Ambient mass spectrometry for rapid diagnosis of psychoactive drugs overdose in an unstable patient.

A 25-year-old man suffered from consciousness change was sent to our emergency department by friends who reported that they were not sure what had happened to him. Physical examination revealed bilateral pupils dilatation, lethargy, slurred speech, and ataxia. Computer-aided tomographic scan of the brain revealed no definite evidence of intracranial lesions. Routine laboratory tests revealed total physiological turmoil. Despite immediate commencement of aggressive treatment, the patient's condition deteriorated long before the traditional drug screen provided an answer for the identities of the multiple drugs overdose. It ended up with the need for cardiopulmonary resuscitation, but in vain. At the end of the tragic event, under the suggestion of a colleague, a portion of the patient's urine specimen was sent to our university esoteric laboratory for rapid analysis by means of a newly-developed thermal desorption-electrospray ionization-mass spectrometry. Ketamine, 3,4-methylenedioxymethamphetamine, and 3,4-methylenedioxyamphetamine were identified in the urine sample within 30s. Conventional toxicological testing techniques like gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry are currently used for identifying abused drugs. One concern is their time-consuming sample pretreatment which leads to relatively low efficiency in terms of turnaround time for revealing the identity of the consumed drugs particularly when the patients are severely overdosed. We learned a lesson from this case that a more efficient toxicological identification technique is essential to expedite the process of emergency care when the patients are so heavily overdosed that they are under critical life-threatening conditions.

"Legal highs"--toxicity in the clinical and medico-legal aspect as exemplified by suicide with bk-MBDB administration.

The easily available "legal highs", which are products containing psychoactive substances, such as cathinones, piperazines and synthetic cannabinoids, are abused by adolescents in Poland and in the world as alternatives to classic drugs, such as amphetamines or marijuana. The majority of these potentially dangerous substances are still legal and they are associated with a risk of severe poisoning or even death, and provide new challenges in clinical and forensic toxicological practice. Investigations in the field of "designer drugs" may be well illustrated by the case of a suicide of a 21-year old male who ingested a specified dose of a preparation called "Amphi-bi-a" that contains bk-MBDB, chemically 2-methylamino-1-(3,4-methylenedioxyphenyl) butan-1-one, which belongs to the cathinone group, as a synthetic euphoric empathogen and psychoactive stimulant that is chemically similar to MDMA. It is one of more common components of "legal highs" examined in Poland and other countries. The documentation of the case includes a clinical assessment of the patient's health status performed during his almost 4-h hospitalization before death, autopsy and histological examinations supported by toxicological findings revealing bk-MBDB at extremely high concentrations (at 20 mg/l in the blood and 33 mg/kg in the liver); hence, this body of evidence contributes to knowledge in the field of "designer drugs". Inventions of designers of new psychoactive xenobiotics, which are much in demand, especially in view of the dynamic Internet marketing, which drums up narcobusiness, must be balanced by a national strategy developed by medical, legal and educational circles in the modern civilized world in order to prevent the spreading of the phenomenon.

Lethal serotonin syndrome after methylone and butylone ingestion.

INTRODUCTION: A new generation of designer phenethylamines have emerged and aggressively marketed as "legal highs." The drugs are labeled "not for human consumption" to avoid widespread recognition and prosecution under the existing analog drug laws. The newest generation includes methylone and butylone. Methylone and butylone have minor structural changes and similar pharmacodynamics properties to scheduled drugs. CASE REPORT: We report a case of a healthy 24-year-old who ingested a capsule containing methylone and butylone sold as "Ecstasy" at a concert. The patient presented to the emergency department, comatose febrile, tachycardic, tachypnic, and hypertensive. On exam, she was diaphoretic, tremulous, hyperreflexic, and had sustained clonus. The patient was aggressively cooled, and despite maximal supportive care, the patient progressed to multi-system organ failure and ultimately expired. We obtained and analyzed both her urine and a capsule found on her person similar to the capsules ingested. In both samples, laboratory analysis identified only methylone and butylone. CONCLUSION: This is the first reported death for methylone or butylone and the first human or animal ingestion of butylone. Clinicians and public health officials should work together as new designer drugs emerge.

Review article: amphetamines and related drugs of abuse.

Acute amphetamine toxicity is a relatively common clinical scenario facing the Australasian emergency medicine physician. Rates of use in Australasia are amongst the highest in the world. Clinical effects are a consequence of peripheral and central adrenergic stimulation producing a sympathomimetic toxidrome and a spectrum of central nervous system effects. Assessment aims to detect the myriad of possible complications related to acute amphetamine exposure and to institute interventions to limit associated morbidity and mortality. Meticulous supportive care aided by judicial use of benzodiazepines forms the cornerstone of management. Beta blockers are contraindicated in managing cardiovascular complications. Agitation and hyperthermia must be treated aggressively. Discharge of non-admitted patients from the emergency department should only occur once physiological parameters and mental state have returned to normal. All patients should receive education regarding the dangers of amphetamine use.

An announced suicide with ecstasy.

Most cases of ecstasy overdose turn out to be accidental, whereas suicide attempts with designer drugs occur only sporadically. We report an announced suicide by means of a combination of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethylamphetamine (MDEA). During autopsy, sampling for toxicological investigation (peripheral blood, urine, cerebrospinal fluid, bile and gastric contents) occurred. Serum concentrations as high as 13.33 mg/l for MDMA, 7.32 mg/l for MDEA and 0.43 mg/l for 3,4-methylenedioxyamphetamine were found. Ecstasy tablets, which were confiscated by the police a few days earlier, showed also a combination of MDMA and MDEA. This fact suggests that the ingested tablets probably came from the same source as the seized pills.

MDMA and MDA concentrations in antemortem and postmortem specimens in fatalities following hospital admission.

Over the last 15 years, numerous deaths involving "Ecstasy" (3,4-methylenedioxymethamphetamine, MDMA) have been reported and described in the literature. In most cases, either antemortem or postmortem concentration data are available. Because of the wide range of results and potential idiosyncratic nature of MDMA toxicity, interpretation of both antemortem and postmortem concentrations is difficult. The possible influence of postmortem redistribution may be an overlooked factor, but existing data involve postmortem concentrations from varying anatomical sites. However, this paper describes for the first time an evaluation of the concentrations of MDMA and 3,4-methylenedioxyamphetamine (MDA) found in five fatalities admitted to hospital where both antemortem and postmortem blood samples were available. Admission MDMA and MDA concentrations ranged between 0.55 and 4.33 mg/L and 0 and 0.10 mg/L, respectively, in antemortem serum/plasma. Postmortem blood MDMA and MDA concentrations ranged between 0.47 and 28.39 mg/L and 0.02 and 1.33 mg/L, respectively. Postmortem concentrations were higher than corresponding antemortem concentrations in all 5 cases with postmortem/antemortem ratios between 1.1 and 6.6 for MDMA and 1.5 and 13.3 for MDA. Differences in concentrations were also observed between anatomical sites, with central sites (e.g., heart) having much higher concentrations than peripheral sites (e.g., femoral). Overall, MDMA and MDA appear to exhibit postmortem redistribution and concentrations measured in postmortem specimens (even from peripheral sites) are not directly comparable with antemortem findings close to or prior to death.

The Epping Jaundice outbreak: mortality after 38 years of follow-up.

OBJECTIVE: To investigate mortality in individuals exposed to 4,4'-methylenedianiline (MDA). METHODS: The mortality of 84 individuals, accidentally poisoned with MDA during the "Epping Jaundice" outbreak of 1965, was compared with expected values based on national rates defined by age, period and sex, for the period 1965-2002. In addition, cancer registration data were analysed for the period 1971-2002. RESULTS: The vital status of 83% of the group was established, with 37 deaths occurring before the end of follow-up. Mortality from all causes was close to expectation among females (Obs, 25; Exp, 30.3; SMR, 82), and below expectation among males (Obs, 12; Exp, 26.7; SMR, 45). There were no observed deaths from cancer of the liver or from nonmalignant liver disease. CONCLUSIONS: This study has found no evidence to suggest that the ingestion of MDA had adversely affected mortality.

Interpretation of a 3,4-methylenedioxymethamphetamine (MDMA) blood level: discussion by means of a distribution study in two fatalities.

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy" is a currently used or abused designer drug and fatalities are frequently encountered in forensic practice. However, the question remains open whether an MDMA blood level can be toxic or even potentially lethal. In order to provide insight in the interpretation of a detected MDMA concentration, the distribution of MDMA and its metabolite 3,4-methylenedioxyamphetamine (MDA) in various body fluids and tissues was studied and discussed in two different fatalities. Apart from peripheral blood samples (such as femoral and subclavian blood), various blood samples obtained centrally in the human body and several body fluids (such as vitreous humour) were examined. In addition, various tissues such as cardiac muscle, lungs, liver, kidneys, and brain lobes were analysed. In contrast to the peripheral blood levels, high MDMA and MDA levels were found in cardiac blood and the majority of the organs, except for the abdominal adipose tissue. The high concentrations observed in all lung lobes, the liver and stomach contents indicate that post-mortem redistribution of MDMA and MDA into cardiac blood can occur and, as a result, blood sampled centrally in the body should be avoided. Therefore, our data confirm that peripheral blood sampling remains "the golden standard". In addition, a distinct difference in peripheral blood MDMA concentrations in our two overdose cases was established (namely 0.271 and 13.508 microg/ml, respectively). Furthermore, our results suggest that, if a peripheral blood sample is not available and when putrefaction is not too pronounced, vitreous humour and iliopsoas muscle can be valuable specimens for toxicological analysis. Finally, referring to the various mechanisms of death following amphetamine intake, which can result in different survival times (e.g. cardiopulmonary complications versus hyperthermia), the anatomo-pathological findings and the toxicological results should be considered as a whole in arriving at a conclusion.

Death rates from ecstasy (MDMA, MDA) and polydrug use in England and Wales 1996-2002.

The present study reports on all deaths related to taking ecstasy (alone, or in a polydrug combination) occurring in England and Wales in the time frame August 1996-April 2002. Data presented here are based on all information recorded in the National Programme on Substance Abuse Deaths (np-SAD) database. The np-SAD regularly receives all information on drug related deaths in addicts and non addicts from coroners. A total of 202 ecstasy-related fatalities occurred in the chosen time-frame, showing a steady increase in the number of deaths each year. The ratio male:female was 4:1 and 3 of 4 victims were younger than 29. In 17% of cases ecstasy was the sole drug implicated in death and in the remaining cases a number of other drugs (mostly alcohol, cocaine, amphetamines and opiates) have been found. According to toxicology results, MDMA accounted for 86% of cases and MDA for 13% of cases; single deaths were associated with MDEA and PMA. This is the largest sample of ecstasy related deaths so far; possible explanations are given for the observed steady increase in ecstasy-related deaths and a tentative 'rationale' for this polypharmacy combination is then proposed.

Tissue concentrations of MDMA and its metabolite MDA in three fatal cases of overdose.

The recreational use of amphetamine derivatives has become increasingly popular in our country in past recent years. Their use is especially common among young people participating in dance parties known as "raves." As a direct consequence of their increased use, the number of fatal cases in which these compounds have been involved have increased dramatically since the second half of the last decade. In our laboratory, we have registered 25 cases related to amphetamine derivatives use since 1996. Three of them were deeply studied and the results obtained are presented in this paper. This information may be useful for the interpretation of the results obtained in toxicological analysis in the cases in which death may be attributed to MDMA use.

Fatality due to combined use of the designer drugs MDMA and PMA: a distribution study.

We present a fatal case involving the combined ingestion of amphetamine, 3,4-methylenedioxymethylamphetamine, 3,4-methylenedioxyamphetamine, and paramethoxyamphetamine. Various postmortem specimens (e.g., several blood samples, urine, and tissue samples) were analyzed to study the distribution of the compounds and their metabolites in the human body. Quantitation took place using liquid chromatography-sonic spray ionization-mass spectrometry after pretreatment with a liquid-liquid extraction. The medico-legal findings were compatible with a disseminated intravascular coagulation induced by hyperthermia caused by the simultaneous intake of the amphetamine analogues.

Altered states: the clinical effects of Ecstasy.

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.

Immunohistochemical demonstration of the amphetamine derivatives 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) in human post-mortem brain tissues and the pituitary gland.

Abuse of amphetamine derivatives such as 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) is an important issue in current forensic practice and fatalities are not infrequent. Therefore, we investigated an immunohistochemical method to detect the amphetamine analogues MDMA and MDA in human tissues. For the staining procedure, the Catalysed Signal Amplification (CSA) method using peroxidase (HRP) provided by Dako and specific monoclonal antibodies were used. Appropriate controls for validation of the technique were included. The distribution of these designer drugs was studied in various brain regions including the four lobes, the basal ganglia, hypothalamus, hippocampus, corpus callosum, medulla oblongata, pons, cerebellar vermis and, additionally, in the pituitary gland. A distinct positive reaction was observed in all cortical brain regions and the neurons of the basal ganglia, the hypothalamus, the hippocampus and the cerebellar vermis but in the brainstem, relatively weak staining of neurons was seen. The reaction presented as a mainly diffuse cytoplasmic staining of the perikaryon of the neurons, and often axons and dendrites were also visualised. In addition, the immunoreactivity was present in the white matter. In the pituitary gland, however, distinct immunopositive cells were observed, with a prominent heterogeneity. The immunohistochemical findings were supported by the toxicological data. This immunostaining technique can be used as evidence of intake or even poisoning with MDMA and/or MDA and can be an interesting tool in forensic practice when the usual samples for toxicological analysis are not available. Furthermore, this method can be used to investigate the distribution of these substances in the human body.

Distribution study of 3,4-methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine in a fatal overdose.

In this study, regional tissue distributions of the amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") and its metabolite 3,4-methylenedioxyamphetamine (MDA) in a fatal overdose are presented. Quantitation of MDMA and MDA levels occurred in blood samples taken centrally (right and left heart and main adjacent great vessels) and peripherally (subclavian and femoral blood). In addition, MDMA and MDA concentrations were determined in cardiac and iliopsoas muscle, both lungs, liver, both kidneys, spleen, the four brain lobes, cerebellum and brainstem, and adipose tissue. Finally, MDMA and MDA levels were determined in serum, vitreous humor, urine, and bile. For all samples, a fully validated high-pressure liquid chromatography procedure with fluorescence detection was used. The found substances were also identified with liquid chromatography-tandem mass spectrometry. Our data confirm that blood sampling from an isolated peripheral vein is recommended for MDMA and MDA. In addition, the vitreous humor MDMA level indicates that this fluid can be an interesting alternative when a suitable blood sample is missing. Considering the substantial differences in concentrations in blood samples taken from various sites in the body and the high levels in some tissues (e.g., in liver), we concluded that the influence of postmortem redistribution should be taken into account in the interpretation of toxicological data when an appropriate peripheral sample cannot be obtained or when blood samples are not available because of putrefaction.

Restraint as a stressor in mice: against the dopaminergic neurotoxicity of D-MDMA, low body weight mitigates restraint-induced hypothermia and consequent neuroprotection.

In experimental studies of stress, restraint of laboratory rodents, perceived as easy to apply and believed to be reproducible, is a commonly used manipulation. The restraint manipulation is utilized as a technique to characterize the physiological, cellular and molecular consequences of stress as well as a tool to understand the ways in which stress may interact with toxic substances. In previous work, we utilized restraint in an examination of the effect of stress on the striatal dopaminergic neurotoxicity engendered by a series of substituted amphetamines. Contrary to our expectations, and most likely due to its body temperature-reducing properties in the mouse, restraint provided total or near total protection against the neurotoxicity of these agents. During subsequent studies utilizing C57Bl6/J female mice of varying weights and ages the degree of temperature reduction and the associated ability to block (20-100%) the dopamine depletion associated with the neurotoxic amphetamine 3,4-methylendioxyamphetamine (D-MDMA, 20 mg/kg of mouse body weight, every 2 h, s.c., total of four doses) were found to vary considerably more than had been previously observed. An in-depth analysis of the role mouse weight plays in the temperature reduction induced by restraint indicates mouse weight is a primary determinant of hypothermia and subsequent neuroprotection. It suggests the induction of stress in rodents by restraint is a complex effect that may lead to unanticipated results. The restraint manipulation is not as straight-forward a procedure as is commonly believed. Our data indicate that consistent application of restraint may require an adjustment of the restrainer device to mouse body weight.

Deaths associated with MBDB misuse.

The use of phenethylamines in the dance scene is now well established. Apart from amphetamine, the commonest phenethylamine encountered in clinical and forensic settings is 3,4-methylenedioxymethamphetamine (MDMA) commonly known as ecstasy. Other phenethylamines, which have similar effects are encountered, such as 3,4-methylenedioxyethylamphetamine (MDEA) and their use has resulted in death. We report two deaths associated with another less commonly encountered member of the group, N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), also known as Methyl-J and Eden.

Adam (MDMA) and Eve (MDEA) misuse: an immunohistochemical study on three fatal cases.

Three fatal cases of MDMA/MDEA misuse have been examined. These referred to white males between 19 and 20 years of age, in which post-mortem toxicology showed the presence of MDMA (in one case), MDEA (in one case) and both (in one case). The clinical data were analysed and the histopathological findings were studied following immunohistochemical investigations. A complete immunohistochemical study has made it possible to demonstrate rhabdomyolysis and myoglobinuria with alterations of the organs typical of a DIC. Clinical, histopathological and toxicological data suggest that severe or fatal complications following ecstasy ingestion could be related to idiosyncratic response.

Intentional overdose and death with 3,4-methylenedioxyethamphetamine (MDEA; "Eve"): case report.

We report a case of suicide following ingestion of a large dose of 3,4-methylenedioxyethamphetamine (MDEA, "Eve") in a 27-year-old woman with a history of depression. Several days before her death, she had attempted suicide with benzodiazepines resulting in a 24-hour hospital admission; at that time, no physiologic abnormalities were detected. Findings on autopsy were nonspecific. Toxicologic analysis showed a high concentration of MDEA and the appearance of benzodiazepines in body fluids. Ethanol and other drugs of abuse were not found. We discuss the clinical manifestations, toxicologic syndromes, and mechanisms of death with amphetamine intoxication. MDEA intoxication in young people may result in sudden death.

[Ecstasy--cool dope with long-lasting effects?]. / Ecstasy--kult dop med senfølger?

The amphetamine derivative MDMA (3,4-methylenedioxymethamphetamine) was first synthesised in 1914 as an appetite suppressant, but was never used as such. MDMA is commonly known as "ecstasy" and has become a popular recreational drug of abuse at dance-clubs and rave parties, where it is combined with all-night dancing, crowded conditions, poor hydration and loud sound. This combination is probably the main reason why we have seen an upsurge in toxicity problems at rave parties, since all these factors are thought to promote or increase the toxicity of MDMA. The desired effects of MDMA are euphoria, increased energy and enhanced communication with others. Adverse effects are hyperthermia, rhabdomyolysis, acute renal failure, hepatotoxicity, depression and psychosis.