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PubMed2000

Attenuation and recovery of evoked overflow of striatal serotonin in rats treated with neurotoxic doses of methamphetamine.

Repeated administration of methamphetamine to animals can lead to long-lasting decreases in striatal monoamine content. In the present study, the effects of neurotoxic doses of methamphetamine on basal and evoked overflow of striatal serotonin and of its primary metabolite 5-hydroxyindoleacetic acid were examined in awake rats using in vivo microdialysis. Male Fischer-344 rats were administered methamphetamine (5 mg/kg, s.c.) or saline four times in 1 day at 2-h intervals. Microdialysis studies were carried out 1 week, 1 month, and 6 months later. At 1 week posttreatment there were significant decreases in potassium- and amphetamine-evoked overflow of serotonin in the striatum of the methamphetamine-treated animals. Basal extracellular levels of 5-hydroxyindoleacetic acid but not of serotonin were also decreased. Evoked overflow of serotonin recovered by 1 month, and extracellular levels of 5-hydroxyindoleacetic acid had recovered by 6 months. Tissue levels of serotonin and 5-hydroxyindoleacetic acid were decreased at 1 week posttreatment but back to control levels by 1 month after treatment. These results indicate that presynaptic serotonergic functioning is attenuated in the striatum of rats treated 1 week earlier with neurotoxic doses of methamphetamine. However, in the model used, the changes are transient, and recovery can occur within 1-6 months posttreatment.

Amphetamine↗

PubMed2000

Methamphetamine rapidly decreases vesicular dopamine uptake.

Vesicular sequestration is important in the regulation of cytoplasmic concentrations of monoamines such as dopamine. Moreover, recent evidence suggests that increases in cytoplasmic dopamine levels, perhaps attributable to changes in vesicular monoamine transporter function, contribute to methamphetamine-induced dopaminergic deficits. Hence, we examined whether striatal vesicular uptake is altered following methamphetamine treatment. Multiple administrations of methamphetamine rapidly (within 1 h) decreased vesicular dopamine uptake and dihydrotetrabenazine binding, an effect that (a) persisted at least 24 h, (b) was associated with dopamine and not serotonin neurons, and (c) was unrelated to residual drug introduced by the original methamphetamine treatment. These data suggest that methamphetamine rapidly decreases vesicular monoamine transporter function in dopaminergic neurons, a phenomenon that may be associated with the long-term damage caused by this stimulant.

Animals↗

PubMed2002

Long-term post-synaptic consequences of methamphetamine on preprotachykinin mRNA expression.

Exposure to repeated high doses of methamphetamine produces long-term toxicity to central monoamine systems and alters striatonigral pathway function 3 weeks after exposure. To determine whether these changes in the striatonigral pathway persist for longer we examined neuropeptide mRNA expression in the striatum and cytochrome oxidase activity in the output nuclei of the basal ganglia after treatment with multiple high doses of methamphetamine. Rats exposed to multiple high doses of methamphetamine had significant depletion in dopamine and serotonin content, decreases in tyrosine hydroxylase immunoreactivity, and decreases in preprotachykinin mRNA expression, 6 and 12 weeks after methamphetamine treatment. Preprotachykinin mRNA expression was significantly reduced by approximately 20% in the middle striatum and approximately 32% in the caudal striatum, 6 weeks after treatment. Twelve weeks after treatment, preprotachykinin mRNA expression continued to be significantly reduced by approximately 20% in the middle striatum and approximately 14% in the caudal striatum. Cytochrome oxidase histochemical staining in the entopeduncular nucleus and substantia nigra pars reticulata was not significantly different from that in controls at either time point. These data suggest that neurotoxic regimens of methamphetamine induce changes in striatonigral neurons that persist for up to 3 months, although there is some recovery.

Animals↗

PubMed2004

Identification of differentially regulated transcripts in mouse striatum following methamphetamine treatment--an oligonucleotide microarray approach.

Methamphetamine is an addictive drug of abuse that can produce neurotoxic effects in dopamine nerve endings of the striatum. The purpose of this study was to identify new genes that may play a role in the highly complex cascade of events associated with methamphetamine intoxication. Using Affymetrix oligonucleotide arrays, 12 488 genes were simultaneously interrogated and there were 152 whose expression levels were changed following methamphetamine treatment. The genes are grouped into broad functional categories with inflammatory/immune response elements, receptor/signal transduction components and ion channel/transport proteins among the most populated. Many genes within these categories can be linked to ion regulation and apoptosis, both of which have been implicated in methamphetamine toxicity, and numerous factors associated with microglial activation emerged with significant changes in expression. For example, brain-derived neurotrophic factor (BDNF), chemokine (C-C) receptor 6 (CCr6) and numerous chemokine transcripts were increased or decreased in expression more than 2.8-fold. These results point to activated microglia as a potential source of the reactive oxygen/nitrogen species and cytokines that have been previously associated with methamphetamine toxicity and other neurotoxic conditions.

Animals↗

PubMedDate not supplied

An exploratory study: the use of paroxetine for methamphetamine craving.

Methamphetamine abuse and dependence are growing problems nationally and worldwide. There are currently no effective pharmocologic treatments. Animal studies with SSRI's suggest that serotonergic modulation alters methamphetamine's behavioral effects. This exploratory study is a trial of the effects of the SSRI paroxetine versus placebo (in a double blind design) on craving and use in a population of methamphetamine users. Many subjects dropped out of the study, but those in active treatment who completed the eight week trial had a decrease in methamphetamine craving compared to the placebo treatment as measured by the OCDS modified for use in this population. Statistical analyses were not performed due to the low number of subjects. The preliminary data suggest that serotonergic agents may play a role in the effective treatment of methamphetamine abuse and dependence within the context of other effective behavioral interventions.

Adult↗

PubMed1997

Integrating treatments for methamphetamine abuse: a psychosocial perspective.

The recent West Coast experience with increased methamphetamine use is showing signs of spreading to other parts of the US. The risk of corresponding medical and psychosocial problems has led to a call to action at the highest levels of government. The next few years will likely witness a substantial increase in treatment research on methamphetamine abuse/dependence, with particular emphasis on the development and application of novel pharmacotherapies. The evaluation of these agents presupposes that we understand the clinical syndrome resulting from chronic methamphetamine use. To establish a clear picture of the biological and psychological sequellae of methamphetamine use, we compare two cohorts (500 methamphetamine and 224 cocaine users) treated at the same outpatient clinic over the past nine years, using identical manualized treatments. The results suggest that while there are important differences in group characteristics and drug effects, the total response to treatment was quite comparable.

Adult↗

PubMedDate not supplied

Crystal methamphetamine and sexual sociality in an urban gay subculture: an elective affinity.

This paper draws on 49 qualitative interviews to explore the contextual antecedents of methamphetamine use in a sample of gay and bisexual Manhattan men. The paper distinguishes itself from the public health literature on crystal methamphetamine use in this population by shifting the analytic focus from individual-level factors of drug use to the role of social context. While individual-level factors--including self esteem and social awkwardness--are related to methamphetamine use, we argue that these factors arise in and are exacerbated by interactional pressures attendant to Manhattan's gay sexual subculture, which revolve around the expectation of peak sexual performance. Because methamphetamine is associated with increased self-esteem, increased libido, greater sexual endurance, diminished sexual inhibition, and a higher threshold for pain, the drug is used strategically by gay and bisexual men to negotiate sexual sociality and increase sexual pleasure. Hence, we suggest that there exists an elective affinity between Manhattan's gay sexual subculture and the particular pharmacological effects of methamphetamine-whereby the former strongly favours the latter as a systematic pattern of response. In turn, this relationship is linked to unsafe sexual practices or the social conditions that put gay men 'at risk of risk' of HIV infection.

Adult↗

PubMed2005

Explanations for methamphetamine use among gay and bisexual men in New York City.

Qualitative interview data from Project Tina, a formative investigation of methamphetamine use among gay and bisexual men in New York City, were used to explore the reasons men use methamphetamine. Interviews were conducted with 48 active methamphetamine users, and coding revealed that a majority of the men used the substance to enhance sexual experiences. However, usage was also related to physical needs, emotional needs, and socialization. Differential explanations were noted across participant HIV serostatus, age, and race/ethnicity. HIV seropositive men indicated significantly greater use of methamphetamine for sexual reasons, as did older respondents. HIV seronegative participants reported significantly greater use of the drug for social reasons, as did younger men. White participants were significantly more likely to use the drug for physical reasons compared to other men. These data suggest that methamphetamine use is multifaceted. Treatment programs should consider individual differences and motivations for drug use in tailoring programs.

Adult↗

PubMedDate not supplied

Quantitation of methamphetamine and amphetamine in urine by capillary GC/MS Part II. Derivatization with 4-carbethoxyhexafluorobutyryl chloride.

An analytical procedure for methamphetamine and amphetamine has been developed using 4-carbethoxyhexafluorobutyryl chloride. This derivatizing reagent has all the previously reported advantages of trichloroacetic anhydride (TCAA) in that it produces stable derivatives having both a higher mass fragmentation pattern and lesser volatility than derivatives of trifluoroacetic anhydride (TFAA) or heptafluorobutyric anhydride (HFBA). In addition, the assay uses deuterated internal standards for both methamphetamine and amphetamine. The procedure employs a liquid-liquid extraction and back extraction followed by acylation of the amines to their respective 4-carbethoxyhexafluorobutyramides. Excess derivatizing reagent is converted to the diethyl ester with anhydrous ethanol. At a column temperature of approximately 180 degrees C, the retention times for amphetamine and methamphetamine are 4 min and 5.5 min respectively. The monitored positive ions are: 248, 266, 294 (amphetamine); 270, 298 (amphetamine-d6); 262, 280, 308 (methamphetamine); 287, 315 (methamphetamine-d9). As a result of this high mass fragmentation pattern, which eliminates the 91 and 118 ions as criteria for both identification and quantitation, potential interferences from phentermine and phenethylamine are totally eliminated.

Amphetamine↗

PubMedDate not supplied

Determination of amphetamine and methamphetamine in blood by derivatization with perfluorooctanoyl chloride and gas chromatography/mass spectrometry.

A relatively simple method for quantitation of amphetamine and methamphetamine in blood was developed. Blood samples were extracted with cyclohexane, and the extracts were derivatized with perfluorooctanoyl chloride prior to gas chromatography/mass spectrometry. Selected ions were monitored at m/z 118 and 440 for amphetamine, m/z 118 and 454 for methamphetamine, and m/z 121 and 443 for the internal standard amphetamine-d3. The imprecision was less than 5% for amphetamine and less than 9% for methamphetamine. Limits of detection were 11 micrograms/L for amphetamine and 13 micrograms/L for methamphetamine, while limits of quantitation were 22 and 34 micrograms/L, respectively. Calibration curves were linear in the ranges 14-2700 micrograms/L and 15-3000 micrograms/L, respectively. Some drugs that were known or suspected to interfere with immunological or chromatographic methods for amphetamine and methamphetamine were tested for interference. None of the drugs tested interfered, except for a substance in putrefied blood samples, which was found to interfere with one ion (m/z 118) for amphetamine but not with the second ion.

Amphetamine↗

PubMed2000

GC-MS analysis of methamphetamine impurities: reactivity of (+)- or (-)-chloroephedrine and cis- or trans-1,2-dimethyl-3-phenylaziridine.

S-(+)-Methamphetamine is frequently found as the only isomer in urine specimens from methamphetamine abuseres. Enantiomerically pure S-(+)-methamphetamine can be synthesized from ephedrine or pseudoephedrine via chloroephedrine intermediates. These intermediates are unstable and capable of cyclizing to form cis- and trans-1,2-dimethyl-3-phenyl aziridine. Studies were done to determine if these intermediates could be detected when using a common gas chromatographic-mass spectrometric analytical method (derivatization with heptafluorobutyric anhydride, HFBA) for toxicological screening of methamphetamine. Analysis of (+)- or (-)-chloroephedrine after extraction into hexane and derivatization with HFBA indicated that both pseudoephedrine and ephedrine were the major compounds detected. Direct derivatization of a hexane solution of cis-1,2-dimethyl-3-phenyl aziridine yielded only the derivatives of ephedrine and pseudoephedrine, indicating that the aziridine intermediate is responsible for the formation of the ephedrine or pseudoephedrine. These studies indicate that the aziridine intermediates would not be detected in methamphetamine samples following HFBA derivatization.

Aziridines↗

PubMed2002

Extraction of amphetamine and methamphetamine from urine specimens with Cerex Polycrom Clin II solid-phase extraction columns and the Speedisk 48 Pressure Processor.

Extraction of amphetamine and methamphetamine in urine was investigated using Cerex Polycrom Clin II solid-phase extraction columns and the Speedisk 48 Pressure Processor as a replacement for our liquid-liquid procedure. Linearity for urine standards extracted with the Cerex-Speedisk method ranged from 50 ng/mL for methamphetamine and from 150 ng/mL for amphetamine to 10,000 ng/mL for both. The mean recovery at the 500-ng/mL cutoff for three different lots of columns was 96.4% for AMP and 95.7% for MET. The mean of the within-run means for three batches was 495.4 ng/mL with a coefficient of variation (CV) of 1.2% or less for amphetamine and 496.4 ng/mL for methamphetamine with a CV of 1.7% or less. Thirty-six specimens containing amphetamine and the same number for methamphetamine were analyzed by both the Cerex-Speedisk and liquid-liquid methods. The correlation for specimens containing amphetamine gave an r2 of 0.9986 with a slope of 0.99; for methamphetamine, the r2 was 0.9997 with a slope of 0.98. The Cerex-Speedisk method cut extraction time in half, was less costly, and greatly reduced the volume of hazardous waste.

Amphetamine↗

PubMed2002

Choice of an ELISA assay for screening postmortem blood for amphetamine and/or methamphetamine.

The object of this study was to evaluate the suitability of the Neogen Corp. microtiter plate enzyme-linked immunoassays (ELISA) for the screening of postmortem blood for amphetamine and methamphetamine and to choose the more appropriate assay for screening. Forty-seven postmortem whole blood specimens were obtained from drug-involved deaths, which had been screened and confirmed positive for methamphetamine and/or amphetamine. Eighty-five negative specimens were obtained from non-amphetamines-involved deaths, 17 of which involved decomposition. Specimens were tested using the Neogen Amphetamine Ultra and Neogen Methamphetamine/MDMA microtiter plate ELISA assays. No matrix effects were found for whole blood in these assays, and a dilution of 1:5 was chosen to facilitate pipetting and to bring the IC50 of the microtiter plate ELISA assay within the range of amphetamines concentrations encountered in medical examiner specimens. True positives, true negatives, false positives, and false negatives were determined relative to gas chromatography-mass spectrometry (GC-MS) and graphed for the ELISA. From these graphs and the receiver operating curves (ROC), the optimal cut-off for the Neogen Methamphetamine/MDMA ELISA was 50 ng/mL methamphetamine equivalents and the optimum cut-off for the Neogen Amphetamine Ultra ELISA was 100 ng/mL amphetamine equivalents. The Neogen Methamphetamine ELISA had a sensitivity of 93.6% +/- 3.5% and a specificity of 77.6% +/- 4.5% versus GC-MS at the cut-off of 50-ng/mL methamphetamine equivalents. The Neogen Amphetamine Ultra ELISA had a sensitivity of 95.7% +/- 3.0% and a specificity of 72.9% +/- 5.2% versus GC-MS at the 100-ng/mL amphetamine equivalents cut-off. The areas under the ROCs were equivalent for the two ELISA assays.

Amphetamine↗

PubMed2005

Longitudinal investigation of methamphetamine use among gay and bisexual men in New York City: findings from Project BUMPS.

In recent years, methamphetamine has become a drug more commonly used among gay and bisexual men in New York City. Part of a longitudinal investigation of drug abuse in this population involved assessing the patterns and context of methamphetamine use during the course of 1 year. Findings indicate that among self-identified club-drug-using men, methamphetamine is widely used by men across age groups, educational level, race/ethnicity, and HIV status. Participants reported use of methamphetamine in combination with numerous other illicit and prescribed substances and in a variety of contexts outside the "club scene." Reasons for and contexts of use are related to HIV status, with HIV-positive men indicating a greater likelihood of use to avoid conflict, unpleasant emotions, and social pressures, and reporting higher levels of use in environments such as bathhouses and "sex parties." These patterns and relationships are consistent across time and suggest a complex interaction between person level factors, environmental factors, and HIV. Findings indicate that treatment of methamphetamine addiction among gay and bisexual men must take into account the complex interrelationships between mental health, drug use, sexual risk taking, and HIV.

Adolescent↗

PubMed1998

Effect of 7-nitroindazole on body temperature and methamphetamine-induced dopamine toxicity.

The present study was undertaken to examine the role of temperature on the ability of 7-nitroindazole (7-NI) to prevent methamphetamine-induced dopamine (DA) neurotoxicity. Male Swiss-Webster mice received methamphetamine alone or in combination with 7-NI at either room temperature (20+/-1 degrees C) or at 28+/-1 degrees C. At 20+/-1 degrees C, 7-NI produced hypothermic effects and afforded total protection against methamphetamine-induced DA depletions in the striatum. At 28+/-1 degrees C, 7-NI produced minimal effects on body temperature and failed to prevent methamphetamine-induced DA reductions. These findings indicate that the neuroprotection afforded by 7-NI is likely related to its ability to produce hypothermia because agents that produce hypothermia and/or prevent hyperthermia are known to attenuate methamphetamine-induced neurotoxicity.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Baclofen decreases methamphetamine self-administration in rats.

In the present study we tested the hypothesis that baclofen, a GABA-B receptor agonist, attenuates methamphetamine self-administration. Fifteen rats were trained to self-administer i.v. injections of methamphetamine (0, 0.0625, 0.125 and 0.25 mg/kg/injection) on a progressive ratio schedule of reinforcement, and then were tested under the influence of two doses of baclofen (2.5 or 5.0 mg/kg, i.p.). Baclofen significantly reduced break points at all doses of methamphetamine, producing a dose-orderly shift of the methamphetamine dose-response function to the right. These data suggest that pretreatment with baclofen reduces methamphetamine reward. These data are consistent with other studies showing impairment of drug reward after pretreatment with baclofen and add further support to the idea that GABA-B agonists may be useful in the treatment of drug addiction.

Amphetamine-Related Disorders↗

PubMedDate not supplied

Cardiovascular effects of methamphetamine in dogs treated chronically with the amine.

Methamphetamine is one of a group of sympathomimetic amines that lower blood pressure upon chronic administration to hypertensive dogs. To determine whether tolerance to the cardiovascular effects of these drugs could play a role in their antihypertensive action, acute blood pressure responses to oral d-methamphetamine were determined in trained conscious renal hypertensive dogs at weekly intervals during treatment with the drug for 2 months. Responses were also obtained in similarly treated normotensive dogs and in normotensive and hypertensive animals receiving l-methamphetamine. Pressor responses to d-methamphetamine in hypertensive dogs remained unchanged throughout treatment, while in all other cases they diminished gradually. Only the dextro isomer reduced blood pressure chronically in the hypertensive group. It was concluded that tolerance is not involved in the antihypertensive effect of methamphetamine and that, considering the stereo specificity of this effect, residual lowering of blood pressure might involve formation of a false mediator metabolite of the amine.

Animals↗

PubMedDate not supplied

The methamphetamine burn patient.

Early aggressive fluid resuscitation has significantly decreased the morbidity and mortality associated with volume losses from large burns. Although most patients are adequately resuscitated using the Parkland formula, we noted increased fluid requirements for shock resuscitation in patients involved in methamphetamine laboratory explosions. Because predominant users are young healthy individuals in their 20s and 30s, we had not anticipated burn shock resuscitation failures in this patient group. We reviewed our experience with burn patients with documented methamphetamine use to determine whether this patient group presents new dilemmas to the burn surgeon. A 2-year retrospective study of 30 patients (15 methamphetamine users, 15 controls) revealed that the methamphetamine burn patient requires two to three times the standard Parkland formula resuscitation. In this study, methamphetamine burns larger than 40% TBSA had a 100% mortality.

Adult↗