NEJM and the Neurobiology of Addiction

[Original Graphic removed due to license expiration]


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

References:

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.

Attribution:

Graphic at the top is from reference 1, with permission from the Massachusetts Medical Society.  License date is Feb 1, 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.

Snow Shoveling Theory and Plasticity

I drove back from my home town to the Twin Cities area yesterday  In this age of connectedness, there are times when you get a false sense of information.  My wife called her friend who was driving north to Duluth on Hwy 35.  She got the message that there was about 6 inches of snow on the freeway and numerous vehicles in the ditch.  I don't mind driving in the snow.  I used to drive north in the winter in some notoriously unreliable vehicles.   Rear wheel drive and no limited slip differential.   Poor weight distribution was an added bonus.  Some of the worst engineered cars in the world.  Most people my age all still use the brand name Positraction, rather than the generic limited slip differential.  More evidence that pharmaceutical companies don't differ much from other businesses in terms of branding of inserting themselves into the public consciousness.  Like most people, when you get to the point where more safety is affordable you buy it.  I am driving a modern four wheel drive sport utility vehicle (4WD SUV).  I was confidant that 6 inches of snow would only be a problem if there was congestion from large trucks and snow removal vehicles.  I was also confidant that would only happen close to the Twin Cities.  Competency in snow removal seems to vary directly with latitude with northern latitudes being the best.   I thought about that as I drove down Hwy 2 across northern Wisconsin.  The road was clean down to the pavement about 4 hours after white out conditions.

As we turned the corner in Duluth, the grey skies lifted and it turned out to be a bright sunny day but 10 degrees colder than the day before (about 22 ℉).  There was no bad road all the way back to the Twin Cities.  That only happened when we pulled into our neighborhood and there was 6 inches of snow in the driveway.  All of my neighbors driveways were clear and in many cases the pavement was dry and clear.  The physical chemistry of snow is always interesting.  In this case the bottom few millimeters of the snow was liquefied, but the upper 5 inches plus was medium density snow, the kind that is good for cross country skiing.  Clear it off and the liquid evaporates in the direct sunlight, even when it is well below the freezing temperature.  In some cases sublimation occurs and the snow vaporizes directly from the solid state.  But I was focused on additional theories.

People living in northern climes think a lot about moving snow.  We have had some epic snowfalls.  Some of my fantasies coming into this season included getting an enclosed tractor with climate control and the ability to move a massive amount of snow.  The image I have is a condensation of a couple of images.  The first is a cola commercial from many years ago - a set of combines cutting wheat.  All of the operators in their climate controlled cabs drinking Coke (or Pepsi?).  The second is a show about building ice castles in Norway and a small vehicle that was described an an airport runway snowblower that could move a tremendous amount of snow through a chute directly over the operators cab.  Those are my grandiose commercial induced fantasies.  Even a small tractor with a cab set up to move snow is ridiculously expensive and it needs a lot of ongoing maintenance.  I have never been able to locate the manufacturer of the Norwegian snow blower.

The reality is that I have a 15 year old Toro 2 stage snow thrower and about 200 square feet of sidewalk and 1,000 square feet of driveway to clear.  The snow thrower cuts a 24 inch path.  In many ways the strategy is mathematical and practical.  What is the most efficient way to clear away the snow?  Is it just going back and forth and turning the chute on the snow blower on every turn or is it something else?  Since moving into this house I have decided it is a right angled arc starting up the left hand side of the driveway and then turning back (and turning the chute on the snowblower) and heading back in the same direction.  This moves all of the blown snow to the eastern side of the lot, away from the sidewalk and areas where ice might accumulate.  It also results in fewer change in the chute direction that just going back and forth or the length of the driveway.

Mathematics aside - what are the practical aspects?  The first of course is the weather.  Is more snow expected?  Do you really want to concentrate the effort if there is going to be another foot?  In some cases of wet and heavy snow it is imperative.  That layer cannot be allowed to freeze and it is the most difficult to handle with a snow blower.  In this case I was left with about 1/2 inch of translucent slush that I had to scrape up with shovel before it all froze in the colder temperatures.  The second is the surface that you are clearing.  There are some web sites that recommend snowblower sizes based on whether your driveway is finished (asphalt or concrete) or not (gravel).  In my case I have two different surfaces - a concrete driveway and a textured concrete sidewalk.   I can't use the steel shovel on the textured concrete.  I use a plastic shovel very similar to the metal shovel that my father used to shovel coal into a steam engine on the 1950s.  One of my earliest recollection was being placed in the cab of a steam locomotive.  My father was a locomotive fireman at the time and the engine was hand fired.  His job was to keep coal burning to keep the steam pressure up.  He explained to me at the time how the scoop shaped shovel was designed to slide large amounts of coal off of it and into the furnace without wasting any energy.  To clear the sidewalk - I clear one edge and then cut across that using the same motion my father used to shovel coal.  Snow is a lot lighter than coal but it takes me about 50 passes to clear it using this motion.

With every pass, I am careful to extend the stroke out onto the grass by about 2-3 inches.  When my father first taught me to shovel snow, he said this was critical in the event that there was any melting of the snow.  Without that 2-3 inch margin the water pooled on the sidewalk and created ice.  With the margin the water soaked into the grass and no ice was formed.  I have tried to pass that knowledge along to other sidewalk shovelers, but it falls on deaf ears.  Either they don't believe me or they have their own theories of shoveling.

In addition to the theory of clearing snow and carrying it out, I get another thought from about 50 years ago.  I have always been an insomniac and one night back then I was waiting for my father to come home from work.  By then he was a railroad engineer and drove freight and iron ore trains.  It was about midnight.  It was snowing and drifting to a depth of about 3 or 4 feet on the street outside of our home.  He told  me that day before he left that they might need to plow snow off the tracks.  The worst case scenario would be hitting deep snow and blowing it into the diesel engine air intakes on the top of the locomotive.  That would kill the engines and result in a long restarting process that would slow him down.  I kept staring out the window.  The wind was so intense that I could not hear any trains even though we were only about 3 blocks from tracks.  I could finally see him leaning into the wind and snow.  He always wore union style clothes and none of it was really made for winter weather.  He wore a chromer cap with ear flaps that offered limited protection.  He was carrying a leather satchel that he called a "grip" that contained all of his important paperwork.  He was wading through hip deep snow, using the exaggerated hurdler motion that you had to use to travel in deep snow without snowshoes.  I was very happy to see him and even happier when he burst into the kitchen and it smelled like the fresh air version of diesel fuel, Lucky Strikes and leather.

I have a greater appreciation of these events than I used to.  Early on it was easy to grasp the psychodynamic significance, especially when it came to countertransferences toward mechanics and anyone else who might smell of diesel fuel and cigarettes in my office.  There were the associated issues of blue collar rage, exploitation of union workers, and a stronger affiliation with workers rather than management.  These days I can think of it in terms of the brain systems that are represented and the underlying mechanisms that allow for this experience.  I still feel happy when I have that image of my father pushing through deep snow toward home.  It probably accounts to some degree for my affiliation with snow and winter weather.  Every month or so I give a lecture and talk about the time frame, neuroscience and structures that are probably responsible for that experience.

Most of all I remind the students about how these structures allow for unique human experience.  I like to say that if there are 7 billion humans on Earth, there are 7 billion unique conscious states.  I suppose planning and fantasizing about clearing the snow is not that unique in the upper midwest.

But I doubt that any two of us learned to do that in the exact same way.


George Dawson, MD, DFAPA    

          

Lessons From Physical Therapy

I remember the first time I experienced any significant knee pain.  My wife and I had just purchased an old house and as part of the sweat equity that young homeowners do we were going to refinish all of the hardwood floors ourselves.  If you have ever tried that, the most imposing part of the task is sanding all of the floors.  Hardwood floor sanders are very heavy pieces of equipment with cast iron bodies.  My first task was to carry this machine that I guess easily weighed over a hundred pounds up to a high second floor in our old house.  That was about 25 steps and a landing.  By the time I got to the top, it felt like both knees had bottomed out and were starting to creak.  At the time I was a competitive cyclist and training by putting in 200-250 miles on the roads and hills of Duluth, Minnesota.  I had never encountered this type of pain before during cycling, speedskating or weight lifting.   I compensated the best I could by taking the sander down just one step at a time and bringing it up and down again after we ruined the first staining attempt.  Eventually the pain went away, but I had learned several valuable lessons.  Cycling for example, did not cause any knee pain even after this acute injury.  I developed a strong preference for cycling and skating and decided to forget about running.

A couple of years went by and I developed some pain in my lateral knee.  I had already been diagnosed with gout in medical school and compared to gout pain most other musculoskeletal pain is minor.   My experience with physicians diagnosing gout was very mixed and I did not want to get a recommendation for medication if something else would work better.  Instead of seeing a primary care physician, I went in to see a physiatrist who happened to be a sports medicine doc.  He jerked my knee around and was satisfied it was stable and showed me some basic iliotibial band stretching exercises.   Within a week the pain was was gone.

My most foolhardy adventure in knee injuries was trying to extend my usual 40-50 miles training rides to 100 miles with no buildup.  I was out riding the roads in Washington County and remembered a theoretical 100 mile loop that I always wanted to ride.  It was a hot summer day, I felt very fast, and I had plenty of daylight so I took off.  At the 3/4 mark I was coming up a long steep grade and felt some left knee soreness that persisted the rest of the way.  My knee was burning when I stopped and I ignored it and did not ice it that night.  By morning I had developed a significant effusion and could not bend it.   I saw an orthopedic surgeon the next day who jerked my knee around, told me it was an overuse injury, and put my leg in a knee immobilizer.  Within two weeks I was out cycling again.

At other times I have allowed my body to get seriously out of whack.  After years of cycling I started to realize that I ended each session with severe neck and shoulder pain.  After numerous adjustments to the stem length on my bike, a physical therapist figured out I was was extending my neck too far to look up from my riding position and fixed the problem by modifications to my riding position and neck exercises.  At one point, I was almost exclusively cycling and got to the point it was painful to walk around the block.   The solution was again exercise modification and exercises to improve hip flexibility.  

All of this experience has led me to be very conscious of knees and other joints and keeping them in good working order as I age.  Not just my joints but the joints of my wife, family and friends.   It is kind of amazing to hear the emphasis on physical activity at all ages and yet there is no information out there on joint preservation or how to preserve your back.  Many people are surprised to learn that the circulation to intervertebral disks in the spinal column is gone at some point in the late 20s.  That makes biomechanics and muscle conditioning some of the most important aspects of joint and back function as you age.  It also makes physical therapy and exercise some of the most important tools to maintain musculoskeletal function with aging.   When I develop some kind of musculoskeletal pain, the first thing I do is call my physical therapist and schedule an appointment to see her.   She does an examination and an analysis of the biomechanics of the problem and tells me how to solve it.  I have been through the process many times with a physician and the main difference is that there is no biomechanical assessment, no actual manipulation at the time that may be useful, and no specific exercise program to make it go away and stay away.

The results of a medical evaluation are as predictable.  You have a diagnosis of muscle or joint strain.  Use ice or heat whichever one makes you feel better.  I have been told by rheumatologists that there is really no scientific basis for the heat versus ice recommendation only the subjective response.  And of course the recommendation for NSAIDs (non-steroidal anti-inflammatory drugs like ibuprofen) or acetaminophen.  I ignore the NSAID recommendations and take as few tablets of naproxen every year as I can.  I consider NSAIDs to be highly toxic drugs and avoid them even though they are effective.  I had a rheumatologist at a famous clinic tell me that the best evidence that NSAIDs were effective was the negligible amount of joint cartilage that was left when patients came in for joint replacement therapy.   Strong evidence that NSAIDs could knock out the pain as the joint deteriorated.   The only time that I was ever offered an opioid was when I had my first gout attack.  I was seen in an emergency department for severe ankle pain and discharged with a bottle of acetaminophen with codeine - a medication that is totally useless for gout pain.

In clinical practice I see a lot of people with chronic pain.   I notice that many of them are taking NSAIDs on a chronic basis and experiencing complications of that therapy like renal insufficiency.   I notice that practically nobody sees a physical therapist.  I notice that many people are now started on oxycodone or hydrocodone for mild sprains and injuries involving much less tissue injury than many of the injuries I have sustained during sports.   There are also many people who do not receive adequate advice on modifying their activities once an injury or series of injuries has been sustained.   For example, should a person keep running if they have sore knees, are 30% overweight, and have radiographic and physical exam evidence of degenerative joint disease?  Many people seem to have the idea that they can just wear out joints and have them replaced and the replacements will be as good as new.   Some will decide that it is just time to hang it up and start to sit on the couch and watch television.  They are surprised that their pain worsens with months of inactivity.   Some of the patients with back pain decide: "This pain is so bad that physical therapy is not going to do anything.  I am going to get surgery as soon as I can."  The widespread ignorance and neglect of musculoskeletal health is mind boggling to me.

I got into an exchange with an orthopedic surgeon in our doctor's lounge one day - over lunch.  He wanted to talk about narcissistic personality disorder and I wanted to talk about the biomechanics of the knee and hip joints.  It was a lively exchange and in the end he agreed with me about the huge importance of biomechanics during physical activity and as a way to prevent injury and degenerative disease.  It turned out he just wanted to hear about the personality disorder and did not have an opinion on it one way or the other.

I teach a lot about central nervous system plasticity in a neurobiology course that I give several times a year to different audiences.  Widely defined, plasticity is experience dependent changes in the nervous system.  There are a number of mechanisms that can lead to these changes.  Kandel and others have pointed out that these are the mechanisms of animal learning.  Two examples jump out of those lectures.  The first is a physical therapy example of knee extension exercises in the treatment of knee injuries.  It has been known for some time that quadriceps strength and balance through the knee are critical factors in knee rehabilitation and the prevention of future injuries.  Research in this area shows that increased quadriceps strength can occur in the same session.  The other example I use is a guy who wants to go to the gym to increase the size of his biceps.  He starts doing curls and within 6 weeks his strength has increased by 25% but there is no muscle hypertrophy.  His biceps diameter is unchanged.  What do these two examples have in common?

The common thread here is CNS plasticity and everything it allows us to do.  Plasticity will allow your to keep your joints healthy and relatively pain free if you allow it to.  You have to be willing to accept the idea that pain can come from deconditioning and biomechanical problems that are reversible by plastic mechanisms.  The only additional information needed is if it is safe to exercise and that can be provided by a physician and a physical therapist.

And the lesson for psychiatry?  Chronic pain patients certainly need to hear this information especially if they are deconditioned.   People addicted to opioid pain medications who are not getting any relief need to hear this information.  Patients in general with exercise modifiable conditions who see psychiatrists need to hear this message.  There is also a lesson for psychotherapy no matter how it is delivered.  Kandel's original example of plasticity was a psychotherapy session.  If your brain is modified by exercise there is no reason to think it can't be modified by anything from straightforward advice to more complicated therapies.   Success in that area can lead to the limited or no use of medications and a conscious focus on what is needed to maintain health like I discuss from my own experience.  I certainly don't take any medication for pain that physical therapy or exercise adequately treats.  The same argument can be applied to anxiety and depression that can be adequately addressed by psychotherapy or other psychological interventions.  On the other hand if most people don't know that physical therapy, exercise and activity modification successfully treats musculoskeletal pain and other problems they are unlikely to try.    


George Dawson, MD, DFAPA

Supplementary 1:  There are currently only 4 Medline references on biomechanics plasticity sports.  This seems like a promising area for sports medicine, physical therapy, and rehab medicine.

Supplementary 2:   The photo at the top of the page is an exercise I do to alleviate knee pain that I learned from the book The Knee Crisis Handbook by Brian Halpern, MD with Laura Tucker.  The exercise is called the quad set (p. 238) and although the author suggests a towel under the knee, I am doing it on a styrofoam roller.  This book contains a wealth of information on knee health.  I do not recommend doing what you see in the picture without reading the book.  I have no conflict of interests related to this book and purchased it online entirely for my education.

Supplementary 3:  I could not figure out where to fit it in above but after 25 years riding with 175 mm crankarms on my bike, I dropped them back to 172.5 mm.  The bike fit expert for my new bike was convinced it was a good thing to do.  My new bike rides so much differently it is difficult to know what to attribute to crankarm length.  

A Molecular Basis for Gateway Drugs

The Gateway Drug hypothesis proposes that using a particular drug increases the likelihood that there will be a progressions to using other drugs of abuse.  The competing hypothesis is that there is a general predisposition to using more than one drug in people susceptible to addiction and that it does not depend on any sequence of exposures.  In this Shattuck Lecture in the New England Journal of Medicine, Eric and Denise Kandel examine the epidemiology and molecular biology of nicotine use and the development of addictions.  Most addiction treatment centers recognize the importance of nicotine cessation in improving abstinence rates from the primary drugs of choice.  Most of that depends on series of cases discharged from treatment centers.  The idea of nicotine also has importance because one of the approaches to nicotine cessation depends on nicotine substitution and it is important to know if that treatment intervention might lead to increased risk for ongoing substance use problems.  It also has implications for electronic cigarettes (e-cigarettes).  There is a general idea that any form of nicotine that does not involve exposure to combustible or chewed tobacco components is preferred because of all of the conditions associated with the physical and combustible products of tobacco.  If nicotine alone places one at risk for using another drug like cocaine, the risk/benefit decision will need to be reconsidered.

The authors briefly reviewed the epidemiology showing of all US adults who had ever used cocaine, the vast majority of them (87.9%) smoked cigarettes before using cocaine.  Only 3.5% used cocaine first.   The rate of cocaine dependence was highest (20.2%) among those who smoked cigarettes before using cocaine.  They proceed to use an animal model to examine the possible priming effects of nicotine and to possible elucidate the mechanism.  The animal models of addiction in mice included locomotor sensitization and  conditioned place preference.  In both of these models, micd primed with nicotine first and then treated with nicotine and cocaine showed the expected addicted response with heightened locomotor sensitization and place preference.  Mice primed with cocaine did not.

They proceed to look at the effect on synaptic plasticity and the model used was long term potentiation (LTP) in the nucleus accumbens (NAcc).   The  predominate neurons in the NAcc are medium spiny neurons (MSNs) and they are innervated by dopaminergic neurons projecting from the ventral tegmental area (VTA) and glutamatergic neurons from the prefrontal cortex and the amygdala.  Reducing excitatory (glutamatergic) input to the NAcc reduces inhibitory output to the VTA leading to more dopaminergic input to the NAcc or greater reward.  Repeated cocaine administration leads to reduced LTP in the excitatory synapses of the NAcc.  A single injection of cocaine in a mouse primed with 7 days of nicotine exposure leads to marked reduction in LTP.  Nicotine alone, or nicotine after cocaine had no effect on LTP.  Priming with nicotine causes a change in neuronal plasticity that increases cocaine associated reward.

The authors turned to known gene expression markers of addiction in the striatum specifically the expression of FosB.  They demonstrated that nicotine alone for seven days increased FosB expression and adding cocaine led to a further 25% expression.  The next step was to examine if nicotine alters the chromatin structure  at FosB promotor of the gene and they looked at the acetylation of histones H3 and H4 at the FosB promotor.  Nicotine alone increased the acetylation of both histones, cocaine alone increased the acetylation of H4 only.  They went on to demonstrate that the acetylation was widespread after nicotine exposure throughout the striatum.  Cocaine alone had no similar effect.  They went on to clarify that increase acetylation was due to inactivation of histone deacetylase activity (HDAC) and not activation of acetylases.  They carried out additional pharmacological studies to confirm that the hypoacetylated state (caused by nicotine) leads to depression of LTP associated with cocaine and that further it cannot be rapidly reversed.  The authors investigated if nicotine enhanced cocaine induced LTP in the amygdala and hippocampus and found that it did.

This fairly intensive research program and series of experiments allowed the authors to conclude that nicotine has a unidirectional priming effect and it works through an acetylation mechanism by affecting HDAC activity.  The mechanism explains what is seen in human populations at the epidemiological level and in mice at the experimental level.   That has obvious implications for treatment as well as drug development.  It  also points out that e-cigarettes are potentially as much of a potential gateway drug as combustible cigarettes.  In clinical practice it is also fairly common to see patients with addiction who are continuing to use nicotine substitutes (gum, lozenge, patch) long after they have stopped smoking.  If the mechanism elucidated by Kandel and Kandel is accurate it will be important to discuss the implications of continued nicotine exposure.

Kandel's work is always compelling because of his broad view of science and psychiatry.  He is as comfortable discussing psychoanalysis and Freud as he is talking about molecular biology.  In this case he combines views on epidemiology and molecular biology in a very compelling story and suggests it might be a broader model for how gateway drugs work.  As he is drawing his conclusions there is still room for the competing hypothesis and he makes this explicit.  His work is always a breath of fresh air compared to the current zeitgeist of political arguments about science and psychiatry often from people who know very little about either subject.  Go to the article at the link below and read this paper and compare it to his 1979 article Psychotherapy and the Single Synapse.  That covers at least 34 years of studying synaptic plasticity and it is a remarkable accomplishment.


George Dawson, MD, DFAPA


1: Kandel ER, Kandel DB. Shattuck Lecture. A molecular basis for nicotine as agateway drug. N Engl J Med. 2014 Sep 4;371(10):932-43. doi: 10.1056/NEJMsa1405092. PubMed PMID: 25184865. (free full text).

Supplementary 1:  Drawing depicts nicotine inhibiting HDAC leading to increased acetylation of histones per the above discussion.  CREB-1 = cyclic AMP response-element-binding protein; CBP = CREB-binding protein (acetylates histone H4);  PKA= protein kinase A; A=acetyl groups, P=phosphate groups; H2a, H2b, H3, H4 = histone proteins in chromatin; Pol II = RNA polymerase II (catalyzes synthesis of DNA to mRNA).

The Denial of Plasticity

For the past couple of months, I have spent a lot of my free time working on a presentation on neurobiology.  The presentation is the lead off in a series of lectures on addiction and the target audience is primary care physicians.  I have a lot of experience with this topic because I give a very similar lecture at least six times a year to physicians and other professionals who take a course on the treatment of addiction at the facility where I work.  I have been preparing and delivering these lectures for 3 1/2 years at this point.  Incorporating some of the most recent data on these topics is always a challenge and I depend a lot on Nature, Science, and Neuron for the latest reviews, research and commentaries.  In order to make it more relevant I ran across a collection of article in Frontiers in Psychiatry on the issue of whether or not addiction is a disease or not and it seems like a lot of that has to do with neurobiology.  Neurobiology has also become en vogue in many ways.  There is a conference posted in my clinic entitled "The Neurobiology of Play Therapy".  I thought I would post my observations of the implications of neurobiology in addiction and psychiatry.

The modern day interest in neurobiology owes a lot to Eric Kandel and his 1979 New England Journal of Medicine article "Psychotherapy and The Single Synapse."  The focus of that article was on the application of his basic science research on plasticity to the psychotherapy situation.  Plasticity was a relatively new concept at the time with the initial description of long-term potentiation (LTP) in 1973.  Kandel's basic argument was that nervous systems of varying complexity are designed to change with the experience of the organism.  The interesting part of his article is that it starts out with his experience as a psychiatric resident and the tension between the psychotherapists and the biological psychiatrists as they were called when I encountered the same dynamic in psychiatric training over twenty years later.  It is an important consideration because people outside of the field often have a skewed perspective of what makes up the training of a psychiatrist and this tension has been present for as long as I can remember - with articulate faculty on both sides.  He discusses this from the perspective of a parent discipline and an "antidiscipline" or one that is narrower in scope than the parent discipline and invigorates but does not displace it.  Neurobiology being the antidiscipline to psychiatry.  Molecular biology being the antidiscipline to cell biology and so on.  At the experimental level Kandel uses habituation and sensitization experiments on the sea snail to illustrate that "dramatic and enduring" changes in neural transmission occur with changes in plasticity.  He develops the theme that the functional-organic pathology based on gross or microscopic brain lesions is a false dichotomy.  Profound changes in networks of neurons can occur with no change in the numbers of neurons involved.  The mind is a function of the brain, but as Kandel later stated we do not have to think that all human behavior can be broken down to a specific biological level.

Getting back to the issue of addiction as a disease as opposed to something else offers a unique look at the plasticity concept and how it applies to brain problems.  I looked at all of the papers in the Frontiers series and briefly describe the details in the table below.  I would encourage reading the actual details in the papers since they are all freely accessible online and my one or two sentence summaries do not capture the complexity of some of these arguments. (click to enlarge)

There was a striking lack of the term "plasticity" in all of these papers.  It only surface in the paper on choice by Heyman in the following sentences: "First, most drug addicts quit.  Thus, drug induced plasticity does not prevent quitting."  That is a restricted view of plasticity.  First, it does not speak to the fact that plastic changes even if they appear to be long term can be reversed.  Second, it treats plasticity as a linear process when it is likely that the brain processes involved in recovery and in all of the other mechanisms cited by these authors as being more important in the recovery process are plasticity based.  The articles in general have the tone of polemics.  There is certainly nothing wrong with that.  As I have written on this blog, science is a dynamic process and part of that is an argument about theories over time.  The argument about the neurobiology of addiction seems to get hung up on both the disease concept and morality.  There can certainly be important neurobiology with or without disease.  That neurobiology is there whether or not medication, social processes, or psychotherapy influences it.  At least two of the authors equate neurobiological disease as the "no fault" condition and suggest that a biology based model is more blameless than one that suggests that addicts do have choices and respond to contingencies.  I think moral interpretations of a mental illness or addiction have less meaning if we are accurately describing the process.  It is much more than biology being no-fault and consciousness capable of decisions implying a moral judgment.  Plasticity mediated mechanisms gets us a lot closer to the science of how the brain works and away from the primitive interpretations of the 19th and 20th centuries.  

Plasticity is the best paradigm for describing addiction and the recovery process. Processes involving plasticity are all testable and the theory is falsifiable.  The most significant obstacle to the application of brain plasticity as a central process is the old functional-organic dichotomy where organic implied a neuroanatomical brain lesion.  It has been known from habituation and sensitization experiments like those described by Kandel in his 1979 paper that "dramatic and enduring" changes in neural transmission, do not require brain lesions or other abnormal anatomical features.  A recent paper (3) proposing that maladaptive NMDA-mediated synaptic plasticity as a unifying theory for tardive dyskinesia is a good example of plasticity mediated illness.  

There is no reason to believe that addiction and recovery may not be mediated by the same mechanisms.

George Dawson, MD, DFAPA


1: Kandel ER. Psychotherapy and the single synapse. The impact of psychiatric thought on neurobiologic research. N Engl J Med. 1979 Nov 8;301(19):1028-37. PubMed PMID: 40128.

" In each case, even in the most socially determined neurotic illness, the end result is biologic. Ultimately, all psychologic disturbances reflect specific alterations in neuronal and synaptic function. And insofar as psychotherapy works, it works by acting on brain functions, not on single synapses, but on synapses nevertheless. Clearly, a shift is needed from a neuropathology also based only on structure to one based on function."

2:  Alternate Models of Addiction.  Frontiers in Psychiatry.

3. Teo JT, Edwards MJ, Bhatia K. Tardive dyskinesia is caused by maladaptive synaptic plasticity: a hypothesis. Mov Disord. 2012 Sep 1;27(10):1205-15. doi: 10.1002/mds.25107. Epub 2012 Aug 1. Review. PubMed PMID: 22865512

Minnesota Passes Medical Marijuana "Research" Bill

It's official.  Both houses of the Minnesota legislature passed a medical marijuana bill last Friday night.  The Governor has already said that he would sign it.  Minnesota ended up taking a unique approach largely because the Governor said he would sign no bill that was not accepted by law enforcement.  The process was also affected by the medical society who did not want physicians in the prescribing loop and the psychiatric society who did not want psychiatric disorders used as an indication for marijuana.

That effectively took marijuana smoking off the table.  The turning point was apparently young mothers testifying that cannabis derivatives were critical to the treatment of refractory epilepsy.  At that point there were several new drafts of the bill looking at the indications, the physicians role, and the role of the government.  The agreed upon indications follow:


Subd. 14. Qualifying medical condition. "Qualifying medical condition" means a
3.15diagnosis of any of the following conditions:
3.16(1) cancer, if the underlying condition or treatment produces one or more of the
3.17following:
3.18(i) severe or chronic pain;
3.19(ii) nausea or severe vomiting; or
3.20(iii) cachexia or severe wasting;
3.21(2) glaucoma;
3.22(3) human immunodeficiency virus or acquired immune deficiency syndrome;
3.23(4) Tourette's syndrome;
3.24(5) amyotrophic lateral sclerosis;
3.25(6) seizures, including those characteristic of epilepsy;
3.26(7) severe and persistent muscle spasms, including those characteristic of multiple
3.27sclerosis;
3.28(8) Crohn's disease;
3.29(9) terminal illness, with a probable life expectancy of under one year, if the illness
3.30or its treatment produces one or more of the following:
3.31(i) severe or chronic pain;
3.32(ii) nausea or severe vomiting; or
3.33(iii) cachexia or severe wasting; or
3.34(10) any other medical condition or its treatment approved by the commissioner.

A couple of issues about the statutory conditions.  First of all, a patient wanting to use cannabis for any of these conditions needs to be certified that they have the conditions.  That is not the same as a medical diagnosis.  Each patient will need to apply to the Department of Health for the certification and that will cost $200.  Physicians are not necessary for the patient to be certified.  Anyone certified and any physician who wants to be involved will be monitored in a registry through the Department of Health.  It is also obvious from the list, that for the conditions, there is really no known medical indication for cannabis.  An excellent example is glaucoma and the review of the pathophysiology and treatment for glaucoma for primary care doctors in this week's JAMA.  Finally, the entire system is going to be implemented as a research program with no controls and (so far) no known research methodology.

The newspaper headline touches on one of the main issues and that is the cannabis will not be smoked.  There was an initial consideration that vaporizers could be used in a physicians office under the supervision of a physician.  That restriction was not in the final bill.   The Commissioner of Health is charged with providing people certified for the following conditions with medical cannabis by July 1, 2015.  In the conference I attended today, there will apparently be competition for two suppliers to provide medical cannabis at 4 outlets each in the state.  Medical cannabis is defined as:

 (e) "Medical cannabis" means the flowers of any species of the genus cannabis plant,
1.20 or any mixture or preparation of them, including extracts and resins which contain a
1.21 chemical composition determined to likely be medically beneficial by the commissioner,
1.22 and that is delivered in the form of:
1.23 (1) liquid, including, but not limited to, oil;
1.24 (2) pill;
2.1 (3) vaporized delivery method with use of liquid or oil but which does not require
2.2 the use of dried leaves or plant form; or
2.3 (4) any other method approved by the commissioner but which shall not include
2.4 smoking.

That last two lines were were surprising, but law enforcement in Minnesota was apparently not on board with legalizing marijuana smoking.  Given the momentum of the marijuana movement at the national level, that was surprising to see in what is considered a liberal state.  The psychiatric society also gets credit for removing Post Traumatic Stress Disorder, from the list of qualifying medical conditions and providing the governor with a rationale to continue negotiating.

The Commissioner is also charged with reviewing the literature on medical cannabis, suggesting doses and additional qualifying medical conditions, and maintaining a registry of the effects of medical cannabis on the target condition.  That aspect of the law seems like a black hole to me, because it means that the Health Department will essentially be providing FDA services on an experimental medication.  What state department of health can pull that off?  The trials will all apparently be observational studies since no group of people wanted to be control subjects.  They apparently have no doubt that cannabis is an effective drug for what ails you.  Since cannabis has been used by humans since the Neolithic Era (4,000-2,500 BCE) and medicinally in many contexts since then, it is always interesting to consider why nobody has not found a consistent medical use in the past 5,000 years.

The Minnesota law is an interesting approach and I think it may be an excellent compromise.  It gets cannabis to the severely ill who claim benefits while avoiding the issue of recreational use.  This is also an an analogous approach currently used in the case of terminally ill patients and getting them access to experimental therapeutics.  According to speaker I was listening to yesterday the case presented by mothers of children with intractable seizures provided some of the most  compelling testimony.

The passage of this law also dovetails with the editorial in Science this week.  DuPont and Lieberman make the case that adolescent exposure to cannabis should be expected by any legalization and the long term effects on that population are really unknown, but that the preliminary evidence in terms of future risk of addiction or psychiatric disorders does not look good so far.  That same issue of Science has an interesting article on neurogenesis in the dentate gyrus at various points in the life cycle of mice pointing out that learning and retention requires a delicate balance in just the right amount of neurogenesis.  Preliminary research suggests that cannabis affects neurogenesis.

I don't often agree with the politicians of either party, but this may be the best compromise available during a cultural trend of increased permissiveness toward drug use.  The main problem with the bill is putting the Department of Health in a regulatory role that may be difficult for them to realize without a significant increase in budget and manpower.  It also makes cannabis seem to be a legitimate medical treatment - when it is not.


George Dawson, MD


References:

1.  Mike Cronin.  Minnesota Senate passes medical marijuana bill; could become only state that bans smoking.  Minneapolis StarTribune May 17, 2014.

2.  Information for S. F. No. 2470

3.  Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014 May 14;311(18):1901-11. doi: 10.1001/jama.2014.3192. PubMed PMID: 24825645.

4.  Mongiat LA, Schinder AF. Neuroscience. A price to pay for adult neurogenesis.  Science. 2014 May 9;344(6184):594-5. doi: 10.1126/science.1254236. PubMed PMID: 24812393.

5.  Akers KG, Martinez-Canabal A, Restivo L, Yiu AP, De Cristofaro A, Hsiang HL, Wheeler AL, Guskjolen A, Niibori Y, Shoji H, Ohira K, Richards BA, Miyakawa T, Josselyn SA, Frankland PW. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science. 2014 May 9;344(6184):598-602. doi: 10.1126/science.1248903. PubMed PMID: 24812394.