Friday, February 19, 2016

NEJM and the Neurobiology of Addiction

From: Volkow ND et al. N Engl J Med 2016;374:363-371 - see attribution.

There are numerous articles in the popular press that attack the disease concept of addiction as well as many that attack the idea that addiction may be a biological based problem,  Volkow, Koob and McLellan have an interesting article in a recent edition of the New England Journal of Medicine that discusses both the neurobiology and some of the biases involved in stating that addiction is neither neurobiologically based or a neurobiologically based disease.  The article is relatively low in the details that reductionists like myself like to read but it is well referenced and a good overview of what is known about the neurobiology of addiction.  It is also a discussion of failed theories and what is currently known.  There is only one graphic and it is the basic one shown at the top of this post.  It shows a basic mapping of typical behaviors associated with addiction and is an elaboration of George Koob's previous all-encompassing one liner that sought to capture the behavioral pharmacology of addiction in one sentence:

"Addiction is a chronic relapsing syndrome that moves from an impulse control disorder involving positive reinforcement to a compulsive disorder involving negative reinforcement."

In this review the authors describe three stages of addiction; binge and intoxication, withdrawal and negative affect, and preoccupation and anticipation.  They are located in the table immediately below the brain graphic in the above infographic.  They break it down at a neurobiological level.  For the binge and intoxication stage increased dopamine release at the reward centers occurs.  With repeated stimulation the dopamine release is attenuated in response to the reward and shifts to anticipation of the reward.  Most authors discuss the initial phase of this process as occurring on the ventral striatum, in dopaminergic neurons from the ventral tegmental area innervating the nucleus accumbens.  I had some initial difficulty seeing the nucleus accumbens but it is there.  The larger message  is that plastic or experience dependent changes occur in not only the nucleus accumbens but also the dorsal striatum, hippocampus, amygdala, and prefrontal cortex.  I also liked the authors' inclusion of the word salience defined as a property of the prefrontal cortex in assigning relative value to a stimulus.  It is common to attend addiction conferences and hear the term being bantered about without any clear reference to the prefrontal cortex attributing salience to a particular stimulus.

Their description of withdrawal and negative affect discusses how with repeated stimulation reward and motivational systems are focused on the more potent effects of addictive drugs rather than the usual correlates including food and fluids, social affiliation, sexual behavior, and even good decision making.  This used to be referred to as the Hijacked Brain Hypothesis which basically stated the same thing.  Any physician working in a large acute care hospital will see a significant number of patients admitted largely because they have been using intoxicants on a chronic basis and ignoring their basic need for food and fluids.  This behavior is consistent with a new set of priorities for the reward and motivational systems, that biases the system heavily in the direction of continued substance use.  The previous theory of increased sensitivity to dopamine and higher levels of dopamine in the dorsal and ventral striatum in persons with addiction was proven to be wrong.  In fact dopamine release is attenuated and the reward system becomes less sensitive to all activating stimuli.  This results in both the loss of drug-induced euphoria and the lack of reward effects for previous enjoyable and preferred activities.  Recovery of this effect takes a prolonged period of abstinence and a sustained effort to get back into previous activity patterns.  At the same time, the stress response mediated by corticotropin releasing factor and dynorphin are involved in further attenuation of reward system dopaminergic cells.  Combined with changes in the extended amygdala this results in a dysphoric state and decreased stress tolerance.  It is captured in the second part of Koob's sentence - addiction becomes "a compulsive disorder involving negative reinforcement."  At this point the person with an addiction is self administering a drug to "feel normal and function" rather than get high.

The preoccupation and  anticipation stage impaired dopaminergic and glutamatergic signalling in the prefrontal cortex inhibits more typical decision making and creates a bias in the direction of continued use.  Self monitoring processes that evaluate the decision, whether or not it was successful and whether or not it was adaptive are similarly affected by these systems.  The value of the reward is depicted in the graphic below from Fuster's text The Prefrontal Cortex:


 The authors clarify their use of the term addiction relative to the more commonly used DSM-5 terms. With the advent of DSM-5 the familiar definitions of use and abuse disappeared and there is a single use category.  Severe use disorder requires 6 or more of the 11 symptoms of the use disorder.  The authors equate severe use disorder with their use of the term addiction.  Thinking about the demographics of people with one or more severe use disorders fits their description of addiction.  It is also much more likely that this group of patients will have markers and behaviors that cannot be dismissed by those who criticize a neurobiological approach to addiction.

Apart from the neurobiology update, the other interesting aspect of this paper was the authors taking on critics of a neurobiological model of addiction.  They are generally the same crowd who is critical of the disease model of addiction.  This paper defines a more specific model of addiction and its features than the disease model, even though popular surveys illustrate that most people see addiction alcoholism, and severe psychiatric illnesses as diseases.  At some level the popular and medical definitions of disease encompass a diverse group of conditions and arbitrary definitions can be adopted to support and argument.  A favorite is always that there is no known observable lesion or pathology in conditions that are not diseases.  I have examined several of these arguments about addiction in a previous post.  The authors here include their examination of 7 arguments entitled:  Criticisms of the Brain Disease Model of Addiction and Counter‐ Arguments.  The only substantial way their differ from my examination of the criticisms of addiction being modulated by a distinct set of pathological neurobiological features is that they include two points about public policy specifically how research is funded and how patients have benefitted.  One of the most common misconceptions about psychiatric illness and addictions when they are approached from a neurobiological perspective is that critics seem to think that this is tantamount to the "medicalization" of a problem and that this means only a medical intervention or medication can be used to treat the disorder.  In the field of addiction, excellent work has been done showing a number of unique paths to recovery that may depend on speculative neurobiological mechanisms, but do not depend on the use of medications or contact with physicians.  Critics of neurobiology seem to see the brain as a turf war rather than a need for a deeper understanding of the most intricate organ in the body.

I encourage a careful reading of this paper, by anyone who wants a brief overview of how addiction may affect the brain.  This is not a comprehensive review by any means and at some point I will come back and point out some of the shortcomings.  If you are a psychiatrist or psychiatric resident - you need to know what is in this paper at the minimum.  That is true if you are involved in the diagnosis and treatment of addiction or not.  The systems discussed in this paper are involved in cognition and complex decision making.  Contrary to popular belief there are no decisions made that are devoid of an emotional component.  That fact does not come alive until you know the relationship between limbic structures and reward/motivational systems.  Thirty years ago, some of the free literature from pharmaceutical companies contained graphics highlighting some of these systems and how they may be affected in schizophrenia and psychosis.  In the intervening time period, the bulk of useful research in the area came from scientists and physicians doing research in addiction.

As the knowledge in this area increases, this neurobiology will have wider applicability across the entire spectrum of psychiatric disorders.  

George Dawson, MD, DLFAPA


1: Volkow ND, Koob GF, McLellan AT. Neurobiologic Advances from the Brain DiseaseModel of Addiction. N Engl J Med. 2016 Jan 28;374(4):363-71. doi: 10.1056/NEJMra1511480. PubMed PMID: 26816013.


Graphic at the top is from reference 1, with permission from the Massachusetts Medical Society.  License date is Feb 01, 2016 - license number is 3801731329358 for 12 months from the date of the license.  According to the publisher I am classified as a free-lancer (not-for-profit publisher) and hence the change in my LinkedIn status to free-lance writer at Real Psychiatry.

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