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RationaleNon-medical prescription opioid use and opioid use disorder (OUD) present a significant public health concern. Identifying behavioral mechanisms underlying OUD will assist in developing improved prevention and intervention approaches. Behavioral economic demand has been extensively evaluated as a measure of reinforcer valuation for alcohol and cigarettes, whereas prescription opioids have received comparatively little attention.ObjectivesUtilize a purchase task procedure to measure the incremental validity and test-retest reliability of opioid demand.MethodsIndividuals reporting past year non-medical prescription opioid use were recruited using the crowdsourcing platform Amazon Mechanical Turk (mTurk). Participants completed an opioid purchase task as well as measures of cannabis demand, delay discounting, and self-reported pain. A 1-month follow-up was used to evaluate test-retest reliability.ResultsMore intense and inelastic opioid demand was associated with OUD and more intense cannabis demand was associated with cannabis use disorder. Multivariable models indicated that higher opioid intensity and steeper opioid delay discounting rates each significantly and uniquely predicted OUD. Increased opioid demand intensity, but not elasticity, was associated with higher self-reported pain, and no relationship was observed with perceived pain relief from opioids. Opioid demand showed acceptable-to-good test-retest reliability (e.g., intensity rxx = .75; elasticity rxx = .63). Temporal reliability was lower for cannabis demand (e.g., intensity rxx = .53; elasticity rxx = .58) and discounting rates (rxx = .42–.61).ConclusionsOpioid demand was incrementally valid and test-retest reliable as measured by purchase tasks. These findings support behavioral economic demand as a clinically useful measure of drug valuation that is sensitive to individual difference variables.

Rationale Tramadol is a prescription analgesic that activates mu opioid and monoamine receptor systems. Tramadol is thought to have limited abuse potential compared to mu opioid agonists, but laboratory data indicate that it shares some of their pharmacodynamic effects. Objectives This study evaluated the effect of mu opioid receptor blockade with naltrexone on the pharmacodynamic action of tramadol in humans. Methods This inpatient, double-blind, randomized, within-subject study examined the effects of oral placebo, tramadol (87.5, 175, and 350 mg), and hydromorphone (4 and 16 mg; positive control) after 1 h pretreatment with oral naltrexone (0 and 50 mg). Ten recreational opioid users completed the study. Pharmacodynamic effects were measured before and for 7 h after initial drug administration. Results Lower doses of tramadol and hydromorphone were generally placebo-like. Hydromorphone (16 mg) produced prototypic mu opioid agonist-like effects that were blocked by naltrexone. Tramadol (350 mg) produced miosis and increased ratings of “Good Effects” and “Liking” but also increased ratings of “Bad Effects.” Naltrexone reversed tramadol-induced physiological effects and mydriasis emerged, but unlike results with hydromorphone, naltrexone only partially attenuated tramadol’s positive subjective effects and actually enhanced several unpleasant subjective ratings. Conclusions Naltrexone can be used to disentangle the mixed neuropharmacological actions of tramadol. High-dose tramadol produces a mixed profile of effects. These data suggest that both mu and non-mu opioid actions play a role in tramadol’s subjective profile of action.

OBJECTIVES/GOALS: Contingency management (CM) procedures yield measurable reductions in cocaine use. This poster describes a trial aimed at using CM as a vehicle to show the biopsychosocial health benefits of reduced use, rather than total abstinence, the currently accepted metric for treatment efficacy. METHODS/STUDY POPULATION: In this 12-week, randomized controlled trial, CM was used to reduce cocaine use and evaluate associated improvements in cardiovascular, immune, and psychosocial well-being. Adults aged 18 and older who sought treatment for cocaine use (N=127) were randomized into three groups in a 1:1:1 ratio: High Value ( $55) or Low Value ($ 13) CM incentives for cocaine-negative urine samples or a non-contingent control group. They completed outpatient sessions three days per week across the 12-week intervention period, totaling 36 clinic visits and four post-treatment follow-up visits. During each visit, participants provided observed urine samples and completed several assays of biopsychosocial health. RESULTS/ANTICIPATED RESULTS: Preliminary findings from generalized linear mixed effect modeling demonstrate the feasibility of the CM platform. Abstinence rates from cocaine use were significantly greater in the High Value group (47% negative; OR = 2.80; p = 0.01) relative to the Low Value (23% negative) and Control groups (24% negative;). In the planned primary analysis, the level of cocaine use reduction based on cocaine-negative urine samples will serve as the primary predictor of cardiovascular (e.g., endothelin-1 levels), immune (e.g., IL-10 levels) and psychosocial (e.g., Addiction Severity Index) outcomes using results from the fitted models. DISCUSSION/SIGNIFICANCE: This research will advance the field by prospectively and comprehensively demonstrating the beneficial effects of reduced cocaine use. These outcomes can, in turn, support the adoption of reduced cocaine use as a viable alternative endpoint in cocaine treatment trials.

Abstract 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.

RationaleUnderstanding mechanisms of drug use decisions will inform the development of treatments for opioid use disorder (OUD). Decision-making experiments using neurobehavioral approaches require many trials or events of interest for statistical analysis, but the pharmacokinetics of most opioids limit dosing in humans.ObjectivesThis experiment characterized the effects of repeated infusions of the ultra-short acting opioid remifentanil in people with OUD and physical opioid dependence.MethodsAn inpatient study using a within-subjects, single-blind, escalating, within-session, pre-post design was conducted. Seven (3 female) subjects were maintained on oral oxycodone (40–60 mg, 4x/day = 160–240 total mg/day) for seven days prior to the dose-ranging session. Subjects received infusions of three ascending remifentanil doses (0.03, 0.1, 0.3 mcg/kg/infusion in 2 subjects; 0.1, 0.3, 1.0 mcg/kg/infusion in 5 subjects) every minute for 40 min per dose, with infusions administered over 5 s to model naturalistic delivery rates. End tidal carbon dioxide, respiration rate, oxygen saturation (SpO2) and heart rate were measured continuously. Blood pressure (BP), pupil diameter and self-reported drug effects were measured every 5 min.ResultsPupil diameter, SpO2 and systolic BP decreased, and ratings on prototypic subjective effects questionnaire items increased, as a function of remifentanil dose. The number of infusions held because of sedation or physiological parameters exceeding predetermined cutoffs also increased with dose.ConclusionsThis experiment established doses and procedures for the safe delivery of rapid, repeated remifentanil infusions to individuals with OUD and physical fentanyl dependence, which can be applied to the mechanistic study of opioid use decisions.

RationaleNo pharmacotherapies are approved for cocaine use disorder. Phendimetrazine, a prodrug of the monoamine-releaser phenmetrazine, attenuates the reinforcing effects of cocaine in preclinical models, has minimal abuse potential, and is safe when combined with cocaine.ObjectivesThis study determined the influence of phendimetrazine maintenance on the reinforcing effects of cocaine (i.e., choice to self-administer cocaine), along with the subjective, performance, and physiological effects of cocaine. We hypothesized that phendimetrazine would attenuate the reinforcing effects of cocaine.MethodsTwenty-nine subjects with cocaine use disorder completed this within-subject, inpatient study. The subjects were maintained on placebo and 210 mg phendimetrazine in a counterbalanced order. After at least 7 days of maintenance on the target dose, the subjects completed experimental sessions in which the effects of single doses of 0, 20, 40, and 80 mg of intranasal cocaine were determined.ResultsCocaine functioned as a reinforcer, producing significant dose-related increases in self-administration. Cocaine increased prototypic effects (e.g., ratings of stimulated and blood pressure). Phendimetrazine attenuated ratings on a select set of subjective outcomes (e.g., ratings of talkative/friendly), but failed to reduce the reinforcing effects of cocaine or a majority of positive subjective cocaine effects. Phendimetrazine increased heart rate, indicating a physiologically active dose was tested, but heart rate increases were not clinically significant.ConclusionsThese results indicate that although phendimetrazine can safely be combined with cocaine, it does not attenuate the abuse-related effects of cocaine. It is unlikely, then, that phendimetrazine will be an effective standalone treatment for cocaine use disorder.

Cocaine use is commonly associated with increased chronic systemic inflammation. However, the drivers for cocaine use-mediated systemic inflammation are not fully understood. In the current study, we recruited individuals with cocaine use disorder and healthy individuals who did not use cocaine and collected paired saliva and blood samples. The saliva samples were used to assess the oral microbiome, and the plasma samples were evaluated for 33 cytokines and chemokines. Cocaine users exhibited decreased saliva microbial diversities compared to non-users. Streptococcus was the only increased genus in the saliva from cocaine users, whereas several genera were decreased in cocaine users compared to non-users. Notably, cocaine users exhibited increased plasma levels of several monocyte activation markers, including monocyte chemoattractant protein (MCP)-4, macrophage inflammatory protein (MIP)-3α, macrophage-derived chemokine (MDC), and thymus and activation-regulated chemokine (TARC), all of which were correlated with increased saliva levels of three Streptococcus species. Furthermore, treatment with Streptococcus or its lipoteichoic acid preferentially activated primary human monocytes to produce proinflammatory cytokines and chemokines, such as MIP-3α and TARC, in vitro compared to controls. However, monocytes failed to produce these chemokines after exposure to cocaine or cocaine plus bacteria compared to medium or bacteria alone. This study revealed that chronic cocaine use-associated inflammation in the blood may result from increased oral Streptococcus and its effects on myeloid cell activation, but does not result from cocaine directly. Graphical abstract

Rationale Theoretical accounts highlight the importance of drug-related cues for the development and persistence of drug-taking behavior. Few studies have evaluated the ability of spatially contiguous drug cues to bias decisions between two concurrently presented non-drug reinforcers. Objective Evaluate the contribution of spatially contiguous cocaine cues to choice between two concurrently presented monetary reinforcers Methods Participants with cocaine use disorder completed a cued concurrent choice task. Two cues (one cocaine and one control image) were presented side-by-side followed by concurrent monetary offers below each image. Concurrent choice was measured for cocaine-side advantageous, equal, and disadvantageous concurrent monetary offers. The primary dependent measure was bias for selecting cocaine-cued monetary reinforcers. Three experiments tested selectivity of cocaine-cued bias in individuals with a cocaine use history (Experiment 1), replication when including additional control trials (Experiment 2), and a potential attentional mechanism evaluated using eye-tracking technology (Experiment 3). Results Significant and robust cocaine-cued bias at equal monetary value was observed in three experiments (mean percent choice = 65–77%) and higher Drug Abuse Screening Test (DAST) scores were associated with greater cocaine-choice bias. These experiments demonstrated that cocaine-cued bias was (1) selective to individuals with a cocaine use history, (2) specific to trials involving a cocaine cue, and (3) partially associated with attentional bias. Conclusions These experiments provide evidence that drug-related cues can influence choice and potentially promote maladaptive decision making during concurrent choice events. Future research evaluating prospective associations of drug-cued bias with drug-associated behaviors will help reveal the clinical relevance for substance use disorder.

Background Combination therapy in managing psychiatric disorders is not uncommon. While combination therapy has been documented for depression and schizophrenia, little is known about combination therapy practices in managing attention-deficit/hyperactivity disorder (ADHD). This study seeks to quantify the combination use of ADHD medications and to understand predictors of combination therapy. Methods Prescription dispensing events were drawn from a U.S. national claims database including over 80 managed-care plans. Patients studied were age 18 or over with at least 1 medical claim with a diagnosis of ADHD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 314.0), a pharmacy claim for ADHD medication during the study period July2003 to June2004, and continuous enrollment 6 months prior to and throughout the study period. Dispensing events were grouped into 6 categories: atomoxetine (ATX), long-acting stimulants (LAS), intermediate-acting stimulants (IAS), short-acting stimulants (SAS), bupropion (BUP), and Alpha-2 Adrenergic Agonists (A2A). Events were assigned to calendar months, and months with combined use from multiple categories within patient were identified. Predictors of combination therapy for LAS and for ATX were modeled for patients covered by commercial plans using logistic regression in a generalized estimating equations framework to adjust for within-patient correlation between months of observation. Factors included age, gender, presence of the hyperactive component of ADHD, prior diagnoses for psychiatric disorders, claims history of recent psychiatric visit, insurance plan type, and geographic region. Results There were 18,609 patients identified representing a total of 11,886 months of therapy with ATX; 40,949 months with LAS; 13,622 months with IAS; 38,141 months with SAS; 22,087 months with BUP; and 1,916 months with A2A. Combination therapy was present in 19.7% of continuing months (months after the first month of therapy) for ATX, 21.0% for LAS, 27.4% for IAS, 23.1% for SAS, 36.9% for BUP, and 53.0% for A2A. For patients receiving LAS, being age 25–44 or age 45 and older versus being 18–24 years old, seeing a psychiatrist, having comorbid depression, or having point-of-service coverage versus a Health Maintenance Organization (HMO) resulted in odds ratios significantly greater than 1, representing increased likelihood for combination therapy in managing adult ADHD. For patients receiving ATX, being age 25–44 or age 45 and older versus being 18–24 years old, seeing a psychiatrist, having a hyperactive component to ADHD, or having comorbid depression resulted in odds ratios significantly greater than 1, representing increased likelihood for combination therapy in managing adult ADHD. Conclusion ATX and LAS are the most likely drugs to be used as monotherapy. Factors predicting combination use were similar for months in which ATX was used and for months in which LAS was used except that a hyperactive component to ADHD predicted increased combination use for ATX but not for LAS.

Rationale Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric-acid A (GABA A ) receptors (e.g., alprazolam) modestly attenuate the abuse-related effects of stimulants like amphetamine. The use of higher doses to achieve greater efficacy is precluded by side effects. Combining naltrexone and alprazolam might safely maximize efficacy while avoiding the untoward effects of the constituent compounds. Objectives The present pilot study tested the hypothesis that acute pretreatment with the combination of naltrexone and alprazolam would not produce clinically problematic physiological effects or negative subjective effects and would reduce the positive subjective effects of d -amphetamine to a greater extent than the constituent drugs alone. Methods Eight nontreatment-seeking, stimulant-using individuals completed an outpatient experiment in which oral d -amphetamine (0, 15, and 30 mg) was administered following acute pretreatment with naltrexone (0 and 50 mg) and alprazolam (0 and 0.5 mg). Subjective effects, psychomotor task performance, and physiological measures were collected. Results Oral d -amphetamine produced prototypical physiological and stimulant-like positive subjective effects (e.g., VAS ratings of Active/Alert/Energetic, Good Effect, and High). Pretreatment with naltrexone, alprazolam, and their combination did not produce clinically problematic acute physiological effects or negative subjective effects. Naltrexone and alprazolam each significantly attenuated some of the subjective effects of d -amphetamine. The combination attenuated a greater number of subjective effects than the constituent drugs alone. Conclusions The present results support the continued evaluation of an opioid receptor antagonist combined with a GABA A -positive modulator using more clinically relevant experimental conditions like examining the effect of chronic dosing with these drugs on methamphetamine self-administration.