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Rationale: There has been growing interest in the role of ghrelin in stress and addiction. Ghrelin regulates central reward mechanisms by mediating the mesolimbic dopaminergic system. Stress also induces neurophysiological activations related to drug reward. However, the extent to which psychosocial stress is associated with changes in ghrelin levels has not been tested in individuals with nicotine dependency undergoing withdrawal, a condition known to induce stress-like symptoms., Objectives: We investigated the association of stress-induced ghrelin, craving, and smoking lapse., Methods: Thirty-six smokers attended a laboratory session that included acute stress tasks during the initial phase of quitting. Self-report measures and biochemical samples were collected for the assessment of smoking status. Blood samples for the measurement of ghrelin and self-report measures of craving were collected multiple times throughout the session RESULTS: Multivariate analysis of variance controlling for gender found a significant main effect of sampling time and lapse group (p < 0.05). Ghrelin levels significantly increased over the pre-stress and post-stress periods (ps < 0.001), suggesting a delayed stress response. Those who lapsed during the study had higher ghrelin levels than those who were able to successfully abstain. A ghrelin stress response was calculated and a significant association was found between this response and craving, which changed across time points (ps < 0.008)., Conclusions: The results of this study demonstrate that ghrelin is sensitive to acute manipulation of stress and that there is potential usefulness for ghrelin as a marker of stress, craving, and smoking lapse., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The aims of this study were to 1) determine whether acute nicotine withdrawal increases the intake of junk food (high in salt, fat, and sugar) and 2) assess whether the endogenous opioid system is involved in junk food intake during nicotine withdrawal using naltrexone as a pharmacological probe., Methods: Smokers were randomly assigned to 24-hr withdrawal from tobacco products (n = 42) or smoking ad libitum (n = 34). A non-smoking group (n = 29) was included. Participants completed two laboratory sessions where a placebo or 50 mg of naltrexone was administered. At the end of each session, participants were given a tray of snack items that differed in high to low energy density and dimensions of salty, sweet, and fat. Self-reported mood and withdrawal measures were collected immediately before the snacks were offered. Generalized linear and logistic models were used to assess the effects of acute smoking withdrawal, drug, and sex on the intake of snack items and self-reported measures., Results: Choice and consumption of food items were impacted by smoking condition (withdrawal > ad lib smoking and non-smokers; p < .05), the opioid blockade (naltrexone < placebo; p < .05), and sex (male > female; p < .05). The effects were evidenced in high sweet and high fat foods. No differences were found in low sweet and fat foods., Conclusions: These findings extend earlier studies indicating impact of tobacco use on appetite, and identify the regulatory influence of the endogenous opioid system on appetite during nicotine withdrawal., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Mobile sensors can now provide unobtrusive measurement of both stress and cigarette smoking behavior. We describe, here, the first field tests of two such methods, cStress and puffMarker, that were used to examine relationships between stress and smoking behavior and lapse from a sample of 76 smokers motivated to quit smoking. Participants wore a mobile sensors suite, called AutoSense, which collected continuous physiological data for 4 days (24-hours pre-quit and 72-hours post-quit) in the field. Algorithms were applied to the physiological data to create indices of stress (cStress) and first lapse smoking episodes (puffMarker). We used mixed effects interrupted autoregressive time series models to assess changes in heart rate (HR), cStress, and nicotine craving across the 4-day period. Self-report assessments using ecological momentary assessment (EMA) of mood, withdrawal symptoms, and smoking behavior were also used. Results indicated that HR and cStress, respectively, predicted smoking lapse. These results suggest that measures of traditional psychophysiology, such as HR, are not redundant with cStress; both provide important information. Results are consistent with existing literature and provide clear support for cStress and puffMarker in ambulatory clinical research. This research lays groundwork for sensor-based markers in developing and delivering sensor-triggered, just-in-time interventions that are sensitive to stress-related lapser risk factors., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: Despite extensive efforts to develop effective smoking cessation interventions, 70-85% of American cigarette smokers who quit relapse within one year. Exercise has shown promise as an intervention; however, many results have been equivocal. This study explored how exercise is associated with smoking-related symptomatology, smoking behavior and impulsivity in male and female smokers., Methods: Participants were recruited throughout the United States using the on-line crowdsourcing platform, Amazon's Mechanical Turk. They completed a survey with self-report measures assessing exercise, smoking-related symptomatology, smoking behavior and impulsivity. Differences between men and women were tested using t- and chi-square tests. Regression analyses tested for associations between exercise and smoking-related symptomatology, smoking behavior and impulsivity., Results: Participants (N = 604) were, on average, 32 (SD = 6.2) years old, mostly Caucasian, with at least some college education and approximately half were women. Women exercised slightly less than men and had more negative affect, craving, physical symptoms and withdrawal. Women smoked more cigarettes per day, had greater nicotine dependency and more years of smoking. Positive affect was positively associated with exercise for both men and women; however, this association was significantly stronger in women. Negative affect and withdrawal were inversely associated with exercise for women only. Impulsivity was inversely associated with exercise for both men and women., Conclusion: Exercise was significantly associated with several smoking-related symptomatology, smoking behavior and impulsivity variables for both men and women, suggesting that exercise may be a useful intervention for smoking cessation. Future prospective research should determine how exercise directly impacts smoking cessation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Stressful situations are among the most commonly cited smoking triggers. Smoking and stress exposure each individually increase cardiovascular and hypothalamic-pituitary-adrenal measures with larger increases occurring when stress and smoking are combined. In this analysis, sex differences in the physiological response to the combination of stress and smoking are examined. Smokers (36 males; 34 females) completed a laboratory session in which systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), plasma epinephrine (Epi), norepinephrine and cortisol concentrations were measured at rest, while smoking a cigarette, during a speech task occurring immediately after smoking and at several time-points following the stressor. Significant period by sex effects were observed for HR, SBP, DBP and Epi but not for cortisol or norepinephrine concentrations. For SBP (p=0.002), the increase between resting and speech were larger in men than in women, primarily due to a larger increase between smoking and speech occurring in men. A similar pattern was observed for DBP and Epi with a significantly larger Epi increase from smoking to speech observed in men than in women (p=0.016). A different pattern emerged for HR - the total increase was larger in women (p<0.001), due to a larger rest to smoking increase (p<0.001). In most measures therefore, overall increases were greater in men than women, primarily due to larger smoking to speech increases. Additional research is needed to determine the clinical implications of these results as they apply to sex difference in smoking cessation success rates and in the cardiovascular risks of smoking., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: The Family Smoking Prevention and Tobacco Control Act authorized the FDA to reduce the nicotine content in cigarettes. Research is needed to guide proposed regulations, including evaluation of consequences to public health. This study evaluated how a reduced nicotine product standard might be moderated by and impact cannabis use., Methods: Secondary analysis of a controlled clinical trial examining the effects of nicotine content in cigarettes in adult daily smokers. Linear regression assessed whether baseline cannabis use moderated behavioral, subjective, or physiological effects of smoking very low nicotine content (VLNC) versus normal nicotine content (NNC) cigarettes. Repeated measures analysis of associations between nicotine condition and prevalence and frequency of cannabis use was completed using generalized estimating equations (GEE)., Results: Cannabis use did not moderate most of the following effects of VLNC cigarettes: Among cannabis users and non-users, smokers randomized to VLNC cigarettes reported lower nicotine dependence, cigarettes per day, biomarkers of nicotine exposure, and craving compared to smokers randomized to NNC cigarettes. Non-cannabis using smokers randomized to VLNC cigarettes also reported lower smoking dependence motives and had lower tobacco-specific nitrosamine exposure and total puff volume versus smokers randomized to NNC cigarettes. For cannabis users, smokers randomized to VLNC cigarettes reported decreased positive affect. VLNC cigarette use did not impact the prevalence or frequency of cannabis use., Discussion: Findings provide evidence that nicotine reduction in cigarettes could have beneficial effects on cigarette smoking regardless of cannabis use. Results suggest that transitioning to VLNC cigarettes is unlikely to alter current rates of cannabis use., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

In this chapter, we briefly review the basic biology of psychological stress and the stress response. We propose that psychological stress and the neurobiology of the stress response play in substance use initiation, maintenance, and relapse. The proposed mechanisms for this include, on the one hand, the complex interactions between biological mediators of the stress response and the dopaminergic reward system and, on the other hand, mediators of the stress response and other systems crucial in moderating key addiction-related behaviors such as endogenous opioids, the sympathetic-adrenal-medullary system, and endocannabinoids. Exciting new avenues of study including genomics, sex as a moderator of the stress response, and behavioral addictions (gambling, hypersexuality, dysfunctional internet use, and food as an addictive substance) are also briefly presented within the context of stress as a moderator of the addictive process., (© 2016 Elsevier B.V. All rights reserved.)

The adipocyte hormone leptin regulates satiety and energy expenditure. Recent evidence suggests that leptin is associated with increased craving for alcohol and with shorter length of abstinence during alcohol treatment. This study examined leptin's associations with craving for cigarettes and smoking relapse among smokers interested in cessation. Participants (32 smokers; 14 women) attended a laboratory session 24h following their designated quit day where circulating leptin levels and craving for smoking were assessed. Other measures of withdrawal symptoms, affect, physical symptoms, as well as neuroendocrine and cardiovascular measures were collected before and after performing two stress tasks (public speaking and cognitive tasks). High circulating leptin levels were associated with increased craving, withdrawal symptoms, negative affect, physical symptoms, and reduced positive affect. Circulating leptin levels were not related to cardiovascular and neuroendocrine measures, responses to acute stressors, or to smoking relapse. These results indicate that circulating leptin is a promising biological marker of craving for smoking and warrant further investigation of the links between appetite regulation and nicotine dependence., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Endogenous opioids are integral in modulating drug reward, but it is believed that these may act through several mechanisms including hypothalamic-pituitary-adrenocortical (HPA) and dopamine pathways. This study was developed to examine how nicotine dependence alters endogenous opioid regulation of prolactin response, a peripheral marker of dopaminergic activity. Smokers and nonsmokers completed two sessions during which placebo or 50mg of naltrexone was administered, using a double-blind, counterbalanced design. Blood samples and mood measures were obtained during a resting absorption period, after exposure to two noxious stimuli (cold pressor and thermal pain), and during an extended recovery period. Opioid blockade increased prolactin response, indicating an inhibitory effect of the endogenous opioid system on prolactin, possibly mediated by reduced stimulatory effects of dopamine on this hormone. These responses were attenuated in smokers relative to nonsmokers. There was also a gender disparity in prolactin response, with women showing a stronger response to endogenous opioid modification than men regardless of smoking status. The attenuated effects of opioid blockade may reflect dysregulated opiodergic and dopaminergic effects. Results extend previous reports showing blunted opioid regulation of the HPA response in dependent smokers., ((c) 2009 Elsevier Inc. All rights reserved.)

Stress has been cited as an important precipitator of smoking relapse. Dysregulation of neurobiological pathways related to stress might mediate effects of stress on smoking relapse. This study assessed the extent to which beta endorphin response to stress is associated with early smoking relapse. Forty-five smokers interested in smoking cessation were recruited and attended a laboratory session 24 h following the beginning of their abstinence period. During this session beta endorphin samples were collected before and after performing two acute stressors (public speaking and cognitive tasks). Participants also attended four weekly follow-up sessions to assess their smoking status. Results were compared between smokers who relapsed within the 4-week follow-up period and those who maintained abstinence over the same period. The acute stressors were associated with significant increases in measures of craving and withdrawal symptoms (ps<0.01). While baseline measures of beta endorphin did not differ between relapsers and successful abstainers (F<1), results demonstrated that smokers who relapsed exhibited attenuated beta endorphin response to the two stressors relative to those who maintained abstinence over the same period (ps<05). These results support recent evidence indicating that a dysregulated stress response is a key component in predicting smoking relapse.

The present study assessed the structure and intensity of the nicotine withdrawal syndrome in 30 (22 male, 8 female) heavy smokers across three experimental conditions: smoking, brief abstinence (3.5 h), and extended abstinence (18 h). Physiological variables (heart rate and blood pressure) and psychological variables (anxious and depressed mood) were examined in terms of symptom validity and as predictors of nicotine withdrawal intensity. As length of abstinence increased, heart rate and blood pressure decreased, and anxious and depressed mood increased. Only anxious and depressed mood were significant individual predictors of withdrawal intensity. The symptom structure of withdrawal did not change over time as abstinence levels increased; each symptom's contribution to nicotine withdrawal intensity remained stable throughout the first 18 h of abstinence.

Nicotine may be used to manage negative emotions, and recent research suggests that smokers with high levels of hostility may use cigarettes to cope with anger provoking situations. This study evaluated the extent to which a high level of trait anger is associated with risk for relapse among smokers interested in cessation. Chronic smokers with different levels of trait anger provided reports of withdrawal symptoms, craving, and state anger, and collected saliva samples for cortisol during 24-hour ad libitum smoking and the first 24-hour abstinence period of a quit attempt. They also attended a laboratory session conducted after the 24-hour abstinence during which they performed brief mental and social stress challenges and provided blood samples for adrenocorticotropin (ACTH) and cortisol assays. High trait anger was associated with greater increases in state anger, withdrawal symptoms, and craving during the first 24 h of abstinence. It was also associated with greater ACTH concentrations during the laboratory session. High trait anger was also associated with increased risk for early relapse. The findings support the hypothesis that smokers high in anger trait may have greater mood difficulties during abstinence and may be more vulnerable to early relapse than smokers with low anger trait.

It has been hypothesized that increased baseline dehydroepiandrosterone sulfate (DHEAS) levels may act as a natural antidepressant to attenuate negative affect during cocaine withdrawal and abstinence, decreasing the probability of relapse. The current study extends this model to assess factors related to risk of relapse in a sample of 68 nicotine dependent participants. Repeated measures ANOVAs were used to examine mood state, salivary DHEAS and cortisol levels across three assessment periods in participants who had relapsed over a 4-week follow-up period (n=51, 23 women) compared to those who maintained abstinence (n=17, 8 women). Total scores on the Profile of Mood States differed between those who had relapsed and those who maintained abstinence (p=0.008). However, DHEAS and cortisol levels, as well as the ratio of cortisol to DHEAS, did not differ significantly between groups. These findings suggest that, although DHEAS-related enhancement of resiliency to withdrawal may occur, the extent of this protective effect may be modulated by additional factors that warrant further research.

Stress is a commonly reported precipitant of relapse to substance use. There is a growing recognition of the need to understand psychobiological alterations in the stress response among chronic drug users, and to determine how they may precipitate relapse. This paper focuses on the hypothalamic-pituitary-adrenocortical (HPA) response to stress among dependent smokers. Nicotine acutely activates the HPA axis, and increased HPA activity has been linked to attenuated CNS nicotinic receptor sensitivity. We will review a series of studies demonstrating that steep decline in cortisol concentrations during early abstinence and hyporesponsiveness to stress predict shorter time to relapse. Our studies show that hormonal associations with smoking relapse tend to be more consistent in men, while intensity of withdrawal symptoms tend to be consistent predictors of smoking relapse in women. We propose that perturbed HPA activity during early smoking abstinence exacerbate withdrawal symptoms and may contribute to the rapid relapse observed in the majority of smokers. Our results also reinforce the need for gender-specific investigation of mechanistic and interventional strategies to combat nicotine addiction.

Studies suggest that among cigarette smokers trying to quit, stress undermines abstinence. Little research has assessed if therapies that increase smoking cessation rates impact physiological measures of stress response. Forty-three subjects completed this repeated-measures study in which a laboratory assessment was completed at baseline and after 17 days of treatment with either placebo (n=15), bupropion sustained release (150 mg twice daily) (n=14) or bupropion with stress reduction counseling (n=14). All subjects quit smoking 3 days prior to the second laboratory assessment. At each laboratory assessment physiological measures of stress (i.e. blood pressure, heart rate, plasma epinephrine, norepinephrine and cortisol concentrations) were measured during rest periods and in response to a speech, a math and a cold pressor task. Among subjects taking placebo, physiological measures of stress were generally lower at rest and during the stressors after smoking cessation. In those taking bupropion these measures were equivalent at the two assessments. Additionally, compared to placebo, those on bupropion had a greater diastolic blood pressure response to the speech stressor and greater systolic blood pressure response to the math stressor during the second laboratory session. This study suggests that bupropion may be maintaining physiological measures of stress during the nicotine withdrawal period.

This study addressed the hypothesis that exaggerated mood and cortisol changes during the first 24h of smoking abstinence are associated with early relapse. Salivary cortisol levels and mood reports were measured during 24-h ad libitum smoking and the first 24-h abstinence period of a quit attempt. Seventy-two habitual smokers (34 women and 38 men) who were interested in smoking cessation participated. Cotinine concentrations in saliva and expired carbon monoxide were measured before and after abstinence and 1 week after the quit date to verify smoking status. Abstinence produced significant withdrawal symptoms in all participants and reduced cotinine and carbon monoxide levels. While participants showed the expected diurnal changes in cortisol levels, those who relapsed within the first week post quitting exhibited a greater drop in morning cortisol concentrations during abstinence relative to their ad libitum smoking levels. Participants who relapsed reported greater withdrawal symptoms, craving for cigarettes, and distress, and they also reported greater reduction in positive affect during the first 24-h period of abstinence than those who maintained abstinence. These results support the hypothesis that early relapse is associated with exaggerated mood and adrenocortical perturbations observed during the first day of abstinence.

Chronic smoking may alter physiological systems involved in the stress response. This study was designed to examine the effects of ad libitum smoking and abstinence on adrenocortical and cardiovascular responses to acute psychological stress in dependent cigarette smokers. We evaluated differences among abstinent smokers, smokers who continued to smoke at their normal rate, and nonsmokers in salivary cortisol concentrations, systolic and diastolic blood pressure (BP), heart rate (HR), and mood reports. Measurements were obtained during rest and in response to acute psychological stress (public speaking) in one session (stress session) and during continuous rest in a control session. Thirty-eight smokers (21 women) and 32 nonsmokers (18 women) participated. Smokers were assigned to either abstain from smoking the night prior to and the day of each session, or to continue smoking at their normal rate before each session. All groups showed significant stress-induced changes in BP and HR. Smokers, regardless of their assigned condition, showed attenuated systolic BP responses to the public-speaking stressor when compared to nonsmokers. While resting cortisol levels were greater among smokers than nonsmokers, no cortisol response to the acute stressor was demonstrated in either ad libitum or abstinent smokers. These results indicate that chronic smoking diminishes adrenocortical and cardiovascular responses to stress, and that short-term abstinence does not correct these alterations.

We tested the hypothesis that psychophysiological responses to behavioral challenges are enhanced by short-term abstinence from smoking. Blood pressure (BP), salivary cortisol levels, and withdrawal symptoms were measured after a period of smoking abstinence (18 h) or ad libitum smoking, during rest, and in response to acute behavioral challenges. Thirty habitual smokers (15 women and 15 men) participated in two laboratory sessions conducted on two separate days (after abstinence or ad libitum smoking). Cotinine concentrations in saliva and expired carbon monoxide were measured in both conditions. Abstinence produced significant withdrawal symptoms in all participants, with women reporting greater desire to smoke than men. Participants showed greater systolic BP responses to the behavioral challenges in the abstinence condition than the control condition. They also showed worse cognitive performance on the challenges in the abstinence than in the ad libitum condition. Men had greater salivary cortisol levels than women, and both men and women showed the expected decline in cortisol levels across time, but showed no difference between the abstinence and ad libitum smoking conditions in the laboratory or during ambulatory measurements. These results indicate that abstinence alters mood, performance, and BP responses to acute challenges but not adrenocortical responses. It is possible that these changes mediate stress-related vulnerability to smoking relapse.