Patients with AUD exhibit dampened heart rate variability during sleep as compared to social drinkers.

Chronic heavy alcohol use profoundly affects the cardiovascular system, contributing to several life-threatening cardiovascular diseases. Heart rate variability (HRV), or the fluctuations in heart rate, reflects dynamic autonomic nervous system processes that change to meet biological demands and environmental challenges. In the current study, we examined whether HRV metrics are altered in alcohol use disorder (AUD) during waking and sleeping with passive biomonitoring as participants went about their daily lives. Social drinkers (standard deviation: n = 10, 5 female) and treatment-seeking individuals with moderate to severe AUD (n = 16, 7 female) provided continuous, real-world heart rate monitoring for 5 days of monitoring on average (M = 5.27 ± 2.22). Five indices of respiration and HRV-respiratory sinus arrhythmia (RSA) amplitude, high frequency (HF), low frequency (LF), HF/LF ratio, root-mean-square standard deviation (RMSSD), and standard deviation of the N-N intervals (SDNN)-were analyzed separately for waking and sleeping hours. Both RMSSD and SDNN decreased the longer the participants were awake (Ps < .013). During sleeping hours, HF, RSA amplitude, RMSSD, and SDNN were significantly higher in light social drinkers as compared to patients with AUD (all Ps < .009), indicating higher parasympathetic activation during sleep in the SD versus AUD group. Sleep and waking HRV measures were significantly correlated with patient-reported symptoms of depression and sleep difficulties in the AUD group (Ps < .05). This natural observational study utilizing continuous autonomic biomonitoring in the real world indicates parasympathetic dysfunction that is clearly detectable during sleep in AUD and HRV measures, which are also related to clinical, patient-related symptoms of AUD.

Stress responding and stress-related changes in cue reactivity in heavy smokers, problem gamblers, and healthy controls.

Addictions, both substance and behavioral, have been conceptualized as involving similar biopsychosocial processes with different opportunistic expressions. A maladaptive stress response in combination with craving or urges to engage in the addictive behavior may be among the underlying factors common to behavioral and substance addictions. The current study compared the neuroendocrine (cortisol) and subjective responses to stress of gamblers and smokers to healthy controls. We assessed if participants responded differently to smoking or gambling cues before and after a psychosocial stressor. To this end, the subjective urges/cravings of all participants were measured in response to smoking or gambling cues versus neutral cues, once under normal conditions and again after exposure to a stressor. Salivary cortisol was measured prior to, immediately following, and 10 minutes after conclusion of the stressor. Smokers and gamblers showed a similar blunted cortisol response to the acute stressor that differed from the control group's response. Following a stressor, subjective craving in smokers increased whereas gamblers' urges decreased. In smokers, a blunted cortisol and subjective stress response were related to increased urges. In contrast, for gamblers, changes in cortisol levels were unrelated to urges, and higher subjective stress was associated with decreased urges. In conclusion, individuals with a substance and a behavioral addiction share common patterns of reactivity to stress. However, while the stressor enhanced cue-related craving in smokers, it generally had the opposite effect on gamblers. Further research is necessary to elucidate the complicated patterns of similarities and differences that underlie substance and behavioral addictions.

Noninvasive determination of human cortisol and dehydroepiandrosterone sulfate using liquid chromatography-tandem mass spectrometry.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) for measurements of steroids in human saliva has garnered increased interest in the area of clinical psychoneuroendocrinological research. However, performance characteristics of LC-MS/MS methods for the analysis of steroids in saliva are limited. Human saliva samples were collected via passive drool. Cortisol and dehydroepiandrosterone sulfate (DHEA-S) in the samples were extracted together, resolved on a C18-A column, and analyzed using tandem mass spectrometry. The LC-MS/MS method had limits of quantitation of 0.03 and 0.06 ng/mL for DHEA-S and cortisol, respectively. Method evaluations showed coefficient variation (%CV) of inter-assay ranging 4.6-17.9% for DHEA-S and cortisol, recoveries of 102.4-109.5% for DHEA-S and 94.6-98.3% for cortisol, and assay linearity with R2 = 0.9964 for DHEA-S (1.0-25.0 ng/mL) and R2 = 0.997 (1.0-25.0 ng/mL) for cortisol. No cross contamination among samples was observed. Human saliva showed 20% and 18% ion enhancement effect for DHEA-S and cortisol assay, respectively. No interference by ten common steroids was detected. Regression analysis of method comparisons with laboratory-developed test (LDT) method revealed R2 = 0.9688 (LC-MS/MS = 0.9665 LDT-LC-MS/MS - 0.7355) for cortisol, and R2 = 0.9039 (LC-MS/MS = 1.0173 LDT-LC-MS/MS + 3.6797) for DHEA-S. Reference ranges for young adults were determined to be 0.3-5.9 ng/mL for females and 0.1-5.6 ng/mL for males for salivary cortisol, and 0.6-7.4 ng/mL for females and 0.6-10.1 ng/mL for males for salivary DHEA-S. An LC-MS/MS method for quantifying cortisol and DHEA-S in human saliva was developed and validated for clinical and psychoneuroendocrinological research that require noninvasive means of measuring these hormones.

Predictors of Topiramate Tolerability in Heavy Cannabis-Using Adolescents and Young Adults: A Secondary Analysis of a Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE/BACKGROUND: Cannabis is the most commonly abused illicit drug and accounts for the greatest number of adolescent substance abuse treatment admissions. Despite urgent need for effective interventions, the best available psychosocial treatment options yield only modest effects. Topiramate showed promise as an adjunctive pharmacotherapy to a psychosocial intervention for cannabis misuse among adolescents and young adults in a recent clinical trial, but it was not well tolerated. This study investigated associations between clinical characteristics and side effects and dropout among adolescents and young adults randomized to topiramate. METHODS: This study involved secondary data analysis of a randomized placebo-controlled trial of topiramate for treating cannabis misuse (ages, 15-24 years; 50% female). We explored the interaction effects of baseline characteristics and medication condition (topiramate vs placebo) on treatment dropout. We also explored the relationship between side effects and dropout. FINDINGS/RESULTS: Higher cannabis problems were significantly associated with reduced hazard of dropout in the topiramate group (P = 0.048) and were nonsignificantly associated with increased hazard of dropout in the placebo group (P = 0.062). Results also showed that memory difficulties were an overwhelming predictor of dropout in the topiramate condition; 42% of participants who dropped out experienced memory difficulties, whereas none of those who remained in the study experienced these effects. IMPLICATIONS/CONCLUSIONS: By identifying who may most benefit from and tolerate this medication, treatment for substance use disorders can become more individualized and positive outcomes may be enhanced.

Internalizing Risk Factors for College Students' Alcohol use: A Combined Person- and Variable-Centered Approach.

BACKGROUND: Most studies that investigate internalizing problems (i.e., depression and anxiety symptoms) and alcohol use disorders use variable-centered approaches, losing important information about differences among individuals. OBJECTIVES: To group college students by different profiles of alcohol-use risk factors using a person-centered cluster analysis in two separate samples. METHODS: Questionnaires were used in both studies to assess positive expectancies regarding alcohol use, coping motives for alcohol use, and symptoms of depression and anxiety. In the first study (2012), we collected information about past month alcohol use, including frequency and binge drinking episode (n = 171). In the second study (2013), we also included measures of externalizing behaviors and negative alcohol-related consequences (n = 526). RESULTS: In Study 1, the cluster analysis identified four groups of students who displayed different patterns of risk: a low-risk group, moderate cognitions/low internalizing cluster, a high internalizing/low coping motives group of drinkers, and a high internalizing/high coping motives cluster of drinkers. This fourth group showed high levels of depression, moderate anxiety, high positive expectancies and coping motives for alcohol use, and reported the highest frequency of alcohol use. Study 2 replicated the findings from the previous study. Three groups of individuals were identified, replicating the low-risk cluster, the moderate cognitions/low internalizing cluster, and the internalizing cluster of drinkers from Study 1. Participants in the latter cluster endorsed the highest number of negative consequences of alcohol use. CONCLUSIONS: Results from both studies highlight the importance of tailoring alcohol abuse prevention efforts to a subgroup young adult who endorse internalizing symptoms.

Effects of Acute Stress on Decision Making.

The study examined the effects of a social stressor (Trier Social Stress Test) on 24 male and 32 female college students' affective and physiological reactivity and their subsequent performance on a decision-making task (Iowa Gambling Task). The 56 participants were randomly assigned to a social stressor or a control condition. Compared to controls, participants in the stress condition responded with higher heart rates and skin conductance responses, reported more negative affect, and on the decision-making task made less advantageous choices. An exploratory regression analysis revealed that among men higher levels of heart rate were positively correlated with riskier choices on the Iowa Gambling Task, whereas for women this relationship was curvilinear. Exploratory correlational analyses showed that lower levels of skin conductance within the stress condition were associated with greater levels of substance use and gambling. The results suggest that the presence of a stressor may generally result in failure to attend to the full range of possible consequences of a decision. The relationship pattern between the degree of stress responding and successful decision making may be different for men and women.

The effects of simultaneous alcohol and cannabis use on subjective drug effects: A narrative review across methodologies.

Over 75% of young adults who use cannabis also report drinking alcohol, leading to increased risks that include impaired cognition, substance use disorders, and more heavy and frequent substance use. Studies suggest that subjective responses to either alcohol or cannabis can serve as a valuable indicator for identifying individuals at risk of prolonged substance use and use disorder. While laboratory studies show additive effects when alcohol and cannabis are used together, the impact of co-using these substances, specifically with respect to cannabidiol, on an individual's subjective experience remains unclear. This narrative review explores the effects of simultaneous alcohol and cannabis (SAM) use on subjective drug effects, drawing from qualitative research, laboratory experiments, and naturalistic studies. Experimental findings are inconsistent regarding the combined effects of alcohol and cannabis, likely influenced by factors such as dosage, method of administration, and individual substance use histories. Similarly, findings from qualitative and naturalistic studies are mixed regarding subjective drug effects following SAM use. These discrepancies may be due to recall biases, variations in assessment methods, and the measurement in real-world contexts of patterns of SAM use and related experiences. Overall, this narrative review highlights the need for more comprehensive research to understand more fully subjective drug effects of SAM use in diverse populations and settings, emphasizing the importance of frequent and nuanced assessment of SAM use and subjective responses in naturalistic settings.

Daily stress predicts later drinking initiation via craving in heavier social drinkers: A prospective in-field daily diary study.

Stress has been linked to increased alcohol use but how stress may increase drinking in social drinkers is not well understood. Negative reinforcement processes may explain this link but the role of specific motivational processes, such as craving, and how these motivational processes are altered by drinking have not been studied. The current study assessed social drinkers (n = 81) for recent quantity and frequency of alcohol intake (quantity and frequency index, QFI) upon study enrollment, who then completed 30 days of electronic daily records of stress, craving, and alcohol intake. Multilevel structural equation models tested if person-averaged (between-person) and daily (within-person) craving mediated the link between stress and later drinking each evening and if recent quantity-frequency of drinking (QFI) moderated these associations. At the between-person level, both greater subjective stress, Est = .38, 95% confidence interval (CI) [.19, .57], and higher QFI predicted higher levels of craving, Est = .34, 95% CI [.20, .49]. Higher craving predicted more frequent drinking throughout the study, Est = .34, 95% CI [.01, .29]. At the within-person level, higher subjective stress predicted higher within-person craving; and the link between craving and later drinking was significant among those who had a higher QFI, Est = .84, 95% CI [.58, 1.12]. The subjective stress-drinking relationship was mediated by a greater alcohol craving response in social drinkers, and higher the QFI, greater the alcohol craving response. These results indicate that both higher levels of stress and greater recent alcohol intake patterns sensitize the craving response that in turn facilitates later alcohol intake. The findings suggest that higher recent alcohol use predict greater stress-potentiated initiation of drinking via higher craving responses. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Noninvasive detection of human dehydroepiandrosterone, progesterone and testosterone using LC-MS/MS revealed effects of birth control pills/devices and body weight on ovulatory prediction.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been increasingly used to measure steroids in human saliva. We studied the performance of a conventional LC-MS/MS for measuring dehydroepiandrosterone (DHEA), testosterone and progesterone in human saliva. These three steroids were co-extracted by liquid-liquid extraction and derivatized. Derivatives were resolved on a C18 column and quantified using an LC-MS/MS (AB Sciex API 2000) instrument. The assay's limits of quantification were 0.03 ng/mL for all three steroids. Inter-assay coefficients of variation were 16.6-18.8% (DHEA), 12.0-15.8% (testosterone), and 12.7-19.3% (progesterone). Assay linearity analysis showed R2 of 0.9926, 0.9750 and 0.9949 for DHEA, testosterone and progesterone, respectively. No carry-over between samplings was observed. An ion-enhancement effect of 11.6% for DHEA determination and ion-suppression effects of 13.9% and 20.7% for analysis of progesterone and testosterone, respectively, were determined. No interferences by 9 steroid analogs were detected. Spiked recoveries were 85.5% (DHEA), 86.5% (testosterone), and 92.6% (progesterone). Comparison with laboratory developed test (LDT)-LC-MS/MS methods by other New York State Department of Health certified laboratories revealed R2 = 0.9425 (DHEA, LC-MS/MS = 1.0267 LDT + 21.989), R2 = 0.9849 (testosterone, LC-MS/MS = 0.9447 LDT + 9.8037), and R2 = 0.9736 (progesterone, LC-MS/MS = 1.1196 LDT + 0.0985). Reference intervals for the 3 steroids in saliva for young males and females were estimated. Results of intra-individual salivary progesterone analysis indicated that caution should be exercised when using progesterone concentrations in predicting ovulation for females who are under treatment with birth control pills/devices or has body a weight of > 90 kg.

Fluctuations in progesterone moderate the relationship between daily mood and alcohol use in young adult women.

BACKGROUND: Research has demonstrated associations between hormonal fluctuations during the menstrual cycle and women's alcohol use. This association has been explained by mood changes that, for some women, accompany decreasing levels of progesterone during the menstrual cycle, particularly during the late luteal/premenstrual phase. The current study examined whether participants' daily ratings of mood interact with changing levels of progesterone to predict alcohol use. METHOD: Young adult women attended two sessions scheduled two weeks apart, during which they completed questionnaires and provided salivary samples for the assay of progesterone levels. In the intervening two weeks, participants completed daily logs of their mood, alcohol use, and menses. Ordered Generalized Linear Mixed Models assessed the effects of daily mood (examined as both a within- and between-subject variable) on the likelihood of drinking, as a function of menstrual cycle phase and changes in progesterone across the two weeks. RESULTS: One standard deviation increase in progesterone corresponded to a 1.61 decrease in the odds of drinking. This main effect was moderated by daily mood. Women were more likely to drink during a decrease in progesterone on days they rated their mood as negative, whereas during an increase in progesterone they were more likely to drink on days they reported a positive mood. Between-subject analyses showed that women who reported lower overall mood during the two-week period were more likely to drink with an increase in progesterone and less likely with a decrease. CONCLUSIONS: Women's likelihood to drink increased when they experienced negative mood in the context of decreasing levels of progesterone, whereas the negative-mood/drinking association was mitigated among those with increasing levels of progesterone. However, compared to women who on average had an overall more positive mood, women with an overall lower mood (and corresponding higher levels of depression and anxiety at baseline) did not experience the protective effects of rising progesterone levels on drinking.

Drug-induced stress responses and addiction risk and relapse.

A number of studies have assessed the effects of psychoactive drugs on stress biology, the neuroadaptations resulting from chronic drug use on stress biology, and their effects on addiction risk and relapse. This review mainly covers human research on the acute effects of different drugs of abuse (i.e., nicotine, cannabis, psychostimulants, alcohol, and opioids) on the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) responses. We review the literature on acute peripheral stress responses in naïve or light recreational users and binge/heavy or chronic drug users. We also discuss evidence of alterations in tonic levels, or tolerance, in the latter relative to the former and associated changes in the phasic stress responses. We discuss the impact of the stress system tolerance in heavy users on their response to drug- and stress-related cue responses and craving as compared to control subjects. A summary is provided of the effects of glucocorticoid responses and their adaptations on brain striatal and prefrontal cortices involved in the regulation of drug seeking and relapse risk. Finally, we summarize important considerations, including individual difference factors such as gender, co-occurring drug use, early trauma and adversity and drug use history and variation in methodologies, that may further influence the effects of these drugs on stress biology.

A day-by-day prospective analysis of stress, craving and risk of next day alcohol intake during alcohol use disorder treatment.

BACKGROUND: Stress has been known to increase craving in individuals with Alcohol Use Disorders (AUD) and predict future alcohol relapse risk, but whether stress on a particular day affects craving on that day to impact prospective alcohol intake in the real world, particularly during early treatment and recovery, has not been studied thus far. METHOD: The first study included 85 AUD individuals who reported their daily stress, craving, and alcohol intake in the first two weeks of early treatment. A second validation study included 28 AUD patients monitored daily during eight weeks of outpatient 12-Step based behavioral counseling treatment for AUD. Data were collected from telephone-based daily diaries for 903 days in Study 1 and 1488 in Study 2. Multilevel latent models tested if daily and person-averaged craving mediated the link between stressful events and next day drinking during treatment. RESULTS: In both Study 1 and 2, exposure to a stressful event on a particular day predicted increased craving on that day (p's≤.002); and such increases in craving predicted the likelihood of drinking the next day (p's≤.014) and the drinking amount (p's< = 008). Individuals who experienced more stressful events reported higher craving (p's≤.012), and higher cravers reported greater next day drinking (p's<.001). CONCLUSIONS: The results across two studies with separate samples are the first to establish that craving directly mediates the association between stress and next day alcohol intake in individuals with AUD. Findings suggest a need for novel treatment approaches to address stress-induced craving to improve alcohol use outcomes.

Weaker Memory Performance Exacerbates Stress-Induced Cannabis Craving in Youths' Daily Lives.

Theories of addiction posit that stimuli associated with drug use, including both exteroceptive (e.g., paraphernalia) and interoceptive (e.g., feeling tense or "stressed"), evoke craving and contribute to the pathogenesis of substance misuse. Control over drug cue response and stress is essential for moderating use. Building from laboratory data supporting associations between cue exposure, stress, and craving, this study tested whether these associations generalize to real-world settings and examined whether a well-vetted neurocognitive control capacity, i.e., working memory (WM), moderated associations. Youth (N = 85; 15-24 years) completed baseline and ecological momentary assessments. Cue exposure and participants' average stress predicted higher craving. Youth with weaker WM experienced stronger craving at higher-stress moments but not when faced with cues. Interactions were present for both previous-moment and same-moment stress. Craving among adolescents with stronger WM was not swayed by momentary stress. Findings suggest stronger WM protects against craving at more stressful moments.

Real-time assessment of alcohol craving and naltrexone treatment responsiveness in a randomized clinical trial.

INTRODUCTION: This secondary data analysis examined whether and how the dopamine receptor D4 gene (DRD4) influenced naltrexone treatment responsiveness in a randomized clinical trial. We leveraged intensive experience sampling methods to test the hypothesis that craving recorded at drinking and non-drinking moments would mediate naltrexone effects on the likelihood of heavy drinking, but only among carriers of the DRD4 long (DRD4-L) allele. METHODS: Participants (Mage=29.8years, SD=12.1) were non-treatment seeking heavy drinkers (n=104, 54.8% female, 61.5% alcohol dependent) randomized to 3weeks of daily naltrexone (50mg) or placebo. During these 3weeks, participants used handheld electronic devices to complete real-time reports of alcohol use and craving multiple times per day in their natural environments. This approach afforded intensive repeated assessment of focal variables and provided in-the-moment data to test whether craving when not drinking or early in drinking episodes explained naltrexone effects on drinking. RESULTS: Moderated-mediation multilevel structural equation models showed that craving during non-drinking moments mediated the treatment effect of naltrexone on heavy drinking but only among carriers of the DRD4-L allele. The same pattern of associations was not shown when evaluating craving while participants were consuming alcoholic beverages. CONCLUSIONS: Findings provide the first in vivo evidence that, among carriers of the DRD4-L allele, naltrexone blunts craving in real-world settings, and this effect in turn reduces the likelihood of heavy drinking. This work highlights the utility of EMA methods for elucidating how treatments work and further demonstrates the importance of genetic factors for understanding individual differences in pharmacotherapy responsiveness.