Search

BACKGROUND: The group-I metabotropic glutamate receptor subtype 5 (mGlu5) has been implicated in methamphetamine exposure in animals and in human cognition. Because people with methamphetamine use disorder (MUD) exhibit cognitive deficits, we evaluated mGlu5 in people with MUD and controls and tested its association with cognitive performance. METHODS: Positron emission tomography was performed to measure the total VT of [18F]FPEB, a radiotracer for mGlu5, in brains of participants with MUD (abstinent from methamphetamine for at least 2 weeks, N = 14) and a control group (N = 14). Drug use history questionnaires and tests of verbal learning, spatial working memory, and executive function were administered. Associations of VT with methamphetamine use, tobacco use, and cognitive performance were tested. RESULTS: MUD participants did not differ from controls in global or regional VT, and measures of methamphetamine use were not correlated with VT. VT was significantly higher globally in nonsmoking vs smoking participants (main effect, P = .0041). MUD participants showed nonsignificant weakness on the Rey Auditory Verbal Learning Task and the Stroop test vs controls (P = .08 and P = .13, respectively) with moderate to large effect sizes, and significantly underperformed controls on the Spatial Capacity Delayed Response Test (P = .015). Across groups, Rey Auditory Verbal Learning Task performance correlated with VT in the dorsolateral prefrontal cortex and superior frontal gyrus. CONCLUSION: Abstinent MUD patients show no evidence of mGlu5 downregulation in brain, but association of VT in dorsolateral prefrontal cortex with verbal learning suggests that medications that target mGlu5 may improve cognitive performance.

ObjectiveMethamphetamine and cannabis are two widely used, and frequently co-used, substances with possibly opposing effects on the central nervous system. Evidence of neurocognitive deficits related to use is robust for methamphetamine and mixed for cannabis. Findings regarding their combined use are inconclusive. We aimed to compare neurocognitive performance in people with lifetime cannabis or methamphetamine use disorder diagnoses, or both, relative to people without substance use disorders.Method423 (71.9% male, aged 44.6 ± 14.2 years) participants, stratified by presence or absence of lifetime methamphetamine (M-/M+) and/or cannabis (C-/C+) DSM-IV abuse/dependence, completed a comprehensive neuropsychological, substance use, and psychiatric assessment. Neurocognitive domain T-scores and impairment rates were examined using multiple linear and binomial regression, respectively, controlling for covariates that may impact cognition.ResultsGlobally, M+C+ performed worse than M-C- but better than M+C-. M+C+ outperformed M+C- on measures of verbal fluency, information processing speed, learning, memory, and working memory. M-C+ did not display lower performance than M-C- globally or on any domain measures, and M-C+ even performed better than M-C- on measures of learning, memory, and working memory.ConclusionsOur findings are consistent with prior work showing that methamphetamine use confers risk for worse neurocognitive outcomes, and that cannabis use does not appear to exacerbate and may even reduce this risk. People with a history of cannabis use disorders performed similarly to our nonsubstance using comparison group and outperformed them in some domains. These findings warrant further investigation as to whether cannabis use may ameliorate methamphetamine neurotoxicity.

Deficits in social cognition are seen in both people living with HIV (PWH) and people with a history of methamphetamine (METH) dependence. Dually affected individuals may experience additive negative effects on social cognition due to these conditions. We evaluated social cognition in 4 diagnostic groups (HIV-/METH-, HIV-/METH+, HIV+/METH-, HIV+/METH+). First, we used traditional social-emotional functioning assessments, the Difficulties in Emotion Regulation Scale and the Faux Pas Task, to determine any significant effects of METH dependence and HIV on social cognition. Next, we quantified social cognition using the Human Behavioral Pattern Monitor by evaluating social behavior represented by interaction with novel objects. METH dependence significantly affected social-emotional functions and HIV significantly affected on object interactions, however no significant additive effects were observed using these methods. The nuanced relationship between HIV and METH dependence suggests that other factors (i.e., adaptive life skills) likely mediate social cognition-related behaviors.

BackgroundEscalating misuse of amphetamine-type stimulants, mainly methamphetamine, has led to a staggering rise in associated overdose deaths and a pressing need to understand the basis of methamphetamine use disorder (MUD). MUD is characterized by disadvantageous decision-making, and people with MUD perform below controls on the Balloon Analogue Risk Task (BART), a laboratory test of decision-making under uncertainty. The BART presents a series of choices with progressively higher stakes-greater risk of loss and greater potential monetary reward. This research aimed to clarify whether impaired behavioral updating contributes to maladaptive performance on the BART.MethodsTwo groups (28 drug-abstinent participants with MUD and 16 healthy control participants) were compared on BART performance. Using a computational model, we deconstructed behavior into risk-taking and behavioral updating. A subset of participants (22 MUD, 15 healthy control) underwent [18F]fallypride positron emission tomography scans to measure dopamine D2-type receptor availability (BPND) in the striatum (caudate and accumbens nuclei and putamen) and the globus pallidus.ResultsParticipants with MUD exhibited slower behavioral updating than the healthy controls (p = 0.0004, d=1.77). BPND in all four bilateral volumes of interest were higher in the healthy control group (ps

It is estimated that a majority of people who use psychostimulants, particularly methamphetamine (MA) and cocaine, experience withdrawal upon abstinence from sustained use. This review of clinical research reports the evidence regarding biomedical and behavioral treatments for psychostimulant withdrawal symptoms. It provides a framework for clinicians and scientists to increase impact on attenuating MA and cocaine withdrawal during initial and sustained abstinence. Articles reviewed included reports of controlled clinical trials (randomized or non-randomized) reporting at least one withdrawal symptom among the outcomes or specifically studying patients in withdrawal. Potential efficacy for MA withdrawal is noted for a few medications (mirtazapine, naltrexone, bupropion) and repetitive transcranial magnetic stimulation during acute (first week), early protracted (weeks 2-4) and late protracted (> 4 weeks) withdrawal phases. Topiramate shows mixed evidence of efficacy for cocaine withdrawal. In general, there is inconsistent signal for biomedical and behavioral treatments on MA and cocaine withdrawal.

Human immunodeficiency virus (HIV) continues to infect millions worldwide, negatively impacting neurobehavioral function. Further understanding of the combined effects of HIV and methamphetamine use is crucial, as methamphetamine use is prevalent in people with HIV. The HIV-associated protein Tat may contribute to cognitive dysfunction, modeled preclinically in mice using doxycycline (DOX)-inducible Tat expression (iTat). Tat may exert its effects on cognitive function via disruption of the dopamine transporter, similar to the action of methamphetamine. Additionally, Tat and methamphetamine both decrease interneuron populations, including those expressing calbindin. It is important to understand the combined effects of Tat and methamphetamine in preclinical models of HIV infection. Here, we used iTat transgenic mice and a chronic binge regimen of methamphetamine exposure to determine their combined impact on reward learning and motivation. We also measured calbindin expression in behavior-relevant brain regions. Before induction with DOX, iTat mice exhibited no differences in behavior. Chronic methamphetamine exposure before Tat induction impaired initial reward learning but did not affect motivation. Furthermore, DOX-induced Tat expression did not alter behavior, but slowed latencies to retrieve rewards. This effect of Tat, however, was not observed in methamphetamine-treated mice, indicative of a potential protective effect. Finally, Tat expression was associated with an increase in calbindin-expressing cells in the VTA, while methamphetamine exposure did not alter calbindin numbers. These findings may indicate a protective role of methamphetamine in HIV neuropathology, which in turn may help in our understanding of why people with HIV use methamphetamine at disproportionately higher rates.

There is a significant overlap between HIV infection and substance-use disorders. Dopamine (DA) is the most abundantly upregulated neurotransmitter in methamphetamine abuse, with receptors (DRD1-5) that are expressed by neurons as well as by a large diversity of cell types, including innate immune cells that are the targets of HIV infection, making them responsive to the hyperdopaminergic environment that is characteristic of stimulant drugs. Therefore, the presence of high levels of dopamine may affect the pathogenesis of HIV, particularly in the brain. The stimulation of HIV latently infected U1 promonocytes with DA significantly increased viral p24 levels in the supernatant at 24 h, suggesting effects on activation and replication. Using selective agonists to different DRDs, we found that DRD1 played a major role in activating viral transcription, followed by DRD4, which increased p24 with a slower kinetic rate compared to DRD1. Transcriptome and systems biology analyses led to the identification of a cluster of genes responsive to DA, where S100A8 and S100A9 were most significantly correlated with the early increase in p24 levels following DA stimulation. Conversely, DA increased the expression of these genes' transcripts at the protein level, MRP8 and MRP14, respectively, which form a complex also known as calprotectin. Interestingly, MRP8/14 was able to stimulate HIV transcription in latent U1 cells, and this occurred via binding of the complex to the receptor for an advanced glycosylation end-product (RAGE). Using selective agonists, both DRD1 and DRD4 increased MRP8/14 on the surface, in the cytoplasm, as well as secreted in the supernatants. On the other hand, while DRD1/5 did not affect the expression of RAGE, DRD4 stimulation caused its downregulation, offering a mechanism for the delayed effect via DRD4 on the p24 increase. To cross-validate MRP8/14 as a DA signature with a biomarker value, we tested its expression in HIV+ Meth users' postmortem brain specimens and peripheral cells. MRP8/14+ cells were more frequently identified in mesolimbic areas such as the basal ganglia of HIV+ Meth+ cases compared to HIV+ non-Meth users or to controls. Likewise, MRP8/14+ CD11b+ monocytes were more frequent in HIV+ Meth users, particularly in specimens from participants with a detectable viral load in the CSF. Overall, our results suggest that the MRP8 and MRP14 complex may serve as a signature to distinguish subjects using addictive substances in the context of HIV, and that this may play a role in aggravating HIV pathology by promoting viral replication in people with HIV who use Meth.

BackgroundMethamphetamine use could jeopardize the current efforts to address opioid use disorder and HIV infection. Evidence-based behavioral interventions (EBI) are effective in reducing methamphetamine use. However, evidence on optimal combinations of EBI is limited. This protocol presents a type-1 effectiveness-implementation hybrid design to evaluate the effectiveness, cost-effectiveness of adaptive methamphetamine use interventions, and their implementation barriers in Vietnam.MethodDesign: Participants will be first randomized into two frontline interventions for 12 weeks. They will then be placed or randomized to three adaptive strategies for another 12 weeks. An economic evaluation and an ethnographic evaluation will be conducted alongside the interventions.ParticipantsWe will recruit 600 participants in 20 methadone clinics.Eligibility criteria(1) age 16+; (2) Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) scores ≥ 10 for methamphetamine use or confirmed methamphetamine use with urine drug screening; (3) willing to provide three pieces of contact information; and (4) having a cell phone.OutcomesOutcomes are measured at 13, 26, and 49 weeks and throughout the interventions. Primary outcomes include the (1) increase in HIV viral suppression, (2) reduction in HIV risk behaviors, and (3) reduction in methamphetamine use. COVID-19 response: We developed a response plan for interruptions caused by COVID-19 lockdowns to ensure data quality and intervention fidelity.DiscussionThis study will provide important evidence for scale-up of EBIs for methamphetamine use among methadone patients in limited-resource settings. As the EBIs will be delivered by methadone providers, they can be readily implemented if the trial demonstrates effectiveness and cost-effectiveness.Trial registrationClinicalTrials.gov NCT04706624. Registered on 13 January 2021. https://clinicaltrials.gov/ct2/show/NCT04706624.

Background and Aims: There is currently no standard of care for pharmacological treatment of amphetamine‐type stimulant (ATS) use disorder (ATSUD). This systematic review with meta‐analysis (PROSPERO CRD42022354492) aimed to pool results from randomized placebo‐controlled trials (RCTs) to evaluate efficacy and safety of prescription psychostimulants (PPs) for ATSUD. Methods: Major indexing sources and trial registries were searched to include records published before 29 August 2022. Eligible studies were RCTs evaluating efficacy and safety of PPs for ATSUD. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. Risk ratio (RR) and risk difference were calculated for random‐effect meta‐analysis of dichotomous variables. Mean difference and standardized mean difference (SMD) were calculated for random‐effect meta‐analysis of continuous variables. Results: Ten RCTs (n = 561 participants) were included in the meta‐analysis. Trials studied methylphenidate (n = 7), with daily doses of 54–180 mg, and dextroamphetamine (n = 3), with daily doses of 60–110 mg, for 2–24 weeks. PPs significantly decreased end‐point craving [SMD −0.29; 95% confidence interval (CI) = −0.55, −0.03], while such a decrease did not reach statistical significance for ATS use, as evaluated by urine analysis (UA) (RR = 0.93; 95% CI = 0.85–1.01). No effect was observed for self‐reported ATS use, retention in treatment, dropout following adverse events, early‐stage craving, withdrawal and depressive symptoms. In a sensitivity analysis, treatment was associated with a significant reduction in UA positive for ATS (RR = 0.89; 95% CI = 0.79–0.99) after removing studies with a high risk of bias. In subgroup analyses, methylphenidate and high doses of PPs were negatively associated with ATS use by UA, while higher doses of PPs and treatment duration (≥ 20 weeks) were positively associated with longer retention. Conclusions: Among individuals with amphetamine‐type stimulant use disorder, treatment with prescription psychostimulants may decrease ATS use and craving. While effect size is limited, it may increase with a higher dosage of medications. [ABSTRACT FROM AUTHOR]

BACKGROUND: In a randomized controlled 8-week trial, we examined the efficacy of aerobic and resistance exercise in reducing craving for methamphetamine (MA) among individuals with MA-use disorder during residential treatment. METHODS: Individuals with MA use disorder (138) who were newly enrolled in residential treatment volunteered for random assignment to either an 8-week exercise intervention (EX) or health education control (HE), with both conditions meeting 3 times weekly; 3 dropped out of the trial, bringing the analysis sample to 135. The majority of participants were male (80%), and 48% were Latino/Hispanic. The mean age of the sample was 31.7 (SD = 6.9) years. Using multivariate mixed models, differences between conditions were examined in: (1) craving for MA, measured by self-reported ratings on a Visual Analog Scale over the 8-week trial and, (2) MA use, measured by self-report and urine drug screens at baseline and 30 and 60 days after discharge from the 8-week study. RESULTS: Results revealed significantly lower craving scores among the participants in the EX group than those in the HE group over the 8-week trial (median daily craving score for EX = 13.5, for HE = 21.8; p = .009). In addition, participants with less craving during treatment had significantly lower rates of MA use after discharge than participants with high craving measured at 30-days (p = .004) and 60-days post-discharge (p

BackgroundMethamphetamine use is a known predictor of riskier sexual behaviors, which can have important public health implications (e.g., HIV-transmission risk). Loneliness also is associated with riskier sexual behaviors, though the relationship between loneliness and beliefs and/or intentions to practice safer sex has not been examined among people dependent on methamphetamine.Materials and methodsIndividuals who met DSM-IV criteria for lifetime methamphetamine dependence and current (≤ 18-months) methamphetamine abuse or dependence (METH+ n = 56) were compared to those without severity and recency of methamphetamine use (METH- n = 59). These groups did not differ on social network size or proportion of people with HIV (∼58% HIV+). Participants completed the NIH Toolbox Loneliness Scale and the Sexual Risks Scale's "Norms" and "Intentions" subscales.ResultsMETH+ individuals were significantly lonelier than METH- controls (t(113) = 2.45, p = .02). Methamphetamine dependence remained significantly associated with greater loneliness, after controlling for HIV status and other relevant covariates (e.g., neurocognitive impairment, history of mood disorder, social network size; F = 3.70, Adjusted R2 = 0.18, p = .0009). Loneliness, above and beyond the aforementioned covariates, was significantly associated with riskier beliefs and intentions to practice safer sex among METH+, but not METH-, individuals (β = 2.92, p = .02).ConclusionsLoneliness is prevalent among individuals dependent on methamphetamine, and is uniquely associated with riskier beliefs and intentions regarding practicing safer sex. Findings may aid in identifying individuals at-risk of engaging in riskier sexual behaviors and guide risk prevention strategies.

INTRODUCTION: Methamphetamine (MA) use disorder is an important public health concern. MA withdrawal is often the first step in ceasing or reducing use. There are no evidence-based withdrawal treatments, and no medication is approved for the treatment of MA withdrawal. Lisdexamfetamine (LDX) dimesilate, used in the treatment of attention deficit hyperactivity disorder and binge eating disorder has the potential as an agonist therapy to ameliorate withdrawal symptoms, and improve outcomes for patients. METHODS: A single arm, open-label pilot study to test the safety and feasibility of LDX for the treatment of MA withdrawal. Participants will be inpatients in a drug and alcohol withdrawal unit, and will receive a tapering dose of LDX over five days: 250mg LDX on Day 1, reducing by 50mg per day to 50mg on Day 5. Optional inpatient Days 6 and 7 will allow for participants to transition to ongoing treatment. Participants will be followed-up on Days 14, 21 and 28. All participants will also receive standard inpatient withdrawal care. The primary outcomes are safety (measured by adverse events, changes in vital signs, changes in suicidality and psychosis) and feasibility (the time taken to enrol the sample, proportion of screen / pre-screen failures). Secondary outcomes are acceptability (treatment satisfaction questionnaire, medication adherence, concomitant medications, qualitative interviews), retention to protocol (proportion retained to primary and secondary endpoints), changes in withdrawal symptoms (Amphetamine Withdrawal Questionnaire) and craving for MA (visual analogue scale), and sleep outcomes (continuous actigraphy and daily sleep diary). DISCUSSION: This is the first study to assess lisdexamfetamine for the treatment of acute MA withdrawal. If safe and feasible results will go to informing the development of multi-centre randomised controlled trials to determine the efficacy of the intervention.

The increasing prevalence of illicit stimulant use among those in opioid treatment programs poses a significant risk to public health, stimulant users have the lowest rate of retention and poorest outcomes among those in addiction treatment, and current treatment options are limited. Oxytocin administration has shown promise in reducing addiction-related behavior and enhancing salience to social cues. We conducted a randomized, double-blind, placebo-controlled clinical trial of intranasal oxytocin administered twice daily for 6 weeks to male Veterans with stimulant use disorder who were also receiving opioid agonist therapy and counseling (n = 42). There was no significant effect of oxytocin on stimulant use, stimulant craving, or therapeutic alliance over 6 weeks. However, participants receiving oxytocin (vs. placebo) attended significantly more daily opioid agonist therapy dispensing visits. This replicated previous work suggesting that oxytocin may enhance treatment engagement among individuals with stimulant and opioid use disorders, which would address a significant barrier to effective care.

Methamphetamine (MA) is a highly addictive psychostimulant drug, and the number of MA-related overdose deaths has reached epidemic proportions. Repeated MA exposure induces a robust and persistent neuroinflammatory response, and the evidence supports the potential utility of targeting neuroimmune function using non-selective phosphodiesterase 4 (PDE4) inhibitors as a therapeutic strategy for attenuating addiction-related behavior. Off-target, emetic effects associated with non-selective PDE4 blockade led to the development of isozyme-selective inhibitors, of which the PDE4B-selective inhibitor A33 was demonstrated recently to reduce binge drinking in two genetically related C57BL/6 (B6) substrains (C57BL/6NJ (B6NJ) and C57BL/6J (B6J)) that differ in their innate neuroimmune response. Herein, we determined the efficacy of A33 for reducing MA self-administration and MA-seeking behavior in these two B6 substrains. Female and male mice of both substrains were first trained to nose poke for a 100 mg/L MA solution followed by a characterization of the dose-response function for oral MA reinforcement (20 mg/L-3.2 g/L), the demand-response function for 400 mg/L MA, and cue-elicited MA seeking following a period of forced abstinence. During this substrain comparison of MA self-administration, we also determined the dose-response function for A33 pretreatment (0-1 mg/kg) on the maintenance of MA self-administration and cue-elicited MA seeking. Relative to B6NJ mice, B6J mice earned fewer reinforcers, consumed less MA, and took longer to reach acquisition criterion with males of both substrains exhibiting some signs of lower MA reinforcement than their female counterparts during the acquisition phase of the study. A33 pretreatment reduced MA reinforcement at all doses tested. These findings provide the first evidence that pretreatment with a selective PDE4B inhibitor effectively reduces MA self-administration in both male and female mice of two genetically distinct substrains but does not impact cue-elicited MA seeking following abstinence. If relevant to humans, these results posit the potential clinical utility of A33 or other selective PDE4B inhibitors for curbing active drug-taking in MA use disorder.

Amphetamines are substances with the ability to increase cognitive performance, as well as energy and concentration levels, and are indicated for people diagnosed with Attention Deficit Hyperactivity Disorder (ADHD). One of the most used medications in this clinical condition is methylphenidate hydrochloride, which stimulates the central nervous system (CNS). In Brazil, the drug is sold under the names Ritalin® and Concerta®. Although they are widely effective in treating ADHD, when used illicitly, they present several adverse effects. Excessive use can lead to increased fatigue, which may lead to the need for more stimulants, consequently leading to physical and psychological dependence, tolerance and habituation. In view of the above, this study aims to review the scientific literature on the indiscriminate use of amphetamines and the psychological consequences of this use. For this purpose, bibliographical research was carried out in three databases (LILACS, MEDLINE and EMBASE), from which articles published from 2017 to 2023 were selected, excluding bibliographical reviews and experiments with animals. After applying the methodology, six articles were used for the discussion. After analyzing the data, a tendency towards the indiscriminate use of amphetamines and other brain stimulants and the development of psychological disorders related to this use was observed. In view of this, it is necessary to raise awareness among adolescents and young people regarding the risks of indiscriminate use of these substances and their harm to health. [ABSTRACT FROM AUTHOR]

Objective: To investigate the demographic characteristics, substance use, and self‐rated health of people entering treatment in New South Wales public health services for alcohol, amphetamine‐type stimulants, cannabis, cocaine, or opioids use, by principal drug of concern. Design: Baseline findings of a cohort study; analysis of data in patient electronic medical records and NSW minimum data set for drug and alcohol treatment services. Setting, participants: People completing initial Australian Treatment Outcomes Profile (ATOP) assessments on entry to publicly funded alcohol and other drug treatment services in six NSW local health districts/networks, 1 July 2016 – 30 June 2019. Main outcome measures: Socio‐demographic characteristics, and substance use and self‐rated health (psychological, physical, quality of life) during preceding 28 days, by principal drug of concern. Results: Of 14 087 people included in our analysis, the principal drug of concern was alcohol for 6051 people (43%), opioids for 3158 (22%), amphetamine‐type stimulants for 2534 (18%), cannabis for 2098 (15%), and cocaine for 246 (2%). Most people commencing treatment were male (9373, 66.5%), aged 20–39 years (7846, 50.4%), and were born in Australia (10 934, 86.7%). Polysubstance use was frequently reported, particularly by people for whom opioids or amphetamine‐type stimulants were the principal drugs of concern. Large proportions used tobacco daily (53–82%, by principal drug of concern group) and reported poor psychological health (47–59%), poor physical health (32–44%), or poor quality of life (43–52%). Conclusions: The prevalence of social disadvantage and poor health is high among people seeking assistance with alcohol, amphetamine‐type stimulants, cannabis, cocaine, or opioids use problems. Given the differences in these characteristics by principal drug of concern, health services should collect comprehensive patient information during assessment to facilitate more holistic, tailored, and person‐centred care. [ABSTRACT FROM AUTHOR]

Background Although methamphetamine abuse is associated with the development of heart failure (HF), nationwide data on methamphetamine-associated HF (MethHF) hospitalizations are limited. This study evaluates nationwide HF hospitalizations associated with substance abuse to better understand MethHF prevalence trends and the clinical characteristics of those patients. Methods and Results This cross-sectional period-prevalence study used hospital discharge data from the National Inpatient Sample to identify adult primary HF hospitalizations with a secondary diagnosis of abuse of methamphetamines, cocaine, or alcohol in the United States from 2002 to 2014. All 2014 MethHF admissions were separated by regional census division to evaluate geographical distribution. Demographics, payer information, and clinical characteristics of MethHF hospitalizations were compared with all other HF hospitalizations. Total nationwide MethHF hospitalizations increased from 547 in 2002 to 6625 in 2014 with a predominance on the West Coast. Methamphetamine abuse was slightly more common among primary HF hospitalizations compared with all-cause hospitalizations (7.4 versus 6.4 per 1000; Cohen h=0.012; P

Methamphetamine abuse leads to devastating consequences, including addiction, crime, and death. Despite decades of research, no medication has been approved by the U.S. Food and Drug Administration for the treatment of Methamphetamine Use Disorder. Thus, there is a need for new therapeutic approaches. Animal studies demonstrate that methamphetamine exposure dysregulates forebrain function involving the Group-I metabotropic glutamate receptor subtype 5 (mGlu5), which is predominantly localized to postsynaptic sites. Allosteric modulators of mGlu5 offer a unique opportunity to modulate glutamatergic neurotransmission selectively, thereby potentially ameliorating methamphetamine-induced disruptions. Negative allosteric modulators of mGlu5 attenuate the effects of methamphetamine, including rewarding/reinforcing properties of the drug across animal models, and have shown promising effects in clinical trials for Anxiety Disorder and Major Depressive Disorder. Preclinical studies have also sparked great interest in mGlu5 positive allosteric modulators, which exhibit antipsychotic and anxiolytic properties, and facilitate extinction learning when access to methamphetamine is removed, possibly via the amelioration of methamphetamine-induced cognitive deficits. Clinical research is now needed to elucidate the mechanisms underlying the mGlu5 receptor-related effects of methamphetamine and the contributions of these effects to addictive behaviors. The growing array of mGlu5 allosteric modulators provides excellent tools for this purpose and may offer the prospect of developing tailored and effective medications for Methamphetamine Use Disorder.

Chronic methamphetamine use is linked to abnormalities in brain structure, which may reflect neurotoxicity related to metabolism of the drug. As the cytochrome P450 2D6 (CYP2D6) enzyme is central to the metabolism of methamphetamine, genotypic variation in its activity may moderate effects of methamphetamine on brain structure and function. This study explored the relationship between CYP2D6 genotype and measures of brain structure and cognition in methamphetamine users. Based on the function of genetic variants, a CYP2D6 activity score was determined in 82 methamphetamine-dependent (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria) and 79 healthy-control participants who completed tests of cognitive function (i.e., attention, memory, and executive function); most were also evaluated with structural magnetic resonance imaging (MRI) (66 methamphetamine-dependent and 52 controls). The relationship between CYP2D6 activity score and whole brain cortical thickness differed by group (interaction p = 0.024), as increasing CYP2D6 activity was associated with thinner cortical thickness in the methamphetamine users (β = -0.254; p = 0.035), but not in control subjects (β = 0.095; p = 0.52). Interactions between CYP2D6 activity and group were nonsignificant for hippocampal volume (ps > 0.05), but both hippocampi showed trends similar to those observed for cortical thickness (negative relationships in methamphetamine users [ps < 0.05], and no relationships in controls [ps > 0.50]). Methamphetamine users had lower cognitive scores than control subjects (p = 0.007), but there was no interaction between CYP2D6 activity score and group on cognition (p > 0.05). Results suggest that CYP2D6 genotypes linked to higher enzymatic activity may confer risk for methamphetamine-induced deficits in brain structure. The behavioral consequences of these effects are unclear and warrant additional investigation.

BackgroundHIV infection and methamphetamine dependence (METH) are each associated with inflammation and premature aging, but their impact on biological aging is difficult to measure. Here we examined the impact of HIV and METH on leukocyte telomere lengths (LTL), and the correlations between LTL and other aging biomarkers.MethodsThe study was a cross-sectional analysis of 161 individuals categorized by HIV and methamphetamine (METH) dependence status into four groups: HIV-METH- (n = 50), HIV-METH+ (n = 29), HIV + METH- (n = 40), and HIV + METH+ (n = 42). We analyzed the relationships of leukocyte telomere length (telomere to single copy gene [T/S] ratio) with demographic and clinical data as well as a panel of biomarkers of inflammation and endothelial activation measured in blood and cerebrospinal fluid (CSF).ResultsHIV and METH were independently associated with shorter T/S ratio, even after adjusting for demographics and leukocyte count (R2 = 0·59, p < 0·0001). Higher plasma C-reactive protein (p = 0·0036) and CSF VCAM-1 (p = 0·0080) were also associated with shorter T/S ratio. A shorter T/S ratio was associated with higher risk for cardiovascular disease (p < 0·0001) and stroke (p < 0·0001), worse motor functioning (p = 0·037) and processing speed (p = 0·023), more depressive symptoms (p = 0·013), and higher CSF neurofilament-light (p = 0·003).ConclusionsHIV and METH dependence were each associated with shorter telomeres. After adjusting for demographics, HIV, and METH, T/S ratio remained associated with aging-related outcomes including neurocognitive impairment, neurodegeneration, risks of cardiovascular disease and stroke. While not establishing causality, this study supports using the T/S ratio as a biomarker for estimating the impact of HIV and comorbidities on long-term health.

Female entertainment and sex workers (FESW) have high rates of alcohol and amphetamine-type stimulant (ATS) use, increasing risk for HIV/sexually transmitted infections (STI), and other negative outcomes. A prospective cohort of 1,198 FESW in a HIV/ATS use prevention intervention in Cambodia was assessed for alcohol and stimulant use disorders (AUD and SUD) using the Alcohol and Substance Use Involvement (ASSIST) scale. STI history was measured by self-report at baseline and at quarterly follow-up visits. Participants were asked if they had been diagnosed with an STI by a medical provider in the past 3 months. Marginal structural models were used to estimate joint effects of AUD and SUD on recent STI. At baseline, one-in-four screened AUD positive and 7% screened positive for SUD. At 18-months, 26% reported ≥1 recent STI. Accounting for time-varying and other known confounders, the adjusted odds ratio (AOR) for recent STI associated with AUD alone and SUD alone were 2.8 (95% CI:1.5-5.1) and 3.5 (95% CI:1.1-11.3), respectively. The AOR for joint effects of AUD and SUD was 5.7 (95% CI:2.2-15.2). AUD and SUD are independently and jointly associated with greater odds of STI among Cambodian FESW. Further research is critical for understanding how AUD and SUD potentiate biological and behavioural pathways that influence STI acquisition and to inform HIV risk-reduction interventions in FESW.

Understanding the mechanisms underpinning individual variance in addiction vulnerability requires the development of validated, high-throughput screens. In a prior study of a large sample of male isogenic C57BL/6J mice, the direction and magnitude of methamphetamine (MA)-induced place-conditioning predicts the propensity to acquire oral MA self-administration, as well as the efficacy of MA to serve as a reinforcer. The present study examined whether or not such a predictive relationship also exists in females. Adult C57BL/6J females underwent a 4-day MA place-conditioning paradigm (once daily injections of 2 mg/kg) and were then trained to nose-poke for delivery of a 20 mg/L MA solution under increasing schedules of reinforcement, followed by dose-response testing (5-400 mg/L MA). Akin to males, 53 % of the females exhibited a conditioned place-preference, while 32 % of the mice were MA-neutral and 15 % exhibited a conditioned place-aversion. However, unlike males, the place-conditioning phenotype did not transfer to MA-reinforced nose-poking behavior under operant-conditioning procedures, with 400 mg/L MA intake being inversely correlated place-conditioning. While only one MA-conditioning dose has been assayed to date, these data indicate that sex does not significantly shift the proportion of C57BL/6J mice that perceive MA's interoceptive effects as positive, neutral or aversive. However, a sex difference appears to exist regarding the predictive relationship between the motivational valence of MA and subsequent drug-taking behavior; females exhibit MA-taking behavior and reinforcement, despite their initial perception of the stimulant interoceptive effects as positive, neutral or negative.

BackgroundThe use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied.MethodsWe conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses.ResultsA total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P

Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose-response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.

Patients and psychotherapists often exhibit behavioral, psychological, and physiological similarity. Here, we test whether oxytocin-a neuropeptide that can enhance expressivity and social perception-influences time-lagged "linkage" of autonomic nervous system responses among participants and facilitators during group therapy. Physiological linkage estimates (n = 949) were created from ten cohorts, each with two facilitators (n = 5) and four to six participants (n = 48), over six weekly sessions of group therapy for methamphetamine use disorder. All participants of a cohort received oxytocin or placebo intranasally in a randomized double-blind procedure before each session. Cardiac interbeat intervals (IBI) were measured continuously during sessions to estimate physiological linkage, operationalized as one cohort-mate's IBI reactivity during one minute predicting another cohort-mate's IBI reactivity during the following minute. In oxytocin cohorts, participants and facilitators experienced significant physiological linkage to their cohort-mates (i.e., their physiological responses were predicted by the prior responses of their cohort-mates) and significantly more linkage than people in placebo cohorts. Both effects occurred during the first and second sessions but not later sessions. Results suggest that oxytocin may enhance psychosocial processes often associated with linkage-such as social engagement-in groups and highlight oxytocin's potential to improve group cohesion during group therapy.Clinical Trials Registration: NCT02881177, First published on 26/08/2016.

IntroductionInteroception, defined as the sense of the internal state of one's body, helps motivate goal-directed behavior. Prior work has shown that methamphetamine (METH) use disorder is associated with altered interoception, and that this may contribute to risky behavior. As people with HIV (PWH) may also experience disrupted bodily sensations (e.g., neuropathy), an important question is whether PWH with a history of METH use disorder might exhibit greater impairment of interoceptive processing.MethodsEighty-three participants stratified by HIV infection and a past history of methamphetamine use disorder experienced a soft touch paradigm that included slow brush strokes on the left forearm and palm during blood-oxygen level-dependent functional MRI acquisition. To assess differences in interoception and reward, voxelwise analyses were constrained to the insula, a hub for the evaluation of interoceptive cues, and the striatum, which is engaged in reward processing.ResultsOverall, individuals with a history of METH use disorder had an attenuated neural response to pleasant touch in both the insula and striatum. Longer abstinence was associated with greater neural response to touch in the insula, suggesting some improvement in responsivity. However, only PWH with no METH use disorder history had lower brain activation in the insula relative to non-using seronegative controls.ConclusionsOur findings suggest that while METH use disorder history and HIV infection independently disrupt the neural processes associated with interoception, PWH with METH use disorder histories do not show significant differences relative to non-using seronegative controls. These findings suggest that the effects of HIV infection and past methamphetamine use might not be additive with respect to interoceptive processing impairment.

Human postmortem specimens are extremely valuable resources for investigating translational hypotheses. Tissue repositories collect clinically assessed specimens from people with and without HIV, including age, viral load, treatments, substance use patterns and cognitive functions. One challenge is the limited number of specimens suitable for transcriptional studies, mainly due to poor RNA quality resulting from long postmortem intervals. We hypothesized that epigenomic signatures would be more stable than RNA for assessing global changes associated with outcomes of interest. We found that H3K27Ac or RNA Polymerase (Pol) were not consistently detected by Chromatin Immunoprecipitation (ChIP), while the enhancer H3K4me3 histone modification was abundant and stable up to the 72 h postmortem. We tested our ability to use HeK4me3 in human prefrontal cortex from HIV+ individuals meeting criteria for methamphetamine use disorder or not (Meth +/-) which exhibited poor RNA quality and were not suitable for transcriptional profiling. Systems strategies that are typically used in transcriptional metadata were applied to H3K4me3 peaks revealing consistent genomic activity differences in regions where addiction and neuronal synapses pathway genes are represented, including genes of the dopaminergic system, as well as inflammatory pathways. The resulting comparisons mirrored previously observed effects of Meth on suppressing gene expression and provided insights on neurological processes affected by Meth. The results suggested that H3K4me3 detection in chromatin may reflect transcriptional patterns, thus providing opportunities for analysis of larger numbers of specimens from cases with substance use and neurological deficits. In conclusion, the detection of H3K4me3 in isolated chromatin can be an alternative to transcriptome strategies to increase the power of association using specimens with long postmortem intervals and low RNA quality.

ObjectiveTo determine if men who have sex with men (MSM) with cocaine use disorder (CUD) and actively-using cocaine could be enrolled and retained in a pharmacologic intervention trial of lorcaserin-a novel 5-HT2cR agonist-and determine the degree to which participants would adhere to study procedures.MethodsThis was a phase II randomized, double-blind, placebo-controlled pilot study with 2:1 random parallel group assignment to daily extended-release oral lorcaserin 20 mg versus placebo (clinicaltrials.gov identifier-NCT03192995). Twenty-two of a planned 45 cisgender MSM with CUD were enrolled and had weekly follow-up visits during a 12-week treatment period, with substance use counseling, urine specimen collection, and completion of audio-computer assisted self-interview (ACASI) behavioral risk assessments. Adherence was measured by medication event monitoring systems (MEMS) caps and self-report. This study was terminated early because of an FDA safety alert for lorcaserin's long-term use.ResultsEighty-six percent completed the trial, with 82% of weekly study follow-up visits completed. Adherence was 55.3% (lorcaserin 51.6% vs. placebo 66.2%) by MEMS cap and 56.9% (56.5% vs. placebo 57.9%) by self-report and did not differ significantly by treatment assignment. Intention-to-treat analyses (ITT) did not show differences in cocaine positivity by urine screen between the lorcaserin and placebo groups by 12 week follow-up (incidence risk ratio [IRR]: 0.96; 95%CI = 0.24-3.82, P = 0.95). However, self-reported cocaine use in timeline follow-back declined more significantly in the lorcaserin group compared to placebo (IRR: 0.66; 95%CI = 0.49-0.88; P = 0.004).ConclusionWe found that it is feasible, acceptable, and tolerable to conduct a placebo-controlled pharmacologic trial for MSM with CUD who are actively using cocaine. Lorcaserin was not associated with significant reductions in cocaine use by urine testing, but was associated with significant reductions in self-reported cocaine use. Future research may be needed to continue to explore the potential utility of 5-HT2cR agonists.

HIV infection and drug use intersect epidemiologically, and their combination can result in complex effects on brain and behavior. The extent to which drugs affect the health of persons with HIV (PWH) depends on many factors including drug characteristics, use patterns, stage of HIV disease and its treatment, comorbid factors, and age. To consider the range of drug effects, we have selected two that are in common use by PWH: methamphetamine and cannabis. We compare the effects of methamphetamine with those of cannabis, to illustrate how substances may potentiate, worsen, or even buffer the effects of HIV on the CNS. Data from human, animal, and ex vivo studies provide insights into how these drugs have differing effects on the persistent inflammatory state that characterizes HIV infection, including effects on viral replication, immune activation, mitochondrial function, gut permeability, blood brain barrier integrity, glia and neuronal signaling. Moving forward, we consider how these mechanistic insights may inform interventions to improve brain outcomes in PWH. This review summarizes literature from clinical and preclinical studies demonstrating the adverse effects of METH, as well as the potentially beneficial effects of cannabis, on the interacting systemic (e.g., gut barrier leakage/microbial translocation, immune activation, inflammation) and CNS-specific (e.g., glial activation/neuroinflammation, neural injury, mitochondrial toxicity/oxidative stress) mechanisms underlying HIV-associated neurocognitive disorders.

BackgroundNumerous reports have led to concerns that fentanyl is added to many street drugs as an adulterant, including to stimulants like cocaine and methamphetamine, and could increase risks for negative health outcomes.MethodsWe collected information regarding recent substance use through self-report and urine toxicology (confirmed with mass spectrometry) once a month for up to 6 monthly study visits from a probability sample of 245 women in San Francisco with a history of housing instability (2016-2019). We compared the presence of fentanyl metabolites with (1) the presence of metabolites for other substances and (2) self-reported past week substance use.ResultsOut of 1050 study visits, fentanyl metabolites were detected 35 times (i.e., at 3% of all study visits and among 19/245, or 8% of all women). In most but not all (91%, or 32/35) of these detected cases, heroin or opioid medication use was self-reported. Among women who reported cocaine or methamphetamine use, but did not use heroin or opioid medication, fentanyl was detected in only 1 of 349 cases (0.3%). In adjusted logistic regression, the presence of fentanyl metabolites was independently associated with (1) presence of opiate, heroin, and benzodiazepine metabolites, and (2) self-reported past week use of heroin and opioid medications. Fentanyl metabolite detection was not independently associated with cocaine or methamphetamine use.ConclusionsThe presence of fentanyl metabolites in this population was almost entirely among women who also reported using heroin or opioid pills. These data do not support the hypothesis that fentanyl is being routinely added to stimulants as an adulterant on a large scale in this region.

BackgroundMethamphetamine use poses a barrier to antiretroviral therapy (ART) adherence. Black and Hispanic men who have sex with men living with HIV (PLWH) shoulder much of the health burden resulting from the methamphetamine and HIV syndemic. Smartphones are nearly ubiquitous in the USA and may be promising vehicles for delivering interventions for ART adherence and drug use cessation. However, the acceptability of using applications to collect sensitive information and deliver feedback in this population has not been adequately explored.ObjectiveThis study examined minority PLWH's appraisals of the risks of participating in smartphone-based research to promote ART adherence in the context of methamphetamine use and explored their views on appropriate steps to mitigate perceived risks of participation.MethodsThree focus groups were conducted among Black and Hispanic PLWH who use methamphetamine. Of the 13 participants, 5 had previously participated in a smartphone-based observational study of ART adherence and substance use. Discussants provided feedback on smartphone-based research, including receiving probes for HIV medication adherence, mood, and substance use as well as feedback on passive location-tracking for personalized messages. Transcribed audio-recordings were thematically coded and analyzed using the qualitative software MAXQDA.ResultsParticipants expressed confidentiality concerns related to potential unintentional disclosure of their HIV status and methamphetamine use and to possible legal consequences. They additionally expressed concerns around the invasiveness of daily assessments and the potential of methamphetamine use questions to trigger cravings. To mitigate these concerns, they suggested maintaining participant privacy by indirectly asking sensitive questions, focusing on positive behaviors (e.g., number of days sober), allowing user-initiated reporting of location to tailor messages, and ensuring adequate data protections. In addition to financial compensation, participants cited altruism (specifically, continuing a tradition of volunteerism in HIV research) as a motivator for potentially engaging in such research.ConclusionsMinority PLWH have concerns regarding the use of smartphones for ART adherence and methamphetamine sobriety intervention research. However, minority PLWH are likely to participate if studies include appropriate protections against risks to confidentiality and experimental harm and are designed to offer future benefit to themselves and other PLWH.

Background and Aims: Socio‐cultural (gender) and biological (sex)‐based differences contribute to psychostimulant susceptibility, potentially affecting treatment responsiveness among women with methamphetamine use disorder (MUD). The aims were to measure (i) how women with MUD independently and compared with men respond to treatment versus placebo and (ii) among women, how the hormonal method of contraception (HMC) affects treatment responsiveness. Design: This was a secondary analysis of ADAPT‐2, a randomized, double‐blind, placebo‐controlled, multicenter, two‐stage sequential parallel comparison design trial. Setting: United States. Participants: This study comprised 126 women (403 total participants); average age = 40.1 years (standard deviation = 9.6) with moderate to severe MUD. Interventions: Interventions were combination intramuscular naltrexone (380 mg/3 weeks) and oral bupropion (450 mg daily) versus placebo. Measurements Treatment response was measured using a minimum of three of four negative methamphetamine urine drug tests during the last 2 weeks of each stage; treatment effect was the difference between weighted treatment responses of each stage. Findings At baseline, women used methamphetamine intravenously fewer days than men [15.4 versus 23.1% days, P = 0.050, difference = −7.7, 95% confidence interval (CI) = −15.0 to −0.3] and more women than men had anxiety (59.5 versus 47.6%, P = 0.027, difference = 11.9%, 95% CI = 1.5 to 22.3%). Of 113 (89.7%) women capable of pregnancy, 31 (27.4%) used HMC. In Stage 1 29% and Stage 2 5.6% of women on treatment had a response compared with 3.2% and 0% on placebo, respectively. A treatment effect was found independently for females and males (P < 0.001); with no between‐gender treatment effect (0.144 females versus 0.100 males; P = 0.363, difference = 0.044, 95% CI = −0.050 to 0.137). Treatment effect did not differ by HMC use (0.156 HMC versus 0.128 none; P = 0.769, difference = 0.028, 95% CI −0.157 to 0.212). Conclusions: Women with methamphetamine use disorder receiving combined intramuscular naltrexone and oral bupropion treatment achieve greater treatment response than placebo. Treatment effect does not differ by HMC. [ABSTRACT FROM AUTHOR]

This study evaluated whether a history of lifetime methamphetamine (MA) use disorder increases risk for poor sleep quality in people with or without HIV infection (HIV+/HIV-). Participants (n = 313) were stratified into four groups based on HIV status and lifetime MA use disorder diagnosis [HIV+/MA+ (n = 84); HIV+/MA- (n = 141); HIV-/MA+ (n = 16); and HIV-/MA- (n = 72)] and compared on global sleep outcomes using the Pittsburgh Sleep Quality Index (PSQI). Significant differences on global sleep were observed between HIV+/MA+ and HIV+/MA- groups, but not between the HIV- groups. Follow-up multiple regression analyses within the HIV+ subgroups examined global sleep scores as a function of MA status and clinical covariates, including those related to HIV disease and demographics. HIV+ individuals with a history of MA use disorder evidenced significantly poorer sleep quality and were more likely to be classified as problematic sleepers than those without a lifetime disorder. This was independent of depressed mood, body mass index, and viral suppression while on treatment. Poorer reported sleep quality among HIV+/MA+ was associated also with multiple adverse functional outcomes, including greater objective cognitive impairment, unemployment, clinical ratings of functional impairment, and self-reported cognitive difficulties, decreased independence in activities of daily living, and poorer overall life quality. Interventions to avoid or curtail MA use in HIV+ individuals may help protect sleep quality and improve functioning.

ObjectivesPeople living with HIV (PWH) are at elevated risk of cardiac disease compared to the general population. Methamphetamine use has been associated with structural heart disease and increased mortality from cardiovascular disease but has not been explored as a cause of cardiac disease among PWH. We sought to evaluate the association of methamphetamine use and cardiac disease among PWH.MethodsWe performed a case-control study of participant data in the HIV Neurobehavioral Research Program. Cases were defined as PWH with a history of myocardial infarction or a history of heart failure (systolic or diastolic). Covariates, including methamphetamine abuse/dependence, were assessed using multiple logistic regression.ResultsAmong 3747 PWH, there was a history of myocardial infarction in 115 subjects (3.1%), and a history of heart failure in 41 (1.1%). Current or prior methamphetamine abuse/dependence was reported in 1036 (27.9%) and was not associated with myocardial infarction (P = 0.27) or heart failure (P = 0.84). In addition to traditional risk factors, variables associated with myocardial infarction included the presence of HIV infection (P = 0.01) and duration of HIV infection (P = 0.05). Variables associated with heart failure among PWH included older age, hypertension and myocardial infarction.ConclusionsNo association between methamphetamine abuse/dependence and a diagnosis of myocardial infarction or heart failure was found among PWH. Significant covariates for myocardial infarction and heart failure included traditional risk factors, the presence of HIV infection and the duration of HIV infection, emphasizing the need for optimal traditional cardiovascular risk factor management among PWH.

ObjectiveHIV disease and methamphetamine (METH) dependence share overlapping mechanisms of neurotoxicity that preferentially compromise monoamine-rich frontostriatal circuitry. However, norepinephrine (NE) function is poorly understood in HIV and METH dependence. We evaluated associations between cerebrospinal fluid (CSF) NE and HIV, METH dependence, and neurocognition.MethodsParticipants included 125 adults, stratified by HIV serostatus (HIV+/HIV-) and recent METH dependence (METH+/METH-), who underwent comprehensive neurocognitive testing and lumbar puncture. CSF NE was assayed using high-performance liquid chromatography. Multivariable regression modelled NE as a function of HIV, METH, and their interaction, adjusting for demographic and clinical factors. Pearson correlations examined relationships between NE and demographically-adjusted neurocognitive domain scores.ResultsHIV significantly interacted with METH (P < 0.001) such that compared with HIV-/METH-, CSF NE was markedly elevated in the single risk-groups (HIV+/METH-: d = 0.96; HIV-/METH+: d = 0.79) and modestly elevated in the dual-risk group (HIV+/METH+: d = 0.48). This interaction remained significant after adjustment for lifetime depression, antidepressant use, and race/ethnicity. In the full sample, higher NE levels significantly correlated with worse global function (r = -0.19), learning (r = -0.23), and delayed recall (r = -0.18). Similar relationships between higher NE and worse neurocognition were detected in the METH- groups (ie, HIV-/METH- and HIV+/METH-) and in the virally-suppressed persons HIV+ subgroup, but not in the METH+ groups (ie, HIV-/METH+, HIV+/METH+).DiscussionHIV and METH independently, but not additively, relate to noradrenergic excess in the central nervous system, and perturbations to noradrenergic function may represent a pathophysiological mechanism of HIV-related neurocognitive dysfunction. Consistent with prior reports that noradrenergic excess compromises hippocampal and prefrontal function, higher NE related to worse neurocognition, even among successfully treated persons with HIV. Pharmacological and psychosocial interventions that stabilize NE function may improve neurocognition in persons with HIV.

The Met-allele of the COMT Val158Met polymorphism slows metabolism and increases bioavailability of dopamine (DA) in the prefrontal cortex compared to the Val-allele. Healthy Met-carriers outperform Val-carriers on executive function (EF) tests, yet this 'advantage' disappears in methamphetamine (METH) dependence. Met-carriers may be disproportionately vulnerable to METH-related perturbations of DA, yet it is unknown whether COMT modulates METH effects on CSF DA biomarkers. Participants were 75 METH+ and 47 METH- men who underwent neurocognitive testing, COMT genotyping, and lumbar puncture. CSF was assayed for DA and its metabolite, homovanillic acid (HVA). Separate linear models regressed DA, HVA, and HVA/DA ratios on COMT, METH and their interaction. Pearson correlations examined associations between DA and EF. Significant interactions indicated that METH+ had lower DA and higher HVA/DA ratios among Met/Met, but not Val/Met-or Val/Val. Met/Met-exhibited the highest DA levels among METH-, whereas DA levels were comparable between Met/Met-and Val-carriers among METH+. Higher DA correlated with better EF in METH- Met/Met, but did not predict EF in the entire sample. DA was expectedly higher in METH- Met/Met, yet a discordant genotype-phenotype profile emerged in METH+ Met/Met, consistent with the notion that slow DA clearance exacerbates METH-associated DA dysregulation.

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;

Background: Emerging evidence suggests that opioid receptor antagonists, such as naltrexone, are effective pharmacotherapies for alcohol, opioid, and possibly stimulant use disorders. It is posited that naltrexone exerts its effects, in part, by increasing functional connectivity between neural reward circuitry and frontal systems implicated in executive function. Yet no studies had examined whether executive function moderates these effects. Objectives: This study examined whether a composite measure of executive function (EF) moderates the effect of naltrexone on craving for methamphetamine and subjective responses following infusion of the drug. Methods: Individuals with methamphetamine use disorder (N = 30; 27% female) completed baseline neurocognitive assessments of premorbid and executive function, and an executive function factor was computed. Participants then underwent a randomized, double-blind, cross-over study of titration with naltrexone and placebo. Participants then received a 30-mg intravenous methamphetamine infusion and completed subjective response questionnaires at 8 times in the 120 minutes post-infusion. Results: Multilevel mixed models indicated a significant EF × medication interaction, reflecting greater effects of naltrexone to decrease "desire to access the drug", "want more of the drug", "crave the drug", "feel drug effects" and "feel high" in participants with low EF compared to those with high EF (Bs = .36-1.29, SEs = .14-.17, ps

Methamphetamine (MA) triggers neuroinflammation and medications that counteract MA-induced neuroinflammation may reduce MA-induced neurodegeneration and improve neurocognition and treatment outcomes in MA use disorder. We performed a randomized, placebo-controlled trial to determine the safety and efficacy of ibudilast (IBUD), a phosphodiesterase inhibitor that reduces neuroinflammation, for the treatment of MA use disorder. Treatment-seeking volunteers with MA use disorder were randomly assigned to receive 12 weeks of IBUD 50 mg twice daily (N = 64) or placebo (N = 61) with medication management counseling. Participants visited the outpatient research clinic twice weekly to provide urine specimens for drug screens and undergo study assessments. The primary outcome was end of treatment MA-abstinence (EOTA) during weeks 11 and 12 of treatment. Serum IBUID levels were measured for IBUD participants during week 3 of treatment. There was no difference in EOTA for IBUD (14%) versus placebo (16%, p > 0.05). There was no correlation between serum IBUD levels and MA use during treatment and mean IBUD levels for participants with (mean = 51.3, SD = 20.3) and without (mean = 54.7, SD = 33.0, p = 0.70) EOTA. IBUD was well tolerated. IBUD did not facilitate MA abstinence in this outpatient trial. Whether targeting neuroinflammation, either with IBUD in other subgroups of MA users or clinical trial designs, or with other anti-inflammatory medications, is an effective strategy for treating MA use disorder is not clear. Graphical Abstract The proportion of urine drug screens negative for methamphetamine (MA) during the two week lead-in period (weeks -2 and - 1) and the 12 week medication treatment period (weeks 1-12) for ibudilast versus placebo.

AimsMethamphetamine Use Disorder is prevalent in South Africa. This analysis uses data from a contingency management (CM) pilot study in South Africa to replicate and expand on a U.S.-based study showing that CM voucher spending was associated with drug abstinence behavior.DesignParticipants with methamphetamine-use disorder were enrolled in an 8-week CM trial requiring thrice weekly visits and received cash vouchers in exchange for stimulant-negative urines at each visit.ParticipantsParticipants were 33 treatment-seeking individuals with methamphetamine use disorder including 22 men (66.7%) and 11 women (33.3%) with a mean age of 34 years (S.D. = 7.7). Participants reported using methamphetamine for a mean of 11.7 years (S.D. = 4.9).SettingAll study procedures took place in South Africa between August 2016 and May 2018.MeasurementsA time-lagged counting process Cox Proportional Hazards model for recurrent event survival analysis examined the relationship between frequency of and participant-categorized type of CM expenditures (hedonic, utilitarian, consumable or durable) and drug abstinence.FindingsAfter controlling for severity of baseline methamphetamine use and accumulated CM earnings (proxied by cumulative negative urines), those spending CM earnings at a previous visit ("spenders") were more likely to produce stimulant-negative urine samples subsequently, compared to those who did not ("savers") [OR = 1.23, CI = 1.08-1.53, p = .002]. There were significantly more cumulative stimulant-negative results among spenders vs. savers, p

This study sought to determine if reducing dopamine D1 receptor (D1R) expression in the dorsal striatum (DS) via RNA-interference alters methamphetamine self-administration. A lentiviral construct containing a short hairpin RNA (shRNA) was used to knock down D1R expression (D1RshRNA). D1RshRNA in male rats increased responding for methamphetamine (i.v.) under a fixed-ratio schedule in an extended access paradigm, compared to D1R-intact rats. D1RshRNA also produced a vertical shift in a dose-response paradigm and enhanced responding for methamphetamine in a progressive-ratio schedule, generating a drug-vulnerable phenotype. D1RshRNA did not alter responding for sucrose (oral) under a fixed-ratio schedule compared to D1R-intact rats. Western blotting confirmed reduced D1R expression in methamphetamine and sucrose D1RshRNA rats. D1RshRNA reduced the expression of PSD-95 and MAPK-1 and increased the expression of dopamine transporter (DAT) in the DS from methamphetamine, but not sucrose rats. Sucrose density gradient fractionation was performed in behavior-naïve controls, D1RshRNA- and D1R-intact rats to determine the subcellular localization of D1Rs, DAT and D1R signaling proteins. D1Rs, DAT, MAPK-1 and PSD-95 predominantly localized to heavy fractions, and the membrane/lipid raft protein caveolin-1 (Cav-1) and flotillin-1 were distributed equally between buoyant and heavy fractions in controls. Methamphetamine increased localization of PSD-95, Cav-1, and flotillin-1 in D1RshRNA and D1R-intact rats to buoyant fractions. Our studies indicate that reduced D1R expression in the DS increases vulnerability to methamphetamine addiction-like behavior, and this is accompanied by striatal alterations in the expression of DAT and D1R signaling proteins and is independent of the subcellular localization of these proteins.

Introduction and aimsAs South Africa, especially the Western Cape Province, faces an epidemic of methamphetamine use disorder, therapeutic approaches suited to the South African context are needed. This secondary analysis assessed retention and methamphetamine abstinence outcomes in response to an 8-week pilot contingency management (CM) intervention trial of neural correlates of methamphetamine abstinence, exploring sociodemographic and clinical differences between responders and non-responders.Design and methodsResearch participants provided thrice-weekly monitored urine samples, which were analysed by qualitative radioimmunoassay. The primary outcome for this analysis was therapeutic response, defined as abstinence from methamphetamine (≥23 of 24 possible methamphetamine-negative urine samples).ResultsData from 30 adults living in Cape Town, South Africa (34 ± 6.1 years of age, mean age ± SD, 21 men) were included. Sixty-three percent (12 men) were responders. In bivariate comparisons, baseline measurements showed fewer responders reported monthly household income ≥25 000+ South African Rand (ZAR; ~USD $1880; vs. ZAR