Thesis (Ph. D.)--University of Texas at Austin, 2004. / Supervisors: Christine L. Duvauchelle and Terrence J. Monks. Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Glasgow, 1997. / Includes bibliographical references. Print version also available.

The clinical application of MDMA has long been an issue of great interest for doctors, counselors, researchers, and users alike. Originally synthesized by a pharmaceutical company and subsequently tested on military personnel, the drug was then used by many clinicians and physicians prior to the DEA's strict regulation of the drug, which began in the mid 1980s (Mithoefer et al, 2010). The DEA has classified MDMA a "Schedule 1" drug, which means that it among the most controlled substances, a fact which has hindered the progress of research. For a detailed explanation of the DEA's scheduling of controlled substances, please refer to appendix A. Exception was made to this restriction, however, in 2003 when the US government permitted one organization, the Multidisciplinary Association for Psychedelic Studies ("MAPS," for short), to conduct studies wherein the drug was to be administered to human participants in a clinically controlled experimental environment--a setting which allows for many of the most prevalent confounds found in MDMA research to be minimized and, in some cases, eliminated (Mithoefer et al., 2007; Mithoefer et al, 2010; MAPS.org, 2012). Though MAPS' studies are only just beginning, they have already had promising results in treating protracted cases of PTSD. These recent developments in MDMA research and the results of the subsequent studies have piqued the interest of academics and advocates alike as well as motive numerous other organizations to lend their support to the MAPS organization. This literature review aims to provide an overview of past and present paradigms within the body of MDMA research in order to provide an informational framework within which the recent works regarding the drug's therapeutic merit can be adequately examined.

Studies using animal models have found considerable evidence of neurological damage resulting from exposure to 3,4- methylenedioxymethamphetamine (MDMA, ecstasy). Yet, studies comparing the cognitive performance of human recreational ecstasy users to ecstasy naïve controls have produced inconsistent results. The present study is a meta-analysis of the published empirical literature on the cognitive sequelae of human recreational ecstasy use. The pooled effect size estimate for combined cognitive domains was statistically significant and moderate in size. Small to large, statistically significant aggregate effect sizes resulted for eight of the nine cognitive ability domains included in the analysis. Moderator analyses suggested that frequent ecstasy use is associated with greater cognitive impairment, cognitive impairment can occur after relatively low amounts of total lifetime cumulative use, and recovery of functioning does not occur within one year post cessation.

The illegal drug ecstasy, chemically known as 3,4-methylenedioxymethamphetamine (MDMA), sometimes contains additional chemicals which can pose health risks to users. This thesis examines strategies that recreational ecstasy users in Victoria, British Columbia utilize to determine the purity of their ecstasy. It also examines why they use these strategies and if they are concerned about impure ecstasy affecting their health because this information can help explain the use of these strategies. I performed a quantitative analysis of data collected by the Centre for Addictions Research of BC’s survey, the Canadian Recreational Drug Use Survey, to determine the strategies participants utilized to minimize potential harms caused by ecstasy use. This analysis revealed that 73.9% of survey participants discussed purity of ecstasy with friends, 33.3% checked drug information websites, 17.4% used an ecstasy testing kit, 2.9% asked harm reduction services for advice, and 0% owned a testing kit. In addition, the data revealed that the participants were more likely to take ecstasy from a friend than a stranger. Next, I developed an interview guide based on these findings and I interviewed 10 female recreational ecstasy users. I chose to interview women only because recreational drug use by women is underrepresented in the drug literature. The most common strategy the women utilized to determine ecstasy purity was to discuss ecstasy with friends. They preferred this strategy because it was a convenient, practical strategy. Also, they perceived their friends to be a trusted source of ecstasy and ecstasy information. Half the women analyzed how they felt after ingesting ecstasy to determine its purity because they believed different chemicals caused different effects. Others assessed the physical characteristics of their ecstasy to try to determine purity because they believed these characteristics could reveal its chemical contents. One participant used an ecstasy testing kit, but the rest cited multiple barriers to their use. Some women also had negative attitudes towards testing kits and felt no social pressure to use them. I asked the participants about their use of ecstasy testing laboratories, but none used this service because they did not know it existed. Overall, none of the women seemed concerned about ecstasy impurity harms. This could be due to four factors. First, their ecstasy use patterns made them feel safe from harms related to ecstasy use. Second, recreational ecstasy use was “normal” amongst young adults in Victoria who attend parties, raves, or clubs. Third, they primarily obtained ecstasy and ecstasy information from trusted friends. Fourth, they had never suffered significant harm caused by ecstasy impurity, even though all of the women believed they had ingested impure ecstasy. / Graduate

Ecstasy é o nome popular do 3,4-metilenodioximetanfetamina (MDMA), uma droga de abuso muito utilizada por adultos jovens. Diferentes relatos de caso têm mostrado correlações positivas entre o abuso do Ecstasy e doenças infecciosas. Muitos estudos em modelos animais mostraram que o MDMA induz alterações de imunidade inata e adquirida; entretanto pouco se sabe sobre os mecanismos pelos quais estes efeitos ocorrem. Buscamos neste trabalho por efeitos da administração i.p. de MDMA sobre parâmetros comportamentais, neuroendócrinos e de atividade de neutrófilos e o fizemos à luz de mecanismos neuroimunomodulatórios. Nossos resultados mostraram que o MDMA (5,0; 8,0; 10,0 e 20,0 mg/kg) produz, 30 minutos após a administração (1) aumento da atividade locomotora avaliada no campo aberto e no LCE e (2) diminuição do burst oxidativo de neutrófilos após indução por Staphylococcus aureus nas doses de 8,0; 10,0 e 20,0 mg/kg. Adicionalmente, 60 minutos após a administração de 10,0 mg/kg observou-se (3) um aumento de atividade locomotora avaliada no campo aberto e no LCE, (4) aumento do turnover de noradrenalina e de dopamina no hipotálamo; (5) aumento do turnover de dopamina no estriato; (6) aumento dos níveis séricos de corticosterona; (7) diminuição do burst oxidativo após indução por SAPI e PMA e, também, da porcentagem e da intensidade de fagocitose por neutrófilos sanguíneos; (8) aumento do número de eritrócitos, da quantidade de hemoglobina e da porcentagem do hematócrito e diminuição do número de linfócitos sanguíneos; (9) diminuição do número total de células na medula óssea; (10) aumento do número de leucócitos e (11) diminuição do peso relativo do baço. A exposição in vitro ao MDMA (12) não alterou o burst oxidativo e a fagocitose por neutrófilos. Esses resultados sugerem que o MDMA produz ao mesmo tempo alterações comportamentais, neuroquímicas, endócrinas e imunológicas em camundongos. A estimulação motora dos animais parece relacionada a um aumento da atividade catecolaminérgica central e, muito especialmente, do sistema dopaminérgico estriatal. É possível sugerir que a alteração na imunidade inata após MDMA esteja relacionada ao aumento de atividade do eixo HHA e, conseqüentemente, dos níveis séricos de corticosterona. Não se descarta, porém, uma possível ativação do SNAS induzida pelo MDMA. Finalmente, observamos que o MDMA não tem efeito direto sobre neutrófilos. / Ecstasy is the popular name of N-metil-3,4 methylenedioxymethamphetamine (MDMA), a drug of abuse widely used by young adults. Different case reports have been demonstrating the existence of a positive correlation between Ecstasy abuse and the presence of infectious disease. Many studies conducted in animal models showed that MDMA reduces innate and adaptative immunity. However, little is known about the mechanisms behind these reported effects. In this work we searched for effects of i.p. MDMA administration on behavioral, neuroendocrines, and neutrophil activity in mice, especially parameters looking for neuroimmune relationships. We showed that MDMA treatment (5,0; 8,0; 10,0; and 20,0 mg/kg) produces after 30 minutes (1) increased locomotor activity in the open field and plus maze apparatuses, (2) decreased neutrophil oxidative burst after Staphylococcus aureus (SAPI) after in vitro induction 8,0, 10,0, and 20,0 mg/kg doses. Additionally, 60 minutes after MDMA (10,0 mg/kg) we observed (3) increased locomotor activity in the open field and plus maze apparatuses, (4) increased noradrenaline and dopamine turnover in the hypothalamus, (5) increased dopamine turnover in the striatum, (6) increased level of serum corticosterone, (7) decreased neutrophil oxidative burst after SAPI and PMA inductions, and also decreased percentage and intensity of neutrophil phagocitosis, (8) increased erythrocyte number, hemoglobin level, and hematocrit, and decreased peripheral blood Iymphocyte number, (9) decreased bane marrow total cell number, (10) increased leucocyte number on spleen and (11) splenic weight reduction. It was also observed that (12) in vitro exposure to MDMA induced no effects on both neutrophil oxidative burst and phagocytosis. These results suggest that MDMA produces at the same time behavioral, neurochemical, endocrine, and immunological alterations in mice. The increased locomotor activity observed seems to be related to an action on central catecholaminergic activity, mainly, at the level of the dopaminergic striatal system. It is also possible to suggest that the observed innate immunity alterations are related to an increased HPA axis activity induced by MDMA, via corticosterone. However, we cannot discharge a possible SNS activation induced by MDMA, a fact that could have contributed to the present reported effects. Finally, and importantly we observed that in vitro MDMA has no effects on neutrophil activity.

O propósito do estudo realizado foi de investigar o comportamento voltamétrico da 3,4-metilenodioximetanfetamina (MDMA), substância psicoativa do ecstasy, uma droga que tem se tornado cada vez mais popular entre os usuários de drogas. Empregou-se o uso da técnica de cromatografia líquida de alta eficiência, para isolar a substância a partir de amostras de ecstasy obtidas em parceria com a Polícia Científica de Ribeirão Preto, bem como a técnica de espectrometria de massas, para confirmar a presença da MDMA nas mesmas. Os estudos voltamétricos foram realizados utilizando-se um sistema de três eletrodos, sendo o eletrodo de trabalho de carbono vítreo, eletrodo de referência Ag/AgCl e eletrodo auxiliar de fio de platina. O comportamento eletroquímico desta substância foi investigado diante de diferentes modalidades voltamétricas: Voltametria cíclica, de pulso diferencial e de onda quadrada, nas quais se pôde observar um pico anódico em Ep = +1,1 V. Foram otimizados os parâmetros voltamétricos de modo a tornar a análise mais rápida e sensível, sem perda de intensidade e qualidade do sinal voltamétrico. Com os parâmetros voltamétricos otimizados, foram construídas curvas analíticas para o analito em questão nas diferentes modalidades voltamétricas estudadas. Foi possível determinar o teor de MDMA nas cinco diferentes amostras de ecstasy utilizadas, das quais quatro apresentaram MDMA com teores variando de 3 a 10% (m/m) e uma na qual não foi constatada a presença da droga, mas sim de outro fármaco, a lidocaína. / The main purpose of the present study was to investigate the voltammetric behavior of 3,4-methylenedioxymethanphetamine (MDMA), the psychoactive substance of ecstasy, a drug that has become increasingly popular among drug users. The high performance liquid chromatography technique was employed in order to isolate the substance from ecstasy samples obtained in partnership with Polícia Científica de Ribeirão Preto and also the mass spectrometry technique was employed to confirm the presence of MDMA. The voltammetric studies were performed using the three electrodes system, being glassy carbon as the working electrode, Ag/AgCl as the reference electrode and platinum wire as counter electrode. The electrochemical behavior of the substance was investigated using different voltammetric techniques: Cyclic, differential pulse and square wave voltammetry modalities, in which an anodic peak was observed at Ep = +1,1 V. The voltammetric parameters were optimized in order to make the analysis faster and more sensitive, without loss of quality and intensity of the voltammetric signal. With the voltammetric parameters optimized, analytical curves of the studied analyte were built for the different voltammetric techniques. It was possible to determine the content of MDMA in the five different ecstasy samples utilized, in which four showed MDMA with contents ranging from 3 to 10% (m/m) and one in which no MDMA was observed but another drug, lidocaine.

Objectives: To investigate the relationship between ecstasy use and mental disorders in a representative sample of adolescents and young adults. Method: Data for this investigation were drawn from the Early Developmental Stages of Psychopathology (EDSP) study, an epidemiological-longitudinal study in which 14-24 year-olds were examined prospectively over a period of about 4 years. Results are based on N=2462 participants who completed the whole study period and for whom drug use behavior could be determined. Results: (1) Ecstasy users, compared with non-users, were at significantly increased risk of DSM-IV substance related disorders, including alcohol use disorders (52.6 vs. 15.6%; OR=5.6, 95% CI=3.8-8.1). Further, ecstasy users also had a higher risk of alcohol use disorders, when compared with users of other illicit substances (52.6 vs. 40.3%; OR=1.7, 95% CI=1.1-2.4). (2) Ecstasy users had significantly higher rates for almost all DSM-IV mental disorders examined when compared with non-users (any non-substance use disorder: 68.7 vs. 44.5%; OR=3.1, 95% CI=2.1-4.4) and compared with users of other illicit drugs (any non substance use disorder: 68.7 vs. 55.5%; OR=1.8, 95% CI=1.2-2.6). (3) Ecstasy users also reported significantly higher rates of prescription medicine use, though they did not use more medical services than non-drug users. (4) Analyses of temporal patterns of ecstasy use and disorder onset revealed that the first use of ecstasy was secondary to the onset of DSM-IV mental disorders in the majority of cases. Still, subjects with mental disorders at baseline also showed a significantly increased risk for initiation of ecstasy use during the 4-year follow-up period. Conclusions: Care should be taken in cross sectional studies in interpreting mental disorder signs and symptoms merely as a consequence of ecstasy use, as ecstasy use might be associated with the use of multiple substances, and onset of mental disorder is more likely to precede rather than to follow use of ecstasy and related substances.

Aim: To explore the role of cannabis use for the availability of ecstasy as a potential pathway to subsequent first ecstasy use. Methods: Baseline and 4-year follow-up data from a prospective-longitudinal community study of originally 3021 adolescents and young adults aged 14–24 years at baseline were assessed using the standardized M-CIDI and DSM-IV criteria. Results: Baseline cannabis users reported at follow-up more frequent access to ecstasy than cannabis non-users. Higher cannabis use frequencies were associated with increased ecstasy availability reports. Logistic regression analyses revealed that cannabis use and availability of ecstasy at baseline are predictors for incident ecstasy use during the follow-up period. Testing simultaneously the impact of prior cannabis use and ecstasy availability including potential confounders, the association with cannabis use and later ecstasy use was confirmed (OR = 6.3; 95% CI = 3.6–10.9). However, the association with ecstasy availability was no longer significant (OR = 1.2; 95% CI = 0.3–3.9). Conclusions: Results suggest that cannabis use is a powerful risk factor for subsequent first onset of ecstasy use and this relation cannot be sufficiently explained by availability of ecstasy in the observation period.

Auf der Grundlage einer epidemiologischen Untersuchung an 3021 Probanden im Alter von 14-24 Jahren (Ausschöpfung 71%) werden Prävalenz von Gebrauch, Miβbrauch und Abhängigkeit von Ecstasy, verwandten Amphetaminen und Halluzinogenen bestimmt sowie Gebrauchsmuster und Korrelate des Gebrauchs untersucht. Als diagnostisches Interview wurde das computerisierte und standardisierte M-CIDI verwendet. Ergebnisse: (1) 14-24jährige gebrauchen Ecstasy häufig (4% aller Manner und 2,3% aller Frauen), XTC-verwandte Amphetamine werden mit 3,6% (Manner) bzw. 1,6% (Frauen) etwas seltener konsumiert. Die LSD-Gebrauchs-Prävalenz liegt bei 2,8% (Manner) bzw. 1,4% (Frauen); verwandte Halluzinogene werden von insgesamt 1,5% der Befragten angegeben. (2) Vergleiche mit Erhebungen aus dem Jahr 1990 lassen eine erhebliche Steigerung (Verdoppelung bzw. Verdreifachung) des Konsums sowohl von Ecstasy und verwandten Präparaten wie auch von Halluzinogenen erkennen. (3) Die Prävalenz klinisch manifester Miβbrauchs– und Abhängigkeitsdiagnosen nach DSM-IV liegen in der Altersgruppe 14-24jähriger bezüglich Ecstasy bei fast 1%, bei Halluzinogenen etwas darunter. Das Verhältnis Gebrauchs-Prävalenz zu diagnostischer Prävalenz von zirka 6:1 läβt auf ein signifikantes «Sucht»potential dieser Substanzen schlieβen. (4) Altersrisikoanalysen lassen erkennen, daβ sich das Einstiegsalter für beide Substanzen in jüngere Altersgruppen verschiebt. Nur für Ecstasy läβt sich über alle Altersstufen hinweg ein stetiger Anstieg von Erstgebrauchsraten nachweisen, demgegenüber bleibt die Rate von Erstkonsumenten bei Halluzinogenen nach dem 18. Lebensjahr stabil. (5) Bezüglich Einstiegs-und Ausstiegsmotivationen ergaben sich für beide Stoffgruppen recht unterschiedliche Muster, die als Hinweis für die Notwendigkeit substanz-spezifischer Präventionskonzepte interpretiert werden. Folgerungen: Die Verbreitung von Ecstasy und Halluzinogenen bei Jugendlichen und jungen Erwachsenen nimmt offensichtlich weiter in beschleunigter Form zu. Im Zusammenhang mit einem bislang häufig unterschätzten «Sucht»potential wird ein rapid wachsender Präventions– und Therapiebedarf absehbar, der für die Verhaltenstherapie eine besondere Herausforderung darstellt.