Neurotoxic Effects of MDMA (Ecstasy) on the Developing Rodent Brain

Dzietko, Mark; Sifringer, Marco; Klaus, Judith A.; Endesfelder, Stefanie; Brait, Daniela; Hansen, Henrik H.; Bendix, Ivo; Felderhoff‐Mueser, Ursula

doi:10.1159/000313473

Cited by 8 publications

(8 citation statements)

References 106 publications

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“…As such, the reductions of cortical rMRGlu in MDMA users might as well be explained by loss of neuronal connections and projections and thus be interpreted as a direct neurotoxic effect of the drug, as they were shown in many pervious animal studies [13], [63]. Interestingly, the thalamic hypometabolism of MDMA users shown here occurred in anatomical areas that are well connected to frontocortical regions presenting also hypometabolism [58].…”

Section: Discussionsupporting

confidence: 62%

Verbal Memory Deficits Are Correlated with Prefrontal Hypometabolism in 18FDG PET of Recreational MDMA Users

et al. 2013

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Introduction3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a recreational club drug with supposed neurotoxic effects selectively on the serotonin system. MDMA users consistently exhibit memory dysfunction but there is an ongoing debate if these deficits are induced mainly by alterations in the prefrontal or mediotemporal cortex, especially the hippocampus. Thus, we investigated the relation of verbal memory deficits with alterations of regional cerebral brain glucose metabolism (rMRGlu) in recreational MDMA users.MethodsBrain glucose metabolism in rest was assessed using 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography (18FDG PET) in 19 male recreational users of MDMA and 19 male drug-naïve controls. 18FDG PET data were correlated with memory performance assessed with a German version of the Rey Auditory Verbal Learning Test.ResultsAs previously shown, MDMA users showed significant impairment in verbal declarative memory performance. PET scans revealed significantly decreased rMRGlu in the bilateral dorsolateral prefrontal and inferior parietal cortex, bilateral thalamus, right hippocampus, right precuneus, right cerebellum, and pons (at the level of raphe nuclei) of MDMA users. Among MDMA users, learning and recall were positively correlated with rMRGlu predominantly in bilateral frontal and parietal brain regions, while recognition was additionally related to rMRGlu in the right mediotemporal and bihemispheric lateral temporal cortex. Moreover, cumulative lifetime dose of MDMA was negatively correlated with rMRGlu in the left dorsolateral and bilateral orbital and medial PFC, left inferior parietal and right lateral temporal cortex.ConclusionsVerbal learning and recall deficits of recreational MDMA users are correlated with glucose hypometabolism in prefrontal and parietal cortex, while word recognition was additionally correlated with mediotemporal hypometabolism. We conclude that memory deficits of MDMA users arise from combined fronto-parieto-mediotemporal dysfunction.

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Section: Discussionsupporting

confidence: 62%

Verbal Memory Deficits Are Correlated with Prefrontal Hypometabolism in 18FDG PET of Recreational MDMA Users

et al. 2013

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“…MDMA treatment prenatally of pregnant rats led to reduced bodyweight and reduced learning of motor skills in adulthood (Adori C et al, 2010), and growth retardation and poorer motor skills in BALB/C mice pups. MDMA exposure in 6 day old rat pups also facilitated neuronal death in cortical, thalamic, and hypothalamic brain regions (Dzietko M et al, 2010), as had been shown previously by Meyer (Meyer JS, Grande M, Johnson K, & Ali SF, 2004). …”

Section: Introductionsupporting

confidence: 70%

Motor delays in MDMA (ecstasy) exposed infants persist to 2years

Singer

Moore

Min

et al. 2016

Neurotoxicology and Teratology

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Background Recreational use of 3,4 methylenedioxymethamphetamine (Ecstasy, MDMA) is increasing worldwide. Its use by pregnant women causes concern due to potentially harmful effects on the developing fetus. MDMA, an indirect monoaminergic agonist and reuptake inhibitor, affects the serotonin and dopamine systems. Preclinical studies of fetal exposure demonstrate effects on learning, motor behavior, and memory. In the first human studies, we found prenatal MDMA exposure related to poorer motor development in the first year of life. In the present study we assessed the effects of prenatal exposure to MDMA on the trajectory of child development through 2 years of age. We hypothesized that exposure would be associated with poorer mental and motor outcomes. Materials and Methods The DAISY (Drugs and Infancy Study, 2003–2008) employed a prospective longitudinal cohort design to assess recreational drug use during pregnancy and child outcomes in the United Kingdom. Examiners masked to drug exposures followed infants from birth to 4, 12, 18, and 24 months of age. MDMA, cocaine, alcohol, tobacco, cannabis, and other drugs were quantified through a standardized clinical interview. The Bayley Scales (III) of Mental (MDI) and Motor (PDI) Development and the Behavior Rating Scales (BRS) were primary outcome measures. Statistical analyses included a repeated measures mixed model approach controlling for multiple confounders. Results Participants were pregnant women volunteers, primarily white, of middle class socioeconomic status, average IQ, with some college education, in stable partner relationships. Of 96 women enrolled, children of 93 had at least one follow-up assessment and 81 (87%) had two assessments. Heavier MDMA exposure, (M = 1.3 ± 1.4 tablets per week) predicted lower PDI (p < .002), and poorer BRS motor quality from 4 to 24 months of age, but did not affect MDI, orientation, or emotional regulation. Children with heavier exposure were twice as likely to demonstrate poorer motor quality as lighter and non-exposed children (O.R. = 2.2, 95%, CI = 1.02–4.70, p < .05). Discussion Infants whose mothers reported heavier MDMA use during pregnancy had motor delays from 4 months to two years of age that were not attributable to other drug or lifestyle factors. Women of child bearing age should be cautioned about the use of MDMA and MDMA-exposed infants should be screened for motor delays and possible intervention.

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“…In particular, they observed an increased cell degeneration determined by stereological cell counts in many of the 17 brain regions analyzed, specially in the frontal, parietal and cingulate cortices, the septum, thalamus, hypothalamus and the cornu ammonis 1 region of the hippocampus. However, this effect was observed 24h after the exposure but not after or days (Dzietko et al, 2010). The other two studies with long gestational and postnatal exposure to MDMA evaluated different parameters of physical, functional and neuromotor maturation.…”

Section: Resultsmentioning

confidence: 96%

“…A common limitation of these rat in vivo studies is the low number of dose-response studies that investigate more than two doses. Only five papers include three dose groups of MDMA plus the control to support the evaluation of dose-response relationships (Barenys et al, 2010;Broening et al, 2001Broening et al, , 1994Dzietko et al, 2010;Vorhees et al, 2009Vorhees et al, , 2004. However, due to the overall low number of publications on the topic, single or two dose group studies were also considered in this review.…”

Section: Resultsmentioning

confidence: 99%

“…Out of the 30 studies in rats only 4 evaluated the effects of postnatal MDMA exposure on growth factor signaling (Dzietko et al, 2010;Koprich et al, 2003a;Piper et al, 2009;Schaefer et al, 2012). Growth factors studied were nerve growth factor (NGF), neurotrophin-3 (NT-3), and brain-derived neurotrophic factor (BDNF; see Table 6).…”

Section: Effects On Growth Factorsmentioning

confidence: 99%

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Developmental neurotoxicity of MDMA. A systematic literature review summarized in a putative adverse outcome pathway

et al. 2020

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The increasing use of illegal drugs by pregnant women causes a public health concern because it is associated with health risks for mothers and their developing children. One of such drugs is MDMA (3,4-methylenedioxymethamphetamine) or ecstasy due to its high consumption in relevant age and sex groups and its adverse effects on human and rodent developing brains. To thoroughly review the current knowledge on the developmentally neurotoxic potential of MDMA we systematically collected and summarized articles investigating developmental neurotoxicity (DNT) of MDMA in humans and animals in in vivo and in vitro. In addition, we summarized the findings in a putative adverse outcome pathway (AOP). From an initial 299 articles retrieved from the bibliographic databases Web of Science, PubMed and DART, we selected 39 articles according to inclusion/exclusion criteria for data collection after title/abstract and full text screening. Of these 3 where epidemiological studies, 34 where in vivo studies in mice and rats and 2 were in vitro studies. The three epidemiological studies reported from the same longitudinal study and suggested that MDMA exposure during pregnancy impairs neuromotor function in infants. In rat, postnatal exposure towards MDMA also caused locomotor deficits as well as impaired spatial learning that might be associated with decreased serotonin levels in the hippocampus. In vitro MDMA caused cytotoxicity at high concentrations and effects on the serotonergic and neuritogenic alterations at lower concentrations which are in line with some of the in vivo alterations observed. Considering the adverse outcomes of developmental MDMA described in humans and in rodents we summarized the first putative AOP on developmental compound exposure leading to impaired neuromotor function in children. For generation of this AOP, MDMA exposure was taken as a model compound. In addition, we hypothesized a second AOP involving developmental disturbance of the dopaminergic system. However, further in vitro mechanistic studies are needed to understand the molecular initiating event(s) (MIE) triggering the downstream cascades and obtain consistent evidences causally linking the adverse outcome to effects at the cellular, organ and organism level.

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Neurotoxic Effects of MDMA (Ecstasy) on the Developing Rodent Brain

Cited by 8 publications

References 106 publications

Verbal Memory Deficits Are Correlated with Prefrontal Hypometabolism in 18FDG PET of Recreational MDMA Users

Verbal Memory Deficits Are Correlated with Prefrontal Hypometabolism in 18FDG PET of Recreational MDMA Users

Motor delays in MDMA (ecstasy) exposed infants persist to 2years

Developmental neurotoxicity of MDMA. A systematic literature review summarized in a putative adverse outcome pathway

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