3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug. In animals, high-dose administration of MDMA produces deficits in serotonin (5-HT) neurons (e.g., depletion of forebrain 5-HT) that have been interpreted as neurotoxicity. Whether such 5-HT deficits reflect neuronal damage is a matter of ongoing debate. OBJECTIVE: The present paper reviews four specific issues related to the hypothesis of MDMA neurotoxicity in rats: (1) the effects of MDMA on monoamine neurons, (2) the use of “interspecies scaling” to adjust MDMA doses across species, (3) the effects of MDMA on established markers of neuronal damage, and (4) functional impairments associated with MDMA-induced 5-HT depletions. RESULTS: MDMA is a substrate for monoamine transporters, and stimulated release of 5-HT, NE, and DA mediates effects of the drug. MDMA produces neurochemical, endocrine, and behavioral actions in rats and humans at equivalent doses (e.g., 1–2 mg/kg), suggesting that there is no reason to adjust doses between these species. Typical doses of MDMA causing long-term 5-HT depletions in rats (e.g., 10–20 mg/kg) do not reliably increase markers of neurotoxic damage such as cell death, silver staining, or reactive gliosis. MDMA-induced 5-HT depletions are accompanied by a number of functional consequences including reductions in evoked 5-HT release and changes in hormone secretion. Perhaps more importantly, administration of MDMA to rats induces persistent anxiety-like behaviors in the absence of measurable 5-HT deficits. CONCLUSIONS: MDMA-induced 5-HT depletions are not necessarily synonymous with neurotoxic damage. However, doses of MDMA which do not cause long-term 5-HT depletions can have protracted effects on behavior, suggesting even moderate doses of the drug may pose risks

The effect of 3,4-methylenedioxymethamphetamine ('Ecstasy') on serotonergic regulation of the mammalian circadian clock mechanism in rats: the role of dopamine and hyperthermia

The recreational drug 3,4-methylenedioxymethamphetamine (MDMA) is known to be a neurotoxin for serotonergic axons ascending from the raphe nucleus including those which terminate on neurons of the suprachiasmatic nuclei (SCN) of the hypothalamus, the putative mammalian circadian clock. Since dopamine release has been implicated in the serotonergic neurotoxicity, we examined the effects of the dopamine synthesis inhibitor alpha-methyl-p-tyrosine (AMPT) and the D2 receptor antagonist haloperidol (HAL) on the long-term effect of MDMA on serotonergic regulation of the SCN neuronal firing rhythm. Co-administration of AMPT or HAL with MDMA eliminated the acute hyperthermic response but had no effect on the MDMA-induced phase shift in the firing rhythm of SCN neurons to the selective 5-HT1A receptor agonist, 8-hydroxy-2-(dipropylamino)-tetralin. It is concluded that neither dopamine metabolism nor hyperthermia account for the altered serotonergic function in the SCN produced by MDMA. Toxic free radical production following MDMA metabolism may be responsible

Prospective memory impairment in ‘ecstasy’ (MDMA) users

Rationale: Considerable research indicates that "ecstasy" users perceive their memory for future intentions (prospective memory) to be impaired. However, only one empirical study to date has directly tested how this capacity is affected by ecstasy use, and this study provided relatively limited information regarding the extent, scope, or implications of problems experienced. Objectives: The present study assessed prospective performance on a laboratory measure of prospective memory that closely represents the types of prospective memory tasks that actually occur in everyday life and provides an opportunity to investigate the different sorts of prospective memory failures that occur ("Virtual Week"). Method: Ecstasy user group (27 current users and 34 nonusers) was between participants, and prospective memory task (regular, irregular, time-check) was within participants. A measure sensitive to specific aspects of psychopathology was also administered. Results: Ecstasy users were significantly impaired on Virtual Week, and these deficits were of a comparable magnitude irrespective of the specific prospective memory task demands. The pattern of results was unchanged after controlling for marijuana use, level of psychopathology, and sleep quality. Further, prospective memory was shown to be significantly impaired for both relatively infrequent and relatively frequent ecstasy users, although for the latter group the magnitude of this deficit was greater. Conclusions: Prospective memory performance is sensitive to regular and even moderate ecstasy use. Importantly, ecstasy users experience generalized difficulties with prospective memory, suggesting that these deficits are likely to have important implications for day-to-day functioning

Reasoning deficits in ecstasy (MDMA) polydrug users

Rationale/objectives: Previous research has shown that ecstasy users are impaired in thinking and reasoning. The present study sought to explore the possibility that syllogistic reasoning errors in ecstasy users were due to an inability to construct a model of the premises due to working memory limitations. Methods: Twenty-nine ecstasy users and 25 nonecstasy user controls completed abstract syllogistic reasoning problems varying in difficulty. Pairs of premises were provided, and participants were required to generate conclusions that followed necessarily from them. Results: On the easier problems, both groups performed at well above chance although nonusers achieved significantly more correct responses. Consistent with existing research, on the more difficult problems, errors by nonusers were characterised by incorrect conclusions suggesting that while nonusers have the working memory capacity to construct a single model of the premises, this is not an exhaustive representation and usually results in an erroneous conclusion. On the other hand, for all problem types, ecstasy users, rather than produce incorrect responses, were more likely to fail to generate a conclusion. Conclusions: The present results are consistent with the possibility that ecstasy users with their reduced working memory capacity may experience difficulty in constructing even a single model of the premises. While this might be attributable to the effects of 3,4-methlylenedioxymethamphetamine neurotoxicity, many of the ecstasy users in the present study were polydrug users. Thus, the possibility that other drugs including cannabis and cocaine might contribute to the present results cannot be excluded

The effect of long-term repeated exposure to 3,4-methylenedioxymethamphetamine on cardiovascular and thermoregulatory changes

Rationale3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") disrupts thermoregulation in rats and can lead to life-threatening hyperthermia in humans. MDMA administration can also lead to long-term neurotoxicity in animals and possibly humans.ObjectivesThe purpose of the current study was to extend previous results on the acute effects of MDMA on behavioral thermoregulation to a repeated dosing regime, simulating regular weekend use of ecstasy, on measures of thermoregulation and heart rate (HR).Materials and methodsSprague-Dawley rats with telemetry implants were administered 40 micromol/kg MDMA on three consecutive days each week for 1 or 6 weeks before being confined to an elevated ambient temperature (TA) (HOT; 30+/-1 degrees C) or an area at room temperature (ROOM; 21.5+/-1.5 degrees C) for 30 min. After the final drug administration, rats were placed in a thermal gradient for 4 h to allow behavioral thermoregulation.ResultsHOT rats showed higher core temperature (TC), HR, and locomotor activity than ROOM rats during confinement to a set TA (PConclusionLong-term treatment with MDMA resulted in apparent tolerance to the effects of the drug on HR, dysregulation of TC in thermal gradient, and depletion of cortical DOPAC and 5-HIAA.Emily Joy Jaehne, Abdallah Salem, Rodney James Irvin

Cannabis and Ecstasy/MDMA (3,4-methylenedioxymethamphetamine): an analysis of their neuropsychobiological interactions in recreational users

The majority of recreational Ecstasy/MDMA users (90–98%) also take cannabis. This co-drug usage is often viewed as a methodological confound, which needs to be removed statistically. Here we take a rather different approach, and debate the potential complexities of their psychobiological interactions. The ring-substituted amphetamine derivate MDMA (3,4-methylendioxymethamphetmaine, or ‘Ecstasy’ is a powerful CNS stimulant, whereas cannabis is a relaxant. Their co-usage may reflect opposing effects in three psychobiological areas: arousal, body temperature, and oxidative stress. Firstly MDMA is alerting whereas cannabis is sedating. Secondly MDMA is hyperthermic whereas cannabis is hypothermic. Thirdly MDMA increases oxidative stress whereas cannabinoids are antioxidant. Hence cannabis may modulate the acute and sub-acute reactions to MDMA, reduce the acute hyperthermia induced by MDMA, and ameliorate the oxidative stress caused by MDMA. The limited empirical evidence on each topic will be critically examined. In terms of chronic effects each drug is functionally damaging, so that polydrug users generally display cumulative neurobiological impairments. However in certain aspects their neuropsychobiological effects may interactive rather than additive. In particular, the combined use of cannabis and MDMA may have rather different neuropsychobiological implications, than their separate usage. In order to investigate these potential complexities, future research will need better empirical data on the exact patterns of co-drug usage