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Ecstasy: the Clinical, Pharmacological and Neurotoxicological Effects of the Drug Mdma Topics in the Neurosciences

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Ecstasy: the Clinical, Pharmacological and Neurotoxicological Effects of the Drug Mdma Topics in the Neurosciences ECSTASY: THE CLINICAL, PHARMACOLOGICAL AND NEUROTOXICOLOGICAL EFFECTS OF THE DRUG MDMA TOPICS IN THE NEUROSCIENCES Other books in the series: Rahamimoff, Rami and Katz, Sir Bernard, eds.: Calcium, Neuronal Function and Transmitter Release. ISBN 0-89838-791-4. Fredrickson, Robert C.A., ed.: Neuroregulation of Autonomic, Endocrine and Immune Systems. ISBN 0-89838-800-7. Giuditta, A., et al., eds.: Role of RNA and DNA in Brain Function. ISBN 0-89838-814-7. Stober, T., et al.,: Central Nervous System Control of the Heart. ISBN 0-89838-820-l. Kelly J., et al., eds.: Polyneuropathies Associated with Plasma Cell Dyscrasias. ISBN 0-89838-884-8. Galjaard, H. et al., eds.: Early Detection and Management of Cerebral Palsy. ISBN 0-89838-890-2. Ferrendelli, J., et al., eds.: Neurobiology of Amino Acids, Pep tides and Trophic Factors. ISBN 0-89838-360-9. ECSTASY: THE CLINICAL, PHARMACOLOGICAL AND NEUROTOXICOLOGICAL EFFECTS OF THE DRUGMDMA Edited by STEPHEN J. PEROUTKA Stanford University Medical Center ~. KLUWER ACADEMIC PUBLISHERS "BOSTON IDORDRECHT ILONDON Distributors for North America: Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Norwell, MA, 02061, USA for all other countries: Kluwer Academic Publishers Group, Distribution Centre, Post Office Box 322, 3300 AH Dordrecht, The Netherlands Library of Congress Cataloging-in-Publication Data Ecstasy: the clinical, pharmacological, and neurotoxicological effects of the drug MDMA / edited by Stephen]. Peroutka. p. cm. - (Topics in the neurosciences; TNSC9) Includes bibliographies and index. ISBN- 13:978- I -4612-8799-5 e-ISBN-13:978- I -4613-1485-1 DOl: 10.1007/978-1-4613-1485-1 1. MDMA (Drug) 2. Central nervous system-Effect of drugs on. I. Peroutka, Stephen]. II. Series. [DNLM: 1. Ampheamines-analogs & derivatives. 2. Amphetamines-pharmacology. 3. Nervous System-drug effects. WI T054VF v. 9/ QV 102 E19] RM666.M35E371989 615' .785-dc 20 DNLMIDLC for Library of Congress Copyright © 1990 by Kluwer Academic Publishers Softcover reprint of the hardcover I st edition 1990 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher, Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Norwell, MA 02061. CONTENTS List of Contributors Vll Preface Xl 1. History ofMDMA ALEXANDER T. SHULGIN 2. The Therapeutic Use of MDMA 21 GEORGE R. GREER and REQUA TOLBERT 3. Testing Psychotherapies and Drug Therapies: The Case of Psychedelic Drugs 37 JAMES B. BAKALAR and LESTER GRINSPOON 4. Recreational Use ofMDMA 53 STEPHEN J. PEROUTKA 5. Human Deaths and Toxic Reactions Attributed to MDMA and MDEA 63 GRAEME P. DOWLING 6. The Public Health Implications ofMDMA Use 77 JEROME BECK 7. Structure-Activity Relationships of MDMA and Related Compounds: A New Class of Psychoactive Agents? 105 DAVID E. NICHOLS and ROBERT OBERLENDER 8. Neurochemical Effects ofMDMA 133 JAMES W. GlBB, DONNA STONE, MICHEL JOHNSON, and GLEN R. HANSON V vi Contents 9. Neurochemical Effects of Methylenedioxymethamphetamine in the Rat: Acute Versus Long-Term Changes 151 CHRISTOPHER J. SCHMIDT and VICKI L. TAYLOR to. MDMA Effects in Brain: Pharmacologic Profile and Evidence of Neurotoxicity from Neurochemical and Autoradiographic Studies 171 GEORGE BATTAGLIA, ROBERT ZACZEK, and ERROL B. DE SOUZA 11. A Tissue Culture Model ofMDMA Toxicity 201 PATRICIA M. WHITAKER-AZMITIA and EFRAIN c. AZMITIA 12. Effect ofMDMA-like Drugs on CNS Neuropeptide Systems 213 GLEN R. HANSON, KALPANA M. MERCHANT, MICHEL JOHNSON, ANITA A. LETTER, LLOYD BUSH, and JAMES W. GIBB 13. Neuroendocrinological Effects ofMDMA in the Rat 225 J. FRANK NASH and HERBERT Y. MELTZER Index 241 LIST OF CONTRIBUTORS Efrain C. Azmitia Department of Biology New York University New York, NY 10003 James B. Bakalar Department of Psychiatry Harvard Medical School Massachusetts Mental Health Center 74 Fenwood Road Boston, MA 02115 George Battaglia Department of Pharmacology Loyola University Medical Center Stritch School of Medicine 2160 South First Avenue Maywood, IL 60153 Jerome Beck School of Public Health University of California, Berkeley, CA and vii vih List of Contributors Institute for Scientific Analysis 2235 Lombard Street San Francisco, CA 94123 Lloyd Bush Department of Pharmacology and Toxicology University of Utah Salt Lake City, UT 84112 Errol B. De Souza Chief, Laboratory of Neurobiology NIDA Addiction Research Center P.O. Box 5180 Baltimore, MD 21224 Graeme P. Dowling Office of the Chief Medical Examiner P.O. Box 2257 Edmonton, Alberta T5J 2P4 Canada James W. Gibb Professor Department of Pharmacology and Toxicology University of Utah Salt Lake City, UT 84112 George Greer 3 Azul Drive Santa Fe, NM 87505 Lester Grinspoon Associate Professor of Psychiatry Harvard Medical School Massachusetts Mental Health Center 74 Fenwood Road Boston, MA 02115 Glen R. Hanson Department of Pharmacology and Toxicology University of Utah Salt Lake City, UT 84112 Michel Johnson Department of Pharmacology and Toxicology ix University of Utah Salt Lake City, UT 84112 Anita A. Letter Department of Pharmacology and Toxicology University of Utah Salt Lake City, UT 84112 Herbert Y. Meltzer Department of Psychiatry School of Medicine Case Western Reserve University Cleveland, OH 44106 Kalpana M. Merchant Department of Pharmacology and Toxicology University of Utah Salt Lake City, UT 84112 ]. Frank Nash Department of Psychiatry School of Medicine Case Western Reserve University Cleveland, OH 44106 David E. Nichols Professor of Medicinal Chemistry Department of Medicinal Chemistry and Pharmacognosy School of Pharmacy and Pharmacal Sciences Purdue University West Lafayette, IN 47907 Robert Oberlender Department of Medicinal Chemistry and Pharmacognosy School of Pharmacy and Pharmacal Sciences Purdue University West Lafayette, IN 49707 Stephen]. Peroutka Assistant Professor of Neurology Departments of Neurology and Pharmacology Stanford University School of Medicine Stanford, CA 94305 x List of Contributors Christopher J. Schmidt Merrell Dow Research Institute 2110 E. Galbraigh Road Cincinnati, OH 45215 Alexander Shulgin 1483 Shulgin Road Lafayette, CA 94549 Donna Stone Department of Pharmacology and Toxicology University of Utah Salt Lake City, UT84112 Vicki L. Taylor Merrell Dow Research Institute 2110 E. Galbraith Road Cincinnati, OH 45215 Requa Tolbert, M.S.N. 3 Azul Drive Santa Fe, NM 87505 Patricia M. Whitaker-Azmitia, Ph.D. Department of Psychiatry SUNY Stony Brook, NY 11794 Robert Zaczek, Ph.D. Laboratory of Neurobiology Neuroscience Branch Addiction Research Center National Institute on Drug Abuse Baltimore, MD 21224 PREFACE The variety of viewpoints expressed in this book illustrate the many contro­ versies surrounding MDMA [1]. On the one hand, the proponents ofMDMA use believe this agent offers a unique psychoactive effect that may have important clinical applications, especially in the field of psychotherapy. On the other hand, the scientific data concerning the neurotoxic effects of the drug are unequivocal. The most striking feature of the human information of MDMA is the paucity of data that has been generated on the drug since it was patented in 1914. As pointed out by Beck (Chapter 6) and others, a clear need exists for better epidemiological and clinical data on MDMA. In the absence of such data, arguments both for and against the cotinued use ofMDMA with humans will be difficult to support. Unfortunately, the currently available data must be used to develop rational policies for potential human users of MDMA. At the present time, there are no data indicating that recreational doses of MDMA permanently damage the human brain. Nonetheless, based on a review of the contents of this book as well as on informal discussions with approximately 200 recreational users of MDMA, the following personal observations suggest that MDMA is radically different from other recreational drugs. MDMA IS NOT "ADDICTING." The most frequent use of MDMA has been reported to occur in the first few months following the initial experience [2]. It is extremely rare to find xi xii Preface individuals who have taken large quantities of this drug. Again, this is quite different from most recreational drugs, which tend to be either psychologically or physically addicting. There are simply no reports of individuals who take frequent and large amounts of MDMA for extended periods of time. If MDMA is such an outstanding psychoactive agent, why is the drug not used in large quantities for prolonged periods of time? MDMA USERS OFTEN DELAY REPEAT DOSES OF THE DRUG. Recreational users ofMDMA state that they usually wait at least two to three weeks between doses of the drug. The reason given for this unusual pattern of recreational drug use is that the "good" effects of the drug appear to diminish, while the "negative" side-effects of the drug appear to increase, if the drug is taken too frequently. For example, taking a double dose of MDMA does not "double" the supposed "good" effects of the drug but simply increases the "negative" effects of the drug. Long-term MDMA users have also been reported to suffer from prolonged "burn-out" periods of one to two days after MDMA use [2]. THE EFFECTS OF MDMA CHANGE WITH TIME. The majority of people who have taken more than five individual doses of MDMA state that the "good" effects of the drug change with successive doses. As stated by one college student, "freshmen love it; sophomores
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