Pharmacology and Toxicology of Amphetamine and Related Designer Drugs pot

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 Lewis S. Seiden and Mark S. Kleven 146 Role of Dopamine in the Neurotoxicity Induced by Amphetamines and Related Designer Drugs James W. Gibb. Donna M. Stone, Michel Johnson, and Glen R. Hanson . 161 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 George Battaglia and Errol B. De Souza 240 Effects of Amphetamine Analogs on Central Nervous System Neuropeptide Systems 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 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 George A. Ricaurte 259 270 306 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 [...]... 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... enantiomer of MDMA is either equipotent to the R isomer or more potent THE ENTACTOGENS As a consequence of these and other studies that have indicated that MDMA has a pharmacology different from the hallucinogenic amphetamines, and in view of the reports by certain psychiatrists (Greer and Tolbert 1986; Wolfson 1986) that MDMA could facilitate the process of psychotherapy, it was hypothesized that MDMA and related. .. unexplored potential as psychiatric drugs (Nichols 1986; Nichols et al 1986) This class of drugs has been called entactogens Recently, efforts have been directed toward understanding the mechanism of action of MDMA and related compounds and testing the hypothesis that entactogens are a novel pharmacological class, distinct both from hallucinogenic agents and from central stimulants such as amphetamine. .. properties of the molecule, but serves primarily to attenuate the hallucinogenic activity of (-)-MDA Nevertheless, (-)-MDA also substitutes, and the psychopharmacology of racemic MDA might be viewed as comprised of the hallucinogenic and entactogenic properties of the (-)-isomer and the entactogenic and psychostimulant properties of the (+)-isomer This illustrates why detailed studies of the mechanism of action... of MDA and MDMA were indeed potent releasers of [³H]serotonin from prelabeled rat brain synaptosomes (Nichols et al 1982) Recently, it was repotted that MDA and MDMA were potent releasers of serotonin from superfused hippocampal slices prelabeled with [³H]serotonin (Johnson et al 1986) In all studies to date, whether of release of monoamines from synaptosomes or brain slices, or of the inhibiting of. .. fenfluramine is more of a sedative and dysphoric A detailed comparison of the pharmacology of fenfluramine and MDMA may be necessary to understand exactly how MDMA works Another study underway has begun to examine the effect of paramethoxyamphetamine (PMA) in MDMA-trained rats After testing a few doses, it appears that full substitution may occur and that the S enantiomcr of PMA 15 is more potent This result... argument that the pharmacology of this enantiomer of MDA is MDMA-like and is not like amphetamine Although amphetamine substitutes for MDMA in our studies, this occurs only at doses that disrupt a significant number of animals Furthermore, the large ED50 for amphetamine substitution in MDMA-trained rats is certainly not consistent with the known potency of amphetamine in measures of its stimulant activity... 4.54 - 9.34 In view of the apparent pleasurable effects of MDMA, it becomes of considerable interest to understand the mechanism of action of substances with a similar effect Major efforts have been directed toward the study of agents that have an effect on serotonin pathways, since that is the neurotransmitter system that seems most implicated in the mechanism of action of MDMA This hypothesis is further... symmetrical transfer did not occur between MDMA and amphetamine These results show that the MDMA cue is complex and may have some similarity to amphetamine However, suggestions that the pharmacology of (+)-MDMA is essentially the same as that of amphetamine are clearly not warranted by the data, This partial amphetamine- like action is believed to 9 be reflective of the effect that MDMA has on dopaminergic... day for a 4-day regimen with MDMA, and then corrected for molecular weight and used an equimolar dose of MBDB, sacrificed the animals 2 weeks later, and then measured We used basically HPLC and used serotonin and 5-HIAA from one hemisphere and then measured tritiated pyroxetine from the other hemisphere And we got something like 60 percent depletion of serotonin, and the pyroxetine binding site Bmax, . Pharmacology and Toxicology of Amphetamine and Related Designer Drugs U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public. Abuse and Mental Health Administration Pharmacology and Toxicology of Amphetamine and Related Designer Drugs Editors: Khursheed Asghar, Ph.D. Division of