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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.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition that often persists into adulthood. Underlying alterations in brain connectivity have been identified but some relevant connections, such as the middle, superior, and inferior cerebellar peduncles (MCP, SCP, and ICP, respectively), have remained largely unexplored; thus, we sought to investigate whether the cerebellar peduncles contribute to ADHD pathophysiology among adults. METHODS: We applied diffusion-weighted spherical deconvolution tractography to dissect the cerebellar peduncles of male adults with ADHD (including those who did or did not respond to methylphenidate, based on at least 30% symptom improvement at 2 months) and controls. We investigated differences in tract metrics between controls and the whole ADHD sample and between controls and treatment-response groups using sensitivity analyses. Finally, we analyzed the association between the tract metrics and cliniconeuropsychological profiles. RESULTS: We included 60 participants with ADHD (including 42 treatment responders and 18 nonresponders) and 20 control participants. In the whole ADHD sample, MCP fractional anisotropy (FA; t 78 = 3.24, p = 0.002) and hindrance modulated orientational anisotropy (HMOA; t 78 = 3.01, p = 0.004) were reduced, and radial diffusivity (RD) in the right ICP was increased (t 78 = -2.84, p = 0.006), compared with controls. Although case-control differences in MCP FA and HMOA, which reflect white-matter microstructural organization, were driven by both treatment response groups, only responders significantly differed from controls in right ICP RD, which relates to myelination (t 60 = 3.14, p = 0.003). Hindrance modulated orientational anisotropy of the MCP was significantly positively associated with hyperactivity measures. LIMITATIONS: This study included only male adults with ADHD. Further research needs to investigate potential sex- and development-related differences. CONCLUSION: These results support the role of the cerebellar networks, especially of the MCP, in adult ADHD pathophysiology and should encourage further investigation. CLINICAL TRIAL REGISTRATION: NCT03709940.

Background: Men who have sex with men (MSM) who use stimulants are at increased risk for HIV infection. Adherence to pre-exposure prophylaxis (PrEP) reduces the risk of HIV infection. We evaluated the efficacy of the individualized Texting for Adherence Building (iTAB) intervention for PrEP adherence compared to standard of care (SoC) among 119 MSM who use stimulants (cocaine, methamphetamine and/or other amphetamine) from the California Collaborative Treatment Group 595 randomized control trial.Method: Three ordered levels of PrEP adherence (non-adherence, adequate adherence, and near-perfect adherence) were compared between intervention arms across study visits (weeks 12 and 48) using ordinal logistic regressions.Results: The effect of intervention arm was not significant in the final model; however, there was a 38% decrease in odds (OR = 0.62, p=.023) of having near-perfect adherence (versus non-adherence or adequate adherence) at week 48 compared to week 12, indicating a significant effect of time. In a follow-up analysis examining week 48 only, logistic regression examining PrEP adherence showed that receiving iTAB (compared to SoC) trended toward higher odds of near-perfect adherence relative to adequate adherence (OR = 2.48, p=.061). Higher HIV knowledge resulted in higher odds (OR = 1.72, p=.020) of near-perfect adherence (versus non-adherence or adequate adherence).Conclusion: HIV knowledge may influence PrEP adherence, and most notably, the iTAB intervention may support near-perfect adherence relative to adequate adherence.

ObjectiveThe combination of d-methylphenidate and guanfacine (an α-2A adrenergic agonist) may be an effective alternative to either agent as monotherapy in children with attention-deficit/hyperactivity disorder (ADHD). This study investigated the neural mechanisms underlying medication effects using cortical source analysis of electroencephalography (EEG) data.MethodA total of 172 children with ADHD (aged 7-14; 118 boys) completed an 8-week randomized, double-blind, comparative study with 3 treatment arms: d-methylphenidate, guanfacine, or their combination. EEG modulations of brain oscillations at baseline and end point were measured during a spatial working memory task from cortical sources localized within the anterior cingulate (midfrontal) and primary visual cortex (midoccipital), based on previously reported ADHD and control differences. Linear mixed models examined treatment effects on EEG and performance measures.ResultsCombined treatment decreased midoccipital EEG power across most frequency bands and task phases. Several midoccipital EEG measures also showed significantly greater changes with combined treatment than with monotherapies. D-methylphenidate significantly increased midoccipital theta during retrieval, while guanfacine produced only trend-level reductions in midoccipital alpha during maintenance and retrieval. Task accuracy improved with combined treatment, was unchanged with d-methylphenidate, and worsened with guanfacine. Treatment-related changes in midoccipital power correlated with improvement in ADHD severity.ConclusionThese findings show that combined treatment ameliorates midoccipital neural activity associated with treatment-related behavioral improvements and previously implicated in visuo-attentional deficits in ADHD. Both monotherapies had limited effects on EEG measures, with guanfacine further showing detrimental effects on performance. The identified midoccipital EEG profile may aid future treatment monitoring for children with ADHD.Clinical trial registration informationSingle Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); https://clinicaltrials.gov/; NCT00429273.Diversity & inclusion statementWe worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. We actively worked to promote sex and gender balance in our author group.

IntroductionInitiation of tobacco products typically occurs in adolescence. Adolescence is a critical period in development where the maturation of brain neurocircuitry is vulnerable to nicotine. Nicotine-containing products and psychostimulants, such as methamphetamine (METH), are often coabused. Rodent studies have shown that nicotine exposure in early adolescence increases subsequent drug intake and reward. Given the exponential increase in e-cigarette use among adolescents, there is a pressing need to understand whether adolescent nicotine exposure impacts concurrent increased METH use. The objective of this study is to evaluate age, sex, and longitudinal effects of nicotine pretreatment on METH reinforcement.Aims and methodsMale and female Sprague-Dawley rats were pretreated with a subchronic, low-dose nicotine (2×, 30 µg/kg/0.1 mL, intravenous) or saline during early adolescence (postnatal days [PN] 28-31) or adulthood (PN 86-89). Following nicotine pretreatment, on PN 32 or PN 90, animals underwent operant intravenous self-administration for METH (20 µg/kg/inf) over a 2-hour period for five consecutive days.ResultsEarly adolescent nicotine exposure enhances intravenous METH self-administration in male, but not female adolescents. Male adult rats self-administer METH over the 5-day testing period, independent of nicotine exposure. In contrast, nicotine exposure increases METH self-administration in female adults during the later sessions of the 5-day testing period.ConclusionsTaken together, our data highlight age- and sex-dependent effects of low dose, subchronic nicotine pretreatment on subsequent intravenous METH self-administration.ImplicationsA majority of polysubstance users begin smoking before the age of 18. Mounting evidence highlights adolescent susceptibility to nicotine exposure on brain and behavior. With the escalation in nicotine-containing products and stimulant use among adolescents, it is important to identify the consequences from adolescent nicotine use, including polysubstance use. Our study provides evidence that adolescent nicotine exposure enhances subsequent METH use, with important sex- and age-dependent effects.

Background: Prescription and illicit drugs are important social environmental variables in many suicides regardless of their role as an immediate cause of death. Objectives: To investigate the presence of prescription and illicit drugs, either through mention in the death record or toxicology reports, among suicides attributed to nonpoisonous causes to identify patterns of risk. Methods: Using the 2003-2017 National Violent Death Reporting System (NVDRS), we examined the presence of prescription and illicit drugs among 143,175 suicides (119,563 males 23,612 females) due to firearms and suffocation/hanging. The presence of drugs (opioids, stimulants, benzodiazepines, muscle relaxants, and cannabis) was determined from toxicology reports and text searches of coroner/medical examiner and law enforcement summaries. We fit multivariable logistic regression models to estimate associations between drug class and suicide method adjusting for decedent characteristics. Results: Overall prescription and illicit drugs were present in 22% of firearm deaths and 28% of suffocation deaths. Among victims with toxicology reports, over 20% tested positive for benzodiazepines. Benzodiazepines were mentioned in 4% of firearm and 5% of suffocation suicides without toxicology testing. Stimulants were more likely to occur in suffocation than firearm deaths among victims with toxicology testing (aOR = 1.44, 95% CI: 1.33-1.56) and without toxicology testing (aOR = 1.61, 95% CI: 1.31-1.98). Conclusions: Benzodiazepines were most frequently identified in both toxicology reports and narratives of suicides by firearms or suffocation. Better distinction of the presence of prescription and illicit drugs in the environment versus apparent ingestion among non-poisoning suicides are needed to inform prevention approaches.

ObjectiveThe aim of this study was to characterize patterns of and factors associated with psychotropic medication use in children with autism spectrum disorder (ASD) receiving publicly funded mental health services.MethodData were extracted from 202 children with ASD participating in a cluster randomized trial of An Individualized Mental Health Intervention for ASD conducted in 29 publicly funded mental health programs. Children with ASD were aged 5 to 13 years (M = 9.1 years, SD = 2.4), and were 84.2% male and 59.9% Latinx. Child ASD and cognitive functioning were determined by standardized assessment. Caregivers reported child psychotropic medication use, behavior problems, ASD symptom severity, mental health symptoms, family demographics, and caregiver strain at the baseline.ResultsNearly half (49.5%) of participants used psychotropic medication(s) within the past 6 months, with stimulants being most commonly reported. Child co-occurring attention-deficit/hyperactivity disorder (ADHD) (B = 1.55, p < 0.01; 95% confidence interval [CI]: 0.53-2.57), lower cognitive functioning (B = -0.03, p = 0.02; 95% CI: -0.05 to

ObjectiveEvaluate whether stimulant medication improves acquisition of academic material in children with attention deficit hyperactivity disorder (ADHD) receiving small-group, content-area instruction in a classroom setting.MethodParticipants were 173 children between the ages of 7 and 12 years old (77% male, 86% Hispanic) who met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for ADHD and were participating in a therapeutic summer camp. The design was a triple-masked, within-subject, AB/BA crossover trial. Children completed two consecutive phases of daily, 25-min instruction in both (a) subject-area content (science, social studies) and (b) vocabulary. Each phase was a standard instructional unit lasting for 3 weeks. Teachers and aides taught the material to small groups in a summer classroom setting. Each child was randomized to be medicated with daily osmotic-release oral system methylphenidate (OROS-MPH) during either the first or second of the instructional phases, receiving placebo during the other.ResultsMedication had large, salutary, statistically significant effects on children's academic seatwork productivity and classroom behavior on every single day of the instructional period. However, there was no detectable effect of medication on learning the material taught during instruction: Children learned the same amount of subject-area and vocabulary content whether they were taking OROS-MPH or placebo during the instructional period.ConclusionsAcute effects of OROS-MPH on daily academic seatwork productivity and classroom behavior did not translate into improved learning of new academic material taught via small-group, evidence-based instruction. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Objective(s)Getting to Zero (GTZ) is an Illinois-based HIV elimination initiative. GTZ identifies younger Black men who have sex with men (YBMSM) as a population who have experienced disproportionate HIV incidence. Rising stimulant use among YBMSM has been determined to impede engagement in the HIV prevention and treatment continua for reducing onward HIV transmission. Given the limited development of dedicated or culturally appropriate interventions for this population, this modeling study explores the impact of stimulant use on HIV incidence among YBMSM and assesses the impact of interventions to treat stimulant use on downstream HIV transmission to achieve GTZ goals.MethodsA previously developed agent-based network model (ABNM), calibrated using data for YBMSM in Illinois, was extended to incorporate the impact of stimulant use (methamphetamines, crack/cocaine, and ecstasy) on sexual networks and engagement in HIV treatment and prevention continua. The model simulated the impact of a residential behavioral intervention (BI) for reducing stimulant use and an outpatient biomedical intervention (mirtazapine) for treating methamphetamine use. The downstream impact of these interventions on population-level HIV incidence was the primary intervention outcome.ResultsBaseline simulated annual HIV incidence in the ABNM was 6.93 [95% Uncertainty Interval (UI): 6.83,7.04] per 100 person years (py) and 453 [95% UI: 445.9,461.2] new infections annually. A residential rehabilitation intervention targeted to 25% of stimulant using persons yielded a 27.1% reduction in the annual number of new infections. Initiating about 50% of methamphetamine using persons on mirtazapine reduced the overall HIV incidence among YBMSM by about 11.2%. A 30% increase in antiretroviral treatment (ART) and preexposure prophylaxis (PrEP) uptake in the non-stimulant using YBMSM population combined with a 25% uptake of BI for stimulant using persons produces an HIV incidence consistent with HIV elimination targets (about 200 infections/year) identified in the GTZ initiative.ConclusionsBehavioral and biomedical interventions to treat stimulant use, in addition to expanding overall ART and PrEP uptake, are likely to enhance progress towards achieving GTZ goals.

Extending from the triple wave epidemic of opioid-related overdose deaths, a fourth wave of high mortality involving methamphetamine and cocaine use has been gathering force. This article provides a review of the published literature on stimulants including epidemiology, pharmacology, neurobiology, medical and psychiatric consequences, withdrawal management, and medical and behavioral treatments.

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.

We analyzed data from a cohort of Black and Latino men who have sex with men (MSM) in order to identify correlates of prevalent and incident incarceration, including potential predictors related to their status as sexual and gender minorities (SGMs). Baseline and follow-up self-administered survey data were examined from Los Angeles County participants' ages 18-45 years at enrollment who were either HIV negative or living with HIV, but recruited to over represent men who used drugs and men with unsuppressed HIV infection. Multivariable logistic regression models were developed to identify predictors of baseline incarceration history and of incident incarceration over study follow-up among 440 and 338 participants, respectively. Older age, Black race, low socioeconomic status, homelessness, stimulant use, and depression symptoms were associated with baseline incarceration history. The only SGM-related factor associated with baseline incarceration history was having experienced violence based on sexual orientation identity. Just one statistically significant, independent positive predictor of incident incarceration was identified: prior incarceration, whereas having four or more friends that could lend money was a statistically significant protective factor against incident incarceration. Fundamental Cause Theory provides a useful framework to explain identified predictors of incarceration. Addressing poverty, housing instability, inadequate access to health care, and their root causes is critical to reducing incarceration rates in this population, as is expanded access to both diversion and anti-recidivism programs and to evidence-based treatment for stimulant use disorders.

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

BackgroundMediated and moderated processes that lead to intervention efficacy may underlie results of trials ruled as nonefficacious. The overall purpose of this study was to examine such processes to explain the findings of one of the largest, rigorously conducted behavioral intervention randomized controlled trials, EXPLORE.MethodsFour thousand two hundred ninety-five HIV-negative men who have sex with men (MSM) in the United States were randomized in a 2-armed trial. Participants completed follow-up and an HIV test every 6 months up to 48 months. We used multiple and causal mediation analyses to test 5 mediators, including safer sex self-efficacy and condomless receptive anal sex with HIV-positive or status-unknown partners on our primary outcome (HIV seroconversion). We also examined whether intervention effects on the mediators would be moderated by robust correlates of HIV among MSM, including stimulant use.ResultsThere were significant effects of the intervention on all hypothesized mediators. Stimulant use moderated the effect on condomless receptive anal sex In stratified multiple mediation models, we found that among MSM with low stimulant use, the intervention significantly prevented HIV by reducing condomless receptive anal sex with HIV-positive or status-unknown partners. Among MSM with higher stimulant use, there were no indirect effects of the intervention on HIV through any of the hypothesized mediators.ConclusionThe results suggest that the null effect found in the original EXPLORE trial might have occurred as a function of previously unexplored mediated and moderated processes. This study illustrates the value of testing mediated and moderated pathways in randomized trials, even in trials ruled out as nonefficacious.

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.

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.

Methamphetamine (MA) is a highly addictive psychomotor stimulant drug. In recent years, MA use has increased exponentially on a global scale, with the number of MA-involved deaths reaching epidemic proportions. There is no approved pharmacotherapy for treating MA use disorder, and we know relatively little regarding the neurobiological determinants of vulnerability to this disease. Extracellular signal-regulated kinase (ERK) is an important signaling molecule implicated in the long-lasting neuroadaptations purported to underlie the development of substance use disorders, but the role for this kinase in the propensity to develop addiction, particularly MA use disorder, is uncharacterized. In a previous MA-induced place-conditioning study of C57BL/6J mice, we characterized mice as MA-preferring, -neutral, or -avoiding and collected tissue from the medial prefrontal cortex (mPFC). Using immunoblotting, we determined that elevated phosphorylated ERK expression within the medial prefrontal cortex (mPFC) is a biochemical correlate of the affective valence of MA in a population of C57BL/6J mice. We confirmed the functional relevance for mPFC ERK activation for MA-induced place-preference via site-directed infusion of the MEK inhibitor U0126. By contrast, ERK inhibition did not have any effect upon MA-induced locomotion or its sensitization upon repeated MA treatment. Through studies of transgenic mice with alanine point mutations on T1123/S1126 of mGlu5 that disrupt ERK-dependent phosphorylation of the receptor, we discovered that ERK-dependent mGlu5 phosphorylation normally suppresses MA-induced conditioned place-preference (MA-CPP), but is necessary for this drug's reinforcing properties. If relevant to humans, the present results implicate individual differences in the capacity of MA-associated cues/contexts to hyper-activate ERK signaling within mPFC in MA Use Disorder vulnerability and pose mGlu5 as one ERK-directed target contributing to the propensity to seek out and take MA.

BackgroundMethylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue.MethodsIn this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed.FindingsBetween Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil).InterpretationAmantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis.FundingPatient-Centered Outcomes Research Institute.

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.

Background and objectivesThe effects of in utero methamphetamine exposure on behavioral problems in school-aged children are unclear. Our objective for this study was to evaluate behavior problems in children at aged 3, 5, and 7.5 years who were prenatally exposed to methamphetamine.MethodsSubjects were enrolled in the Infant Development, Environment, and Lifestyle study, a longitudinal prospective study of prenatal methamphetamine exposure and child outcomes. Exposed and comparison groups were matched on birth weight, race, education, and health insurance.  At ages 3, 5, and 7.5 years, 339 children (171 exposed) were assessed for behavior problems by using the Child Behavior Checklist. Generalized estimating equations were used to determine the effects of prenatal methamphetamine exposure, age, and the interaction of exposure and age on behavior problems. Caregiver psychological symptoms were assessed by using the Brief Symptom Inventory.ResultsAnalyses adjusted for covariates revealed that relative to age 3, children at 5 years had less externalizing and aggressive behavior and more internalizing behavior, somatic complaints, and withdrawn behavior.  By age 7.5, aggressive behavior continued to decrease, attention problems increased and withdrawn behavior decreased. There were no main effects for methamphetamine exposure and no interactions of exposure and age.  Caregiver psychological symptoms predicted all behavior problems and the quality of the home predicted externalizing problems and externalizing syndrome scores.ConclusionsBehavioral effects longitudinally from ages 3 to 7.5 years were not associated with prenatal methamphetamine exposure, whereas caregiver psychological symptoms and the quality of the home were predictors of behavior problems.

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.

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

BackgroundMethamphetamine (METH) use is a public health crisis that disproportionately affects men who have sex with men (MSM). There are currently no FDA-approved pharmacological interventions to treat methamphetamine use disorder (MUD). MUD is associated with social impairments and extremely high treatment attrition rates. Administration of oxytocin, a neuropeptide involved in social attachment, may be a novel approach to addressing these issues. Moreover, oxytocin administration has shown promise for reducing METH-related addictive behavior in animal models, but has not yet been investigated in clinical trials for MUD. Last, oxytocin is known to modulate stress responsivity via regulation of the autonomic nervous system, which is dysregulated in METH users. We hypothesize that oxytocin, in combination with group psychotherapy, will increase treatment engagement, reduce addiction behavior, and mitigate stress hyperreactivity.MethodsThis is a randomized, double blind trial of oxytocin 40-IU (n = 24) or placebo (n = 24) administered intranasally prior to each of six weekly motivational interviewing group therapy (MIGT) sessions for MUD in MSM.Primary outcome(a) session attendance.Secondary outcomes(b) group cohesion, (c) anxiety, (d) METH craving, (e) METH use, and (f) in-session cardiac physiology.ResultsParticipants receiving oxytocin had significantly higher group therapy attendance than those receiving placebo, OR 3.26, 95% CI [1.27-8.41], p = .014. There was a small effect of oxytocin on group cohension, but not anxiety or craving. METH use did not change over the six-week MIGT course in either treatment arm. Participants receiving oxytocin had lower average heart rates during MIGT sessions and higher heart rate variability. There were positive main effects of MIGT over Time regardless of study drug.ConclusionsThis evidence, and the lack of any serious adverse events, suggests that oxytocin may safely increase treatment attendance. One possible mechanism by which it may do so is its modulation of the autonomic nervous system. Further investigation is warranted.

We previously identified a 210 kb region on chromosome 11 (50.37-50.58 Mb, mm10) containing two protein-coding genes (Hnrnph1, Rufy1) that was necessary for reduced methamphetamine-induced locomotor activity in C57BL/6J congenic mice harboring DBA/2J polymorphisms. Gene editing of a small deletion in the first coding exon supported Hnrnph1 as a quantitative trait gene. We have since shown that Hnrnph1 mutants also exhibit reduced methamphetamine-induced reward, reinforcement, and dopamine release. However, the quantitative trait variants (QTVs) that modulate Hnrnph1 function at the molecular level are not known. Nine single nucleotide polymorphisms and seven indels distinguish C57BL/6J from DBA/2J within Hnrnph1, including four variants within the 5' untranslated region (UTR). Here, we show that a 114 kb introgressed region containing Hnrnph1 and Rufy1 was sufficient to cause a decrease in MA-induced locomotor activity. Gene-level transcriptome analysis of striatal tissue from 114 kb congenics vs Hnrnph1 mutants identified a nearly perfect correlation of fold-change in expression for those differentially expressed genes that were common to both mouse lines, indicating functionally similar effects on the transcriptome and behavior. Exon-level analysis (including noncoding exons) revealed decreased 5' UTR usage of Hnrnph1 and immunoblot analysis identified a corresponding decrease in hnRNP H protein in 114 kb congenic mice. Molecular cloning of the Hnrnph1 5' UTR containing all four variants (but none of them individually) upstream of a reporter induced a decrease in reporter signal in both HEK293 and N2a cells, thus, identifying a set of QTVs underlying molecular regulation of Hnrnph1.

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.

Caffeine is the most widely consumed psychoactive substance in the world. However, there is controversy about whether becoming addicted to caffeine is possible and a lack of well-established animal models to examine caffeine consumption. The present study sought to establish a model of caffeine consumption in Wistar rats, identify different rat populations based on caffeine preference, and determine whether extended voluntary caffeine consumption produces compulsive-like caffeine intake and withdrawal symptoms. Male Wistar rats were used throughout the experiment. The optimal concentration of caffeine to maximize caffeine consumption and caffeine preference was determined. Rats were then given continuous access to caffeine, followed by intermittent access. Rats were tested for signs of withdrawal-like behavior by measuring mechanical nociception and irritability-like behavior. Rats were further examined for compulsive-like caffeine consumption using quinine adulteration. Dose-response testing indicated an optimal caffeine concentration of 0.3 mg/mL. During intermittent access to caffeine, the rats did not escalate their caffeine intake and instead exhibited a decrease in intake over sessions. Three groups of rats were identified based on caffeine preference (high, medium, and low) across continuous and intermittent access. These three groups of rats matched low (1 cup), medium (2 cups), and high (4 cups) levels of daily coffee consumption in humans. Caffeine-consuming rats did not exhibit differences in mechanical nociception or irritability-like behavior compared with controls. In high caffeine-preferring rats but not in medium or low caffeine-preferring rats, compulsive-like caffeine consumption was observed. The present study established a rodent model of caffeine consumption that resulted in large individual differences in caffeine intake, similar to humans. Compulsive-like caffeine consumption in high caffeine-preferring rats and differences in caffeine preference between groups suggest that caffeine may result in compulsive-like intake in a subpopulation of subjects. Further testing is necessary to determine the factors that contribute to differences in caffeine preference and compulsive-like intake.

Objectives: Despite the prevalence of methamphetamine-associated psychosis, how characteristics of drug use affect the severity and clinical course, and its optimal treatments have not been established. We addressed these questions, assessing clinical features of methamphetamine-associated psychosis, and compared it with primary psychosis.Methods: Hospitalised patients with methamphetamine-associated (n = 70) or primary schizophrenic psychosis (n = 70) were matched on sex, age and duration of psychosis. Association of drug use variables (age at initiation, duration of methamphetamine use) with the Brief Psychiatric Rating Scale (BPRS) scores and psychosis duration were examined for patients with methamphetamine-associated psychosis, and the groups were compared on the BPRS scores.Results: Methamphetamine use initiation age correlated negatively with the BPRS total score and the Activation subscale score; methamphetamine use duration correlated positively with psychosis duration. Methamphetamine-associated psychosis group scored lower on the Hostility-Suspiciousness and Anergia subscales of the BPRS (adjusted p values < .05).Conclusions: Association of early initiation of methamphetamine with psychosis severity may suggest a lasting effect on brain development. Correlation of drug use and psychosis durations may suggest a cumulative effect of methamphetamine exposure. Less severe paranoia and negative symptoms in the methamphetamine-using group could implicate better social functioning of these patients. Further mechanistic studies are warranted.Key pointsEarly initiation of methamphetamine use is associated with psychosis severity.Methamphetamine use duration associates with psychosis duration.Methamphetamine-associated and primary schizophrenic psychoses were similar in symptoms.Methamphetamine psychosis patients were less severe in paranoia and negative symptoms.

The abuse of stimulants, such as methamphetamine (METH), is associated with treatment non-compliance, a greater risk of viral transmission, and the more rapid clinical progression of immunological and central nervous system human immunodeficiency virus (HIV) disease. The behavioral effects of METH in the setting of HIV remain largely uncharacterized. We used a state-of-the-art paradigm of the escalation of voluntary intravenous drug self-administration in HIV transgenic (Tg) and wildtype rats. The rats were first allowed to self-administer METH under short-access (ShA) conditions, which is characterized by a nondependent and more "recreational" pattern of METH use, and then allowed to self-administer METH under long-access (LgA) conditions, which leads to compulsive (dependent) METH intake. HIV Tg and wildtype rats self-administered equal amounts of METH under ShA conditions. HIV Tg rats self-administered METH under LgA conditions following a 4-week enforced abstinence period to model the intermittent pattern of stimulant abuse in humans. These HIV Tg rats developed greater motivation to self-administer METH and self-administered larger amounts of METH. Impairments in function of the medial prefrontal cortex (mPFC) contribute to compulsive drug and alcohol intake. Gene expression profiling of the mPFC in HIV Tg rats with a history of escalated METH self-administration under LgA conditions showed transcriptional evidence of increased inflammation, greater neural injury, and impaired aerobic glucose metabolism than wildtype rats that self-administered METH under LgA conditions. The detrimental effects of the interaction between neuroHIV and escalated METH intake on the mPFC are likely key factors in the greater vulnerability to excessive drug intake in the setting of HIV.

Objective: To describe trends in prevalent and incident stimulant prescribing between 2008 and 2017 in California. Method: Statewide trends were estimated by age and sex category for prevalent (any) and incident (no prescriptions in the preceding 2 years) stimulant prescribing while adjusting for area-level covariates. Results: Prevalent prescribing rates increased by 126%, while incident prescribing increased 23%. Patients aged 25 to 44 years experienced over 200% increases in prevalent prescribing and 34% to 55% increases in incident prescribing. Among patients older than 25, women had consistently higher prescribing rates than men. ZIP code tabulation areas with the largest minority populations had the lowest baseline prescribing rates but experienced the greatest annual prescription rate increases. Conclusion: Adult stimulant prescribing increased substantially for early working aged adults. Prescription rates were greater for women than men.

BackgroundPreclinical studies suggest that the non-selective phosphodiesterase inhibitor, Ibudilast (IBUD) may contribute to the treatment of methamphetamine (METH) use disorder through the attenuation of METH-induced inflammatory markers such as adhesion molecules, sICAM-1 and sVCAM-1, and cytokines, IL-6 and TNF-α.ObjectiveThe present study aimed to test whether treatment with IBUD can attenuate peripheral markers of inflammation during a METH challenge in an inpatient clinical trial of 11 patients.MethodsThis trial followed a randomized, within-subjects crossover design where participants received a METH challenge, during which five participants were treated with placebo then with IBUD, while the remaining six participants were treated with IBUD prior to placebo. Mixed effects regression modeled changes in peripheral markers of inflammation-sICAM-1, sVCAM-1, TNF-α, IL-6, MIF, and cathepsin D-by treatment condition, with measurements at baseline, 60 min post-METH infusion, and 360 min post-METH infusion.ResultsWhile on placebo, sICAM-1, sVCAM-1, and cathepsin D significantly increased by 60 min post-METH infusion, while IL-6 significantly increased 360 min post-METH infusion. Treatment with IBUD significantly reduced METH-induced levels of sICAM-1, sVCAM-1, and cathepsin D at 60 min post-METH infusion.ConclusionsOur findings demonstrate that IBUD attenuated acute pro-inflammatory effects of METH administration, which may have implications for treatment of METH use disorder.

The greatest proportion of new HIV infections among men who have sex with men (MSM) is occurring among young Black MSM (YBMSM) ages 13-24. Consequently, research is needed to understand the psychosocial pathways that influence HIV risk and resilience in YBMSM. Minority Stress Theory proposes that the stigma, prejudice, and discrimination facing sexual and racial minorities are chronic stressors that lead to increased engagement in risk behaviors. The present study examined whether minority stress is associated with stimulant use and sexual risk behaviors by depleting psychosocial resilience. We recruited 1817 YBMSM, ages 18-29, from multiple venues in two major cities in Texas for participation in a brief survey. Results from structural equation modeling indicated that decreased resilience partially mediated the association of minority stress with sexual risk behavior. Resilience was also negatively associated with stimulant use. Interventions focused on cultivating psychosocial resilience could mitigate the deleterious consequences of minority stress and reduce stimulant use in YBMSM.

We did a global review to synthesise data on the prevalence, harms, and interventions for stimulant use, focusing specifically on the use of cocaine and amphetamines. Modelling estimated the effect of cocaine and amphetamine use on mortality, suicidality, and blood borne virus incidence. The estimated global prevalence of cocaine use was 0·4% and amphetamine use was 0·7%, with dependence affecting 16% of people who used cocaine and 11% of those who used amphetamine. Stimulant use was associated with elevated mortality, increased incidence of HIV and hepatitis C infection, poor mental health (suicidality, psychosis, depression, and violence), and increased risk of cardiovascular events. No effective pharmacotherapies are available that reduce stimulant use, and the available psychosocial interventions (except for contingency management) had a weak overall effect. Generic approaches can address mental health and blood borne virus infection risk if better tailored to mitigate the harms associated with stimulant use. Substantial and sustained investment is needed to develop more effective interventions to reduce stimulant use.

PrEP's potential benefit for men who have sex with men (MSM) who use stimulants may be limited by adherence or prescriber willingness to recommend PrEP due to concerns of non-compliance. Using data from PATH-PrEP, a 48-week study evaluating PrEP for MSM in Los Angeles, we modeled an interaction between stimulant use and condomless sex with multiple partners (CAS-MP) on prevention-effective dried blood spot tenofovir-diphosphate concentrations. At week 4, participants reporting stimulant use and CAS-MP had a decreased odds of prevention-effective adherence compared to non-stimulant use and non-CAS-MP (AOR 0.15, 95% CI 0.04-0.57). From week 4-48, participants reporting stimulant use and CAS-MP had increased odds of prevention-effective adherence (AOR 1.06 per week, 95%CI 1.01-1.12). Participants reporting CAS-MP without stimulant use had no significant change in prevention-effective adherence (AOR 0.99 per week, 95%CI 0.96-1.02). Stimulant use moderated the association of CAS-MP on prevention-effective PrEP adherence over time.

ObjectivesMethamphetamine (MA) dependence contributes to neurotoxicity and neurocognitive deficits. Although combined alcohol and MA misuse is common, how alcohol consumption relates to neurocognitive performance among MA users remains unclear. We hypothesized that alcohol and MA use would synergistically diminish neurocognitive functioning, such that greater reported alcohol consumption would exert larger negative effects on neurocognition among MA-dependent individuals compared to MA-nonusing persons.MethodsEighty-seven MA-dependent (MA+) and 114 MA-nonusing (MA-) adults underwent neuropsychological and substance use assessments. Linear and logistic regressions examined the interaction between MA status and lifetime average drinks per drinking day on demographically corrected global neurocognitive T scores and impairment rates, controlling for recent alcohol use, lifetime cannabis use, WRAT reading performance, and lifetime depression.ResultsMA+ displayed moderately higher rates of impairment and lower T scores compared to MA-. Lifetime alcohol use significantly interacted with MA status to predict global impairment (ORR = 0.70, p = .003) such that greater lifetime alcohol use increased likelihood of impairment in MA-, but decreased likelihood of impairment in MA+. Greater lifetime alcohol use predicted poorer global T scores among MA- (b = -0.44, p = .030) but not MA+ (b = 0.08, p = .586).ConclusionsContrary to expectations, greater lifetime alcohol use related to reduced risk of neurocognitive impairment among MA users. Findings are supported by prior research identifying neurobiological mechanisms by which alcohol may attenuate stimulant-driven vasoconstriction and brain thermotoxicity. Replication and examination of neurophysiologic mechanisms underlying alcohol use in the context of MA dependence are warranted to elucidate whether alcohol confers a degree of neuroprotection.

ObjectiveTo compare the clinical characteristics and outcomes of primary intracerebral hemorrhage (ICH) with and without methamphetamine exposure.MethodsWe performed a retrospective analysis of patients diagnosed with spontaneous, nontraumatic ICH over a 3-year period between January 2013 and December 2016. Demographics, clinical measures, and outcomes were compared between ICH patients with positive methamphetamine toxicology tests vs those with negative methamphetamine toxicology tests.ResultsMethamphetamine-positive ICH patients were younger than methamphetamine-negative ICH patients (52 vs 67 years, p < 0.001). Patients with methamphetamine-positive ICH had higher diastolic blood pressure (115 vs 101, p = 0.003), higher mean arterial pressure (144 vs 129, p = 0.01), longer lengths of hospital (18 vs 8 days, p < 0.001) and intensive care unit (ICU) stay (10 vs 5 days, p < 0.001), required more days of IV antihypertensive medications (5 vs 3 days, p = 0.02), and had more subcortical hemorrhages (63% vs 46%, p = 0.05). The methamphetamine-positive group had better premorbid modified Rankin Scale (mRS) scores (p < 0.001) and a greater change in functional ability as measured by mRS at the time of hospital discharge (p = 0.001). In multivariate analyses, methamphetamine use predicted both hospital length of stay (risk ratio [RR] 1.54, confidence interval [CI] 1.39-1.70, p < 0.001) and ICU length of stay (RR 1.36, CI 1.18-1.56, p < 0.001), but did not predict poor outcome (mRS 4-6).ConclusionsMethamphetamine use is associated with earlier age at onset of ICH, longer hospital stays, and greater change in functional ability, but did not predict outcome.

Reward-related behavior is complex and its dysfunction correlated with neuropsychiatric illness. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been associated with different aspects of reward function, but it remains to be disentangled how distinct VTA DA neurons contribute to the full range of behaviors ascribed to the VTA. Here, a recently identified subtype of VTA neurons molecularly defined by NeuroD6 (NEX1M) was addressed. Among all VTA DA neurons, less than 15% were identified as positive for NeuroD6. In addition to dopaminergic markers, sparse NeuroD6 neurons expressed the vesicular glutamate transporter 2 (Vglut2) gene. To achieve manipulation of NeuroD6 VTA neurons, NeuroD6(NEX)-Cre-driven mouse genetics and optogenetics were implemented. First, expression of vesicular monoamine transporter 2 (VMAT2) was ablated to disrupt dopaminergic function in NeuroD6 VTA neurons. Comparing Vmat2lox/lox;NEX-Cre conditional knock-out (cKO) mice with littermate controls, it was evident that baseline locomotion, preference for sugar and ethanol, and place preference upon amphetamine-induced and cocaine-induced conditioning were similar between genotypes. However, locomotion upon repeated psychostimulant administration was significantly elevated above control levels in cKO mice. Second, optogenetic activation of NEX-Cre VTA neurons was shown to induce DA release and glutamatergic postsynaptic currents within the nucleus accumbens. Third, optogenetic stimulation of NEX-Cre VTA neurons in vivo induced significant place preference behavior, while stimulation of VTA neurons defined by Calretinin failed to cause a similar response. The results show that NeuroD6 VTA neurons exert distinct regulation over specific aspects of reward-related behavior, findings that contribute to the current understanding of VTA neurocircuitry.

Methamphetamine use is highly prevalent among gay, bisexual, and other men who have sex with men (MSM) in the United States and has been associated with condomless anal intercourse (CAI), a common route of HIV infection. Text messaging is a very low-cost method of delivery for intervention content. This paper presents a cost-effectiveness analysis of a randomized controlled trial testing three nested methods of text message delivery designed to reduce methamphetamine use and HIV sexual risk behaviors among MSM (Project Tech Support2). From March 2014 to January 2016, 286 non-treatment seeking methamphetamine-using MSM were randomized into one of three study arms: 1) Interactive text message conversations with Peer Health Educators, plus five daily automated, unidirectional theory-based messages, plus a weekly self-monitoring text message assessment (TXT-PHE; n = 94); or, 2) Five daily automated, unidirectional theory-based messages plus a weekly self-monitoring text message assessment (TXT-Auto; n = 99); or, 3) The weekly self-monitoring text message assessment only (AO; n = 93). Methamphetamine use at nine months post-enrollment was lower than at baseline in all three arms. The addition of Peer Health Educators and/or theory-based text messages did not produce cost-effective reductions in methamphetamine use over the weekly AO text messages. However, both intervention arms outperformed the AO arm in reducing HIV risk behaviors, but the TXT-Auto arm dominated the TXT-PHE arm in achieving greater reductions in days of methamphetamine use and CAI at lower cost. The TXT-Auto arm achieved greater reductions in CAI than the attentional control at a cost in the base case of ~$37.50 per episode of CAI reduced per month. Sensitivity analyses showed that results were robust to a number of changes in assumptions. Interventions seeking to reduce methamphetamine use among non-treatment-seeking MSM may seek to add minimal attentional control-style text messages to their routines querying about recent methamphetamine use and/or high-risk sex. Interventions seeking to additionally reduce HIV sexual risk behaviors among non-treatment-seeking MSM, specifically engagement in CAI, may seek to additionally apply theory-based text messages.

BackgroundElectronic nicotine delivery systems (ENDS, e-cigarettes) are increasingly used for the self-administration of nicotine by various human populations, including previously nonsmoking adolescents. Studies in preclinical models are necessary to evaluate health impacts of ENDS including the development of nicotine addiction, effects of ENDS vehicles, flavorants and co-administered psychoactive substances such as Δ9-tetrahydrocannabinol (THC). This study was conducted to validate a rat model useful for the study of nicotine effects delivered by inhalation of vapor created by ENDS.MethodsMale Sprague-Dawley rats (N = 8) were prepared with radio telemetry devices for the reporting of temperature and activity. Experiments subjected rats to inhalation of vapor generated by an electronic nicotine delivery system (ENDS) adapted for rodents. Inhalation conditions included vapor generated by the propylene glycol (PG) vehicle, Nicotine (1, 10, 30 mg/mL in the PG) and THC (12.5, 25 mg/mL).ResultsNicotine inhalation increased spontaneous locomotion and decreased body temperature of rats. Pretreatment with the nicotinic cholinergic receptor antagonist mecamylamine (2 mg/kg, i.p.) prevented stimulant effects of nicotine vapor inhalation and attenuated the hypothermic response. Combined inhalation of nicotine and THC resulted in apparently independent effects which were either additive (hypothermia) or opposed (activity).ConclusionsThese studies provide evidence that ENDS delivery of nicotine via inhalation results in nicotine-typical effects on spontaneous locomotion and thermoregulation in male rats. Effects were blocked by a nicotinic antagonist, demonstrating mechanistic specificity. This system will therefore support additional studies of the contribution of atomizer/wick design, vehicle constituents and/or flavorants to the effects of nicotine administered by ENDS.

BackgroundThe prevalence of methamphetamine use disorder (MUD) in the United States has risen dramatically in the past four decades and is concentrated in populations such as men who have sex with men (MSM). Despite the public health consequences of MUD, there are no FDA-approved psychopharmacological treatments. Psychosocial treatment alone has been shown to reduce methamphetamine use, but high attrition rates limit treatment efficacy. Promising findings from animal models of MUD using exogenous oxytocin, a social neuropeptide, have set the stage for translational work. Along with unique anti-addiction effects, oxytocin holds a primary role in enhancing social salience and modulating stress. In humans, oxytocin administration, combined with evidence-based psychosocial interventions, may act synergistically to improve addiction treatment outcomes and improve retention rates in current MUD treatment.Methods/designWe are conducting a randomized, double-blind, placebo-controlled trial of oxytocin-enhanced motivational interviewing group therapy (MIGT). Oxytocin or placebo 40 IU is administered intranasally in conjunction with six, weekly MIGT sessions. We will recruit 50 MSM, initiating treatment for MUD from specialized community health programs in San Francisco, CA, USA. Individuals will be randomized (1:1) to receive six, weekly sessions of MIGT with or without oxytocin. Our primary outcome is session attendance. Other outcomes of interest include: measures of group cohesion, anxiety, psychophysiology, and stimulant craving and use.DiscussionThis will be the first study of oxytocin's effects in humans with MUD. Findings from this novel protocol will attempt to bridge existing animal data with the need for innovative clinical treatments for MUD, inform the growing field of pharmacologically-enhanced psychotherapy, and help to elucidate mechanisms behind oxytocin's potential anti-addiction effects.Trial registrationClinicalTrials.gov, ID: NCT02881177 . Registered on 26 August 2016.

RATIONALE: Attentional bias toward drug-related stimuli is a feature of drug addiction that is linked to craving and drug-seeking behavior. OBJECTIVES/METHOD: An attentional bias modification (ABM) program was tested in 42 methamphetamine-dependent clients (DSM-IV criteria) receiving residential treatment for their drug use. Participants were randomly assigned to one of two groups (N = 21 each), receiving 12 sessions of either computerized ABM training (designed to train attention away from methamphetamine stimuli 100% of the time) or an attentional control condition (designed to train attention away from methamphetamine stimuli 50% of the time). Outcome measures included attentional bias to methamphetamine-related stimuli on a probe detection task, self-reported craving, and preferences to view methamphetamine-related images on a Simulated Drug Choice Task. A subset of participants (N = 17) also underwent fMRI in a cue-induced craving paradigm. RESULTS: Poor split-half reliability was observed for the probe detection task. Using this task, attentional bias toward methamphetamine-related stimuli was greater after training than at baseline, irrespective of group (p = 0.037). Spontaneous and cue-induced methamphetamine craving diminished with time (ps  0.05). ABM training did not influence selection of methamphetamine-related pictures in the Simulated Drug Choice task (p > 0.05). In the fMRI assessment, cue-induced activation in the ventromedial prefrontal cortex was reduced over time, without an effect of ABM training. CONCLUSIONS: ABM training did not improve several clinically relevant variables in treatment-seeking methamphetamine users. Additional research is needed to improve the measurement of attentional bias.

Methamphetamine use disorder is associated with a high likelihood of relapse. Identifying robust predictors of relapse that have explanatory power is critical to develop secondary prevention based on a mechanistic understanding of relapse. Computational approaches have the potential to identify such predictive markers of psychiatric illness, with the advantage of providing a finer mechanistic explanation of the cognitive processes underlying psychiatric vulnerability. In this study, sixty-two recently sober methamphetamine-dependent individuals were recruited from a 28-day inpatient treatment program, and completed a Stop Signal Task (SST) while undergoing functional magnetic resonance imaging (fMRI). These individuals were prospectively followed for 1 year and assessed for relapse to methamphetamine use. Thirty-three percent of followed participants reported relapse. We found that neural activity associated with two types of Bayesian prediction error, i.e. the difference between actual and expected need to stop on a given trial, significantly differentiated those individuals who remained abstinent and those who relapsed. Specifically, relapsed individuals exhibited smaller neural activations to such Bayesian prediction errors relative to those individuals who remained abstinent in the left temporoparietal junction (Cohens d = 0.91), the left inferior frontal gyrus (Cohens d = 0.57), and left anterior insula (Cohens d = 0.63). In contrast, abstinent and relapsed participants did not differ in neural activation to non-model based task contrasts or on various self-report clinical measures. In conclusion, Bayesian cognitive models may help identify predictive biomarkers of relapse, while providing a computational explanation of belief processing and updating deficits in individuals with methamphetamine use disorder.

BackgroundMethamphetamine induces neuronal N-acetyl-aspartate synthesis in preclinical studies. In a preliminary human proton magnetic resonance spectroscopic imaging investigation, we also observed that N-acetyl-aspartate+N-acetyl-aspartyl-glutamate in right inferior frontal cortex correlated with years of heavy methamphetamine abuse. In the same brain region, glutamate+glutamine is lower in methamphetamine users than in controls and is negatively correlated with depression. N-acetyl and glutamatergic neurochemistries therefore merit further investigation in methamphetamine abuse and the associated mood symptoms.MethodsMagnetic resonance spectroscopic imaging was used to measure N-acetyl-aspartate+N-acetyl-aspartyl-glutamate and glutamate+glutamine in bilateral inferior frontal cortex and insula, a neighboring perisylvian region affected by methamphetamine, of 45 abstinent methamphetamine-dependent and 45 healthy control participants. Regional neurometabolite levels were tested for group differences and associations with duration of heavy methamphetamine use, depressive symptoms, and state anxiety.ResultsIn right inferior frontal cortex, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate correlated with years of heavy methamphetamine use (r = +0.45); glutamate+glutamine was lower in methamphetamine users than in controls (9.3%) and correlated negatively with depressive symptoms (r = -0.44). In left insula, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate was 9.1% higher in methamphetamine users than controls. In right insula, glutamate+glutamine was 12.3% lower in methamphetamine users than controls and correlated negatively with depressive symptoms (r = -0.51) and state anxiety (r = -0.47).ConclusionsThe inferior frontal cortex and insula show methamphetamine-related abnormalities, consistent with prior observations of increased cortical N-acetyl-aspartate in methamphetamine-exposed animal models and associations between cortical glutamate and mood in human methamphetamine users.

BackgroundHIV-positive persons who use stimulants such as methamphetamine experience difficulties navigating the HIV care continuum that undermine the benefits of antiretroviral therapy (ART). However, few studies have examined the association of stimulant use with viral suppression in the era of universal ART.SettingZuckerberg San Francisco General Hospital.MethodsHIV-positive persons participating in a clinical cohort study and taking ART completed assessments every 4-6 months. The exposure was the cumulative, time-varying proportion of assessments with any self-reported stimulant use. The time-varying outcome, HIV viral suppression (ie,

BackgroundA limited number of published case reports suggest a positive effect of dextroamphetamine, an adrenergic agonist affecting both the central nervous system (CNS) and peripheral nervous system, on physical activity and weight in patients with hypothalamic obesity (intractable obesity following CNS insult). Here, we present our clinical experience with dextroamphetamine treatment for hypothalamic obesity.MethodsThe clinical course of all patients started on dextroamphetamine treatment for severe hypothalamic obesity at our institution between 2010 and 2013 is reported. Dextroamphetamine administration was initiated at a single dose of 5 mg per day and titrated to effect up to a dose of 20 mg/day. BMI z-score velocity was calculated as change in BMI z-score over standardized intervals of 12 months. Parameters of treatment success and adverse events were assessed in a standardized fashion.ResultsSeven patients (2 males; mean age 17.6 years [range 12.9-24.5]) underwent individual treatment attempts with dextroamphetamine between 2010 and 2013. The primary diagnoses were craniopharyngioma (n = 4), ganglioglioma WHO I (n = 1), astrocytoma (n = 1), and neonatal meningitis (n = 1). Time from initial CNS insult to initiation of dextroamphetamine treatment averaged 5.2 years (range 2.4 months to 16.5 years). All patients demonstrated a steady increase in BMI z-score from the time of initial diagnosis until initiation of dextroamphetamine treatment. Mean baseline BMI z-score was +3.17 ± 0.93 (+1.9 to +4.4). Mean BMI z-score velocity decelerated to -0.18 ± 0.12 per year during the first year of treatment and stabilized at +0.05 ± 0.32 per year during the second year of treatment. No significant adverse events were reported.ConclusionDextroamphetamine treatment led to stabilization or reduction of BMI z-score in a cohort of 7 patients with hypothalamic obesity, with no adverse effects. Considering the projected increase in BMI z-score according to the natural course of the disease, these findings are promising and warrant further study.

Objective: Stimulant medication and behavior therapy are efficacious for youth with attention-deficit/hyperactivity disorder (ADHD). However, research suggests that stimulants may start and/or worsen sleep problems for youth. Further, the impact of behavior therapy for ADHD on sleep is unknown. This study examined the frequency of sleep problems and effects of stimulant medication, behavior therapy, and their combination on sleep problems in youth with ADHD. This study also explored the influence of dimensional baseline ratings of ADHD symptom subtype and psychiatric comorbidity on sleep outcomes. Methods: Participants were 576 children (aged 7-9 years) with ADHD-Combined type from the Multimodal Treatment of ADHD study that compared methylphenidate, behavior therapy, and their combination to community care. Before treatment, parents completed the Child Behavior Checklist used to derive a total sleep problems score. Parents also completed ratings of oppositionality and ADHD symptom severity, whereas youth completed ratings of depression and anxiety. These ratings were readministered after treatment. Results: General linear mixed-effects models were used to assess change in total sleep problems across treatment. The combined group exhibited a statistically significant reduction in total sleep problems (z = -5.81, p  0.99) did not reach statistical significance. Change in psychiatric symptoms did not significantly moderate change in total sleep problems by treatment assignment. Greater baseline oppositional defiant disorder severity predicted less reduction in total sleep problems, χ2(1) = 3.86, p

BackgroundIn the United States, problematic stimulant use is a prevalent and difficult to treat problem among men who have sex with men (MSM), as well as a major driver of HIV transmission through the large number of sexual partners and concomitant condomless anal sex (CAS). Evidence-based behavioral studies that address problematic stimulant use in MSM at risk for HIV infection are also lacking. In this paper, we describe the design of a behavioral intervention trial to reduce sexual risk behavior and stimulant use in HIV-uninfected MSM.MethodsThis study, funded by the National Institute on Drug Abuse (NIDA), is a randomized controlled trial (RCT) testing an integrated HIV risk reduction and behavioral activation counseling intervention (IMPACT) for HIV-uninfected, stimulant using MSM in Boston, MA, and Miami, FL. Participants are randomized (2:2:1) to either (1) the IMPACT intervention; (2) a relaxation condition, an active therapy time- and intensity-matched control; or (3) a standard of care risk reduction counseling comparison. At enrollment, all participants receive an HIV test and pre- and post-test counseling. The primary outcome is the difference in the rate of change in the number of self-reported condomless anal sex acts without the protection of consistent Pre-Exposure Prophylaxis (PrEP) use, as well as reductions in stimulant use during the prior 4-months. Major assessments are conducted at baseline, 4-, 8-, and 12-month follow-up visits.DiscussionEffective and sustainable behavioral interventions are sorely needed to reduce HIV acquisition in stimulant using MSM at risk for HIV infection. In this study, we will evaluate the evidence of efficacy of the IMPACT intervention to reduce HIV acquisition in HIV-uninfected, stimulant-using MSM. If found effective, the intervention tested here holds promise for being readily integrated into real-world clinical settings.Trial registrationClinicalTrials.gov number NCT03175159 , registered June 5, 2017.

BackgroundContingency management (CM) is an evidence-based intervention providing rewards in exchange for biomarkers that confirm abstinence from stimulants such as methamphetamine. We tested the efficacy of a positive affect intervention designed to boost the effectiveness of CM with HIV-positive, methamphetamine-using sexual minority men.MethodsThis attention-matched, randomized controlled trial of a positive affect intervention delivered during CM was registered on www.clinicaltrials.gov (NCT01926184). In total, 110 HIV-positive sexual minority men with biologically confirmed, recent methamphetamine use were enrolled. Five individual sessions of a positive affect intervention (n = 55) or an attention-control condition (n = 55) were delivered during three months of CM. Secondary outcomes examined over the 3-month intervention period included: 1) psychological processes relevant to affect regulation (i.e., positive affect, negative affect, and mindfulness); 2) methamphetamine craving; 3) self-reported stimulant use (past 3 months); and 4) cumulative number of urine samples that were non-reactive for stimulants (i.e., methamphetamine and cocaine) during CM.ResultsThose randomized to the positive affect intervention reported significant increases in positive affect during individual sessions and increases in mindfulness over the 3-month intervention period. Intervention-related improvements in these psychological processes relevant to affect regulation were paralleled by concurrent decreases in methamphetamine craving and self-reported stimulant use over the 3-month intervention period.ConclusionsDelivering a positive affect intervention may improve affect regulation as well as reduce methamphetamine craving and stimulant use during CM with HIV-positive, methamphetamine-using sexual minority men.

BackgroundOccasional recreational stimulant (amphetamine and cocaine) use is an important public health problem among young adults because 16% of those who experiment develop stimulant use disorder. This study aimed to determine whether behavioral and/or neural processing measures can forecast the transition from occasional to problematic stimulant use.MethodsOccasional stimulant users completed a Risky Gains Task during functional magnetic resonance imaging and were followed up 3 years later. Categorical analyses tested whether blood oxygen level-dependent (BOLD) responses differentiated occasional stimulant users who became problem stimulant users (n = 35) from those who desisted from stimulant use (n = 75) at follow-up. Dimensional analyses (regardless of problem stimulant user or desisted stimulant use status; n = 144) tested whether BOLD responses predicted baseline and follow-up stimulant and marijuana use.ResultsCategorical results indicated that relative to those who desisted from stimulant use, problem stimulant users 1) made riskier decisions after winning feedback; 2) exhibited lower frontal, insular, and striatal BOLD responses to win/loss feedback after making risky decisions; and 3) displayed lower thalamic but greater temporo-occipital BOLD responses to risky losses than to risky wins. In comparison, dimensional results indicated that lower BOLD signals to risky choices than to safe choices in frontal, striatal, and additional regions predicted greater marijuana use at follow-up.ConclusionsTaken together, blunted frontostriatal signals during risky choices may quantify vulnerability to future marijuana consumption, whereas blunted frontostriatal signals to risky outcomes mark risk for future stimulant use disorder. These behavioral and neural processing measures may prove to be useful for identifying ultra-high risk individuals prior to onset of problem drug use.

Individuals with cognitive problems may be predisposed to develop substance use disorders; therefore, differences in cognitive function between methamphetamine users and control participants may be attributable to premorbid factors rather than methamphetamine use. The goal of this study was to clarify the extent to which this is the case. Childhood academic transcripts were obtained for 37 methamphetamine-dependent adults and 41 control participants of similar educational level and premorbid IQ. Each participant completed a comprehensive cognitive battery and received a structural magnetic resonance imaging scan. Data from control participants and linear regression were used to develop a normative model to describe the relationship between childhood academic performance and scores on the cognitive battery. Using this model, cognitive performance of methamphetamine users was predicted from their premorbid academic scores. Results indicated that methamphetamine users' childhood grade point average was significantly lower than that of the control group (p