Plasma,oral fluid and sweat wipe ecstasy concentrations in controlled and real life conditions

In a double-blind placebo controlled study on psychomotor skills important for car driving (Study 1), a 75 mg dose of +/- 3,4-methylenedioxymethamphetamine (MDMA) was administered orally to 12 healthy volunteers who were known to be recreational MDMA-users. Toxicokinetic data were gathered by analysis of blood, urine, oral fluid and sweat wipes collected during the first 5h after administration. Resultant plasma concentrations varied from 21 to 295 ng/ml, with an average peak concentration of 178 ng/ml observed between 2 and 4h after administration. MDA concentrations never exceeded 20 ng/ml. Corresponding MDMA concentrations in oral fluid, as measured with a specific LC-MS/MS method (which required only 50 microl of oral fluid), generally exceeded those in plasma and peaked at an average concentration of 1215 ng/ml. A substantial intra- and inter-subject variability was observed with this matrix, and values ranged from 50 to 6982 ng/ml MDMA. Somewhat surprisingly, even 4-5h after ingestion, the MDMA levels in sweat only averaged 25 ng/wipe. In addition to this controlled study, data were collected from 19 MDMA-users who participated in a driving simulator study (Study 2), comparing sober non-drug conditions with MDMA-only and multiple drug use conditions. In this particular study, urine samples were used for general drug screening and oral fluid was collected as an alternative to blood sampling. Analysis of oral fluid samples by LC-MS/MS revealed an average MDMA/MDEA concentration of 1121 ng/ml in the MDMA-only condition, with large inter-subject variability. This was also the case in the multiple drug condition, where generally, significantly higher concentrations of MDMA, MDEA and/or amphetamine were detected in the oral fluid samples. Urine screening revealed the presence of combinations such as MDMA, MDEA, amph, cannabis, cocaine, LSD and psilocine in the multiple-drug condition.     

Involvement of Amphetamines in Sudden and Unexpected Death

Abstract:  In the present study, the effects of amphetamine-class drugs were examined in cases reported to the Victorian coroner from 2001 to 2005 to determine if death can occur from the use of amphetamine-class drugs alone. A total of 169 cases were reviewed where a forensic autopsy detected amphetamine(s) in the blood. Pathology, toxicology, and police reports were analyzed in all cases to ascertain the involvement of amphetamine-class drugs in these deaths. In Victoria, methamphetamine (MA) is the principal abused amphetamine-class followed by methylenedioxymethamphetamine (MDMA). There were six cases in which a cerebral hemorrhage caused death and three cases in which serotonin syndrome was established as being caused by the interaction of MDMA and moclobemide. There were 19 cases in which long-term use of amphetamines was associated with heart disease. There were three cases where amphetamine-class drugs alone were regarded as the cause of death, of which two cases exhibited high levels of MDMA and lesser amounts of MA and/or amphetamine. There were no cases in which significant natural disease was absent and death was regarded as caused by the use of MA. There was no correlation between blood concentration of drug and outcome.     

Serotonin toxicity involving MDMA (ecstasy) and moclobemide

The use of MDMA (ecstasy) in Australia is a widespread and growing problem, promoting acute toxicity and disease which can lead to premature death in users. We report four cases of fatal serotonin toxicity caused by the combination of MDMA and moclobemide, a reversible MAO-A inhibitor with potent serotonergic activity. Despite the highly reported toxicity of this drug combination, there are very few reports of fatalities attributed to a MDMA and moclobemide interaction. Pathology and toxicology reports, initial police reports and coroners' findings were examined to determine the circumstances of the deaths. Symptoms of some of the four cases as reported by paramedics and medical staff included hyperthermia, hyperkalemia, profuse sweating, twitching and shaking. Two cases involved moclobemide concentrations consistent with common prescribed doses, while the other two cases involved much higher concentrations often associated with toxicity. Three of these cases presented with some form of heart disease.     

Does Hyperthyroidism Increase Risk of Death Due to the Ingestion of Ecstasy?

Ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is a psychoactive amphetamine derivative widely used for recreational purposes. Deaths caused by acute drug intoxication with MDMA are rare but can often involve a severe hyperthermic episode. The factors underlying the increased risk of some ecstasy users to a fatal drug reaction are not known. We present a case report of a 24-year-old woman who developed fatal hyperthermia with multi-organ complications following MDMA use and was found at autopsy to have diffuse thyroid hyperplasia (Graves' disease). An antemortem blood MDMA concentration of 0.68 mg/L was measured in a sample obtained on admission to hospital. Although a cause and effect cannot be established, as the thyroid hormone is a major regulator of thermogenesis, we suggest that hyperthyroidism predisposed the subject to ecstasy-induced hyperthermia and that a pre-existing defect affecting temperature status could be one factor in explaining some ecstasy intoxication deaths.     

Aortic dissection after ingestion of "ecstasy" (MDMA)

The authors report a case of aortic dissection and cardiac tamponade in a 29-year-old man after ingestion of ecstasy (methylenedioxymethamphetamine, MDMA) at a "rave" party. There was no history of hypertension, myxoid heart disease, or other risk factors for aortic dissection in the deceased, although a minor degree of cystic medial necrosis was noted on histologic examination of the aorta. Autopsy toxicology revealed low residual levels of MDMA in the blood about 48 hours after ingestion of the drug. This case report describes a probable association between MDMA ingestion and aortic dissection in a previously well young adult. The likely mechanisms are discussed, and the difficulties in diagnosing this complication are highlighted.     

Zaleplon and driving impairment

Zaleplon, a sedative-hypnotic, was identified in the blood of a subject arrested for impaired driving. Symptoms reported were those of central nervous system (CNS) depression. The zaleplon concentration was determined to be 0.13 microg/mL. Symptoms included slow movements and reactions, poor coordination, and lack of balance. Although no quantitative relationship between blood concentrations and degree of driving impairment is currently possible, it is reasonable to conclude that because of its specific activity as a sedative-hypnotic, blood concentrations consistent with doses exceeding therapeutic concentrations of zaleplon have the potential to cause impairment of psychomotor function, and would impair a person's level of consciousness and driving ability.     

Use of MDA (the "love drug") and methamphetamine in Toronto by unsuspecting users of ecstasy (MDMA)

It has recently been reported that purity of illicit tablets of ecstasy (MDMA) is now high. Our objective was to confirm whether hair of drug users, who request only ecstasy from their supplier, contains MDMA in the absence of other drugs. GC-MS analysis of scalp hair segments disclosed the presence of MDMA in 19 of 21 subjects and amphetamine/methamphetamine in eight subjects. Surprisingly, seven subjects had hair levels of the MDMA metabolite, MDA, equal to or greater than those of MDMA, suggesting use of MDA in addition to that of MDMA. These amphetamine derivatives might be included by clandestine laboratories to enhance effects of the drug cocktail or because of a perception that MDA synthesis might be simpler than that of MDMA. Drug users and investigators examining possible brain neurotoxic effects of MDMA need to consider that "ecstasy" tablets can contain MDA and methamphetamine despite no demand for the drugs.     

Post-mortem cases involving amphetamine-based drugs in The Netherlands. Comparison with driving under the influence cases

In this study we reviewed the post-mortem cases in the years 1999-2004 that were presented at the Netherlands Forensic Institute. The concentrations of amphetamine-based drugs in femoral blood from cases of suspected unnatural death were compared with concentrations in whole blood from non-fatal cases of driving under the influence (DUI cases) and with literature. Furthermore, the combinations with other drugs and/or alcohol were investigated. Amphetamine-based drugs were present in 70 post-mortem cases and 467 DUI cases. The most detected amphetamine-based drug was MDMA, followed by amphetamine. The presence of MDA could usually be explained by metabolism of MDMA. Methamphetamine and MDEA were rarely present. Frequently, the amphetamine-based drugs were taken in combination with alcohol and/or other non-amphetamine-based drugs such as cocaine or cannabinoids. The 70 post-mortem cases were divided into 38 amphetamine-based drug caused (i.e. the amphetamine-based drug directly caused or contributed to the death) and 32 amphetamine-based drug related deaths (i.e. death was not directly caused by the amphetamine-based drug). In the latter category, other (poly)drug intoxications and death by violence or drowning were the most frequent causes of death. In 30 cases, MDMA caused death directly. The range in blood concentrations of MDMA in these cases was substantial, i.e. 0.41-84 mg/L with a median concentration of 3.7 mg/L (n=30). MDMA blood concentrations in the MDMA related deaths (n=20) and in the DUI cases (n=360) varied up to 3.7 and 4.0 mg/L, respectively. Seven victims died from the direct effects of amphetamine; the blood concentration of amphetamine ranged from 0.24 to 11.3 mg/L, with a median concentration of 1.7 mg/L (n=7). The median concentrations of amphetamine in the amphetamine related deaths (n=13) and the DUI cases (n=208) were much lower, i.e. 0.28 and 0.22 mg/L, respectively. Amphetamine blood concentrations up to 6.0 and 2.3 mg/L were seen in the drug related deaths and DUI cases, respectively. The most frequently encountered amphetamine-based drugs in the investigated deaths were MDMA and amphetamine. The majority of MDMA- and amphetamine-caused deaths, i.e. 90% of these deaths, occurred with blood concentrations above 1.5 and 0.80 mg/L, respectively. MDMA and amphetamine blood concentrations in drug related deaths and DUI cases, however, overlap the range of fatal concentrations. Therefore, MDMA or amphetamine concentrations should never be used alone to establish the cause of death.     

Toluene-Impaired Drivers: Behavioral Observations, Impairment Assessment, and Toxicological Findings

Abstract:  Toluene is an aromatic hydrocarbon solvent frequently abused for its euphoric and intoxicating properties. This report describes a series of six cases involving drivers arrested for driving under the influence who subsequently tested positive for toluene. Case data including driving behavior, physiological signs and symptoms, evidence of impairment, and toxicology findings were reviewed. Blood toluene concentrations in the drivers ranged from 12 to 45 mg/L (median 23 mg/L, mean 25 mg/L, SD 12.1 mg/L). All drivers were determined to be intoxicated, and displayed symptoms including balance problems, confusion and disorientation, loss of coordination, and inability to follow instructions. They also displayed horizontal but not vertical nystagmus, elevated pulse and blood pressure, and lower body temperature. These findings are consistent with prior reports that subjects with blood toluene concentrations above 10 mg/L are invariably under the influence and their driving skills are affected.     

The behavioral and cognitive effects of two benzodiazepines associated with drug-facilitated sexual assault

Recently, sexual assaults have included the use of benzodiazepines to impair the victim. Our aim was to examine the physiological, cognitive, and behavioral effects of flunitrazepam (FN) and clonazepam (CLO). In the first study, ten healthy volunteers received a single oral dose of 2 mg of FN. Mini Mental State Examination (MMSE), behavioral reports and staff observations were then collected. In the second study, ten healthy volunteers received a single oral dose of 3 mg of CLO. Vital signs, performance on the MMSE and Digit Symbol Substitution Test, and behavioral changes were examined. FN significantly decreased systolic and diastolic blood pressure 4 h post drug ingestion with diastolic remaining low at 6 h. CLO was associated with changes in temperature and decreased systolic pressure. FN affected memory and attention 4 h following ingestion. CLO affected memory and attention throughout the study (6 h), and psychomotor performance was decreased 2 h post ingestion. In both studies, subjects were disinhibited and did not perceive their own impairment.     

Post-mortem cases involving amphetamine-based drugs in the Netherlands: Comparison with driving under the influence cases

In this study we reviewed the post-mortem cases in the years 1999–2004 that were presented at the Netherlands Forensic Institute. The concentrations of amphetamine-based drugs in femoral blood from cases of suspected unnatural death were compared with concentrations in whole blood from non-fatal cases of driving under the influence (DUI cases) and with literature. Furthermore, the combinations with other drugs and/or alcohol were investigated. Amphetamine-based drugs were present in 70 post-mortem cases and 467 DUI cases. The most detected amphetamine-based drug was MDMA, followed by amphetamine. The presence of MDA could usually be explained by metabolism of MDMA. Methamphetamine and MDEA were rarely present. Frequently, the amphetamine-based drugs were taken in combination with alcohol and/or other non-amphetamine-based drugs such as cocaine or cannabinoids. The 70 post-mortem cases were divided into 38 amphetamine-based drug caused (i.e. the amphetamine-based drug directly caused or contributed to the death) and 32 amphetamine-based drug related deaths (i.e. death was not directly caused by the amphetamine-based drug). In the latter category, other (poly)drug intoxications and death by violence or drowning were the most frequent causes of death.In 30 cases, MDMA caused death directly. The range in blood concentrations of MDMA in these cases was substantial, i.e. 0.41–84 mg/L with a median concentration of 3.7 mg/L (n = 30). MDMA blood concentrations in the MDMA related deaths (n = 20) and in the DUI cases (n = 360) varied up to 3.7 and 4.0 mg/L, respectively. Seven victims died from the direct effects of amphetamine; the blood concentration of amphetamine ranged from 0.24 to 11.3 mg/L, with a median concentration of 1.7 mg/L (n = 7). The median concentrations of amphetamine in the amphetamine related deaths (n = 13) and the DUI cases (n = 208) were much lower, i.e. 0.28 and 0.22 mg/L, respectively. Amphetamine blood concentrations up to 6.0 and 2.3 mg/L were seen in the drug related deaths and DUI cases, respectively. The most frequently encountered amphetamine-based drugs in the investigated deaths were MDMA and amphetamine. The majority of MDMA- and amphetamine-caused deaths, i.e. 90% of these deaths, occurred with blood concentrations above 1.5 and 0.80 mg/L, respectively. MDMA and amphetamine blood concentrations in drug related deaths and DUI cases, however, overlap the range of fatal concentrations. Therefore, MDMA or amphetamine concentrations should never be used alone to establish the cause of death.     

GHB and driving impairment.

Gamma hydroxybutyrate (GHB) was identified in the blood of 13 subjects arrested for impaired driving. GHB concentrations ranged from 26 to 155 mg/L (mean 87 mg/L, median 95 mg/L). In eight cases, GHB was the only drug detected, and signs of impairment were consistent with those of a CNS depressant, including erratic driving (weaving, swerving, ignoring road signs), confusion, incoherent speech, unresponsiveness, lack of balance, unsteady coordination, poor performances on field sobriety tests, and varying states of wakefulness. Given the ability of GHB to induce sleep and unconsciousness, it is evident from these cases that recreational use of the drug has the potential to impair a person's driving ability.     

Zolpidem and driving impairment

Zolpidem, a non-benzodiazepine hypnotic, was identified in the blood of 29 subjects arrested for impaired driving. Zolpidem concentrations ranged from 0.05 to 1.4 mg/L (mean 0.29 mg/L, median 0.19 mg/L). In the subjects whose cases we reviewed where zolpidem was present with other drugs and/or alcohol, symptoms reported were generally those of CNS depression. Symptoms included slow movements and reactions, slow and slurred speech, poor coordination, lack of balance, flaccid muscle tone, and horizontal and vertical gaze nystagmus. In five separate cases, where zolpidem was the only drug detected (0.08-1.40 mg/L, mean 0.65 mg/L, median 0.47 mg/L), signs of impairment included slow and slurred speech, slow reflexes, disorientation, lack of balance and coordination, and "blacking out." Although no quantitative relationship between blood concentrations and degree of driving impairment is currently possible, it is reasonable to conclude that because of its specific activity as a sleep inducer, blood concentrations consistent with therapeutic doses of zolpidem have the potential to affect driving in a negative way, and that concentrations above the normal therapeutic range would further impair a person's level of consciousness and driving ability.     

Population drug use in Australia: a wastewater analysis

Accurate information on drug use in communities is essential if health, social and economic harms associated with illicit drug use are to be addressed efficiently. In most countries population drug use is estimated indirectly via surveys, medical presentations and police and custom seizures. All of these methods have at least some problems due to bias, small samples and/or long time delays between collecting the information and analysing the results. Recently the direct quantification of drug residues in wastewater has shown promise as a means of monitoring drug use in defined geographical areas. In this study we measured 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine and benzoylecgonine in sewage inflows in metropolitan and regional areas of Australia and compared these data with published European data. Cocaine use was small compared to European cities (p<0.001) but was compensated for by much greater consumption of methamphetamine (p<0.001) and MDMA (p<0.05). MDMA was more popular in regional areas (p<0.05) whereas methamphetamine and cocaine were mainly consumed in the city (p<0.05). Greater than 5-fold increases in MDMA use were detected on weekends (p<0.001). This approach has the potential to improve our understanding of drug use in populations and should be further developed to improve prevention and treatment programs.     

The modern trends in alcohol, drugs and driving research

Research on alcohol, drugs and driving can be broadly separated into experimental and epidemiological studies. Every approach has its inherent advantages and disadvantages. Experimental studies can result in an interpretation by single cause, but can only identify potential risks, and the results can sometimes be of limited value because of the use of non-realistic doses or because of the drug use history or inter-individual differences of the volunteers. Recent studies have used higher, more realistic doses and paid more attention to the combination of alcohol and drugs and have shown that the chronic use of illicit drugs can be associated with some cognitive and/or psychomotor impairment, and can lead to a decrease in driving performance even when the subject is no longer intoxicated.Epidemiological studies include roadside surveys, studies in a subset of drivers, accident risk studies, responsibility analyses, surveys and pharmaco-epidemiological studies. Between studies, results may be incomparable due to testing different populations, different kinds of samples, etc. More large-scale roadside studies are conducted now.Advances in analytical toxicology have also contributed to a better understanding of the risks associated with driving under the influence. While older studies measured the inactive metabolite THC-COOH and did not show an increased risk in cannabis-positive drivers, more recent studies measured the active THC in blood and did show a concentration dependent increase in crash risk. The use of LC–MS/MS has allowed more broad-range screening as this technique can measure many different drugs in a small sample volume. While some older studies used saliva but had many analytical problems (including an insufficient sample volume in up to a third of the cases), newer methods of saliva sampling and analysis give better results. The use of saliva for roadside surveys allows non-invasive sampling, but the lack of correlation with the concentrations in blood makes interpretation of results difficult.The results of both epidemiological and experimental studies should be combined to obtain a good estimate of the impact of certain drugs on driving performance and accident risk. In 2006–07 a committee of international experts drafted guidelines for future research into drugs and driving. These have been taken on board by the DRUID project, a large-scale EU funded project on driving under the influence of drugs, alcohol and medicines.     

MDMA的死后再分布及其机制

对MDMA死后再分布及其发生机制进行的动物实验和案例研究的文献,阐述MDMA死后心血浓度升高、死后通过胃肠道和气管内MDMA的再分布、MDMA在死后代谢再分布中的作用,以及死后再分布的发生机制与死后血液流动、顺浓度梯度扩散、毒物的代谢等有关的问题。     

Swollen Lips After a Night of Partying—An Allergic Reaction to Ecstasy?

Ecstasy (MDMA) is a mood‐lifting drug with numerous somatic side effects, for example, dehydration or continuous chewing and biting. We describe the case of a young woman who underwent a forensic medical examination for suspected sexual assault. She claimed to have suffered from a memory lapse, and she had a painful swelling of her lips with a plaque‐like coating on her lips and buccal mucosa. The attending physician suspected that these findings might have been caused by strong sucking pressure on her lips within the context of a sexual assault. A toxicological examination of a blood specimen verified that she had been under the influence of an extremely high dose of ecstasy (1.456 mg/L MDMA and 0.0213 mg/L MDA). Pursuant to the forensic medical assessment, the described findings on her lips, and buccal mucosa were interpreted as an allergic and mechanical reaction (through continuous chewing and biting) to ecstasy.     

A Polydrug Intoxication Involving Methoxetamine in a Drugs and Driving Case

Methoxetamine ((RS)2‐(3‐methoxyphenyl)‐2‐(ethylamino)cyclohexanone)) is becoming a drug of interest among practitioners of forensic toxicology. In this case report, we describe the case background, standard field sobriety tests, sampling, and analysis of this drug in a whole blood sample as well as screening methods and analysis from a driver operating under the influence of intoxicating substances. Methoxetamine was isolated from the blood sample using mixed mode solid phase extraction. After elution and evaporation, the residue was dissolved in mobile phase (consisting of acetonitrile and aqueous formic acid) for analysis by liquid chromatography–tandem mass spectrometry (LC–MS/MS) and gas chromatography–mass spectrometry (GC–MS). The case sample was found to contain clonazepam, 7‐aminoclonazepam, carboxy‐THC, Ddphenhydramine, and MDMA. The case sample was found to contain 10 ng/mL of the drug (methoxetamine) in whole blood. The results of this drug analysis and previous analyses are discussed in terms of this driver operating under the influence of drugs.     

The prevalence of MDMA/MDA in both hair and urine in drug users

The prevalence and age distribution of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) in hair samples by gas chromatography/mass spectrometry (GC/MS) were studied. The recoveries obtained from hair were 97% and 99% for MDMA and MDA, respectively. The inter- and intra-assay precision and accuracy were determined. Out of 791 hair samples, 44 (5.6 %) contained MDMA and/or MDA. Out of these 44 subjects, urinalyses from 35 were negative for both MDMA and MDA, while only 9 were positive. We also evaluated concentrations of MDMA and MDA, and the metabolite-to-parent drug ratios. This study showed that the abuse of MDMA or MDA was found principally among young adults and male abusers. We found the epidemiology of ecstasy users in Korea between March 2002 and April 2003.