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BackgroundCocaine is an illegal recreational drug used worldwide, yet little is known about whether cocaine inhalation (smoking/snorting) increases the risk of head and neck cancer (HNC).MethodsThe analyses were conducted by pooling data from three case-control studies with 1639 cases and 2506 controls from the International Head and Neck Cancer Epidemiology Consortium. Epidemiologic data, including cocaine use histories, were obtained in face-to-face interviews. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using hierarchical logistic regression models.ResultsControlling for cumulative tobacco and alcohol use, we observed a weak positive association between cocaine use and HNC (ORever vs. never  = 1.35, 95% CI: 0.96, 1.90). In stratified analysis, while we did not detect associations among never tobacco or alcohol users due to the limited sample size, the association with cocaine use was observed among tobacco users and alcohol drinkers. ORs for ever and high cumulative use (>18 times) versus never use were 1.40 (95% CI: 0.98, 2.00) and 1.66 (95% CI: 1.03, 2.69) among tobacco users, and 1.34 (95% CI: 0.93, 1.92) and 1.59 (95% CI: 1.00, 2.51) among alcohol drinkers, respectively.ConclusionIn this pooled analysis, we observed a weak positive association between cocaine inhalation and HNC risk. Our findings provide preliminary evidence of the potential carcinogenic effect of cocaine on HNC. Because of study limitations, including limited number of cocaine users, confounding, and heterogeneity across studies, future investigations will require larger studies with more detailed information on cocaine use history.

Organisms must regulate their behavior flexibly in the face of environmental challenges. Failure can lead to a host of maladaptive behavioral traits associated with a range of neuropsychiatric disorders, including attention deficit hyperactivity disorder, autism, and substance use disorders. This maladaptive dysregulation of behavior is influenced by genetic and environmental factors. For example, environmental enrichment produces beneficial neurobehavioral effects in animal models of such disorders. The present study determined the effects of environmental enrichment on a range of measures related to behavioral regulation using a large cohort of male, outbred heterogeneous stock (HS) rats as subjects. Subjects were reared from late adolescence onwards either in pairs in standard housing with minimal enrichment (n = 200) or in groups of 16 in a highly enriched environment consisting of a large multi-level cage filled with toys, running wheels, and shelters (n = 64). Rats were subjected to a battery of tests, including: (i) locomotor response to novelty, (ii) light reinforcement, (iii) social reinforcement, (iv) reaction time, (v) a patch-depletion foraging test, (vi) Pavlovian conditioned approach, (vii) conditioned reinforcement, and (viii) cocaine conditioned cue preference. Results indicated that rats housed in the enriched environment were able to filter out irrelevant stimuli more effectively and thereby regulate their behavior more efficiently than standard-housing rats. The dramatic impact of environmental enrichment suggests that behavioral studies using standard housing conditions may not generalize to more complex environments that may be more ethologically relevant.

Substance use disorder is a growing public health challenge in the United States. People who use drugs may be more vulnerable to ambient heat due to the effects of drugs on thermoregulation and their risk environment. There have been limited population-based studies of ambient temperature and drug-related morbidity. We examined short-term associations between daily ambient temperature and emergency department (ED) visits for use or overdose of amphetamine, cocaine and opioids in California during the period 2005 to 2019. Daily ZIP code-level maximum, mean, and minimum temperature exposures were derived from 1-km data Daymet products. A time-stratified case-crossover design was used to estimate cumulative non-linear associations of daily temperature for lag days 0 to 3. Stratified analyses by patient sex, race, and ethnicity were also conducted. The study included over 3.4 million drug-related ED visits. We found positive associations between daily temperature and ED visits for all outcomes examined. An increase in daily mean temperature from the 50th to the 95th percentile was associated with ED visits for amphetamine use (OR = 1.072, 95% CI: 1.058, 1.086), cocaine use (OR = 1.044, 95% CI: 1.021, 1.068 and opioid use (OR = 1.041, 95% CI: 1.025, 1.057). Stronger positive associations were also observed for overdose: amphetamine overdose (OR = 1.150, 95% CI: 1.085, 1.218), cocaine overdose (OR = 1.159, 95% CI: 1.053, 1.276), and opioid overdose (OR = 1.079, 95% CI: 1.054, 1.106). In summary, people who use stimulants and opioids may be a subpopulation sensitive to short-term higher ambient temperature. Mitigating heat exposure can be considered in harm reduction strategies in response to the substance use epidemic and global climate change.

The amygdala processes positive and negative valence and contributes to addiction, but the cell-type-specific gene regulatory programs involved are unknown. We generated an atlas of single-nucleus gene expression and chromatin accessibility in the amygdala of outbred rats with high and low cocaine addiction-like behaviors following prolonged abstinence. Differentially expressed genes between the high and low groups were enriched for energy metabolism across cell types. Rats with high addiction index (AI) showed increased relapse-like behaviors and GABAergic transmission in the amygdala. Both phenotypes were reversed by pharmacological inhibition of the glyoxalase 1 enzyme, which metabolizes methylglyoxal-a GABAA receptor agonist produced by glycolysis. Differences in chromatin accessibility between high and low AI rats implicated pioneer transcription factors in the basic helix-loop-helix, FOX, SOX and activator protein 1 families. We observed opposite regulation of chromatin accessibility across many cell types. Most notably, excitatory neurons had greater accessibility in high AI rats and inhibitory neurons had greater accessibility in low AI rats.

BackgroundWhile substance use is known to influence cardiovascular health, most prior studies only consider one substance at a time. We examined associations between the concurrent use of multiple substances and left ventricular mass index (LVMI) in unhoused and unstably housed women.MethodsBetween 2016 and 2019, we conducted a cohort study of unstably housed women in which measurements included an interview, serum/urine collection, vital sign assessment, and a single transthoracic echocardiogram at baseline. We evaluated independent associations between 39 separate substances confirmed through toxicology and echocardiography-confirmed LVMI.ResultsThe study included 194 participants with a median age of 53.5 years and a high proportion of women of color (72.6%). Toxicology-confirmed substance use included: 69.1% nicotine, 56.2% cocaine, 28.9% methamphetamines, 28.9% alcohol, 23.2% opioid analgesics, and 9.8% opioids with catecholaminergic effects. In adjusted analysis, cocaine was independently associated with higher LVMI (Adjusted linear effect: 18%; 95% CI 9.9, 26.6). Associations with other substances did not reach levels of significance and did not significantly interact with cocaine.ConclusionIn a population of vulnerable women where the use of multiple substances is common, cocaine stands out as having particularly detrimental influences on cardiac structure. Blood pressure did not attenuate the association appreciably, suggesting direct effects of cocaine on LVMI. Routinely evaluating stimulant use as a chronic risk factor during risk assessment and preventive clinical care planning may reduce end organ damage, particularly in highly vulnerable women.

Stimulant use among unstably housed individuals is associated with increased risks of psychiatric co-morbidity, violence, HIV transmission, and overdose. Due to a lack of highly effective treatments, evidence-based policies targeting the prevention of stimulant use disorder are of critical importance. However, little empirical evidence exists on risks associated with initiating or returning to stimulant use among at-risk populations. In a longitudinal cohort of unstably housed women in San Francisco (2016-2019), self-reported data on stimulant use, housing status, and mental health were collected monthly for up to 6 months, and factors associated with initiating stimulants after a period of non-use were identified through logistic regression. Among 245 participants, 42 (17.1%) started using cocaine and 46 (18.8%) started using methamphetamine. In analyses adjusting for demographics and socio-structural exposures over the preceding month, experiencing street homelessness was associated with initiating cocaine use (AOR: 2.10; 95% CI: 1.04, 4.25) and sheltered homelessness with initiating methamphetamine use (AOR: 2.57; 95% CI: 1.37, 4.79). Other factors-including race, income, unmet subsistence needs, mental health, and treatment adherence-did not reach levels of significance, suggesting the paramount importance of policies directed toward improving access to permanent supportive housing to prevent stimulant use among unstably housed women.

BackgroundCancer patients often face multiple comorbidities and are at risk for various mental health conditions and substance use disorders. Tobacco/nicotine dependence (TND) is a known risk factor for poor health outcomes and has been associated with psychiatric disorders including substance use disorder. However, the specific relationship between TND and the risk of substance use disorder and mental health conditions among cancer patients remains underexplored. This study aimed to assess the association between TND and the risk of comorbid conditions among cancer patients.MethodsData were obtained from a database of electronic health records for patients from the University of California health system. The odds for every condition among cancer patients with TND were calculated and compared with those for cancer patients without TND. ORs were adjusted for gender, ethnicity, and race.ResultsThree thousand seven hundred and ninety-one cancer patients with TND had 252,619 total conditions, and 51,711 cancer patients without TND had 2,310,880 conditions. After adjusting for confounders, the condition for which TND most exacerbated risk was psychoactive substance-induced organic anxiety disorder (OR = 16.3, p

BACKGROUND: Historically, overdose mortality rates among Hispanics have been lower than non-Hispanics. The purpose of this analysis was to characterize the U.S. overdose crisis among Hispanics compared to non-Hispanics. METHODS: We used the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiological Research (WONDER) platform to obtain drug overdose mortality rates per 100,000 population between 2010 and 2021 for Hispanics and non-Hispanics. We examined the relative percent change and specific drug involvement (2010-2021) and state-level disparities (2010-2020) among Hispanics versus non-Hispanics. We calculated rate ratios by state and annual percent change in total and for each specific drug. Statistical analyses were performed using R software version 4.0.3 (R Project for Statistical Computing). RESULTS: Nationally, from 2010 to 2021, Hispanic overdose rates rose from 5.6 to 21.7 per 100,000, an increase of 287.5 % compared to 13.5-35.1 per 100,000, an increase of 160 % among non-Hispanics. The average annual percent change was 12 % for Hispanics and 9 % for non-Hispanics. The three most common drug classes involved in overdose deaths among both groups included: Fentanyls and synthetic opioids; cocaine; and prescription opioids. Hispanic overdose rates were higher than non-Hispanic rates in New Mexico, Colorado, Massachusetts, and Pennsylvania in 2020, versus only Michigan in 2010. CONCLUSIONS: We observed disparities in overdose mortality growth among Hispanics compared to non-Hispanics from 2010 to 2021. These disparities highlight the urgency to develop community-centered solutions that take into consideration the social and structural inequalities that exacerbate the effects of the opioid overdose crisis on Hispanic communities.

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.

BACKGROUND: Self-report measures are important in substance use assessment, yet they are susceptible to reporting errors. Urine drug screens (UDS) are often considered a more valid alternative. However, collecting in-person UDS may not always be feasible, contributing to the need to understand factors that influence the validity of self-reported substance use. METHODS: In this secondary analysis of data from 295 women with co-occurring PTSD and substance use disorders (SUD) who participated in a clinical trial testing behavioral interventions, we examined concordance and discordance between self-reported drug use and associated UDS results. Generalized linear mixed models were used to examine the impact of treatment type and participant characteristics on the associations between self-reported drug use and UDS results. RESULTS: Findings revealed higher disagreement between self-report and UDS for opioids and sedatives (ranging from.77 to.90) and lower disagreement rates for cannabis and cocaine (ranging from.26 to.33). Treatment type was not a significant moderator of the associations between self-report and UDS across all drugs. Among those with a positive opioid UDS, those who reported employment in the past three years were more likely to self-report no opioid use compared to their counterparts without employment in the past three years. CONCLUSIONS: Findings add to the literature that supports the validity of self-reported cannabis and cocaine use. The greater discrepancies between self-report and UDS test results of opioids and sedatives suggest adjunctive UDS may be required, although a variety of factors other than inaccurate self-report may be associated with this discrepancy.

BackgroundDespite the high prevalence of polysubstance use, outcomes and potential risks associated with common drug combinations are not well characterized. Many individuals who use cocaine also use cannabis, yet little is known about how interactions between the two drugs might contribute to continued co-use.MethodsThe aim of this double-blind, placebo-controlled study was to determine the physiological and subjective effects of smoked cannabis with smoked cocaine, to identify variables that may contribute to the continued use of this drug combination. Healthy, non-treatment seeking volunteers who reported smoking both cocaine and cannabis (N = 9, all males) completed a 13-day inpatient protocol. On session days, cannabis [0.0 or 5.6 % tetrahydrocannabinol (THC)] was administered 28 min prior to cocaine (0, 12, or 25 mg). Dependent measures included pharmacokinetic assessment of THC and cocaine and their respective metabolites, in addition to subjective and cardiovascular effects.ResultsActive cannabis (5.6 % THC) increased plasma levels of THC and the metabolite 11-nor-9-carboxy-Δ9-THC (THCCOOH), as well as subjective ratings of cannabis effects and heart rate relative to inactive cannabis. Cocaine dose-dependently increased plasma cocaine and metabolites and subjective ratings of cocaine effects. Active cannabis pre-treatment decreased plasma levels of cocaine and metabolites. Furthermore, active cannabis attenuated cocaine-related reductions in 'Hunger' and 'Calm.'ConclusionsCannabis pre-treatment altered the subjective experience of smoked cocaine and reduced peak plasma levels of cocaine. Future studies should explore additional doses of each drug and whether these changes also impact cocaine's reinforcing effects.

BackgroundChronic pain affects one-fifth of US adults. Reductions in opioid prescribing have been associated with increased non-prescription opioid use and, chronologically, increased stimulant (methamphetamine and cocaine) use. While non-prescription opioid use is commonly attributed to pain self-management, the role of stimulants in managing pain is unclear.MethodsWe analyzed baseline data from a longitudinal study of patients with chronic non-cancer pain in an urban safety-net healthcare system who had been prescribed an opioid for ≥3 of the last 12 months, and had a history of non-prescription opioid, cocaine, or amphetamine use (N = 300). We estimated the prevalence and identified correlates of stimulant use to treat pain among a subgroup of patients who reported past-year stimulant use (N = 105). Data sources included computer-assisted questionnaire (demographics, substance use, pain), clinical exam and procedures (pain, pain tolerance), and chart abstraction (opioid prescriptions). We conducted bivariate analyses to assess associations between demographics, pain characteristics, non-opioid therapies, substance use, opioid prescriptions, and self-reported symptoms, with reporting using stimulants to treat pain. Demographic variables and those with significant bivariate associations were included in a multivariable logistic regression model.ResultsFifty-two percent of participants with past-year stimulant use reported using stimulants in the past year to treat pain. Participants who used stimulants for pain reported slightly higher average pain in the past 3 months (median of 8 (IQR: 6-8) vs 7 (7-9) out of 10, p = 0.049). In the multivariable analysis, female gender (AOR= 3.20, 95% CI: 1.06-9.63, p = 0.039) and higher score on the Douleur Neuropathique 4 neuropathic pain questionnaire (AOR = 1.34, 95% CI: 1.05-1.70, p = 0.017) were associated with past-year stimulant use to treat pain.ConclusionStimulants may be used for pain self-management, particularly for neuropathic pain and among women. Our findings suggest an underexplored motivation for stimulant use in an era of reduced access to prescribed opioids.

BackgroundDrug-related emergency department (ED) visits are escalating, especially for stimulant use (i.e., cocaine and psychostimulants such as methamphetamine). We sought to characterize rates, presentation, and management of ED visits related to cocaine and psychostimulant use, compared to opioid use, in the United States (US).MethodsWe used 2008-2018 National Hospital Ambulatory Medical Care Survey data to identify a nationally representative sample of ED visits related to cocaine and psychostimulant use, with opioids as the comparator. To make visits mutually exclusive for analysis, we excluded visits related to 2 or more of the three possible drug categories. We estimated annual rate trends using unadjusted Poisson regression; described demographics, presenting concerns, and management; and determined associations between drug-type and presenting concerns (categorized as psychiatric, neurologic, cardiopulmonary, and drug toxicity/withdrawal) using logistic regression, adjusting for age, sex, race/ethnicity, and homelessness.ResultsCocaine-related ED visits did not significantly increase, while psychostimulant-related ED visits increased from 2008 to 2018 (2.2 visits per 10,000 population to 12.9 visits per 10,000 population; p

OBJECTIVE: To examine associations between frailty and drug, alcohol, and tobacco use among a large diverse cohort of people with HIV (PWH) in clinical care in the current era. METHODS: PWH at 7 sites across the United States completed clinical assessments of patient-reported measures and outcomes between 2016 and 2019 as part of routine care including drug and alcohol use, smoking, and other domains. Frailty was assessed using 4 of the 5 components of the Fried frailty phenotype and PWH were categorized as not frail, pre-frail, or frail. Associations of substance use with frailty were assessed with multivariate Poisson regression. RESULTS: Among 9336 PWH, 43% were not frail, 44% were prefrail, and 13% were frail. Frailty was more prevalent among women, older PWH, and those reporting current use of drugs or cigarettes. Current methamphetamine use (1.26: 95% CI 1.07-1.48), current (1.65: 95% CI 1.39-1.97) and former (1.21:95% CI 1.06-1.36) illicit opioid use, and former cocaine/crack use (1.17: 95% CI 1.01-1.35) were associated with greater risk of being frail in adjusted analyses. Current smoking was associated with a 61% higher risk of being frail vs. not frail (1.61: 95% CI 1.41-1.85) in adjusted analyses. CONCLUSIONS: We found a high prevalence of prefrailty and frailty among a nationally distributed cohort of PWH in care. This study identified distinct risk factors that may be associated with frailty among PWH, many of which, such as cigarette smoking and drug use, are potentially modifiable.

The Reln gene encodes for the extracellular glycoprotein Reelin, which regulates several brain functions from development to adulthood, including neuronal migration, dendritic growth and branching and synapse formation and plasticity. Human studies have implicated Reelin signaling in several neurodevelopmental and psychiatric disorders. Mouse studies using the heterozygous Reeler (HR) mice have shown that reduced levels of Reln expression are associated with deficits in learning and memory and increased disinhibition. Although these traits are relevant to substance use disorders, the role of Reelin in cellular and behavioral responses to addictive drugs remains largely unknown. Here, we compared HR mice to wild-type (WT) littermate controls to investigate whether Reelin signaling contributes to the hyperlocomotor and rewarding effects of cocaine. After a single or repeated cocaine injections, HR mice showed enhanced cocaine-induced locomotor activity compared with WT controls. This effect persisted after withdrawal. In contrast, Reelin deficiency did not induce cocaine sensitization, and did not affect the rewarding effects of cocaine measured in the conditioned place preference assay. The elevated cocaine-induced hyperlocomotion in HR mice was associated with increased protein Fos expression in the dorsal medial striatum (DMS) compared with WT. Lastly, we performed an RNA fluorescent in situ hybridization experiment and found that Reln was highly co-expressed with the Drd1 gene, which encodes for the dopamine receptor D1, in the DMS. These findings show that Reelin signaling contributes to the locomotor effects of cocaine and improve our understanding of the neurobiological mechanisms underlying the cellular and behavioral effects of cocaine.

BACKGROUND: Methamphetamine misuse affects 27 million people worldwide and is associated with cardiovascular disease (CVD); however, risk factors for CVD among users have not been well studied. METHODS AND RESULTS: We studied hospitalized patients in California, captured by the Healthcare Cost and Utilization Project database, between 2005 and 2011. We studied the association between methamphetamine use and CVD (pul-monary hypertension, heart failure, stroke, and myocardial infarction). Among 20 249 026 persons in the Healthcare Cost and Utilization Project, 66 199 used methamphetamines (median follow-up 4.58 years). Those who used were more likely younger (33 years versus 45 years), male (63.3% versus 44.4%), smoked, misused alcohol, and had depression and anxiety compared with nonusers. Methamphetamine use was associated with the development of heart failure (hazard ratio [HR], 1.53 [95% CI, 1.45–1.62]) and pulmonary hypertension (HR, 1.42 [95% CI, 1.26–1.60]). Among users, male sex (HR, 1.73 [95% CI, 1.37– 2.18]) was associated with myocardial infarction. Chronic kidney disease (HR, 2.38 [95% CI, 1.74– 3.25]) and hypertension (HR, 2.26 [95% CI, 2.03– 2.51]) were strong risk factors for CVD among users. When compared with nonuse, methamphetamine use was associated with a 32% significant increase in CVD, alcohol abuse with a 28% increase, and cocaine use with a 47% increase in CVD. CONCLUSIONS: Methamphetamine use has a similar magnitude of risk of CVD compared with alcohol and cocaine. Prevention and treatment could be focused on those with chronic kidney disease, hypertension, and mental health disorders.

Cocaine is an established cardiovascular toxin, but the impact of cocaine use on clinical outcomes in heart failure (HF) remains unknown. Although nonselective β-blocker use in cocaine users with HF and reduced ejection fraction (HFrEF) appears to be safely tolerated, selective β-blockers have not been evaluated. This study aimed to assess whether cocaine use is associated with worse clinical outcomes in patients with HF and evaluate the safety of β-blocker prescription upon discharge in cocaine users with HFrEF. This was a single-center retrospective cohort study of patients with incident HF hospitalization at a safety-net hospital. Primary outcomes included all-cause mortality and readmissions, including HF. Cocaine users were compared with nonusers matched by age, gender, and year of index admission. In cocaine users with HFrEF, outcomes were compared according to β-blocker prescription at discharge. From 2001 to 2019, 738 cocaine users were identified and compared with 738 matched nonusers. Cocaine use was associated with increased mortality (adjusted hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.00 to 1.48) and 90-day readmission (all-cause: adjusted HR 1.49; 95% CI 1.20 to 1.85; HF: adjusted HR 1.49; 95% CI 1.10 to 2.01), persisting at 1 year. In cocaine users who were prescribed metoprolol, carvedilol, or no β-blocker at discharge, the rates of 1-year mortality and 30-day readmission were similar. In conclusion, cocaine use is associated with increased all-cause mortality, HF readmission, and all-cause readmission. Both nonselective and selective β-blocker may be safe in managing patients with HFrEF and cocaine use.

Substance use disorders (SUDs) represent a significant public health crisis. Worldwide, 5.4% of the global disease burden is attributed to SUDs and alcohol use, and many more use psychoactive substances recreationally. Often associated with comorbidities, SUDs result in changes to both brain function and physiological responses. Mounting evidence calls for a precision approach for the treatment and diagnosis of SUDs, and the gut microbiome is emerging as a contributor to such disorders. Over the last few centuries, modern lifestyles, diets, and medical care have altered the health of the microbes that live in and on our bodies; as we develop, our diets and lifestyle dictate which microbes flourish and which microbes vanish. An increase in antibiotic treatments, with many antibiotic interventions occurring early in life during the microbiome's normal development, transforms developing microbial communities. Links have been made between the microbiome and SUDs, and the microbiome and conditions that are often comorbid with SUDs such as anxiety, depression, pain, and stress. A better understanding of the mechanisms influencing behavioral changes and drug use is critical in developing novel treatments for SUDSs. Targeting the microbiome as a therapeutic and diagnostic tool is a promising avenue of exploration. This review will provide an overview of the role of the gut-brain axis in a wide range of SUDs, discuss host and microbe pathways that mediate changes in the brain's response to drugs, and the microbes and related metabolites that impact behavior and health within the gut-brain axis.

Although midbrain dopamine (DA) circuits are central to motivated behaviors, our knowledge of how experience modifies these circuits to facilitate subsequent behavioral adaptations is limited. Here we demonstrate the selective role of a ventral tegmental area DA projection to the amygdala (VTADA→amygdala) for cocaine-induced anxiety but not cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach reveals a persistent elevation in spontaneous and task-related activity of inhibitory GABAergic cells from the bed nucleus of the stria terminalis (BNST) and downstream VTADA→amygdala cells that can be detected even after a single cocaine exposure. Activity in BNSTGABA→midbrain cells is related to cocaine-induced anxiety but not reward or sensitization, and silencing this projection prevents development of anxiety during protracted withdrawal after cocaine administration. Finally, we observe that VTADA→amygdala cells are strongly activated after a challenge exposure to cocaine and that activity in these cells is necessary and sufficient for reinstatement of cocaine place preference.

BackgroundSubstance use disorders (SUD) elevate the risk for COVID-19 hospitalization, but studies are inconsistent on the relationship of SUD to COVID-19 mortality.MethodsVeterans Health Administration (VHA) patients treated in 2019 and evaluated in 2020 for COVID-19 (n=5,556,315), of whom 62,303 (1.1%) tested positive for COVID-19 (COVID-19+). Outcomes were COVID-19+ by 11/01/20, hospitalization, ICU admission, or death within 60 days of a positive test. Main predictors were any ICD-10-CM SUDs, with substance-specific SUDs (cannabis, cocaine, opioid, stimulant, sedative) explored individually. Logistic regression produced unadjusted and covariate-adjusted odds ratios (OR; aOR).ResultsAmong COVID-19+ patients, 19.25% were hospitalized, 7.71% admitted to ICU, and 5.84% died. In unadjusted models, any SUD and all substance-specific SUDs except cannabis use disorder were associated with COVID-19+(ORs=1.06-1.85); adjusted models produced similar results. Any SUD and all substance-specific SUDs were associated with hospitalization (aORs: 1.24-1.91). Any SUD, cocaine and opioid disorder were associated with ICU admission in unadjusted but not adjusted models. Any SUD, cannabis, cocaine, and stimulant disorders were inversely associated with mortality in unadjusted models (OR=0.27-0.46). After adjustment, associations with mortality were no longer significant. In ad hoc analyses, adjusted odds of mortality were lower among the 49.9% of COVID-19+ patients with SUD who had SUD treatment in 2019, but not among those without such treatment.ConclusionsIn VHA patients, SUDs are associated with COVID-19 hospitalization but not COVID-19 mortality. SUD treatment may provide closer monitoring of care, ensuring that these patients received needed medical attention, enabling them to ultimately survive serious illness.

A widely held dogma in the preclinical addiction field is that females are more vulnerable than males to drug craving and relapse. Here, we first review clinical studies on sex differences in psychostimulant and opioid craving and relapse. Next, we review preclinical studies on sex differences in psychostimulant and opioid reinstatement of drug seeking after extinction of drug self-administration, and incubation of drug craving (time-dependent increase in drug seeking during abstinence). We also discuss ovarian hormones role in relapse and craving in humans and animal models and speculate on brain mechanisms underlying their role in cocaine craving and relapse in rodent models. Finally, we discuss imaging studies on brain responses to cocaine cues and stress in men and women.The results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. However, this conclusion is tentative because most of the studies reviewed were correlational, not sufficiently powered, and not a priori designed to detect sex differences. Additionally, imaging studies suggest sex differences in brain responses to cocaine cues and stress. The results of the preclinical studies reviewed provide evidence for sex differences in stress-induced reinstatement and incubation of cocaine craving but not cue- or cocaine-induced reinstatement of cocaine seeking. These sex differences are modulated in part by ovarian hormones. In contrast, the available data do not support the notion of sex differences in craving and relapse/reinstatement for methamphetamine or opioids in rodent models. SIGNIFICANCE STATEMENT: This systematic review summarizes clinical and preclinical studies on sex differences in psychostimulant and opioid craving and relapse. Results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. Results of preclinical studies reviewed provide evidence for sex differences in reinstatement and incubation of cocaine seeking but not for reinstatement or incubation of methamphetamine or opioid seeking.

BackgroundExtracellular vesicles (EVs) are regulators of cell-cell interactions and mediators of horizontal transfer of bioactive molecules between cells. EV-mediated cell-cell interactions play roles in physiological and pathophysiological processes, which maybe modulated by exposure to pathogens and cocaine use. However, the effect of pathogens and cocaine use on EV composition and function are not fully understood.ResultsHere, we used systems biology and multi-omics analysis to show that HIV infection (HIV +) and cocaine (COC) use (COC +) promote the release of semen-derived EVs (SEV) with dysregulated extracellular proteome (exProtein), miRNAome (exmiR), and exmiR networks. Integrating SEV proteome and miRNAome revealed a significant decrease in the enrichment of disease-associated, brain-enriched, and HIV-associated miR-128-3p (miR-128) in HIV + COC + SEV with a concomitant increase in miR-128 targets-PEAK1 and RND3/RhoE. Using two-dimensional-substrate single cell haptotaxis, we observed that in the presence of HIV + COC + SEV, contact guidance provided by the extracellular matrix (ECM, collagen type 1) network facilitated far-ranging haptotactic cues that guided monocytes over longer distances. Functionalizing SEV with a miR-128 mimic revealed that the strategic changes in monocyte haptotaxis are in large part the result of SEV-associated miR-128.ConclusionsWe propose that compositionally and functionally distinct HIV + COC + and HIV-COC- SEVs and their exmiR networks may provide cells relevant but divergent haptotactic guidance in the absence of chemotactic cues, under both physiological and pathophysiological conditions.

BackgroundNicotine and illicit stimulants are very addictive substances. Although associations between grey matter and dependence on stimulants have been frequently reported, white matter correlates have received less attention.MethodsEleven international sites ascribed to the ENIGMA-Addiction consortium contributed data from individuals with dependence on cocaine (n = 147), methamphetamine (n = 132) and nicotine (n = 189), as well as non-dependent controls (n = 333). We compared the fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) of 20 bilateral tracts. Also, we compared the performance of various machine learning algorithms in deriving brain-based classifications on stimulant dependence.ResultsThe cocaine and methamphetamine groups had lower regional FA and higher RD in several association, commissural, and projection white matter tracts. The methamphetamine dependent group additionally showed lower regional AD. The nicotine group had lower FA and higher RD limited to the anterior limb of the internal capsule. The best performing machine learning algorithm was the support vector machine (SVM). The SVM successfully classified individuals with dependence on cocaine (AUC = 0.70, p

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.

Both Human Immunodeficiency Virus (HIV) and cocaine use have been associated with impairment in neuropsychological functioning. The high comorbidity between HIV and cocaine use highlights the importance of ascertaining whether there is a compounding effect of cocaine use in individuals with HIV. Among neuropsychological domains impacted by HIV, verbal memory deficits have received substantial attention partly because they have been associated with declines in functional status in HIV positive individuals. We collected California Verbal Learning Test-II data from HIV participants who met lifetime diagnostic criteria of cocaine abuse and/or dependence (HIV/CocDx+, N = 80 & HIV/CocDx-, N = 30, respectively) and those with and without recent cocaine use, which was confirmed by toxicology analysis (HIV/Coc+, N = 56 & HIV/Coc-, N = 57, respectively). The Item Specific Deficit Approach (ISDA) was employed to determine any additional cocaine-associated deficits in encoding, consolidation, and retrieval, which attempts to control for potential confounding factors of memory such as attention. Using conventional methods of evaluating memory profiles, we found that the HIV/Coc + group demonstrated worse learning, immediate and delayed free recall, and recognition in contrast to the HIV/Coc - group; although using the ISDA, we found that encoding was the only significant difference between HIV/Coc + and HIV/Coc-participant, with HIV/Coc - performing better. Our data suggest that for individuals with HIV, cocaine use is associated with a temporary decline in verbal memory, is characterized by greater encoding deficits, and these effects may reduce with abstinence. Clinically, our findings suggest that reduced encoding is the likely contributor to verbal memory decline in HIV/Coc + and these effects are partially reversible-at least to the level of their HIV/Coc - counterparts.

BackgroundUS rates of overdose deaths involving stimulants (e.g., cocaine or methamphetamine) have increased, but little is known about non-fatal stimulant overdoses, particularly among vulnerable populations. We characterized rates of non-fatal stimulant overdose identified outside of health care settings among women at high risk.MethodsHomeless and unstably housed women in San Francisco, California using stimulants were administered questionnaires on drug use and outcomes (stimulant overdose, health care utilization) monthly for six months. Based on pilot interviews, stimulant overdose during follow-up was defined as acute toxicity from stimulant use ("over-amping") resulting in "feeling sick, really scared, or like one's life may be in danger". Poisson regression estimated unadjusted incidence rate ratio (IRR) comparing participant characteristics.ResultsWe included 160 women (41% Black, 26% White, 15% Latina, median age 54 years) using crack cocaine (81%), methamphetamine (48%), and powdered cocaine (36%). Participants reported 67 non-fatal stimulant overdoses over 685 person-months of observation, a rate of 117.4 per 100 person-years (95% CI 85.8-160.5). Rates were higher among participants who were Latina vs. White (IRR 4.18 [1.60-10.94]), used methamphetamine (IRR 1.80 [0.96-3.38]), or used any stimulant daily/almost daily (IRR 2.63 [1.41-4.91]). Among women reporting stimulant overdose, 4% received emergency and 3% inpatient care for overdose of any drug.ConclusionsWomen in this setting, particularly those who used stimulants frequently or used methamphetamine, experienced high non-fatal stimulant overdose and rarely received health care for these events. Efforts should be made to increase awareness and reduce harms of stimulant toxicity in vulnerable populations.

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

Purpose of reviewThis review provides an update on recently published literature on the rise of illicit fentanyls, risks for overdose, combinations with other substances, e.g. stimulants, consequences, and treatment.Recent findingsOverdose due to illicit synthetic opioids (e.g. fentanyl and fentanyl analogs) continues to rise in the US both preceding and during the COVID-19 pandemic. Fentanyl-related overdose is rising in new geographic areas e.g. the western USA. Stimulant-related overdose is also increasing nationwide driven by methamphetamine and cocaine. Polysubstance use, e.g. the use of a stimulant along with an opioid is driving stimulant-related overdose. Other medical consequences of injection drug use are rising including HIV and hepatitis C infections. Medication approaches to treating opioid use disorder remain the standard of care and there are new promising pharmacological approaches to treating methamphetamine use disorder.SummaryA 'fourth wave' of high mortality involving methamphetamine and cocaine use has been gathering force in the USA. Availability and use of illicit fentanyls are still the major drivers of overdose deaths and the current rise in stimulant-related deaths appears entwined with the ongoing opioid epidemic.

ObjectivesCocaine use has been linked to stroke in several studies. However, few studies have considered the influence of cocaine use on stroke mechanisms such as small vessel disease (SVD). We conducted a study to assess associations between the toxicology-confirmed use of multiple drugs, including cocaine, and a marker of SVD, white matter hyperintensities (WMH).Materials and methodsWe conducted a nested case-control study (n = 30) within a larger cohort study (N = 245) of homeless and unstably housed women recruited from San Francisco community venues. Participants completed six monthly study visits consisting of an interview, blood draw, vital sign assessment and baseline brain MRI. We examined associations between toxicology-confirmed use of multiple substances, including cocaine, methamphetamine, heroin, alcohol and tobacco, and WMH identified on MRI.ResultsMean study participant age was 53 years, 70% of participants were ethnic minority women and 86% had a history of cocaine use. Brain MRIs indicated the presence of WMH (i.e., Fazekas score>0) in 54% (18/30) of imaged participants. The odds of WMH were significantly higher in women who were toxicology-positive for cocaine (Odd Ratio=7.58, p=0.01), but not in women who were toxicology-positive for other drugs or had several other cerebrovascular risk factors.ConclusionsOver half of homeless and unstably housed women showed evidence of WMH. Cocaine use is highly prevalent and a significant correlate of WMH in this population, while several traditional CVD risk factors are not. Including cocaine use in cerebrovascular risk calculators may improve stroke risk prediction in high-risk populations and warrants further investigation.

While thirty years of research into an effective cocaine pharmacotherapy has yielded no treatments, knowledge gained doing this work underscores the importance of rigorous clinical design, of attention to medication adherence and of defining endpoints. The field needs a high-risk/high-reward strategy to engineer new compounds that help people to use less cocaine and to preserve gains made during treatment, particularly during lapse/relapse.

The COVID-19 pandemic generated large amounts of stress across the globe. While acute stress negatively impacts health, defining exact consequences and behavioral interventions can be difficult. We hypothesized that a generalized increase in stress and anxiety caused by continuation of the global pandemic would negatively impact sleep quality and that ever users of e-cigarettes and conventional tobacco would have more profound alterations over time. Participants were recruited via social media to complete an online survey in April 2020 (n = 554). Inhalant use was assessed through the UCSD Inhalant Questionnaire and sleep quality was gauged through the Pittsburgh Sleep Quality Index (PSQI). A set of participants (n = 217) retook the survey in June 2020. Inhalant users-historical or current e-cigarette vapers, conventional tobacco smokers, and dual users-had higher PSQI scores than never smoker/never vapers, demonstrating worse sleep quality in inhalant users. Non-smoking/non-vaping subjects who retook the survey in June 2020 had improvement in their PSQI scores by paired t test, indicating better sleep quality as the pandemic continued, while inhalant users of all types had persistently high PSQI scores (poor sleep quality). These data suggest that ever users of tobacco products may be susceptible to overall diminished sleep quality in the setting of stressful life circumstances. These data also suggest that pandemic-initiated lifestyle changes may have led to improvements in sleep quality. Finally, these findings raise concerns for correlations between either past or active e-cigarette use on sleep, and thus overall health.

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.

Pituitary adenylyl cyclase activating polypeptide (PACAP) was originally isolated from the hypothalamus and found to stimulate adenylyl cyclase in the pituitary. Later studies showed that this peptide and its receptors (PAC1, VPAC1, and VPAC2) are widely expressed in the central nervous system (CNS). Consistent with its distribution in the CNS, the PACAP/PAC1 receptor system is involved in several physiological responses, such as mediation of the stress response, modulation of nociception, regulation of prolactin release, food intake, etc. This system is also implicated in different pathological states, e.g., affective component of nociceptive processing, anxiety, depression, schizophrenia, and post-traumatic stress disorders. A review of the literature on PubMed revealed that PACAP and its receptors also play a significant role in the actions of addictive drugs. The goal of this review is to discuss the literature regarding the involvements of PACAP and its receptors in the motivational effects of addictive drugs. We particularly focus on the role of this peptide in the motivational effects of morphine, alcohol, nicotine, amphetamine, methamphetamine, and cocaine. This article is part of the special issue on Neuropeptides.

BACKGROUND: Single room occupancy (SRO) buildings, also known as residential hotels, are a form of affordable housing common to cities in North America, and residents of these buildings face elevated rates of substance use, physical and mental multimorbidity, and mortality. Identifying distinct populations at greater risk of overdose death is crucial to the planning of interventions aiming to reduce drug-related mortality, yet no studies have assessed the population burden of overdose mortality among SRO residents. The present study quantifies and characterizes drug overdose mortality among residents of SRO buildings in a large U.S. city. METHODS: We used mortality records and a database of SRO buildings to calculate rate ratios comparing overdose mortality due to opioids, cocaine, and methamphetamine among SRO residents and non-SRO residents in San Francisco, CA 2010-2017 and assessed bivariate differences in decedent and death location characteristics between SRO resident and other overdose decedents. RESULTS: There were 1,551 overdose deaths during the study period, with an overall rate of 21.3 per 100,000 residents (95%CI = 20.2-22.6). The rate among SRO residents (278.7, 95%CI = 252.9-306.5) was 19.3 (95%CI = 17.1-21.7) times that of non-SRO residents (21.3, 95%CI = 20.2-22.6). An additional 79 (5%) deaths among non-residents occurred in SRO buildings, and 86% of SRO resident decedents died at home compared to 64% of non-SRO residents (p

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.

BackgroundPeople living with HIV (PLWH) often experience decreases in HIV viral suppression (VS) after release from jail. The Linking Inmates to Care in LA (LINK LA) peer navigation intervention helped maintain VS 12 months after release from jail compared to standard of care. In this study, we analyzed correlates of substance use and tested whether substance use was an independent correlate of decreased VS in LINK LA participants.MethodsWe analyzed LINK LA data collected at baseline, 3, and 12 months. We defined high-risk drug use as any reported methamphetamine, cocaine, or opioid use in the 30 days prior to a study visit (or jail entry at baseline). We used generalized linear mixed models to test associations of sociodemographic variables with type of substance used, and we tested correlates of VS while controlling for time, the intervention, and their interaction.ResultsAt baseline (n = 356), 71% of participants reported high-risk drug use: 58%, methamphetamine; 17%, cocaine; 7%, heroin; and 4%, prescription opioids. Non-Hispanic Whites and those younger than 35 were most likely to use methamphetamine; Blacks were most likely to use cocaine; people who inject drugs were most likely to use opioids. Participants who used high-risk drugs had 53% lower adjusted odds than non-users of maintaining VS (AOR 0.47, 95% CI 0.31-0.70, p

BackgroundConcomitant use of cocaine and HIV pre-exposure prophylaxis (PrEP) raises important clinical questions around adherence, retention in care, and renal toxicity.MethodsWe assessed the associations of confirmed cocaine use with PrEP adherence (both ascertained through objective measures), care engagement, and renal function in the iPrEx open-label extension. Cocaine use was measured in scalp hair samples and categorized as light (500-3000 pg/mg) and moderate to heavy (>3000 pg/mg). PrEP adherence in the first 3 months was measured through plasma tenofovir concentrations. Disengagement from PrEP care was defined as a gap in follow-up greater than 4 months. Serum creatinine was assessed at baseline and quarterly visits.ResultsOf the 400 participants included in this analysis, 90% were men who have sex with men, 10% transgender women, 74% Hispanic/Latino; 21% tested positive for cocaine use in the last 3 months. In adjusted analysis, light cocaine use [adjusted odds ratio 2.10 (95% confidence interval: 1.07 to 4.14)] and moderate to heavy use [adjusted odds ratio 2.32 (1.08 to 5.00)] were associated with greater odds of having plasma tenofovir concentrations below the level of quantitation. Participants with moderate to heavy use had a nearly 3-fold higher rate of disengagement from PrEP care compared with nonusers (adjusted hazard ratio 2.90 [1.48 to 5.66]). We found no statistically or clinically significant differences in creatinine clearance and serum creatinine between participants who tested positive for cocaine and those who did not.ConclusionsCocaine use decreases PrEP adherence and care engagement. Comprehensive approaches are needed to reduce cocaine use and enhance engagement along the PrEP care continuum.

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,

Addiction is a chronic relapsing disorder, in that most addicted individuals who choose to quit taking drugs fail to maintain abstinence in the long-term. Relapse is especially likely when recovering addicts encounter risk factors like small "priming" doses of drug, stress, or drug-associated cues and locations. In rodents, these same factors reinstate cocaine seeking after a period of abstinence, and extensive preclinical work has used priming, stress, or cue reinstatement models to uncover brain circuits underlying cocaine reinstatement. Here, we review common rat models of cocaine relapse, and discuss how specific features of each model influence the neural circuits recruited during reinstated drug seeking. To illustrate this point, we highlight the surprisingly specific roles played by ventral pallidum subcircuits in cocaine seeking reinstated by either cocaine-associated cues, or cocaine itself. One goal of such studies is to identify, and eventually to reverse the specific circuit activity that underlies the inability of some humans to control their drug use. Based on preclinical findings, we posit that circuit activity in humans also differs based on the triggers that precipitate craving and relapse, and that associated neural responses could help predict the triggers most likely to elicit relapse in a given person. If so, examining circuit activity could facilitate diagnosis of subgroups of addicted people, allowing individualized treatment based on the most problematic risk factors.

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.

Cannabis use is typically initiated during adolescence and is a significant risk factor for the development of cocaine use in adulthood. However, no preclinical studies have examined the effects of adolescent cannabinoid exposure on cocaine dependence in adulthood using the escalation model of cocaine self-administration and the assessment of negative emotional states. In the present study, we found that exposure to the cannabinoid receptor agonist WIN55,212-2 (WIN) in adolescence produced irritability-like behavior and psychomotor cross-sensitization to cocaine in adolescence. In adulthood, rats were allowed to self-administer cocaine. The acquisition of cocaine self-administration was lower in rats with adolescent WIN exposure compared with controls. However, both WIN-exposed and control rats escalated their cocaine intake at the same rate, had similar responding under a progressive-ratio schedule of reinforcement, and had similar psychomotor responses to cocaine. Interestingly, the increase in irritability-like behavior that was previously observed in adolescence after WIN exposure persisted into adulthood. Whether the persisting increase in irritability-like behavior after WIN exposure has translational relevance remains to be studied. In summary, these results suggest that psychoactive cannabinoid exposure during adolescence is unlikely to have a major effect on the escalation of cocaine intake or the development of compulsive-like responding per se in adulthood in a rat model of cocaine self-administration. However, whether the persisting irritability-like behavior may predispose an individual to mood-related impairments in adulthood or predict such impairments warrants further investigation.

Several studies have reported on wide-spread contamination of U.S. paper currency with cocaine and to a lesser extent other illicit drugs. Canines are trained and employed to search for and alert to drugs. Canine alert to currency has been used as evidence that currency has been directly involved in illicit drug trafficking to justify currency seizure and forfeiture. This assertion, particularly when the only evidence is based upon canine alert, has been challenged in the courts considering that most currency in circulation is contaminated with cocaine. Comprehensive review of the scientific literature establishes that (i) 67-100% of circulated U.S. currency is contaminated with cocaine ranging from a few nanograms to over one milligram/bill (ii) various biological and environmental parameters impact canine alert to drugs. It is concluded that canine alert to U.S. currency is not sufficiently reliable to determine that currency was directly used in an illicit drug transaction.

Stimulant use may accelerate HIV disease progression through biological and behavioral pathways. However, scant research with treated HIV-positive persons has examined stimulant-associated alterations in pathophysiologic processes relevant to HIV pathogenesis. In a sample of 55 HIV-positive, methamphetamine-using sexual minority men with a viral load less than 200 copies/mL, we conducted RNA sequencing to examine patterns of leukocyte gene expression in participants who had a urine sample that was reactive for stimulants (n = 27) as compared to those who tested non-reactive (n = 28). Results indicated differential expression of 32 genes and perturbation of 168 pathways in recent stimulant users. We observed statistically significant differential expression of single genes previously associated with HIV latency, cell cycle regulation, and immune activation in recent stimulant users (false discovery rate p

ObjectiveMicrobial translocation and monocyte activation predict mortality in treated HIV. We examined whether substance use independently contributes to these pathophysiologic processes.DesignCross-sectional study at baseline for a randomized controlled trial.MethodsHIV-positive, methamphetamine-using MSM with undetectable HIV viral load (less than 40 copies/ml) were enrolled. We examined if plasma biomarkers of monocyte activation and intestinal barrier integrity were associated with the following: reactive urine toxicology results (Tox+) for stimulants (i.e., methamphetamine or cocaine) and substance use severity measured by the Addiction Severity Index. Multiple linear regression models adjusted for age, antiretroviral therapy regimen, CD4 T-cell count, interleukin-6, and alcohol use severity.ResultsThe sample of 84 virally suppressed MSM had a median CD4 T-cell count of 645 cells/μl. Those who were Tox+ for stimulants displayed higher soluble CD14 (sCD14) levels (2087 versus 1801 ng/ml; P = 0.009), and this difference remained significant after adjusting for covariates (standardized beta = 0.23, P = 0.026). Greater substance use severity was also independently associated with higher sCD14 after adjusting for covariates (standardized beta = 0.29, P = 0.013). Being Tox+ for stimulants and substance use severity were not associated with soluble CD163 (sCD163) or intestinal fatty acid binding protein (iFABP) levels (P > 0.05).ConclusionsMonocyte activation is one plausible mechanism by which stimulant use may increase clinical HIV progression.

A diagnostic criterion for drug addiction, persistent drug-craving continues to be the most treatment-resistant aspect of addiction that maintains the chronic, relapsing, nature of this disease. Despite the high prevalence of psychomotor stimulant addiction, there currently exists no FDA-approved medication for craving reduction. In good part, this reflects our lack of understanding of the neurobiological underpinnings of drug-craving. In humans, cue-elicited drug-craving is associated with the hyperexcitability of prefrontal cortical regions. Rodent models of cocaine addiction indicate that a history of excessive cocaine-taking impacts excitatory glutamate signaling within the prefrontal cortex to drive drug-seeking behavior during protracted withdrawal. This review summarizes evidence that the capacity of cocaine-associated cues to augment craving in highly drug-experienced rats relates to a withdrawal-dependent incubation of glutamate release within prelimbic cortex. We discuss how stimulation of mGlu1/5 receptors increases the activational state of both canonical and noncanonical intracellular signaling pathways and present a theoretical molecular model in which the activation of several kinase effectors, including protein kinase C, extracellular signal-regulated kinase and phosphoinositide 3-kinase (PI3K) might lead to receptor desensitization to account for persistent cocaine-craving during protracted withdrawal. Finally, this review discusses the potential for existing, FDA-approved, pharmacotherapeutic agents that target kinase function as a novel approach to craving intervention in cocaine addiction.

Although most people who inject drugs (PWID) report receiving assistance during injection initiation events, little research has focused on risk factors among PWID for providing injection initiation assistance. We therefore sought to determine the influence of non-injection drug use among PWID on their risk to initiate others. We used generalized estimating equation (GEE) models on longitudinal data among a prospective cohort of PWID in Tijuana, Mexico (Proyecto El Cuete IV), while controlling for potential confounders. At baseline, 534 participants provided data on injection initiation assistance. Overall, 14% reported ever initiating others, with 4% reporting this behavior recently (i.e., in the past 6 months). In a multivariable GEE model, recent non-injection drug use was independently associated with providing injection initiation assistance (adjusted odds ratio [AOR] = 2.42, 95% confidence interval [CI] = 1.39-4.20). Further, in subanalyses examining specific drug types, recent non-injection use of cocaine (AOR = 9.31, 95% CI = 3.98-21.78), heroin (AOR = 4.00, 95% CI = 1.88-8.54), and methamphetamine (AOR = 2.03, 95% CI = 1.16-3.55) were all significantly associated with reporting providing injection initiation assistance. Our findings may have important implications for the development of interventional approaches to reduce injection initiation and related harms. Further research is needed to validate findings and inform future approaches to preventing entry into drug injecting.

BackgroundCocaine is a well-known risk factor for acute cardiac events, but the effects in users outside of acute events are less clear. We investigated a possible association between cocaine use and the concentration of a novel biomarker for cardiac stress and heart failure, ST2.MethodsA case-control study was conducted to compare ST2 concentrations by the presence of cocaine in patients presenting for care, but not cardiac care, at an urban safety net hospital.ResultsIn samples taken from 100 cocaine-positive and 100 cocaine-negative patients, the presence of cocaine was associated with ST2 concentrations>35ng/mL. Serum concentrations of benzoylecgonine, a major cocaine metabolite, were significantly correlated with ST2 concentrations.ConclusionsCocaine use is associated with subclinical cardiac stress and damage outside of acute cardiac events. This information could add to better stratification of cocaine users with elevated ST2 concentrations who may be at higher risk for developing heart failure and other cardiac complications.

The need to calibrate to correct for sensor-to-sensor fabrication variation and sensor drift has proven a significant hurdle in the widespread use of biosensors. To maintain clinically relevant (±20% for this application) accuracy, for example, commercial continuous glucose monitors require recalibration several times a day, decreasing convenience and increasing the chance of user errors. Here, however, we demonstrate a "dual-frequency" approach for achieving the calibration-free operation of electrochemical biosensors that generate an output by using square-wave voltammetry to monitor binding-induced changes in electron transfer kinetics. Specifically, we use the square-wave frequency dependence of their response to produce a ratiometric signal, the ratio of peak currents collected at responsive and non- (or low) responsive square-wave frequencies, which is largely insensitive to drift and sensor-to-sensor fabrication variations. Using electrochemical aptamer-based (E-AB) biosensors as our test bed, we demonstrate the accurate and precise operation of sensors against multiple drugs, achieving accuracy in the measurement of their targets of within better than 20% across dynamic ranges of up to 2 orders of magnitude without the need to calibrate each individual sensor.

AimsTo examine the association between a life-time history of insomnia and hypersomnia compared with no sleep disturbance and substance use patterns and amounts before and after a substance use treatment episode.DesignSecondary analysis of data from the Drug Abuse Treatment Outcome Studies conducted from 1991 to 1994.SettingData were collected at 96 substance use treatment programs in 11 United States cities, including short-term in-patient, long-term residential, methadone maintenance and out-patient drug-free treatment modalities.ParticipantsStudy samples included 7168 adults at treatment entry and 2965 at 12 months post-treatment entry whose primary substance use at entry was alcohol (14.7%), cocaine (62.7%) or heroin (22.6%).MeasurementsLife-time history of insomnia and hypersomnia was assessed via self-report. Type and frequency of substance use were assessed at treatment entry. Substance use was also assessed 12 months following treatment completion. Associations were examined using linear and logistic regression with age, sex, race, education level, depression history, treatment modality and in-treatment substance use as covariates.FindingsLife-time history of insomnia, hypersomnia, both or neither was reported by 26.3, 9.5, 28.0 and 36.2% of participants, respectively. Compared with no sleep disturbance, life-time insomnia and hypersomnia were associated at treatment entry with unique substance use patterns and a higher frequency of any substance use (P

Concurrent use of tobacco and alcohol or psychostimulants represents a major public health concern, with use of one substance influencing consumption of the other. Co-abuse of these drugs leads to substantial negative health outcomes, reduced cessation, and high economic costs, but the underlying mechanisms are poorly understood. Epidemiological data suggest that tobacco use during adolescence plays a particularly significant role. Adolescence is a sensitive period of development marked by major neurobiological maturation of brain regions critical for reward processing, learning and memory, and executive function. Nicotine exposure during this time produces a unique and long-lasting vulnerability to subsequent substance use, likely via actions at cholinergic, dopaminergic, and serotonergic systems. In this review, we discuss recent clinical and preclinical data examining the genetic factors and mechanisms underlying co-use of nicotine and alcohol or cocaine and amphetamines. We evaluate the critical role of nicotinic acetylcholine receptors throughout, and emphasize the dearth of preclinical studies assessing concurrent drug exposure. We stress important age and sex differences in drug responses, and highlight a brief, low-dose nicotine exposure paradigm that may better model early use of tobacco products. The escalating use of e-cigarettes among youth necessitates a closer look at the consequences of early adolescent nicotine exposure on subsequent alcohol and drug abuse.