Integrating the Science of Addiction Into Psychiatric Practice

United States

Introduction

Integrating the Science of Addiction Into Psychiatric Practice was a special research-based program track between NIDA and APA, and was presented at APA’s 157th Annual Meeting. Recent epidemiologic studies show that between 30 and 60 percent of drug abusers have concurrent mental health diagnoses. The nearly 30 NIDA-supported sessions featured in this track, including 7 major lectures, addressed an array of topics linked to mental illness and drug abuse. These topics included stress, trauma, and drug abuse; obesity and addiction; smoking and comorbid mental disorders; and attention deficit hyperactivity disorder (ADHD) and drug use.

ADHD Subtypes and Subgroups at Risk for Substance Use Disorders

During this section of the program, presenters discussed relationships between childhood and adolescent ADHD and substance use disorders.

ADHD Subtypes and Subgroups at Risk for Substance Use Disorders

Naimah Weinberg, M.D.

Summary

Dr. Naimah Weinberg, as chair of this session, opened the discussion with a brief presentation outlining the relationship between substance use disorders (SUD) and ADHD. Weinberg began by distinguishing between SUD and substance use, and moved to examining the implication that ADHD is indeed a risk factor for SUD. She pointed out that the limitations of existing clinical studies and reports weaken the suggested link between ADHD and SUD, and stressed that further, more encompassing studies are needed to disentangle the etiologic role of ADHD in risk for drug abuse.

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Subtypes of ADHD Youth at Risk for Substance Abuse

Timothy E. Wilens, M.D.

Summary

Dr. Timothy Wilens evaluated existing literature depicting the developmental relationship of substance use disorders (SUD) in ADHD males and females. Prospective studies of boys, girls, and their siblings and parents as well as retrospective studies of adults with ADHD were evaluated for the relationship between SUD and ADHD. Specific developmental issues, with an emphasis on the role of psychiatric comorbidity, were evaluated, as well as data from epidemiologic and clinic samples. Wilens showed that studies of ADHD children and adults demonstrate an increased risk of SUD in those with persistent ADHD, and that psychiatric comorbidity with conduct disorder continues to be the most robust risk factor for SUD in ADHD. ADHD with comorbid bipolar disorder also poses a major risk for SUD.

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Childhood ADHD, Comorbidity, and Risk for Late-Adolescent Drug Abuse

Ken C. Winters, Ph.D.

Summary

Dr. Ken Winters presented findings from a young adult (mean age 20) followup assessment as part of the University of Minnesota ADHD Prospective Study. Community-recruited ADHD and control children were regularly assessed during an 8-year span. Winters’ presentation focused on the drug use behavior outcomes of the subjects with respect to several measures of drug use behaviors, including SUDs. The findings indicated reliable elevations in drug use behaviors for the ADHD + Externalizing group when compared with controls, but no group differences were found for the other comparisons (ADHD alone vs. controls and ADHD + Internalizers vs. controls). Implications of the findings in light of the community-based ADHD sample also were discussed.

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Developmental Twin Studies of Relations Between Substance Use and ADHD

James J. Hudziak, M.D.

Summary

Dr. James Hudziak combined two approaches, a developmental twin study of 25,000 Dutch twin pairs followed since birth to determine the contributions of maternal smoking and drinking behavior to offspring with ADHD, ODD, and other psychopathologies; to determine the genetic and environmental contributions to these phenotypes; and lastly, to determine the stability of these behavioral problems across the 12 years of development. The MOTWIN data set was presented in order to shed light on the relations between ADHD and its subtypes and substance use. Data also were presented that indicate natural age of onset for substance use behavior and how inattention, delinquency, and aggressive behavior problems of childhood both precede and predict later substance use behavior.

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Variability in Risk for Substance Use and Disorder Among Children Diagnosed with ADHD

Brooke S.G. Molina, Ph.D.

Summary

Dr. Brooke Molina addressed questions regarding the persistent risk of vulnerability to adult substance use for those diagnosed with ADHD in childhood. She reported results from her team’s longitudinal study on children with ADHD (Pittsburgh ADHD Longitudinal Study, Co-Pls Molina and William E. Pelham, Jr., Ph.D., funded by NIAAA/NIDA), in which they followed more than 350 children diagnosed with ADHD and 240 without ADHD through adolescence into early adulthood. Unique features of this study include a wealth of standardized and objective childhood data that characterize the probands in childhood, a large sample size that allows previously underpowered examinations of comorbidity, and a comprehensive assessment at followup of alcohol, tobacco, and drug use/disorder through adolescence and early adulthood with annual interviews. Molina reported variability in characteristics in their sample and relations to risk for later substance-related outcomes such as frequency and quantity of consumption and substance-related impairment. Implications for clinicians and future research also were discussed.

[Slides not available.]

Behavioral and Cognitive Predictors of Adolescent Substance Use in Children with ADHD

Jeffrey M. Halperin, Ph.D.

Summary

Children with ADHD are at heightened risk for substance use during adolescence. However, the degree to which this association is specific to ADHD or whether it is more closely linked to (1) the presence of early conduct disorder (CD); (2) the persistence of CD into adolescence; and/or (3) the manifestation of ADHD symptoms during adolescence remains unclear. Further, it is unknown how this risk is affected by level of cognitive function. Dr. Jeffrey Halperin presented data from an ongoing longitudinal study of youth who were evaluated and diagnosed with ADHD combined type, when they were 7 to 11 years old. These patients, along with controls, are being re-evaluated at age 16 to 21 years. Preliminary analyses indicate that adolescent substance use in ADHD is best accounted for by an interaction between early CD and Full Scale IQ. Among patients with ADHD + CD, those with high IQ scores were most likely to use drugs and alcohol. In contrast, among those without early CD, increased adolescent substance use was associated with low IQ scores.

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Long-Term Followup of Childhood ADHD: Development of Adult Substance Abuse

F. Xavier Castellanos, M.D.

Summary

Dr. F. Xavier Castellanos presented study results consistent with basic science studies suggesting that low doses of methylphenidate may have enduring effects, which are greatest in younger individuals. From 1970 to 1977, 226 cross-situationally hyperactive children were enrolled in a long-term followup study after undergoing standardized treatment with methylphenidate. Based on data available for 171 male probands and 178 male contemporaneously recruited comparisons, Castellanos’ team observed significantly greater rates of substance abuse in probands, along with a significant relationship between age of first treatment with stimulants and the lifetime prevalence of drug abuse disorders (OR=2.3; p=.01). Younger age at first treatment predicted lower risk, independently of potential confounds such as severity of hyperactivity, social class, or intelligence. In an independent sample of children and adolescents with ADHD who had longitudinal anatomic MRI scans, Castellanos observed strikingly low white matter volumes in previously untreated ADHD children, and an apparent increase in white matter volume in those children once they began stimulant treatment.

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Anticraving Medication: A New Class of Psychoactive Medication?

This part of the program focused on the newly emerging phenomenon of medications that suppress drug cravings, thus improving the outcome of addiction therapies.

Charles P. O’Brien, M.D., Ph.D.

Summary

Basic and clinical data show that repeated drug use produces changes in the brain that are represented by learned responses to drug-related cues. Numerous studies have shown that cues previously associated with drug taking can act as conditioned stimuli and produce reflexive changes in former drug users. Many of these changes are perceived as compulsive drug craving. Medications have now been discovered that suppress craving and lead to an improved treatment outcome, although the mechanism of this compulsive drug craving is poorly understood. Dr. Charles O’Brien suggests that the empirical finding from clinical trials of craving-suppression by specific medications may signal a new class of medications available to the psychiatrist.

[Slides not available.]

Signal Integration in the Brain

The presenter in this portion of the program discussed the molecule DARPP-32, which plays an essential role in mediating the actions and interactions of numerous neurotransmitters, therapeutic agents, and drugs of abuse in many brain regions.

Paul Greengard, Ph.D.

Summary

Dr. Paul Greengard stated that a major step forward in his team’s attempts to discern how dopamine achieves its affects was the discovery of the molecule dopamine and cAMP-regulated phospho-protein, MW=32kDa (DARPP-32). The researchers discovered that DARPP-32 is involved in mediating the actions of virtually all neurotransmitters in all parts of the brain. According to Dr. Greengard, virtually every known drug of abuse works through DARPP-32. Greengard offered as evidence that fact that, in his team’s research, mice from which the researchers removed DARPP-32 no longer responded to drugs of abuse. Substances they studied included opiates, cocaine, and amphetamines. The same response was observed when antipsychotic medications were tested.

[Slides not available.]

Behavioral Treatments for Drug Dependence

In this section, researchers presented several behavioral counseling methods for treating substance abuse and their rates of efficacy.

Durability of Cognitive-Behavioral Therapy Efficacy for Substance Abusers

Bruce J. Rounsaville, M.D.

Summary

Dr. Bruce Rounsaville reviews the evidence for Cognitive Behavioral Therapy’s (CBT) enduring effects, presents findings on the potentially mediational role of homework completion and skill acquisition, and proposes strategies for maximizing the efficacy of CBT. Based on social learning theories of substance use disorders, CBT focuses on implementation of effective coping skills for recognizing, avoiding, and coping with situations that increase risk of drug use. CBT’s efficacy is supported by randomized clinical trials of patients with dependence on alcohol, nicotine, cocaine, and marijuana. A particularly distinctive CBT characteristic is that benefits appear not only to be durable but to become stronger after treatment ends. Rounsaville suggests that efficacy may be enhanced by augmenting CBT with contingency management interventions focused on treatment retention and homework compliance.

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HIV Risk Reduction and Substance Abuse Treatment

George E. Woody, M.D.

Summary

Dr. George Woody’s presentation reviewed studies showing that behavioral treatments for persons with a wide range of substance use disorders reduce HIV risk. Behavioral treatments explored include: individual drug counseling, group drug counseling, cognitive therapy, and supportive-expressive therapy. Studies have consistently shown that methadone maintenance reduces HIV risk. The contribution of drug counseling and psychotherapy beyond that achieved with methadone alone has not been well studied but it would be expected to have additional effects. No effective pharmacotherapy is available for cocaine, amphetamine, or other stimulant dependence, but behavioral treatments, particularly drug counseling, have been shown to be associated with reductions in HIV risk behavior, mainly due to reduction in unprotected sex. HIV-risk reduction in alcohol treatment has not been well studied but reduction in unprotected sex is likely.

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Low-Cost Contingency Management in Community Settings

Nancy M. Petry, Ph.D.

Summary

Dr. Nancy Petry presented a series of studies demonstrating the efficacy of contingency management when implemented with a range of substance abusing patients in community-based treatment settings. Specifically, studies comparing the voucher and prize systems were described, as well as studies evaluating magnitudes of prize reinforcers and the adaptation of this technique for use in group treatment format. In addition, studies comparing different targets of reinforcement (drug abstinence, compliance with goal-related activities, and attendance at treatment) were reviewed.

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Cognitive-Behavioral Therapy and Naltrexone for Cocaine Dependence

Joy M. Schmitz, Ph.D.

Summary

Dr. Joy Schmitz evaluated the effects of naltrexone (NTX) and cognitive-behavioral therapy (CBT) for cocaine dependence (Study 1) and cocaine-alcohol dependence (Study 2). Both studies utilized a full factorial design in which randomized subjects received one of four treatment conditions for 12 weeks: NTX and CBT; NTX and drug counseling (DC); placebo and CBT; placebo and DC. NTX was 50mg per day or a matching placebo, administered in double-blind fashion. The CBT focused on coping skills training and relapse prevention, while the DC emphasized education and support. Results from Study 1 revealed a significant three-way interaction (time X medication X therapy), suggesting less cocaine use over time among subjects receiving CBT and 50mg NTX. In contrast, Study 2 results suggested initial improvement in the CBT (vs. DC) group, but failed to support a medication effect. Together, these studies address the potential value and limitations of combined NTX-CBT treatment.

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Behavioral Family Counseling and Naltrexone Compliance for Male Opioid-Dependent Patients

William S. Fals-Stewart, Ph.D.

Summary

Dr. William Fals-Stewart examined the effects of using family members to observe naltrexone ingestion by opioid-dependent patients as part of a medication compliance contract. Men entering treatment for opioid dependence who were living with a family member were randomly assigned to one of two 24-week treatments: (1) behavioral family counseling (BFC) plus individual treatment (patients had both individual and family sessions and took naltrexone daily in presence of family member) or (2) individual-based treatment only (IBT; patients were prescribed naltrexone and were asked in counseling sessions about compliance, but there was no family involvement). Results showed that BFC patients, compared with their IBT counterparts, ingested more doses of naltrexone; attended more scheduled treatment sessions; had more days abstinent from opioids and other drugs during treatment and during the year after treatment; and had fewer drug-related, legal, and family problems at 1-year followup. Fals-Stewart concluded that family-involved medication contracts can enhance naltrexone compliance among opioid-dependent patients, leading to improved treatment response and outcomes.

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Conceptual and Methodological Flaws in the Evaluation of Addiction Treatment

This presentation focused on major inconsistencies between how addictions are classified (that is, as a chronic illness) and whether or not current methodologies address the implications of such a classification. The presenter urged the re-evaluation of findings from prior addiction treatment studies and suggested a significant underestimation of the potential effectiveness of addiction treatments.

A. Thomas McLellan, Ph.D.

Summary

This presentation argues that there is a disconnect between the realistic limits of the effects of addiction treatments and the traditional methods used to evaluate those effects, producing a significant underestimation of the potential effectiveness of addiction treatments and restricting the clinical and policy relevance of the existing research data on addiction treatment. To illustrate, Dr. Thomas McLellan presents three sets of findings from prior addiction treatment studies: 1) Few outcome differences exist between more intensive inpatient or residential forms of treatment and less intensive outpatient treatments; 2) Little outcome enhancement created from efforts to “match” patients to treatments; and 3) Lack of robust findings occurred in medication trials. These perplexing findings are explained by the explicit acute care assumption that some finite amount, duration, or intensity of services will sustain symptom remission and enhance functional status 6–12 months following the cessation of the intervention. McLellan argues that these expectations are not consistent with a chronic care approach and may have limited the development of more appropriate approaches. The presentation concludes with an illustration of a more appropriate treatment and evaluation model.

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Consequences and Treatment of Marijuana Abuse

Presentations in this section focused on effects of marijuana abuse such as cognitive deficits, psychosocial impairments, effects on motor function, and consequences of fetal marijuana exposure compared to in-utero exposure to cigarettes.

Cognitive Toxicity of Cannabis: The Devil Is in the Confounding Variables

Harrison G. Pope, Jr., M.D.

Summary

Dr. Harrison Pope presented an overview of the difficulties in determining whether observed cognitive deficits are attributable to toxic effects of cannabis itself by long-term, heavy cannabis abusers, or simply to confounding factors associated with heavy cannabis use. At present, it appears reasonable to conclude that deficits in attention and memory persist for at least several days after discontinuing regular heavy cannabis use. It is less clear, however, whether heavy cannabis use can cause neurotoxicity that persists long after discontinuation of use, or whether cognitive deficits magnify with increasing lifetime cannabis exposure.

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Cognitive Effects in Adolescents Exposed Prenatally to Marijuana or Cigarettes

Peter A. Fried, Ph.D.

Summary

Dr. Peter Fried discussed the consequences of prenatal exposure to marijuana on aspects of cognitive functioning and visual analysis/hypothesis testing in early and late adolescent offspring as described in a middle-class, low-risk sample that was studied prospectively from birth. These data were compared to the effect of prenatal cigarette exposure on the same sample. Fried concluded that the consequences of fetal marijuana exposure are subtle and appear not to have a deleterious effect on global intelligence, but rather on aspects of executive functioning. In contrast, in-utero exposure to cigarettes showed effects on overall intelligence, particularly with many aspects of verbal performance.

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Effects of Chronic Marijuana Use and THC on Brain Function in Humans: An fMRI Study

Alan S. Bloom, Ph.D.

Summary

Dr. Alan Bloom’s goal was to improve the understanding of THC’s effect on certain sites of action in the human brain and how these sites are involved in the drug’s effects. His team studied, in frequent marijuana users, the effects of doses of THC that produce subjective effects similar to those seen with marijuana use in a social situation on regional brain activity using BOLD and arterial spin labeling (ASL) fMRI techniques. Significant findings include: (1) THC produces a dose-related increase in the activity of the nucleus accumbens, (2) THC administration decreases brain activation induced by the performance of both cognitive and motor tasks, and (3) global brain perfusion was greater in frequent marijuana users than nondrug-using control subjects. Bloom demonstrated that THC produces significant effects on brain activity and cognitive task-induced activation at doses that produce effects similar to those produced by marijuana in a social situation.

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Behavioral and Treatment Research on Marijuana Withdrawal and Dependence

Alan J. Budney, Ph.D.

Summary

Dr. Alan Budney provided highlights from six clinical studies on marijuana dependence, withdrawal, and treatment. The first was a 1999 Withdrawal Study providing information on 54 adults seeking treatment for marijuana dependence. Another study was a 2003 Timecourse Study in which data were collected for withdrawal discomfort, restlessness, aggression, weight change, and strange dreams. The third study outlined was the “Pharmacological Specificity Dronabinol (Oral THC) Attentuates Marijuana Withdrawal” study. Budney’s presentation ended with a summary of treatment outcome research to date. He discussed three treatment studies: the Marijuana Treatment project—a behavioral treatment study comparing behavioral coping-skills therapy (BT), BT plus vouchers therapy, and vouchers only; a Relapse and Lapse study; and a CYT Adolescent Study of Abstinence at Discharge. The presentation also addressed implications for future studies and treatment.

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The Endogenous Cannabinoids and the Control of Drug Craving

Presenter: Billy R. Martin, Ph.D. (CDD Director: Alexandros Makriyannis, Ph.D.)

Summary

Dr. Billy Martin reviewed new information regarding the regulation of drug craving by CB1 receptors activated by endocannabinoids, as well as the broader role of this regulation in the control of rewarding mechanisms in the brain. Martin speculated as to whether our understanding of the endocannabinoid system can be used to design treatments for substance abuse and other psychiatric disorders.

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Drug Abuse Treatment Issues in Women

This section of the program focused on how certain factors affect drug addiction and treatment, such as gender, PTSD, depression, partner violence, and pregnancy.

Gender Differences in Treatment Needs, Services, Utilization, and Outcomes

Karol A. Kaltenbach, Ph.D.

Summary

Dr. Karol Kaltenbach addressed the state of gender-specific, drug abuse treatment availability in the U.S. today. In reviewing the history of women’s special needs and the delineation of treatment strategies during the past 25 years, she has determined that although efforts have resulted in the development of gender-specific treatment models, treatment remains limited. Although programs have been developed to address the addiction, medical, psychosocial, parenting, educational, and vocational needs of women and their children, only 15% of residential programs in the U.S. are for women and only 3% of outpatient programs are for women only.

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Treatment Issues in Drug-Dependent Women with Comorbid Depression

Rajita Sinha, Ph.D.

Summary

Dr. Rajita Sinha summarized findings on the effects of major depression and acute stress responses on cocaine relapse in humans, and discussed treatment issues related to comorbid depression and drug abuse. Dr. Sinha presented data on cocaine-dependent men and women participating in inpatient treatment who were evaluated for psychiatric diagnoses, neurobiological responses to stress, and on cocaine relapse during a 90-day postdischarge period. Findings indicated that while men and women are not different in rates of major depression, women with greater neurobiological reactivity to acute emotional stress in the laboratory are significantly more likely to relapse as compared with men. She also discussed pharmacological and psychosocial treatment implications for comorbid depression and drug abuse; specifically, treatments that target stress regulation in comorbid drug-dependent women.

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Trauma and PTSD: Issues in the Treatment of Drug-Dependent Women

Denise Hien, Ph.D.

Summary

In her presentation, Dr. Denise Hien reviewed main cognitive behavioral therapy (CBT) approaches that have been empirically examined to treat women with trauma. She focused on findings of one randomized clinical trial comparing two active CBT treatments with a nonrandomized comparison treatment as usual (TAU) condition in a population of substance-abusing urban women with histories of chronic emotional, physical, and sexual abuse, dually diagnosed with PTSD and SUD. Outcomes revealed statistically significant improvements on primary outcome measures for both active treatments compared with the community control group.

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Drug-Dependent Women with Partner Violence: Treatment Issues

Brenda A. Miller, Ph.D.

Summary

Dr. Brenda Miller provided an overview of mechanisms by which women’s comorbid disorders—drug/alcohol abuse, depression, anxiety, and PTSD symptoms—are related to partner violence, and gave evidence for bi-directional relationships. She explained how recent findings from a study measuring partner violence, depression and anxiety, and drug and alcohol use among female substance users showed high prevalence of partner violence, other forms of victimization, and depression and anxiety. Not only are relationships between comorbid disorders and partner violence important to consider for comprehensive treatment planning, but also for planning followup for women in treatment. These research findings are important indicators of the connections between comorbid disorders and partner violence and can be used to guide future clinical protocols.

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Drug Treatment Issues in Drug-Dependent, Pregnant Women

Hendrée E. Jones, Ph.D.

Summary

Methadone is currently the recommended standard of care for opioid-dependent pregnant women, improving maternal and neonatal outcomes when provided as a part of a comprehensive care model. However, methadone treatment during pregnancy remains controversial. Dr. Hendrée Jones’ presentation aimed to dispel myths and provide evidence-based recommendations for the appropriate use of methadone during pregnancy. Jones also recognizes the need for information on the safety and efficacy of buprenorphine, the latest opioid pharmacotherapy to be approved for the treatment of opioid dependence in nonpregnant patients. Jones provided the latest results from a double-blind, randomized, controlled trial comparing methadone and buprenorphine in the treatment of opioid-dependent pregnant women and the effects of prenatal exposure to these medications on the neonate. Novel behavioral approaches examined in the context of methadone and comprehensive care were also presented.

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Functional Brain Imaging of Addiction

Researchers in this portion of the program discussed the generalized circuitry for processing motivationally salient stimuli, and focused on neurotransmitter systems thought to mediate some of the responses to drugs of abuse.

Neuropsychiatric Implications of Mapping Reward/Aversion Circuitry

Hans C. Breiter, M.D.

Summary

Dr. Hans Breiter addressed the question of how the experience of reward is similar across category of reinforcer, and how these reinforcers are experienced relative to aversive or painful events. Studies using fMRI across multiple categories of rewarding and aversive stimuli now suggest that at the scale of their measurements, there is a generalized circuitry for processing motivationally salient stimuli, comprised of subcortical gray matter and paralimbic cortices. Breiter presented evidence from his studies that the motivationally salient features of monetary gains and losses, infusions of drugs of abuse, visual processing of beautiful faces, and somatosensory experience of pain, are evaluated by these brain regions, and produce putative signatures for rewarding vs. aversive events. These studies and others point to a general integrative model for motivated behavior that has implications for understanding neuropsychiatric illness, and may point toward a new foundation for psychiatry.

[Slides not available.]

Endogenous Opioid Neurotransmission: Interfacing Reward and Stress Regulation

Jon-Kar Zubieta, M.D., Ph.D.

Summary

Dr. Jon-Kar Zubieta’s presentation focused on neurotransmitter systems in the ventral basal ganglia and interconnected cortical and subcortical regions thought to mediate some of the responses to drugs of abuse and in drug reinforcement. PET studies using receptor selective radiotracers in human subjects demonstrate the activation of these circuits by nonrewarding, stressful, or noxious stimuli. Zubieta’s research showed that activation of endogenous opioid neurotransmission was associated with the suppression of affective and sensory ratings of these experiences, and accounted for some of the sex differences in the responses to these stimuli. Alterations in the metabolism of dopamine conferred by a common genetic polymorphism were also shown to dysregulate the response of the opioid system. These data demonstrate a point of interaction between the direct effect of drugs of abuse and stress regulatory responses.

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Chronic Effects of Drug Use and HIV

Linda Chang, M.D.

Summary

Dr. Linda Chang presented preliminary data demonstrating the additive effects of HIV and methamphetamine on brain injury to evaluate possible relationships between these physiological abnormalities and cognitive or behavior dysfunction. She stressed the need for further research to determine whether treatments, both pharmacological and behavioral, will lead to improvement on these physiological parameters. A major challenge in neuroimaging studies is that many drug users abuse multiple drugs concurrently; therefore, attributing the effects to a particular drug requires extensive screening for and exclusion of confounding variables (e.g., other drug use, concurrent neuropsychiatric disorders, and other medications).

[Slides not available.]

Neurobiological Substrates of Stimulant Action and Reward

Elliot A. Stein, Ph.D.

Summary

Dr. Elliot Stein used fMRI to investigate the common sites of action in the human brain for methylphenidate and cocaine use. His study exploits the high spatial resolution and sensitivity of fMRI in a within-subjects design incorporating multiple doses of each drug with online behavioral measures. He showed that modeling of the pharmacokinetic profiles of IV cocaine and methylphenidate from fMRI data yield similar sites of activation, which partially agree with previous PET findings. These data suggest that incomplete overlap may reflect the influence that each drug’s different pharmacological profiles has on their behavioral consequences.

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Genetic and Environmental Factors Contributing to Vulnerability to Addiction

This group presented research on the identification of genes that could indicate a susceptibility to drug abuse and addiction.

Using Twin Data To Identify Alternative Drug Abuse Phenotypes

Ming T. Tsuang, M.D., Ph.D.

Summary

Undoubtedly, some of the difficulty in identifying the susceptibility genes for drug abuse stems from the underlying etiologic complexity of this phenotype. In his study, Dr. Ming Tsuang suggests that the most genetically informative alternative phenotypes could be applied to existing molecular genetic datasets utilizing linkage analysis in an efficient approach that would capitalize on existing resources. These alternative phenotypes may be subtypes and/or quantitative traits. Tsuang shows how twin data can be used to assess the genetic and environmental determinants of the subtypes and/or quantitative traits with an emphasis on identifying maximally heritable alternative phenotypes that can be applied in molecular genetic research.

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Common and Specific Genetic Factors in the Development of Substance Dependence

Laura J. Bierut, M.D.

Summary

Dr. Laura Bierut compares and contrasts genetic findings for alcohol dependence with other substance dependence diagnoses (habitual smoking, and marijuana and cocaine dependence) using COGA-identified individuals with alcoholism in chemical dependency treatment centers. All subjects were assessed using SSAGA to evaluate alcohol and other substance dependence, and genetic analyses using affected sibling pair methods were conducted. Genetic analyses of COGA data provided further support for chromosomal regions that may be specific in the development of alcohol dependence, but not other substance dependence. There was also evidence of chromosomal regions that may represent shared genetic factors for the development of multiple substance dependence diagnoses.

[Slides not available.]

Addiction Molecular Genetics: Remarkably Converging Results

George R. Uhl, M.D., Ph.D.

Summary

Dr. George Uhl’s presentation focused on results from his laboratory and others’ that identify several genomic regions highly likely to contain allelic variants that confer vulnerability to addictions, and the nature of some of the candidates for this allelic variability. Association and linkage-based genome scans of polysubstance, alcohol, and nicotine abuse were utilized to study samples of European-Americans, African-Americans, and Asians in several sites. Uhl concluded that substance abuse vulnerability is conferred, in part, by common allelic variants that predispose to abuse of multiple substances. Allelic variants present in several populations are good candidates for direct use in several clinical applications at this time, including identifying responders/nonresponders to different drug treatments, and identifying allelic variants that could predispose to addiction comorbidities.

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Using the Systems Biology of Motivation for Genetic Studies in Psychiatry

Gregory P. Gasic, Ph.D.

Summary

Dr. Gregory Gasic’s objective was to show use of mMRI and fMRI as a screen for heritable quantitative markers for addictions and mood disorders. He used fMRI and mMRI combined with multiple paradigms that cover brain systems processing reward/aversion stimuli to probe individuals/families with at least one proband that met criteria for (1) cocaine addiction, (2) recurrent major depressive disorder, or (3) controls to produce a systems biology map. Circuit-based endophenotypes were derived from high throughput multimodal imaging paradigms to produce a saturated sampling of a functional domain. He determined that circuit-based endophenotype delineation may allow a more biological-based classification of these disorders, and ultimately lead to the identification of susceptibility alleles, loci, and genes.

[Slides not available.]

Genetic and Environmental Factors Modulate Cocaine Abuse in Monkey Models

Michael A. Nader, Ph.D.

Summary

Dr. Michael Nader investigated the relationship between D2 receptors, the environment, and vulnerability to self-administer cocaine in monkey models of drug abuse. PET was used to examine D2 levels in adult male macaques. In individually housed monkeys, there was a significant negative correlation between baseline D2 levels and rates of cocaine self-administration. Social housing produced changes in D2 levels such that subordinate monkeys had lower D2 levels than dominants; moreover, subordinates self-administered cocaine at higher rates. In all monkeys, cocaine exposure produced large and robust reductions in D2 levels, highlighting the importance of D2 receptors and the powerful influence of environmental variables on drug abuse.

[Slides not available.]

Moving the Targets: The Neurobiology of Addiction

This part of the program focused on the neurobiological consequences of repeated drug abuse; possible long-term changes in circuitry for behavior, psychological function, and motivation; and elements of the brain reward system implicated in the development of addiction.

Neuroadaptation in Addiction: The Extended Amygdala and Brain Reward System

George F. Koob, Ph.D.

Summary

Dr. George Koob discussed the conceptual structure for drug addiction focused on allostatic changes in reward function that lead to excessive drug intake. He provided a heuristic framework with which to identify the neurobiologic and neuroadaptive mechanisms involved in the development of drug addiction. Koob reviewed the key elements of the brain reward system implicated in the development of addiction—activation of the extended amygdala and its connections; the dysregulation of specific neurochemical mechanisms (opioid peptides, gamma-aminobutyric acid, glutamate and dopamine); recruitment of brain stress systems (corticotropin-releasing factor and norepinephrine); and dysregulation of brain antistress systems (neuropeptide Y). The changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for development of dependence and relapse in addiction.

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Neural Circuitry of Relapse

Peter W. Kalivas, Ph.D.

Summary

Dr. Peter Kalivas described a neural circuitry mediating relapse model in rats trained to self-administer cocaine. Using microdialysis to examine changes in glutamate release, Kalivas discovered that the glutamatergic projection from the prefrontal cortex to the nucleus accumbens was a neural substrate shared between drug and stress primers, and that the increase resulted from alterations in presynaptic regulation of glutamate release caused by a deficit in cystine glutamate exchange. The reinstatement of drug seeking was abolished by reactivating the cystine-glutamate exchanger with a systemic injection of N-acetylcysteine, which is currently used clinically to restore glutathione levels.

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Drugs, Neuroplasticity, and Addiction

Terry E. Robinson, Ph.D.

Summary

Recent studies suggest that the transition from drug use to addiction is due in part to a drug-induced reorganization of brain systems involved in incentive motivational processes and those involved in decisionmaking and judgment that usually exert inhibitory control over behavior. Dr. Terry Robinson’s presentation focused on some of the long-term neurobehavioral consequences of repeated exposure to drugs of abuse, conditions that promote or retard drug-induced neuroplasticity, and the effects of drug-induced changes in mesolimbocortical circuitry for behavior and psychological function.

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How Do Drugs of Abuse Rewire the Motivational Circuitry?

Marina E. Wolf, Ph.D

Summary

During this presentation, Dr. Marina Wolf discussed her investigation of LTP-mediated neuronal plasticity. Her study focused on identifying mechanisms through which dopamine-releasing drugs can directly influence LTP, during which glutamate synapses are strengthened by phosphorylation of AMPA-type glutamate receptors and by insertion of new AMPA receptors into synapses. Using primary neuronal cultures prepared from nucleus accumbens or prefrontal cortex, her team showed that stimulation of D1 dopamine receptors produces rapid increases in AMPA receptor phosphorylation and externalization of AMPA receptors at extra-synaptic sites, which may promote LTP by increasing the AMPA receptor pool available for synaptic insertion.

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Obesity: Lessons Learned from Addiction

During this section of the program, researchers discussed how findings pertaining to addiction may be beneficial in understanding the neurobiologic etiology of obesity and eating disorders.

Genetic, Motivational, and Metabolic Factors Modulate the Neural Drive To Maintain Body Weight

Barry Levin, M.D.

Summary

Dr. Barry Levin used rat studies to show that the brain controls behavioral, neuroendocrine, and metabolic systems that regulate the level of defended body fat, and that body weight is dependent upon a complex interaction among motivational, metabolic, and developmental factors imposed by the environment upon specific sets of interconnected, but separate plastic neural systems. Levin explained that rats with a genetic predisposition to develop diet-induced obesity (DIO) share many characteristics with polygenic forms of human obesity where increased dietary fat produces obesity and insulin resistance. Once rats develop DIO, the central and peripheral systems controlling energy homeostasis “reset” and they avidly defend their increased adiposity. This type of obesity and the neural systems regulating it are dependent on the adipose-derived hormone leptin, and DIO rats have an inborn reduction in their sensitivity to the catabolic effects of leptin. Levin also discussed leptin-independent neural pathways that respond to diet palatability and the manipulation of dietary availability, content, and palatability for producing long-term, genotype-dependent reorganization of neural pathways involved in energy homeostasis.

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Cortico-Striatal-Hypothalamic Networks and Motivation for Food: Integration of Cognition, Reward, and Energy

Ann E. Kelley, Ph.D.

Summary

The neural circuits affected by rewarding drugs and presumed to be profoundly altered in addiction are the very pathways that control intake of our most vital natural reward, food. Dr. Ann Kelley has been exploring the role of neurotransmitter systems within the nucleus accumbens, a brain region implicated in natural reward processes as well as addiction, in the control of food motivation and intake. Her research team examined local GABAergic, dopaminergic, and opioid peptide systems as well as the influence of input and output structures such as the amygdala and lateral hypothalamus. Their work has shown that these neurochemical systems play specific and dissociable roles in different aspects of food seeking and food intake. The influence of central and basolateral amygdala, as well as lateral hypothalamus, in regulating accumbens reward mechanisms appears particularly critical. Kelley proposes that the nucleus accumbens integrates information related to cognitive and emotional processing with hypothalamic mechanisms mediating energy balance and that this system as a whole enables complex hierarchical control of adaptive ingestive behavior.

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Food and Drug Cravings: Metaphor or Common Mechanisms?

Marcia L. Pelchat, Ph.D.

Summary

The objective of Dr. Marcia Pelchat’s presentation was to provide a better understanding of neural mechanisms for food cravings and to review the evidence for common mechanisms for desires of all kinds, whether healthy or pathological. Her literature review involved studies on the effects of neurotransmitters (including endogenous opiates, serotonin, and GABA) on ingestive behavior and drug cravings; and recent neuroimaging studies on drug and alcohol craving and on feeding and the chemical senses. Pelchat also summarized data from her laboratory on food craving in cocaine addicts as well as an fMRI study of food cravings in healthy adults. Taken together, the facts support the hypothesis that there are common brain mechanisms for food and for drug cravings. Such knowledge could prove to be useful in the development of treatments for both substance abuse and eating disorders.

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Common and Diverging Neurobiological Features of Feeding and Drug Self-Administration in Humans

Dana M. Small, Ph.D.

Summary

Feeding and drug self-administration share many common neural substrates, but there appear to be important differences between the brain mechanisms supporting adaptive and nonadaptive ingestive behaviors. Dr. Dana Small reported on findings from a series of neuroimaging studies to elucidate brain mechanisms of food reward in healthy human volunteers. Taken in conjunction with other findings in the literature, results suggest there is considerable overlap between brain activation produced by drugs of abuse and a highly palatable food (e.g., chocolate). However, dissociations are also evident. Consumption of a drug has been shown to lead to dopamine release in the ventral striatum, whereas consumption of a favorite food leads to dopamine release in the dorsal striatum. Moreover, dopamine release in response to drugs is correlated with degree of drug wanting, whereas dopamine release in response to feeding is related to perceived meal pleasantness and not to desire to eat or degree of hunger or satiation.

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Obesity and Addiction: Neuroimaging Studies

Gene-Jack Wang, M.D.

Summary

Dr. Gene-Jack Wang conducted neuroimaging studies to implicate the involvement of brain dopamine (DA) in normal and pathological food intake in humans. In normal body weight fasting subjects, food presentation that could not be consumed was associated with increases in striatal extracellular DA, which provides evidence of an involvement of DA in nonhedonic motivational properties of food intake. In pathologically obese subjects, Wang found reductions in striatal DA D2 receptors similar to that in drug-addicted subjects, as well as increased metabolism in the somatosensory cortex. In the case of obese individuals, the reduction in receptors coupled with the enhanced sensitivity to food palatability puts them at risk for food overconsumption as their most salient reinforcer.

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Smoking and Comorbid Mental Disorders

In this segment, researchers focused on the reward dysfunction hypothesis and how this process relates to mental disorders (such as schizophrenia and depression) and smoking.

Psychiatric Comorbidity of Smoking and Nicotine Dependence: An Epidemiologic Perspective

Naomi Breslau, Ph.D.

Summary

Associations of smoking with mental and substance use disorders have been consistently reported in clinical and epidemiologic studies. Both causal and noncausal explanations have been proposed. Dr. Naomi Breslau examined recent cross-sectional epidemiologic studies on age of onset of daily smoking and psychiatric disorders and a few prospective studies estimating the relationship between smoking and specific disorders. Elevated risks for subsequent first onset of panic disorder and agoraphobia in current smokers were reported in both types of studies. Breslau found results on smokers’ relative risk for major depression to be inconsistent, and explained details of these studies during her presentation.

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The Neurobiology of Nicotine Dependence and Comorbid Psychiatric Disorders

George F. Koob, Ph.D.

Summary

Dr. George Koob outlined the reward dysfunction hypothesis, which states that the neurochemical changes related to nicotine use and addiction are similar to those reward and stress function changes that are key elements of affective, anxiety, and psychotic disorders. Koob argued that the dysregulation of these specific neurochemical mechanisms (affecting serotonin, dopamine, gamma-aminobutyric acid, corticotropin-releasing factor, norepinephrine, and neuropeptide Y) may link the comorbidity of some psychiatric disorders with nicotine dependence. The reward dysfunction hypothesis provides a heuristic model with which to integrate molecular, cellular, and circuitry neuroadaptations in brain motivational systems involved in addiction and comorbid psychiatric disorders.

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Nicotine-Dependence Treatment in Individuals with Schizophrenia

Douglas M. Ziedonis, M.D.

Summary

Although evidence suggests that existing nicotine dependence treatments can be effective for the schizophrenic population, under-recognition and under-treatment of nicotine dependence in this population continue to be common. Dr. Douglas Ziedonis’ presentation stressed that the unique mental health treatment setting and schizophrenia-specific characteristics contribute to the onset and maintenance of nicotine dependence in individuals with schizophrenia, and that there is both an immediate need to address tobacco use in this population and to expand research agendas. Ziedonis discussed innovative psychosocial interventions and reviewed research supporting medications and psychosocial treatments for this population. Effective model programs and system changes were presented, including the specialized program for schizophrenic smokers at the University of Medicine and Dentistry of New Jersey Tobacco Dependence Program (tobaccoprogram.org).

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Behavioral and Pharmacological Treatments for Smokers with Depression

Richard A. Brown, Ph.D.

Summary

Dr. Richard Brown’s presentation reviewed existing clinical research evidence for the efficacy of adding cognitive-behavioral mood management treatment and for the use of antidepressant pharmacotherapy for smokers at risk for poor outcomes due to depression-related characteristics. Research has demonstrated significant associations between depression and cigarette smoking, and evidence suggests that depression is a risk factor resulting in poor smoking cessation outcomes. Early studies suggested that past major depressive disorder was a primary risk factor for poor outcomes in smoking cessation, but more recent evidence suggests that current depressive symptoms and a history of recurrent major depressive episodes convey the greatest risk in this regard.

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Stress and Relapse to Substance Use Disorders

This researcher focused on how stress plays into substance use, abuse, and relapse, and discussed neurobiological connections between the changes produced by stress and the changes produced by both short-term and long-term substance use.

Kathleen T. Brady, M.D., Ph.D.

Summary

The notion that life stressors can cause susceptible people to initiate or relapse to substance use has intuitive appeal as well as laboratory support. Dr. Kathleen Brady explained that although several neurobiological connections between the changes produced by stress and the changes produced by substance use have been identified in the lab, the relationship between stress and substance use has been more difficult to study in the clinical arena. Brady suggests that stress and the body’s response to it likely play a role in the vulnerability to initial substance use, initiation of treatment, and relapse in recovering users. She hypothesized that this relationship may be mediated in part by common neurochemical systems, such as the serotonin, dopamine, and opiate peptide systems, as well as the HPA axis. Further exploration of these connections should lead to important pharmacological developments in the prevention and treatment of substance use disorders.

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The Epidemiology and Treatment of Psychiatric Comorbidities

This portion of the program centered on current research on the patterns of comorbidity between mental, addictive, and medical disorders. Antecedent psychopathology and subsequent addictive disorders in youth and the fundamentals of the epidemiology of comorbid addictive and psychiatric disorders were discussed.

Epidemiology of Comorbid Psychiatric and Addictive Disorders

Presenter: Kevin Conway, Ph.D. (Senior Investigator: Kathleen Ries Merikangas, Ph.D.)

Summary

Dr. Kevin Conway discussed current research on the patterns of comorbidity between mental, addictive, and medical disorders, identifying key patterns emerging from epidemiologic data. These patterns reveal information on cross-cultural prevalences; the risk for drug dependence versus drug abuse; risk variations by mental disorder (e.g., anxiety, mood, ASPD); risk by gender; and risk by type and number of drug disorders. Conway briefly discussed the implications of a heterogeneous phenotype for classification, treatment, and genetics research.

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Comorbidity of Psychiatric and Addictive Disorders in Children

Joseph Biederman, M.D.

Summart

Dr. Joseph Biederman presented extensive information on antecedent psychopathological disorders to subsequent substance use disorders in youth. Biederman specifically focused on common comorbid diagnoses with children diagnosed with ADHD and the impact these dual diagnoses have on smoking prevalence. The presentation also covered the risk factors for ADHD and ADHD-associated comorbities leading to SUDs. Lastly, data were presented on ADHD and SUDs in adults, as a form of comparison.

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Depression in Hepatitis C Patients and Interferon Treatment

Paul J. Thuluvath, M.D.

Summary

Dr. Paul Thuluvath presented evidence on the increased prevalence of depression or associated symptoms (fatigue, impaired quality of life, cognitive impairment) for HCV patients in treatment. This increased prevalence may be related to the disease or to patient characteristics that predispose them to HCV infection. Interferon-based treatment may cause significant depression and other neuropsychiatric symptoms in up to 30 percent of patients. Further, Thuluvath discussed how pre-existing depression worsens during interferon treatment, how the adequate treatment of depression enables successful completion of HCV treatment and better outcomes, and the current role of antidepressants in the treatment of interferon-related depression.

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Research Advances in HIV Care

Joel E. Gallant, M.D.

Summary

Dr. Joel Gallant discussed the latest developments in the care of the primary HIV infection and indications for treatment, current guidelines for care, complications of treatment, and the management of treatment failure. Gallant touched on recommended regimens for treatment-naïve patients, neuropsychiatric effects of efavirenz toxicity, and the global view of HIV-1 infection. He concluded with a synopsis of antiretroviral agents in the development phase, obstacles to vaccine development, and research approaches.

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Treatment of Chronic Pain in Recovering Addicts

In this section, researchers presented studies of aberrant drug-related behaviors in patients with AIDS, cancer, and nonmalignant pain and the difficulties associated with assessing and treating addicts who suffer from pain.

Pain Assessment and Issues in Screening

Russell K. Portenoy, M.D.

Summary

Chronic pain is an extremely complex health issue, and a comprehensive assessment is essential in creating and sustaining a multimodal treatment strategy that can enhance comfort, improve functioning, and avoid complications in those with comorbid chronic pain recovering from substance abuse. Dr. Russell Portenoy discussed important aspects of the clinical assessment process, stressing that data collection should always involve elements related to substance use including: past history and current use of prescription drugs, prescription drug abuse, and illicit drug use; adverse drug-related consequences; drug abuse treatment; and family history of drug abuse. With this information, the clinician can develop a better understanding of the pain (etiology, pathophysiology, and syndrome), functional impairments, comorbidities that may influence pain treatment strategies, and risks of abuse; and provide the foundation for selection of a multimodal pain management strategy.

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Assessing Aberrant Drug-Taking Behaviors in Medically Ill Patients with Pain

Steven D. Passik, Ph.D.

Summary

In his presentation, Dr. Steve Passik discussed the multiple etiologies of aberrant drug-taking in medically ill patients with pain to focus attention on aspects of compliance with drug therapy and to differentiate the phenomenology of the pain treatment setting from that of the addiction treatment setting. Passik described the outcome domains of assessment and management of opioid therapy; provided data from studies of aberrant drug-related behaviors in patients with AIDS, cancer, and nonmalignant pain; and discussed clinical implications and future research directions.

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The Development and Treatment of Opioid-Induced Hyperalgesia

Summary

Dr. Walter Ling recently explored the development of opioid-induced hyperalgesia (OIH) in methadone- and buprenorphine-maintained, opiate-dependent patients by measuring cold pressor and electrically induced pain. Results of these studies indicate that methadone maintenance increases the level of OIH from baseline while buprenorphine neither increases nor decreases OIH over time. Ling also discussed findings from another study of opiate maintenance patients who appeared to be cross-tolerant to the effects of morphine. He pointed out that more and more people will be taking opioids chronically, either for pain or for addiction, and management of pain in these patients will be an increasing challenge.

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Prescribing Pain Medication for Recovering Addicts with Chronic Pain

Richard L. Brown, M.D.

Summary

Dr. Richard Brown reviewed ways in which many recovering addicts can be treated safely and effectively for chronic pain with opioid analgesics, nonopioid analgesics, and nonpharmacologic modalities. Brown outlined the parameters of medication agreements for the proper dispensation of pain relief medication as well as the clinician’s responsibility for monitoring patients for analgesia, adverse effects, activity, and adherence. He specified the patient’s responsibilities under these agreements, which include adhering to dosage instructions and obtaining potentially addictive medicines from only one clinician and pharmacy; participating in other recommended treatments for pain, addictions, and other psychiatric disorders; and submitting to urine drug screening on request. For most patients, a respectful, empathic approach with clear limit-setting allows continuation of opioids, promotes participation in addiction treatment, provides pain relief, and augments function.

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Principles of Pain Treatment in Addictive Disorders

Seddon R. Savage, M.D.

Summary

Dr. Seddon Savage presented a rational approach to addressing pain in persons with substance use disorders by discussing the neurobiology and clinical phenomenology of drug reward, abuse, and addiction, as relevant for pain treatment. She outlined key principles of acute and chronic pain treatment in persons with substance use disorders, and reviewed the many complications involved. For instance, opioid tolerance may dictate a need for high doses to achieve analgesia. Drug craving may shape pain reporting and clinicians often fear that opioids provided for analgesia will exacerbate substance-use problems or be diverted by patients. Chronic pain and addictive disorders each may adversely affect mood, sleep, function, and overall quality of life, and may reinforce one another. Savage argued that pain may be physiologically facilitated by episodes of intoxication and withdrawal, and behaviors driven by addiction may impair compliance with pain treatment.

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Why Does the Human Brain Become Addicted?

This researcher discussed how dysfunction in inhibitory control systems decreases the addict’s ability to refrain from seeking and consuming drugs, and ultimately results in the compulsive drug intake that characterizes the disease.

Nora D. Volkow, M.D.

Summary

Addiction is a disorder that involves complex interactions between a wide array of biological and environmental variables. Strategies for its prevention and treatment therefore, necessitate an integrated approach incorporating systems of analysis that span the molecular to the social. Pairing rapidly evolving technologies such as neuroimaging with sophisticated behavioral measurement paradigms has allowed extraordinary progress in elucidating many of the neurochemical and functional changes that occur in the brains of addicts. Although large and rapid increases in dopamine have been linked with the rewarding properties of drugs, the addicted state, in striking contrast, is marked by significant decreases in brain dopamine function. Such decreases are associated with dysfunction of prefrontal regions including orbitofrontal cortex (involved in salience attribution) and cingulate gyrus (involved in inhibitory control). Dysfunction of brain circuits involved in motivation and drive, inhibitory control, reward, and memory and learning all contribute to addiction. Treatments for addiction that include altering reward and motivational systems, interfering with conditioned responses, and promoting brain plasticity are currently being studied.

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