This Conference was held at the Natcher Auditorium on the NIH Campus, July 19-20, 2001.
Speaker Abstracts and Biographies
MDMA Research: What Next?
Jerry Frankenheim, Ph.D., Chair
Dr. Frankenheim is a pharmacologist and program official in the Pharmacology, Integrative, and Cellular Neurobiology Research Branch, Division of Neuroscience and Behavioral Research, NIDA. He was a researcher and teacher in pharmacology at Downstate Medical Center (Brooklyn, NY) and the Universities of North Carolina (Chapel Hill), Western Australia (Perth), and Connecticut (Storrs). Just before joining NIDA, he did research at Pennwalt (Rochester, NY) to discover and develop novel antidepressants, anticonvulsants, cerebroprotectives (remacemide), and other drugs for psychiatric and neurologic indications. His interests at NIDA include neurotoxicology and neuro-HIV/AIDS; phencyclidine, ketamine, other glutamate antagonists, and synaptic plasticity, including pharmacologic models of psychosis; LSD-like "hallucinogens"; amphetamines; cannabinoids; and GHB. He chaired the organizing committee for this conference.
Acute Effects of MDMA: What Don't We Know?
Gantt P. Galloway, Pharm.D.
Dr. Galloway is Chief of Pharmacological Research at the Haight Ashbury Free Clinics in San Francisco. His research focuses on the consequences of drug abuse and pharmacotherapy for the treatment of addiction. He was a co-investigator on one of the first National Institute on Drug Abuse-funded sociologic studies of use of MDMA.
Long-Term Consequences of Ecstasy Use Upon Cognition
Euphrosyne Gouzoulis-Mayfrank, M.D.
What We Know
Ecstasy (3,4-methylenedioxymethamphetamine = MDMA and related congeners) is a group of recreational drugs with neurotoxic effects upon central serotonergic systems in experimental animals. Recent evidence suggests that humans may also be susceptible to the neurotoxicity of ecstasy. So far, the most convincing evidence for long-term alterations of cerebral functions after ecstasy use derives from cognitive studies, which demonstrate relative memory impairment in regular ecstasy users.
Most ecstasy users are polydrug users. Their lifestyle (e.g., regular attendance at all-night raves · sleep deprivation) makes it difficult to compare them with "control subjects," who do not belong to the drug and dance scene. In addition, the chemical composition and dosage of ecstasy tablets vary strongly. Therefore, the following question arises: Is the relative memory impairment of ecstasy users due to their ecstasy use? And, if yes: Is it due to the neurotoxic effects of ecstasy upon central serotonergic systems? However, irrespective of these difficulties, recent data do support the view that ecstasy use (possibly in conjunction with the use of other drugs) leads to a decline of memory functions. This relative deficit is likely to be related to the well-recognized neurotoxic potential of ecstasy upon brain serotonergic systems.
Future studies should include followup investigations of people with continued ecstasy use and former users after longer abstinence periods. In addition, morphological and functional neuroimaging studies should add to our understanding of how ecstasy may alter and impair neurocognitive functioning.
Bolla KI, McCann DU, Ricaurte GA. (1998) Memory impairment in abstinent MDMA ("ecstasy") users. Neurology 51:1532-1537.
Gouzoulis-Mayfrank E, Daumann J, Tuchtenhagen F, Pelz S, Becker S, Kunert H-J, Fimm B, Sass H. (2000) Impaired cognitive performance in drug-free recreational ecstasy (MDMA) users. J Neurol Neurosurg Psychiatry 68:719-725.
Parrott AC. (2000) Human research on MDMA (3,4-methylenedioxymethamphetamine) neurotoxicity: Cognitive and behavioural indices of change. Neuropsychobiology 42:17-24.
Dr. Gouzoulis-Mayfrank is a neurologist and psychiatrist holding a clinical and research position in the Department of Psychiatry and Psychotherapy at the University of Technology in Germany. Her primary areas of scientific and clinical interest are the acute neurobiological effects of hallucinogens, stimulants, and ecstasy in humans, the long-term consequences of ecstasy use in humans, neurocognitive functioning in schizophrenia, and the treatment of dual diagnosis patients (schizophrenia and addiction).
Public Health Perspective on MDMA
James N. Hall, B.A.
The evolution of MDMA abuse as a public health issue is tracked over the past quarter century. Applying Golub and Johnson's model of drug abuse epidemics to patterns of MDMA abuse reveals an extended incubation period before 1996 among distinct groups. The MDMA epidemic's expansion phase has been fueled by dramatic increases in the drug's trafficking and its availability to younger populations. An update on MDMA abuse will include patterns reported at the June 2001 NIDA Community Epidemiology Work Group. A comparison with previous stimulant epidemics offers clues for reversing MDMA abuse.
Challenges and Opportunities
Tracking MDMA abuse reveals the classic pattern of a drug epidemic emerging among hidden populations. This particular epidemic has also introduced the need to identify and track hidden consequences of the drug's abuse. Problems related to MDMA are observed in the abuse of multiple drugs, thus revealing "ecstasy" use as a polydrug abuse phenomenon. The global nature of MDMA trafficking makes this a multinational problem mandating international research networks for its surveillance and prevention.
Technological advances and changes of the post-communist age have fueled the worldwide spread of MDMA abuse, foreshadowing how widespread future drug epidemics could be. Earlier detection, sharing of research findings, and faster responses to emerging epidemics are required for the modern drug abuse era. This conference will expose multiple determinants of MDMA abuse, which are the factors to target for its prevention. Linking supply-side intelligence with demand-side epidemiology assists development of both criminal justice and public health strategies.
Advance Report - Proceedings of the Community Epidemiology Work Group, June 2001. U.S. Department of Health and Human Services, National Institute on Drug Abuse: Rockville, MD, July 2001.
Club Drugs. The Drug Abuse Warning Network (DAWN) Report. U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Office of Applied Studies: Rockville, MD, December 2000.
Joint Assessment of MDMA Trafficking Trends. U.S. Department of Justice, National Drug Intelligence Center: Johnstown, PA, July 2000.
Golub AL, Johnson BD. Crack's Decline: Some Surprises Across U.S. Cities. NIJ Research in Brief. U.S. Department of Justice, Office of Justice Programs, National Institute of Justice: Washington, DC, July 1997.
Mr. Hall has begun his 20th year as Executive Director of Miami's Up Front Drug Information Center. He has represented South Florida on NIDA's Community Epidemiology Work Group since 1985. Mr. Hall was the first to report in the public health literature on the abuse of the medication flunitrazepam (Rohypnol) in the United States. He also organized the Texas-Florida Rohypnol Response Group. Mr. Hall founded the Institute for the Prevention and Prosecution of Drug-Rape. He serves as a consultant to the Federal National Drug Intelligence Center and as Director of Research and Information for The Miami Coalition for a Safe and Drug-Free Community.
Overview of MDMA-Induced Persistent Neurotoxicity: Preclinical Perspective
Glen R. Hanson, D.D.S., Ph.D.
The potential neurotoxic properties of amphetamine-related drugs were suggested by observations in the rat of Gibb and Koda (JPET 185  42) and Seiden et al. (Drug Alcoh Depend 1  215) that high-dose methamphetamine (METH) treatment causes persistent deficits in the dopamine (DA) system associated with the basal ganglia. Gibb and Hotchkiss (JPET 214  257) later reported that similar METH administrations also cause similar long-term declines in the serotonin (5HT) systems associated with the frontal cortex, striatum, and hippocampus. These findings suggested that heavy METH use can be neurotoxic to critical systems in the brain associated with memory, information processing, and motor functions. Because MDMA is a METH analogue, its effects on DA and 5HT systems have also been studied. Moderate-to-high doses of MDMA cause METH-like long-term deficits in brain 5HT, but not DA systems. These persistent serotonergic effects appear to be (1) at least partially mediated by MDMA-related stimulation of DA systems, (2) linked to production of free radicals, (3) dependent on the serotonin transporters, and (4) facilitated by hyperthermia. However, reactive MDMA metabolites do not appear to be necessary for this neurotoxic effect of MDMA. These preclinical findings in rat predict that, in humans, MDMA substantially enhances the activity of DA systems and is a potential neurotoxin to some 5HT systems.
As with many animal models, the relevance of these findings to humans and real-life circumstances has been questioned. With new and more sophisticated methodologies, we are now able to determine whether our findings in the laboratory are predictive of the human experience.
If we are to effectively deal with persons who have experienced long-term brain consequences from using MDMA, we must identify more precisely how and why this drug damages the central nervous system. With such knowledge, we should be able to develop better strategies to prevent and treat MDMA-induced functional deficits.
Che S, Johnson M, Hanson GR, Gibb JW. (1995) Body temperature effect on MDMA-induced acute decrease in tryptophan hydroxylase activity. Eur J Pharmacol 293:447-453.
Sandoval V, Riddle E, Ugarte Y, Hanson GR, Fleckenstein AE. (2001) Methamphetamine-induced rapid and reversible changes in dopamine transporter function: An in vitro model. J Neurosci 21:1413-1419.
Stone DM, Stahl DC, Hanson GR, Gibb JW. (1986) The effects of MDMA and MDA on monoaminergic systems in the rat brain. Eur J Pharmacol 128:41-48.
Dr. Hanson was appointed Director of the Division of Neuroscience and Behavioral Research at the National Institute on Drug Abuse (NIDA) in September 2000. This Division administers extramural research programs in basic neurobiological and behavioral sciences related to issues of drug abuse and addiction. Dr. Hanson is also a tenured full professor in pharmacology at the University of Utah. He is actively involved in research that until now has resulted in (1) approximately 150 papers in peer-reviewed scientific journals and (2) approximately 200 abstracts presented at scientific meetings around the world. Dr. Hanson is recognized as an expert on the psychostimulants and is particularly known for his work on the neurotoxic properties of ecstasy and the amphetamines and the role of brain peptides (small proteins) in psychiatric and neurological functions. Dr. Hanson has been supported by grants from NIDA and the National Institute of Mental Health since the early 1980s and in 1998 received a Senior Scientist Award from NIDA. He has served on several grant review committees for NIH and on the editorial board of the Journal of Pharmacology and Experimental Therapeutics and is a frequent reviewer for most of the major pharmacology and neuroscience journals.
"Ecstasy" Deaths - More Than Just MDMA: An Australian Perspective
Rodney J. Irvine, Ph.D.
What We Know
Acute adverse reactions after taking "ecstasy" can result in death. In nearly all cases, the symptoms include disruption of body temperature and cardiovascular regulation. Research on MDMA has identified mechanisms that explain some of these effects and support clinical observations suggesting that high ambient temperatures and high physical activity may contribute to the onset of these symptoms (Dafters, 1995). Unfortunately, this research still does not clearly explain why these adverse events are unpredictable and do not occur after every administration. It is likely there are many reasons, including genetic predisposition and drug interactions as well as the behavioral and environmental factors already mentioned.
In many situations, ecstasy is not only MDMA but also includes a number of other drugs or drug combinations. This vastly complicates the pharmacology of ecstasy poisonings and makes the design of treatment problematic. For example, in Australia, p-methoxyamphetamine (PMA) is commonly sold as ecstasy and has resulted in deaths (Byard et al., 1998). Furthermore, our data suggest that PMA is the drug responsible for most of the ecstasy poisonings in our study population (Ling et al., 2001). Our animal studies also indicate that PMA has potent effects on thermoregulation and the cardiovascular system (Irvine et al., 2001).
In order to advance our understanding of acute toxic effects of ecstasy, a number of issues must be addressed. The adverse effects of agents such as MDMA and PMA in animal models need to be clearly characterized and the roles of fundamental variables such as gender, ambient temperature, and metabolism examined. These studies will allow examination of more complicated aspects of acute ecstasy toxicity such as drug interactions.
Byard RW, Gilbert J, James R, Lokan RJ. (1998) Amphetamine derivative fatalities in South AustraliaŅIs 'ecstasy' the culprit? American J Forensic Med Path 19:261-265.
Dafters RI. (1995) Hyperthermia following MDMA administration in rats: Effects of ambient temperature, water consumption and chronic dosing. Physiology and Behavior 58:877-882.
Irvine RJ, Toop N, Phillis B, Lewanowitsch T. (2001) Cardiovascular effects of MDMA and PMA in the rat. Addiction Biology 6:45-54.
Ling HL, Marchant C, Buckley NA, Prior M, Irvine RJ. (2001) Poisoning with the recreational drug paramethoxyamphetamine ("death"). Med J Aust 174:453-455.
Originally from Aberdeen, Scotland, Dr. Irvine is an in vivo pharmacologist undertaking primarily animal-based research on drugs of abuse. These projects include examination of the pharmacology of MDMA and PMA as well as opioids. He is particularly interested in the acute and long-term adverse effects of these drugs. Dr. Irvine is also involved in human-based research conducted in a major teaching hospital.
Ruth L. Kirschstein, M.D.
Dr. Kirschstein was named Acting Director of the National Institutes of Health (NIH) on January 1, 2000.
She served as the NIH Deputy Director between November 1993 and December 31, 1999. She also served as the Acting NIH Director between July 1993 and November 22, 1993. Prior to that, Dr. Kirschstein was the Director of the National Institute of General Medical Sciences (NIGMS), beginning that appointment on September 1, 1974. A native of Brooklyn, New York, she received her B.A. degree in 1947 from Long Island University and her M.D. in 1951 from Tulane University School of Medicine. Dr. Kirschstein has twice taken part in World Health Organization (WHO) deliberations in Geneva, Switzerland, in 1965 as a member of the WHO Expert Group on International Requirements for Biological Substances and in 1967 as a consultant on problems related to the use of live poliovirus oral vaccine. She has received many honors and awards, including the Presidential Meritorious Executive Rank Award, 1980; election to the Institute of Medicine, 1982; selection by the Office of Personnel Management as 1 of 10 outstanding executives and organizations for its first group of "Profiles in Excellence," 1989; election as a fellow of the American Academy of Arts and Sciences, 1992; and the Public Service Award from the Federation of American Societies for Experimental Biology in 1993.
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