Fatal uncertainty: death-rate from use of ecstasy or heroin

doi:10.1016/S0140-6736(99)02729-4

The Lancet

Volume 354, Issue 9186, 9 October 1999, Pages 1265-1266

https://doi.org/10.1016/S0140-6736(99)02729-4 Get rights and content

Summary

We provide a 25-fold range for the ecstacy-related death rate per 10 000 15–24-year-old users in the UK: from 0·2 to 5·3, compared with the death rate of 1·0 from road traffic accidents in the same age-group. The heroin-related death rate in 15–24-year-old heroin users was much higher, but also imprecisely estimated: from 9·1 to 81·5 deaths per 10 000 15–24-year-old users. Data deficiencies which inhibit the calculation of drug-specific rates in this population should be remedied.

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Ecstasy and the dance of death: severe reactions are unpredictable
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Cited by (43)

A review on the mitochondrial toxicity of “ecstasy” (3,4-methylenedioxymethamphetamine, MDMA)
2022, Current Research in Toxicology
Citation Excerpt :
Fulminant hyperthermia, with core temperatures higher than 42 °C, which usually precede disseminated intravascular coagulation, rhabdomyolysis, hepatoxicity, acute renal failure, and (multiple) organ failure that may lead to death (Hall and Henry, 2006; Campbell and Rosner, 2008). The MDMA-related death rate in the 15 to 24-year-old MDMA users in the UK has been estimated to lay from 0.2 to 5.3 per 10,000 (Gore, 1999). Both hepatoxicity and nephrotoxicity have been well described, both in animal and human studies.
3,4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a drug of abuse used by millions worldwide. MDMA human abuse and dependence is well described, but addictive properties are not always consistent among studies. This amphetamine is a substrate type releaser, binding to monoamine transporters, leading to a pronounced release of serotonin and noradrenaline and to a minor extent dopamine. The toxicity of MDMA is well studied at the pre-clinical level, with neurotoxicity and hepatotoxicity being particularly described.
In this review, we describe the most relevant MDMA effects at the mitochondrial level found in in vitro and in vivo models, these later conducted in mice and rats. Most of these reports focus on the mitochondria of brain or liver. In in vitro models, MDMA causes depletion of ATP levels and inhibition of mitochondrial complex I and III, loss in mitochondrial membrane potential (ΔΨm) and induction of mitochondrial permeability transition. The involvement of mitochondria in the apoptotic cell death evoked by MDMA has also been shown, such as the release of cytochrome c. Additionally, MDMA or its metabolites impaired mitochondrial trafficking and increased the fragmentation of axonal mitochondria. In animal studies, MDMA decreased mitochondrial complex I activity and decreased ATP levels. Moreover, MDMA-evoked oxidative stress has been shown to cause deletion on mitochondrial DNA and impairment in mitochondrial protein synthesis.
Although the concentrations and doses used in some studies do not always correlate to the human scenario, the mitochondrial abnormalities evoked by MDMA are well described and are in part responsible for its mechanism of toxicity.
An in vitro approach to assessing a potential drug interaction between MDMA (ecstasy) and caffeine
2014, Toxicology in Vitro
Citation Excerpt :
It is a psychostimulant that induces many subjective effects including euphoria and increased empathy (Liechti and Vollenweider, 2001). Although human deaths associated with MDMA abuse are relatively rare (Gore, 1999; Schifano et al., 2003) there is considerable evidence that MDMA causes a variety of adverse effects to many organs in the body (see review by Rietjens et al. (2012)). The correlation between the dose of ecstasy ingested and the severity of ecstasy-related symptoms in humans is poor making it difficult to predict clinical outcome (Henry et al., 1992; Ramcharan et al., 1998; Burgess et al., 2000).
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a popular recreational drug which causes long-term neurotoxicity and increased risk of fatality. In rats, MDMA toxicity is exacerbated by co-administration of caffeine. The aim of this study was to investigate whether caffeine altered the effects of MDMA in a battery of in vitro tests selected to model some of the known actions of MDMA in vivo. In cytotoxicity studies, caffeine modestly enhanced the effect of MDMA on neuronal N2a cell viability but not that of liver, intestinal or kidney cells. MDMA inhibited the formation of fluorescent metabolites by CYP2D6 ≫ CYP3A4 > CYP1A2 but this was not altered by caffeine. Similarly, the inhibition of synaptosomal [³H] 5-HT uptake by MDMA was not affected by the presence of caffeine. Thus, these in vitro tests failed to detect any substantial interaction between caffeine and MDMA, highlighting the difficulty of modelling in vivo drug interactions using in vitro tests. However, the results show that the inhibition of synaptosomal [³H] 5-HT uptake by MDMA was greater at 41 °C and 25 °C than at 37 °C which raises the possibility that MDMA’s effect on SERT in vivo may be increased as body temperature increases, contributing to its harmful effects in users.
Mortality among amphetamine users: A systematic review of cohort studies
2009, Drug and Alcohol Dependence
To report the results of a comprehensive literature search of studies of mortality among people who use amphetamines.
Three electronic databases were searched (EMBASE, Medline and PsycINFO) and “grey” literature was located. Shortlists of papers were circulated to experts to ascertain whether any important papers had been missed. Papers were hand-searched to retrieve any additional relevant articles.
Studies meeting inclusion criteria were prospective cohort studies examining mortality risk among dependent and problematic amphetamine users. Crude mortality rates (CMR/100PY) and standardised mortality ratios (SMRs) were the primary outcome measures considered. Data on overall mortality, and rates for specific causes of death, were of interest.
2187 articles and 9 grey literature sources were obtained. After thorough review, 72 articles were identified as reporting on amphetamine-related mortality, 7 provided data from cohort studies of users. An additional study of Swedish military conscripts was identified by the authors during correspondence with other researchers. The geographic spread of cohorts was restricted to high income countries with the exception of one Thai study; reporting of standard parameters in mortality studies was often sparse. The estimated CMRs ranged from 0 in Australia to 2.95 (1.46–4.59) in Thailand. The Czech cohort reported the only SMR: 6.22 overall, males: 5.87, females: 7.84.
Given the widespread use of amphetamines, the known non-fatal adverse effects of use and the mortality rates reported here, cohort studies investigating the morbidity and mortality associated with such drug use should be a research priority.
Acute toxic effects of 'Ecstasy' (MDMA) and related compounds: Overview of pathophysiology and clinical management
2006, British Journal of Anaesthesia
Since the late 1980s ‘Ecstasy’ (3,4-methylenedioxymethamphetamine, MDMA) has become established as a popular recreational drug in western Europe. The UK National Criminal Intelligence Service estimates that 0.5–2 million tablets are consumed weekly in Britain. It has been reported that 4.5% of young adults (15–34 yr) in the UK have used MDMA in the previous 12 months. Clinically important toxic effects have been reported, including fatalities. While the phenomenon of hyperpyrexia and multi-organ failure is now relatively well known, other serious effects have become apparent more recently. Patients with acute MDMA toxicity may present to doctors working in Anaesthesia, Intensive Care and Emergency Medicine. A broad knowledge of these pathologies and their treatment is necessary for anyone working in an acute medical speciality. An overview of MDMA pharmacology and acute toxicity will be given followed by a plan for clinical management.
Hyponatremia associated with 3,4-methylenedioxymethylamphetamine ("ecstasy") abuse
2003, American Journal of the Medical Sciences
Citation Excerpt :
A few cases had low urinary sodium and clinical signs of volume depletion that might have contributed to the development of hyponatremia. MDMA abuse is associated with mortality ranging from 0.2 to 5.3 cases per 10,000 users in the United Kingdom.28 According to the literature, the majority of deaths were caused by hyperthermia with disseminated intravascular coagulation.29–33
We present a case of acute, symptomatic hyponatremia in a young woman that developed after use of 3,4-methylenedioxymethylamphetamine (MDMA), more commonly known as “ecstasy.” The patient was treated with 5% saline and had complete recovery. The pathogenesis of MDMA-associated hyponatremia involves excessive water intake and inappropriately elevated antidiuretic hormone (ADH) levels. It seems that young, premenopausal women are at particularly high risk for the development of severe, symptomatic hyponatremia after use of this drug. Review of the literature revealed 4 fatal outcomes from MDMA-associated hyponatremia. All were women and all died from cerebellar tonsillar herniation. We suggest that acute hyponatremia that develops after MDMA use may be a life-threatening condition. Recent recommendation that MDMA users should drink large volumes of water may not be appropriate.
Altered states: The clinical effects of Ecstasy
2003, Pharmacology and Therapeutics
Citation Excerpt :
The death rate per 10,000 Ecstasy users in England was estimated to be 5 times lower than the death rate from traffic accidents in the same age group as a whole, although it was comparable in Scotland. Using estimates of the pattern of use within this group, Gore (1999) argues that the death rate varies according to how users are classified, but as this was not done on the death certificates themselves, these post hoc estimates are unreliable. There are, at present, no statistics in the United Kingdom for hospital admissions with successful outcomes.
Ecstasy is the second most widely abused illegal drug in Europe. Ecstasy is the colloquial name for 3,4-methylenedioxymethamphetamine (MDMA), but not all Ecstasy tablets contain MDMA. When taken in hot, crowded environments, Ecstasy/MDMA users have developed acute complications that have had fatal consequences. Epidemiological evidence indicates that adverse reactions to Ecstasy/MDMA intoxication are rare and idiosyncratic. Potential mechanisms of action are reviewed. In animal studies, MDMA damages serotonergic fibres and reduces the number of serotonin transporter sites within the CNS. Demonstration of neurotoxicity in human users of Ecstasy is hampered by a number of confounds that the majority of published studies have failed to address. These confounds are reviewed and their impact is discussed.

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Research LettersFatal uncertainty: death-rate from use of ecstasy or heroin

Summary

Ecstasy and the dance of death: severe reactions are unpredictable

BMJ

Research Letters
Fatal uncertainty: death-rate from use of ecstasy or heroin