: 15066894]

59.

Center for Behavioral Health Statistics and Quality. Results from the 2015 National Survey on Drug Use and Health: Detailed tables. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2016.

60.

Chilcoat HD, Menard C. Epidemiological investigations: Comorbidity of posttraumatic stress disorder and substance use disorder. In: Ouimette P, Brown PJ, editors. Trauma and substance abuse: Causes, consequences, and treatment of comorbid disorders. Washington, DC: American Psychological Association; 2003. pp. 9–28.

61.

Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry. 2005;62(6):593–602. [PubMed: 15939837]

62.

Jacobsen LK, Southwick SM, Kosten TR. Substance use disorders in patients with posttraumatic stress disorder: A review of the literature. American Journal of Psychiatry. 2001;158(8):1184–1190. [PubMed: 11481147]

63.

Leeies M, Pagura J, Sareen J, Bolton JM. The use of alcohol and drugs to self-medicate symptoms of posttraumatic stress disorder. Depression and Anxiety. 2010;27(8):731–736. [PubMed: 20186981]

64.

Kumari V, Postma P. Nicotine use in schizophrenia: The self medication hypotheses. Neuroscience and Biobehavioral Reviews. 2005;29(6):1021–1034. [PubMed: 15964073]

65.

Anthenelli RM. Focus on: Comorbid mental health disorders. Alcohol Research & Health. 2010;33(1-2):109–117. [PMC free article: PMC3887501] [PubMed: 23579941]

66.

Holmes A, Fitzgerald PJ, MacPherson KP, DeBrouse L, Colacicco G, Flynn SM, Marcinkiewcz CA. Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding. Nature Neuroscience. 2012;15(10):1359–1361. [PMC free article: PMC3471649] [PubMed: 22941108]

67.

Kelley ME, Wan CR, Broussard B, Crisafio A, Cristofaro S, Johnson S, Walker EF. Marijuana use in the immediate 5-year premorbid period is associated with increased risk of onset of schizophrenia and related psychotic disorders. Schizophrenia Research. 2016;171(1-3):62–67. [PMC free article: PMC4929616] [PubMed: 26785806]

68.

Keyes KM, Grant BF, Hasin DS. Evidence for a closing gender gap in alcohol use, abuse, and dependence in the United States population. Drug and Alcohol Dependence. 2008;93(1):21–29. [PMC free article: PMC3163892] [PubMed: 17980512]

69.

Hasin DS, Grant BF. The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) Waves 1 and 2: Review and summary of findings. Social Psychiatry and Psychiatric Epidemiology. 2015;50(11):1609–1640. [PMC free article: PMC4618096] [PubMed: 26210739]

70.

Brady KT, Randall CL. Gender differences in substance use disorders. Psychiatric Clinics of North America. 1999;22(2):241–252. [PubMed: 10385931]

71.

Greenfield SF, Back SE, Lawson K, Brady KT. Substance abuse in women. Psychiatric Clinics of North America. 2010;33(2):339–355. [PMC free article: PMC3124962] [PubMed: 20385341]

72.

Kosten TA, Gawin FH, Kosten TR, Rounsaville BJ. Gender differences in cocaine use and treatment response. Journal of Substance Abuse Treatment. 1993;10(1):63–66. [PubMed: 8450576]

73.

Chanraud S, Pitel A-L, Müller-Oehring EM, Pfefferbaum A, Sullivan EV. Remapping the brain to compensate for impairment in recovering alcoholics. Cerebral Cortex. 2013;23(1):97–104. [PMC free article: PMC3513953] [PubMed: 22275479]

74.

Becker JB, Koob GF. Sex differences in animal models: Focus on addiction. Pharmacological Reviews. 2016;68(2):242–263. [PMC free article: PMC4813426] [PubMed: 26772794]

75.

Okuyemi KS, Powell JN, Savage CR, Hall SB, Nollen N, Holsen LM, Ahluwalia JS. Clinical and imaging study: Enhanced cue-elicited brain activation in African American compared with Caucasian smokers: An fMRI study. Addiction Biology. 2006;11(1):97–106. [PubMed: 16759342]

76.

Brooks PJ, Enoch M-A, Goldman D, Li T-K, Yokoyama A. The alcohol flushing response: An unrecognized risk factor for esophageal cancer from alcohol consumption. PLOS Medicine. 2009;6(3) [PMC free article: PMC2659709] [PubMed: 19320537]

77.

Yokoyama A, Omori T. Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers. Japanese Journal of Clinical Oncology. 2003;33(3):111–121. [PubMed: 12672787]

78.

Fukuda K, Yuzuriha T, Kinukawa N, Murakawa R, Takashima Y, Uchino A, Hirano M. Alcohol intake and quantitative MRI findings among community dwelling Japanese subjects. Journal of the Neurological Sciences. 2009;278(1):30–34. [PubMed: 19059611]