Neurobiologic Advances from the Brain Disease Model of Addiction – Nora D. Volkow, M.D., George F. Koob, Ph.D., and A. Thomas McLellan, Ph.D. | January 28, 2016
In this uncharacteristically sensible article, Nora Volkow, the head of the National Institute on Drug Abuse, acknowledges the drug-war has failed.
This article reviews scientific advances in the prevention and treatment of substance-use disorder and related developments in public policy.
In the past two decades, research has increasingly supported the view that addiction is a disease of the brain.
Although the brain disease model of addiction has yielded effective preventive measures, treatment interventions, and public health policies to address substance-use disorders, the underlying concept of substance abuse as a brain disease continues to be questioned, perhaps because the aberrant, impulsive, and compulsive behaviors that are characteristic of addiction have not been clearly tied to neurobiology.
Here we review recent advances in the neurobiology of addiction to clarify the link between addiction and brain function and to broaden the understanding of addiction as a brain disease.
We conclude that neuroscience continues to support the brain disease model of addiction.
Neuroscience research in this area not only offers new opportunities for the prevention and treatment of substance addictions and related behavioral addictions (e.g., to food, sex, and gambling) but may also improve our understanding of the fundamental biologic processes involved in voluntary behavioral control.
After centuries of efforts to reduce addiction and its related costs by punishing addictive behaviors failed to produce adequate results, recent basic and clinical research has provided clear evidence that addiction might be better considered and treated as an acquired disease of the brain. (see Box 1 for definitions of substance-use disorder and addiction)
I’m stunned that Nora Volkow, the head of the National Institute on Drug Abuse, is acknowledging that the drug-war has failed.
Box 1. Definitions.
In this article, the terms apply to the use of alcohol, tobacco and nicotine, prescription drugs, and illegal drugs.
Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
Research guided by the brain disease model of addiction has led to the development of more effective methods of prevention and treatment and to more informed public health policies.
Nonetheless, despite the scientific evidence and the resulting advances in treatment and changes in policy, the concept of addiction as a disease of the brain is still being questioned.
The concept of addiction as a disease of the brain challenges deeply ingrained values about self-determination and personal responsibility that frame drug use as a voluntary, hedonistic act. In this view, addiction results from the repetition of voluntary behaviors. How, then, can it be the result of a disease process?
The concept of addiction as a brain disease has even more disconcerting implications for public attitudes and policies toward the addict.
This concept of addiction appears to some to excuse personal irresponsibility and criminal acts instead of punishing harmful and often illegal behaviors.
Additional criticisms of the concept of addiction as a brain disease include the failure of this model to identify genetic aberrations or brain abnormalities that consistently apply to persons with addiction and the failure to explain the many instances in which recovery occurs without treatment.
Advances in neurobiology have begun to clarify the mechanisms underlying the profound disruptions in decision-making ability and emotional balance displayed by persons with drug addiction.
These advances also provide insight into the ways in which fundamental biologic processes, when disrupted, can alter voluntary behavioral control, not just in drug addiction but also in other, related disorders of self-regulation, such as obesity and pathologic gambling and video-gaming — the so-called behavioral addictions.
This research has also begun to show how and why early, voluntary drug use can interact with environmental and genetic factors to result in addiction in some persons but not in others.
Stages of Addiction
we have divided addiction into three recurring stages:
- binge and intoxication,
- withdrawal and negative affect, and
- preoccupation and anticipation (or craving).
Each stage is associated with the activation of specific neurobiologic circuits and the consequential clinical and behavioral characteristics (see Figure 1).
Binge and Intoxication
All known addictive drugs activate reward regions in the brain by causing sharp increases in the release of dopamine.
At the receptor level, these increases elicit a reward signal that triggers associative learning or conditioning. In this type of Pavlovian learning, repeated experiences of reward become associated with the environmental stimuli that precede them
With repeated exposure to the same reward, dopamine cells stop firing in response to the reward itself and instead fire in an anticipatory response to the conditioned stimuli (referred to as “cues”) that in a sense predict the delivery of the reward
This process involves the same molecular mechanisms that strengthen synaptic connections during learning and memory formation. (See Box 2 – “Drug-Induced Neuroplasticity” at end of this post)
This is why Maia Szalavitz explains addiction as a learning disorder: Addiction More Like a Learning Disorder Than a Disease and Addiction Is a Learning Disorder.
In this way, environmental stimuli that are repeatedly paired with drug use — including environments in which a drug has been taken, persons with whom it has been taken, and the mental state of a person before it was taken — may all come to elicit conditioned, fast surges of dopamine release that trigger craving for the drug. (see Box 2 for the mechanisms involved), motivate drug-seeking behaviors, and lead to heavy “binge” use of the drug
These conditioned responses become deeply ingrained and can trigger strong cravings for a drug long after use has stopped (e.g., owing to incarceration or treatment) and even in the face of sanctions against its use.
As is true with other types of motivational learning, the greater the motivational attribute associated with a reward (e.g., a drug), the greater the effort a person is willing to exert and the greater the negative consequences he or she will be willing to endure in order to obtain it
However, whereas dopamine cells stop firing after repeated consumption of a “natural reward” (e.g., food or sex) satiating the drive to further pursue it, addictive drugs circumvent natural satiation and continue to directly increase dopamine levels,
Withdrawal and Negative Affect
An important result of the conditioned physiologic processes involved in drug addiction is that ordinary, healthful rewards lose their former motivational power
This attenuated release of dopamine renders the brain’s reward system much less sensitive to stimulation by both drug-related and non–drug-related rewards. As a result, persons with addiction no longer experience the same degree of euphoria from a drug as they did when they first started using it.
In addition to resetting the brain’s reward system, repeated exposure to the dopamine-enhancing effects of most drugs leads to adaptations in the circuitry of the extended amygdala in the basal forebrain; these adaptations result in increases in a person’s reactivity to stress and lead to the emergence of negative emotions
As a result of these changes, the person with addiction transitions from taking drugs simply to feel pleasure, or to “get high,” to taking them to obtain transient relief from dysphoria (Figure 1).
Unfortunately, although the short-acting effects of increased dopamine levels triggered by drug administration temporarily relieve this distress, the result of repeated bingeing is to deepen the dysphoria during withdrawal, thus producing a vicious cycle.
Preoccupation and Anticipation
The changes that occur in the reward and emotional circuits of the brain are accompanied by changes in the function of the prefrontal cortical regions, which are involved in executive processes
Specifically, the down-regulation of dopamine signaling that dulls the reward circuits’ sensitivity to pleasure also occurs in prefrontal brain regions and their associated circuits, seriously impairing executive processes, among which are the capacities for self-regulation, decision making, flexibility in the selection and initiation of action, attribution of salience (the assignment of relative value), and the monitoring of error.
In persons with addiction, the impaired signaling of dopamine and glutamate in the prefrontal regions of the brain weakens their ability to resist strong urges or to follow through on decisions to stop taking the drug.
Thus, altered signaling in prefrontal regulatory circuits, paired with changes in the circuitry involved in reward and emotional response, creates an imbalance that is crucial to both the gradual development of compulsive behavior in the addicted disease state and the associated inability to voluntarily reduce drug-taking behavior, despite the potentially catastrophic consequences.
Biologic and Social Factors Involved in Addiction
Only a minority of people who use drugs ultimately become addicted — just as not everyone is equally at risk for the development of other chronic diseases.
A more comprehensive understanding of the brain disease model of addiction may help to moderate some of the moral judgment attached to addictive behaviors and foster more scientific and public health–oriented approaches to prevention and treatment.
Behavioral and Medical Interventions
The findings from neurobiologic research show that addiction is a disease that emerges gradually and that has its onset predominantly during a particular risk period: adolescence
Adolescence is also a period of enhanced neuroplasticity during which the underdeveloped neural networks necessary for adult-level judgment (the prefrontal cortical regions) cannot yet properly regulate emotion.
Awareness of individual and social risk factors and the identification of early signs of substance-use problems make it possible to tailor prevention strategies to the patient.
When prevention has failed and there is need for treatment, research based on the brain disease model of addiction has shown that medical treatment can help to restore healthy function in the affected brain circuitry and lead to improvements in behavior.
The health care system already has at its disposal several evidence-based treatment interventions that could improve clinical outcomes in patients with substance-use disorders if properly and comprehensively implemented.
During treatment, medication can assist in preventing relapse while the brain is healing and normal emotional and decision-making capacities are being restored.
For patients with opioid-use disorder, maintenance therapy with agonists or partial agonists such as methadone or buprenorphine can be essential in helping to control symptoms of withdrawal and cravings
The brain disease model of addiction has also fostered the development of behavioral interventions to help restore balance in brain circuitry that has been affected by drugs
Public Health Policy
A compelling argument for the translational value of the brain disease model of addiction is the knowledge that the prefrontal and other cortical networks that are so critical for judgment and self-regulation do not fully mature until people reach 21 to 25 years of age
As a result, the adolescent brain is much less able to cognitively modulate strong desires and emotions
there are early indications that the integration of primary care and specialty behavioral health care can substantially improve the management of substance-use disorders and the treatment of many addiction-related medical conditions, including the human immunodeficiency virus, hepatitis C virus, cancer, cirrhosis, and trauma
mobilizing support for further research will require the public to become better educated about the genetic, age-related, and environmental susceptibilities to addiction as they relate to structural and functional changes in the brain
Box 2. Drug-Induced Neuroplasticity.
The drug-induced release of dopamine triggers neuroplasticity (systematic changes in the synaptic signaling, or communication, between neurons in various reward regions of the brain). These neuroplastic changes are fundamental to learning and memory. Experience-dependent learning (such as that which occurs in repeated episodes of drug use) may invoke both long-term potentiation, in which the transmission of signals between neurons increases, and long-term depression, in which signal transmission decreases.
Synaptic strength is controlled by the insertion or removal of receptors that are stimulated by the excitatory neurotransmitter glutamate (which acts largely through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and N-methyl-d-aspartate [NMDA] receptors) and by changes in the composition of the subunits of these receptors. Specifically, the insertion of a subunit of the AMPA receptor that is highly permeable to calcium, glutamate receptor 2 (GluR2), enhances the efficiency of transmission and has been shown to contribute to long-term potentiation in animal studies of addiction.17 Changes in long-term potentiation and long-term depression are in turn associated with larger or smaller synapses, respectively, and with differences in the shapes of the dendritic spines in the receptive site of the receiving neuron.18
The up-regulation of AMPA receptors that are highly permeable to calcium increases the responsiveness of the nucleus accumbens to glutamate, which is released by cortical and limbic terminals when exposed to drugs or drug cues.17 Neuroplastic changes triggered by drugs have been uncovered not only in the nucleus accumbens (a crucial brain-reward region) but also in the dorsal striatum (a region implicated in the encoding of habits and routines), the amygdala (a region involved in emotions, stress, and desires), the hippocampus (a region involved in memory), and the prefrontal cortex (a region involved in self-regulation and the attribution of salience [the assignment of relative value]). All these regions of the brain participate in the various stages of addiction, including conditioning and craving (see Figure 1). These regions also regulate the firing of dopamine cells and the release of dopamine.