Acamprosate For Alcohol: Why the Research Might Be Wrong

Calcium may be curbing the urge to drink.

“Occasionally,” reads the opening sentence of a commentary published online last month in Neuropsychopharmacology, “a paper comes along that fundamentally challenges what we thought we knew about a drug mechanism.” The drug in question is acamprosate, and the mechanism of action under scrutiny is the drug’s ability to promote abstinence in alcoholics. The author of the unusual commentary is Markus Heilig, Chief of the Laboratory of Clinical and Translational Studies at the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Acamprosate, in use worldwide and currently the most widely prescribed medication for alcohol dependence in the U.S., may work by an entirely different mechanism than scientists have believed on the basis of hundreds of studies over decades. Rainer Spanagel of the Institute of Psychopharmacology at the University of Heidelberg, Germany, led a large research group in revisiting research that he and others had performed on acamprosate ten years earlier. In their article  for Neuropsychopharmacology, Spanagel and coworkers concluded that a sodium salt version of acamprosate was totally ineffective in animal models of alcohol-preferring rats.

“Surprisingly,” they write, “calcium salts produce acamprosate-like effects in three animal models…. We conclude that N-acetylhomotaurinate is a biologically inactive molecule and that the effects of acamprosate described in more than 450 published original investigations and clinical trials and 1.5 million treated patients can possibly be attributed to calcium.”

At present, the Food and Drug Administration (FDA] has approved three drugs for alcoholism— Antabuse, naltrexone, plus acamprosate in 2004. In addition, there is considerable clinical evidence behind the use of four other drugs—topiramate, baclofen, ondansetron, and varenicline. Acamprosate as marketed is the calcium salt of N-acetyl-homotaurinate, a close relative of the amino acid taurine. It has also been found effective in European studies.

What did scientists think acamprosate was doing? Various lines of research had linked acamprosate to glutamate transmission. Changes in glutamate transmission have been directly implicated in active alcoholism. A decade ago, the Spanagel group had decided that acamprosate normalized overactive glutamate systems, and hypothesized that acamprosate was modulating GABA transmission. So it became known as a “functional glutamate antagonist.”  But specific mechanisms have remained elusive ever since.

Now, as Heilig comments, “the reason it has been difficult to pin down the molecular site of acamprosate action may simply be because it does not exist. Instead, the authors propose that the activity attributed to acamprosate has all along reflected actions of the Ca++ it carries.” As the researcher paper explains it: “N-acetylhomotaurinate by itself is not an active psychotropic molecule…. We have to conclude that the proposed glutamate receptor interactions of acamprosate cannot sufficiently explain the anti-relapse action of this drug.” Further work shows that acamprosate doesn’t interact with glutamate binding sites at all.  In other words, calcium appears to be the major active ingredient in acamprosate. Animal studies using calcium chloride or calcium gluconate reduced alcohol intake in animals at rates similar to those seen in acamprosate, the researchers claim.

Subsequently, the researchers revisited the earlier clinical studies, subjected them to secondary analysis, and concluded that “in acamprosate-treated patients positive outcomes are strongly correlated with plasma Ca++ levels. No such correlation exists in placebo-treated patients.” In addition, calcium salts delivered via different carrier drugs replicated the suppression of drinking in the earlier animal findings. 

Where there cues pointing toward calcium? The researchers conclude that “calcium sensitivity of the synapse is important for alcohol tolerance development, calcium given intraventricularly significantly enhances alcohol intoxication in a dose-dependent manner,” and “activity of calcium-dependent ion channels modulate alcohol drinking.”

Interestingly, in the late 50s and early 60s, there was a brief period of interest in calcium therapy for the treatment of alcoholism. In 1964, the Journal of Psychology ran an article titled “Intensive Calcium Therapy as an Initial Approach to the Psychotherapeutic Relationship in the Rehabilitation of the Compulsive Drinker.” Now it appears possible that a daily dose of acamprosate is effective for some abstinent alcoholics because it raises calcium plasma levels. Calcium supplements may be in for a round of intensive clinical testing if these findings hold up.

The authors now call for “ambitious randomized controlled clinical trials,” to directly compare “other means of the Ca++ delivery as an approach to treat alcohol addiction. Data in support of a therapeutic role of calcium would open fascinating clinical possibilities.”  Indeed it would.

Spanagel R., Vengeliene V., Jandeleit B., Fischer W.N., Grindstaff K., Zhang X., Gallop M.A., Krstew E.V., Lawrence A.J. & Kiefer F.  (2013). Acamprosate Produces Its Anti-Relapse Effects Via Calcium, Neuropsychopharmacology, 39 (4) 783-791. DOI: 10.1038/npp.2013.264

Narco-Deforestation Accelerates Loss of Biodiversity

In Central America, drug policies become conservation policies.

The Central American isthmus exploded into prominence as a drug trafficking corridor in 2006, when pressure on Mexican cartels pushed smuggling operations to the south and into the remote forest frontiers of Honduras, Guatemala, and Nicaragua. Since then, vigorous interdiction programs have pushed traffickers into ever more remote zones, back and forth from country to country, bringing money, manpower, and greater opportunities for deforestation.

Kendra McSweeney of the Department of Geography at Ohio State University and co-workers dug into the recent comprehensive report by the Organization of American States (OAS), titled The Drug Problem in the Americas, and wrote up their findings in a recent contribution to Science's Policy Forum. They found that “mounting evidence suggests that the trafficking of drugs (principally cocaine) has become a crucial—and overlooked—accelerant of forest loss in the isthmus.” (See graph above, representing forest clearings in Eastern Honduras.)

In the Caribbean lowlands area known as the Mesoamerican Biological Corridor, and in protected rural regions like Laguna del Tigre National Park in Guatemala and the Rio Platano Biosphere Reserve in Honduras (now listed as “in danger” by UNESCO due to forest loss), there is no shortage of reasons why deforestation in Central American is increasing. Among the causes are weak or corrupt government agencies, climate change, poverty, illegal logging, ill-advised development, and rampant agribusiness expansion. However, what has been called the “compounding pressure” of drug trafficking on biodiverse forestlands and associated rural communities is making things worse. The report in Science documented that an unprecedented flow of cocaine into Central America “coincided with a period of extensive forest loss” as narco-traffickers purchase large ranches in “contested rural landscapes.”

What are the active causal connections between drug trafficking and deforestation? The researchers identified three interrelated mechanisms “by which forest loss follows the establishment of a drug transit hub.”

1. Drug traffickers cut down forests to establish secret roads and aircraft landing strips.

2. Drug money amps up the pressure on weakly governed frontier areas, resulting in “narco-capitalized” land speculators and timber harvesting operations. In the process, local small landowners get priced out, even though the conversion of forests to farmlands is illegal in protected areas.

3. Drug trafficking organizations are themselves drawn into local forest-to-agriculture development plans like pastures and oil-palm plantations. Buying up and developing land is a preferred method of laundering drug money. These vague “narco-estates” monopolize land use in some territories and serve as cover for expanded smuggling operations.

What could mitigate this form of additional pressure on tropical deforestation? The researchers suggest that the heart of the problem is the traditional emphasis on supply-side policies, such as interdiction and crop eradication on foreign soil. “Analysts have long noted that eradication policies often push coca (and opium poppy and marijuana) growers into ever more ecologically sensitive zones, with substantial environmental impacts.”

The authors of the Science article view all of this as something to be added to “the long list of negative unintended consequences borne by poor countries as a result of the overwhelming emphasis on supply-side drug reduction policies…. Recognizing the ecological costs of drug trafficking in transit countries would improve full-cost pricing analyses of the drug policy scenarios explored by the OAS.”

McSweeney K., Nielsen E.A., Taylor M.J., Wrathall D.J., Pearson Z., Wang O. & Plumb S.T. (2014). Drug Policy as Conservation Policy: Narco-Deforestation, Science, 343 (6170) 489-490. DOI: 10.1126/science.1244082

The Anthropology of Addiction

Can we ever integrate neuroscience and social science?

Bielefeld, Germany—
The last in a series of posts about a recent conference, Neuroplasticity in Substance Addiction and Recovery: From Genes to Culture and Back Again.  The conference, held at the Center for Interdisciplinary Research (ZiF)  at Bielefeld University, drew neuroscientists, historians, psychologists, philosophers, and even a freelance science journalist or two, coming in from Germany, the U.S., The Netherlands, the UK, Finland, France, Italy, Australia, and elsewhere. The organizing idea was to focus on how changes in the brain impact addiction and recovery, and what that says about the interaction of genes and culture. The conference co-organizers were Jason Clark and Saskia Nagel of the Institute of Cognitive Science at the University of Osnabrück, Germany.   Part One is here.   Part Two is here.  Part Three is here.


The disciplines of psychiatry and neurology are being brought intellectually closer to each other. One can foresee the day in the not-too-distance future when resident physicians in both disciplines will share a common year of training, comparable to the year of residency training in internal medicine for physicians who go on to specialize in widely different areas.
— Eric Kandel, In Search of Memory

Anthropology is arguably a perfect discipline within which to connect the two often-conflicting facets of addiction—its fundamental neuroarchitecture, and the socioenvironmental influences that shape this basic biological endowment. In The Encultured Brain, published by MIT Press, co-editors Daniel H. Lende and Greg Downey make an articulate call for a merger of interests, in an attempt to combine laboratory research with anthropological fieldwork. The term “neuroanthropology,” meant to denote this combination of anthropology and brain science, was evidently coined by Stephen Jay Gould. A number of thinkers have dipped into this arena over the years, including Melvin Konner, Sarah Hrdy, Norman Cousins, Robert Sapolsky, and Antonio Damasio. The term gained a more solid foothold when Lende and Downey began their Neuroanthropology blog, now at PLOS blogs. 

The term has the advantage of meaning exactly what it says: an integrative approach to the complicated matter of how our genetic endowment is influenced by our cultural endowment. Or vice versa, if you prefer. Here, from the introductory chapter, is the short definition of neuroanthropology: “Forms of enculturation, social norms, training regimens, ritual, language, and patterns of experience shape how our brains work and are structured…. Without material change in the brain, learning, memory, maturation, and even trauma could not happen…. Through systematic change in the nervous system, the human body learns to orchestrate itself. Cultural concepts and meanings become neurological anatomy.” From the point of view of actual study, there is no choice but to join these two when possible—a task make more difficult by the rampant “biophilia” found among anthropologists and sociologists, as well as the countering notion among biologists that anthropology does not make the cut as a “real” science.

Co-author Daniel Lende, an associate professor in the Department of Anthropology at the University of South Florida, was one of the presenters at the Bielenfeld conference. Lende did his Ph.D. work on adolescent substance abuse in Bogota, Colombia, and told the group that years of research “showed me that addiction is profoundly neuranthropological.” Lende told the audience that the “combination of neuroscience and ethnography revealed that addiction is a problem of involvement, not just of pleasure or of self.”

 This approach calls for applying a critical eye to strictly brain-based explanations that ignore both environmental influence and biochemical individuality. And it opens up the possibility that anthropologists may be incorporating neuroimaging technology into their working tool kit. While the neuroanthropology movement has been mostly a product of the anthropology side thus far, Lende said. But increasingly, cognitive scientists are joining in.

“As neuroanthropologists, we’re not trying to solve problems in the lab or in the clinic, but rather to take the results of that sort of work, and look at what’s happening to those brains in the wild,” Lende said.

Repeated patterning comes from social environments, he said. “We have to deal with how cultural practices and developmental experiences can shape and mold the brain, and how that has an effect on the production of human variation, not just sets of beliefs you can take on and put off.”  The cultural practice of skull shaping, for example, is “impossible to understand without taking into account both the cultural practices that drive it, and the early plasticity in bone formation that allows it biologically.”

Culture, said Dr. Lende, “can bring different elements into one package. It doesn’t have to be the biology side that does all the work. You can take the cultural strands and knit them into something really unusual that you wouldn’t necessarily see in the world. With cultural tools, we are using are brain in ways not necessarily built into it from the start.”

But attending to all of this requires thinking of neural plasticity in novel ways, Lende said. “Hardwiring isn’t quite as hard as we once thought. The lifespan of these circuits set early in life isn’t what we thought.” The brain can use sensory input in ways we don’t yet understand. Lende pointed to “significant recovery from stroke, which was not viewed as possible a couple of decades ago.”

“You have to be critical both of the neuroscience and some of its limitations, and also the anthropologists, who are sometimes saying, ‘it’s got to be all sociocultural.’ That’s not always a good explanation for something as complex as addiction.”

Lende believes that anthropology needs to pursue the impact of “biological embedding, or how experiences get under the skin” to alter human biological and developmental processes. “You can have differential vulnerabilities to biological embedding, coupled with differential environmental vulnerability.”

Dr. Lende points to the well documented clinical finding that exercise enhances neuroplasticity. “And exercising has been shown in various labs to reduce craving,” he said. “What’s important from my community-based orientation is, what sort of interventions or strategies can we have that are low cost and be used in non-professional settings. Can we motivate people to do it? What are the barriers?”

 Subjective experience is hard to get at, but that’s a problem anthropologists think about all the time. “I asked the kids in Columbia, if your drug use were a place, Lende said, “ then what sort of place would that be? Kids who’d never tried drugs didn’t get the question, but a kid with heavy cigarette use who had just quit, and who had recovered recently from using too much cocaine and crack, looked at his fingers, referring to cigarettes, and said, ‘a world in there? No. But with cocaine, yes.”

Going Deep: Surgery For Addiction?

Controversial DBS technique shows early promise for Parkinson’s, Tourette’s.

Bielefeld, Germany—

The third in an irregular series of posts about a recent conference, Neuroplasticity in Substance Addiction and Recovery: From Genes to Culture and Back Again. The conference, held at the Center for Interdisciplinary Research (ZiF) at Bielefeld University, drew neuroscientists, historians, psychologists, philosophers, and even a freelance science journalist or two, coming in from Germany, the U.S., The Netherlands, the UK, Finland, France, Italy, Australia, and elsewhere. The organizing idea was to focus on how changes in the brain impact addiction and recovery, and what that says about the interaction of genes and culture. The conference co-organizers were Jason Clark and Saskia Nagel of the Institute of Cognitive Science at the University of Osnabrück, Germany.  Part One is here.  Part Two is here.

All addictive drugs increase the production of dopamine in the nucleus accumbens, as do other highly pleasurable activities. Part of the medial forebrain bundle (MFB), which mediates punishment and reward, the nucleus accumbens is the ultimate target for the dopamine released by the ingestion of cocaine, for example. The nucleus accumbens is a very old and evolutionarily well-preserved structure in the brain. If you remove large slices of the nucleus accumbens, or knock it out entirely, animals no longer want addictive drugs.

This is essentially the same pathway that regulates our food and water-seeking behavior. By directly or indirectly influencing the molecules of pleasure, alcohol and other drugs trigger key neurochemical events that are central to our feelings of both reward and disappointment. In this sense, the reward pathway is a route to both pleasure and pain. Studies of the nucleus accumbens have demonstrated abnormal firing rates in scanned addicts who were deep into episodes of craving. The craving for a reward denied causes dopamine levels in the nucleus accumbens to crash dramatically, as they do when users go off drugs.

During his presentation in Bielefeld, “Stimulating the Addictive Brain,” Dr. Jens Kuhn of the University Hospital of Cologne walked the audience through an explanation of one of the most controversial addiction treatment options of all, known as deep brain stimulation. For those unfamiliar with DBS, this surgical procedure uses implanted brain electrodes and a subdermal set of wires connected to a small power source to directly stimulate a designated area of the brain via electric current.  Deep brain stimulation (DBS) is becoming an established treatment option for some movement disorders, in particular Parkinson’s disease. It is also being investigated for obsessive–compulsive disorder, major depression, and Tourette’s syndrome.

Kuhn and his researchers, the first German group to investigate deep brain stimulation beginning in 2002, started by investigating Tourette’s and OCD. But soon, Kuhn said, it became clear that “valid animal studies show significant induced improvement in cocaine, morphine and alcohol addiction behavior following DBS of the nucleus accumbens…. the few patients who underwent DBS surgery for addiction remained abstinent or had a major reduction of relapses.” 

Carrie Wade and others at the Scripps Research Institute and Aix-Marseille University in France  electrically stimulated the subthalamic nucleus and got addicted rats to take less heroin and become less motivated for the task of bar pressing to receive the drug. Earlier work had demonstrated a similar effect in rats’ motivation for cocaine use. “This research takes a non-drug therapy that is already approved for human use and demonstrates that it may be an option for treating heroin abuse,” Wade said in a prepared statement.

Dr. Kuhn told the audience that DBS is a “focused neuromodulation procedure to enrich electrical activity” applied to certain brain regions and requiring only “minimally invasive” surgery. In the case of DBS surgery for addiction, which Dr. Kuhn has performed in clinical settings, the target is the nucleus accumbens, which Kuhn called “the key player in the so-called limbic reward loop.”

The problem is that these investigations, while positive in many cases, are small and scattered thus far, and do not represent a systematic investigation of the procedure by the field of neuroscience at large. Not yet, anyway. And maybe not ever. There are very few published studies on human addicts, Kuhn said, “but luckily, the ethical implications of DBS are being more and more discussed.”

Unfortunately, as Kuhn pointed out, “neurosurgical interventions in psychiatric patients raise ethical considerations not only based on the disreputable experiences of the era of psychosurgery.” But that’s a good starting point. The procedure, despite one’s best efforts, conjures up images of “psychosurgery”—prefrontal lobotomies, or early electroconvulsive shock therapy (ECT). It doesn’t help that the likeliest mechanism of action that explains DBS is that high frequency stimulation causes functional lesions at the specific brain sites. From almost every angle, it seems ham-handed and crude—until you see some videos of results, like this one of a Tourette’s patient: Video

Kuhn acknowledged that a number of medical professional believe DBS is a poor choice for addiction, and its use “is premature due to expenses, possible risks and the assumed poor scientific rationale of the method in this field.”  In a letter to the journal Addiction, Adrian Carter and Wayne Hall of the University of Queensland, Australia, noted that some of the positive reports come from China, where scientists have experimented with ablation of portions of the nucleus accumbens and other brain areas. And it seems to work. So, one cure for addiction has been discovered already—but surgically removing chunks of the midbrain isn’t likely to catch on, except as a seminar topic for medical ethicists. Carter and Hall call the evidence base for the safety and efficacy of DBS in addiction “weak,” and argue that “the addition of an expensive neurosurgical treatment that costs of the order of $50,000 will worsen this situation by utilizing scare health resources to treat a very small number of patients with the income to pay for it.”

In a history of “stereotactic lesions” as a treatment for movement disorders, researchers at The George Washington University School of Medicine and Health Sciences reviewed efforts to expand the use of DBS to include specific psychiatric disorders like depression and obsessive-compulsive disorders. Writing in the Journal of Neurosurgery in 2010, they concluded that “addiction and schizophrenia showed the least improvement from surgery. Therefore, pursuing the treatment of these disorders with DBS using the targets in these studies may be ineffective.”

The Neurotech Business Report recently documented that St. Jude Medical, a manufacturer of surgical devices, has shut down its clinical trial of DBS for depression (h/t Vaughan Bell). The company’s website said “The BROADEN (BROdmann Area 25 DEep brain Neuromodulation) Study” has been closed and is no longer enrolling participants. The article suggests that “the complexity of specifying the precise brain circuits involved with major depression” may have been the reason for halting the trial.

Known risks associated with deep brain stimulation placement include: dizziness, infection, loss of balance, and speech or vision problems. In addition, the devices, wires and leads that make up the system, which are all implanted in the brain or under the skin, can break or fail in various ways. DBS can also alter glucose metabolism and food intake in lab rats. Altogether, there are few case reports, and the mechanism of action remains essentially uncharacterized. In the case of addiction, this is one treatment that does not seem ready for prime time. It would be premature to move DBS beyond the clinical trial stage in humans without additional data.

Photo Credit: http://biomed.brown.edu

Drug Craving, or How to Be Your Own Worst Enemy

Plus the disease model, warts and all.

Bielefeld, Germany—

The second in an irregular series of posts about a recent conference, Neuroplasticity in Substance Addiction and Recovery: From Genes to Culture and Back Again. The conference, held at the Center for Interdisciplinary Research (ZiF) at Bielefeld University, drew neuroscientists, historians, psychologists, philosophers, and even a freelance science journalist or two, coming in from Germany, the U.S., The Netherlands, the UK, Finland, France, Italy, Australia, and elsewhere. The organizing idea was to focus on how changes in the brain impact addiction and recovery, and what that says about the interaction of genes and culture. The conference co-organizers were Jason Clark and Saskia Nagel of the Institute of Cognitive Science at the University of Osnabrück, Germany.  Part One is here.

Marc Lewis, a developmental neuroscientist who is currently professor of human development and applied psychology at Radboud University in The Netherlands, and who spent five days discussing addiction with the Dalai Lama and a small group of scientists, scholars, and addiction specialists in Dharamsala, India, last year, was a late but welcome addition to the speaker list at the conference.

Author of Memoirs of an Addicted Brain, and a self-confessed “drug addict turned neuroscientist,” Dr. Lewis always brings a thought-provoking dual perspective to his work on addiction. (See my review of his book here.) He also blogs here.

In Bielefeld, Dr. Lewis offered up a wide-ranging view of what addiction is and is not, linking neuroscience, psychology, and Buddhism in the process. 

Craving is “the one condition all addicts agree is their worst enemy,” Lewis said. “This is one place where science and subjectivity have to come together. Scientists need to focus on this, because addicts are completely unanimous about it. This is the enemy. It’s not physical withdrawal symptoms, it’s not relief. It is craving.”

Buddhism teaches that “craving is the fundamental engine of personality development,” Lewis said. “It’s what keeps us going around and around.” But if you don’t much like the notion of the wheel of reincarnation, Lewis suggested, then you can contemplate “the cyclical nature of how we repeat patterns in life that lead to suffering.”

“Craving is such an unpleasant state, that after a while, you end up doing it, you get the drugs. I did opiates, and I would spend hours and hours trying to sit on my hands, trying to watch something on TV, trying to go for a walk, and finally, there’s this thing that keeps rising in the background, and it doesn’t go away. It was a constantly growing tension, an anxiety and discomfort, that came from very deep down. You spend most of your energy trying to hold this thing at bay, and according to the ego depletion literature, you can’t do that for very long. These cognitive control centers just give up. They are limited resources.”

Craving is not a steady state. It grows. “Neuroscience helps us understanding why craving is so nasty.” Enter “delay discounting,” a term from behavioral economics used by several speakers during the conference. Delay discounting is the proposition that the perceived value of something rises steeply as the reward gets closer in time. A variation of this idea is seen in the classic marshmallow test for children: One marshmallow now, or two if you wait until later?

“Craving traps you in delay discounting,” said Lewis. “Immediate reward is worth more than imagined future happiness. The job of dopamine in the striatum is to increase the attractiveness or value of one goal, and to reduce the attractiveness and value of all the other goals. This is a brain that is well designed for addiction. You get tons of dopamine rising up in anticipation of reward. So you’re really stuck in the immediate. At which point you’ve effectively lost contact with the rest of your life. In the narrative of who you are, you can’t even include next week, or the next morning.”

Nonetheless, Lewis finds serious problems with the standard disease model of addiction, as championed by NIDA’s Nora Volkow and other in the NIH, however brain-based he may be. As a developmental neuroscientist, Lewis is predisposed to viewing the brain as a locus of change by definition. “The disease model uses brain change as a foundational premise. But brains change with development, anyway. And in fact, brains are designed to change.”

Any proper model of addiction, he insisted, has to correspond with what we know about brain change. “But it also has to correspond with addicts’ experiences. I was a drug addict from about age 25 to 30. I was in really bad shape. And now I talk with a lot of drug addicts, and one of the things that I keep hearing is that scientists and clinicians don’t really know what they’re doing—they don’t know where to go with it. They know that addiction is really nasty, but they don’t know what it’s like, unless they’ve been there.”

Lewis offered a view of addiction that shifts the semantic focus from disease to development. The drug is not the culprit. By reconceptualizing addiction as a developmental disorder, he suggested, we can move the debate forward into the world, where the action is:

Addiction results from accelerated learning, the acquisition of thought patterns that rapidly self-perpetuate because of the brain’s tendency to become sensitized to highly attractive rewards. This is a developmental process, accelerated by a neurochemical feedback loop that is particular to strong attractions. Like other developmental outcomes, addiction isn’t easy to reverse, because it’s based on synaptic restructuring. Like other developmental outcomes, it arises from neural plasticity, and uses it up at the same time.

And the mechanisms responsible are the same ones responsible for many things that involve desire, learning, reward seeking, and compulsive behavior—including the so-called behavioral addictions like overeating and compulsive sex. However, “the severe consequences of addiction don’t make it a disease, any more than the consequences of violence make violence a disease.”

In an email exchange after the conference, I followed up with Dr. Lewis on some of these matters, and he sent me the following additional thoughts on the “diseasing” of addiction:

Proponents of the disease model argue that addiction changes the brain. And they're right: it does. But the brain changes anyway, at every level, from gene expression, to cell density, to the size and shape of the cortex itself. Of course, neuroscientists who subscribe to the disease model must know that brains change over development. Their take on pathological brain change would have to be very specific in order to be convincing. For example, they would have to show that the kind (or extent or location) of brain change characteristic of addiction is nothing like that observed in normal learning and development. But this they cannot do. The kind of brain changes seen in addiction also show up when people take up rock collecting, fall in love, learn how to cook, or become obsessed with their appearance. The brain contains only a few major traffic routes for learning and goal seeking. And, like the main streets of a busy city, they are often under construction.  Brain disease may be a useful metaphor for how addiction seems, but it's not a valid explanation for how it actually works.

What is This Thing Called Neuroplasticity?

And how does it impact addiction and recovery?

Bielefeld, Germany—

The first in an irregular series of posts about a recent conference, Neuroplasticity in Substance Addiction and Recovery: From Genes to Culture and Back Again. The conference, held at the Center for Interdisciplinary Research (ZiF) at Bielefeld University, drew neuroscientists, historians, psychologists, philosophers, and even a freelance science journalist or two, coming in from Germany, the U.S., The Netherlands, the UK, Finland, France, Italy, Australia, and elsewhere. The organizing idea was to focus on how changes in the brain impact addiction and recovery, and what that says about the interaction of genes and culture. The conference co-organizers were Jason Clark and Saskia Nagel of the Institute of Cognitive Science at the University of Osnabrück, Germany.

One of the stated missions of the conference at Bielefeld’s Center for Interdisciplinary Research was to confront the leaky battleship called the disease model of addiction. Is it the name that needs changing, or the entire concept? Is addiction “hardwired,” or do things like learning and memory and choice and environmental circumstance play commanding roles that have been lost in the excitement over the latest fMRI scan?

What exactly is this neuroplasticity the conference was investigating? From a technical point of view, it refers to the brain’s ability to form new neural connections in response to illness, injury, or new environmental situations, just to name three. Nerve cells engage in a bit of conjuring known as “axonal sprouting,” which can include rerouting new connections around damaged axons. Alternatively, connections are pruned or reduced. Neuroplasticity is not an unmitigated blessing. Consider intrusive tinnitus, a loud and continuous ringing or hissing in the ears, which is thought to be the result of the rewiring of brain cells involved in the processing of sound, rather than the sole result of injury to cochlear hair cells.

The fact that the brain is malleable is not a new idea, to be sure. Psychologist Vaughn Bell, writing at Mind Hacks, has listed a number of scientific papers, from as early as 1896, which discuss the possibility of neural regeneration. But there is a problem with neuroplasticity, writes Bell, and it is that “there is no accepted scientific definition for the term, and, in its broad sense, it means nothing more than ‘something in the brain has changed.’” Bell quotes the introduction to the science text, Toward a Theory of Neuroplasticity: “While many scientists use the word neuroplasticity as an umbrella term, it means different things to different researchers in different subfields… In brief, a mutually agreed upon framework does not appear to exist.”

So the conference was dealing with two very slippery semantic concepts when it linked neuroplasticity and addiction. There were discussions of the epistemology of addiction, and at least one reference to Foucault, and plenty of arguments about dopamine, to keep things properly interdisciplinary. “Talking about ‘neuroscience,’” said Robert Malenka of Stanford University’s Institute for Neuro-Innovation and Translational Neurosciences, “is like talking about ‘art.’”

What do we really know about synaptic restructuring, or “brains in the wild,” as anthropologist Daniel Lende of the University of South Florida characterized it during his presentation? Lende, who called for using both neurobiology and ethnography in investigative research, said that more empirical work was needed if we are to better understand addiction “outside of clinical and laboratory settings.” Indeed, the prevailing conference notion was to open this discussion outwards, to include plasticity in all its ramifications—neural, medical psychological, sociological, and legal—including, as well, the ethical issues surrounding addiction.

Among the addiction treatment modalities discussed in conference presentations were optogenetics, deep brain stimulation, psychedelic drugs, moderation, and cognitive therapies modeled after systems used to treat various obsessive-compulsive disorders. Some treatment approaches, such as optogenetics and deep brain stimulation, “have the potential to challenge previous notions of permanence and changeability, with enormous implications for legal strategies, treatment, stigmatization, and addicts’ conceptions of themselves,” in the words of Clark and Nagel.

Interestingly, there was little discussion of anti-craving medications, like naltrexone for alcohol and methadone for heroin. Nor was the standard “Minnesota Model” of 12 Step treatment much in evidence during the presentations oriented toward treatment. The emphasis was on future treatments, which was understandable, given that almost no one is satisfied with treatment as it is now generally offered. (There was also a running discussion of the extent to which America’s botched health care system and associated insurance companies have screwed up the addiction treatment landscape for everybody.)

It sometimes seems as if the more we study addiction, the farther it slips from our grasp, receding as we advance. Certainly health workers of every stripe, in every field from cancer to infectious diseases to mental health disorders, have despaired about their understanding of the terrain of the disorder they were studying. But even the term addiction is now officially under fire. The DSM5 has banished the word from its pages, for starters.

Developmental psychologist Reinout Wiers of the University of Amsterdam used a common metaphor, the rider on an unruly horse, to stand in for the bewildering clash of top-down and bottom-up neural processes that underlie addictive behaviors. The impulsive horse and the reflective rider must come to terms, without entering into a mutually destructive spiral of negative behavior patterns. Not an easy task.

Who Smokes Dope, And How Much?

Marijuana stats skew perceptions of use.

Most statistical surveys of marijuana focus on a single quantitative measurement: How many people are using? But there’s a problem: More marijuana use does not necessarily translate into more marijuana users. And that’s because a clear majority of the consumption, and black market dollars, come from the heaviest smokers.

Drug policy researchers at the RAND corporation decided that frequency of use and amount of consumption were valuable parameters gone missing in most policy discussions. So they put the focus not just on use, but also on “use-days,” and pulled a number of buried tidbits from a very big data pile. If you zero in on consumption, and not just consumers, they insist, you will find a wholly different set of inferences.

For example: “Although daily/near-daily users represented less than one-quarter of past-month cannabis users in 2002 and roughly one-third of past-month users in 2011, they account for the vast majority of use-days and are thus presumably responsible for the majority of consumption,” write Rachel M. Burns and her RAND colleagues in Frontiers of Psychiatry. As with alcohol, the majority of cannabis consumption can be accounted for by a minority of users. The heaviest users, the upper 20 percent, consume 88 percent of the U.S. marijuana supply, say the RAND researchers. “Furthermore, if over time there were no change in the number of cannabis users, but the ratio of light vs. heavy users switched from 80/20 to 20/80, then consumption would increase by 250% even though there was no change whatsoever in the number of users.”

The RAND group used two data sets on cannabis consumption—the National Survey on Drug Use and Health (NSDUH) in the U.S., and the EU Drugs Markets II (EUMII) in Europe. Data included figures for past-year and past-month use, past-month use days, and past-month purchases.

Other intriguing figures come to light when you study cannabis use, as opposed to cannabis users. The researchers declared that “only 14% of past-year cannabis users [primarily males] meet the criteria for cannabis abuse or dependence, but they account for 26% of past-month days of use and 37% of past-month purchases.”

Happen to smoke blunts? That turns out to be very telling, according to the RAND study. “Perhaps the most striking contrast concerns blunts. Only 27% of past-year cannabis users report using a blunt within the last month, but those individuals account for 73% of cannabis purchases.” Casual users, it seems, don’t do blunts.

Clearly, it takes a lot of casual users to smoke as much marijuana as one heavy user. But exactly how many? The RAND researchers ran the numbers and concluded that, in terms of grams consumed per month, it would take more than 40 casual smokers to equal the intake of a single heavy user. The share of the market represented by daily/near-daily users is clearly the motive force in their analysis.

The study in Frontiers in Psychiatry also found patterns of interest on the buy side. General use took an upswing beginning in 2007. While the probability of arrest per marijuana smoking episode hovers somewhere in the neighborhood of 1 in 3,000, everything changes if you are purchasing cannabis. RAND reported that young people collectively make more purchases per day of reported use than do older users. Therefore, “statistics indicating that the burden of arrest falls disproportionately on youth relative to their share of all users may not be prima facie evidence of discrimination if making more purchases per day of use increases the risk of arrests per year of use.” Once again, those aging Baby Boomer potheads get the best deal. They have more money with which to buy bigger amounts less often, thereby greatly lessening their chances of arrest and prosecution.

This also applies to minority arrests for marijuana offenses. “Non-Hispanic blacks represent 13% of past-year cannabis users vs. 23% of drug arrests reported by those users, but they report making 24% of the buys. Thus, some of their higher arrest rate may be a consequence of purchase patterns… African-Americans may not only make more buys but also make riskier buys (e.g., more likely to buy outdoors).”

The researchers were able to draw some conclusions about the growth in marijuana usage from 2002 through 2011, based on the NSDUH data. Their main conclusion, after exploring the demographics of this 10-year record of use, is that “consumption grew primarily because of an increase in the average frequency of use, not just because of an increase in the overall number of users.”  The driver of consumption turns out to be… greater consumption. And that increased consumption is coming from… older adults. Those older adults, it turns out, are smoking more weed.

The shift is dramatic: “In 2002, there were more than three times as many youth as older adults using cannabis on a daily/near-daily basis; in 2011 there were 2.5 times more older adults than youth using on a daily/near-daily basis.” The record of alcohol and cigarette use over the same period showed no such inversion of use patterns.  And the tweeners? “In 2002, 12-17-year-olds represented 13% of daily/near-daily users; in 2011, that had dwindled to 7%.” These trends are not just the obvious result of an increase in the proportion of older adults in the population at large. Increases in the proportion of older heavy cannabis users were much greater than the general population drift.

Among the questions raised by the RAND analysis:

— Are older marijuana smokers primarily recreational, or medicinal?

—Do increased use days among older, college-educated marijuana smokers indicate greater social acceptance, or something else?

—Are younger people replacing traditional cannabis use with other substances?

—Why did Hispanic use increase more over the study period than other ethnic groups?

Burns R.M., Caulkins J.P., Everingham S.S. & Kilmer B. (2013). Statistics on Cannabis Users Skew Perceptions of Cannabis Use, Frontiers in Psychiatry, 4   DOI: 10.3389/fpsyt.2013.00138

Photo Credit: http://www.sho.com/sho/weeds/home