Chronic Methamphetamine Users Research Articles

Imaging of methamphetamine incorporated into hair by MALDI-TOF mass spectrometry

Matrix-assisted laser desorption ionization (MALDI)–time-of-flight (TOF) mass spectrometry (MS) was used for visual demonstration of methamphetamine (MA) incorporation into human hair. Longitudinal sections of human scalp hair shafts from chronic MA users were directly subjected to imaging MS. Numerous MA-positive spots with various intensities were observed in the specimens, which probably reflect habitual MA abuse and the different MA blood levels upon each administration. This imaging MS method for drugs in hair seems to give much more accurate chronological information on drug use, and clearer discrimination between deliberate drug use and passive exposure, using only a single hair shaft. This is the first report of imaging MS applied to forensic toxicology. This method is expected open a new field in analyses of drugs in hair.

Pharmacologic Treatment with GABAB Receptor Agonist of Methamphetamine-Induced Cognitive Impairment in Mice

Methamphetamine (METH) is a highly addictive drug, and addiction to METH has increased to epidemic proportions worldwide. Chronic use of METH causes psychiatric symptoms, such as hallucinations and delusions, and long-term cognitive deficits, which are indistinguishable from paranoid schizophrenia. The GABA receptor system is known to play a significant role in modulating the dopaminergic neuronal system, which is related to behavioral changes induced by drug abuse. However, few studies have investigated the effects of GABA receptor agonists on cognitive deficits induced by METH. In the present review, we show that baclofen, a GABA receptor agonist, is effective in treating METH-induced impairment of object recognition memory and prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating in mice. Acute and repeated treatment with METH induced a significant impairment of PPI. Furthermore, repeated but not acute treatment of METH resulted in a long-lasting deficit of object recognition memory. Baclofen, a GABAB receptor agonist, dose-dependently ameliorated the METH-induced PPI deficits and object recognition memory impairment in mice. On the other hand, THIP, a GABAA receptor agonist, had no effect on METH-induced cognitive deficits. These results suggest that GABAB receptors may constitute a putative new target in treating cognitive deficits in chronic METH users.

Microglial and astrocytic changes in the striatum of methamphetamine abusers

Little is known about the role of glial cells in the striatum of chronic methamphetamine (METH) users. In this study, we immunohistochemically examined glial reactions in the striatum of chronic METH users who did not abstain from METH use and died of drug intoxication. Human glucose transporter 5 (hGLUT), a useful marker of microglia, and CR3.43, a major histocompatibility complex class II antigen specific for reactive microglia, were immunostained. Glial fibrillary acidic protein (GFAP) and S100Β were used for astrocyte immunohistochemistry. We analyzed 12 chronic METH users and 13 control subjects, and detected a 200–240% increase in the number of hGLUT5-positive cells in chronic METH users ( p < 0.01). However, we did not detect any proliferation of CR3.43-positive cells. The number of GFAP-positive astrocytes increased, but this increase was not significant ( p > 0.05). Moreover, S100B-positive cell density between the two groups was not significant ( p > 0.05). This study demonstrates the absence of reactive gliosis in the striatum of chronic METH users who did not abstain for prolonged periods from METH use. The results suggest that chronic METH use by itself did not activate glial cells in humans and reactive gliosis may not be involved in the mechanism underlying the loss of control in drug intake, which is a characteristic feature of drug addiction.

An association study of monoamine oxidase A (MAOA) gene polymorphism in methamphetamine psychosis

Methamphetamine continues to be the most widely abused drug in Japan. Chronic methamphetamine users show psychiatric signs, including methamphetamine psychosis. Monoamine oxidase A (MAOA) is one of the major enzymes responsible for the degradation of neurotransmitters. Abnormalities in MAO levels have been related to a wide range of psychiatric disorders. We examined whether or not the MAOA-u variable-number tandem repeat (VNTR) has a functional polymorphism in methamphetamine psychosis and whether or not such a polymorphism is related to the prolongation of psychosis. As expected, there was a significant difference in the MAOA-u VNTR between males with persistent versus transient methamphetamine psychosis ( p = 0.018, odds ratio (OR) = 2.76, 95% CI: 1.18–6.46). Our results suggest that the high-activity allele class of MAOA-u VNTR in males may be involved in susceptibility to a persistent course of methamphetamine psychosis. We found no differences among females. The sample size of females with methamphetamine psychosis was too small to have significant analysis.

Brain serotonin transporter in human methamphetamine users

Research on methamphetamine (MA) toxicity primarily focuses on the possibility that some of the behavioural problems in human MA users might be caused by damage to brain dopamine neurones. However, animal data also indicate that MA can damage brain serotonin neurones, and it has been suggested that cognitive problems and aggression in MA users might be explained by serotonergic damage. As information on the brain serotonin system in human MA users is fragmentary, our objective was to determine whether protein levels of serotonin transporter (SERT), a key marker of serotonin neurones, are decreased in brain of chronic MA users. SERT immunoreactivity was measured using an immunoblotting procedure in autopsied brain of 16 chronic MA users testing positive for the drug in blood and brain and matched controls. SERT levels were non-significantly decreased (-14% to -33%) in caudate, putamen and thalamus (normal in hippocampus), and, unlike the robust striatal dopamine reduction, there was marked overlap between control and MA user ranges. Concentrations of SERT were significantly decreased (-23% to -39%) in orbitofrontal and occipital cortices (normal in frontopolar and temporal cortices). Our data suggest that MA might modestly damage brain serotonin neurones and/or inhibit SERT protein expression, with cerebral cortex being more affected than sub-cortical regions. The SERT reduction in orbitofrontal cortex complements other data suggesting involvement of this area in MA-related behaviour. Decreased brain SERT could also be related to the clinical finding that treatment with a selective serotonin re-uptake inhibitor might increase relapse to MA.

Extended methamphetamine self-administration enhances reinstatement of drug seeking and impairs novel object recognition in rats

Methamphetamine is a highly addictive psychostimulant, and chronic methamphetamine users show high rates of relapse. Furthermore, prolonged methamphetamine abuse can lead to psychiatric symptoms and has been associated with various cognitive dysfunctions. However, the impact of self-administered methamphetamine on cognitive dysfunction and relapse has not been concurrently examined in an animal model. The present study determined the effects of short- vs. long-access contingent methamphetamine on self-administration, extinction responding, reinstatement of methamphetamine seeking, and cognitive performance on an object exploration task. Long-Evans rats self-administered methamphetamine i.v. (0.02 mg/infusion) or received saline during daily sessions (1 or 2 h) for 10 days, followed by either maintained short- (1 or 2 h) or long-access (6 h) self-administration for 14 days. Lever responding was extinguished prior to reinstatement, which consisted of presentation of drug-paired cues or a priming injection of methamphetamine (1.0 mg/kg). Animals were also tested on an object exploration task prior to self-administration and at 10-12 days after cessation of self-administration, thus providing a comparison of pre-methamphetamine exposure with post-methamphetamine exposure. Long-access methamphetamine self-administration resulted in escalation of daily intake. Furthermore, animals in both short- and long-access groups showed robust conditioned-cued and drug-primed reinstatement, with long access resulting in enhanced methamphetamine-primed reinstatement. Methamphetamine self-administration also led to access-dependent impairments on novel object recognition but failed to impair recognition of spatial reconfiguration. Extended methamphetamine self-administration enhances drug-primed reinstatement and decreases novel object recognition, indicating that prolonged contingent methamphetamine increases motivation for drug seeking following withdrawal while increasing cognitive deficits.

Self-vaccination by methamphetamine glycation products chemically links chronic drug abuse and cardiovascular disease.

Methamphetamine abuse is spreading rapidly throughout the United States and is characterized by significant health consequences. The powerfully rewarding effects of methamphetamine are attributed to multiple neuropharmacological actions such as its ability to block plasma membrane transporters of all monoamines, reduce dopamine transporter expression, and inhibit monoamine oxidase activity while increasing tyrosine hydroxylase activity. However, subsequent neuroreceptor changes including monoamine deficits complement this striking increase in monoamine release. Chronic methamphetamine abuse, as studied via self-administration paradigms in rodents, causes progressive dopaminergic neurotoxicity, a neuroanatomical change accompanied by increasing drug tolerance and escalating intake, two behavioral parameters of addiction. We have recently proposed that methamphetamine covalently glycates endogenous proteins. Such an event spurs antibody production against these immunoconjugates, possibly leading to drug sequestration by antibody binding of drug. Here we demonstrate that this drug-dependent glycation mechanism is operative in vivo through the dose-dependent detection of antibodies against methamphetamine-derived advanced glycation end products in rats chronically self-administering methamphetamine. Furthermore, increased levels of proinflammatory cytokines, evidence of potent immunoactivation, were also detected. Given the known role of advanced glycation end products in the alteration of protein function in vivo and the participation of these molecules in various diseases, methamphetamine-derived advanced glycation end products provide an unrecognized molecular mechanism for the development of vasculitis and other cardiovascular maladies reported with high incidence in chronic methamphetamine users.

Methamphetamine and cardiovascular pathology: a review of the evidence

To examine the literature pertaining to the cardiovascular effects of methamphetamine and discuss the implications for methamphetamine users. Relevant literature was identified through comprehensive MEDLINE and EMBASE searches. There is sufficient clinical and experimental evidence to suggest that methamphetamine can have adverse and potentially fatal effects on the cardiovascular system. The existing literature suggests that: (1) methamphetamine users are at elevated risk of cardiac pathology; (2) risk is not likely to be limited to the duration of their methamphetamine use, because of the chronic pathology associated with methamphetamine use; (3) the risk of cardiac pathology is greatest among chronic methamphetamine users; (4) pre-existing cardiac pathology, due to methamphetamine use or other factors, increases the risk of an acute cardiac event; and (5) methamphetamine use is likely to exacerbate the risk of cardiac pathology from other causes, and may therefore lead to premature mortality.

Brain levels of neuropeptides in human chronic methamphetamine users

Animal data show that neuropeptide systems in the dopamine-rich brain areas of the striatum (caudate, putamen, and nucleus accumbens) are influenced by exposure to psychostimulants, suggesting that neuropeptides are involved in mediating aspects of behavioral responses to drugs of abuse. To establish in an exploratory study whether levels of neuropeptides are altered in brain of human methamphetamine users, we measured tissue concentrations of dynorphin, metenkephalin, neuropeptide Y, neurotensin, and substance P in autopsied brains of 16 chronic methamphetamine users and 17 matched control subjects. As expected, levels of most neuropeptides were enriched in dopamine-linked brain regions such as the nucleus accumbens and striatum of normal human brain. In contrast to animal findings of increased neuropeptide levels following short-term methamphetamine exposure, striatal neuropeptide concentrations were either normal or moderately decreased in the methamphetamine users. In other examined dopamine-poor cortical and subcortical brain areas, neuropeptide levels were generally either normal or variably reduced. Although the neuropeptide differences might be explained by methamphetamine-induced damage to neuropeptide-containing neurons, our human data are consistent with the possibility that, at least in the human striatum, long-term methamphetamine exposure leads to an adaptive process that is distinct from that which increases neuropeptide levels after acute methamphetamine exposure.

Methamphetamine use and violence among young adults

The current research analyzed the relationship between methamphetamine use and violence among young adults eighteen to twenty-five years old. Interviews were conducted with a sample of 106 respondents. The research was based primarily on in-depth, life-history interviews with individuals who used methamphetamine for a minimum of three months and who resided in Los Angeles County. Of the 106 respondents, 37 (34.9 percent) had committed violence while under the influence of methamphetamine. Males comprised two-thirds of the 37 respondents (N = 24). Of the total sample, 38 percent of males and 30 percent of females committed methamphetamine-related violence, respectively. Overall, the 37 respondents reported fifty-four separate violent events while using methamphetamine. Of these fifty-four events, thirty-three (61.1 percent) acts of violence involved domestic relationships, nine (16.7 percent) of the violent events were drug related, seven (13 percent) were gang related, and five (9.3 percent) involved random acts of violence (e.g., road rage, stranger assault). The findings suggest that methamphetamine use is a risk factor for violence. There was, however, no evidence of a single, uniform career path that all chronic methamphetamine users follow. Violence is not an inevitable outcome of even chronic methamphetamine use.

Levels of 4-Hydroxynonenal and Malondialdehyde Are Increased in Brain of Human Chronic Users of Methamphetamine

Animal studies suggest that the widely used psychostimulant drug methamphetamine (MA) can harm brain dopamine neurones, possibly by causing oxidative damage. However, evidence of oxidative damage in brain of human MA users is lacking. We tested the hypothesis that levels of two "gold standard" products generated from lipid peroxidation, 4-hydroxynonenal (one of the most reactive lipid peroxidation aldehyde products) and malondialdehyde, would be elevated in post mortem brain of 16 dopamine-deficient chronic MA users compared with those in 21 matched control subjects. Derivatized aldehyde concentrations were determined by gas chromatography-mass spectrometry. In the MA group, we found significantly increased levels of 4-hydroxynonenal and malondialdehyde in the dopamine-rich caudate nucleus (by 67 and 75%, respectively) and to a lesser extent in frontal cortex (48 and 36%, respectively) but not in the cerebellar cortex. Approximately half of the MA users had levels of 4-hydroxynonenal falling above the upper limit of the control range in caudate and frontal cortex. A subgroup of MA users with high brain drug levels had higher concentrations of the aldehydes. Our data suggest that MA exposure in human causes, as in experimental animals, above-normal formation of potentially toxic lipid peroxidation products in brain. This provides evidence for involvement of oxygen-based free radicals in the action of MA in both dopamine-rich (caudate) and -poor (cerebral cortex) areas of human brain.

Immunohistochemical investigation of dopaminergic terminal markers and caspase-3 activation in the striatum of human methamphetamine users

Methamphetamine (METH) has been shown to induce neurotoxicity. In a previous human study using quantitative Western blotting and radioligand binding assay, dopaminergic terminal marker deficits were induced in chronic METH users. In this study, we examined the suitability of the immunohistochemical detection of tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter-2 (VMAT2) levels, and caspase-3 activation in the striatum to diagnose METH abuse. Decreases in TH immunoreactivity in the nucleus accumbens and DAT in the nucleus accumbens and putamen were induced in METH users, whereas a significant difference of VMAT2 was not evident between METH and control groups. However, in the nucleus accumbens of two METH users, levels of VMAT2, a stable marker of striatal dopaminergic terminal integrity, were reduced remarkably. These findings might indicate that dopaminergic terminal degeneration is induced in the striatum of some METH abusers. On the other hand, we observed little caspase-3 activation, indicative of apoptosis, in the striatal neurons of chronic METH users. Overall, the findings of dopaminergic terminal markers were similar to those in the previous human study. Therefore, it is suggested that immunohistochemical techniques could be used to examine dopaminergic terminal marker levels and could also give useful information on chronic and/or lethal METH use in cases of METH-related death, where METH intoxication may not be toxicologically demonstrated.

Methamphetamine use and Violence

The current research analyzed the relationship between methamphetamine use and violence. Interviews were conducted with a sample of 205 respondents. The research was based on life history interviews with individuals who used methamphetamine for a minimum of three months and who resided in Los Angeles County. Of the 205 respondents, 55 (26.8%) had committed violence while under the influence of methamphetamine. Males comprised two thirds of the 55 respondents (N=36). Of the total sample, 30% of males and 23% of females committed methamphetamine-related violence, respectively. Overall, the 55 respondents reported 80 separate violent events while using methamphetamine. Of these 80 events, 41 (51.4%) acts of violence involved domestic relationships, 28.6% (N=23) of the violent events were drug related, 8.6% (N=7) were gang related, and 11.3% (N=9) involved random acts of violence (e.g., road rage, stranger assault). The study findings suggest that methamphetamine use heightens the risk for violence. Everyone interviewed agreed that methamphetamine has clear abuse and violence potential. Having said this, it is crucial to state that there was no evidence of a single, uniform career path that all chronic methamphetamine users follow. Progression from controlled use to addiction is not inexorable. Furthermore, a significant number of sample members experienced limited or no serious social, psychological, or physical dysfunction as a result of their methamphetamine use. Most germane to this study, we found that violence is not an inevitable outcome of even chronic methamphetamine use.

Methamphetamine use among young adults: Health and social consequences

The current research analyzed the relationship between methamphetamine use and health and social outcomes. Interviews were conducted with a sample of 106 respondents. Virtually all of the respondents experienced negative consequences of methamphetamine use. The most serious, but least prevalent, methamphetamine-related health problem was seizures and convulsions. The most prevalent health effect was weight lose. A substantial number of respondents experienced severe psychological symptoms: depression, hallucinations, and paranoia. Of the 106 respondents, 34.9% had committed violence while under the influence of methamphetamine. The data suggest that methamphetamine-based violence was more likely to occur within private domestic contexts, both family and acquaintance relationships. It is apparent from the findings that methamphetamine use heightens the risk for negative health, psychological, and social outcomes. Having said this, it is crucial to acknowledge that there was no evidence of a single, uniform career path that all chronic methamphetamine users follow. Furthermore, a significant number of sample members experienced limited or no serious social, psychological, or physical dysfunction as a result of their methamphetamine use.

Implications of Chronic Methamphetamine Use: A Literature Review

Methamphetamine (MA) abuse is increasing to epidemic proportions, both nationally and globally. Chronic MA use has been linked to significant impairments in different arenas of neuropsychological function. To better understand this issue, a computerized literature search (PubMed, 1964-2004) was used to collect research studies examining the neurobiological and neuropsychiatric consequences of chronic MA use. Availability of MA has markedly increased in the United States due to recent technological improvements in both mass production and clandestine synthesis, leading to significant public health, legal, and environmental problems. MA intoxication has been associated with significant psychiatric and medical comorbidity. Research in animal models and human subjects reveals complicated mechanisms of neurotoxicity by which chronic MA use affects catecholamine neurotransmission. This pathology may underlie the characteristic cognitive deficits that plague chronic MA users, who experience impairments in memory and learning, psychomotor speed, and information processing. These impairments have the potential to compromise, in turn, the ability of MA abusers to engage in, and benefit from, psychosocially based chemical-dependency treatment. Development of pharmacological interventions to improve these cognitive impairments in this population may significantly improve the degree to which they may be able to participate in treatment. Atypical antipsychotics may have some promise in this regard.

Why is parkinsonism not a feature of human methamphetamine users?

For more than 50 years, methamphetamine has been a widely used stimulant drug taken to maintain wakefulness and performance and, in high doses, to cause intense euphoria. Animal studies show that methamphetamine can cause short-term and even persistent depletion of brain levels of the neurotransmitter dopamine. However, the clinical features of Parkinson's disease, a dopamine deficiency disorder of the brain, do not appear to be characteristic of human methamphetamine users. We compared dopamine levels in autopsied brain tissue of chronic methamphetamine users with those in patients with Parkinson's disease and in a control group. Mean dopamine levels in the methamphetamine users were reduced more in the caudate (-61%) than in the putamen (-50%), a pattern opposite to that of Parkinson's disease. Some methamphetamine users had severely decreased dopamine levels, within the parkinsonian range, in the caudate (up to 97% dopamine loss) but not in the putamen. As the putamen and caudate subserve aspects of motor and cognitive function, respectively, our data suggest that methamphetamine users are not parkinsonian because dopamine levels are not sufficiently decreased in the motor component of the striatum. However, the near-total reduction in the caudate could explain reports of cognitive disturbances, sometimes disabling, in some drug users, and suggests that treatment with dopamine substitution medication (e.g. levodopa) during drug rehabilitation might be helpful.

Regional distribution of methamphetamine in autopsied brain of chronic human methamphetamine users

We measured levels of methamphetamine and those of its metabolite amphetamine in 15 autopsied brain regions of 14 human methamphetamine users. Only slight regional differences were observed in drug concentrations among the brain areas. Although, some redistribution of the drugs probably occurred postmortem, these data suggest that methamphetamine might not be preferentially retained in dopamine-rich brain areas but is heterogenously distributed in brain of chronic human users of the drug. The possible pharmacological actions of methamphetamine in both dopamine-rich and poor brain areas of chronic drug users need to be considered.

Dopamine D1 receptor protein is elevated in nucleus accumbens of human, chronic methamphetamine users.

Animal data have long suggested that an adaptive upregulation of nucleus accumbens dopamine D1 receptor function might underlie part of the dependency on drugs of abuse. We measured by quantitative immunoblotting protein levels of dopamine D1 and, for comparison, D2 receptors in brain of chronic users of methamphetamine, cocaine, and heroin. As compared with the controls, brain dopamine D1 receptor concentrations were selectively increased (by 44%) in the nucleus accumbens of the methamphetamine users, whereas a trend was observed in this brain area for reduced protein levels of the dopamine D2 receptor in all three drug groups (-25 to -37%; P < 0.05 for heroin group only). Our data support the hypothesis that aspects of the drug-dependent state in human methamphetamine users might be related to increased dopamine D1 receptor function in limbic brain.

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.