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Research-Educator Track
Associate Professor (with Tenure)
Room 218
313-993-3965
E-Mail: mgreen@med.wayne.edu
Dr. Greenwald is Director of the Substance Abuse Research Division, and Chief of its Human Pharmacology Laboratory, in the Dept. of Psychiatry and Behavioral Neurosciences (DPBN). He is also Director (Graduate Officer) of the Translational Neuroscience Program , a Ph.D. training program in the neurosciences that is based in the DPBN. See Dr. Greenwald’s Community of Science profile for more complete professional information.
Statement of Interests
I became fascinated with opioids due to the multiple physiological/pharmacological effects they produce, the availability of specific pharmacological tools to investigate their effects, the dual-edge problem of using opioids to treat pain balanced against their high potential for abuse, and the public health problems associated with their non-medical and illegal use. As a psychologist, I believe in the importance of focusing on behavior and the contingencies/circumstances that control behavior, but also attempt to meld this understanding with biology. I am attentive at the individual-subject level of analysis to obtain clues about the reliability of the effects I observe and for potential mechanistic and treatment implications.
My first grant occurred during intense scientific interest in drug craving as a correlate of abuse and treatment response. I investigated pharmacological and environmental determinants of heroin craving and drug use in opioid-dependent individuals. Major novel findings from these studies were that: (1) craving can be reliably measured and is pharmacologically sensitive if the item set is sufficiently large (Schuster et al. 1995; Greenwald 2002 ); (2) opioid agonist and antagonist challenges produce differential change in symptom reports: antagonists reliably increase heroin craving (Schuster et al. 1995; Eissenberg et al. 1996 ; Greenwald 2005 ) whereas agonists dose-dependently decrease heroin craving ( Greenwald 2002 ; Greenwald et al. 1999 ), thereby showing specificity; (3) craving is not prerequisite to opioid drug seeking/use during methadone induction, maintenance or dose-tapering ( Greenwald 2002 ; Greenwald 2005 ; Greenwald 2006 ); (4) different schedules of methadone induction produce different craving and mood effects, with a stepwise dose increase approach producing greater craving, withdrawal symptom and negative mood – but not drug use – suppression than a rapid-loading approach ( Greenwald 2006 ); (5) unlike pharmacological changes, instructions about acute methadone dose changes do not have a significant effect on craving ( Greenwald 2002 ); and (6) opioid self-administration yields a higher-magnitude and different spatial distribution of EEG activation than passive opioid administration ( Greenwald and Roehrs 2005 ).
I maintain significant interest in buprenorphine (BUP) as a pharmacotherapy for heroin dependence, due to its unique (and still not completely elucidated) mechanisms of action and because its partial mu-agonist profile may provide a useful model for treatment of other forms of drug abuse. I have been directing a Center grant project in which we have been exploring effects of BUP using multiple in vivo functional levels of analysis: mu-opioid receptor availability using [ 11C]-carfentanil and PET imaging, pharmacokinetics, and agonist and antagonist effects. This strategy has revealed important individual differences that can be translated into improved treatment. We established BUP dose-dependent occupancy of mu-opioid receptors ( Zubieta et al. 2000 ; Greenwald et al. 2003 ). The fact that a 16 mg/day BUP maintenance dose can occupy nearly all brain mu-receptors and that 32 mg/day produces little additional receptor occupancy has reassured many physicians that BUP is (1) safe and (2) has diminishing returns at doses higher than administered in standard clinical practice. We also recently showed BUP’s duration of action in the brain over 76 hours, with time-dependent correlations between mu-opioid receptor availability, plasma levels, opioid withdrawal symptoms, and antagonist blockade ability ( Greenwald et al. 2007 ). These data are consistent with our previous findings that BUP blocked opioid drug-seeking behavior using an every-other-day dosing regimen ( Greenwald et al. 2002 ). Ongoing work in my lab is examining in vivomu-opioid receptor availability (using PET and [ 11C]-carfentanil) and brain chemistry (using high-field MR spectroscopy) during methadone maintenance.
In the past few years, I have developed a human laboratory model of drug-seeking behavior, with an emphasis on behavioral economic analysis. This work focuses on the use of choice progressive ratio models (i.e. different fixed ratio values) combined with different doses to arrange variations in drug “price”, and to plot drug consumption (choices) under varying experimental conditions, e.g. closed vs. open economy, different non-drug alternative reinforcers. In our initial study with this model, we ( Greenwald and Hursh 2006 ) found significant that the availability of drug supplements (similar to cheap heroin on the street) significantly reduced drug-seeking behavior; and that subjects who have recently used cocaine exhibit greater opioid drug-seeking behavior. This work extends our earlier findings on individual differences in opioid choice in the laboratory as a function of outpatient opioid abstinence status ( Greenwald et al. 1999 ). We are also examining candidate genetic polymorphisms that may be related to drug choice behavior, delay discounting (and other measures of impulsive/risky behavior), and the propensity toward opioid relapse during detoxification. We plan to use this information to develop a behavioral pharmacogenetic approach to treatment. We are also conducting behavioral economic studies of naturalistic drug seeking behavior, income and expenditures (Roddy and Greenwald, under review) to examine the external validity and treatment implications of our laboratory models.
In a new NIDA R01 grant, we are advancing this laboratory model to examine polydrug (opioid and cocaine) use and its treatment with dual agonist replacement therapy (buprenorphine and sustained release oral d-amphetamine), and to translate our methods and findings as rapidly as possible into clinical relapse prevention for these challenging patients. This extremely important area is clinically relevant but vastly under-studied; the results from this new project are likely to have a major impact on the field.
Recent Honors
Editorial Board, Experimental and Clinical Psychopharmacology, 2001-2005
Career Development Chair Award, Wayne State University, 2005-2006
American Psychological Association Fellow, Division 28, pending
Selected Peer-Reviewed Publications
Greenwald MK, Johanson CE, Schuster CR (1999) Opioid reinforcement in heroin-dependent volunteers during buprenorphine maintenance. Drug and Alcohol Dependence 56: 191-203
Greenwald MK, Stitzer ML (2000) Antinociceptive, subjective and behavioral effects of smoked marijuana in humans. Drug and Alcohol Dependence 59: 261-275
Greenwald MK (2002) Heroin craving and drug use in opioid-maintained volunteers: effects of methadone dose variations. Experimental and Clinical Psychopharmacology 10: 39-46
Greenwald MK, Schuh KJ, Hopper J, Schuster CR, Johanson CE (2002) Effects of buprenorphine sublingual tablet maintenance on opioid drug-seeking behavior by humans. Psychopharmacology 160: 344-352
Greenwald MK, Johanson, CE, Moody DE, Woods JH, Kilbourn MR, Koeppe RA, Schuster CR, Zubieta JK (2003) Effects of buprenorphine maintenance dose on mu-opioid receptor binding potential, plasma concentration, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology 28: 2000-2009
Greenwald MK, Roehrs TA (2005) Mu-opioid self-administration versus passive administration in heroin abusers produces differential EEG activation. Neuropsychopharmacology 30: 212-221
Greenwald MK (2005) Opioid craving and seeking behavior in physically dependent volunteers: Effects of acute withdrawal and drug reinforcement opportunity. Experimental and Clinical Psychopharmacology 13: 3-14
Marco AP, Greenwald MK, Higgins MS (2005) A preliminary study of 24-hour post-Cesarean patient-controlled analgesia: postoperative pain reports and morphine requests/utilization are greater in abstaining smokers than non-smokers. Medical Science Monitor 11(6): 255-261
Greenwald MK (2006) Early impact of methadone induction for heroin dependence: Differential effects of two dose sequences in a randomized controlled study. Experimental and Clinical Psychopharmacology 14: 52-67
Greenwald MK, Hursh SR (2006) Behavioral economic analysis of opioid consumption in heroin-dependent individuals: Effects of unit price and pre-session drug supply. Drug and Alcohol Dependence 85: 35-48
Greenwald MK, Johanson, CE, Bueller J, Chang Y, Moody DE, Kilbourn MR, Koeppe RA, Zubieta JK (2007) Buprenorphine duration of action: Mu-opioid receptor availability, pharmacokinetic and behavioral indices. Biological Psychiatry 61: 101-110
Selected Book Chapters:
Greenwald MK (2006) Human experimental therapeutic models in opioid dependence: translational research advances and implications. In: McKenna CR (Ed.), Trends in Substance Abuse Research, pp. 1-55. New York: Nova Science Publishers, Inc.
Greenwald MK, Steinmiller CL (in press) Imaging opioid receptors: applications to substance use disorders. In: Dean R, Negus SS, Bilsky E (Eds.), Opioid Receptors and Antagonists: From Bench to Clinic. New York: Humana Press.
Active Grant Projects
2003-2007 "Pharmacological Studies of Opioid Dependence in Humans" (Mark Greenwald, Project PI, 15% effort), NIH/NIDA P50 DA00254, clinical research component of Center Grant to Univ. of Michigan titled, “Narcotic Drug and Opioid Peptide Basic Research” (James Woods, Center Director). Purpose: Determine methadone's duration of action on mu-receptor binding potential, plasma methadone and saliva cortisol levels; spontaneous opioid withdrawal symptoms, and the ability of methadone to attenuate effects of hydromorphone; and whether opioid dependence alters impulsive drug preference, using delayed discounting procedures. Funding period: July 1, 2003-June 30, 2007. Total direct costs (subcontract): $398,221. Year 4 direct costs: $100,000.
2003-2008 "Biobehavioral Studies of Opioid Drug-Seeking Behavior" (Mark Greenwald, PI, 50% effort), NIH/NIDA R01 DA15462. Purpose: Examine environmental factors that influence drug-seeking behavior in opioid-dependent humans. Funding period: Sept. 20, 2003-May 31, 2008. Total direct costs: $1,395,000. Year 4 direct costs: $279,281.
2004-2007 Supplement to “Biobehavioral Studies of Opioid Drug-Seeking Behavior" (Mark Greenwald, PI), NIH/NIDA R01 DA15462-02S1. Purpose: Determine the effects of several genetic poly-morphisms on relapse to drug use in opioid-dependent individuals. Funding period: April 1, 2004-March 31, 2007. Total direct costs: $123,061. Year 3 direct costs: $37,386.
2003-2007 “Prenatal Cocaine Exposure and School Age Outcome” (Virginia Delaney-Black, PI), NIH/NIDA R01 DA0116373. Co-investigator, 5% effort. Purpose: Assess behavioral outcomes of early adolescent males and females with prenatal cocaine exposure. Outcomes are focused on externalizing behaviors; initiation of substance use; and problems with aggression and impulsivity. Funding period: June 1, 2003-May 31, 2007. Year 5 direct costs: $373,327.
2005-2006 “Brain Chemistry in Opioid Dependent Volunteers Using MR Spectroscopy” (Mark Greenwald, PI), Wayne State University Career Development Chair Award. Purpose: Use high-field (4T) magnetic resonance proton spectroscopy ( 1H-MRS) to determine whether opioid withdrawal increases brain glutamate and/or glutamine in heroin-dependent, methadone-maintained research volunteers. Funding period: July 1, 2005 – June 30, 2006 (no cost extension). Total costs: $19,000.
2006-2007 “The Effects of Three Dose Ratios of Fentanyl and Naloxone in Opioid-Dependent Volunteers” (Mark Greenwald, single site PI), contract with BioDelivery Sciences International, Inc. Purpose: Dose ranging study to formulate a novel opioid analgesic with reduced abuse liability. Funding period: April 22, 2006 – Dec. 31, 2007. Costs per completed subject: $22,718.
2006-2009 “Reducing Cocaine/Heroin Abuse with SR-Amphetamine and Buprenorphine” (Mark Greenwald, PI), NIH/NIDA R01 DA022243, 10% effort (3 years). Purpose: Determine in cocaine/heroin-dependent volunteers whether maintenance on the combination of sustained release oral d-amphetamine with buprenorphine sublingual tablet is safe and well tolerated, decreases cocaine choice in a human laboratory polydrug abuse model (Study 1), and protects against relapse (Study 2). Funding period: 9/30/06-6/30/09. Total direct costs: $750,000. Year 1 direct costs: $250,000.
2006-2011 “Neurochemistry of Opiate Abuse Risk in Chronic Pain” (Jon-Kar Zubieta, PI, Univ. of Michigan), NIH/NIDA R01 DA22520, Co-investigator (PI on subcontract), 10% effort (5 years). Purpose: Determine functioning of the endogenous opioid (mu-receptor) and dopamine (D2 receptor) systems and behavioral risk measures in chronic pain patients relative to matched controls in the presence and absence of experimental pain, in relation to sensitivity to exogenous opioid challenge. Funding period: 09/30/06-8/31/11. Total direct costs (subcontract): $ 142,689. Year 1 direct costs: $36,403.
2007-2008 “A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study of Probuphine ® in Patients with Opioid Dependence” (Mark Greenwald, site PI), 5% effort, contract with Titan Pharmaceuticals, Inc. Purpose: Determine the safety and efficacy of a long-acting buprenorphine implant for treating opioid-dependent patients. Funding period: 04/15/07-04/14/08. Costs per completed patient: $14,680.
Teaching Highlights
Dr. Greenwald serves as the Director (Graduate Officer) of the Translational Neuroscience Program , a Ph.D. training program in the neurosciences that is based in the DPBN.
Service Highlights
Consulting reviewer (year first reviewed) for:
Experimental and Clinical Psychopharmacology (1996; Editorial Board, 2001-2005); Drug and Alcohol Dependence (1996); Pharmacology, Biochemistry and Behavior (1996); Psychophysiology (1996); Biological Psychiatry (1998); Analgesia (1998); Psychopharmacology (1999); Behavioural Pharmacology (2001); Depression and Anxiety (2001); Clinical Pharmacokinetics (2003); Journal of Pain (2003); Behavior Research Methods, Instruments, and Computers (2004); American Journal of Psychiatry (2005); Archives of Medical Research (2005)
Member of professional organizations:
College on Problems of Drug Dependence (CPDD), Program Committee
American Psychological Association, Division 28 (Psychopharmacology of Substance Abuse)
International Study Group Investigating Drugs as Reinforcers (ISGIDAR)
University of Michigan Substance Abuse Research Center (UMSARC)
Recent grant reviewer for:
National Institutes of Health (NIH)/National Institute on Drug Abuse
Veterans Affairs Merit Review Neurobiology-A Core Committee
Civilian Research and Development Foundation Cooperative Grants Program
Department of Psychiatry and Behavioral Neurosciences service:
Chair, Promotion and Tenure Committee
Graduate Officer, Translational Neuroscience Program
Member, Appointments Committee
Past Chair/Advisor, Departmental Review Board
Asselin Award Committee
School of Medicine service:
Research and Development Committee
Graduate Affairs Committee
Community service:
Detroit/Wayne County Fentanyl Task Force