Serotonin Neurotoxicity after (±)3,4-Methylenedioxymethamphetamine (MDMA; “Ecstasy”): A Controlled Study in Humans

McCann, Una D.; Ridenour, Alison; Shaham, Yavin; Ricaurte, George A.

doi:10.1038/npp.1994.15

Cited by 307 publications

(206 citation statements)

References 27 publications

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“…Given the well-known role of DA in modulating activity, it is possible that the reduced ambulation and rearing observed in the MDMA-treated animals was due to abnormalities in the dopaminergic system. In addition to the previously mentioned ability of high MDMA doses to acutely release catecholamines, longer lasting alterations in catecholaminergic function have been reported not only in mice (which are known to exhibit dopamine neurotoxicity following MDMA), but also in rats, monkeys, and humans exposed to this compound (Commins et al, 1987;Gerra et al, 2002Gerra et al, , 2003Mayerhofer et al, 2001;McCann et al, 1994;Ricaurte et al, 1992). Moreover, we recently found that the same MDMA binge regimen used in the present study (ie with a 1-h interdose interval) significantly reduced DA transporter binding in the striatum .…”

Section: Discussionmentioning

confidence: 94%

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

Piper

Fraiman

Owens

et al. 2007

Neuropsychopharmacol

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High or repeated doses of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy') produce long-lasting deficits in several markers of serotonin (5-HT) system integrity and also alter behavioral function. However, it is not yet clear whether MDMA-induced serotonergic neurotoxicity is responsible for these behavioral changes or whether other mechanisms are involved. The present experiment tested the hypothesis that blocking serotonergic neurotoxicity by pretreatment with the selective 5-HT reuptake inhibitor citalopram will also prevent the behavioral and physiological consequences of an MDMA binge administration. Male, SpragueDawley rats (N ¼ 67) received MDMA (4 Â 10 mg/kg) with or without citalopram (10 mg/kg) pretreatment. Core temperature, ejaculatory response, and body weight were monitored during and immediately following drug treatments. A battery of tests assessing motor, cognitive, exploratory, anxiety, and social behaviors was completed during a 10-week period following MDMA administration. Brain tissue was collected at 1 and 10 weeks after drug treatments for measurement of regional 5-HT transporter binding and (for the 1-week samples) 5-HT and 5-HIAA concentrations. Citalopram pretreatment blocked MDMA-related reductions in aggressive and exploratory behavior measured in the social interaction and hole-board tests respectively. Such pretreatment also had the expected protective effect against MDMA-induced 5-HT neurotoxicity at 1 week following the binge. In contrast, citalopram did not prevent most of the acute effects of MDMA (eg hyperthermia and weight loss), nor did it block the decreased motor activity seen in the binge-treated animals 1 day after dosing. These results suggest that some of the behavioral and physiological consequences of a high-dose MDMA regimen in rats are mediated by mechanisms other than the drug's effects on the serotonergic system. Elucidation of these mechanisms requires further study of the influence of MDMA on other neurotransmitter systems.

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Section: Discussionmentioning

confidence: 94%

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

Piper

Fraiman

Owens

et al. 2007

Neuropsychopharmacol

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“…It indicates that MDMA's effect on spatial memory is not due to its action within the dopaminergic system. Though MDMA exerts its effects in the brain through a multitude of transmitter systems, it is generally assumed that MDMA induced memory deficits that are related to changes in serotonergic function (Bolla et al 1998;McCann et al 1994;Reneman et al 2002;Verkes et al 2001). The present data seem to support this general notion.…”

Section: Discussionmentioning

confidence: 99%

Acute dose of MDMA (75 mg) impairs spatial memory for location but leaves contextual processing of visuospatial information unaffected

Kuypers

Ramaekers

2006

Psychopharmacology

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Rationale: Research concerning spatial memory in 3,4-methylenedioxymethamphetamine (MDMA) users has presented conflicting results showing either the presence or absence of spatial memory deficits. Two factors may have confounded results in abstinent users: memory task characteristics and polydrug use. Objectives: The present study aims to assess whether a single dose of MDMA affects spatial memory performance during intoxication and withdrawal phase and whether spatial memory performance after MDMA is task dependent. Materials and methods: Eighteen recreational MDMA users participated in a doubleblind, placebo-controlled, three-way crossover design. They were treated with placebo, MDMA 75 mg, and methylphenidate 20 mg. Memory tests were conducted between 1.5 and 2 h (intoxication phase) and between 25.5 and 26 h (withdrawal phase) post-dosing. Two spatial memory tasks of varying complexity were used that required either storage of stimulus location alone (spatial memory task) or memory for location as well as processing of content or contextual information (change blindness task). Results: After a single dose of MDMA, the subjects made larger localization errors and responded faster compared to placebo in the simple spatial memory task during intoxication phase. Inaccuracy was not due to increased response speed, as determined by regression analysis. Performance in the change blindness task was not affected by MDMA. Methylphenidate did not affect performance on any of the tasks. Conclusion: It is concluded that a single dose of MDMA impairs spatial memory for location but leaves processing of contextual information intact.

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“…Improved impulse control during serotonergic suppletion seems in line with reports on impaired impulse control in heavy users of MDMA during periods of abstinence. Studies on serotonergic function in recreational MDMA users have repeatedly shown low levels of 5HIAA in CSF (Bolla et al, 1998;McCann et al, 1994;Peroutka et al, 1987;Ricaurte et al, 1990), reduced density of 5-HT transporters (Reneman et al, 2002) and blunted neuro-endocrine responses in serotonergic challenge tests (Gerra et al, 1998;McCann et al, 1999;Verkes et al, 2001) when compared to nondrug using controls. In addition, serotonergic depletion has been linked to behaviors characterized by impaired impulse control (Linnoila et al, 1983(Linnoila et al, , 1993.…”

Section: Discussionmentioning

confidence: 99%

“…Studies that have examined the effect of MDMA on impulsivity in abstinent MDMA users have provided conflicting results. McCann et al (1994) reported a decrement in impulsivity ratings of MDMA users as measured by the Multidimensional Personality Questionnaire, whereas others reported elevated scores of impulsivity in heavy MDMA users, using different subjective measures of impulsivity (Butler and Montgomery, 2004;Morgan, 1998Morgan, , 2000Parrott, 2000). Elevated levels of impulsiveness have been associated with lower levels of 5HT and CSF-5HIA (Linnoila et al, 1983(Linnoila et al, , 1993 and with dopaminergic activation in the prefrontal cortex leading to a reduction in 'inhibitory control' over behavioral functions (Jentsch and Taylor, 1999).…”

Section: Introductionmentioning

confidence: 99%

Acute Effects of 3,4-Methylenedioxymethamphetamine (MDMA) on Behavioral Measures of Impulsivity: Alone and in Combination with Alcohol

Ramaekers

Kuypers

2005

Neuropsychopharmacol

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The use of 3,4-methylenedioxymethamphetamine (MDMA) has frequently been associated with increased levels of impulsivity during abstinence. The effects of MDMA on measures of impulsivity, however, have not yet been studied during intoxication. The present study was designed to assess the acute effects of MDMA and alcohol, alone and in combination, on behavioral measures of impulsivity and risktaking behavior. A total of 18 recreational users of MDMA entered a double-blind placebo-controlled six-way crossover study. The treatments consisted of MDMA 0, 75, and 100 mg with and without alcohol. Alcohol dosing was designed to achieve a peak blood alcohol concentration (BAC) of about 0.06 g/dl during laboratory testing. Laboratory tests of impulsivity were conducted between 1.5 and 2 h post-MDMA and included a stop-signal task, a go/no-go task, and the Iowa gambling task. MDMA decreased stop reaction time in the stop-signal task indicating increased impulse control. Alcohol increased the proportion of commission errors in the stop-signal task and the go/no-go task. Signal detection analyses of alcohol-induced commission errors indicated that this effect may reflect impairment of perceptual or attentive processing rather than an increase of motor impulsivity per se. Performance in the Iowa gambling task was not affected by MDMA and alcohol, but there was a nonsignificant tendency towards improvement following alcohol intake. None of the behavioral measures of impulsivity showed a MDMA Â alcohol interaction effect. The lack of interaction indicated that the CNS stimulant effects of MDMA were never sufficient to overcome alcohol-induced impairment of impulse control or risk-taking behavior.

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Serotonin Neurotoxicity after (±)3,4-Methylenedioxymethamphetamine (MDMA; “Ecstasy”): A Controlled Study in Humans

Cited by 307 publications

References 27 publications

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

Acute dose of MDMA (75 mg) impairs spatial memory for location but leaves contextual processing of visuospatial information unaffected

Acute Effects of 3,4-Methylenedioxymethamphetamine (MDMA) on Behavioral Measures of Impulsivity: Alone and in Combination with Alcohol

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