MDMA Exposure Research Articles

Erratum for Protective Effects of Vitamin E on Heart and Testis Histology Following MDMA (Ecstasy) Exposure in Mice [Int J High Risk Behav Addict. 2018; 8(4):e84212]

Erratum for Protective Effects of Vitamin E on Heart and Testis Histology Following MDMA (Ecstasy) Exposure in Mice [Int J High Risk Behav Addict. 2018; 8(4):e84212]

Role of Microglia in 3, 4 Methylenedioxymethamphetamine (MDMA) -Induced Neurotoxicity: A Mini Review

MDMA (3, 4 Methylenedioxymethamphetamine) is a psychoactive drug under the amphetamine-type stimulant group. While the modulatory effects of MDMA on serotonin neurotransmission and its neurotoxicity in the central nervous system are well studied, MDMA’s effects on modulating microglial neuroimmune functions have attracted considerable attention. Resident glial cells, including microglia in the brain, are implicated in contributing to MDMA-induced neurotoxicity. In their response to the disturbances around neurons, microglia can take on the role of the first line of defence against pathogens by the production of a variety of inflammatory mediators such as tumour necrosis factor-alpha (TNF-α), interleukin (IL) 1β, IL-6, nitric oxide (NO), and reactive oxygen species (ROS). They also can act as anti-inflammatory mediators to initiate recovery from an insult. Hence, the current review illuminates MDMA-induced neurotoxicity by summarising studies reporting microglial activation after MDMA exposure in vitro and in vivo. A modulation between cytotoxic states to a neuroprotective state of microglia probably can make up an important strategy to reduce the negative impairments made by MDMA on neuronal cells by targeting microglial cells.

Behavioral metabolomics: how behavioral data can guide metabolomics research on neuropsychiatric disorders

IntroductionMetabolomics produces vast quantities of data but determining which metabolites are the most relevant to the disease or disorder of interest can be challenging.ObjectivesThis study sought to demonstrate how behavioral models of psychiatric disorders can be combined with metabolomics research to overcome this limitation.MethodsWe designed a preclinical, untargeted metabolomics procedure, that focuses on the determination of central metabolites relevant to substance use disorders that are (a) associated with changes in behavior produced by acute drug exposure and (b) impacted by repeated drug exposure. Untargeted metabolomics analysis was carried out on liquid chromatography-mass spectrometry data obtained from 336 microdialysis samples. Samples were collected from the medial striatum of male Sprague-Dawley (N = 21) rats whilst behavioral data were simultaneously collected as part of a (±)-3,4-methylenedioxymethamphetamine (MDMA)-induced behavioral sensitization experiment. Analysis was conducted by orthogonal partial least squares, where the Y variable was the behavioral data, and the X variables were the relative concentrations of the 737 detected features.ResultsMDMA and its derivatives, serotonin, and several dopamine/norepinephrine metabolites were the greatest predictors of acute MDMA-produced behavior. Subsequent univariate analyses showed that repeated MDMA exposure produced significant changes in MDMA metabolism, which may contribute to the increased abuse liability of the drug as a function of repeated exposure.ConclusionThese findings highlight how the inclusion of behavioral data can guide metabolomics data analysis and increase the relevance of the results to the phenotype of interest.

Exposure to 3,4-methylenedioxymethamphetamine (MDMA) induced biochemical but not behavioral effects in Daphnia magna

Among amphetamine like stimulants (ATS), the 3,4-methylenedioxymethamphetamine (MDMA) is often detected in sewage and surface waters, representing a potential threat for organisms because of its peculiar mechanism of action (i.e., stimulatory and hallucinogenic). The present study aimed at investigating biochemical (i.e., oxidative stress and energetic biomarkers) and behavioral (i.e., swimming activity) effects induced by a 21-days exposure to two concentrations (50 ng/L and 500 ng/L) of MDMA towards Daphnia magna. The amount of reactive oxygen species (ROS), the activity of antioxidant (SOD, CAT, GPx) and detoxifying (GST) enzymes and lipid peroxidation were measured as oxidative stress-related endpoints. Total energy content was estimated from the measurement of protein, carbohydrate and lipid content to assess energy reserves. The modulation of swimming activity was assessed as behavioral endpoint. Slight effects of MDMA exposure on oxidative stress responses and energy reserves were observed, while no alterations of the swimming behavior was noted.

Effect of MDMA exposure during pregnancy on cell apoptosis, astroglia, and microglia activity in rat offspring striatum.

Objective(s):Ecstasy is a popular recreational psychostimulant with side effects on the central nervous system. This study examined the corpus striatum tissue of adult rats that received ecstasy during the embryonic period for histological and molecular studies.Materials and Methods:Rats were divided into control and ecstasy groups. The ecstasy group was given MDMA 15 mg/kg intraperitoneally twice daily at 8-hour intervals on days 7–15 of gestation. At the age of 15 weeks, adult offspring of both groups were examined for learning and memory study by the Morris water maze test. Then, ventral striatum tissue was harvested for TUNEL assay, Nissl staining, and real-time PCR for the expression of the GFAP and CD11b. Results:Ecstasy up-regulated the GFAP and CD11b expression in the striatum of offspring (*P˂0.05). Furthermore, the Morris water maze test showed that exposure to ecstasy significantly impaired learning and spatial memory (*P˂0.05). TUNEL assay results did not show any significant change in the number of apoptotic cells in the striatum tissue of ecstasy offspring compared with controls, while Nissl staining showed a significant decrease in the number of neurons in the ecstasy group (*P˂0.05).Conclusion:Exposure to ecstasy during pregnancy causes long-lasting changes in brain regions underlying learning and memory, including the striatum, and impaired working memory in the offspring. In addition, these data provide the first evidence that exposure to ecstasy during the embryonic period causes a persistent change in the activity of microglial cells and the number of astrocyte cells in the striatum.

Cerebrospinal Fluid Serotonin level as Biomarker for Neurotoxicity after 3,4-Methylenedioxymethamphetamine (MDMA)

A persistent 3,4-Methylenedioxymethamphetamine (MDMA) exposure may disrupt the human body serotonergic system which subsequently leads to physical and psychiatric chaos. Serotonin, a well-known monoamine neurotransmitter which is the main target of MDMA can be found in cerebrospinal (CSF) fluid. Its variation reflects the severity of neuronal damage caused by MDMA exposure. Hence, this article aimed to review the potential of serotonin as biomarker for neuronal damage posed by MDMA. Articles from main databases including PubMed, Scopus and Web of Science were analysed and its information about serotonin variation in cerebrospinal fluid in response to MDMA exposure were extracted. MDMA is affine to serotonergic system, and can represents as a change in the level of serotonin in the CSF. It provides critical information about underlying mechanisms of neuronal damage from neurotoxicity, neurodegenerative process, excitotoxicity and hallucination due to MDMA exposure. Since serotonin variation in the CSF reflects the severity of neuronal damages, serotonin is potentially be used as an early indicator to assess neural injury caused by MDMA that plays an important role in intervention purpose. Serotonin variation in the CSF reflects the severity of neuronal damages. Its variation in CSF can be used as a biomarker for assessing neuronal damage following MDMA exposure.

Prelimbic medial prefrontal cortex has bidirectional control over the expression of behavioral sensitization to 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) depending on the context of drug administration

Behavioral sensitization to MDMA is observed in the vast majority of rats if tested in the same environment in which previous MDMA exposure occurred, but not if tested in a novel, unpaired context. Previous studies have revealed a critical role for the prelimbic region of medial prefrontal cortex (PL) in the expression of sensitization to MDMA, but these studies assessed sensitization only in MDMA-paired environments. Given that PL activity can both facilitate and suppress behavior depending on context, we tested the hypothesis that PL has bidirectional control over the expression of locomotor sensitization to MDMA depending on the context of drug administration. Rats were treated with either saline or MDMA (5.0 mg/kg) twice daily for 5 days, in either their home cages (unpaired groups) or the activity monitors that were used for tests of sensitization on challenge days (paired groups). Prior to MDMA challenge injections (2.5 mg/kg; at ∼ 2 weeks of withdrawal), rats received bilateral PL microinjections of either lidocaine (100 μg/0.5 μl/side) or physiological saline (0.5 μl/side). Locomotor activity in response to MDMA challenge was unaffected by PL inactivation in saline pretreated rats. However, PL inactivation caused a decrease in locomotion to the challenge injection in MDMA/paired rats and an increase in locomotion in MDMA/unpaired rats. These results establish a novel role for PL in suppressing the expression of behavioral sensitization when subjects are challenged in a drug-unpaired context, adding to the literature implicating PL activity in both the expression and inhibition of other drug-related behaviors.

The role of extracellular serotonin and MDMA in the sensitizing effects of MDMA

MDMA is a non-selective monoamine releasing stimulant with potent serotonergic effects - a pharmacological effect not typically associated with drugs of misuse or efficacious reinforcers. Nonetheless, MDMA is misused by humans and self-administered by laboratory animals. We have previously shown that repeated exposure to MDMA sensitized both the locomotor activating and reinforcing effects of MDMA in rats. Because repeated MDMA exposure often results in decreased markers of serotonin neurotransmission, it is possible that this might underlie the sensitizing effects of MDMA. This was examined in the current study. Male Sprague-Dawley rats were stereotaxically implanted with guide cannula in the medial striatum. They were then pre-treated with saline (n = 11) or MDMA (10 mg/kg, i.p.; n = 10), once daily for five days. Two-days later, all rats received ascending doses of MDMA (0.0, 5.0, 10.0, mg/kg, i.p.) administered at 2 hr intervals, during which locomotor activity was measured and microdialysis samples were collected. Microdialysates were analyzed using liquid chromatography-mass spectrometry and the concentrations of serotonin and MDMA were quantified. Acute MDMA administration produced dose-dependent increases in locomotor activity, which was significantly enhanced by MDMA pre-treatment. Acute MDMA also produced dose-dependent increases in medial-striatal serotonin and MDMA, but this was not impacted by MDMA pre-treatment. These results suggest that the sensitizing effects of MDMA are not due to changes in MDMA-produced synaptic overflow of serotonin in the medial striatum or the absorption/elimination of systemically administered MDMA. More likely candidates are alterations in serotonin receptor mechanisms and/or dopamine neurotransmission following repeated exposure.

Remembering Molly: Immediate and delayed false memory formation after acute MDMA exposure

The entactogen 3,4-Methylenedioxymethamphetamine (MDMA) is increasingly being recognized for its therapeutic potential but is also widespread in nightlife settings where it may co-occur with crime. Since previous research detected impaired verbal memory during acute MDMA intoxication, understanding the drug's ramifications in an applied legal context becomes crucial. We conducted a double-blind, placebo-controlled trial to examine acute and delayed effects of MDMA (75 mg) on false memory in 60 healthy volunteers with a history of MDMA use, using three well-established false memory methods: a basic, associative word list (Deese/Roediger-McDermott (DRM)) paradigm and two applied misinformation tasks using a virtual reality crime. Memory was tested immediately (encoding and retrieval under drug influence) and 1 week later (retrieval when sober). Small MDMA-induced impairments of true memory in the word list task were detected at both time points. MDMA increased false memory for related but non-critical lures during the immediate test, and decreased false memory for critical lures after a delay. Episodic memory assessed in the misinformation tasks was not consistently affected. Findings indicate a complex memory profile but no heightened vulnerability to external suggestion in response to MDMA intoxication. Recommendations for future applied legal psychological research include adding measures of recall on top of recognition, using study designs that separate the different memory phases, and potentially testing higher doses. Further research on false memories and suggestibility using imagination procedures can also be relevant for the clinical context.

Neuroprotective effects of thymoquinone against MDMA-induced neurotoxicity

MDMA (3, 4-methylenedioxymethamphetamine) is a psychoactive substance that is associated with neurotoxicity. MDMA exposure to human results in the degeneration of neuronal cells in the hippocampus. Hence, the purpose of this study was to examine the potential of a natural compound known as thymoquinone (TQ) to protect against neuronal damage and memory impairment in rats stimulated by MDMA. The administration of TQ into MDMA-induced neuronal damage rats was carried out in male Sprague Dawley via a 1-week treatment dividing into four groups (n=36, 7-9 per group). The studied groups involved with the treatments comprise i) Control (1 mL/kg saline), ii) MDMA (10 mg/kg MDMA), iii) MDMA+TQ (10 mg/kg MDMA + 40 mg/kg TQ) and iv) TQ control (40 mg/kg TQ). A novel object recognition test (NORT) was carried out to evaluate the memory performance of the rats, followed by a histopathological assessment of the hippocampal dentate gyrus. The histopathology analysis revealed a significant increase in numbers of positive cells by Fluoro-Jade C following the effect of MDMA on neuronal damage (MDMA induced group) compared to control (P<0.05). Next, the TQ treatments observed in MDMA+TQ exhibited a decline in positive cells from Fluoro-Jade C. The index of recognition memory was found to be increased in MDMA+TQ compared to the MDMA alone (P<0.05). This study suggests that the neuronal damage inflicted by MDMA in a rat model has the potential to be treated by TQ.

Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse

Methylenedioxymethamphetamine (MDMA) is an amphetamine analogue that preferentially stimulates the release of serotonin (5HT) and results in relatively small increases in synaptic dopamine (DA). The ratio of drug-stimulated increases in synaptic DA, relative to 5HT, predicts the abuse liability; drugs with higher DA:5HT ratios are more likely to be abused. Nonetheless, MDMA is a drug that is misused. Clinical and preclinical studies have suggested that repeated MDMA exposure produces neuroadaptive responses in both 5HT and DA neurotransmission that might explain the development and maintenance of MDMA self-administration in some laboratory animals and the development of a substance use disorder in some humans. In this paper, we describe the research that has demonstrated an inhibitory effect of 5HT on the acquisition of MDMA self-administration and the critical role of DA in the maintenance of MDMA self-administration in laboratory animals. We then describe the circuitry and 5HT receptors that are positioned to modulate DA activity and review the limited research on the effects of MDMA exposure on these receptor mechanisms.

Garcinia kola Attenuates MDMA-Induced Neuroinflammation in the CA1 Region of the Hippocampus in the Rat Model.

Background:Garcinia kola (GK) has been experimentally tested for its potential usefulness against oxidative stress-related disorders in a number of body tissues, as well as a number of pathogenic and parasitic diseases. Studies investigating GK extracts’ usefulness in combating nervous tissue toxicity, neuroinflammatory disorders, and neuronal degeneration are still inadequate and not yet conclusive.Purpose:To evaluate the effects of 3,4-methylenedioxymethamphetamine (MDMA)-induced neuroinflammation on the pyramidal neurons and astrocytes of the cornu ammonis 1 (CA1) region of the hippocampus and the role of GK extract (GKE) in attenuating the effects in the rat model.Methods:The study was carried out by using 60 healthy adult male Wistar rats, which were randomly assigned into six groups, A, B, C, D, E, and F (n = 10)—A (control), B (100 mg/kg body weight of GKE only), C (200 mg/kg body weight of GKE only), D (20 mg/kg body weight of MDMA only), E (100 mg/kg body weight of GKE and 20 mg/kg body weight of MDMA), and F (200 mg/kg body weight of GKE and 20 mg/kg body weight of MDMA). Treatment was given for 21 days. Following 24 hours after the last administration, five rats in each group were anesthetized with diether and perfused intracardially, and the brains were excised and fixed in 10 percent neutral buffered formalin for the histological hematoxylin and eosin (H&E) and immunohistochemical glial fibrillary acidic proteins (GFAP). A thin-slice coronal section of the brain was obtained at the level of the optic chiasma and processed via the paraffin-embedding method. Also, the remaining five brains were used to assess neurotransmitter levels (serotonin and dopamine) and cytochrome c-oxidase. The statistical analysis was done using a one-way analysis of variance (ANOVA).Results:A significant reduction (P < .05) in body weight was observed in the group that was administered with MDMA when compared with the control and the rest of the treated groups. Dopamine and serotonin levels were significantly decreased (P < .05) in the MDMA-only group when compared with the control and the rest of the treated groups. The control group and groups B, C, and F showed intact pyramidal neurons, unlike group D, which showed vacuolated and degenerating neurons. The expressions of vacuolation and degeneration in group D were less than those in group E, which received a low dose of GKE and MDMA.Hippocampal astrocytic expressions were significantly higher (P > .05) in the MDMA-only group when compared with the control and other groups.Conclusion:GKE has significant neuroprotective potential against MDMA-induced toxicity in brain tissue. This is evident in its prevention of MDMA-induced oxidative stress, pyramidal neuronal vacuolation, dispersion, and reactive astrogliosis in the CA1 region of the hippocampus. Our findings are dose-dependent, with 200 mg/kg of the extract being novel. We, however, recommend further study into the mechanism of action of GKE, on how it attenuates the astrocytic reaction caused by MDMA exposure.

Developmental neurotoxicity of MDMA. A systematic literature review summarized in a putative adverse outcome pathway

The increasing use of illegal drugs by pregnant women causes a public health concern because it is associated with health risks for mothers and their developing children. One of such drugs is MDMA (3,4-methylenedioxymethamphetamine) or ecstasy due to its high consumption in relevant age and sex groups and its adverse effects on human and rodent developing brains. To thoroughly review the current knowledge on the developmentally neurotoxic potential of MDMA we systematically collected and summarized articles investigating developmental neurotoxicity (DNT) of MDMA in humans and animals in vivo and in vitro. In addition, we summarized the findings in a putative adverse outcome pathway (AOP). From an initial 299 articles retrieved from the bibliographic databases Web of Science, PubMed and DART, we selected 39 articles according to inclusion/exclusion criteria for data collection after title/abstract and full text screening. Of these 3 where epidemiological studies, 34 where in vivo studies in mice and rats and 2 were in vitro studies. The three epidemiological studies reported from the same longitudinal study and suggested that MDMA exposure during pregnancy impairs neuromotor function in infants. In rat, postnatal exposure towards MDMA also caused locomotor deficits as well as impaired spatial learning that might be associated with decreased serotonin levels in the hippocampus. In vitro MDMA caused cytotoxicity at high concentrations and effects on the serotonergic and neuritogenic alterations at lower concentrations which are in line with some of the in vivo alterations observed. Considering the adverse outcomes of developmental MDMA described in humans and in rodents we summarized the first putative AOP on developmental compound exposure leading to impaired neuromotor function in children. For generation of this AOP, MDMA exposure was taken as a model compound. In addition, we hypothesized a second AOP involving developmental disturbance of the dopaminergic system. However, further in vitro mechanistic studies are needed to understand the molecular initiating event(s) (MIE) triggering the downstream cascades and obtain consistent evidences causally linking the adverse outcome to effects at the cellular, organ and organism level.

The acute toxic and neurotoxic effects of 3,4-methylenedioxymethamphetamine are more pronounced in adolescent than adult mice

3,4-methylenedioxymethamphetamine (MDMA) recently achieved breakthrough status from the Food and Drug Administration (FDA) for post-traumatic stress disorder (PTSD). However, evidence indicates that exposure to toxic doses of MDMA can lead to long-lasting dysregulation of brain monoaminergic neurotransmitters, primarily from studies conducted in young adult rodents. To date, there is a paucity of data on whether toxic doses of MDMA can differentially affect neurotransmitter systems in adolescents and mature adults, which is an important question as adolescents and adults may be differentially vulnerable to MDMA abuse.In the current study, adolescent (6–7 weeks of age) and mature adult (16–18 weeks of age) male, Swiss-Webster mice were exposed to MDMA (20 mg/kg) using a binge-like dosing regimen (4 administrations spaced every 2 h). Acute lethality, acute hyperthermia, and acute decreases in body weight following MDMA administration were more pronounced in adolescent than adult mice. Likewise, acute loss of striatal dopamine neurochemistry was also exacerbated in adolescents, as determined by high-pressure liquid chromatography coupled to electrochemical detection. Exposure to MDMA induced greater turnover of dopamine into its major metabolite dihydroxyphenylacetic acid (DOPAC) in adolescents, but not in adults, suggesting a novel mechanism through which adolescents may show increased vulnerability to the acute toxic and neurotoxic effects of MDMA, or conversely that mature adults show greater protection. These data caution that MDMA exposure in adolescence may be particularly dangerous and that the therapeutic window for MDMA may differ between adolescents and mature adults.

MDMA and the Brain: A Short Review on the Role of Neurotransmitters in Neurotoxicity.

N-Methyl-3, 4-methylenedioxyamphetamine (MDMA), or ecstasy is a recreational drug of abuse. It is a synthetic substance that affects the body’s systems, which its mechanism of action and treatment should be more investigated. MDMA provides an immediate enjoyable feeling by stimulating the release of neurotransmitters, such as dopamine and serotonin in the brain. Unfortunately, abnormal regulation of the brain neurotransmitters, as well as the increased oxidative stress causes damage to the brain neurons after the MDMA exposure. Only a few studies have been done regarding its treatment. Thus, the treatment of MDMA complications should be further explored mainly by targeting its mechanism of action in the neurotransmitter systems. Hence, this study presents a short review regarding the recent findings on the role of neurotransmitters to cause MDMA neurotoxicity. The results will be useful for future research in elucidating the potential treatment based on the targeted mechanisms to treat the neurotoxic effects of MDMA.

Protective Effects of Vitamin E on Heart and Testis Histology Following MDMA (Ecstasy) Exposure in Mice

Background: Acute exposure to MDMA (methylenedioxymethamphetamine) has some adverse effects on reproductive and cardiovascular systems, possibly because of oxidative stress induction. Supplementary vitamins such as vitamin E can decrease the rate of oxidative stress and prevent the incidence of dysfunction in organs. Objectives: This study was designed to evaluate the adverse effects of MDMA exposure on the testis and heart tissue and elucidate the protective effect of vitamin E as a potent antioxidant. Patients and Methods: We assigned 28 male albino mice into four equal groups including control, MDMA, MDMA + vitamin E, and olive oil as a solvent of the vitamin. Mice were killed at the end of day 35 to conduct histological and plasma examinations. To find the relationship and make pair-wise comparisons, the one-way ANOVA test and Tukey test were used, respectively. Results: The mean values of seminiferous epithelial height (SEH), seminiferous tubular diameter (STD), spermatogenesis indices, and the average number of Leydig and Sertoli cells were significantly lower in testicular tissues of the MDMA group. The mentioned parameters were significantly higher in the MDMA + vitamin E group than in the MDMA group (P < 0.05). The apoptosis rate in both testis and heart tissues was significantly lower in the MDMA + vitamin E group than in the MDMA group (P < 0.05). Moreover, CPK and LDH as cardiac markers were significantly higher in the MDMA group than in the other groups. Conclusions: The results clearly suggest that vitamin E considerably attenuates the deleterious effects of MDMA.

Extinction training following cocaine or MDMA self-administration produces discrete changes in D2-like and mGlu5 receptor density in the rat brain.

Several studies strongly support the role of the dopamine D2-like and glutamate mGlu5 receptors in psychostimulant reward and relapse. The present study employed cocaine or MDMA self-administration with yoked-triad procedure in rats to explore whether extinction training affects the drug-seeking behavior and the D2-like and mGlu5 receptor Bmax and Kd values in several regions of the animal brain. Both cocaine and MDMA rats developed maintenance of self-administration, but MDMA evoked lower response rates and speed of self-administration acquisition. During reinstatement tests, cocaine or MDMA seeking behavior was produced by either exposure to the drug-associated cues or drug-priming injections. The extinction training after cocaine self-administration did not alter significantly D2-like receptor expression the in the limbic and subcortical brain areas, while MDMA yoked rats showed a decrease of the D2-like binding density in the nucleus accumbens and increase in the hippocampus and a rise of affinity in the striatum and hippocampus. Interestingly, in the prefrontal cortex a reduction in the mGlu5 receptor density in cocaine- or MDMA-abstinent rats was demonstrated, with significant effects being observed after previous MDMA exposure. Moreover, rats self-administered cocaine showed a rise in the density of mGlu5 receptor for the nucleus accumbens. This study first time shows that abstinence followed extinction training after cocaine or MDMA self- or passive-injections changes the D2-like and mGlu5 density and affinity. The observed changes in the expression of both receptors are brain-region specific and related to either pharmacological and/or motivational features of cocaine or MDMA.

RETRACTED ARTICLE: MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials

BackgroundPosttraumatic stress disorder is a prevalent mental health condition with substantial impact on daily functioning that lacks sufficient treatment options. Here we evaluate six phase 2 trials in a pooled analysis to determine the study design for phase 3 trials of MDMA-assisted psychotherapy for PTSD.MethodsSix randomized, double-blind, controlled clinical trials at five study sites were conducted from April 2004 to February 2017. Active doses of MDMA (75–125 mg, n = 72) or placebo/control doses (0–40 mg, n = 31) were administered to individuals with PTSD during manualized psychotherapy sessions in two or three 8-h sessions spaced a month apart. Three non-drug 90-min therapy sessions preceded the first MDMA exposure, and three to four followed each experimental session.ResultsAfter two blinded experimental sessions, the active group had significantly greater reductions in CAPS-IV total scores from baseline than the control group [MMRM estimated mean difference (SE) between groups − 22.0 (5.17), P < 0.001]. The between-group Cohen’s d effect size was 0.8, indicating a large treatment effect. After two experimental sessions, more participants in the active group (54.2%) did not meet CAPS-IV PTSD diagnostic criteria than the control group (22.6%). Depression symptom improvement on the BDI-II was greatest for the active group compared to the control group, although only trended towards significant group differences [MMRM, estimated mean difference (SE) between groups − 6.0 (3.03), P = 0.053]. All doses of MDMA were well tolerated, with some expected reactions occurring at greater frequency for the active MDMA group during experimental sessions and the 7 days following.ConclusionsMDMA-assisted psychotherapy was efficacious and well tolerated in a large sample of adults with PTSD. These studies supported expansion into phase 3 trials and led to FDA granting Breakthrough Therapy designation for this promising treatment.Trial registrationClinicalTrials.gov Identifier: NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.

The Effects of Vitamin E on Prevention of Damages Due to MDMA (Ecstasy) Exposure on Sperm Parameters in Mice

Background: MDMA (Ecstasy; 3, 4-methylenedioxymethylamphetamine), an illicit drug that has been increasingly abused by young people, affects target organs including reproductive system induced by oxidative stress. In biological systems, lipid peroxidation is probably reduced effectively by Vitamin E, a strong antioxidant inhibiting free radicals. Objectives: The current study was an attempt to assess the protective effects of Vitamin E on serum biochemical indices and sperm quality parameters in MDMA treated mice. Materials and Methods: In the present study, 28 male albino mice were randomly assigned to four equal groups. Group 1 (control) received saline by gastric gavage and i.p.; Group 2 (MDMA) received MDMA (10 mg/kg) i.p. and saline by gastric gavage; Group 3 (MDMA + Vitamin E) received MDMA (10 mg/kg) i.p.and vitamin E (150 mg/kg) by gastric gavage; and Group 4 (olive oil) received virgin olive oil (150 mg/kg) by gastric gavage and saline i.p. MDMA was injected with single daily dose, three sequential days/week for 5 weeks (35 days). Blood samples were collected, and then the animals were sacrificed by cervical dislocation. Animals’ cauda epididymis were dissected and used for analyzing and evaluating sperm parameters including sperm count, motility, viability, DNA damage, nuclear maturation, and sperm morphology. Results: Comparison of the MDMA group with the other groups indicated a significant (P < 0.05) decrease in total antioxidant capacity (TAC) and sperm parameters including sperm count, motility, viability, nuclear maturation, and sperm morphology. A significant increase (P < 0.05) was observed in the malondialdehyde (MDA) and percentage of sperm with DNA damage of the MDMA group compared to the other groups. We observed a significant increase (P < 0.05) in TAC and sperm parameters including sperm count, motility, viability, nuclear maturation, and sperm morphology along with a significant decrease (P < 0.05) in MDA and DNA sperm damage in the MDMA + Vit E group compared to the MDMA group. While, the MDMA+Vit E group showed a significant decrease (P < 0.05) in sperm motility, sperm morphology, and viability along with a significant increase (P < 0.05) in DNA sperm damage and nuclear maturation compared to the control group. TAC, MDA, and sperm count study showed no significant difference when compared to the control group. Conclusions: The results of the present study showed that MDMA caused induced toxicity in sperm parameters, reduced TAC, and increased MDA level. However, Vitamin E was proven to decrease effectively the deleterious and harmful effects of MDMA on sperm parameters.

Additive Effects of Former Methylenedioxymethamphetamine and Cannabis Use on Subclinical Psychotic Symptoms.

Methylenedioxymethamphetamine (MDMA) is an amphetamine-derived psychostimulant, usually known as "ecstasy." The long-term neuropsychological effects of MDMA are examined in several studies with conflicting results. The most common findings reported are depression, anxiety, and memory and attention deficits. In addition to acute psychotic reactions observed after MDMA use, serotonergic and dopaminergic toxicities may increase the psychosis risk in the long-term. Cannabis usage among MDMA users is very high. The aim of this study was, therefore, to examine the additive effects of cannabis and MDMA on subclinical psychotic symptoms (SPS). Here, 131 healthy controls (hC), 54 former cannabis and MDMA users (C&M), and 46 former cannabis users (C) were evaluated for SPS. The definition of former user was based on the Munich Composite International Diagnostic Interview. The SPS scores were assessed by using the Schizotypal Personality Questionnaire (SPQ). The relationship between substance-free periods and total MDMA exposure with SPS was also examined. The C&M group had higher levels of SPS than both C and hC groups. This is true not only for the total SPQ scores but both positive and negative schizotypy scores as well as cognitive-perceptual, disorganized, and interpersonal schizotypy scores aligned hierarchically in the 3 study groups (C&M>C>hC). The total MDMA exposure was positively correlated and MDMA-free period was negatively correlated with the SPS score. We found that the former use of cannabis and MDMA is associated with marked elevation in SPS. Moreover, the exposure amount of MDMA and MDMA-free periods are important determinants of SPS. The longer the cannabis and ecstasy free periods, the larger is the waning of SPS.