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Memory function loss
Prospective memory, everyday cognitive failure and
central executive function in recreational users of
Heffernan TM, Jarvis H, Rodgers J, Scholey AB, Ling J.
Human Cognitive Neuroscience Unit, University of Northumbria,
Newcastle upon Tyne NE1 8ST, UK.
Chronic use of MDMA (3,4-methylenedioxymethamphetamine),
or Ecstasy, is believed to lead to impaired psychological
performance, including well-documented decrements in laboratory
and field tests of retrospective memory. Less is known about the
impact of Ecstasy on aspects of 'everyday' memory, despite
obvious concerns about such effects. The three studies reported
here focused on the impact of chronic Ecstasy use on prospective
memory (PM), associated central executive function and other
aspects of day-to-day cognition. In study 1 46 regular Ecstasy
users were compared with 46 Ecstasy-free controls using the
Prospective Memory Questionnaire (PMQ). Ecstasy users reported
significantly more errors in PM (remembering to do something in
the future); these findings persisted after controlling for other drug
use and the number of strategies used to aid memory. No
difference was found between representative subgroups on the Lies
Scale of the Eysenck Personality Questionnaire. In study 2 a
different group of 30 regular Ecstasy users and 37 Ecstasy-free
controls was assessed on the PMQ and on a central executive task
comprising verbal fluency measures. The results confirmed the
significant impairments in long- and short-term PM and revealed
corresponding impairments in verbal fluency. In study 3 15
Ecstasy users, 15 cannabis users and 15 non-drug users were
assessed using the Cognitive Failures Questionnaire, which
requires participants to provide ratings of the frequency of various
day-to-day cognitive slips. The results indicate that the Ecstasy
users did not perceive their general cognitive performance to be
worse than that of controls. Taken together, these results suggest
that Ecstasy users have impaired PM that cannot be explained by
an increased propensity to exaggerate cognitive failures. These
may be attributable, in part, to central executive deficits that are
due to frontal lobe damage associated with Ecstasy use. Copyright
2001 John Wiley & Sons, Ltd.
: Biochim Biophys Acta 2002 Oct 9;1588(1):26-32
Articles, Links
3,4-Methylenedioxymethamphetamine ("Ecstasy")
induces apoptosis of cultured rat liver cells.
Montiel-Duarte C, Varela-Rey M, Oses-Prieto JA, LopezZabalza MJ, Beitia G, Cenarruzabeitia E, Iraburu MJ.
Department of Biochemistry, University of Navarra, Navarra,
Pamplona, Spain.
"Ecstasy" (3,4-methylenedioxymethamphetamine, MDMA) has
been shown to be hepatotoxic for human users, but molecular
mechanisms involved in this effect remained poorly understood.
MDMA-induced cell damage is related to programmed cell death
in serotonergic and dopaminergic neurons. However, until now
there has been no evidence of apoptosis induced by MDMA in
liver cells. Here we demonstrate that exposure to MDMA caused
apoptosis of freshly isolated rat hepatocytes and of a cell line of
hepatic stellate cells (HSC), as shown by chromatin condensation
of the nuclei and accumulation of oligonucleosomal fragments in
the cytoplasm. In both cell types, apoptosis correlated with
decreased levels of bcl-x(L), release of cytochrome c from the
mitochondria and activation of caspase 3. In HSC, but not in
hepatocytes, MDMA induced poly(ADP-ribose)polymerase
(PARP) proteolysis. These results suggest that apoptosis of liver
cells could be involved in the hepatotoxicity of MDMA.
Hum Psychopharmacol 2001 Dec;16(8):557-577
Related Articles,
Human psychopharmacology of Ecstasy (MDMA): a
review of 15 years of empirical research.
Parrott AC.
Department of Psychology, University of East London, UK.
MDMA (3,4-methylenedioxymethamphetamine) or 'Ecstasy' was
scheduled as an illegal drug in 1986, but since then its recreational
use has increased dramatically. This review covers 15 years of
research into patterns of use, its acute psychological and
physiological effects, and the long-term consequences of repeated
use. MDMA is an indirect monoaminergic agonist, stimulating the
release and inhibiting the reuptake of serotonin (5-HT) and, to a
lesser extent, other neurotransmitters. Single doses of MDMA have
been administered to human volunteers in double-blind placebocontrolled trials, although most findings are based upon
recreational MDMA users. The 'massive' boost in neurotransmitter
activity can generate intense feelings of elation and pleasure, also
hyperactivity and hyperthermia. This psychophysiological arousal
may be exacerbated by high ambient temperatures, overcrowding,
prolonged dancing and other stimulant drugs. Occasionally the
'serotonin syndrome' reactions may prove fatal. In the days after
Ecstasy use, around 80% of users report rebound depression and
lethargy, due probably to monoaminergic depletion. Dosage
escalation and chronic pharmacodynamic tolerance typically occur
in regular users. Repeated doses of MDMA cause serotonergic
neurotoxicity in laboratory animals, and there is extensive
evidence for long-term neuropsychopharmacological damage in
humans. Abstinent regular Ecstasy users often display reduced
levels of 5-HT, 5-HIAA, tryptophan hydroxylase and serotonin
transporter density; functional deficits in learning/memory, higher
cognitive processing, sleep, appetite and psychiatric well-being,
and, most paradoxically, 'loss of sexual interest/pleasure'. These
psychobiological deficits are greatest in heavy Ecstasy users and
may reflect serotonergic axonal loss in the higher brain regions,
especially the frontal lobes, temporal lobes and hippocampus.
These problems seem to remain long after the recreational use of
Ecstasy has ceased, suggesting that the neuropharmacological
damage may be permament. Copyright 2001 John Wiley & Sons,
FASEB J 1997 Feb;11(2):141-6 Related Articles, Links
The abused drug MDMA (Ecstasy) induces
programmed death of human serotonergic cells.
Simantov R, Tauber M.
Department of Molecular Genetics, Weizmann Institute of Science,
Rehovot, Israel.
The widely abused amphetamine analog 3,4methylenedioxymethamphetamine (MDMA, also called "ecstasy")
induces hallucination and psychostimulation, as well as long-term
neuropsychiatric behaviors such as panic and psychosis. In rodents
and monkeys, MDMA is cytotoxic to serotonergic neurons, but
this is less clear with humans. Herein, MDMA was cytotoxic to
human serotonergic JAR cells; it altered the cell cycle, increased
G2/M phase arrest, and induced DNA fragmentation in a
cycloheximide-sensitive way. This apoptosis was not observed in
nonserotonergic human NMB cells. The stereospecific effect of
amphetamines in JAR cells, and the key role of NO and dopamine
in MDMA-induced apoptosis were determined. The relevancy of
MDMA-induced cell death to drug users is discussed.
1: Synapse 2002 Dec;46(3):199-205
Related Articles, Links
Validity of [123I]beta-CIT SPECT in detecting MDMAinduced serotonergic neurotoxicity.
Reneman L, Booij J, Habraken JB, De Bruin K,
Hatzidimitriou G, Den Heeten GJ, Ricaurte GA.
Department of Nuclear Medicine, Academic Medical Center, 1105
AZ Amsterdam, The Netherlands.
Recent [(123)I]beta-CIT single-photon emission computed
tomography (SPECT) studies revealed decreased serotonin
transporters (SERT) density in the brain of humans with a history
of MDMA ("Ecstasy") use. However, [(123)I]beta-CIT SPECT has
until now not been validated as a method for detecting such
serotonergic lesions. Therefore, the present study was undertaken.
Following baseline [(123)I]beta-CIT SPECT scans, a rhesus
monkey was treated with MDMA (5 mg/kg, s.c. twice daily for 4
consecutive days). SPECT studies 4, 10, and 31 days after MDMA
treatment revealed decreases in [(123)I]beta-CIT binding ratios in
the SERT-rich brain region studied (hypothalamic/midbrain
region), with SERT density reduced by 39% in this brain region 31
days after treatment. Data obtained with SPECT studies correlated
well with SERT density determined with autoradiography after
sacrifice of the animal (-34%). In addition, ex vivo [(123)I]betaCIT binding studies in rats 1 week after treatment with neurotoxic
doses of MDMA (20 mg/kg s.c. twice daily for 4 consecutive days)
revealed significant reductions in [(123)I]beta-CIT binding in
SERT-rich regions (including the hypothalamus) when compared
to saline-treated rats. The combined results of these studies
indicate that SPECT imaging of SERT with [(123)I]beta-CIT can
detect changes in SERT density secondary to MDMA-induced
neurotoxicity in the hypothalamic/midbrain region, and possibly
other brain
Severe Dopaminergic Neurotoxicity in Primates After
a Common Recreational Dose Regimen of MDMA
George A. Ricaurte,1* Jie Yuan,1 George Hatzidimitriou,1
Branden J. Cord,2 Una D. McCann3
The prevailing view is that the popular recreational drug
(±)3,4-methylenedioxymethamphetamine (MDMA, or "ecstasy")
is a selective serotonin
neurotoxin in animals and possibly in humans. Nonhuman
primates exposed to several
sequential doses of MDMA, a regimen modeled after one used by
humans, developed
severe brain dopaminergic neurotoxicity, in addition to less
pronounced serotonergic
neurotoxicity. MDMA neurotoxicity was associated with
increased vulnerability to motor
dysfunction secondary to dopamine depletion. These results have
implications for
mechanisms of MDMA neurotoxicity and suggest that
recreational MDMA users may
unwittingly be putting themselves at risk, either as young adults
or later in life, for
developing neuropsychiatric disorders related to brain dopamine
and/or serotonin
1: Proc Natl Acad Sci U S A 1992 Mar 1;89(5):1817-21Related
Articles, Links
The molecular mechanism of "ecstasy" [3,4methylenedioxy-methamphetamine (MDMA)]:
serotonin transporters are targets for MDMA-induced
serotonin release.
Rudnick G, Wall SC.
Department of Pharmacology, Yale University School of
Medicine, New Haven, CT 06510.
MDMA ("ecstasy") has been widely reported as a drug of abuse
and as a neurotoxin. This report describes the mechanism of
MDMA action at serotonin transporters from plasma membranes
and secretory vesicles. MDMA stimulates serotonin efflux from
both types of membrane vesicle. In plasma membrane vesicles
isolated from human platelets, MDMA inhibits serotonin transport
and [3H]imipramine binding by direct interaction with the Na(+)dependent serotonin transporter. MDMA stimulates radiolabel
efflux from plasma membrane vesicles preloaded with
[3H]serotonin in a stereo-specific, Na(+)-dependent, and
imipramine-sensitive manner characteristic of transporter-mediated
exchange. In membrane vesicles isolated from bovine adrenal
chromaffin granules, which contain the vesicular biogenic amine
transporter, MDMA inhibits ATP-dependent [3H]serotonin
accumulation and stimulates efflux of previously accumulated
[3H]serotonin. Stimulation of vesicular [3H]serotonin efflux is due
to dissipation of the transmembrane pH difference generated by
ATP hydrolysis and to direct interaction with the vesicular amine