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Pharmacology and Toxicology of Amphetamine and Related Designer Drugs

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Pharmacology and Toxicology of Amphetamine and Related Designer Drugs U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol Drug Abuse and Mental Health Administration Pharmacology and Toxicology of Amphetamine and Related Designer Drugs Editors: Khursheed Asghar, Ph.D. Division of Preclinical Research National Institute on Drug Abuse Errol De Souza, Ph.D. Addiction Research Center National Institute on Drug Abuse NIDA Research Monograph 94 1989 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, DC 20402 Pharmacology and Toxicology of Amphetamine and Related Designer Drugs ACKNOWLEDGMENT This monograph is based upon papers and discussion from a technical review on pharmacology and toxicology of amphetamine and related designer drugs that took place on August 2 through 4, 1988, in Bethesda, MD. The review meeting was sponsored by the Biomedical Branch, Division of Preclinical Research, and the Addiction Research Center, National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder’s permission is required. All other matieral in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. Citation of the source is appreciated. Opinions expressed in this volume are those of the authors and do not necessarily reflect the opinions or official policy of the National Institute on Drug Abuse or any other part of the U.S. Department of Health and Human Services. The U.S. Government does not endorse or favor any specific commercial product or company. Trade, proprietary, or company names appearing in this publication are used only because they are considered essential in the context of the studies reported herein. DHHS publication number (ADM)89-1640 Printed 1989 NIDA Research Monographs are indexed in the Index Medicus. They are selectively included in the coverage of American Statistics Index, Biosciences Information Service, Chemical Abstracts, Current Contents, Psychological Abstracts, and Psychopharmacology Abstracts. iv Contents Page Preface ix Structure-Activity Relationships of MDMA-Like Substances 1 David E. Nichols and Robert Oberlender Self-Injection in Baboons of Amphetamines and Related Designer Drugs 30 CA. Sannerud, J.V. Brady, and R.R. Griffiths Stimulus Properties of Hallucinogenic phenalkylamines and Related Designer Drugs: Formulation of Structure-Activity Relationships 43 Richard A. Glennon Amphetamines: Aggressive and Social Behavior 68 Klaus A. Miczek and Jennifer W. Tidey Neurochemical Mechanisms Involved in Behavioral Effects of Amphetamines and Related Designer Drugs 101 Lisa H. Gold, Mark A. Geyer, and George F. Koob Neuronal Actions of Amphetamine in the Rat Brain 127 Philip M. Groves, Lawrence J. Ryan, Marco Diana, Stephen J. Young, and Lisa J. Fisher v Page Methamphetamine and Related Drugs: Toxicity and Resulting Behavioral Changes in Response to Pharmacological Probes 146 Lewis S. Seiden and Mark S. Kleven Role of Dopamine in the Neurotoxicity Induced by Amphetamines and Related Designer Drugs . 161 James W. Gibb. Donna M. Stone, Michel Johnson, and Glen R. Hanson Acute and Long-Term Neurochemical Effects of Methylenedioxymethamphetamine in the Rat 179 Christopher J. Schmidt Effects of MDMA and MDA on Brain Serotonin Neurons: Evidence from Neurochemical and Autoradiographic Studies 196 Errol B. De Souza and George Battaglia Characterization of Brain Interactions With Methylenedioxyamphetamine and Methylenedioxymethamphetamine 223 Robert Zaczek, Stephen Hurt, Steven Culp, and Errol B. De Souza Pharmacologic profile of Amphetamine Derivatives at Various Brain Recognition Sites: Selective Effects on Serotonergic Systems 240 George Battaglia and Errol B. De Souza Effects of Amphetamine Analogs on Central Nervous System Neuropeptide Systems 259 Glen R. Hanson, Patricia Sonsalla, Anita Letter, Kalpana M. Merchant, Michel Johnson, Lloyd Bush, and James W. Gibb Effects of Neurotoxic Amphetamines on Serotonergic Neurons: Immunocytochemical Studies 270 Mark E. Molliver, Laura A. Mamounas, and Mary Ann Wilson Studies of MDMA-Induced Neurotoxicity in Nonhuman Primates: A Basis for Evaluating Long-Term Effects in Humans 306 George A. Ricaurte vi Page Dose- and Time-Dependent Effects of Stimulants 323 Everett H. Ellinwood, Jr., and Tong H. Lee Recommendations for Future Research on Amphetamines and Related Designer Drugs 341 Ray W. Fuller List of NIDA Research Monographs 358 vii Preface The abuse of amphetamines is of national concern from a public health perspective. Review of this subject is timely and important, because the problem of amphetamine-like drugs has recently been amplified by the introduction of designer drugs in the illicit market. There has been an increasing number of attempts by chemists in clandestine laboratories to synthesize structurally altered congeners that might intensify the mood- altering property of this class of compounds. While attention over the last few decades has been centered on research related to amphetamine, methamphetamine, and clinically prescribed amphetamine derivatives including fenfluramine, recent attention has focused on a variety of amphetamine-related designer drugs. These designer drugs include ring- substituted derivatives of amphetamine and methamphetamine such as 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymetham- phetamine (MDMA “ecstasy”), respectively. MDMA has been the focus of a great deal of recent attention, since it represents one of a number of “designer drugs” that is being increasingly abused among certain segments of the population, especially among college students. This popularity is ascribed to the drugs’ mixed central nervous system (CNS) stimulant and hallucinogenic effects. Furthermore, MDMA has been the subject of recent scientific and legal debate, as several psychiatrists have reported that MDMA may “enhance emotions” and “feelings of empathy” and thus serve as an adjunct in psychotherapy. While the psychotherapeutic usefulness of this drug remains to be determined, a great deal of research has been carried out on the abuse liability, behavioral effects, and neurotoxic effects of the amphetamine-related designer drugs. A technical review meeting entitled “Pharmacology and Toxicology of Amphetamine and Related Designer Drugs” was held at the National Institutes of Health on August 2-4, 1988. The purpose of the technical review was to bring together scientists who have been carrying out research in the area to (1) summarize the research findings, (2) understand the neuronal mechanisms through which the amphetamines produce their effects, and (3) develop a consensus regarding future directions that may lead to better characterization of the effects of these drugs on various physiological parameters. An understanding of the mechanisms is critical to the development of therapeutic approaches for the treatment of intoxication, addiction, and adverse effects. The proceedings of this meeting are presented in the following chapters. ix Khursheed Asghar, Ph.D. Division of Preclinical Research National Institute on Drug Abuse Rockville, MD Errol B. De Souza, Ph.D. Neurobiology Laboratory Neurosciences Branch Addiction Research Center National Institute on Drug Abuse Baltimore, MD x Structure-Activity Relationships of MDMA-Like Substances David E. Nichols and Robert Oberlender INTRODUCTION There is virtually no one who is involved in drug abuse research, or who studies the properties of recreationally used drugs, that is not by now fami- liar with 3,4-methylenedioxymethamphetamine (MDMA) (figure 1). Over the past 4 years this substance, usually referred to in the popular press as “Ecstasy,” has received widespread media attention, This chapter will relate recent fmdings with respect to the potential dangers attendant on the use of MDMA and explore its pharmacological properties. MDMA (1) FIGURE 1. MDMA As the title implies, MDMA has pharmacological properties that set it apart from other classes of drugs. This is one of the most intriguing aspects of MDMA, largely overlooked as researchers examined the potential risks to health of MDMA use. Basic questions of how drugs work and why some are pleasurable and some are not are fundamental to our understanding of why humans use drugs. Although much of the popularity of MDMA can no doubt be attributed to curiosity following media attention, the drug itself must have some rewarding qualities. MDMA typifies a central problem with the substituted amphetamine-type substances: The fact that we know so little about any of these kinds of drugs. What does MDMA actually do? What are the psychopharmacologi- cal properties that make it attractive for recreational use? Is it “just another hallucinogenic amphetamine,” as some have asserted? In the following 1 discussion, an attempt will be made to address some of these issues, and to put the questions into a broader perspective. MDMA was patented in 1914 by a German pharmaceutical firm
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