Attention-Deficit/Hyperactivity Disorder Symptoms Are Associated with Greater Delay Discounting of Condom-Protected Sex and Money.

Attention-deficit/hyperactivity disorder (ADHD) is associated with increased risk of detrimental life outcomes. Recent research also indicates that ADHD is associated with sexual risk behavior, such as unprotected sex. Some risky sexual behaviors may be driven, in part, by preference for immediate rewards, referred to as delay discounting, which is prominent in etiological models of ADHD. Therefore, the present study examined the effect of delay on preference for both monetary and sexual outcomes in adults with many ADHD symptoms (both on and off medication) and with fewer ADHD symptoms. Online participants (N = 275; n = 161 males, n = 114 females) completed a monetary delay discounting task, assessing preference for smaller sooner versus larger delayed hypothetical money, and the Sexual Delay Discounting Task, assessing preference for condom use in hypothetical casual sex scenarios based on delay until condom availability. Those with greater ADHD symptoms discounted delayed monetary outcomes as well as delayed condom-protected sex (i.e., preferred sooner money rewards and immediate unprotected sex) significantly more than those with fewer symptoms; however, no effect of current medication use was found across monetary or sexual delay discounting among those with greater ADHD symptoms. This study is the first to demonstrate the relation between ADHD symptoms and reduced condom-use likelihood. Increased discounting of delayed condom-protected sex might constitute one mechanism of risky sexual behavior among individuals with ADHD symptoms. Interventions geared toward increasing condom use in situations in which condoms may otherwise be unavailable, may mitigate risky sexual behaviors and their associated harms in this population.

Topical 'dual-soft' glucocorticoid receptor agonist for dermatology.

Steroidal glucocorticoids (GR agonists) have been widely used for the topical treatment of skin disorders, including atopic dermatitis. They are a very effective therapy, but they are associated with both unwanted local effects in the skin (skin thinning/atrophy) and systemic side effects. These effects can limit the long-term utility of potent steroids. Here we report on a topically delivered non-steroidal GR agonist, that has the potential to deliver high efficacy in the skin, but due to rapid metabolism in the blood & liver ("dual-soft") it should have greater systemic safety than existing treatments. In addition, compared to less selective steroidal GR agonists, the new non-steroidal Selective Glucocorticoid Agonists (SEGRAs) have the potential to avoid the skin atrophy observed with existing topical steroids. Due to its potential for reduced skin atrophy and low systemic exposure, LEO 134310 (17) may be suitable for long term topical treatment of skin diseases such as atopic dermatitis and psoriasis.

The Hotel Room Purchase Task: Effects of Gender and Partner Desirability on Demand for Hypothetical Sex in Individuals with Disordered Cocaine Use and Controls.

Hypothetical purchase tasks allow for rapid assessment of behavioral economic demand for numerous commodities and are useful in evaluating reinforcer pathologies, such as substance and behavioral addiction. Currently, there is not a task for evaluating demand for sex without requiring implicit engagement in sex work. The current study used a novel purchase task with hotel rooms for sex as the hypothetical commodity to assess demand for sex in individuals with disordered cocaine use, a population that frequently engages in risky sexual behavior. Adults meeting criteria for cocaine abuse or dependence (13 males, ten females) and noncocaine-using controls (eight males, three females) chose hypothetical sexual partners from a series of photographs and endorsed two partners with whom they would most and least like to have sex. Participants then completed the hotel purchase task for both partners, wherein they reported how many nights at a hotel room, at prices from $10 to $1280 per night, they would purchase in a year. Demand intensity was significantly greater and demand elasticity was significantly lower for the most preferred relative to the less preferred partner. Males demonstrated significantly greater intensity and lesser elasticity for sex than females. Demand metrics did not differ between the cocaine and control group. This task may serve as a useful measure of demand for sex without requiring implicit hypothetical engagement in sex work. Future studies exploring the relation between task performance and other characteristics such as sexual dysfunction, in addition to acute substance administration effects, may further determine the task's clinical utility.

Sexual Probability Discounting: A Mechanism for Sexually Transmitted Infection Among Undergraduate Students.

Lack of condom use among youth is a major contributor to the spread of sexually transmitted infections (STIs) including HIV/AIDS, which has lifelong deleterious health consequences. College students (N = 262) completed the Sexual Probability Discounting Task in which participants reported their likelihood of condom use under various probabilities of contracting an STI. Each participant completed the task in regard to different STIs including HIV/AIDS and different partners. Results showed that the likelihood of condom-protected sex generally decreased as HIV/AIDS and other STI contraction became less probable. Moreover, condom-protected sex likelihood was related to STI type (e.g., decreased condom-protected sex in chlamydia relative to HIV/AIDS condition) and partner desirability (decreased condom-protected sex with more desirable partners). Results are the first to show that compared to other STIs, HIV/AIDS had the most influence on condom-protected sex. Results showed probability discounting contributed to lack of condom-protected sex and offers a novel framework for examining determinants of within-subject variability in condom use.

Discounting of Condom-Protected Sex as a Measure of High Risk for Sexually Transmitted Infection Among College Students.

The study examined sexual delay discounting, or the devaluation of condom-protected sex in the face of delay, as a risk factor for sexually transmitted infection (STI) among college students. Participants (143 females, 117 males) completed the sexual delay discounting task (Johnson & Bruner, 2012) and questionnaires of risky sexual behavior, risk perception, and knowledge. Participants exhibited steeper sexual delay discounting (above and beyond general likelihood of having unprotected sex) when partners were viewed as more desirable or less likely to have a STI, with males demonstrating greater sexual delay discounting than females across most conditions. Importantly, greater self-reported risky sexual behaviors were associated with higher rates of sexual delay discounting, but not with likelihood of using a condom in the absence of delay. These results provide support for considering sexual delay discounting, with particular emphasis on potential delays to condom use, as a risk factor for STI among college students.

Alcohol Increases Delay and Probability Discounting of Condom-Protected Sex: A Novel Vector for Alcohol-Related HIV Transmission.

BACKGROUND: Alcohol use, especially at binge levels, is associated with sexual HIV risk behavior, but the mechanisms through which alcohol increases sexual risk taking are not well-examined. Delay discounting, that is, devaluation of future consequences as a function of delay to their occurrence, has been implicated in a variety of problem behaviors, including risky sexual behavior. Probability discounting is studied with a similar framework as delay discounting, but is a distinct process in which a consequence is devalued because it is uncertain or probabilistic. METHODS: Twenty-three, nondependent alcohol users (13 male, 10 female; mean age = 25.3 years old) orally consumed alcohol (1 g/kg) or placebo in 2 separate experimental sessions. During sessions, participants completed tasks examining delay and probability discounting of hypothetical condom-protected sex (Sexual Delay Discounting Task, Sexual Probability Discounting Task) and of hypothetical and real money. RESULTS: Alcohol decreased the likelihood that participants would wait to have condom-protected sex versus having immediate, unprotected sex. Alcohol also decreased the likelihood that participants would use an immediately available condom given a specified level of sexually transmitted infection (STI) risk. Alcohol did not affect delay discounting of money, but it did increase participants' preferences for larger, probabilistic monetary rewards over smaller, certain rewards. CONCLUSIONS: Acute, binge-level alcohol intoxication may increase sexual HIV risk by decreasing willingness to delay sex in order to acquire a condom in situations where one is not immediately available, and by decreasing sensitivity to perceived risk of STI contraction. These findings suggest that delay and probability discounting are critical, but heretofore unrecognized, processes that may mediate the relations between alcohol use and HIV risk.

Examining Delay Discounting of Condom-Protected Sex Among Men Who Have Sex with Men Using Crowdsourcing Technology.

Some men who have sex with men (MSM) have unprotected anal intercourse (UAI) in situations that put them at risk for HIV infection despite having the knowledge and skills to avoid these risks. The present study examined the potential role of delay discounting in sexual HIV risk behavior among MSM. Participants (n = 108) completed the Sexual Discounting Task and a questionnaire regarding UAI and other variables associated with HIV risk (e.g., age, socioeconomic status, substance use, psychiatric problems). MSM discounted the value of condom-protected anal intercourse in a manner that was orderly, hyperbolic, and sensitive to partner characteristics that likely influence realworld decisions about using condoms. Steeper discounting was associated with UAI, and other factors related to sexual HIV risk among MSM, including young age, socioeconomic disadvantage, substance use, sex under the influence of substances, and depression). Delay discounting is likely a critical, but underappreciated facet of HIV risk among MSM.

Investigation of "bath salts" use patterns within an online sample of users in the United States.

"Bath salts" are synthetic stimulant "legal highs" that have recently been banned in the US. Epidemiological data regarding bath salts use are limited. In the present study, 113 individuals in the US reporting use of bath salts completed an anonymous, online survey characterizing demographic, experiential, and psychological variables. Respondents were more often male, 18-24 years old, and Caucasian/White with some college education. Past-year use was typically low (≤ 10 days), but marked by repeated dosing. Intranasal was the most frequently reported administration route and subjective effects were similar to other stimulants (e.g., cocaine, amphetamines). Bath salts use was associated with increased sexual desire and sexual HIV risk behavior, and met DSM-5 diagnostic criteria for disordered use in more than half of respondents. Bath salts use persists in the US despite federal bans of cathinone-like constituents. Self-reported stimulant-like effects of bath salts suggest their use as substitutes for traditional illicit stimulants. Data revealed more normative outcomes vis-à-vis extreme accounts by media and medical case reports. However, indications of product abuse potential and sexual risk remain, suggesting bath salts pose potential public health harm.

The Blinded-Dose Purchase Task: assessing hypothetical demand based on cocaine, methamphetamine, and alcohol administration.

RATIONALE: Behavioral economic drug purchase tasks quantify the reinforcing value of a drug (i.e., demand). Although widely used to assess demand, drug expectancies are rarely accounted for and may introduce variability across participants given diverse drug experiences. OBJECTIVES: Three experiments validated and extended previous hypothetical purchase tasks by using blinded drug dose as a reinforcing stimulus, and determined hypothetical demand for experienced effects while controlling for drug expectancies. METHODS: Across three double-blind, placebo-controlled, within-subject experiments, cocaine (0, 125, 250 mg/70 kg; n=12), methamphetamine (0, 20, 40 mg; n=19), and alcohol (0, 1 g/kg alcohol; n=25) were administered and demand was assessed using the Blinded-Dose Purchase Task. Participants answered questions regarding simulated purchasing of the blinded drug dose across increasing prices. Demand metrics, subjective effects, and self-reported real-world monetary spending on drugs were evaluated. RESULTS: Data were well modeled by the demand curve function, with significantly higher intensity (purchasing at low prices) for active drug doses compared to placebo for all experiments. Unit-price analyses revealed more persistent consumption across prices (lower α) in the higher compared to lower active dose condition for methamphetamine (a similar non-significant finding emerged for cocaine). Significant associations between demand metrics, peak subjective effects, and real-world spending on drugs also emerged across all experiments. CONCLUSIONS: Orderly demand curve data revealed differences across drug and placebo conditions, and relations to real-world measures of drug spending, and subjective effects. Unit-price analyses enabled parsimonious comparisons across doses. Results lend credence to the validity of the Blinded-Dose Purchase Task, which allows for control of drug expectancies.

Methamphetamine administration dose effects on sexual desire, sexual decision making, and delay discounting.

Correlational evidence has linked methamphetamine use and HIV sexual risk behavior, but the direct effects of methamphetamine on sexual desire and sexual decision making in humans have not been tested. This study was designed to test the effect of methamphetamine administration on sexual desire and hypothetical condom-use decisions as measured by the Sexual Delay Discounting Task. Recreational stimulant users (n = 19) participated in this within-subject, placebo-controlled study comparing the effects of 0 mg, 20 mg, and 40 mg of oral methamphetamine. Compared to placebo, methamphetamine caused dose-related and time-related increases in a single-item sexual desire rating and some standard stimulant abuse liability ratings, as well as dose-related increases in the Sexual Arousal and Desire Inventory (SADI; a multidimensional scale capturing positive and negative aspects of desire/arousal). However, methamphetamine caused no significant mean differences in likelihood of condom use within the Sexual Delay Discounting Task or the Monetary Discounting Task. SADI scores were negatively correlated with change from placebo in condom use likelihood in the Sexual Delay Discounting Task for some partner conditions (i.e., decreased reported likelihood of condom use in participants who experienced increased desire/arousal and vice versa). These mixed results may be consistent with methamphetamine's role as both a treatment for attention-deficit/hyperactivity disorder and as a drug of abuse associated with increased delay discounting, and they suggest that methamphetamine's effects on discounting may be modulated by the reinforcing properties of what is being discounted. Delay discounting may be an understudied element of risky sexual decision making, particularly among individuals who use methamphetamine. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Discovery of PF-184563, a potent and selective V1a antagonist for the treatment of dysmenorrhoea. The influence of compound flexibility on microsomal stability.

The V1a receptor has emerged as an attractive target for a range of indications including Raynaud's disease and dysmenorrhoea. As part of an effort to discover a new class of orally active V1a antagonist, we optimised a highly lipophilic, metabolically unstable lead into a range of potent, selective and metabolically stable V1a antagonists. In this communication, we demonstrate the series-dependent effect of limiting the number of rotatable bonds in order to decrease Cytochrome P450-mediated metabolism. This effort culminated in the discovery of PF-184563, a novel, selective V1a antagonist with excellent in vitro and in vivo properties.

Optimisation of a pyrazole series of progesterone antagonists; Part 1.

The design and synthesis of a novel series of non-steroidal progesterone receptor antagonists is described. Ligand-lipophilicity efficiency (LLE) was used in the selection of a prototype agent for in vivo pharmacology studies.

Potential for limited reinforcing and abuse-related subjective effects of intranasal oxytocin.

BACKGROUND: There has been growing interest in using oxytocin as a pharmacotherapy for psychiatric disorders, including substance use disorder. Limited data exist regarding oxytocin's reinforcing efficacy, which is a necessary consideration for novel pharmacotherapies, especially in substance-using populations. AIMS: This study aimed to determine the potential reinforcing effects of intranasally administered oxytocin by assessing behavioral economic demand and subjective effects. METHODS: Healthy adults (n = 23) participated in a double-blind, repeated-measures, laboratory study wherein they received intranasal oxytocin (40 IU) or placebo in a randomized order across two sessions. Participants completed drug purchasing tasks at the conclusion of both sessions. Throughout both sessions, subjective and physiological effects were assessed. RESULTS: Demand-curve analysis of purchasing tasks revealed greater median purchasing for oxytocin relative to placebo. Physiological and subjective effects did not significantly differ between oxytocin and placebo. However, a nonsignificant trend was observed for moderately greater drug liking for oxytocin relative to placebo. There was a significant, positive correlation between the difference in drug liking (between oxytocin and placebo) and the difference in lowest-price purchasing (between oxytocin and placebo). CONCLUSIONS: These data suggest the potential for limited reinforcing and abuse-related subjective effects of intranasal oxytocin. Given the small sample, the greater drug liking of oxytocin compared to placebo, and the positive relation between demand and drug liking, it is possible that oxytocin may produce reinforcing effects in some participants. Therefore, additional studies of oxytocin reinforcement are warranted.

Randomized controlled trial of d-cycloserine in cocaine dependence: Effects on contingency management and cue-induced cocaine craving in a naturalistic setting.

Cocaine dependence constitutes a significant public health concern. This randomized, double-blind, placebo-controlled trial tested a novel approach to reducing cocaine use among cocaine-dependent individuals with d-cycloserine, a drug known to enhance learning and some learning-based therapies. Urine samples and cocaine craving were assessed across three phases: induction (Weeks 1-2), treatment (Weeks 3-5; urinalysis-based contingency management plus exposure therapy), and posttreatment (Weeks 6-7). During the treatment phase, either 50 mg of d-cycloserine or placebo was administered after delivery of urinalysis feedback with potential monetary reward and before exposure therapy sessions in naturalistic contexts individually associated with cocaine use. d-cycloserine significantly improved learning on an operant laboratory task. Contingency management significantly reduced cocaine use and craving. d-cycloserine did not significantly affect cocaine use or craving in the treatment phase. Craving significantly increased for the d-cycloserine group during the post treatment phase. Therefore, although the study showed that d-cycloserine was capable of improving learning, enhancement of learning-based therapy was not observed. Moreover, no differences in behavioral measures of cocaine demand (cocaine purchasing task) or monetary or sexual delay discounting were observed across phases or between groups in any phase. These results are somewhat consistent with previous findings suggesting that d-cycloserine administration increases cocaine craving, although they differ from other findings showing that d-cycloserine administration reduces alcohol or nicotine cravings. Methodological variables (e.g., guided vs. unguided exposure therapy sessions, length of extinction exposure) likely play a role in dissimilar findings observed across studies. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Demographic and sexual risk predictors of delay discounting of condom-protected sex.

Objective: Sexual delay discounting describes the decreased likelihood of condom-protected sex if a condom is not immediately available, which can be quantitatively summarised using the Sexual Delay Discounting Task (SDDT). The present studies determined the extent to which condom use likelihood as assessed by the SDDT is associated with self-reported sexual risk behaviours and demographics in two online samples of adults. Design: Study 1 (n = 767) assessed demographics, sexual risk behaviour, and delay discounting, and examined relations between these variables using correlation and regression. Study 2 (n = 267) examined whether real-world instances of unprotected sex because a condom was not immediately available predicted greater sexual discounting. Main outcome measures: Sexual delay discounting, condom use. Results: Both studies observed significant positive relations between sexual delay discounting and self-reported sexual risk behaviours, and found that males tended to show greater sexual discounting. In Study 2, 46% of the sample self-reported having unprotected sex because a condom was not immediately available, and these individuals showed significantly greater sexual delay discounting. Conclusion: These results extend prior findings by demonstrating that delay is a critical variable underlying real-life sexual risk behaviour among non-clinical samples. The SDDT is an ecologically valid measure of these processes.

Designing rapid onset selective serotonin re-uptake inhibitors. Part 3: Site-directed metabolism as a strategy to avoid active circulating metabolites: structure-activity relationships of (thioalkyl)phenoxy benzylamines.

A series of thio-alkyl containing diphenylethers were designed and evaluated, as a strategy to competitively direct metabolism away from unwanted amine N-demethylation and deliver a pharmacologically inactive S-oxide metabolite. Overall, sulfonamide 20 was found to possess the best balance of target pharmacology, pharmacokinetics and metabolism profile.

Designing rapid onset selective serotonin re-uptake inhibitors. 2: structure-activity relationships of substituted (aryl)benzylamines.

A series of substituted benzylamines 2-48 were prepared as part of a strategy to identify structurally differentiated and synthetically more accessible selective serotonin reuptake inhibitors, relative to clinical candidate 1. In particular, 44 and 48; demonstrated low nanomolar potency and good selectivity, in a structurally simplified template and, in vivo, very low Vdu, significantly lower than l, and a more rapid T(max), consistent with our clinical objectives.

Steady-state assessment of impulsive choice in Lewis and Fischer 344 rats: between-condition delay manipulations.

Previous research has shown that Lewis rats make more impulsive choices than Fischer 344 rats. Such strain-related differences in choice are important as they may provide an avenue for exploring genetic and neurochemical contributions to impulsive choice. The present systematic replication was designed to determine if these findings could be reproduced using a procedure less susceptible to within- or between-session carry-over effects that may have affected previous findings. Specifically, delays to the larger-later food reinforcer were manipulated between conditions following steady-state assessments of choice, and the order of delays across conditions was mixed. The results confirmed previous findings that Lewis rats made significantly more impulsive choices than Fischer 344 rats. Fischer 344 rats' preference for the larger-later reinforcer, on the other hand, was less extreme than reported in prior research, which may be due to carry-over effects inherent to the commonly used technique of systematically increasing delays within session. Previously reported across-strain motor differences were reproduced as Lewis rats had shorter latencies than Fischer 344 rats, although these latencies were not correlated with impulsive choice. Parallels between reduced dopamine function in Lewis rats and clinical reports of impulse-control disorders following treatment of Parkinson patients with selective D2/D3 dopamine agonists are discussed.

Differential relations between delay discounting and distress tolerance as a function of opportunity cost and alcohol use.

Delay discounting refers to one process by which an individual devalues delayed outcomes. Typical discounting tasks provide no information about events during delays to larger-later rewards. Imposing opportunity costs during the delay increases how steeply delayed rewards are discounted (P. S. Johnson, Herrmann, & Johnson, 2015). The present research evaluated whether distress tolerance (i.e., one's ability to tolerate distressing emotions and events) is related to discounting rates when opportunity costs are low, high, or unspecified. In a sample of predominantly female college students, we partially replicated that delay discounting was related to distress tolerance when opportunity costs were unspecified (significant relations confined to particular facets of distress tolerance), but distress tolerance was not related to delay discounting when opportunity costs were specified as low or high. The nature of the relation between distress tolerance and discounting when opportunity costs were unspecified was clarified by a significant interaction between alcohol use and distress tolerance; distress tolerance was unrelated to delay discounting except among participants with problematic alcohol use. Further research is needed to characterize relations between alcohol use, distress tolerance, and delay discounting and inform prevention and treatment efforts in at-risk populations. (PsycINFO Database Record

To take or not to take: the association between perceived addiction risk, expected analgesic response and likelihood of trying novel pain relievers in self-identified chronic pain patients.

BACKGROUND AND AIMS: Probability discounting refers to the effect of outcome uncertainty on decision making. Using probability discounting, we examined the degree to which self-identified chronic pain patients (CPP) were likely to try a novel analgesic medication given increasing addiction risk. We postulated that propensity for opioid misuse, trait impulsivity and previous opioid experience would be associated positively with likelihood of risky medication use. DESIGN: This cross-sectional on-line study determined state/trait associations with addiction-related medication decisions in CPP. SETTING: US-based CPP participated via Amazon Mechanical Turk; data were collected and analyzed in Baltimore, Maryland. PARTICIPANTS: A total of 263 CPP (70.6% female) participated in the study from 12-13 December 2014. MEASUREMENTS: CPP responded to the Benefit versus Addiction Risk Questionnaire (BARQ) assessing likelihood of taking a hypothetical once-daily oral analgesic medication as a function of two factors: risk of addiction (0-50%) and duration of expected complete pain relief (3, 30 or 365 days). The primary outcome was the BARQ, quantified as area under the curve (AUC). Grouping of CPP at high or low risk for opioid misuse was based on the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R). Predictors included previous experience with opioids, as well as various measures of chronic pain and mental health. FINDINGS: Across hypothetical addiction risk assessed in the BARQ, the likelihood of taking a novel analgesic medication was elevated significantly in patients with high (≥18; n = 137) versus low (<18; n = 126) SOAPP-R scores [P < 0.001; 3-day: Cohen's d = 0.66, 95% confidence interval (CI) = 0.63, 0.69; 30-day: d = 0.74, 95% CI = 0.71, 0.78; 365-day: d = 0.75, 95% CI = 0.72, 0.79]. CONCLUSIONS: In the United States, self-identified chronic pain patients (CPP) at higher risk for opioid misuse were more likely to report willingness to try a novel analgesic despite increasing addiction risk than CPP with low risk of opioid misuse.