S. Lester, M. Baggott, S. Welm
Dec 19, 2000
Citations
8
Influential Citations
122
Citations
Quality indicators
Journal
Annals of Internal Medicine
Abstract
3,4-Methylenedioxymethamphetamine (MDMA),also known as ecstasy, is a psychostimulant with structural similarities to both amphetamine and the hallucinogenic phenethylamine mescaline. 3,4-Methylenedioxymethamphetamine (and its analogues) seems to produce a spectrum of pharmacologic effects distinct from such structurally similar compounds, suggesting that MDMA may represent a new class of psychotropic agents (1-4). Use of MDMA may be increasing. Emergency department visits related to MDMA increased from 637 in 1997 to 1143 in 1998. In 1998, the estimated lifetime prevalence and annual prevalence of MDMA use, respectively, were 2.7% and 1.8% in 8th graders, 5.8% and 3.6% in 12th graders, and 7.2% and 2.9% in young adults (5). Use of MDMA has been associated with sudden death and cardiovascular collapse (6). Acute cardiovascular effects of MDMA (and its analogues) include tachycardia and hypertension (7, 8). Understanding the cardiovascular effects of MDMA may improve prediction of and intervention in cases of MDMA cardiotoxicity. The purpose of this study was to measure the acute cardiovascular effects of oral MDMA and to compare these effects with those of a well-characterized cardiostimulant, the -agonist dobutamine. The cardiovascular response to MDMA and dobutamine were measured by using quantitative two-dimensional echocardiography. Methods The study was approved by the University of California, San Francisco, Committee on Human Research and was performed under an investigational new drug (IND) protocol approved by the U.S. Food and Drug Administration (IND 53,648). All participants provided informed consent. The eight healthy paid volunteers had used MDMA at least four times in the past 3 years. At least 1 week after dobutamine echocardiography, participants were tested in 3 weekly sessions with an ascending-dose, double-blind, placebo-controlled design using orally administered MDMA hydrochloride, 0.5 mg/kg of body weight or 1.5 mg/kg, or placebo. Participants underwent a medical examination and laboratory screening tests to confirm good general health. Exclusion criteria were significant medical or psychiatric illness; dependence on drugs (except caffeine or nicotine), according to criteria defined by the Diagnostic and Statistical Manual of Mental Disorder, 4th edition; history of adverse reactions to study drugs or recent use of psychoactive drugs; cardiovascular risk factors (total cholesterol level>6.48 mmol/L [250 mg/dL] or smoking>2 packs of tobacco cigarettes per day); deficient cytochrome P450 2D6 activity (assessed by using dextromethorphan phenotyping); or inability to give informed consent. Women were required to have negative results on a serum pregnancy test (Unilab, San Jose, California) on admission to the study and negative results on a urine pregnancy test (TestPack Plus, Abbott Laboratories, Abbott Park, Illinois) before each MDMA session. Participants were asked to refrain from use of illicit psychoactive drugs for at least 7 days and ethanol for at least 48 hours before testing. Nicotine and caffeine were restricted during MDMA sessions until 8 hours after drug administration and were otherwise not allowed within 30 minutes of any measure. To rule out recent psychoactive drug use, qualitative urinalysis (Unilab, San Jose, California) was performed the day before MDMA sessions and on each day that data were collected. Dobutamine hydrochloride (Dobutrex, Lilly, Indianapolis, Indiana) was administered in ascending doses of 5, 20, and 40 g/kg per minute. Doses were delivered intravenously and increased every 5 minutes until the dose of 40 g/kg per minute was completed. Heart rate, systolic blood pressure, and diastolic blood pressure were obtained before MDMA administration and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours after MDMA administration. The ratepressure product (heart rate systolic blood pressure) was calculated. Metabolite and MDMA pharmacokinetics, neuroendocrine measures, subjective mood ratings, and structured psychiatric measurements are reported in detail elsewhere (Jones and colleagues. In preparation). Echocardiography was performed 1 hour after MDMA administration by using a commercially available Doppler echocardiography machine (Sequoia, Acuson, Mountain View, California). End-diastolic and end-systolic volumes were calculated by using the bi-plane method of discs (9). From these measurements, standard calculations of stroke volume, ejection fraction, and cardiac output were made. Meridional systolic wall stress was calculated by using previously defined formulas (10). The response to MDMA (0.5 mg/kg, 1.5 mg/kg, or placebo) was compared with the response to dobutamine (5, 20, and 40 g/kg per minute) by using repeated-measures analysis of variance. Drug condition and observation times were considered within-participant factors. After a significant F test, pairwise comparisons were performed by using the least-squares means analysis. Effects were considered statistically significant at a Pvalue less than or equal to 0.05. Data were adjusted for sphericity by using the HuynhFeldt adjustment factor. The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results The mean age (SD) of the five men and three women who completed the study was 29 5 years (range, 24 to 39 years). The participants had reportedly used MDMA 49 65 times (range, 5 to 200 times). After completing part of the first MDMA session, one additional participant chose to withdraw from the study because of professional obligations. Data from this participant are excluded from analysis. Peak hemodynamic effects (defined as the maximal observed value) occurred 1 to 1.5 hours after MDMA administration. Because all echocardiograms were obtained at least 1 hour after the MDMA dose and required approximately 15 minutes to complete, we used peak hemodynamic effects for comparison with echocardiographic data. Except for diastolic blood pressure, there were no significant differences between the peak hemodynamic effects and those measured 1 hour after administration of MDMA. Although diastolic blood pressure 1 hour after administration of 1.5 mg/kg of MDMA was statistically less than the peak (69 5 mm Hg vs. 76 10 mm Hg; P<0.01), the absolute magnitude was small and does not substantially change the results. The cardiovascular effects of MDMA and dobutamine are summarized in the Table. Table. Comparative Cardiovascular Effects of MDMA and Dobutamine in Eight Participants We found that MDMA, 1.5 mg/kg, and dobutamine, 20 and 40 g/kg per minute, increased heart rate (by 28 beats/min), systolic and diastolic blood pressures (by 25 mm Hg and 7 mm Hg, respectively), and ratepressure product, whereas MDMA, 0.5 mg/kg, and dobutamine, 5 g/kg per minute, did not. Peak heart rate changes after administration of MDMA or dobutamine are shown in the top part of the Figure. The peak increases in heart rate, systolic blood pressure, and ratepressure product after 1.5 mg/kg of MDMA were significantly greater than after 20 g/kg per minute of dobutamine but less than after 40 g/kg of dobutamine. Figure. Comparison of the effects of dobutamine or 3,4-methylenedioxymethamphetamine ( MDMA ) on peak heart rate ( top ), cardiac output ( middle ), and ratio of meridional wall stress to ejection fraction ( bottom ). Changes in cardiac output after administration of MDMA or dobutamine are shown in the middle part of the Figure. We found that 1.5 mg/kg of MDMA and 20 and 40 g/kg per minute of dobutamine increased cardiac output, but 0.5 mg/kg of MDMA and 5 g/kg per minute of dobutamine did not. The increase of 2 L/min in cardiac output after 1.5 mg/kg of MDMA was similar to that after 20 g/kg per minute of dobutamine but less than that after 40 g/kg per minute of dobutamine. Neither dobutamine nor MDMA changed left ventricular end-diastolic volume. Consistent with its inotropic properties, dobutamine decreased left ventricular end-systolic volume and produced dose-dependent increases in ejection fraction. In contrast, neither dose of MDMA significantly decreased end-systolic volume. Consequently, ejection fraction was unchanged after MDMA administration. Meridional wall stress was used to compare the inotropic effects of MDMA and dobutamine by correcting for ejection fraction. Meridional wall stress did not change significantly with any dose of either agent. Consistent with the inotropic properties of dobutamine, the ratio of meridional wall stress to ejection fraction progressively decreased with each successive dobutamine dose and was significantly reduced at a dose of 40 g/kg per minute. This variable was unchanged with either dose of MDMA (Figure, bottom). Subjective effects of MDMAfeelings of relaxation, well-being, and improved moodreached their maximum between 1.5 and 3 hours. Most participants felt that 0.5 mg/kg of MDMA produced very weak effects (although two felt that it was of medium strength), whereas 1.5 mg/kg was considered a medium to somewhat strong dose. Further details on the pharmacokinetic and dynamic effects of MDMA will be reported elsewhere (Mendelson and colleagues. In preparation). Discussion We compared the effects of a well-known cardiostimulatory -agonist to those of an uncharacterized illicit compound by using clinically validated outcome measures. Contrasting the effects of these compounds may help physicians better understand the cardiovascular risks associated with illicit MDMA use. Dobutamine and MDMA both produce dose-dependent increases in heart rate, blood pressure, and cardiac output. Although both compounds are cardiostimulants, dobutamine has positive inotropic effects whereas MDMA has no measurable inotropic effects. In the absence of inotropism, incremental increases in afterload produce proportional increases in force or tension per unit of cross-sectional area of the ventricular wall. This i