Amphetamine Toxicity Research Articles

Amphetamine-Related Fatalities and Altered Brain Chemicals: A Preliminary Investigation Using the Comparative Toxicogenomic Database.

Amphetamine is a psychostimulant drug with a high risk of toxicity and death when misused. Abuse of amphetamines is associated with an altered organic profile, which includes omega fatty acids. Low omega fatty acid levels are linked to mental disorders. Using the Comparative Toxicogenomic Database (CTD), we investigated the chemical profile of the brain in amphetamine-related fatalities and the possibility of neurotoxicity. We classified amphetamine cases as low (0-0.5 g/mL), medium (>0.5 to 1.5 g/mL), and high (>1.5 g/mL), based on amphetamine levels in brain samples. All three groups shared 1-octadecene, 1-tridecene, 2,4-di-tert-butylphenol, arachidonic acid (AA), docosahexaenoic acid (DHA), eicosane, and oleylamide. We identified chemical-disease associations using the CTD tools and predicted an association between DHA, AA and curated conditions like autistic disorder, disorders related to cocaine, Alzheimer's disease, and cognitive dysfunction. An amphetamine challenge may cause neurotoxicity in the human brain due to a decrease in omega-3 fatty acids and an increase in oxidative products. Therefore, in cases of amphetamine toxicity, a supplement therapy may be needed to prevent omega-3 fatty acid deficiency.

Hot weather and death related to acute cocaine, opioid and amphetamine toxicity in British Columbia, Canada: a time-stratified case-crossover study.

Previous research has shown that cocaine-associated deaths occur more frequently in hot weather, which has not been described for other illicit drugs or combinations of drugs. The study objective was to evaluate the relation between temperature and risk of death related to cocaine, opioids and amphetamines in British Columbia, Canada. We extracted data on all deaths with cocaine, opioid or amphetamine toxicity recorded as an underlying or contributing cause from BC vital statistics for 1998-2017. We used a time-stratified case-crossover design to estimate the effect of temperature on the risk of death associated with acute drug toxicity during the warmer months (May through September). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for each 10°C increase in the 2-day average maximum temperature at the residential location. We included 4913 deaths in the analyses. A 10°C increase in the 2-day average maximum temperature was associated with an OR of 1.43 (95% CI 1.11-1.86) for deaths with only cocaine toxicity recorded (n = 561), an OR of 1.15 (95% CI 0.99-1.33) for deaths with opioids only (n = 1682) and an OR of 1.11 (95% CI 0.60-2.04) for deaths with amphetamines only (n = 133). There were also elevated effects when toxicity from multiple drugs was recorded. Sensitivity analyses showed differences in the ORs by sex, by climatic region, and when the location of death was used instead of the location of residence. Increasing temperatures were associated with higher odds of death due to drug toxicity, especially for cocaine alone and combined with other drugs. Targeted interventions are necessary to prevent death associated with toxic drug use during hot weather.

Synthetical effect of microplastics and chiral drug amphetamine on a primary food source algae Chlorella pyrenoids.

The biological effects and fate of the chiral illicit drug amphetamine in the presence and absence of microplastics on freshwater algae (Chlorella pyrenoids), including acute toxicity, growth inhibition, photosynthetic pigment content, oxidative stress, lipid peroxidation, and enantioselective fate were assessed. An agglomeration and the shading effects of microplastics in algae suspension were also determined. Microplastics were observed to increase the toxicity of amphetamine to algae and reduce algae cell growth. Exposed Chlorella pyrenoids exhibited a reduced algae cell counts in an agglomeration test, wherein algae cells decreased between 18% and 56% among treatment groups exposed to 5-50mgL-1 of microplastics. The agglomeration test suggested that microplastics might significantly increase the adverse effect on algae. Furthermore, our experiments demonstrated enantioselective degradation of amphetamine in algae, and demonstrated that the S-enantiomer was preferably degraded by algae cells. Adding microplastics to the algae suspension significantly reduced the enantioselectivity, with an EF value of 0.41 compared with amphetamine-alone group (0.34) after 21d exposure. These results demonstrated the first evidence of microplastics acting as a vehicle to enhance amphetamine toxicity to Chlorella pyrenoids, as well as provided new insights into the co-effect of microplastics and organic contaminants on food source.

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.

Catecholaminergic axons in the neocortex of adult mice regrow following brain injury

Serotonin axons in the adult rodent brain can regrow and recover their function following several forms of injury including controlled cortical impact (CCI), a neocortical stab wound, or systemic amphetamine toxicity. To assess whether this capacity for regrowth is unique to serotonergic fibers, we used CCI and stab injury models to assess whether fibers from other neuromodulatory systems can also regrow following injury. Using tyrosine-hydoxylase (TH) immunohistochemistry we measured the density of catecholaminergic axons before and at various time points after injury. One week after CCI injury we observed a pronounced loss, across cortical layers, of TH+ axons posterior to the site of injury. One month after CCI injury the same was true of TH+ axons both anterior and posterior to the site of injury. This loss was followed by significant recovery of TH+ fiber density across cortical layers, both anterior and posterior to the site of injury, measured three months after injury. TH+ axon loss and recovery over weeks to months was also observed throughout cortical layers using the stab injury model. Double label immunohistochemistry revealed that nearly all TH+ axons in neocortical layer 1/2 are also dopamine-beta-hyroxylase+ (DBH+; presumed norepinephrine), while TH+ axons in layer 5 are a mixture of DBH+ and dopamine transporter+ types. This suggests that noradrenergic axons can regrow following CCI or stab injury in the adult mouse neocortex and leaves open the question of whether dopaminergic axons can do the same.

Para-Halogenation Affects Monoamine Transporter Inhibition Properties and Hepatocellular Toxicity of Amphetamines and Methcathinones.

Halogenated derivatives of amphetamine-type stimulants are appearing on the drug market, often with altered pharmacological profile and sometimes different legal status compared to the non-halogenated substances. The aim of the present study was to investigate the pharmacological profile and hepatocellular toxicity of para-halogenated amphetamines and cathinones. The potential of amphetamine, 4-fluoroamphetamine, 4-chloroamphetamine, methcathinone, 4-fluoromethcathinone, and 4-chloromethcathinone to inhibit the monoamine transporters for norepinephrine, dopamine, and serotonin was determined in transporter-transfected human embryonic kidney 293 cells. Cell membrane integrity, ATP content, oxygen consumption rate, and superoxide levels were measured in human hepatoma HepG2 cells after exposure to the substances for 24 h. All compounds inhibited the norepinephrine transporter at submicromolar concentrations and the dopamine transporter at low micromolar concentrations. The selectivity of the compounds to inhibit the dopamine versus serotonin transporter decreased with increasing size of the para-substituent, resulting in potent serotonin uptake inhibition for the halogenated derivatives. All substances depleted the cellular ATP content at lower concentrations (0.25–2 mM) than cell membrane integrity loss occurred (≥0.5 mM), suggesting mitochondrial toxicity. The amphetamines and 4-chloromethcathinone additionally impaired the mitochondrial respiratory chain, confirming mitochondrial toxicity. The following toxicity rank order for the para-substituents was observed: chloride > fluoride > hydrogen. In conclusion, para-halogenation of stimulants increases the risk for serotonergic neurotoxicity. Furthermore, para-halogenation may increase hepatic toxicity mediated by mitochondrial impairment in susceptible users.

β-Phenylethylamine and various monomethylated and para-halogenated analogs. Acute toxicity studies in mice

Phenylethylamine’s acute toxic effects in a population of adult (10 to 12 weeks old; ∼30 g) Swiss male albino mice are significantly increased by para-position aromatic ring halogenation. LDLO, LD50, and LD100 values (mg/kg; x ± SEM) for p-F- (116.7 ± 3.3, 136.7 ± 1.7, and 160.0 ± 2.9), p-Br- (126.7 ± 3.3, 145.0 ± 2.9, and 163.3 ± 3.3), p-Cl- (133.3 ± 3.3, 146.7 ± 1.7, and 165.0 ± 2.9), and p-I-PEA (133.3 ± 3.3, 153.3 ± 1.7, and 168.3 ± 1.7), compared to PEA 203.3 ± 3.3, 226.7 ± 4.4, and 258.3 ± 8.8). Like PEA, the difference between LDLO and LD50, and LD50 and LD100 for individual amines were similar and in the range (10 to 20%). Toxicity variation between the various p-halogenatedPEAs also fell within a relatively narrow range (as a group: LDLO 116.7 ± 3.3 to 133.3 ± 3.3, LD50 136.7 ± 1.7 to 153.3 ± 1.7, and LD100 160.0 ± 2.9 to 168.3 ± 1.7 mg/kg). PEA methylation, (exception of its α-methyl derivative), results in relatively modest changes in acute toxicity. LDLO, LD50, and LD100 values (mg/kg; x ± SEM) for N-Me- (176.6 ± 3.3, 200.0 ± 2.9, and 221.7 ± 3.3), p-Me- (183.3 ± 3.3, 206.7 ± 3.3, and 225.0 ± 2.9), o-Me- (210.0 ± 5.8, 233.3 ± 3.3, and 258.3 ± 1.7), and β-MePEA (220.0 ± 5.8, 243.3 ± 4.4, and 278.3 ± 44). Similar to PEA, and the p-HPEAs, the difference between LDLO and LD50 and LD50 and LD100 values for individual amines fell within a relatively narrow range (10 to 20%). Variation in toxicity among the methylatedPEAs also fell within a limited range (as a group: LDLO 176 ± 3.3 to 220 ± 5.8, LD50 200.0 ± 2.9 to 243.3 ± 4.4 and LD100 221.7 ± 3.3 to 278.3 ± 4.4 mg/kg). With the exception of PEA’s methyl derivative (amphetamine) all the amines studied are rapidly metabolized by monoamine oxidase. This pharmacokinetics difference would help to explain the markedly higher amphetamine toxicity [(LDLO, LD50 and LD100 (mg/kg; x ± SEM) of 21.3 ± 0.9, 25.0 ± 0.6, and 29.3 ± 0.7, respectively)].

Antipsychotics for the treatment of sympathomimetic toxicity: A systematic review

ObjectiveBenzodiazepines are often recommended first-line for management of cocaine and amphetamine toxicity while antipsychotic treatment is discouraged due to the potential for lowering seizure threshold, prolonging the QT interval, and decreasing heat dissipation. We performed a systematic review including animal and human studies to elucidate the efficacy and safety of antipsychotics in managing sympathomimetic toxicity specifically evaluating the effect of treatment on mortality, seizures, hyperthermia, and cardiovascular effects. MethodsWe searched MEDLINE, Embase, BIOSIS Previews, Web of Science, Scopus, CENTRAL and gray literature from inception to 31 May 2017 to answer: Can antipsychotics be used safely and effectively to treat cocaine or amphetamine toxicity? Citations were screened by title and abstract. Additional citations were identified with citation tracking. Data were extracted from full-texts. Results6539 citations were identified; 250 full-text articles were assessed. Citation tracking identified 2336 citations; 155 full texts were reviewed. Seventy-three papers were included in this review. In 96 subjects with cocaine toxicity treated with an antipsychotic, there were three deaths, two cardiac arrests, two seizures, and one episode of hyperthermia. In 330 subjects with amphetamine toxicity treated with an antipsychotic, there were two episodes of coma and QT prolongation and one episode of each: hypotension, NMS, cardiac arrest, and death. ConclusionThis systematic review represents an exhaustive compilation of the available evidence. There is neither a clear benefit of antipsychotics over benzodiazepines nor a definitive signal of harm noted. We encourage clinicians to adapt treatment based on specific circumstances and characteristics of their individual patients.

Role of autophagy, apoptosis and oxidative stress in the toxicity of β-keto amphetamines to human dopaminergic SH-SY5Y cells

Role of autophagy, apoptosis and oxidative stress in the toxicity of β-keto amphetamines to human dopaminergic SH-SY5Y cells

Keto amphetamine toxicity-focus on the redox reactivity of the cathinone designer drug mephedrone.

The β-keto amphetamine (cathinone, β-KA) designer drugs such as mephedrone (4-methylmethcathinone, 4-MMC) show a large degree of structural similarity to amphetamines like methamphetamine (METH). However, little is currently known about whether these substances also share the potential neurotoxic properties of their non-keto amphetamine counterparts, or what mechanisms could be involved. Here, we evaluate the cytotoxicity of β-KAs in SH-SY5Y cells using lactate dehydrogenase (LDH) assays, assess the redox potential of a range of β-KAs and non-keto amphetamines using the sensitive redox indicator 2-(4-Iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1), and explore the effect of 4-MMC on the formation of protein adducts using ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry (UHPLC-HR-TOFMS) and on the mitochondrial respiratory chain using high-resolution respirometry. We show that treatment with β-KAs increases LDH release. Further, we demonstrate that even under physiological pH, β-KAs are effective and selective-as compared with their non-keto analogues-reductants in the presence of electron acceptors. Increased pH (range 7.6-8.0) greatly enhanced the reactivity up to sixfold. We found no evidence of protein adduct formation, suggesting the reactivity is due to direct electron transfer by the β-KAs. Finally, we show that 4-MMC and METH produce dissimilar effects on the respiratory chain. Our results indicate that β-KAs such as 4-MMC possess cytotoxic properties in vitro. Furthermore, in the presence of an electron-accepting redox partner, the ketone moiety of β-KAs is vital for pH-dependent redox reactivity. Further work is needed to establish the importance of β-KA redox properties and its potential toxicological importance in vivo.

An insight into the hepatocellular death induced by amphetamines, individually and in combination: the involvement of necrosis and apoptosis

The liver is a vulnerable target for amphetamine toxicity, but the mechanisms involved in the drug's hepatotoxicity remain poorly understood. The purpose of the current research was to characterize the mode of death elicited by four amphetamines and to evaluate whether their combination triggered similar mechanisms in immortalized human HepG2 cells. The obtained data revealed a time- and temperature-dependent mortality of HepG2 cells exposed to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy; 1.3 mM), methamphetamine (3 mM), 4-methylthioamphetamine (0.5 mM) and D-amphetamine (1.7 mM), alone or combined (1.6 mM mixture). At physiological temperature (37 °C), 24-h exposures caused HepG2 death preferentially by apoptosis, while a rise to 40.5 °C favoured necrosis. ATP levels remained unaltered when the drugs where tested at normothermia, but incubation at 40.5 °C provoked marked ATP depletion for all treatments. Further investigations on the apoptotic mechanisms triggered by the drugs (alone or combined) showed a decline in BCL-2 and BCL- XL mRNA levels, with concurrent upregulation of BAX, BIM, PUMA and BID genes. Elevation of Bax, cleaved Bid, Puma, Bak and Bim protein levels was also seen. To the best of our knowledge, Puma, Bim and Bak have never been linked with the toxicity induced by amphetamines. Time-dependent caspase-3/-7 activation, but not mitochondrial membrane potential (∆ψm) disruption, also mediated amphetamine-induced apoptosis. The cell dismantling was confirmed by poly(ADP-ribose)polymerase proteolysis. Overall, for all evaluated parameters, no relevant differences were detected between individual amphetamines and the mixture (all tested at equieffective cytotoxic concentrations), suggesting that the mode of action of the amphetamines in combination does not deviate from the mode of action of the drugs individually, when eliciting HepG2 cell death.

Comparison of the global gene expression of choroid plexus and meninges and associated vasculature under control conditions and after pronounced hyperthermia or amphetamine toxicity

BackgroundThe meninges (arachnoid and pial membranes) and associated vasculature (MAV) and choroid plexus are important in maintaining cerebrospinal fluid (CSF) generation and flow. MAV vasculature was previously observed to be adversely affected by environmentally-induced hyperthermia (EIH) and more so by a neurotoxic amphetamine (AMPH) exposure. Herein, microarray and RT-PCR analysis was used to compare the gene expression profiles between choroid plexus and MAV under control conditions and at 3 hours and 1 day after EIH or AMPH exposure. Since AMPH and EIH are so disruptive to vasculature, genes related to vasculature integrity and function were of interest.ResultsOur data shows that, under control conditions, many of the genes with relatively high expression in both the MAV and choroid plexus are also abundant in many epithelial tissues. These genes function in transport of water, ions, and solutes, and likely play a role in CSF regulation. Most genes that help form the blood–brain barrier (BBB) and tight junctions were also highly expressed in MAV but not in choroid plexus. In MAV, exposure to EIH and more so to AMPH decreased the expression of BBB-related genes such as Sox18, Ocln, and Cldn5, but they were much less affected in the choroid plexus. There was a correlation between the genes related to reactive oxidative stress and damage that were significantly altered in the MAV and choroid plexus after either EIH or AMPH. However, AMPH (at 3 hr) significantly affected about 5 times as many genes as EIH in the MAV, while in the choroid plexus EIH affected more genes than AMPH. Several unique genes that are not specifically related to vascular damage increased to a much greater extent after AMPH compared to EIH in the MAV (Lbp, Reg3a, Reg3b, Slc15a1, Sct and Fst) and choroid plexus (Bmp4, Dio2 and Lbp).ConclusionsOur study indicates that the disruption of choroid plexus function and damage produced by AMPH and EIH is significant, but the changes may not be as pronounced as they are in the MAV, particularly for AMPH. Expression profiles in the MAV and choroid plexus differed to some extent and differences were not restricted to vascular related genes.

Amphetamine-like stimulants hit the headlines

Drug abuse is a worldwide health issue and a global cause ofpremature mortality and morbidity. A substantial proportionof young adults have used an illicit drug at some time intheir lives. In 2011, the UN Office on Drugs and Crimereported that 149–271 million people aged 15–64 wereestimated to have used an illicit drug at least once in 2009.Of these, between 14 million and 56 million were estimatedto have used an amphetamine-type stimulant (correspond-ing to 0.3–1.3 % of the population) (UNODC, World DrugReport 2011). Therefore, I am very happy to see a very nicewell-written and well comprehensive review entitled‘‘Toxicity of Amphetamine: An Update’’ contributed byCarvalho et al. (2012).Stimulants, including amphetamine derivatives, areamong the most widely abused illegal substances. Over thelast five decades, their popularity has paralleled with cul-tural literary, cinematographic and musical movements. Infact, there are indicators that both consumption and manu-facture of amphetamines have increased. Data from surveysof college students also show that illicit use of stimulants isstill growing (Ciccarone 2011).The detrimental health consequences of stimulant abuseare accompanied by relevant economic and societal costs.Mental disorders, road-traffic accidents, suicides and vio-lence seem to be increased in amphetamine users. However,causal associations remain unclear due to several con-founding variables and poor quantification of risk. Accord-ing to a survey in 2006, one in three of all drug-relatedemergency visits in the United States involved cocaine.Methamphetamineand amphetamine were associated with 5and 2 % of these visits, respectively, representing a totalnumber of 107,575 visits. MDMA alone accounted for16,749 visits (Substance Abuse and Mental Health ServicesAdministration 2008).Acute clinical features include intoxication and over-dose. Chronic use is associated with psychological andbehavioral disturbances. Cognitive impairment and psy-chotic symptoms such as paranoia, delusions and halluci-nations may persist for years following abstinence fromuse. Bloodborne bacterial and viral infections are alsoworrisome due to risks of unsafe injection (Schep et al.2011; Degenhardt and Hall 2012).The high prevalence of stimulant abuse and its harmfulconsequences make the screening, diagnosis and treatmentof persons with stimulant abuse a top concern for primarycare providers. Having a working knowledge of use pat-terns, clinical features and target-organ effects is thereforeessential.The review ‘‘Toxicity of amphetamines: an update’’,published in the current issue of Archives of Toxicology(Carvalho et al. 2012), addresses the pharmacokinetics;toxicity mechanisms; target-organ toxicity; individual pre-disposition (genetic polymorphisms); and relevant druginteractions of the classical amphetamines: amphetamineitself, as well as methamphetamine and 3,4-methylene-dioxymethamphetamine (MDMA, ecstasy). All issues cov-ered are of utmost importance for increased awareness ofdanger and for management and treatment of the intoxicatedpatients.Recently, a new class of ‘‘designer drugs’’ has emergedon the drug market, known as ‘‘legal highs’’ or ‘‘herbalhighs’’ ‘‘bath salt’’. They include a wide range of products,from natural plant-originated substances to synthetic

Toxicity of amphetamines: an update

Amphetamines represent a class of psychotropic compounds, widely abused for their stimulant, euphoric, anorectic, and, in some cases, emphathogenic, entactogenic, and hallucinogenic properties. These compounds derive from the β-phenylethylamine core structure and are kinetically and dynamically characterized by easily crossing the blood-brain barrier, to resist brain biotransformation and to release monoamine neurotransmitters from nerve endings. Although amphetamines are widely acknowledged as synthetic drugs, of which amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are well-known examples, humans have used natural amphetamines for several millenniums, through the consumption of amphetamines produced in plants, namely cathinone (khat), obtained from the plant Catha edulis and ephedrine, obtained from various plants in the genus Ephedra. More recently, a wave of new amphetamines has emerged in the market, mainly constituted of cathinone derivatives, including mephedrone, methylone, methedrone, and buthylone, among others. Although intoxications by amphetamines continue to be common causes of emergency department and hospital admissions, it is frequent to find the sophism that amphetamine derivatives, namely those appearing more recently, are relatively safe. However, human intoxications by these drugs are increasingly being reported, with similar patterns compared to those previously seen with classical amphetamines. That is not surprising, considering the similar structures and mechanisms of action among the different amphetamines, conferring similar toxicokinetic and toxicological profiles to these compounds. The aim of the present review is to give an insight into the pharmacokinetics, general mechanisms of biological and toxicological actions, and the main target organs for the toxicity of amphetamines. Although there is still scarce knowledge from novel amphetamines to draw mechanistic insights, the long-studied classical amphetamines-amphetamine itself, as well as methamphetamine and MDMA, provide plenty of data that may be useful to predict toxicological outcome to improvident abusers and are for that reason the main focus of this review.

The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and d-amphetamine

Amphetamine ('Speed'), methamphetamine ('Ice') and its congener 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') are illicit drugs abused worldwide for their euphoric and stimulant effects. Despite compelling evidence for chronic MDMA neurotoxicity in animal models, the physiological consequences of such toxicity in humans remain unclear. In addition, distinct differences in the metabolism and pharmacokinetics of MDMA between species and different strains of animals prevent the rationalisation of realistic human dose paradigms in animal studies. Here, we attempt to review amphetamine toxicity and in particular MDMA toxicity in the pathogenesis of exemplary human pathologies, independently of confounding environmental factors such as poly-drug use and drug purity.

Review article: Amphetamines and related drugs of abuse

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

Choc cardiogénique après ingestion d’amphétamines sur un terrain de myocardite à Mycoplasme

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.

Speed, Ecstasy, Ritalin: the science of amphetamines

This book is a mix of science, history and social commentary on the medical and illicit use of amphetamine and its derivatives, from the introduction of Benzedrine inhalers in 1932. As with many new drugs, amphetamine was widely regarded as a wonder drug, initially used as a decongestant and antidepressant, but by 1946 one US physician claimed he could list 39 indications for the drug. After a popular rise in the use of amphetamines as appetite suppressants, the chief uses today are for narcolepsy and attention deficit hyperactivity disorder (ADHD), although in some countries, l-methamphetamine (deoxyephedrine) can be found in over-the-counter cold remedies. There are nine chapters; a brief introduction is followed by a chapter on the mechanism of action of amphetamines and their effects on mood, performance, sexual function and appetite. Chapter 3, Medical Uses of Amphetamines, examines the failed attempts at using amphetamines, including fenfluramine and dexfenfluramine, to treat obesity. The important distinction between low-dose oral amphetamine, and the rapid rise in brain levels, as craved by addicts, when methamphetamine is injected intravenously or smoked, is made to explain the seemingly paradoxical use of methylphenidate in hyperactive children. The chapters dealing with amphetamines as performance enhancers and their illicit use around the world give a fascinating insight into the lengths to which people will go to improve performance. Amphetamines have been widely used by the military and athletes to increase endurance and stamina. However, this can come at a price, as in the case of cyclist Tom Simpson, who died in the Tour de France in 1967, having taken amphetamine. That several well-known entertainers and film stars took amphetamine is hardly surprising, but more disturbing was the revelation that a US President and a British Prime Minister were regular users. Amphetamine-induced psychosis is considered in Chapter 6, while the evidence for amphetamine toxicity, including neurotoxicity and adverse behavioural effects, is discussed in Chapter 7. The next chapter is devoted to Ecstasy: its chemistry and history, mechanism of action and descriptions of its behavioural and adverse effects. The neurotoxicological effects of Ecstasy appear to be due to drug-induced hyperthermia, as reduction of body temperature has a protective effect. The conclusion that methylene-dioxy-methamphetamine induces Parkinson's disease had to be retracted when it was realized that the experiments had in fact been conducted with methamphetamine, not methylene-dioxy-methamphetamine, as had been the intention. The book concludes with a short chapter, The Future with Amphetamines. There seems no doubt that illicit use is not in decline, indeed, the popularity of methamphetamine (crystal meth, ice), which can be smoked, is on the increase. Modafinil may replace amphetamine for treatment of narcolepsy, but the Food and Drug Administration's recent rejection of the drug for ADHD means that amphetamines, prescribed and illicit, are likely to be available for some time to come. There is no Preface, but explanation of terms such as ‘double-blind’ and ‘placebo’ suggests that the book is aimed not only at professionals but also interested lay readers. Written in a factual style, without dogma, the book makes perfect additional reading for students in the appropriate disciplines, giving them an insight into the development and use of drugs that they are unlikely to appreciate from standard teaching texts.

Differential cytotoxic responses of PC12 cells chronically exposed to psychostimulants or to hydrogen peroxide

Repeated abuse of stimulant drugs, cocaine and amphetamine, is associated with extraneuronal dopamine accumulation in specific brain areas. Dopamine may be cytotoxic through the generation of reactive oxygen species, namely hydrogen peroxide (H 2O 2), resulting from dopamine oxidative metabolism. In this work, we studied the cytotoxicity in PC12 cells (a dopaminergic neuronal model) chronically and/or acutely exposed to cocaine or amphetamine, as compared to H 2O 2 exposure. Chronic cocaine treatment induced sensitization to acute cocaine insult and increased cocaine-evoked accumulation of extracellular dopamine, although no changes in dihydroxyphenylacetic acid (DOPAC) levels were observed. Moreover, dopamine was depleted in cells chronically exposed to amphetamine and acute amphetamine toxicity persisted in these cells, indicating that dopamine was not involved in amphetamine cytotoxicity. PC12 cells chronically treated with H 2O 2 were totally resistant to acute H 2O 2, but not to acute cocaine or amphetamine exposure, suggesting that the toxicity induced by these stimulant drugs is unrelated to adaptation to oxidative stress. Interestingly, chronic cocaine treatment largely, but not completely, protected the cells against a H 2O 2 challenge, whilst a decrement in intracellular ATP was observed. This study shows that chronic treatment of PC12 cells with cocaine or H 2O 2 modifies the cytotoxic response to an acute exposure to these agents.

NTP‐CERHR Expert Panel Report on the reproductive and developmental toxicity of amphetamine and methamphetamine

Birth Defects Research Part B: Developmental and Reproductive ToxicologyVolume 74, Issue 6 p. 471-584 Review Article NTP-CERHR Expert Panel Report on the reproductive and developmental toxicity of amphetamine and methamphetamine†‡§¶ Mari Golub, Mari Golub California Environment Protection Agency, Sacramento, CaliforniaSearch for more papers by this authorLucio Costa, Lucio Costa University of Washington, Seattle, WashingtonSearch for more papers by this authorKevin Crofton, Kevin Crofton U.S. Environmental Protection Agency, Research Triangle Park, North CarolinaSearch for more papers by this authorDeborah Frank, Deborah Frank Boston Medical Center, Boston, MassachusettsSearch for more papers by this authorPeter Fried, Peter Fried Carleton University, Ottawa, OntarioSearch for more papers by this authorBeth Gladen, Beth Gladen National Institute of Environmental Health Sciences, Research Triangle Park, North CarolinaSearch for more papers by this authorRogene Henderson, Rogene Henderson Lovelace Respiratory Research Institute, Albuquerque, New MexicoSearch for more papers by this authorErica Liebelt, Erica Liebelt University of Alabama at Birmingham School of Medicine, Birmingham, AlabamaSearch for more papers by this authorShari Lusskin, Shari Lusskin New York University School of Medicine, New York, New YorkSearch for more papers by this authorSue Marty, Sue Marty The Dow Chemical Company, Midland, MichiganSearch for more papers by this authorAndrew Rowland, Andrew Rowland University of New Mexico, Albuquerque, New MexicoSearch for more papers by this authorJohn Scialli, John Scialli Phoenix, ArizonaSearch for more papers by this authorMary Vore, Mary Vore University of Kentucky, Lexington, KentuckySearch for more papers by this author Mari Golub, Mari Golub California Environment Protection Agency, Sacramento, CaliforniaSearch for more papers by this authorLucio Costa, Lucio Costa University of Washington, Seattle, WashingtonSearch for more papers by this authorKevin Crofton, Kevin Crofton U.S. Environmental Protection Agency, Research Triangle Park, North CarolinaSearch for more papers by this authorDeborah Frank, Deborah Frank Boston Medical Center, Boston, MassachusettsSearch for more papers by this authorPeter Fried, Peter Fried Carleton University, Ottawa, OntarioSearch for more papers by this authorBeth Gladen, Beth Gladen National Institute of Environmental Health Sciences, Research Triangle Park, North CarolinaSearch for more papers by this authorRogene Henderson, Rogene Henderson Lovelace Respiratory Research Institute, Albuquerque, New MexicoSearch for more papers by this authorErica Liebelt, Erica Liebelt University of Alabama at Birmingham School of Medicine, Birmingham, AlabamaSearch for more papers by this authorShari Lusskin, Shari Lusskin New York University School of Medicine, New York, New YorkSearch for more papers by this authorSue Marty, Sue Marty The Dow Chemical Company, Midland, MichiganSearch for more papers by this authorAndrew Rowland, Andrew Rowland University of New Mexico, Albuquerque, New MexicoSearch for more papers by this authorJohn Scialli, John Scialli Phoenix, ArizonaSearch for more papers by this authorMary Vore, Mary Vore University of Kentucky, Lexington, KentuckySearch for more papers by this author First published: 15 September 2005 https://doi.org/10.1002/bdrb.20048Citations: 35 † This article is a U.S. Government work and, as such, is in the public domain in the United States of America. ‡ A report of the CERHR Expert Panel with the support of CERHR Staff: NTP/NIEHS, Michael Shelby, Ph.D. (Director, CERHR), Christopher Portier, Ph.D. (Associate Director, National Toxicology Program); Sciences International, Inc., Anthony Scialli, M.D. (Principal Scientist), Annette Iannucci, M.S. (Toxicologist), Gloria Jahnke, D.V.M. (Toxicologist), Jessie Poulin, B.A. (Associate). § This report is prepared according to the Guidelines for CERHR Panel Members established by NTP/NIEHS. The guidelines are available on the CERHR web site (http://cerhr.niehs.nih.gov/). The format for Expert Panel Reports includes synopses of studies reviewed, followed by an evaluation of the Strengths/Weaknesses and Utility (Adequacy) of the study for CERHR evaluation. Statements and conclusions made under Strengths/Weaknesses and Utility evaluations are those of the Expert Panel and are prepared according to the NTP/NIEHS guidelines. In addition, the Panel often makes comments or notes limitations in the synopses of the study. Bold, square brackets are used to enclose such statements. As discussed in the guidelines, square brackets are used to enclose key items of information not provided in a publication, limitations noted in the study, conclusions that differ from those of the authors, and conversions or analyses of data conducted by the Panel. ¶ Michael D. Shelby, Ph.D., NIEHS EC-32, PO Box 12233, Research Triangle Park, NC 27709. 919-541-3455 E-mail: shelby@niehs.nih.gov Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume74, Issue6December 2005Pages 471-584 RelatedInformation