The Neurobiology of Substance Use, Misuse, and Addiction

Substance use disorders result from changes in the brain that can occur with repeated use of alcohol or drugs. The most severe expression of the disorder, addiction, is associated with changes in the function of brain circuits involved in pleasure (the reward system), learning, stress, decision making, and self-control.

Every substance has slightly different effects on the brain, but all addictive drugs, including alcohol, opioids, and cocaine, produce a pleasurable surge of the neurotransmitter dopamine in a region of the brain called the basal ganglia; neurotransmitters are chemicals that transmit messages between nerve cells. This area is responsible for controlling reward and our ability to learn based on rewards. As substance use increases, these circuits adapt. They scale back their sensitivity to dopamine, leading to a reduction in a substance’s ability to produce euphoria or the “high” that comes from using it. This is known as tolerance, and it reflects the way that the brain maintains balance and adjusts to a “new normal”—the frequent presence of the substance. However, as a result, users often increase the amount of the substance they take so that they can reach the level of high they are used to. These same circuits control our ability to take pleasure from ordinary rewards like food, sex, and social interaction, and when they are disrupted by substance use, the rest of life can feel less and less enjoyable to the user when they are not using the substance.

Repeated use of a substance “trains” the brain to associate the rewarding high with other cues in the person’s life, such as friends they drink or do drugs with, places where they use substances, and paraphernalia that accompany substance-taking. As these cues become increasingly associated with the substance, the person may find it more and more difficult not to think about using, because so many things in life are reminders of the substance.

Changes to two other brain areas, the extended amygdala and the prefrontal cortex, help explain why stopping use can be so difficult for someone with a severe substance use disorder. The extended amygdala controls our responses to stress. If dopamine bursts in the reward circuitry in the basal ganglia are like a carrot that lures the brain toward rewards, bursts of stress neurotransmitters in the extended amygdala are like a painful stick that pushes the brain to escape unpleasant situations. Together, they control the spontaneous drives to seek pleasure and avoid pain and compel a person to action. In substance use disorders, however, the balance between these drives shifts over time. Increasingly, people feel emotional or physical distress whenever they are not taking the substance. This distress, known as withdrawal, can become hard to bear, motivating users to escape it at all costs. As a substance use disorder deepens in intensity, substance use is the only thing that produces relief from the bad feelings associated with withdrawal. And like a vicious cycle, relief is purchased at the cost of a deepening disorder and increased distress when not using. The person no longer takes the substance to “get high” but instead to avoid feeling low. Other priorities, including job, family, and hobbies that once produced pleasure have trouble competing with this cycle.

Healthy adults are usually able to control their impulses when necessary, because these impulses are balanced by the judgment and decision-making circuits of the prefrontal cortex. Unfortunately, these prefrontal circuits are also disrupted in substance use disorders. The result is a reduced ability to control the powerful impulses toward alcohol or drug use despite awareness that stopping is in the person’s best long-term interest.

This explains why substance use disorders are said to involve compromised self-control. It is not a complete loss of autonomy—addicted individuals are still accountable for their actions—but they are much less able to override the powerful drive to seek relief from withdrawal provided by alcohol or drugs. At every turn, people with addictions who try to quit find their resolve challenged. Even if they can resist drug or alcohol use for a while, at some point the constant craving triggered by the many cues in their life may erode their resolve, resulting in a return to substance use, or relapse.


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