A Voxel-Based PET Investigation of the Long-Term Effects of “Ecstasy” Consumption on Brain Serotonin Transporters

Buchert, Ralph; Thomasius, Rainer; Wilke, Florian; Petersen, Kay Uwe; Nebeling, B.; Obrocki, Jost; Schulze, Oliver; Schmidt, Ulrich; Clausen, M.

doi:10.1176/appi.ajp.161.7.1181

Cited by 165 publications

(152 citation statements)

References 24 publications

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“…Consistent with the outcomes of previous studies (e.g., Buchert et al 2004;Thomasius et al 2006) the results revealed that SERT densities were significantly reduced in all cortical areas with the occipital and temporal cortices most affected. No significant differences in SERT binding emerged in the basal ganglia structures or the thalamus.…”

Section: Discussionsupporting

confidence: 92%

Prospective memory deficits in illicit polydrug users are associated with the average long-term typical dose of ecstasy typically consumed in a single session.

Gallagher¹,

Hadjiefthyvoulou²,

Fisk³

et al. 2014

Neuropsychology

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Prospective memory deficits in illicit polydrug users are associated with the average long term typical dose of ecstasy typically consumed in a single session. AbstractRationale Neuroimaging evidence suggests that ecstasy-related reductions in SERT densities relate more closely to the number of tablets typically consumed per session rather than estimated total lifetime use. In order to better understand the basis of drug related deficits in prospective memory (PM) we explored the association between PM and average long-term typical dose and long-term frequency of use. Method Study 1: Sixty five ecstasy/polydrug users and 85 non-ecstasy users completed an event based, a short-term and a long-term time based PM task. Study 2: Study 1 data were merged with outcomes on the same PM measures from a previous study creating a combined sample of 103 ecstasy/polydrug users, 38 cannabis-only users and 65 nonusers of illicit drugs. Results Study 1: Ecstasy/polydrug users had significant impairments on all PM outcomes compared to non-ecstasy users. Study 2:Ecstasy/polydrug users were impaired in event based PM compared to both other groups and in long-term time based PM compared to non illicit drug users. Both drug using groups did worse on the short-term time based PM task compared to nonusers. Higher long-term average typical dose of ecstasy was associated with poorer performance on the event and short-term time based PM tasks and accounted for unique variance in the two PM measures over and above the variance associated with cannabis and cocaine use. Conclusions The typical ecstasy dose consumed in a single session is an important predictor of PM impairments with higher doses reflecting increasing tolerance giving rise to greater PM impairment.

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Section: Discussionsupporting

confidence: 92%

Prospective memory deficits in illicit polydrug users are associated with the average long-term typical dose of ecstasy typically consumed in a single session.

Gallagher¹,

Hadjiefthyvoulou²,

Fisk³

et al. 2014

Neuropsychology

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“…The purpose of the present study was to produce robust depletions in order to evaluate the long-term behavioral consequences for those heavy users who do experience serotonin depletion rather than model typical human use patterns. An emerging literature in humans and animals does suggest that humans who are heavy MDMA users experience measurable loss of serotonergic markers (Buchert et al 2004;De Win et al 2004;Ricaurte et al 2000;Semple et al 1999), although recovery in these markers may occur (Buchert et al 2004;De Win et al 2004) and the mediating mechanisms are still unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Several clinical studies report greater loss of serotonin terminal markers in women than in men (Buchert et al 2004;De Win et al 2004;McCann et al 1994). These differences in humans could reflect the average greater dose women ingest due to the fixed dose that most human users receive rather than a specific vulnerability to serotonin depletion in women.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, men experience greater increases in blood pressure (Liechti et al 2001). Sex differences in the persevering effects of MDMA are more poorly understood, although greater reductions in the density of 5-HT transporters and the levels of 5-HIAA in women have been reported (Buchert et al 2004;De Win et al 2004;McCann et al 1994). Although these reports suggest that the effects of MDMA are not equivalent in men and women, a number of factors affect this conclusion.…”

mentioning

confidence: 98%

“…This second phase is characterized by decreases in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), tryptophan hydroxylase activity, and the density of 5-HT reuptake sites (see review by Lyles and Cadet 2003). Although the patterns of exposure are quite different in rodent exposure models and typical human use and mediating mechanisms might be different, similar MDMAinduced decrements in 5-HT systems are reported in heavy MDMA users, including decreased concentrations of 5-HT and 5-HIAA in cerebrospinal fluid (McCann et al 1994) and a decrease in the number of 5-HT transporter binding (Buchert et al 2004;De Win et al 2004;Ricaurte et al 2000;Semple et al 1999).…”

mentioning

confidence: 99%

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Sex differences in the neurochemical and functional effects of MDMA in Sprague–Dawley rats

et al. 2006

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Rationale 3,4-Methylenedioxymethamphetamine (MDMA; "Ecstasy") use has been associated with acute toxicities and persistent depletion of the neurotransmitter serotonin (5-HT). Objectives This study investigates whether sex differences in the acute and long-term effects of MDMA exist. Methods Male and female rats received saline or 15 mg/kg MDMA, ip, bid for 4 days. Temperature was monitored on days 1 and 4. Locomotor activity was measured in a second cohort of animals on days 1 and 4 and after recovery on day 14. The effects of MDMA on performance in a plus maze task and brain levels of serotonin (5-HT) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in a third cohort of animals 2 weeks after the last MDMA treatment. Results Locomotor activity and temperature increased after MDMA administration on day 1. The drug-induced increases in temperature but not locomotion attenuated with repeated MDMA administration. Male and female MDMA-treated rats spent less time in the open arms of the elevated plus maze and had less 5-HT and 5-HIAA in all brain regions 2 weeks after the end of treatment. Temperature effects of MDMA and persistent effects on plus maze and brain serotonin content were similar in males and females. In contrast, females exhibited markedly greater locomotor stimulation after acute MDMA and also showed sensitization to an acute challenge 2 weeks later. Conclusions MDMA elicits substantially greater locomotor activation in female rats than in males, but persistent effects on anxiety and serotonin content were similar in males and females.

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Evidence for Chronically Altered Serotonin Function in the Cerebral Cortex of Female 3,4-Methylenedioxymethamphetamine Polydrug Users

Iorio

Watkins²,

Dietrich³

et al. 2012

Arch Gen Psychiatry

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Context MDMA (ecstasy) is a popular recreational drug that produces loss of serotonin (5-HT) axons in animal models. Whether MDMA produces chronic reductions in 5-HT signaling in humans remains controversial. Objective To determine if MDMA use is associated with chronic reductions in serotonin signaling in female human cerebral cortex as reflected by increased 5-HT2A receptors. Design Cross sectional case-control study comparing 5-HT2A receptor levels in abstinent female MDMA polydrug users to MDMA-naive females; within-group design assessing the association of lifetime MDMA use and 5-HT2A receptors. Subjects had at least 90 days abstinence from MDMA use as verified by hair sampling. Cortical 5-HT2A receptor levels were assayed with the 5HT2A-specific Positron Emission Tomography (PET) radioligand [18F]setoperone. Setting Academic Medical Center Research Laboratory. Participants Volunteer female MDMA users (N=14) and MDMA-naive controls (N=10). Main exclusion criteria were non-drug-related DSM-IV axis I psychiatric disorders and general medical illness. Main Outcome Measure Cortical 5-HT2A receptor non-displaceable binding potential (5-HT2ABPND). Results MDMA users had increased 5-HT2ABPND in occipital-parietal (19.7%), temporal (20.5%), occipito-temporal-parietal (18.3%), frontal (16.6%), and fronto-parietal (18.5%) regions (p<0.05; corrected). Lifetime MDMA use associated positively with 5-HT2ABPND in fronto-parietal (β=0.665;p=0.007), occipito-temporal (β=0.798;p=0.002), fronto-limbic (β=0.634;p=0.024), and frontal (β=0.691;p=0.008) regions. In contrast, there were no regions in which MDMA use was inversely associated with receptor levels. There were no statistically significant effects of the duration of MDMA abstinence on 5-HT2ABPND. Conclusions Human recreational MDMA use is associated with long-lasting increases in 5-HT2A receptor density. 5-HT2A receptor levels correlate positively with lifetime MDMA use and do not decrease with abstinence. These results suggest that MDMA produces chronic 5-HT neurotoxicity in humans. Given the broad role of 5-HT in human brain function, the possibility for therapeutic MDMA use, and the widespread recreational popularity of this drug, these results have critical public health implications.

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A Voxel-Based PET Investigation of the Long-Term Effects of “Ecstasy” Consumption on Brain Serotonin Transporters

Cited by 165 publications

References 24 publications

Prospective memory deficits in illicit polydrug users are associated with the average long-term typical dose of ecstasy typically consumed in a single session.

Prospective memory deficits in illicit polydrug users are associated with the average long-term typical dose of ecstasy typically consumed in a single session.

Sex differences in the neurochemical and functional effects of MDMA in Sprague–Dawley rats

Evidence for Chronically Altered Serotonin Function in the Cerebral Cortex of Female 3,4-Methylenedioxymethamphetamine Polydrug Users

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