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Cocaine use disorder (CUD) is a major public health issue, and greater cocaine use severity has been associated with worse treatment retention and outcomes. Therefore, greater understanding of processes that influence cocaine use is needed. Both anhedonia (i.e., undervaluation of nondrug rewards) and cocaine demand (i.e., cocaine valuation) are related to cocaine use severity and thematically related to each other at face value, but no studies have directly compared these outcomes to our knowledge. The present study represents a secondary analysis from a two-phase sequential, multiple assignment, randomized trial aimed at developing adaptive interventions for CUD. We examined the relationship between anhedonia and cocaine demand and how these measures were related to cocaine use severity. Participants ( N = 116) were treatment-seeking adults with CUD. All measures were taken at baseline before treatment initiation. Analyses revealed (a) moderate and very strong evidence of relationships between cocaine demand factors (i.e., persistence, amplitude) and anhedonia (PP values ≥ 77.8%); (b) positive association between cocaine demand (both persistence and amplitude) and measures of cocaine use severity, with the exception of one relationship, which was in the opposite direction; and (c) demand amplitude continued to be positively related to cocaine use severity, even when considering anhedonia. Overall, findings from this study indicate cocaine demand relates to cocaine use severity more strongly than anhedonia. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Behavioral therapies are considered best practices in the treatment of substance use disorders (SUD) and used as first-line approaches for SUDs without FDA-approved pharmacotherapies. Decades of research on the neuroscience of drug reward and addiction have informed the development of current leading behavioral therapies that, while differing in focus and technique, have in common the overarching goal of shifting reward responding away from drug and toward natural non-drug rewards. This review begins by describing key neurobiological processes of reward in addiction, followed by a description of how various behavioral therapies address specific reward processes. Based on this review, a conceptual 'map' is crafted to pinpoint gaps and areas of overlap, serving as a guide for selecting and integrating behavioral therapies., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background: Firefighters are at heightened risk of posttraumatic stress disorder (PTSD), underscoring the importance of understanding clinically targetable factors to inform evidence-based intervention development. Hedonic capacity, or the ability to experience pleasure, is a facet of reward functioning. Anhedonia (i.e., low or absent hedonic capacity) is a hallmark symptom of PTSD. Distress tolerance (DT), or the perceived ability to withstand negative emotional states, has also demonstrated associations with PTSD., Objective: The purpose of the present study was to examine the main and interactive effects of self-reported hedonic capacity (Snaith-Hamilton Pleasure Scale) and DT (Distress Tolerance Scale) on PTSD symptom severity among firefighters., Method: A hierarchical linear regression was performed among a sample of 802 trauma-exposed career firefighters, who completed a battery of self-report questionnaires. Covariates included trauma load (i.e., number of trauma types), years in the fire service, and depression symptoms (excluding anhedonia)., Results: Both hedonic capacity ( B = 2.71, SE = .95, p = .005) and DT ( B = -.21, SE = .03, p < .001) were incrementally associated with PTSD symptom severity. The interactive effect of hedonic capacity and DT was associated with heightened PTSD symptom severity ( B = .25, SE = .07, p < .001)., Conclusions: Hedonic capacity and DT were independently and transactionally associated with heightened PTSD symptom severity among trauma-exposed firefighters. These findings provide evidence for the utility in developing interventions that target DT and impaired hedonic capacity among firefighters, particularly those experiencing PTSD symptomatology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The behavioral economic measure drug demand and the neural measure late positive potential (LPP) are two measures of motivational value that have been associated with drug relapse risk and treatment outcomes. Despite having overlapping themes, no studies have directly compared drug demand and LPP. Participants ( N = 59) included treatment-seeking individuals with cocaine use disorder that had completed both a baseline cocaine demand task and an electroencephalogram (EEG) picture-viewing task of drug-related and pleasant picture cues. Associations between the LPP difference score amplitude (drug-pleasant) and five demand indices ( Q ₀, essential value [EV], O max , P max , and breakpoint [BP]) were evaluated via Bayesian generalized linear modeling. Positive associations (posterior probabilities ≥ 75%) were found between LPP amplitude and four demand indices ( Q ₀, EV, O max , BP). These results suggest that individuals who attach greater relevance to cocaine cues also exhibit greater valuation of cocaine reward. Implications for incorporating methodology from behavioral science and brain imaging are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background and Aims: Identifying modifiable neuropsychological factors associated with more severe CUD could improve CUD treatment. Impairments in processing of non-drug rewards may be one such factor. This study assessed the relationship between reward functioning and cocaine use severity using multi-modal measures of three distinct reward functions: consummatory reward (pleasure or "liking"); motivational reward ("wanting") and reward learning., Methods: Fifty-three adults with at least moderate CUD completed self-report and behavioral measures of consummatory reward, motivational reward and reward learning, and a composite cocaine use severity measure including quantity, frequency and life impacts of cocaine use. We conducted parallel Frequentist and Bayesian multiple regressions with measures of reward functioning as predictors of cocaine use severity., Results: Less self-reported ability to experience pleasure, a hypothesized measure of consummatory reward, significantly predicted greater severity after adjustment for covariates and multiple hypothesis testing, β = 0.39, t(38) = 2.86, p = 0.007. Bayesian analyses confirmed a highly likely association between severity and ability to experience pleasure, and provided moderate evidence for associations with willingness to exert effort and reward learning., Conclusions: Our results suggest that less experience of subjective pleasure is related to greater cocaine use severity. This cross-sectional study cannot establish whether differences in consummatory reward are pre-existing, a result of CUD, or both. However, these results suggest interventions focused on increasing subjective pleasure, such as mindful "savoring", should be investigated for CUD., Competing Interests: Declaration of Competing Interest No conflicts declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Acute inflammation is associated with sickness behavior characterized by reduced motivation for pleasurable activities in humans. The current study investigated the effect of an experimentally induced inflammatory stimulus on motivational reward in people who remitted from depression., Methods: This randomized, double-blind crossover study involved 12 participants, 5 with remitted major depressive disorder (rMDD) and 7 healthy controls (HC), who received an injection of typhoid vaccine and placebo (or vice-versa) intramuscularly at least one week apart. At baseline and between 4 and 6 h post-injection on both days, participant mood was measured using the profile of mood states (POMS), and injection blood samples were collected for cytokines measurement. All participants completed the Effort Expenditure for Rewards Task (EEfRT), a behavioral paradigm measuring effort-based decision-making before and 4 h post-both injections. Generalized linear mixed modeling was used to evaluate group differences in choosing the hard over easy task to obtain a monetary reward., Results: Typhoid vaccine increased IL-6 in all participants. On the EEfRT, a significant interaction between treatment condition (typhoid vs. placebo) and participant group (HC vs. rMDD) was found (p = .004). Analyses of simple effects within treatment conditions found that after placebo, HCs were more likely to choose the harder task than rMDD (OR = 3.21; p = .013). However, after the typhoid vaccine, no differences were found between rMDD and HC (p = .397). Analyses within participant groups found that the probability of choosing a hard task was higher after placebo for HC (OR = 1.37; p = .045), but not different within rMDD (p = .241). For HC at baseline, mood was significantly lower following injection with typhoid vaccine, relative to placebo (b = -1.03, p < .001); however, this effect should be considered coincidental, given that mood rating was taken prior to injection. For rMDD patients 4-6 h post-injection, mood was significantly lower following typhoid vaccine, relative to placebo (b = -0.981, p < .001 b = -0.77, p < .001). Finally, for HC receiving placebo, mood was significantly lower 4-6 h post-injection, relative to baseline (b = -1.76, p < .001)., Conclusions: Our preliminary findings suggest persistent deficits in motivational reward processing function despite clinical improvement in remitted depressed patients., Competing Interests: Declaration of competing interest Dr. Selvaraj has received honoraria from British Medical Journal Publishing Group and Psychiatry Education Forum. He has received research support from Flow Neuroscience and study/sub investigator for clinical research, Compass Pathways, LivaNova, Janssen and Relmada. He received consultant fee for DSMB from Vicore pharma and worldwide clinical trials/Inversago. Dr. Soares has received grants/research support from BMS, Forrest, J&J, Merck, Compass pathways, Relmada, Stanley Medical Research Institute, NIH, and has been a speaker for Pfizer and Abbott. All other authors have no conflicts of interest to report., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background : Firefighters represent an understudied population with high rates of hazardous alcohol use and alcohol use disorder. This population is also at an increased risk of mental health disorders and related symptoms such as anger. Anger is a relatively understudied negative mood state with clinical relevance to alcohol use among firefighters. Anger is associated with greater alcohol use and may spur more approach-motivated reasons for drinking compared to other negative emotions. Objectives : This study sought to examine: 1. whether anger significantly contributes to alcohol use severity in firefighters above and beyond general negative mood; 2. which of four validated drinking motives (e.g., coping, social, enhancement and conformity) act as moderators in the relationship between anger and alcohol use severity in this population. The current study is a secondary analysis of data from a larger study examining health and stress behaviors among firefighters (N = 679) at a large urban fire department in the southern United States. Results : Results revealed that anger was positively associated with alcohol use severity, even after controlling for general negative mood. Further, social and enhancement motives for drinking were significant moderators of the relationship between anger and alcohol use severity. Conclusions : These findings identify anger specifically as an important factor to be considered when assessing alcohol use in firefighters, especially those who are drinking to make social experiences more enjoyable or to enhance their mood. These findings can be used to inform more specialized interventions for alcohol use by targeting anger more specifically in firefighters and other male-dominated first-responder populations.

Many mental health disorders are characterized by an impaired ability, or willingness, to exert effort to obtain rewards. This impairment is modeled in effort-based decision tasks, and neuropharmacological studies implicate dopamine in this process. However, other transmitter systems such as opioidergic and cholinergic systems have received less attention. Here, in two separate studies we tested the acute effects of naltrexone and nicotine on effort-based decision-making in healthy adults. In Study 1, we compared naltrexone (50mg and 25mg) to placebo, and in Study 2, a pilot study, we compared nicotine (7mg) to placebo. In both studies, participants completed the Effort Expenditure for Rewards Task (EEfRT), which measured effort-based decision-making related to monetary rewards. Although subjects expended greater effort for larger reward magnitude and when there was a higher probability of receiving the reward, neither naltrexone nor nicotine affected willingness to exert effort for monetary rewards. Although the drugs produced significant and typical drug effects on measures of mood and behavior, they did not alter effort-based decision-making. This has implications both for the clinical use of these drugs, as well as for understanding the neuropharmacology of effort-related behavior., Competing Interests: The authors have declared that no competing interests exist.

Smokers with stronger neuroaffective responses to drug-related cues compared to nondrug-related pleasant images (C > P) are more vulnerable to compulsive smoking than individuals with the opposite brain reactivity profile (P > C). However, it is unknown if these neurobehavioral profiles exist in individuals abusing other drugs. We tested whether individuals with cocaine use disorder (CUD) show similar neuroaffective profiles to smokers. We also monitored eye movements to assess attentional bias toward cues and we further performed exploratory analyses on demographics, personality, and drug use between profiles. Participants with CUD ( n = 43) viewed pleasant, unpleasant, cocaine, and neutral images while we recorded electroencephalogram. For each picture category, we computed the amplitude of the late positive potential (LPP), an event-related potential component that reflects motivational relevance. k-means clustering classified participants based on their LPP responses. In line with what has been observed in smokers, clustering participants using LPP responses revealed the presence of two groups: one with larger LPPs to pleasant images compared to cocaine images (P > C) and one group with larger LPPs to cocaine images compared to pleasant images (C > P). Individuals with the C > P reactivity profile also had higher attentional bias toward drug cues. The two groups did not differ on demographic and drug use characteristics, however individuals with the C > P profile reported lower distress tolerance, higher anhedonia, and higher posttraumatic stress symptoms compared to the P > C group. This is the first study to report the presence of these neuroaffective profiles in individuals with CUD, indicating that this pattern may cut across addiction populations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background: The use of cannabis has been clinically associated with decreased motivation to engage in normally rewarding activities. However, evidence from previous controlled studies is mixed., Method: In this study, we examined the effects of acute delta-9-tetrahydrocannabinol (THC) versus placebo on a task measuring willingness to exert effort for rewards. This is a secondary analysis of a larger study examining interactions between ovarian hormones and THC. In this within-subjects study, oral THC and placebo were administered under double-blind conditions in counterbalanced order to healthy young adult (M age = 24 years) women with previous cannabis experience who were not regular users. Forty subjects completed three 4-h sessions with PL, 7.5 and 15 mg THC, while an additional 18 completed only PL and 15 mg THC sessions (design abridged due to pandemic). At each session, they completed a task consisting of making repeated choices between a hard and an easy task, which were worth varying amounts of money at varying probabilities., Results: THC dose-dependently decreased hard task choices (drug effect, b =  - 0.79, SE = 0.29, z =  - 2.67, p < 0.01), especially at moderate to high expected values of reward (drug × probability × amount interaction, b = 0.77, SE = 0.38, z = 1.99, p = 0.04). THC also slowed task performance (drug effect, b = 0.01, SE = 0.005, t(5.24) = 2.11, p = 0.04), but the effect of THC on choice was still significant after controlling for this psychomotor slowing., Conclusions: These findings support the idea that cannabis acutely reduces motivation to earn non-drug rewards. Still to be determined are the neurochemical mechanisms underlying this effect., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The present investigation examined the predictive utility of nonjudgmental acceptance, a facet of mindfulness defined as the ability to remain aware and nonevaluative about internal experience, in terms of substance-related cue reactivity among adults with substance use disorders (SUD) and posttraumatic stress (PTS) symptomatology. We hypothesized that higher nonjudgmental acceptance, indexed via self-report, would predict higher levels of self-reported control over oneself and safety 'in the moment', broadly, and lower levels of substance-related craving in response to substance script cues. Effects were expected after subtracting reactivity to neutral script cues from each outcome rating. PTS severity was included as a covariate. The sample was comprised of 53 adults (48.1% women; 75.9% African American; 74.1% with past-month PTSD) with substance dependence per DSM-IV and at least four symptoms of PTSD per DSM-5. Higher baseline nonjudgmental acceptance predicted greater safety and control in response to substance cues; no effects were found for craving. These experimental laboratory results elucidate the potential clinical utility of mindfulness-based interventions in bolstering recovery from addiction among adults with SUD/PTS by fostering safety and control in response to substance cues., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: While studies have investigated the effects of posttraumatic stress disorder (PTSD) symptoms on substance use, information on these associations in the context of drug cue reactivity is lacking, which can provide meaningful information about risk for relapse. The current study assessed the associations between PTSD symptom clusters and reactivity to cues in trauma-exposed adults with cocaine use disorder., Methods: We recorded electroencephalogram on 52 trauma-exposed participants (M age = 51.3; SD = 7.0; 15.4 % women) diagnosed with cocaine use disorder while they viewed pleasant (i.e., erotic, romantic, sweet foods), unpleasant (i.e., mutilations, violence, accidents), neutral, and cocaine-related images. Reactivity was measured with the late positive potential (LPP), an indicator of motivational relevance. It was hypothesized that individuals with greater PTSD avoidance and negative alterations in cognition and mood (NACM) symptoms, as determined by the PTSD Checklist for DSM-5 (PCL-5), would have higher LPPs to cocaine-related images, indicating greater cue reactivity., Results: Linear mixed modeling indicated that higher NACM symptomatology was associated with higher LPPs to cocaine cues and higher arousal/reactivity was associated with lower LPPs to cocaine cues., Conclusions: These results highlight the potential clinical utility of the LPP in assessing drug cue reactivity in trauma-exposed adults with substance use disorder., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Rationale: Misuse of dextroamphetamine occurs in work and recreational contexts. While acute drug effects broadly predict abuse liability, few studies have considered the relationship between acute effects and context., Objectives: This study examined how individual differences in acute effects of dextroamphetamine relate to desire to take dextroamphetamine again in different contexts., Methods: This secondary analysis used data from healthy adults with no history of moderate-to-severe substance use disorder, who received oral doses of placebo and dextroamphetamine (10 and 20 mg) over 3 sessions under double-blind, randomized conditions. Subjects rated subjective effects and completed reward-related behavioral tasks. Subjects rated their desire to take dextroamphetamine again in hypothetical work and recreational contexts. Multilevel models examined within-subjects change scores (10 mg-placebo; 20 mg-placebo) to determine how subjective effects and behavioral outcomes predicted desire to take dextroamphetamine again for work versus recreation., Results: Subjects reported more desire to take 20 mg dextroamphetamine again for work than for recreation. At 20 mg, there was an interaction between context and liking/wanting, such that liking/wanting predicted desire to use dextroamphetamine for work only. There was also an interaction at 20 mg between context and psychomotor speed, such that psychomotor speed predicted interest in using dextroamphetamine for recreation only., Conclusions: We found that positive subjective effects predicted desire to use dextroamphetamine again for work, while increased motor effects predicted desire to use dextroamphetamine recreationally. Hedonic effects may be perceived as advantageous when working, while increased physical energy may be preferred during recreation, suggesting that context of intended use is important when examining abuse liability., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Effort-related decision-making and reward learning are both dopamine-dependent, but preclinical research suggests they depend on different dopamine signaling dynamics. Therefore, the same dose of a dopaminergic medication could have differential effects on effort for reward vs. reward learning. However, no study has tested how effort and reward learning respond to the same dopaminergic medication within subjects. The current study aimed to test the effect of therapeutic doses of d-amphetamine on effort for reward and reward learning in the same healthy volunteers. Participants (n = 30) completed the Effort Expenditure for Reward Task (EEfRT) measure of effort-related decision-making, and the Probabilistic Reward Task (PRT) measure of reward learning, under placebo and two doses of d-amphetamine (10 mg, and 20 mg). Secondarily, we examined whether the individual characteristics of baseline working memory and willingness to exert effort for reward moderated the effects of d-amphetamine. d-Amphetamine increased willingness to exert effort, particularly at low to intermediate expected values of reward. Computational modeling analyses suggested this was due to decreased effort discounting rather than probability discounting or decision consistency. Both baseline effort and working memory emerged as moderators of this effect, such that d-amphetamine increased effort more in individuals with lower working memory and lower baseline effort, also primarily at low to intermediate expected values of reward. In contrast, d-amphetamine had no significant effect on reward learning. These results have implications for treatment of neuropsychiatric disorders, which may be characterized by multiple underlying reward dysfunctions.

Substance use disorders (SUD) commonly co-occur with posttraumatic stress disorder (PTSD) symptoms, and the comorbidity is prevalent and difficult-to-treat. Few studies have objectively analyzed language use in psychotherapy as a predictor of treatment outcomes. We conducted a secondary analysis of patient language use during cognitive-behavioral therapy (CBT) in a randomized clinical trial, comparing a novel, integrated CBT for PTSD/SUD with standard CBT for SUD. Participants included 37 treatment-seeking, predominantly African-American adults with SUD and at least four symptoms of PTSD. We analyzed transcripts of a single, matched session across both treatment conditions, using the Linguistic Inquiry and Word Count (LIWC) program. The program measures language use across multiple categories. Compared to standard CBT for SUD, patients in the novel, integrated CBT for PTSD/SUD used more negative emotion words, partially consistent with our hypothesis, but less positive emotion words. Further, exploratory analyses indicated an association between usage of cognitive processing words and clinician-observed reduction in PTSD symptoms, regardless of treatment condition. Our results suggest that language use during therapy may provide a window into mechanisms active in therapy.

Background: Inflammation is implicated in cocaine use and associated problems, including depression and cognitive impairment., Objective: We assessed 18 cytokines, cocaine use, cognition, and depression in individuals with Cocaine Use Disorder. Our general hypothesis was that higher pro-inflammatory cytokines would relate to more cocaine use, poorer cognition, and more depression, while higher anti-inflammatory cytokines would relate to less cocaine use, better cognition, and less depression., Methods: Data were collected from 85 individuals (76.5% male, 80% African American) aged 18-65. The ASI, Shipley-2, and BDI-II assessed frequency and duration of cocaine use, cognition, and depression. Cytokines were tested using Bio-Plex Pro™ assays. Elastic net regression identified which cytokines related to each measure, controlling for confounds., Results: Lower IL-29 (B = -0.08, bootstrapped 95%CI = [-0.24,0.07]), scD163 (B = -0.11, bootstrapped 95%CI = [-0.27,0.04]), Eotaxin-1 CCL11 (B = -0.11, bootstrapped 95%CI = [-0.30,0.08]), and higher APRIL/TNFSF13 (B = 0.11, bootstrapped 95%CI = [-0.08,0.30]) related to more frequent cocaine use. Lower IL-29 (B = -0.24, bootstrapped 95% CI = [-2.26,1.79]) and IL-20 (B = -1.62, bootstrapped 95%CI = [-3.53,0.29]) related to longer duration of cocaine use. Higher Eotaxin-2 CCL24 (B = 2.79, bootstrapped 95%CI = [-0.59,6.17]) and TWEAK (B = 2.83, bootstrapped 95%CI = [-0.80,6.45]) related to better cognition. Finally, higher IL-20 (B = -1.83, bootstrapped 95%CI = [-3.70,0.04]) and Osteocalcin (B = -1.56, bootstrapped 95%CI = [-3.81,0.70]) related to lower depressive symptoms. However, none of these relationships survived bootstrapped analyses., Conclusion: Pro- and anti-inflammatory cytokines may relate to cocaine use, cognition, and depression, but inconsistent with our hypotheses, higher pro-inflammatory cytokines related to better functioning in several domains. Additionally, cytokines were selected at low frequencies and demonstrated weak relationships with outcomes. These preliminary findings suggest complex relationships between inflammation and cocaine use.

Dopamine (DA) plays a key role in reward processing and is implicated in psychological disorders such as depression, substance use, and schizophrenia. The role of DA in reward processing is an area of highly active research. One approach to this question is drug challenge studies with drugs known to alter DA function. These studies provide good experimental control and can be performed in parallel in laboratory animals and humans. This review aimed to summarize results of studies using pharmacological manipulations of DA in healthy adults. 'Reward' is a complex process, so we separated 'phases' of reward, including anticipation, evaluation of cost and benefits of upcoming reward, execution of actions to obtain reward, pleasure in response to receiving a reward, and reward learning. Results indicated that i) DAergic drugs have different effects on different phases of reward; ii) the relationship between DA and reward functioning appears unlikely to be linear; iii) our ability to detect the effects of DAergic drugs varies depending on whether subjective, behavioral, imaging measures are used., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Rationale: A reduced willingness to perform effort based on the magnitude and probability of potential rewards has been associated with diminished dopamine function and may be relevant to chronic drug use., Objectives: Here, we investigated the influence of smoking status on effort-based decisions. We hypothesized that smokers would make fewer high-effort selections than ex-smokers and never-smokers., Methods: Current smokers (n = 25), ex-smokers (≥ 1 year quit, n = 23), and never-smokers (n = 19) completed the Effort Expenditure for Rewards Task in which participants select between low-effort and high-effort options to receive monetary rewards at varying levels of reward magnitude, probability and expected value., Results: Overall, participants selected more high-effort options as potential reward magnitude and expected value increased. Smokers did not make fewer high-effort selections overall, but smokers were less sensitive to the changes in magnitude, probability, and expected value compared to never-smokers. Smokers were also less sensitive to the changes in probability and expected value, but not magnitude, compared to ex-smokers. Among smokers and ex-smokers, less nicotine dependence was associated with an increased likelihood of high-effort selections., Conclusions: These results demonstrate the relevance of smoking status to effort-based decisions and suggest that smokers have diminished sensitivity to nondrug reward value. Among ex-smokers, greater pre-existing sensitivity to reward value may have been conducive to smoking cessation, or sensitivity was improved by smoking cessation. Future prospective studies can investigate whether effort-related decision making is predictive of smoking initiation or cessation success., Implications: Willingness to perform effort to achieve a goal and sensitivity to changes in reward value are important aspects of motivation. These results showed that smokers have decreased sensitivity to changes in effort-related reward probability and expected value compared to ex-smokers and never-smokers. Potentially, improved sensitivity to rewards among ex-smokers may be a cause or consequence of smoking cessation. These findings may help explain why some smokers are able to achieve long-term abstinence.

The detection of changes in mental states such as those caused by psychoactive drugs relies on clinical assessments that are inherently subjective. Automated speech analysis may represent a novel method to detect objective markers, which could help improve the characterization of these mental states. In this study, we employed computer-extracted speech features from multiple domains (acoustic, semantic, and psycholinguistic) to assess mental states after controlled administration of 3,4-methylenedioxymethamphetamine (MDMA) and intranasal oxytocin. The training/validation set comprised within-participants data from 31 healthy adults who, over four sessions, were administered MDMA (0.75, 1.5 mg/kg), oxytocin (20 IU), and placebo in randomized, double-blind fashion. Participants completed two 5-min speech tasks during peak drug effects. Analyses included group-level comparisons of drug conditions and estimation of classification at the individual level within this dataset and on two independent datasets. Promising classification results were obtained to detect drug conditions, achieving cross-validated accuracies of up to 87% in training/validation and 92% in the independent datasets, suggesting that the detected patterns of speech variability are associated with drug consumption. Specifically, we found that oxytocin seems to be mostly driven by changes in emotion and prosody, which are mainly captured by acoustic features. In contrast, mental states driven by MDMA consumption appear to manifest in multiple domains of speech. Furthermore, we find that the experimental task has an effect on the speech response within these mental states, which can be attributed to presence or absence of an interaction with another individual. These results represent a proof-of-concept application of the potential of speech to provide an objective measurement of mental states elicited during intoxication.

Objective: The neutrophil to lymphocyte ratio (NLR) is a non-specific, easy-to-obtain marker of inflammation associated with morbidity and mortality in systemic, psychiatric, and age-related inflammatory conditions. Given the growing trend of substance use disorder (SUD) in older adults, and the relationship between inflammation and SUD elevated NLR may serve as a useful inflammatory biomarker of the combined burden of aging and SUD. The present study focused on cocaine use disorder (CUD) to examine if cocaine adds further inflammatory burden among older adults, by comparing NLR values between older adults with CUD and a non-cocaine using, aged-matched, nationally representative sample., Methods: The dataset included 107 (86% male) participants (aged 50-65 years) with cocaine use disorder. NLR was derived from complete blood count tests by dividing the absolute value of peripheral neutrophil concentration by lymphocyte concentration. For comparison, we extracted data from age-matched adults without CUD using the National Health and Nutrition Examination Survey. Individuals with immunocompromising conditions were excluded (e.g., rheumatoid arthritis and sexually transmitted infections such as HIV). A doubly-robust inverse probability-weighted regression adjustment (IPWRA) propensity score method was used to estimate group differences on NLR while controlling for potential confounding variables (age, gender, race, income, nicotine, marijuana and alcohol use)., Results: The IPWRA model revealed that the CUD sample had significantly elevated NLR in comparison to non-cocaine users, with a moderate effect size (β weight = 0.67)., Conclusion: Although non-specific, NLR represents a readily obtainable inflammatory marker for SUD research. CUD may add further inflammatory burden to aging cocaine users.

Post-traumatic stress disorder (PTSD) symptoms are highly prevalent among individuals with substance use disorders (SUD), presenting a difficult-to-treat, complex comorbidity. Prognostic factors for treatment outcomes may characterize heterogeneity of the treated population and/or implicate mechanisms of action that are salient for improving treatments. High frequency heart rate variability (HF-HRV) is a suggested biomarker for emotion regulation-the ability to generate appropriate emotional responses via the influence of the parasympathetic nervous system on the heart. This initial study investigated the utility of baseline resting HF-HRV for predicting PTSD symptoms and substance use outcomes following treatment of 37 SUD participants with comorbid PTSD symptoms. Participants completed either standard cognitive- behavioral therapy (CBT) for SUD or a novel treatment of integrated post-traumatic stress and substance use that combined CBT for SUD with cognitive processing therapy for PTSD. Analyses demonstrated that higher HF-HRV predicted greater reduction in PTSD symptoms following both types of treatment. This suggests prognostic value of HF-HRV as a predictor of PTSD treatment outcomes; those with poorer autonomic emotional regulation may not respond as well to psychotherapy in general. This hypothesis-generating analysis identifies a putative biomarker that might have utility in treatment prediction., (© 2019 Society for Psychophysiological Research.)

Background: Depressive symptoms may contribute to cocaine use. However, tests of the relationship between depression and severity of cocaine use have produced mixed results, possibly due to heterogeneity in individual symptoms of depression. Our goal was to establish which symptoms of depression are most strongly related to frequency of cocaine use (one aspect of severity) in a large sample of current cocaine users. We utilized generalized additive modeling to provide data-driven exploration of the relationships between depressive symptoms and cocaine use, including examination of non-linearity. We hypothesized that symptoms related to anhedonia would demonstrate the strongest relationship to cocaine use., Method: 772 individuals screened for cocaine use disorder treatment studies. To measure depressive symptoms, we used the items of the Beck Depression Inventory, 2nd Edition. Cocaine use frequency was measured as proportion of self-reported days of cocaine use over the last 30 days using the Addiction Severity Index., Results: Models identified 18 significant predictors of past-30-day cocaine use. The strongest predictors were Crying, Pessimism, Changes in Appetite, Indecisiveness, and Loss of Interest. Noteworthy effect sizes were found for specific response options on Suicidal Thoughts, Worthlessness, Agitation, Concentration Difficulty, Tiredness, and Self Dislike items., Conclusions: The strongest predictors did not conform to previously hypothesized "subtypes" of depression. Non-linear relationships between items and use were typical, suggesting BDI-II items may not be monotonically increasing ordinal measures with respect to predicting cocaine use. Qualitative analysis of strongly predictive response options suggested emotional volatility and disregard for the future as important predictors of use., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Treatments for Cocaine Use Disorder (CUD) are variably effective, and there are no FDA-approved medications. One approach to developing new treatments for CUD may be to investigate and target poor prognostic signs. One such sign is anhedonia (i.e. a loss of pleasure or interest in non-drug rewards), which predicts worse outcomes in existing CUD treatments. Inflammation is thought to underlie anhedonia in many other disorders, but the relationship between anhedonia and inflammation has not been investigated in CUD. Therefore, we assessed peripheral genome-wide gene expression in n = 48 individuals with CUD with high (n = 24) vs. low (n = 24) levels of anhedonia, defined by a median split of self-reported anhedonia. Our hypothesis was that individuals with high anhedonia would show differential gene expression in inflammatory pathways. No individual genes were significantly different between the low and high anhedonia groups when using t-tests with a stringent false discovery rate correction (FDR-corrected p < 0.05). However, an exploratory analysis identified 166 loci where t-tests suggested group differences at a nominal p < 0.05. We used DAVID, a bioinformatics tool that provides functional interpretations of complex lists of genes, to examine representation of this gene list in known pathways. It confirmed that mechanisms related to immunity were the top significant associations with anhedonia in the sample. Further, the two top differentially expressed genes in our sample, IRF1 and GBP5, both have primary inflammation and immune functions, and were significantly negatively correlated with total scores on our self-report of anhedonia across all 48 subjects. These results suggest that prioritizing development of anti-inflammatory medications for CUD may pay dividends, particularly in combination with treatment-matching strategies using either phenotypic measures of anhedonia or biomarkers of inflammatory gene expression to individualize treatment., Competing Interests: The authors have declared that no competing interests exist.

Exercise has been proposed as a treatment for several psychiatric disorders. Exercise may act in part through beneficial effects on reward functioning, as it alters neurotransmitter levels in reward-related circuits. However, there has been little investigation of the effect of exercise on reward functions in humans. We hypothesized an acute bout of exercise would increase motivation for and pleasurable responses to rewards in healthy humans. In addition, we examined possible moderators of exercise's effects, including demographics, fitness and previous exercise experience. Thirty-five participants completed exercise and sedentary control sessions in randomized, counterbalanced order on separate days. Immediately after each activity, participants completed measures of motivation for and pleasurable responses to rewards, consisting of willingness to exert effort for monetary rewards and subjective responses to emotional pictures. Exercise did not increase motivation or pleasurable responses on average. However, individuals who had been running for more years showed increases in motivation for rewards after exercise, while individuals with less years running showed decreases. Further, individuals with higher resting heart rate variability reported lower arousal in response to all emotional pictures after exercise, while individuals with low heart rate variability reported increased arousal in response to all emotional pictures after exercise. General fitness did not have similar moderating effects. In conclusion, acute exercise improved reward functioning only in individuals accustomed to that type of exercise. This suggests a possible conditioned effect of exercise on reward functioning. Previous experience with the exercise used should be examined as a possible moderator in exercise treatment trials., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Research in animals suggests that decisions about physical versus cognitive effort have distinct neural bases, but exploration of this question in humans is hampered by lack of parallel measures of physical and cognitive effort for rewards. We developed a novel measure of willingness to exert cognitive effort for rewards, the C-EEfRT, paralleling the validated physical effort expenditure for rewards task (EEfRT). To validate the C-EEfRT we: (a) tested whether EEfRT and C-EEfRT tasks were equivalently difficult; (b) tested whether decisions on the EEfRT and C-EEfRT were equivalently responsive to changes in reward; (c) examined relationships between the C-EEfRT and anhedonia, intelligence, and working memory. Last, we tested the relationship between willingness to exert physical and cognitive effort for rewards in humans. Sixty healthy adults completed the EEfRT, the C-EEfRT, an anhedonia self-report, an intelligence test, and a working memory task. Overall willingness to exert effort was higher on the C-EEfRT than the EEfRT, particularly when reward probability and amount were low. This was despite participants perceiving the cognitive task as more difficult, and having greater difficulty completing it. Differential effects of physical fatigue may have contributed. Anhedonia was not related to effort on either measure. Working memory, but not intelligence, was associated with cognitive effort. There was a moderate relationship between cognitive and physical effort. These findings suggest the importance of measuring cognitive effort as distinct from physical effort in humans. Future studies should consider calibrating task difficulty for each individual, and exploring cognitive effort in clinical populations. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Clinical and preclinical findings suggest that individuals with abnormal responses to reward cues (stimuli associated with reward) may be at risk for maladaptive behaviors including obesity, addiction and depression. Our objective was to develop a new paradigm for producing appetitive conditioning using primary (food) rewards in humans, and investigate the equivalency of several outcomes previously used to measure appetitive responses to conditioned cues. We used an individualized food reward, and multimodal subjective, psychophysiological and behavioral measures of appetitive responses to a conditioned stimulus (CS) that predicted delivery of that food. We tested convergence among these measures of appetitive response, and relationships between these measures and action impulsivity, a putative correlate of appetitive conditioning. 90 healthy young adults participated. Although the paradigm produced robust appetitive conditioning in some measures, particularly psychophysiological ones, there were not strong correlations among measures of appetitive responses to the CS, as would be expected if they indexed a single underlying process. In addition, there was only one measure that related to impulsivity. These results provide important information for translational researchers interested in appetitive conditioning, suggesting that various measures of appetitive conditioning cannot be treated interchangeably., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cue reactivity has great potential to advance our understanding of posttraumatic stress disorder (PTSD), substance use disorder (SUD), and PTSD/SUD comorbidity. The present investigation examined distress tolerance (DT) with regard to trauma and substance cue reactivity. Participants included 58 low-income, inner-city adults (49.1% women; M age = 45.73, SD = 10.00) with substance dependence and at least 4 symptoms of PTSD. A script-driven cue reactivity paradigm was utilized. Four DT measures were administered, including the Distress Tolerance Scale (DTS), Mirror-Tracing Persistence Task (MTPT), Breath-Holding Task (BH), and Paced Auditory Serial Addition Task (PASAT). Lower DT, as indexed by MTPT duration, was significantly predictive of greater levels of self-reported substance cravings/urges in response to trauma cues, above and beyond covariates. Lower DTS scores predicted lower levels of self-reported control/safety ratings in response to substance cues. None of the DT indices was significantly predictive of heart rate variability. Clinical and research implications are discussed. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Posttraumatic stress disorder (PTSD) and substance use disorders (SUD) are complex psychiatric conditions that commonly co-occur. Research on PTSD-SUD comorbidity has increasingly focused upon better understanding biopsychosocial factors that may contribute to their co-occurring etiology, maintenance, and treatment. Anhedonia, defined as a lack of pleasure from or interest in rewards, stems from deficits in reward functioning and is associated with specific neurocircuitries. Few studies have investigated the role of reward functioning in PTSD-SUD. The overarching aims of this review are to: define the major facets of reward functioning, summarize the research on reward functioning-PTSD and reward functioning-SUD, review the literature on associations between reward functioning and PTSD-SUD comorbidity, and discuss clinical implications and future directions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This study explored anhedonia (lack of interest or pleasure in non-drug rewards) as a potentially modifiable individual difference associated with the effectiveness of Contingency Management (CM). It also tested the hypothesis that a dopaminergic drug, levodopa (L-DOPA), would improve the effectiveness of CM, particularly in individuals high in anhedonia. The study was a single-site, randomized, double-blind, parallel group, 12-week trial comparing L-DOPA with placebo, with both medication groups receiving voucher-based CM targeting cocaine-negative urines. Participants were N=85 treatment-seeking adults with CUD. Anhedonia was measured at baseline using a validated self-report measure and a progressive ratio behavioral measure. Treatment Effectiveness Score (TES) was defined as the total number of cocaine-negative urines submitted. Analyses based on Frequentist general linear models were not significant, but Bayesian analyses indicated a high probability (92.6%) that self-reported anhedonia was associated with poor treatment outcomes (lower TES). L-DOPA did not significantly improve outcomes, nor was the effect of L-DOPA moderated by anhedonia. While the study failed to replicate positive findings from previous studies of L-DOPA in combination with CM, it does provide preliminary evidence that anhedonia may be a modifiable individual difference associated with poorer CM outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Endogenous opioids have complex social effects that may depend on specific receptor actions and vary depending on the "stage" of social behavior (e.g., seeking vs. responding to social stimuli). We tested the effects of a nonspecific opioid antagonist, naltrexone (NTX), on social processing in humans. NTX is used to treat alcohol and opiate dependence, and may affect both mu and kappa-opioid systems. We assessed attention ("seeking"), and subjective and psychophysiological responses ("responding") to positive and negative social stimuli. Based on literature suggesting mu-opioid blockade impairs positive social responses, we hypothesized that NTX would decrease responses to positive social stimuli. We also tested responses to negative stimuli, which might be either increased by NTX's mu-opioid effects or decreased by its kappa-opioid effects. Thirty-four healthy volunteers received placebo, 25 mg, or 50 mg NTX across three sessions under double-blind conditions. At each session, participants completed measures of attention, identification, and emotional responses for emotional faces and scenes. NTX increased attention to emotional expressions, slowed identification of sadness and fear, and decreased ratings of arousal for social and nonsocial emotional scenes. These findings are more consistent with anxiolytic kappa-antagonist than mu-blocking effects, suggesting effects on kappa receptors may contribute to the clinical effects of NTX., Competing Interests: statement No potential conflict of interest was reported by the authors.

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") enhances desire to socialize and feelings of empathy, which are thought to be related to increased oxytocin levels. Thus, variation in the oxytocin receptor gene (OXTR) may influence responses to the drug. Here, we examined the influence of a single OXTR nucleotide polymorphism (SNP) on responses to MDMA in humans. Based on findings that carriers of the A allele at rs53576 exhibit reduced sensitivity to oxytocin-induced social behavior, we hypothesized that these individuals would show reduced subjective responses to MDMA, including sociability. In this three-session, double blind, within-subjects study, healthy volunteers with past MDMA experience (N = 68) received a MDMA (0, 0.75 mg/kg, and 1.5 mg/kg) and provided self-report ratings of sociability, anxiety, and drug effects. These responses were examined in relation to rs53576. MDMA (1.5 mg/kg) did not increase sociability in individuals with the A/A genotype as it did in G allele carriers. The genotypic groups did not differ in responses at the lower MDMA dose, or in cardiovascular or other subjective responses. These findings are consistent with the idea that MDMA-induced sociability is mediated by oxytocin, and that variation in the oxytocin receptor gene may influence responses to the drug., Competing Interests: statement No potential conflict of interest was reported by the authors.

There has been modest examination of attentional bias in individuals with cannabis use disorders. Clinical implications of this work are directly relevant to better informing extant evidence-based treatment for substance use disorders (e.g., relapse prevention) and/or developing novel interventions. The overarching aim of this investigation was to examine a novel attentional bias task in adults with cannabis use disorders. Participants were comprised of 25 adults (8 women: M age = 31, SD = 6.8; range = 22-45) with cannabis use disorders (n = 12) and controls (n = 13) without any current (past month) psychopathology. Relative to controls, adults with cannabis use disorders had greater attentional bias scores. These differences were present only at the 125-ms probe time, where the cannabis use disorders group showed greater attentional bias to cannabis cues than the control group (adjusted p = .001, cannabis use disorders mean = 59.9, control mean = -24.8, Cohen's d-effect size for 125 ms = 1.03). The cannabis use disorders group also reported significantly greater perceived stress and post-task stress scores than the control group, but stress was not related to attentional bias. This study informs understanding of the influence of cannabis cues on visual detection and reaction time under different cue-target onset times, as attentional bias was most prevalent under time pressure to detect the probe.

Polydrug use is common, and might occur because certain individuals experience positive effects from several different drugs during early stages of use. This study examined individual differences in subjective responses to single oral doses of d-amphetamine, alcohol, and delta-9-tetrahydrocannabinol (THC) in healthy social drinkers. Each of these drugs produces feelings of well-being in at least some individuals, and we hypothesized that subjective responses to these drugs would be positively correlated. We also examined participants' drug responses in relation to personality traits associated with drug use. In this initial, exploratory study, 24 healthy, light drug users (12 male, 12 female), aged 21-31 years, participated in a fully within-subject, randomized, counterbalanced design with six 5.5-hour sessions in which they received d-amphetamine (20mg), alcohol (0.8 g/kg), or THC (7.5 mg), each paired with a placebo session. Participants rated the drugs' effects on both global measures (e.g. feeling a drug effect at all) and drug-specific measures. In general, participants' responses to the three drugs were unrelated. Unexpectedly, "wanting more" alcohol was inversely correlated with "wanting more" THC. Additionally, in women, but not in men, "disliking" alcohol was negatively correlated with "disliking" THC. Positive alcohol and amphetamine responses were related, but only in individuals who experienced a stimulant effect of alcohol. Finally, high trait constraint (or lack of impulsivity) was associated with lower reports of liking alcohol. No personality traits predicted responses across multiple drug types. Generally, these findings do not support the idea that certain individuals experience greater positive effects across multiple drug classes, but instead provide some evidence for a "drug of choice" model, in which individuals respond positively to certain classes of drugs that share similar subjective effects, and dislike other types of drugs.

MDMA is a stimulant with unique "prosocial" effects, the physiological and pharmacological mechanisms of which are unknown. Here, we examine the relationship of measures of parasympathetic and sympathetic nervous system activity to the prosocial effects of MDMA. Parasympathetic activity was measured using respiratory sinus arrhythmia (RSA) and sympathetic activity using pre-ejection period (PEP). Over three sessions, 33 healthy volunteers received placebo, 0.75 mg/kg, and 1.5 mg/kg MDMA under counterbalanced, double-blind conditions, while we measured subjective feelings, RSA, and PEP. RSA and PEP data were available for 26 and 21 participants, respectively. MDMA increased prosocial and stimulated feelings, decreased RSA, and decreased PEP. At 1.5 mg/kg, subjective prosocial effects correlated with stimulated feelings and PEP, but not RSA. This suggests sympathetic, rather than parasympathetic, effects relate to the prosocial effects of MDMA., (© 2014 Society for Psychophysiological Research.)

Rationale: Evidence from animal and human studies suggests that opiate drugs decrease emotional responses to negative stimuli and increase responses to positive stimuli. Such emotional effects may motivate misuse of oxycodone (OXY), a widely abused opiate. Yet, we know little about how OXY affects neural circuits underlying emotional processing in humans., Objective: We examined effects of OXY on brain activity during presentation of positive and negative visual emotional stimuli. We predicted that OXY would decrease amygdala activity to negative stimuli and increase ventral striatum (VS) activity to positive stimuli. Secondarily, we examined the effects of OXY on other emotional network regions on an exploratory basis., Methods: In a three-session study, healthy adults (N = 17) received placebo, 10 and 20 mg OXY under counterbalanced, double-blind conditions. At each session, participants completed subjective and cardiovascular measures and underwent functional MRI (fMRI) scanning while completing two emotional response tasks., Results: Our emotional tasks reliably activated emotional network areas. OXY produced subjective effects but did not alter either behavioral responses to emotional stimuli or activity in our primary areas of interest. OXY did decrease right medial orbitofrontal cortex (MOFC) responses to happy faces., Conclusions: Contrary to our expectations, OXY did not affect behavioral or neural responses to emotional stimuli in our primary areas of interest. Further, the effects of OXY in the MOFC would be more consistent with a decrease in value for happy faces. This may indicate that healthy adults do not receive emotional benefits from opiates, or the pharmacological actions of OXY differ from other opiates.

Background: ±3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") produces "prosocial" effects, such as feelings of empathy and closeness, thought to be important to its abuse and its value in psychotherapy. However, it is not fully understood how MDMA alters basic emotional processes to produce these effects, or whether it produces corresponding changes in actual social behavior. Here, we examined how MDMA affects perceptions of and responses to emotional expressions, and tested its effects on behavior during a social interaction. We also examined whether MDMA's prosocial effects related to a measure of abuse liability., Methods: Over three sessions, 36 healthy volunteers with previous ecstasy use received MDMA (0.75, 1.5 mg/kg) and placebo under double-blind conditions. We measured (i) mood and cardiovascular effects, (ii) perception of and psychophysiological responses to emotional expressions, (iii) use of positive and negative words in a social interaction, and (iv) perceptions of an interaction partner. We then tested whether these effects predicted desire to take the drug again., Results: MDMA slowed perception of angry expressions, increased psychophysiological responses to happy expressions, and increased positive word use and perceptions of partner empathy and regard in a social interaction. These effects were not strongly related to desire to take the drug again., Conclusions: MDMA alters basic emotional processes by slowing identification of negative emotions and increasing responses to positive emotions in others. Further, it positively affects behavior and perceptions during actual social interaction. These effects may contribute to the efficacy of MDMA in psychotherapy, but appear less closely related to its abuse potential.

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') is used recreationally to improve mood and sociability, and has generated clinical interest as a possible adjunct to psychotherapy. One way that MDMA may produce positive 'prosocial' effects is by changing responses to emotional stimuli, especially stimuli with social content. Here, we examined for the first time how MDMA affects subjective responses to positive, negative and neutral emotional pictures with and without social content. We hypothesized that MDMA would dose-dependently increase reactivity to positive emotional stimuli and dampen reactivity to negative stimuli, and that these effects would be most pronounced for pictures with people in them. The data were obtained from two studies using similar designs with healthy occasional MDMA users (total N = 101). During each session, participants received MDMA (0, 0.75 and 1.5 mg/kg oral), and then rated their positive and negative responses to standardized positive, negative and neutral pictures with and without social content. MDMA increased positive ratings of positive social pictures, but reduced positive ratings of non-social positive pictures. We speculate this 'socially selective' effect contributes to the prosocial effects of MDMA by increasing the comparative value of social contact and closeness with others. This effect may also contribute to its attractiveness to recreational users., (© The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

MDMA (± 3,4-methylenedioxymethamphetamine, 'ecstasy') is used recreationally, reportedly because it increases feelings of empathy, sociability, and interpersonal closeness. One line of evidence suggests that MDMA produces these effects by releasing oxytocin, a peptide involved in social bonding. In the current study, we investigated the acute effects of MDMA and oxytocin on social and emotional processing in healthy human volunteers. MDMA users (N = 65) participated in a 4-session, within-between-subjects study in which they received oral MDMA (0.75, 1.5 mg/kg), intranasal oxytocin (20 or 40 IU), or placebo under double-blind conditions. The primary outcomes included measures of emotion recognition and sociability (desire to be with others). Cardiovascular and subjective effects were also assessed. As expected, MDMA dose-dependently increased heart rate and blood pressure and feelings of euphoria (eg, 'High' and 'Like Drug'). On measures of social function, MDMA impaired recognition of angry and fearful facial expressions, and the larger dose (1.5 mg/kg) increased desire to be with others, compared with placebo. Oxytocin produced small but significant increases in feelings of sociability and enhanced recognition of sad facial expressions. Additionally, responses to oxytocin were related to responses to MDMA with subjects on two subjective measures of sociability. Thus, MDMA increased euphoria and feelings of sociability, perhaps by reducing sensitivity to subtle signs of negative emotions in others. The present findings provide only limited support for the idea that oxytocin produces the prosocial effects of MDMA.

3-4-Methylenedioxymethamphetamine (MDMA) increases self-reported positive social feelings and decreases the ability to detect social threat in faces, but its effects on experiences of social acceptance and rejection have not been determined. We examined how an acute dose of MDMA affects subjective and autonomic responses to simulated social acceptance and rejection. We predicted that MDMA would decrease subjective responses to rejection. On an exploratory basis, we also examined the effect of MDMA on respiratory sinus arrhythmia (RSA), a measure of parasympathetic cardiac control often thought to index social engagement and emotional regulation. Over three sessions, healthy adult volunteers with previous MDMA experience (N=36) received capsules containing placebo, 0.75 or 1.5 mg/kg of MDMA under counter-balanced double-blind conditions. During expected peak drug effect, participants played two rounds of a virtual social simulation task called "Cyberball" during which they experienced acceptance in one round and rejection in the other. During the task we also obtained electrocardiograms (ECGs), from which we calculated RSA. After each round, participants answered questionnaires about their mood and self-esteem. As predicted, MDMA decreased the effect of simulated social rejection on self-reported mood and self-esteem and decreased perceived intensity of rejection, measured as the percent of ball tosses participants reported receiving. Consistent with its sympathomimetic properties, MDMA decreased RSA as compared to placebo. Our finding that MDMA decreases perceptions of rejection in simulated social situations extends previous results indicating that MDMA reduces perception of social threat in faces. Together these findings suggest a cognitive mechanism by which MDMA might produce pro-social behavior and feelings and how the drug might function as an adjunct to psychotherapy. These phenomena merit further study in non-simulated social environments., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The ability to initiate and sustain trust is critical to health and well-being. Willingness to trust is in part determined by the reputation of the putative trustee, gained via direct interactions or indirectly through word of mouth. Few studies have examined how the reputation of others is instantiated in the brain during trust decisions. Here we use an event-related functional MRI (fMRI) design to examine what neural signals correspond to experimentally manipulated reputations acquired in direct interactions during trust decisions. We hypothesized that the caudate (dorsal striatum) and putamen (ventral striatum) and amygdala would signal differential reputations during decision-making. Twenty-nine healthy adults underwent fMRI scanning while completing an iterated Trust Game as trusters with three fictive trustee partners who had different tendencies to reciprocate (i.e., likelihood of rewarding the truster), which were learned over multiple exchanges with real-time feedback. We show that the caudate (both left and right) signals reputation during trust decisions, such that caudate is more active to partners with two types of "bad" reputations, either indifferent partners (who reciprocate 50% of the time) or unfair partners (who reciprocate 25% of the time), than to those with "good" reputations (who reciprocate 75% of the time). Further, individual differences in caudate activity related to biases in trusting behavior in the most uncertain situation, i.e. when facing an indifferent partner. We also report on other areas that were activated by reputation at p < 0.05 whole brain corrected. Our findings suggest that the caudate is involved in signaling and integrating reputations gained through experience into trust decisions, demonstrating a neural basis for this key social process.

The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is an important regulator of dopamine in the prefrontal cortex, an area critical to working memory. Working memory deficits are present in several psychiatric disorders, and there is wide variation in working memory capacity in the normal population. Association studies of COMT and working memory in healthy volunteers have yielded inconsistent results, possibly because of small sample sizes. Here we examine COMT in relation to N-Back working memory task performance in a large population-based cohort of young adults. We predicted individuals with one or two copies of the Met allele would perform better, and that this relationship would be more evident in males than females. Participants (N=1857-2659) tested at 18 years of age, were enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). We used multiple regression to examine effects of sex and COMT genotype on N-Back hits, false positives, discriminability (d'), and reaction time while controlling for important covariates. COMT genotype did not predict hits or d'. There was a nominally significant interaction between COMT and sex on false positives, but this was not in the predicted direction, and was not significant after controlling for covariates. COMT genotype was not related to working memory in this large population-based cohort. It is possible COMT is not meaningfully associated with working memory in healthy young adults, or that COMT effects are detectable only in assessments reflecting neural processes underlying cognition, such as fMRI, rather than in behavioral performance.

In a widely cited study, Mattay et al. reported that amphetamine (0.25 mg/kg oral, or 17 mg for a 68 kg individual) impaired behavioral and brain indices of executive functioning, measured using the Wisconsin Card Sorting Task (WCST) and N-Back working memory task, in 6 individuals homozygous for the met allele of the val158met polymorphism in the catechol-O-methyltransferase (COMT) gene, whereas it improved executive functioning in 10 individuals homozygous for the more active val allele. We attempted to replicate their behavioral findings in a larger sample, using similar executive functioning tasks and a broader range of amphetamine doses. Over four sessions, n = 200 healthy normal adults received oral placebo, d-amphetamine 5, 10, and 20 mg (average of 0.07, 0.15 and 0.29 mg/kg), under counterbalanced double-blind conditions and completed WCST and N-back tests of executive functioning. Amphetamine had typical effects on blood pressure and processing speed but did not affect executive functioning. COMT genotype (val158met) was not related to executive functioning under placebo or amphetamine conditions, even when we compared only the homozygous val/val and met/met genotypes at the highest dose of amphetamine (20 mg). Thus, we were not able to replicate the behavioral interaction between COMT and amphetamine seen in Mattay et al. We discuss possible differences between the studies and the implications of our findings for the use of COMT genotyping to predict clinical responses to dopaminergic drugs, and the use of intermediate phenotypes in genetic research., (© 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.)

Preclinical studies suggest that cost/benefit decision-making involves interactions between adenosine and dopamine (DA). In rats, DA depletion decreases willingness to incur effort costs, while adenosine antagonism reverses these effects, likely by increasing DA transmission. Caffeine is a non-selective adenosine antagonist commonly used to facilitate effortful tasks, and thus may affect decisions involving effort costs in humans. The current study examined acute effects of 200 mg of caffeine on willingness to exert effort for monetary rewards at varying levels of reward value and reward probability, in young adult light caffeine users. Based on previous findings with amphetamine, we predicted that caffeine would increase willingness to exert effort. At separate sessions, 23 healthy normal adults received placebo or 200 mg caffeine under counterbalanced double-blind conditions, then completed the effort expenditure for rewards task (EEfRT). Measures of subjective and cardiovascular effects were obtained at regular intervals. Caffeine produced small but significant subjective and cardiovascular effects, and sped psychomotor performance on the EEfRT. Caffeine did not alter willingness to exert effort, except in high cardiovascular responders to caffeine, in whom it decreased willingness to exert effort. These results were contrary to our predictions, but consistent with rodent studies suggesting that moderate doses of caffeine alone do not affect effort, but rather only influence effort in the context of DA antagonism. Our results demonstrate that psychomotor speeding and decisional effects on the EEfRT are dissociable, providing additional evidence for the EEfRT as a specific measure of effort-based decision-making. This study provides a starting point for exploring contributions of the adenosine system to motivation in humans., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Rationale: Drug users often report using drugs to enhance social situations, and empirical studies support the idea that drugs increase both social behavior and the value of social interactions. One way that drugs may affect social behavior is by altering social processing, for example by decreasing perceptions of negative emotion in others., Objectives: We examined effects of d-amphetamine on processing of emotional facial expressions and on the social behavior of talking. We predicted amphetamine would enhance attention, identification, and responsivity to positive expressions, and that this in turn would predict increased talkativeness., Methods: Over three sessions, 36 healthy normal adults received placebo, 10, and 20 mg d-amphetamine under counterbalanced double-blind conditions. At each session, we measured processing of happy, fearful, sad, and angry expressions using an attentional visual probe task, a dynamic emotion identification task, and measures of facial muscle activity. We also measured talking., Results: Amphetamine decreased the threshold for identifying all emotions, increased negative facial responses to sad expressions, and increased talkativeness. Contrary to our hypotheses, amphetamine did not alter attention to, identification of, or facial responses to positive emotions specifically. Interestingly, the drug decreased the threshold to identify all emotions, and this effect was uniquely related to increased talkativeness, even after controlling for overall sensitivity to amphetamine., Conclusions: The results suggest that amphetamine may encourage sociability by increasing sensitivity to subtle emotional expressions. These findings suggest novel social mechanisms that may contribute to the rewarding effects of amphetamine.

Rationale: Post-error slowing has long been considered a sign of healthy error detection and an important component of cognitive function. However, the neuropharmacological processes underlying post-error slowing are poorly understood., Objectives: This study investigated the effect of the dopamine agonist d-amphetamine on post-error slowing and secondarily, the potential mediator of drug-induced euphoria and potential moderators of personality and baseline task performance., Methods: Healthy male and female participants (N = 110) completed four study sessions, at which d-amphetamine (placebo 5, 10, 20 mg) was administered under double-blind, counter-balanced conditions. At each session, participants completed subjective drug effect assessments and a working memory task (N-back) to measure post-error slowing. They completed the Multidimensional Personality Questionnaire (MPQ) during screening., Results: Amphetamine (20 mg) reduced post-error slowing, consistent with a dampened behavioral reactivity to errors. This was not related to drug-induced euphoria. Although higher scores on MPQ constraint were related to less post-error slowing under placebo conditions, neither personality nor baseline cognitive performance moderated the effects of amphetamine on post-error slowing., Conclusions: The finding that amphetamine reduced post-error slowing supports the idea that dopamine plays a role in error stimulus processing. The finding is discussed in relation to an existing literature on the mechanisms and function of behavioral and electrophysiological indices of error sensitivity.

Rationale: Most studies of the reinforcing effects of stimulants have focused on the drugs' capacity to induce positive mood (i.e., euphoria). However, recent findings suggest drugs may also alter emotional reactivity to external stimuli, and that this may occur independently of direct effects on mood., Objectives: We aimed to examine effects of D: -amphetamine, a prototypic stimulant, on self-reported and psychophysiological reactivity to emotional stimuli as well as overall subjective mood. We predicted that amphetamine would enhance reactivity to pleasant stimuli, particularly, stimuli with social content and that these effects would be independent of the drug's direct effects on mood., Methods: Over three sessions, 36 healthy normal adults received placebo, D: -amphetamine 10 and 20 mg under counterbalanced double-blind conditions. At each session, emotional reactivity to standardized positive, neutral, and negative pictures with and without social content was measured in self-reports and facial muscles sensitive to emotional state. Drug effects on cardiovascular variables and subjective mood were also measured., Results: Amphetamine produced euphoria, feelings of drug effect, and increased blood pressure. Most notably, amphetamine enhanced self-reported positive reactions to all pictures and psychophysiological reactions to positive pictures. These effects were not significantly related to drug-induced mood changes. Contrary to our hypothesis, effects of amphetamine on emotional reactivity were not moderated by social content., Conclusions: This study demonstrates a previously unexamined and potentially reinforcing effect of stimulant drugs in humans, distinct from more typically measured euphorigenic effects, and suggests new areas of research in stimulant abuse risk and adaptations occurring during drug dependence.

Both the subjective response to d-amphetamine and the risk for amphetamine addiction are known to be heritable traits. Because subjective responses to drugs may predict drug addiction, identifying alleles that influence acute response may also provide insight into the genetic risk factors for drug abuse. We performed a Genome Wide Association Study (GWAS) for the subjective responses to amphetamine in 381 non-drug abusing healthy volunteers. Responses to amphetamine were measured using a double-blind, placebo-controlled, within-subjects design. We used sparse factor analysis to reduce the dimensionality of the data to ten factors. We identified several putative associations; the strongest was between a positive subjective drug-response factor and a SNP (rs3784943) in the 8(th) intron of cadherin 13 (CDH13; P = 4.58×10(-8)), a gene previously associated with a number of psychiatric traits including methamphetamine dependence. Additionally, we observed a putative association between a factor representing the degree of positive affect at baseline and a SNP (rs472402) in the 1(st) intron of steroid-5-alpha-reductase-α-polypeptide-1 (SRD5A1; P = 2.53×10(-7)), a gene whose protein product catalyzes the rate-limiting step in synthesis of the neurosteroid allopregnanolone. This SNP belongs to an LD-block that has been previously associated with the expression of SRD5A1 and differences in SRD5A1 enzymatic activity. The purpose of this study was to begin to explore the genetic basis of subjective responses to stimulant drugs using a GWAS approach in a modestly sized sample. Our approach provides a case study for analysis of high-dimensional intermediate pharmacogenomic phenotypes, which may be more tractable than clinical diagnoses.

Animal studies suggest the neurotransmitter dopamine (DA) plays an important role in decision-making. In rats, DA depletion decreases tolerance for effort and probability costs, while drugs enhancing DA increase tolerance for these costs. However, data regarding the effect of DA manipulations on effort and probability costs in humans remain scarce. The current study examined acute effects of d-amphetamine, an indirect DA agonist, on willingness of healthy human volunteers to exert effort for monetary rewards at varying levels of reward value and reward probability. Based on preclinical research, we predicted amphetamine would increase exertion of effort, particularly when reward probability was low. Over three sessions, 17 healthy normal adults received placebo, d-amphetamine 10 mg, and 20 mg under counterbalanced double-blind conditions and completed the Effort Expenditure for Rewards Task. Consistent with predictions, amphetamine enhanced willingness to exert effort, particularly when reward probability was lower. Amphetamine did not alter effects of reward magnitude on willingness to exert effort. Amphetamine sped task performance, but its psychomotor effects were not strongly related to its effects on decision-making. This is the first demonstration in humans that dopaminergic manipulations alter willingness to exert effort for rewards. These findings help elucidate neurochemical substrates of choice, with implications for neuropsychiatric diseases characterized by dopaminergic dysfunction and motivational deficits.

Rationale: Relapse to smoking is often precipitated by stress, yet little is known about the effects of nicotine withdrawal on responses to acute stress, or whether nicotine replacement reverses withdrawal-induced changes in stress response., Objectives: The aim of the present study is to use an effective social stressor, the Trier Social Stress Test (TSST), to study subjective, cardiovascular and hormonal responses to stress during withdrawal, and examine whether nicotine replacement moderates responses to stress during withdrawal., Methods: Forty-nine current regular smokers were randomly assigned to smoke as normal (SM), 12-h abstention with placebo patch (PL), or 12-h abstention with nicotine patch (NIC). They participated in a single session using the TSST, during which subjective affect, heart rate (HR), mean arterial blood pressure (MAP) and salivary cortisol were measured., Results: The TSST produced expected increases in subjective negative affect, HR, MAP, and cortisol. Groups did not differ in subjective or cardiovascular responses, but the PL group exhibited larger stress-induced increase in cortisol than the other groups., Conclusions: The increased cortisol response might indicate a greater hormonal stress response during nicotine withdrawal. Alternatively, considering that cortisol also provides negative feedback to the stress system, and blunted cortisol responses are predictive of smoking relapse, the lower cortisol responses in the NIC and SM groups might indicate chronic dysregulation of the stress system. In this case, restoration of cortisol response by nicotine treatment to the lower levels seen during regular smoking may actually represent an undesired side effect of nicotine replacement.