What Is Addiction?


The Development and Maintenance of Drug Addiction

Wise RA, Koob GF

Neuropsychopharmacology. 2014;39:254-262

The Path of No Return in Addiction

How does someone develop substance dependence? The path is not as straightforward as one might think. The psychic alterations induced by substances are not necessarily of evolutionary advantage. Many individuals have tried illegal drugs at some point without succumbing to dependence or abuse. There is a path of no return, though, for some. Some can use once and will never try again; some only use once and are hooked for life.

The differences between both groups are many and mounting, as research reveals: individual development; social background; and unidentified disorders of mood, unopposed and chronic stress responses, and genetic predispositions, among others. Yet, the question that arises is, what is the point of no return for those who do become dependent — how does it begin?

The answer has perhaps both a clinical component and one that researchers will provide. For clinicians, the observation that someone has lost control over a substance over which there was once control determines the threshold where diagnosis can safely be made. For researchers, it is the mechanism — the constellation of behavioral and biological steps, not the “losing control” end result — to which attention is paid. But what specifically leads to that threshold, the point of no return? This might also help clinicians to better understand the putative mechanisms whereby use becomes abuse and dependence, because preventive measures could potentially be instituted before it is too late.

Genetic and Molecular Factors in the Path to Addiction

The popular view among laypeople (and many clinicians too) is that substance abuse or dependence is a choice, and should not be labeled as an illness; that somehow the sufferer “had it coming,” and in no way should a comparison be made with other psychiatric diagnoses, such as major depression. Yet, we fail to realize that clinical depression, for instance, could also potentially be the end result of environmental stressors in the form of poor choices (eg, the impulsive, grand financial decision that lead to disastrous results, or the inappropriate choice in romantic relationships). The person who impulsively tries alcohol for the first time (the environmental insult) is no different from the one who impulsively makes a business decision without proper measure of the risks involved, has an economic catastrophe, and ends up in the midst of clinical depression.

The commonality in both cases is not a moral one, but rather one of genetic predisposition. Environmental insults have an “on/off” switch effect on genes, where syndromes can be triggered to manifest themselves.[1] Many individuals who try alcohol do not get hooked, just as many who go into bankruptcy do not develop clinical depression.

The main question is how someone becomes hooked or dependent, and not whether one can get hooked to begin with. How is it that the life of a seemingly normal individual can become disrupted on so many levels as a result of becoming substance-dependent?

The general question posed by Wise and Koob in their article is how can we know when someone is addicted, or better yet, what the mechanism is whereby normal biological homeostatic parameters proceed to altered biological homeostasis — that is, addiction. There is no definitive answer, and therefore Wise and Koob bring forward arguments based on considerable research data as to the processes that ensue in the transition to addiction. Specifically, the concepts of positive reinforcement (hedonic gratification) as the initial driving force that leads to tolerance and dependence is examined against the concept of negative reinforcement (running away from pain and discomfort).

In the case of substance abuse and dependence, running toward pleasure by using a drug leads to a heightened dopamine influx from the midbrain to the ventral striatal areas (part of the brain’s pleasure center) and the prefrontal cortex (the thinking part) that leads to the conscious experience of pleasure. Pleasure begets pleasure, and it is impossible to not want more (positive reinforcement). There is no point along the continuum where one can safely define the beginning of addiction. How can we discern that somebody is “50% addicted,” and when can one be certain that severe addiction has ensued? The best answer is that it runs along a continuum that is further complicated by the addition of other critical variables, including emotional temperament and the cultural, societal, and economic context.[2]

At the molecular and protein level, it gets fuzzier still. The mu-opioid receptor protein (opioid receptor located in the human brain) and the gene that codes for it are a case in point.

The mu-opioid receptor gene (OPRM) can give rise to 2 genetic variants or polymorphisms. One of those, the Asp40 allele variant, confers an increased functional activity to the mu-receptor, elevating its response to endogenous (natural) opioids, such as enkephalins and beta-endorphins — but most important, enhancing its response to drugs of abuse, including synthetic opioids and alcohol.[3] In other words, individuals with that genetic variant will have a heightened response to the euphoric effects of alcohol and opioids, which makes it more likely that behavior leading to that response will be repeated; drinking alcohol, for instance, will lead to more drinking. It so happens that increased receptor sensitivity will lead to a rapid onset of tolerance, which is the sure way to dependence.

Most of us have had a drink at some point; many of us are not alcohol dependent, but we believe in the fallacy that somehow we possess more will power than the guy who can’t live a single day without drinking. Chances are that we are not alcohol-dependent because we have been blessed with a less receptor-sensitive variant of some gene, be it OPRM1 or another.

Two important biological systems in the concept of negative reinforcement are neuropeptide Y (NPY) and corticotropin-releasing factor (CRF). Work by Heilig and colleagues[4] and by Koob[5] has clarified that although positive reinforcement is a key process in the development of addiction (“I like it, so I want more”), the neurobiological effects leading to and after withdrawal from a substance, as well as the stage of protracted abstinence, can best be understood with the concept of negative reinforcement.

NPY (located all over the central nervous system, mostly in interneurons) has been described as a stress buffer, working in opposition to the stress-promoting properties of CRF.[6] In the trajectory to alcohol dependence, for instance, there is no absolute point demarcating individuals who are still abusing drugs from those who are already addicted. There is, however, a constellation of biological processes that begin to occur in those who are predisposed to addiction.

With repeated drinking episodes, followed by sobriety, the delicate balance between the anxiolysis brought about by alcohol and NPY, and the anxiogenic effects of CRF, are in the long run reversed. As a result, CRF/glutamate tone is heightened (glutamate is the main excitatory neurotransmitter), and NPY/GABA is reduced (GABA is the main inhibitory brain transmitter). The anxious dysphoria that arises in the period between drinks is relieved only momentarily by further drinking, thereby shifting the motivation from a hedonic (pleasure-seeking) one to the prevention of further stress and dysphoria.[5]

Conclusions and Treatment Implications

In summary, with increasing amounts of alcohol ingestion, there is over time a reduction in NPY/GABA (the natural anxiolytic system) and a concomitant increase in CRF/glutamate (the natural stress system). The implication is that at least in alcoholism, there is a shift over time in the balance between the excitatory and inhibitory systems of the brain to overexcitation, which is more pronounced in brain areas related to the stress response. In other words, there is both a biologic sensitization of the stress response and a concomitant psychological state of anxiety and restlessness, leading to dysphoria that subsides only momentarily with renewed ingestion of alcohol.

Similarities can be drawn between alcohol withdrawal and cocaine withdrawal — namely, the intense dysphoria brought about by anhedonia and apathy, along with restlessness and anxiety.[6] It is precisely this abnormal negative emotional state that leads to craving and renewed use. An abnormal sensitivity in the stress response plays a vital role in the response to drug cues that leads to relapse.[7,8]

Thus, it is not as simple as a categorical notion of having vs not having an addiction disorder; the brain is more complicated than that. Overall, there is a predisposition toward an exaggerated effect of a substance (for instance, greater euphoria in response to an average amount of alcohol) in brain pathways that regulate emotional and hedonic response, leading to impulsive, compulsive use, which ultimately results in negative emotionality (negative reinforcement) and an ever-growing attempt to prevent dysphoria by further substance ingestion.

Addiction is therefore not a single entity and cannot be encapsulated in a categorical diagnosis. It comprises many different biological findings that run in a continuum spanning multiple brain changes and multiple layers of complexity. The brains of individuals who are susceptible to addiction are different. The brains of those who are already addicted are different.

The concepts of positive and negative reinforcement are of great importance in understanding how the illness of addiction evolves. There is no clear beginning or end. Once a patient initiates treatment, many processes have already taken place at the genetic and neurochemical levels.

Understanding the biological processes that lead to a predisposition for addiction is as important as understanding the processes taking place in the full-blown addict. A better grasp of the sociocultural, developmental, and dynamic factors influencing the biological predisposition to addiction presents an opportunity to tackle it from different perspectives. That is precisely why a multidisciplinary treatment approach is needed in which medication is but one factor, and perhaps the least important one. The recognition of predisposing factors early on in at-risk individuals is perhaps the best way to avert the path of no return in addiction.


  1. Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci. 2007;8:355-367. Abstract
  2. Nesse RM, Berridge. Psychoactive drug use in evolutionary perspective. Science. 1997;278:63-66. Abstract
  3. Anton RF, Oroszi G, O’Malley S, et al. An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry. 2008;65:135-144. Abstract
  4. Heilig M, Koob GF, Ekman R, Britton KT. Corticotropin-releasing factor and neuropeptide Y: role in emotional integration. Trends Neurosci. 1994;17:80-85. Abstract
  5. Koob GF. Alcoholism: allostasis and beyond. Alcohol Clin Exp Res. 2003;27:232-243. Abstract
  6. Heilig M. The NPY system in stress, anxiety and depression. Neuropeptides. 2004;38:213-224. Abstract
  7. Fox HC, Axelrod SR, Paliwal P, Sleeper J, Sinha R. Difficulties in emotion regulation and impulse control during cocaine abstinence. Drug Alcohol Depend. 2007;89:298-301. Abstract
  8. Sinha R, Fox HC, Hong KA, Bergquist K, Bhagwagar Z, Siedlarz KM. Enhanced negative emotion and alcohol craving, and altered physiological responses following stress and cue exposure in alcohol dependent individuals. Neuropsychopharmacology. 2009;34:1198-1208. Abstract