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Neurological and Psychopathological Sequelae Associated With a Lifetime Intake of 40,000 Ecstasy Tablets

Authors:
Letters
86 http://psy.psychiatryonline.org Psychosomatics 47:1, January-February 2006
Neurological and
Psychopathological Sequelae
Associated With a Lifetime
Intake of 40,000 Ecstasy
Tablets
T
O THE
E
DITOR
: The medical and psy-
chopathological consequences of both
acute and chronic “ecstasy” (MDMA,
MDA, and derivatives) consumption
have been extensively described, but
little is known with respect to the re-
lationship between both severity and
persistence of these disturbances and
lifetime number of ecstasy tablets in-
gested. At-risk MDMA intake seems to
be related to long-term functional dys-
regulation in 5-HT
2
pathways, result-
ing in altered regulation of mood, im-
pulse control, and memory.
1,2
Ecstasy
consumption has spread since the late
‘80s, and the reduction in price ob-
served over the last few years has pos-
sibly increased access to the drug. Cli-
nicians are now meeting with a
generation of patients who have been
exposed to the drug for more than a de-
cade. In this report, we describe both
the transient and persisting sequelae as-
sociated with an unusual amount of ec-
stasy consumption.
Case Report
Mr. A, 37 years old, used ecstasy be-
tween the ages of 21 and 30. For the
first 2 years, he took 5 tablets every
weekend, escalating to an average daily
use of 3.5 tablets for the next 3 years,
and further escalation to an average of
25 tablets daily over the next 4 years.
An estimate of lifetime consumption
yielded a total intake of more than
40,000 tablets. At the time of his pre-
sentation, Mr. A reported current can-
nabis consumption, together with a pre-
vious history of polydrug misuse (i.e.,
solvents, benzodiazepines, ampheta-
mines, LSD, cocaine, heroin). After
three episodes of “collapsing” at par-
ties, Mr. A finally stopped his ecstasy
use. For a few months, he felt as if he
was still under the influence of ecstasy
and suffered several episodes of “tun-
nel vision.” He eventually developed
severe panic attacks, recurrent anxiety,
depression, muscle rigidity (particu-
larly at the neck and jaw levels), func-
tional hallucinations, and paranoid ide-
ation. His family and before-drug-use
psychiatric history were negative. The
Mini-Mental State Exam revealed dis-
orientation to time, poor concentration,
and short-term memory difficulties.
Decrease in level of cannabis intake led
both to disappearance of his paranoid
ideas and hallucinations and reduction
of his panic attacks, but remaining
symptomatology persisted. Adminis-
tration of the Wechsler Memory Scale
(3rd Edition)
3
suggested the existence
of global memory-function impair-
ment, with no subtest score being
above the 10th percentile. Assessment
of daily functioning skills identified
major behavioral consequences of his
memory loss (i.e., repeating activities
several times). Although Mr. A was
able to fully understand the instructions
given, his concentration and attention
were so impaired that he was unable to
follow the sequence of the tasks re-
quired. A structural MRI brain scan re-
vealed no focal cerebral lesions; spe-
cifically, both temporal lobes showed
normal symmetrical hippocampal ar-
eas. The structural areas of the “Dealy-
Brion” system were normal. There was
no evidence to suggest atrophy. Mr. A
was then prescribed olanzapine 10 mg
and admitted to a brain-injury unit,
where there was some improvement of
his memory skills as a result of the use
of compensatory strategies.
Comment
To our knowledge, this is the largest
amount of ecstasy lifetime consump-
tion ever described, the heaviest life-
time intake previously reported being
around 2,000 tablets.
2
Although much
information is self-reported and might
have been affected by Mr. A’s memory
impairment, the history given was con-
firmed by notes from another service he
attended just after having stopped ec-
stasy use.
All ecstasy misusers would de-
velop a (mild-degree, in most cases) se-
rotonin syndrome after acute drug in-
take, which is characterized by
enhanced physical activity, hyperther-
mia and sweating, increased muscle ri-
gidity, rhabdomyolysis, hyperreflexia,
trismus, jaw-clenching, myoclonus,
tremor, and nystagmus.
4
An additional,
non-serotonergic mechanism of
MDMA activity at the neuromuscular
junction-level has recently been sug-
gested.
5
Although these observations
relate to acute MDMA intoxication ef-
fects, they might partly explain the per-
sistent muscle rigidity of which Mr. A
was complaining. The “tunnel vision”
effect observed by Mr. A in the first few
months after withdrawing from
MDMA had never been reported before
in this context. The neurocognitive pro-
file here described was very similar to
that shown by current heavy ecstasy
users; it has been suggested that the ex-
tent of memory decline positively cor-
relates with intensity or frequency of
ecstasy consumption.
6
It is also con-
firmed here that selective impairments
of neuropsychological performance as-
sociated with regular ecstasy use are
not reversed by prolonged abstinence.
Letters
Psychosomatics 47:1, January-February 2006 87
Contrary to results of other neuroim-
aging observations,
7
Mr. As brain scan
did not show any gross cerebral abnor-
malities, especially at the hippocampal
level.
We feel that this case report adds
to the existing limited knowledge of
persistent sequelae associated with
heavy and regular ecstasy intake.
Mr. A gave consent to his history
being reported to a medical journal.
Christos Kouimtsidis
Fabrizio Schifano,
University of London, UK
Tim Sharp, Watford, UK
Lisa Ford
Justin Robinson
Colm Magee, Slippers Hill, UK
References
1. Green AR, Cross AJ, Goodwin GM:
Review of the pharmacology and clinical
pharmacology of 3,4-
methylenedioxymethamphetamine
(MDMA or “ecstasy”). Psychopharmacol
(Berl) 1995; 119:247–260
2. Schifano F, Di Furia L, Forza G, et al:
MDMA (“ecstasy”) consumption in the
context of poly-drug abuse: a report on
150 patients. Drug Alcohol Depend
1998; 52:85–90
3. Wechsler D (ed): Wechsler Memory
Scale; 3rd Edition. London, UK, The
Psychological Corporation, Harcourt
Brace Jovanovich and Company, 1997
4. Schifano F: A bitter pill? overview of
ecstasy (MDMA; MDA)-related fatalities.
Psychopharmacol (Berl) 2004; 173:242–
248
5. Sparks GM, Dasari S, Cooper RL:
Actions of MDMA at glutamatergic
neuromuscular junctions. Neurosci Res
2004; 48:431–438
6. Zakzanis KK, Young DA: Memory
impairment in abstinent MDMA
(“ecstasy”) users: a longitudinal
investigation. Neurology 2001; 56:966–
999
7. Cowan RL, Lyoo IK, Sung SM, et al:
Reduced cortical gray-matter density in
human MDMA (ecstasy) users: a voxel-
based morphometry study. Drug Alcohol
Depend 2003; 72:225–235
Parental Magico-Religious
Illness Beliefs in an
Adolescent Girl With Major
Depression and Systemic
Lupus Erythematosus
T
O THE
E
DITOR
: We report the case of
a 15-year-old girl with major depres-
sion, which occurred in the course of
systemic lupus erythematosus (SLE).
We choose here to describe how the un-
derstanding of her parents’ illness be-
liefs has been of therapeutic support in
the psychiatric follow-up. Actually,
many aspects of psychiatry, as diag-
nosis, illness behavior, help-seeking,
and perceived quality of care, are af-
fected by illness beliefs.
1
This is why
medical anthropology and transcultural
psychiatry encourage understanding of
patients’ own illness experiences.
1,2
Case Report
Ms. A was born in France, near Paris.
She lived with her parents who were
Muslim and came from Algeria, having
left 20 years ago. She had two older
brothers. A younger sister died at the
age of 3 months from a cardiac mal-
formation when Ms. A was 8 years old.
Her oldest brother has had non-Hodg-
kin’s lymphoma, in remission for 3
years. Her SLE was diagnosed 2 years
ago, but began at the age of 10 with a
malar rash and arthritis. The treatment,
with a favorable outcome, consisted of
hydroxychloroquine and prednisone,
10 mg/day.
When she was referred to consul-
tation–liaison psychiatry, Ms. A was
troubled by feelings of sadness, insom-
nia, and worthlessness, without sui-
cidal intent. These symptoms of major
depression (by DSM–IV) had appeared
several weeks earlier. There was no
evidence of SLE activity or neurolog-
ical symptoms. Ms. A had no history
of psychiatric disorders. The outpatient
psychiatric follow-up, with a favorable
outcome, lasted for 11
2
years and in-
cluded individual psychotherapy and
psychiatric consultation with her fam-
ily in our transcultural psychiatric
clinic.
3
Her parents had cultural explana-
tions that coexisted with biomedical
meanings. Ms. A and her parents had
been invited to a wedding in Algeria
when she was 14. According to them,
the malar rash might be interpreted as
make-up by the bride’s parents. Ms. A
might be perceived as a possible rival
to the bride, and someone could have
thrown the evil eye on Ms. A and her
family in order to neutralize her and
protect the bride. Another cultural ex-
planation was sorcery. Her mother had
asked herself whether the spirit of Ms.
A’s younger sister, who had died of car-
diac malformation, could be in Ms. A’s
body. Despite these magico-religious
beliefs, no traditional help-seeking ex-
periences were described. Ms. A dis-
agreed with her parents’ representa-
tions, but she was sensitive to the
possible role of her sister’s death.
Discussion
This case illustrates how, in consulta-
tion–liaison psychiatry, it is essential to
understand patients’ own illness expe-
rience, especially in immigrants or in
immigrants’ children.
3
The most ap-
parent symptom of the disease, the ma-
lar rash, supported the construction of
one of the parental explanations, the
evil eye. Taking into account those
ideas and the family conflicts around
the important position of Ms. A in the
series of family misfortunes (the
younger sister’s death, the brother’s
lymphoma, and the SLE) was a major
issue for psychiatric treatment and was
accompanied by progressively more
flexibility and a wider range of parental
beliefs. The transcultural setting, a
... The ANOVA confirmed a main effect of block (F 2,42 = 37.24; p<0.0001), time within the session (F 6,126 = 86.46; p<0.0001) and the interaction of [17][18][19][20][21][22][23][24][25][26][27] and the 1 st saline substitution (session 16) grouped by the ambient temperature (Hot = 30° C, Cold = 20° C) under which self-administration occurred. Significant differences between group is indicated by *, differences from first session (except saline) by % and between the saline substitution and the average of the prior and subsequent sessions by #. ...
Preprint
Rationale MDMA alters body temperature in rats with a direction that depends on the ambient temperature (T A ). The thermoregulatory effects of MDMA and T A may affect intravenous self-administration (IVSA) of MDMA but limited prior reports conflict. Objective To determine how body temperature responses under high and low T A influence MDMA IVSA. Methods Male Sprague-Dawley rats were trained to IVSA MDMA (1.0 mg/kg/infusion; 2-hr sessions; FR5 schedule of reinforcement) under T A 20°C or 30°C. Radiotelemetry transmitters recorded body temperature and activity during IVSA. Results MDMA intake increased under both T A during acquisition, but to a greater extent in the 30°C group. The magnitude of hypothermia was initially equivalent between groups but diminished over training in the 30°C group. Within-session activity was initially lower in the 30° C group, but by the end of acquisition and maintenance, activity was similar for both groups. When T A conditions were swapped, the hot-trained group increased MDMA IVSA under 20 °C T A and a modest decrease in drug intake was observed in the cold-trained group under 30 °C T A . Subsequent non-contingent MDMA (1.0-5.0 mg/kg, i.v.) found that rats with higher MDMA IVSA rates showed blunted hypothermia compared with rats with lower IVSA levels; however, within-session activity did not differ by group. High T A increased intracranial self-stimulation thresholds in a different group of rats and MDMA reduced thresholds below baseline at low, but not high, T A . Conclusions High T A appears to enhance acquisition of MDMA IVSA through an aversive effect and not via thermoregulatory motivation.
... MDMA-induced cognitive impairment at a dose of 15 mg/kg. Using the interspecies scaling formula (Dose Human = Dose Animal (WT Human/WTAnimal) 0.7 ), this dose in a 225-g rat is equivalent to a dose of 188 mg in a 70 kg human (Mordenti and Chappell, 1989), which may actually be lower than the doses used by chronic abusers (Scholey et al., 2004;Kouimtsidis et al., 2006). Furthermore, it has been shown that administering 10-15 mg/kg to rats creates similar plasma concentrations of MDMA to those of a human who consumes a 150mg tablet (Green et al., 2003). ...
... These differences are critical to explore since prior experience with designer amphetamines such as MDMA and d-methamphetamine (MA) can reveal distinct constellations of potential health threats with respect to liability for acute behavioral effects, compulsive versus episodic use and lasting neurochemical toxicities (De La Garza et al., 2006;Fantegrossi et al., 2009;Kitamura et al., 2006;Ricaurte et al., 1988;Yuan et al., 2006). There are also case reports of Ecstasy/MDMA use patterns that are daily or at least several times per week (Hurault de Ligny et al., 2005;Jansen, 1999;Kouimtsidis et al., 2006), highly consistent with compulsive use patterns that are common to reference standard drugs of abuse such as methamphetamine Such differences may be important in the development of evidence-based public policy actions such as the preliminary action to add cathinones to the list of controlled substances within the United States (DEA, 2011b). ...
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To examine the neurotoxic potential of continued MDMA ("Ecstasy") use in humans and its functional consequences over the course of 1 year, 15 MDMA users participated in a longitudinal study in which they completed a brief neuropsychological test battery composed mainly of retrospective and prospective memory tasks. Subjects were abstinent for 2 weeks on initial and 1-year testing. Continued use of MDMA was associated with progressive decline in terms of immediate and delayed recall.
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The issue of ecstasy-related fatalities has extensively attracted the attention of both the media and the general public, but less so of the scientific literature. The aim of the present review is to focus on the epidemiological, clinical and pharmacological issues related to ecstasy fatalities. Possibly due to a number of different reasons, the rates of ecstasy-related deaths seem to have peaked in recent years. MDMA metabolism is regulated by the levels of CYP2D6 and COMT (both exhibit some genetic polymorphism), and range of activity of these enzymes may account for some inter-individual differences in terms of toxic responses to the drug. A small increase in MDMA dosage can lead to a significant rise in drug plasma concentration. Due to their tolerance to MDMA psychoactive effects, some individuals may binge with dosages that may be the cause of serious concern. In experienced users, a reverse tolerance phenomenon can also be observed. Together with ecstasy, most of the misusers take a number of different compounds and the possible rationale of this style of consumption is commented upon here. Frequently, the lethal complications observed after acute MDMA administration can be the consequence of the occurrence of a serotonin syndrome and/or of sympathomimetic overstimulation (both conditions are exacerbated by environmentally induced overheating). A number of methodological problems can contribute to making difficult the interpretation of the role played by ecstasy in so-called ecstasy-related deaths, especially so if accurate information is not available.
Article
3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") compels mammalian serotonergic neurons to release serotonin (5-HT). In this study, MDMA altered synaptic transmission presynaptically by enhancing quantal release in two model glutamatergic synapses-the neuromuscular junction (NMJ) of the crayfish opener muscle, which is enhanced by exogenous 5-HT application, and the NMJ of a larval body wall muscle in Drosophila melanogaster, which is insensitive to exogenous 5-HT application. At the crayfish NMJ, MDMA mimicked the actions of 5-HT but only at a substantially higher concentration. At the Drosophila NMJ, MDMA altered synaptic transmission but not through a 5-HT receptor. Using simple invertebrate preparations, we have demonstrated an additional non-serotonergic mechanism of MDMA activity that has not yet been addressed in vertebrate systems and that may play an important role in understanding the mechanism of action for a commonly abused drug.
Article
The popular recreational drug, 3,4-methylenedioxymethamphetamine (MDMA) exerts its actions in part via blockade of serotonin and dopamine reuptake. Many animal and human studies have demonstrated long-lasting reductions in measures of central nervous system (CNS) serotonin function following MDMA administration. One emerging role of serotonin function in the CNS is a positive trophic effect via stimulation of intracellular signaling pathways and trophic factors. We hypothesized that human MDMA users might display neocortical gray matter reductions due to loss of serotonergically mediated trophic effects on cortical cells. However, unlike animal models, most human MDMA users worldwide are polydrug users, thereby complicating the assessment of MDMA toxicity in this group. Structural magnetic resonance imaging (MRI) scans of 31 MDMA polydrug users versus 29 non-MDMA users were compared using voxel-based morphometry (VBM) to assess regional brain gray and white matter concentration. VBM employs gray/white matter segmentation and statistical parametric mapping (SPM) analysis to calculate a voxel-wise comparison of regional gray or white matter concentration. Using this method, we consistently found several brain regions having decreased gray matter concentration in MDMA polydrug users. These regions were localized to neocortex in bilateral Brodmann area (BA) 18, left BA 21, and left BA 45, as well as bilateral cerebellum, and midline brainstem. Overall, these preliminary findings suggest that MDMA polydrug users have multiple regions of gray matter reduction, potentially accounting for previously reported neuropsychiatric impairments in MDMA users. Additional animal model and human studies of the CNS effects of MDMA and combined MDMA-polydrug toxicity are needed to further explain these findings. Potential explanations for our results including pre-existing brain differences predisposing to MDMA polydrug use, direct MDMA and polydrug toxicity, indirect changes due to MDMA and polydrug toxicity, or combinations of all these factors.
MDMA ("ecstasy") consumption in the context of poly-drug abuse: a report on 150 patients
  • F Schifano
  • Di Furia
  • L Forza
Schifano F, Di Furia L, Forza G, et al: MDMA ("ecstasy") consumption in the context of poly-drug abuse: a report on 150 patients. Drug Alcohol Depend 1998; 52:85-90
The Psychological Corporation
  • D Wechsler
Wechsler D (ed): Wechsler Memory Scale; 3rd Edition. London, UK, The Psychological Corporation, Harcourt Brace Jovanovich and Company, 1997
MDMA (“ecstasy”) consumption in the context of poly-drug abuse: a report on 150 patients
  • Schifano