The role of exercise in the treatment of depression: biological underpinnings and clinical outcomes.

Globally, depression is a leading cause of disability and has remained so for decades. Antidepressant medications have suboptimal outcomes and are too frequently associated with side effects, highlighting the need for alternative treatment options. Although primarily known for its robust physical health benefits, exercise is increasingly recognized for its mental health and antidepressant benefits. Empirical evidence indicates that exercise is effective in treating individuals with depression; however, the mechanisms by which exercise exerts anti-depressant effects are not fully understood. Acute bouts of exercise have been shown to transiently modulate circulating levels of serotonin and norepinephrine, brain-derived neurotrophic factor, and a variety of immuno-inflammatory mechanisms in clinical cohorts with depression. However, exercise training has not been demonstrated to consistently modulate such mechanisms, and evidence linking these putative mechanisms and reductions in depression is lacking. The complexity of the biological underpinnings of depression coupled with the intricate molecular cascade induced by exercise are significant obstacles in the attempt to disentangle exercise's effects on depression. Notwithstanding our limited understanding of these effects, clinical evidence uniformly argues for the use of exercise to treat depression. Regrettably, exercise remains underutilized despite being an accessible, low-cost alternative/adjunctive intervention that can simultaneously reduce depression and improve overall health. To address the gaps in our understanding of the clinical and molecular effects of exercise on depression, we propose a model that leverages systems biology and multidisciplinary team science with a large-scale public health investment. Until the science matches the scale of complexity and burden posed by depression, our ability to advance knowledge and treatment will continue to be plagued by fragmented, irreproducible mechanistic findings and no guidelines for standards of care.

Effects of Ovarian Hormone Levels on Stress, Cigarette Craving, and Smoking in a Laboratory Relapse Paradigm Among Females Who Smoke Daily.

INTRODUCTION: Females, versus males, have shown a slower decline in smoking prevalence, greater smoking-related mortality and morbidity, and tend to have more difficulty achieving and maintaining abstinence. Identifying sex-specific risk factors is needed to improve outcomes. Though ovarian hormones have been evaluated for their role in smoking and relapse, measures tend to be static and infrequent, failing to capture the influence of increasing or decreasing levels. AIMS AND METHODS: The present study evaluated the effect of static and fluctuating levels of ovarian hormones (ie, progesterone, estradiol, and estrogen to progesterone [E/P] ratio) on stress reactivity, cigarette craving, and smoking during a laboratory relapse paradigm. Female participants (assigned female at birth) reporting daily cigarette smoking (N = 91, ages 18-45) were recruited from the community. Participants provided daily salivary ovarian hormone levels leading up to a laboratory session, in which stress was induced and stress reactivity, cigarette craving, latency to smoke, and ad-libitum smoking were measured. RESULTS: Static levels of estradiol were associated with stress reactivity (ß = 0.28, SE = 0.13) and static E/P ratio was associated with smoking in the laboratory (HR = 1.4). Preceding 3-day changes in estradiol and E/P ratio, but neither static levels nor preceding 3-day changes in progesterone were associated with stress reactivity, cigarette craving, or smoking in a relapse paradigm. CONCLUSIONS: Ovarian hormones are among several sex-specific factors involved in the complex neuroendocrine response to stress, and their interaction with other biological, social, and psychological factors in the real-world environment is not yet fully understood. IMPLICATIONS: Findings of the present study provide novel information regarding the role of ovarian hormones among female participants who smoke daily in stress reactivity and smoking in the context of a laboratory relapse paradigm and highlight several avenues for future research. We found that same-day estradiol levels were associated with increased subjective stress reactivity and same-day estrogen to progesterone ratio was associated with increased likelihood of smoking in a relapse paradigm. Ovarian hormones are among several sex-specific factors contributing to the complex neuroendocrine response to stress, and their interaction with other biological, social, and psychological factors in the real-world environment is not yet fully understood.

Differential prevalence of Adverse Childhood Experiences (ACEs) by gender and substance used in individuals with cannabis, cocaine, opioid, and tobacco use disorders.

Background: Adverse childhood experiences (ACEs) show a graded association with the development of substance use disorders (SUDs) and engagement in risky substance use behaviors. Women are overrepresented among individuals with more severe childhood adversity (≥4 types of ACEs) and may be at particular risk for aberrant substance use.Objectives: To assess the prevalence of ACEs among men and women with cannabis, opioid, cocaine, and tobacco use disorders.Methods: Non-treatment-seeking individuals participating in clinical addiction research at a single site completed the ACE questionnaire and provided a detailed substance use history. Data were analyzed using proportional odds models and logistic regression.Results: Most participants (424/565; 75%) reported at least one ACE, and more than one-quarter (156/565; 27%) reported severe childhood adversity. Relative to men (n = 283), women (n = 282) reported more ACEs (OR = 1.49; p = .01) and more experiences of emotional/physical abuse (OR = 1.52; p = .02), sexual abuse (OR = 4.08; p = .04), and neglect (OR = 2.30; p < .01). Participants in the cocaine (OR = 1.87; n = .01) and opioid (OR = 2.21; p = .01) use disorder, but not cannabis use disorder (OR = 1.46; p = .08), studies reported more severe adversity relative to the tobacco group. Relative to tobacco users, emotional/physical abuse (OR = 1.92; p = .02) and neglect (OR = 2.46; p = .01) scores were higher in cocaine users and household dysfunction scores were higher in opioid users (OR = 2.67; p = .01).Conclusion: The prevalence of ACEs differs with respect to both participant gender and primary substance used. Novel SUD treatment strategies that incorporate ACEs may be uniquely beneficial in specific subpopulations of people with SUDs.

Characterization of Salivary Progesterone in Female Smokers.

INTRODUCTION: Fluctuations in ovarian hormones have been associated with changes in cigarette smoking behavior, which can be measured through both serum or less invasive salivary procedures. The primary aim of this exploratory study is to characterize the progesterone profiles of salivary progesterone measurements and to compare that with the profiles estimated from a previously measured serum sample. AIMS AND METHODS: Nontreatment-seeking, cigarette smoking women (n = 82; ages 18-45 years) provided daily salivary hormone samples every morning for 14 consecutive days. Time-dependent random effects functions were used to approximate daily salivary progesterone (ng/mL) levels over the course of a standardized menstrual cycle. Serum measures of progesterone from a previous study of female cigarette smokers were examined for consistency with established profiles and compared with the salivary profile using the same methodology. RESULTS: The salivary model fit exhibits relative stability during the follicular phase and a clear unimodal peak during the luteal phase. Parameter estimates from the non-linear function show correspondence to serum data. Although the profiles estimated from salivary and serum data agree in functional form, we observed larger between-subject heterogeneity both in the follicular level and the peak luteal level in salivary measures. CONCLUSIONS: The pattern of salivary and serum progesterone measured across the menstrual cycle is similar in form, which is noteworthy given that the saliva and serum samples were drawn from independent sample of female smokers. Inter- and intra-individual variation in salivary measures may be greater than in serum measures. IMPLICATIONS: Measuring progesterone level variation across the menstrual cycle via saliva samples has several benefits relative to serum sampling methods in that they are easily obtained, noninvasive, and low-cost. Inter- and intra-individual variation in measurements may be greater than those in serum measurements. However, the functional form of the salivary progesterone profile is isomorphic to serum progesterone.

A Pilot Randomized Clinical Trial of Remote Varenicline Sampling to Promote Treatment Engagement and Smoking Cessation.

INTRODUCTION: Medication sampling is a clinically useful tool to engage smokers in the quitting process. Whether varenicline is suitable for sampling purposes is unclear. The purpose of this study was to examine the feasibility, uptake, and preliminary outcomes of varenicline sampling. METHODS: Smokers (N = 99), both motivated to quit and not, were recruited and randomized to varenicline sampling versus not, with 12 week follow-up. The intervention consisted of mailing one-time samples of varenicline (lasting 2-4 wks), with minimally suggestive guidance on use. RESULTS: Uptake of varenicline was strong, at 2 weeks (54% any use, 66% daily use) and 4 weeks (38%, 46%), with 58% of medication users seeking additional medication. Most users followed conventional titration patterns, self-titrating from 0.5 mg to 2 mg. Relative to control, varenicline sampling increased motivation (p = 0.006) and confidence to quit (p = 0.02), and decreased cigarette smoking (p = 0.02). Smokers receiving varenicline samples were significantly more likely to achieve 50% reduction in cigarettes per day (CPD), both immediately following the sampling exercise (Adjusted Odds Ratio [AOR] = 4.12; 95% CI: 1.39 to 12.17) and at final follow-up (AOR = 4.50; 95% CI: 1.56 to 13.01). Though cessation outcomes were not statistically significant, there was a 1.5 to 3-fold increase in quit attempts and abstinence from varenicline sampling throughout follow-up. These outcomes were comparable among smokers motivated to quit and not. CONCLUSIONS: Unguided, user-driven sampling of varenicline sampling is a concrete behavioral exercise that is feasible to do and seems to suggest clinical utility. Sampling is a pragmatic clinical approach to engage more smokers in quitting. IMPLICATIONS: Use of evidence-based pharmacotherapies for smoking cessation is low. Medication sampling is a pragmatic behavioral exercise that allows smokers to experience the benefits of using them, while promoting positive downstream effects towards quitting. While previous studies have shown that nicotine replacement therapy (NRT) sampling is viable and effective, whether this extends to varenicline is unclear. Results from this trial demonstrate that varenicline sampling is feasible, safe, and suggestive of clinically important steps toward quitting, deserving of a larger trial. CLINICAL TRIAL REGISTRATION: NCT #03742154.

Increases in endogenous progesterone attenuate smoking in a cohort of nontreatment seeking women: An exploratory prospective study.

Despite advances in prevention and treatment, cigarette smoking remains a leading cause of preventable death in the United States. Although men and women are equally likely to attempt to quit smoking cigarettes, women are far less likely to achieve abstinence both during and following cessation treatment. Recent evidence suggests that ovarian hormone levels may play a role in successful abstinence attempts in women smokers. The primary goal of this exploratory prospective observational study was to estimate the association between within-participant levels of progesterone and estradiol with associated cigarettes smoked per day in adult women smokers (n = 104). The primary study outcome was self-reported cigarettes smoked per day (CPD) during a 2-week observational period collected using a daily smoking diary. Additionally, participants collected saliva daily, from which hormone levels (progesterone and estradiol) were derived. Higher within-participant progesterone levels were associated with a significant decrease in CPD (p = .008) whereas within-participant estradiol levels were unrelated to CPD (p = .25). Regression models indicated a single change in the trajectory of smoking behavior for both within-participant progesterone and estradiol. When progesterone values were below the change point, there was a significant inverse relationship between within-participant progesterone levels and smoking behavior (p = .025) whereas the relationship was attenuated for higher within-participant progesterone levels (p = .59). The effect of estradiol on smoking behavior was not significant when it was either below (p = .92) or above (p = .16) the change point. Higher within-participant levels of progesterone but not estradiol are associated with reduced CPD in nontreatment seeking women smokers.

Sex Differences in Subjective and Behavioral Responses to Stressful and Smoking Cues Presented in the Natural Environment of Smokers.

INTRODUCTION: Some evidence suggests that female smokers may show more context-dependent smoking and that males may show more stereotyped smoking (regardless of stress or cue exposure). The goal of this study was to characterize sex differences in response to stressful and smoking cues ecologically presented in daily life and variability in day-to-day smoking behavior. METHODS: Adult smokers (N = 177) provided ratings of mood and cigarette craving before and after stress and smoking cues were presented four times daily for 14 days via a mobile device. Linear mixed models tested whether (1) female smokers exhibited greater reactivity to stressful cues than male smokers; (2) pre-cue negative affect increased reactivity to smoking cues more in female smokers than male smokers; (3) across both sexes, greater reactivity to stressful and smoking cues correlated with greater quantity of smoking within a day; and (4) female smokers exhibited greater variability in cigarettes per day (CPD) relative to males. RESULTS: Relative to male smokers, female smokers reported greater negative affect, stress, and craving in response to stressful cues, but not smoking cues, after accounting for time since last cigarette and pre-cue responding. No sex differences in CPD or variability in CPD were detected. Days with higher subjective reactivity to cues were not associated with increased smoking, in either males or females. CONCLUSIONS: Sex differences were observed in response to stress but not smoking cues in the natural environment of regular cigarette smokers. Further research is necessary to evaluate whether stress reactivity in female smokers is associated with reduced latency to smoke following stress exposure in daily life. IMPLICATIONS: This study provides naturalistic evidence that female smokers may not be more reactive to smoking cues than males, but experience heightened stress and craving following stress exposure. There was no evidence to support the hypothesis that amount smoked per day varied more for females, relative to males, as a result of more context-driven smoking for females.

Gender differences in responses to cues presented in the natural environment of cigarette smokers.

INTRODUCTION: Although the evidence is mixed, female smokers appear to have more difficulty quitting smoking than male smokers. Craving, stress, and negative affect have been hypothesized as potential factors underlying gender differences in quit rates. METHODS: In the current study, the cue-reactivity paradigm was used to assess craving, stress, and negative affect in response to cues presented in the natural environment of cigarette smokers using ecological momentary assessment. Seventy-six daily smokers (42% female) responded to photographs (smoking, stress, and neutral) presented 4 times per day on an iPhone over the course of 2 weeks. RESULTS: Both smoking and stress cues elicited stronger cigarette craving and stress responses compared to neutral cues. Compared with males, females reported higher levels of post-stress cue craving, stress, and negative affect, but response to smoking cues did not differ by gender. DISCUSSION: Findings from this project were largely consistent with results from laboratory-based research and extend previous work by measuring response to cues in the natural environment of cigarette smokers. This study extends previous cue reactivity ecological momentary assessment research by using a new platform and by measuring response to stress cues outside of the laboratory. Findings from this project highlight the importance of addressing coping in response to stress cues in clinical settings, especially when working with female smokers.

Menstrual cycle phase effects in the gender dimorphic stress cue reactivity of smokers.

INTRODUCTION: We previously reported that female smokers evidence greater subjective craving and stress/emotional reactivity to personalized stress cues than males. The present study employed the same dataset to assess whether females in the follicular versus luteal phase of the menstrual cycle accounted for the gender differences. METHODS: Two objective criteria, onset of menses and luteinizing hormone surge (evaluated via home testing kits), were used to determine whether female smokers were in either the follicular (n = 22) or the luteal (n = 15) phase of their menstrual cycle, respectively. The females and a sample of male smokers (n = 53) were then administered a laboratory-based cue reactivity paradigm that involved assessment of craving, stress, and emotional reactivity in response to counterbalanced presentations of both a personalized stress script and neutral/relaxed script. RESULTS: While there were no significant differences between females in the follicular versus luteal phase on any outcome measure, females in the luteal menstrual phase reported greater craving than males whereas females in the follicular phase reported greater stress and arousal than males and perceived the stress cues as more emotionally aversive than males. CONCLUSIONS: This preliminary investigation suggests that gender differences in craving versus affective responding to stress cues may, in part, be explained variation by menstrual cycle phase. Study limitations and implications of the findings for future research and treatment are briefly discussed.

Increasing progesterone levels are associated with smoking abstinence among free-cycling women smokers who receive brief pharmacotherapy.

INTRODUCTION: Preclinical and human laboratory research suggests that (a) progesterone may decrease drug reward, craving, and smoking behavior, and (b) estradiol may enhance drug reward and smoking behavior. A modest majority of treatment research examining the relationship between menstrual cycle phase and outcomes suggests that the luteal menstrual phase, with its uniquely higher progesterone levels, is associated with better cessation outcomes. However, no studies to date have examined the effects of naturally occurring variation in progesterone and estradiol levels on medication-assisted smoking cessation. The present study sought to fill this notable gap in the treatment literature. METHODS: Weekly plasma progesterone and estradiol levels were obtained from nicotine-dependent female smokers enrolled in a 4-week cessation trial. Participants (N = 108) were randomized to receive a 4-week course of either varenicline (VAR) tablets and placebo patches or placebo tablets and nicotine patches. Plasma samples were obtained 1 week before their cessation attempt and weekly during medication administration. Abstinence was assessed weekly. RESULTS: Weekly hormone data replicated commonly observed menstrual cycle patterns of progesterone and estradiol levels. Importantly, increases in progesterone level were associated with a 23% increase in the odds for being abstinent within each week of treatment. This effect was driven primarily by nicotine patch-treated versus VAR-treated females. CONCLUSIONS: This study was the first to identify an association between progesterone level (increasing) and abstinence outcomes in free-cycling women smokers who participated in a medication-based treatment. Furthermore, the potential benefits of progesterone may vary across different pharmacotherapies. Implications of these findings for smoking cessation intervention are discussed.

Systematic and meta-analytic review of research examining the impact of menstrual cycle phase and ovarian hormones on smoking and cessation.

INTRODUCTION: To determine the effect of ovarian hormones on smoking, we conducted a systematic review of menstrual cycle effects on smoking (i.e., ad lib smoking, smoking topography, and subjective effects) and cessation-related behaviors (i.e., cessation, withdrawal, tonic craving, and cue-induced craving). METHODS: Thirty-six papers were identified on MEDLINE that included a menstrual-related search term (e.g., menstrual cycle, ovarian hormones), a smoking-related search term (e.g., smoking, nicotine), and met all inclusion criteria. Thirty-two studies examined menstrual phase, 1 study measured hormone levels, and 3 studies administered progesterone. RESULTS: Sufficient data were available to conduct meta-analyses for only 2 of the 7 variables: withdrawal and tonic craving. Women reported greater withdrawal during the luteal phase than during the follicular phase, and there was a nonsignificant trend for greater tonic craving in the luteal phase. Progesterone administration was associated with decreased positive and increased negative subjective effects of nicotine. Studies of menstrual phase effects on the other outcome variables were either small in number or yielded mixed outcomes. CONCLUSIONS: The impact of menstrual cycle phase on smoking behavior and cessation is complicated, and insufficient research is available upon which to conduct meta-analyses on most smoking outcomes. Future progress will require collecting ovarian hormone levels to more precisely quantify the impact of dynamic changes in hormone levels through the cycle on smoking behavior. Clarifying the relationship between hormones and smoking-particularly related to quitting, relapse, and medication response-could determine the best type and timing of interventions to improve quit rates for women.

D-cycloserine combined with cue exposure therapy fails to attenuate subjective and physiological craving in cocaine dependence.

BACKGROUND: Based on preclinical studies showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitates extinction of cocaine self-administration and cocaine-induced conditioned place preference, we evaluated whether 50 mg of DCS would reduce craving to cocaine cues when combined with cue exposure (CE) in cocaine dependent humans. METHODS: In this double-blind placebo-controlled pilot study, 47 cocaine dependent participants were randomized to DCS or placebo (PBO), plus CE. Participants received DCS or PBO 30 minutes prior to two CE sessions, conducted one day apart. Craving and heart rate was assessed prior to CE sessions, during CE trials, and after CE trials. These measures were assessed again at a 1-week follow-up (session 3) after the second CE session. RESULTS: DCS failed to significantly attenuate cocaine cue reactivity based on subjective craving and physiological reactivity (heart rate) compared to PBO. The CE protocol, consisting of repeated exposure to drug cues combined with skills training, resulted in extinction to cocaine cues as suggested by decreased craving within and between sessions in both treatment conditions. All participants exhibited elevated heart rate with repeated exposures, demonstrating a potentiation in heart rate between sessions. CONCLUSIONS: 50 mg of DCS may not be effective for extinguishing reactivity to drug cues for individuals with cocaine dependence. SCIENTIFIC SIGNIFICANCE: Future studies examining the effect of DCS on facilitating extinction to drug cues should examine variations in cue exposure length, number of CE presentations, and timing of DCS dose administration prior to cue exposures, which may differentially impact drug cue reactivity.

Craving, cue reactivity, and stimulus control among early-stage young smokers: effects of smoking intensity and gender.

INTRODUCTION: Smoking initiation usually begins in adolescence, but how and for whom nicotine dependence emerges during this period is unclear. The cue-reactivity paradigm is well suited to examine one marker of dependence: craving-related stimulus control, i.e., the ability of environmental cues to elicit craving to smoke. This study examined the effects of both level of smoking involvement (daily vs. occasional smoking) and gender on reactivity to both smoking and alcohol cues. METHODS: Young (age range 16-20; 42% female) daily (n = 55) and occasional (n = 52) smokers were exposed to each of three counterbalanced cues: (a) in vivo smoking (e.g., sight, smell, lighting of cigarette), (b) alcohol (e.g., opening, pouring, and smell of preferred beverage), and (c) neutral cue. RESULTS: Daily smokers exhibited higher levels of tonic (i.e., noncue-elicited) craving than did occasional smokers. Both groups showed significant increases in craving in response to cues (i.e., cue-elicited craving), with little evidence that cue-elicited craving differed between groups. Females were more cue reactive to both the alcohol and smoking cues than males, particularly for the positively reinforced aspects of smoking (i.e., hedonic craving). There were no gender × group interaction effects in response to either the alcohol or the smoking cue. CONCLUSIONS: Findings show the presence of cue-elicited craving even among occasional smokers and are consistent with literature demonstrating heightened sensitivity to environmental cues among females. Cue-elicited craving may be one mechanism that contributes to the maintenance of smoking behavior and perhaps to the development of nicotine dependence within early stage smokers.

Affective motives for smoking among early stage smokers.

BACKGROUND: As most smokers initiate smoking during adolescence, assessment of smoking motives that underlie trajectories of dependence is critical for both prevention and cessation efforts. In the current study, we expected participants with higher nicotine dependence would smoke (a) less for positive reinforcement (PR) and (b) more for negative reinforcement (NR) motives. We secondarily assessed the relative contribution of PR to NR motives across levels of dependence. METHODS: Data were drawn from a study on cue-elicited craving among occasional versus daily adolescent smokers aged 16-20 years (N = 111). Smoking motives were assessed in relation to 3 commonly used measures of nicotine dependence: (a) Fagerström Test for Nicotine Dependence (FTND), (b) Autonomy over Smoking Scale (AUTOS), and (c) Nicotine Dependence Syndrome Scale (NDSS). RESULTS: Compared to occasional smokers, daily smokers had significantly higher scores on each dependence measure and endorsed more prominent NR smoking motives. Each measure of nicotine dependence was strongly associated with NR motives for smoking, although measures differed in their association with PR motives. As expected, the FTND, AUTOS, and NDSS each significantly predicted smoking motive difference score (PR - NR), such that higher dependence was associated with more prominent NR motives for smoking. CONCLUSIONS: Results are consistent with our understanding of dependence and provide further support for 3 common measures of nicotine dependence among early stage smokers.

Acute effects of aerobic exercise on corticomotor plasticity in individuals with and without depression.

BACKGROUND: Although complex in nature, the pathophysiology of depression involves reduced or impaired neuroplastic capabilities. Restoring or enhancing neuroplasticity may serve as a treatment target for developing therapies for depression. Aerobic exercise (AEx) has antidepressant benefits and may enhance neuroplasticity in depression although the latter has yet to be substantiated. Therefore, we sought to examine the acute effect of AEx on neuroplasticity in depression. METHODS: Sixteen individuals with (DEP; 13 female; age = 28.5 ± 7.3; Montgomery-Äsberg Depression Rating Scale [MADRS] = 21.3 ± 5.2) and without depression (HC; 13 female; age 27.2 ± 7.5; MADRS = 0.8 ± 1.2) completed three experimental visits consisting of 15 min of low intensity AEx (LO) at 35% heart rate reserve (HRR), high intensity AEx (HI) at 70% HRR, or sitting (CON). Following AEx, excitatory paired associative stimulation (PAS25ms) was employed to probe neuroplasticity. Motor evoked potentials (MEP) were assessed via transcranial magnetic stimulation before and after PAS25ms to indicate acute changes in neuroplasticity. RESULTS: PAS25ms primed with HI AEx led to significant increases in MEP amplitude compared to LO and CON. HI AEx elicited enhanced PAS25ms-induced neuroplasticity for up to 1-h post-PAS. There were no significant between-group differences. CONCLUSION: HI AEx enhances PAS measured neuroplasticity in individuals with and without depression. HI AEx may have a potent influence on the brain and serve as an effective primer, or adjunct, to therapies that seek to harness neuroplasticity.

Development of two novel treatments to promote smoking cessation: Savor and retrieval-extinction training pilot clinical trial findings.

Despite decades of progress, cigarette smoking remains a significant contributor to disease burden. This effect is especially pronounced for specific priority populations, such as individuals who live in rural communities, in that the burden of tobacco smoking is greater among these groups than in urban areas and the general population. The present study aims to evaluate the feasibility and acceptability of two novel tobacco treatment interventions delivered through remote telehealth procedures to individuals who smoke in the state of South Carolina. Results also include exploratory analyses of smoking cessation outcomes. Study I evaluated savoring, a strategy based on mindfulness practices, alongside nicotine replacement therapy (NRT). Study II evaluated retrieval-extinction training (RET), a memory-modification paradigm alongside NRT. In Study I (savoring), recruitment and retention data showed high interest and engagement in the intervention components, and participants who received this intervention decreased cigarette smoking throughout the course of the treatment (ps < .05). In Study II (RET), results showed high interest and moderate engagement in treatment, although exploratory outcome analyses did not demonstrate significant treatment effects on smoking behaviors. Overall, both studies showed promise in generating interest among individuals who smoke in participating in remotely delivered, telehealth smoking cessation interventions with novel therapeutic targets. A brief savoring intervention appeared to have effects on cigarette smoking throughout treatment, whereas RET did not. Gaining insight from the present pilot study, future studies may improve the efficacy of these procedures and incorporate the treatment components into more robust available treatments. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Sustained reduction of nicotine craving with real-time neurofeedback: exploring the role of severity of dependence.

BACKGROUND: Neurofeedback delivered via real-time functional magnetic resonance imaging (rtfMRI) is a promising therapeutic technique being explored to facilitate self-regulation of craving in nicotine-dependent cigarette smokers. The current study examined the role of nicotine-dependence severity and the efficacy of multiple visits of neurofeedback from a single region of interest (ROI) in the anterior cingulate cortex (ACC) on craving reduction. METHODS: Nine nicotine-dependent cigarette smokers participated in three rtfMRI visits that examined cue-induced craving and brain activation. Severity of nicotine dependence was assessed with the Fagerström Test for Nicotine Dependence. When viewing smoking-related images with instructions to "crave," patient-tailored ROIs were generated in the vicinity of the ACC. Activity levels from the ROI were fed back while participants viewed smoking cues with the instruction to reduce craving. RESULTS: Neurofeedback from a single ROI in the ACC led to consistent decreases in self-reported craving and activation in the ACC across the three visits. Dependence severity predicted response to neurofeedback at Visit 3. CONCLUSIONS: This study builds upon previous rtfMRI studies on the regulation of nicotine craving in demonstrating that feedback from the ACC can reduce activation to smoking cues across three separate visits. Individuals with lower nicotine-dependence severity were more successful in reducing ACC activation over time. These data highlight the need to consider dependence severity in developing more individualized neurofeedback methods.

Volitional reduction of anterior cingulate cortex activity produces decreased cue craving in smoking cessation: a preliminary real-time fMRI study.

Numerous research groups are now using analysis of blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) results and relaying back information about regional activity in their brains to participants in the scanner in 'real time'. In this study, we explored the feasibility of self-regulation of frontal cortical activation using real-time fMRI (rtfMRI) neurofeedback in nicotine-dependent cigarette smokers during exposure to smoking cues. Ten cigarette smokers were shown smoking-related visual cues in a 3 Tesla MRI scanner to induce their nicotine craving. Participants were instructed to modify their craving using rtfMRI feedback with two different approaches. In a 'reduce craving' paradigm, participants were instructed to 'reduce' their craving, and decrease the anterior cingulate cortex (ACC) activity. In a separate 'increase resistance' paradigm, participants were asked to increase their resistance to craving and to increase middle prefrontal cortex (mPFC) activity. We found that participants were able to significantly reduce the BOLD signal in the ACC during the 'reduce craving' task (P=0.028). There was a significant correlation between decreased ACC activation and reduced craving ratings during the 'reduce craving' session (P=0.011). In contrast, there was no modulation of the BOLD signal in mPFC during the 'increase resistance' session. These preliminary results suggest that some smokers may be able to use neurofeedback via rtfMRI to voluntarily regulate ACC activation and temporarily reduce smoking cue-induced craving. Further research is needed to determine the optimal parameters of neurofeedback rtfMRI, and whether it might eventually become a therapeutic tool for nicotine dependence.

Sex differences in the relationship between cannabis use motives and cannabis craving in daily life in emerging adults.

OBJECTIVE: Cannabis use motives and craving are associated with increased risk for cannabis-related problems and are ideal targets for prevention and early intervention. Patterns of motives and craving reactivity to cannabis cues differ by sex; however, few studies closely examine the relationship between motives and craving and how it may differ by valence (±) across men and women. METHOD: The present study used Cue Reactivity Ecological Momentary Assessment to assess reward (+) and relief (-) craving four semirandom times per day for 2 weeks in a sample of 63 emerging adults (age 18-21; 54% cisgender women; 85.7% White) who frequently use cannabis (≥ 3 times per week). We assessed craving before and after exposure to brief neutral or cannabis image cues and examined within- and between-participant effects of cue type, motives, sex/gender, and their interactions, on postcue cannabis craving. RESULTS: Regardless of cue type, women with high coping motives (-) reported less postcue relief (-) craving, and men with high enhancement motives (+) reported more postcue reward (+) craving. High enhancement motives (+), regardless of sex/gender, were associated with elevated relief (-) craving reactivity to cannabis cues, and women with high coping motives (-) reported elevated reward (+) craving reactivity to cannabis cues. CONCLUSIONS: Sex/gender differences in the relationships between cannabis motives and craving reactivity indicate the value of a more targeted examination of valence (±) of craving experiences in addition to motives for use. Higher levels of precision may better inform interventions for emerging adults at risk for experiencing cannabis-related problems. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Methodological approach for an integrated female-specific study of anxiety and smoking comorbidity.

Two primary ovarian hormones that fluctuate across the female menstrual cycle-estradiol and progesterone-have been independently linked in separate literatures to nicotine reinforcement and anxiety psychopathology. We identify existing methodological limitations in these literatures, describe an example protocol that was developed to address such limitations, highlight case examples, and offer insights on the resulting advantages and challenges. This protocol was an observational, prospective, within-subjects study of female cigarette smokers who were followed over the course of a complete menstrual cycle. Non-treatment seeking, female cigarette smokers (N = 50), between the ages of 18-40 who have a normal menstrual cycle (25-35 days in length) were recruited from the community. Females with anxiety or mood psychopathology represented 38.0% of the sample. Salivary progesterone and estradiol were assessed each morning via at-home saliva collection methods. Self-reported within-day momentary ratings of anxiety and nicotine reinforcement were collected using ecological momentary assessment (EMA) via a mobile app. Protocol compliance was >85%. Within- and between-subjects heterogeneity was observed in the progesterone and estradiol, anxiety, and nicotine craving measures, especially in the context of anxiety psychopathology. We aimed to integrate the anxiety and nicotine dependence literatures and advance the empirical study of the role of ovarian hormones. This protocol reflects an intensive, yet feasible approach to collecting daily-level naturalistic data related to estradiol, progesterone, anxiety, and nicotine reinforcement.