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Methamphetamine and time estimation.

Three experiments were conducted to determine the effect of methamphetamine on the performance of rats in two timing tasks. When food sometimes followed the first response after T sec of a signal, the response rate increased to a peak near T sec and then declined. Methamphetamine decreased the time of the peak (Experiments 1 and 2). When one response (called a "short response") was reinforced following a short signal and a different response (a "long response") was reinforced following a long signal (where the short and long signals were 1 and 4, 2 and 8, or 4 and 16 sec), the probability of a long response increased as a function of signal duration. The point of indifference (50% long response) occurred near the geometric mean of the extreme durations, and methamphetamine decreased the point of indifference by about 10%. These results suggest that methamphetamine increases the speed of an internal clock used by rats in time discrimination tasks.

Animals↗

Effects of methamphetamine on duration discrimination.

Experiments 1 and 2 address the controversy regarding the reliability of methamphetamine effects on interval timing. A temporal discrimination procedure was used, in which the rats were reinforced for pressing the left or the right levers after short and long signals, respectively. Methamphetamine (0.5 mg/kg sc) severely disrupted operant performance at 20-100 min after injection, which disabled the measurement of drug effects on temporal perception (Experiment 1). The same dose of methamphetamine shifted the psychometric function to the left at 100-180 min after injection, indicating an increase in subjective durations (Experiment 2). Although these results confirm the role of dopamine in interval timing, that a change in the speed of a neural clock mediates the methamphetamine-induced change in temporal perception is still a working hypothesis.

Animals↗

Striatal dopamine nerve terminal markers in human, chronic methamphetamine users.

Methamphetamine is a drug that is significantly abused worldwide, Although long-lasting depletion of dopamine and other dopamine nerve terminal markers has been reported in striatum of nonhuman primates receiving very high doses of the psychostimulant, no information is available for humans. We found reduced levels of three dopamine nerve terminal markers (dopamine, tyrosine hydroxylase and the dopamine transporter) in post-mortem striatum (nucleus accumbens, caudate, putamen) of chronic methamphetamine users. However, levels of DOPA decarboxylase and the vesicular monoamine transporter, known to be reduced in Parkinson's disease, were normal. This suggests that chronic exposure to methamphetamine does not cause permanent degeneration of striatal dopamine nerve terminals at the doses used by the young subjects in our study. However, the dopamine reduction might explain some of the dysphoric effects of the drug, whereas the decreased dopamine transporter could provide the basis for dose escalation occurring in some methamphetamine users.

Adult↗

Brain choline acetyltransferase activity in chronic, human users of cocaine, methamphetamine, and heroin.

Cognitive impairment has been reported in some chronic users of psychostimulants, raising the possibility that long-term drug exposure might damage brain neuronal systems, including the cholinergic system, which are responsible for normal cognition. We measured the activity of choline acetyltransferase (ChAT), the marker enzyme for cholinergic neurones, in autopsied brain of chronic users of cocaine, methamphetamine, and, for comparison, heroin. As compared with the controls, mean ChAT levels were normal in all cortical and subcortical brain areas examined. However, the two of 12 methamphetamine users, who had the highest brain/blood drug levels at autopsy, had a severe (up to 94%) depletion of ChAT activity in cerebral cortex, striatum, and thalamus. Based on the subjects examined in the present study, our neurochemical data suggest that brain cholinergic neurone damage is unlikely to be a typical feature of chronic use of cocaine, methamphetamine, or heroin, but that exposure to very high doses of methamphetamine could impair, at least acutely, cognitive function requiring a normal nucleus basalis cholinergic neuronal system. Reduced brain ChAT might be explained in part by a hyperthermia-related mechanism as low ChAT levels have also been observed in brain of some patients with neuroleptic drug-associated hyperthermia. Studies of cognitive and brain cholinergic status in high dose users of MA are warranted.

Adult↗

4-Hydroxytamoxifen attenuates methamphetamine-induced nigrostriatal dopaminergic toxicity in intact and gonadetomized mice.

The present study was undertaken to assess the ability of 4-hydroxytamoxifen (4-OHT) to alter methamphetamine-induced nigrostriatal dopaminergic toxicity. Three daily doses of 4-OHT (6 micro g/day) effectively attenuated methamphetamine-induced nigrostriatal dopamine depletions in both sexes of intact and gonadectomized C57BL/6 J mice. 4-OHT alone did not alter the dopamine content levels in the striatum. Both male and female mice exhibited similar Cu, Zn-superoxide dismutase protein levels in the striata whether after gonadectomy or 4-OHT treatment. Furthermore, basal body temperature and methamphetamine-induced hyperthermia were not affected by 4-OHT treatment in either sex of mice. Using a lucigenen-derived chemiluminescence assay, we found that 4-OHT by itself can serve as a potent superoxide anion radical scavenger in vitro. The protective effects of 4-OHT against methamphetamine-induced nigrostriatal dopamine depletion can be, in part, due to its antioxidative characteristics. The free radical-scavenging ability of 4-OHT calls for further investigations for its uses in clinical practice.

3,4-Dihydroxyphenylacetic Acid↗

A single dose of methamphetamine leads to a long term reversal of the blunted dopamine D1 receptor-mediated neocortical c-fos responses in mice deficient for D2 and D3 receptors.

Dopamine D(1) receptors play an essential role in the induction of expression of the immediate-early gene c-fos in response to pharmacological stimuli. In the forebrain of wild-type mice, administration of a D(1) receptor agonist leads to c-fos mRNA expression levels that are substantially higher than corresponding levels expressed after indirect stimulation of dopamine receptors with methamphetamine. In mice deficient for D(2) and D(3) receptors, c-fos mRNA levels expressed in response to D(1) agonist administration are significantly blunted. However, a single dose of methamphetamine (5 mg/kg) leads to a long lasting reversal of the blunted c-fos responses in these mutants. In the forebrain, this reversal is restricted to the neocortex. Moreover, methamphetamine also enhances c-fos expression levels in preadolescent wild-type mice that normally express low c-fos mRNA in response to D(1) agonist stimulation. Thus, a single dose of methamphetamine leads to a long term increase in D(1) receptor-dependent c-fos responses in brains with either low (preadolescent mice) or blunted (adult D(2) and D(3) mutant mice) c-fos expression levels. A similar long term reversal of the blunted c-fos responses is achieved with a single dose of a full D(1) agonist. These results indicate that the constitutive inactivation of D(2) and D(3) receptors leads to a decrease in agonist-promoted D(1) receptor activity that can be reversed by intermittent agonist stimulation.

Animals↗

Drug and alcohol treatment services effective for methamphetamine abuse.

BACKGROUND: Methamphetamine abuse has become a major public health problem as demonstrated by increases in the number of emergency room visits, substance abuse treatment episodes, and arrests attributable to methamphetamine manufacture and abuse. We examine the effectiveness of conventional substance abuse treatment in the recovery of individuals seeking voluntary treatment for methamphetamine abuse. METHODS: At the request of the Iowa Department of Public Health, the Iowa Consortium for Substance Abuse Research and Evaluation contacted clients who had been admitted to voluntary treatment for methamphetamine abuse. Staff from the Consortium asked subjects to volunteer for follow-up interviews at designated intervals following admission. Agency staff conducted interviews based on the Mini International Neuropsychiatric Interview (MINI) at admission and at designated intervals and reported results to the Consortium for analysis. RESULTS: Subjects were predominantly Caucasian and over one half were female with an average age of 30 years. The criminal justice system was a primary referral source. Reported psychiatric symptoms dropped substantially in the first 60 days following admission and appeared to remain low at 6 and 12 months. Most clients reported abstinence and employment and denied arrests at the 6-month interview. Outcomes were not correlated with psychiatric symptoms. CONCLUSIONS: Psychiatric symptoms improved over time with usual substance abuse treatment. There was no evidence that referral by the court system or symptoms of antisocial personality disorder affected outcome. Conventional treatment resulted in sobriety, employment, and fewer arrests at 6 and 12 months following treatment.

Adult↗

Negative self-perceptions and sexual risk behavior among heterosexual methamphetamine users.

This research examined the relationship between negative self-perceptions and sexual risk behavior in a sample of 156 heterosexually identified, methamphetamine users from San Diego, California. The Beck Depression Inventory and the Self Esteem Rating Scale, respectively, were used to assess depression and negative self-perceptions. Measures of sexual risk behavior and methamphetamine use were developed specifically for this research. Data were gathered in 2001-2002. Participants were primarily male (76%), Caucasian (56%), never married (51%), and unemployed (73%), with a mean age of 39.1 years. Participants with high levels of negative self-perceptions evidenced the greatest degree of sexual risk behavior, including significantly more unprotected vaginal sex and a larger number of sexual partners as compared to individuals with low levels of negative self-perceptions. In cross-sectional analyses, negative self-perceptions predicted intensity of methamphetamine use and depressive symptoms. However, neither of these variables were found to mediate the relationship between negative self-perceptions and sexual risk behavior. Findings are discussed in relation to the need for further research into the role of negative self-perceptions as a determinant of sexual risk behavior among methamphetamine users.

Adolescent↗

"Parachuting" meth: a novel delivery method for methamphetamine and delayed-onset toxicity from "body stuffing".

BACKGROUND: Methamphetamine is an illicit stimulant that is typically smoked, insufflated, or injected. We report an unusual method of ingesting methamphetamine called "parachuting" and its implications for the treatment of "body stuffers." CASE REPORT: A 25-year-old man wrapped methamphetamine into a plastic baggie and ingested it in an attempt to "parachute." He presented to an Emergency Department 10 hours after his ingestion because he realized that he forgot to puncture the baggie. He had no complaints and had a transient tachycardia. He was treated with activated charcoal and whole bowel irrigation, observed for 24 hours, and discharged. He returned 42 hours after his ingestion with tachycardia (220 bpm), agitation, hypertension (179/74 mmHg), and rhabdomyolysis (CPK 7771 U/L), requiring mechanical ventilation and a midazolam drip (10 mg/hr). CONCLUSION: "Parachuting" is a novel method of ingesting methamphetamine. We report a case of a single-packet "body stuffer" with severe symptom onset that was delayed over 36 hours. Treatment protocols for "body stuffers" using this technique may require more prolonged observation and/or imaging studies to determine the absence of gastrointestinal packets.

Administration, Oral↗

"Meth mouth": rampant caries in methamphetamine abusers.

Rampant dental caries is a characteristic finding in methamphetamine abusers. The popularity of methamphetamine, particularly among the gay community where it is linked to the spread of HIV, its ready availability, and rapid spread across the nation have placed methamphetamine use in an epidemic status in many communities unaccustomed to dealing with drug abuse. We present a case of a 25-year-old male "meth" abuser of unknown HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) status to promote recognition by the health care team of the association of rampant dental caries with methamphetamine abuse for appropriate intervention to ensure successful treatment and prevention of disease progression.

Adult↗

Halothane potentiates the effect of methamphetamine and nomifensine on extracellular dopamine levels in rat striatum: a microdialysis study.

Brain microdialysis was used to study the in vivo release and metabolism of dopamine (DA) in the rat striatum during halothane anaesthesia. Concentrations were measured in microdialysates collected every 20 min and applied directly to an on-line high-performance liquid chromatograph. Halothane was administered at concentrations of 0.5, 1.0, 1.5 and 2.0%. In another series of experiments, rats were treated intraperitoneally or locally with methamphetamine, a drug of abuse, or with nomifensine, a dopamine uptake blocker and antidepressant, in combination with 0.5 or 1.5% halothane. Halothane anaesthesia did not affect the dialysate (extracellular) concentration of DA at 2.0%. By contrast, the concentrations of DA metabolites [3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] increased during inhaled halothane anaesthesia in a dose-dependent manner and recovered after anaesthesia. Halothane potentiated the ability of methamphetamine to increase the extracellular concentration of DA when administered systemically, whereas only a small increase in DA accumulation was seen when methamphetamine was administered locally via the perfusate. Similarly, the increase in extracellular DA was accentuated by systemic nomifensine during halothane anaesthesia, but no obvious enhancement was observed when it was applied locally. It has been shown that the neurotoxic effect of methamphetamine is mediated by the suboxidation of DA released from the cytoplasm into the extracellular space and transformed into highly reactive free radicals. On the basis of our results, it is suggested that care should be exercised when halothane anaesthesia is used in patients abusing phenylethylamines (amphetamines) or being treated with DA uptake blockers (nomifensine).

Analysis of Variance↗

Quantitation of methamphetamine and amphetamine in urine by capillary GC/MS. Part I. Advantages of trichloroacetyl derivatization.

A urine assay for methamphetamine and amphetamine that is compatible with our existing high-volume GC/MS assays for other drugs of abuse has been developed. Trichloroacetic anhydride is used for derivatization and its derivative is substantially less volatile than other commonly used derivatives. The internal standard is the primary amine 2-methylphenethylamine. The procedure utilizes an initial liquid-liquid extraction, a liquid-liquid back extraction for specimen cleanup, and derivatization for removal of excess trichloroacetic anhydride and acid by-product. A GC temperature of about 180 degrees C results in retention times of approximately 2.8, 3.2, and 4.3 min for amphetamine, the internal standard, and methamphetamine, respectively. Five ions are monitored: 91+, 118+, 188+ for amphetamine; 105+, 118+ for 2-methylphenethylamine; and 91+, 118+, 202+ for methamphetamine. Full scan GC/MS data from a variety of other derivatives are examined and used to illustrate the advantages of derivatizing molecules with strongly electronegative atoms near the reaction site. This situation forces fragmentation patterns in which positive charges are located on larger and structurally acceptable identifying mass fragments of the original methamphetamine or amphetamine molecule.

Acetic Anhydrides↗

Analysis of methamphetamine in hair, nail, sweat, and saliva by mass fragmentography.

A method for the detection and quantitation of methamphetamine and its major metabolite in hair, nails, sweat, and saliva from habitual users of methamphetamine by mass fragmentography has been developed. Hair and nail samples were washed with water and methanol to remove the external contamination, processed with 0.6M HCl, alkalinized, and extracted with CHCl3/isopropanol (3:1 v/v). Sweat and saliva samples were extracted with methanol. After trifluoroacetyl derivatization, the samples were analyzed by mass fragmentography. Methamphetamine and its major metabolite, amphetamine, were detected in hair, nail, and sweat samples, but methamphetamine alone was detected in saliva samples.

Amphetamine↗

Detection of amphetamine and methamphetamine in urine by gas chromatography/mass spectrometry following derivatization with (-)-menthyl chloroformate.

A gas chromatography/mass spectrometry assay was developed for the detection of amphetamine and methamphetamine in urine. These drugs were detected as carbamate derivatives following reaction with (-)-menthyl chloroformate. Selected ion monitoring of the 226, 182, and 227 dalton ions for amphetamine and the 240, 102, and 196 dalton ions for methamphetamine provided positive analyte identification. Quantitative values obtained by isotope dilution mass spectrometry displayed a linear response from below 50 to above 6,000 ng/mL. Differentiation of over-the-counter (R)-methamphetamine from illicit (S)-methamphetamine was accomplished by chromatographic separation of the diastereomeric derivatives on an achiral column. No interferences were observed from ephedrine, pseudoephedrine, phentermine, phenylpropanolamine, or 2-phenylethylamine.

Amphetamine↗

Identification of methamphetamines and over-the-counter sympathometic amines by full-scan GC-ion trap MS with electron impact and chemical ionization.

An underivatized methane chemical ionization (CI) assay for measuring amphetamines in urine was evaluated against derivatized electron impact (EI) assays using a gas chromatograph-ion trap mass spectrometer. The full-scan CI mass spectra of methamphetamine, ephedrine/pseudoephedrine, and phentermine were compared with the full scan and three-ion EI mass spectra of heptafluorobutyric anhydride (HFBA) and 4-carbethoxyhexafluorobutyryl chloride (CB) derivatives. The fragmentation patterns for these compounds were nearly identical for the three major high molecular weight ions (m/z 254, 210, and 169 for EI-HFBA derivatives, and m/z 308, 262, and 280 for EI-CB derivatives). The CI mass spectra of the underivatized drugs contained more discernible differences at the higher molecular weights, including m/z 119, 148, and 150 for methamphetamine, 148, 166, and 176 for ephedrine/pseudoephedrine, and 91, 133, and 150 for phentermine. The within-run precision ranged from 7-9% for CI versus 5-6% for EI with HFBA derivatization (mean 500 ng/mL, n = 5). The limits of detection (LOD) for amphetamine and methamphetamine were 2.4 and 8.6 ng/mL, respectively, for CI versus 0.7 and 1.4 ng/mL for EI. The limits of quantitation (LOQ) were 4.5 and 19.1 ng/mL for CI versus 1.4 and 5.7 ng/mL for EI. The use of full-scan mass spectral analysis with either electron impact or chemical ionization provides additional qualitative data that may be helpful for measuring methamphetamine in the presence of other sympathomimetic amines.

Amphetamine↗

Detection of a GC/MS artifact peak as methamphetamine.

Recently, certain laboratories reported the presence of methamphetamine in several negative urine specimens. We have demonstrated an artifact peak, by SIM GC/MS, in negative urine specimens, that frequently matches the retention time and identity ion ratio criteria for methamphetamine. This peak resulted from the presence of high levels of pseudoephedrine (PS) or ephedrine (EP) and was produced after derivatization with 4-carbethoxyhexafluorobutyryl chloride (CB), heptafluorobutyric anhydride (HFB), and N-trifluoroacetyl-l-prolyl chloride (TFAP). Use of N-methyl trideuterated PS and two deuterated EP compounds in spiked samples provided additional proof that PS and EP can produce the artifact peak. The above results were achieved using a GC injection port temperature of 300 degrees C and low split and isothermal conditions. Thermal transformation in the injector is involved because lowering and raising the injector temperature results in the disappearance and subsequent reappearance of the artifact peak. Proof that the artifact peak is actually methamphetamine was provided by full-scan GC/MS data of the artifact peak produced after use of all three derivatizing reagents. GC/MS analysis has demonstrated that urine (65 specimens) with concentrations of PS or EP ranging from 100,000 to 1,100,000 ng/mL will test negative for methamphetamine, while the same specimens will trigger positive results by radioimmunoassay and the Emit monoclonal assay. Full-scan GC/MS of the CB derivative for PS and EP reveals what appears to be both mono- and diderivatized products. SIM analysis can differentiate between PS and EP in urine specimens because the relative amounts of mono- and diderivatized products are very different for PS than for EP.(ABSTRACT TRUNCATED AT 250 WORDS)

Artifacts↗

Amphetamine as an artifact of methamphetamine during periodate degradation of interfering ephedrine, pseudoephedrine, and phenylpropanolamine: an improved procedure for accurate quantitation of amphetamines in urine.

During periodate degradation of interfering ephedrine, pseudoephedrine, and phenylpropanolamine in the extraction of methamphetamine from urine, it was observed that a small amount of methamphetamine was demethylated to amphetamine. although all three interfering phenylpropanolamines could be degraded by periodate at pH 5.2 and above, this periodate-mediated transformation of methamphetamine to amphetamine was observed only at pH 9.1 and above. Therefore, to avoid this transformation, a pH of 6.2 was used for the oxidative degradation of phenylpropanolamines. The excess periodate was then reduced with thiosulfate or ascorbic acid prior to the extraction of methamphetamine using a basic pH.

Amphetamine↗

Fetal and infant deaths associated with maternal methamphetamine abuse.

Eight cases of fetal and infant death related to maternal methamphetamine abuse are presented. The mean fetal blood concentration of methamphetamine was 0.36 microgram/mL (range, 0.03-1.20 micrograms/mL), and the mean concentration of amphetamine was 0.05 microgram/mL (range, 0-0.08 microgram/mL). Both maternal and fetal blood methamphetamine concentrations were obtained in two cases. The maternal and fetal methamphetamine concentrations for these two cases were 0.21 and 0.40 microgram/mL and 0.18 and 1.20 micrograms/mL, respectively. The cause of death for each case, as listed by the pathologist, is also discussed.

Abortion, Spontaneous↗