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Genetics contribute to smoking cessation, which is important for cancer prevention. Prior genetic studies, limited by short-term follow-up, have not examined multiple quit attempts and relapse events experienced by most smokers. This research investigated genetic associations with smoking relapse throughout adulthood. Participants were from two, all-female longitudinal cohort studies and included 12,060 European ancestry ever-smokers with existing genotype data who quit smoking at ≥1 timepoint. Median follow-up was 32 years. Associations between selected SNPs and odds of relapse and, conditional on relapse, SNP associations with proportion of follow-up relapsed were modeled using zero-inflated beta regression. Genotype by menopausal status interactions were evaluated. Women with AA genotypes for CHRNA5 SNP rs16969968 G>A or CHRNA3 SNP rs1051730 G>A (P-value = 0.04 for both) had lower odds of relapse. Among women who relapsed, those with CC genotypes of CHRNA5 SNPs rs588765 T>C (P-value = 0.04) and rs680244 T>C (P-value = 0.048) and AA genotype of DRD2 SNP rs6277 G>A (P-value = 0.01) had higher proportion follow-up in relapse. Associations were stronger among postmenopausal women (genotype by menopause interactions: rs588765 P-value = 0.003, rs680244 P-value = 0.001, rs6277 P-value = 0.04). Women with AA or AG genotypes for COMT SNP rs4680 G>A (P-value = 0.03) had lower proportion follow-up relapsed. This study identified SNP associations with likelihood of relapse or proportion of follow-up in relapse. Several associations were stronger among postmenopausal women. The findings demonstrate the importance of long-term follow-up and factors unique to women when characterizing smoking phenotypes. Prevention Relevance: This study is the first to quantify genetic associations with smoking relapse among female smokers throughout adulthood. These findings could inform precision medicine approaches to improve long-term smoking relapse prevention to reduce smoking attributable cancer morbidity and mortality.

Introduction Smoking cessation is more than 50% heritable. Genetic studies of smoking cessation have been limited by short-term follow-up or cross-sectional design. Aims and Methods This study tests single nucleotide polymorphism (SNP) associations with cessation during long-term follow-up throughout adulthood in women. The secondary aim tests whether genetic associations differ by smoking intensity. Associations between 10 SNPs in CHRNA5, CHRNA3, CHRNB2, CHRNB4, DRD2, and COMT and the probability of smoking cessation over time were evaluated in two longitudinal cohort studies of female nurses, the Nurses’ Health Study (NHS) (n = 10 017) and NHS-2 (n = 2793). Participant follow-up ranged from 2 to 38 years with data collected every 2 years. Results Women with the minor allele of either CHRNA5 SNP rs16969968 or CHRNA3 SNP rs1051730 had lower odds of cessation throughout adulthood [OR = 0.93, p-value = .003]. Women had increased odds of cessation if they had the minor allele of CHRNA3 SNP rs578776 [OR = 1.17, p-value = .002]. The minor allele of DRD2 SNP rs1800497 was associated with lower odds of cessation in moderate-to-heavy smokers [OR = 0.92, p-value = .0183] but increased odds in light smokers [OR = 1.24, p-value = .096]. Conclusions Some SNP associations with short-term smoking abstinence observed in prior studies were shown in the present study to persist throughout adulthood over decades of follow-up. Other SNP associations with short-term abstinence did not persist long-term. The secondary aim findings suggest genetic associations may differ by smoking intensity. Implications The results of the present study expand on previous studies of SNP associations in relation to short-term smoking cessation to demonstrate some of these SNPs were associated with smoking cessation throughout decades of follow-up, whereas other SNP associations with short-term abstinence did not persist long-term. The rate of relapse to smoking remains high for several years after quitting smoking, and many smokers experience multiple quit attempts and relapse episodes throughout adulthood. Understanding genetic associations with long-term cessation has potential importance for precision medicine approaches to long-term cessation management.

Aims: Substance use disorders (SUD) are associated with cognitive deficits that are not always addressed in current treatments, and this hampers recovery. Cognitive training and remediation interventions are well suited to fill the gap for managing cognitive deficits in SUD. We aimed to reach consensus on recommendations for developing and applying these interventions. Design, Setting and Participants: We used a Delphi approach with two sequential phases: survey development and iterative surveying of experts. This was an on-line study. During survey development, we engaged a group of 15 experts from a working group of the International Society of Addiction Medicine (Steering Committee). During the surveying process, we engaged a larger pool of experts (n = 54) identified via recommendations from the Steering Committee and a systematic review. Measurements: Survey with 67 items covering four key areas of intervention development: targets, intervention approaches, active ingredients and modes of delivery. Findings: Across two iterative rounds (98% retention rate), the experts reached a consensus on 50 items including: (i) implicit biases, positive affect, arousal, executive functions and social processing as key targets of interventions; (ii) cognitive bias modification, contingency management, emotion regulation training and cognitive remediation as preferred approaches; (iii) practice, feedback, difficulty-titration, bias modification, goal-setting, strategy learning and meta-awareness as active ingredients; and (iv) both addiction treatment work-force and specialized neuropsychologists facilitating delivery, together with novel digital-based delivery modalities. Conclusions: Expert recommendations on cognitive training and remediation for substance use disorders highlight the relevance of targeting implicit biases, reward, emotion regulation and higher-order cognitive skills via well-validated intervention approaches qualified with mechanistic techniques and flexible delivery options., Medical Research Future Fund (MRFF) MRF1141214, National Health and Medical Research Council (NHMRC) of Australia GNT2009464

While commendable strides have been made in reducing smoking initiation and improving smoking cessation rates, current available smoking cessation treatment options are still only mildly efficacious and show substantial interindividual variability in their therapeutic responses. Therefore, the primary goal of preclinical research has been to further the understanding of the neural substrates and genetic influences involved in nicotine's effects and reassess potential drug targets. Pronounced advances have been made by investing in new translational approaches and placing more emphasis on bridging the gap between human and rodent models of dependence. Functional neuroimaging studies have identified key brain structures involved with nicotine-dependence phenotypes such as craving, impulsivity, withdrawal symptoms, and smoking cessation outcomes. Following up with these findings, rodent-modeling techniques have made it possible to dissect the neural circuits involved in these motivated behaviors and ascertain mechanisms underlying nicotine's interactive effects on brain structure and function. Likewise, translational studies investigating single-nucleotide polymorphisms (SNPs) within the cholinergic, dopaminergic, and opioid systems have found high levels of involvement of these neurotransmitter systems in regulating the reinforcing aspects of nicotine in both humans and mouse models. These findings and coordinated efforts between human and rodent studies pave the way for future work determining gene by drug interactions and tailoring treatment options to each individual smoker.

BackgroundNeuropsychopharmacologic effects of long-term opioid therapy (LTOT) in the context of chronic pain may result in subjective anhedonia coupled with decreased attention to natural rewards. Yet, there are no known efficacious treatments for anhedonia and reward deficits associated with chronic opioid use. Mindfulness-Oriented Recovery Enhancement (MORE), a novel behavioral intervention combining training in mindfulness with savoring of natural rewards, may hold promise for treating anhedonia in LTOT.MethodsVeterans receiving LTOT (N = 63) for chronic pain were randomized to 8 weeks of MORE or a supportive group (SG) psychotherapy control. Before and after the 8-week treatment groups, we assessed the effects of MORE on the late positive potential (LPP) of the electroencephalogram and skin conductance level (SCL) during viewing and up-regulating responses (i.e. savoring) to natural reward cues. We then examined whether these neurophysiological effects were associated with reductions in subjective anhedonia by 4-month follow-up.ResultsPatients treated with MORE demonstrated significantly increased LPP and SCL to natural reward cues and greater decreases in subjective anhedonia relative to those in the SG. The effect of MORE on reducing anhedonia was statistically mediated by increases in LPP response during savoring.ConclusionsMORE enhances motivated attention to natural reward cues among chronic pain patients on LTOT, as evidenced by increased electrocortical and sympathetic nervous system responses. Given neurophysiological evidence of clinical target engagement, MORE may be an efficacious treatment for anhedonia among chronic opioid users, people with chronic pain, and those at risk for opioid use disorder.

Introduction Identifying genetic factors associated with smoking cessation could inform precision cessation interventions. Of major interest is genetic variation in nicotine metabolism, largely predicted by CYP2A6 variations. Aims and Methods We conducted a systematic literature review to summarize the population-based evidence of the association between CYP2A6 and smoking cessation. In the 12 studies meeting the inclusion criteria, the known functional metabolic effect of CYP2A6 variants was used to classify nicotine metabolism as normal (>75% metabolic activity), intermediate (50.1%–75% activity), slow (25%–50% activity), and poor ( Results Among untreated people of European ancestry (n = 4 studies), those with CYP2A6 reduced metabolism were more likely to quit smoking than those with normal metabolism (Summary OR = 2.05, 95% CI 1.23 to 3.42) and the likelihood of cessation increased as nicotine metabolism decreased. Nicotine replacement therapy attenuated the association at end-of-treatment, while bupropion modified the association such that intermediate/slow metabolizers were less likely to quit than normal metabolizers (Summary OR = 0.86, 95% CI 0.79 to 0.94). Among untreated Asian people (n = 3 studies), results differed compared with those with European ancestry: those with slow metabolism were less likely to have quit smoking than normal metabolizers (Summary OR = 0.52, 95% CI 0.38 to 0.71). Evidence for people of African ancestry (n = 1 study) suggested the CYP2A6 association with cessation may differ compared with those of European ancestry. Conclusions and Implications Most studies included in this review were of European ancestry populations; these showed slower nicotine metabolism was associated with increased likelihood of smoking cessation in a dose-related manner. Pharmacotherapy appeared to attenuate or modify this association among people of European ancestry, but it is unclear whether the change in the association remains consistent after treatment ceases. This finding has implications for precision medicine cessation interventions. Based on only a few studies of people of Asian or African ancestry, the association between CYP2A6 variants and cessation may differ from that observed among those of European ancestry, but more evidence is needed.

Self-regulation is instantiated by theta oscillations (4 to 8 Hz) in neurons of frontal midline brain regions. Frontal midline theta (FMΘ) is inversely associated with default mode network (DMN) activation, which subserves self-referential processing. Addiction involves impaired self-regulation and DMN dysfunction. Mindfulness is an efficacious self-regulatory practice for treating addiction, but little is known about the mechanisms by which mindfulness reduces addictive behavior. In this mechanistic study of long-term opioid users ( N = 165), we assessed meditation-induced FMΘ as a mediator of changes in opioid misuse. Relative to a supportive psychotherapy control, participants treated with Mindfulness-Oriented Recovery Enhancement (MORE) exhibited increased FMΘ during a laboratory-based meditation session. FMΘ during meditation was associated with self-transcendent experiences characterized by ego dissolution, nondual awareness, and bliss. MORE’s effects on decreasing opioid misuse were mediated by increased FMΘ. Given the role of aberrant self-referential processing in addiction, mindfulness-induced endogenous theta stimulation might “reset” DMN dysfunction to inhibit addictive behavior.

Background and AimsSubstance use disorders (SUD) are associated with cognitive deficits that are not always addressed in current treatments, and this hampers recovery. Cognitive training and remediation interventions are well suited to fill the gap for managing cognitive deficits in SUD. We aimed to reach consensus on recommendations for developing and applying these interventions.DesignDelphi approach with two sequential phases: survey development and iterative surveying of experts.SettingOnline study.ParticipantsDuring survey development, we engaged a group of 15 experts from a working group of the International Society of Addiction Medicine (Steering Committee). During the surveying process, we engaged a larger pool of experts (n=53) identified via recommendations from the Steering Committee and a systematic review.MeasurementsSurvey with 67 items covering four key areas of intervention development, i.e., targets, intervention approaches, active ingredients, and modes of delivery.FindingsAcross two iterative rounds (98% retention rate), the experts reached a consensus on 50 items including: (i) implicit biases, positive affect, arousal, executive functions, and social processing as key targets of interventions; (ii) cognitive bias modification, contingency management, emotion regulation training, and cognitive remediation as preferred approaches; (iii) practice, feedback, difficulty-titration, bias-modification, goal setting, strategy learning, and meta-awareness as active ingredients; and (iv) both addiction treatment workforce and specialized neuropsychologists facilitating delivery, together with novel digital-based delivery modalities.ConclusionsExpert recommendations on cognitive training and remediation for SUD highlight the relevance of targeting implicit biases, reward, emotion regulation, and higher-order cognitive skills via well-validated intervention approaches qualified with mechanistic techniques and flexible delivery options.

Cigarette smoking is a major contributor to the cancer burden, so identifying genetic variants associated with smoking cessation is important for cancer prevention. Prior genetic studies of smoking cessation have been limited by short-term follow-up and not accounting for quit attempts and relapse events experienced by most smokers. In this study, candidate SNPs previously found to be associated with smoking cessation were studied in relation to smoking relapse throughout adulthood. Participants were from two, all-female longitudinal cohort studies with repeated smoking behavior measurements collected every 2 years. The study included 12,060 ever-smokers of European ancestry with genotype data who quit smoking at ≥1 timepoint. Median follow-up after first quitting smoking was 32 years. Associations between selected single nucleotide polymorphisms (SNPs) and odds of smoking relapse and, conditional on relapse, SNP associations with the proportion of follow-up in relapse were modeled using zero-inflated beta regression. Genotype by menopausal status interactions were evaluated. Women with AA genotypes for CHRNA5 SNP rs16969968 G>A or CHRNA3 SNP rs1051730 G>A (p-value = 0.04 for both) had lower odds of relapse. Among women who relapsed, those with AA genotypes for CHRNA5 SNPs rs588765 G>A or rs680244 G>A had 2.6% [95% CI 0.1 - 5.0%] and 2.4% [95% CI 0.2 - 4.9%] more follow-up in smoking relapse, respectively, compared to women with AG or GG genotypes. Women with AA or AG genotypes for DRD2 SNP rs6277 G>A had 3.3% [95% CI 0.8 - 5.7%] more follow-up in relapse than women with GG genotypes. In contrast, women with AA genotypes for COMT SNP rs4680 G>A had 2.7% [95% CI 0.2 - 5.2%] lower proportion of follow-up in relapse than women with AG or GG genotypes. These associations with the proportion of follow-up in relapse were stronger among post-menopausal women. The association of SNPs rs588765, rs680244, and rs6277 with a higher proportion of follow-up in relapse was significantly stronger among women who quit smoking post-menopause [rs588765 difference in proportion follow-up in relapse = 9.5% (95% CI 3.8 -15.2%), rs680244 difference in proportion follow-up in relapse = 10.1% (95% CI 4.4% - 15.9%), rs6277 difference in proportion follow-up in relapse = 7.6% (95% CI 1.5 - 13.6%)]. No statistically significant difference in proportion follow-up in relapse by genotype was observed among women who quit smoking prior to menopause. Several SNPs were not associated with odds of smoking relapse but, conditional on relapse, were associated with the proportion of follow-up in relapse. The findings show selected genetic variants contribute to susceptibility to smoking relapse in the long term and that the genetic risk can differ by the stage of smoking cessation. For several SNPs stronger associations were observed among post-menopausal women, indicating the importance of menopausal status. Citation Format: Stephanie K. Jones, Anthony J. Alberg, Kristin Wallace, Brett Froeliger, Matthew J. Carpenter, Bethany J. Wolf. Genetic associations with smoking relapse and proportion of follow-up in relapse throughout adulthood in pre- and post-menopausal women. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4182.

Nicotine produces its effects by binding to nicotinic acetylcholine receptors (nAChRs). Variants of genes encoding properties of nAChRs are candidates for affecting likelihood of smoking cessation.A systematic review was conducted summarizing evidence of associations between single nucleotide polymorphisms (SNPs) of nAChR genes and smoking cessation. From 24 articles meeting inclusion criteria, summary odds ratios (ORs) for associations between nine SNPs and smoking cessation were calculated from 26 studies (N = 233-29,072) stratified by gene, ancestry, study design, and pharmacotherapy; SNPs in linkage disequilibrium were pooled. Results for a tenth SNP from two GWAS were summarized.People of European ancestry with minor alleles of CHRNA5 rs16969968 and CHRNA3 rs1051730 had longer time to cessation [HR = 0.90, 95 % CI 0.88 - 0.92 (n = 2 studies)] and lower odds of cessation [OR = 0.88, 95 % CI 0.80 - 0.97 (n = 5 cohort studies), OR = 0.64, 95 % CI 0.45 - 0.90 (n = 4 placebo arms)]. Risk of persistent smoking associated with these alleles was attenuated in smokers receiving nicotine replacement therapy (NRT). Recipients of bupropion alone or with NRT with these alleles had higher, though not statistically significant, odds of cessation. Results for CHRNA5 rs588765 and rs680244 were similar to rs16969968/rs1051730 findings. Evidence was limited for other SNPs.Evidence consistently indicates the minor alleles of four SNPs within CHRNA3 or CHRNA5 are risk alleles for cessation failure. Analysis by pharmacotherapy revealed bupropion may be the most efficacious intervention for people with these alleles.

Successful treatment of opioid misuse among people with chronic pain has proven elusive. Guidelines recommend nonopioid therapies, but the efficacy of mindfulness-based interventions for opioid misuse is uncertain.To evaluate the efficacy of Mindfulness-Oriented Recovery Enhancement (MORE) for the reduction of opioid misuse and chronic pain.This interviewer-blinded randomized clinical trial enrolled patients from primary care clinics in Utah between January 4, 2016, and January 16, 2020. The study included 250 adults with chronic pain receiving long-term opioid therapy who were misusing opioid medications.Treatment with MORE (comprising training in mindfulness, reappraisal, and savoring positive experiences) or supportive group psychotherapy (control condition) across 8 weekly 2-hour group sessions.Primary outcomes were (1) opioid misuse assessed by the Drug Misuse Index (self-report, interview, and urine screen) and (2) pain severity and pain-related functional interference, assessed by subscale scores on the Brief Pain Inventory through 9 months of follow-up. Secondary outcomes were opioid dose, emotional distress, and ecological momentary assessments of opioid craving. The minimum intervention dose was defined as 4 or more completed sessions of MORE or supportive group psychotherapy.Among 250 participants (159 women [63.6%]; mean [SD] age, 51.8 [11.9] years), 129 were randomized to the MORE group and 121 to the supportive psychotherapy group. Overall, 17 participants (6.8%) were Hispanic or Latino, 218 (87.2%) were White, and 15 (6.0%) were of other races and/or ethnicities (2 American Indian, 3 Asian, 1 Black, 2 Pacific Islander, and 7 did not specify). At baseline, the mean duration of pain was 14.7 years (range, 1-60 years), and the mean (SD) morphine-equivalent opioid dose was 101.0 (266.3) mg (IQR, 16.0-90.0 mg). A total of 203 participants (81.2%) received the minimum intervention dose (mean [SD], 5.7 [2.2] sessions); at 9 months, 92 of 250 participants (36.8%) discontinued the study. The overall odds ratio for reduction in opioid misuse through the 9-month follow-up period in the MORE group compared with the supportive psychotherapy group was 2.06 (95% CI, 1.17-3.61; P = .01). At 9 months, 36 of 80 participants (45.0%) in the MORE group were no longer misusing opioids compared with 19 of 78 participants (24.4%) in the supportive psychotherapy group. Mixed models demonstrated that MORE was superior to supportive psychotherapy through 9 months of follow-up for pain severity (between-group effect: 0.49; 95% CI, 0.17-0.81; P = .003) and pain-related functional interference (between-group effect: 1.07; 95% CI, 0.64-1.50; P .001). Participants in the MORE group reduced their opioid dose to a greater extent than those in the supportive psychotherapy group. The MORE group also had lower emotional distress and opioid craving.In this randomized clinical trial, among adult participants in a primary care setting, the MORE intervention led to sustained improvements in opioid misuse and chronic pain symptoms and reductions in opioid dosing, emotional distress, and opioid craving compared with supportive group psychotherapy. Despite attrition caused by the COVID-19 pandemic and the vulnerability of the sample, MORE appeared to be efficacious for reducing opioid misuse among adults with chronic pain.ClinicalTrials.gov Identifier: NCT02602535.

Nicotine addiction is a chronic relapsing brain disorder, and cigarette smoking is the leading cause of preventable death in the United States. Currently, the most effective pharmacotherapy for smoking cessation is Varenicline (VRN), which reduces both positive and negative reinforcement by nicotine. Clinically, VRN attenuates withdrawal symptoms and promotes abstinence, but50% of smokers relapse within 3 months following a quit attempt. This may indicate that VRN fails to ameliorate components of nicotine-induced neuroplasticity that promote relapse vulnerability. Animal models reveal that glutamate dysregulation in the nucleus accumbens is associated with nicotine relapse. N-acetylcysteine (NAC) normalizes glutamate transmission and prolongs cocaine abstinence. Thus, combining VRN and NAC may promote and maintain, respectively, nicotine abstinence. In rats, we found that VRN effectively reduced nicotine self-administration and seeking in early abstinence, but not seeking later in abstinence. In contrast, NAC reduced seeking only later in abstinence. Because VRN and NAC are sometimes associated with mild adverse effects, we also evaluated a sequential approach combining subthreshold doses of VRN during self-administration and early abstinence with subthreshold doses of NAC during late abstinence. As expected, subthreshold VRN did not reduce nicotine intake. However, subthreshold VRN and NAC reduced seeking in late abstinence, suggesting a combined effect. Overall, our results suggest that combining subthreshold VRN and NAC is a viable and drug-specific approach to promote abstinence and reduce relapse while minimizing adverse effects. Our data also suggest that different components and time points in addiction engage the different neurocircuits targeted by VRN and NAC.

Alcohol-induced blackout is associated concurrently and prospectively with alcohol-related harm, including emergency room visits and sexual coercion. Although sleep has not been linked empirically to blackout, symptoms of insomnia have also been linked to memory impairment, in which case insomnia symptoms may compound alcohol's negative effects on memory. This study tested insomnia symptoms as a moderator of the association between heavy drinking and alcohol-induced blackout.Heavy-drinking young adults in college (N = 461, 69% female) completed assessments online from remote locations. Hierarchical linear regression was used to test a moderation model predicting blackout frequency. Logistic regression was used to test post hoc hypotheses.In contrast to our main hypothesis, heavy drinking was more weakly (not more strongly) associated with blackout in the context of more severe insomnia. Post hoc analyses tested insomnia symptoms as a unique moderator of the association between heavy drinking and likelihood of acute physiological consequences of alcohol use (blackout, passing out, nausea/throwing up, and hangover). Insomnia severity at least marginally moderated the association between heavy drinking and 4 out of 5 physiological consequences of alcohol use, and only moderated the association between drinking and 1 of 19 remaining consequences.Symptoms of insomnia are associated with alcohol-related harm, but may buffer associations between drinking and acute physiological consequences of alcohol. Additional research is needed to determine if alcohol heightens sensitivity to the acute physiological effects of alcohol, in which case less alcohol may be required for young adults with insomnia to experience these effects.

Although distress tolerance (DT) is associated with smoking lapse and relapse outcomes, few studies have conducted a rigorous assessment of DT across domain and method in the context of acute abstinence. In a human laboratory-based study of 106 adult daily smokers, we examined between multiple indices of DT and smoking lapse, withdrawal processes, and motivation to quit. We expected that low DT would be associated with shorter latency to smoke, greater withdrawal severity, and lower motivation to quit. Following a smoking abstinence period (≥ 6 hr deprived), participants completed an assessment battery including both behavioral (mirror-tracing, serial addition, cold pressor, and breath-holding tasks) and self-report measures of DT (general and smoking-specific), withdrawal processes (craving, negative affect, and positive affect), and motivation to quit. Latency to smoke (range = 0-50 min) was assessed in a laboratory analogue task in which delaying smoking was monetarily rewarded. Behavioral and self-report DT indices displayed only modest intercorrelations, indicating different facets of this construct by domain and method of assessment. Tolerance of physical pain was uniquely associated with smoking choice. Both self-report DT measures were associated with abstinence-induced increases in negative affect, while only smoking-specific DT was positively associated with craving. Results are discussed within the context of guiding targeted behavioral interventions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

BACKGROUND: Individuals who use illicit substances exhibit cue-elicited craving and autonomic cue-reactivity when exposed to cues associated with past drug use. However, little is known about this phenomenon among chronic pain patients on long-term opioid therapy (LTOT). Negative cognitive-emotional reactivity in general (e.g., distress) and cognitive-emotional reactivity specific to pain (e.g., pain catastrophizing) might drive cue-reactivity independent of pain severity. Here we examined emotional distress and pain catastrophizing as predictors of cue-reactivity among a sample of chronic pain patients receiving LTOT. We also tested whether associations between distress, catastrophizing, and cue-reactivity differed as a function of opioid misuse status. MATERIALS AND METHODS: Patients receiving LTOT (N=243) were classified as exhibiting aberrant behavior consistent with opioid misuse (MISUSE+, n=145) or as using opioids as prescribed (MISUSE−, n=97). Participants completed assessments of pain catastrophizing and emotional distress and then participated in an opioid cue-reactivity task one week later. Cue-elicited opioid craving and autonomic cue-reactivity were measured with craving ratings and high-frequency heart rate variability (HRV), respectively. RESULTS: Distress and catastrophizing predicted cue-elicited craving and HRV, whereas pain severity did not. Misuser status moderated the relationship between emotional distress and self-reported craving, such that higher levels of distress predicted craving among the MISUSE+ group, but not among the MISUSE− group. No moderating effects were found for catastrophizing. CONCLUSIONS: Findings suggest that although opioids are prescribed for analgesia, the exacerbating influence of negative cognitive-emotional reactivity, both in general and specific to pain, on cue-elicited opioid craving extends beyond the effects of pain severity alone.

OBJECTIVES Physiological stress responses have been suggested as a mechanism through which social and biological factors contribute to racial disparities in breast cancer outcomes. Many African Americans experience stressful life events and circumstances. These social factors may contribute to an increased risk of advanced stage disease at diagnosis and/or faster progression, but not all African American women exposed to adverse social factors develop advanced stage disease. Similarly, women who have a limited number of stressors can develop advanced stage breast cancer. Highly individualized stress reactivity may account for these inconsistent associations. METHOD This report describes the rationale, design, and methods for an exploratory study that uses the experimental medicine approach to: (a) characterize the nature and distribution of stress reactivity among African American breast cancer survivors based on socioeconomic, clinical, and social stressors; (b) examine the impact of stress reactivity on temporal discounting; and (c) determine the extent to which stress reactivity and temporal discounting are associated with adherence to recommendations for cancer control behaviors and treatment compliance as part of the Science of Behavior Change Network. RESULTS This study addresses several empirical gaps about the most effective ways to develop behavior change interventions for a medically underserved population that continues to experience disparities in cancer morbidity and mortality. CONCLUSIONS Results from this research will provide the empirical and conceptual basis for future intervention protocols that target mechanisms that are critical to disparities in African American breast cancer survivors. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

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.

BACKGROUND While there have been many technological advances in studying the neurobiological and clinical basis of tobacco use disorder and nicotine addiction, there have been relatively minor advances in technologies for monitoring, characterizing, and intervening to prevent smoking in real time. Better understanding of real-time smoking behavior can be helpful in numerous applications without the burden and recall bias associated with self-report. OBJECTIVE The goal of this study was to test the validity of using a smartwatch to advance the study of temporal patterns and characteristics of smoking in a controlled laboratory setting prior to its implementation in situ. Specifically, the aim was to compare smoking characteristics recorded by Automated Smoking PerceptIon and REcording (ASPIRE) on a smartwatch with the pocket Clinical Research Support System (CReSS) topography device, using video observation as the gold standard. METHODS Adult smokers (N=27) engaged in a video-recorded laboratory smoking task using the pocket CReSS while also wearing a Polar M600 smartwatch. In-house software, ASPIRE, was used to record accelerometer data to identify the duration of puffs and interpuff intervals (IPIs). The recorded sessions from CReSS and ASPIRE were manually annotated to assess smoking topography. Agreement between CReSS-recorded and ASPIRE-recorded smoking behavior was compared. RESULTS ASPIRE produced more consistent number of puffs and IPI durations relative to CReSS, when comparing both methods to visual puff count. In addition, CReSS recordings reported many implausible measurements in the order of milliseconds. After filtering implausible data recorded from CReSS, ASPIRE and CReSS produced consistent results for puff duration (R2=.79) and IPIs (R2=.73). CONCLUSIONS Agreement between ASPIRE and other indicators of smoking characteristics was high, suggesting that the use of ASPIRE is a viable method of passively characterizing smoking behavior. Moreover, ASPIRE was more accurate than CReSS for measuring puffs and IPIs. Results from this study provide the foundation for future utilization of ASPIRE to passively and accurately monitor and quantify smoking behavior in situ.

Background Associative learning undergirds the development of addiction, such that drug-related cues serve as conditioned stimuli to elicit drug-seeking responses. Plausibly, among opioid misusing chronic pain patients, pain-related information may serve as a conditioned stimulus to magnify opioid cue-elicited autonomic and craving responses through a process of second-order conditioning. Methods We utilized a novel psychophysiological probe of pain-opioid conditioned associations, the Cue-Primed Reactivity (CPR) task. In this task, participants were presented with images as primes (200 ms) and cues (6000 ms) in pairs organized in four task blocks: “control-opioid,” “pain-opioid,” “control-pain,” and “opioid-pain.” Opioid-treated chronic pain patients (N = 30) recruited from an Army base in the Western United States were classified as opioid misusers (n = 17) or non-misusers (n = 13) via a validated cutpoint on the Prescription Drug Use Questionnaire (PDUQ; Compton et al., 2008). Opioid misuse status was examined as a predictor of HRV, craving, and mood responses on the CPR task. Results HRV increased to a greater extent during the pain-opioid block compared to the control-opioid block for non-misusers compared to misusers (p = .003, η2partial = 0.27). In contrast, craving increased to a greater extent from baseline to the pain-opioid block for misusers than for non-misusers (p = .03, η2partial = .16). Conclusions Findings suggest that opioid-treated chronic pain patients exhibit Pavlovian conditioned responses to opioid cues strengthened by an associative learning process of second-order conditioning when primed by pain-related images. This pain-opioid contingency appears to become disrupted among individuals who engage in opioid misuse, such that opioid-related stimuli elicit motivational responses irrespective of pain-related contextual stimuli.

Background: A subset of chronic pain patients misuse prescription opioids as a means of regulating negative emotions. However, opioid misuse may result in deficits in emotion regulation strategies ...

The psychological flexibility model (PFM) provides a framework for understanding and treating behavioural dysregulation in addictions. Rather than modulating the intensity of subjective experience, interventions based on, or consistent with, the PFM (PFM interventions) seek to alter the individual’s relationship to internal states, such as craving, negative affect and drug-related thoughts, using mindfulness, acceptance and related strategies. Experimental (non-clinical) studies in smokers have examined the effects of specific isolated strategies informed by or consistent with the PFM (PFM strategies). Here, we systematically review these studies and determine the extent to which they conform to methodological standards indicative of high levels of internal validity. Eligible studies were identified through electronic database searches and assessed for the presence of specific methodological features. Provisional aggregate effect sizes were determined depending on availability of data. Of 1499 screened publications, 12 met the criteria. All examined aspects of private subjective experience relevant to abstinence (craving n = 12; negative affect n = 10), demonstrating effects favouring PFM strategies relative to inactive control conditions. However, only six assessed outcome domains consistent with the PFM and provided no consistent evidence favouring PFM strategies. Overall, most studies had methodological limitations. As such, high-quality experimental studies continue to be needed to improve our understanding of necessary and/or sufficient constituents of PFM-guided smoking cessation interventions. Recommendations for future research are discussed.

OBJECTIVE Despite the heightened urgency of the current prescription opioid crisis, few psychotherapies have been evaluated for chronic pain patients receiving long-term opioid analgesics. Current psychological pain treatments focus primarily on ameliorating negative affective processes, yet basic science suggests that risk for opioid misuse is linked with a dearth of positive affect. Interventions that modulate positive psychological processes may produce therapeutic benefits among patients with opioid-treated chronic pain. The aim of this study was to conduct a theory-driven mechanistic analysis of proximal outcome data from a Stage 2 randomized controlled trial of Mindfulness-Oriented Recovery Enhancement (MORE), an integrative intervention designed to promote positive psychological health. METHOD Patients with opioid-treated chronic pain (N = 95; age = 56.8 ± 11.7; 66% female) were randomized to 8 weeks of therapist-led MORE or support group (SG) interventions. A latent positive psychological health variable comprised of positive affect, meaning in life, and self-transcendence measures was examined as a mediator of the effect of MORE on changes in pain severity at posttreatment and opioid misuse risk by 3-month follow-up. RESULTS Participants in MORE reported significantly greater reductions in pain severity by posttreatment (p = .03) and opioid misuse risk by 3-month follow-up (p = .03) and significantly greater increases in positive psychological health (p < .001) than SG participants. Increases in positive psychological health mediated the effect of MORE on pain severity by posttreatment (p = .048), which in turn predicted decreases in opioid misuse risk by follow-up (p = .02). CONCLUSIONS Targeting positive psychological mechanisms via MORE and other psychological interventions may reduce opioid misuse risk among chronic pain patients receiving long-term opioid therapy. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Preclinical studies have shown effects of chronic exposure to addictive drugs on glutamatergic-mediated neuroplasticity in frontostriatal circuitry. These initial findings have been paralleled by human functional magnetic resonance imaging (fMRI) research demonstrating weaker frontostriatal resting-state functional connectivity (rsFC) among individuals with psychostimulant use disorders. However, there is a dearth of human imaging literature describing associations between long-term prescription opioid use, frontostriatal rsFC, and brain morphology among chronic pain patients. We hypothesized that prescription opioid users with chronic pain, as compared with healthy control subjects, would evidence weaker frontostriatal rsFC coupled with less frontostriatal gray matter volume (GMV). Further, those opioid use-related deficits in frontostriatal circuitry would be associated with negative affect and drug misuse. Prescription opioid users with chronic pain (n = 31) and drug-free healthy controls (n = 30) underwent a high-resolution anatomical and an eyes-closed resting-state functional scan. The opioid group, relative to controls, exhibited weaker frontostriatal rsFC, and less frontostriatal GMV in both L.NAc and L.vmPFC. Frontostriatal rsFC partially mediated group differences in negative affect. Within opioid users, L.NAc GMV predicted opioid misuse severity. The current study revealed that prescription opioid use in the context of chronic pain is associated with functional and structural abnormalities in frontostriatal circuitry. These results suggest that opioid use-related abnormalities in frontostriatal circuitry may undergird disturbances in affect that may contribute to the ongoing maintenance of opioid use and misuse. These findings warrant further examination of interventions to treat opioid pathophysiology in frontostriatal circuitry over the course of treatment.

Mindfulness-based therapy changes brain responses to drug cues and healthy natural rewards in chronic opioid users., Addiction neuroscience models posit that recurrent drug use increases reactivity to drug-related cues and blunts responsiveness to natural rewards, propelling a cycle of hedonic dysregulation that drives addictive behavior. Here, we assessed whether a cognitive intervention for addiction, Mindfulness-Oriented Recovery Enhancement (MORE), could restructure reward responsiveness from valuation of drug-related reward back to valuation of natural reward. Before and after 8 weeks of MORE or a support group control, prescription opioid users (N = 135) viewed opioid and natural reward cues while an electroencephalogram biomarker of target engagement was assessed. MORE was associated with decreased opioid cue-reactivity and enhanced capacity to regulate responses to opioid and natural reward cues. Increased positive affective responses to natural reward cues were associated with decreased craving and mediated MORE’s therapeutic effects on opioid misuse. This series of randomized experiments provide the first neurophysiological evidence that an integrative behavioral treatment can remediate hedonic dysregulation among chronic opioid users.

Background Among opioid-treated chronic pain patients, deficient response inhibition in the context of emotional distress may contribute to maladaptive pain coping and prescription opioid misuse. Interventions that aim to bolster cognitive control and reduce emotional reactivity (e.g., mindfulness) may remediate response inhibition deficits, with consequent clinical benefits. Purpose To test the hypothesis that a mindfulness-based intervention, Mindfulness-Oriented Recovery Enhancement (MORE), can reduce the impact of clinically relevant, negative affective interference on response inhibition function in an opioid-treated chronic pain sample. Methods We examined data from a controlled trial comparing adults with chronic pain and long-term prescription opioid use randomized to either MORE (n = 27) treatment or to an active support group comparison condition (n = 30). Participants completed an Emotional Go/NoGo Task at pre- and post-treatment, which measured response inhibition in neutral and clinically relevant, negative affective contexts (i.e., exposure to pain-related visual stimuli). Results Repeated-measures analysis of variance indicated that compared with the support group, participants in MORE evidenced significantly greater reductions from pre- to post-treatment in errors of commission on trials with pain-related distractors relative to trials with neutral distractors, group × time × condition F(1,55) = 4.14, p = .047, η2partial = .07. Mindfulness practice minutes and increased nonreactivity significantly predicted greater emotional response inhibition. A significant inverse association was observed between improvements in emotional response inhibition and treatment-related reductions in pain severity by 3-month follow-up. Conclusions Study results provide preliminary evidence that MORE enhances inhibitory control function in the context of negative emotional interference.

Background While there have been many technological advances in studying the neurobiological and clinical basis of tobacco use disorder and nicotine addiction, there have been relatively minor advances in technologies for monitoring, characterizing, and intervening to prevent smoking in real time. Better understanding of real-time smoking behavior can be helpful in numerous applications without the burden and recall bias associated with self-report. Objective The goal of this study was to test the validity of using a smartwatch to advance the study of temporal patterns and characteristics of smoking in a controlled laboratory setting prior to its implementation in situ. Specifically, the aim was to compare smoking characteristics recorded by Automated Smoking PerceptIon and REcording (ASPIRE) on a smartwatch with the pocket Clinical Research Support System (CReSS) topography device, using video observation as the gold standard. Methods Adult smokers (N=27) engaged in a video-recorded laboratory smoking task using the pocket CReSS while also wearing a Polar M600 smartwatch. In-house software, ASPIRE, was used to record accelerometer data to identify the duration of puffs and interpuff intervals (IPIs). The recorded sessions from CReSS and ASPIRE were manually annotated to assess smoking topography. Agreement between CReSS-recorded and ASPIRE-recorded smoking behavior was compared. Results ASPIRE produced more consistent number of puffs and IPI durations relative to CReSS, when comparing both methods to visual puff count. In addition, CReSS recordings reported many implausible measurements in the order of milliseconds. After filtering implausible data recorded from CReSS, ASPIRE and CReSS produced consistent results for puff duration (R2=.79) and IPIs (R2=.73). Conclusions Agreement between ASPIRE and other indicators of smoking characteristics was high, suggesting that the use of ASPIRE is a viable method of passively characterizing smoking behavior. Moreover, ASPIRE was more accurate than CReSS for measuring puffs and IPIs. Results from this study provide the foundation for future utilization of ASPIRE to passively and accurately monitor and quantify smoking behavior in situ.

OBJECTIVE We examine whether having depressive symptoms (DS) is associated with different responses to cigarette package health warning labels (HWLs) before and after the implementation of pictorial HWLs in Mexico. METHOD We analyze data from adult smokers from Wave 4 and Wave 5 (n = 1,340) of the International Tobacco Control Policy Evaluation Project in Mexico. Seven Center for Epidemiological Studies Depression Scale (CES-D) items assessed DS, with scores ≥7 indicating elevated DS. Outcomes included: attention to HWLs, cognitive responses to HWLs, tobacco constituents awareness, putting off smoking due to HWLs, avoidance of HWLs, and awareness of telephone support for cessation (i.e., quitlines). Mixed effects models were used to assess main and interactive effects of DS and time (i.e., survey wave) on each outcome. RESULTS All HWL responses increased over time, except putting off smoking. Statistically significant interactions were found between DS and time for models of tobacco constituents awareness (b = -0.36, SE = 0.15, p = .022), putting off smoking (OR = 0.41, 95% CI [0.25, 0.66]), avoidance of HWLs (OR = 1.84, 95% CI [1.03, 3.29]), and quitline awareness (OR = 0.35, 95% CI [0.21, 0.56]). Compared to smokers with low DS, smokers with elevated DS reported stronger HWL responses at baseline; however, HWL responses increased over time among smokers with low DS, whereas HWL responses showed little or no change among smokers with elevated DS. DISCUSSION Population-level increases in HWL responses after pictorial HWLs were introduced in Mexico appeared mostly limited to smokers with low DS. In general, however, smokers with elevated DS reported equivalent or stronger HWL responses than smokers with low DS.

Several decades of scientific research provide strong evidence that individuals who suffer from emotion dysregulation, such as that observed in depression and anxiety, are more vulnerable to addictive behavior. Furthermore, a growing body of studies indicates that chronic use of addictive substances dysregulates emotional responding. Emerging research also suggests that recurrent drug use and addiction are associated with deficits in the capacity to proactively regulate negative and positive emotions. This chapter synthesizes evidence from clinical and neuroscientific studies on effects of addictive behavior (including misuse of prescription opioids, addiction to cigarettes, and addiction to more powerful stimulants) on emotion dysregulation to outline an integrative model of emotion dysregulation in addiction. This model has implications for treatment development and further scientific investigation.

Graphic health warning labels (HWLs) depicting bodily injury due to smoking are effective for producing changes in affect, cognition and smoking behavior in adult smokers. However, little is known about the effects of repeated presentation of graphic HWL's on the aforementioned processes. The goal of this study was to examine neural and behavioral responses to graphic HWL's and evaluate whether the repeated presentation of graphic HWL's leads to repetition suppression (RS). Smokers (N = 16) performed an event-related HWL cue task while blood oxygen level dependent (BOLD) signal was collected during a functional magnetic resonance imaging (fMRI) experimental session. Consistent with prior literature, graphic HWL's, as compared to scrambled images, elicited increased BOLD response in brain regions involved in self-referential and emotion processing. Importantly, BOLD response at sites in this network diminished during repeated presentation of the same HWL. These findings suggest that while novel graphic HWL's may have a significant effect on smokers' brain activity, repeated presentation may lead to muted responses and thus limit their potential to induce behavioral change.

Chronic exposure to drugs of abuse disrupts frontostriatal glutamate transmission, which in turn meditates drug seeking. In animal models, N-Acetylcysteine normalizes dysregulated frontostriatal glutamatergic neurotransmission and prevents reinstated drug seeking; however, the effects of N-Acetylcysteine on human frontostriatal circuitry function and maintaining smoking abstinence is unknown. Thus, the current study tested the hypothesis that N-Acetylcysteine would be associated with stronger frontostriatal resting-state functional connectivity (rsFC), attenuated nicotine withdrawal and would help smokers to maintain abstinence over the study period.The present study examined the effects of N-Acetylcysteine on frontostriatal rsFC, nicotine-withdrawal symptoms and maintaining abstinence. Healthy adult, non-treatment seeking smokers (N=16; mean (SD) age 36.5±11.9; cigs/day 15.8±6.1; years/smoking 15.7±8.9) were randomized to a double-blind course of 2400mg N-Acetylcysteine (1200mg b.i.d.) or placebo over the course of 3½ days of monetary-incentivized smoking abstinence. On each abstinent day, measures of mood and craving were collected and participants attended a lab visit in order to assess smoking (i.e., expired-air carbon monoxide [CO]). On day 4, participants underwent fMRI scanning.As compared to placebo (n=8), smokers in the N-Acetylcysteine group (n=8) maintained abstinence, reported less craving and higher positive affect (all p's.01), and concomitantly exhibited stronger rsFC between ventral striatal nodes, medial prefrontal cortex and precuneus-key default mode network nodes, and the cerebellum [p.025; FWE]).Taken together, these findings suggest that N-Acetylcysteine may positively affect dysregulated corticostriatal connectivity, help to restructure reward processing, and help to maintain abstinence immediately following a quit attempt.

The Mindfulness-to-Meaning Theory (MMT; Garland et al., in press) is a process model for explaining how mindfulness might facilitate an upward spiral of positive psychological growth via both eliminative and generative mechanisms. Unlike models that strictly describe the eliminative aspects of mindfulness, MMT provides a theoretical framework for how the iterative cycle of appraisal→ decentering→ metacognitive awareness, coupled with positive reappraisals that extend into broader contexts, may help to extinguish conditioned negative affective sequela and promote positive affectivity and eudaimonic well-being. One of the largest challenges facing the self-aware individual is the filtering and selection of interoceptive and exteroceptive information, particularly with regard to how one regulates what information is attended to and what meanings are construed from experience (Delle Fave, Massimini et al. 2011). MMT proposes that mindfulness practice, over time, can lead to a deepened capacity for meaning-making – or rather, a capacity to positively reappraise experiences of suffering and to amplify the affective experience related to natural rewards through savoring, transforming the context of these experiences in such a way that the experiences become supportive of the individual’s growth-process, thus engendering eudaimonic well-being while transforming the nature of the personal narrative or ‘autobiographical self’ (Garland et al., in press). Over the course of mindfulness practice, agency and self-awareness are often transformed in ways that seem to tune attentional processes towards positive information in the internal and external environment (Kiken and Shook 2011). MMT hypothesizes that, at least in part, this process of attentional tuning towards positive stimuli, and reframing ones relationship with negative stimuli, along with proactive cognitive reappraisal feedback loops, will further generate positive affect, ultimately engendering eudaimonic well-being and spurring motivation towards prosociality (Garland et al., in press). In this manner, MMT hones in on key, heretofore neglected, generative aspects of mindfulness, implicitly contextualized in the framework of Barbara Fredrickson’s “Broaden-and-build” theory of positive emotions (Fredrickson 2004). The “Broaden-and-Build” theory models what happens at the affect-attention interface, proposing that positive and negative affect will either broaden or constrict the attentional field – resulting either in the accumulation or the conservation of psychosocial resources, respectively (Fredrickson 2004). MMT applies this theory to mindfulness practice, posturing mindfulness as a generative mechanism through which positive affect can be increased, positive reappraisals generated, and eudaimonic meaning construed from experiences of adversity. The MMT is a novel and intriguing theoretical model that holds great potential for direct application in modern western society. Though a nascent database of scientific research on the effects of mindfulness practices on mood, cognition and well-being have begun to provide insight into both the behavioral and neural mechanisms underlying the processes described in the MMT, a significant amount of research is still needed to identify pathways from dysregulation to well-being. It remains to be seen whether mindfulness-associated positive affect, along with its sequelae, are both necessary and sufficient to provide for the construal of eudaimonic meaning from conditioned and unconditioned stimulus-response sequences. In other words, are the key elements of MMT (decentering, metacognitive awareness, positive reappraisal, attention to positive affect and amplification of natural rewards) necessary and sufficient to provide constant fuel to the self-realizing individual traversing the upward spiral of eudaimonic well-being? Additional longitudinal research on mindfulness will help to assess the MMT and the generalizability of this model to diverse populations (e.g., individual differences, substance use disorders, psychiatric disorders). Notwithstanding these questions, the MMT bridges a significant gap in the literature by explicating a translational model of mindfulness that may be applied to evaluating the effectiveness of mindfulness for treating the pathophysiology of dysregulated behavior, in particular drug addiction. In the commentary to follow, we frame our discussion of the MMT in the context of a brief overview of the neural correlates of mindfulness practice, particularly with regard to distributed neural network connectivity, and discuss the relevance of mindfulness from the perspective of treating the pathophysiology of drug addiction.

Impulsivity is a multi-dimensional construct that is robustly related to cigarette smoking. While underlying factors that account for this relation are not well understood, craving has been proposed as a central mechanism linking impulsivity to smoking. In order to further refine our understanding of associations between impulsivity and cigarette craving, the current study examined the association between impulsivity and tonic and cue-elicited craving among a sample of adolescent smokers. We expected trait impulsivity would be positively associated with both tonic and cue-elicited craving, and that this relationship would be stronger among daily vs. occasional smokers.106 smokers (ages 16-20) completed the questionnaires and reported their cigarette craving prior to and immediately following presentation of each of three counterbalanced cue types: (a) in vivo smoking, (b) alcohol, and (c) neutral cue.Impulsivity was positively associated with tonic craving for daily smokers (β=.38; p=.005), but not occasional smokers (β=.01; p=.95), with a significant impulsivity x smoker group interaction (β=1.31; p=.03). Impulsivity was unrelated to craving following smoking or alcohol cue, regardless of smoker group (all p's.16).Results suggest a moderated effect in which impulsivity is positively associated with tonic craving for daily smokers, but not occasional smokers. Tonic craving may serve as a mechanism linking impulsivity, smoking persistence, and nicotine dependence among daily smokers.

The primary goal of this pilot feasibility study was to examine the effects of Mindfulness-Oriented Recovery Enhancement (MORE), a behavioral treatment grounded in dual-process models derived from cognitive science, on frontostriatal reward processes among cigarette smokers. Healthy adult (N=13; mean (SD) age 49 ± 12.2) smokers provided informed consent to participate in a 10-week study testing MORE versus a comparison group (CG). All participants underwent two fMRI scans: pre-tx and after 8-weeks of MORE. Emotion regulation (ER), smoking cue reactivity (CR), and resting-state functional connectivity (rsFC) were assessed at each fMRI visit; smoking and mood were assessed throughout. As compared to the CG, MORE significantly reduced smoking (d=2.06) and increased positive affect (d=2.02). MORE participants evidenced decreased CR-BOLD response in ventral striatum (VS; d=1.57) and ventral prefrontal cortex (vPFC; d=1.7) and increased positive ER-BOLD in VS (dVS=2.13) and vPFC (dvmPFC=2.66). Importantly, ER was correlated with smoking reduction (r’s = .68 to .91) and increased positive affect (r’s = .52 to .61). These findings provide preliminary evidence that MORE may facilitate the restructuring of reward processes and play a role in treating the pathophysiology of nicotine addiction.

Importance Recent research on addiction-related memory processes suggests that protracted extinction training following brief cue-elicited memory retrieval (ie, retrieval-extinction [R-E] training) can attenuate/eradicate the ability of cues to elicit learned behaviors. One study reported that cue-elicited craving among detoxified heroin addicts was substantially attenuated following R-E training and through 6-month follow-up. Objective To build on these impressive findings by examining whether R-E training could attenuate smoking-related craving and behavior. Design, Setting, and Participants This prospective, mixed-design, human laboratory randomized clinical trial took place between December 2013 and September 2015. Participants were recruited in Charleston, South Carolina. Study sessions took place at the Medical University of South Carolina. The participants were 168 screened volunteer smokers, of whom 88 were randomized; 72 of these 88 participants (81.8%) attended all the follow-up sessions through 1 month. The primary eligibility criteria were current nicotine dependence ( DSM criteria), smoking 10 or more cigarettes per day, and a willingness to attempt smoking cessation. Interventions Participants were randomly assigned to receive either smoking-related memory retrieval followed by extinction training (the R-E group) or nonsmoking-related retrieval followed by extinction training (the NR-E group). Main Outcomes and Measures Primary outcomes were cue-elicited craving and physiological responding to familiar and novel cues in the R-E group vs the NR-E group over a 1-month follow-up period. Secondary outcomes were smoking-related behaviors. Results A total of 44 participants were randomly assigned to the R-E group (mean age, 48.3 years; 72.7% male); a total of 44 participants were randomly assigned to the NR-E group, with 43 attending at least 1 training session (mean age, 46.7 years; 55.8% male). The mean craving response to both familiar and novel smoking cues was significantly lower for participants in the R-E group than for participants in the NR-E group at 1-month follow-up (for both cue types: t 1225 = 2.1, P = .04, d = 0.44, and Δ = 0.47 [95% CI, 0.04-0.90]). The mean numbers of cigarettes smoked per day at 2 weeks and 1-month were significantly lower for the R-E group than for the NR-E group (treatment main effect: F 1,68 = 5.4, P = .02, d = 0.50, and Δ = 2.4 [95% CI, 0.4-4.5]). Significant differences in physiological responses, urine cotinine level, number of days abstinent, lapse, and relapse were not observed between groups (all between P = .06 and .75). Conclusions and Relevance Retrieval-extinction training substantially attenuated craving to both familiar and novel smoking cues and reduced the number of cigarettes smoked per day by participants 1 month after treatment relative to extinction training alone. Between-group differences were not observed for physiological responses, cotinine level, number of days abstinent, relapse, or lapse. In summary, R-E training is a brief behavioral treatment that targets smoking-related memories and has the potential to enhance relapse prevention. Trial Registration clinicaltrials.gov Identifier:NCT02154685

Dysregulated processing of natural rewards may be a central pathogenic process in the etiology and maintenance of prescription opioid misuse and addiction among chronic pain patients. This study examined whether a Mindfulness-Oriented Recovery Enhancement (MORE) intervention could enhance natural reward processing through training in savoring as indicated by event-related brain potentials (ERPs). Participants were chronic pain patients at risk for opioid misuse who were randomized to eight weeks of MORE (n=11) or a support group control condition (n=18). ERPs to images representing naturally rewarding stimuli (e.g., beautiful landscapes, intimate couples) and neutral images were measured before and after 8 weeks of treatment. Analyses focused on the late positive potential (LPP) - an ERP response in the 400 – 1000 ms time window thought to index allocation of attention to emotional information. Treatment with MORE was associated with significant increases in LPP response to natural reward stimuli relative to neutral stimuli which were correlated with enhanced positive affective cue-responses and reductions in opioid craving from pre- to post-treatment. Findings suggest that cognitive training regimens centered on strengthening attention to natural rewards may remediate reward processing deficits underpinning addictive behavior.

Prescription opioid misuse is an emerging public health concern with significant health and psychological risks. Though opioid analgesic therapy for chronic pain is often efficacious, and most patients take medicine as prescribed, some individuals exhibit addictive tendencies toward opioids (Fishbain, Cole, Lewis, Rosomoff, & Rosomoff, 2007). Opioid addiction among chronic pain patients involves cognitive, affective, and behavioral dysregulation that, when coupled with persistent or worsening pain, may result in significant functional impairment and suffering (Hojsted, Nielsen, Guldstrand, Frich, & Sjogren, 2010). Opioid addiction may be presaged by the occurrence of opioid misuse behaviors, such as dose escalation or use of prescribed opioids to self-medicate negative emotions and stress (Butler et al., 2007); these medication-misusing behaviors are common, with more than one-in-ten chronic pain patients exhibiting signs of opioid misuse (Fishbain et al., 2007). Although opioid agents with lower addiction liability like buprenorphine can effectively substitute for unauthorized opioid use (Ling et al., 2002), extant treatments for opioid addiction are typically ineffective in the absence of ongoing maintenance pharmacotherapy (Weiss et al., 2011). Further, persons seeking treatment for chronic pain respond especially poorly to motivational and behavioral addiction treatments (Larson et al., 2007). Current best practices for persons with chronic pain who are at risk for prescription opioid misuse and addiction (e.g., Jamison, Serraillier, & Michner, 2011; Oliver et al., 2012) include frequent opioid adherence monitoring, opioid treatment agreements and compliance training, and cognitive-behavioral substance misuse counseling (Jamison et al., 2010). Yet, new interventions are needed to effectively address the maladaptive cognitive-affective processes and appetitive responses elicited by pain, stress, and drug-related cues that undergird the risk chain from chronic pain to opioid misuse and addiction. This risk chain initiates from prolonged use of opioids, which produces physical dependence via neuroadaptations resulting in tolerance, withdrawal, and, in some cases, opioid-induced hyperalgesia (Chu, Angst, & Clark, 2008). Heightened pain sensitivity, when coupled with tolerance to the analgesic effects of opioids, can result in increased opioid craving (Ren, Shi, Epstein, Wang, & Lu, 2009) and consumption (Martell et al., 2007), and can elicit negative emotions that feed back to magnify pain perception. This process may result in appraisal of pain sensations as threatening and perseveration on the affective components of pain (Garland, 2012). Consequently, opioids are often misused to self-medicate (Khantzian, 1997; Kirsh, Jass, Bennett, Hagen, & Passik, 2007) the negative affective states and autonomic arousal that cause, co-occur with, or result from pain (Janig, 1995; Martenson, Cetas, & Heinricher, 2009). As with pain, stress and negative affect can become internal cues associated with past opioid use episodes that elicit the habit of opioid use, particularly among opioid misusers who take opioids to cope with emotional distress. Concomitantly, the habitual drive to engage in prescription opioid misuse (including unauthorized dose escalation) involves implicit neurocognitive operations that promote craving and aberrant drug taking (Goldstein et al., 2009; Stacy & Wiers, 2010) by biasing attention towards opioid-related cues (e.g., the sight of a pill bottle) (Garland, Froeliger, Passik, & Howard, 2012). Theory suggests that addiction occurs when the appetitive motivation to obtain natural rewards is re-organized around seeking drug-induced reward and the desire to alleviate dysphoria stemming from withdrawal and aversive experiences (e.g., pain and stress) (Alcaro & Panksepp, 2011; Koob & Le Moal, 2008). In that regard, decreased responsiveness to natural reinforcers has been observed among opiate dependent individuals and is robustly predictive of future opiate consumption (Lubman et al., 2009; Lubman, Allen, Peters, & Deakin, 2007, 2008). Hence, the problem of co-occurring chronic pain and prescription opioid misuse may involve a cycle of behavioral escalation where nociception and stress amplify pain and provoke recurrent self-medication with opioids, which in turn biases attention towards opioid-related cues that come to elicit the habit of opioid use despite ever diminishing analgesia and increasing dysphoria (Garland, Froeliger, Zeidan, Partin, & Howard, 2013). Despite such risks, opioids remain medically necessary for many individuals experiencing prolonged and intractable pain. Thus, therapeutic interventions are needed to target comorbid pain and opioid misuse. Though cognitive-behavioral therapy (CBT) has been shown to produce therapeutic reductions in pain (Williams, Eccleston, & Morley, 2012) and opioid misuse (Jamison et al., 2010) in isolation, there is scant research on psychological treatments that simultaneously address symptoms of co-occurring chronic pain and opioid misuse. To that end, we conducted an early-stage randomized controlled trial of Mindfulness-Oriented Recovery Enhancement (MORE) (Garland, 2013), a novel multimodal intervention that integrates mindfulness training, cognitive reappraisal skills, and positive emotion regulation into a therapeutic approach designed to modify attentional biases, habit behavior, affective dysregulation, and autonomic stress responses underlying the feedback loop between chronic pain, craving, and opioid misuse behaviors. Each of these three intervention components has been shown to be beneficial in isolation. Mindfulness training leads to reductions in pain (Gaylord et al., 2011; Kabat-Zinn et al., 1992; Rosenzweig et al., 2010; Zeidan et al., 2011) that are mediated by increased nonreactivity to aversive mental experiences and reinterpretation of affectively-laden pain sensations as innocuous sensory signals (Garland, Gaylord, Palsson, Faurot, Mann, & Whitehead, 2012). Moreover, mindfulness training produces salutary effects on emotional distress (Grossman, Niemann, Schmidt, & Walach, 2004; Hofmann, Sawyer, Witt, & Oh, 2010) and addiction-related factors (Bowen et al., 2009; Garland, Froeliger, & Howard, 2013), including attentional bias and autonomic cue-reactivity (Garland, Gaylord, Boettiger, & Howard, 2010). Similarly, cognitive reappraisal has been shown to significantly decrease negative emotions and downregulate stress physiology (Ochsner & Gross, 2005), as well as reduce substance craving (Kober et al., 2011). In complementary fashion, positive emotion regulatory strategies (e.g., savoring pleasant events) may upregulate positive affect, reduce anhedonia, and promote psychological resilience (Garland, Fredrickson, Kring, Johnson, Meyer, & Penn, 2010). MORE, which was originally tested as a treatment for alcohol dependence (Garland, Gaylord et al., 2010), capitalizes on the synergy of these three treatment components by integrating them into a multimodal intervention. The aim of this study was to evaluate the feasibility of developing a clinical trial comparing acute (pre-post) and longer-term (3-month follow-up) efficacy of MORE with that of a conventional support group (SG) in reducing chronic pain and prescription opioid misuse. The study employed an active control condition which attempted to control for non-specific therapeutic factors such as social interaction and support. We hypothesized that participation in MORE would be associated with significantly greater reductions in pain severity, pain interference, stress symptoms, and desire for opioids than would participation in a SG. We also hypothesized that compared to SG participants, a significantly greater proportion of individuals completing MORE who met clinical criteria for prescription opioid use disorder before treatment would no longer meet opioid use disorder criteria following treatment. Insofar as clinicians in the field must often make dichotomous diagnostic judgments in practice and may need to ascertain the extent to which a disorder can be rendered subclinical following treatment (cf., Eftekhari et al., 2013), we were interested in whether MORE could reduce symptoms below the clinical threshold for opioid use disorder. Lastly, although MORE was designed to target a wide array of cognitive, affective, and autonomic mechanisms as detailed above, in the present study we tested the effects of the intervention on a focused set of mediators selected for their direct relevance to primary study outcomes. Because emotional reactivity and maladaptive appraisals of pain and stress undergird the risk chain linking chronic pain and opioid misuse, we hypothesized that the therapeutic effects of MORE on pain severity and opioid use disorder status would be associated with increased nonreactivity, cognitive reappraisal, and reinterpretation of pain sensations as innocuous sensory information.

Smoking cessation results in withdrawal symptoms such as craving and negative mood that may contribute to lapse and relapse. Little is known regarding whether these symptoms are associated with the nicotine or non-nicotine components of cigarette smoke. Using arterial spin labeling, we measured resting-state cerebral blood flow (CBF) in 29 adult smokers across four conditions: (1) nicotine patch+denicotinized cigarette smoking, (2) nicotine patch+abstinence from smoking, (3) placebo patch+denicotinized cigarette smoking, and (4) placebo patch+abstinence from smoking. We found that changes in self-reported craving positively correlated with changes in CBF from the denicotinized cigarette smoking conditions to the abstinent conditions. These correlations were found in several regions throughout the brain. Self-reported craving also increased from the nicotine to the placebo conditions, but had a minimal relationship with changes in CBF. The results of this study suggest that the non-nicotine components of cigarette smoke significantly impact withdrawal symptoms and associated brain areas, independently of the effects of nicotine. As such, the effects of non-nicotine factors are important to consider in the design and development of smoking cessation interventions and tobacco regulation.

Cocaine abuse is associated with a high prevalence of nicotine dependence. In animals, nicotinic antagonists have been reported to block the development of cocaine behavioral sensitization and to attenuate cocaine place preference or self-administration. In the present study, we have determined: (1) changes in the locomotor responses to nicotine challenge during the first week of withdrawal from daily cocaine pretreatment; and (2) effects of the non-selective nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine given during the first 5 days of cocaine withdrawal on the maintenance of cocaine behavioral sensitization. Male Sprague-Dawley rats were pretreated with daily saline (SI) or cocaine (CI) injections for 14 days. In Experiment 1, separate animals in the SI and CI groups received a single nicotine challenge on day 1, 3, or 7 of withdrawal from their respective pretreatments. The CI group displayed enhanced locomotor responses to nicotine as compared to SI controls on days 3 and 7 of withdrawal, but not day 1. In Experiment 2, SI and CI animals were treated once a day with either saline or mecamylamine during the first 5 days of withdrawal, and were subsequently challenged with single cocaine injections on both withdrawal days 7 and 14. Mecamylamine treatment significantly attenuated expression of cocaine behavioral sensitization on both withdrawal days 7 and 14. Time-dependent changes in nicotinic responses occur during the first week of cocaine withdrawal, and intact nAChR neurotransmission during this period may be necessary for maintenance of cocaine behavioral sensitization.