Commentaries BREAKING UP WITH YOUR DRUG CAN BE HARD TO DO, BUT IS IT MAINLY BECAUSE COMPULSIVE BEHAVIOR INVOLVES SPECIFIC BRAIN REGIONS?

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1 Commentaries BREAKING UP WITH YOUR DRUG CAN BE HARD TO DO, BUT IS IT MAINLY BECAUSE COMPULSIVE BEHAVIOR INVOLVES SPECIFIC BRAIN REGIONS? Reading Lubman et al. (2004) stirred a memory. Years ago, The Royal Society of Canada convened a committee at the request of Health and Welfare Canada to consider whether nicotine in cigarettes was addictive (Kalant et al. 1989). Fortunately the chair of this committee was the distinguished Harold Kalant who had the experience of decades of working on prominent international committees (e.g. for the World Health Organization) concerned with the definition of drug dependence and addiction. (LTK also served on this RSC committee). The beginning of this report benefited especially from Kalant s experience with historical changes in terminology and definitions. It was judged that Earlier definitions of drug addiction have evolved over the past 40 years, in the direction of diminishing emphasis on tolerance and physical dependence as defining features of addiction, and growing emphasis on the behavioural aspects of compulsive drug-seeking and drug-taking, reinforced by the psychoactive effects of the drug, and on the great difficulty in cessation of drug-taking and the high probability of relapse (p. v). The definition was: Drug addiction is a strongly established pattern of behaviour characterized by (1) The repeated selfadministration of a drug in amounts which produce reinforcing psychoactive effects, and (2) great difficulty in achieving voluntary long-term cessation of such use, even when the user is strongly motivated to stop. (p. v) This definition might be shortened to: a drug use that is difficult to stop. Part of our intent was to avoid terms like withdrawal, psychological dependence, and physical dependence because of their unclear relationship to the underlying fact of difficulty in stopping. At the time we expressed reluctance to employ the imprecise and mechanistically questionable term compulsive. Now, almost 15 years later, developments in brain imaging and neuroscience and progress in research on obsessive-compulsive disorder may have increased precision and have made it less questionable to explore what it means to say that addiction is a form of compulsive behavior, and there may be a promising idea of which brain regions are involved. In pursuing this program of research we would ask for more work to clarify what comes first the addictive behavior or the brain dysfunction. We would also encourage a re-reading of an even older paper in addiction research. Did Lee Robins famous US soldiers who were addicted to heroin in Vietnam, but not when they returned home, have their brains (now their prefrontal cortexes) hi-jacked in South- East Asia, but freed in the US (Robins 1973)? Would longitudinal studies of changes in inhibitory brain dysfunction in these soldiers have helped explain this effect or were broader ecological issues more likely at play? Advancing our understanding of addiction will probably benefit from models that include measures of context as well as brain. LYNN T. KOZLOWSKI & BETH QUINIO EDWARDS Program in Biobehavioral Health 210 Health and Human Development East Pennsylvania State University University Park Pennsylvania USA ltk1@psu.edu Kalant, H., Clarke, P. B. S., Corrigall, W. A., Ferrence, R. G., Friedland, M. L. & Kozlowski, L. T. (1989) The Royal Society of Canada/La Société royale du Canada. Tobacco, Nicotine, and Addiction: A Committee Report. Health and Protection Branch, Health and Welfare Canada. of compulsive behaviour? Neuroimaging and neuropsychological evidence of inhibitory dysregulation. Addiction, 99, Robins, L. N. (1973) A Follow-Up of Vietnam Drug Users. Special Action Office Monograph, Series A, no. 1. Washington, DC: Executive Office of the President Society for the Study of Addiction doi: /j x Addiction, 99,

2 1504 Commentaries Blackwell Science, LtdOxford, UKADDAddiction Society for the Study of Addiction99Original Article ADDICTION AND THE SEARCH FOR INTEGRATED THEORY A lot has happened since the findings of Olds & Milner (1954), which represented a milestone in neurobiological addiction research. Year after year, interesting new studies are being published, each of which can contribute to our understanding of addiction. At present, the models such as biologically determined dysfunction, disposition and neuroadaptation coexist in the literature. In this context, the efforts of Lubman et al. (2004) to bring together numerous findings neuroadaptations and sensitisation of the dopaminergic reward system, evolution of drug cues and malfunction or dysfunction of the inhibitory function and to create an integrated model are admirable. The authors explored whether compulsive behaviour is a result of dysregulation of inhibitory control or an overregulated activating and reinforcing system. We must admit that our limited understanding of addiction contributes to weaknesses in current neurobiological research. The discrepant conceptualisations of addiction, particularly our predominantly syndromal definitions found in DSM IV and ICD 10, complicates research population selection, and may thus conceal important etiological differences within an addiction population. Ultimately, the complexity of addiction research may not only stem from our inadequate understanding of possible interconnections but also from the idea that addiction may be the final outcome of various pathogenic mechanisms. The multiple pathways hypothesis may explain why findings from animal research may not be applied successfully to human behaviour. The fact that addictive behaviour is expressed in the context of widely differing psychiatric disorders, may be an indicator of the multiplicity of underlying reasons. These observations then beg the question, what is the purpose of neurobiological research? Is it just developing an animal model of addiction or does it aid in the development of new therapies for addicted humans? Do the results replace a moral model of addiction with scientific information that may pave the way patients shed feelings of guilt, thus paving the way for successful treatment? The authors drew an insightful connection between the neurobiological results concerning the inhibitory system and therapeutic strategies which may address patients ability to cope with the craving. It is, however, doubtful whether these links can be oversimplified to that extent. It is also not clear whether craving can be understood as a psychological dimension or purely as the result of biological mechanisms. This uncertainty suggests, understandably, recourse to pharmaceutical strategies to influence the craving. At the same time, primary effects of substances on the dopaminergic system, secondary neuromodulation, and inadequate inhibitory facilities cannot be imagined without the psychological dimensions of the human experience, which are represented by way of reward expectation, life events, skills and self-consciousness. The question remains: are the findings from animal research transferable to humans? Can human addiction be projected biologically? Or is the neural basis of addiction mediated by reward expectations, cognitive attitudes, abilities and behavioural components, which are rooted in and formed by the social environment? Many such questions have been subjectively and controversially answered by researchers, therapists, psychologists, biologists and medical doctors on the basis of their individual experience, but there is as yet no consensus. The hope remains that an integrated conceptualisation concept of addiction, based on biological, social and psychological findings may lead to better understanding of addiction and the enhancement of the efficacy of existing therapies. ANIL BATRA University Hospital of Tuebingen Department of Psychiatry and Psychotherapy Osianderstrasse 24 D Tuebingen Germany anil.batra@med.uni-tuebingen.de Lubman, D. I., Yucel, M. & Pantelis, C. (2004) Addiction, a condition of compulsive behavior? Neuroimaging and neuropsychological evidence of inhibitory dysregulation. Addiction, 99, Olds, J. & Milner, P. (1954) Positive reinforcement produced by electrical stimulation of septal area and other regions of the rat brain. The Journal of Comparative and Physiological Psychology, 47, LET S NOT BE IMPULSIVE: COMMENTS ON LUBMAN ET AL. (2004) In their provocative review, Lubman et al. (2004) propose that dysfunction of inhibitory control systems in the brain is a core feature of the study for substance abuse. There is substantial merit in this concept. Once stated, it appears obvious that an impaired ability to suppress one s behavior would lead to excessive drug use, so it is surprising how little research there has been in this area. But it is precisely because this approach has such a strong intuitive appeal that it is in danger of being tautological, i.e. that the definition becomes the solution. In fact, it is in the definition of the problem wherein lie the greatest

3 Commentaries 1505 challenges to obtaining sound empirical support for this hypothesis. Inhibitory control is the third major paradigm in investigation of the neuronal basis of addiction. The first paradigm was withdrawal and the second was positive reinforcement. Yet each of these paradigms has something that the inhibitory control framework currently lacks: a clearly defined operational definition and experimental implementation (e.g. abstinence signs and symptoms, drug self-administration). Unlike the prior models of addiction, inhibition is both a subject of scientific inquiry and regular part of everyday conversation. To paraphrase William James famous comment regarding attention, everyone knows what inhibition is. Unfortunately everyone may have a different meaning for inhibition. Putting aside the connotations of morality and character often conveyed when loss of inhibition is used in everyday speech, the major impediment to the scientific study of inhibitory control at this time is the diversity of competing definitions and approaches. Starting with the title, the authors tend to use terms such as loss of inhibition, impulsive and compulsive interchangeably. However, there are reasons to consider that these terms are not identical, but rather may represent anchors on a continuous dimension. If so, then seemingly similar pathological repetition of behavior may be due to entirely different dysfunctions, and therefore may require entirely different treatment approaches. Hollander & Rosen (2000) have proposed that avoidance of harm underlies compulsive behavior whereas during impulsive behavior, harmful consequences are ignored and/or there is excessive attention on positive consequences. Hollander and Rosen s approach provides an entry point for designing studies to determine more precisely what type of dysfunction underlies the loss of control of drug use that characterizes addiction. Beyond issues of definition are the problems of measurement. The construct of impulsivity is a good example. There have been numerous studies using psychometric instruments to study impulsivity as a normal personality factor. Clinical criteria exist for diagnosing pathological aspects of impulsivity. There are also a variety of behavioral, cognitive and even economic tasks that can be used to gauge impulsivity in humans and animals. The problem is that there is not a consistent pattern of agreement across these measures, in that an individual may be considered impulsive by some measures, and not impulsive at all by other measures. Thus, it is becoming increasingly apparent that impulsivity is not a monolithic function. Rather, it is likely that taxonomy of impulsivity will eventually emerge, similar to what has developed for other broad psychological functions such as attention, memory, and emotion. As impulsivity becomes better defined, it is likely that only a subset of processes related to impulsivity will be related to addiction. The problem of specificity also exists at the neurobiological level. The authors cite studies implicating the anterior cingulate and orbitofrontal cortex in both inhibitory control and obsessive-compulsive disorder. However, both the anterior cingulate and orbitofrontal cortex are now known to be heterogeneous neuronal structures, with studies in both animals and humans beginning to delineate the functional differences between sub-regions of the frontal lobe (cf. reviews in Cavada & Schultz 2000). Attending to such regional differentiations may be especially critical when applying these findings to specific aspects of addiction (Kaufman et al. 2003; Fuchs et al. 2004). In summary, there is great merit using dysfunction of inhibitory control as a conceptual framework to guide addiction research. However, the current lack of agreement regarding the definition and measurement of the critical psychological constructs, let alone their neurobiological counterparts, represent significant challenges in conducting research that can be translated into effective methods to prevent and treat drug addiction. STEVEN GRANT Clinical Neurobiology Branch Division of Clinical Neurobiology, Development and Treatment Research National Institute on Drug Abuse National Institutes of Health, HHS 6001 Executive Blvd Bethesda MD USA sgrant@nida.nih.gov Cavada, C. & Schultz, W., eds. (2000) Special issue: The mysterious orbitofrontal cortex. Cerebral Cortex, 10, Fuchs, R. A., Evans, K. A., Parker, M. P. & See, R. E. (2004) Differential involvement of orbitofrontal cortex subregions in conditioned cue-induced and cocaine-primed reinstatement of cocaine seeking in rats. Journal of Neuroscience, 24, Hollander, E. & Rosen, J. (2000) Impulsivity. Journal of Psychopharmacology, 14, S39 S44. Kaufman, J. N., Ross, T. J., Stein, E. A. & Garavan, H. (2003) Cingulate hypoactivity in cocaine users during a GO NO GO task as revealed by event-related functional magnetic resonance imaging. Journal of Neuroscience, 23, of compulsive behavior? Neuroimaging and neuropsychological evidence of inhibitory dysfunction. Addiction, 99,

4 1506 Commentaries ADDICTION, DISINHIBITION, IMPULSIVITY, COMPULSIVITY: WHAT S THE DIFFERENCE, WHY DOES IT MATTER AND WHAT IS THE ROLE OF CONTEXT? The commentaries by Batra (2004), Grant (2004) and Kozlowski & Edwards (2004) highlight the importance of efforts that attempt to bridge findings across research areas into an integrated model, and suggest that there is substantial merit in using dysfunction of inhibitory control as a conceptual framework to guide addiction research. However, the commentaries also raise a number of important questions and issues about the lack of precision regarding the definition, measurement and neurobiological correlates of such psychological constructs, as well as the role of context. We know that some drugs appear to be more addictive in certain societies/environments, in certain individuals, at certain times. This is another way of saying that addiction is a complex and multifaceted condition involving factors internal to the individual (neurobiological; such as genetics, neurochemistry, cognitiveaffective regulation, personality) and factors external to the individual (contextual; such as environmental, cultural, spiritual, situational). As such, we strongly support the suggestion that context has an important role in the addictive process. We would argue that neurobiological vulnerabilities set the stage for psychopathology, but they by no means determine its onset, nature and course. In support of this, we know that neurobiological vulnerabilities expressed in different contexts often lead to vastly different outcomes. An example of this might be that only 6% of American soldiers who had used heroin in Vietnam became re-addicted three years after returning to the United States of America, despite 75% feeling that they had been addicted in Vietnam (Robins 1993). However, heroin was certainly more available and acceptable in Vietnam, and the relative consequences of ongoing use (in the face of a constant external threat) were likely to be much less severe than on return to the USA. This suggests that ongoing drug use in certain contexts does not necessarily equate to intractable addiction, but rather addiction should include the notion of continued use in the face of severe adverse consequences that far outweigh the benefits of using. In fact, the strongest predictors of continued use on return to the USA were preservice use of drugs and the extent of drug use in Vietnam, suggesting that the aetiology of addictive behaviour is unlikely to be found in the study of context alone. Thus, the construct is multidimensional, involving psychological and contextual/environmental factors, in addition to key neurobiological aspects. The future success of research in this area demands integration of studies that are relevant to both the internal/neurobiological characteristics of the individual as well as their context, and will require the collaboration of scientists across disciplines. In our review (Lubman et al. 2004), we offer an integrated framework from a neuroscience perspective, but acknowledge that greater effort is required to bridge the gap between this field and other areas of science, and support research agendas that are more integrated. We also agree that greater attention needs to be paid to the definition of inhibition (or disinhibition ) and its measurement an issue that also needs to be reflected in neurobiological studies that attempt to identify associated brain substrates/regions (and subregions). As highlighted in the commentary, this has significant implications, as a pathological repetition of behaviour may be due to entirely different psychological dysfunctions, with different underlying neurobiological correlates, requiring different treatment approaches. However, we believe that the issue is even more complex, in that the problem of definition and measurement exists not only at the behavioural level, but also across different levels of central nervous system functioning (e.g. does inhibition mean the same thing at a cellular, neurophysiological, neurochemical or functional/metabolic level?), as well as across development (e.g. understanding the normative course of inhibitory development). Such issues have significant implications for the integration of findings from across multiple levels of central nervous system functioning, for understanding the evolution of addictive behaviour, and for designing novel approaches to prevention and treatment across the lifespan, including early intervention strategies. It remains a challenge both within and across different fields of research, as well as across development, to reach consensus around issues of definition and measurement of terms such as inhibition. This is a challenge that we wrestled with in our review, and which requires additional work to resolve. Such efforts (which include those of Evenden 1999; Hollander & Rosen 2000; Moeller et al. 2001) are likely to lead to better designed studies, yielding more accurate and robust findings that can be translated more readily into effective methods to prevent and treat drug addiction. Moreover, better definitions and measurement of processes such as inhibition, impulsivity and compulsivity may also provide an alternative dimensional or phenomenological means to studying aetiology that avoids the limitations of current syndromal definitions that may be relevant to not only addiction, but other comorbid psychiatric conditions (where inhibitory dysfunction is also implicated e.g. conduct disorder, bipolar disorder, schizophrenia and a number of personality disorders).

5 Commentaries 1507 DR MURAT YÜCEL 1,2,3, DR DAN I. LUBMAN 1,2 & PROFESSOR CHRISTOS PANTELIS 2 1 Substance Use Research and Recovery Focused (SURRF) Program ORYGEN Research Centre murat.yucel@wh.org.au 2 Melbourne Neuropsychiatry Centre Department of Psychiatry University of Melbourne 3 Mental Health Research Institute (MHRI) Victoria Australia Batra, A. (2004) Addiction and the search for integrated theory. Addiction, 99, Evenden, J. L. (1999) Varieties of impulsivity. Psychopharmacology., 146, Grant, S. (2004) Let s not be impulsive: comments on Lubman et al. (2004). Addiction, 99, Hollander, E. & Rosen, J. (2000) Impulsivity. Journal of Psychopharmacology., 14, S39 S44. Kozlowski, L. & Quinio Edwards, B. (2004) Breaking up with your drug can be hard to do, but is it mainly because compulsive behavior involves specific brain regions? Addiction, 99, of compulsive behaviour? Neuroimaging and neuropsychological evidence of inhibitory dysregulation. Addiction, 99, Moeller, G. F., Barratt, E. S., Dougherty, D. M., Schmitz, J. M. & Swann, A. C. (2001) Psychiatric aspects of impulsivity. American Journal of Psychiatry, 158, Robins, L. N. (1993) Vietnam veterans rapid recovery from heroin addiction: a fluke or normal expectation? Addiction, 88,