Eric Kandel Comes To Minnesota

Eric Kandel, MD

Nobel Laureates don't come to Minnesota very often but they apparently come at least once a year to Gustavus Adolphus College and the annual Nobel Conference.  This year's conference was particularly interesting to me because it starred the only modern psychiatrist to be a Nobel Laureate - Eric Kandel.  He shared the podium with his wife and research collaborator Denise Kandel.  Eric Kandel is a giant in neuroscience and has continued to extend his research well into the time in life where most people have been retired for years.  In my addiction lectures, I use his well known paper Psychotherapy and the Single Synapse published in 1979 and his recent work on nicotine exposure and the risk of cocaine use entitled A Molecular Basis for Nicotine as a Gateway Drug published in 2014 as lecture references.  Kandel has been a neuroscientist and a psychiatrist longer than I have been a psychiatrist.  The other aspect of Kandel's more accessible work is his ability to integrate basic neuroscience and cognitive neuroscience into a coherent story of possibilities.  The best example is the book The Age of Insight that I briefly reviewed on this blog.  It is clear from reading Kandel that he has a lot on his mind and he is actively seeking answers and organizing his observations.  Another feature that piqued my interest in this case was why he was presenting at an addiction conference in a state where many people believe that addiction treatment was invented.  I did not find out about the conference until it was too late to take time off of work to attend.  I was very pleased to find the presentations and Q&A sessions by Eric Kandel and Denise Kandel available online.  There are a total of 4 videos and they will load and play in succession.  There may be more videos with the Kandels but I only watched these four.

In the first session Kandel discusses some of the early discoveries in brain systems and how the idea of localization of brain function played out.  For most physicians with a passing knowledge of aphasia and strokes it is a bit tedious.  Eventually he gets to a discussion of memory localization and talks about implicit and explicit memory.  That allows him to look at different features, animal models and the molecular biology of these types of memory.  He goes on to look at age-associated memory loss and Alzheimer's Disease and the different brain substrates and mechanisms.  At that point some of his slides illustrate chromatin and transcription sites but he does not get bogged down in the details as he defers the chromatin issue to a later presentation and discusses RbAp48 as a critical transcription factor in the formation of long term memories.  He showed a plausible mechanism for exercise leading to osteocalcin secretion from bones and improvement in memory as one possible humoral factor associated with vigorous exercise.  In terms of style points, he had great graphics especially the diagram of the DNA strand wrapped around histone octamers and how the transcription process is affected by various molecules. He was clearly there to present a lot of information to non-molecular biologists.  He was a little hurried at times.  He makes a few misstatements and gets distracted like all of us do during presentations.   He interjects some humor along the way.  As the presentation continues it is clear that this is important information.

The Q & A session was focused primarily on the question: "Is addiction a brain disease?"  The other panelists and their biographical sketches can be viewed at this page.  I did not realize it until after I had viewed all of the sessions that the lectures were not a good fit in terms of answering that question.  The lectures were focused on the neurobiology of learning and how epigenetic changes due to nicotine exposure lead to other addictions.  They were not lectures on the neurobiology of addiction per se, but there were some partially suggested mechanisms related to Kandel's work on memory.  Addiction being a brain disease was really not the point of the lectures.    It was obvious that the other panelists were at the minimum resistant to the idea but there was also open opposition.  If you read the biographical sketches one of the panelists has written a book on why addiction is not a disease.  If they really wanted to argue that point they could have brought me down for a Neurobiology of Addiction lecture and I could have dissected the arguments about addiction being a disease or not.  A much better idea would be to bring Eric Nestler in for the lecture.

 The panelists seemed of the opinion that plastic changes in the brain were normal and therefore plastic changes in the brain caused by addictive compounds was not a sign of pathology.  Some seemed not to be focused on the brain at all but cultural or social factors that they thought were important.  In at least one case, they seemed to suggest that addiction needs to occur in a certain context - that all addictions are not created equal.  The example given was a wealthy white guy with a cocaine addiction could just jet off to the Caribbean and go swimming as a way to deal with his addiction.  Someone else would not have that opportunity.  Kandel had a singular focus that all human behavior, that everything that we are occurs because of what is happening in the brain.  He kept going back to this idea and pointed out that alterations in brain plasticity certainly occur during addiction but they are negative and not positive changes.  He of course agrees that social and psychological processes are important intervening factors but all of the processing occurs at the level of the brain.  Some of the panelists seemed uncomfortable with this basic idea and he got into it with one of them, but eventually summarized the problem as a lack of a common culture.  He extended that comment to include the idea that the panel is discussing these problems so that younger generations in the audience will not have to start at that contentious point.  To me it came back to the mismatch between the Kandels' lectures on the epidemiology and molecular biology of nicotine as a gateway drug and the other panelists arguing that addiction was not a disease.

Denise Kandel began the third session reviewing the epidemiology of when people start using addictive substances and what the relationship is to nicotine.  In general, nicotine use is a strong predictor of cocaine use and ongoing cocaine use.   She analyzed three databases that are essentially cross sectional surveys of substance use including the NSDUH (National Survey On Drug Use and Health),  MTF (Monitoring the Future) and NESARC (The National Epidemiologic Survey on Alcohol and Related Conditions).  She discussed the concept of Translational Epidemiology or making population wide observations and then looking at models to explain the observations.  She had what I would call a critical observation on the observed drop in cocaine use and cocaine related mortality and cigarette use.  The recent drop in cocaine related mortality seems to correlate with a decrease in smoking.  Eric Kandel stepped in for the basic science section to elaborate on the mechanism of histone acetylation and how that occurs from nicotine exposure.  Denise Kandel returned to talk about the problems with e-cigarettes as potentiating factors for the use of other drugs and also as probably not a good way to stop smoking.  If you had time to watch one of the videos I would recommend this one.

The final Q & A session was an interesting one.  One of the panelists talked about the sociological theories of drug use rather than a gateway involving a biological substance.  For example, the fact that you take a substance that makes you feel good, increases the likelihood that you will take additional compounds that will do the same and that you will associate with people who have common interests and they will encourage further drug use.  Kandel had three comments during this session that I thought were very interesting.  The first involved the scientific rationale of a reductionist approach.  When you hear it explicitly stated rather than being used in a vague and rhetorical manner - it makes a lot more sense.  The second had to do with a painting by Gustav Klimt called Judith beheading Holofernes (Judith I and the head of Holofernes).  He tells the story about this biblical incident and discusses how this is a painting that combines elements of aggression and sensuality and how recent work by Anderson has shown that there is a 20% overlap between areas of the brain that govern aggressive behavior and areas that govern sexuality and reproductive behavior.  At one point Kandel seemed frustrated by some other panel members and made a reference to reproducibility that may have startled a few of them.  Denise Kandel had previously alluded to the bias against reductionism in her discussion with the statement:   "It's a reductionist approach to which some members of this audience are going to object strenuously"

The videos were very affirming for me.  When I think about the lectures I give on Kandel's work and some of the posts on this blog - I am confident that I have come to the same conclusions that he comes to about the brain and about reductionism.  Of course it is easier for me, because he provides the conclusions and I merely teach them.  I don't think that everybody has come to those conclusions either at a scientific or philosophical level.  It is too easy to get hung up on polarizing questions and political debates about science these days, especially using imprecise definitions like the word disease or claiming that reductionism is a fatal flaw rather than a good way to do science.  It is too easy to mistake journalism - in many cases hatchet-job journalism - for science.  The other striking factor is that this is a brain centric view of the world and that seems like the only logical approach to me.  Various critics will attack the brain centric view of neuroscience or psychiatry in ways that seem to miss the point.  Much of the criticism comes down to the definitions of diseases or disorders and the idea that a biomedical approach to the brain means that only biomedical treatments are possible.

I think that it might be easier to reconcile the brain centric view if the ultimate result of that view is considered and that is tremendous computational power that results in billions of people with billions of unique conscious states.  That is the ultimate product of what Dr. Kandel is talking about in terms of human learning - how it affects the conscious state and the associated brain substrate.  That may have something to do with biomedical treatments, but it also applies to every other intervention that can be brought to bear to facilitate recovery.  To make an even more obvious argument - the cure is in your head - not out in the ether somewhere.  The corollary is that it is important to know what those mechanisms are.

If you have time, watch these videos.  It is a rare chance to see one of the brightest guys in psychiatry and neuroscience in action.  I would also encourage reading The Age of Insight.  It left me with the impression that this is a scientist at the top of his game and it is inspirational reading.


George Dawson, MD, DFAPA  


References:

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.

2: Kandel DB, Kandel ER. A molecular basis for nicotine as a gateway drug. N Engl J Med. 2014 Nov 20;371(21):2038-9. doi: 10.1056/NEJMc1411785. PubMed PMID: 25409384.

3: Anderson DJ. Optogenetics, sex, and violence in the brain: implications for psychiatry. Biol Psychiatry. 2012 Jun 15;71(12):1081-9. doi: 10.1016/j.biopsych.2011.11.012. Epub 2011 Dec 29. Review. PubMed PMID: 22209636.

Attribution:  The picture of Eric Kandel is By Bengt Oberger (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons.  The file URL is:  https://upload.wikimedia.org/wikipedia/commons/c/ca/Eric_Kandel_01.JPG.



Supplementary 1:  I am fully aware of the fact that Denise Kandel and the other participants in the conference were there and are all scholars.  The title of this post reflects that fact that the Nobel Laureate came to the Noble Conference.

Supplementary 2:  This is a blog and it should be obvious that none of the speakers, institutions, or content producers mentioned in this blog post endorse this work or even know about it.  This statement is for anyone who does not think it is that obvious.  I did not attend this meeting and had no input into its content.

"Junk" Neuroscience?

A recent comment on my observation that normal function of human memory could explain what he considered to be obvious lies prompted a reading suggestion.  The author suggested that I should read a book called "Junk Neuroscience" by Satel. The only book I could find with a similar title was  Brainwashed: The Seductive Appeal of Mindless Neuroscience.   I am reluctant to spend good money on a polemics when I can get as much polemic as I want by reading it for free on the internet.  It turns out I am familiar with the author's work from a Frontiers in Psychiatry series that I reviewed last year before presenting a CME course lecture on the neurobiology of addiction.  There are currently 19 papers collected there including Satel and Lilienfeld's.  It is somewhat ironic that the entire series is based on a what I would see as assumptions that have a faulty historical, medical and certainly neurobiological premise and that is:

"For much of the 20th Century, theories of addictive behavior and motivation were polarized between two models. The first model viewed addiction as a moral failure for which addicts are rightly held responsible and judged accordingly. The second model, in contrast, viewed addiction as a specific brain disease caused by neurobiological adaptations occurring in response to chronic drug or alcohol use, and over which addicts have no choice or control....."

The first few lines captures the main problem with debates about any topic but it is particularly pernicious when it comes to addiction and neuroscience.  It leads to a number of false observations that seem to be cropping up in the popular press at an increased frequency.  The observation that most addictions spontaneously remit is taken as evidence that they do not require treatment or that neurobiological factors do not need to be considered.  There is the idea that you can be a "heavy drinker" without being an alcoholic suggesting that "heavy drinking" is protective against the factors leading excessive mortality and morbidity in alcoholism.  Those same arguments lead back to the idea that addiction is either a choice or a bad habit.  Both are gross oversimplifications of how complex decision-making is affected in addictions.  One of the main diagnostic systems for addiction from the American Society of Addiction Medicine (ASAM) describes addiction as:  "Addiction is a primary, chronic disease of brain reward, motivation, memory and related circuitry".  It does not however suggest that addicts "have no choice or control".  In fact, much treatment of addiction depends on a 12-step recovery model that is designed to help learn new controls, improve social affiliation, and re-engineer living environments to remove triggers for relapse.  The learning, affiliation, cravings and relapse triggers all have neurobiological substrates.  Against that backdrop there are 19 papers offered and Satel and Lilienfeld's is one of them.

I happen to be fortunate enough to work at a residential center that specializes in treating addictions.  In addition to the clinical work I present a number of lectures to graduate students, physicians, and residents.  The residents are in primary care and psychiatry.  The two slides that follow are right out of my PowerPoint on the neurobiology of addiction.  The Theories of Addiction slide is intended as a rapid survey of addiction theories.  I put it out there as a warm up and free associate to the theories on the slide.  As an an example, I will look at the nutritional deficiency theory of alcohol or look at alcohol being considered a medicine by itself and how that correlates with per capita alcohol consumption in the US.  I can build on that point by looking at the cultural factors that affect per capita alcohol consumption int he US and the UK.  I might ask groups of physicians if Self Medication is a legitimate theory of addiction.  Practically all physicians have heard: "Listen doc, if you can't do something about my (pain, depression, anxiety, insomnia) - I know what I can do to make it go away for a few hours."  Everybody in the room also knows that in the long run, none of those symptoms/syndromes/disorders can be treated and in fact many become considerably worse as a result of the drug or alcohol use.  Even the example of availability proneness that I typically use only partially accounts for addiction.

Any approach to neurobiology has to account for pathways to recovery as well as pathways to addiction.  In treatment centers most of those pathways are based on learning interventions.  I digress to talk about the how learning occurs both in the addiction process and in the recovery process.  I start out with Kandel's example from his classic New England Journal of Medicine article on plasticity.  His original example talks about two people in a room during a psychotherapy session, and the brain changes that occur in both as a result of that session.  Both people leave the room and their brains have been changed by the discussion.  Experience dependent changes in the brain.  That brief introduction brings me to the four considerations of the neurobiology lecture.  They are listed in the second slide below.  

I think that these are all fairly basic starting points for a lectures on neurobiology and proceed to talk about a number of systems and structures that are thought to be important from a neurobiological standpoint.  I bring in the concept that nobody knows how it all works together by a brief discussion of Chalmers hard problem or the fact that we don't know how anyone's unique conscious state comes about and what that implies.  I am evolving to a new lecture that looks at complex decision making and its roots in the neuroanatomical structures that I discuss in this lecture.  Studying this field is what I consider to be fun.  It brings together a number of concepts from my previous scientific studies.  I would probably be focused on this if I was practicing clinical psychiatry or retired.  I will be the first to admit that I am not a trained neuroscientist, but I have been trained in science and worked in scientific research.

That brings me to Satel and Lilienfeld's paper.  I don't know either author.  If you read the paper it is definitely well written and it has 121 references.  There is a bolded statement before the text begins saying that this paper is excerpted from the book Brainwashed: The Seductive Appeal of Mindless Neuroscience.  As far as I know that is the book that would apparently straighten out my views about neuroscience.  The author's begin with: "The brain-disease model implies erroneously that the brain is necessarily the most important and useful level of analysis for understanding and treating addiction." and build rapidly to a second: "In short, the brain-disease model obscures the dimension of choice in addiction, the capacity to respond to incentives, and also the essential fact people use drugs for reasons (as consistent with a self-medication hypothesis)."

Working at an addiction treatment center and talking with thousands of people in my career with severe addictions leads me to have an explosion of associations whenever I see broad generalizations about the problem.  I don't know that the concept of disease means that an affected organ system is necessarily "the most important and useful level of analysis."  There seem to me to be many diseases where that is not true.  On the issue of "reasons to take drugs" it is seldom as rational as the author's suggest.  A classic example is one that I frequently use when lecturing about the current opioid epidemic.  A significant portion of the population is prone to get a hypomanic euphorigenic effect from taking opioids.  For nonpsychiatrists, that mean the person becomes extremely euphoric, energetic, productive, and socially outgoing.  On the initial night or two, they may engage in work or creative activities at a rate that surprises them.  Many will say: "I thought I had become the person I always wanted to be."  Carefully interviewing that person several months later will get the description that they developed a tolerance to that effect.  Now they were taking the opioid "just to stay well" or prevent withdrawal symptoms.  Koob has described this cycle as  "a chronic relapsing syndrome that moves from an impulse control disorder involving positive reinforcement to a compulsive disorder involving negative reinforcement."  Consistent with this definition is that the drug has both positive (euphoria) and negative (prevents withdrawal) reinforcing effects.  The reason to take the drug is an addiction or the specific match of drug effects on a specific nervous system.  Even in a case when addictive drugs are taken for other reasons (there is a long list) it often is due to the fact that the drug is perceived as having magical qualities or as a rationalization for continuing the addiction.

I could make similar arguments for all of the main points in this paper that I have laid out in the following table.  The authors provide ample details examples to support their contentions.  Part of the problem is that the concept of disease is complex.  When you try to dissect it the problems become apparent.  The other problem is that if this is a disease, it is a disease of complex decision making and very few people focus on that.  

What after all is considered a disease?  Any reader can come up with conditions that they consider diseases for many of the ten points above.  That is easiest for the points involving the clearest comparisons with disease (1, 2, 6, 10).  In other cases (4), their point seems to be somewhat arbitrary.  With any chronic illnesses it is usually possible to function with limited incapacity due to the illness until the late stages.   In some cases the critique has more to do with the unique capacity of the organ than anything else.  For example in point (3), emergent properties that are less obvious can be considered a property an any electrical tissue.  Cardiac tissue can produce electrical patterns of decreasing complexity as a heart ages or is affected by disease.  The brain can produce a very similar pattern (see Supplementary 1).  The only difference is that heart tissue is unable to produce a conscious state.  Two of the points (5, 9) minimize the role of a systems involved in complex decision-making.  This is no trivial matter because it is associated with addictive behaviors that lead most people to classify alcohol and drug use disorders as diseases.  Common examples include people who are unable to stop using drugs and alcohol despite life threatening illnesses, repeated pleas from family members, or repeated problems with relationships, employment or the law.  Deaths due to addiction are common and they impact on a large population.  You are much more likely to see a condition as a disease if you know it has killed somebody.  Point (7) is a curious argument.  In the past several years, I have attended seminars showing for example that in some trials of buprenorphine maintenance for opioid use disorders that the addition of counseling adds nothing to the outcome beyond the medication.   I don't personally believe that, but I am used to seeing people with severe addiction who cannot stop until they are taken out of their using environment.  In every residential treatment center that I am aware of, the main focus is on "personal agency" whether that is 12-step recovery (Alcoholics Anonymous, Narcotics Anonymous) or other methods for psychological change.  As part of that process there is often a focus on neurobiology not as an excuse but as an explanation for how people can become somebody that they never thought they could become and how that process can be reversed.  The other reason for a focus on neurobiology is medication assisted treatment and a discussion of how those medications might work as part of both informed consent and interest on the part of the patients.

I wonder if the best characterization of what is going on here has more to do with philosophy than neuroscience.  As I previously pointed out in a critique of a philosopher's attack on psychiatry - a straw man approach was used.  He suggested that something was true about the field and then proceeded with his attack as if it was true.  When confronted with that single fact and asked about any evidence to support the contention - the people supporting that contention drew an apparent blank.  To this day as far as I know there is no rational way to argue that the APA has an implicit position in the DSM-5 that teaches people how to live their lives.  Even as I write it on the page it is absurd and yet that was the form of the argument.   The current paper is much more sophisticated than that.   It points out the limitations of the disease concept and how that can be used rhetorically but then proceeds to eschew what they refer to as a "neurocentric view" of addiction.  I don't think that argument carries the day largely because there is very little evidence that the people who know neuroscience have the adverse effects that the authors suggest.  There is plenty of evidence that the neuroscientist-clinicians are focused on multiple levels of care.  I have a lot more to say about what is a disease and diseases of complex decision-making but I am going to stop here.  Look for those topics to be addressed in individual posts in the future.  In the meantime, read about the neuroscience of addiction.  The field has added more to brain neuroscience than just about any other discipline in the past three decades.  

I think an additional explanation of my intent in the reply is necessary.  I use the term "political" a lot when referring to editorials, rhetoric, and other polemics.  People who should know better seem to respond to a lot of these articles as though they are either the "truth" or the "facts" that happen to support their viewpoint.  I like my science very dry.  I ascribe to Pigliucci's observation that science is a process and if there is a truth it only occurs at the end of a very long process or a series of approximations.

Seeing it any other way shuts down that process and we are left with something that is ideologically based and no longer science.

George Dawson, MD, DFAPA

1: Satel S, Lilienfeld SO. Addiction and the brain-disease fallacy. Front Psychiatry. 2014 Mar 3;4:141. doi: 10.3389/fpsyt.2013.00141. eCollection 2013.   Review. PubMed PMID: 24624096


Supplementary 1:

I attached these graphics to illustrate that electrically active tissue can have emergent properties that are really unknown by either looking at the tissue or doing other kinds of biological analyses.  That is true for both the brain and the heart.  I don't have the heart graphs but could probably find them.  They are identical.  I do have the graphs of brain activity from a patient with Alzheimer's Disease and a normal control patient.  Recordings are from a single parietal electrode in the delta frequency and show the degree of variability over the same time interval.

Single Electrode EEG - Control

Single Electrode EEG - Alzheimer's Disease

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).