Neuroscience: The Brain in Addiction and Recovery

The plasticity of the human brain contributes to both the development of and recovery from alcohol use disorder (AUD). Within the brain, individual genetic and environmental factors interact at molecular, neuronal, and circuit levels to influence a person’s vulnerability to AUD.^1,2 Thus, each person’s path to AUD is shaped by a unique set of variables, and as a result, different people will have different levels of severity and types of dysfunction that may require different treatment approaches.³

Alcohol produces chemical imbalances in specific neurocircuits and can be neurotoxic. Chronic heavy drinking can, for example, damage brain regions involved in memory, decision-making, impulse control, attention, sleep regulation, and other cognitive functions.^4,5 Once AUD develops and progresses, these and other brain changes can make it very difficult to stop drinking without assistance.¹

Here, we outline a framework for understanding alcohol-induced changes in the brain, which can help you appreciate the challenges faced by many patients with AUD when they try to cut back or quit drinking. We then describe evidence-based treatments you can recommend to patients to help the brain, and the patient as a whole, to recover.

How does the brain change as AUD develops?

The brain mediates our motivation to repeat behaviors that lead to pleasurable, rewarding states or reduce uncomfortable, distressing physical or emotional states. In this context, drinking alcohol can be motivated by its ability to provide both relief from aversive states and reward. These dual, powerful reinforcing effects help explain why some people drink and why some people use alcohol to excess. With repeated heavy drinking, however, tolerance develops and the ability of alcohol to produce pleasure and relieve discomfort decreases.

During acute and protracted withdrawal, a profound negative emotional state evolves, termed hyperkatifeia (hyper-kuh-TEE-fee-uh). Hyperkatifeia is defined as a hypersensitive negative emotional state consisting of symptoms such as dysphoria, malaise, irritability, pain, and sleep disturbances.⁶ Heavy drinking may also produce deficits in executive function that contribute to symptoms such as impulsivity, compulsivity, impaired cognitive function, and impaired decision making. These brain changes related to excessive alcohol use underlie many AUD symptoms.

Below is a brief overview of the current knowledge of the brain structures and circuitry involved in the cycle of alcohol addiction,¹ which aligns symptomatically with moderate to severe AUD.⁷ (The current AUD diagnostic criteria are listed in the Core articles on AUD and assessment.)

• Alcohol produces pleasure. Alcohol produces pleasurable or rewarding effects by increasing activity in brain systems related to reward processing. In the basal ganglia, activation of opioid receptors in the nucleus accumbens may be responsible for some of the pleasure associated with alcohol intoxication (see Figure 1). In addition, alcohol causes the ventral tegmental area to send dopamine signals to the nucleus accumbens. Dopamine is critical for learning to associate alcohol and its related “cues”—people, places, or things—with the rewarding effects of alcohol. This learning process can lead to “incentive salience,” a motivation for reward that is driven by both a person’s current physiological state and previously learned associations between cues and the reward. Some people are initially drawn to alcohol more for its rewarding effects, while others seek it largely to alleviate physical or emotional discomfort, as detailed next.
• Habit formation makes it harder to stop drinking. When drinking behavior patterns are repeated, the brain shifts control over the sequence of actions involved in drinking from conscious control via the prefrontal cortex to habit formation using the basal ganglia. This transition from incentive salience toward habitual responding, mediated by changes in brain circuitry, can make it more likely that someone will continue their drinking pattern and harder for them to stop.
• Alcohol initially reduces, then promotes negative emotional states and pain. Alcohol may temporarily reduce negative emotional states in part by dampening activity in the extended amygdala. This brain structure mediates the fight or flight stress response and helps us learn to associate certain cues with danger or threat. Neurons interacting within the extended amygdala release stress-related neurotransmitters such as corticotropin releasing factor and dynorphin, which in turn influence other brain areas involved in stress responses, including the hypothalamus and brain stem structures.

Although alcohol initially suppresses activity in the extended amygdala and reduces stress responses, excessive alcohol use can lead to tolerance and the need to drink more to find relief. After drinking stops, during withdrawal, the amygdala circuits become hyperactive, leading to hyperkatifeia, or heightened negative emotional states, such as irritability, anxiety, dysphoria, and emotional pain. This discomfort, often described as misery, can motivate some people to drink alcohol again and repeat the cycle of drinking and withdrawal. Research suggests that among people with negative emotional states, self-medication with alcohol to help cope with mood symptoms increases the risk for developing AUD.⁸

Like its effects on emotional pain, alcohol can temporarily reduce physical pain. Research suggests that reduction of pain only occurs at or above binge levels of drinking (reaching a blood alcohol concentration of 0.08% or above, typically after 4 or more drinks for women and 5 or more drinks for men within about 2 hours).^9,10 As blood alcohol concentrations decrease, however, the sensation of pain returns even more intensely. This again leads to a cycle of misregulation,¹¹ that is, using a “solution” that ultimately makes the problem worse. The discomfort or misery felt during withdrawal, including negative emotional states, is the leading precipitant of relapses in patients recovering from AUD.^12,13

• The brain becomes motivated to continue drinking. As noted earlier, negative emotional states or hyperkatifeia, can persist into protracted withdrawal and are a major driver for relapse in AUD.¹⁴ Also, the powerful effects of alcohol on neurocircuits relating to reward and relief cause the brain to attach strong motivational value or incentive salience to the cues associated with alcohol, whether in the immediate environment or recalled from memory. These environmental stimuli, or thoughts of them, can prompt a return to alcohol seeking via connections made between the prefrontal cortex and the basal ganglia using the neurotransmitter glutamate. Especially when combined with negative emotional or physical states, the sight or thought of alcohol or related cues can trigger cravings, or the urge to drink.
• Executive function becomes dysregulated. Alcohol disrupts function in the prefrontal cortical areas involved in executive function, impulse control, decision-making, and emotional regulation.¹ These functional deficits make it harder to withstand urges and avoid repeating the behaviors related to the addiction cycle, particularly in the face of stress and physical and emotional discomfort.¹ In severe cases, impairments in prefrontal cortical function can persist despite months to years of abstinence, making it particularly difficult to recover from or compensate for deficits in executive function.¹⁵

Figure 1. Conceptual framework for the neurobiological bases of addiction (and the brain areas involved)

Addiction can be described as a repeating three-stage cycle, with each stage associated with different brain regions, neurocircuits, and neurotransmitters.¹ Drawn from decades of research, this cycle models processes that people with addiction may experience repeatedly over the course of a day, weeks, or months.^1,16,17

Image

The binge/intoxication stage (associated with circuits in the basal ganglia): The person drinks alcohol, which activates reward circuits and engages “incentive salience” circuits. Incentive salience circuits link the pleasurable, rewarding experience with “cues,” that is, the people, places, and things present when drinking, such that the cues themselves gain motivational significance. These and other neurocircuits help develop and strengthen habitual drinking and may lay the groundwork for compulsive use of alcohol. Neurotransmitters associated with this stage include dopamine, GABA, glutamate, and opioid peptides.

The withdrawal/negative affect stage (associated with circuits in the extended amygdala): When the person stops drinking, reward circuit activity decreases while stress circuits activate. Together, these changes fuel negative emotional states such as anxiety, dysphoria, and irritability. The person feels alcohol is needed for temporary relief from discomfort and emotional pain. This stage involves (1) the loss of reward neurotransmitters—as in a hypodopaminergic state, (2) the activation of stress neurotransmitters—such as corticotropin releasing factor, dynorphin, norepinephrine, hypocretin, and vasopressin—and possibly proinflammatory immune agents, and (3) the inhibition of anti-stress neurotransmitters—such as neuropeptide Y, nociceptin, endocannabinoids, and oxytocin.

The preoccupation/anticipation stage (associated with circuits in the prefrontal cortex): The person with an addiction has impairments in executive function processes that normally limit impulsive and compulsive responses. The person has strong urges or cravings to drink, especially in response to stress, related negative emotions, and cues that are part of the incentive salience circuits activated in the first stage of the cycle. Neurotransmitters associated with this stage include glutamate and ghrelin.

While people who drink heavily often enter the addiction cycle via the binge/intoxication stage, they can also enter via the withdrawal/negative affect stage (by attempting, for example, to self-medicate physical or emotional pain), or the preoccupation/anticipation stage (by attempting, for example, to self-medicate a high impulsivity condition).

For more information, see this seven-minute video on the Neurocircuitry of AUD.

What do healthcare professionals who work with adolescents need to know about alcohol?

The developing adolescent brain is particularly vulnerable to alcohol-related harm. Alcohol is a powerful reinforcer in adolescents because the brain’s reward system is fully developed while the executive function system is not, and because there is a powerful social aspect to adolescent drinking. Specifically, prefrontal regions involved in executive functions and their connections to other brain regions are not fully developed in adolescents, which may make it harder for them to regulate the motivation to drink. Because the brain is adaptable and learns quickly during adolescence, and because alcohol is such a strong reinforcer for adolescents, alcohol use is more likely to be repeated, become a habit, and eventually evolve into a problematic drinking pattern that may lead to AUD.

When adolescents drink heavily, alcohol can disrupt critical brain development patterns^18,19 by accelerating the volume decline in frontal cortical gray matter that typically occurs in early adolescence and by slowing the volume increase in white matter that typically occurs in late adolescence.²⁰ In addition, heavy drinking in adolescence increases the risk for developing AUD later in life, with the earlier the onset of any drinking, the greater the AUD risk.^21,22

In short, alcohol use during adolescence can interfere with structural and functional brain development and increase the risk for AUD not only during adolescence but also into adulthood. To help clinicians prevent alcohol-related harm in adolescents, NIAAA developed a clinician’s guide that provides a quick and effective screening tool (see Resources below).

How does the brain recover?

Just as brain plasticity contributes to the development of AUD, it can be harnessed to help the brain heal and to establish healthy behavior patterns that facilitate recovery. The extent of the brain’s capacity to return to “normal” following long-term sobriety is not fully understood.²³ However, a growing number of studies indicate that at least some AUD-induced brain changes—and the changes in thinking, feeling, and behaving that accompany them—can improve and possibly reverse with months of abstinence.^15,24 Even in individuals with lingering alterations in brain circuitry and function due to AUD, there is evidence that other circuits can compensate to help restore compromised function.^20,25,26

Healthcare professionals offer two types of evidence-based treatments for AUD that help the brain and the patient as a whole to recover: FDA-approved AUD medications and behavioral healthcare.

• Medications. Medications to treat AUD can facilitate healthy brain changes by helping people to cut down or quit drinking. Three non-addicting medications are FDA-approved to treat AUD and can be easily prescribed in primary care—acamprosate, naltrexone, and disulfiram. Acamprosate helps prevent relapse by acting to blunt the activity of glutamatergic neurocircuits, which drive the emotional discomforts of anxiety, irritability, dysphoria, and insomnia. This emotional discomfort often occurs during protracted abstinence, and often triggers a relapse.²⁷ Naltrexone, an opioid receptor antagonist, reduces the pleasurable effects of alcohol by interfering with its effects on opioid peptide activity in the basal ganglia circuitry.^28,29 In contrast, disulfiram does not work on brain circuitry, but instead interferes with alcohol metabolism by preventing the breakdown of the toxic alcohol metabolite acetaldehyde. Consuming alcohol while taking disulfiram causes acetaldehyde to build up in the blood stream, producing facial flushing, throbbing headache, nausea, and other highly aversive effects.³⁰ Each of these medications can help the patient maintain sobriety, or reduce drinking significantly, which may allow behavioral health treatments to be applied to best advantage.
• Behavioral healthcare. When people become preoccupied with drinking alcohol, their cognitive control neurocircuits can struggle to regulate urges to drink, particularly when under stress.³¹ Alcohol also can directly damage these brain circuits, making it even harder to regulate urges. Neuroimaging studies indicate that behavioral health interventions for AUD can normalize activity in the reward and stress circuitry of the brain, while strengthening cognitive networks that help inhibit the drive to drink.³² For example, therapeutic approaches that teach mindfulness and coping skills can alter neural circuits associated with craving and help people tolerate and resist urges to drink.^33,34 Other behavioral health interventions include cognitive behavioral therapy, motivational enhancement therapy, contingency management, couples and family counseling, and twelve-step facilitation to encourage active involvement in mutual support groups such as AA, SMART Recovery, and Secular AA (See Resources, below).

Together, medication and behavioral health treatments can facilitate functional brain recovery. For more details, see the Core article on treatment.

In closing, brain alterations underlying addiction not only drive the addiction process itself but also make it difficult for many people with AUD to change their drinking behavior, particularly if they are struggling to cope with the considerable discomfort of acute or protracted withdrawal. You can promote healthy changes in the brains and behaviors of patients with AUD by encouraging them to take a long-term, science-based approach to getting better. For practical, evidence-based tips on supporting your patients with AUD, see the Core articles on treatment, referral, and recovery.