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PubMed1991

Effects of chronic treatment with haloperidol and methamphetamine on hippocampal kindled seizures in the cat.

We assessed the effects of chronic treatment with haloperidol (0.5-2 mg/kg/day, p.o., 17 days) and methamphetamine (1-2 mg/kg/day, p.o., 17 days; 4 mg/kg/day, p.o. 9 days) on hippocampal kindled seizures using a kindling procedure with low-frequency (about 3 Hz) electrical stimulation in cats. The number of stimulating pulses required to trigger epileptic afterdischarge (pulse-number threshold, PNT) was considered an indicator of seizure threshold. Haloperidol, 0.5 and 1.0 mg/kg, reduced the duration of epileptic afterdischarge (afterdischarge duration, ADD) without affecting PNT, and 2.0 mg/kg strongly reduced PNT and ADD. Methamphetamine, 2.0 mg/kg, reduced PNT and ADD, and 4.0 mg/kg preferentially reduced PNT. The effects of the two drugs on hippocampal kindled seizures were found to be partially opposite to those on amygdala kindled seizures, suggesting the different response of these limbic structures to dopamine receptor manipulation.

Animals↗

PubMed2005

Impairment related to blood amphetamine and/or methamphetamine concentrations in suspected drugged drivers.

Experimental studies have investigated effects of low oral doses of amphetamine and methamphetamine on psychomotor functions, while less work has been done on effects of high doses taken by abusers in real-life settings. There are indications that intake of high doses may impair traffic related skills, and that abuse of amphetamines may cause hypersomnolence at the end-of-binge. The present study aimed at investigating the concentration-effect relationship between blood amphetamines concentrations and impairment in a population of real-life users. Eight hundred and seventy-eight cases with amphetamine or methamphetamine as the only drugs present in the blood samples were selected from the impaired driver registry at The Norwegian Institute of Public Health. In each case the police physician had concluded on whether the driver was impaired or not. 27% of the drivers were judged as not impaired, while 73% were judged as impaired. There was a positive relationship between blood amphetamines concentrations and impairment. The relationship reached a ceiling at blood amphetamines concentrations of 0.27-0.53 mg/l. Younger drivers were more often judged impaired than older drivers at similar concentrations. Despite the performance enhancing qualities of amphetamines demonstrated in some low dose laboratory experiments; this study revealed a positive relationship between blood amphetamines concentration and traffic related impairment.

Accidents, Traffic↗

PubMed2007

Thai War on Drugs: measuring changes in methamphetamine and other substance use by school students through matched cross sectional surveys.

In 2003 the Thai government announced a radical shift in drug policy with the implementation of a War on Drugs. Although consequences of this controversial measure (e.g. drug dealer deaths) have received widespread attention relatively little work has evaluated changes in substance use. We used two anonymous representative samples of secondary school students to compare drug use in Northeast Thailand before (1998; n=4217) and after (2004/5; n=3489) the War on Drugs. Results indicate that reported levels of current illicit drug use reduced significantly between 1998 and 2004/5 (for methamphetamine from 4.2% to 0.9%). By examining trends in year of first methamphetamine use we identify that observed reductions in drug initiation are temporally consistent with the War on Drugs. However, while prevalence of alcohol use has also fallen, there was a three-fold increase in daily alcohol use. We suggest that this rise, combined with other negative impacts of 'wars' on drugs, means drug control requires a public health perspective that sees eliminating drug use as part of a wider strategy that has improvement in population health, not just drug prevention, as its core objective.

Adolescent↗

PubMed2004

Quantitative analyses of methamphetamine's effects on self-control choices: implications for elucidating behavioral mechanisms of drug action.

The purpose of the present research was to utilize quantitative methods to identify behavioral mechanisms involved in the effects of stimulant drugs on choice in a self-control procedure. A logarithmic equation based upon a combination of the matching law and hyperbolic discounting was used to separate drug-induced changes in sensitivity to reinforcement delay from drug-induced changes in sensitivity to reinforcement amount. Pigeons responded under a concurrent-chains schedule. In the initial link, two keys were illuminated simultaneously and access to the terminal link was controlled by a single random-interval (RI) schedule; pecks on one or the other key lead to its terminal link with a 0.5 probability. In the terminal links, one alternative provided 1-s access to food (the smaller reinforcer) and the other alternative provided 4-s access to food (the larger reinforcer). The signaled delay to the smaller reinforcer always was 2s, whereas the signaled delay to the larger reinforcer increased from 2 to 40s within each session, across 10-min blocks. In general, intermediate doses of methamphetamine increased preference for the larger more delayed reinforcer. Quantitative analyses indicated that, in most cases, methamphetamine decreased sensitivity to reinforcement delay. In a few instances, concomitant decreases in sensitivity to reinforcement amount also occurred. These results suggest that a reduced sensitivity to reinforcement delay may be important behavioral mechanism of the effects of stimulants on self-control choices, and that this effect sometimes can be accompanied by a decreased sensitivity to reinforcement amount.

Animals↗

PubMed2006

Methamphetamine administration causes death of dopaminergic neurons in the mouse olfactory bulb.

BACKGROUND: Methamphetamine (METH) is an addictive drug that can cause neurological and psychiatric disorders. In the rodent brain, toxic doses of METH cause damage of dopaminergic terminals and apoptosis of nondopaminergic neurons. The olfactory bulb (OB) is a brain region that is rich with dopaminergic neurons and terminals. METHODS: Rats were given a single injection of METH (40 mg/kg) and sacrificed at various time points afterward. The toxic effects of this injection on the OB were assessed by measuring monoamine levels, tyrosine hydroxylase (TH) immunocytochemistry, terminal deoxynucleotidyl transferase-mediated deoxyribonucleotide triphosphate (dNTP) nick end labeling (TUNEL) histochemistry, and caspase-3 immunochemistry. RESULTS: Methamphetamine administration caused marked decreases in dopamine (DA) levels and TH-like immunostaining in the mouse OB. The drug also caused increases in TUNEL-labeled OB neurons, some of which were also positive for TH expression. Moreover, there was METH-induced expression of activated caspase-3 in TH-positive cells. Finally, the METH injection was associated with increased expression of the proapoptotic proteins, Bax and Bid, but with decreased expression of the antideath protein, Bcl2. CONCLUSIONS: These observations show, for the first time, that METH can cause loss of OB DA terminals and death of DA neurons, in part, via mechanisms that are akin to an apoptotic process.

Animals↗

PubMed2005

Learning in the Place navigation task, not the New-learning task, is altered by prenatal methamphetamine exposure.

Adult rats (prenatally methamphetamine-exposed, saline-exposed and controls) were tested for learning in the Morris water maze. Rats were tested in 4 consecutive days using two different types of learning tests: "Place navigation test" (stable platform position) and "New-learning test" (platform position changed daily). Males exposed prenatally to methamphetamine were slower in the Place navigation learning test than were both the control and saline-exposed males. There were no differences in the New-learning test between groups.

Amphetamine-Related Disorders↗

PubMed2006

Concurrent use of methamphetamine, MDMA, LSD, ketamine, GHB, and flunitrazepam among American youths.

BACKGROUND: The magnitude and the characteristics of the use of methamphetamine, MDMA (Ecstasy), LSD (d-lysergic acid diethylamide), ketamine, GHB (gamma-hydroxybutyrate), and flunitrazepam (Rohypnol) were examined in a probability sample of the U.S. civilian population that included multiethnic urban, suburban, and rural youths aged 16-23 (N=19,084). METHODS: Data were drawn from the National Survey on Drug Use and Health (NSDUH). Logistic regression analyses were conducted to identify the characteristics associated with the use of each of these drugs and of multiple drugs. RESULTS: Approximately 20% of youths aged 16-23 reported having ever used one or more of these drugs. Less than 1% of club drug users used club drugs only, and 82% of them had ever used three or more drug classes. Females were more likely than males to report using multiple club drugs. Recent users of methamphetamine were most likely to be females and adolescents aged 16 or 17. Recent users of MDMA tended to be young adults aged 18-21 and residents of metropolitan areas. Most recent users of LSD were adolescents aged 16-19 and those in low-income families. Ketamine users were primarily employed youths. Staying in school and getting married were associated with decreased odds of club drug use. Club drug use was highly associated with the presence of criminal behaviors and recent alcohol abuse or dependence. CONCLUSIONS: Adolescents are more likely than young adults to use multiple drugs. The clustering of multidrug use and alcohol use disorder is a cause of concern.

Adolescent↗

PubMed2004

The acetylcholine fiber density of the neocortex is altered by isolated rearing and early methamphetamine intoxication in rodents.

Alterations in the cholinergic physiology of the brain were the first to be observed when research on environmental influences on postnatal brain development began 35 years ago. Since then, the effects of isolated rearing (IR) or early pharmacological insults have been shown not only on the physiology, but also the anatomy of a variety of transmitter systems. The cholinergic fiber density, however, still remained to be assessed. We therefore used a histochemical procedure to stain cholinergic fibers in the brains of young adult gerbils reared either in groups in enriched environments or isolated in standard makrolon cages. Half of the animals from each rearing condition had received a single high dose of methamphetamine on postnatal day 14. Fiber densities were measured by computerized image analysis in the medial and orbital prefrontal cortex (PFC), dysgranular and granular insular cortex, sensorimotor cortices, and the entorhinal cortex of both hemispheres. Isolation rearing increased the cholinergic fiber densities in the prefrontal cortices of the left hemisphere and in the entorhinal cortex of the right hemisphere by about 10%, with no effect in the respective contralateral side. The early methamphetamine intoxication showed no influence in prefrontal and entorhinal cortices, but diminished the acetylcholine (ACh) innervation of the forelimb area of cortex in both hemispheres in IR gerbils and of the left hemisphere in ER gerbils, and reduced the acetylcholine innervation in the hindlimb area in both sides in both rearing groups. These results demonstrate that (a) cholinergic fiber density is differentially regulated in different cortical areas and (b) the plasticity of the cholinergic system can only be understood in the interplay with other neuromodulatory innervations.

Acetylcholine↗

PubMed2006

Simultaneous quantification of methamphetamine, cocaine, codeine, and metabolites in skin by positive chemical ionization gas chromatography-mass spectrometry.

A positive chemical ionization gas chromatography-mass spectrometric method was validated to simultaneously quantify drugs and metabolites in skin collected after controlled administration of methamphetamine, cocaine, and codeine. Calibration curves (2.5-100 ng/skin biopsy) for methamphetamine, amphetamine, cocaine, norcocaine, benzoylecgonine, cocaethylene, norcocaethylene, anhydroecgonine methyl ester, morphine, codeine, and 6-acetylmorphine (5-100 ng/skin biopsy for ecgonine methyl ester and ecgonine ethyl ester) exhibited correlation coefficients >0.999 and concentrations +/-20% of target. Intra- and inter-run precisions were <10%. This procedure should be useful for postmortem analysis; data are included on drug concentrations in skin after controlled drug administration.

Calibration↗

PubMed2006

A validated gas chromatographic-electron impact ionization mass spectrometric method for methylenedioxymethamphetamine (MDMA), methamphetamine and metabolites in oral fluid.

An analytical method to simultaneously quantify amphetamine (AMP), methamphetamine (MAMP), methylenedioxymethamphetamine (MDMA), methylenedioxyamphetamine (MDA), methylenedioxyethylamphetamine (MDEA), 3-hydroxy-4-methoxy-methamphetamine (HMMA) and 3-hydroxy-4-methoxy-amphetamine (HMA) in oral fluid is presented. Four hundred microlitres of oral fluid collected via expectoration was extracted by solid phase extraction. GC/MS-EI with selected ion monitoring (SIM) yielded linear curves 5-250 ng/mL for AMP, MAMP, MDMA and MDEA, 5-500 ng/mL for MDA and 25-1,000 ng/mL for HMA and HMMA. Recoveries were greater than 85%, accuracy 87-104%, and precision less than 8.3% coefficient of variation. This assay will be used to investigate distribution of sympathomimetic amines into human oral fluid following controlled drug administration.

Chromatography, Gas↗

PubMed2004

The effect of relapse on cognition in abstinent methamphetamine abusers.

Data from 75 participants in a longitudinal study of methamphetamine (MA) abuse were used to differentiate the cognitive performance of those who remained abstinent, relapsed, or continued to use during treatment. Participants were divided into three groups: continuous abstinence, initial abstinence but relapse, and continuous use. Groups did not differ on age, education, gender or ethnicity. Participants in the longitudinal study completed a battery of cognitive tests within 7 days of their last use of MA, then were re-tested monthly for up to 6 months (average time for this analysis was 92 days). For episodic memory, the relapse groups performance was worse than the abstinent and significantly worse than that of the continued use group who had the best performance on all measures. Relapse to methamphetamine use may affect episodic memory differently than it affects the other cognitive functions measured.

Adult↗

PubMed2005

When treatment meets research: clinical perspectives from the CSAT Methamphetamine Treatment Project.

Integrating research-based treatments into clinical settings has become a priority in the substance abuse treatment field. This article examines the introduction of research, via manualized treatment (i.e., the Matrix Model), into community treatment settings that participated in the Center for Substance Abuse Treatment Methamphetamine Treatment Project, a multi-site randomized controlled trial (RCT) that provided free treatment to 1016 methamphetamine-dependent individuals. With both empirical (qualitative) and anecdotal data from those involved clinically in the project, the article utilizes the framework of practitioner concerns set forth by Addis, Wade, and Hatgis (1999) to assess the issues realized during the implementation of this manualized treatment. Despite fairly smooth implementation of the model, the authors conclude that introducing manualized treatment in the context of an RCT may not be the best way to bring research-based treatment into the practice world.

Amphetamine-Related Disorders↗

PubMed2005

Impulsivity and methamphetamine use.

The purpose of this study was to explore the relationship between methamphetamine (meth) use and impulsivity in a sample of 385 HIV-negative heterosexually identified meth users. Participants who scored highest on a self-report measure of impulsivity were compared with those who scored lower in terms of background characteristics, meth use patterns, use of alcohol and other illicit drugs, sexual risk behavior, and psychiatric health variables. Methamphetamine users in the high impulsivity group were younger, less educated, used larger quantities of meth, were more likely to be binge users, had a larger number of sexual partners, engaged in more unprotected vaginal and oral sex, and scored higher on the Beck Depression Inventory as compared with those in the low impulsivity group. In a logistic regression analysis, Beck depression was the factor that best distinguished between meth users who scored high and those who scored low on impulsivity. Neurophysiological pathways that may underlie the relationship between impulsivity and meth use are discussed.

Adolescent↗

PubMed2004

A nonsynonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia.

Genetic contributions to the etiology of substance abuse and dependence are topics of major interest. Acute and chronic cannabis use can produce drug-induced psychosis resembling schizophrenia and worsen positive symptoms of schizophrenia. The endocannabinoid system is one of the most important neural signaling pathways implicated in substance abuse and dependence. The fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme of endocannabinoids. To clarify a possible involvement of FAAH in the etiology of methamphetamine dependence/psychosis or schizophrenia, we examined the genetic association of a nonsynonymous polymorphism of the FAAH gene (Pro129Thr) by a case-control study. We found no significant association in allele and genotype frequencies of the polymorphism with either disorder. Because the Pro129Thr polymorphism reduces enzyme instability, it is unlikely that dysfunction of FAAH and enhanced endocannabinoid system induce susceptibility to either methamphetamine dependence/psychosis or schizophrenia.

Adult↗

PubMed2005

Alteration of striatal [11C]raclopride and 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine uptake precedes development of methamphetamine-induced rotation following unilateral 6-hydroxydopamine lesions of medial forebrain bundle in rats.

We studied the positron emission tomography (PET) tracer distributions of ligands for dopamine D1 receptors ([11C]SCH23390) and D2 receptors ([11C]raclopride) and of the dopamine precursor analog 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]FDOPA) in the brain after 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle in rats. The number of methamphetamine-induced rotation was higher at 14 days than at 3 days after the 6-OHDA lesions. The brains of 6-OHDA-treated rats were analyzed by tissue dissection following i.v. bolus of each tracer at 3 days (acute stage) or 3 weeks (chronic stage) postlesion. [11C]Raclopride, but not [11C]SCH23390, showed higher accumulation in the striatum on the lesion side than on the non-lesion (intact) side both at 3 days and 3 weeks postlesion. On the other hand, lower accumulation of [18F]FDOPA was observed in the striatum on the lesion side at 3 days postlesion and in both the striatum and cerebral cortex on the lesion side at 3 weeks postlesion. Our studies demonstrate that an increase in [11C]raclopride and a decrease in [18F]FDOPA uptake in the denervated striatum is evident even at 3 days after the 6-OHDA lesions when the methamphetamine-induced rotational behavior is not established.

Animals↗

PubMed2005

Dietary cadmium exposure attenuates D-amphetamine-evoked [3H]dopamine release from striatal slices and methamphetamine-induced hyperactivity.

Prolonged exposure to environmentally relevant amounts of CdCl2 results in cadmium accumulation in dopamine-rich brain regions, such as striatum. Exposure to these low levels of cadmium also diminishes cocaine-induced hyperactivity and conditioned reinforcement. The goal of the present study was to assess the effect of cadmium on amphetamine pharmacology. Direct application of cadmium (0.1-100 microM), within the concentrations reported in brain after chronic exposure, to preloaded rat striatal slices did not alter D-amphetamine-evoked [3H]dopamine release. To determine the effect of dietary cadmium exposure on amphetamines, rats received ad libitum access to diet containing CdCl2 (10 or 100 ppm) or to control diet for 30 days and then D-amphetamine-evoked [3H]dopamine release and methamphetamine-induced hyperactivity were measured. Dietary CdCl2 exposure produced a marked increase in cadmium blood and brain levels, approximate to environmental metal exposure. Dietary cadmium exposure was associated with decreased potency of D-amphetamine to evoke [3H]dopamine release. Cadmium-exposed rats were also less sensitive to the locomotor-activating effect of acute methamphetamine (0.3 or 1.0 mg/kg) injection. The present findings demonstrate that the presence of cadmium in brain is not sufficient for the inhibition of D-amphetamine-evoked dopamine release. This suggests that cadmium does not directly interfere with the mechanism of action for amphetamine pharmacology; rather, it suggests that long-term cadmium exposure induces a change in the number and/or function of striatal neurons.

Animals↗

PubMed2006

Baicalein attenuates methamphetamine-induced loss of dopamine transporter in mouse striatum.

Methamphetamine (METH) has been shown to cause dopaminergic neurotoxicity. By using the loss of dopamine transporter (DAT) as a marker of neurotoxicity, this study was aimed to investigate the neuroprotective effect of baicalein against METH-induced striatal damages in mice. Results from Western blotting showed that repeated METH administration (5 mg/kg, i.p., four injections at 2-h interval) caused 40% decrease of DAT level in mouse striatum measured at 72h after the last injection. Despite of the ineffectiveness at high dose (3.0 mg/kg, i.p.), pretreatment with lower doses of baicalein (0.3-1.0 mg/kg, i.p.) significantly attenuated the METH-induced striatal DAT loss in a dose-dependent manner. Furthermore, baicalein diminished METH-induced increase in striatal malondialdehyde content and myeloperoxidase activity, markers for lipid peroxidation and neutrophil increase, respectively. In addition, the present study also revealed that baicalein effectively diminished the ROS production by leukocytes stimulated with METH or PMA, a phorbol ester used as a positive control of stimulant. Surprisingly, we found that METH-induced nNOS overexpression was further increased by the pretreatment with baicalein while the level of nNOS was not altered significantly by baicalein treatment alone. These results suggested that baicalein may attenuate methamphetamine-induced DAT loss by inhibiting the neutrophil increase and the lipid peroxidation caused by neutrophil-derived reactive oxygen species in striatum.

Animals↗

PubMed1992

Sudden retinal manifestations of intranasal cocaine and methamphetamine abuse.

We examined two patients who had sudden decrease in vision after intranasal cocaine or methamphetamine abuse. A 38-year-old woman with a history of systemic arterial hypertension developed a central retinal artery occlusion four hours after intranasal use of cocaine. A 26-year-old woman had blurred vision and intraretinal hemorrhages shortly after using methamphetamine nasally. The adrenomimetic response and sudden increase in blood pressure associated with the intranasal use of these drugs may have contributed to the retinal vascular manifestations observed in these patients.

Cocaine↗