{"id":4386,"date":"2009-08-18T14:38:26","date_gmt":"2009-08-18T13:38:26","guid":{"rendered":"https:\/\/drugprevent.org.uk\/ppp\/?p=4386"},"modified":"2009-08-21T16:20:12","modified_gmt":"2009-08-21T15:20:12","slug":"executive-summary-the-harmful-health-effects-of-recreational-ecstasy","status":"publish","type":"post","link":"https:\/\/drugprevent.org.uk\/ppp\/2009\/08\/executive-summary-the-harmful-health-effects-of-recreational-ecstasy\/","title":{"rendered":"The harmful health effects of recreational ecstasy"},"content":{"rendered":"<p><span style=\"font-size: 10pt; font-family: Verdana;\"><strong>Background<\/strong>Street drugs known as \u2018ecstasy\u2019 have been sold for<br \/>\nabout 20 years in the UK. The active substance that<br \/>\nsuch tablets contain \u2013 or purport to contain \u2013 is<br \/>\n3,4-methylenedioxymethamphetamine (MDMA).<br \/>\nShortly after consumption, MDMA releases<br \/>\nchemicals in the brain that tend to bring about<br \/>\na sense of euphoria, exhilaration and increased<br \/>\nintimacy with others. It is thought to be the third<br \/>\nmost commonly used illegal drug in the UK after<br \/>\ncannabis and cocaine, with estimates suggesting<br \/>\nthat between 500,000 and 2 million tablets are<br \/>\nconsumed each week. Most people who take<br \/>\necstasy also use other legal and illegal drugs,<br \/>\nsometimes at the same time. Ecstasy is commonly<br \/>\ntaken in nightclubs and at parties and is very often<br \/>\nassociated with extended sessions of dancing.<br \/>\nAlong with the pleasurable effects sought by users<br \/>\nof MDMA, it has become clear that the drug can<br \/>\ncause a range of unintended harms. In the short<br \/>\nterm, a range of adverse events have been reported<br \/>\n\u2013 some fatal \u2013 and consumption of MDMA may<br \/>\nalso have long-term consequences, especially with<br \/>\nregard to users\u2019 mental health.<br \/>\nObjectives<br \/>\nThis review aims to address the question: \u2018What<br \/>\nare the harmful health effects of taking ecstasy<br \/>\n(MDMA) for recreational use?\u2019 It does not examine<br \/>\nthe harmful indirect and\/or social effects, such as<br \/>\neffects on driving and road traffic accidents and<br \/>\nthe consequences of any effect MDMA may have on<br \/>\nsexual behaviour.<\/p>\n<p>Previous research syntheses<br \/>\n(Level I evidence)<br \/>\nFor each identified Level I synthesis, it was difficult<br \/>\nto ascertain the exact methods adopted and<br \/>\nevidence included. Three reviews reported worse<br \/>\nperformance for ecstasy users compared to controls<br \/>\nin a variety of neurocognitive domains (attention,<br \/>\nverbal learning and memory, non-verbal learning<br \/>\nand memory, motor\/psychomotor speed, executive<br \/>\nsystems functioning, short- and long-term<br \/>\nmemory). A fourth study reviewed self-reported<br \/>\ndepressive symptoms and found that ecstasy users<br \/>\nhad increased levels compared to controls. The<br \/>\nfinal synthesis was primarily concerned with the<br \/>\nacute intoxication effects of ecstasy rather than<br \/>\nhealth harms. In all analyses, the effect sizes seen<br \/>\nwere considered to be small.<br \/>\nControlled observational<br \/>\nstudies (Level II evidence)<br \/>\nOf the 110 controlled observational studies<br \/>\nincluded, there was one prospective study, the<br \/>\nNetherlands XTC Toxicity (NeXT) study, which<br \/>\nrecruited a cohort of participants likely to start<br \/>\nusing ecstasy and followed them for a year. Those<br \/>\nwho started using ecstasy were then compared to<br \/>\na group of matched controls who had remained<br \/>\necstasy-na\u00efve. Ecstasy-exposed participants had<br \/>\npoorer performance in some memory tests,<br \/>\nalthough the absolute test scores for both cohorts<br \/>\nwere comfortably within the normal range.<br \/>\nOther tests suggested an association between<br \/>\necstasy exposure and certain aspects of sensation seeking,<br \/>\nbut there was no evidence of an effect on<br \/>\ndepression or impulsivity. The cumulative dose of<br \/>\necstasy consumed was small (median 3\u20136 tablets).<br \/>\nThe remaining Level II evidence consisted of cross sectional<br \/>\nstudies only. Data were directly pooled<br \/>\nfor seven individual outcomes. Six were common<br \/>\nmeasures of immediate and delayed verbal recall,<br \/>\nin which ecstasy users performed significantly<br \/>\nworse than polydrug controls. Effect sizes appeared<br \/>\nto be small, with the mean scores for each group<br \/>\nfalling within the normal range for the instrument<br \/>\nconcerned. No difference was seen between ecstasy<br \/>\nusers and polydrug and drug-na\u00efve controls in the<br \/>\nremaining measure, IQ.<br \/>\nA total of 915 outcome measures were grouped<br \/>\ninto broad outcome domains as suggested in<br \/>\nthe literature and after consultation with expert<br \/>\nadvisers. For 16 of these meta-outcomes, there<br \/>\nwere sufficient data for meta-analysis: immediate<br \/>\nand delayed verbal and visual memory, working<br \/>\nmemory, sustained and focused attention, three<br \/>\nmeasures of executive function (planning, response<br \/>\ninhibition and shifting), perceptual organisation,<br \/>\nself-rated depression, memory, and anxiety and<br \/>\nimpulsivity measured objectively and subjectively.<br \/>\nEcstasy users performed significantly worse than<br \/>\npolydrug controls on all outcome domains with<br \/>\nthe exception of executive function (response<br \/>\ninhibition and shifting) and objective measures of<br \/>\nimpulsivity. Fewer comparisons were possible with<br \/>\ndrug-na\u00efve controls, with statistically significant<br \/>\neffects seen for verbal and working memory and<br \/>\nself-rated measures of depression, memory and<br \/>\nimpulsivity. With both control groups, former<br \/>\necstasy users frequently showed deficits that<br \/>\nmatched or exceeded those seen among current<br \/>\nusers.<br \/>\nThe small effect sizes seen were not consistently<br \/>\nmodified by any study-level demographic variables.<br \/>\nThere was little evidence of a dose\u2013response<br \/>\neffect: studies reporting heavier average use<br \/>\nof ecstasy did not provide more extreme effect<br \/>\nmeasures than those consisting of lighter users,<br \/>\nand there was no demonstrable effect of length<br \/>\nof abstinence from ecstasy. When assessing the<br \/>\nimpact of inter-arm differences on results, no<br \/>\nconsistent effect was seen for imbalances in age<br \/>\nor gender. However, in several cases, it appeared<br \/>\nthat imbalances in intelligence between cohorts<br \/>\nmay have been important. Use of other drugs also<br \/>\nappeared to modify effects: alcohol consumption<br \/>\nproved the most consistent effect modifier, with<br \/>\nincreased exposure in ecstasy-exposed populations<\/p>\n<p>apparently reducing the magnitude of deficits<br \/>\nacross a range of neurocognitive outcomes.<br \/>\nFor the remaining outcome domains, there<br \/>\nwere insufficient data for quantitative synthesis<br \/>\nand the results were summarised narratively.<br \/>\nFor psychopathological symptoms, there was a<br \/>\nsignificant deficit for ecstasy users compared to<br \/>\npolydrug controls in the obsessive\u2013compulsive<br \/>\ndomain only, with greater deficits seen in<br \/>\ncomparison to drug-na\u00efve controls. In a few studies,<br \/>\necstasy users have been shown to have higher<br \/>\nlevels of subjectively rated aggression than drug na\u00efve<br \/>\ncontrols. It was not possible to draw clear<br \/>\nconclusions about the possible effects of ecstasy<br \/>\nconsumption on dental health, loneliness, motor<br \/>\nfunction or sleep disturbance.<br \/>\nCase series and case reports<br \/>\n(Level III evidence)<br \/>\nRegistry data from the np-SAD and GMR are not<br \/>\ndirectly comparable due to differences in data<br \/>\nsources and recording of drug use. The GMR<br \/>\n(1993\u20132006) suggests that there were, on average,<br \/>\n17 deaths a year where ecstasy was recorded as the<br \/>\nsole drug involved (2.5% of all deaths ascribed to a<br \/>\nsingle drug) and another 33 per year where it was<br \/>\nreported as co-drug use. Ecstasy-associated deaths<br \/>\nappear to have increased up to 2001 but to have<br \/>\nstabilised thereafter. In the 10 years to 2006, the<br \/>\nnp-SAD recorded an average of 50 drug-related<br \/>\ndeaths in which ecstasy was present (69 in 2006; 5%<br \/>\nof the total for the year). Ecstasy was believed to be<br \/>\nthe sole drug implicated in an average of 10 deaths<br \/>\nannually over the same time period. According to<br \/>\nthis registry, the typical victim of an ecstasy death<br \/>\nis an employed white male in his twenties, who<br \/>\nis a known drug user co-using a number of other<br \/>\nsubstances. Nearly half of ecstasy-related deaths<br \/>\noccur on a Saturday or Sunday night.<br \/>\nPublished case series and case reports document<br \/>\na wide range of fatal and non-fatal acute harms,<br \/>\noften very selectively. Two major syndromes<br \/>\nare most commonly reported as the immediate<br \/>\ncause of death in fatal cases: hyperthermia (with<br \/>\nconsequences including disseminated intravascular<br \/>\ncoagulation, rhabdomyolysis and acute liver and<br \/>\nrenal failure) and hyponatraemia (commonly<br \/>\npresenting with confusion and seizures due to<br \/>\ncerebral oedema). Ecstasy users presenting with<br \/>\nhyponatraemia have invariably consumed a large<br \/>\namount of water. We found 41 deaths relating to<br \/>\nhyperthermia reported in the literature and 10<br \/>\nfrom hyponatraemia (all women).<br \/>\nOther acute harms associated with fatal cases<br \/>\ninclude cardiovascular dysfunction, neurological<br \/>\ndysfunction (seizures and haemorrhage) and<br \/>\nsuicide. Acute renal failure and sub acute liver<br \/>\nfailure can occur without association with<br \/>\nhyperthermia. All these presentations were also<br \/>\nseen in non-fatal cases, alongside an additional<br \/>\nrange of symptoms including acute psychiatric<br \/>\neffects, urinary retention and respiratory<br \/>\nproblems including pneumothorax and<br \/>\npneumomediastinum.<br \/>\nThere are difficulties in estimating taken dose<br \/>\nof MDMA from the available literature, and it is<br \/>\nnot clear why some people seem to have acute,<br \/>\neven fatal, reactions to doses that are commonly<br \/>\ntolerated in others.<br \/>\nDiscussion<br \/>\nThe evidence we identified for this review<br \/>\nprovides a fairly consistent picture of deficits in<br \/>\nneuro-cognitive function for ecstasy users compared<br \/>\nto ecstasy-na\u00efve controls. Although the effects<br \/>\nare consistent and strong for some measures,<br \/>\nparticularly verbal and working memory, the effect<br \/>\nsizes generally appear to be small: where single<br \/>\noutcome measures were pooled, the mean scores of<br \/>\nall participants tended to fall within normal ranges<br \/>\nfor the instrument in question and, where multiple<br \/>\nmeasures were pooled, the estimated effect sizes<br \/>\nwere typically in the range that would be classified<br \/>\nas \u2018small\u2019.<br \/>\nHowever, there are substantial shortcomings in the<br \/>\nmethodological quality of the studies analysed.<br \/>\nBecause none of the studies was blinded, observer<br \/>\nor measurement bias may account for some of<br \/>\nthe apparent effect. There is a suggestion of<br \/>\npublication bias in some analyses, and we saw clear<br \/>\nevidence of selective reporting of outcomes.<br \/>\nSelection bias is an inevitable problem: due to the<br \/>\nobservational nature of all relevant evidence, there<br \/>\nis no guarantee that the cohorts being compared<br \/>\nwere not subject to differences in areas other than<br \/>\nexposure to ecstasy. This effect will have been<br \/>\nexaggerated in those studies comparing ecstasy exposed<br \/>\nparticipants to drug-na\u00efve controls; in<br \/>\nthese instances, it is impossible to isolate the effect<br \/>\nof ecstasy exposure from the impact of other<br \/>\nsubstances. Within-study imbalances in intelligence<br \/>\nand the use of other substances, particularly<br \/>\nalcohol, appeared to explain some of the effects<br \/>\nseen. We suggest that the apparently beneficial<br \/>\nMethods<br \/>\nThe following databases were searched using<br \/>\na comprehensive search syntax: MEDLINE,<br \/>\nEMBASE, PsycINFO (run 19 September 2007)<br \/>\nand Web of Knowledge (run 7 October 2007).<br \/>\nThe search outputs were considered against pre specified<br \/>\ninclusion\/exclusion criteria; the full text<br \/>\nof all papers that could not confidently be excluded<br \/>\non title and abstract alone was then retrieved and<br \/>\nscreened. Only studies published in English were<br \/>\nincluded. Meeting abstracts were included only<br \/>\nif sufficient methodological details were given<br \/>\nto allow appraisal of study quality. Studies were<br \/>\ncategorised according to a hierarchy of research<br \/>\ndesign, with systematic research syntheses (Level<br \/>\nI evidence) being preferred as the most valid and<br \/>\nleast open to bias. Where Level I evidence was<br \/>\nnot available, controlled observational studies<br \/>\n(Level II evidence) were systematically reviewed. If<br \/>\nneither Level I nor Level II evidence was available,<br \/>\nuncontrolled case series and case reports (Level<br \/>\nIII evidence) were systematically surveyed. Data<br \/>\nextraction was undertaken by one reviewer and a<br \/>\nsample checked by a second.<br \/>\nSynthesising Level II evidence posed substantial<br \/>\nchallenges due to the heterogeneity of the included<br \/>\nstudies, the number and range of outcome<br \/>\nmeasures reported, the multiplicity of comparisons<br \/>\n(differing ecstasy exposures, differing comparator<br \/>\ngroups) and outcomes, repeated measures and<br \/>\nthe observational nature of the data. Analyses<br \/>\nwere stratified for current and former ecstasy<br \/>\nusers, with separate analyses for control groups<br \/>\nusing other illegal drugs but not ecstasy (polydrug<br \/>\ncontrols) or controls na\u00efve to illegal drugs (drug na\u00efve<br \/>\ncontrols). Random-effects meta-analyses were<br \/>\nused throughout. Heterogeneity was also explored<br \/>\nthrough study-level regression analysis (meta regression).<br \/>\nWhere a sufficient number of studies<br \/>\nhad reported identical outcomes, they were meta analysed<br \/>\non their original scale. Other outcome<br \/>\nmeasures were grouped into broad domains<br \/>\nand effect sizes expressed as standardised mean<br \/>\ndifferences in order to combine data derived from<br \/>\nmultiple instruments. Objective and self-reported<br \/>\noutcome measures within each domain were<br \/>\nanalysed separately.<br \/>\nFor the Level III evidence, only narrative synthesis<br \/>\nwas possible.<br \/>\nResults<br \/>\nOf 4394 papers identified by our searches, 795<br \/>\nwere reviewed in full and 422 met the inclusion<br \/>\ncriteria. Five systematic syntheses, 110 controlled<br \/>\nobservational studies and 307 uncontrolled<br \/>\neffect of alcohol consumption may be explained<br \/>\nin two ways: either alcohol may mitigate the<br \/>\nhyperthermic effects of ecstasy in the acute setting,<br \/>\nattenuating damage to the brain, or ecstasy users<br \/>\nwho co-use alcohol may represent a population of<br \/>\nmore casual ecstasy takers than those who tend not<br \/>\nto drink.<br \/>\nAlthough the NeXT study suggests that small<br \/>\ndeficits in memory may be secondary to ecstasy<br \/>\nexposure, all other included studies were<br \/>\ncross-sectional in nature; without evidence of<br \/>\nthe temporal relationship between exposure<br \/>\nand outcome, it is difficult to draw any causal<br \/>\ninferences.<br \/>\nWe did not find any studies directly investigating<br \/>\nthe quality of life of participants, and we found<br \/>\nno attempts to assess the clinical meaningfulness<br \/>\nof any inter-cohort differences. The clinical<br \/>\nsignificance of any exposure effect is thus<br \/>\nuncertain; it seems unlikely that these deficits<br \/>\nsignificantly impair the average ecstasy user\u2019s<br \/>\neveryday functioning or quality of life. However,<br \/>\nour methods are unlikely to have identified<br \/>\nsubgroups that may be particularly susceptible<br \/>\nto ecstasy. In addition, it is difficult to know how<br \/>\nrepresentative the studies are of the ecstasy-using<br \/>\npopulation as a whole. Generalising the findings is<br \/>\ntherefore problematic.<br \/>\nEcstasy is associated with a wide range of<br \/>\nacute harms, but remains a rare cause of death<br \/>\nwhen reported as the sole drug associated with<br \/>\ndeath related to drug use. Hyperthermia and<br \/>\nhyponatraemia and their consequences are the<br \/>\ncommonest causes of death, but a wide range of<br \/>\nother acute fatal and non-fatal harms are reported.<br \/>\nDue to the poor quality of the available evidence, it<br \/>\nis not possible to quantify the risk of acute harms in<br \/>\nany meaningful way.<br \/>\nResearch recommendations<br \/>\nLarge, population-based, prospective studies are<br \/>\nrequired to examine the time relationship between<br \/>\necstasy exposure and neuro-cognitive deficits and<br \/>\npsychopathological symptoms.<br \/>\nFurther research synthesis of the social and other<br \/>\nindirect health harms of ecstasy would provide a<br \/>\nmore complete picture. Similar synthesis of the<br \/>\nhealth harms of amphetamines generally would<br \/>\nprovide a useful comparison.<br \/>\nFuture cross-sectional studies will only add to the<br \/>\nevidence-base if they are large, as representative as<br \/>\npossible of the ecstasy-using population, use well validated<br \/>\noutcome measures, measure outcomes<br \/>\nas objectively as possible with researchers blind<br \/>\nto the ecstasy-using status of their subjects, report<br \/>\non all outcomes used, and provide complete<br \/>\ndocumentation of possible effect modifiers.<br \/>\nCohorts should be matched for baseline factors,<br \/>\nincluding IQ and exposure to alcohol.<br \/>\nThe heterogeneity of outcome measures used by<br \/>\ndifferent investigators is unhelpful: consensus on<br \/>\nthe most appropriate instruments to use should be<br \/>\nsought. Investigators should collect data directly<br \/>\nreflecting the quality of life of participants and\/or<br \/>\nattempt to assess the clinical meaningfulness of any<br \/>\ninter-cohort differences.<br \/>\nA registry of adverse events related to illegal<br \/>\nintoxicants presenting to medical services (akin to<br \/>\nthe \u2018yellow card\u2019 system for prescription medicines)<br \/>\nwould enable useful estimation of the incidence of<br \/>\nharmful effects of ecstasy in comparison to other<br \/>\nsubstances.<br \/>\nFuture case reports of acute harms of ecstasy are<br \/>\nunlikely to contribute valuable information to the<br \/>\nevidence-base. Where novel findings are presented,<br \/>\ncare should be taken to report toxicological<br \/>\nfindings confirming the precise identity of the<br \/>\nsubstance(s) consumed by the individual(s) in<br \/>\nquestion.<\/p>\n<p><span style=\"font-size: 10pt; font-family: Verdana;\"><em>Source: Rogers G, Elston J, Garside R, Roome C, Taylor<br \/>\nR, Younger P, et al. The harmful health effects<br \/>\nof recreational ecstasy: a systematic review of<br \/>\nobservational evidence. Health Technol Assess<br \/>\n2009;13<\/em><\/p>\n<p><\/span><\/span><\/p>\n","protected":false},"excerpt":{"rendered":"<p>BackgroundStreet drugs known as \u2018ecstasy\u2019 have been sold for about 20 years in the UK. The active substance that such tablets contain \u2013 or purport to contain \u2013 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. [&hellip;]<\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[22],"tags":[],"class_list":["post-4386","post","type-post","status-publish","format-standard","hentry","category-effects-of-drugs-papers"],"_links":{"self":[{"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/posts\/4386","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/comments?post=4386"}],"version-history":[{"count":0,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/posts\/4386\/revisions"}],"wp:attachment":[{"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/media?parent=4386"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/categories?post=4386"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/tags?post=4386"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}