A 3,4-metilenodioximetanfetamina (MDMA) é a principal substância psicoativa comercializada ilegalmente em comprimidos de ecstasy. O MDMA é uma droga de ação psicotrópica e uso proscrito, conforme lista F (grupo F2) da ANVISA, pois apresenta propriedades alucinógenas e estimulantes e seu uso/abuso pode gerar uma série de danos à saúde dos usuários. O desenvolvimento de eletrodos quimicamente modificados (EQMs) na eletroanalítica tem por finalidade a obtenção de sistemas de detecção mais sensíveis e seletivos para o analito de interesse. Também, considera-se necessário desenvolver novas técnicas e métodos para a detecção de compostos em amostras de interesse forense, a fim de obter ferramentas para auxiliar os cientistas forenses no combate ao comércio ilícito de substâncias. Conforme problemática exposta, este trabalho teve por finalidade o desenvolvimento de eletrodos quimicamente modificados utilizando como modificadores da superfície eletródica de carbono vítreo o Nafion e Nafion/CB[7], utilizando deposição por drop coating e spin coating para a detecção de MDMA através das técnicas de voltametria cíclica e onda quadrada. Conforme o sistema empregado, os melhores EQMs desenvolvidos foram de Nafion (1,5% v/v) e Nafion (1,5% v/v)/CB[7] (10,0 µg.mL-1). Os EQMs desenvolvidos apresentaram limite de detecção e quantificação na faixa de traços e menores que aqueles reportados em outros trabalhos da literatura. Considerando a aplicação dos EQMs para a detecção de MDMA em amostras de ecstasy, verificaram-se as respostas voltamétricas de outras substâncias: cafeína, metanfetamina, teobromina, lidocaína, cloridrato de procaína, (±)-metanfetamina e cloridrato de cocaína. Nas condições experimentais empregadas, observou-se que as substâncias estudadas não atuam como falsos positivos para o MDMA. Paralelamente, obtiveram-se onze lotes de comprimidos de ecstasy (apreendidos e cedidos pela Polícia técnico-científica de Ribeirão Preto-SP) e realizaram-se análises qualitativas e quantitativas nos mesmos, utilizando técnicas colorimétricas (Marquis, Ácido sulfúrico, Simon e Simon com acetona) e cromatográficas (CG-EM E CLAE-EM). Considerando o melhor EQM desenvolvido, quantificaram-se 11 lotes de ecstasy pela técnica voltamétrica e cromatográfica, dentre os lotes estudados, dois não continham MDMA, um apresentou uma mistura de MDMA e cafeína e os demais continham MDMA. A concentração de MDMA presente nos lotes variou de 0 até 61 % em massa. A detecção de MDMA em ecstasy pelo método voltamétrico desenvolvido se mostrou viável e sensível para o analito de interesse. / The 3,4-methylenedioxymethamphetamine (MDMA) is the main psychoactive component of ecstasy tablets, that have an illicit trade. MDMA has been an illicit psychotropic drug, and it has a prohibited use (group F2, in ANVISAs F list), because of its hallucinogenic and stimulating effects, and the use/abuse can poses serials health risks. The development of chemically modified electrodes (CME) in electroanalytical methods aims to get more sensitive and selective systems to detect the analytes. In this context, it is necessary to develop new techniques and methodologies to the detection of illicit samples; it provides more tools to help the forensic scientists to combat the illicit drug trade. So, this work focused in the development of chemically modified electrodes (CMEs) with modifications on the glassy carbon surface by drop coating and spin coating using Nafion and Nafion/CB[7] solutions. The CMEs were tested using cyclic, and square wave voltammetry to detect MDMA. Considering the employed system, the best CMEs were made by Nafion (1.5% v/v), and Nafion (1.5% v/v)/CB[7] (10.0 µg.mL-1) thin films. It was possible to observe better sensitivities for these sensors, in comparison to other MDMA studies reported in the literature. The specificity of the proposed sensors was checked in relation to other drugs: caffeine, methamphetamine, theobromine, lidocaine, procaine hydrochloride, and cocaine hydrochloride. These drugs do not interfere in this voltammetric method. Additionally, we studied eleven lots of ecstasy samples, allowed by the Scientific Police - Ribeirão Preto-SP, and we provide qualitative and quantitative studies using colorimetric techniques (Marquis, Sulfuric acid, Simon, and Simon with acetone), and chromatografic techniques (GC-MS and HPLC-MS). The MDMA quantification in real samples was obtained by high performance liquid chromatography with a mass spectrophotometer, and we compared with the voltammetric technique, using the developed CME. Between the analyzed lots, two of them didnt present in their composition, one lot had a mix of caffeine and MDMA, and another presented MDMA. The MDMAs concentration in lots had a large variation, with 0 to 61 % w/w. The MDMAs voltammetric detection in ecstasy lots was viable. And, it is also possible to apply this methodology to analyze MDMA traces.

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.

The psychedelic psilocybin and the entactogen 3,4-methylenedioxymethamphetamine (MDMA) are being scientifically studied again after a long hiatus, and especially for their potential in the treatment of psychiatric disorders. Their profound effect on cognitive, perceptual, and affective processes have led to several clinical studies during the last decade that have forced the reconsideration of the utility of these substances. The research includes clinical trials with psilocybin-assisted psychotherapy for depressive and anxiety symptoms, and MDMA-assisted psychotherapy for the treatment of post-traumatic stress disorder (PTSD). The results have shown a significant reduction in depressive and anxiety symptoms in psilocybin-assisted psychotherapy, and in PTSD symptoms in MDMA-assisted psychotherapy, with acceptable adverse effects. Moreover, the reductions in symptoms have been shown to be sustained several years later. Given the results indicate short- and long-term safety and efficacy, even for treatment resistant conditions, this suggest that these substances administered with psychotherapy are promising and deserve to be taken seriously as a therapeutic tool. The present thesis provides an overview of the latest clinical studies on the treatment of depression, anxiety, and PTSD with psilocybin and MDMA, respectively, as well as reviews the history, mechanisms of action, the therapeutic process used with psilocybin and MDMA, and any adverse physiological and psychological effects of both substances.

The regulation and modulation of the serotonergic system is clinically significant in humans. Abnormally low levels of serotonin can result in depression and conditions like panic disorder, obsessive-compulsive disorder, social anxiety disorder, sudden infant death syndrome, and eating disorders. The mechanistic role of serotonin (5-HT) on the neural circuits related with these diseases is not definitively known. Drosophila is a simple model system that provides an advantage over vertebrates to modify genetically and for electrophysiological studies on identifiable cells. In this organism the sensory-CNS-motor circuit is modulated by 5-HT, octopamine (OA), and dopamine (DA), which gives one insight that these neuromodulators are playing a role in central neuronal circuits. The role of 5-HT in the behavior and development of Drosophila melanogaster larvae is being studied. p-CPA (para-chlorophenylalanine) blocks the synthesis of 5-HT by inhibiting tryptophan hydroxylase. The development, behavior and physiology in 3rd instar larvae are affected after feeding this drug. MDMA (3,4 methylenedioxyamphetamine), an analog of methamphetamine is a drug of abuse that has been shown to cause depletion of 5-HT from nerve terminals. It causes the 5-HT transporter to work in reverse. Thus, a dumping of 5-HT results. In Drosophila 3rd instar larva development, physiology and behavior are effected when MDMA is fed throughout their development period. Also at the fly neuromuscular junction, (NMJ) MDMA is causing more evoked vesicular release of glutamate from the presynaptic nerve terminal. Also using anti-sense expression of the 5-HT2dro receptor, role of 5-HT and one of its receptors is studied on development, physiology and behavior. Knock down of 5-HT2dro resulted in developmental delay. Physiology and behavior were also abnormal in these animals.

3,4-(±)-Methylenedioxymethamphetamine (MDMA, ecstasy) is a widely abused amphetamine derivative. The metabolism of MDMA is thought to be a necessary component of MDMA-induced neurotoxicity, as direct administration of MDMA into the central nervous system of rats failed to reproduce the hallmark serotonin deficits seen following systemic administration of MDMA. Mechanistic questions remain regarding how MDMA elicits this neurotoxicity. Work of this thesis was undertaken to examine how MDMA-induced neurotoxicity is affected by the activity of two polymorphic enzymes involved in the metabolism of MDMA, namely cytochrome P450 family member 2D6 (CYP2D6) and catechol-O-methyltransferase (COMT), as well as the potential role microglia play in the facilitation of this neurotoxicity. Inhibition of CYP2D1, the homolog of human CYP2D6 in the rat, resulted in an attenuation of serotonergic neurotoxicity following MDMA-administration. In both a pharmacological model and a genetic model of CYP2D1 inhibition, serotonin deficits were alleviated when compared to normal-activity CYP2D1 counterparts. Inhibition of COMT, the primary detoxication enzyme in the MDMA pathway, resulted in potentiation of MDMA-induced neurotoxicity. In a pharmacological model of COMT inhibition, rats displayed greater long-term serotonin deficits after COMT inhibition. Mice devoid of COMT proved sensitive to the lethal hyperthermic effects of MDMA, illustrating the importance of this enzyme in preventing the acute toxicity of MDMA. Brain lesions often elicit a microglial response. Microglia have the potential of both beneficial and deleterious actions in the brain. Whether microglia are activated by nerve terminal degeneration produced by MDMA is an area of ongoing debate. Systemically delivered MDMA produces a modest increase in the amount of microglial cells present in the parietal cortex of rats over a one-week period. MDMA also increased the phagocytic activity of microglia in the cortex. The studies described herein support the hypothesis that metabolism is critical in MDMA-induced neurotoxicity. Furthermore, as both CYP2D6 and COMT are polymorphic in the human population, certain individuals are more at risk for severe serotonergic toxicity following MDMA administration. Finally, while microglia are likely not the cause of MDMA-induced neurotoxicity, contributions of these cells cannot be dismissed.

3,4-(±)-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a widely abused amphetamine derivative with potent stimulant properties. The neuropharmacological effects of MDMA are biphasic in nature. MDMA initially causes synaptic monoamine release, primarily of serotonin (5-HT), producing hyperthermia and hyperactivity (5-HT syndrome). Conversely, the long-term effects of MDMA manifest as a prolonged depletion in 5-HT, and structural damage to serotonergic nerve terminals. Monoamine transporter systems at the plasma membrane and storage vesicles of 5-HT neurons have been implicated in MDMA toxicity. Nonetheless, many mechanistic questions remain regarding the precise role of uptake transporters in MDMA neurotoxicity. The present study was designed to address the importance of the serotonin reuptake transporter (SERT) and the vesicular monoamine transporter 2 (VMAT2) to the physiological, behavioral and neurotoxic responses to MDMA. SERT functions as a primary regulator of 5-HT homeostasis, mediating the reuptake of 5-HT from the synaptic space following its release during neurotransmission. SERT is a molecular target site for MDMA and many antidepressant agents such as the selective serotonin reuptake inhibitor (SSRI) class. Pharmacological inhibition of SERT protects against MDMA-induced serotonergic neurotoxicity. Thus, the effects of MDMA are in part mediated by an ability to interact with and inhibit SERT. Using a SERT-knockout (SERT-KO) rat model, we determined that SERT deficiency modulated the acute toxicities of MDMA, such as hyperthermia and hyperactivity, whilst completely preventing long-term depletions in tissue 5-HT levels, indicating the abolishment of neurotoxicity. Disruption of vesicular monoamine storage via interaction with VMAT2 has also been implicated in MDMA neurotoxicity. VMAT2 participates in the transport of monoamine neurotransmitters, in particular 5-HT and dopamine (DA), into intra-neuronal storage vesicles. As such, VMAT2 is critical in maintaining neuronal health by preventing neurotransmitter oxidation within the cytosol. Pharmacological inhibition of VMAT2 with Ro4-1284 reduced MDMA-induced hyperactivity and averted hyperthermia along with persistent serotonergic deficits. Overall, our results corroborate the hypothesis that SERT and VMAT2 are critical to the in vivo effects of MDMA. Furthermore, given that VMAT2 inhibition diminished the behavioral response to MDMA in rats, pharmacological manipulation of this transporter could be used in the treatment of MDMA abuse and overdose.

Drug use and abuse for recreational purposes is a common phenomenon, with club drugs such as MDMA (3,4-methylendioxymethamphetamine) being popular for its energetic and euphoric effects – recreating an artificial feeling of “Ecstasy”. Although use of the drug itself has remained relatively constant over the years, the population among which it is popular has been shifting toward younger users, with MDMA use among adolescents becoming more prominent. However research on the effects that MDMA has on the developing adolescent brain has been limited. The current study focuses on the long term effects in rats following chronic MDMA exposure during either early or late adolescence. In adulthood, the rats’ memory, activity and emotional reactivity were assessed through frequency of ambulation, grooming, rearing, defecation, and corner or center occupancy of an open-field, novel object-recognition in the open-field, emergence from a dark chamber into a bright area, and recognition of the changed arm of the Y-maze. The results showed that there were significant long-term effects resulting in increased anxiety for rats treated with MDMA during late adolescence only. This increase of emotional reactivity was indicated through decreased ambulation on the open-field measures, decreased movement between the dark and light chambers, and decreased entries of both arms of the Y-maze. Sex of the animal was also found to differentiate MDMA effects, with females showing a greater increase in anxiety. Measures regarding spatial and working memory were not significant. Overall, the results suggest that animals are more susceptible to long-term effects following MDMA administration in late, but not early adolescence. Furthermore, memory appears to remain unaffected regardless of the age of administration, and only anxiety levels were affected by the drug.

High doses of 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") are known to reduce levels of various serotonergic markers outside of the raphe nuclei. To test the hypothesis that these deficits reflect a degeneration of distal axons/terminals, we investigated the effects of an MDMA binge (10mg/kg x 4) on the relative protein and genetic expression of several serotonergic markers in rats, as well as the effects of this compound on the quantity of serotonergic terminals in these animals. In experiment I, we examined whether MDMA alters serotonin transporter (SERT) levels as determined by lysate binding and immunoblotting analyses. Both methods of analysis revealed MDMA-induced reductions in regional SERT content. Experiment II investigated MDMA-induced changes in terminal-specific levels of SERT and the vesicular monoamine transporter 2 (VMAT-2) in the hippocampus, a region with sparse dopaminergic innervation, after lesioning noradrenergic input with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). Animals were administered 100 mg/kg DSP-4 or saline 1 week prior to MDMA (or saline). As determined by immunoblotting of synaptosomal tissue, the DSP-4/MDMA group showed little change in hippocampal VMAT-2 protein expression compared to DSP-4/Saline controls, despite large reductions in SERT levels in all regions examined in the MDMA-treated animals. Experiment III examined whether MDMA alters genetic expression of SERT and VMAT-2. When compared to saline-treated controls, animals given MDMA showed a striking decrease in SERT gene expression (and a lesser effect on VMAT-2) in dorsal/median raphe as assessed by quantitative RT-PCR. Experiment IV(a) investigated the effects of MDMA on gene and protein expression of tryptophan hydroxylase (TPH) in the hippocampus. Levels of TPH protein were unchanged between treatment groups, while transcript levels were decreased 15-fold in the dorsal/median raphe. In experiment IV(b), flow cytometry was used to measure whether MDMA alters the quantity of serotonergic terminals in the hippocampus. MDMA-treated animals showed an increase in the number of serotonergic synaptosomes identified by co-labeling for synaptosome-associated protein of 25 kDa (SNAP-25) and TPH. These results demonstrate that MDMA causes substantial regulatory changes in the expression of serotonergic markers with no evidence for synaptic loss, questioning the need to invoke distal axotomy as an explanation of MDMA-related serotonergic deficits.

Psychedelics—also known as hallucinogens and entheogens—comprise a family of psychoactive molecules that are both found in nature and synthetically engineered in the lab. As a class, psychedelic compounds produce phenomenologically complex and novel experiences that have recently captured the attention of mental health clinicians and researchers. However, psychedelic clinical research and treatment remain limited, with most studies exploring the efficacy and safety of protocols for individuals with anxiety, depression, substance use, and posttraumatic stress disorder (PTSD), while individuals with personal or familial histories of psychosis, psychotic disorders, and bipolar disorder are mostly excluded from treatment and research. The overarching objectives of this thesis included determining 1) whether excluding this group from psychedelic clinical research is justified, 2) when psychedelic drug administration and psychedelic-assisted psychotherapy (PAP) may be contraindicated for this group, 3) if people with a history of psychosis or a psychotic disorder may be able to treat their psychotic symptoms with PAP, 4) if people with a history of psychosis or psychotic disorder may be able to treat their co-morbid conditions like anxiety, depression, substance use, or PTSD with PAP, 5) what a PAP treatment protocol for this group could look like 6) how individuals with reported histories of psychosis and psychotic disorders describe their experiences of psychedelic drug use and 7) whether naturalistic psychedelic use has an overall positive or negative effect on emotional well-being and psychological functioning for this group. Results from the first study—a qualitative study with experts in medicine, mental health, and psychedelics—suggest that certain individuals with histories of psychosis and psychotic disorders may benefit from PAP under the right conditions, such as when psychosis is etiologically connected to traumatic events, when the protocol offers extensive support for the patient, and when psychosis is not the result of amphetamine use or medical conditions such as epilepsy. Moreover, results suggest that the effects of the specific psychedelic that is administered must be carefully considered and support outside of therapy must also be assessed. Other factors such as personality traits, ability to form rapport with a guide or sitter, symptom severity, specific symptom endorsement, symptom duration, age, the presence of physiopathology and more must also be taken into consideration. For the second study, a cross-sectional, retrospective, phenomenological survey report was administered to individuals who reported a history of one or more psychotic experiences and/or diagnosis of a psychotic condition who also had at least one psychedelic drug experience in their lifetime. The survey asked participants to describe one memorable instance of psychedelic drug use and found that in a sample of 100, most individuals (n=88) describe some degree of personal growth resulting from their experience. Many also describe mystical-type experiences, gaining insight or awareness during their experience, heightened appreciation for life, and improved mental health and emotional well-being. Descriptions of symptomatic relief included reduced paranoid thinking, changes in relationships with symptoms, and decreased suicidal ideation. Approximately 11% of the sample described negative experiences including perseverating psychological impairment, symptom exacerbation, and psychedelic-induced suicidality. A slightly larger portion of the sample described mixed-type experiences, i.e., experiencing positive and negative effects alongside each other. The findings of these studies fill a major gap in the literature by suggesting that individuals with histories of psychotic symptoms and disorders may be able to partake in psychedelic studies and treatment under certain circumstances. This is because experts have explicitly stated that psychedelic use is not necessarily contraindicated for everyone with psychotic conditions and symptoms, but rather that most PAP protocols for anxiety, depression and other conditions do not offer enough support. At the same time, exclusion criteria are required by the FDA. Additionally, survey reports from individuals with lived experiences of psychosis further back the position that PAP could be a viable treatment option for this group through their survey reports. Specifically, the high prevalence of positive and therapeutic experiences with psychedelics in naturalistic settings suggests that clinically supervised psychedelic drug use may generate similar or even better outcomes for this population. Although a minority had adverse experiences, it remains to be studied as to whether similar effects might be experienced at a similar rate or similar degree of frequency in clinical studies, which utilize harm reduction strategies, maximize safety, and implement preparatory and integration sessions, elements which were notably absent from reports of adverse experiences in the survey. Results also shed light on what a psychedelic treatment protocol could look like for this group, and how individuals with histories of psychotic experiences and diagnosed psychotic conditions describe their experiences of psychedelic use and the effects of psychedelic drugs on their emotional and psychological functioning.

No description available.