Fatal 4-MEC Intoxication: Case Report and Review of Literature.

ABSTRACT: Synthetic cathinones are one of the major pharmacological families of new psychoactive substances and 4-methylethcathinone (4-MEC) has emerged in recent years as a recreational psychostimulant. We report a case of a 35-year-old man found dead and naked at home by his friend. Although no anatomic cause of death was observed at autopsy, toxicological analysis identified 4-MEC and hydroxyzine at therapeutic level (160 ng/mL). 4-Methylethcathinone was quantified in autopsy samples by a validated method consisting in liquid-liquid extraction and gas chromatography coupled to tandem mass spectrometry: peripheral blood, 14.6 µg/mL; cardiac blood, 43.4 µg/mL; urine, 619 µg/mL; vitreous humor, right 2.9 µg/mL and left 4.4 µg/mL; bile, 43.5 µg/mL; and gastric content, 28.2 µg/mL. The cause of death was 4-MEC intoxication and the manner of death could be either accidental or suicidal. The literature concerning 4-MEC was reviewed, focusing on distribution in classical postmortem matrices and 4-MEC metabolism and postmortem redistribution and stability.

Toxicity of acute exploratory amphetamine-salt medication in amphetamine-naïve pediatrics: a retrospective cohort study.

Background and Objectives: Pediatric ingestions of amphetamines used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) are on the rise. Little data provide an amphetamine dose at which to refer pediatric unintentional ingestions to a healthcare facility for monitoring. We studied the dose at which unintentional ingestions of amphetamines develop symptoms and receive benzodiazepines.Methods: We performed a retrospective study from a single poison center from 1/1/2005 through 11/30/2018. We included single substance ingestion of amphetamine salts to treat ADHD in amphetamine-naïve children age 0-12 years followed to a known outcome. Poison center documentation was reviewed for signs and symptoms related to amphetamine toxicity and use of benzodiazepines.Results: We screened 1,394 cases and 160 met inclusion criteria. The mean age of patients was 1.8 years and 55% were male. The median dose of symptomatic patients (1.38 mg/kg) was greater than those without symptoms (0.83 mg/kg). The median amphetamine dose of patients receiving benzodiazepines (1.58 mg/kg) was also greater than for patients not receiving benzodiazepines (1.0 mg/kg). A dose threshold of greater than 0.75 mg/kg was 100% sensitive and 36.8% specific for benzodiazepine administration and 93.9% sensitive and 47.4% specific for presence of any symptoms.Conclusions: The median dose of amphetamines ingested by patients receiving benzodiazepines was greater than those not receiving benzodiazepines. No child with a dose of ≤0.75 mg/kg received benzodiazepines. Prospective studies should be performed to assess triage guidelines and referral doses.

Potential undercounting of overdose deaths caused by specific drugs in vital statistics data: An analysis of Florida.

INTRODUCTION: Due largely to ambiguous or incomplete information provided on death certificates, the widely cited Multiple Cause of Death (MCOD) data reported by the U.S. Centers for Disease Control and Prevention has been shown to undercount the number of fatal overdoses caused by specific drugs. However, the extent of the undercounts is unclear. METHODS: We obtained the number of fatal overdoses from 2003 to 2017 in Florida caused by the three drug groups (amphetamines, benzodiazepines, and opioids) and three drugs (methadone, cocaine, and heroin) that we could map across the MCOD data and data reported by the Florida Medical Examiners Commission (FMEC). The FMEC data are based on state-mandated reporting of the causal drugs in overdose deaths. We analyzed the differences across all deaths and by gender, age group, and race. RESULTS: Depending on the drug, the numbers of deaths across all individuals reported in the FMEC data ranged from 19 %-39 % higher than the counts in the MCOD data. The differences varied over time and by some demographic factors. CONCLUSIONS: The MCOD data appear to undercount the number of fatal overdoses caused by the drugs we investigated. Our analysis did not identify a cause or pattern to explain the differences. Efforts to improve the reporting of fatal overdoses may enhance our understanding of and subsequently may improve the response to the drug overdose epidemic.

Epidemiología de las intoxicaciones agudas por drogas de abuso en las urgencias de un hospital del Centro de España basada en datos de análisis toxicológico de orina / Epidemiology of acute poisonings for drugs of abuse in the emergency room of a hospital from the Center of Spain based on analysis data toxicological urine

Introducción: las intoxicaciones agudas son motivo de consulta cada vez más frecuente en los Servicios de Urgencia hospitalarios (SUH) debido a la mayor disponibilidad y acceso a productos químicos tóxicos. Se observan diferentes patrones en cada área sanitaria según el tipo de población, geografía y perfil epidemiológico de consumo. Material y métodos: el objetivo de nuestro estudio es realizar un perfil epidemiológico y describir el manejo del paciente que acude por clínica compatible con intoxicación aguda por drogas de abuso (IA) basado en la determinación de tóxicos en orina para seis sustancias (cannabis, opiáceos, cocaína, anfetaminas, benzodiazepinas y éxtasis) solicitados en el período de estudio 2010-2012. Resultados: se solicitaron 2755 peticiones, de las cuales fueron positivas 1429, y se estudiaron al azar 661 historias clínicas. El perfil de paciente intoxicado de nuestra área es el de varón de entre 30 y 40 años, consumidor preferentemente de cannabis y cocaína; las benzodiazepinas son el tóxico más frecuente en las mujeres, con clínica mayoritariamente neurológica, sin diferencias en cuanto a la franja horaria o el mes del año en que recibió el alta desde el propio SUH en casi el 60% de los casos. Discusión: las IA en los SUH representan casi el 1% de las consultas y tienen una escasa mortalidad. En algunos casos, el médico de urgencias comienza el tratamiento antes de conocer el resultado toxicológico, lo que nos hace plantearnos la utilidad real y el coste-efectividad de estas determinaciones en todos los pacientes con alteración del nivel de conciencia. (AU)

Introduction: acute intoxications are a rising and common query demand on the emergency rooms because of the easy access and disponibility to toxic substances, where we can observe different patterns attending to type of population, geography and epidemiologic consume profile. Material and methods: our objective is to analyze the epidemiology and patient handling coming to the Emergency Room (ER) with compatible symptoms of street drugs abuse, based on the determination of cannabis, cocaine, amphetamine, benzodiazepine, opiates and ectasy urine levels in the period 2010-2012. Results: the ER requested 2755 determinations being positive 1429 and randomly examined 661 clinical histories. The profile of intoxicated patient was male, 30 to 40 years old, preferently cannabis and cocaine consumer (benzodiazepine in women), mostly with neurological symptoms when arrive, without differences between months or day time and, almost 60% of them, discharged directly from the ER. Conclusions: acute intoxications barely represent 1% of ER demands and produce poor or scarce mortality. Sometimes, doctors in charge start with therapeutic measures before knowing the results of toxicology, what leads us to ask about actual usefulness and cost-efficiency of the toxicology assay to every patient with low conscious level. (AU)

Studies on Para-Methoxymethamphetamine (PMMA) Metabolite Pattern and Influence of CYP2D6 Genetics in Human Liver Microsomes and Authentic Samples from Fatal PMMA Intoxications.

Para-methoxymethamphetamine (PMMA) has caused numerous fatal poisonings worldwide and appears to be more toxic than other ring-substituted amphetamines. Systemic metabolism is suggested to be important for PMMA neurotoxicity, possibly through activation of minor catechol metabolites to neurotoxic conjugates. The aim of this study was to examine the metabolism of PMMA in humans; for this purpose, we used human liver microsomes (HLMs) and blood samples from three cases of fatal PMMA intoxication. We also examined the impact of CYP2D6 genetics on PMMA metabolism by using genotyped HLMs isolated from CYP2D6 poor, population-average, and ultrarapid metabolizers. In HLMs, PMMA was metabolized mainly to 4-hydroxymethamphetamine (OH-MA), whereas low concentrations of para-methoxyamphetamine (PMA), 4-hydroxyamphetamine (OH-A), dihydroxymethamphetamine (di-OH-MA), and oxilofrine were formed. The metabolite profile in the fatal PMMA intoxications were in accordance with the HLM study, with OH-MA and PMA being the major metabolites, whereas OH-A, oxilofrine, HM-MA and HM-A were detected in low concentrations. A significant influence of CYP2D6 genetics on PMMA metabolism in HLMs was found. The catechol metabolite di-OH-MA has previously been suggested to be involved in PMMA toxicity. Our studies show that the formation of di-OH-MA from PMMA was two to seven times lower than from an equimolar dose of the less toxic drug MDMA, and do not support the hypothesis of catechol metabolites as major determinants of fatal PMMA toxicity. The present study revealed the metabolite pattern of PMMA in humans and demonstrated a great impact of CYP2D6 genetics on human PMMA metabolism.

The prognosis following amphetamine poisoning.

AIMS: This study investigated the long-term mortality following poisoning by amphetamine or substituted amphetamines. Furthermore, we examined the social problems and somatic and psychiatric co-morbidity related to amphetamine poisoning, and their impact on the long-term survival. METHODS: We identified amphetamine poisoned patients from the Danish Poison Information Centre database and correlated their personal identification numbers with seven Danish national registries related to different social and health aspects. For each case, we sampled 100 age and gender matched controls from the background population. RESULTS: From August 2006 to December 2013 we identified 1444 patients (70% males) who experienced amphetamine poisoning; 52% of the cases were classified as mixed poisonings and the average age at first contact was 24.8 years (SD 8.6). The prevalence of psychiatric disorders, HIV, viral hepatitis, and previous prison incarceration was approximately 10 times higher than among healthy controls. After seven years 11% were deceased as opposed to 0.6% in the control group, and 64% of the patients died from unnatural causes. Male gender (HR 2.29, 95% CI (1.07-4.90)), age (HR 1.06, 95% CI (1.03-1.09)), opioid dependence (HR 2.88, 95% CI (1.42-5.85)), schizophrenia (HR 3.09,95% CI (1.63-5.86)), affective disorders (HR 2.65, 95% CI (1.44-4.90)) and HIV (HR 5.45, 95% CI (1.19-24.90)) were associated with a high mortality. Furthermore, a significant proportion of these patients experienced social and health related deterioration in the years following poisoning. CONCLUSIONS: Amphetamine poisoning is associated with a poor long-term prognosis and is complicated by additional social and health related issues.

Medicolegal aspects of PMA-related deaths.

Unlike amphetamine, amphetamine-like substances accessible on the drug market are less expensive and more easily available; they also produce hallucinogenic effects expected by the users. Such properties render them more attractive as compared to amphetamine. On the other hand, the knowledge of the toxicity of these compounds is very limited, what in consequence generates problems that create ever-expanding research areas, including analytical, clinical and medicolegal issues, thus leading to development of systemic databases. An example here is paramethoxyamphetamine (PMA), which appeared on the drug market in recent years as a result of creative inventiveness of producers of psychoactive substances, who aimed at PMA replacing the popular ecstasy (MDMA) as a less expensive and more available product. It is more potent than MDMA, but has a slower onset of action, which encourages users to take more. The problem is illustrated in the present paper by three fatal cases involving PMA, which were comprehensively investigated taking into consideration case histories, pathological and toxicological findings obtained with the use of LC-MS-MS method. In blood samples taken from all the three victims, very high concentrations of PMA were found (in the range of 10-27mg/L) and thus the cause of deaths was determined as overdoses of PMA with the underlying mechanism of acute cardiorespiratory failure.

Reporting Two Fatalities Associated with the Use of 4-Methylethcathinone (4-MEC) and a Review of the Literature.

We report two fatalities that are related to the cathinone 4-methylethcathinone (4-MEC) and review the current knowledge of 4-MEC. Qualitative and quantitative analysis of 4-MEC was performed by validated high performance liquid chromatography-tandem mass spectrometry methods. In the first case a 22-year-old male died in hospital following collapse and seizures after using 4-MEC. Toxicological analysis of postmortem femoral blood revealed the presence of 4-MEC (0.167 mg/L), ethanol (27 mg/100 mL) and paracetamol (5 mg/L). Death was attributed solely to 4-MEC toxicity. The second case involved a 54-year-old man found with a taped plastic bag over his head. Toxicological analysis of postmortem femoral blood revealed the presence of 4-MEC (1.73 mg/L) along with ethanol (229 mg/100 mL), propranolol (0.036 mg/L), venlafaxine (0.284 mg/L) and its metabolite O-desmethylvenlafaxine (0.205 mg/L), and diazepam (<0.005 mg/L) and its metabolite nordiazepam (0.033 mg/L). Death was attributed primarily to asphyxiation. These cases and a review of the current knowledge of 4-MEC pharmacology/toxicology adds to the body of case material for 4-MEC and will assist with interpretation in postmortem toxicology cases in which 4-MEC is detected.

A fatal case of paramethoxyamphetamine poisoning and its detection in hair.

Paramethoxyamphetamine (PMA) is a phenethylamine derivative that is structurally related to 3,4-methylenedioxymethamphetamine (MDMA), but has higher toxicity than MDMA. Here, we report a fatal intoxication case involving PMA. A 36-year-old man was found dead in a hotel room. Toxicological analysis revealed that PMA concentrations were 0.57 and 0.59mg/L in peripheral and heart blood, respectively. Ketamine and diazepam were also detected in his blood. Based on toxicological results and autopsy findings, the cause of death was determined to be acute fatal intoxication with PMA. Hair analysis using gas chromatography/mass spectrometry was performed and PMA was detected at a concentration of 20.1ng/mg after methanol extraction for 20h. This is the first report of the determination of PMA concentration in the hair from a drug abuser.

CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants.

INTRODUCTION: Cytochrome P450 2D6 (CYP2D6) is a member of the cytochrome P450 (CYP) superfamily involved in the biotransformation of drugs and substances of abuse encountered in clinical toxicology. Among the CYP superfamily, the CYP2D6 gene is considered as the most polymorphic as more than 105 different alleles have been identified so far. CYP2D6 genetic polymorphisms have the potential to affect the toxicity of their substrates. OBJECTIVE: This review will focus specifically on CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants in humans. METHODS: PubMed (up to August 2013) was searched with the following selection criteria: 'CYP2D6 AND (toxicology OR poisoning OR intoxication OR overdose)'. Of the 454 citations retrieved, only 46 papers dealt with the impact of CYP2D6 polymorphisms on poisoning due to amfetamines, opioid analgesics and antidepressants. amfetamines. While some in vitro studies suggest that CYP2D6-mediated metabolites of 3,4-methylenedioxymethamfetamine (MDMA) are substantially more cytotoxic compared with unchanged MDMA, it is not yet confirmed in human cases of MDMA intoxication that extensive/ultra-rapid CYP2D6 metabolisers could be at higher risk. This would also apply to methamfetamine exposure and the related cardiac and central nervous system toxicity. Opioid analgesics. CYP2D6 ultra-rapid metabolisers are more likely to experience the adverse effects of codeine and tramadol. Opioid analgesics that do not rely on CYP2D6 for therapeutic activity, such as morphine and hydromorphone, may therefore be a better alternative to codeine and tramadol, with the limitation that these drugs have their own set of adverse reactions. Antidepressants. CYP2D6 poor metabolisers are generally more prone to adverse effects. Among them, the four drugs with the highest level of evidence are amitriptyline, nortriptyline, venlafaxine and fluoxetine. Further data are needed, however, for doxepin and paroxetine, while citalopram adverse effects seem definitely less influenced by CYP2D6 genetic polymorphisms. CONCLUSIONS: Either poor or extensive/ultra-rapid CYP2D6 metabolisers may be exposed to toxic effects of amfetamines, opioid analgesics and antidepressants. In these three categories, the level of evidence is substance dependent, with differences within the same pharmacological class.

Cardiogenic shock after use of fluoroamphetamine confirmed with serum and urine levels.

CONTEXT: 4-Fluoroamphetamine (4-FA) is a para-substituted phenethylamine-type synthetic stimulant that has in recent years gained popularity through internet blogs and market share according to confiscated drug data. No serious toxicity has previously been reported. We report a case of a young man who developed severe toxicity and cardiogenic shock after using 4-FA, with laboratory confirmation. CASE DETAILS: An 18-year-old man presented to the emergency department with vomiting, shortness of breath, chest tightness, and altered mental status about 5 h after using a new and unfamiliar street drug. Two days prior, he had received naltrexone intramuscular injection as part of an opioid addiction treatment program and was taking fluoxetine and trazodone. Five hours after presentation, he developed cardiogenic shock requiring intraaortic balloon pump, inotropic and ventilatory support. An echocardiogram showed left ventricular (LV) hypokinesia, sparing the apex and ejection fraction (EF) = 10%. Comprehensive toxicology serum testing revealed FA, naproxen, trazodone, and cotinine. The 4-FA urine level was 64,000 ng/ml and serum level was 118 ng/ml. With slow recovery, the patient was discharged after 2 weeks of hospitalization. DISCUSSION: Although no previously reported 4-FA clinical poisoning cases have been published for comparison, by examining 4-FA pharmacology compared with other stimulant drugs, and given this patient's presentation and echocardiogram suggestive of reverse takotsubo cardiomyopathy we suspect the toxic mechanism was an acute cardiomyopathy caused by 4-FA catecholamine-induced myocarditis and/or small vessel myocardial ischemia. CONCLUSION: Recreational use of 4-FA may present with life threatening toxicity including cardiomyopathy, cardiogenic shock, and pulmonary edema.

Toxic leukoencephalopathy in the intensive care unit.

In this article, we report two cases of acute toxic leukoencephalopathy to highlight this acute clinicoradiological syndrome as an important, although uncommon, consideration in the undifferentiated comatose patient who fails to wake following drug overdose or has unexplained neurology with a history of drug exposure. We then review the current literature and discuss potential differential diagnoses in this setting, along with proposed treatments for this condition. The cases presented demonstrate a more fulminant onset than previously well-defined acute toxic leukoencephalopathy subtypes and highlight the prognostic importance of magnetic resonance imaging in diagnosing a condition from which significant functional recovery seems possible.

Common ocular effects reported to a poison control center after systemic absorption of drugs in therapeutic and toxic doses.

PURPOSE OF REVIEW: Ocular effects resulting from medications assist toxicologists in determining substances involved when treating a poisoned patient. The intention of this review is to discuss the most common ocular effects, the medications that cause them, and the mechanisms by which they occur. RECENT FINDINGS: According to National Poison Data System, the most common reported ocular effects following a drug ingestion/injection/inhalation are mydriasis, miosis, and nystagmus. The most common drug/drug classes reported to a regional poison control center causing these ocular effects include the following: first, mydriasis - amphetamines and diphenhydramine; second, miosis - clonidine and opioids; third, nystagmus - dextromethorphan. However, many other drugs/substances can cause these effects along with other systemic effects. SUMMARY: Ocular findings are a pertinent component of any patient assessment involving therapeutic and/or toxic exposure to medications and other substances.

"PMA sounds fun": negotiating drug discourses online.

In 2007, a young woman, Annabel Catt, died after consuming a capsule sold as "ecstasy" that contained para-methoxyamphetamine. In this paper, we describe how this death was depicted in online drug-user communities and illustrate how the meanings of drug use are negotiated in online settings. News articles, public online discussions, and online fieldwork formed the data. This paper demonstrates how dominant drug discourses may be resisted by drug users, drawing on theories of health resistance and Kane Race's concept of counterpublic health. Online environments may offer ways of engaging people who use drugs that acknowledge both pleasure and safety. The study's limitations are noted.

The evolving high: new designer drugs of abuse.

Over the past decade, emerging drugs of abuse and synthetic derivatives of more traditional agents have flooded the market. While Europe was the first to experience a surge in the use of drugs such as synthetic cathinones and cannabinoids, poison centers throughout the United States have seen a dramatic rise in calls related to these new designer drugs of abuse. In the majority of cases, care is largely supportive but significant medical and traumatic complications may occur. Providers must be aware of the ever-changing trends in abuse, so that they may optimally care for poisoned patients.

Adderall® (amphetamine-dextroamphetamine) toxicity.

The American Psychiatric Association estimates that 3-7% of US school-aged children exhibit attention-deficit/hyperactivity disorder (ADHD). Adderall(®) (amphetamine dextroamphetamine) and a variety of brand names and generic versions of this combination are available by prescription to treat ADHD and narcolepsy. Both immediate and sustained release products are used as are single agent amphetamine medication. Knowing the exact agent ingested can provide information of dose labeled and length of clinical effects. These drugs are used off label by college students for memory enhancement, test taking ability, and for study marathons. These agents are DEA Schedule II controlled substances with high potential for abuse. For humans with ADHD or narcolepsy, standard recommended dosage is 5-60 mg daily. Amphetamine and its analogues stimulate the release of norepinephrine affecting both α- and ß-adrenergic receptor sites. α-Adrenergic stimulation causes vasoconstriction and an increase in total peripheral resistance. ß-Adrenergic receptor stimulation leads to an increase in heart rate, stroke volume, and skeletal muscle blood flow. Clinical signs of Adderall(®) overdose in humans and dogs include hyperactivity, hyperthermia, tachycardia, tachypnea, mydriasis, tremors, and seizures. In addition, Adderall intoxication in dogs has been reported to cause hyperthermia, hypoglycemia, hypersegmentation of neutrophils, and mild thrombocytopenia. Diagnosis can be confirmed by detecting amphetamine in stomach contents or vomitus, or by positive results obtained in urine tests for illicit drugs. Treatment is directed at controlling life-threatening central nervous system and cardiovascular signs. Seizures can be controlled with benzodiazepines, phenothiazines, pentobarbital, and propofol. Cardiac tachyarrhythmias can be managed with a ß-blocker such as propranolol. Intravenous fluids counter the hyperthermia, assist in maintenance of renal function, and help promote the elimination of amphetamine and its analogues. Prognosis after poisoning with Adderall(®) depends upon the severity and duration of clinical signs at presentation. Differential diagnoses that should be considered in cases of suspected amphetamine overdose are any other agents that can cause central nervous system stimulation, tremors, and seizures. This article discusses our present understanding of Adderall(®) intoxication and examines 3 dogs presented to our practice after ingestion of large amounts of the drug.

[Intoxation with paramethoxymethamphetamine]. / Forgiftning med parametoksymetamfetamin.

BACKGROUND: Since the summer of 2010, there has been an epidemic of deaths related to paramethoxymethamphetamine (PMMA) in Norway. We present a review of the pharmacology and toxicology of the substance. MATERIAL AND METHOD: The review is based on a literature search in the databases PubMed, Ovid and MEDLINE. A discretionary selection was made of relevant articles. RESULTS: Paramethoxymethamphetamine and paramethoxyamphetamine (PMA) are two so-called designer amphetamines which appear from time to time on the illegal narcotics market in many countries. They are frequently sold as ecstasy or amphetamine, often mixed with amphetamine or methamphetamine. The substances, known on the street as «Death¼, have potent serotonergic effects and are associated with significant toxicity. Many deaths have been reported worldwide, even after intake of an «ordinary user dose¼. The narcotic effect is not very pronounced and the onset is slow, which may lead to unintentional overdosing. INTERPRETATION: In cases of severe intoxation that are apparently related to intake of amphetamine or ecstasy, PMMA/PMA intoxation should be suspected.