Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings

McCann, UD; Szabó, Zsolt; Scheffel, Ursula; Dannals, R. F.; Ricaurte, G.A.

doi:10.1016/s0140-6736(98)04329-3

Cited by 573 publications

(298 citation statements)

References 21 publications

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“…In keeping with previous findings (Frankle et al, 2004;McCann et al, 1998) Figure 1). There was also a significant correlation within individual subjects (overall r ¼ 0.55, Control r ¼ 0.53; MDMA r ¼ 0.49; Figure 2).…”

Section: Resultssupporting

confidence: 93%

“…For example, abstinent MDMA users, like monkeys with documented serotonin neurotoxicity (Ricaurte et al, 1988;Taffe et al, 2002) have reduced levels of CSF 5-HIAA (McCann et al, , 1994 but reductions in CSF 5-HIAA could represent persistent alterations in serotonin metabolism, rather than neurotoxicity. Positron emission tomography (PET) studies with [ 11 C]McN5652 have also demonstrated reductions in brain SERT in abstinent MDMA users (Buchert et al, 2003(Buchert et al, , 2004McCann et al, 1998), but these studies have had limitations. In particular, our study (McCann et al, 1998) applied a method for determination of the plasma input function of the radioligand that led to high estimates of SERT density, and were associated with a high degree of variability that necessitated use of logarithmic transforms to permit parametric statistical analyses.…”

Section: Introductionmentioning

confidence: 99%

“…Positron emission tomography (PET) studies with [ 11 C]McN5652 have also demonstrated reductions in brain SERT in abstinent MDMA users (Buchert et al, 2003(Buchert et al, , 2004McCann et al, 1998), but these studies have had limitations. In particular, our study (McCann et al, 1998) applied a method for determination of the plasma input function of the radioligand that led to high estimates of SERT density, and were associated with a high degree of variability that necessitated use of logarithmic transforms to permit parametric statistical analyses. The studies by Buchert et al (2003Buchert et al ( , 2004 did not include determination of the arterial input function for quantitative PET analysis but, rather, used the cerebellum as a reference region to correct for nonspecific binding.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative PET Studies of the Serotonin Transporter in MDMA Users and Controls Using [11C]McN5652 and [11C]DASB

McCann¹,

Szabó²,

Seckin³

et al. 2005

Neuropsychopharmacol

188

163

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(7)3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') is a widely used illicit drug that produces toxic effects on brain serotonin axons and axon terminals in animals. The results of clinical studies addressing MDMA's serotonin neurotoxic potential in humans have been inconclusive. In the present study, 23 abstinent MDMA users and 19 non-MDMA controls underwent quantitative positron emission tomography (PET) studies using [ 11 C]McN5652 and [ 11 C]DASB, first-and second-generation serotonin transporter (SERT) ligands previously validated in baboons for detecting MDMA-induced brain serotonin neurotoxicity. Global and regional distribution volumes (DVs) and two additional SERT-binding parameters (DV spec and DVR) were compared in the two subject populations using parametric statistical analyses. Data from PET studies revealed excellent correlations between the various binding parameters of [ 11 C] McN5652 and [ 11 C]DASB, both in individual brain regions and individual subjects. Global SERT reductions were found in MDMA users with both PET ligands, using all three of the above-mentioned SERT-binding parameters. Preplanned comparisons in 15 regions of interest demonstrated reductions in selected cortical and subcortical structures. Exploratory correlational analyses suggested that SERT measures recover with time, and that loss of the SERT is directly associated with MDMA use intensity. These quantitative PET data, obtained using validated first-and second-generation SERT PET ligands, provide strong evidence of reduced SERT density in some recreational MDMA users.

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Section: Resultssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quantitative PET Studies of the Serotonin Transporter in MDMA Users and Controls Using [11C]McN5652 and [11C]DASB

McCann¹,

Szabó²,

Seckin³

et al. 2005

Neuropsychopharmacol

188

163

View full text Add to dashboard Cite

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“…Indeed, at the time of this writing, there exist no published reports describing frank cell loss, argyrophilia, or reactive gliosis in postmortem human brain tissue from MDMA users. As such, some researchers have relied instead on more ambiguous measures of axon terminal integrity in human MDMA users, such as depletion of serotonin (5-HT) content (see, e.g., Kish et al 2000), reduced binding to plasmalemmal 5-HT transporters (see, e.g., McCann et al 1998McCann et al , 2005Semple et al 1999), or compensatory upregulation of postsynaptic 5-HT receptors (see, e.g., Reneman et al 2002). Other researchers have eschewed the study of human drug users in favor of animal models, which frequently involved the application of various interspecies dose scaling procedures.…”

Section: Introductionmentioning

confidence: 99%

Reinforcing effects of methylenedioxy amphetamine congeners in rhesus monkeys: are intravenous self-administration experiments relevant to MDMA neurotoxicity?

Fantegrossi

2006

Psychopharmacology

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Rationale: Many animal models relevant to the persistent effects of drugs of abuse necessitate the application of interspecies dose scaling procedures to approximate drug administration regimens in humans, but drug self-administration procedures differ in that they allow animal subjects to control their own drug intake. Objectives: This report reviews the reinforcing effects of 3,4-methylenedioxymethamphetamine (MDMA), its enantiomers, and several structural analogs in rhesus monkeys, paying particular attention to the pharmacological mechanisms of such reinforcing effects, the development of structure activity relationships among these compounds, the stability of MDMA self-administration behavior over time, and the persistent effects of selfadministered MDMA on monoamines. Results: The methylenedioxy amphetamine congeners MDMA, 3, 4-methylenedioxyamphetamine, N-ethyl-3,4-methylenedioxyamphetamine, and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine function as reinforcers in rhesus monkeys, maintaining self-administration behavior greater than that engendered by contingent saline but less than that engendered by traditional psychostimulants. These findings are remarkable as structurally distinct serotonergic hallucinogen-like drugs do not maintain reliable selfadministration in laboratory animals. During prolonged MDMA self-administration, MDMA-maintained responding progressively weakens, and MDMA eventually fails to maintain significant self-administration. The neurochemical correlates of this effect have not yet been identified. Conclusions: Procedures in which MDMA and related compounds are self-administered can be established in rhesus monkeys. These techniques can be used to engender contingent MDMA exposure without resorting to controversial methods of interspecies dose scaling. As such, further application of self-administration methods may provide important new insights into the persistent effects of MDMA on brain and behavior in nonhuman primates.

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“…A number of studies have found evidence of neurotoxicity among ecstasy users. For example, using PET neuroimaging, McCann, et al (1998), investigated 5-HT neural damage in the brains of ecstasy users. Regions of interest included the frontal cortex, pariental cortex, temporal cortex, occipital cortex and cingulate cortex, as well as the caudate, putamen, thalamus, mid-brain, pons, hypothalamus and cerebellum.…”

mentioning

confidence: 99%

The effects of concurrent cannabis use among ecstasy users: neuroprotective or neurotoxic?

Fisk

Montgomery

Wareing

et al. 2006

Human Psychopharmacology

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Edge Hill College of Higher EducationRunning head: concurrent cannabis use among ecstasy users. The research evidence regarding the potential effects of ecstasy suggests that it may be neurotoxic and that its use is associated with cognitive impairment. In recent years evidence has emerged suggesting that cannabinoids, the active ingredients in cannabis, can be neuroprotective under certain conditions. Given that many ecstasy users also consume cannabis at the same time, the possibility emerges that these individuals might be less susceptible to ecstasy-related impairment. The present paper reanalyses the data from a number of previous studies, contrasting the performance of those individuals who generally consume cannabis and ecstasy at the same time with those who generally consume ecstasy on its own. The two ecstasy-using groups are compared with non-ecstasy users on a range of measures including processing speed, random letter generation, verbal and visuo-spatial working memory span, reasoning and associative learning. The two ecstasy user groups did not differ significantly from each other on any of the measures. Both user groups were significantly worse than non-ecstasy users on measures of associative learning, verbal and visuo-spatial working memory, and reasoning. The results suggest that consuming cannabis at the same time as ecstasy does not reduce the likelihood of cognitive impairment.There is abundant evidence that ecstasy (MDMA) is neurotoxic, disrupting serotonergic systems in diverse brain regions. There is also a considerable body of evidence that cannabis can have neuroprotective as well as neurotoxic properties.Given that most ecstasy users are also cannabis users (Morgan, 2000) the question arises as to whether concurrent use of cannabis by ecstasy users might make them less susceptible to MDMA related neurotoxicity. The present paper is intended to investigate this issue.Although there is abundant evidence that MDMA is neurotoxic in a range of animal species, evidence of neurotoxicity in humans is less extensive and sometimes controversial (Curran, 2000). A review of the neuroimaging evidence can be found in Reneman et al (2006). A number of studies have found evidence of neurotoxicity among ecstasy users. For example, using PET neuroimaging, McCann, et al (1998), investigated 5-HT neural damage in the brains of ecstasy users. Regions of interest included the frontal cortex, pariental cortex, temporal cortex, occipital cortex and cingulate cortex, as well as the caudate, putamen, thalamus, mid-brain, pons, hypothalamus and cerebellum. The results showed that, compared to a control group, ecstasy users had significantly lower densities of 5HT transporter sites in all brain regions. Further, the reductions observed were correlated with the extent of ecstasy use. Reneman, et al (2002a) also assessed neural injury in ecstasy users using single-voxel (1H) MR spectroscopy imagining. N-Acetylasportate (NAA)/Creatine (CR), NAA Choline (CHO), and Myoinositol (MI) CR ratios in ecstasy users were meas...

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Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings

Cited by 573 publications

References 21 publications

Quantitative PET Studies of the Serotonin Transporter in MDMA Users and Controls Using [11C]McN5652 and [11C]DASB

Quantitative PET Studies of the Serotonin Transporter in MDMA Users and Controls Using [11C]McN5652 and [11C]DASB

Reinforcing effects of methylenedioxy amphetamine congeners in rhesus monkeys: are intravenous self-administration experiments relevant to MDMA neurotoxicity?

The effects of concurrent cannabis use among ecstasy users: neuroprotective or neurotoxic?

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