Use of drug purchase tasks in medications development research: orexin system regulation of cocaine and drug demand.

Commodity purchase tasks provide a useful method for evaluating behavioral economic demand in the human laboratory. Recent research has shown how responding to purchase tasks for blinded drug administration can be used to study abuse liability. This analysis uses data from a human laboratory study to highlight how similar procedures may be particularly useful for understanding momentary changes in drug valuation when screening novel interventions. Eight nontreatment-seeking participants with cocaine use disorder (one with partial data) were enrolled in a cross-over, double-blind, randomized inpatient study. Participants were maintained on the Food and Drug Administration-approved insomnia medication suvorexant (oral; 0, 5, 10, 20 mg/day) in randomized order with experimental sessions completed after at least 3 days of maintenance on each suvorexant dose. Experimental sessions included administration of a sample dose of 0, 10 and 30 mg/70 kg intravenous cocaine. Analyses focused on purchase tasks for the blinded sample dose as well as alcohol, cigarettes and chocolate completed 15 min after the sample dose. As expected based on abuse liability, near zero demand was observed for placebo with dose-related increases in cocaine demand. Suvorexant maintenance increased cocaine demand in a dose-related manner with the greatest increase observed for the 10 mg/kg cocaine dose. Increased demand under suvorexant maintenance was also observed for alcohol. No effect of cocaine administration was observed for alcohol, cigarette, or chocolate demand. These data support the validity of demand procedures for measuring blinded drug demand. Findings also parallel self-administration data from this study by showing increases in cocaine use motivation under suvorexant maintenance.

Differential impacts of economic and demographic variables on substance use patterns during the COVID-19 pandemic.

Background: The COVID-19 pandemic and subsequent economic crisis has provided a unique opportunity to investigate the effects of economic shifts on substance use. Existing literature on this relationship is limited and conflicting, warranting further exploration.Objective: This study aimed to identify relationships between socioeconomic status (SES), demographic variables, and substance use patterns before and after government-mandated business closures due to COVID-19.Methods: Participants were recruited based on self-reported substance use through Amazon's Mechanical Turk (MTurk). Qualifying participants (N = 315, 43% female, mean age = 35.35) reported their substance use and SES for two-week periods before and after pandemic-related business closures. Regression models analyzed relationships between substance use and study variables.Results: Regression models found that, during COVID-19 closures, greater financial strain predicted decreased benzodiazepine (ß = -1.12) and tobacco (ß = 1.59) use. Additionally, certain predictor variables (e.g., participants' age [ß = 1.22], race [ß = -4.43], psychiatric disorders including ADHD [ß = -2.73] and anxiety [ß = 1.53], and concomitant substance use [ß = 3.38]) predicted changes in substance use patterns; however, the directionality of these associations varied across substances.Conclusion: Specific substance use patterns were significantly and differentially impacted by economic strain, psychiatric diagnoses, and concomitant substance use. These results can help direct harm reduction efforts toward populations at greatest risk of harmful substance use following the pandemic.

E-Cigarette Demand: Impact of Commodity Definitions and Test-Retest Reliability.

INTRODUCTION: Behavioral economic demand provides a multidimensional understanding of reinforcement. Commodity purchase tasks are an efficient method for measuring demand in human participants. One challenge in translating these procedures to electronic nicotine delivery systems (ENDS or e-cigarettes) is defining commodity units given the lack of standardization in the e-cigarette marketplace. AIMS AND METHODS: The purpose of this study was to directly compare methods of operationalizinge-cigarette purchases, puffs, cartridges, and mLs liquid, using a within-subject design. Participants (N = 132) reporting past week e-cigarette use were recruited using crowdsourcing. Purchase tasks were completed operationalizing e-cigarette units as puffs or cartridges at baseline and puffs or mLs liquid at a 3-month follow-up. RESULTS: Bivariate associations supported convergent and discriminant validity with the largest effect size correlations for intensity and elasticity observed for the puff version. Interaction models suggested that product preferences moderated the relationship between time-to-first use and cartridge demand with larger effect size correlations among persons reporting a preference for JUULs, but weaker relationships among persons reporting other device preferences. Puff intensity (rxx = .61) and elasticity (rxx = .62) showed good test-retest reliability for participants reporting stable consumption, but poor test-retest reliability for individuals with changed consumption levels (intensity rxx = -.08; elasticity rxx = -.10). CONCLUSIONS: This study highlights the relevance of commodity definitions in the e-cigarette purchase task. Puffs as an experimental commodity may provide flexibility for studying e-cigarette demand in heterogenous or unknown populations, whereas more tailored or personalized approaches like cartridge or mL-based tasks will likely be helpful when studying known subgroups. IMPLICATIONS: The commodity purchase task procedure is widely used for understanding cigarette and e-cigarette demand in nicotine dependence research. This study evaluates the importance of operational definitions of e-cigarette commodities in the purchase task (ie, puffs, cartridges, or mLs liquid). Puffs may provide a more flexible commodity unit when evaluating e-cigarette demand in general or heterogenous populations, whereas device-specific units may prove more valuable when studying populations with consistent and known product use.

Researcher perspectives on including people who use drugs in clinical research.

Background: People who use drugs are commonly excluded from clinical research despite being disproportionately impacted by numerous health conditions. Recent work indicates that community-recruited individuals report low support of research inclusion for persons reporting substance use.Objective: This study conducted a mixed-method assessment of researchers' attitudes on including persons reporting substance use in clinical research.Methods: Respondents (N = 168; 58% female; 58% psychologists) recruited via scientific society listservs and Twitter completed a survey containing two hypothetical research vignettes. Quantitative items evaluated respondents' endorsement of research participation by healthy adults, people who use drugs, and vulnerable populations. Qualitative items included open-ended questions asking reasons why people who use drugs should and should not participate in research.Results: Respondents reported significantly lower support for research participation by people who use drugs compared to healthy adults (p <.001). Open-ended responses concerning the inclusion of people who use drugs included themes relevant to the Belmont Principles (e.g., capacity to consent) and data quality (e.g., "bad data," poor compliance).Conclusion: Although lower support for research participation by people who use drugs was observed compared to healthy adults, the magnitude of this difference was smaller than reported for prior community-recruited respondents. These findings emphasize salient factors that may serve as both protections for and barriers to inclusion of people who use drugs in research. Initiatives including adoption of person-first language, addressing stereotyping of people who use drugs, and emphasizing the benefits of including these populations in clinical research should be explored to reduce bias while retaining needed protections.

Utilizing content-knowledge questionnaires to assess study eligibility and detect deceptive responding.

Background: Deceptive responding during eligibility screening presents a significant concern for assessing inclusion/exclusion criteria. This problem is compounded in settings for which biomarkers or other objective verification (e.g., urinalysis) are not feasible.Objectives: Introduce and describe content-knowledge questionnaires as an objective method for collaterally assessing study eligibility.Methods: Participants (N = 3772; 66.1% female) recruited using the crowdsourcing resource Amazon Mechanical Turk (mTurk) completed a Cannabis Knowledge Questionnaire (CKQ). The CKQ contained four-items indexing knowledge of typical cannabis costs, weights, and terminology. Self-reported cannabis use history was collected and compared to individual item and total scale scores. A separate in-laboratory assessment evaluated participants during in-person screening for cannabis, alcohol, and cocaine research protocols (N = 43).Results: Good internal consistency (α = .74) was observed. The most common correctly answered question was about dabbing (41.4%) followed by cannabis cost (37.6%), hybrid strains (36.6%), and estimated weight (29.7%). Current cannabis use was associated with large effect size increases in the rate of correct responses (RR = 3.64) as well as odds of a correct response on individual items (OR = 5.88-21.48). In the laboratory study, participants with a positive urine drug test for cannabis or those reporting lifetime regular cannabis use scored higher than those without this history (RR = 1.89-2.61).Conclusion: These findings highlight the efficiency and efficacy of including content-knowledge questionnaires for collateral assessment of study eligibility, especially when biomarkers are not possible. Future studies will be useful for extending this initial demonstration to alternative settings and substances.

Feasibility, Acceptability, and Initial Efficacy of Delivering Alcohol Use Cognitive Interventions via Crowdsourcing.

BACKGROUND: Inhibitory control training and working memory training are 2 cognitive interventions that have been considered for alcohol use disorder (AUD). Existing studies have typically relied on small samples that preclude the evaluation of small effects. Crowdsourcing is a sampling method that can address these limitations by effectively and efficiently recruiting large samples with varying health histories. This study tested the feasibility and acceptability of delivering cognitive training interventions via crowdsourcing. METHODS: Participants with AUD were recruited from the crowdsourcing website Amazon Mechanical Turk (mTurk) (ClinicalTrials.gov; NCT03438539). Following completion of a baseline survey, participants were randomized to an inhibitory control, working memory, or control training condition. Participants were asked to complete training tasks daily over a 2-week period. Follow-up assessments evaluating acceptability measures and alcohol and soda consumption were completed immediately following and 2 weeks after training. RESULTS: Response rates were satisfactory over the 2-week intervention period (65% of training tasks completed), and performance on training tasks was consistent with expected effects. A majority of participants indicated that they were satisfied with the study procedures (94.6%), would participate again (97.4%), and would consider incorporating the training task in their daily life (81.1%). Modest reductions in alcohol consumption were observed (e.g., 0.5 drinking day/wk), primarily in the inhibitory control group, and these effects were selective to alcohol use and did not extend to soda consumption. CONCLUSIONS: These findings demonstrate the feasibility and acceptability of utilizing crowdsourcing methods for interventions development. Such a demonstration helps establish the crowdsourcing setting for future large sample studies testing novel interventions for AUD and other substance use disorders.

Creation of an institutional semi-independent data monitoring committee.

BACKGROUND: A major goal of the National Institutes of Health's Clinical and Translational Science Award program is to facilitate clinical research and enhance the transition of basic to clinical research. As such, a number of Clinical and Translational Science Award centers have developed services to facilitate the conduct of clinical research, including support with fulfilling regulatory requirements. METHODS: The University of Kentucky sought to establish an institutional semi-independent monitoring committee to provide oversight for clinical research studies per National Institutes of Health requirements and recommendations. Our semi-independent monitoring committee was initiated in 2010. RESULTS: Since the inception of our semi-independent monitoring committee we have restructured its operations and protocols to improve efficiency. This article discusses our experiences with semi-independent monitoring committee creation and growth. CONCLUSION: This article summarizes our experience in creating and maturing an institutional data monitoring committee.

Evaluation of the "Pipeline" for Development of Medications for Cocaine Use Disorder: A Review of Translational Preclinical, Human Laboratory, and Clinical Trial Research.

Cocaine use disorder is a persistent public health problem for which no widely effective medications exist. Self-administration procedures, which have shown good predictive validity in estimating the abuse potential of drugs, have been used in rodent, nonhuman primate, and human laboratory studies to screen putative medications. This review assessed the effectiveness of the medications development process regarding pharmacotherapies for cocaine use disorder. The primary objective was to determine whether data from animal and human laboratory self-administration studies predicted the results of clinical trials. In addition, the concordance between laboratory studies in animals and humans was assessed. More than 100 blinded, randomized, fully placebo-controlled studies of putative medications for cocaine use disorder were identified. Of the 64 drugs tested in these trials, only 10 had been examined in both human and well-controlled animal laboratory studies. Within all three stages, few studies had been conducted for each drug and when multiple studies had been conducted conclusions were sometimes contradictory. Overall, however, there was good concordance between animal and human laboratory results when the former assessed chronic drug treatment. Although only seven of the ten reviewed drugs showed fully concordant results across all three types of studies reviewed, the analysis revealed several subject-related, procedural, and environmental factors that differ between the laboratory and clinical trial settings that help explain the disagreement for other drugs. The review closes with several recommendations to enhance translation and communication across stages of the medications development process that will ultimately speed the progress toward effective pharmacotherapeutic strategies for cocaine use disorder.

Influence of Cocaine-Related Images and Alcohol Administration on Inhibitory Control in Cocaine Users.

BACKGROUND: Alcohol use and impulsivity, including decreased inhibitory control, predict poor treatment outcomes for individuals with cocaine use disorders. This study sought to determine the effects of alcohol administration on inhibitory control following cocaine-related and neutral cues on the Attentional Bias-Behavioral Activation (ABBA) task in cocaine users. We hypothesized that the proportion of inhibitory failures would increase following cocaine, compared to neutral, cues. We further hypothesized that there would be an interaction between alcohol administration and task version, such that alcohol would impair inhibitory control following cocaine, but not neutral cues. METHODS: Fifty current cocaine users completed this mixed-model, double-blind, placebo-controlled, crossover study over 2 experimental sessions. The ABBA task was completed following alcohol administration (0.0 and 0.65 g/kg). Subject-rated drug effect and physiological measures were collected prior to and after alcohol administration. RESULTS: Proportion of inhibitory failures was increased following cocaine-related cues compared to neutral cues independent of alcohol dose. Alcohol administration also produced prototypical subject-rated drug effects. CONCLUSIONS: A better understanding of the relationship between alcohol consumption and inhibitory control in cocaine users could direct the development of interventions to decrease the risk of relapse in individuals who drink and display impaired inhibitory control.

Effects of acute buspirone administration on inhibitory control and sexual discounting in cocaine users.

OBJECTIVE: Cocaine users display deficits in inhibitory control and make impulsive choices that may increase risky behavior. Buspirone is an anxiolytic that activates dopaminergic and serotonergic systems and improves impulsive choice (i.e., reduces sexual risk-taking intent) in cocaine users when administered chronically. We evaluated the effects of acutely administered buspirone on inhibitory control and impulsive choice. METHODS: Eleven subjects with a recent history of cocaine use completed this within-subject, placebo-controlled study. Subjects performed two cued go/no-go and a sexual risk delay-discounting task following oral administration of buspirone (10 and 30 mg), triazolam (0.375 mg; positive control), and placebo (negative control). Physiological and psychomotor performance and subject-rated data were also collected. RESULTS: Buspirone failed to change inhibitory control or impulsive choice; however, slower reaction times were observed at the highest dose tested. Buspirone did not produce subject-rated drug effects but dose-dependently decreased diastolic blood pressure. Triazolam impaired psychomotor performance and increased ratings of positive subject-rated effects (e.g., Like Drug). CONCLUSIONS: These findings indicate that acutely administered buspirone has little impact on behavioral measures of inhibitory control and impulsive sexual decision-making. Considering previous findings with chronic dosing, these findings highlight that the behavioral effects of buspirone differ as a function of dosing conditions.

Separate and Combined Effects of Naltrexone and Extended-Release Alprazolam on the Reinforcing, Subject-Rated, and Cardiovascular Effects of Methamphetamine.

Opioid antagonists (eg, naltrexone) and positive modulators of γ-aminobutyric acid type A receptors (eg, alprazolam) each modestly attenuate the abuse-related effects of stimulants. A previous study demonstrated that acute pretreatment with the combination of naltrexone and alprazolam attenuated a greater number of the subject-rated effects of D-amphetamine than the constituent drugs alone. This study tested the hypothesis that maintenance on the combination of naltrexone and alprazolam XR would attenuate the reinforcing and "positive" subject-rated effects of methamphetamine to a greater extent than the constituent drugs alone.Eight non-treatment-seeking, stimulant-using individuals completed a placebo-controlled, crossover, double-blind inpatient protocol. Participants were maintained on naltrexone (0 and 50 mg), alprazolam XR (0 and 1 mg), and the combination of naltrexone and alprazolam XR (50 mg and 1 mg, respectively) for 6 to 7 days. Under each maintenance condition, participants sampled intranasal doses of methamphetamine (0, 10, and 30 mg), and were then offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. Subject-rated drug effect questionnaires, psychomotor, and physiology assessments were collected.Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like "positive" subject-rated and physiological effects. Maintenance on naltrexone significantly decreased the reinforcing, but not subject-rated drug effects of 10-mg methamphetamine. Alprazolam XR and the combination of naltrexone and alprazolam XR did not impact methamphetamine self-administration or subject-rated drug effects. The results support the continued evaluation of naltrexone for methamphetamine dependence, as well as the identification of other drugs that enhance its ability to reduce drug-taking behavior.

Cigarette Cue Attentional Bias in Cocaine-Smoking and Non-Cocaine-Using Cigarette Smokers.

INTRODUCTION: Cigarette smoking in cocaine users is nearly four times higher than the national prevalence and cocaine use increases cigarette smoking. The mechanisms underlying cigarette smoking in cocaine-using individuals need to be identified to promote cigarette and cocaine abstinence. Previous studies have examined the salience of cigarette and cocaine cues separately. The present aim was to determine whether cigarette attentional bias (AB) is higher in cigarettes smokers who smoke cocaine relative to individuals who only smoke cigarettes. METHODS: Twenty cigarette smokers who smoke cocaine and 20 non-cocaine-using cigarette smokers completed a visual probe task with eye-tracking technology. During this task, the magnitude of cigarette and cocaine AB was assessed through orienting bias, fixation time, and response time. RESULTS: Cocaine users displayed an orienting bias towards cigarette cues. Cocaine users also endorsed a more urgent desire to smoke to relieve negative affect associated with cigarette craving than non-cocaine users (g = 0.6). Neither group displayed a cigarette AB, as measured by fixation time. Cocaine users, but not non-cocaine users, displayed a cocaine AB as measured by orienting bias (g = 2.0) and fixation time (g = 1.2). There were no significant effects for response time data. CONCLUSIONS: Cocaine-smoking cigarettes smokers display an initial orienting bias toward cigarette cues, but not sustained cigarette AB. The incentive motivation underlying cigarette smoking also differs. Cocaine smokers report more urgent desire to smoke to relieve negative affect. Identifying differences in motivation to smoke cigarettes may provide new treatment targets for cigarette and cocaine use disorders. IMPLICATIONS: These results suggest that cocaine-smoking cigarette smokers display an initial orienting bias towards cigarette cues, but not sustained attention towards cigarette cues, relative to non-cocaine-using smokers. Smoked cocaine users also report a more urgent desire to smoke to relieve negative affect than non-cocaine users. Identifying differences in motivation to smoke cigarettes may provide new treatment targets for both cigarette and cocaine use disorders.

Alcohol Administration Increases Cocaine Craving But Not Cocaine Cue Attentional Bias.

BACKGROUND: Alcohol consumption is a known antecedent to cocaine relapse. Through associative conditioning, it is hypothesized that alcohol increases incentive motivation for cocaine and thus the salience of cocaine-related cues, which are important in maintaining drug-taking behavior. Cocaine-using individuals display a robust cocaine cue attentional bias as measured by fixation time during the visual probe task. The purpose of this study was to evaluate the influence of alcohol administration on cocaine cue attentional bias using eye-tracking technology to directly measure attentional allocation. METHODS: Twenty current cocaine users completed a double-blind, placebo-controlled, within-subjects study that tested the effect of 3 doses of alcohol (0.00, 0.325, and 0.65 g/kg) on cocaine cue attentional bias using the visual probe task with eye-tracking technology. The participant-rated and physiological effects of alcohol were also assessed. RESULTS: Participants displayed a robust cocaine cue attentional bias following both placebo and alcohol administration as measured by fixation time, but not response time. Alcohol administration did not influence cocaine cue attentional bias, but increased craving for cocaine in a dose-dependent manner. Alcohol produced prototypic psychomotor and participant-rated effects. CONCLUSIONS: Alcohol administration increases cocaine craving but not cocaine cue attentional bias. Alcohol-induced cocaine craving suggests that alcohol increases incentive motivation for cocaine but not the salience of cocaine-related cues.

Profile of internet access in active cocaine users.

BACKGROUND AND OBJECTIVES: Web-based interventions have received attention for substance abuse treatment. Few studies have examined Internet use among substance users. METHODS: Internet-use data were examined for 66 participants screened to participate in behavioral pharmacology studies. RESULTS: A majority of active cocaine users reported regular Internet use. Demographic profiles generally did not impact Internet use, but Internet users were more likely to be younger and report other drug use. DISCUSSION AND CONCLUSIONS: Active cocaine users have similar rates of Internet access as the general population. SCIENTIFIC SIGNIFICANCE: Our findings contribute to the limited data on Internet use in active drug users by demonstrating Internet access in cocaine-using populations, supporting the use of this medium to conduct research and clinical interventions.

Methamphetamine self-administration in humans during D-amphetamine maintenance.

Agonist replacement may be a viable treatment approach for managing stimulant use disorders. This study sought to determine the effects of D-amphetamine maintenance on methamphetamine self-administration in stimulant using human participants. We predicted that D-amphetamine maintenance would reduce methamphetamine self-administration. Eight participants completed the protocol, which tested 2 D-amphetamine maintenance conditions in counterbalanced order (0 and 40 mg/d). Participants completed 4 experimental sessions under each maintenance condition in which they first sampled 1 of 4 doses of intranasal methamphetamine (0, 10, 20, or 30 mg). Participants then had the opportunity to respond on a computerized progressive-ratio task to earn portions of the sampled methamphetamine dose. Subject-rated drug effect and physiological measures were completed at regular intervals prior to and after sampling methamphetamine. Methamphetamine was self-administered as an orderly function of dose regardless of the maintenance condition. Methamphetamine produced prototypical subject-rated effects on 12 items of the drug-effects questionnaires, 8 of which were attenuated by D-amphetamine maintenance (eg, increased ratings were attenuated on items such as Any Effect, Like Drug, and Willing to Take Again on the Drug Effect Questionnaire). Methamphetamine produced significant increases in systolic blood pressure, which were attenuated by D-amphetamine maintenance compared to placebo maintenance. Methamphetamine was well tolerated during D-amphetamine maintenance and no adverse events occurred. Although D-amphetamine attenuated some subject-rated effects of methamphetamine, the self-administration results are concordant with those of clinical trials showing that D-amphetamine did not reduce methamphetamine use. Unique pharmacological approaches may be needed for treating amphetamine use disorders.

Relationship between intranasal cocaine self-administration and subject-rated effects: predictors of cocaine taking on progressive-ratio schedules.

OBJECTIVE: Subject-rated measures and drug self-administration represent two of the most commonly used methods of assessing abuse potential of drugs, as well as screening intervention efficacy in the human laboratory. Although the results from these methods are often consistent, dissociations between subject-rated and self-administration data have been observed. The purpose of the present retrospective analysis was to examine the relationship between subject-rated effects and intranasal cocaine self-administration to help guide future research design and intervention assessment. METHODS: Data were combined from two previous studies in which drug and an alternative reinforcer (i.e., money) were available on concurrent progressive-ratio schedules of reinforcement. Pearson correlation coefficients and regression model selection utilizing corrected Akaike information criterion were used to determine which subject-rated measures were associated with and best predicted cocaine self-administration. RESULTS: Eleven subject-rated effects were positively associated with cocaine-maintained breakpoints. A combination of three of these subject ratings (i.e., Like Drug, Performance Improved, and Rush) best predicted cocaine taking. CONCLUSIONS: The present findings suggest that, at least under certain conditions with intranasal cocaine, some, but not all, positive subject-rated effects may predict drug self-administration. These findings will be useful in guiding future examinations of putative interventions for cocaine-use disorders.

Opioid craving does not incubate over time in inpatient or outpatient treatment studies: Is the preclinical incubation of craving model lost in translation?

Within addiction science, incubation of craving is an operational label used to describe time-dependent increases in drug seeking during periods of drug deprivation. The purpose of this systematic review was to describe the preclinical literature on incubation of craving and the clinical literature on craving measured over extended periods of abstinence to document this translational homology and factors impacting correspondence. Across the 44 preclinical studies that met inclusion criteria, 31 reported evidence of greater lever pressing, nose pokes, spout licks, or time spent in drug-paired compartments (i.e., drug seeking) relative to neutral compartments after longer periods of abstinence relative to shorter periods of abstinence, labelled as "incubation of craving." In contrast, no clinical studies (n = 20) identified an increase in opioid craving during longer abstinence periods. The lack of clinical evidence for increases in craving in clinical populations weakens the translational utility of operationalizing the time-dependent increase in drug-seeking behavior observed in preclinical models as models of incubation of "craving".

The subjective value of social context in people who use cannabis.

Disordered cannabis use is linked to social problems, which could be explained by a subjective devaluation of nondrug social contexts and/or an overvaluation of cannabis-paired options relative to nondrug alternatives. To examine these hypotheses, measures to assess the subjective value of social- and/or cannabis-paired contexts were collected in people who use cannabis (n = 85) and controls (n = 98) using crowdsourcing methods. Measures included a cued concurrent choice task that presented two images (cannabis, social, social cannabis, and neutral images) paired with monetary options, hypothetical purchase tasks that included access to social parties with and without a cannabis "open bar," and the Social Anhedonia Scale (SAS). Little evidence was found to suggest that the cannabis group undervalued social contexts. People who used cannabis demonstrated a preference for social- versus neutral-cued options, and no preference for cannabis- versus social cannabis-cued options on the choice task. In addition, social party demand and SAS scores did not differ between groups. In contrast, we observed evidence for an overvaluation of cannabis context in people who use cannabis, including preference for social cannabis- versus social-cued options, and more disadvantageous choices for cannabis-cued options on the choice task, as well as more intense and inelastic demand for the social cannabis party compared to the social party. These results suggest that social problems associated with cannabis use could be at least partially explained by an overvaluation of cannabis-paired options, rather than devaluation of nondrug social-paired options, in the value calculations underlying drug use decisions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Oxycodone withdrawal is associated with increased cocaine self-administration and aberrant accumbens glutamate plasticity in rats.

Individuals with opioid use disorder (OUD) frequently use other substances, including cocaine. Opioid withdrawal is associated with increased likelihood of cocaine use, which may represent an attempt to ameliorate opioid withdrawal effects. Clinically, 30% of co-using individuals take opioids and cocaine exclusively in a sequential manner. Preclinical studies evaluating mechanisms of drug use typically study drugs in isolation. However, polysubstance use is a highly prevalent clinical issue and thus, we established a novel preclinical model of sequential oxycodone and cocaine self-administration (SA) whereby rats acquired oxycodone and cocaine SA in an A-B-A-B design. Somatic signs of withdrawal were evaluated at 0, 22, and 24h following oxycodone SA, with the 24h timepoint representing somatic signs immediately following cocaine SA. Preclinically, aberrant glutamate signaling within the nucleus accumbens core (NAcore) occurs following use of cocaine or opioids, whereby medium spiny neurons (MSNs) rest in a potentiated or depotentiated state, respectively. Further, NAcore glial glutamate transport via GLT-1 is downregulated following SA of either drug alone. However, it is not clear if cocaine can exacerbate opioid-induced changes in glutamate signaling. In this study, NAcore GLT-1 protein and glutamate plasticity were measured (via AMPA/NMDA ratio) following SA. Rats acquired SA of both oxycodone and cocaine regardless of sex, and the acute oxycodone-induced increase in somatic signs at 22h was positively correlated with cocaine consumption during the cocaine testing phase. Cocaine use following oxycodone SA downregulated GLT-1 and reduced AMPA/NMDA ratios compared to cocaine use following food SA. Further, oxycodone SA alone was associated with reduced AMPA/NMDA ratio. Together, behavioral signs of oxycodone withdrawal may drive cocaine use and further dysregulate NAcore glutamate signaling.

Impacts of xylazine on fentanyl demand, body weight, and acute withdrawal in rats: A comparison to lofexidine.

The opioid use landscape has recently shifted to include xylazine, a veterinary anesthetic, as an adulterant in the fentanyl supply. The health impacts of xylazine as an emerging fentanyl adulterant has raised alarm regarding xylazine as a public health threat, warranting research on the impacts of xylazine on fentanyl's behavioral effects. No prior studies have evaluated the effects of xylazine on fentanyl consumption at various unit doses, fentanyl demand, or withdrawal as compared to the Food and Drug Administration-approved opioid withdrawal medication, lofexidine (Lucemyra®). This is important because lofexidine and xylazine are both adrenergic α2a (A2aR) agonists, however, lofexidine is not a noted fentanyl adulterant. Here we evaluated xylazine and lofexidine combined with self-administered fentanyl doses in male and female rats and evaluated fentanyl demand, body weight, and acute withdrawal. Consumption of fentanyl alone increased at various unit doses compared to saline. Xylazine but not lofexidine shifted fentanyl consumption downward at a number of unit doses, however, both lofexidine and xylazine suppressed fentanyl demand intensity as compared to a fentanyl alone control group. Further, both fentanyl + lofexidine and fentanyl + xylazine reduced behavioral signs of fentanyl withdrawal immediately following SA, but signs increased by 12 h only in the xylazine co-exposed group. Weight loss occurred throughout fentanyl SA and withdrawal regardless of group, although the xylazine group lost significantly more weight during the first 24 h of withdrawal than the other two groups. Severity of weight loss during the first 24 h of withdrawal was also correlated with severity of somatic signs of fentanyl withdrawal. Together, these results suggest that body weight loss may be an important indicator of withdrawal severity during acute withdrawal from the xylazine/fentanyl combination, warranting further translational evaluation.