Substance Abuse

Herbert D. Kleber, M.D., Director
Marian W. Fischman, Ph.D., Co-Director, and Director, Substance Use Research Center
Efrat Aharonovich, Ph.D., Research Scientist III
Evaristo Akerele, M.D., Psychiatrist II
Adam Bisaga, M.D., Psychiatrist II
Susan Carden, Ph.D., Administrator
Kenneth Carpenter, Ph.D., Research Scientist III
Sarah Church, Ph.D., Research Scientist III
Eric Collins, M.D., Psychiatrist II
Sandra D. Comer, Ph.D., Research Scientist V
Suzette M. Evans, Ph.D., Research Scientist V
Richard W. Foltin, Ph.D., Research Scientist VI
Margaret Haney, Ph.D., Research Scientist V
Carl Hart, Ph.D., Research Scientist III
Frances R. Levin, M.D., Psychiatrist II
David M. McDowell, M.D., Psychiatrist II
Jami Rothenberg, Ph.D., Research Scientist IV
Eric Rubin, M.D., Ph.D., Psychiatrist II
Maria Sullivan, M.D., Ph.D., Psychiatrist II
Suzanne Vosburgh, Ph.D., Research Scientist II
Amie Ward, Ph.D., Research Scientist IV

Research in the division focuses on the antecedents and consequences of substance use and abuse, with particular emphasis on the development and testing of novel approaches to the treatment of substance abuse. The division is unique in its ability to examine substance abuse issues at three levels: in non-human primates, in controlled laboratory research with human volunteers and, clinically, in treating cocaine-, heroin-, marijuana- and alcohol-abusing patients
Medications Development Research Centers
Two NIDA-funded Medication Development Centers are now active in the division. The first of these, under the direction of Dr. Kleber (Co-Principal Investigator, Levin) consists of: a Central Administrative Core; a Training, Education and Biostatistics Core; and four separate projects. Project 1 (Principal Investigator, Fischman) has developed a laboratory model of heroin abuse to evaluate new medications for opiate addiction as well as improving outcome and acceptability of existing medications such as methadone and naltrexone. This year, the work of Drs. Fischman, Comer, and Collins focused on evaluating a depot formulation of naltrexone, as well as the partial opioid agonist buprenorphine and the combination product containing buprenorphine and naloxone. The depot naltrexone was found to block heroin for up to five weeks. Project 2 (Principal Investigator, Laruelle), in collaboration with the Division of Brain Imaging, measures mesolimbic dopamine D1/D2 receptors in response to cocaine administration as a possible marker for cocaine medication. Project 3 (Principal Investigator, Nunes) continues to explore pharmacological treatments for depressed cocaine abusers. A new double-blind, placebo-controlled trial assessing the efficacy of venlafaxine has begun. Project 4 (Principal Investigator, Haney), with the collaboration of Drs. Hart, Ward, Comer, Foltin, and Fischman, studies possible treatment medications for marijuana withdrawal and craving. During the past year, she completed a residential laboratory study in marijuana smokers demonstrating that sustained-release bupropion worsens mood during marijuana withdrawal. An ongoing study is investigating how nefazodone, an antidepressant with sedative side effects, influences symptoms of marijuana withdrawal.
The Central Administrative Core, headed by Dr. Susan Carden, in addition to providing centralized coordination and resources, supports pilot studies on promising medications and provides funding for small pilot studies. Several pilot studies focus on dually-diagnosed patients, based on our approach to medications development that substance abusers are not a homogenous group, and that we may have more success if medications are targeted to subpopulations of substance abusers. For instance, based on Dr. Sullivan's previous pilot study that assessed current patterns of nicotine use in individuals with schizophrenia or schizoaffective disorder, she is now pursuing a small treatment trial with bupropion for schizophrenic cigarette smokers. These pilot data served as the basis for Dr. Sullivan's recently funded K23 award, Opiate and Nicotine Dependence: Medications and Therapy. Dr. Levin and colleagues are completing a small double-blind crossover study comparing divalproex for the treatment of marijuana abuse and explosive mood disorder. In addition, pilot studies address sex differences in response to two treatments for cocaine abuse and test an intervention for substance abusers who have high HIV risk behavior, and two pilot studies are related to memantine and opioid abuse. Suzanne Vosburg, Ph.D., who joined the division this year, acts as a departmental resource for experimental design and statistical analysis issues, conducting seminars in these areas and consulting privately with investigators. In addition, she serves as the department's data analyst and often works closely with the Biostatistics department in this capacity.
The second Center grant awarded to the division, Novel Pharmacotherapies for Cocaine Dependence, (Principal Investigator, Fischman, and Co-Principal Investigator, Nunes) supports an Administrative Core and two Projects. Project 1 (Principal Investigator, Nunes) is currently evaluating gabapentin for the treatment of cocaine abusers, and Project 2 (Principal Investigator, Foltin) will evaluate a series of potentially useful gaba-ergic and glutamatergic compounds for the treatment of cocaine abuse.
Inpatient Laboratory Research with Human Participants
Residential Laboratory In their ongoing characterization of drug use by the workforce, Drs. Fischman, Foltin, Haney, Ward, and Hart have begun a series of studies examining the effects of stimulants and sedatives in shift workers. Sleep-wake cycles are manipulated experimentally, and behavioral variables, such as task performance, sleep, food intake, and mood, are assessed under controlled conditions. Using portable sleep monitors, Dr. Ward continues to investigate the effects of drug use and abstinence on sleep. Dr. Haney and colleagues completed two studies in the residential laboratory demonstrating that abstinence following chronic exposure to smoked marijuana or to oral delta-9-THC results in withdrawal symptoms, including increased anxiety, irritability, and decreases in food intake and sleep. These studies suggest that withdrawal symptoms may play a role in maintaining chronic marijuana use. As a follow-up to these studies, and supported by her NIDA funds (Project 4 of Dr. Kleber's Medication Development Center), Dr. Haney is investigating potential pharmacological treatments to alleviate symptoms of marijuana withdrawal.
Cocaine Laboratory Four NIDA-funded grants awarded to Drs. Fischman and Foltin support this cocaine research. In a series of studies, Dr. Haney and colleagues have shown that the D1 receptor subtype is active in the reinforcing effects of cocaine and that enhancing rather than blocking the effects of cocaine at the D1 receptor may be a more useful approach to treating cocaine abuse. Most recently, Dr. Ward and colleagues have intriguing new data suggesting that the GABA system may be a target for pharmacological intervention for the treatment of cocaine abuse. Dr. Haney and colleagues are developing a human laboratory procedure to evaluate, at a more precise level, changes in cocaine's subjective effects, and Dr. Hart and colleagues continue work on sleep disruption and cognitive changes related to "binge" cocaine use.
Imaging Studies A number of collaborative imaging studies are being conducted in cocaine abusers. Using positron emission tomography (PET), Dr. Rubin continues his studies of cocaine's acute and chronic effects on the human brain. A second PET protocol in progress measures regional cerebral metabolism to examine long-term changes in cocaine-dependent individuals who have developed depression. In collaboration with Dr. Dikoma Shungu (Department of Radiology), Dr. Rubin is also continuing a study using magnetic resonance spectroscopy to examine regional brain metabolites during acute cocaine administration and compare the data to findings in the PET study. Dr. Roman Koetitz has joined the imaging effort, and Drs. Marc Laruelle and Diana Martinez from the Division of Functional Brain Mapping are collaborating with Drs. Foltin and Fischman to examine dopamine D1 and D2 receptors with PET and relating brain DA/D2 ratios to the behavioral effects of cocaine in humans as part of Dr. Kleber's Medication Development Center.
Opiate Inpatient Studies Drs. Comer and Fischman have been investigating the safety, time course, and effectiveness of a depot formulation of naltrexone during a two-month inpatient study. The clinical effectiveness of depot naltrexone in an outpatient study in treatment-seeking heroin-dependent individuals has also been initiated. Dr. Comer recently assessed the reinforcing effects of i.v. buprenorphine in non-heroin-dependent individuals and found that buprenorphine was self-administered at higher rates than placebo, suggesting that buprenorphine has potential abuse liability. Drs. Kleber and Collins continue to assess various procedures for opiate detoxification. A current study tests the safety and efficacy of rapid opiate detoxification under general anesthesia to detoxify heroin-dependent individuals. In addition, Dr. Collins continues to test other methods of heroin detoxification, as part of his ongoing Mentored Clinical Scientist Development Award.
Alcohol Inpatient Studies The division expanded its medications development focus to include alcohol. Drs. Evans and Bisaga are developing human laboratory and clinical models to screen promising medications and establish whether modulation of the NMDA receptor system with memantine has beneficial effects in the treatment of alcohol dependence.
Outpatient Laboratory Research with Human Participants
Dr. Evans continues to focus on several behavioral and electrophysiological markers that may be associated with increased risk for drug or alcohol abuse in women. She is collaborating with Dr. Gerard Bruder in the Department of Biopsychology, adding electrophysiological measures and assessing changes across the menstrual cycle in her study of vulnerability to abuse of these substances in females with and without a family history of alcoholism. She is also investigating women with depressive symptoms, women who are social drinkers, and women with multiple risk factors (e.g., depressive symptoms and a paternal history of alcoholism). Drs. Comer, Evans, and Bisaga are evaluating sex differences in response to pain stimuli at five difference phases of the menstrual cycle to provide information regarding sex differences in response to pain. Dr. Haney has also completed a series of outpatient studies, investigating the mechanism of marijuana's reinforcing effects. Drs. Haney and Foltin received NIDA funding to compare the effects of marijuana and oral THC in individuals with HIV-related weight loss. Dr. Hart has recently completed two outpatient studies: 1) an investigation of methamphetamine's discriminative stimulus effects following administration of memantine, and 2) an assessment of complex cognitive functioning during marijuana intoxication.
Research with Non-human Primates
Dr. Foltin's studies examined how drugs with different neuropharmacological mechanisms affect the incentive value of stimuli paired with food. Drugs that increase dopamine decrease food intake, but increase the reinforcing effects of stimuli paired with food. In contrast, drugs that increase serotonin decrease food intake, and decrease the reinforcing effects of stimuli paired with food. Drs. Foltin and Evans also demonstrated that monkeys, when permitted to smoke heroin a limited number of times each day, develop a preference for the chamber in which they smoke the drug. This learned preference, which occurs in the absence of heroin dependence, demonstrates how environmental cues can elicit drug craving in laboratory animals. Drs. Foltin and Evans received a grant to study cocaine use in rhesus monkeys across the menstrual cycle.
Clinical Treatment Studies
Substance Treatment and Research Service (STARS) A new NIDA- sponsored clinical trial of nefazodone and bupropion for the treatment of marijuana dependence (Dr. McDowell, Principal Investigator) builds on our previous work, showing that the abrupt cessation of marijuana use leads to withdrawal symptoms similar to those of depression and nicotine withdrawal. Dr. McDowell, a long-time member of the Scientific Program Committee of the American Psychiatric Association, has been promoted to the position of vice chair starting this May. Dr. Jami Rothenberg, Director of Psychosocial Research for the division, has developed a training site at STARS where clinical psychology graduate students may rotate as part of their predoctoral internship experience at the NYSPI. Dr. Levin continues her study comparing the efficacy of methylphenidate and placebo in cocaine abusers with adult ADHD. Similarly, as part of the Medications Development Center grant, Drs. Nunes and McDowell are conducting a controlled treatment trial to test the efficacy of venlafaxine in depressed cocaine abusers. Drs. Nunes, Carpenter, and Aharonovich received funding for the systematic evaluation of behavioral treatments for depression in drug dependence. Drs. Nunes and Bisaga have also started a double-blind, placebo-controlled trial of gabapentin for treatment of cocaine dependence, which is part of Dr. Fischman's new Center grant.
A competing renewal was funded for Drs. Nunes, Sullivan, and Rothenberg to continue the assessment of the effectiveness of naltrexone in combination with behavioral therapy for opiate dependence. As an extension of this, Dr. Maria Sullivan is assessing nefazodone with open-label naltrexone for opiate dependence. Drs. Rothenberg and Carpenter are collecting pilot data with this novel therapy with an alcohol-dependent population, a new treatment population at STARS. In addition, STARS has branched into neuropsychological and cognitive research. Drs. Church and Carpenter are currently working on a small pilot study to develop and test a computerized neuropsychological test that will enable them to investigate changes in cognitive schemas as a result of cognitive behavioral treatments for substance abuse. With the use of computerized neuropsychological assessment battery, Dr. Aharonovich began data collection for a pilot study on the effects of cognitive deficits in cocaine dependent users on therapy compliance and outcome.
Other Treatment Studies Dr. Collins is examining methods to improve the utility of naltrexone in the treatment of heroin dependence by improving methods to start patients on the drug. Dr. Maria Sullivan is conducting a double-blind, placebo-controlled trial of bupropion for nicotine dependence in schizophrenics. Dr. Bisaga continues work supported by his K23 award to evaluate NMDA antagonists for opiate dependence and has also established a new collaboration with the Department of Biopsychology to assess the effects of memantine on acute nicotine-withdrawal symptoms, including alterations in electrophysiological response. Drs. Levin and Akerele received support to evaluate the efficacy of two atypical antipsychotic agents for substance abusing schizophrenic patients.
Education and Training
Dr. Levin organizes the training for the Addiction Psychiatry Fellowship and serves as the Addiction Psychiatry Fellowship Director. She was appointed to the new Q.J. Kennedy Associate Professor of Clinical Psychiatry Chair in recognition of her ongoing educational work and commitment to improving substance abuse training for the medical center. This year, a symposium on adolescent substance abuse has been added to the Clinical Practice Course for second-year medical students. Drs. Levin and McDowell continue to coordinate the second- and third-year psychiatric resident course. In addition, Dr. Levin initiated a program to enhance substance abuse education and training for medical house staff. Working with Internal Medicine and the Hazelden Foundation, she is piloting a new program.
The NIDA-funded Research Fellowship in Substance Abuse Disorders This year we have six fellows: Jennifer Nasser, Ph.D.; Reynolds Clodfelter, Psy.D; Jeffrey J. Wilson, M.D.; Vladimir Ginzburg, M.D.; Anthony Tranguch, M.D., Ph.D.; and Carlos Zubaran, M.D., Ph.D., a Brazilian psychiatrist funded by CNPq Brazilian Research Council. Dr. Akerele completed his Postdoctoral Fellowship and became the latest addition to our faculty. He received a NIDA/APA K award to support his study of dually diagnosed patients coping with schizophrenia and cocaine and/or marijuana abuse, and he completed a study assessing the effects of cocaine dependence on treatment outcome in methadone-maintained patients. He continues to serve as the associate director of the Substance Treatment and Research Services (STARS), and is currently the co-chair for the Early Career Psychiatrists, New York State. Overall the division has five faculty with K awards and a total of 30 grants.

 

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Dr. Margaret Haney, standing, and Dr. Frances Levin at the Psychiatric Institute Annual Scientific Conference

 
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