BackgroundStreet drugs known as ‘ecstasy’ have been sold for
about 20 years in the UK. The active substance that
such tablets contain – or purport to contain – is
3,4-methylenedioxymethamphetamine (MDMA).
Shortly after consumption, MDMA releases
chemicals in the brain that tend to bring about
a sense of euphoria, exhilaration and increased
intimacy with others. It is thought to be the third
most commonly used illegal drug in the UK after
cannabis and cocaine, with estimates suggesting
that between 500,000 and 2 million tablets are
consumed each week. Most people who take
ecstasy also use other legal and illegal drugs,
sometimes at the same time. Ecstasy is commonly
taken in nightclubs and at parties and is very often
associated with extended sessions of dancing.
Along with the pleasurable effects sought by users
of MDMA, it has become clear that the drug can
cause a range of unintended harms. In the short
term, a range of adverse events have been reported
– some fatal – and consumption of MDMA may
also have long-term consequences, especially with
regard to users’ mental health.
Objectives
This review aims to address the question: ‘What
are the harmful health effects of taking ecstasy
(MDMA) for recreational use?’ It does not examine
the harmful indirect and/or social effects, such as
effects on driving and road traffic accidents and
the consequences of any effect MDMA may have on
sexual behaviour.

Previous research syntheses
(Level I evidence)
For each identified Level I synthesis, it was difficult
to ascertain the exact methods adopted and
evidence included. Three reviews reported worse
performance for ecstasy users compared to controls
in a variety of neurocognitive domains (attention,
verbal learning and memory, non-verbal learning
and memory, motor/psychomotor speed, executive
systems functioning, short- and long-term
memory). A fourth study reviewed self-reported
depressive symptoms and found that ecstasy users
had increased levels compared to controls. The
final synthesis was primarily concerned with the
acute intoxication effects of ecstasy rather than
health harms. In all analyses, the effect sizes seen
were considered to be small.
Controlled observational
studies (Level II evidence)
Of the 110 controlled observational studies
included, there was one prospective study, the
Netherlands XTC Toxicity (NeXT) study, which
recruited a cohort of participants likely to start
using ecstasy and followed them for a year. Those
who started using ecstasy were then compared to
a group of matched controls who had remained
ecstasy-naïve. Ecstasy-exposed participants had
poorer performance in some memory tests,
although the absolute test scores for both cohorts
were comfortably within the normal range.
Other tests suggested an association between
ecstasy exposure and certain aspects of sensation seeking,
but there was no evidence of an effect on
depression or impulsivity. The cumulative dose of
ecstasy consumed was small (median 3–6 tablets).
The remaining Level II evidence consisted of cross sectional
studies only. Data were directly pooled
for seven individual outcomes. Six were common
measures of immediate and delayed verbal recall,
in which ecstasy users performed significantly
worse than polydrug controls. Effect sizes appeared
to be small, with the mean scores for each group
falling within the normal range for the instrument
concerned. No difference was seen between ecstasy
users and polydrug and drug-naïve controls in the
remaining measure, IQ.
A total of 915 outcome measures were grouped
into broad outcome domains as suggested in
the literature and after consultation with expert
advisers. For 16 of these meta-outcomes, there
were sufficient data for meta-analysis: immediate
and delayed verbal and visual memory, working
memory, sustained and focused attention, three
measures of executive function (planning, response
inhibition and shifting), perceptual organisation,
self-rated depression, memory, and anxiety and
impulsivity measured objectively and subjectively.
Ecstasy users performed significantly worse than
polydrug controls on all outcome domains with
the exception of executive function (response
inhibition and shifting) and objective measures of
impulsivity. Fewer comparisons were possible with
drug-naïve controls, with statistically significant
effects seen for verbal and working memory and
self-rated measures of depression, memory and
impulsivity. With both control groups, former
ecstasy users frequently showed deficits that
matched or exceeded those seen among current
users.
The small effect sizes seen were not consistently
modified by any study-level demographic variables.
There was little evidence of a dose–response
effect: studies reporting heavier average use
of ecstasy did not provide more extreme effect
measures than those consisting of lighter users,
and there was no demonstrable effect of length
of abstinence from ecstasy. When assessing the
impact of inter-arm differences on results, no
consistent effect was seen for imbalances in age
or gender. However, in several cases, it appeared
that imbalances in intelligence between cohorts
may have been important. Use of other drugs also
appeared to modify effects: alcohol consumption
proved the most consistent effect modifier, with
increased exposure in ecstasy-exposed populations

apparently reducing the magnitude of deficits
across a range of neurocognitive outcomes.
For the remaining outcome domains, there
were insufficient data for quantitative synthesis
and the results were summarised narratively.
For psychopathological symptoms, there was a
significant deficit for ecstasy users compared to
polydrug controls in the obsessive–compulsive
domain only, with greater deficits seen in
comparison to drug-naïve controls. In a few studies,
ecstasy users have been shown to have higher
levels of subjectively rated aggression than drug naïve
controls. It was not possible to draw clear
conclusions about the possible effects of ecstasy
consumption on dental health, loneliness, motor
function or sleep disturbance.
Case series and case reports
(Level III evidence)
Registry data from the np-SAD and GMR are not
directly comparable due to differences in data
sources and recording of drug use. The GMR
(1993–2006) suggests that there were, on average,
17 deaths a year where ecstasy was recorded as the
sole drug involved (2.5% of all deaths ascribed to a
single drug) and another 33 per year where it was
reported as co-drug use. Ecstasy-associated deaths
appear to have increased up to 2001 but to have
stabilised thereafter. In the 10 years to 2006, the
np-SAD recorded an average of 50 drug-related
deaths in which ecstasy was present (69 in 2006; 5%
of the total for the year). Ecstasy was believed to be
the sole drug implicated in an average of 10 deaths
annually over the same time period. According to
this registry, the typical victim of an ecstasy death
is an employed white male in his twenties, who
is a known drug user co-using a number of other
substances. Nearly half of ecstasy-related deaths
occur on a Saturday or Sunday night.
Published case series and case reports document
a wide range of fatal and non-fatal acute harms,
often very selectively. Two major syndromes
are most commonly reported as the immediate
cause of death in fatal cases: hyperthermia (with
consequences including disseminated intravascular
coagulation, rhabdomyolysis and acute liver and
renal failure) and hyponatraemia (commonly
presenting with confusion and seizures due to
cerebral oedema). Ecstasy users presenting with
hyponatraemia have invariably consumed a large
amount of water. We found 41 deaths relating to
hyperthermia reported in the literature and 10
from hyponatraemia (all women).
Other acute harms associated with fatal cases
include cardiovascular dysfunction, neurological
dysfunction (seizures and haemorrhage) and
suicide. Acute renal failure and sub acute liver
failure can occur without association with
hyperthermia. All these presentations were also
seen in non-fatal cases, alongside an additional
range of symptoms including acute psychiatric
effects, urinary retention and respiratory
problems including pneumothorax and
pneumomediastinum.
There are difficulties in estimating taken dose
of MDMA from the available literature, and it is
not clear why some people seem to have acute,
even fatal, reactions to doses that are commonly
tolerated in others.
Discussion
The evidence we identified for this review
provides a fairly consistent picture of deficits in
neuro-cognitive function for ecstasy users compared
to ecstasy-naïve controls. Although the effects
are consistent and strong for some measures,
particularly verbal and working memory, the effect
sizes generally appear to be small: where single
outcome measures were pooled, the mean scores of
all participants tended to fall within normal ranges
for the instrument in question and, where multiple
measures were pooled, the estimated effect sizes
were typically in the range that would be classified
as ‘small’.
However, there are substantial shortcomings in the
methodological quality of the studies analysed.
Because none of the studies was blinded, observer
or measurement bias may account for some of
the apparent effect. There is a suggestion of
publication bias in some analyses, and we saw clear
evidence of selective reporting of outcomes.
Selection bias is an inevitable problem: due to the
observational nature of all relevant evidence, there
is no guarantee that the cohorts being compared
were not subject to differences in areas other than
exposure to ecstasy. This effect will have been
exaggerated in those studies comparing ecstasy exposed
participants to drug-naïve controls; in
these instances, it is impossible to isolate the effect
of ecstasy exposure from the impact of other
substances. Within-study imbalances in intelligence
and the use of other substances, particularly
alcohol, appeared to explain some of the effects
seen. We suggest that the apparently beneficial
Methods
The following databases were searched using
a comprehensive search syntax: MEDLINE,
EMBASE, PsycINFO (run 19 September 2007)
and Web of Knowledge (run 7 October 2007).
The search outputs were considered against pre specified
inclusion/exclusion criteria; the full text
of all papers that could not confidently be excluded
on title and abstract alone was then retrieved and
screened. Only studies published in English were
included. Meeting abstracts were included only
if sufficient methodological details were given
to allow appraisal of study quality. Studies were
categorised according to a hierarchy of research
design, with systematic research syntheses (Level
I evidence) being preferred as the most valid and
least open to bias. Where Level I evidence was
not available, controlled observational studies
(Level II evidence) were systematically reviewed. If
neither Level I nor Level II evidence was available,
uncontrolled case series and case reports (Level
III evidence) were systematically surveyed. Data
extraction was undertaken by one reviewer and a
sample checked by a second.
Synthesising Level II evidence posed substantial
challenges due to the heterogeneity of the included
studies, the number and range of outcome
measures reported, the multiplicity of comparisons
(differing ecstasy exposures, differing comparator
groups) and outcomes, repeated measures and
the observational nature of the data. Analyses
were stratified for current and former ecstasy
users, with separate analyses for control groups
using other illegal drugs but not ecstasy (polydrug
controls) or controls naïve to illegal drugs (drug naïve
controls). Random-effects meta-analyses were
used throughout. Heterogeneity was also explored
through study-level regression analysis (meta regression).
Where a sufficient number of studies
had reported identical outcomes, they were meta analysed
on their original scale. Other outcome
measures were grouped into broad domains
and effect sizes expressed as standardised mean
differences in order to combine data derived from
multiple instruments. Objective and self-reported
outcome measures within each domain were
analysed separately.
For the Level III evidence, only narrative synthesis
was possible.
Results
Of 4394 papers identified by our searches, 795
were reviewed in full and 422 met the inclusion
criteria. Five systematic syntheses, 110 controlled
observational studies and 307 uncontrolled
effect of alcohol consumption may be explained
in two ways: either alcohol may mitigate the
hyperthermic effects of ecstasy in the acute setting,
attenuating damage to the brain, or ecstasy users
who co-use alcohol may represent a population of
more casual ecstasy takers than those who tend not
to drink.
Although the NeXT study suggests that small
deficits in memory may be secondary to ecstasy
exposure, all other included studies were
cross-sectional in nature; without evidence of
the temporal relationship between exposure
and outcome, it is difficult to draw any causal
inferences.
We did not find any studies directly investigating
the quality of life of participants, and we found
no attempts to assess the clinical meaningfulness
of any inter-cohort differences. The clinical
significance of any exposure effect is thus
uncertain; it seems unlikely that these deficits
significantly impair the average ecstasy user’s
everyday functioning or quality of life. However,
our methods are unlikely to have identified
subgroups that may be particularly susceptible
to ecstasy. In addition, it is difficult to know how
representative the studies are of the ecstasy-using
population as a whole. Generalising the findings is
therefore problematic.
Ecstasy is associated with a wide range of
acute harms, but remains a rare cause of death
when reported as the sole drug associated with
death related to drug use. Hyperthermia and
hyponatraemia and their consequences are the
commonest causes of death, but a wide range of
other acute fatal and non-fatal harms are reported.
Due to the poor quality of the available evidence, it
is not possible to quantify the risk of acute harms in
any meaningful way.
Research recommendations
Large, population-based, prospective studies are
required to examine the time relationship between
ecstasy exposure and neuro-cognitive deficits and
psychopathological symptoms.
Further research synthesis of the social and other
indirect health harms of ecstasy would provide a
more complete picture. Similar synthesis of the
health harms of amphetamines generally would
provide a useful comparison.
Future cross-sectional studies will only add to the
evidence-base if they are large, as representative as
possible of the ecstasy-using population, use well validated
outcome measures, measure outcomes
as objectively as possible with researchers blind
to the ecstasy-using status of their subjects, report
on all outcomes used, and provide complete
documentation of possible effect modifiers.
Cohorts should be matched for baseline factors,
including IQ and exposure to alcohol.
The heterogeneity of outcome measures used by
different investigators is unhelpful: consensus on
the most appropriate instruments to use should be
sought. Investigators should collect data directly
reflecting the quality of life of participants and/or
attempt to assess the clinical meaningfulness of any
inter-cohort differences.
A registry of adverse events related to illegal
intoxicants presenting to medical services (akin to
the ‘yellow card’ system for prescription medicines)
would enable useful estimation of the incidence of
harmful effects of ecstasy in comparison to other
substances.
Future case reports of acute harms of ecstasy are
unlikely to contribute valuable information to the
evidence-base. Where novel findings are presented,
care should be taken to report toxicological
findings confirming the precise identity of the
substance(s) consumed by the individual(s) in
question.

Source: Rogers G, Elston J, Garside R, Roome C, Taylor
R, Younger P, et al. The harmful health effects
of recreational ecstasy: a systematic review of
observational evidence. Health Technol Assess
2009;13