This Conference was held at the Natcher Auditorium on the NIH Campus, July 19-20, 2001.
Speaker Abstracts and Biographies
MDMA-Induced Brain Serotonin Neurotoxicity: Preclinical Studies
George A. Ricaurte, M.D., Ph.D.
Animals treated with MDMA develop long-lasting depletions of brain serotonin (5-HT) axonal markers including 5-HT, 5-HIAA, 5-HT transporters (SERTs), and tryptophan hydroxylase (TPH). In addition, neocortical vesicular monoamine transporter (VMAT) density is reduced in MDMA-treated monkeys, and recent findings indicate that there is also a lasting impairment in 5-HT axonal transport. Further, brains of non-human primates treated with MDMA and evaluated 7 years later show evidence of "pruning," a phenomenon also seen following neurotoxic injury with various well-established monoaminergic neurotoxins, including 5,7-DHT. Doses of MDMA that damage brain serotonin neurons in animals overlap with those typically used by humans. Indeed, recent studies in squirrel monkeys and baboons using a dosing regimen of MDMA that closely parallels that used by humans attending "raves" reveal severe 5-HT neurotoxic injury 2 weeks after MDMA exposure.
More data are needed on MDMA's effects in non-human primates, particularly data regarding the long-term fate of serotonin neurons with aging. In addition, there is a paucity of information regarding the functional consequences of MDMA-induced 5-HT damage in animals.
Additional research is needed to better characterize the long-term effects of MDMA on brain 5-HT neurons of non-human primates, and potential functional consequences. Studies in non-human primates should also be conducted to validate methods of detecting brain 5-HT injury suitable for use in humans. Finally, preclinical studies aimed at determining the mechanisms of MDMA-induced 5-HT neurotoxicity may have important scientific and clinical implications.
Hatzidimitriou G, McCann UD, Ricaurte GA. (1999) Altered serotonin innervation patterns in the forebrain of monkeys treated with MDMA seven years previously: Factors influencing abnormal recovery. J Neurosci 191(12):5096-5107.
Ricaurte GA, McCann UD. (2001) Experimental studies on 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") and its potential to damage brain serotonin neurons. Neurotoxicity Res 3(1):85-99.
Ricaurte GA, Yuan J, McCann UD. (2000) (±) 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy")-induced serotonin neurotoxicity: Studies in animals. Neuropsychobiology 42(1):5-10.
Dr. Ricaurte is an associate professor in the Department of Neurology at Johns Hopkins Medical Institutions. He obtained his M.D. degree at Northwestern University School of Medicine and his Ph.D. degree at the University of Chicago. He trained in neurology at the Stanford University School of Medicine. At Johns Hopkins, he directs his neurotoxicology laboratory and heads the Movement Disorders Clinic at the Johns Hopkins Bayview Medical Center.
The Diffusion of MDMA Use Among Urban Youth in Hartford, Connecticut; Implications for Drug and HIV Prevention in Club Drug Users and Their Networks
Jean J. Schensul, Ph.D.
In spite of Federal and local efforts to inform the wider public about the dangers associated with MDMA, use has increased dramatically over the past 2 years. Once viewed as a "suburban" or "rave" drug, MDMA is now widely used among some networks of urban youth, who have limited access to accurate sources of information with consequent higher levels of exposure to risks associated with use, selling, and exposure to hard drug use. This paper combines data obtained through participant observation in urban party and club settings with network and survey data collected from urban youth between the ages of 16 and 24 to identify changing rates of diffusion of MDMA through street youth networks between 1999 and 2001, ways in which urban youth are introduced to MDMA and other dance drugs through attendance at "regular" and "after-hour and after-school clubs," the role of drugs in these settings, the means through which MDMA has diffused from these venues to urban street environments, and the changing role of media and other social influences in promoting and supporting MDMA use.
Research challenges in conducting ethnographic, epidemiologic, and network research with urban youth and in party settings include staffing, network recruitment, attrition, and confidentiality. Prevention strategies involving community media, youth networks, and local neighborhood economies and future research directions including longitudinal studies, intervention research, and ethnographic studies of drug diffusion and polydrug use will be discussed.
Community Epidemiology Work Group. (2000) Epidemiologic Trends in Drug Abuse. Volume 1: Proceedings of the Community Epidemiology Work Group. U.S. Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse.
Saunders N, Doblin R. (1996) Ecstasy: Dance Trace and Transformation. Oakland, CA: Quick American Archives.
Schensul J, Huebner C, Singer M, Snow M, Feliciano P, Broomhall L. (2000) The high, the money and the fame: Smoking bud among urban youth. Medical Anthropology 18:389-414.
Dr. Schensul is Executive Director of the Institute for Community Research and recipient of NIH grants on substance use and sexual risk and HIV exposure in urban youth and adults. She received her doctoral degree in anthropology from the University of Minnesota in 1974. Recent publications include the Ethnographer's Toolkit (7 books) (Altamira Press, 1999) and articles on ethnicity, social networks, and HIV risk in older drug users (Advances in Medical Sociology, Vol. 8, Oxford University Press, in press), high THC marijuana use in urban adolescents (Medical Anthropology, 2000), and action research for prevention and service learning with adolescents (Service Learning Research, Vol. 1, Information Age Publishers, 2001).
A Burning Candle: Challenges in Ecstasy Research
Claire E. Sterk, Ph.D.
Data reveal ecstasy use to be worldwide. Its availability and use continue to increase in the United States, Western Europe, Australia, Southeast/East Asia, South and Western Africa, the Middle East, and South America. Globally, ecstasy use appears to be most common among adolescents and young adults from all socioeconomic strata. Ecstasy use continues to shift away from large dance events to more diffuse settings. Ecstasy is known to have positive as well as acute adverse effects. Less is known about its long-term impact.
Ecstasy is perceived as a safe, nonaddictive drug, and the term refers to a wide range of phenethylamines that are classified as entactogens. A challenge is the uncertainty regarding the content of street samples of ecstasy. In addition, methodological challenges occur because most ecstasy users are polydrug users, making it difficult to determine the effects of ecstasy. Furthermore, the lack of baseline data on the functioning of ecstasy users makes it difficult to draw any conclusions about the causality of use-related adverse social and health consequences. Finally, no efficient treatment options have been identified.
Phenomenological research, in addition to continued clinical and neurological research, is needed to develop effective prevention interventions, including drug treatment. Such research also will provide insights into the developmental progression of ecstasy use, gender differences, and risk and protective factors. Longitudinal research is needed to investigate the long-term consequences of use. Finally, epidemiological and phenomenological trend data need to be collected worldwide using a shared methodology (e.g., for sampling and data collection).
Sterk C. (1999) Fast Lives: Women Who Use Crack Cocaine. Philadelphia: Temple University Press.
Sterk C, Elifson K. (2000) Fluctuating drug markers and consequences for HIV risk-taking: Findings from an ethnographic study among female drug users. Medical Anthropology 18:439-455.
Sterk C, Elifson K, Theall K. (2000) Women and drug treatment experiences: A generational comparison of mothers and daughters. Journal of Drug Issues 30:839-862.
Dr. Sterk is a professor in the Department of Behavioral Sciences and Health Education at the Rollins School of Public Health of Emory University. She holds doctoral degrees in anthropology (University of Utrecht) and sociology (Erasmus University). Her research interests encompass substance abuse, including stages of use, emerging drug trends, and the consequences of use, women's health, mental health, and prevention interventions. She serves on NIDA's Community Epidemiology Working Group and was a member of the Institute of Medicine Panel on the Contributions of the Social and Behavioral Sciences to the Public's Health.
Subjective, Reinforcing, and Discriminative Stimulus Effects of MDMA in Humans
Manuel E. Tancer, M.D.
Administration of MDMA under controlled laboratory conditions in humans has opened up important research areas. Unlike animals, human volunteers can describe the subjective effects of a drug. These subjective effects may play a critical part in the drug experience and may be related to the pattern of drug use and abuse.
The overarching goal of the studies under way at Wayne State University is to understand the role of serotonin and dopamine systems in the subjective experience of MDMA ingestion.
Study 1 directly compares the subjective, physiological, and reinforcing effects of MDMA (1 and 2 mg/kg) with the serotonergic agent (metachlorophenylpiperazine [mCPP], 0.5 and 0.75 mg/kg), a dopaminergic drug (d-amphetamine, 10 mg and 20 mg), and placebo. MDMA was observed to have robust subjective effects (with features of both mCPP and d-amphetamine), to be highly reinforcing, and to have significant physiological effects.
Study 2 is a three-way drug discrimination study. Training drugs were mCPP, d-amphetamine, and placebo. MDMA was identified by some participants as mCPP and as d-amphetamine by others, confirming that both serotonergic and dopaminergic cues were being employed.
Although the laboratory studies can help answer important questions concerning the pharmacology and acute effects of MDMA, the laboratory differs significantly from the conditions under which MDMA is consumed recreationally. Another challenge is to integrate findings from observational studies in MDMA users to develop hypotheses that can be more precisely tested under controlled conditions.
Future laboratory studies should employ multiple methods such as neuropsychological testing and functional brain imaging during MDMA administration.
Tancer ME, Johanson C-E. The subjective effects of MDMA and mCPP in moderate MDMA users. Drug and Alcohol Dependence, in press.
Dr. Tancer is a psychiatrist with extensive research and clinical experience. Trying to objectively describe the subjective experience of anxiety led him to develop a collaboration with Dr. Chris-Ellyn Johanson, a behavioral pharmacologist. This collaboration led to the submission of a training grant to look at serotonin/dopamine interactions in mediating stimulant drug effects. MDMA was selected as a mixed serotonin/dopamine drug. The explosion of MDMA use over the past few years has led to a new direction of inquiry, namely, examining the consequences of MDMA use.
Developmental Effects of MDMA
Charles V. Vorhees, Ph.D.
Little is known about the effect of MDMA or methamphetamine on the developing brain. In animals, methamphetamine (given when granule cells are dividing in the hippocampus) causes impairments in spatial learning. Rats treated with MDMA during this same stage show spatial and sequential learning impairments. MDMA animals had no difficulty learning a cued version of the maze. Amphetamines suppress appetite and therefore growth. To determine whether this could explain the learning effects of MDMA, we treated four groups: (1) MDMA, litter size = 8, (2) S8 = saline, litter size = 8, (3) S16 = saline, litter size = 16, and
(4) HC = no saline (handled), litter size = 8. Groups S8 and HC grew similarly, while S16 grew at the same reduced rate as the MDMA group. Only MDMA-treated animals showed impaired spatial learning. Therefore, spatial learning effects in MDMA offspring are not secondary to undernutrition. In adult brain, MDMA induces
5-HT release, blocks reuptake, and causes long-term depletion. In our rats, small changes were found in NE and 5-HT, but not in DA. These changes did not correlate with any measure of cognitive impairment.
No data are available on earlier stages of brain development, i.e., during embryogenesis or early fetogenesis. No data exist on the developmental pharmacokinetics of MDMA. No information is available on the reversibility of the effects seen thus far or on the cellular changes accompanying these effects.
Human investigations are urgently needed. Animal studies are also needed in order to forecast effects, characterize the range of central nervous system changes, establish dose-response and critical period relationships, and determine the pathophysiology and molecular mechanisms of action of MDMA on the developing brain.
Broening HW, Morford LL, Inman-Wood SL, Fukumura M, Vorhees CV. (2001) 3,4-Methylenedioxymeth-amphetamine (ecstasy) induced learning and memory impairments in adult offspring depend on the age of exposure during early development. J Neurosci 21:3228-3235.
Dr. Vorhees is Professor of Pediatrics and Environmental Health in the Division of Developmental Biology at the Children's Hospital Research Foundation and University of Cincinnati College of Medicine. He is also the Director of the Graduate Program in Molecular and Developmental Biology and Editor in Chief of Neurotoxicology and Teratology. His research interests include effects of substituted amphetamines on brain development and behavior and understanding the biological basis of learning and memory using gene targeting of proteins such as PDE1B, PTPa, dopamine D1, DFF45, and c-fos.
Neurochemical Mediators and Neurophysiological Consequences of Acute MDMA Exposure in Rats
Bryan K. Yamamoto, Ph.D.
The neurotoxicity of MDMA has been extensively characterized in animals. This is evidenced by the destruction of fine-diameter serotonergic fibers, loss of tryptophan hydroxylase and serotonin transporter activities, and a long-term depletion of serotonin content in tissue. Convergent lines of evidence point to the roles of oxidative damage and hyperthermia in mediating the toxicity to serotonin terminals (for reviews, see Fleckenstein et al., 2000; Huether et al., 1997; and Shankaran et al., 1999).
Despite extensive descriptive evidence of MDMA-induced neurotoxicity in laboratory animals, the mechanistic underpinnings that mediate this damage to 5HT terminals remain to be defined. Since the amphetamines, in general, cause hyperthermia, sympathetic arousal, and increased metabolism, there is a reasonable possibility that high doses of MDMA also cause a metabolic stress that interacts with oxidative damage and hyperthermia to produce long-term damage to 5HT nerve terminals. To date, however, few studies have examined metabolic stress as a factor in MDMA neurotoxicity. In addition, there are few studies on the interaction between MDMA and environmental/psychological stressors as well as the impact of MDMA on normal physiological processes such as sleep/wakefulness activity. Recent data from our laboratory will provide evidence supportive of the role of metabolic stress and will indicate that an acute exposure to MDMA alters the reactivity to environmental stress and disrupts sleep/wakefulness physiology.
Future research directions highlighted by the above results include the precise mechanisms underlying a compromised bioenergetic state, changes in stress reactivity, and altered sleep/wakefulness physiology caused by MDMA that could provide insight into the development of effective therapeutic treatments for the long-term consequences of MDMA intoxication.
Fleckenstein AE, Gibb JW, Hanson GR. (2000) Differential effects of stimulants on monoaminergic transporters: Pharmacological consequences and implications for neurotoxicity. European Journal of Pharmacology 406:1-13.
Huether G, Zhou D, Ruther E. (1997) Causes and consequences of the loss of serotonergic presynapses elicited by the consumption of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") and its congeners.
J Neural Transmission 104:771-794.
Shankaran M, Yamamoto BK, Gudelsky GA. (1999) Effect of 3,4-methylenedioxymethamphetamine (MDMA) on hydroxyl radical formation in the striatum. J Neurochemistry 72:2516-2522.
Dr. Yamamoto received his B.A. degree from the University of California, Los Angeles, and his Ph.D. degree in psychobiology from Syracuse University. He was a postdoctoral fellow in pharmacology at the University of Colorado Health Sciences Center. Dr. Yamamoto has been at Case Western Reserve University in the Department of Psychiatry since 1990 and is currently Professor of Psychiatry and Neurosciences and Director of the Program in Basic and Clinical Neuroscience in the Department of Psychiatry. This fall, he will be a Professor of Pharmacology at the Boston University Medical School. Dr. Yamamoto has served on numerous NIH study sections and currently is a regular member of a NIDA study section. NIH has funded his research continuously for the past 15 years, and his work on the neurotoxicity of methamphetamine and MDMA has been funded by NIDA for the past 10 years.
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