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They skip their first class and sneak into the woods near their upscale high school. One of them takes out six rolls — six ecstasy pills — and they each swallow one. Then back to school, flying on a drug they once used only on weekends. That night they will all go out and drop more ecstasy, rolling into the early hours of another school day. A continent away in Prague, Eva, 19, is sipping a Coke at Chateau, a downtown bar. She had her first hit of ecstasy when she was All my worries seem to go away. I am just enjoying the present moment. So we know that ecstasy is versatile. The evolution of ecstasy, from an underground urban drug to an almost mundane feature of middle-class life in the U. In the U. But in the past year or so, ecstasy has returned to the American heartland; and in Europe, it has gone positively mainstream, sampled casually by suburban teens and dot com professionals alike. Established drug-running rings, most of which have their origins in Europe, have taken over the trade. Production of the drug in laboratories in the Netherlands and Eastern Europe has continued to heat up. So has smuggling: in April, Italian officials in Trieste intercepted a cache of , pills — 60, more than they picked up in all of At the height of the ecstasy craze in Europe, more than 1 million doses of e were consumed in U. While the numbers of habitual users are small, recreational rolling soars at this time of the year, when young Europeans hit the sweaty clubs in tourist meccas like Ibiza. Ecstasy use in the U. Igor, a year-old lawyer in Belgrade, has been using e for four years. On a recent Saturday night, Daniela, a year-old university student from Bologna, celebrated the end of exams with beer and pizza, then bought some ecstasy on the street and headed to Cocoric — , a pyramid-shaped superdisco. Giorgio, 19, who drove in from Milan, was offered e at a video-game arcade in Rimini that afternoon. Indeed, much of the ecstasy taking — and the law enforcement underway to end it — has been accompanied by breathlessness. At ecstasy. Ecstasy is popular because it appears to have few negative consequences. But one reason ecstasy is so fascinating is that it appears to be a safer drug than heroin and cocaine, at least in the short run, and appears to have more potentially therapeutic benefits. Even so, the U. Senate has introduced a new law under which someone caught selling about hits of ecstasy could be charged as a drug trafficker; current law sets the threshold at about , pills. A report by the British Police Federation this year recommended a loosening of penalties for ecstasy possession. Pot relaxes but sometimes confuses; lsd stupefies; cocaine wires. Ecstasy has none of those immediate downsides. All this marveling should raise suspicions, however. And even as they help open the mind to new experiences, drugs also can distort the reality to which users ineluctably return. Is ecstasy snake oil? And how harmful is it? This is what we know:. It is also unlike pretty much every other illicit drug. Ecstasy pills are or at least they are supposed to be made of a compound called methylenedioxymethamphetamine, or MDMA. Instead, its chemists simply thought it could be a promising intermediary substance that might be used to help develop more advanced therapeutic drugs. Yet MDMA all but disappeared until The cold war was on, and for years its combatants had been researching scores of substances as potential weapons. The Michigan study found that none of the compounds under review was particularly toxic — which means there will be no war machines armed with ecstasy-filled bombs. Broadly speaking, there are two dangers: first, a pill you assume to be MDMA could actually contain something else. Second, MDMA itself might do harm. The theory is that its perils spring from the same neurochemical reaction that causes its pleasures. MDMA causes these cells to disgorge their contents and flood the brain with serotonin. But forcibly catapulting serotonin levels could be risky. Of course, millions of people manipulate serotonin when they take Prozac. But ecstasy actually shoves serotonin from its storage sites, according to Dr. Normally, serotonin levels are exquisitely maintained, which is crucial because the chemical helps manage not only mood but also body temperature. At such extremes, the blood starts to coagulate. In the past two decades, dozens of users around the world have died this way. There are long-term dangers too. By forcing serotonin out, MDMA resculpts the brain cells that release the chemical. The changes to these cells could be permanent. Johns Hopkins neurotoxicologist George Ricaurte has shown that serotonin levels are significantly lower in animals that have been given about the same amount of MDMA as you would find in just one ecstasy pill. In the s, Ricaurte helped record for the first time the effects of ecstasy on the human brain. Eventually he gave memory tests to people who said they had last used ecstasy two weeks before, and he compared their results with those of a control group of people who said they had never taken e. The ecstasy users fared worse on the tests. Computer images that give detailed snapshots of brain activity also showed that e users have fewer serotonin receptors than nonusers, even two weeks after their last exposure. Ricaurte thinks the damage may be irreversible. The major problem is that his research subjects had used all kinds of drugs, not just ecstasy. And there was no way to tell that the ecstasy they had taken was pure MDMA. And critics say even if MDMA does cause the changes to the brain he has documented, those changes may carry no functional consequences. We have a lot of unanswered questions. He believes that the compound has a special ability to help people make sense of themselves and the world, that taking MDMA can lead people to inner truths. At that time, MDMA had a small following among avant-garde psychotherapists, who gave it to blindfolded patients in quiet offices and then asked them to discuss traumas. According to Shulgin, another therapist to whom he gave the drug in turn named it Adam and introduced it to more than 4, people. Manufacturers at the time flaunted the legality of the drug, promoting it as lacking the hallucinatory effects of lsd and the addictive properties of coke and heroin. But after governments in the U. She believes e enabled Shane find the right attitude to fight his illness, and she helps Doblin advocate limited legal use. Soon his association will partly fund the first approved study of MDMA in psychotherapy, involving 30 victims of rape in Spain diagnosed with post-traumatic stress disorder. In , Dr. Charles Grob, a ucla psychiatrist, who believes MDMA could be used as a pain reliever for end-stage cancer patients, concluded the drug is safe if used in controlled situations under careful monitoring. The body is much less likely to overheat in such a setting. In , emergency rooms participating in the Drug Abuse Warning Network reported receiving 1, mentions of ecstasy during admissions, compared with just in In European hotspots, such as the stretch of discos between Rimini and Riccione, Italy, 20 people are rushed to hospitals each weekend because of excessive heat, alcohol and e. The two most common short-term side effects of MDMA — both of which remain rare in the aggregate — are overheating and something harder to quantify, psychological trauma. A few users have mentally broken down on ecstasy, unprepared for its powerful psychological effects. A schoolteacher in San Francisco who took ecstasy a year ago began to recall, in horrible detail, an episode of sexual abuse. She became severely depressed for three months and had to seek psychiatric treatment. Others have suffered physical trauma. Melanie, a year-old from Lausanne, Switzerland, unknowingly consumed a drink spiked with ecstasy last summer at a club in Spain. She woke up in a hospital. Another downside: because users feel empathetic, ecstasy can lower sexual inhibitions. Men generally cannot get erections when high on e, but they are often ferociously randy when its effects begin to fade. Still, the majority of people who end up in the E. The most common adulterants in such pills are aspirin, caffeine and other over-the-counters. Contrary to lore, fake e virtually never contains heroin. But the most insidious adulterant is dxm dextromethorphan , a cheap cough suppressant that causes hallucinations in the mg dose usually found in fake e 13 times the amount in a dose of Robitussin. Because dxm inhibits sweating, it easily causes heatstroke. Another dangerous adulterant is PMA paramethoxyamphetamine , an illegal drug that in May killed two Chicago-area teenagers who took it thinking they were dropping e. Established dealers, by contrast, operate under the opposite incentive. As writer Joshua Wolf Shenk has pointed out, we tend to have opposing views about drugs: they can kill or cure; the addiction will enslave you, or the new perceptions will free you. Aldous Huxley typified this duality with his two most famous books, Brave New World — about a people in thrall to a drug called soma — and The Doors of Perception — an autobiographical work in which Huxley begins to see the world in a brilliant new light after taking mescaline. Ecstasy can occasionally enslave and occasionally offer transcendence. Usually, it does neither. For Adrienne, an American woman who has been a frequent user for the past five years, ecstasy is a key part of life. I allowed myself to get closer to people. Everything was more positive. Contact us at letters time. Join Us. Customer Care. Reach Out. Connect with Us. Is Adrenal Fatigue Real? Home U. All Rights Reserved. TIME may receive compensation for some links to products and services on this website. Offers may be subject to change without notice.

The Lure of Ecstasy

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Official websites use. Share sensitive information only on official, secure websites. This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. These results suggest that the mechanisms of MDMA-induced neurotoxic effects are sex-dependent and dopaminergic neurons of males could be more sensitive to SOD2- and UPS-mediated toxic effects. Keywords: gluthatione peroxidase, hyperthermia, superoxide dismutase, tyrosine hydroxylase, ubiquitin-proteasome system. MDMA has high affinity for the serotonin transporter, and serotonergic damage elicited by MDMA has been described in several animal species and hypothesized to occur also in humans who consume this amphetamine-related drug Stone et al. Notably, studies in mice have demonstrated that MDMA elicits a peculiar profile of neurotoxicity in this species that involves the DAergic nigrostriatal and mesolimbic systems Colado et al. It is now well acknowledged that the neurotoxic effects of MDMA are influenced by several mechanisms that may be correlated to different factors such as sex, body temperature and also the environment where MDMA is experienced de Win et al. In particular, sex is increasingly emerging as a key factor that underlies the vulnerability to neuronal death that occurs in the course of neurodegenerative diseases and in response to drugs Della Torre and Maggi, Previous studies from our and other laboratories have suggested that hyperthermia, which is a commonly observed noxious effect of MDMA Green et al. However, other authors have demonstrated that MDMA can induce the release of ROS and neurotoxicity in experimental animals by means of mechanisms that are independent of hyperthermia Green et al. Collectively, these data claim for further investigation in order to clarify whether MDMA may disrupt the antioxidant barrier through modulation of these enzymes, and whether the effects of MDMA on specific antioxidant systems may be sex-dependent. These subunits share a common proteolytic mechanism although they target different substrates with caspase-, trypsin- and chymotrypsin-like activities, respectively Groll et al. In this frame, it has been reported that protein degradation is fundamental to counteract oxidative stress Goldberg, ; Jung and Grune, Indeed, different intracellular proteins can be degraded by the UPS system and it is well known that proteasome dysfunction can be associated with an increase of oxidative products and subsequent protein aggregation Aiken et al. Interestingly, different drugs of abuse, such as opioid agonists Caputi et al. Based on these considerations, we have investigated whether pro-oxidant and proteolytic mechanisms may participate in the neurotoxic effects that MDMA induces in the DAergic nigrostriatal system of mice and whether these proposed mechanisms of toxicity may be influenced by sex. To this end, we treated adult 12 weeks old male and female mice with MDMA according to an administration regimen that has previously been shown to induce nigrostriatal DAergic damage Granado et al. Experimental protocols were reviewed and approved by the Italian Ministry of Health decree No. Experiments were designed to minimize animal discomfort to the least possible extent and to reduce the number of animals used. MDMA was synthesized and solubilized in physiological saline, as described elsewhere Frau et al. Mice in the control groups were treated with vehicle i. A total number of 45 mice were used in this study five to six mice for each experimental group. The general health of mice was evaluated every 30 min during the treatment and no signs of distress or suffering i. Although the dose of MDMA administered in this study is higher than those usually taken by recreational users Vollenweider et al. Temperature was recorded prior to the first administration of either MDMA or vehicle baseline temperature , and then 1 h after each administration of either MDMA or vehicle. Temperature was recorded by holding each mouse at the base of its tail and inserting the probe past the rectum into the colon for 4—5 s, until stable rectal temperature was maintained for 3 s. The phase of the estrus cycle was identified according to the presence and ratio of the following three types of cells: 1 round epithelial and nucleated cells, 2 irregular shaped and cornified cells, 3 smaller and dark stained leukocytes. The following phases of the estrus cycle were identified: proestrus, prevalence of round, large and nucleated epithelial cells which could be grouped in form of layers, estrus, prevalence of large and irregular shaped cornified cells; metestrus, leucocytes, epithelial and cornified cells in equal ratio; diestrus, prevalence of leukocytes Contini et al. Stained vaginal smears were blindly inspected by two independent observers, in order to avoid possible misinterpretations of the results. Two hours after the completion of pharmacological treatments, all mice were treated with equithesin pentobarbital 0. Brains were then removed, post-fixed for 24 h, and processed according to the procedures previously described Costa et al. For each mouse, three sections were collected from the two brain regions analyzed at the following coordinates: from 1. Mice used for biochemical assays and for quantitative real-time protein chain reaction qRT-PCR studies, were decapitated and the striatum 1. All the brain areas were identified according to the mouse brain atlas of Paxinos and Franklin The time of sacrifice was selected based on previous experiments performed in our laboratories, showing that: 1 repeated treatment with MDMA followed by sacrifice 2 h after discontinuation causes a reduction of TH-positive terminals and neurons in the nigrostriatal DAergic system of mice Granado et al. Free-floating sections were rinsed in 0. Thereafter, the sections were rinsed three times in 0. Afterwards, the sections were rinsed and immediately mounted onto glass slides coated with gelatin in Mowiol mounting medium. For single staining studies, images of single wavelength were obtained with an epifluorescence microscope Axio Scope A1, Zeiss, Oberkochen, Germany connected to a digital camera 1. The ImageJ software U. Sections were captured in black and white 8-bit monochrome and the density of fibers was determined in fixed regions using a threshold level that was kept constant across all images. All the sections obtained where then evaluated with the manual particle counting option of ImageJ. For each level of the striatum and SNc, the value obtained was first normalized with respect to vehicle, then values from different levels were averaged. No significant differences in the density of either immunoreacted fibers or neurons were found among the three coronal sections of a given area in the same mouse. The correlation of signal intensity was calculated as Pearson correlation coefficient Rr , as previously described Sirabella et al. The absorbance was measured at nm and the SOD activity was determined as follows:. The NADPH standards were used to generate the standard curve which was used to calculate the GPx activity in the tissue samples as follows:. The assay is based on the detection of the fluorophore 7-aminomethylcoumarin AMC after cleavage from the labeled substrates. The free AMC fluorescence was quantified at nm excitation and nm emission wavelengths using the same microplate reader cited above. An AMC standard curve was generated for reference by preparing a dilution series of AMC standard reagent in the concentration range of 0. The assay was validated by analyzing UPS positive control incubated with the inhibitor lactacystin and two independent experiments were carried out for each tissue analyzed. Relative expression of different gene transcripts was calculated by the Delta-Delta Ct DDCt method and converted to relative expression ratio 2-DDCt for statistical analysis Livak and Schmittgen, Normality of data was assessed by the D'Agostino-Pearson test and no dataset deviated from normal distribution. No randomization was performed to allocate mice to the different experimental groups and no exclusion criteria were used, resulting in the inclusion of all mice. Assessment of the phase of estrus cycle in female mice, analysis of images from immunohistochemistry, activity assay and gene expression studies were all performed by six different experimenters blinded to the experimental groups. We did not carry out a power analysis, since we relied on our previous studies that employed the same experimental protocol to pre-define the group sizes. Two hours after the last administration mice were sacrificed and processed for markers of neurodegeneration, oxidative stress and protein degradation in the striatum and SNc. Treatment with MDMA increased body temperature since the first administration, although this effect reached statistical significance starting from the second administration. Effects of treatment with MDMA on body temperature in mice. Effects of treatment with MDMA on the immunoreactivity for the dopamine transporter DAT in the striatum and on the immunoreactivity for tyrosine hydroxylase TH in the striatum and substantia nigra pars compacta SNc. In the striatum, sex-dependent modifications in SOD activity were observed. In the midbrain, sex-dependent modifications in SOD activity were observed. In the midbrain, significant modifications in the expression of the SOD1 and SOD2 genes were observed in both male and female mice. In the striatum, no significant differences in GPx activity were observed among experimental groups. The present study adds important findings to the current evidence on the neurotoxic effects of MDMA Cadet et al. It has been previously proposed that hyperthermia induced by amphetamine-related drugs may increase the formation of ROS and reactive nitrogen species Chipana et al. However, other studies have demonstrated that MDMA may increase the levels of oxidative stress by mechanisms other than the induction of hyperthermia Jayanthi et al. We first evaluated whether sex differences may exist in the hyperthermic and neurotoxic effects elicited by MDMA administration in mice. These effects were observed in both male and female mice, which indicates that sex does not influence the neurotoxicity and hyperthermia elicited in adult mice by the protocol of MDMA administration applied in this study. The absence of sex differences in the MDMA-induced nigrostriatal neurotoxic effects may appear unexpected, since clinical studies have suggested that in MDMA users a greater depletion of serotonin may occur in women than in men Pardo-Lozano et al. Therefore, it should be considered that the mechanisms of neurotoxicity are complex and multiple factors are involved, suggesting that dysfunctions in the antioxidant system may be part of the mechanism underlying the neurotoxic effects of MDMA at the level of the dopaminergic nigrostriatal system. Starting from the results that showed similar neurotoxic effects of MDMA in male and female mice, we evaluated whether the nigrostriatal system of male and female mice coped with the neurotoxic stimulus induced by MDMA by activating the same antioxidant systems, since earlier studies have demonstrated that sex differences may exist in the activation of neuroprotective pathways after exposure to neurotoxins Yuan et al. The results of the present study demonstrate that sex differences exist in the antioxidant systems that are activated in the nigrostriatal pathway in response to the neurotoxic damage induced by MDMA. Indeed, an increased co-localization of SOD1 with TH-positive fibers was observed in the striatum of both male and female mice, whereas an increased co-localization of SOD2 with TH-positive fibers and neurons was observed in the striatum and SNc of male mice only. In order to explain these discrepant results, we may hypothesize that SOD1 mRNA was synthesized in the midbrain and then transported by axons to the striatal presynaptic terminals. In this regard, SOD1 should be considered as a first line of defense against oxidative stress because of its immediate ROS scavenging properties Tsang et al. In fact, similar modifications involving SOD1 and its gene have been demonstrated also in rodents treated with drugs of abuse other than MDMA, including cocaine Dietrich et al. Moreover, in neurodegenerative diseases, mutations in SOD enzymes have been characterized and linked to the synthesis of cytotoxic protein aggregates that may influence the antioxidant function of SOD enzymes themselves Pasinelli et al. Collectively, these results let us to hypothesize that male mice were more prone to activate endogenous antioxidant systems following MDMA administration, in particular at the mitochondrial level. In the present study we have also evaluated GPx activity, in order to verify whether the H 2 O 2 produced by the increase in SOD1 and SOD2 was detoxified by the conversion to water, or a lack of detoxification could contribute to the nigrostriatal neurodegenerative process. We observed a general higher GPx activity in the midbrain of female mice, but no modifications in GPx activity in the striatum of male and female mice, as well as in the midbrain of male mice after MDMA exposure. Importantly, the lack of alterations in GPx activity after MDMA treatment could be explained by the evidence that the activity of this enzyme is strictly dependent on the amount of glutathione, and that the latter seems to be reduced following MDMA exposure Puerta et al. In particular, it has been reported that even a small reduction in the levels of glutathione in the striatum can be sufficient to exacerbate the DA depletion induced by MDMA in the same region Sanchez et al. The results of the present study showed that the increase in SOD activity in the midbrain of female mice observed after MDMA administration was not associated with an increase in GPx activity. Furthermore, in physiological conditions, GPx also reduces H 2 O 2 derived from polyunsaturated fatty acids, counteracting the toxic effects of lipid peroxidation Lee et al. We may speculate that in MDMA-treated female mice increased lipid peroxidation may occur, possibly contributing to neuronal degeneration. Future studies are required to confirm this hypothesis also in the protocol of MDMA administration applied in the present study. Finally, starting from the results obtained with SOD1 and SOD2 co-localization, activity, and gene expression, we evaluated the activity of the UPS, since all these cellular pathways are interconnected. UPS, as a highly regulated mechanism of intracellular protein degradation and turnover, mainly works to eliminate damaged proteins that may potentially contribute to the neurodegenerative process Caputi et al. Hence, we aimed at evaluating whether, under oxidative stress conditions that may be induced by exposure to MDMA, activation of the UPS represented an additional way that neurons could use to eliminate damaged proteins Caputi et al. These results are noteworthy, since they are the first to characterize the activity of the UPS subunits in basal conditions and after MDMA administration in male and female mice. The idea that in conditions of heightened oxidative stress the UPS activity in male mice may be more affected than in female mice is supported by recent data in a SOD1 amyotrophic lateral sclerosis mouse model, that revealed an impaired UPS activity in males compared with females Jenkins et al. In conclusion, the results of the present study provide further evidence that MDMA administration induces neurotoxic effects in the nigrostriatal system of male and female mice, and suggest that the mechanisms underlying these effects may be, at least in part, sex-dependent. In particular, the nigrostriatal system of male mice appears to be more sensitive to mitochondria-mediated oxidative effects and UPS activity deficits, compared to the nigrostriatal system of female mice. The results obtained in this study appear of particular interest, since the possible existence of sex-related differences in the neurotoxic effects elicited by drugs of abuse is a hot topic in neuropharmacology, and since most of the studies performed so far involve male animals only. Nevertheless, mechanisms other than oxidative stress and protein degradation deficits deserve further investigation in the context of MDMA-induced neurotoxicity, in order to thoroughly characterize other sex-related differences in the noxious central effects of MDMA. The authors are grateful to Prof. All authors agree with the publication of these data. The raw data supporting the conclusions of this article will be available upon reasonable request to MM. All authors have read and agreed to the published version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Front Pharmacol. Find articles by Giulia Costa. Find articles by Francesca Felicia Caputi. Find articles by Marcello Serra. Find articles by Nicola Simola. Find articles by Laura Rullo. Find articles by Serena Stamatakos. Find articles by Fabrizio Sanna. Find articles by Marc Germain. Find articles by Maria-Grazia Martinoli. Find articles by Sanzio Candeletti. Find articles by Micaela Morelli. Find articles by Patrizia Romualdi. Received May 23; Accepted Jul 12; Collection date Features and dilutions of the primary and secondary antibodies used in this study. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

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