Adverse Effects Of MDMA Research Articles

The entactogen 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) as a treatment aid in psychotherapy and its safety concerns.

The phenylethylamine, 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'), is the prototypical example of an entactogen. Its original placement in highly restrictive drug usage categories in the US and UK, led to an inevitable restriction on MDMA neuroscience research and treatment. The dominant pharmacological effects of MDMA are its properties of release and inhibition of reuptake of amine neurotransmitter transporters for dopamine, norepinephrine, and serotonin. MDMA is an agonist of a wide range of receptors; its mood-altering effects are mediated via 5-HT2A receptors; this receptor may also mediate its effects on body temperature, analgesia, and anxiolytic properties. The mechanisms underlying MDMA's entactogenic properties of sociability and interpersonal closeness are not known but release and involvement of oxytocin, a peptide thought by some to be involved in social bonding, has been suggested. Adverse effects of MDMA are mostly transient; acute multiorgan adverse effects occurring during raves or crowded dance gatherings include dehydration, hyperthermia, seizures, rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. Deaths following MDMA taken by itself are rare compared to fatalities following coadministration with other drugs. A recent FDA-approved phase 3 clinical trial of MDMA for post-traumatic stress disorder (PTSD) led to the conclusion that MDMA-assisted therapy represents a potential breakthrough treatment meriting expedited clinical evaluation. Despite the ongoing deliberations by the FDA and EMA for approval of MDMA treatment of PTSD, the Australian Therapeutic Goods Administration (TGA) recently announced that after an evaluation of the therapeutic value, benefits, and risks of MDMA, it will permit its prescribing for the treatment of PTSD. Further examples of regulatory relaxation toward MDMA-assisted psychotherapy are underway. These include the FDA's recently approved clinical trial to assess MDMA's efficacy in the treatment of "asociality" in patients with schizophrenia and an open trial of MDMA treatment for alcohol-use disorder which showed decreased alcohol consumption. There are also ongoing studies on the little understood startle response, anxiety associated with life-threatening illness, and social anxiety in autistic adults.

Locomotor effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in mice: psychostimulant effects, stereotypy, and sensitization.

There is a renewed interest in the use of 3,4-methylenedioxymethamphetamine (MDMA) for treating psychiatric conditions. Although MDMA has entered phase II clinical trials and shows promise as an adjunct treatment, there is an extensive literature detailing the potential neurotoxicity and adverse neurobehavioral effects associated with MDMA use. Previous research indicates that the adverse effects of MDMA may be due to its metabolism into reactive catechols that can enter the brain and serve directly as neurotoxicants. One approach to mitigate MDMA's potential for adverse effects is to reduce O-demethylation by deuterating the methylenedioxy ring of MDMA. There are no studies that have evaluated the effects of deuterating MDMA on behavioral outcomes. The purpose of the present study was to assess the motor-stimulant effects of deuterated MDMA (d2-MDMA) and compare them to MDMA in male mice. Two experiments were performed to quantify mouse locomotor activity and to vary the drug administration regimen (single bolus administration or cumulative administration). The results of Experiments 1 and 2 indicate that d2-MDMA is less effective at eliciting horizontal locomotion than MDMA; however, the differences between the compounds diminish as the number of cumulative administrations increase. Both d2-MDMA and MDMA can elicit sensitized responses, and these effects cross-sensitize to the prototypical drug of abuse methamphetamine. Thus, d2-MDMA functions as a locomotor stimulant similar to MDMA, but, depending on the dosing regimen, may be less susceptible to inducing sensitization to stereotyped movements. These findings indicate that d2-MDMA is behaviorally active and produces locomotor effects that are similar to MDMA, which warrant additional assessments of d2-MDMA's behavioral and physiological effects to determine the conditions under which this compound may serve as a relatively safer alternative to MDMA for clinical use.

How MDMA's Pharmacology and Pharmacokinetics Drive Desired Effects and Harms

3,4-Methylenedioxymethamphetamine (MDMA) is an agent of abuse that has been used by over 16 million Americans. Increased energy, elevated mood, bonding with others, and psychedelic effects are desired effects while liver damage, extended depressed mood, sexual assault, rhabdomyolysis, serotonin syndrome, multiorgan failure, cardiovascular events, arrhythmias, and death are possible adverse effects. These desirable and adverse effects of MDMA are extensions of its fascinating pharmacologic and pharmacokinetic profile. In addition to methamphatemine like effects, MDMA also has mescaline like effects and increases the release of cortisol, oxytocin, and antidiuretic hormone. The desirable effects of MDMA are accentuated by the rave or electronic dance music scene where warm temperatures, vigorous dancing, loud music, and light shows accentuate some of the responses. However, the same environment increases the risk of certain harms. Knowledge of the constellation of these factors is needed for education, prevention of harm, and treatment.

Residual social, memory and oxytocin-related changes in rats following repeated exposure to γ-hydroxybutyrate (GHB), 3,4-methylenedioxymethamphetamine (MDMA) or their combination

There has been little investigation of the possible lasting adverse effects of γ-hydroxybutyrate (GHB). This study aims to study whether GHB produces residual adverse effects on memory and social behaviour in rats and lasting changes in brain monoamines and oxytocin-related gene expression. Rats received daily intraperitoneal injections of GHB (500 mg/kg), methylenedioxymethamphetamine (MDMA; 5 mg/kg) or their combination (GHB/MDMA) over ten consecutive days. Locomotor activity and body weight were assessed during the dosing period and withdrawal-related anxiety was assessed 24 h after drug cessation. After a washout of 4 weeks, rats were tested on the emergence, social interaction, and object recognition tasks over a 2-week period. Monoamine levels in cortex and striatum, and hypothalamic oxytocin and oxytocin receptor mRNA, were then assessed. MDMA and GHB/MDMA caused modest sensitization of locomotor activity over time, while sedative effects of GHB diminished with repeated exposure. GHB-treated rats showed reduced social interaction 24 h after the final dose, indicating GHB withdrawal-induced anxiety. All drug-treated groups displayed residual deficits in social interaction and object recognition. No changes in monoamine levels were detected 8 weeks post-drug. However, MDMA pre-exposure increased hypothalamic oxytocin mRNA while GHB pre-exposure upregulated oxytocin receptor mRNA. GHB/MDMA pre-exposure caused intermediate changes in both of these measures. GHB treatment caused residual impairments in memory and social behaviour and increases in anxiety, paralleling the lasting adverse effects of MDMA. Both drugs caused lasting neuroadaptations in brain oxytocin systems and this may be related to the long-term social interaction deficiencies caused by both drugs.

Post-Mortem (Re)Distribution of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”): Human and Animal Data

In this paper, the distribution and redistribution of the amphetamine derivative, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is brought into focus. Animal experimental data were compared with internationally reported MDMA-related human fatalities: in general, these turned out to be parallel with each other. Due to its inherent properties (e.g. significant volume of distribution), MDMA is liable to postmortem redistribution. Indeed, very high concentrations have been found in cardiac blood and tissues located centrally in the body (blood-rich organs such as lungs and liver in particular). This confirms that post-mortem redistribution due to diffusion from higher to lower concentration can easily take place, mainly at longer post-mortem intervals and when putrefaction occurs. Therefore, we can conclude that for post-mortem quantitation of amphetamine and derivatives, and MDMA in particular, peripheral blood sampling (e.g. femoral vein) remains compulsory. However, if the latter is impossible, MDMA quantification in a few alternative matrices such as vitreous humour and iliopsoas muscle may provide additional information to come to a reliable conclusion. Furthermore, it should be stressed that--at present--it is impossible to estimate the individual susceptibility to the various possible adverse effects of MDMA, which implies that it is impossible to provide a "safe" or "therapeutic" blood MDMA level. Therefore, in current forensic practice, the post-mortem pathological and toxicological findings should form an entity in order to draw a well-grounded conclusion.

Effects of a β-blocker on the cardiovascular response to MDMA (Ecstasy)

BackgroundMDMA (3,4-methylenedioxymethamphetamine, ‘Ecstasy’) produces tachycardia and hypertension and is rarely associated with cardiovascular and cerebrovascular complications. In clinical practice, β-blockers are often withheld in patients with stimulant intoxication because they...

Paramethoxyamphetamine (PMA) poisoning; a ‘party drug’ with lethal effects

Among young people in Norway the recreational use of amphetamine derivatives seems to be increasing. Methylenedioxymethamphetamine (MDMA), known as ecstasy, is the dominant substance, having both stimulant and psychedelic properties. Depending on the illegal source of these so-called 'party drugs' the content and purity can vary. This case report describes the first lethal case of paramethoxyamphetamine (PMA) and paramethoxymethamphetamine (PMMA) intoxication reported in Norway. A 16-year-old male was admitted to a local hospital in a coma with seizures and hyperthermia after he had been found undressed and barefooted in a local forest (temperature 2 degrees C). He was intubated and given supportive care. Blood chemistry revealed hypoglycaemia, hypocalcaemia and hyperkalaemia. Shortly after transfer to the central hospital he developed bradycardia with continuous seizures and asystole. Adverse effects of MDMA are well described and include serotonergic and sympathomimetic symptoms with hyperthermia, coagulopathy, rhabdomyolysis and acute kidney and liver failure. Case reports of PMA deaths collectively suggest PMA to be more toxic than MDMA. A delayed effect after intake of PMA compared with MDMA can lead to increased intake. Hypoglycaemia and hyperkalaemia may be specific to PMA poisoning. Increased thermo genesis will result in a search for cooling, which explains the attempt to undress and a desire to submerge in water. In a cool climate this behaviour itself can be lethal. Measures to treat seizures, hypoglycaemia, electrolyte anomalies and hyperthermia are the therapeutic goals. No specific treatment is available.

Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies.

In preclinical studies, 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') has been shown to release serotonin (5-HT), dopamine and norepinephrine. However, the role of these neurotransmitters and their corresponding receptor sites in mediating the subjective effects of MDMA has not yet been studied in humans. Therefore, we investigated the effects of three different neuroreceptor pretreatments on the subjective, cardiovascular and adverse effects of MDMA (1.5 mg/kg orally) in 44 healthy human volunteers. Pretreatments were: the selective serotonin reuptake inhibitor citalopram (40 mg intravenously) in 16 subjects, the 5-HT(2) antagonist ketanserin (50 mg orally) in 14 subjects, and the D(2) antagonist haloperidol (1.4 mg intravenously) in 14 subjects. Each of these studies used a double-blind placebo-controlled within-subject design and all subjects were examined under placebo, pretreatment, MDMA and pretreatment plus MDMA conditions. Citalopram markedly reduced most of the subjective effects of MDMA, including positive mood, increased extraversion and self-confidence. Cardiovascular and adverse effects of MDMA were also attenuated by citalopram. Haloperidol selectively reduced MDMA-induced positive mood but had no effect on other subjective effects of MDMA or the cardiovascular or adverse responses to MDMA. Ketanserin selectively reduced MDMA-induced perceptual changes and emotional excitation. These results indicate that the overall psychological effects of MDMA largely depend on carrier-mediated 5-HT release, while the more stimulant-like euphoric mood effects of MDMA appear to relate, at least in part, to dopamine D(2) receptor stimulation. The mild hallucinogen-like perceptual effects of MDMA appear to be due to serotonergic 5-HT(2) receptor stimulation. Copyright 2001 John Wiley & Sons, Ltd.

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"): pharmacology and toxicology in animals and humans.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"), a ring-substituted amphetamine derivative first synthesized in 1914, has emerged as a popular recreational drug of abuse over the last decade. Pharmacological studies indicate that MDMA produces a mixture of central stimulant and psychedelic effects, many of which appear to be mediated by brain monoamines, particularly serotonin and dopamine. In addition to its pharmacologic actions, MDMA has been found to possess toxic activity toward brain serotonin neurones. Serotonergic neurotoxicity after MDMA has been demonstrated in a variety of experimental animals (including non-human primates). In monkeys, the neurotoxic dose of MDMA closely approaches that used by humans. While the possibility that MDMA is also neurotoxic in humans is under investigation, other adverse effects of MDMA in humans have been documented, including various systemic complications and a number of untoward neuropsychiatric sequelae. Notably, many of the adverse neuropsychiatric consequences noted after MDMA involve behavioral domains putatively influenced by brain serotonin (e.g., mood, cognition and anxiety). Given the restricted status of MDMA use, retrospective clinical observations from suspecting clinicians will probably continue to be a primary source of information regarding MDMA's effects in humans. As such, this article is intended to familiarize the reader with the behavioral pharmacology and toxicology of MDMA, with the hope that improved recognition of MDMA-related syndromes will provide insight into the function of serotonin in the human brain, in health as well as disease.