Inhibition of activin receptor 2 signalling ameliorates metabolic dysfunction-associated steatotic liver disease in western diet/L-NAME induced cardiometabolic disease.

OBJECTIVE: Blockade of activin 2 receptor (ACVR2) signaling has been shown to improve insulin sensitivity and aid in weight loss. Inhibition of ACVR2 signaling restores cardiac function in multiple heart failure models. However, its potential in the treatment of obesity-related cardiometabolic disease remains unknown. Here, we investigated targeting ACVR2 signaling in cardiometabolic disease manifested with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: Mice were fed a high-fat, high-sugar diet combined with the administration of nitric oxide synthase inhibitor L-NAME in drinking water, which causes hypertensive stress. For the last eight weeks, the mice were treated with the soluble ACVR2B decoy receptor (sACVR2B-Fc). RESULTS: sACVR2B-Fc protected against the development of comorbidities associated with cardiometabolic disease. This was most pronounced in the liver where ACVR2 blockade attenuated the development of MASLD including cessation of pro-fibrotic activation. It also significantly reduced total plasma cholesterol levels, impeded brown adipose tissue whitening, and improved cardiac diastolic function. In vitro, ACVR2 ligands activin A, activin B and GDF11 induced profibrotic signaling and the proliferation of human cardiac fibroblasts. CONCLUSIONS: Blockade of ACVR2B exerts broad beneficial effects for therapy of cardiometabolic disease. By reducing obesity, ameliorating cardiovascular deterioration and restraining MASLD, blockade of ACVR2B signaling proves a potential target in MASLD and its comorbidities.

Apelin regulates skeletal muscle adaptation to exercise in a high-intensity interval training model.

Plasma apelin levels are reduced in aging and muscle wasting conditions. We aimed to investigate the significance of apelin signaling in cardiac and skeletal muscle responses to physiological stress. Apelin knockout (KO) and wild-type (WT) mice were subjected to high-intensity interval training (HIIT) by treadmill running. The effects of apelin on energy metabolism were studied in primary mouse skeletal muscle myotubes and cardiomyocytes. Apelin increased mitochondrial ATP production and mitochondrial coupling efficiency in myotubes and promoted the expression of mitochondrial genes both in primary myotubes and cardiomyocytes. HIIT induced mild concentric cardiac hypertrophy in WT mice, whereas eccentric growth was observed in the left ventricles of apelin KO mice. HIIT did not affect myofiber size in skeletal muscles of WT mice but decreased the myofiber size in apelin KO mice. The decrease in myofiber size resulted from a fiber type switch toward smaller slow-twitch type I fibers. The increased proportion of slow-twitch type I fibers in apelin KO mice was associated with upregulation of myosin heavy chain slow isoform expression, accompanied with upregulated expression of genes related to fatty acid transport and downregulated expression of genes related to glucose metabolism. Mechanistically, skeletal muscles of apelin KO mice showed defective induction of insulin-like growth factor-1 signaling in response to HIIT. In conclusion, apelin is required for proper skeletal and cardiac muscle adaptation to high-intensity exercise. Promoting apelinergic signaling may have benefits in aging- or disease-related muscle wasting conditions.NEW & NOTEWORTHY Apelin levels decline with age. This study demonstrates that in trained mice, apelin deficiency results in a switch from fast type II myofibers to slow oxidative type I myofibers. This is associated with a concomitant change in gene expression profile toward fatty acid utilization, indicating an aged-muscle phenotype in exercised apelin-deficient mice. These data are of importance in the design of exercise programs for aging individuals and could offer therapeutic target to maintain muscle mass.

Longitudinal stability of reward and relief drinking phenotypes in community and treatment-seeking individuals who engage in heavy drinking.

BACKGROUND: Precision medicine approaches aim to improve treatment outcomes by identifying which treatments work best for specific individual phenotypes. In the treatment of alcohol use disorder (AUD), precision medicine approaches have been proposed based on phenotypes characterized by individuals who drink primarily to enhance rewarding experiences (i.e., reward drinking) or those who drink primarily to relieve negative states (i.e., relief drinking). This study examined these phenotypes across treatment- and nontreatment-seeking individuals and the stability of the phenotypes over time. METHODS: We used latent profile and latent transition analyses to identify and assess longitudinal stability (over 3 or 4 months) of reward and relief drinking subgroups within a nontreatment-seeking community sample that engaged in hazardous drinking (n = 189) and two treatment-seeking samples of individuals with AUD enrolled in two large clinical trials (n = 1726, n = 1383). We examined prospective associations with alcohol consumption and consequences at long-term follow-up (15 or 18 months). RESULTS: Results supported four subgroups: low reward/low relief, low reward/high relief, high reward/low relief, and high reward/high relief. The community sample contained more individuals classified within the high reward/low relief subgroup than treatment-seeking samples. Subgroups were generally more stable over time in the community sample than in the treatment-seeking samples. Alcohol consumption and consequences decreased over time for the treatment-seeking samples, with consequences and drinking frequency decreasing for the community sample. Participants classified within the high reward/high relief and low reward/high relief groups reported the most consequences and consumption at long-term follow-up. CONCLUSION: Reward and relief drinking phenotypes can be identified within community and treatment-seeking samples of individuals who drink heavily. The phenotypic subgroups appear to be stable over time in the absence of treatment, change somewhat during treatment, and provide utility in predicting alcohol consumption and consequences.

Opioid receptor antagonism and neural response to monetary rewards: Pilot studies in light and heavy alcohol users.

Alcohol use disorder (AUD) is a prevalent condition associated with high degree of comorbidity and mortality. Among the few approved pharmacotherapies for AUD, two involve opioid receptor antagonism. Naltrexone and nalmefene are thought to act via opioid receptor blockage to reduce neural response to alcohol and drug-associated cues and consumption, but there have been limited efforts to characterize these effects in humans. In these studies, we sought to test the magnitude of opioid antagonism effects on neural response to monetary rewards in two groups: light drinkers (for the naltrexone study) and heavy drinkers (for the nalmefene study). We conducted double-blind, randomized, crossover pilot studies of reward activation in the brain following acute administration of opioid antagonist and placebo in 11 light and 9 heavy alcohol users. We used a monetary incentive delay task during functional MRI. We found a main effect of cue type on BOLD activation in the nucleus accumbens, demonstrating a neural reward response. The effect of opioid antagonism, relative to placebo, was small and nonsignificant for reward activation in the accumbens for both light and heavy alcohol users. Based on the results of two pilot studies, opioid antagonist medications do not appear to decrease neural activation to monetary rewards in the nucleus accumbens relative to placebo.

Effects of lexical frequency on the post-exposure magnitude of recalibration in lexically guided perceptual learning: An explorative analysis.

Listeners use lexical information to guide the mapping between acoustic signals and representations of speech sound. This process is known as perceptual learning and results in recalibration of phonetic categories. The current work examines the effect of lexical frequency of exposure words on the magnitude of recalibration. Results showed comparable levels of perceptual learning for listeners exposed to high-frequency vs low-frequency critical words, in line with empirical findings that suggest that if frequency affects recalibration, such effects may be difficult to detect. These findings warrant further empirical probing and theoretical characterization of the role of lexical frequency in perceptual learning.

Decreased levels of discomfort in repeatedly handled mice during experimental procedures, assessed by facial expressions.

Mice are the most commonly used laboratory animal, yet there are limited studies which investigate the effects of repeated handling on their welfare and scientific outcomes. Furthermore, simple methods to evaluate distress in mice are lacking, and specialized behavioral or biochemical tests are often required. Here, two groups of CD1 mice were exposed to either traditional laboratory handling methods or a training protocol with cup lifting for 3 and 5 weeks. The training protocol was designed to habituate the mice to the procedures involved in subcutaneous injection, e.g., removal from the cage, skin pinch. This protocol was followed by two common research procedures: subcutaneous injection and tail vein blood sampling. Two training sessions and the procedures (subcutaneous injection and blood sampling) were video recorded. The mouse facial expressions were then scored, focusing on the ear and eye categories of the mouse grimace scale. Using this assessment method, trained mice expressed less distress than the control mice during subcutaneous injection. Mice trained for subcutaneous injection also had reduced facial scores during blood sampling. We found a clear sex difference as female mice responded to training faster than the male mice, they also had lower facial scores than the male mice when trained. The ear score appeared to be a more sensitive measure of distress than the eye score, which may be more indicative of pain. In conclusion, training is an important refinement method to reduce distress in mice during common laboratory procedures and this can best be assessed using the ear score of the mouse grimace scale.

A clinical science guide for reviewing the cross-cultural rigor of assessments in an alcohol training clinic.

A standard component of service delivery in alcohol treatment clinics is evidence-based assessment (EBA). Although EBA is essential for selecting appropriate treatment modalities for alcohol use and associated problems, there are limitations in existing EBAs concerning evidence of cultural equivalence and utility among individuals seeking alcohol treatment. However, training in EBA, addictions, and clinical applications with diverse populations all are gaps in clinical training in doctoral programs in clinical psychology. The present work used the clinical science model to review the psychometric properties, cross-cultural utility, and measurement invariance of measures in an assessment battery used in an alcohol treatment training clinic. This article describes the results of that review, recommendations for retaining or replacing common assessment measures used in alcohol treatment clinics, and recommendations for alcohol treatment clinics interested in engaging in similar processes. Findings suggested that more research is needed to evaluate the psychometric properties of EBAs utilized in an alcohol treatment assessment battery, particularly among American Indian and Alaska Native people, and to test measurement invariance across race/ethnicity and other identity groups in alcohol treatment-seeking populations. Overall, routine reviews of cultural relevance are needed in clinical settings to stay current with the emerging literature. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Individual and Community Social Determinants of Health and Recovery from Alcohol Use Disorder Three Years following Treatment.

Prior research on recovery from alcohol use disorder (AUD) has often focused on individual-level factors that promote recovery. Given systemic health inequities, it is also important to study community-level social determinants of health (SDOH) that may promote recovery from AUD. This study extended prior work examining individual profiles of recovery from AUD to assess how individual and community SDOH at the time of treatment entry were associated with recovery from AUD three years after treatment. Data were utilized from the COMBINE study (n = 664), a multisite randomized clinical trial evaluating pharmacological and behavioral treatments for AUD. Public community data sources associated with participants' study sites were used to measure community SDOH. Multilevel latent profile analyses with individual- and community-level variables as predictors of recovery profiles were estimated. Four profiles were identified based on participants' alcohol consumption and functioning. Individual SDOH variables, such as fewer years of education and lower income, and community SDOH, including lower rates of health insurance, lower income, and greater income inequality, were each associated with lower functioning profiles. The findings highlight the importance of community SDOH in AUD recovery and the value of including both individual and community SDOH variables in research on long-term recovery.

Within-AUD outpatient treatment heavy drinking transitions and associations with long-term outcomes.

OBJECTIVES: The purpose of this study was to examine whether changes in heavy drinking occurring within alcohol treatment predict long-term functioning. METHOD: Latent profile analyses were conducted using data from Project MATCH and COMBINE. Observed changes in heavy and nonheavy drinking within consecutive 2-week periods over the respective treatment durations were characterized for each participant and were used to identify latent profiles. RESULTS: Both data sets revealed 6 profiles: (1) continuous "remission" (nonheavy drinking); (2) transition from heavy drinking ("relapse") to remission; (3) mostly remission, limited relapse; (4) numerous short transitions between relapse and remission; (5) transition to relapse; and (6) continuous relapse. Profiles 1 and 2 had the best long-term outcomes, Profiles 5 and 6 had the worst, and Profiles 3 and 4 fell between these groups. Within-treatment patterns of heavy drinking and nonheavy drinking were also associated with post-treatment patterns of relapse and remission. CONCLUSIONS: Patterns of transition between episodes that respectively include heavy and nonheavy drinking predict long-term alcohol use and psychosocial outcomes and seem essential for clinicians to discuss with their patients. Relapses during outpatient treatment do not necessarily indicate treatment failure, provided they are relatively brief and/or infrequent. In addition, some individuals can and do change from transition patterns of heavy drinking within treatment that are predictive of poorer long-term functioning to transition patterns that predict better functioning within the first year post-treatment.

Validity and measurement invariance of the Addictions Neuroclinical Assessment incentive salience domain among treatment-seekers with alcohol use disorder.

Incentive salience, or the attribution of motivational value to stimuli, is a biopsychological process that is disrupted in alcohol use disorder (AUD). The Addictions Neuroclinical Assessment (ANA) is a framework to characterize heterogeneity in addiction and establish a common assessment battery for research and clinical use. The ANA framework hypothesizes three constructs that correspond to processes in the etiology, course, and treatment of addiction: incentive salience, negative emotionality, and executive function. The current study extends prior findings on the ANA by validating the incentive salience construct among participants (n = 563) in a multisite prospective study of individuals entering treatment for AUD. We used confirmatory factor analysis to test a one-factor model of incentive salience. Indicators included items assessing perception of urges to drink from the Alcohol Dependence Scale, Impaired Control Scale, and Marlatt Relapse Interview. Results indicated the one-factor model fit the data well (χ2 (12) = 19.42, p = .08; RMSEA = 0.034 [90% CI: 0.000, 0.060], CFI = 0.992) and was measurement invariant across sex. Incentive salience was associated with drinking patterns (e.g., drinks per day, r = 0.447 [95% CI: 0.379, 0.514]); reasons for drinking (urges/temptation r = 0.529 [95% CI: 0.460, 0.599]); testing personal control, r = 0.384 (95% CI: 0.308, 0.461); social pressure, r = 0.549 (95% CI: 0.481, 0.617); and family history of AUD, r = 0.134. The incentive salience factor demonstrated greater predictive validity for drinking outcomes compared to alternative preexisting scales. Overall, this study provides support for the construct validity and measurement invariance of the ANA incentive salience construct in a sample of individuals seeking AUD treatment.

Can Individuals With Alcohol Use Disorder Sustain Non-abstinent Recovery? Non-abstinent Outcomes 10 Years After Alcohol Use Disorder Treatment.

OBJECTIVE: Four decades ago, the "controlled drinking" controversy roiled the alcohol field. Data have subsequently accumulated indicating that nonabstinent alcohol use disorder (AUD) recovery is achievable, but questions remain whether it is sustainable long-term. This study examined whether nonabstinent recovery at 3 years after AUD treatment is associated with better functioning at 10 years after treatment. METHODS: Data were from the 10-year follow-up of Project MATCH (New Mexico site only, n  = 146; 30.1% female, 58.6% non-White). Recovery was defined by latent profile analyses based on psychosocial functioning and alcohol consumption 3 years after treatment. Drinking practices and consequences, depression, purpose in life, and anger were assessed 10 years after treatment. Distal outcome analyses examined differences in drinking and functional outcomes at 10 years as a function of the 3-year latent profiles. Analyses were preregistered at https://osf.io/3hbxr. RESULTS: Four latent profiles identified at 3 years after treatment (ie, low functioning frequent heavy drinkers, low functioning infrequent heavy drinkers, high functioning heavy drinkers, and high functioning infrequent nonheavy drinkers) were significantly associated with outcomes 10 years after treatment. The 2 high functioning profiles at 3 years had the highest level of psychological functioning at 10 years posttreatment, regardless of alcohol consumption level. Abstinence at 3 years did not predict better psychological functioning at 10 years. CONCLUSIONS: Nonabstinent AUD recovery is possible and is sustainable for up to 10 years after treatment. The current findings align with recent proposals to move beyond relying on alcohol consumption as a central defining feature of AUD recovery.

Patterns of transitions between relapse to and remission from heavy drinking over the first year after outpatient alcohol treatment and their relation to long-term outcomes.

OBJECTIVES: Studying clinical course after alcohol use disorder (AUD) treatment is central to understanding longer-term recovery. This study's two main objectives were to (a) replicate a recent study that identified heterogeneity in patterns of remission from/relapse to heavy drinking during the first year after outpatient treatment in an independent data set and (b) extend these recent findings by testing associations between patterns of remission/relapse and long-term alcohol-related and functioning outcomes. METHOD: Latent profile analyses were conducted using data from Project MATCH (N = 952; M age = 38.9; 72.3% female) and COMBINE (N = 1,383; M age = 44.4; 69.1% male). Transitions between heavy and nonheavy drinking within consecutive 2-week periods over a 1-year posttreatment period were characterized for each participant. From this, latent profiles were identified based on participants' initial 2-week heavy drinking status, the number of observed transitions between 2-week periods of relapse and remission, and the average duration of observed remission/relapse episodes. RESULTS: In both MATCH and COMBINE, we identified six profiles: (a) "continuous remission," 25.3% of COMBINE sample/25.3% of MATCH sample; (b) "transition to remission," 19.6%/9.6%; (c) "few long transitions," 15.9%/33.7%; (d) "many short transitions," 13.2%/13.6%; (e) "transition to relapse," 7.2%/7.1%; and (f) "continuous relapse," 18.8%/10.5%. Profiles 1 and 2 had the best long-term outcomes, Profiles 5 and 6 had the worst, and Profiles 3 and 4 fell between these groups. CONCLUSIONS: That many individuals can remit from heavy drinking following one or more relapses to heavy drinking may be of direct interest to individuals in recovery from AUD. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Can Alcohol Use Disorder Recovery Include Some Heavy Drinking? A Replication and Extension up to 9 Years Following Treatment.

BACKGROUND: Recent research indicates some individuals who engage in heavy drinking following treatment for alcohol use disorder fare as well as those who abstain with respect to psychosocial functioning, employment, life satisfaction, and mental health. The current study evaluated whether these findings replicated in an independent sample and examined associations between recovery profiles and functioning up to 6 years later. METHODS: Data were from the 3-year and 7- to 9-year follow-ups of subsamples initially recruited for the COMBINE study (3-year follow-up: n = 694; 30.1% female, 21.0% non-White; 7- to 9-year follow-up: n = 127; 38.9% female, 27.8% non-White). Recovery at 3 years was defined by latent profile analyses including measures of health functioning, quality of life, employment, alcohol consumption, and cannabis and other drug use. Functioning at the 7- to 9-year follow-up was assessed using single items of self-rated general health, hospitalizations, and alcohol consumption. RESULTS: We identified 4 profiles at the 3-year follow-up: (i) low-functioning frequent heavy drinkers (13.9%), (ii) low-functioning infrequent heavy drinkers (15.8%), (iii) high-functioning heavy drinkers (19.4%), and (iv) high-functioning infrequent drinkers (50.9%). At the 7- to 9-year follow-up, the 2 high-functioning profiles had the best self-rated health, and the high-functioning heavy drinking profile had significantly fewer hospitalizations than the low-functioning frequent heavy drinking profile. CONCLUSIONS: Previous findings showing heterogeneity in recovery outcomes were replicated. Most treatment recipients functioned well for years after treatment, and a subset who achieved stable recovery engaged in heavy drinking and reported good health outcomes up to 9 years after treatment. Results question the long-standing emphasis on drinking practices as a primary outcome, as well as abstinence as a recovery criterion in epidemiologic and treatment outcome research and among stakeholder groups and funding/regulatory agencies. Findings support an expanded recovery research agenda that considers drinking patterns, health, life satisfaction, and functioning.

Systemic blockade of ACVR2B ligands attenuates muscle wasting in ischemic heart failure without compromising cardiac function.

Signaling through activin receptors regulates skeletal muscle mass and activin receptor 2B (ACVR2B) ligands are also suggested to participate in myocardial infarction (MI) pathology in the heart. In this study, we determined the effect of systemic blockade of ACVR2B ligands on cardiac function in experimental MI, and defined its efficacy to revert muscle wasting in ischemic heart failure (HF). Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) to study its effect on post-MI cardiac remodeling and on later HF. Cardiac function was determined with echocardiography, and myocardium analyzed with histological and biochemical methods for hypertrophy and fibrosis. Pharmacological blockade of ACVR2B ligands did not rescue the heart from ischemic injury or alleviate post-MI remodeling and ischemic HF. Collectively, ACVR2B-Fc did not affect cardiomyocyte hypertrophy, fibrosis, angiogenesis, nor factors associated with cardiac regeneration except modification of certain genes involved in metabolism or cell growth/survival. ACVR2B-Fc, however, was able to reduce skeletal muscle wasting in chronic ischemic HF, accompanied by reduced LC3II as a marker of autophagy and increased mTOR signaling and Cited4 expression as markers of physiological hypertrophy in quadriceps muscle. Our results ascertain pharmacological blockade of ACVR2B ligands as a possible therapy for skeletal muscle wasting in ischemic HF. Pharmacological blockade of ACVR2B ligands preserved myofiber size in ischemic HF, but did not compromise cardiac function nor exacerbate cardiac remodeling after ischemic injury.

miR-1468-3p Promotes Aging-Related Cardiac Fibrosis.

Non-coding microRNAs (miRNAs) are powerful regulators of gene expression and critically involved in cardiovascular pathophysiology. The aim of the current study was to identify miRNAs regulating cardiac fibrosis. Cardiac samples of age-matched control subjects and sudden cardiac death (SCD) victims with primary myocardial fibrosis (PMF) were subjected to miRNA profiling. Old SCD victims with PMF and healthy aged human hearts showed increased expression of miR-1468-3p. In vitro studies in human cardiac fibroblasts showed that augmenting miR-1468-3p levels induces collagen deposition and cell metabolic activity and enhances collagen 1, connective tissue growth factor, and periostin expression. In addition, miR-1468-3p promotes cellular senescence with increased senescence-associated ß-galactosidase activity and increased expression of p53 and p16. AntimiR-1468-3p antagonized transforming growth factor ß1 (TGF-ß1)-induced collagen deposition and metabolic activity. Mechanistically, mimic-1468-3p enhanced p38 phosphorylation, while antimiR-1468-3p decreased TGF-ß1-induced p38 activation and abolished p38-induced collagen deposition. RNA sequencing analysis, a computational prediction model, and qPCR analysis identified dual-specificity phosphatases (DUSPs) as miR-1468-3p target genes, and regulation of DUSP1 by miR-1468-3p was confirmed with a dual-luciferase reporter assay. In conclusion, miR-1468-3p promotes cardiac fibrosis by enhancing TGF-ß1-p38 signaling. Targeting miR-1468-3p in the older population may be of therapeutic interest to reduce cardiac fibrosis.

The Role of Affect in Psychosocial Treatments for Substance Use Disorders.

PURPOSE OF REVIEW: This paper provides a narrative review of studies published over the past five years that have examined the role of affect, including both affective symptoms and affective disorders, in psychosocial treatments for substance use disorder. RECENT FINDINGS: A growing body of literature suggests that affective symptoms and affective disorders may moderate substance use disorder treatment efficacy, mediate the effects of treatment on substance use outcomes, and may be directly changed by substance use disorder treatment. SUMMARY: Substance use disorders and affective disorders commonly co-occur, and both affect and affective disorders are associated with substance use disorder treatment outcomes. Future research should continue to examine affect as a moderator, mediator, and outcome of substance use disorder treatments. In particular, new studies that are designed to test precision medicine hypotheses would greatly expand our understanding of the role of affective symptoms and disorders in substance use disorder treatment.

The relationship between delay discounting and alcohol dependence in individuals with and without comorbid psychopathology.

RATIONALE: Alcohol use disorder (AUD) has been associated with greater discounting of delayed monetary rewards, but it is unclear whether this association is primarily related to alcohol consumption or is secondary to the presence of psychiatric comorbidities. It is also unclear if steeper rates of discounting are associated with greater AUD severity. OBJECTIVE: We sought to determine whether the presence of comorbid psychiatric disorders affected the relationship between AUD and delay discounting. We also examined whether more severe AUD was associated with greater delay discounting. METHODS: In this cross-sectional study, 793 adults completed a delay discounting task. Subjects were divided into four groups based on diagnosis: current AUD with psychiatric comorbidities (N = 226), current AUD without psychiatric comorbidities (N = 203), past AUD (N = 69), and healthy controls (N = 295). In those with AUD, we investigated the relationship between delay discounting and alcohol dependence symptom count and recent drinking history. We also compared individuals seeking treatment to non-treatment seeking individuals. Psychiatric comorbidities examined included mood disorders, anxiety disorders, and substance use disorders. RESULTS: After adjusting for age, sex, income, and education, individuals with current AUD showed significantly higher rates of delay discounting than healthy controls and individuals with a past diagnosis of AUD. The presence of comorbid psychiatric diagnoses was not associated with steeper discounting. Among those with AUD, there was no evidence for a continuous relationship between delay discounting and AUD severity or alcohol consumption. Finally, non-treatment seekers with AUD had steeper delay discounting than treatment seekers. CONCLUSIONS: Individuals with AUD show steeper delay discounting than healthy adults, but the effect is small and there is no added effect from comorbid psychopathology or increased AUD severity. This suggests that steeper delay discounting may have a more limited effect on human alcohol use than previously supposed.