History Of Methamphetamine Dependence Research Articles

Both HIV and Tat expression decrease prepulse inhibition with further impairment by methamphetamine

HIV infection and methamphetamine (METH) use are highly comorbid and represent a significant public health problem. Both conditions are known to negatively impact a variety of brain functions. One brain function that may be affected by HIV and METH use is sensorimotor gating, an automatic, pre-conscious filtering of sensory information that is thought to contribute to higher order cognitive processes. Sensorimotor gating is often measured using prepulse inhibition (PPI), a paradigm that can be conducted in both humans and animals, thereby enabling cross-species translational studies. While previous studies suggest HIV and METH may individually impair PPI, little research has been conducted on the effects of combined HIV and METH on PPI. The goal of this cross-species study was to determine the effects of METH on PPI in the inducible Tat (iTat) mouse model of HIV and in people with HIV. PPI was measured in the iTat mouse model before, during, and after chronic METH treatment and after Tat induction. Chronic METH treatment decreased PPI in male but not female mice. PPI normalized with cessation of METH. Inducing Tat expression decreased PPI in male but not in female mice. No interactions between chronic METH treatment and Tat expression were observed in mice. In humans, HIV was associated with decreased PPI in both men and women. Furthermore, PPI was lowest in people with HIV who also had a history of METH dependence. Overall, these results suggest HIV and METH may additively impair early information processing in humans, potentially affecting downstream cognitive function.

Sustained attention and vigilance deficits associated with HIV and a history of methamphetamine dependence

BackgroundHuman immunodeficiency virus (HIV)-associated neurocognitive disorders persist in the era of antiretroviral therapy. One factor that is elevated among persons with HIV (PWH) and independently associated with neurocognitive impairment is methamphetamine dependence (METH). Such dependence may further increase cognitive impairment among PWH, by delaying HIV diagnosis (and thus, antiretroviral therapy initiation), which has been posited to account for persistent cognitive impairment among PWH, despite subsequent treatment-related viral load suppression (VLS; <50 copies of the virus per milliliter in plasma or cerebrospinal fluid). This study examined the main and interactive (additive versus synergistic) effects of HIV and history of METH on the sustained attention and vigilance cognitive domain, while controlling for VLS. MethodsParticipants included 205 (median age = 44 years; 77% males; HIV-/METH- n = 67; HIV+/METH - n = 49; HIV-/METH+ n = 36; HIV+/METH+ n = 53) individuals enrolled in the Translational Methamphetamine AIDS Research Center, who completed Conners’ and the 5-Choice continuous performance tests (CPTs). ResultsMETH participants exhibited deficits in sustained attention and vigilance; however, these effects were not significant after excluding participants who had a positive urine toxicology screen for methamphetamine. Controlling for VLS, PWH did not have worse sustained attention and vigilance, but consistently displayed slower reaction times across blocks, relative to HIV- participants. There was no HIV x METH interaction on sustained attention and vigilance. ConclusionsRecent methamphetamine use among METH people and detectable viral loads are detrimental to sustained attention and vigilance. These findings highlight the need for prompt diagnosis of HIV and initiation of antiretroviral therapy, and METH use interventions.

Metabolites Alterations in the Medial Prefrontal Cortex of Methamphetamine Users in Abstinence: A 1H MRS Study.

Background: The medial prefrontal cortex (mPFC) contains various neurotransmitter systems and plays an important role in drug use. Broad body of literature on how methamphetamine (MA) affects the structure and metabolism in the animal's mPFC is emerging, while the effects on metabolites of mPFC among human is still unclear. In this study, proton magnetic resonance spectroscopy (1H MRS) was used to measure metabolites of mPFC in methamphetamine dependent subjects.Methods: Sixty-one subjects with a history of MA dependence (fulfiled the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria) and 65 drug-naïve control subjects (age19–45) completed 1H MRS scans using 3.0T Siemens MRI scanner. Single voxel spectra were acquired from the mPFC bilaterally using a point resolved spectroscopy sequence (PRESS). The 1H MRS data were automatically fit with linear combination model for quantification of metabolite levels of n-acetyl-aspartate (NAA), myo-inositol (mI), glycerophosphocholine plus phosphocholine(GPC+PC), phosphocreatine plus creatine (PCr+Cr), and glutamate (Glu). Metabolite levels were reported as ratios to PCr+Cr.Results: The MA group showed a significant reduction in NAA/PCr+Cr ratio and elevation in Glu/PCr+Cr ratio and mI/PCr+Cr ratio, compared with healthy control. No significant correlation was found between metabolite ratios and MA use variables.Conclusions: MA use is associated with a significant increased Glu/PCr+Cr ratio, mI/PCr+Cr ratio and reduced NAA/PCr+Cr ratio in the mPFC of MA dependence subjects. These findings suggest that Glu may play a key role in MA induced neurotoxicity.

F273. Plasma Soluble CD14 is Associated With Apathy in Adults With a History of Methamphetamine Dependence

F273. Plasma Soluble CD14 is Associated With Apathy in Adults With a History of Methamphetamine Dependence

Parallel Effects of Methamphetamine on Anxiety and CCL3 in Humans and a Genetic Mouse Model of High Methamphetamine Intake

Background: Methamphetamine (MA) abuse causes immune dysfunction and neuropsychiatric impairment. The mechanisms underlying these deficits remain unidentified. Methods: The effects of MA on anxiety-like behavior and immune function were investigated in mice selectively bred to voluntarily consume high amounts of MA [i.e., MA high drinking (MAHDR) mice]. MA (or saline) was administered to mice using a chronic (14-day), binge-like model. Performance in the elevated zero maze (EZM) was determined 5 days after the last MA dose to examine anxiety-like behavior. Cytokine and chemokine expressions were measured in the hippocampus using quantitative polymerase chain reaction (qPCR). Human studies were also conducted to evaluate symptoms of anxiety using the General Anxiety Disorder-7 Scale in adults with and without a history of MA dependence. Plasma samples collected from human research participants were used for confirmatory analysis of murine qPCR results using an enzyme-linked immunosorbent assay. Results: During early remission from MA, MAHDR mice exhibited increased anxiety-like behavior on the EZM and reduced expression of chemokine (C-C motif) ligand 3 (ccl3) in the hippocampus relative to saline-treated mice. Human adults actively dependent on MA and those in early remission had elevated symptoms of anxiety as well as reductions in plasma levels of CCL3, relative to adults with no history of MA abuse. Conclusions: The results highlight the complex effects of MA on immune and behavioral function and suggest that alterations in CCL3 signaling may contribute to the mood impairments observed during remission from MA addiction.

Fibroblast growth factors 1 and 2 in cerebrospinal fluid are associated with HIV disease, methamphetamine use, and neurocognitive functioning.

BackgroundHuman immunodeficiency virus (HIV) and methamphetamine use commonly affect neurocognitive (NC) functioning. We evaluated the relationships between NC functioning and two fibroblast growth factors (FGFs) in volunteers who differed in HIV serostatus and methamphetamine dependence (MAD).MethodsA total of 100 volunteers were categorized into four groups based on HIV serostatus and MAD in the prior year. FGF-1 and FGF-2 were measured in cerebrospinal fluid by enzyme-linked immunosorbent assays along with two reference biomarkers (monocyte chemotactic protein [MCP]-1 and neopterin). Comprehensive NC testing was summarized by global and domain impairment ratings.ResultsSixty-three volunteers were HIV+ and 59 had a history of MAD. FGF-1, FGF-2, and both reference biomarkers differed by HIV and MAD status. For example, FGF-1 levels were lower in subjects who had either HIV or MAD than in HIV− and MAD− controls (P=0.003). Multivariable regression identified that global NC impairment was associated with an interaction between FGF-1 and FGF-2 (model R2=0.09, P=0.01): higher FGF-2 levels were only associated with neurocognitive impairment among subjects who had lower FGF-1 levels. Including other covariates in the model (including antidepressant use) strengthened the model (model R2=0.18, P=0.004) but did not weaken the association with FGF-1 and FGF-2. Lower FGF-1 levels were associated with impairment in five of seven cognitive domains, more than FGF-2, MCP-1, or neopterin.ConclusionThese findings provide in vivo support that HIV and MAD alter expression of FGFs, which may contribute to the NC abnormalities associated with these conditions. These cross-sectional findings cannot establish causality and the therapeutic benefits of recombinant FGF-1 need to be investigated.

Epigenetic alterations in the brain associated with HIV-1 infection and methamphetamine dependence.

HIV involvement of the CNS continues to be a significant problem despite successful use of combination antiretroviral therapy (cART). Drugs of abuse can act in concert with HIV proteins to damage glia and neurons, worsening the neurotoxicity caused by HIV alone. Methamphetamine (METH) is a highly addictive psychostimulant drug, abuse of which has reached epidemic proportions and is associated with high-risk sexual behavior, increased HIV transmission, and development of drug resistance. HIV infection and METH dependence can have synergistic pathological effects, with preferential involvement of frontostriatal circuits. At the molecular level, epigenetic alterations have been reported for both HIV-1 infection and drug abuse, but the neuropathological pathways triggered by their combined effects are less known. We investigated epigenetic changes in the brain associated with HIV and METH. We analyzed postmortem frontal cortex tissue from 27 HIV seropositive individuals, 13 of which had a history of METH dependence, in comparison to 14 cases who never used METH. We detected changes in the expression of DNMT1, at mRNA and protein levels, that resulted in the increase of global DNA methylation. Genome-wide profiling of DNA methylation in a subset of cases, showed differential methylation on genes related to neurodegeneration; dopamine metabolism and transport; and oxidative phosphorylation. We provide evidence for the synergy of HIV and METH dependence on the patterns of DNA methylation on the host brain, which results in a distinctive landscape for the comorbid condition. Importantly, we identified new epigenetic targets that might aid in understanding the aggravated neurodegenerative, cognitive, motor and behavioral symptoms observed in persons living with HIV and addictions.

Methamphetamine and Dave’s Story

This story and history are derived from multiple discussions with Dave Park that began when I was a psychiatrist at Turning Point’s Pathways out of Homelessness and Dave was the case manager for many of my patients; a good number of these patients had a current or past history of methamphetamine dependence. When we both left Turning Point, we continued our discussions and thought it might be worth having something in print including Dave’s first-hand eyewitness perspective of the history of methamphetamine use in California. I gave lists of questions and thoughts to Dave and I would then organize his written responses and integrate our research findings. Methamphetamine abuse first appeared in California in the early 1950’s, primarily among former military personnel who had been exposed to methamphetamine or Benzedrine during World War II. The German and Japanese military supplied troops with these drugs to increase aggressiveness and alertness, and Allied soldiers often encountered the stimulants with captured supplies. US and British troops used captured German methamphetamine in North Africa [Amphetamine at War Web Site]. US Air Force pilots used meth during the long-range bombing missions of World War II [Vermont Department of Health Website, 2013; Methamphetamine at War]. After these users returned to civilian life, some became involved in the early motorcycle clubs and gangs, and by the early 1960’s methamphetamine abuse was widespread within the biker community. At one time access to methamphetamine typically had been through physicians, who prescribed stimulants for allergy problems or for weight loss, or through unscrupulous physicians who wrote prescriptions in exchange for cash or favors. In the early 1960’s, bikers or their associates who were college chemistry majors or friends of chemistry majors began manufacturing methamphetamine, which led to the involvement of the motorcycle clubs in the manufacture and distribution of the drug. Although in the early 1960’s methamphetamine was used and abused mostly within the biker community, physicians increasingly prescribed it for women in the general population as an agent for weight loss. In this early period most illegal methamphetamine was pharmaceutical grade, produced from chemical formulas gleaned from the Merck Manual or from information bought from employees of pharmaceutical companies. Though some sellers (connections or dealers) claimed to be using “original German formulas,” buyers usually dismissed these claims as bragging to justify a higher asking price. Rumors of “original German formulas” persist to this day. In the mid-to-late 1960’s, soldiers began coming home from the

Effect of methamphetamine dependence on everyday functional ability

Background Methamphetamine (METH) is an increasingly popular and highly addictive psychostimulant with a significant impact on public health. Chronic METH exposure has been associated with neurotoxic effects, profound neuropsychological deficits, and impaired quality of life, but few studies have examined the effect of the drug on the ability to carry out everyday activities. We assessed the effect of METH dependence on everyday functioning using the UCSD Performance-Based Skills Assessment (UPSA-2), a performance-based measure designed to evaluate real-life skills. Method UPSA-2 performance was quantified in 15 currently abstinent individuals with a history of METH dependence and 15 drug-free comparison subjects. The Positive and Negative Syndrome Scale (PANSS) and Wisconsin Card Sorting Task (WCST) were administered to assess psychopathology and executive function. Results METH-dependent participants exhibited significant impairment on the UPSA-2 total score and several UPSA-2 subscales, including comprehension, finance, transportation, communication, and medication management compared to drug-free comparison subjects. Lower UPSA-2 scores were associated with impaired performance on the WCST, higher PANSS scores, and drug use at an earlier age. Conclusion METH dependence may be associated with decreased everyday functioning ability potentially mediated by frontal cortex dysfunction or the emergence of psychopathology related to chronic drug use.

Social‐cognitive difficulties in former users of methamphetamine

Objectives. Methamphetamine (MA) abuse is associated with neurocognitive impairment. We investigated whether important aspects of social‐cognitive function are similarly disrupted.Method. A total of 12 adults with a history of MA dependence (average duration of use, 3.9 years), currently engaged in rehabilitation and abstinent for an average period of 6 months, and 12 MA naive participants completed measures of facial affect recognition, theory of mind, executive function and memory.Results. MA users were impaired on the measures of facial affect recognition and theory of mind (ds=1.75 and 2.32, respectively), with the magnitude of these deficits comparable or larger to those observed on the cognitive measures.Conclusions. Social‐cognitive difficulties are associated with MA use and have potentially important implications for rehabilitative practice.

Book Reviews

Methamphetamine (MA) abuse is associated with neurocognitive impairment. We investigated whether important aspects of social-cognitive function are similarly disrupted. A total of 12 adults with a history of MA dependence (average duration of use, 3.9 years), currently engaged in rehabilitation and abstinent for an average period of 6 months, and 12 MA naive participants completed measures of facial affect recognition, theory of mind, executive function and memory. MA users were impaired on the measures of facial affect recognition and theory of mind (ds = 1.75 and 2.32, respectively), with the magnitude of these deficits comparable or larger to those observed on the cognitive measures. Social-cognitive difficulties are associated with MA use and have potentially important implications for rehabilitative practice.

Adaptation of Brain Glutamate Plus Glutamine during Abstinence from Chronic Methamphetamine Use

Methamphetamine (METH) is a stimulant drug that is toxic primarily to dopaminergic and serotonergic neurons and may lead to inflammatory changes in the brain. Additionally, the glutamatergic system is altered following METH exposure. Therefore, concentrations of brain glutamate + glutamine (GLX) were assessed during abstinence from chronic METH abuse. Twenty-five subjects with a history of METH dependence (age 31.8 +/- 7.4 years, 14 women and 11 men) and 28 control subjects without a history of drug abuse (age 32.6 +/- 8.8 years, 14 women) were enrolled. Twelve of the METH subjects were followed and rescanned 5 months later. METH users had used the drug 5.9 +/- 1.7 times per week, for 109 +/- 69 months, and had been abstinent for 2.1 +/- 3.0 months. GLX was measured in the basal ganglia and frontal gray and white matter, using proton magnetic resonance spectroscopy. While overall GLX concentrations at baseline were similar between METH and control subjects, METH users with less than or equal to 1 month of abstinence showed reduced frontal gray matter GLX (p = 0.01). Time of abstinence correlated positively with GLX in frontal gray (p < 0.0001) and white matter (p = 0.03). After 5 months, changes in frontal gray matter GLX showed a trend to correlate inversely with the duration of abstinence (p = 0.07). Subjects with craving symptoms had lower frontal gray matter GLX than those without craving (-8%, p = 0.05). These findings suggest dynamic abnormalities in brain GLX in recently abstinent METH users, with a depletion of the glutamatergic system in METH users within the first 2 months of abstinence and some normalization during prolonged abstinence. Since craving may contribute to relapse, medications that normalize GLX may minimize craving in METH users.

Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine

To examine the contribution of hepatitis C virus (HCV) infection to neurocognitive dysfunction in individuals with comorbid HIV infection or methamphetamine (METH) dependence. Neurocognitive functioning was examined in 430 study participants who were either normal controls or had HCV infection, HIV infection, history of METH dependence, or combinations of these factors as risks for cognitive deficits. Rates of global and domain-specific neuropsychological (NP) impairment increased with the number of risk factors. HCV serostatus was a significant predictor of NP performance both globally and in the areas of learning, abstraction, and motor skills, with trends in speeded information processing and delayed recall. HCV serostatus did not predict scores in attention/working memory or verbal fluency. Hepatitis C virus infection contributes to the neuropsychological deficits observed among HIV-infected and stimulant-dependent populations.

Neurocognitive performance of methamphetamine users discordant for history of marijuana exposure

Abuse of the stimulant drug methamphetamine is associated with neural injury and neuropsychological (NP) deficits, while the residual effects of marijuana use remain uncertain. We sought to determine if methamphetamine dependent persons who also met criteria for marijuana abuse or dependence evidenced different NP performance than those with dependence for methamphetamine alone. We examined three groups that did not differ significantly on important demographic factors: (1) subjects with a history of methamphetamine dependence and history of marijuana abuse/dependence (METH+/MJ+, n = 27); (2) methamphetamine dependent subjects without history of marijuana abuse/dependence (METH+/MJ−, n = 26); (3) a control group with minimal or no drug use ( n = 41). A comprehensive NP battery was administered and performance was quantified for five cognitive ability areas. The METH+/MJ− group generally demonstrated the greatest NP impairment, with statistically significant differences observed between the METH+/MJ− and control group in learning, retention/retrieval, and a summary score of global NP performance. The METH+/MJ+ group did not differ significantly from the control or METH+/MJ− group on any NP ability. However, there was a significant linear trend in the global NP score suggesting that the METH+/MJ+ performed intermediate to the control and METH+/MJ− groups. Based on these findings, we cannot conclude that there is a protective effect of marijuana use in methamphetamine users; however, marijuana use clearly did not appear to exacerbate methamphetamine neurotoxicity. Further investigations are needed to determine if the emerging literature, suggesting that certain cannabinoids might have neuroprotective actions, is generalizable to community-dwelling substance abusers.

Evidence for long-term neurotoxicity associated with methamphetamine abuse: A 1H MRS study.

To determine whether proton MRS (1H MRS) can detect long-term metabolite abnormalities in abstinent methamphetamine users. Methamphetamine is toxic to dopaminergic and serotonergic neurons in rodents; however, little data are available on the toxic effects of methamphetamine on the human brain. 1H MRS was performed in 26 abstinent methamphetamine abusers with a history of methamphetamine dependence (median total cumulative lifetime exposure, 3,640 g; median recency of last methamphetamine use, 4.25 months) and 24 healthy subjects without a history of drug abuse. Cerebral metabolite concentrations on 1H MRS were measured in the frontal cortex, frontal white matter, and basal ganglia. The concentration of N-acetylaspartate ([NA]), a neuronal marker, was reduced significantly (-5 to -6%) in the basal ganglia and frontal white matter of methamphetamine users compared with control subjects. The frontal white matter [NA] correlated inversely with the logarithm of the lifetime methamphetamine use. The methamphetamine users also showed significantly reduced total creatine in the basal ganglia (-8%), and increased choline-containing compounds ([CHO], +13%) and myo-inositol ([MI], +11%) in the frontal grey matter. The reduced [NA] on 1H MRS provides evidence for long-term neuronal damage in abstinent methamphetamine users.