Addressing Substance Use in the Adolescent Transplant Population.

Adolescence is a unique period of physical and psychosocial changes as youth transition, over many years, to adulthood. The psychosocial changes that accompany adolescence include emotional separation from parents, greater influence of peer groups, an interest in self-identification and autonomy, and increased risk-taking behaviors. Substance use is a common form of risk-taking behavior in the adolescent developmental stage. Alcohol, nicotine, and cannabis are the most common types of substances used in the United States. In the adolescent transplant population, rates of substance use appear to be at, or slightly below, their peer counterparts. Substance use can lead to deleterious health outcomes for adolescent transplant patients as a result of impaired decision-making, reduction in medication and clinic visit compliance, increases in mental health disorders, and risk for developing dependence and a substance use disorder. Given the close relationship that many pediatric transplant providers have with their patients and families, transplant care teams are in an excellent position to help their patients by addressing adolescent substance use. This narrative review describes how providers can use proactive standardized approaches to identify and intervene with substance use behavior.

Tobacco Withdrawal Symptoms Before and After Nicotine Deprivation in Veteran Smokers with Posttraumatic Stress Disorder and with Major Depressive Disorder.

INTRODUCTION: The high smoking prevalence amongst individuals with psychiatric disorders constitutes a major public health disparity. Negative reinforcement models of addiction posit that severe tobacco withdrawal symptoms, related to the affective vulnerabilities of these smokers, may thwart their quitting smoking successfully. However, relatively few studies have prospectively examined the effects of nicotine deprivation on withdrawal symptoms in these groups. METHODS: This study compared the level of withdrawal symptoms both before and after nicotine deprivation in those diagnosed with posttraumatic stress disorder (PTSD) or major depressive disorder (MDD) and in those without psychiatric diagnoses. Participants were US veterans who smoked (≥10 cigarettes/day) and met diagnostic criteria for PTSD (n = 38), MDD (n = 43), or no psychiatric diagnosis ("controls" n = 44). Participants attended study visits before and during 48-hour nicotine deprivation to report tobacco withdrawal symptoms. Analyses evaluated withdrawal symptom levels (baseline and during nicotine deprivation) and the change in symptoms related to nicotine deprivation and compared (1) participants with a psychiatric diagnosis versus controls, and (2) participants with PTSD versus MDD. RESULTS: Contrary to hypotheses, nicotine deprivation produced greater increases in most withdrawal symptoms amongst controls than in those with psychiatric diagnoses. Compared with controls, those with PTSD or MDD reported elevated symptom levels both before and after tobacco deprivation for most withdrawal symptoms. CONCLUSIONS: These findings suggest that chronically high levels of distress and craving, rather than acute increases in withdrawal symptoms because of nicotine deprivation, may account for the quitting difficulties of those with comorbid conditions such as PTSD and MDD. IMPLICATIONS: Severe tobacco withdrawal may account for the higher quitting difficulties of smokers with either posttraumatic stress disorder (PTSD) or major depressive disorder (MDD). Paradoxically, this study showed that individuals with no psychiatric diagnosis had greater increases in tobacco withdrawal severity because of nicotine deprivation than did those with either PTSD or MDD. Those with either PTSD or MDD showed high stable levels of withdrawal symptom severity both before and during two days of abstinence, suggesting that their quitting difficulties may be related to their chronically high levels of distress rather than nicotine deprivation per se.

Stress Allostasis in Substance Use Disorders: Promise, Progress, and Emerging Priorities in Clinical Research.

Clinicians and researchers alike have long believed that stressors play a pivotal etiologic role in risk, maintenance, and/or relapse of alcohol and other substance use disorders (SUDs). Numerous seminal and contemporary theories on SUD etiology posit that stressors may motivate drug use and that individuals who use drugs chronically may display altered responses to stressors. We use foundational basic stress biology research as a lens through which to evaluate critically the available evidence to support these key stress-SUD theses in humans. Additionally, we examine the field's success to date in targeting stressors and stress allostasis in treatments for SUDs. We conclude with our recommendations for how best to advance our understanding of the relationship between stressors and drug use, and we discuss clinical implications for treatment development.

Motives for Smoking in Those With PTSD, Depression, and No Psychiatric Disorder.

Objective: Approaches for effectively treating smoking in those with posttraumatic stress disorder (PTSD) and with major depressive disorder (MDD) could be improved by identifying motivational processes underlying their tobacco dependence. The goal of this study was to identify the motivational processes influencing smoking dependence among smokers with PTSD and with MDD relative to non-diagnosed controls. Methods: Participants were United States (US) veterans who smoked daily (N = 162) and met DSM-IV criteria for either PTSD (n = 52), MDD (n = 52), or no current psychiatric disorder (controls; n = 58). Smoking dependence motives were assessed via the Brief Wisconsin Inventory for Smoking Dependence Motives (Brief WISDM). The 11 Brief WISDM subscales are categorized into two major factors: Primary Dependence Motives and Secondary Dependence Motives. Results: Smokers with PTSD scored higher than non-diagnosed controls on the following Primary Dependence Motives subscales: Automaticity, Craving, and Tolerance (all p-values <.05). Smokers with PTSD, relative to controls, also scored higher on the overall Secondary Dependence Motives subscale, and on five of the seven Secondary Dependence Motives subscales: Cue Exposure/Associative Processes, Affective Enhancement, Affiliative Attachment, Cognitive Enhancement, and Weight Control (all p-values < .05). Smokers with MDD scored significantly higher than controls on one Primary Dependence Motives subscale: Craving and on four of seven Secondary Dependence Motives subscales: Affective Enhancement, Affiliative Attachment, Cognitive Enhancement, and Weight Control (all p-values <.05). Finally, exploratory analyses directly contrasting the PTSD group with the MDD group showed that smokers with PTSD were higher than those with MDD in the overall Secondary Dependence Motives subscale and one of the seven Secondary Dependence Motives subscales: Cue Exposure/Associative Processes (all p-values < .05). Conclusions: Results suggest that both Primary Dependence Motives and Secondary Dependence Motives play a meaningful role in motivation to use tobacco in smokers with PTSD; smoking dependence in those with MDD may be primarily influenced by Secondary Dependence Motives.

Intolerance of uncertainty and physiological responses during instructed uncertain threat: A multi-lab investigation.

Individuals with high self-reported Intolerance of uncertainty (IU) tend to interpret uncertainty negatively. Recent research has been inconclusive on evidence of an association between IU and physiological responses during instructed uncertain threat. To address this gap, we conducted secondary analyses of IU and physiology data recorded during instructed uncertain threat tasks from two lab sites (Wisconsin-Madison; n = 128; Yale, n = 95). No IU-related effects were observed for orbicularis oculi activity (auditory startle-reflex). Higher IU was associated with: (1) greater corrugator supercilii activity to predictable and unpredictable threat of shock, compared to the safety from shock, and (2) poorer discriminatory skin conductance response between the unpredictable threat of shock, relative to the safety from shock. These findings suggest that IU-related biases may be captured differently depending on the physiological measure during instructed uncertain threat. Implications of these findings for neurobiological models of uncertainty and anticipation in anxiety are discussed.

Nine years of smoking data from incarcerated men: A call to action for tobacco dependence interventions.

People who are incarcerated use tobacco in high numbers before incarceration and the vast majority resume tobacco use soon after release despite institutional smoking bans. Nine years of surveys collected at a correctional facility in the Midwest, U.S., were analyzed to identify the needs of this high-risk population and suggest future directions for research and intervention development. For the most part, survey respondents considered themselves no longer addicted to tobacco and intended to remain tobacco free after release. They increasingly expected support to remain tobacco free from their home environment despite no change in home tobacco use. Over this nine-year period, significantly fewer respondents wanted materials and help to remain tobacco free, suggesting they have become more challenging to assist. Implications for intervention development and future research are discussed.

Revision of the Wisconsin Smoking Withdrawal Scale: Development of brief and long forms.

The assessment of tobacco withdrawal is important for both research and clinical purposes. This study describes the psychometric development of a revised version of the 28-item Wisconsin Smoking Withdrawal Scale (WSWS; Welsch et al., Experimental and Clinical Psychopharmacology, 1999, 7, p. 354). Because the different contexts of use sometimes permit only brief assessment, this revision has produced both a brief and longer form using an updated pool of candidate items. For the revised Wisconsin Smoking Withdrawal Scale 2 (WSWS2), a candidate pool of 37 items was developed to measure nine putative withdrawal constructs. The stem and wording of items were revised as was the response scale. Data for psychometric analyses were derived from three smoking cessation randomized clinical trials conducted at the University of Wisconsin Center for Tobacco Research and Intervention. Dimensionality, internal consistency, and item characteristic analyses of the candidate items were conducted in a derivation sample to ascertain the factor structure and to identify items that could be used in the WSWS2 scales. Confirmatory factor analyses (CFAs) of reduced item sets and factor structure were conducted in two validation samples along with reliability and validity analyses. Derivation and validation sample analyses yielded a longer version of the WSWS2 (WSWS2-L) with 19 items and six subscales (Craving, Negative Affect, Hunger, Sleep, Restlessness, and Concentration) and a brief 6-item version (WSWS2-B). In validation sample analyses, both the WSWS2-L and the WSWS2-B demonstrated good reliability and validity as well as good fit in CFAs. The WSWS2-L and WSWS2-B possess improved construct coverage, fewer items, and other enhancements relative to the WSWS. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Searching for Personalized Medicine for Binge Drinking Smokers: Smoking Cessation Using Varenicline, Nicotine Patch, or Combination Nicotine Replacement Therapy.

OBJECTIVE: Heavy drinking is common among smokers and is associated with especially poor health outcomes. Varenicline may affect mechanisms and clinical outcomes that are relevant for both smoking cessation and alcohol use. The current study examines whether varenicline, relative to nicotine replacement therapy, yields better smoking cessation outcomes among binge drinking smokers. METHOD: Secondary data analyses of a comparative effectiveness randomized controlled trial of three smoking cessation pharmacotherapies (12 weeks of varenicline, nicotine patch, or nicotine patch and lozenge) paired with six counseling sessions were conducted. Adult daily cigarette smokers (N = 1,078, 52% female) reported patterns of alcohol use, cigarette craving, and alcohol-related cigarette craving at baseline and over 4 weeks after quitting. Smoking cessation outcome was 7-day biochemically confirmed point-prevalence abstinence. RESULTS: Binge drinkers had higher relapse rates than moderate drinkers at 4-week post-target quit day but not at the end of treatment or long-term follow up (12 and 26 weeks). Varenicline did not yield superior smoking cessation outcomes among binge drinkers, nor did it affect alcohol use early in the quit attempt. Varenicline did produce relatively large reductions in alcohol-related cigarette craving and overall cigarette craving during the first 4 weeks after quitting. CONCLUSIONS: Varenicline did not yield higher smoking abstinence rates or reduce alcohol use among binge drinkers. Varenicline did reduce alcohol-related cigarette craving but this did not translate to meaningful differences in smoking abstinence. Varenicline's effects on smoking abstinence do not appear to vary significantly as a function of drinking status.

Acute prazosin administration does not reduce stressor reactivity in healthy adults.

RATIONALE: Norepinephrine plays a critical role in the stress response. Clarifying the psychopharmacological effects of norepinephrine manipulation on stress reactivity in humans has important implications for basic neuroscience and treatment of stress-related psychiatric disorders, such as posttraumatic stress disorder and alcohol use disorders. Preclinical research implicates the norepinephrine alpha-1 receptor in responses to stressors. The No Shock, Predictable Shock, Unpredictable Shock (NPU) task is a human laboratory paradigm that is well positioned to test cross-species neurobiological stress mechanisms and advance experimental therapeutic approaches to clinical trials testing novel treatments for psychiatric disorders. OBJECTIVES: We hypothesized that acute administration of prazosin, a noradrenergic alpha-1 antagonist, would have a larger effect on reducing stress reactivity during unpredictable, compared to predictable, stressors in the NPU task. METHODS: We conducted a double-blind, placebo-controlled, crossover randomized controlled trial in which 64 healthy adults (32 female) completed the NPU task at two visits (2 mg prazosin vs. placebo). RESULTS: A single acute dose of 2 mg prazosin did not reduce stress reactivity in a healthy adult sample. Neither NPU startle potentiation nor self-reported anxiety was reduced by prazosin (vs. placebo) during unpredictable (vs. predictable) stressors. CONCLUSIONS: Further research is needed to determine whether this failure to translate preclinical neuroscience to human laboratory models is due to methodological factors (e.g., acute vs. chronic drug administration, brain penetration, study population) and/or suggests limited clinical utility of noradrenergic alpha-1 antagonists for treating stress-related psychiatric disorders.

Probing for Neuroadaptations to Unpredictable Stressors in Addiction: Translational Methods and Emerging Evidence.

Stressors clearly contribute to addiction etiology and relapse in humans, but our understanding of specific mechanisms remains limited. Rodent models of addiction offer the power, flexibility, and precision necessary to delineate the causal role and specific mechanisms through which stressors influence alcohol and other drug use. This review describes a program of research using startle potentiation to unpredictable stressors that is well positioned to translate between animal models and clinical research with humans on stress neuroadaptations in addiction. This research rests on a solid foundation provided by three separate pillars of evidence from (a) rodent behavioral neuroscience on stress neuroadaptations in addiction, (b) rodent affective neuroscience on startle potentiation, and (c) human addiction and affective science with startle potentiation. Rodent stress neuroadaptation models implicate adaptations in corticotropin-releasing factor and norepinephrine circuits within the central extended amygdala following chronic alcohol and other drug use that mediate anxious behaviors and stress-induced reinstatement among drug-dependent rodents. Basic affective neuroscience indicates that these same neural mechanisms are involved in startle potentiation to unpredictable stressors in particular (vs. predictable stressors). We believe that synthesis of these evidence bases should focus us on the role of unpredictable stressors in addiction etiology and relapse. Startle potentiation in unpredictable stressor tasks is proposed to provide an attractive and flexible test bed to encourage tight translation and reverse translation between animal models and human clinical research on stress neuroadaptations. Experimental therapeutics approaches focused on unpredictable stressors hold high promise to identify, repurpose, or refine pharmacological and psychosocial interventions for addiction.

Increased startle potentiation to unpredictable stressors in alcohol dependence: Possible stress neuroadaptation in humans.

Stress plays a key role in addiction etiology and relapse. Rodent models posit that following repeated periods of alcohol and other drug intoxication, compensatory allostatic changes occur in the central nervous system (CNS) circuits involved in behavioral and emotional response to stressors. We examine a predicted manifestation of this neuroadaptation in recently abstinent alcohol-dependent humans. Participants completed a translational laboratory task that uses startle potentiation to unpredictable (vs. predictable) stressors implicated in the putative CNS mechanisms that mediate this neuroadaptation. Alcohol-dependent participants displayed significantly greater startle potentiation to unpredictable than predictable stressors relative to nonalcoholic controls. The size of this effect covaried with alcohol-related problems and degree of withdrawal syndrome. This supports the rodent model thesis of a sensitized stress response in abstinent alcoholics. However, this effect could also represent premorbid risk or mark more severe and/or comorbid psychopathology. Regardless, pharmacotherapy and psychological interventions may target unpredictable stressor response to reduce stress-induced relapse. (PsycINFO Database Record

Psychometric properties of startle and corrugator response in NPU, affective picture viewing, and resting state tasks.

The current study provides a comprehensive evaluation of critical psychometric properties of commonly used psychophysiology laboratory tasks/measures within the NIMH RDoC. Participants (N = 128) completed the no-shock, predictable shock, unpredictable shock (NPU) task, affective picture viewing task, and resting state task at two study visits separated by 1 week. We examined potentiation/modulation scores in NPU (predictable or unpredictable shock vs. no-shock) and affective picture viewing tasks (pleasant or unpleasant vs. neutral pictures) for startle and corrugator responses with two commonly used quantification methods. We quantified startle potentiation/modulation scores with raw and standardized responses. We quantified corrugator potentiation/modulation in the time and frequency domains. We quantified general startle reactivity in the resting state task as the mean raw startle response during the task. For these three tasks, two measures, and two quantification methods, we evaluated effect size robustness and stability, internal consistency (i.e., split-half reliability), and 1-week temporal stability. The psychometric properties of startle potentiation in the NPU task were good, but concerns were noted for corrugator potentiation in this task. Some concerns also were noted for the psychometric properties of both startle and corrugator modulation in the affective picture viewing task, in particular, for pleasant picture modulation. Psychometric properties of general startle reactivity in the resting state task were good. Some salient differences in the psychometric properties of the NPU and affective picture viewing tasks were observed within and across quantification methods.

Not just noise: individual differences in general startle reactivity predict startle response to uncertain and certain threat.

General startle reactivity reflects defensive reactivity independent of affective foreground. We examined the relationship between general startle reactivity and startle response to threat in three tasks with distinct manipulations of threat uncertainty. General startle reactivity was a stronger predictor of startle response during threat (vs. no threat) and uncertain (vs. certain threat). These results confirm that including general startle reactivity in our analyses can increase the power and/or precision to test effects of other focal experimental manipulations or grouping variables. Moreover, this suggests that individual differences in defensive reactivity moderate responding to threats of various types in our environment. As such, individual differences in general startle reactivity may index important psychological attributes related to trait affectivity, premorbid vulnerability for psychopathology, and manifest psychopathology.

Cannabis cue reactivity and craving among never, infrequent and heavy cannabis users.

Substance cue reactivity is theorized as having a significant role in addiction processes, promoting compulsive patterns of drug-seeking and drug-taking behavior. However, research extending this phenomenon to cannabis has been limited. To that end, the goal of the current work was to examine the relationship between cannabis cue reactivity and craving in a sample of 353 participants varying in self-reported cannabis use. Participants completed a visual oddball task whereby neutral, exercise, and cannabis cue images were presented, and a neutral auditory oddball task while event-related brain potentials (ERPs) were recorded. Consistent with past research, greater cannabis use was associated with greater reactivity to cannabis images, as reflected in the P300 component of the ERP, but not to neutral auditory oddball cues. The latter indicates the specificity of cue reactivity differences as a function of substance-related cues and not generalized cue reactivity. Additionally, cannabis cue reactivity was significantly related to self-reported cannabis craving as well as problems associated with cannabis use. Implications for cannabis use and addiction more generally are discussed.

Contextual Variation in Automatic Evaluative Bias to Racially-Ambiguous Faces.

Three studies examined the implicit evaluative associations activated by racially-ambiguous Black-White faces. In the context of both Black and White faces, Study 1 revealed a graded pattern of bias against racially-ambiguous faces that was weaker than the bias to Black faces but stronger than that to White faces. Study 2 showed that significant bias was present when racially-ambiguous faces appeared in the context of only White faces, but not in the context of only Black faces. Study 3 demonstrated that context produces perceptual contrast effects on racial-prototypicality judgments. Racially-ambiguous faces were perceived as more prototypically Black in a White-only than mixed-race context, and less prototypically Black in a Black-only context. Conversely, they were seen as more prototypically White in a Black-only than mixed context, and less prototypically White in a White-only context. The studies suggest that both race-related featural properties within a face (i.e., racial ambiguity) and external contextual factors affect automatic evaluative associations.

Acupressure as a non-pharmacological intervention for traumatic brain injury (TBI).

Acupressure is a complementary and alternative medicine (CAM) treatment using fingertips to stimulate acupoints on the skin. Although suggested to improve cognitive function, acupressure has not been previously investigated with a controlled design in traumatic brain injury (TBI) survivors, who could particularly benefit from a non-pharmacological intervention for cognitive impairment. A randomized, placebo-controlled, single-blind design assessed the effects of acupressure (eight treatments over 4 weeks) on cognitive impairment and state of being following TBI, including assessment of event-related potentials (ERPs) during Stroop and auditory oddball tasks. It was hypothesized that active acupressure treatments would confer greater cognitive improvement than placebo treatments, perhaps because of enhanced relaxation response induction and resulting stress reduction. Significant treatment effects were found comparing pre- to post-treatment change between groups. During the Stroop task, the active-treatment group showed greater reduction in both P300 latency (p = 0.010, partial η² = 0.26) and amplitude (p = 0.011, partial η² = 0.26), as well as a reduced Stroop effect on accuracy (p = 0.008, partial η² = 0.21) than did the placebo group. Additionally, the active-treatment group improved more than did the placebo group on the digit span test (p = 0.043, Cohen's d = 0.68). Together, these results suggest an enhancement in working memory function associated with active treatments. Because acupressure emphasizes self-care and can be taught to novice individuals, it warrants further study as an adjunct treatment for TBI.

Tobacco withdrawal components and their relations with cessation success.

RATIONALE: Tobacco withdrawal is a key factor in smoking relapse, but important questions about the withdrawal phenomenon remain. OBJECTIVES: This research was intended to provide information about two core components of withdrawal (negative affect and craving): (1) how various withdrawal symptom profile dimensions (e.g., mean level, volatility, extreme values) differ between negative affect and craving; and (2) how these dimensions relate to cessation outcome. METHODS: Adult smokers (N = 1,504) in a double-blind randomized placebo-controlled smoking cessation trial provided real-time withdrawal symptom data four times per day for 4 weeks (2 weeks pre-quit and 2 weeks post-quit) via palmtop computers. Cessation outcome was biochemically confirmed 8-week point-prevalence abstinence. RESULTS: Examination of craving and negative affect dimensions following a cessation attempt revealed that craving symptoms differed from negative affect symptoms, with higher means, greater variability, and a greater incidence of extreme peaks. Regression analyses revealed that abstinence was associated with lower mean levels of both craving and negative affect and fewer incidences of extreme craving peaks. In a multivariate model, the increase in mean craving and negative affect scores each uniquely predicted relapse. CONCLUSIONS: Real-time reports revealed different patterns of abstinence-related negative affect and craving and that dimensions of both predict cessation outcome, suggesting that negative affect and craving dimensions each has motivational significance. This underscores the complexity of withdrawal as a determinant of relapse and the need to measure its distinct components and dimensions.

Nicotine withdrawal increases threat-induced anxiety but not fear: neuroadaptation in human addiction.

BACKGROUND: Stress response neuroadaptation has been repeatedly implicated in animal addiction models for many drugs, including nicotine. Programmatic laboratory research that examines the stress response of nicotine-deprived humans is necessary to confirm that stress neuroadaptations observed in animal models generalize to humans. METHODS: Two experiments tested the prediction that nicotine deprivation selectively increases startle response associated with anxiety during unpredictable threat but not fear during imminent, predictable threat. Dependent smokers (n = 117) were randomly assigned to 24-hour nicotine-deprived or nondeprived groups and participated in one of two experiments wherein electric shock was administered either unpredictably (noncontingent shock; Experiment 1) or predictably (cue-contingent shock; Experiment 2). RESULTS: Nicotine deprivation increased overall startle response in Experiment 1, which involved unpredictable administration of shock. Age of first cigarette and years of daily smoking were significant moderators of this deprivation effect. Self-reported withdrawal symptoms also predicted startle response during unpredictable shock. In contrast, nicotine deprivation did not alter overall or fear-potentiated startle in Experiment 2, which involved predictable administration of shock. CONCLUSIONS: These results provide evidence that startle response during unpredictable threat may be a biomarker of stress neuroadaptations among smokers in nicotine withdrawal. Contrast of results across unpredictable versus predictable shock experiments provides preliminary evidence that these stress neuroadaptations manifest selectively as anxiety during unpredictable threat rather than in every stressful context. Individual differences in unpredictable threat startle response associated with withdrawal symptoms, age of first cigarette, and years daily smoking link this laboratory biomarker to clinically relevant indexes of addiction risk and relapse.