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Posttraumatic stress disorder (PTSD) is a debilitating and prevalent psychiatric pathology across the world and highly effective treatments for it are lacking. PTSD is characterized by frequent and intrusive memories of trauma that arise several months after experiencing or witnessing a traumatic event. These memories elicit strong emotional responses in PTSD patients and initiate many somatic and psychiatric comorbidities. Treatments for PTSD exist, but the clinical trials evaluating them have produced inconsistent results including highly variable data on effect sizes and tolerability. Recent meta-analyses on these randomized clinical studies, comparing the effects of the approved treatments on PTSD symptom severity with control groups (employing inactive placebos or intent-to-treat groups), have shown similar safety profiles and low-to-medium effects sizes. Treatments currently approved for use in PTSD include manualized, trauma-focused psychotherapies (cognitive processing therapy (CPT) and prolonged exposure therapy) and pharmacotherapies that employ selective serotonin reuptake inhibitors (SSRIs). Conclusive data comparing the efficacy and tolerability of these therapies must be derived from head-to-head comparisons in randomized clinical trials. These studies are not yet available for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for the treatment of PTSD; the first phase 3 clinical trial of this treatment was published in early 2021. The development, and history of the treatment is also discussed. MDMA is a commonly used drug of abuse. In the context of its illicit use, it is often referred to as ecstasy or molly, where it is used in dance-party and music festival settings. It is a Drug Enforcement Agency (DEA) schedule I substance. The DEA scheduling of drugs under the controlled substance act is discussed to explain MDMA’s legal status relative to other drugs of abuse. MDMA’s legal designation has slowed research on this treatment and is therefore an important aspect of the history and development of the treatment. In MDMA-assisted psychotherapy, MDMA is administered to the participant prior to an eight-hour manualized therapy session. In this context, “manualized” refers to the strict adherence to a protocol and methodology of psychotherapeutic treatment by the therapist. Consistent with phase 2 clinical trials, the first and only published phase 3 trial for MDMA-assisted psychotherapy has shown it to be a highly efficacious and safe treatment for PTSD. There are many common subjective psychological effects of MDMA that have been reported in the literature, but its ability to enhance sociability, self-esteem, trust in others (especially the therapist), and reduce anxiety and defensiveness during the therapy session have long been thought to be the primary benefit in therapy. These behavioral traits are characteristically impaired in trauma-related disease states, which adversely affects the therapeutic processes. Acute cessation of some PTSD symptoms due to the subjective effects of MDMA may provide a “window of tolerance”, in which the patient can discuss traumatic memories without shutting down socially and mentally, which is common in psychotherapeutic treatment for PTSD. This thesis will also discuss MDMA pharmacology, chemistry, its role as a drug of abuse, and some of its molecular mechanisms of action that may confer its psychiatric subjective effects that have been reported in humans. Early studies on the toxicity of MDMA indicated adverse public health implications due to safety concerns and largely led to this designation of the molecule as a schedule I material. Further research has brought the validity of this early research into question, although serotonergic neurotoxicity seems to be the most prevalent. In short, single-dose MDMA administration in normal dosing ranges of MDMA used in illicit contexts has been shown to elicit some of the same histological and cellular changes produced by long-term SSRI use, further calling the toxicity of MDMA into question. An overview of PTSD will follow this discussion on MDMA. Specifically, this section will discuss the pathology, symptoms, diagnosis, comorbidities, risk factors, and the underlying neurobiology of PTSD and stress-related disease states. Resilience is an important feature of PTSD risk; more resilient people tend to develop PTSD less frequently upon exposure to trauma. Resilience is correlated with one’s capacity for regulating his or her own emotions, which is characteristically impaired in stress-related disease states and strongly contributes to many of the symptoms involved in this pathology. Understanding resilience and emotional regulation, their neurological basis, and role in PTSD pathology is therefore important for understanding these aspects of the disease state and are discussed thoroughly. The information presented in the MDMA and PTSD sections will then be discussed together in the following section on MDMA-assisted psychotherapy as it relates to the treatment and its proposed therapeutic mechanisms of action. The treatment methods in the stage 2 and 3 clinical trials of MDMA-assisted psychotherapy for PTSD are discussed and compared, the major focus of this section, however, will be the methods used in the first phase 3 clinical trial, as well as the results and limitations of this study. In short, the first stage 3 trial for the treatment showed a significantly improved efficacy in treating PTSD and its comorbid psychiatric pathologies as compared to both the current FDA-approved pharmaceutical and psychotherapeutic treatments for PTSD. Three main mechanisms of action that may account for the efficacy of MDMA-assisted psychotherapy for PTSD treatment have been discussed in the literature. These are not necessarily mutually exclusive and may all partly explain the treatment effects. These include the “window of tolerance” mechanism discussed above, the critical-period reopening mechanism, and the fear extinction facilitation mechanism. MDMA-assisted psychotherapy is a novel and creative approach to treating psychiatric pathologies. It is also the first treatment regime approved for investigation by the US Food and Drug Administration (FDA) in which a psychedelic or psychedelic-like agent is employed therapeutically or in which a psychoactive agent is employed alongside psychotherapeutic treatments. Other clinical trials of drug-assisted psychotherapy treatments using similar methods while employing different psychoactive drugs for the treatment of many psychiatric diseases are currently ongoing, MDMA- assisted psychotherapy has been the first of this novel method of therapy to be stringently studied under modern scientific randomized, placebo-controlled clinical is now being investigated for applications in other psychiatric pathologies. Further research into this treatment is critical for finding new ways for improving the treatment protocol, therefore improving treatment efficacy and safety. Such research will include addressing the limitations of the first published phase 3 clinical trial, investigating the mechanisms of action by which the treatment works, and conducting clinical trials in larger or more specific populations.

A 3,4-metilenodioximetanfetamina (MDMA, ecstasy), derivada da anfetamina, é uma droga largamente utilizada para fins recreacionais devido à sensação de euforia, energia e desejo de socialização. Apesar de ter a reputação de ser uma droga segura, um número crescente de relatos clínicos e estudos experimentais indica que a MDMA pode produzir toxicidade no SNC, rim, fígado e coração. Embora esteja contida nos comprimidos de ecstasy como racemato (uma mistura de 50% de seus enantiômeros), sua biotransformação é enantioseletiva; em ratos, o enantiômero R é biotransformado mais rapidamente que o S. Como a biotransformação de MDMA é capaz de produzir metabólitos reativos, muito provavelmente, a forma R tenha um maior potencial para gerar ERO/ERN e dano oxidativo nos tecidos do que a forma S. Nos seres humanos ocorre o inverso. Portanto, o presente trabalho teve como objetivo avaliar a contribuição individual de cada enantiômero da MDMA isoladamente, tendo como referência a mistura racêmica, no estresse oxidativo hepático renal e estriatal de ratos. Ratos Wistar machos adultos (180-220g) foram divididos em quatro grupos: controle (salina), MDMA racêmico, R-MDMA e S-MDMA. (2 doses consecutivas de 10 mg/kg no intervalo de 24h, gavage). Parâmetros de estresse oxidativo serão utilizados como a medida da formação de malonaldeído, a determinação de níveis de glutationa reduzida e a atividade da glutationa-S-transferase. Os enantiômeros da MDMA racêmica foram separados por meio da cromatografia em fase líquida de alta eficiência em fase estacionária quiral. Os enantiômeros obtidos mostraram um alto grau de pureza e um bom rendimento. Nossos resultados mostraram que o conteúdo hepático de glutationa total dos ratos do grupo R,S-MDMA e do grupo R-MDMA, foi significativamente menor do que os do controle e os do S-MDMA, revelando que é o enantiômero R que contribui para a depleção de glutationa hepática induzida pela mistura racêmica. A alta reatividade do enantiômero R no fígado também pode ser constatada nos animais tratados apenas com R-MMDA, uma vez que houve uma produção significativamente aumentada de MDA, comparativamente aos outros grupos tratados e o controle. O conteúdo renal de glutationa total foi significantemente menor para todos os grupos tratados quando comparados com o controle. Com relação ao estriado, apenas os animais tratados com o isômero S isoladamente mostraram uma queda significativa da atividade da GST em comparação aos demais grupos tratados e controle. Tomando todos esses dados em conjunto, esse trabalho mostrou que os enantiômeros isolados da MDMA podem atuar de formas distintas no que se refere ao estado redox, principalmente no fígado, uma vez que o isômero R foi o que mais contribuiu para um dano oxidativo. / MDMA (3,4-methylenedioxymethamphetamine) is an amphetamine derivate that is largely used for recreational purpose due to its feeling of euphoria, energy and the desire to socialize. Although MDMA has the reputation of being safe, a growing number of clinical reports and experimental studies indicate that MDMA can produce toxicity in the CNS, kidney, liver and heart.Although MDMA is present in ecstasy tablets as a racemate (a 50% mixture of its enantiomer) it has an enantioselective metabolism; in rats, the S-enantiomer is metabolized faster than the R-enantiomer and it is the more active pharmacological form. As the MDMA biotransformation can produce reactive metabolites, probably the R form has a greater potential to generate ROS / ERN and oxidative damage in tissues than the S. In humans, the opposite occurs. Therefore, this aim of the present study was to evaluate the individual contribution of single MDMA enantiomers, compared to racemic mixture in liver, kidney and striatal rats oxidative stress. Adult male Wistar rats (180- 220g) will be divided into four groups: control treatment (saline), racemic MDMA, R-MDMA and S-MDMA (two consecutive doses 24h apart with 10mg/kg, gavage). Oxidative stress status parameters will be used to measure malondialdehyde formation, the reduced glutathione levels determination and the glutathione-S-transferase activity. The enantiomers of racemic MDMA were separated by liquid chromatography high-efficiency chiral stationary phase. The enantiomers showed a high degree of purity and a good recovery. Our results showed that the total glutathione content in liver of rats in R,S-MDMA and R-MDMA group was significantly lower than the control and S-MDMA, revealing that the R-enantiomer that contributes to hepatic glutathione depletion induced by the racemic mixture. The high reactivity of the R enantiomer in the liver can also be observed in animals treated with R-MMDA, since there was a significantly increased production of MDA, compared with other treated and control groups. The total glutathione content in kidney was significantly lower for all treated groups compared with control. With respect to the striatum, only animals treated with the S isomer alone showed a significant decrease in GST activity compared to other treatment and control groups. Taking all these data together, this study shows that the isolated enantiomers of MDMA can act differently with regard to the redox state, mainly in the liver, since the R isomer was the largest contributor to oxidative damage.

A 3,4-metilenodioximetanfetamina (MDMA, ecstasy), derivada da anfetamina, é uma droga largamente utilizada para fins recreacionais devido à sensação de euforia, energia e desejo de socialização. Apesar de ter a reputação de ser uma droga segura, um número crescente de relatos clínicos e estudos experimentais indica que a MDMA pode produzir toxicidade no SNC, rim, fígado e coração. Embora esteja contida nos comprimidos de ecstasy como racemato (uma mistura de 50% de seus enantiômeros), sua biotransformação é enantioseletiva; em ratos, o enantiômero R é biotransformado mais rapidamente que o S. Como a biotransformação de MDMA é capaz de produzir metabólitos reativos, muito provavelmente, a forma R tenha um maior potencial para gerar ERO/ERN e dano oxidativo nos tecidos do que a forma S. Nos seres humanos ocorre o inverso. Portanto, o presente trabalho teve como objetivo avaliar a contribuição individual de cada enantiômero da MDMA isoladamente, tendo como referência a mistura racêmica, no estresse oxidativo hepático renal e estriatal de ratos. Ratos Wistar machos adultos (180-220g) foram divididos em quatro grupos: controle (salina), MDMA racêmico, R-MDMA e S-MDMA. (2 doses consecutivas de 10 mg/kg no intervalo de 24h, gavage). Parâmetros de estresse oxidativo serão utilizados como a medida da formação de malonaldeído, a determinação de níveis de glutationa reduzida e a atividade da glutationa-S-transferase. Os enantiômeros da MDMA racêmica foram separados por meio da cromatografia em fase líquida de alta eficiência em fase estacionária quiral. Os enantiômeros obtidos mostraram um alto grau de pureza e um bom rendimento. Nossos resultados mostraram que o conteúdo hepático de glutationa total dos ratos do grupo R,S-MDMA e do grupo R-MDMA, foi significativamente menor do que os do controle e os do S-MDMA, revelando que é o enantiômero R que contribui para a depleção de glutationa hepática induzida pela mistura racêmica. A alta reatividade do enantiômero R no fígado também pode ser constatada nos animais tratados apenas com R-MMDA, uma vez que houve uma produção significativamente aumentada de MDA, comparativamente aos outros grupos tratados e o controle. O conteúdo renal de glutationa total foi significantemente menor para todos os grupos tratados quando comparados com o controle. Com relação ao estriado, apenas os animais tratados com o isômero S isoladamente mostraram uma queda significativa da atividade da GST em comparação aos demais grupos tratados e controle. Tomando todos esses dados em conjunto, esse trabalho mostrou que os enantiômeros isolados da MDMA podem atuar de formas distintas no que se refere ao estado redox, principalmente no fígado, uma vez que o isômero R foi o que mais contribuiu para um dano oxidativo. / MDMA (3,4-methylenedioxymethamphetamine) is an amphetamine derivate that is largely used for recreational purpose due to its feeling of euphoria, energy and the desire to socialize. Although MDMA has the reputation of being safe, a growing number of clinical reports and experimental studies indicate that MDMA can produce toxicity in the CNS, kidney, liver and heart.Although MDMA is present in ecstasy tablets as a racemate (a 50% mixture of its enantiomer) it has an enantioselective metabolism; in rats, the S-enantiomer is metabolized faster than the R-enantiomer and it is the more active pharmacological form. As the MDMA biotransformation can produce reactive metabolites, probably the R form has a greater potential to generate ROS / ERN and oxidative damage in tissues than the S. In humans, the opposite occurs. Therefore, this aim of the present study was to evaluate the individual contribution of single MDMA enantiomers, compared to racemic mixture in liver, kidney and striatal rats oxidative stress. Adult male Wistar rats (180- 220g) will be divided into four groups: control treatment (saline), racemic MDMA, R-MDMA and S-MDMA (two consecutive doses 24h apart with 10mg/kg, gavage). Oxidative stress status parameters will be used to measure malondialdehyde formation, the reduced glutathione levels determination and the glutathione-S-transferase activity. The enantiomers of racemic MDMA were separated by liquid chromatography high-efficiency chiral stationary phase. The enantiomers showed a high degree of purity and a good recovery. Our results showed that the total glutathione content in liver of rats in R,S-MDMA and R-MDMA group was significantly lower than the control and S-MDMA, revealing that the R-enantiomer that contributes to hepatic glutathione depletion induced by the racemic mixture. The high reactivity of the R enantiomer in the liver can also be observed in animals treated with R-MMDA, since there was a significantly increased production of MDA, compared with other treated and control groups. The total glutathione content in kidney was significantly lower for all treated groups compared with control. With respect to the striatum, only animals treated with the S isomer alone showed a significant decrease in GST activity compared to other treatment and control groups. Taking all these data together, this study shows that the isolated enantiomers of MDMA can act differently with regard to the redox state, mainly in the liver, since the R isomer was the largest contributor to oxidative damage.

There is a growing body of evidence that the main psychoactive ingredient of the recreational drug “ecstasy” (methylendioxymethamphetamine; MDMA) causes lasting changes to the serotonin system in both animals and humans, including the hippocampus (involved in memory) and the occipital lobe (involved in visual perception). Previous studies have often found memory deficits in ecstasy users. However, the results have been far from consistent across studies. None of the methods used to date have adequately isolated the hippocampal component of memory from the contribution of other brain regions. Three memory studies were conducted in this thesis to clarify which components and processes of memory are in deficit in ecstasy users.¶ In the first memory study, ecstasy users (n=32) did not differ from non-drug using controls (n=29) on implicit memory (automatic non-conscious retrieval, as revealed by a stem-completion task), or explicit memory (conscious recollection, as revealed by stem-cued recall). In the second memory study, no significant differences were found between ecstasy users (n=30) and non-drug using controls (n=34) on tests designed to clarify the findings on explicit memory, or on two standard neuropsychological tests of long-term memory (prose recall and Auditory Verbal Learning Test) that allowed greater use of elaborative processing at study. In the third memory study, a number of tests were applied that differed in their elaborative processing demands, including the California Verbal Learning Test, Visual Paired Associates, and Verbal Paired Associates. Ecstasy users (n=32) had poorer recall, and made less strategic use of elaborative processing compared to both cannabis-using controls (n=33) and non-drug using controls (n=33). Also, on a novel test of elaborative processing (“Verbal Triplet Associates”), both cannabis users and ecstasy users had memory deficits on the first trial, but only ecstasy users had a significant learning deficit over successive trials. On the basis of the localisation of the components and processes of memory in literature, it was concluded that long-term memory deficits in ecstasy users may reflect changes in elaborative processes localised in the frontal lobes, or global deficits, rather than just changes to the memory functions of the hippocampus.¶ With regard to visual perception, no studies have been published to date that have examined MDMA-related changes to the behavioural functioning of the occipital lobe in humans. In the current thesis, this was investigated using the tilt aftereffect illusion. In accordance with expectations, ecstasy users had a larger tilt aftereffect compared to non-drug using controls (n=34). Unexpectedly, this result was only obtained for a subset of 12 ecstasy users (out of n=30) who had not used amphetamines in the recent past. It was concluded that the results for ecstasy users who had not recently used amphetamines were consistent with the proposal that ecstasy-related serotonergic changes in the occipital lobe broaden the tuning bandwidth of orientation sensitive neurons, and that the recent use of amphetamines appears to counteract that effect.

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No / Recreational use of 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy") poses worldwide potential health problems. Clinical studies show that repeated exposure to low oral doses of MDMA has toxic effects on the brain, altering cognitive and psychosocial behavior. Functional magnetic resonance imaging in conscious marmoset monkeys was used to evaluate the sensitivity of the brain to an oral dose of MDMA (1 mg/kg). Following MDMA administration, the midbrain raphe nuclei and substantia nigra, major sources of serotonin and dopamine, were activated as were the hippocampus, hypothalamus and amygdala. The corticostriatal circuit of dorsal thalamus, sensorimotor cortex and basal ganglia showed a robust, coherent activation pattern. Two key reward areas, the nucleus accumbens and prefrontal cortex, and most other cortical regions showed little activation. The visual cortex, however, showed intense activation without applied visual stimuli. These data identify brain areas and functional circuits sensitive to a recreational dose of MDMA, some of which may be vulnerable to long-term intermittent exposure to this drug.

No description available.

3,4-(±)-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative commonly used as a recreational drug. Although the selectivity of MDMA for the serotonergic system in rat and humans is well established, the specific mechanism associated with MDMA-induced neurotoxicity is not fully understood. The long-term neurotoxicity of MDMA appears to be dependent upon systemic metabolism since direct administration of MDMA into the brain fails to reproduce the neurotoxic effects seen following peripheral administration, indicating that the parent compound alone is unlikely to be responsible for the neurotoxicity. MDMA is O-demethylenated to the catechol metabolite N-methyl-α-methyldopamine (N-Me-α-MeDA) and N-demethylated to MDA by cytochrome (s) P450 (CYP450). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-α-MeDA and α-MeDA are neurotoxic and can be found in rat brain following s.c. injection of MDMA. Because multidose administration of MDMA is typical of drug intake during rave parties, we investigated the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. Administration of MDMA at 12-h intervals for a total of four injections led to a significant accumulation of the N-Me-α-MeDA thioether metabolites in striatal dialysate. In contrast, acute release of 5-HT concentrations was decreased. Since isoenzymes of the CYP2D subfamily (30% metabolism), and the CYP2B or CYP3A1 isoforms, catalyze the low and high KM O-demethylenation reactions, respectively, we subsequently examined the potential role of CYP2D1 in both a genetic and pharmacological model. The data is consistent with the hypothesis that systemic metabolism of MDMA contributes to MDMA-induced serotonergic neurotoxicity via the 20) generation of reactive metabolites. In both the genetic and pharmacological models of CYP2D1 deficiency, attenuation of MDMA-mediated decreases in brain 5-HT concentrations were in the same range (30-40%). Finally, we examined the contribution of various transporters using genetic and pharmacological models to investigate the mechanisms regulating the concentration of thioether metabolites in MDMA neurotoxicity. The data suggest that by regulating various transporters and brain concentrations of the neurotoxic thioether metabolites of MDMA, may subsequently modulate the degree of neurotoxicity. However, further studies are necessary to understand the precise mechanism by which Mrp’s and Oat1 transporters modulate MDMA-neurotoxicity. Taken together, these studies are consistent with the view that neurotoxicity of MDMA requires systemic metabolism to form α-MeDA and N-Me-α- MeDA by CYP2D6. Therefore, It is likely that neurotoxicity is mediated by the formation of systemic neurotoxic metabolites.