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IntroductionPTSD is a chronic, debilitating condition with limited treatment efficacy. Accessing traumatic memories often leads to overwhelming distress, impacting treatment process. Current approved pharmacological treatments have exhibited small to moderate effects when compared with placebo. Evidence suggests 3,4,-methylene-dioxymethamphetamine(MDMA)-assisted psychotherapy as a viable option for refractory PTSD.ObjectivesComprehensive review of early clinical research, proposed mechanisms, safety and emerging therapeutic models.MethodsEligible studies will be identified through strategic search of MEDLINE.ResultsPre-clinical and imaging studies suggest memory reconsolidation and fear extinction as candidate psychological and neurological mechanisms, involving MDMA’s combined effects of increasing serotonergic activity, as well the release of oxytocin and brain-derived neurotrophic factor in key memory and emotional circuits. Resulting reduction in amygdala and insula activation and increasing connectivity between the amygdala and hippocampus may create a “tolerance window” of neuroplasticity for emotional engagement and reprocessing of traumatic memories during psychotherapy. Early clinical trials report impressive and durable reduction in PTSD symptoms, with a safety profile comparable to that of SSRIs. A recently completed randomized, double-blind, placebo-controlled phase 3 trial reported full remission of PTSD symptoms in 67% of patients at 2 months, with no increase in suicidality, cardiovascular events or abuse behavior. Emerging treatment models underline the importance of unmedicated therapeutic sessions for preparation for the experience and subsequent integration as essential for full benefit and safety of the clinical context.ConclusionsThe psychological impact associated with the COVID-19 pandemic is an reminder of the emotional and economic burden associated with PTSD. MDMA-assisted therapy may be a breakthrough approach meriting further multidisciplinary investment and clinical research.DisclosureNo significant relationships.

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.

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.

It has recently been demonstrated that aromatic bromination at C(2) abolishes all typical psychomotor, and some key prosocial effects of the entactogen MDMA in rats. Nevertheless, the influence of aromatic bromination on MDMA-like effects on higher cognitive functions remains unexplored. In the present work, the effects of MDMA and its brominated analog 2Br-4,5-MDMA (1 mg/kg and 10 mg/kg i.p. each) on visuospatial learning, using a radial, octagonal Olton maze (4 × 4) which may discriminate between short-term and long-term memory, were compared with their influence on in vivo long-term potentiation (LTP) in the prefrontal cortex in rats. The results obtained indicate that MDMA diminishes both short- and long-term visuospatial memory but increases LTP. In contrast, 2Br-4,5-MDMA preserves long-term visuospatial memory and slightly accelerates the occurrence of short-term memory compared to controls, but increases LTP, like MDMA. Taken together, these data are consistent with the notion that the modulatory effects induced by the aromatic bromination of the MDMA template, which abolishes typical entactogenic-like responses, might be extended to those effects affecting higher cognitive functions, such as visuospatial learning. This effect seems not to be associated with the increase of LTP in the prefrontal cortex.

Considered the β-keto analogue of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), 3,4-Methylenedioxymethcathinone (methylone) is a synthetic cathinone. Over the years, methylone has been used as a substitute for conventional psychostimulants, such as MDMA. To date, little is known about the human pharmacology of methylone; the only available information has been provided by surveys or published intoxication reports. In the present observational–naturalistic study, we evaluate the acute subjective and physiological effects of methylone after oral self-administration in comparison to MDMA in healthy poly-drug users. Fourteen participants (10 males, 4 females) selected their single oral doses of methylone from 100 to 300 mg (n = 8, mean dose 187.5 mg) or MDMA from 75 to 100 mg (n = 6, mean dose 87.5 mg) based on their experience. Study variables were assessed at 0, 1, 2, and 4 h (h) and included vital signs (non-invasive blood pressure, heart rate, cutaneous temperature) and subjective effects using visual analogue scales (VAS), the 49-item Addiction Research Centre Inventory (ARCI) short form, and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) questionnaire. Additionally, oral fluid concentrations of methylone and MDMA were determined. Acute pharmacological effects produced by methylone followed the prototypical psychostimulant and empathogenic profile associated with MDMA, although they were less intense. Methylone concentrations in oral fluid can be considered a useful biomarker to detect acute exposure in oral fluid. Oral fluid concentrations of MDMA and methylone peaked at 2 h and concentrations of MDMA were in the range of those previously described in controlled studies. Our results demonstrate that the potential abuse liability of methylone is similar to that of MDMA in recreational subjects.

Background Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. Methods Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. Discussion This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. Trial registration Trial registered on Australian New Zealand Clinical Trials Registry. Registration number: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true

Amphetamines are a class of psychotropic drugs with high abuse potential, as a result of their stimulant, euphoric, emphathogenic, entactogenic, and hallucinogenic properties. Although most amphetamines are synthetic drugs, of which methamphetamine, amphetamine, and 3,4-methylenedioxymethamphetamine (“ecstasy”) represent well-recognized examples, the use of natural related compounds, namely cathinone and ephedrine, has been part of the history of humankind for thousands of years. Resulting from their amphiphilic nature, these drugs can easily cross the blood–brain barrier and elicit their well-known psychotropic effects. In the field of amphetamines’ research, there is a general consensus that mitochondrial-dependent pathways can provide a major understanding concerning pathological processes underlying the neurotoxicity of these drugs. These events include alterations on tricarboxylic acid cycle’s enzymes functioning, inhibition of mitochondrial electron transport chain’s complexes, perturbations of mitochondrial clearance mechanisms, interference with mitochondrial dynamics, as well as oxidative modifications in mitochondrial macromolecules. Additionally, other studies indicate that amphetamines-induced neuronal toxicity is closely regulated by B cell lymphoma 2 superfamily of proteins with consequent activation of caspase-mediated downstream cell death pathway. Understanding the molecular mechanisms at mitochondrial level involved in amphetamines’ neurotoxicity can help in defining target pathways or molecules mediating these effects, as well as in developing putative therapeutic approaches to prevent or treat the acute- or long-lasting neuropsychiatric complications seen in human abusers.

Rationale Most studies on the subjective effects of ecstasy are based on the assumption that the substance that was taken is 3,4-methylenedioxymethamphetamine (MDMA). However, many tablets sold as ecstasy contain other substances and MDMA in varying doses. So far, few attempts have been made to take this into account while assessing subjective effects. Objectives This study aims to link the pharmacological content of tablets sold as ecstasy to the subjective experiences reported by ecstasy users. Methods Self-reported effects on ecstasy tablets were available from 5,786 drug users who handed in their tablets for chemical analysis at the Drug Information and Monitoring System (DIMS) in the Netherlands. Logistic regression was employed to link the pharmacological content of ecstasy tablets to the self-reported subjective effects and compare effects with MDMA to other substances present. Results MDMA showed a strong association with desirable subjective effects, unparalleled by any other psychoactive substance. However, the association of MDMA was dose-dependent, with higher doses (>120 mg/tablet) likely to evoke more adverse effects. The novel psychostimulants mephedrone and p -fluoroamphetamine were considered relatively desirable, whereas meta -chlorophenylpiperazine (mCPP) and p -methoxymethamphetamine (PMMA) were strongly associated with adverse subjective effects. Also, 3,4-methylene-dioxyamphetamine (MDA) and benzylpiperazine (BZP) were not appreciated as replacement for MDMA. Conclusion Linking the pharmacological content of ecstasy sold on the street to subjective experiences contributes to a better understanding of the wide range of subjective effects ascribed to ecstasy and provides a strong rationale for the prolonged endurance of MDMA as the key ingredient of the ecstasy market.

Anorexia nervosa is a growing concern in mental health, often inducing death. The potential neuronal deficits that may underlie abnormal inhibitions of food intake, however, remain largely unexplored. We hypothesized that anorexia may involve altered signaling events within the nucleus accumbens (NAc), a brain structure involved in reward. We show here that direct stimulation of serotonin (5-hydroxytryptamine, 5-HT) 4 receptors (5-HT₄R) in the NAc reduces the physiological drive to eat and increases CART (cocaine- and amphetamine-regulated transcript) mRNA levels in fed and food-deprived mice. It further shows that injecting 5-HT₄R antagonist or siRNA-mediated 5-HT₄R knockdown into the NAc induced hyperphagia only in fed mice. This hyperphagia was not associated with changes in CART mRNA expression in the NAc in fed and food-deprived mice. Results include that 5-HT₄R control CART mRNA expression into the NAc via a cAMP/PKA signaling pathway. Considering that CART may interfere with food- and drug-related rewards, we tested whether the appetite suppressant properties of 3,4-N-methylenedioxymethamphetamine (MDMA, ecstasy) involve the 5-HT₄R. Using 5-HT₄R knockout mice, we demonstrate that 5-HT₄R are required for the anorectic effect of MDMA as well as for the MDMA-induced enhancement of CART mRNA expression in the NAc. Directly injecting CART peptide or CART siRNA into the NAc reduces or increases food consumption, respectively. Finally, stimulating 5-HT₄R- and MDMA-induced anorexia were both reduced by injecting CART siRNA into the NAc. Collectively, these results demonstrate that 5-HT₄R-mediated up-regulation of CART in the NAc triggers the appetite-suppressant effects of ecstasy.

MDMA-induced impairments of memory performance have been reported in different human and animal studies. However, the correlation between spatial memory impairment, brain mitochondrial function, and concentrations of MDMA and its metabolites has not yet been investigated despite it being needed for comparison with human studies. Therefore, the aim of this study was to investigate the dose concentration and spatial memory as well as brain mitochondrial function association after MDMA administration in rats. We assessed the effects of MDMA [0.5, 2.5, 5, 10 and 15 mg/kg; intraperitoneally (I.P)] on spatial memory of male Wistar rats in the Morris water maze test (MWM) and brain mitochondrial function (i.e., reactive oxygen species, mitochondrial membrane potential, swelling and outer membrane damage, cytochrome c release, and ADP/ATP ratio). Concentrations of MDMA and its metabolite, MDA, were determined in plasma, cerebrospinal fluid (CSF) and brain which was obtained immediately after probe test of MWM (i.e., 4 h after last training trial). The results of this study indicate nonlinear kinetics of MDMA after I.P adminstration. Also, an insignificant correlation was observed between MDMA doses and the MDA/MDMA ratio in plasma, CSF, and brain. Moreover, the results showed that MDMA, but not MDA, accumulated in brain tissue by increasing the administered doses. Beside, MDMA-induced impairments of spatial memory and brain mitochondrial function were significantly correlated with the concentrations of both MDMA and MDA in plasma, CSF, and brain. Therefore, it can be suggested that MDMA and its metabolite, MDA, affect spatial memory and brain mitochondrial function.