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Effects of methamphetamine on development of circadian rhythms in rats.

To determine the effect of continuous methamphetamine treatment on development of the circadian system, the daily courses of spontaneous locomotor activity and plasma corticosterone level were determined in infant rats. Methamphetamine was dissolved in drinking water at a concentration of 0.005%, and administered to rats from postnatal day 14. The circadian locomotor rhythm in methamphetamine treated rats was not significantly different from that in non-treated rats for the first 4 weeks of drug treatment. Then the rhythm began to show signs of relative coordination and finally split into two activity components. One component entrained to the light-dark cycle, whereas the other free-ran in spite of the light cycle. The rhythm of plasma corticosterone in the methamphetamine treated group was not different from that in the control group at 4 weeks after birth, but was significantly phase-delayed at 8 weeks. Splitting was not observed for the corticosterone rhythm. It is concluded that continuous administration of methamphetamine to infant rats affects the circadian rhythms for spontaneous locomotor activity and plasma corticosterone level. Possible mechanisms of methamphetamine effects were discussed in terms of the circadian system underlying these rhythms.

Administration, Oral↗

Effects of isradipine, a dihydropyridine-class calcium channel antagonist, on D-methamphetamine-induced cognitive and physiological changes in humans.

D-methamphetamine is abused for its euphoric effects and stimulatory action on cognitive function. Its abuse can, however, be associated with massive hypertension resulting in strokes, ruptured aneurysms, or myocardial infarction. We examined the utility of isradipine, a dihydropyridine-class calcium channel antagonist, in treating d-methamphetamine induced hypertension and evaluated its effects on cognitive function, both of which are mediated by dopaminergic mechanisms. D-methamphetamine dose-dependently increased all vital signs (systolic, diastolic, and mean arterial pressure, and pulse rate) parameters. Isradipine significantly reduced d-methamphetamine-induced increases in diastolic and mean arterial pressure; however, this potentially beneficial therapeutic effect was offset by a significant reflex rise in pulse rate. D-methamphetamine also improved attention, accuracy of reasoning ability, and performance on computerized cognitive function tasks. D-methamphetamine's cognitive improving effects were not altered significantly by isradipine. Isradipine increased the false responding rate but was without significant effect on any other attentional task, or on reasoning ability, or performance. Isradipine does not appear to enhance cognitive function in healthy humans.

Adult↗

Determination of origin of ephedrine used as precursor for illicit methamphetamine by carbon and nitrogen stable isotope ratio analysis.

The sale of ephedrine, one of the precursors of methamphetamine, is strictly controlled and monitored in various countries to prevent the production of illicit methamphetamine. There are three kinds of production scheme for ephedrine manufacture, and it is very useful for precursor control to investigate the origin of ephedrine used for the synthesis of illicit methamphetamine. By means of stable isotope ratio mass spectrometry (IR-MS), we investigated the origin of ephedrine based on the delta(13)C and delta(15)N values. The various origins of ephedrine (biosynthetic, semisynthetic, or synthetic) could be discriminated clearly by using these values. The delta(15)N values of synthetic ephedrine were more negative than those of ephedrine from other sources. By the repeated distillation of methylamine in our laboratory, we confirmed that this could be due to isotope separation during distillation for the purification of methylamine used for ephedrine synthesis. The values for ephedrine used as the precursor were well-correlated with those for methamphetamine synthesized from it. This drug characterization analysis should be useful to illuminate the origin of the precursors used for clandestine methamphetamine and to trace the diversion of medicinal ephedrine for illicit manufacture of methamphetamine.

Carbon Isotopes↗

Differential interactions of desipramine with amphetamine and methamphetamine: evidence that amphetamine releases dopamine from noradrenergic neurons in the medial prefrontal cortex.

Amphetamine is more effective than methamphetamine at raising dopamine levels in the prefrontal cortex. The current study tested the hypothesis that norepinephrine transporters are involved in this difference. Using microdialysis, dopamine, norepinephrine, and serotonin were measured in the rat prefrontal cortex after administration of methamphetamine or amphetamine, with and without perfusion of desipramine. Amphetamine raised norepinephrine levels more than methamphetamine did. Desipramine raised dopamine and serotonin levels but did not alter metabolite levels. Desipramine attenuated the increase in dopamine by amphetamine while increasing the dopamine released by methamphetamine. These data suggest that methamphetamine and amphetamine differ in altering prefrontal cortical dopamine levels and in interacting with norepinephrine transporters. It is proposed that amphetamine releases dopamine in the prefrontal cortex primarily through norepinephrine transporters, whereas methamphetamine interacts minimally with norepinephrine transporters.

Amphetamine↗

Bupropion reduces methamphetamine-induced subjective effects and cue-induced craving.

Bupropion is an antidepressant with stimulant properties, which inhibits the reuptake of dopamine (DA) and norepinepherine, and is purported to enhance DA neurotransmission. Bupropion is considered an appealing candidate medication for the treatment of methamphetamine dependence. The current laboratory study was set forth to assess the impact of bupropion treatment on the subjective effects produced by methamphetamine in the laboratory. We also assessed the effects of bupropion treatment on craving elicited by exposure to videotaped methamphetamine cues. A total of 26 participants were enrolled and 20 completed the entire study (n=10 placebo and n=10 bupropion, parallel groups design). Bupropion treatment was associated with reduced ratings of 'any drug effect' (p<0.02), and 'high' (p<0.02) following methamphetamine administration. There was also a significant bupropion-by-cue exposure interaction on General Craving Scale total score (p<0.002), and on the Behavioral Intention subscale (p<0.001). Overall, the data reveal that bupropion reduced acute methamphetamine-induced subjective effects and reduced cue-induced craving. Importantly, these data provide a rationale for the evaluation of bupropion in the treatment of methamphetamine dependence.

Adolescent↗

Increased methamphetamine-induced locomotor activity and behavioral sensitization in histamine-deficient mice.

We have recently suggested that the brain histamine has an inhibitory role on the behavioral effects of methamphetamine by pharmacological studies. In this study, we used the histidine decarboxylase gene knockout mice and measured the spontaneous locomotor activity, the changes of locomotion by single and repeated administrations of methamphetamine, and the contents of brain monoamines and amino acids at 1 h after a single administration of methamphetamine. In the histidine decarboxylase gene knockout mice, spontaneous locomotor activity during the dark period was significantly lower than in the wild-type mice. Interestingly, methamphetamine-induced locomotor hyperactivity and behavioral sensitization were facilitated more in the histidine decarboxylase gene knockout mice. In the neurochemical study, noradrenaline and O-phosphoserine were decreased in the midbrain of the saline-treated histidine decarboxylase gene knockout mice. On the other hand, single administration of methamphetamine decreased GABA content of the midbrain of the wild-type mice, but did not alter that of histidine decarboxylase gene knockout mice. These results suggest that the histamine neuron system plays a role as an awakening amine in concert with the noradrenaline neuron system, whereas it has an inhibitory role on the behavioral effects of methamphetamine through the interaction with the GABAergic neuron system.

3,4-Dihydroxyphenylacetic Acid↗

Blockade by ginseng total saponin of the development of methamphetamine reverse tolerance and dopamine receptor supersensitivity in mice.

Repeated administration of methamphetamine (2 mg/kg) developed reverse tolerance to the ambulation-accelerating effect. Intraperitoneal administration of ginseng total saponin (GTS, 200 mg/kg of body weight) prior to and during chronic administration of methamphetamine inhibited the development of reverse tolerance. Dopamine receptor supersensitivity was also developed in reverse tolerant mice which had received the same methamphetamine. The development of dopamine receptor supersensitivity was evidenced by the enhanced hypothermic response to apomorphine (1 mg/kg) and the enhanced ambulatory activity of apomorphine (4 mg/kg). GTS also prevented the development of dopamine receptor supersensitivity induced by the chronic administration of methamphetamine. These results show that GTS may be useful for the prevention of and therapy for the adverse action of methamphetamine. It is concluded that the development of reverse tolerance to methamphetamine may be associated with the enhanced dopamine receptor supersensitivity since both phenomena were blocked by GTS.

Animals↗

Human immunodeficiency virus type 1 Tat and methamphetamine affect the release and activation of matrix-degrading proteinases.

Human immunodeficiency virus (HIV) dementia (HIVD) is associated with an increase in the number of activated monocytes within the central nervous system (CNS), a pathological feature that may be more remarkable in the setting of superimposed substance abuse. Monocytes may transport HIV to the brain, and, moreover, activated and/or infected monocytes have been shown to release a number of potent neurotoxins. Although the mechanisms responsible for the increase in the CNS ingress of monocytes are multiple, blood-brain barrier (BBB)-degrading matrix metalloproteinases (MMPs) are likely to play an important role. The current study investigates the effects of the HIV-1-encoded protein Tat, and the drug of abuse methamphetamine, on MMP release from brain derived cells. The release of urokinase plasminogen activator (uPA), an activator of MMPs, was also investigated. Mixed human neuron/astrocyte cultures were stimulated with Tat or methamphetamine, and supernatants were analyzed by enzyme-linked immunosorbent assay (ELISA) and/or gelatin substrate zymography. Results showed that Tat and methamphetamine increased the release of MMP-1 from these cultures. Tat also increased supernatant levels of active MMP-2. In addition, both Tat and methamphetamine stimulated the release of the MMP activator uPA, and in a manner that was sensitive to inhibition with pertussis toxin. Together, these results suggest that in HIVD, Tat and methamphetamine may contribute to CNS inflammation by stimulating increased release and/or activation of matrix-degrading proteinases through mechanisms that include Gi/Go-coupled signaling. These results also suggest a potential mechanism for acceleration of HIVD with methamphetamine use.

AIDS Dementia Complex↗

Drug-induced psychosis associated with crystalline methamphetamine.

OBJECTIVE: A case of drug-induced psychosis related to crystalline methamphetamine is described, highlighting the phenomenology and relevant treatment. RESULTS: A 44-year-old woman with borderline personality traits and severe drug dependence developed a protracted drug-induced psychosis related to chronic high-dose crystalline methamphetamine use. Complete resolution of symptoms occurred with antipsychotic medication and abstinence from methamphetamine. Rapid recurrence of symptoms occurred at a time of high stress associated with minimal methamphetamine use and cessation of low-dose quetiapine. Symptoms rapidly resolved with abstinence, quetiapine and reduction of stressors. CONCLUSIONS: A drug-induced psychosis resembling paranoid schizophrenia can occur with repeated or high-dose use of methamphetamine. While this generally resolves rapidly with cessation of stimulant use, some cases of protracted drug-induced psychosis in vulnerable individuals have been documented. Behavioural sensitization can also occur, and neuroleptics may prevent the recurrence of further psychosis triggered by ongoing low-dose methamphetamine use.

Adult↗

An ethnographic comparison of HIV risk behaviors among heroin and methamphetamine injectors.

Drug injection and other practices affecting the risk of human immunodeficiency virus (HIV) infection were studied among 154 heroin users and 45 methamphetamine users in San Antonio, Texas. Amphetamine users were younger, mostly white, and had less-severe drug dependence. Heroin users had significantly higher levels of needle risk, as indicated by frequency of injection, number of persons sharing equipment, and place of injection. Methamphetamine users tended to buy syringes in lots of 10 or more from pharmacies and to use a syringe less than 5 times before discarding it. Heroin users tended to buy 1 needle at a time from an illicit source and to use it more than 20 times. Of methamphetamine users, 71% had more than one sex partner, compared to 39% of heroin users. Partners of methamphetamine users were more likely to be drug injectors than were partners of heroin users. Fewer methamphetamine users reported a behavior change in response to the acquired immunodeficiency syndrome (AIDS) epidemic, and fewer had been contacted by AIDS Education/Outreach. We suggest that efforts to promote risk reduction among methamphetamine users be stepped up because this population has been underserved and because less-sweeping behavior changes are needed to reduce needle-related risks to acceptable levels.

Adult↗

Methamphetamine toxicity secondary to intravaginal body stuffing.

BACKGROUND: People who ingest packets of illicit drugs or insert them into body cavities in an attempt to smuggle them are termed body packers. People who do this in an attempt to hide the drugs when encountered by law enforcement are called body stuffers. Severe toxicity and death occurs in body packers and body stuffers, and this is usually secondary to leaking of drug from packets in the gastrointestinal tract. This is well reported with cocaine and heroin and occurs less commonly with methamphetamine. We report an unusual case of intravaginal body stuffing that lead to severe methamphetamine toxicity in a young woman. CASE REPORT: A 20-year old female, who was in police custody, developed multiple seizures, altered mental status, tachycardia and hypertension shortly after admitting to having drugs enclosed in plastic bags in her vagina. She was hospitalized for 4 days with gradual improvement in her symptoms with the exception of a resting tachycardia. Gas chromatography and mass spectrometry of the urine at this time confirmed the presence of methamphetamine and the amphetamine metabolite, co-intoxicants were excluded based on comprehensive urine drug screening using GCMS. Quantitative serum levels of methamphetamine and amphetamine were 3100 ng/ml and 110 ng/ml, repectively. CONCLUSION: We report an unusual case of intravaginal body stuffing that lead to severe methamphetamine toxicity in a young woman. This case highlights the potential for severe methamphetamine poisoning secondary to intravaginal stuffing. If either body packing or stuffing is suspected, a vaginal exam may be warranted.

Administration, Intravaginal↗

Crystal methamphetamine, its analogues, and HIV infection: medical and psychiatric aspects of a new epidemic.

The use of the recreational drug crystal methamphetamine among younger homosexual men is expanding, and with it, unsafe sex behaviors that increase the transmission of human immunodeficiency virus (HIV). This article reviews available literature on the medical and psychiatric morbidities associated with methamphetamine abuse in HIV-infected patients. Medical complications include hypertension, hyperthermia, rhabdoymyolysis, and stroke. One fatal case of ingestion of methamphetamine with HIV medication has been documented. Two fatal cases of ingestion of HIV medication with the amphetamine analogue n-methyl-3,4 methylenedioxymethamphetamine (MDMA, or "ecstasy") have also been reported. Some molecular researchers suggest that dopaminergic systems are vulnerable to the combined neurotoxicity of HIV infection and methamphetamine. Population surveys indicate high rates of HIV infection among methamphetamine abusers and high rates of unprotected anal intercourse during drug intoxication. Intoxication can sometimes produce paranoia, auditory hallucinations, and, occasionally, violent behavior. Amphetamine withdrawal commonly results in symptoms of depression. Methamphetamine is a new challenge related to treatment and prevention of HIV infection.

Amphetamine-Related Disorders↗

Distinguishing sympathomimetic amines from amphetamine and methamphetamine in urine by gas chromatography/mass spectrometry.

Derivatives of seven commonly used sympathomimetic amines and two "designer amines" were isolated from urine, separated chromatographically from amphetamine and methamphetamine, and determined by mass spectrometry with selected ion monitoring. The drugs included ephedrine, propylhexedrine, pseudoephedrine, phenylpropanolamine, hydroxynorephedrine, phenylephrine, phentermine, methylenedioxyamphetamine (MDA), and methylenedioxy methamphetamine (MDMA). The drugs were liquid extracted from urine and derivatized by either heptafluorobutyric anhydride (HFBA) or 4-carbethoxyhexafluorobutyryl chloride (4-CB). Because the base peak ions for ephedrine, pseudoephedrine, propylhexedrine, MDMA, and phentermine are identical to methamphetamine (e.g. 254 amu for HFBA) and those for phenylephrine, hydroxynorephedrine, phenylpropanolamine, and MDA are identical to amphetamine (e.g. 240 amu for HFBA), a table of selected ions was developed for all 11 drugs that distinguished amphetamine and methamphetamine from the sympathomimetic amines with either HFBA or 4-CB. The distinguishing ions rely on the ring structure of the different drugs and fragmentation associated with that structure. The 4-CB reagent partially derivatized the hydroxy-containing sympathomimetic amines, while the HFBA completely derivatized all the sympathomimetic amines. Furthermore, false positive results for the 4-CB reagent were found only for methamphetamine (20-2250 ng/mL of methamphetamine) when high concentrations (greater than 5 micrograms) of ephedrine or pseudoephedrine were present in the specimen. These results are related to a combination of injection port temperature and cleanliness of the injection port sleeve.

Amphetamine↗

Preliminary evaluation of the Abbott TDx for screening of D-methamphetamine in whole blood specimens.

The Abbott TDx Urine Amphetamine/Methamphetamine II fluorescence polarization immunoassay technique was applied to the determination of D-methamphetamine in hemolyzed whole blood. The assay was found to have 100% cross-reactivity with D-methamphetamine and only an 8% cross-reactivity with L-methamphetamine. Whole blood was fortified with D-methamphetamine at concentrations ranging from 25 to 1000 ng/mL. These whole blood calibrators were used to evaluate the following sample preparation techniques: direct, diluted and buffer, and precipitated using methanol, acetone, sulfosalicylic acid, trichloroacetic acid, and zinc sulfate. Calibrators and samples were prepared by mixing 200 microL of whole blood and 200 microL precipitation reagent and centrifuging at 10,000 rpm for 5 min (9600 x g). A 50-microL aliquot of the supernatant was used for the assay. Using the zinc sulfate precipitation, blood calibration curves showed a linear range of 25-1000 ng/mL. The within-run precision for the 25-, 60-, and 200-ng/mL D-methamphetamine blood controls showed percent coefficients of variation of 17.8, 17.0, and 5.4, respectively. The TDx results were compared to RIA and GC/MS assays for the methamphetamine controls and for eight positive case specimens and found reliable for the screening of hemolyzed whole blood.

Cross Reactions↗

Evaluation of internal standards for the analysis of amphetamine and methamphetamine.

Deuterium-labeled analogues are available for a variety of drugs, but the amphetamines (amphetamine and methamphetamine) have more options available than any other drug. The analytical method and circumstances of its use can have a significant impact on the decision of what is the best internal standard to use. More than one method can give acceptable results; however, some circumstances can make a given internal standard a poor choice for a particular analysis. Increased choices of available candidates make the evaluation of an internal standard even more difficult. Thorough evaluation of the available options is a major undertaking and is presented here to assist laboratories in selection of the most appropriate internal standard for their individual needs. All commercially available deuterated analogues to amphetamine and methamphetamine were evaluated as part of this study. in addition, nonisotopically labeled propylamphetamine was also evaluated for comparison purposes. The compounds were analyzed underivatized and derivatized with trifluoroacetic anhydride, pentafluoropropionic anhydride, heptafluorobutyric anhydride, and 4-carbethoxyhexafluorobutyryl chloride on HP-1, HP-5, and DB-I 7 capillary columns. Mass spectral analysis revealed that several of the internal standards were not viable for monitoring ions typically associated with selected ion monitoring analysis of amphetamine and methamphetamine. These included amphetamine-d3 (1-phenyl-2-aminopropane-3,3,3-d3) and amphetamine-d5 (phenyl-d5), neither of which exhibits three unique ions. The d3 standard shares the common ion at m/z 91, acid d5 (phenyl) shares the base peak ion with derivatized amphetamine. Although methamphetamine-d6 and methamphetamine-d10 show three unique ions, they do not allow monitoring of the ion fragments typically used for methamphetamine. Evaluation of the limit of detection, linear range, and within-run and between-run variability was accomplished for each viable internal standard.

Acetic Anhydrides↗

Detection of methamphetamine in sweat by EIA and GC-MS.

Sweat was collected with the PharmChekTM sweat patch and drugs were eluted from the collection pad of the patch. A solid phase, enzyme immunoassay using microtiter plates was modified for analysis of methamphetamine in sweat. After methamphetamine administration, sweat contains primarily parent methamphetamine. The immunoassay was determined to have crossreactivity relative to 100% for the methamphetamine (MA) calibrators; to 144% for methylenedioxymethamphetamine (MDMA); to 30% for d-amphetamine; to 21% for methylenedioxyamphetamine (MDA); and to 8% for I-methamphetamine. The optimum cutoff concentration for this modified assay was determined by receiver operating characteristic analysis to be 10 ng/mL amphetamine equivalents. At this cutoff concentration the assay had a diagnostic sensitivity of 84.5% and a diagnostic specificity of 93.2% versus gas chromatography-mass spectrometry (GC-MS). The positive predictive value at a prevalence of 50% was 86%. The intra-assay precision at 10 ng/mL was 9.9% (coefficient of variation, CV) and the interassay CV was 13%. Analysis of spiked patches at plus or minus 25 and 50% around the cutoff gave a percent positive threshold of approximately 50% at a cutoff of 10 ng/mL and a 95% confidence level for a positive result by the EIA between 15 and 20 ng/mL. Of 18 potential adulterants that might be injected into or under the patch, two (tile cleaner and cough syrup) caused a false-positive response by immunoassay. All results were confirmed by GC-MS. The clinical sensitivity and specificity of the overall analysis system (sweat collection and analysis) were 85 and 100%, respectively, using known methamphetamine dosing of volunteers (10, 20, and 25 mg) as the reference standard.

Calibration↗

Effects of methamphetamine on trauma patients: a cause of severe metabolic acidosis?

OBJECTIVE: Presentation of a trauma patient with severe unexplained metabolic acidosis, possibly attributable to the vasoconstrictive properties of smokable "crystal" methamphetamine. In addition, a review of trauma registry data was undertaken to determine the effects of methamphetamine on trauma patients. DESIGN: Case report and retrospective case-control study. SETTING: Urban tertiary teaching hospital. PATIENTS: Two controls were obtained for each case controlling for age, Injury Severity Score, and mechanism of injury. Patients > or =16 yrs of age with a urine toxicology screen positive for methamphetamine were included. MEASUREMENTS AND MAIN RESULTS: Data were obtained from the trauma registry for the period of January 1994 to June 1995. Trauma patients using methamphetamine had a significantly lower blood alcohol level compared with the control group. Otherwise, there were no significant differences detected in vital signs, laboratory values, procedures, treatment, or outcome between the two groups. Details regarding one patient who presented with severe life-threatening acidosis are presented. CONCLUSIONS: Trauma patients with recent use of smokable methamphetamine may present with severe acidosis requiring urgent attention and treatment. This acidosis may exaggerate the severity of the actual injury. However, urine testing for methamphetamine does not identify patients who may harbor this acidosis.

Acidosis↗

Biphasic inotropic effects of methamphetamine and methylphenidate on ferret papillary muscles.

Methamphetamine and methylphenidate are structurally related agents that have direct negative inotropic (NIEs) and indirect positive inotropic effects (PIEs) in cardiac tissues. This study was designed to determine and compare cellular mechanisms of the NIEs of methamphetamine and methylphenidate by using a mammalian animal model. Isometric tension was measured in ferret papillary muscles in physiologic salt solution. A subset of muscles was loaded with the bioluminescent calcium indicator, aequorin. Further, to investigate the NIE of methamphetamine, the dose-response relations to isoproterenol, histamine, and calcium were measured with or without methamphetamine (2 x 10(-4) M), after adrenergic neuronal blockade with reserpine. Both methamphetamine and methylphenidate had direct NIEs at higher doses (>10(-4) M). A shift in the slope of the isoproterenol dose-response curve suggested involvement of the beta-adrenoceptor pathways. The direct NIE of methylphenidate was more prominent. Our results suggest that the negative inotropic effects of methamphetamine and methylphenidate may be important with clinically used and abused concentrations of these drugs and may be difficult to reverse with beta-adrenergic inotropic agents in cases of toxicity.

Adrenergic Agents↗