Amphetamine Toxicity Research Articles

Amphetamine toxicity in the emergency department

XTC and other amphetamines are considered to be safe by the majority of partying young people who are unaware of (or unwilling to know about) the acute and chronic toxicity of these substances, and these drugs are widespread, illicit stimulants. In this article, we describe four cases of severe acute toxicity due to recreational use of amphetamines 3,4-methylene-dioxymethamphetamine, 3,4-methylenedioxyethylamphetamine, 3,4-methylenedioxyamphetamine, 4-methylthioamphetamine or p-methoxyamphetamine, with emphasis on the presenting symptoms and acute treatment in the emergency department.

Amphetamine‐induced movement disorder

Recreational use of amphetamines is common in Australia and New Zealand when compared with other developed nations. The clinical effects are variable because of the potential of these drugs to increase the proportion of different biogenic amines in the central nervous system (CNS). The substances affected are adrenaline, noradrenaline, serotonin and dopamine. Movement disorders represent one of the less common presentations of amphetamine toxicity but one that health care workers should be aware of nonetheless.

Rat brain serotonin neurones that express neuronal nitric oxide synthase have increased sensitivity to the substituted amphetamine serotonin toxins 3,4-methylenedioxymethamphetamine and p-chloroamphetamine

Substituted amphetamines such as p-chloroamphetamine and the abused drug methylenedioxymethamphetamine cause selective destruction of serotonin axons in rats, by unknown mechanisms. Since some serotonin neurones also express neuronal nitric oxide synthase, which has been implicated in neurotoxicity, the present study was undertaken to determine whether nitric oxide synthase expressing serotonin neurones are selectively vulnerable to methylenedioxymethamphetamine or p-chloroamphetamine. Using double-labeling immunocytochemistry and double in situ hybridization for nitric oxide synthase and the serotonin transporter, it was confirmed that about two thirds of serotonergic cell bodies in the dorsal raphé nucleus expressed nitric oxide synthase, however few if any serotonin transporter immunoreactive axons in striatum expressed nitric oxide synthase at detectable levels. Methylenedioxymethamphetamine (30mg/kg) or p-chloroamphetamine (2×10mg/kg) was administered to Sprague–Dawley rats, and 7 days after drug administration there were modest decreases in the levels of serotonin transporter protein in frontal cortex, and striatum using Western blotting, even though axonal loss could be clearly seen by immunostaining. p-Chloroamphetamine or methylenedioxymethamphetamine administration did not alter the level of nitric oxide synthase in striatum or frontal cortex, determined by Western blotting. Analysis of serotonin neuronal cell bodies 7 days after p-chloroamphetamine treatment, revealed a net down-regulation of serotonin transporter mRNA levels, and a profound change in expression of nitric oxide synthase, with 33% of serotonin transporter mRNA positive cells containing nitric oxide synthase mRNA, compared with 65% in control animals. Altogether these results support the hypothesis that serotonin neurones which express nitric oxide synthase are most vulnerable to substituted amphetamine toxicity, supporting the concept that the selective vulnerability of serotonin neurones has a molecular basis.

Conversation with Charles R. Schuster.

Conversation with Charles R. Schuster.

Cognitive Performance of MDMA-Treated Rhesus Monkeys: Sensitivity to Serotonergic Challenge

Recreational users of (±)3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) exhibit poor performance on a number of neurocognitive measures, with tests of memory and attention most commonly affected. Cognitive impairments can be persistent or possibly permanent, since users who have been abstinent from MDMA for many months are also impaired. Repeated treatment of rats or nonhuman primates with MDMA has consistently been demonstrated to produce specific, lasting depletions of brain serotonin (5-HT) markers, a potential source of such cognitive symptoms. We have shown, however, that monkeys treated with a regimen of MDMA (4 days, 10 mg/kg i.m., b.i.d.), sufficient to produce a 50% reduction of the 5-HT metabolite 5-hydroxyindoleacetic acid in cerebrospinal fluid, do not exhibit lasting deficits in a range of cognitive domains. Acute drug challenges are often effective at unmasking consequences of amphetamine toxicity. Here, the performance of MDMA-treated and control monkeys on tests of spatial working memory (self-ordered spatial search), vigilance and reaction time (5-choice reaction time), reinforcer efficacy and sustained attention (progressive ratio responding) and fine motor control (bimanual motor skill task) was challenged with ketanserin (0.1–1.7 mg/kg, i.m.), 1-(3-Chlorophenyl)piperazine dihydrochloride (mCPP, 0.03–0.5 mg/kg, i.m.) and (±)8-hydroxy-DPAT hydrobromide (8-OH-DPAT, 0.032–0.1 mg/kg, i.m.). MDMA-exposed animals exhibited increased sensitivity to challenge with mCPP on the reaction time and progressive ratio tasks but otherwise were equivalently sensitive to drug challenge. Post-mortem analysis demonstrated that 76–93% reductions of 5-HT in neocortex persist 17–20 months post-MDMA. These observations suggest that large depletions of brain 5-HT produced by MDMA can persistently alter behavioral sensitivity to the disrupting effects of serotonergic agents.

Effect of Mutant α-Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line

Mutations in alpha-synuclein have been linked to rare, autosomal dominant forms of Parkinson's disease. Despite its ubiquitous expression, mutant alpha-synuclein primarily leads to the loss of dopamine-producing neurons in the substantia nigra. alpha-Synuclein is a presynaptic nerve terminal protein of unknown function, although several studies suggest it is important for synaptic plasticity and maintenance. The present study utilized a new human mesencephalic cell line, MESC2.10, to study the effect of A53T mutant alpha-synuclein on dopamine homeostasis. In addition to expressing markers of mature dopamine neurons, differentiated MESC2.10 cells are electrically active, produce dopamine, and express wild-type human alpha-synuclein. Lentivirus-induced overexpression of A53T mutant alpha-synuclein in differentiated MESC2.10 cells resulted in down-regulation of the vesicular dopamine transporter (VMAT2), decreased potassium-induced and increased amphetamine-induced dopamine release, enhanced cytoplasmic dopamine immunofluorescence, and increased intracellular levels of superoxide. These results suggest that mutant alpha-synuclein leads to an impairment in vesicular dopamine storage and consequent accumulation of dopamine in the cytosol, a pathogenic mechanism that underlies the toxicity of the psychostimulant amphetamine and the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium. Interestingly, cells expressing A53T mutant alpha-synuclein were resistant to amphetamine-induced toxicity. Because extravesicular, cytoplasmic dopamine can be easily oxidized into reactive oxygen species and other toxic metabolites, mutations in alpha-synuclein might lead to Parkinson's disease by triggering protracted, low grade dopamine toxicity resulting in terminal degeneration and ultimately cell death.

CDNA array analysis of gene expression profiles in the striata of wild-type and Cu/Zn superoxide dismutase transgenic mice treated with neurotoxic doses of amphetamine.

Amphetamine (AMPH) is a drug of abuse that causes the degeneration of striatal dopamine terminals in mammals. Superoxide radicals seem to participate in AMPH-induced damage because its toxicity is attenuated in Cu/Zn superoxide dismutase transgenic (SOD-tg) mice. To provide a detailed analysis of molecular changes associated with AMPH toxicity, we used cDNA arrays consisting of 1176 genes to detect differential changes in gene expression in the striata of wild-type and SOD-tg mice treated with neurotoxic doses of the drug. We found 42 genes that showed >1.8-fold changes in at least two consecutive time points during the course of the study and were differentially affected by AMPH in the two genotypes. Specifically, more transcription factors and genes involved in responses to injury/inflammation were affected in wild-type mice after AMPH administration. Some of these stimulant-induced superoxide-dependent alterations in gene expression might affect neuronal functions and promote neuronal damage. Other changes might help to provide some degree of protection against AMPH toxicity. These results support the view that the use of global array analysis of gene expression will help to identify novel molecular mediators of AMPH-induced neurodegeneration.

Noradrenergic loss enhances MDMA toxicity and induces ubiquitin-positive striatal whorls.

Movement disorders involve a number of neurodegenerative conditions, mostly affecting basal ganglia. Parkinson's disease (PD) is classically defined by the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Administration of specific neurotoxins represents a common tool to reproduce this lesion. Among these, amphetamine derivatives act as powerful monoamine neurotoxins, impairing striatal dopamine (DA) axons in mice. Despite the well-investigated effects on striatal DA terminals, only sporadic studies have focused on the potential toxicity of amphetamines towards post-synaptic neurons within the striatum. In the present work we found that 3,4-methylenedioxymethamphetamine (MDMA) produces ultrastructural alterations in striatal cells, featuring as membraneous whorls, positive for ubiquitin and heat shock protein 70. These morphological alterations were enhanced in locus coeruleus-lesioned mice.

Hydrogen peroxide production in mouse tissues after acute d-amphetamine administration. Influence of monoamine oxidase inhibition.

The toxicity of amphetamines is conditioned by a complex array of mechanisms, involving the increase of neurotransmission (e.g. leading to hyperthermia) and enzymatic and non-enzymatic oxidation of amphetamines and biogenic amines. Considering that all these processes may increase the generation of hydrogen peroxide (H2O2) by metabolic or non-metabolic redox pathways, the main objective of this work was to evaluate d-amphetamine-induced H2O2 production in mice liver, kidney and heart. The contribution of monoamine oxidase (MAO) to H2O2 production after d-amphetamine administration was studied using the MAO inhibitor pargyline. H2O2 production was measured indirectly using the catalase-H2O2 complex I irreversible inhibitor 3-amino-1,2,4-triazole (AT). Using this method, the measurement of residual catalase activity following administration of AT permits the monitoring of H2O2 production in vivo. Charles River CD-1 mice (30-35 g body weight) were injected with AT just before the injection of d-amphetamine sulphate (20 mg/kg). d-Amphetamine stimulated the production of H2O2 in all tissues studied, although to different degrees. MAO inhibition by itself led to a remarkable decrease of basal H2O2 production in the kidney and a slight decrease in the liver, although no effect was observed in the heart. d-Amphetamine-induced H2O2 production in the heart and kidney was reduced in MAO-inhibited mice. However, in the liver, H2O2 production was transiently potentiated at 30 min under MAO inhibition. In conclusion, d-amphetamine administration leads to an increase in H2O2 production in mouse liver, kidney and heart, and monoamine oxidase plays an important role in this effect.

Neuropharmacology of an Extract derived from Convolvulus microphyllus

Neuropharmacological activities of the methanol extract of the whole plant of Shankhapushpi, Convolvulus microphyllus Sieb ex Spreng (Convolvulaceae), were studied in experimental animals. The extract was found to produce alterations in the general behaviour pattern, reduction in spontaneous motor activity, hypothermia, potentiation of pentobarbitone-sleeping time, reduction in exploratory behavioural pattern, and suppression of aggressive behaviour. The extract also showed an inhibitory effect on conditioned avoidance response and antagonism to amphetamine toxicity. These findings explicitly suggest that the whole plant extract of C. microphyllus possesses a potential CNS-depressant activity.

P2E105 - Mechanisms of neurotoxicity of substituted amphetamines

A series of pharmacological trials conducted on AF 1161 are described. AF 1161 explicates, at doses much lower than toxic ones, certain effects on behaviour characterized by a picture of sedation and diminished reactivity to external stimuli. Even at very high doses, the drug does not provoke catatonia, paralysis, or a true hypnotic state. Death is preceded by a state of prostration, overtaken by clonic convulsion. The conditioned avoidance reflex in rats and reactions to different types of painful stimuli are inhibited at doses that scarcely influence general behaviour. Duration of sleep induced by hexobarbital is increased immediately after AF 1161 administration, but returns to normal after 24 hr. No significant hypothermic effect in normal animals was noted. Toxicity of amphetamine in grouped mice is inhibited. A depressant action on the linguomandibular reflex and, no a slight extent, on the knee jerk has been observed. AF 1161 possesses a very slight anti-histamine action, a moderate adrenolytic action and a powerful anti-serotonin action. Convulsions due to pentetrazol, electroshock and strychnine are not inhibited. A local anesthetic effect was also observed.These results are discussed, and possible therapeutic use in man of AF 1161 is postulated.

Gluconeogenic Activity in Response to Chronic Administration of Amphetamine Sulphate and Drug Withdrawal

1. Chronic amphetamine administration (10 mg/kg ) to young rats (Rattus norvegius) (40–90 g) produced an initial hyperglycemia following the initial drug administration. This was followed by progressive hypoglycemia with the continuous drug treatment. 2. The present data also demonstrate increases in levels of serum ACTH and corticosterone that were maintained after drug withdrawal, in the case of corticosterone. 3. The Analysis of the transaminase activity revealed the occurrence of significant increases in serum GOT level. Furthermore, progressive increase in the G-6-Pase activity was recorded, reaching its maximum level by the end of the experiment, which demonstrates that induced amphetamine toxicity is time-dependent.

Studies on the Neuropharmacological Effects ofPsidium guyanensis andPsidium pohlianum Essential Oils

The essential oils extracted from the leaves of Psidium guyanensis Pers. and Psidium pohlianum Berg, were evaluated for their neuropharmacological effects. Both the oils (400 mg/kg, p.o.) in mice displayed potentiation of pentobarbital sleeping time and an increase of immobility time in the behavioural forced swimming test. Also at a similar dose, they reduced the mortality associated with amphetamine toxicity and pentylenetetrazol-induced convulsions. The Psidium essential oils demonstrated no influence on small intestinal secretion but caused significant inhibition of intestinal transit. No overt toxicity was observed in mice that received essential oils orally up to 4 g/kg. The results suggest a probable depressant action of the essential oils of Psidium on central and peripheral nervous systems.

Developmental toxicity of 4-substituted amphetamines in mice

Despite overwhelming and tragic evidence of their detrimental and dangerous consequences, amphetamines remain significant drugs of abuse and addiction. The effects of 4-substituted amphetamines: 4-hydroxyamphetamine (4-HA), 4-methoxyamphetamine (4-MEA), 4-ethoxyamphetamine (4-ETA), 4-propoxyamphetamine (4-PPA), and 4-benzyloxyamphetamine (4-BEA) on intrauterine development, pregnancy outcome, postnatal growth, and survival were compared in Swiss-Webster mice. Single daily doses (0, 50,or 100 mg/kg) of an aqueous solution of different amphetamines were administered on pregnancy days 6 through 18. The 50 mg/kg doses of all amphetamines were well tolerated by the mothers and did not produce any overt signs of maternal toxicity or death. However, a few mothers died on different days of gestation after receiving 100 mg/kg of 4-HA, 4-MEA, 4-ETA, and 4-BEA. The mothers that failed to deliver naturally (3 d after the due date) were killed and their uteri were examined for live/dead fetuses and resorption sites. In comparison with respective controls, the incidence of resorptions was markedly higher in the 4-MEA- and 4-ETA-dosed groups. Delivery was prolonged in the 4-PPA- and 4-BEA-treated dams. Apparently well-formed but dead pups were delivered by 4-HA-, 4-PPA-, and 4-BEA-dosed mice. Marked reductions in average litter size and weight occurred after intrauterine exposure to 100 mg/kg 4-BEA. Treatment with 4-ETA, 4-PPA, and 4-BEA not only resulted in a high incidence of cannibalism within 24 h after birth but also caused an increase in cumulative pup mortality during the first 3 weeks of age. Body weight gain was significantly lower in 3-week-old offspring exposed to 4-HA and 4-PPA than in the controls. The findings suggest that 4-substituted amphetamines exhibit a wide variation in their effects on maternal toxicity and pregnancy wastage, and produce adverse effects on parturition, pup survival, and postnatal development.

Transient Cortical Blindness in an Infant Exposed to Methamphetamine

An 11-month-old boy was brought to the pediatric emergency department for evaluation of acute onset of irritability and involuntary side-to-side turning of the head. Neurologic examination revealed cortical blindness. Toxicologic studies of blood and urine were positive for methamphetamine. The infant's vision and activity returned to normal within 12 hours. The possible mechanisms of this unusual form of amphetamine toxicity are discussed.[Gospe SM: Transient cortical blindness in an infant exposed to methamphetamine. Ann Emerg Med September 1995;26:380-382.]

Amphetamine and Methamphetamine During the 1990s

A 1981 review of toxicity and illicit use of amphetamine noted that governmental actions had diminished the diversion of pharmaceutical amphetamine and methamphetamine. Much of the illicit market prior to 1972 had been supplied by diversion of legitimately manufactured material, chiefly through careless (or even criminal) wholesaling. Following the reduced availability of diverted amphetamine, a number of events transpired. A market of fake "look-alike" products evolved. These were produced in formulations that resembled popular amphetamine products and that contained available over-the-counter stimulants, such as ephedrine and caffeine. Between 1980 and 1982, a very popular "triple product" appeared that contained caffeine, ephedrine, and phenylpropanolamine. The look-alike problem was diminished by a series of actions taken by the federal Food and Drug Administration in 1984 that outlawed the legal marketing of any such combinations. Illicit synthesis and marketing of methamphetamine continues. Although distribution remains limited chiefly to southern California, it has clinical importance. While a volatile version of methamphetamine ("ice") has received wide exposure in the American media, its true clinical impact apparently remains limited. Definitions and Terminology Amphetamine refers to a unique chemical, for which there are a number of precise terms: methylphenethylamine, phenylisopropylamine, and 2-amino-1-phenylopropane. Use of the term "amphetamines" is careless; there is no basis for using the plural term.

Amphetamine and methamphetamine during the 1990s.

A 1981 review of toxicity and illicit use of amphetamine noted that governmental actions had diminished the diversion of pharmaceutical amphetamine and methamphetamine. Much of the illicit market prior to 1972 had been supplied by diversion of legitimately manufactured material, chiefly through careless (or even criminal) wholesaling. Following the reduced availability of diverted amphetamine, a number of events transpired. A market of fake products evolved. These were produced in formulations that resembled popular amphetamine products and that contained available over-the-counter stimulants, such as ephedrine and caffeine. Between 1980 and 1982, a very popular triple product appeared that contained caffeine, ephedrine, and phenylpropanolamine. The look-alike problem was diminished by a series of actions taken by the federal Food and Drug Administration in 1984 that outlawed the legal marketing of any such combinations. Illicit synthesis and marketing of methamphetamine continues. Although distribution remains limited chiefly to southern California, it has clinical importance. While a volatile version of methamphetamine (ice) has received wide exposure in the American media, its true clinical impact apparently remains limited. Definitions and Terminology Amphetamine refers to a unique chemical, for which there are a number of precise terms: methylphenethylamine, phenylisopropylamine, and 2-amino-1-phenylopropane. Use of the term amphetamines is careless; there is no basis for using the plural term.

Potentiation of cocaine and d-amphetamine toxicity with caffeine.

The effect of caffeine when combined with cocaine or amphetamine was studied in rats. Animals were pretreated with intraperitoneal vehicle (normal saline [NS]) or caffeine 100 mg/kg, then challenged with intraperitoneal cocaine (0, 35, 50, 70, or 90 mg/kg) or intraperitoneal d-amphetamine (0, 15, 25, 35, or 42 mg/kg). Animal behavior, time to, and incidences of seizures and death were recorded. This dose of caffeine alone did not cause seizures or death. Caffeine pretreatment significantly increased the incidence of overt seizures induced by either cocaine or amphetamine. Caffeine increased the incidence of cocaine-induced death from 10% to 90% at the 70 mg/kg cocaine dose (P less than .01). Caffeine increased amphetamine-induced death from 0% to 80% at 15 mg/kg (P less than or equal to .01), 10% to 70% at 25 mg/kg (P less than or equal to .01), and 30% to 80% at 35 mg/kg (P less than or equal to .01). To investigate mechanisms, additional animals were pretreated with the adenosine agonist, 2-chloroadenosine (2.5 and 10 mg/kg), before being challenged with NS, 90 mg/kg cocaine, or 42 mg/kg amphetamine. Pretreatment with 2-chloroadenosine had no affect in reducing cocaine or amphetamine toxicity. Combination pretreatment with caffeine and 2-chloroadenosine potentiated cocaine toxicity. The phosphodiesterase inhibitor, pentoxifylline, did not potentiate cocaine toxicity. The authors conclude that caffeine potentiates the acute toxicity of both cocaine and amphetamine, and that the failure of 2-chloroadenosine to alter this suggests that the toxicity of the stimulants cocaine and amphetamine may be modulated by nonspecific rather than specific adenosine- or phosphodiesterase-induced mechanisms.

Super-reactivity to amphetamine toxicity induced by schedule of reinforcement

The chronic exposure of rats to a schedule of operant water reinforcement coupled with chronically restricted access to water sensitized the animals to intermittent d-amphetamine injections (0.31-2.5 mg/kg with intervals of 12-23 days between any two injections) in such a way that this drug came to produce catastrophic losses of body weight (32.4% of control levels). In the sessions when d-amphetamine was administered, the rats were also given a total of 12 brief electric shocks. Loss of body weight was unaccompanied by parallel changes in operant behavior performance, or in food or water intake. Remarkably, in other studies with the same interventions (sham schedule sessions, water deprivation, and foot shocks), with the exception that reinforcers were never delivered, d-amphetamine did not produce catastrophic falls in body weight. This super-reactivity to d-amphetamine toxicity may be mediated by a possible stressor action of the schedule of reinforcement. Its mechanism might be analogous to the known sensitization produced by classical experimental stressor stimuli to the repeated administration of d-amphetamine.

Central nervous system studies on an ethanol extract of Acorus calamus rhizomes

An ethanol extract of Acorus calamus rhizomes was screened for CNS effects using a battery of 20 tests in rats and mice. The extract exhibited a large number of actions similar to α-asarone (an active principle of A. calamus) but differed from the latter in several other respects including the responses to electroshock, apomorphine- and isolation-induced aggressive behaviour, amphetamine toxicity in aggregated mice, behavioural despair syndrome in forced swimming, etc. These differences could be due to chemical substances yet to be isolated from the plant extract.