Effects of MDMA on body temperature in humans

Hyperthermia is a severe complication associated with the recreational use of 3,4-methylenedioxymethamphetamine(MDMA, Ecstasy). In this review, the clinical laboratory studies that tested the effects of MDMA on body temperature are summarized. The mechanisms that underlie the hyperthermic effects of MDMA in humans and treatment of severe hyperthermia are presented. The data show that MDMA produces an acute and dose-dependent rise in core body temperature in healthy subjects. The increase in body temperature is in the range of 0.2-0.8C and does not result in hyperpyrexia (>40C) in a controlled laboratory setting. However, moderately hyperthermic body temperatures >38.0C occur frequently at higher doses, even in the absence of physical activity and at room temperature. MDMA primarily releases serotonin and norepinephrine. Mechanistic clinical studies indicate that the MDMA-induced elevations in body temperature in humans partially depend on the MDMA-induced release of norepinephrine and involve enhanced metabolic heat generation and cutaneous vasoconstriction, resulting in impaired heat dissipation. The mediating role of serotonin is unclear. The management of sympathomimetic toxicity and associated hyperthermia mainly includes sedation with benzodiazepines and intravenous fluid replacement. Severe hyperthermia should primarily be treated with additional cooling and mechanical ventilation

Pharmacology of novel psychoactive substances

This PhD work consists of an in vitro and in vivo part. In the in vivo part, we investigated the role of dopamine in the acute clinical effects of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) in healthy human subjects. The role of dopamine in the addictive effects of drug of abuse is well established, but whether it contributes to the acute psychotropic effects of MDMA is unclear. In this pharmacological interaction study, we used the dopamine and weak norepinephrine transporter inhibitor bupropion (Stahl et al. 2004) as a pharmacological tool to block the MDMA-induced dopamine release and to study the role of dopamine in the effects of MDMA. We hypothesized that bupropion would decrease the subjective effects of MDMA to the extent that they depend on MDMA-induced release of dopamine. We included 16 healthy human subjects in this double-blind, placebo-controlled, crossover study. Bupropion pretreatment slightly increased MDMA plasma concentration and prolonged but not reduced the subjective effects contrary to our hypothesis. Additionally, bupropion reduced the MDMA-induced elevations in plasma norepinephrine concentrations and the heart rate response to MDMA. These findings support a role for norepinephrine in the MDMA-induced cardiostimulant effects but no role for MDMA-induced transporter-mediated dopamine release in the elevated mood effects after MDMA administration. Possibly, most of the acute psychotropic effects of MDMA are mediated via transporter-mediated release of serotonin and norepinephrine as previously shown (Hysek et al. 2011, Hysek et al. 2012). In the second and main part of this work we characterized the pharmacological profiles of novel psychoactive substances (NPS). Specifically, we studied whether and how potently NPS interacted with the human transporters for norepinephrine, dopamine, and serotonin, stably expressed in human embryonic kidney (HEK293) cells. Additionally, we assessed binding affinity to the serotonin 5-HT1A, 5-HT2A, 5-HT2C-receptors and the activation potency and activation efficacy at 5-HT2A and 5-HT2B receptors. Furthermore, binding to alpha1A/2A-adrenergic, dopamine D1-3, histamine H1 receptors, as well as trace amine-associated receptor 1 (TAAR1) was also assessed. The NPS studied in this project included para-4-halogenated amphetamine derivatives, which were shown to be relatively more serotonergic than their non-4-halogenated counterparts and pyrovaleronering-substituted cathinones, which were highly potent dopamine transporter inhibitors with a high risk for abuse. Para-halogenated drugs (4-fluoroephedrine, 4-fluoroamphetamine, 4-fluoromethamphetamine, 4-fluoromethcathinone, and 4-bromomethcathinone) also released monoamines, similar to MDMA, whereas pyrovalerones were found to be pure uptake inhibitors. Most benzofurans were similar to MDMA but slightly more serotoninergic than MDMA and additionally activated the serotonin 5-HT2B receptor. The last big group of NPS studied in this project, were novel hallucinogens, which predominantly interacted with the 5-HT2A receptor. This serotonin receptor subtype mediates the hallucinogenic and hallucinogenic-like visual effects of classic serotonergic hallucinogens (Vollenweider et al. 1998, Nichols 2004, Halberstadt et al. 2013, Halberstadt et al. 2014, Halberstadt 2015). Compounds tested in this project included the benzodifuran 8-Bromo-2,3,6,7-benzo-dihydro-difuran-ethylamine (2C-B-FLY), 2C-drugs with their highly potent N-(2-methoxy)benzyl (NBOMe)-derivatives, and lysergic acid diethylamide (LSD). Interestingly, NBOMe derivatives displayed higher affinities at the 5-HT2A receptor than LSD, together with a high selectivity for 5-HT2A over the 5-HT1A receptor, contrary to LSD. NBOMes were partial 5-HT2A receptor agonists, similar to LSD. These novel drugs likely carry a high hallucinogenic potential when used recreationally by humans and the high binding to α1A-receptor (Ki < 1µM) may result in additional vasocontrictive and cardiovascular stimulant effects. Taken together, this PhD contributed to the understanding of the role of dopamine in the effects of MDMA, an important recreational substances. Additionally, we characterized the in vitro pharmacology of many novel designer drugs, which will be helpful in the prediction of the clinical toxicological effects of these newly used recreational drugs

Dopamine receptors gene expression in male rat hippocampus after administration of MDMA (Ecstasy) [La Expresión Génica de Receptores de Dopamina en el Hipocampo de Ratas Macho Después de la Administración de MDMA (Éxtasis)]

Ecstasy is one of the most popular amusing drugs among young people. Documents indicate some effects of Ecstasy on hippocampus and close relations between dopaminergic functions with reward learning. Therefore, the aim of this study was evaluation of the chronic effects of Ecstasy on memory in male Wistar rats and determination of dopamine receptors' gene expression in hippocampus. Forty adult male Wistar rats randomly distributed in five groups: Control, sham (received 1 ml/kg 0.9 saline) and three experimental groups were: Exp. 1 (2.5 mg/kg), Exp. 2 (5 mg/kg), and Exp. 3 (10 mg/kg) received MDMA intraperitoneally once every 7 days (3 times a day, 3 hours apart) for 4 weeks. Before the first injection animals trained in Shuttle Box memory and tested after the last injection. 24 hours after the final testing, brains of rats were dissected and hippocampus was removed and homogenized. After total RNA extraction and cDNA synthesis, expression of dopamine receptor genes in the hippocampus determined with Real-Time PCR. Our results showed that 2.5 and 5 mg/kg MDMA-treated groups had memory impairment. Also we found that MDMA increased the mRNA expression of dopamine receptors in hippocampus and the highest increase found in dopamine D1 receptors in the 5 mg/kg experimental group. We concluded that low doses of Ecstasy could increase Dopamine takers gene expression in hippocampus and disorder avoidance memory. But in high doses the increase in Dopamine takers gene expression was not as much as that in low doses and avoidance memory disorder was not observed. © 2015, Universidad de la Frontera. All rights reserved

Constructing Drug Using Victims: Race and Class in Policy Debates on Ecstasy Use in the U.S.

Sociologists and political scientists examining the social construction of public anxiety surrounding drug use in the United States have argued that racial minorities are the targets of the harshest drug laws, while middle-class whites are shielded. In this article, I provide further evidence that middle-class, white drug users are shielded from harsh punishment by analyzing the process through which U.S. legislators and policymakers decide which drug users need punishment and which deserve protection and treatment. Analyzing transcripts from federal Congressional hearings, I examine the rhetoric of legislators and stakeholder witnesses concerning the use of 3,4-Methylenedioxymethamphetamine (MDMA) by middle-class whites. Building on the social construction literature, I use social identity theory to demonstrate how legislators within Congressional hearings create in- and out-groups in order to categorize different drug users and dealers. My analysis of Congressional hearing language concerning white MDMA use demonstrates that Congressional speakers use rhetoric to convince committee members and the wider public that middle-class, white drug users are different from drug users of color and that the appropriate policy response is education and treatment, rather than punishment. My findings highlight how middle-class, white drug users are characterized differently from drug users of color, providing further evidence that U.S. drug policy has historically favored middle-class, white drug users

Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans : lost in translation

We greatly appreciate the comments offered by Drs Rolle, Takematsu, and Hoffman and the opportunity to put our work into a wider perspective. We share the view that our work does not reflect the clinical situation but rather provides a proof of mechanism study, which aims to help to translate preclinical findings (Sprague et al., 2005) into the clinic. As we noted in the discussion of our work (Hysek et al., 2012b) the primary goal of the study was to investigate the role of adrenoceptors in the mechanism of action of MDMA in humans. Therefore, the study provided only indirect support for the use of carvedilol in the treatment of stimulant toxicity in which carvedilol would be administered following the ingestion of Ecstasy or other stimulants. Furthermore, we noted the limitation that the MDMA-induced increase in body temperature in our study was moderate and we do not know whether carvedilol would also be effective in cases of severe hyperthermia following ecstasy use

Ecstasy/MDMA attributed problems reported by novice, moderate and heavy recreational users

The recreational use of MDMA/Ecstasy (3,4-methylenedioxymethamphetamine) is associated with many psychobiological problems, but there is a paucity of data on how these relate to the level of past use. Objectives: to assess the incidence of Ecstasy-attributed problems as reported by novice, moderate and heavy users. Methods: 763 unpaid volunteers took part in a WWW study of recreational drug use. This report is based on the 282 Ecstasy users from that sample, who comprised 109 novice users (1–9 occasions), 136 moderate users (10–99 occasions), and 36 heavy users (+100 occasions). Yes/no responses were automatically recorded to a series of questions covering psychobiological problems experienced when drug-free, which were attributed by the respondents to their Ecstasy use. Results: Depression, memory problems, anxiety, mood fluctuation, poor concentration, infections, tremors/twitches and weight loss, were all significantly associated with the extent of Ecstasy use. Thus memory problems attributed to Ecstasy were reported by 19% of novice users, 52% of heavy users and 73% of heavy users (chi-square 42.74, df=2, p<0.001); many of the other variables showed similar trends

Direct and long-lasting effects elicited by repeated drug administration on 50-kHz ultrasonic vocalizations are regulated differently: Implications for the study of the affective properties of drugs of abuse

Several studies suggest that 50-kHz ultrasonic vocalizations (USVs) may indicate a positive affective state in rats, and these vocalizations are increasingly being used to investigate the properties of psychoactive drugs. Previous studies, however, have focused on dopaminergic psychostimulants and morphine, whereas little is known about how other drugs modulate 50-kHz USVs. To further elucidate the neuropharmacology of 50-kHz USVs, the present study characterized the direct and long-lasting effects of different drugs of abuse, by measuring the number of 50-kHz USVs and their 'trill' subtype emitted by adult male rats. Rats received repeated administrations of amphetamine (2 mg/kg, i.p.), 3,4-methylenedioxymethamphetamine (MDMA, 7.5 mg/kg, i.p.), morphine (7.5 mg/kg, s.c.), or nicotine (0.4 mg/kg, s.c.), on either consecutive or alternate days (five administrations in total) in a novel environment. Seven days later, rats were re-exposed to the drug-paired environment, subjected to USVs recording, and then challenged with the same drug. Finally, 7 d after the challenge, rats were repeatedly exposed to the drug-paired environment and vocalizations were measured. Amphetamine was the only drug to stimulate 50-kHz USVs and 'trill' subtype emission during administration and challenge. Conversely, all rats emitted 50-kHz USVs when re-exposed to the test cage, and this effect was most marked in morphine-treated rats, and less evident in nicotine-treated rats. This study demonstrates that the direct and long-lasting effects of drugs on 50-kHz USVs are regulated differently, providing a better understanding of the usefulness of these vocalizations in the study of psychoactive drugs

Chaos-modified detrended moving average methodology for monitoring the depth of anaesthesia

This paper proposes a new method to monitor the depth of anaesthesia (DoA) based on the EEG signal. This approach firstly uses discrete wavelet transform (DWT) to to remove the spikes and the low frequency noise from raw EEG signals. After de-noising the EEG signals, the modified Hurst parameter is proposed with two new indices (CDoA and CsDoA), to estimate the anaesthesia states of the patients. To reduce the fluctuation of the new DoA index, a combination of Modified Chaos and Modifying Detrended Moving Average is used (MC-DMA). Analyses of variance (ANOVA) for C-MDMA and BIS distributions are presented The results indicate that the C-MDMA distributions at each anaesthesia state level are significantly different and the C-MDMA can distinguish five depths of anaesthesia. Compared with BIS trends, MC-DMA trend is close to BIS trend covering the whole scale from 100 to 0 with a full recording time