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

Speaker Abstracts and Biographies

Alan I. Leshner, Ph.D.

Biography

Dr. Leshner was appointed Director of the National Institute on Drug Abuse (NIDA) in February 1994. NIDA, one of the Institutes within the National Institutes of Health (NIH), supports more than 85 percent of the world's research on the health aspects of drug abuse and addiction. Before joining NIDA, Dr. Leshner had been with the National Institute of Mental Health (NIMH) since 1988, holding the position of Deputy Director and then Acting Director. He came to NIMH from the National Science Foundation (NSF), where he held a variety of senior positions focusing on basic research in the biological, behavioral, and social sciences, as well as on science education. Dr. Leshner joined the NSF after 10 years at Bucknell University, where he was a professor of psychology. His research has focused on the biological bases of behavior. He is the author of a major textbook on the relationship between hormones and behavior and numerous book chapters and papers in professional journals. Dr. Leshner received his undergraduate degree in psychology from Franklin and Marshall College and his master's and doctoral degrees in physiological psychology from Rutgers University. He also holds honorary Doctor of Science degrees from Franklin and Marshall College and the Pavlov Medical University in St. Petersburg, Russia. He has been elected a fellow of many professional societies, is a member of the Institute of Medicine of the National Academy of Sciences, and has received numerous awards from both professional and lay groups. In 1996, President Clinton conferred on Dr. Leshner the Presidential Distinguished Executive Rank Award, the highest award in Federal service. In 1998, Dr. Leshner was elected to membership in the Institute of Medicine of the National Academy of Sciences.

Minda R. Lynch, Ph.D.

Biography

Dr. Lynch directed a program of preclinical investigation at the SUNY Health Science Center and Veterans Administration Medical Center in Syracuse, New York, for 13 years before joining the National Institute on Drug Abuse (NIDA) as a Program Administrator in 1998. Her multidisciplinary research program investigated the neurobiological substrates underlying (a) motivated behaviors (e.g., responses to incentive motivational stimuli) and (b) response patterns mimicking symptom profiles of psychiatric disease. As research faculty in the Graduate Neuroscience Program, she also served as course coordinator for Cognitive and Behavioral Neuroscience and was responsible for medical student instruction in Neurotransmitters and Behavior and Pathophysiological Substrates of Psychiatric Disorders. She is the Acting Chief of the Behavioral and Cognitive Science Research Branch at NIDA and Chair of the trans-institute Behavioral Working Group.

MDMA-Induced Brain Serotonin Neurotoxicity: Clinical Studies
Una D. McCann, M.D.

Advances

Studies indicating that MDMA is a potent brain serotonin (5-HT) neurotoxin in animals have raised concern that humans who use MDMA may also incur brain serotonergic neuronal injury. However, the paucity of methods available for assessing the status of brain serotonin neurons in living humans has been a significant obstacle for clinical studies of MDMA-induced 5-HT neurotoxicity. To date, two methods for detecting brain 5-HT neurotoxicity have been validated in nonhuman primates and subsequently used in human MDMA users. In particular, cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid (5-HIAA) have been shown to be reduced in primates with documented brain 5-HT neurotoxicity as well as abstinent human MDMA users. Similarly, positron emission tomography (PET) studies using a radioligand that binds to the serotonin transporter (SERT) show reductions in abstinent MDMA users similar to those seen in baboons with documented MDMA-induced neurotoxicity. In addition to validated measures of neurotoxicity, there is growing evidence that MDMA users have abnormalities in cognitive and neuroendocrine function, both of which are known to involve brain serotonin systems.

Challenges

Studies in MDMA users are limited by their retrospective nature and the possibility that other drugs of abuse or preexisting abnormalities play a role in the abnormal findings in this cohort.

Future Directions

Additional research should be focused on developing more sensitive and specific methods for detecting brain serotonin neurotoxicity in living humans as well as better defining its functional consequences. Studies are also needed to determine whether cognitive and neuroendocrine abnormalities in MDMA users are related to brain 5-HT deficits. Finally, longitudinal studies will be useful for determining whether MDMA users are more likely to develop neuropsychiatric problems with age.

References

McCann UD, Eligulashvili V, Mertl M, Murphy DL, Ricaurte GA. (1999) Altered neuroendocrine and behavioral responses to m-chlorophenylpiperazine in 3,4-methylenedioxymethamphetamine (MDMA) users. Psychopharmacology 147:56-65.

McCann UD, Mertl MM, Eligulashvili V, Ricaurte GA. (1999) Cognitive performance in (±) 3,4-methylenedioxy-methamphetamine (MDMA, "ecstasy") users: A controlled study. Psychopharmacology 143:417-425.

McCann UD, Ridenour A, Shaham Y, Ricaurte GA. (1994) Brain serotonergic neurotoxicity after MDMA ("ecstasy"): A controlled study in humans. Neuropsychopharmacology 10:129-138.

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

Biography

Dr. McCann is an associate professor of psychiatry at Johns Hopkins School of Medicine. Her research is in the area of drug abuse with a particular focus on the neurotoxic amphetamine analogues. Dr. McCann also serves as Associate Program Director of the Johns Hopkins Bayview General Clinical Research Center and is an attending physician at the Johns Hopkins Anxiety Disorders Program.

The Acute Cardiovascular, Endocrine, and Pharmacokinetic Effects of MDMA in Humans
John Mendelson, M.D.

What We Know

MDMA is a sympathomimetic phenethylamine structurally related to the endogenous catecholamines such as epinephrine and dopamine, medications such as terbutaline and phenylephrine, and the hallucinogenic amphetamines such as mescaline. In addition to euphoria, MDMA produces robust cardiovascular stimulation and activates the hypothalamic-pituitary axis. MDMA increases heart rate, blood pressure, and myocardial oxygen consumption. In contrast with the cardiostimulatory beta agonist dobutamine, MDMA has little direct inotropic effect on the heart. The lack of inotropy may increase myocardial oxygen consumption more than expected on the basis of MDMA-induced increases in heart rate and blood pressure. MDMA increases plasma cortisol, prolactin, and dehydroepiandrosterone (DHEA). These hormonal changes may mediate some of the pleasurable effects of MDMA. The biodisposition of MDMA is both stereoselective and dose dependent. Therefore, plasma concentrations (with concomitant increases in toxicity) may rise dramatically when illicit users take multiple doses over brief time periods. In people, MDMA is probably metabolized by cytochrome p450 2D6. Increased plasma concentrations (and medical complications) are possible when MDMA is co-administered with other CYP 2D6 substrates such as dextromethorphan. Illicit MDMA ingestion has been associated with several poorly characterized adverse reactions (such as hyponatremia, rhabdomyolysis, seizures, and hyperthermia) that result in severe outcomes, including death. The frequency of occurrence and mechanisms of action causing these events are unknown but may be due to altered cardiovascular physiology, nonlinear pharmacokinetics, or inadvertent drug-drug interactions.

Challenges

MDMA use is increasing and idiosyncratic drug reactions are difficult to predict. A prime challenge will be delineating both the frequency of occurrence and the mechanism of these idiosyncratic drug reactions. For example, a very real issue is the substitution of dextromethorphan for MDMA by illicit dealers. The pharmacologic effects of this combination have received little study.

Directions

Studies of the effects of MDMA when co-administered with other CYP 2D6 substrates (such as dextromethorphan and methamphetamine) and the effects of MDMA on cardiac, hepatic, renal, and thermoregulatory physiology are needed.

References

Baggott M, Heifets B, Jones RT, Mendelson J, Sferios E, Zehnder J. (2000) Chemical analysis of ecstasy pills. JAMA Nov 1;284(17):2190.

Cami J, Farre M, Mas M, Roset PN, Poudevida S, Mas A, San L, de la Torre R. (2000) Human pharmacology of 3,4-methylenedioxymethamphetamine ("ecstasy"): Psychomotor performance and subjective effects. J Clin Psychopharmacol Aug;20(4):455-466.

de la Torre R, Farre M, Ortuno J, Mas M, Brenneisen R, Roset PN, Segura J, Cami J. (2000) Non-linear pharmacokinetics of MDMA ('ecstasy') in humans. Br J Clin Pharmacol Feb;49(2):104-109.

Lester SJ, Baggott M, Welm S, Schiller NB, Jones RT, Foster E, Mendelson J. (2000) Cardiovascular effects of 3,4-methylenedioxymethamphetamine. A double-blind, placebo-controlled trial. Ann Intern Med Dec 19;133(12):969-973.

Biography

Dr. Mendelson is a practicing internist and Associate Clinical Professor of Psychiatry at the University of California, San Francisco. His research involves studies of the pharmacology of abused drugs in humans. He has conducted NIH-funded human laboratory-based experiments on the pharmacokinetics and dynamics of MDMA, the stereoisomers of methamphetamine, cocaine and ethanol interactions, and the combination of buprenorphine and naloxone.

Are the Psychological Problems Associated With Regular MDMA Use Reversed by Prolonged Abstinence?
Michael John Morgan, Ph.D.

What We Know

Chronic, regular recreational use of "ecstasy" (MDMA) is associated with elevated psychopathology (Morgan, 2000), behavioral impulsivity (Morgan, 1998), and persistent impairment of memory performance (Morgan, 1999). The aim of the present study was to investigate which of these sequelae persist after at least 6 months of abstinence from MDMA. Four groups of participants were compared: 18 current regular recreational MDMA users, 15 ex-regular MDMA users who had abstained from using the drug for an average of 2 years, 16 polydrug users who had never taken MDMA, and 15 drug-naive controls. Both current and ex-MDMA users exhibited elevated psychopathology and behavioral impulsivity compared with polydrug users and drug-na•ve controls, and both groups also exhibited impaired working memory and recall performance compared with drug-naive controls, although only ex-users exhibited impaired delayed recall compared with polydrug users. Thus, the present data suggest that psychological problems associated with regular MDMA use are not reversed by prolonged abstinence.

Challenges

• Adequate sampling
• Verification of drug histories (including the purity and quantity of MDMA consumed)
• Polydrug use by MDMA users presenting difficulty in determining specific sequelae of MDMA use
• Determining the causality of these sequelae
• Converting media interest into sustained research funding

Future Directions

• Further investigation of the psychological sequelae of different patterns of consumption of MDMA and other substances
• Prospective longitudinal studies
• fMRI studies of the effects of MDMA, and tryptophan depletion, on brain activity and cognitive function in regular MDMA users

References

Morgan MJ. (2000) Ecstasy (MDMA): A review of its possible persistent psychological effects. Psychopharmacology 152:230-248.

Morgan MJ. (1999) Memory deficits associated with recreational use of "ecstasy" (MDMA). Psychopharmacology 141:30-36.

Morgan MJ. (1998) Recreational use of "ecstasy" (MDMA) is associated with elevated impulsivity. Neuropsychopharmacology 19(4):252-264.

Biography

Dr. Morgan spent 2 years as a visiting fellow in the neuroimaging laboratory at NIDA before returning to the United Kingdom in the early 1990s to develop his MDMA research at the University of Wales. He was one of the first investigators to report that regular MDMA use is specifically associated with particular persistent psychological deficits. He has recently moved to assume a senior position at the University of Sussex to develop his collaboration with Philip McGuire at the Institute of Psychiatry on fMRI studies of the effects of MDMA, and tryptophan depletion, on brain activity and cognitive function in regular MDMA users.

Jacques L. Normand, Ph.D.

Biography

Dr. Normand is Acting Chief of the Epidemiology Research Branch in the Division of Epidemiology, Services and Prevention Research at the National Institute on Drug Abuse (NIDA), National Institutes of Health. As Branch Chief, he is responsible for planning, developing, and administering a national and international research program on the epidemiology and etiology of drug abuse and drug-related behavioral, social, and health consequences. Prior to his work at NIDA, he was a study director at the National Research Council and the Institute of Medicine of the National Academy of Sciences in Washington, D.C., where he directed the Panel on Needle Exchange and Bleach Distribution Programs and the Committee on Drug Use in the Workplace. His earlier professional experience included research positions in both the private and public sectors. He has published in various professional research journals and has spoken at numerous professional meetings on evaluation issues.

Neuropsychopathology Associated With MDMA
Andy C. Parrott, Ph.D., C.Psychol.

Advances

Recreational users of ecstasy/MDMA demonstrate a wide range of psychobiological problems that are consistent with impaired serotonergic functions. A number of surveys have assessed self-reported functioning while off drug. The psychobiological problems reported include altered sleep, changed appetite, and loss of sexual interest or pleasure. Psychiatric symptoms include depression, phobic anxiety, general anxiety, obsessive-compulsive disorder, impulsivity, and psychoticism. Interpersonal relationship difficulties, financial loss, and occupational problems have also been described. In studies involving non-drug user controls, psychiatric symptom rates are often significantly higher. But when other illicit drug user groups are included, they also tend to show high rates of psychobiological distress.

Challenges

Since most recreational ecstasy/MDMA users are heavy polydrug users, the main challenge is to tease out which neuropsychobiological problems are specific to MDMA and which are characteristic of illicit polydrug use in general.

Future Directions

Prospective studies are needed to monitor how the initial uptake of ecstasy and other specific drugs leads to changes in psychobiological functioning. Such studies could also be used to assess the effects of drug discontinuation. However, the prospects are not promising. We recently assessed a young former heavy user who had stopped using ecstasy 7 years ago. He demonstrated poor neurocognitive test performance and was still suffering from profound sleep disturbance, phobic anxiety, severe depression, and sexual impotence.

References

Parrott AC, Lasky J. (1998) Ecstasy (MDMA) effects upon mood and cognition: Before, during, and after a Saturday night dance. Psychopharmacology, vol 139, pages 261-268.

Parrott AC, Milani R, Parmar R, Turner JJD. (2000) Recreational drug use and psychobiological problems, collaborative UK/Italy study (1): Overview and main findings. Journal of Psychopharmacology, vol 14, pages a14-a15.

Parrott AC, Sisk E, Turner JJD. (2000) Psychobiological problems in heavy ecstasy (MDMA) polydrug users. Drug Alcohol Dependence, vol 60, pages 105-110.

Biography

After earning a Ph.D. degree at the University of Leeds, Dr. Parrott worked as a research fellow at the Human Psychopharmacology Research Unit, where he focused on benzodiazepines and second-generation antidepressants. At the Institute of Naval Medicine in Hampshire, he assessed the practical utility of transdermal scopolamine and other anti-motion sickness drugs in land and sea trials. At the University of East London, he assessed a wide variety of recreational drugs, including stimulants, anabolic steroids, LSD, ketamine, and cannabis (while based at Humboldt State University in California). At the University of East London, it has become increasingly apparent that nicotine dependency is psychobiologically damaging and leads to increased stress and depression. Dr. Parrott has also been investigating the acute and chronic effects of MDMA/ecstasy in humans for the past 7 years.

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