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

Poster Abstracts

Reactive Oxygen, Nitrogen Species: Implications for Neurotoxicity
Samuel Park, Donald M. Kuhn
Department of Psychiatry and Behavioral Neurosciences
Wayne State University School of Medicine
Detroit, MI

Ecstasy Use and Sexual Risk Behaviors Among Urban Youth
Raul Pino, Gary Burkholder, Jay Schensul, Julie Eiserman, Gustavo Lopez
The Institute for Community Research
Hartford, CT

This poster focuses on the transition to ecstasy use among urban youth in a 15-month period and the different factors associated with it specifically related to sexual risk behavior and sexually transmitted disease (STD). It is based on 3 years of research on factors influencing pathways to high-risk drug abuse and other health risks in urban youth and young adults. Ecstasy use is recognized nationally as a growing problem among youth, and Connecticut has recently experienced an increase in the use of this substance.

Our study utilized a targeted sampling plan and a panel design (repeat interview) with two time points 15 months apart. We recruited 400 African American and Latino/Puerto Rican youth between the ages of 16 and 24. In this poster, we will utilize baseline data to report on factors associated with ecstasy use. Next we will present data from the second interview on those who made the transition to ecstasy use and the factors associated with it. We will review STDs associated with this transition.

Use of Antisense Technologies To Study the Role of Dopamine in MDMA Neurotoxicity
Jon E. Sprague, Ph.D., Arthi Kanthasamy, Ph.D., David E. Nichols, Ph.D.
Department of Pharmaceutical and Biomedical Sciences
Ohio Northern University
Ada, OH

Department of Medicinal Chemistry and Molecular Pharmacology
Purdue University
West Lafayette, IN

Antisense (AS) regulation of protein expression represents a new and innovative approach to investigating the role of dopamine (DA) in the serotonergic neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA). Previous work from this laboratory has suggested a role for DA metabolism in the serotonergic toxicity induced by MDMA. The monoamine oxidase-B (MAO-B) inhibitor L-deprenyl protects against the serotonergic toxicity of MDMA. However, L-deprenyl possesses ancillary pharmacological actions (e.g., free-radical scavenging), which may account for the neuroprotection. In order to avoid these confounding effects, AS technology was utilized. Osmotic minipump administration of an AS targeted against the DA transporter (DAT) resulted in a 70 percent reduction in DAT levels and attenuated the serotonergic toxicity induced by MDMA (2 X 20 mg/kg, sc) 1 week later, in a region-specific manner. This protective effect is presumably due to a decrease in DA release following MDMA in the AS-treated animals. Furthermore, AS targeted against MAO-B resulted in a 40 percent reduction in MAO-B activity, which was comparable to the reduction in MAO-B produced by a single 2 mg/kg dose of L-deprenyl. We shall report the effects of the AS to MAO-B on MDMA (40 mg/kg, sc) neurotoxicity alone or in combination with L-deprenyl and the details of the results with the DAT AS. Neither AS reduced the hyperthermia induced by MDMA. Thus, AS technology represents a novel method for investigating MDMA neurotoxicity. The present results do provide further support for the role of DA in this neurotoxic process.

Psychobiologic Effects of 3,4-Methylenedioxymethamphetamine in Humans: A Pilot Study
Rosanne C. State, M.D.,1 Charles S. Grob, M.D.,1 Russell E. Poland, Ph.D.2
1Harbor-UCLA Medical Center
Torrance, CA

2Cedars-Sinai Medical Center
Los Angeles, CA

3,4-Methylenedioxymethamphetamine (MDMA) is a phenethylamine with potent effects on serotonergic neurotransmission that has been the object of controversy over its potential as a therapeutic adjunct versus its possible risk for causing neurotoxic injury. Methodological design and preliminary data of the first FDA-approved Phase 1 study prospectively evaluating the effects of MDMA administration in human subjects will be presented. Eighteen subjects with prior experience with MDMA were administered two different dosages of MDMA and an inactive placebo utilizing a randomized, double-blind methodological design. Dosages from 0.25 to 2.5 mg/kg were administered orally. Subjects tolerated the procedures without evidence of psychological distress or physical discomfort, although two subjects did experience transient hypertensive episodes. Modest elevation of temperature was observed at higher dosages. The threshold dose for the stimulation of ACTH, cortisol, and prolactin appeared to be between 0.5 and 0.75 mg/kg, with higher doses clearly stimulating neuroendocrine secretion. Baseline and followup neuropsychological measures did not reveal signs of cognitive dysfunction. Within the well-monitored, approved clinical research setting, the prospective administration of MDMA to experienced human subjects appears to be a safe procedure that may provide valuable data to further elucidate the effects of the drug.

Behavioral Sensitivity to Serotonergic Challenge in MDMA-Treated Rhesus Monkeys
M.A. Taffe,1 S. Davis,1 R. Schroeder,1 G. Hatzidimitriou,2 L.H. Parsons,1 G.A. Ricaurte,2 L.H. Gold1
1Department of Neuropharmacology
The Scripps Research Institute
La Jolla, CA

2Department of Neurology
Johns Hopkins Medical Institutions
Baltimore, MD

Rhesus monkeys (N = 3) were exposed to a high-dose, short-course regimen of (±)3,4-methylenedioxy-methamphetamine (MDMA) (4 days, 10 mg/kg i.m., b.i.d.). Following treatment, concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were reduced by approximately 50 percent in comparison with both pretreatment and control (N = 3) values. Homovanillic acid concentrations in CSF were unchanged. We have previously reported (Taffe et al., Neuropsychopharm 24:230-9, 2001) that the MDMA regimen temporarily disrupts cognitive/behavioral performance on a variety of neuropsychological test battery measures; however, no persisting alterations in performance were observed during a 4-month period in which CSF 5-HIAA levels remained suppressed. In the present study, the monkeys' behavioral performance in several cognitive domains was challenged acutely with ketanserin (0.1-1.7 mg/kg, i.m.), mCPP (0.03-0.5 mg/kg, i.m.), and 8-OH-DPAT (0.032-0.1 mg/kg, i.m.). Each compound affected performance on one or more tasks in a dose-dependent manner and to an equivalent extent in each treatment group. Animals were then sacrificed and brain tissue from a number of regions was assayed for serotonin and 5-HIAA. The MDMA-treated animals exhibited fourfold to fivefold reductions in 5-HT in cortex 17 months after MDMA exposure. In total, the present observations indicate that a substantial reduction in cortical 5-HT content does not make rhesus monkeys' cognitive performance more susceptible to the disrupting effects of serotonergic agents.

Research was supported by USPHS grants DA13390 (MAT), DA11004 (LHP), and DA09111 (LHG).

"Just a Little Pill": Patterns and Trends Among Young Adult Ecstasy Users in Atlanta, Georgia
Katherine P. Theall, M.P.H., Kari B. Greene, Rachel Kachur, M.P.H., Kirk Elifson, Ph.D.
Department of Behavioral Sciences and Health Education
Rollins School of Public Health
Emory University
Atlanta, GA

Advances

Little is known about the behaviors of ecstasy users or the social and health consequences of use. Findings from our own preliminary research show a typology of users, including experimental, occasional, and regular users. All users describe rapidly developing a tolerance for the drug as well as strategies to cope with this. Many view ecstasy as a harmless pill, and few ecstasy users anticipate the negative consequences of use. Typically, ecstasy is described as a "bonding" drug, with physical contact being limited to hugging and touching. However, some users also describe engaging in unsafe sex when high on ecstasy in a private setting.

Challenges

Behavioral and social scientists conducting ecstasy research encounter several major challenges. Drawing a representative sample of ecstasy users is hindered by their relatively hidden nature, especially of those who do not use at raves, clubs, or bars. Self-reported data on the amount and frequency of use may have limited validity. Self-reported data also reflect the user's limited knowledge of the pill's content. Finally, ecstasy use is often combined with other substances, thus complicating attempts to isolate its pharmacological and social consequences.

Future Directions

More research is needed on ecstasy users, the context of use, and use patterns, including the route of administration and polydrug use. Such studies should include cross-sectional phenomenological studies as well as more large-scale, longitudinal quantitative studies. The baseline information from such studies should be used to develop appropriate risk reduction interventions.

Neurocognitive Impairment in MDMA Users: A Meta-analytic Review
Geoffrey R. Twitchell, Ph.D.
UCLA Integrated Substance Abuse Programs
Los Angeles, CA

Applicability and Reliability of Ecstasy Abuse and Dependence Criteria
Among Persons Aged 12 to 17 Years
Sharon Womack, Ph.D., Linda B. Cottler, Ph.D.
Washington University School of Medicine
St. Louis, MO

As part of an ongoing NIDA study on the reliability and applicability of the computerized CIDI-SAM, 120 adolescents and young adults have been interviewed to date about illicit drug use and its consequences. The SAM includes DSM and ICD criteria for 10 classes of drugs and was recently revised to include club drugs. Respondents are being recruited from a local inpatient substance abuse program as well as through high school newspaper advertisements, flyers posted at college dormitories, raves, and chain referral methods. To date, nearly one-quarter (24 percent) reported more than five times use of club drugs lifetime, with all reporting at least ecstasy and several reporting two or three additional club drugs. This sample is 64 percent female, 16 percent non-white, and 32 percent between 12 and 15 years of age. Among the 25 users, reliability as well as rates of DSM-IV criteria were surprisingly high. Specifically, "continuing to use despite knowledge of harm" was the most prevalent criterion (64 percent), being reported with excellent 1-week retest agreement (kappa = .80). Withdrawal from use was endorsed by over one-half of the users (59 percent; kappa = .56). "Tolerance" to club drugs and "spending a great deal of time to use, obtain, or recover" from club drugs were each reported with high reliability (kappa = .70/.65) by over one-third of the users. Of note, 85 percent of users received a diagnosis of either abuse or dependence when DSM-IV criteria were applied to ecstasy; 40 percent met at least three criteria and thus received a diagnosis of dependent while 45 percent met criteria for abuse. This is the first effort to assess the reliability of club drug abuse and dependence. A larger sample that includes ethnically diverse users both in and out of treatment assessed with a club drug-specific assessment is needed.

In Utero Exposure to (±)-Methylenedioxymethamphetamine Enhances the Development and Metabolism of Serotonergic Neurons in Reaggregate Tissue Culture
Lisa Won, Nancy Bubula, Alfred Heller
Department of Neurobiology, Pharmacology, and Physiology
The University of Chicago
Chicago, IL

Methylenedioxymethamphetamine (MDMA, ecstasy) is a potent psychomotor stimulant with neurotoxic potential that is widely abused by females of childbearing age. This raises serious public health concerns in terms of exposure of the fetus to the drug. The current study was conducted utilizing the three-dimensional reaggregate tissue culture system as an approach to the assessment of risk to fetal monoaminergic neurons following exposure to MDMA during early to mid-gestation. In this culture system, the serotonergic and dopaminergic mesencephalic-striatal projections are reconstructed and develop with a time course similar to that observed in vivo. Pregnant C57Bl/6 mice were injected twice daily with 40 mg/kg (±)-MDMA or saline from gestational day 6 to 13. On gestational day 14, mesencephalic and striatal cells from MDMA and saline-exposed embryos were used to prepare reaggregate cultures. Levels of monoamines and their metabolites in the reaggregates and culture medium were assessed at 22 and 36 days of culture. There was a long-term enhancement of serotonergic development and metabolism by fetal exposure to MDMA as evidenced by increased reaggregate serotonin levels as well as the elevated production and release of 5-hydroxyindoleacetic acid in cultures prepared from MDMA-exposed embryos that persisted for up to 36 days of culture. Dopaminergic neurons in such cultures also exhibited increased transmitter turnover as indicated by elevated levels of dihydroxyphenylacetic acid in reaggregate tissue and culture medium. The data obtained suggest that exposure to MDMA in utero during early to mid-gestation may result in more active serotonergic and dopaminergic neurons.

Research was supported by DA09764.

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