Toxicokinetics of MDMA and Its Metabolite MDA in Rats.

OBJECTIVES: To investigate the toxicokinetic differences of 3,4-methylenedioxy-N-methylamphetamine (MDMA) and its metabolite 4,5-methylene dioxy amphetamine (MDA) in rats after single and continuous administration of MDMA, providing reference data for the forensic identification of MDMA. METHODS: A total of 24 rats in the single administration group were randomly divided into 5, 10 and 20 mg/kg experimental groups and the control group, with 6 rats in each group. The experimental group was given intraperitoneal injection of MDMA, and the control group was given intraperitoneal injection of the same volume of normal saline as the experimental group. The amount of 0.5 mL blood was collected from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. In the continuous administration group, 24 rats were randomly divided into the experimental group (18 rats) and the control group (6 rats). The experimental group was given MDMA 7 d by continuous intraperitoneal injection in increments of 5, 7, 9, 11, 13, 15, 17 mg/kg per day, respectively, while the control group was given the same volume of normal saline as the experimental group by intraperitoneal injection. On the eighth day, the experimental rats were randomly divided into 5, 10 and 20 mg/kg dose groups, with 6 rats in each group. MDMA was injected intraperitoneally, and the control group was injected intraperitoneally with the same volume of normal saline as the experimental group. On the eighth day, 0.5 mL of blood was taken from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. Liquid chromatography-triple quadrupole tandem mass spectrometry was used to detect MDMA and MDA levels, and statistical software was employed for data analysis. RESULTS: In the single-administration group, peak concentrations of MDMA and MDA were reached at 5 min and 1 h after administration, respectively, with the largest detection time limit of 12 h. In the continuous administration group, peak concentrations were reached at 30 min and 1.5 h after administration, respectively, with the largest detection time limit of 10 h. Nonlinear fitting equations for the concentration ratio of MDMA and MDA in plasma and administration time in the single-administration group and continuous administration group were as follows: T=10.362C-1.183, R2=0.974 6; T=7.397 3C-0.694, R2=0.961 5 (T: injection time; C: concentration ratio of MDMA to MDA in plasma). CONCLUSIONS: The toxicokinetic data of MDMA and its metabolite MDA in rats, obtained through single and continuous administration, including peak concentration, peak time, detection time limit, and the relationship between concentration ratio and administration time, provide a theoretical and data foundation for relevant forensic identification.

Recreational MDMA doses do not elicit hepatotoxicity in HepG2 spheroids under normo- and hyperthermia.

MDMA (3,4-methylenedioxymethamphetamine), an entactogen with empathogenic and prosocial effects, is widely used in music festivals and other festive settings. High MDMA doses have been associated with drug-induced liver injury and cases of hyperthermia. Although the latter condition is thought to increase MDMA hepatotoxicity, this correlation remains poorly explored for recreational MDMA doses. On the other hand, the fact that MDMA acts to extinguish fear and to reconsolidate memory could be explored as an adjunct to psychotherapy during treatment of neuropsychiatric disorders such as post-traumatic stress disorder. In this context, assessing MDMA toxicity is relevant, and tridimensional cell culture has emerged as an alternative to animal models in toxicity assessment. Herein, we have used HepG2 spheroids to evaluate MDMA-induced hepatotoxicity at recreational doses, under normo- or hyperthermia. The MTT reduction assay did not evidence significantly reduced cell viability. Moreover, MDMA did not increase reactive oxygen species production, deplete the mitochondrial membrane potential, arrest the cell cycle, or induce apoptotic cell death. These findings support further pre-clinical investigation of MDMA safety from the perspective of both harm reduction and therapy given that non-abusive recreational and therapeutic doses overlap.

Daphnia magna an emerging environmental model of neuro and cardiotoxicity of illicit drugs.

Cocaine, methamphetamine, ectasy (3,4-methylenedioxy amphetamine (MDMA)) and ketamine are among the most consumed drugs worldwide causing cognitive, oxidative stress and cardiovascular problems in humans. Residue levels of these drugs and their transformation products may still enter the aquatic environment, where concentrations up to hundreds of ng/L have been measured. In the present work we tested the hypothesis that psychotropic effects and the mode of action of these drugs in D. magna cognitive, oxidative stress and cardiovascular responses are equivalent to those reported in humans and other vertebrate models. Accordingly we expose D. magna juveniles to pharmacological and environmental relevant concentrations. The study was complemented with the measurement of the main neurotransmitters involved in the known mechanisms of action of these drugs in mammals and physiological relevant amino acids. Behavioural cognitive patters clearly differentiate the 3 psychostimulant drugs (methamphetamine, cocaine, MDMA) from the dissociative one ketamine. Psychostimulant drugs at pharmacological doses (10-200 µM), increased basal locomotion activities and responses to light, and decreased habituation to it. Ketamine only increased habituation to light. The four drugs enhanced the production of reactive oxygen species in a concentration related manner, and at moderate concentrations (10-60 µM) increased heartbeats, diminishing them at high doses (200 µM). In chronic exposures to environmental low concentrations (10-1000 ng/L) the four drugs did not affect any of the behavioural responses measured but methamphetamine and cocaine inhibited reproduction at 10 ng/L. Observed effects on neurotransmitters and related metabolites were in concern with reported responses in mammalian and other vertebrate models: cocaine and MDMA enhanced dopamine and serotonin levels, respectively, methamphetamine and MDMA decreased dopamine and octopamine, and all but MDMA decreased 3 MT levels. Drug effects on the concentration of up to 10 amino acids evidence disruptive effects on neurotransmitter synthesis, the urea cycle, lipid metabolism and cardiac function.

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.

Therapeutic effects of methimazole on 3,4-methylenedioxymethamphetamine-induced hyperthermia and serotonergic neurotoxicity.

3,4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug, however over 200 studies demonstrate that acute (e.g. hyperthermia, rhabdomyolysis) and chronic (e.g. neurotoxicity) toxicity effects of MDMA were observed in different animals. Methimazole (MMI), an inhibitor of thyroid hormone synthesis, was found to significantly reduce the HSP72 expression of heat stress induced in fibroblasts. Hence, we attempted to understand the effects of MMI on MDMA induced changes in vivo. Male SD rats were randomly divided into four groups as follows:(a) water-saline (b) water-MDMA (c) MMI-saline and (d) MMI-MDMA group. In the temperature analysis test, MMI was found to alleviate MDMA-induced hyperthermia and increase the heat loss index (HLI), revealing its peripheral vasodilation effect. PET experiment suggested that MDMA induced elevated glucose uptake by skeletal muscles, which was resolved by MMI pretreatment. IHC staining (serotonin transporter, SERT) showed the evidence of neurotoxicity caused by MDMA (serotonin fiber loss), which was alleviated by MMI. Furthermore, the animal behaviour test (forced swimming test, FST) showed higher swimming time but lower immobility time in MMI-MDMA and MMI-saline groups. Taken together, treatment of MMI shows benefits such as lowered body temperature, alleviation of neurotoxicity and excited behaviour. However, further investigations should be conducted in the future to provide in-depth evidence for its clinical use.

An unusual route of non-intentional intoxication by ecstasy in a toddler.

We report a pediatric case of ecstasy intoxication via an unusual route. A mother called the emergency services after her daughter had inserted an ecstasy pill into her nose. During transportation, the child developed hypertension, tachycardia, and tachypnea. She was admitted to the nearest regional hospital, where a physical examination revealed psychomotor agitation, mydriasis, hypertension, tachycardia, and no hyperthermia. Blood tests showed no abnormalities. She was subsequently transferred to a tertiary-level pediatric hospital. During transportation, she was described as being intensely agitated with persistent mydriasis, tachycardia, and high blood pressure. Urinary toxicological screening confirmed the presence of MDMA. She was discharged after 24 h.

Withania somnifera influences MDMA-induced hyperthermic, cognitive, neurotoxic and neuroinflammatory effects in mice.

Withania somnifera (WS) is utilized in Ayurvedic medicine owing to its central and peripheral beneficial properties. Several studies have accrued indicating that the recreational amphetamine-related drug (+/-)- 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) targets the nigrostriatal dopaminergic system in mice, inducing neurodegeneration and gliosis, causing acute hyperthermia and cognitive impairment. This study aimed to investigate the effect of a standardized extract of W. somnifera (WSE) on MDMA-induced neurotoxicity, neuroinflammation, memory impairment and hyperthermia. Mice received a 3-day pretreatment with vehicle or WSE. Thereafter, vehicle- and WSE-pretreated mice were randomly divided into four groups: saline, WSE, MDMA alone, WSE plus MDMA. Body temperature was recorded throughout treatment, and memory performance was assessed by a novel object recognition (NOR) task at the end of treatment. Thereafter, immunohistochemistry was performed to evaluate in the substantia nigra pars compacta (SNc) and striatum the levels of tyrosine hydroxylase (TH), as marker of dopaminergic degeneration, and of glial fibrillary acidic protein (GFAP) and TMEM119, as markers of astrogliosis or microgliosis, respectively. MDMA-treated mice showed a decrease in TH-positive neurons and fibers in the SNc and striatum respectively, an increase in gliosis and body temperature, and a decrease in NOR performance, irrespective of vehicle or WSE pretreatment. Acute WSE plus MDMA counteracted the modifications in TH-positive cells in SNc, GFAP-positive cells in striatum, TMEM in both areas and NOR performance, as compared to MDMA alone, while no differences were observed as compared to saline. Results indicate that WSE acutely administered in combination with MDMA, but not as pretreatment, protects mice against the noxious central effects of MDMA.

Striatal Iron Deposition in Recreational MDMA (Ecstasy) Users.

BACKGROUND: The common club drug MDMA (also known as ecstasy) enhances mood, sensory perception, energy, sociability, and euphoria. While MDMA has been shown to produce neurotoxicity in animal models, research on its potential neurotoxic effects in humans is inconclusive and has focused primarily on the serotonin system. METHODS: We investigated 34 regular, largely pure MDMA users for signs of premature neurodegenerative processes in the form of increased iron load in comparison to a group of 36 age-, sex-, and education-matched MDMA-naïve control subjects. We used quantitative susceptibility mapping, a novel tool able to detect even small tissue (nonheme) iron accumulations. Cortical and relevant subcortical gray matter structures were grouped into 8 regions of interest and analyzed. RESULTS: Significantly increased iron deposition in the striatum was evident in the MDMA user group. The effect survived correction for multiple comparisons and remained after controlling for relevant confounding factors, including age, smoking, and stimulant co-use. Although no significant linear relationship between measurements of the amounts of MDMA intake (hair analysis and self-reports) and quantitative susceptibility mapping values was observed, increased striatal iron deposition might nevertheless point to MDMA-induced neurotoxic processes. Additional factors (hyperthermia and simultaneous co-use of other substances) that possibly amplify neurotoxic effects of MDMA during the state of acute intoxication are discussed. CONCLUSIONS: The demonstrated increased striatal iron accumulation may indicate that regular MDMA users have an increased risk potential for neurodegenerative diseases with progressing age.

Toxicity of the 3,4-Methylenedioxymethamphetamine and Its Enantiomers to Daphnia magna after Isolation by Semipreparative Chromatography.

MDMA (3,4-methylenedioxymethamphetamine) is a chiral psychoactive recreational drug sold in illicit markets as racemate. Studies on the impact of MDMA on aquatic organisms are scarce. While enantioselectivity in toxicity in animals and humans has been reported, none is reported on aquatic organisms. This study aimed to investigate the ecotoxicological effects of MDMA and its enantiomers in Daphnia magna. For that, enantiomers (enantiomeric purity > 97%) were separated by liquid chromatography using a homemade semipreparative chiral column. Daphnids were exposed to three concentrations of (R,S)-MDMA (0.1, 1.0 and 10.0 µg L-1) and two concentrations of (R)- and (S)-enantiomers (0.1 and 1.0 µg L-1) over the course of 8 days. Morphophysiological responses were dependent on the substance form and daphnia development stage, and they were overall not affected by the (R)-enantiomer. Changes in swimming behaviour were observed for both the racemate and its enantiomers, but enantioselective effects were not observed. Reproductive or biochemical changes were not observed for enantiomers whereas a significant decrease in acetylcholinesterase and catalase activity was noted at the highest concentration of (R,S)-MDMA (10 µg L-1). Overall, this study showed that sub-chronic exposure to MDMA racemate and its enantiomers can interfere with morphophysiological and swimming behaviour of D. magna. In general, the (R)-enantiomer demonstrated less toxicity than the (S)-enantiomer.

Cardiac effects of ephedrine, norephedrine, mescaline, and 3,4-methylenedioxymethamphetamine (MDMA) in mouse and human atrial preparations.

The use of recreational drugs like ephedrine, norephedrine, 3,4-methylenedioxymethamphetamine (MDMA), and mescaline can lead to intoxication and, at worst, to death. One reason for a fatal course of intoxication with these drugs might lie in cardiac arrhythmias. To the best of our knowledge, their inotropic effects have not yet been studied in isolated human cardiac preparations. Therefore, we measured inotropic effects of the hallucinogenic drugs ephedrine, norephedrine, mescaline, and MDMA in isolated mouse left atrial (mLA) and right atrial (mRA) preparations as well as in human right atrial (hRA) preparations obtained during cardiac surgery. Under these experimental conditions, ephedrine, norephedrine, and MDMA increased force of contraction (mLA, hRA) and beating rate (mRA) in a time- and concentration-dependent way, starting at 1-3 µM but these drugs were less effective than isoprenaline. Mescaline alone or in the presence of phosphodiesterase inhibitors did not increase force in mLA or hRA. The positive inotropic effects of ephedrine, norephedrine, or MDMA were accompanied by increases in the rate of tension and relaxation and by shortening of time of relaxation and, moreover, by an augmented phosphorylation state of the inhibitory subunit of troponin in hRA. All effects were greatly attenuated by cocaine (10 µM) or propranolol (10 µM) treatment. In summary, the hallucinogenic drugs ephedrine, norephedrine, and MDMA, but not mescaline, increased force of contraction and increased protein phosphorylation presumably, in part, by a release of noradrenaline in isolated human atrial preparations and thus can be regarded as indirect sympathomimetic drugs in the human atrium.

Ecstasy metabolites and monoamine neurotransmitters upshift the Na+/K+ ATPase activity in mouse brain synaptosomes.

3,4-Methylenedioximethamphetamine (MDMA; "ecstasy") is a psychotropic drug with well-known neurotoxic effects mediated by hitherto not fully understood mechanisms. The Na+- and K+-activated adenosine 5'-triphosphatase (Na+/K+ ATPase), by maintaining the ion gradient across the cell membrane, regulates neuronal excitability. Thus, a perturbation of its function strongly impacts cell homeostasis, ultimately leading to neuronal dysfunction and death. Nevertheless, whether MDMA affects the Na+/K+ ATPase remains unknown. In this study, we used synaptosomes obtained from whole mouse brain to test the effects of MDMA, three of its major metabolites [α-methyldopamine, N-methyl-α-methyldopamine and 5-(glutathion-S-yl)-α-methyldopamine], serotonin (5-HT), dopamine, 3,4-dihydroxy-L-phenylalanine (L-Dopa) and 3,4-dihydroxyphenylacetic acid (DOPAC) on the Na+/K+ ATPase function. A concentration-dependent increase of Na+/K+ ATPase activity was observed in synaptosomes exposed to the tested compounds (concentrations ranging from 0.0625 to 200 µM). These effects were independent of protein kinases A and C activities. Nevertheless, a rescue of the compounds' effects was observed in synaptosomes pre-incubated with the antioxidant N-acetylcysteine (1 mM), suggesting a role for reactive species-regulated pathways on the Na+/K+ ATPase effects. In agreement with this hypothesis, a similar increase in the pump activity was found in synaptosomes exposed to the chemical generator of superoxide radicals, phenazine methosulfate (1-250 µM). This study demonstrates the ability of MDMA metabolites, monoamine neurotransmitters, L-Dopa and DOPAC to alter the Na+/K+ ATPase function. This could represent a yet unknown mechanism of action of MDMA and its metabolites in the brain.

Evaluation of Cytotoxic, Necrotic, Apoptotic, and Autophagic Effects of Methamphetamine and 3,4-Methylenedioxymethamphetamine on U-87 MG (Glial) and B104-1-1 (Neuronal) Cell Lines.

Methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA) are empathogen (entactogen) psychoactive designer drugs which are mainly used for recreational purposes. Both MA and MDMA are central nervous system stimulants which are classified as monoamine neurotransmitter reuptake inhibitors. They have strong cytotoxic effects on dopaminergic and serotonergic neurons. Neurotoxicities of MA and MDMA by glial activation have been shown. The present work has investigated and measured cytotoxic, necrotic and apoptotic, and autophagic effects of MA and MDMA on U-87 MG (glial) and B104-1-1 (neuronal) cell lines by janus green, ethidium bromide/acridine orange, and monodansylcadaverine/propidium iodide staining to evaluate and compare their effects on glial and neuronal cells, respectively. The results of the present work showed that: (1) MDMA induced more potent mitochondrial toxicity, stronger necrotic and autophagic effects than MA in both B104-1-1 (neuronal) and U-87 MG (glial) cell lines; (2) although MDMA induced stronger apoptotic effect than MA on U-87 MG cell line, it had equal apoptotic effect on B104-1-1 cell line with MA; and (3) MDMA induced more potent mitochondrial toxicity, stronger necrotic, apoptotic, and autophagic effects than MA in B104-1-1 cell line than U-87 MG cell line.

Brain-derived neurotrophic factor protects serotonergic neurons against 3,4-methylenedioxymethamphetamine ("Ecstasy") induced cytoskeletal damage.

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") use has been linked to persistent alterations of the brain serotonergic (5-HT) system in animal and human studies, but the molecular underpinnings are still unclear. Cytoskeletal structures such as neurofilament light chain (NfL) are promising markers of drug-induced brain toxicity and may be involved in MDMA neurotoxicity. The brain-derived neurotrophic factor (BDNF) promotes the growth and sprouting of 5-HT neurons and its differential response to MDMA administration was suggested to mediate dose- and region-dependent 5-HT damage by MDMA. However, the role of BDNF pre-treatment in preventing MDMA neurotoxicity and the potential effects of MDMA on NfL are still elusive. Therefore, a differentiated 5-HT neuronal cell line obtained from rat raphe nucleus (RN46A) was treated in vitro with either MDMA, BDNF, MDMA + BDNF, or vehicle. Cell viability (measured by MTT) and intracellular NfL levels (immunocytochemistry assay) were reduced by MDMA, but partially rescued by BDNF co-treatment. Our findings confirmed that BDNF levels can influence MDMA-induced 5-HT damage, and support BDNF to be a crucial target for neuroprotective interventions of the 5-HT system. We also provide evidence on the sensitivity of NfL to MDMA neurotoxicity, with potential implications for in-vivo monitoring of drug-induced neurotoxicity.

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.

MDMA related neuro-inflammation and adenosine receptors.

3,4-methylenedioxymethamphetamine (MDMA) is a world-wide abused psychostimulant, which has the neurotoxic effects on dopaminergic and serotonergic neurons in both rodents and non-human primates. Adenosine acts as a neurotransmitter in the brain through the activation of four specific G-protein-coupled receptors and it acts as a neuromodulator of dopamine neurotransmission. Recent studies suggest that stimulation of adenosine receptors oppose many behavioral effects of methamphetamines. This review summarizes the specific cellular mechanisms involved in MDMA neuroinflammatory effects, along with the protective effects of adenosine receptors.

Developmental exposure to MDMA (ecstasy) in zebrafish embryos reproduces the neurotoxicity adverse outcome 'lower motor activity' described in humans.

The recreational use of MDMA (ecstasy) by pregnant women is associated with impaired neuromotor function in infants, but the Adverse Outcome Pathway behind this effect is not clear yet. We present for the first time the evaluation of developmental neurotoxic (DNT) effects of MDMA in zebrafish embryos. The aim of the study was to determine whether the zebrafish model reproduces the adverse outcome occurring in humans. We have studied the DNT effects of MDMA in zebrafish within a range of 5-250 µM performing different behavioural tests: spontaneous tail-coiling and light-dark locomotor response; after exposing the embryos to 4 different scenarios combining changes in pH, in starting exposure time and exposure duration. In these scenarios we evaluated the effects of MDMA in general embryonic development and compared the concentrations producing them with those inducing specific DNT effects. As a result, we have established the experimental conditions leading to the adverse outcome "lower motor activity" in zebrafish without producing general developmental delay or general toxicity. The experimental condition chosen opens the door to use this model in future mechanistic investigations to better characterize the Adverse Outcome Pathway associated with the adverse effects caused by MDMA prenatal exposure in humans.

Protective effects of atorvastatin and rosuvastatin on 3,4-methylenedioxymethamphetamine (MDMA)-induced spatial learning and memory impairment.

3,4-Methylenedioxymethamphetamine (MDMA) or "Ecstasy", which has been used for recreational purposes, is shown to impair memory and brain functions. Statins, beyond their efficient cholesterol-lowering impact through inhibition of HMG-COA reductase enzyme, possess multiple actions referred to as pleiotropic effects. In this regard, we aimed to investigate the neuroprotective effects of atorvastatin and rosuvastatin on MDMA-induced neurotoxicity. Adult male Wistar rats received atorvastatin (5, 10, and 20 mg/kg; orally) and rosuvastatin (5, 10, 20 mg/kg; orally) for 21 consecutive days. Then, spatial memory and learning were evaluated by Morris water maze (MWM) test. Rats were intraperitoneally injected with MDMA (2.5, 5, and 10 mg/kg) 30 min before the first training session in 4 training days of MWM task. Afterward, rats were euthanized and their hippocampuses were dissected to evaluate reactive oxygen species (ROS) production, lipid peroxidation (LPO), and caspase-3 and -9 activities. Our findings showed that MDMA (5 and 10 mg/kg) significantly impaired spatial memory functions and dramatically increased ROS production, LPO, and caspase-3 and -9 activities compared to control. Also, atorvastatin (5, 10, and 20 mg/kg) and rosuvastatin (20 mg/kg) significantly improved memory performances and inhibited the elevation of ROS, LPO, and caspase-3 and -9 activities induced by MDMA. In conclusion, the results indicated that MDMA-induced cognitive impairment is followed by oxidative stress and activation of apoptotic pathways in the hippocampus. However, atorvastatin and rosuvastatin suppressed these deleterious consequences of MDMA and revealed protective effects against activation of pathways leading to cell damage.

Three regulatory compliant test systems show no signs of MDMA-related genotoxicity.

3,4 Methylenedioxymethamphetamine (MDMA)-assisted therapy has been recently found to be highly effective for treatment of posttraumatic stress disorder (PTSD). Previous studies have been inconclusive in elucidating potential MDMA genotoxicity. We performed three regulatory compliant studies to investigate the potential of genotoxic effects of MDMA treatment in humans: (1) an in vitro bacterial reverse mutation (Ames) assay, (2) an in vitro chromosome aberration test in Chinese hamster ovary cells, and (3) an in vivo micronucleus study in male Sprague Dawley rats. MDMA was found to not have genotoxic effects in any of the assays at or above clinically relevant concentrations.

Nicotine and modafinil combination protects against the neurotoxicity induced by 3,4-Methylenedioxymethamphetamine in hippocampal neurons of male rats.

MDMA (3,4-Methylenedioxymethamphetamine) is a common recreational drug of abuse which causes neurodegeneration. Nicotine and modafinil provide antioxidant and neuroprotective properties and may be beneficial in the management of MDMA-induced neurotoxicity. The purpose of this study was to characterize how acute and chronic administration of nicotine and/or modafinil exert protective effects against the MDMA-induced impaired cognitive performance, oxidative stress, and neuronal loss. Adult male rats were divided into three groups, namely control, MDMA and treatment (modafinil and/or nicotine). MDMA (10 mg/kg) was administered intraperitoneally during a three-week schedule (two times/day for two consecutive days/week). The treated-groups were classified based on the acute or chronic status of treatment. In the groups which underwent acute treatments, nicotine (0.5 mg/kg) and/or modafinil (100 mg/kg) were injected just prior to the MDMA administration (acute nicotine (NA), acute modafinil (MA), and acute nicotine and modafinil (NMA)). In the rats which received chronic treatments, nicotine (0.5 mg/kg) and/or modafinil (100 mg/kg) were injected every day during the three week-schedule administration of MDMA (chronic nicotine (NC), chronic modafinil (MC), and chronic nicotine and modafinil (NMC)). Learning and memory performance, as well as avoidance response, were assessed by Morris water maze and Shuttle box, respectively. Our findings indicate enhanced learning and memory and avoidance response in the NMC group. By TUNEL test and Cresyl Violet staining we evaluated neuronal loss and apoptosis in the hippocampal CA1 and found increased neuronal viability in the NMC group. On the other hand, chronic administration of modafinil and nicotine significantly down-regulated the caspase 3 and up-regulated both BDNF and TrkB levels in the MDMA-received rats. The serum levels of glutathione peroxidase (GPx) and total antioxidant capacity (TAC) were evaluated and we found that the alterations of serum levels of GPx and TAC were considerably prevented in the NMC group. The overall results indicate that nicotine and modafinil co-administration rescued brain from MDMA-induced neurotoxicity. We suggest that nicotine and modafinil combination therapy could be considered as a possible treatment to reduce the neurological disorders induced by MDMA.

Breathing new life into neurotoxic-based monkey models of Parkinson's disease to study the complex biological interplay between serotonin and dopamine.

Numerous clinical studies have shown that the serotonergic system also degenerates in patients with Parkinson's disease. The causal role of this impairment in Parkinson's symptomatology and the response to treatment remains to be refined, in particular thanks to approaches allowing the two components DA and 5-HT to be isolated if possible. We have developed a macaque monkey model of Parkinson's disease exhibiting a double lesion (dopaminergic and serotonergic) thanks to the sequential use of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MDMA (3,4-methylenedioxy-N-methamphetamine) (or MDMA prior MPTP). We characterized this monkey model by multimodal imaging (PET, positron emission tomography with several radiotracers; DTI, diffusion tensor imaging), behavioral assessments (parkinsonism, dyskinesia, neuropsychiatric-like behavior) and post-mortem analysis (with DA and 5-HT markers). When administrated after MPTP, MDMA damaged the 5-HT presynaptic system without affecting the remaining DA neurons. The lesion of 5-HT fibers induced by MDMA altered rigidity and prevented dyskinesia and neuropsychiatric-like symptoms induced by levodopa therapy in MPTP-treated animals. Interestingly also, prior MDMA administration aggravates the parkinsonian deficits and associated DA injury. Dystonic postures, action tremor and global spontaneous activities were significantly affected. All together, these data clearly indicate that late or early lesions of the 5-HT system have a differential impact on parkinsonian symptoms in the macaque model of Parkinson's disease. Whether MDMA has an impact on neuropsychiatric-like symptoms such as apathy, anxiety, depression remains to be addressed. Despite its limitations, this toxin-based double-lesioned monkey model takes on its full meaning and provides material for the experimental study of the heterogeneity of patients.