By Dr. Wilson Compton, MD, MPE, Consultation Event Co-Chair & Deputy Director, National Institute on Drug Abuse (NIDA), National Institutes of Health, Department of Health and Human Services, USA.

Drugs, both legal (e.g., alcohol, nicotine) and illegal (e.g., cocaine, methamphetamine, heroin, marijuana) as well as abused psychotherapeutics (opioid analgesics, stimulant medications, benzodiazepines) can be abused for several reasons, including the pursuit of pleasure, altered mental states, improved performance or, in certain instances, alleviation of a psychiatric disorder. However, stunning advances in the neurosciences have shown that, whatever the reason behind the initiation of an abuse trajectory, chronic drug abuse affects the brain in ways that undergird the stereotypic behavioural disruptions that characterise addicted individuals.

Addiction researchers have started to shed light on the ways in which chronic drug abuse changes the brain to cause the profound disruption we see in the behaviour of an addicted person. This is because drugs of abuse co-opt the brain’s neuronal circuits necessary for insight, reward, motivation, and social behaviours. These drug-induced changes are long-lasting, persisting even after years of drug discontinuation, which has led to the recognition of addiction as a chronic and relapsing disease. This model of addiction explains why addicted individuals make poor choices despite awareness of the negative consequences; why previously rewarding life situations and the threat of judicial punishment may not stop drug taking and why a medical rather than a criminal approach is more effective in curtailing addiction. When considered together, these effects amount to a compelling argument for considering addiction a bona fide chronic and relapsing disease of the brain. Importantly, they also point the way for the development of more effective interventions for the prevention and treatment of addiction.

Addiction: A developmental Disorder

The propensity to use drugs is based in both individual predisposition and in environmental influences. Both of these factors, individual predisposition and their associated environments, interact with one another across human development. Environments that may influence future drug use include the prenatal intrauterine environment, infancy and childhood family environments, as well as the broader peer, neighbourhood, cultural, legal and social environments.

What has been observed is that experimentation with psychoactive substances generally starts in adolescence, a developmental stage characterised by risk-taking, novelty-seeking, and heightened sensitivity to peer-pressure, which might reflect incomplete development of brain regions involved in, eg. executive control, motivation, and decision making. In addition, epidemiological evidence shows that the process of addiction is much more likely to be triggered in an adolescent brain: convergent lines of evidence suggest that exposure to drugs or alcohol during adolescence may result in different neuroadaptations from those that occur during adulthood. Recent studies demonstrate eg. that the adolescent period is distinctly sensitive to long-term alteration by chronic exposure to ethanol or nicotine. This may explain the greater vulnerability of our youth to addiction. It appears that the fine balance in connections that normally exists between brain areas active in reward, motivation, learning and memory, and inhibitory control becomes severely disrupted in addiction.

Dopamine Neurobiology of Drugs of Abuse

Many different neurotransmitters have been implicated in the process of addiction, but dopamine, in particular, stands out as being consistently associated with the reinforcing effects of nearly all substances that humans abuse. Through various, often indirect mechanisms, drugs of abuse increase extracellular dopamine concentrations in limbic regions, including the nucleus accumbens (NAc) in ways that surpass the magnitude and/or duration of the fast dopamine increases that occur in the NAc when triggered by natural reinforcers such as food or sex. This is important because abnormally high or protracted increases of dopamine-mediated neuronal activity in these subcortical and related cortical brain structures are translated into vastly different (corrupted) messages about reward prediction, stimulus-response, approach behavior, learning and decision-making.

The effects of excessive dopamine stimulation become more pronounced, widespread, and long lasting once substance use becomes chronic. For example, whether tested during early or protracted withdrawal, addicted subjects show lower levels of dopamine D2 receptors in striatum (including NAc), which are associated with decreases in baseline activity in frontal brain regions implicated in salience attribution (orbitofrontal cortex) and inhibitory control (anterior cingulate gyrus), whose disruption results in compulsivity and impulsivity. In addition, drug-induced increases in dopamine also facilitate conditioned learning, so previously neutral stimuli become salient after being associated with the drug. These previously neutral stimuli can then increase dopamine, and elicit the desire for the drug, by themselves. This explains why an addicted individual is at risk of relapsing when exposed to an environment where he or she has previously taken the drug. Taken together, these results suggest that drug abuse creates an imbalance between the dopaminergic circuits that underlie reward and conditioning and those that underlie executive function (emotional control and decision making), an imbalance that is postulated to contribute to the compulsive drug use and loss of control in addiction.

Neurobiology of Addiction

Drug and alcohol addiction can be conceptualised as a reward deficit disorder characterised by a transition from impulsive to compulsive drug intake that is mediated by positive and negative reinforcement, respectively. Once a person has transitioned to compulsive drug use, negative reinforcement (i.e. behaviours designed to alleviate a negative emotional state in the absence of drug) becomes a main driver of continued, escalated drug use. The characteristic compulsive drug intake despite adverse consequences that characterises this stage appears to rely on neuroadaptations in the brain reward and stress systems. Reward system changes include decreases of dopamine and GABA in the ventral striatum coupled with stress system enhancement of corticotropin-releasing factor (CRF) in the extended amygdala as well as blunting of the activity in the hypothalamic–pituitary–adrenal (HPA) axis.

Compulsive drug consumption also involves poor inhibitory control and poor executive functioning, which are mediated by prefrontal cortical regions of the brain. For example, for alcohol, regions of the prefrontal cortex are selectively damaged by chronic intermittent use and result in poor decision making that can perpetuate the addiction cycle. The combined research of the last decade reveals that drug induced impairments in the prefrontal cortex (PFC) areas exert a two-fold impact on addiction, first through its perturbed regulation of reward limbic regions and second through its involvement in higher-order executive function (for example, self-control, salience attribution and awareness). Thus, abnormalities in these frontal regions may underlie both the compulsive nature of drug administration in addicted individuals and their inability to control their urges to take the drug when they are exposed to drugs or drug cues. These frontal abnormalities are also likely to contribute to the impaired judgment and cognitive deficits seen in many addicted individuals.

At a cellular level, drugs have been reported to alter the expression of specific genetic transcription factors (nuclear proteins that bind to regulatory regions of genes, thereby modulating the rate of their transcription), as well as a wide variety of proteins involved in neurotransmission in several key brain regions. And there is growing evidence suggesting that many of the drug-induced changes in the patterns of gene expression lead to structural, synaptic, and behavioural plasticity in the brain.

At the neurotransmitter level, addiction-related adaptations have been documented not only for dopamine, but also for glutamate, GABA, opiates, serotonin, and various neuropeptides; and these changes contribute to the abnormal function of brain circuits. For example, in individuals who are addicted to cocaine, imaging studies have documented that disrupted dopamine activity in the brain (shown by reductions in dopamine D2 receptors in striatum) is associated with reduced baseline activity in the orbitofrontal cortex (OFC) and in the anterior cingulate gyrus—brain regions that are involved in salience attribution and inhibitory control.

Addiction Vulnerability

Genetic Factors: It is estimated that 40% to 60% of the vulnerability to addiction is attributable to genetic factors. Animal studies have identified several genes that are involved in drug responses and whose experimental modification markedly affects drug self-administration. In addition, animal studies have also identified candidate genes and genetic loci for alcohol responses, which overlap with genes and loci identified in human studies. Progress in identifying candidate genes for alcoholism and alcohol-related responses continues at a rapid pace. However, identifying the biological function of these new candidate genes has emerged as a major challenge for the next decade. The hope is that a better understanding of the myriad interacting genetic factors and networks that influence addiction risk and trajectory will help increase the efficacy of addiction treatments and reduce the likelihood of relapse. One of the best examples of moving from gene identification to biological function is the association between drug metabolising genes and protection against drug/alcohol dependence. These genetic variations operate by modulating the accumulation of toxic (aversive) metabolites; therefore, if alcohol or drugs are consumed by individuals who carry variants that metabolise their substrate at unusually high or low rates, then the accumulation of toxic metabolites may occur and serve as a negative stimulus to discourage further consumption.

More recent evidence points to polymorphisms in receptor genes that can mediate drug effects and be associated with a higher risk of addiction. For example, a number of convergent results support a CHRNA5/A3/B4 gene cluster association with nicotine dependence and with the risk of such smoking-related diseases as lung cancer and peripheral arterial disease.

Environmental Factors: Environmental factors that have been consistently associated with a propensity to self-administer drugs include low socioeconomic status, poor parental support, within peer group deviancy, and drug availability. Stress might be a common feature in a wide variety of environmental factors that increase the risk for drug abuse and may help explain, for example, why social isolation (which increases anxiety) during a critical period of adolescence increases addiction vulnerability.

Imaging techniques now allow us to investigate how environmental factors affect the brain and how these, in turn, affect the behavioural responses to drugs of abuse. For example, animal studies have shown that environmental manipulations that increase D2 receptors in NAc markedly decrease drug consumption; a finding that could provide a mechanism by which a social stressor could modify the propensity to self-administer drugs. Many of the long-lasting changes in gene expression induced by an environmental event such as drug or alcohol exposure are now being studied as a means to identify how the environment can contribute to drug and alcohol addiction. They also provide a unique window into probing the complex mechanisms that connect environmental conditions to genetic output.

Comorbidity with Mental Illness: The risk for substance abuse and addiction in individuals with mental illness is significantly higher than in the general population. This high rate of comorbidity probably reflects, in part, overlapping environmental, genetic, and neurobiological factors that influence drug abuse and mental illness. In addition, alcoholism often presents in combination with the abuse of other drugs and with psychiatric disorders including mood, anxiety, sleep, and psychotic disorders. Among alcohol dependent individuals, nearly 40% have at least one lifetime psychiatric diagnosis and more than 20% have another drug abuse disorder. Almost 30% of people with psychiatric disorders exhibit substance abuse with 25% abusing alcohol and 15% abusing other drugs. These co-occurrences are problematic because they can complicate treatment and lead to synergistic negative health effects that are worse than either disorder alone.

It has been proposed that comorbidity might be due to the use of the abused drugs to self-medicate the mental illness in cases in which the onset of mental illness is followed by abuse of some types of drug. But, when drug abuse is followed by mental illness, the chronic exposure could lead to neurobiological changes, which might explain the increased risk of mental illness. The higher risk of drug abuse in individuals with mental illnesses highlights the relevance of the early evaluation and treatment of mental diseases as an effective strategy to prevent drug addiction that starts as self-medication.

Strategies to Combat Addiction

The knowledge of the neurobiology of drugs and the adaptive changes that occur with addiction is guiding new strategies for prevention and treatment, and identifying areas in which further research is required.

Preventing Addiction: The greater vulnerability of adolescents to experimentation with drugs of abuse and to subsequent addiction underscores why preventing early exposure is such an important strategy to combat drug addiction. Epidemiologic studies show that the prevalence of drug use in adolescents has shifted up and down significantly over the past 30 years, and some of the shifts are associated with attitudes towards drugs. For example, the changing pattern in marijuana use is associated with perception of the risks associated with the drug: when adolescents perceived marijuana to be risky, the rate of use was low; whereas, when perceived risk was low, the rate of use was high. At present, prevention strategies include not only educational interventions based on comprehensive school-based programmes and effective media campaigns and strategies that decrease access to drugs and alcohol, but also strategies to provide supportive family and community environments that engage adolescents in productive and creative ways.

Treating Addiction: The adaptations in the brain that result from chronic drug exposure are long-lasting; therefore, addiction must be viewed as a chronic disease. This is why long-term treatment is required for many addiction cases, just as it is for other chronic diseases, like hypertension, diabetes, or asthma. By recognising the likelihood of relapse, this perspective radically modifies our expectations of addiction treatment outcomes, establishing the need for a more rational, chronic management model.

The involvement of multiple brain circuits (reward, motivation, memory, learning, interoception, inhibitory control, and executive function) and the associated behavioural disruptions point to the need for a multimodal approach in the treatment of the addicted individual. Therefore, interventions should not be limited to inhibiting the rewarding effects of a drug, but also explore and include strategies to enhance the saliency value of natural reinforcers (including social support), strengthen inhibitory control, decrease conditioned responses, improve mood (if disrupted), and strengthen executive function and decision making.

Among the recommended multimodal approaches, the most obvious rely on the combination of pharmacologic (i.e., designed to interfere with the reinforcing effect of a drug or compensate neuroplastic maladaptations) and behavioural (i.e., aimed at strengthening/correcting specific circuits or cognitive domains) interventions, which might target different underlying factors and therefore yield synergistic effects. Such combined treatment is strongly recommended because behavioural and pharmacological treatments are thought to operate by different yet complementary mechanisms that can have additive or even synergistic effects.

Finally, the treatment of comorbid conditions requires the treatment of the mental illness concurrent with the treatment for drug abuse. Because drugs of abuse adversely affect many organs in the body, they can contribute to the burden of many medical diseases, including cancer, cardiovascular and pulmonary diseases, HIV/AIDS, and hepatitis C, as well as to accidents and violence. Therefore, substance-abuse treatment will help to prevent or improve the outcome for many other clinical conditions.

Challenges for Society

In many cases, drug abuse and addiction alienate the individual from both family and community, increasing isolation, and interfering with treatment and recovery. Because both the family and the community provide integral aspects of effective treatment and recovery, this identifies an important challenge: to reduce the stigma of addiction that interferes with intervention and proper rehabilitation.

Effective treatment of drug addiction in many individuals requires consideration of multiple social policies. For example, because of the considerable overlap of addiction and criminality, inclusion of effective drug treatment practices into criminal justice domains can lead to improvements in both health as well as safety. Addressing poverty or chronic adverse circumstance may also reduce overall vulnerability to the use of drugs.

The recognition of addiction as a disease that affects the brain might be essential for large-scale prevention and treatment programs that include participation of the medical community. Engagement of pediatricians and family physicians (including the teaching of addiction medicine as part of medical students’ training) might facilitate early detection of drug abuse in childhood and adolescence. Moreover, screening for drug use could help clinicians to better manage medical diseases that are likely to be adversely affected by the concomitant use of drugs, such as cardiac and pulmonary diseases. Unfortunately, physicians, nurses, psychologists, and social workers receive little training in the management of addiction, despite it being one of the most common chronic disorders

Another considerable obstacle in the treatment of addiction is the limited involvement of the pharmaceutical industry in the development of new medications. Issues such as stigma, lack of reimbursement for drug-abuse treatment, and the lack of a large market all contribute to the limited involvement of the pharmaceutical industry in the development of medications to treat drug addiction. The importance of this issue had been identified by the Institute of Medicine of the United States, which has recommended a programme to provide incentives to the

pharmaceutical industry as a way of helping to address this problem.

As we learn more about the neurobiology of normal and pathologic human behaviour, a challenge for society will be to harness this knowledge to effectively guide public policy. For example, presently, critics of the medical model of addiction argue that this model removes the responsibility of the addicted individual from his or her behaviour. However, the value of the medical model of addiction as a public policy guide does not reside in its misguided use as an excuse for the maladaptive behaviour of the addicted individual, but in its ability to provide a framework to understand the underlying disease and treat it more effectively.

Summary

Remarkable scientific advances have been made in genetics, molecular biology, behavioural neuropharmacology, and brain imaging that offer important new insights into how the human brain works and regulates behaviour. In the case of addiction, we can now investigate questions that were previously inaccessible, such as how environmental factors and genes affect the responses of the brain to drugs and produce neural adaptations that lead to the aberrant and stereotypic behaviours seen in addiction. This new knowledge is helping us to understand why addicted individuals relapse even in the face of threats such as divorce, loss of child custody, and incarceration, even when, in some cases, the drug is no longer perceived as pleasurable. It is also changing our approach to the prevention and treatment of addiction. However, the translation of these findings into clinical practice is hampered by structural roadblocks, including the limited involvement of the medical community in the treatment of addiction and of the pharmaceutical industry in the development of new medications. One of the main challenges for agencies like the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism is how to develop knowledge that will help us overcome these obstacles.

Note: Views expressed in this paper are those of the author and do not necessarily represent the views of the National Institute on Drug Abuse or the United States Government.