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Introduction: Amphetamine poisoning in children is a significant public health concern due to its potential for severe adverse effects on physical and mental health. In this article, we describe a case series of 29 children under the age of 14 presenting with sympathomimetic toxidrome due to confirmed amphetamine poisoning., Material and Method: In this cross-sectional study, children (1 month to 14 years old) who were hospitalized in the emergency and pediatric departments of Imam Reza and Akbar Hospital in Mashhad from the beginning of April 2021 to September 2022 were identified with the diagnosis of amphetamine poisoning. Their demographic, clinical, and paraclinical (laboratory and electrocardiogram) information, which was included in the relevant checklists, were analyzed and reported., Findings: Out of 29 children included in the study, 18 (62%) were male and the rest were female. The average age of children was 44.75 ±43.9 months; most of them were less than 4 years old. In all patients, glasgow coma scale (GCS) was 15. In 25.92% of cases (8 patients) blood pressure was above the 90% percentile for age and sex, 82.60% (24 cases) were tachycardia, 72.41% crying (21 cases), 86.20% were restless (25 cases), 10.34% tremor (3 cases), 10.34% had body pain (3 cases), and 6.89% (2 cases) had delusions. None of the subjects had a seizure. The serum level of creatine phosphokinase was on average 771.99 ± 966 units/L. All children had an increase in creatine phosphokinase (CPK) and 25.9% of children had an increase in CPK to more than 1000 units/L., Conclusion: Based on the results, in children with symptoms such as restlessness, crying, and tachycardia, poisoning with amphetamine group substances should be included in the differential diagnosis list, and also measuring CPK and investigating the possible occurrence of rhabdomyolysis in cases of poisoning of children with amphetamine seems necessary., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: The authors report no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

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.

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

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.

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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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.

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.

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.

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.

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., (© The Author(s) 2014.)

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.

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 «Death», have potent serotonergic effects and are associated with significant toxicity. Many deaths have been reported worldwide, even after intake of an «ordinary user dose». 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.

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 β-adrenergic receptor sites. α-Adrenergic stimulation causes vasoconstriction and an increase in total peripheral resistance. β-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 β-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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The consumption of illicit substances represents a considerable threat to the health and wellbeing of particular sectors of our communities. Hospitalisation is sometimes required for the treatment of the direct toxic effects of the drugs as well as for injuries sustained while under their influence. Although poisoning with 'traditional' substances of abuse such as opioids, cocaine and cannabis still predominate in terms of numbers, the availability and use of new psychoactive substances are on the rise. These latter agents, some of which began life as failed pharmaceutical products, have enjoyed renewed status as recreational stimulants, entactogens or hallucinogens, properties that originally precluded them from legitimate use. These drugs may act by enhancing endogenous release of neurotransmitters, inhibiting their reuptake back into neurons or having direct effects on receptors, and may involve adrenergic, dopaminergic or serotonergic systems. The use of intravenous lipid emulsion for the symptomatic treatment of drug overdose has become a fertile ground for research and may hold promise as a non-specific treatment for poisoning with illicit substances. Dexmedetomidine, an α(2)-receptor agonist with a central sympatholytic effect, may be able to counteract the cardiovascular and central nervous system overstimulation that may accompany stimulant toxicity., (Anaesthesia © 2012 The Association of Anaesthetists of Great Britain and Ireland.)

Objective: Amphetamine use is a global public health problem. We examined hospitalisations in a cohort of 138 patients who presented with an amphetamine-related problem to an ED in 2005., Methods: A record linkage study, using the morbidity, ED and mortality databases in the Data Linkage Unit of the Department of Health, Western Australia. The main outcome measures were hospital separations and length of stay (LOS) 5 years before and 4 years after entry into the cohort., Results: One hundred and thirty patients (94%) with an amphetamine-related presentation had a link with the hospital morbidity dataset. The most common diagnosis before and after cohort entry was mental disorders (before: F00-F99; 405 separations, total LOS 2570 days; after: 309 separations, total LOS 3671 days). Injury and poisoning was the next most common in both time periods. Men had an increased relative risk (RR) for all days of psychiatric care (RR 2.12, 95% CI 1.04-4.35). After adjusting for age and sex, the highest risks of increased LOS occurred within 1 year before (RR 2.22, 95% CI 1.01-4.91) and 2 years post entry into the cohort (RR 4.21, 95% CI 1.87-9.46 and RR 2.82, 95% CI 1.25-6.34). There were four (2.9%, 95% CI 0.9-7.7%) deaths, which occurred within 2 years post cohort entry., Conclusion: Amphetamine-related presentations to the ED are associated with a significant cluster of hospitalisations around that episode. This is most prominent for psychiatric diagnoses, with a large increase in the total LOS in the year following cohort entry. Counselling less risky behaviour might decrease the burden of illness., (© 2012 The Authors. EMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.)

Introduction: We report a case of ethcathinone and methylone poisoning with severe clinical toxicity. This is to our knowledge the first case reported in the medical toxicology literature., Case Report: A 22-year-old woman was brought to the emergency department following several episodes of tonicoclonic seizures, a few hours after ingesting "legal ecstasy". The patient needed intubation for recurrent seizures, and she was found to have severe hyponatremia (120 mmol/L) that was corrected with hypertonic saline. The patient's mental status improved rapidly, and she was extubated the day following her admission. However, she developed prolonged rhabdomyolysis (CK 34.537 U/L) that required a 6-day hospitalisation., Discussion: The seizures and the hyponatremia may be explained by the MDMA-like characteristics of methylone that may induce inappropriate secretion of antidiuretic hormone mediated via the serotonin system. The combination of methylone and ethcatinone (both acting like serotonin reuptake inhibitors) might have contributed to neurologic manifestations compatible with serotonin toxicity, although our patient never had autonomic instability. Our patient had a prolonged period of rhabdomyolysis which may also be explained by excessive serotonin activity resulting in an increased motor hyperactivity. The public has to be aware of this growing health problem. Clinicians must report future cases of toxicity related to the use of cathinone synthetic derivatives in order to increase our knowledge of these substances.

Two types of drugs are generally used for treating attention-deficit/hyperactivity disorder or attention-deficit disorder in humans: amphetamines or similar stimulants and the nonamphetamine atomoxetine. We describe the toxicity and treatment of both amphetamines and similar medications and atomoxetine in dogs and cats. Amphetamine intoxication can cause life-threatening stimulatory signs. Treatment is aimed at preventing absorption, controlling the stimulatory signs, and protecting the kidneys; prognosis is generally good. Atomoxetine also has a fast onset of action; stimulatory signs such as hyperactivity and tachycardia are often seen. There are little published data about treatment of atomoxetine toxicity in cats and dogs.

Context: Paramethoxymethamphetamine (PMMA) is a hallucinogenic synthetic substituted amphetamine that was not included in the Israeli Controlled Substance Act (CSA)., Objective: To report a severe PMMA and paramethoxyamphetamine (PMA) outbreak., Patients and Methods: The Israeli national forensic toxicology laboratory analyzes the body fluids of unnatural deaths by means of screening immunoassays and chromatographic confirmation and quantification. Samples are referred to this laboratory by the Israeli Forensic Medicine Institute and by hospitals following consultation with the Israel Poison Information Center. The forensic toxicology laboratory began determining PMMA and PMA in February 2007. In all fatal cases with a positive immunoassay screen for amphetamines, a chromatographic analysis of PMA and PMMA was performed. The laboratory and demographic data of consecutive patients in whom PMMA or PMA were detected, were collected during 1 year and subjected to descriptive analysis., Results: Of 108 fatal cases with a positive screen for amphetamines, 32 were confirmed. Twenty-four of the 32 cases tested positive for PMMA and PMA--age 27 ± 5 years, 79.2% males, post mortem whole blood PMMA and PMA concentrations 0.35 ± 0.24 and 2.72 ± 1.67 mcg/mL, respectively. Co-exposures were detected in 17 (70.8%) fatalities; including methylenedioxymethamphetamine, methylenedioxyamphetamine, cocaine, cannabinoids, cathinone derivatives, ephedrine/pseudoephedrine, opiates, and ethanol. In addition, five non-fatal male cases were identified; age 32 ± 5 years, four had co-exposures to cocaine, cathinone derivatives, and cannabinoids. These findings led to the inclusion of PMMA in the CSA in July 2007, resulting in only three more fatalities in the following year., Discussion: We report an outbreak of PMMA and PMA poisoning resulting in 24 fatalities, and the post mortem whole blood and urine concentrations of these two compounds. PMA was probably the result of PMMA metabolism. Stimulant co-exposures may have contributed to the severity of the poisoning., Conclusion: Forensic laboratory and poison center co-operation is important in identifying a new drug of abuse.

Introduction: We investigated fatal poisonings among drug addicts in 2007. The cause of death, abuse pattern and geographic differences are presented., Material and Methods: All drug-related deaths examined at the three forensic medicine institutes in Denmark in 2007 were evaluated., Results: The number of drug-related deaths in 2007 was 226. Methadone deaths had increased since 1997 while heroin/morphine deaths decreased. In earlier studies, very few deaths from central stimulants like cocaine and amphetamines occurred (1-1.5%), but in 2007 6% of the deaths were caused by these drugs. Multiple drug use was common. Heroin/morphine, cocaine, amphetamine, cannabis, methadone, benzodiazepines and alcohol were included in the poly-drug use., Conclusion: This investigation shows stabilization in the number of fatal poisonings in drug addicts. Geographic differences were observed. Methadone was the most frequent cause of fatal poisoning and there was a continuous decrease in heroin/morphine deaths. Fatal deaths from cocaine and amphetamine have increased considerably. Multiple drug use was common., Funding: not relevant., Trial Registration: not relevant.

Two recent cases of death due to p-methoxyamphetamine (PAM) intake, a methoxylated phenethylamine derivative, were described and compared with previous PMA related deaths that occurred in many countries. Following a review of the available literature from 1974 to 2011 three periods of resurgence of an unsuspected increase of lethal PMA causation were considered. Signs of intoxications, concentrations of PMA found in biological materials were discussed. Based on the case reports can be concluded the great number of victims were unconscious of taking PMA as substitute of MDMA. Two new methods for screening, identification and quantification of amphetamine derivatives in biosamples (blood and urine) using LC-MS/MS techniques were developed. The methods have proven to be appropriate for clinical and forensic toxicology purposes.

Background: Studying drugged drivers gives complementary information about mortality of drug users, which mainly has been studied among opioid abusers. The aim of this study was to analyse mortality rates and causes of death among drivers under the influence of drugs (DUID) in Finland and compare them with the general Finnish population during 1993-2006., Methods: Register data from 5832 DUID suspects apprehended by the police were studied, with a reference group (n=74 809) drawn from the general Finnish population. Deaths were traced from the National Death Register. Survival and differences in mortality hazards were estimated using Kaplan-Meier plots and Cox regression models., Results: The hazard of death was higher among male (HR 9.6, CI 8.7 to 10.6) and female (HR 9.1, CI 6.4 to 12.8) DUID suspects compared to the reference population. Among male DUID suspects, cause-specific hazards were highest for poisoning/overdose, violence and suicide. 24% of DUID suspects and 8% of reference subjects were under the influence of drugs/alcohol at the time of death. Poly-drug findings indicated excess in mortality among drugged drivers. Hazard of death was higher among male DUID suspects who had findings for benzodiazepines only (HR 10.0, CI 8.4 to 11.9) or benzodiazepines with alcohol (HR 9.6, CI 8.2 to 11.2), than with findings for amphetamines (HR 4.6, CI 2.7 to 7.6)., Conclusion: DUID suspects had an increased risk of death in all observed causes of death. Findings for benzodiazepines indicated excessive mortality over findings for amphetamines. Preventive actions should be aimed especially at DUID subgroups using benzodiazepines.

Adderall, consisting of a mixture of amphetamine salts and dextroamphetamine salts, is a prescription drug for attention deficit/hyperactivity disorder (ADHD) and narcolepsy. Labeled or unlabeled use of Adderall is gaining popularity among young children and college students. Although it is rare, Adderall use is associated with myocardial infarction and even sudden death. We report a case of a young man with acute myocardial infarction after taking 2 15-mg tablets of Adderall XR with alcohol and discuss the clinical features, diagnosis, and management of the cardiovascular effect of amphetamine-containing drugs.

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.

A liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous identification and quantification of amphetamines, diazepam and its metabolites, cocaine and its metabolites, and opiates from hair using a single extraction method. As part of the method development, Gemini C18, Synergi Hydro RP, and Zorbax Stablebond-Phenyl LC columns were tested with three different mobile phases. Analyte recovery and limit of detection were evaluated for two different solid-phase extraction methods that used Bond Elut Certify and Clean Screen cartridges. Phosphate buffer (pH 5.0) was chosen as the optimum hair incubation medium because of the high stability of cocaine and 6-monoacetylmorphine using this method and faster sample preparation. The optimized method was fully validated. Linearity was established over the concentration range 0.2-10 ng/mg hair, and the correlation coefficients were all greater than 0.99. Total extraction recoveries were greater than 76%, detection limits were between 0.02 and 0.09 ng/mg, and the intra- and interday imprecisions were generally less than 20% in spiked hair. The intra- and interbatch imprecision of the method for a pooled authentic hair sample ranged from 1.4 to 23.4% relative standard deviation (RSD) and 8.3 to 25.4% RSD, respectively, for representative analytes from the different drug groups. The percent matrix effect ranged from 63.5 to 135.6%, with most analytes demonstrating ion suppression. Sixteen postmortem samples collected from suspected drug-related deaths were analyzed for the 17 drugs of abuse and metabolites included in the method. The method was sufficiently sensitive and specific for the analysis of drugs and metabolites in postmortem hair samples. There is scope for the inclusion of other target drugs and metabolites in the method.

A 1-year-old intact male Boxer was presented to the Texas Veterinary Medical Center for emergency treatment following suspected ingestion of a large number of tablets of Adderall, a pharmaceutical amphetamine. The dog had a temperature of 41.7 degrees C, heart rate of 192 beats per minute, and a respiratory rate of 100 breaths per minute. The dog was anxious and agitated with bilaterally dilated pupils, and shortly thereafter became recumbent and incontinent. Initial CBC results included mild leukopenia and mild thrombocytopenia. The dog was not anemic (HCT 39.9%) and had only slight polychromasia, but had 48 nucleated RBCs/100 WBC (7500/microL). Moderate numbers of neutrophils had hypersegmented nuclei and several pyknotic cells were noted. The metarubricytosis persisted for approximately 56 hours while hypersegmentation and pyknotic cells were no longer found at 8 hours after presentation. The dog received supportive care and recovered uneventfully. We hypothesized that hyperpyrexia associated with Adderall toxicity resulted in inappropriate metarubricytosis due to damaged bone marrow endothelium, and resulted in hypersegmentation and pyknosis due to damaged or accelerated aging of neutrophils in peripheral blood. Metarubricytosis has been reported previously in dogs with heat-induced illness, such as heat stroke.

Amphetamines are considered as narcotics in France. Their use induces modifications of the central nervous system and of the cardiovascular, respiratory and urinary systems by a sympathomimetic indirect effect. Here is reported the observation of a young woman who absorbed amphetamines causing a cardiogenic shock on a ground of acute myocarditis. The constitution of haemodynamic, respiratory and neurologic distresses lead to the endotracheal intubation of the patient. The haemodynamic status remaining shaky, despite the use of vasoactive drugs, a circulatory assistance by intra-aortic counter pulsation balloon was carried out. The initial echocardiography showed a left ventricular ejection fraction lower than 20%. Amphetamine's toxicity mechanisms still remain complicated; on cardiovascular plan, some cases of coronary artery spasm have been described. The coronarography, not accomplished immediately, was normal. Toxicological samples revealed an abnormally high amphetamines concentration. The severity of the cardiac attack was amplified by a Mycoplasma pneumoniae myocarditis. There was a positive evolution in eight days. Intoxication and infection can difficultly be dissociated in this case of cardiogenic shock.

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.

Paramethoxyamphetamine (PMA) and paramethoxymethamphetamine (PMMA) are methoxylated phenylethylamine derivatives that have been banned in Taiwan since December 2005. The case history and pathological and toxicological findings of eight recent PMMA fatalities were investigated. All specimens from these cases were initially identified by an AxSYM fluorescence polarization immunoassay screening test for amphetamines with a 300 ng/mL cutoff. Specimens screened positive were confirmed and quantitated by gas chromatography-mass spectrometry. The mean age of these PMMA-related fatalities was 18.9 +/- 4.4 years in the range of 14-25. Seven (87.5%) of these eight cases were men. The mean, standard deviation, and range of PMA found in the heart blood collected from these 8 cases were 0.213, 0.144, and 0.079-0.489 microg/mL, respectively. The corresponding data for PMMA were 4.312, 4.806, and 1.208-15.824 microg/mL, respectively. Other drugs, such as MDA, MDMA, ketamine, norketamine, hydroxymidazolam, methamphetamine, and pentobarbital, were also found in these cases.

Introduction: Amphetamine and its analogues belong to the large group of psychoactive compounds. Due to the growing problem of amphetamine poisoning, author decided to review and improve the laboratory diagnostic procedures with regard to forensic toxicology analysis., Material and Methods: Biological material of 8 persons taken during autopsy for routine toxicological tests was used to examine characteristic of biological matrix. Following excludion the presence of xenobiotics during expertise process, material was divided and kept in sealed containers, then analysed after defined time period: 0, 30 and 90 days. Blood, urine, liver, brain and kidney were considered, 96 samples were examined in total. Biological material was analysed using gas chromatography equipped with flame ionization detector (GC-FID), liquid chromatography with diode array detector (HPLC-DAD), and magnetic resonance spectrometer (H NMR)., Conclusions: 1. Workout analytical GC-FID method enable to verify positive initial result of amphetamine and metamphetamine analysis in urine. 2. Biological matrix is composed mainly of low molecular aliphatic organical compounds which cause significant impact in analytical and opinion problem in amphetamine analysis. Its influence determine in proportion as time of biological material self-decomposition and noted cross-reactivity concern both immunological and chromatographic methods (HPLC-DAD). 3. H NMR method may be used to confirm amphetamine presence in biological material for confirmation of positive results obtained using immunological and enzymatic methods used in forensic toxicology.

Abuse of amphetamine (AMP) and its derivatives, such as 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy'), 3,4-methylenedioxyethylamphetamine (MDEA, MDE), and 3,4-methylenedioxyamphetamine (MDA) is an important public issue. Fatalities following ingestion of these substances are not infrequent in current forensic practice. The aim of this study was twofold. Firstly, considering the wide range of blood levels reported in fatalities, to provide insight into the interpretation of a quantified blood level and, secondly, to examine and discuss possible causes, mechanisms and manners of death. All the medico-legal files between January 1976 and December 2004 were skimmed through to investigate whether amphetamine and/or derivatives were involved in the fatal outcome. Particularly, in addition to overdose cases due to or including amphetamines, all amphetamines-related fatalities were examined. In addition to AMP, MDMA, MDEA, and MDA, two other amphetamine derivatives, namely 4-methylthioamphetamine (4-MTA) and para-methoxyamphetamine (PMA) were considered. In 34 fatalities, amphetamines were involved and the majority were men, under the age of 25 years. A wide range of blood levels was found: e.g. MDMA blood concentrations in cases of 'pure' intoxication were found between 0.27 and 13.51 microg/ml. The age and sex distribution as well as the broad range of quantified amphetamines blood levels were in line with those reported in the literature. In our study group, 'pure' intoxications with amphetamines, polydrug overdoses, and the combination of amphetamines use and polytrauma were the most prominent causes of death. Considering the manner of death in these fatalities, unintentional overdoses were most frequent, though suicides, traffic accidents, and criminal offences associated with amphetamines use also accounted for significant percentages. Acute to subacute cardiopulmonary failure was the most frequent mechanism of death, followed by (poly)trauma, mechanical asphyxia, and hyperthermia, respectively. In conclusion, although amphetamines-related fatalities are only a fraction of the total number of fatalities studied at our Department, their contribution to current forensic practice has been increasing during the last few years. As there is still considerable debate as to what level of amphetamines can be toxic or even potentially lethal, it is strongly advisable to interpret the anatomo-pathological findings and the toxicological results together in arriving at a conclusion. This guideline is important in view of the different possible mechanisms of death which implicate quite different survival times following intake of amphetamine and/or its derivatives (e.g. cardiopulmonary complications, hyperthermia).

4-Methylthioamphetamine (4-MTA) is a scheduled designer drug that has appeared on the illicit drug market and led to several non-fatal or even fatal poisonings. Only few data are available on its metabolism. The first aim of this study was to identify the 4-MTA metabolites in human urine and then to study whether the authors' STA procedure is suitable for screening for and identification of 4-MTA and/or its metabolites in urine. After enzymatic cleavage of conjugates, solid-phase extraction (SPE) and acetylation the following metabolites could be identified by full-scan gas chromatography-mass spectrometry (GC-MS): deamino-oxo 4-MTA, deamino-hydroxy 4-MTA, ring hydroxy and beta-hydroxy 4-MTA. 4-MTA sulfoxide could be identified as possible artifact. In urine samples after enzymatic hydrolysis, acidic extraction, and methylation, 4-methylthiobenzoic acid could be identified. The authors' systematical toxicological analysis (STA) procedure using full-scan GC-MS after acid hydrolysis, liquid-liquid extraction (LLE) and acetylation allowed detection of 4-MTA as target analyte plus all the above-mentioned metabolites with the exception of 4-methylthiobenzoic acid. The extraction efficiency of 4-MTA was approximately 70% and the limit of detection (LOD) was 30 ng/ml (S/N 3).

A simple and miniaturized sample preparation method for determination of amphetamines in urine was developed using on-column derivatization and gas chromatography-mass spectrometry (GC-MS). Urine was directly applied to the extraction column that was pre-packed with Extrelut and sodium carbonate. Amphetamine (AP) and methamphetamine (MA) in urine were adsorbed on the surface of Extrelut. AP and MA were then converted to a free base and derivatized to N-propoxycarbonyl derivatives using propylchloroformate on the column. Pentadeuterated MA was used as an internal standard. The recoveries of AP and MA from urine were 100 and 102%, respectively. The calibration curves showed linearity in the range of 0.50-50 microg/mL for AP and MA in urine. When urine samples containing two different concentrations (0.50 and 5.0 microg/mL) of AP and MA were determined, the intra-day and inter-day coefficients of variation were 1.4-7.7%. This method was applied to 14 medico-legal cases of MA intoxication. The results were compared and a good agreement was obtained with a HPLC method.

Acute respiratory failure is a common complication of drug abuse. It is more likely to develop in the setting of chronic lung disease or debility in those with limited respiratory reserve. Drugs may acutely precipitate respiratory failure by compromising respiratory pump function and/or by causing pulmonary pathology. Polysubstance overdoses are common, and clinicians should anticipate complications related to multiple drugs. Impairment of respiratory pump function may develop from central nervous system (CNS) depression (suppression of the medulla oblongata, stroke or seizures) or respiratory muscle fatigue (increased respiratory workload, metabolic acidosis). Drug-related respiratory pathology may result from parenchymal (aspiration-related events, pulmonary edema, hemorrhage, pneumothorax, infectious and non-infectious pneumonitides), airway (bronchospasm and hemorrhage), or pulmonary vascular insults (endovascular infections, hemorrhage, and vasoconstrictive events). Alcohol, cocaine, amphetamines, opiates, and benzodiazepines are the most commonly abused drugs that may induce events leading to acute respiratory failure. While decontamination and aggressive supportive measures are indicated, specific therapies to correct seizures, metabolic acidosis, pneumothorax, infections, bronchospasm, and agitation should be considered. Drug-related respiratory failure when due to CNS depression alone may portend well, but in patients with drug-related significant pulmonary pathology, a protracted course of illness may be anticipated.

Conducting toxicology on post-mortem specimens provides a number of very significant challenges to the scientist. The range of additional specimens include tissues such as decomposing blood and other tissues, hair, muscle, fat, lung, and even larvae feeding on the host require special techniques to isolate a foreign substance and allow detection without interference from the matrix. A number of drugs of abuse are unstable in the post-mortem environment that requires careful consideration when trying to interpret their significance. Heroin, morphine glucuronides, cocaine and the benzodiazepines are particularly prone to degradation. Moreover, redistributive process can significantly alter the concentration of drugs, particularly those with a higher tissue concentration than the surrounding blood. The designer amphetamines, methadone and other potent opioids will increase their concentration in blood post-mortem. These processes together with the development of tolerance means that no concentration of a drug of abuse can be interpreted in isolation without a thorough examination of the relevant circumstances and after the conduct of a post-mortem to eliminate or corroborate relevant factors that could impact on the drug concentration and the possible effect of a substance on the body. This article reviews particular toxicological issues associated with the more common drugs of abuse such as the amphetamines, cannabinoids, cocaine, opioids and the benzodiazepines.

Intoxications present in many forms including: known drug overdose or toxic exposure, illicit drug use, suicide attempt, accidental exposure, and chemical or biological terrorism. A high index of suspicion and familiarity with toxidromes can lead to early diagnosis and intervention in critically ill, poisoned patients. Despite a paucity of evidence-based information on the management of intoxicated patients, a rational and systematic approach can be life saving.

Amphetamine abuse in human beings has increased, resulting in many reports of toxicity and death. In the US over 4 million people have abused amphetamines at least once, thus small animals are exposed to increased accidental poisoning risk. This report describes an acute amphetamine poisoning in a dog due to ingestion of 15 mg/kg fenproporex, leading to typical signs of catecholamines release and effects in different organ systems. Similar clinical and laboratory findings observed in human beings are reviewed and physiopathogenic mechanisms discussed, as well as the therapeutic approaches available in veterinary medicine.