This Conference was held at the Natcher Auditorium on the NIH Campus, July 19-20, 2001.

Speaker Abstracts and Biographies

Jean Lud Cadet, M.D.

Biography

Dr. Cadet graduated from Columbia University, College of Physicians and Surgeons, in 1979. He did a residency in neurology at Mount Sinai and in psychiatry at Columbia University in New York City. He subsequently did a fellowship in neuropsychiatry at the National Institute of Mental Health at the National Institutes of Health (NIH), after which he joined Columbia University as an assistant professor of neurology and psychiatry. He joined the National Institute on Drug Abuse (NIDA) in 1992. He is presently Chief, Molecular Neuropsychiatry Section, and Clinical Director of the NIH/NIDA Intramural Research Program. His research interests include (1) clinical neurobiology of drug abuse and addiction, (2) cellular and molecular neurotoxicology of drug abuse, (3) the involvement of free radicals in neurodegeneration, (4) the role of cell death-related genes in the toxicity of drug abuse, and (5) the participation of catecholamines in neurodegenerative disorders.

Patterns and Trends of MDMA Use and Sexual Risk Behavior in Central Ohio
Robert G. Carlson, Ph.D.

Advances

Recent qualitative research on patterns and trends of MDMA use in central Ohio has revealed different user groups, varying patterns of use, and increasingly diverse contexts of use. No longer limited to the "rave scene" or dance clubs, MDMA use has moved to concerts, parks, house parties, and a variety of other venues. MDMA is increasing in popularity among high school and college students as well as other young people not in school. Preliminary findings also indicate that some MDMA users engage in high-risk sexual behaviors while others do not; however, the characteristics of high-risk takers versus others are not clear.

Challenges

Participants emphasized a significant contradiction between messages they hear about the potential negative effects of MDMA use and those they hear about positive experiences of people who have used the drug. Although sporadic horror stories in the media about the negative effects of MDMA use impact some users, most people rationalize that "that won't happen to me." Convincing young people that significant health risks are associated with MDMA use is a major challenge to future prevention efforts.

Future Directions

National MDMA prevention efforts appear to be having limited impact. Because MDMA is often distributed and used in small groups, a peer-driven network approach to prevention may be appropriate. In addition, epidemiologic data on long-term patterns of MDMA and other drug use, sexual risk behavior, and health service needs among different user groups are urgently needed to develop effective prevention strategies.

References

Carlson RG. (2000) Shooting galleries, dope houses, and "doctors": Examining the social ecology of HIV risk behaviors among drug injectors in Dayton, Ohio. Human Organization 59(3):325-333.

Carlson RG, Falck RS, Siegal HA. (2000) Crack-cocaine injection in the heartland: An ethnographic perspective. Medical Anthropology 18:305-323.

Carlson RG, Siegal HA, Falck RS. (1995) Qualitative research methods in drug abuse and AIDS prevention research: An overview. In Qualitative Methods in Drug Abuse and HIV Research. Elizabeth Y. Lambert, Rebecca S. Ashery, and Richard H. Needle, eds. (NIDA Research Monograph 157. NIH Publication No. 95-4025, pp. 6-26). Washington, DC: U.S. Department of Health and Human Services.

Biography

Dr. Carlson is a medical anthropologist and professor in the Center for Interventions, Treatment, and Addictions Research, Wright State University School of Medicine, Dayton, Ohio. He is principal investigator on a new study funded by NIDA entitled "MDMA/Club Drug Use and STD/HIV Sex Risk Behavior in Ohio," co-investigator on a natural history study of crack-cocaine users, and Project Administrator for the Ohio Substance Abuse Monitoring Network, a statewide epidemiologic surveillance system. Dr. Carlson received his Ph.D. degree from the University of Illinois at Urbana-Champaign in cultural anthropology and conducted his doctoral research on alcohol use among the Haya of Tanzania. For the past 12 years, he has conducted research on HIV risk behavior and health service use among injection drug and crack-cocaine users in Ohio. His research interests include psychoactive drug use, ethnographic methods, natural history research, AIDS prevention, and political economy. Dr. Carlson is past Chair of the AIDS and Anthropology Research Group and recipient of the 1996 Steven Polgar Award from the Society for Medical Anthropology.

Patterns of MDMA Use Among Men Who Have Sex With Men in Boston and New York City
Patricia Case, Sc.D.

Advances

Preliminary ethnographic findings suggest that, as has been reported for other population groups, men who have sex with men (MSM) in Boston and New York City commonly use MDMA. MDMA use is prevalent among diverse groups of MSM and in multiple contexts: dance parties, bars and clubs, house parties, sex clubs, and other venues in both cities. There are regional variations in the ways that MDMA is acquired and used; in New York City, there are well-established professional dealers and open sales of the drug, but this is less common in Boston. MSM rarely report using MDMA alone; instead, it is used in combination with other drugs as part of a "menu" of drugs selectively administered over a period of time or as an ingredient in mixtures of ketamine, cocaine, methamphetamine, Viagra, or other drugs. MSM report unprotected oral and anal sex in the context of MDMA use; however, unsafe sex is more often attributed to the use of other drugs such as ketamine and methamphetamine.

Challenges

Prevention messages centered on the risks of MDMA have had little effect in reducing the use of MDMA among MSM. An important challenge to prevention efforts is one of competing risks. In both cities, well-publicized overdose deaths from GHB in the MSM community have caused concern and reductions in use among MSM, but there are fewer reported problems associated with MDMA and, as a result, less concern about its use.

Future Directions

Epidemiological, ethnographic, clinical, and animal studies of emergent, complex patterns of MDMA use are needed to understand the health and medical consequences of MDMA use alone and in combination with other drugs. Interventions to reduce and prevent MDMA use should target specific risk groups and take into account the regional variations and complex patterns of MDMA administration.

References

Case P, Beckett GA, Jones TS. (1998) Access to syringes in Maine: Pharmacy practice after the 1993 repeal of the syringe prescription law. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 18 Suppl 1:S94-101.

Wolf RC, Case P, Pagano M. (1998) Estimation of the prevalence of injection drug use in greater Boston in 1993. Journal of Psychoactive Drugs 30:21-24.

Biography

Dr. Case is a social epidemiologist on the faculty of the Department of Social Medicine at Harvard Medical School. She is the Director of the Program in Urban Health and principal investigator of a NIDA-funded study, "HIV Risk and Club Drugs Among MSM: A Two City Comparison." She also serves as co-investigator of a NIDA-funded study," Social Course of Adherence to HAART in Active Users of Illegal Drugs." Dr. Case received her doctorate from the Harvard School of Public Health. Her research interests include emerging drug use patterns, infectious disease, HIV and drug policy, sexual minorities and patterns of drug use, and social network analysis.

Neuroimaging Studies in Chronic Effects of MDMA/Ecstasy Use
Linda Chang, M.D.

Advances

3,4-Methylenedioxymethamphetamine (MDMA) is an illicit and popular drug that has been associated with serotonergic axonal degeneration in animals. Until recently, much less is known in humans regarding the neurotoxic effects of MDMA. In vivo neuroimaging studies have shown significant decreases in 5-HT transporters (McCann et al., 1998) and abnormalities in 5-HT receptors (Reneman et al., 2000a; Reneman et al., 2000b). Although resting cerebral blood flow (rCBF) (Chang et al., 2000) and brain activation (Gamma et al., 2001) do not differ between ecstasy users and controls, decreases in rCBF may be observed in individuals 2 weeks after MDMA is administered in a controlled setting (Chang et al., 2000). Furthermore, abstinent recreational users showed increased myoinositol, a glial marker, on magnetic resonance spectroscopy (Chang et al., 1999).

Challenges

Many MDMA users are polydrug users who tend to experiment also with hallucinogens, LSD, mushrooms, and cocaine. Therefore, extensive screening procedures are needed in order to recruit "pure" MDMA users; even these pure users may not be truthful about their drug use history. Another challenge is to assess and ensure the accurate duration since the drug was last used and when the imaging studies occurred. These problems are not unique to MDMA users but are common problems in all drug abuse research involving human subjects.

Future Directions

• What are the long-term effects of chronic MDMA abuse on brain function (cognition) sleep, and other physiological parameters and neurochemistry?
• Can these changes recover or improve?
• What, if any, are the interaction effects of other amphetamines with MDMA in terms of brain function and neurochemistry?
• Are there interaction effects with MDMA and HIV?

Studies were supported by NIDA, K-20 DA00280-05, and the GCRC MO1 000425.

References

Chang L, Ernst T, Grob CS, Poland RE. (1999) Cerebral 1H MRS abnormalities in 3,4-methylenedioxy-methamphetamine (MDMA, "ecstasy") users. Journal of Magnetic Resonance Imaging 10(4):521-526.

Chang L, Grob C, Ernst T, Itti L, Mishkin F, Jose-Melchor R, et al. (2000) Effect of ecstasy [3,4-methylenedioxy-methamphetamine (MDMA) on cerebral blood flow: A co-registered SPECT and MRI study. Psychiatry Research 98(1):15-28.

Gamma A, Buck A, Berthold T, Vollenweider F. (2001) No difference in brain activation during cognitive performance between ecstasy (3,4-methylenedioxymethamphetamine) users and control subjects: A [H2(15)O]-positron emission tomography study. Journal of Clinical Psychopharmacology 21(1):66-71.

McCann UD, Szabo Z, Scheffel U, Dannals RF, Ricaurte GA. (1998) Positron emission tomographic evidence of toxic effect of MDMA ("ecstasy") on brain serotonin neurons in human beings. The Lancet 352:1433-1437.

Reneman L, Booij J, Schmand B, van den Brink W, Gunning B. (2000a) Memory disturbances in "ecstasy" users are correlated with an altered brain serotonin neurotransmission. Psychopharmacology 148(3):322-324.

Reneman L, Habraken J, Majoie C, Booij J, den Heeten G. (2000b) MDMA ("ecstasy") and its association with cerebrovascular accidents: Preliminary findings. American Journal of Neuroradiology 21(6):1001-1007.

Biography

Dr. Chang was recently appointed Scientist and Chair of the Medical Department at Brookhaven National Laboratory. She received her M.D. and M.S. degrees in physiology and biophysics from Georgetown University and completed her internship in internal medicine at the University of Southern California and her neurology residency training at the University of California, Los Angeles (UCLA). She also completed two fellowships in electrophysiology and neuroimaging. While at UCLA, she applied physiological and functional MR techniques, as well as SPECT and PET, to evaluate brain injury associated with drug abuse (including cocaine, methamphetamine, and MDMA), HIV dementia, and opportunistic brain lesions in AIDS.

Long-Term Functional Consequences of MDMA Abuse: Discussion
H. Valerie Curran, Ph.D.

Where We Have Been

How far have we come in understanding the consequences of MDMA abuse on cognition function, mood, and behavior? Different strands of evidence from neurobiological, behavioral, and psychiatric studies with humans differ in the degree to which causal links can be drawn between MDMA use and functional consequences. Although research has looked at the effects of single doses administered to human volunteers, our understanding of the effects of longer term use relies on studies of people self-administering MDMA, and these are fraught with methodological difficulties (Hatzidimitriou et al., 1999). Nevertheless, there are some emerging consistencies. This discussion aims to draw together themes from the afternoon's talks and link these with the morning session on long-term toxicity.

Challenges

One central, practical challenge is overcoming methodological problems including how to verify drug use history, how to allow for multiple drug use, how to establish baseline (pre-morbid) levels of function, and how to determine the time course of effects.

Future Directions

Given that 5-HT neurotoxic effects persist in primates for several years (Curran, 2000), it is important to determine what happens to humans when they stop using MDMA. Some new data on this will be presented. Are there factors that predispose some to experience negative consequences of MDMA more than others? To what extent does this depend on extent of MDMA use, combined use with other drugs, and individual differences? What are the implications for treatment?

References

Curran HV. (2000) Is MDMA neurotoxic in humans? An overview of evidence and methodological problems in research. Neuropsychobiology 42:34-41.

Hatzidimitriou, McCann, and Ricaurte. (1999) Altered serotonin innervation patterns in the forebrain of monkeys treated with (+/-)3,4-methylenedioxymethamphetamine seven years previously: Factors influencing abnormal recovery. J Neuroscience 191:5096-5107.

Biography

Dr. Curran is Professor of Psychopharmacology in the Psychopharmacology Research Unit, Clinical Health Psychology, at University College London. Her research examines how psychotropic drugs affect memory, mood, and, more recently, the processing of emotional stimuli. Her studies are carried out in various settings with volunteers, psychiatric patients, and drug abusers. Recent research on abuse has included studies of benzodiazepines, ketamine, MDMA, and methadone.

Degeneration in Brain Following Binge Stimulants: All Dopaminergics Induce Degeneration in Fasciculus Retroflexus, but MDMA Also Includes Degeneration in Oral Pontine Serotonin Terminals
Gaylord D. Ellison, Ph.D.

Advances

MDMA has both common and unique properties. It shares, with other amphetamine-like drugs that potentiate dopamine (d-amphetamine, methamphetamine, cathinone), the characteristic of inducing degeneration in axons in fasciculus retroflexus, projecting from lateral habenula ventrally to target cells in SN, VTA, and raphe nuclei. As such, it destroys an important descending negative feedback system from forebrain projections onto the monoaminergic cells that innervate them. Some of these drugs also induce degeneration in other neuropil (for example, the amphetamines on dopamine terminals in caudate), but studies of degeneration also show that MDMA has other, unique long-lasting effects on brain. There is a very pronounced profile of degenerating terminals in ventral pons (presumably serotonergic terminals on the giant oral pontine cells) and also scattered axons in the trigeminal nerve.

Challenges

Why should this drug induce such pronounced degeneration in oral nuclei? This presumably underlies the oral syndromes and aftereffects of prolonged MDMA abuse.

Future Directions

Can other drugs that combine dopamine and serotonergic hyperactivity also induce this distinctive profile?

Biography

Dr. Ellison received his Ph.D. degree from Yale University in 1963 and then went, as the first Postdoctoral Scholar sent by the National Institute of Mental Health behind the "Iron Curtain," to Warsaw, Poland, where he spent a year working with Jerzi Konorski, one of Pavlov's most famous students. He then returned to Yale for a year in psychiatry and then moved to the Department of Psychology and the Brain Research Institute at the University of California, Los Angeles. Since that time, he has been the author of over 150 papers, chiefly in the area of psychopharmacology, including models of stimulant and PCP psychosis, tardive dyskinesia, and antidepressants. He first discovered the neurotoxic effects of amphetamines in caudate and the neurotoxic effects of all amphetamine-like substances on fasciculus retroflexus.

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