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

86 Psychosomatics 47:1, January-February 2006
Neurological and
Psychopathological Sequelae
Associated With a Lifetime
Intake of 40,000 Ecstasy
: 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
pathways, result-
ing in altered regulation of mood, im-
pulse control, and memory.
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)
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.
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.
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.
An additional,
non-serotonergic mechanism of
MDMA activity at the neuromuscular
junction-level has recently been sug-
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.
It is also con-
firmed here that selective impairments
of neuropsychological performance as-
sociated with regular ecstasy use are
not reversed by prolonged abstinence.
Psychosomatics 47:1, January-February 2006 87
Contrary to results of other neuroim-
aging observations,
Mr. As brain scan
did not show any gross cerebral abnor-
malities, especially at the hippocampal
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
1. Green AR, Cross AJ, Goodwin GM:
Review of the pharmacology and clinical
pharmacology of 3,4-
(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–
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–
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
: 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.
This is why
medical anthropology and transcultural
psychiatry encourage understanding of
patients’ own illness experiences.
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
years and in-
cluded individual psychotherapy and
psychiatric consultation with her fam-
ily in our transcultural psychiatric
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.
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.
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 #. ...
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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Reports from US, UK and European drug policy entities, and ongoing media accounts, show increasing recreational use of 4-methylmethcathinone (4-MMC, mephedrone) and 3,4-methylenedioxypyrovalerone (MDPV). Severe sympathomimetic symptoms, hallucinations, psychoses, and even deaths have been reported, yet little scientific information is available on the effects of these compounds in laboratory models. Available studies on the neurochemistry of these drugs show that 4-MMC and MDPV enhance DA neurotransmission, while 4-MMC additionally enhances 5-HT neurotransmission - a pattern much like that reported for methamphetamine versus 3,4-methylenedioxymethamphetamine (MDMA). As is the case for designer amphetamines, these neurochemical distinctions may predict differential potential for repetitive versus episodic abuse and distinct lasting toxicities. This study determined relative locomotor stimulant effects of 4-MMC (1-10mg/kg, s.c.) and MDPV (0.5-5.6mg/kg, s.c.), in comparison with d-methamphetamine (MA; 0.5-5.6mg/kg, s.c.) and MDMA (1-7.5mg/kg, s.c.) on a measure of locomotor activity - voluntary wheel running - in male Wistar rats (N=8). Compared to counts of wheel rotations after saline, a biphasic change in the pattern of counts was observed after injections of MA and MDPV, with relatively higher counts following lower doses and lower counts following the highest dose. However, monophasic, dose-dependent reductions in counts were observed in response to injections of MDMA and 4-MMC. Thus, voluntary wheel running yielded the same categorical distinctions for these drugs as did prior experiments testing the effects of these drugs on monoaminergic neurotransmission. These data indicate that MDPV produces prototypical locomotor stimulant effects whereas 4-MMC is more similar to the entactogen MDMA.
There are global concerns about the proliferation and misuse of club drugs and novel psychoactive substances, yet we know little about their harms and research on clinical management and treatment remains limited. This book fills the knowledge gap by providing a detailed overview of the research evidence available to date. The book provides a framework that allows readers to understand this large number of new drugs, using classifications based on primary psychoactive effect. Within this framework, the book provides detailed reviews of the more commonly used drugs. Each chapter explores pharmacology, patterns and mode of use, acute and chronic harms, and clinical interventions supported by research evidence. An invaluable resource for clinical staff, this book will support clinicians working in the emergency department, substance misuse and addiction services, mental health services, primary care, sexual health services and more. It will also be of interest to academics and those developing drug policy.
Technical Report
Full-text available
Executive Summary MDMA is well established as a popular psychoactive substance across much of the Western world. Hundreds of thousands of people break the law to access its effects, which include increased energy, euphoria, and enhanced sociability. The categorisation of MDMA as a Class A drug in the UK and Schedule 1 drug internationally – categories reserved for drugs deemed to pose the highest risk to individuals and society – has never meaningfully disrupted its supply, nor its widespread use. MDMA is cheaper and purer than ever before and is available at the click of a mouse via darknet drug markets. For several years, MDMA-related adverse events and fatalities have been increasing in the UK, with some claiming that taking MDMA today is the riskiest it has ever been. Responses are polarised between those who assert that the risks of MDMA use necessitate mitigation through prohibition and increased law enforcement, and those who perceive prohibition to be exacerbating these risks by exposing users to an unregulated market of pills and powder of unknown strength and quality. Whichever view you take, current policy is not meeting its goal of reducing harms, and greater control of MDMA production, distribution, purchase, and consumption is needed in order to prevent MDMArelated emergencies. This report examines the acute, sub-acute, and chronic harms related to MDMA use in detail. We examine the production, distribution, purchase, and consumption of the drug; related risks and harms; and the impact prohibition has on these, as well as the potential impact of alternative policies. Crucially, our evidence shows that many harms associated with MDMA use arise from its unregulated status as an illegal drug, and that any risks inherent to MDMA could be more effectively mitigated within a legally regulated market. 10 MDMA: Roadmaps to Regulation Under prohibition, people purchase MDMA pills, crystal, and powder from an illegal market, with little certainty as to what these products contain. Given that illegal drugs are not subject to strict production standards, consumers are exposed to the risks of poisoning or accidental overdose as a result of contamination, adulteration, and unknown strength and purity. Naïve commentators demonise the drug and simply urge young people to ‘just say no’, whilst failing to account for those who say ‘yes’. In the meantime, preventable deaths continue to occur, and otherwise law-abiding people are punished for non-violent offences such as the possession or social supply of MDMA. Governments and the mainstream media persist in perpetuating the myth that the War on Drugs is winnable if it were fought harder, and those calling for drug policy reform – as we do here – are framed as ‘radicals’ who have little or no regard for the health and wellbeing of citizens. This characterisation could not be further from the truth. Those calling for careful reform to existing drug policy include the parents of young people whose lives have been lost or ruined by harms related to the prohibition of MDMA. We incorporate their voices in this report alongside those of academics and former police officers, highlighting the ‘broad church’ of those dedicated to fighting for reform. This includes scientists undertaking ground-breaking research into the therapeutic potential of MDMA, who work within a regulatory regime that makes such research exorbitantly expensive and time-consuming, because of the Schedule 1 status that MDMA holds in the UK. As we enter the fourth decade of MDMA’s widespread use, new thinking is needed on how to better control production and distribution, and on how to reduce the risks associated with its consumption. There is growing evidence to support reorienting drug policy away from an ideologically driven criminal justice-led model to one rooted in pragmatic health and harm reduction principles. This is reflected in the widespread reform of cannabis laws occurring in numerous jurisdictions around the world, and the growth of treatment 11 Executive Summary programmes for heroin users which include prescription heroin and supervised injecting rooms. These hard-fought policy changes acknowledge the failure of prohibition to meet its goals and produce a ‘drug-free world’. They are built on a robust and ever-growing evidence base which demonstrates how permitting or prescribing the use of legally regulated drugs improves health and safety outcomes for people who use drugs and their communities at a reduced cost to the state, whilst also providing wider employment and economic opportunities. This logic can be extended to the use of MDMA and other currently prohibited psychoactive substances. Roadmaps to Regulation: MDMA follows this pragmatic path and pursues policy aims which many of us share, such as improvements in public health promotion, targeted harm reduction, evidence-informed policy and practice, human rights, social justice, participatory democracy, and effective governmental expenditure. For the first time, we outline detailed recommendations for drug policy reform to better control the production, distribution, purchase, and consumption of MDMA products. Reform and the reduction in MDMArelated harms this will bring cannot happen overnight. The changes we outline here, which culminate in a strictly regulated legal market for MDMA, are to be phased in gradually and closely evaluated through independent policy research to ensure health and social outcomes are properly documented, with findings folded back into the ongoing reform process.
Rationale: MDMA alters body temperature in rats with a direction that depends on the ambient temperature (TA). The thermoregulatory effects of MDMA and TA may affect intravenous self-administration (IVSA) of MDMA but limited prior reports conflict. Objective: To determine how body temperature responses under high and low TA influence MDMA IVSA. Methods: Male Sprague-Dawley rats were trained to IVSA MDMA (1.0mg/kg/infusion; 2-h sessions; FR5 schedule of reinforcement) under TA 20°C or 30°C. Radiotelemetry transmitters recorded body temperature and activity during IVSA. Results: MDMA intake increased under both TA 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 TA conditions were swapped, the hot-trained group increased MDMA IVSA under 20°C TA and a modest decrease in drug intake was observed in the cold-trained group under 30°C TA. Subsequent non-contingent MDMA (1.0-5.0mg/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 TA increased intracranial self-stimulation thresholds in a different group of rats and MDMA reduced thresholds below baseline at low, but not high, TA. Conclusions: High TA appears to enhance acquisition of MDMA IVSA through an aversive effect and not via thermoregulatory motivation.
Animal models of drug self-administration are currently the gold standard for making predictions regarding the relative likelihood that a recreational drug substance will lead to continued use and addiction. Such models have been found to have high predictive accuracy and discriminative validity for a number of drug classes including ethanol, nicotine, opioids, and psychostimulants such as cocaine and methamphetamine. Members of the entactogen class of psychostimulants (drugs that produce an “open mind state” including feelings of interpersonal closeness, intimacy and empathy) have been less frequently studied in self-administration models. The prototypical entactogen 3,4-methylenedioxymethamphetamine (MDMA; “Ecstasy”) supports self-administration but not with the same consistency nor with the same efficacy as structurally related drugs amphetamine or methamphetamine. Consistent with these observations, MDMA use is more episodic in the majority of those who use it frequently. Nevertheless, substantial numbers of MDMA users will meet the criteria for substance dependence at some point in their use history. This review examines the currently available evidence from rodent self-administration studies of MDMA and two of the new and emerging psychoactive substances (NPS) that produce entactogen type neuropharmacological responses – mephedrone (4-methylmethcathinone; 4MMC; “meow meow”) and methylone (3,4-methylenedioxymethcathinone). Overall, the current evidence predicts that these NPS entactogens have enhanced abuse liability compared with MDMA.
For nearly 30 years, there has been a steady flow of research papers highlighting the dangers of MDMA and the implications for ecstasy users. After such a long time, it would be reasonable to expect that these dangers would be obvious due to the large number of ecstasy users. The available evidence does not indicate that there are millions of ecstasy users experiencing any problems linked to their ecstasy use. The “precautionary principle” suggests that, in the absence of knowing for certain, “experts” should argue that MDMA be avoided. However, this may have been taken too far, as the dire warnings do not seem to be reducing with the lack of epidemiological evidence of clinically relevant problems. The “ecstasy paradigm” is one way of articulating this situation, in that the needs of research funders and publication bias lead to a specific set of subcultural norms around what information is acceptable in the public domain. By digging a little deeper, it is easy to find problems with the evidence base that informs the public debate around MDMA. The key question is whether it is acceptable to maintain this status quo given the therapeutic potential of MDMA.
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Abstract The 20th century brought with it the so-called club drugs (the most notorious being amphetamine derivatives), which are used by young adults at all-night dance parties. Methamphet-amine and 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) are synthetic drugs with stimulant and psychoactive properties that belong to the amphetamine family. Here, we have reviewed the literature about the cognitive impairment induced by these two amphetamine derivatives and the preclinical and clinical outcomes. Although there is controversial evidence about the effect of methamphetamine and MDMA on learning and memory in laboratory animals, results from published papers demonstrate that amphetamines cause long-term impairment of cognitive functions. A large number of pharmacological receptors have been studied and screened as targets of amphetamine-induced cognitive dysfunction, and extensive research efforts have been invested to provide evidence about the molecular mechanisms behind these cognitive deficits. In humans, there is a considerable body of evidence indicating that methamphetamine and MDMA seriously disrupt memory and learning processes. Although an association between the impairments of memory performance and a history of recreational amphetamine ingestion has also been corroborated, a number of methodological difficulties continue to hamper research in this field, the most important being the concomitant use of other illicit drugs.
With the use of psychotomimetic compounds, psychiatric hospitalizations have seen a definite increase over the last few years, at least in the European scene. This paper offers an overview of the most frequently abused recreational drugs, including ecstasy and ecstasy look-alikes, cocaine/crack cocaine, amphetamines, poppers, cathinones, LSD, DMT, methylphenidate, GHB, dextromethorphan, ketamine, and smart drugs/smart drinks. We also provide an overview of the legislative and epidemiological issues related to compulsory psychiatric treatments in the United Kingdom.
3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") was first synthesised 80 years ago, but has recently received prominence as an illegally synthesised recreational drug of abuse. There is a widely held belief among misusers that it is safe. In the last 2-3 years there have been a number of reports of the drug producing severe acute toxicity and death and there are concerns that it may cause long term toxic damage to 5-hydroxytryptamine (5-HT) nerve terminals. There is a considerable literature on the acute pharmacological effects of MDMA in experimental animals, and this is reviewed. The drug produces both hyperthermia and the "serotonin syndrome", a series of behavioural changes which result from increased 5-HT function. Acute clinical toxicity problems following MDMA ingestion also include hyperthermia and the appearance of the serotonin syndrome. The hyperthermia appears to precipitate other severe clinical problems and the outcome can be fatal. In agreement with others, we suggest that the recent increase in the number of reports of MDMA toxicity probably results from the widespread use of the drug at all night dance parties or "raves". The phenomenon of amphetamine aggregation toxicity in mice was reported 40 years ago. If applicable to MDMA-induced toxicity in humans, all the conditions necessary to induce or enhance toxicity are present at raves: crowded conditions (aggregation), high ambient temperature, loud noise and dehydrated subjects. Administration of MDMA to rodents and non-human primates results in a long term neurotoxic decrease in 5-HT content in several brain regions and there is clear biochemical and histological evidence that this reflects neurodegeneration of 5-HT terminals. Unequivocal data demonstrating that similar changes occur in human brain do not exist, but limited and indirect clinical evidence gives grounds for concern. There are also data suggesting that long term psychiatric changes can occur, although there are problems of interpretation and these are reviewed. Suggestions for the rational treatment of the acute toxicity are made on the basis of both pharmacological studies in animals and current clinical practice. Cases presenting clinically are usually emergencies and unlikely to allow carefully controlled studies. Proposals include decreasing body temperature (possibly with ice), the use of dantrolene and anticonvulsant and sedative medication, particularly benzodiazepines. The use of neuroleptics requires care because of the theoretical risk of producing the neuroleptic malignant syndrome and the possibility of precipitating seizures. In rats, chlormethiazole antagonises the hyperthermia produced by MDMA and has been shown clinically to block MDMA-induced convulsive activity.
The present study examined the characteristics and the possible psychopathological consequences of ecstasy (MDMA, 3,4-methylenedioxymethamphetamine) use. One hundred and fifty consecutive patients, presenting to the Padova (Italy) Addiction Treatment Unit and who had taken ecstasy on at least one occasion, were examined and studied using a semi-structured interview. Ninety-five percent of the patients had experimented with another drug of abuse at least once in their lifetime. Ecstasy was mainly self-administered at disco clubs, and reported acute psychoactive effects confirmed previous reports. Fifty-three percent of the total sample were found to be affected by one or more psychopathological problems; the most frequent were depression, psychotic disorders, cognitive disturbances, bulimic episodes, impulse control disorders, panic disorders, social phobia. Those who were free from any psychopathological problem, compared to the others, had taken a smaller number of MDMA tablets in their lifetime, for a shorter duration and with a lower frequency. Again, they were less likely to have used alcohol together with ecstasy but more likely to have used opiates. Longer-term, larger dosage (acute or cumulative) MDMA consumers were found to be at high risk of developing psychopathological disturbances. The results are discussed, taking into account both the ecstasy suggested serotonin (5-hydroxytryptamine) neurotoxicity and the various methodological issues pertaining to this kind of large-scale clinical study describing people for whom MDMA is far from being the only drug of abuse.
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.
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.
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.
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