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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 (β  = 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. [ABSTRACT FROM AUTHOR]

Cannabis use disorder (CUD) presents differently in men and women, particularly in symptoms of cannabis withdrawal. Novel pharmacotherapeutic interventions for CUD, such as those that target the endocannabinoid (eCB) system, must be developed in a manner consistent with these sex differences. The present pilot study sought to prospectively assess sex differences in cannabis withdrawal in a small sample of adults with moderate‐to‐severe CUD and to determine if withdrawal was associated with peripheral eCB and eCB congener tone. Men and women (n = 5/sex) completed 2 weeks of study participation separated by 1 month; in the latter week, participants abstained from cannabis use. Each week, participants attended in‐person laboratory visits during which blood was drawn repeatedly to assess plasma eCB and eCB congener tone. Participants also completed multiple daily ambulatory assessments to assess cannabis use and withdrawal symptoms. As anticipated, women reported a greater increase in withdrawal symptoms during the abstinent week [Δ = 9.4 (SE = 1.1); p < 0.001] than men [Δ = 1.2 (SE = 1.2); p = 0.35]. Sex differences in levels of the eCB N‐arachidonoylethanolamide (AEA), as well as the eCB congeners stearoylethanolamide (SEA) and linoleylethanolamide (LEA), were evident during abstinence at the morning time point only (p's < 0.05). LEA was associated with withdrawal symptom expression in both sexes [β = 0.16 (SE = 0.09)] and palmitoylethanolamide (PEA) [β = 0.22 (SE = 0.13)] and 2‐arachidonoylglycerol (2‐AG) [β = 0.32 (SE = 0.15)] were associated with withdrawal symptoms in women only. Pharmacotherapeutic development for CUD should consider evident sex differences in eCB and eCB congener tone during abstinence and their associations with cannabis withdrawal, as eCB‐based interventions may produce differential effects by sex. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Rationale: The hypothalamic–pituitary–adrenal (HPA) axis is a critical hormonal system involved in stress response. A number of studies have investigated the HPA axis response of drug-dependent individuals to stressors. Stress-induced vulnerabilities in the HPA axis may differ in response to chronic use of different substances, possibly leading to different target therapies. There has not been a direct comparison of HPA axis and subjective response between individuals with different types of substance use disorders following a laboratory stress intervention. Objectives: The primary goal of the current study was to compare subjective and neuroendocrine response to the Trier Social Stress Task (TSST) across multiple primary types of substance use disorders and investigate differential response between males and females. Methods: Four hundred participants were drawn from seven studies completed at the Medical University of South Carolina between 2011 and 2021. The TSST was utilized across studies and subjective and neuroendocrine responses measured following completion. Generalized linear mixed effects models and area under the response curve analysis were used to compare both substance type and sex differences. Results: The study groups involving individuals with cocaine use disorder had blunted stress, craving and cortisol response following the TSST as compared to other substance use groups. Females in the cocaine groups reported higher subjective stress but lower cortisol than males. Conclusions: The study results indicate that there may be differential effects of substances on the HPA axis, with cocaine using individuals exhibiting more blunting of the HPA axis response as compared to users of other substances. [ABSTRACT FROM AUTHOR]

Apolipoprotein M (apoM), primarily carried by HDL, has been associated with several conditions, including cardiovascular disease and diabetic nephropathy. This study proposes to examine whether plasma apoM levels are associated with the development of diabetic kidney disease, assessed as progression to macroalbuminuria (MA) and chronic kidney disease (CKD). Plasma apoM was measured using an enzyme immunoassay in 386 subjects from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) cohort at DCCT entry and closeout and the concentrations used to determine the association with risk of progression to kidney dysfunction from the time of measurement through 18 years of EDIC follow-up. apoM levels, at DCCT baseline, were higher in patients who developed CKD than in those who retained normal renal function. At DCCT closeout, participants who progressed to MA, CKD, or both MA and CKD also had significantly higher apoM levels than those who remained normal, and increased levels of apoM were associated with increased risk of progression to both MA (risk ratio [RR] 1.30 [95% CI 1.01, 1.66]) and CKD (RR 1.69 [95% CI 1.18, 2.44]). Our results strongly suggest that alterations in apoM and therefore in the composition and function of HDL in type 1 diabetes are present early in the disease process and are associated with the development of nephropathy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: The co-use of cannabis and alcohol among tobacco-using youth is common. Alcohol co-use is associated with worse tobacco cessation outcomes, but results are mixed regarding the impact of cannabis on tobacco outcomes and if co-use leads to increased use of non-treated substances. This secondary analysis from a youth smoking cessation trial aimed to (1) evaluate the impact of cannabis or alcohol co-use on smoking cessation, (2) examine changes in co-use during the trial, and (3) explore secondary effects of varenicline on co-use.Methods: The parent study was a 12-week, randomized clinical trial of varenicline for smoking cessation among youth (ages 14-21, N = 157; Mage = 19, 40% female; 76% White). Daily cigarette, cannabis, and alcohol use data were collected via daily diaries during treatment and Timeline Follow-back for 14 weeks post-treatment.Results: Baseline cannabis co-users (68%) had double the odds of continued cigarette smoking throughout the trial compared with noncannabis users, which was pronounced in males and frequent cannabis users. Continued smoking during treatment was associated with higher probability of concurrent cannabis use. Baseline alcohol co-users (80%) did not have worse smoking outcomes compared with nonalcohol users, but continued smoking was associated with higher probability of concurrent drinking. Varenicline did not affect co-use.Conclusions: Inconsistent with prior literature, results showed that alcohol co-users did not differ in smoking cessation, whereas cannabis co-users had poorer cessation outcomes. Youth tobacco treatment would benefit from added focus on substance co-use, particularly cannabis, but may need to be tailored appropriately to promote cessation.Implications: Among youth cigarette smokers enrolled in a pharmacotherapy evaluation clinical trial, alcohol and/or cannabis co-use was prevalent. The co-use of cannabis affected smoking cessation outcomes, but more so for males and frequent cannabis users, whereas alcohol co-use did not affect smoking cessation. Reductions in smoking were accompanied by concurrent reductions in alcohol or cannabis use. Substance co-use does not appear to affect all youth smokers in the same manner and treatment strategies may need to be tailored appropriately for those with lower odds of smoking cessation. [ABSTRACT FROM AUTHOR]

Rationale: Cocaine use disorder (CUD) is associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which plays a critical role in the human stress response. Men and women with CUD differ in reactivity to social stressors. The hypothalamic neuropeptide oxytocin is involved in anxiolytic and natural reward processes, and has shown therapeutic potential for addictive disorders and stress reduction. Objectives: To examine the impact of oxytocin (oxytocin (OXY) vs. placebo (PBO)) and gender (female (F) vs. male (M)) on response to a social stress task in individuals with CUD. To explore whether ovarian hormones moderate this stress response. Methods: One hundred twelve adults with CUD were randomized to receive 40 IU intranasal oxytocin (n = 56) or matching placebo (n = 56). Forty minutes after drug administration, participants were exposed to a social stressor. Generalized linear mixed models were used to examine neuroendocrine (cortisol) and subjective (craving, stress) response at pre-stressor, stressor + 0, + 10, + 30, + 60 min. Results: Gender moderated the effect of oxytocin on neuroendocrine response (p = 0.048); women receiving oxytocin (F + OXY) showed blunted cortisol response compared to the other three groups (F + PBO; M + OXY; M + PBO). There was a main effect of gender on subjective stress response; women reported greater stress following the stressor compared to men (p = 0.016). Oxytocin had no significant effect on craving or stress, and gender did not moderate the effect of oxytocin on either measure. Higher endogenous progesterone was associated with lower craving response in women (p = 0.033). Conclusions: Oxytocin may have differential effects in men and women with CUD. Women may be at greater risk for relapse in response to social stressors, but ovarian hormones may attenuate this effect. [ABSTRACT FROM AUTHOR]

Rationale: Female cigarette smokers tend to show greater cessation failure compared with males. Variables that contribute to the maintenance of smoking, including stress and craving, may differentially impact male and female smokers. Novel pharmacotherapies, such as oxytocin, may attenuate stress reactivity and craving in smokers, but work in this area is limited. Objectives: This study assessed the influence of gender and oxytocin on stress reactivity, craving, and smoking in a randomized, placebo-controlled laboratory relapse paradigm. Methods: Male and female adult cigarette smokers (ages 18–45) were enrolled (women oversampled 2:1) and completed a laboratory session, in which intranasal oxytocin or placebo was administered followed by a laboratory social stress task. The role of gender and oxytocin were assessed on measures of stress reactivity, cigarette craving, latency to smoke in a resistance task, subjective responses to smoking, and ad-libitum smoking. Results: Participants (N = 144) had a mean age of 31 were 63% female and 56% White. Following stress induction, female smokers evidenced greater subjective stress than males, though males demonstrated greater neuroendocrine reactivity and smoking intensity than females. No gender differences were demonstrated for craving. Oxytocin did not attenuate any aspect of stress reactivity, craving, smoking, or subjective responses to smoking compared with placebo. Conclusions: Gender differences in stress reactivity were shown in the hypothesized direction, but oxytocin appeared to exert little impact on subjective or behavioral metrics. Results highlight the complex relationship between gender, stress, and smoking, as well as the implications for oxytocin as a potential pharmacotherapy for smoking cessation. [ABSTRACT FROM AUTHOR]

Rationale: Depression is common among individuals with cannabis use disorder (CUD), particularly individuals who present to CUD treatment. Treatments that consider this comorbidity are essential. Objectives: The goal of this secondary analysis was to examine whether N-acetylcysteine (NAC) reduced depressive symptoms among adults (age 18–50) with CUD (N = 302) and whether the effect of NAC on cannabis cessation varied as a result of baseline levels of depression. Bidirectional associations between cannabis use amount and depression were also examined. Methods: Data for this secondary analysis were from a National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) multi-site clinical trial for CUD. Adults with CUD (N = 302) were randomized to receive 2400 mg of NAC daily or matched placebo for 12 weeks. All participants received abstinence-based contingency management. Cannabis quantity was measured by self-report, and weekly urinary cannabinoid levels (11-nor-9-carboxy-Δ9-tetrahydrocannabinol) confirmed abstinence. Depressive symptoms were measured by the Hospital Anxiety and Depression Scale. Results: Depressive symptoms did not differ between the NAC and placebo groups during treatment. There was no significant interaction between treatment and baseline depression predicting cannabis abstinence during treatment. Higher baseline depression was associated with decreased abstinence throughout treatment and a significant gender interaction suggested that this may be particularly true for females. Cross-lagged panel models suggested that depressive symptoms preceded increased cannabis use amounts (in grams) during the subsequent month. The reverse pathway was not significant (i.e., greater cannabis use preceding depressive symptoms). Conclusions: Results from this study suggest that depression may be a risk factor for poor CUD treatment outcome and therefore should be addressed in the context of treatment. However, results do not support the use of NAC to concurrently treat co-occurring depressive symptoms and CUD in adults. Trial Registration: Clinicaltrials.gov: NCT01675661 [ABSTRACT FROM AUTHOR]

Complementary integrative medicine, such as mindfulness-based interventions, (MBI) have demonstrated efficacy in the treatment of depression, anxiety, substance use disorders (SUDs), and pain. Mindfulness-based relapse prevention (MBRP) is an aftercare intervention targeting SUD relapse that integrates cognitive-behavioral relapse prevention and mindfulness meditation practices, raising awareness of substance use triggers and reactive behavioral patterns. This study evaluated the efficacy of MBRP in reducing relapse in veterans following completion of an SUD treatment program. This study was a two-site, randomized controlled trial comparing MBRP to 12-step facilitation (TSF) aftercare in military veterans following completion of intensive treatment for SUDs. The 8 weeks of 90-minute, group-based MBRP or TSF sessions were followed by 3-, 6- and 10-month follow-up periods with assessments of alcohol/substance use and secondary outcomes of depression, anxiety, and mindfulness. Forty-seven percent of veterans attended ≥75 % of sessions. Veterans in both the MBRP and TSF aftercare groups maintained reductions in alcohol and illicit substance use during the aftercare treatment. Nineteen participants (11 %; 19/174) reported returning to alcohol use during the study treatment period and the study found no difference between study groups [MBRP: 9 % vs. TSF 13 %; p = 0.42]. Thirteen participants (7.5 %; 13/174) reported a return to illicit substance use during study treatment [MBRP: 5.4 % vs. TSF 10.3 % p = 0.34]. The number of days of drinking and illicit substance use was not different between groups (alcohol, p = 0.53; illicit substance use, p = 0.28). Although retention in treatment limits interpretation of the findings, both MBRP and TSF were effective in maintenance of treatment gains following an intensive treatment program for veterans with SUDs. Future studies should focus on strategies to improve treatment participation. • Veterans receiving aftercare MBRP or TSF were less likely to use alcohol or illicit substances as before intensive treatment. • Veterans receiving aftercare MBRP or TSF had fewer days of alcohol and illicit substance use. • Veterans receiving aftercare MBRP or TSF maintained reductions in drinking and substance use at 10-month follow-up. [ABSTRACT FROM AUTHOR]

Background: It is common for cannabis users to also use tobacco. While data suggest that tobacco users have more difficulty achieving cannabis cessation, secondary analyses of clinical trial data sets may provide insight into the moderating variables contributing to this relationship, as well as changes in tobacco use during cannabis treatment. Those were the aims of this secondary analysis.Methods: The parent study was a multi-site trial of N-acetylcysteine for cannabis dependence conducted within the National Drug Abuse Treatment Clinical Trials Network. Participants were treatment-seeking adults (ages 18-50) who met criteria for cannabis dependence (N = 302). For cigarette smokers (n = 117), tobacco use was assessed via timeline follow-back and nicotine dependence was assessed via the Fagerström Test for Nicotine Dependence (FTND). Outcome measures included: 1) changes in tobacco use based on treatment assignment, nicotine dependence, and concurrent cannabis reduction/abstinence, and 2) independent associations between nicotine dependence and cannabis abstinence.Results: Cigarette smokers accounted for 39% of the sample (117/302), with a median FTND score of 3.0 (10-point scale). Among those with lower baseline nicotine dependence scores, cigarette smoking was reduced in the active treatment group compared to placebo. Those with moderate/high levels of nicotine dependence showed slight increases in smoking following active treatment. Nicotine dependence did not affect cannabis cessation.Conclusions: Cigarette smoking during cannabis treatment was affected, but depended on baseline nicotine dependence severity, though dependence levels did not impact cannabis abstinence. Interventions that address both tobacco and cannabis are needed, especially due to an increasing prevalence of cannabis use. [ABSTRACT FROM AUTHOR]

Introduction: The Intolerance for Smoking Abstinence Discomfort Questionnaire (IDQ-S) assesses distress tolerance specific to nicotine withdrawal. Though developed to assess withdrawal-related distress, the IDQ-S has not been validated among nicotine-deprived, treatment-seeking smokers. The present study extended previous research by examining the predictive utility of the IDQ-S among abstinent, motivated-to-quit smokers.Methods: Abstinent, treatment-seeking smokers completed the IDQ-S Withdrawal Intolerance and Lack of Cognitive Coping scales, assessments of nicotine dependence and reinforcement, and smoking history at baseline. At baseline and at 24-h, 2-week, and 1-month follow-up, participants completed a smoking cue-reactivity task (collection of cue-elicited craving and negative affect), and assessments of cigarettes per day (CPD; daily diaries at follow-up), carbon monoxide (CO), and cotinine.Results: Greater IDQ-S Withdrawal Intolerance was associated with younger age, higher nicotine dependence and reinforcement, and less smoking years (ps < .03). Greater IDQ-S Lack of Cognitive Coping was associated with less education, lower nicotine dependence and reinforcement, higher baseline CPD, and no prior quit attempts (ps < .04). IDQ-S scales did not significantly predict cue-elicited craving or negative affect, CPD, CO, or cotinine levels at follow-up (ps > .10).Conclusions: Withdrawal intolerance and lack of cognitive coping did not predict smoking outcomes among nicotine-deprived, treatment-seeking smokers, but were associated with smoking characteristics, including nicotine dependence and reinforcement. Withdrawal intolerance and lack of cognitive coping may not be especially useful in predicting craving and smoking behavior, but future studies should replicate the present study's findings and assess the stability of the IDQ-S before forming firm conclusions about its predictive utility. [ABSTRACT FROM AUTHOR]

Introduction This study sought to compare medication efficacy in participants with medical comorbidities who smoke in the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) trial, a double-blind, triple-dummy, placebo- and active-controlled randomized controlled trial. Aims and Methods Participants were from the U.S. cohort of the main trial and randomized (1:1:1:1) to varenicline, bupropion, nicotine replacement therapy (NRT) patch, or placebo for 12 weeks with follow-up through week 24. Medical comorbidity data were derived from the baseline medical screening questionnaire and categorized into four subgroups (cardiac, respiratory, vascular, and diabetes). Within each comorbidity, generalized linear mixed models were used to assess the association between treatment and continuous abstinence rates from weeks 9–12 to 9–24. Similar models were used to test the effect of number of comorbidities on abstinence. Results Varenicline resulted in the highest week 12 abstinence rates across all pharmacotherapies and compared to placebo in all comorbidity subgroups: Cardiac (40.0% vs. 3.6%; odds ratios [OR] = 23.3 [5.1–107.1]), respiratory (24.7% vs. 12.8%; OR = 2.2 [1.3–3.8]), vascular (29.1% vs. 10.4%; OR = 3.6 [2.3–5.7]), and diabetes (30.9% vs. 8.3%; OR = 6.5 [2.3–19.0]). This was maintained at week 24 for those with cardiac (23.3% vs. 1.8%; OR = 21.7 [2.7–178.2]), vascular (18.9% vs. 7.1%; OR = 3.1 [1.8–5.3]), and diabetes (20.6% vs. 4.2%; OR = 8.4 [2.1–33.7]) comorbidities. Treatment contrasts within some comorbidity subgroups revealed superior efficacy of varenicline over other pharmacotherapies. All pharmacotherapies increased the odds of abstinence regardless of number of comorbidities. Conclusions Varenicline is the most efficacious option for patients with manageable cardiac, respiratory, vascular, and diabetes conditions to quit smoking, supporting recent clinical practice guidelines that recommend varenicline as first-line pharmacotherapy. Bupropion and NRT demonstrated efficacy for some comorbidity subgroups. Implications This secondary analysis of the EAGLES trial demonstrated that varenicline is the most efficacious option for patients with cardiac, respiratory, vascular, and diabetes diagnoses to quit smoking. This demonstration of varenicline efficacy among individuals with comorbid medical conditions supports recent clinical practice guidelines that recommend varenicline as a first-line pharmacotherapy for smoking cessation. [ABSTRACT FROM AUTHOR]

Background: The agreement between self-reported cannabis abstinence with urine cannabinoid concentrations in a clinical trials setting is not well characterized. We assessed the agreement between various cannabinoid cutoffs and self-reported abstinence across three clinical trials, one including contingency management for abstinence.Methods: Three cannabis cessation clinical trials where participants reported use and provided weekly urine samples for cannabis and creatinine concentration measurements were included. Bootstrapped data were assessed for agreement between self-reported 7+ day abstinence and urine cannabinoid tests using generalized linear mixed effects models for clustered binary outcomes. One study implemented contingency management for cannabis abstinence. Four hundred and seventy-three participants with 3787 valid urine specimens were included. Urine was analyzed for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol and creatinine using immunoassay methods Biological cutoffs of 50, 100, and 200 ng/ml, as well as changes in CN normalized THCCOOH (25%/50% decrease), were assessed for agreement with self-reported abstinence during the three clinical trials.Results: Agreement between measured THCCOOH and self-reported abstinence increases with increasing cutoff concentrations, while the agreement with self-reported non-abstinence decreases with increasing cutoff concentrations. Combining THCCOOH cutoffs with recent changes in CN-THCCOOH provides a better agreement in those self-reporting abstinence. Participants in the studies that received CM for abstinence had a lower agreement between self-reported abstinence and returned to use than those in studies that did not have a contingency management component.Conclusion: Using combinations of biological measurements and self-reported abstinence, confirmation of study related abstinence may be verifiable earlier and with greater accuracy than relying on a single measurement. [ABSTRACT FROM AUTHOR]

Background: More effective treatments for cannabis use disorder (CUD) are needed. Evidence suggests that biases in cognitive processing of drug-related stimuli are central to the development and maintenance of addiction. The current study examined the feasibility and effect of a novel intervention - approach bias modification (ApBM) - on cannabis approach bias and cue-reactivity.Methods: A randomized, double-blind, sham-controlled proof-of-principle laboratory experiment investigated the effect of a four-session computerized ApBM training protocol on cannabis approach bias and cue-reactivity in non-treatment seeking adults age 18-65 with CUD (N = 33). ApBM procedures involved responding to cannabis or neutral stimuli using a computer joystick to model approach or avoidance behavior. Reactivity to tactile, olfactory, and auditory cue sets was assessed with physiological (blood pressure and heart rate) and subjective (cannabis craving) measures. Cannabis use was assessed via self-report.Results: Participants receiving ApBM showed blunted cannabis cue-induced craving at the end of training compared to those in the sham-ApBM condition (p = .05). A preliminary gender effect on cannabis use was also found; men receiving ApBM reported fewer cannabis use sessions per day at the end of training compared to women (p = .02), while there were no differences between men and women in the sham condition. ApBM did not attenuate cannabis approach bias following training.Conclusion: Preliminary results indicate that ApBM may be efficacious in reducing cannabis cue-reactivity and improving cannabis use outcomes. While encouraging, the results should be interpreted with caution. Investigation of ApBM as an adjunct to psychosocial treatments for treatment-seeking adults with CUD is warranted. [ABSTRACT FROM AUTHOR]

Background: Cannabis use disorder (CUD) is a common condition with few treatments. Several studies in other substance use disorders have found that applying repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) decreases cue-elicited craving and possibly decreases use. To date, there have been no studies attempting to use rTMS in CUD.Objectives: This study was conducted to determine if rTMS could be feasibly delivered to a group of non-treatment seeking CUD participants. Secondarily, the study aimed to estimate the effect of rTMS on craving.Methods: In a double-blind, sham-controlled, crossover design, a single session of active or sham rTMS (Left DLPFC, 10 Hz, 110% rMT, 4000 pulses) was delivered during a validated cannabis cue paradigm. Participants crossed over to complete the other condition one week later. The feasibility and tolerability were measured by the rate of retention, and the percentage of participants able to tolerate full dose rTMS, respectively. Craving was measured using the Marijuana Craving Questionnaire (MCQ).Results: Eighteen non-treatment seeking CUD participants were recruited from the community; 16 (three women) completed the trial (89% retained for the three study visits). All of the treatment completers tolerated rTMS at full dose without adverse effects. There was not a significant reduction in the total MCQ when participants received active rTMS as compared to sham rTMS.Conclusion: rTMS can be safely and feasibly delivered to CUD participants, and treatment is well tolerated. A single session of rTMS applied to the DLPFC may not reduce cue-elicited craving in heavy cannabis users. [ABSTRACT FROM AUTHOR]

Background: Quantifying cannabis use is complex due to a lack of a standardized packaging system that contains specified amounts of constituents. A laboratory procedure has been developed for estimating physical quantity of cannabis use by utilizing a surrogate substance to represent cannabis, and weighing the amount of the surrogate to determine typical use in grams.Method: This secondary analysis utilized data from a multi-site, randomized, controlled pharmacological trial for adult cannabis use disorder (N=300), sponsored by the National Drug Abuse Treatment Clinical Trials Network, to test the incremental validity of this procedure. In conjunction with the Timeline Followback, this physical scale-based procedure was used to determine whether average grams per cannabis administration predicted urine cannabinoid levels (11-nor-9-carboxy-Δ9-tetrahydrocannabinol) and problems due to use, after accounting for self-reported number of days used (in the past 30 days) and number of administrations per day in a 12-week clinical trial for cannabis use disorder.Results: Likelihood ratio tests suggest that model fit was significantly improved when grams per administration and relevant interactions were included in the model predicting urine cannabinoid level (X2=98.3; p<0.05) and in the model predicting problems due to cannabis use (X2=6.4; p<0.05), relative to a model that contained only simpler measures of quantity and frequency.Conclusions: This study provides support for the use of a scale-based method for quantifying cannabis use in grams. This methodology may be useful when precise quantification is necessary (e.g., measuring reduction in use in a clinical trial). [ABSTRACT FROM AUTHOR]

Objective: To determine whether biomarkers of inflammation and endothelial dysfunction are associated with the development of kidney dysfunction and the time frame of their association.Research Design and Methods: Biomarkers were measured at four time points during 28 years of treatment and follow-up in patients with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. In addition to traditional biomarkers of inflammation (C-reactive protein and fibrinogen), we measured interleukin-6 (IL-6) and soluble tumor necrosis factor receptors 1 and 2 (sTNFR-1/2), markers of endothelial dysfunction (soluble intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin [sE-selectin]), and fibrinolysis (total and active plasminogen activator inhibitor-1 [PAI-1]). Renal outcomes were defined as progression to incident chronic kidney disease (stage 3 or more severe) or macroalbuminuria (albumin excretion rate ≥300 mg/24 h). Prospective multivariate event-time analyses were used to determine the association of each biomarker with each subsequent event within prespecified intervals (3-year and 10-year windows).Results: Multivariate event-time models indicated that several markers of inflammation (sTNFR-1/2), endothelial dysfunction (sE-selectin), and clotting/fibrinolysis (fibrinogen and PAI-1) are significantly associated with subsequent development of kidney dysfunction. Although some markers showed variations in the associations between the follow-up windows examined, the results indicate that biomarkers (sTNFR-1/2, sE-selectin, PAI-1, and fibrinogen) are associated with progression to chronic kidney disease in both the 3-year and the 10-year windows.Conclusions: Plasma markers of inflammation, endothelial dysfunction, and clotting/fibrinolysis are associated with progression to kidney dysfunction in type 1 diabetes during both short-term and long-term follow-up. [ABSTRACT FROM AUTHOR]

Most adult daily smokers try their first cigarette during adolescence. Attention-Deficit Hyperactivity Disorder (ADHD) in adolescents is associated with increased risk for cigarette smoking. The impact of ADHD symptoms on smoking cessation among adolescents has been less well-studied. The present secondary data analysis from a clinical trial of varenicline examined ADHD symptoms as a moderator of smoking cessation in adolescents and young adults. The double-blind, placebo-controlled trial included treatment-seeking daily cigarette smokers ages 14 – 21 (N = 157) randomized to receive a 12-week course of varenicline or placebo, added to weekly smoking cessation counseling. At pre-treatment assessment, participants were administered a self-report measure of ADHD symptoms, the ADHD – Rating Scale (ADHD-RS). High (≥5) versus low (<5) and continuous ADHD-RS symptom counts in both hyperactive/impulsive (HI) and inattention (IA) domains were examined as predictors of smoking outcomes. Participants with high IA symptoms at baseline were less likely to achieve 7-day point prevalence abstinence (PPA) at weekly visits (p =.001) during active treatment and end-of-treatment (p =.002) compared to those with low IA symptoms. In contrast, high HI symptoms did not predict differences in 7-day PPA or end-of-treatment abstinence versus low symptoms (p's ≥.07). These findings were not modified by varenicline versus placebo treatment assignment. ADHD IA symptoms were associated with poorer cessation outcomes among adolescent smokers. These findings warrant additional investigation into how ADHD symptoms may be accounted for in smoking cessation interventions for adolescents and young adults. • Few studies have examined the impact of ADHD symptoms count on smoking outcomes. • Greater inattentive symptoms predicted less abstinence and more cigarettes per day. • Hyperactive-impulsive symptoms did not consistently predict smoking outcomes. • Varenicline did not moderate the effect of ADHD symptoms on smoking cessation. [ABSTRACT FROM AUTHOR]

Aims: Current adolescent alcohol treatments have modest effects and high relapse rates. Evaluation of novel pharmacotherapy treatment is warranted. N-acetylcysteine (NAC), an over-the-counter antioxidant supplement with glutamatergic properties, is a promising treatment for marijuana cessation in adolescents; however, its effects on adolescent drinking have not been examined. To that end, this secondary analysis evaluated: (1) the effect of NAC vs. placebo on alcohol use over an eight-week adolescent marijuana cessation trial and (2) the role of marijuana cessation and reduction on subsequent alcohol use.Methods: Marijuana-dependent adolescents (ages 15-21; N=116) interested in treatment were randomized to NAC 1200mg or matched placebo twice daily for eightweeks. Participants were not required to be alcohol users or interested in alcohol cessation to qualify.Results: There were no demographic or baseline alcohol use differences between participants randomized to NAC vs. placebo (ps>0.05). Of the 89 participants returning for ≥one visit following randomization, 77 reported ≥one alcoholic drink in the 30days prior to study entry and averaged 1.3 (SD=1.4) binge drinking days per week. During treatment, less marijuana use (measured via urine cannabinoid levels) was associated with less alcohol use in the NAC-treated group but not in the placebo-treated group (p=0.016).Conclusions: There was no evidence of compensatory alcohol use during marijuana treatment. In fact, in the NAC group, lower levels of marijuana use were associated with less alcohol use, suggesting NAC effects may generalize to other substances and could be useful in decreasing adolescent alcohol use. NAC trials specifically focused on alcohol-using adolescents are warranted. [ABSTRACT FROM AUTHOR]

Introduction: Gender differences in cannabis use and cannabis use disorder have been established. Regarding treatment, some evidence suggests that women are less responsive, though the mechanisms are not well understood. Motivation to change and self-efficacy are associated with better outcomes overall, and may help explain gender differences in cannabis use outcomes.Methods: A secondary data analysis of a double-blind placebo controlled trial of buspirone treatment for cannabis dependence (N=175) was conducted. Self-report assessments of motivation to change, self-efficacy, and other clinical correlates were completed at baseline, and cannabis use was measured throughout the study.Results: There was a significant interaction between gender and taking steps on abstinence. Counter to hypothesis, higher taking steps reduced likelihood of achieving abstinence among women; there was no association among men. Subsequently, taking steps was associated with self-efficacy and quantity of use among men, and cannabis related problems among women. There was a significant interaction between gender and readiness to change on creatinine adjusted cannabinoid levels. Change readiness was positively associated with cannabinoid levels among women, but not men.Conclusions: Motivation to change and initiation of change behavior predict worse cannabis outcomes in women. Men and women differ in what motivates change behavior. Social desirability, neurobiology, and treatment type may impact these effects. Gender differences in cannabis use and treatment responsiveness must be considered in future studies. [ABSTRACT FROM AUTHOR]

Background and Objectives: The purpose of this study was to evaluate the efficacy of vilazodone, a selective serotonin receptor inhibitor and partial 5-HT1A agonist, for treatment of cannabis dependence.Methods: Seventy-six cannabis-dependent adults were randomized to receive either up to 40 mg/day of vilazodone (n = 41) or placebo (n = 35) for 8 weeks combined with a brief motivational enhancement therapy intervention and contingency management to encourage study retention. Cannabis use outcomes were assessed via weekly urine cannabinoid tests; secondary outcomes included cannabis use self-report and cannabis craving.Results: Participants in both groups reported reduced self-reported cannabis use over the course of the study; however, vilazodone provided no advantage over placebo in reducing cannabis use. Men had significantly lower creatinine-adjusted cannabinoid levels and a trend for increased negative urine cannabinoid tests than women.Discussion and Conclusions: Vilazodone was not more efficacious than placebo in reducing cannabis use. Important gender differences were noted, with women having worse cannabis use outcomes than men.Scientific Significance: Further medication development efforts for cannabis use disorders are needed, and gender should be considered as an important variable in future trials. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to evaluate the efficacy of buspirone, a partial 5-HT1A agonist, for treatment of cannabis dependence.Methods: One hundred seventy-five cannabis-dependent adults were randomized to receive either up to 60mg/day of buspirone (n=88) or placebo (n=87) for 12 weeks combined with a brief motivational enhancement therapy intervention and contingency management to encourage study retention. Cannabis use outcomes were assessed via weekly urine cannabinoid tests.Results: Participants in both groups reported reduced cannabis craving over the course of the study; however, buspirone provided no advantage over placebo in reducing cannabis use. Significant gender by treatment interactions were observed, with women randomized to buspirone having fewer negative urine cannabinoid tests than women randomized to placebo (p=0.007), and men randomized to buspirone having significantly lower creatinine adjusted cannabinoid levels as compared to those randomized to placebo (p=0.023). An evaluation of serotonin allelic variations did not find an association with buspirone treatment response.Conclusions: Buspirone was not more efficacious than placebo in reducing cannabis use. Important gender differences were noted, with women having worse cannabis use outcomes with buspirone treatment. Considerations for future medication trials in this challenging population are discussed. [ABSTRACT FROM AUTHOR]

The current study compared adherence rates as measured by two indirect measurement methods (pill count and daily medication diary) to two direct measurement methods (urine riboflavin and serum 6-OH-buspirone level measurement) among participants (n = 109) in a medication treatment trial for cannabis dependence. Pill count and diary data showed high levels of percent agreement and strong kappa coefficients throughout the study. Riboflavin levels indicated lower level of percent in adherence during the study as compared to both pill count and self-report. In the subset of participants with 6-OH-buspirone levels (n = 58), the kappa coefficient also showed low to moderate agreement between the pill count and medication diaries with 6-OH-buspirone levels. In contrast to pill count and medication diaries, adherence as measured by riboflavin and 6-OH-buspirone significantly decreased over time. The findings from this study support previous work demonstrating that pill count and patient self-report of medication taking likely overestimate rates of medication adherence, and may become less reliable as the duration of a clinical trial increases. [ABSTRACT FROM AUTHOR]

Background Drug dependence and adverse childhood experiences (ACE) are commonly reflected by dysregulation of the hypothalamic-pituitary-adrenal axis (HPA). Accumulating research indicates that the neuropeptide oxytocin may regulate HPA function, resulting in reductions in neuroendocrine reactivity to social stress among individuals with drug dependence. However, emerging literature suggests that individual differences may differentially impact intranasal oxytocin's effects on human social behaviors. Methods This study employed a double-blind, placebo-controlled design to examine the extent to which ACE influenced the effects of intranasal oxytocin (40 IU) on neuroendocrine reactivity to a laboratory social stress paradigm in a sample of 31 cocaine-dependent individuals. Results ACE scores modified the relationship between intranasal oxytocin and cortisol reactivity. While ACE modified the relationship between intranasal oxytocin and DHEA response in a similar direction to what was seen in cortisol, it did not reach statistical significance. Conclusions Findings are congruent with the emerging hypothesis that intranasal oxytocin may differentially attenuate social stress reactivity among individuals with specific vulnerabilities. Future research examining the nuances of intranasal oxytocin's therapeutic potential is necessary. [ABSTRACT FROM AUTHOR]

OBJECTIVE There is considerable interest in identifying biomarkers that predict high risk for the development of macrovascular complications in patients with diabetes. Therefore, the longitudinal association between subclinical atherosclerosis as measured by internal carotid artery intima-media thickness (IMT) and acute-phase reactants, cytokines/adipokines, thrombosis, and adhesion molecules was examined. RESEARCH DESIGN AND METHODS Biomarkers were measured at four time points over 20 years in 886 DCCT/EDIC participants with type 1 diabetes. Four composite scores were created by combining z scores generated from within the data set of individual biomarkers: acutephase reactants (fibrinogen, C-reactive protein), thrombosis (fibrinogen, active and total plasminogen activator inhibitor [PAI]-1), cytokines/adipokines (tumor necrosis factor receptor-1 and -2, active and total PAI-1, IL-6), and endothelial dysfunction (soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and soluble E-selectin). Internal carotid IMT was measured at EDIC years 1, 6, and 12, with elevated IMT defined at each time point as being in the upper quintile of its distribution. RESULTS Logistic regression models indicate that while individual biomarkers were not predictive of or associated with subclinical atherosclerosis, composite scores of acute-phase reactants (odds ratio [OR] 2.78 [95% CI 1.42, 5.42]), thrombolytic factors (OR 2.83 [95% CI 1.45, 5.52]), and cytokines/adipokines (OR 2.83 [95% CI 1.48, 5.41])measured at our final time point EDIC years 8-11 were associated with higher levels of atherosclerosis at EDIC year 12, but findings were not consistent at early time points. The endothelial dysfunction score was not appreciably predictive of or associated with subclinical atherosclerosis at any of the time points measured. CONCLUSIONS The pathophysiologic relationship between higher biomarker levels and progression of subclinical atherosclerosis remains unclear. [ABSTRACT FROM AUTHOR]

Background Adolescent marijuana use is associated with neurocognitive impairment, but further work is needed to assess the relationship between treatment-associated abstinence and cognitive performance. Methods This secondary analysis, conducted in the context of a marijuana cessation pharmacotherapy trial in adolescents, examined cognitive performance at baseline and at two time points during treatment using the CNS Vital Signs assessment battery. Results Abstinence from marijuana, relative to continued use, as assessed via urine cannabinoid testing, was associated with significant improvement in composite memory ( p < 0.001), verbal memory (the most impacted component of composite memory) ( p < 0.001), and psychomotor performance ( p = 0.045) scores. Conclusions These findings suggest that some domains of cognitive performance improve significantly even in the early stages of treatment-associated abstinence. [ABSTRACT FROM AUTHOR]

Background: Stress and drug-paired cues increase drug craving and noradrenergic activity in cocaine-dependent individuals. Thus, medications that attenuate noradrenergic activity may be effective therapeutic treatment options for cocaine-dependent individuals. Objectives: To examine the impact of acute administration of the α2 adrenergic receptor agonist guanfacine on responses to multiple risk factors for relapse in cocaine-dependent individuals. Methods: In a double-blind, placebo-controlled study, cocaine-dependent individuals ( n = 84), were randomized to receive either 2 mg guanfacine ( n = 50) or placebo ( n = 34). Within each treatment arm, subjects were randomized to either a stress (guanfacine n = 26; placebo n = 15) or a no-stress (guanfacine n = 24; placebo n = 19) group. Participants in the stress group performed the Trier Social Stress Test. Subjects in each group were exposed to a neutral cue and then to cocaine-related cues. Plasma cortisol and subjective responses were compared between the four groups. Results: The no-stress guanfacine group reported greater craving in response to cocaine cues as compared to the neutral cue ( p < 0.001). The guanfacine stress group reported greater subjective stress at the neutral cue than at baseline ( p = 0.032). The cocaine cue increased subjective stress in the guanfacine ( p < 0.001) no-stress group. There were no effects of guanfacine on cortisol levels in either the stress or no stress groups (all p > 0.70). Conclusion: This study found no effects of a single 2 mg dose of guanfacine on reactivity to stress and cues alone or on the interaction of stress and drug cues. In cocaine-dependent individuals an acute 2 mg dose of guanfacine may not be an effective therapeutic treatment strategy. [ABSTRACT FROM AUTHOR]

Background: Varenicline (VAR) has demonstrated superior efficacy over other smoking cessation pharmacotherapies, though 50-60% of those treated do maintain abstinence. Some preclinical findings suggest that new nicotine dependence pharmacotherapies should target the glutamatergic system, given its demonstrated role in addiction. Attention has been given to N-acetylcysteine (NAC), which appears to restore normal glutamate signaling in animal models. It is possible that NAC and VAR may work in concert to promote abstinence at higher rates than with either medication alone. Objective: To demonstrate the feasibility and safety of co-administering NAC and VAR in nicotine-dependent participants. Methods: Participants ( n = 19) were daily cigarette smokers, and did not need to be seeking treatment. They received 4 weeks of open-label treatment with NAC (1200 mg twice daily) and VAR (1 mg twice daily, following titration) and were assessed weekly for adverse events (AEs), smoking, craving and withdrawal. Results: Sixteen participants reported a total of 40 AEs, and most were mild (88%). The most commonly reported AE was nausea (15%). Medication adherence, assessed via self-reports and pill counts, was excellent (98%). Exploratory analyses showed reductions in cigarettes per day, though point prevalence abstinence at the end of the study was low. Conclusions: These preliminary data provide the first demonstration of safety and feasibility of the co-administration of NAC and VAR in cigarette smokers. AEs were consistent with those typically reported for VAR and NAC. These data support future efficacy research on NAC and VAR for smoking cessation. [ABSTRACT FROM AUTHOR]

Aims: This study was undertaken to determine whether levels of inflammation and endothelial dysfunction biomarkers in serum samples collected at baseline in the Diabetes Control and Complications Trial (DCCT) cohort could predict the development of retinopathy. Methods: Levels of clotting/fibrinolysis, inflammation and endothelial dysfunction biomarkers were measured in 1391 subjects with type 1 diabetes to determine whether their levels predicted increased risk to develop or accelerate progression of retinopathy during 16 years of follow-up. Results: Using regression models adjusted for DCCT treatment group, duration of diabetes, baseline retinopathy scores, HbA1c and albumin excretion rate, the baseline levels of sE-selectin and PAI-1 (active) were significantly associated with increased risk of a 3-step progression in retinopathy score in the primary prevention cohort (PPC). After adjusting for additional covariates (e.g., ACE/ARB and statin therapy), this association persisted. Levels of active and total PAI-1 in the same group were also significantly associated, after similar adjustments, with the time to progress to severe non-proliferative retinopathy during the followup period (54 and 29%, respectively of increased risk). No associations were observed in the secondary intervention cohort for any of the outcomes. Conclusions: High levels of sE-selectin and PAI-1 are associated with the development of retinopathy in patients with uncomplicated type 1 diabetes. [ABSTRACT FROM AUTHOR]

Motivational enhancement therapy (MET) is efficacious in reducing cannabis use, yet benefits are generally short-lived. Oxytocin is a hypothalamic neuropeptide that promotes prosocial behaviors and plays a role in drug-related neuroadaptations; as such, oxytocin may enhance the effect of MET on cannabis outcomes. Cannabis dependent adults were randomized to receive MET plus oxytocin ( n =8) or placebo ( n =8). Participants receiving oxytocin showed reductions in amount of cannabis used daily and number of sessions per day. Participants receiving placebo did not evidence significant reductions. Powered clinical trials of oxytocin-enhanced MET for cannabis use disorder are warranted. [ABSTRACT FROM AUTHOR]

Background and objectives: Tobacco and cannabis use are both highly prevalent worldwide. Their co-use is also common in adults and adolescents. Despite this frequent co-occurrence, cessation from both substances is rarely addressed in randomized clinical trials. Given evidence that tobacco use may increase during cannabis cessation attempts, and additionally that tobacco users have poorer cannabis cessation outcomes, we explored tobacco outcomes, specifically cigarette smoking, from an adolescent cannabis cessation trial that tested the efficacy of N-acetylesteine (NAC). Methods: Cannabis-dependent adolescents (ages 15-21; n = 116) interested in cannabis treatment were randomized to NAC (1200 mg bid) or matched placebo for 8 weeks. Participants did not need to be cigarette smokers or be interested in smoking cessation to qualify for inclusion. Results: Approximately 59% of enrolled participants were daily and non-daily cigarette smokers, and only differed from non-smoking participants on the compulsion sub-scale of the Marijuana Craving Questionnaire. Among cigarette smokers who were retained in the study, there was no change in cigarettes per day for either NAC or placebo groups during the eight-week treatment phase. Being a cigarette smoker did not appear to influence the effects of NAC on cannabis abstinence, though there was a trend in the placebo group of poorer cannabis outcomes for cigarette smokers vs. non-smokers. Conclusions: No evidence was found of compensatory cigarette smoking during this cannabis cessation trial in adolescents. Further work assessing interventions to reduce both cannabis and tobacco use in this population is greatly needed. [ABSTRACT FROM AUTHOR]

OBJECTIVE--The current study aimed to determine in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications cohort whether or not abnormal levels of markers of inflammation and endothelial dysfunction measured in samples collected at DCCT baseline were able to predict the development of macroalbuminuria. RESEARCH DESIGN AND METHODS--Levels of inflammation and endothelial cell dysfunction biomarkers were measured in 1,237 of 1,441 patients enrolled in the DCCT study who were both free of albuminuria and cardiovascular disease at baseline. To test the association of log-transformed biomarkers with albuminuria, generalized logistic regression models were used to quantify the association of increased levels of biomarkers and development of abnormal albuminuria. Normal, micro-, and macroalbuminuria were the outcomes of interest. RESULTS--In the logistic regression models adjusted by DCCT treatment assignment, baseline albumin excretion rate, and use of ACE/angiotensin receptor blocker drugs, one unit increase in the standardized levels of soluble E-selectin (sE-selectin) was associated with an 87% increase in the odds to develop macroalbuminuria and one unit increase in the levels of interleukin-6 (IL-6), plasminogen activator inhibitor 1 (PAI-1; total and active), and soluble tumor necrosis factor receptors (TNFR)-1 and -2 lead to a 30-50% increase in the odds to develop macroalbuminuria. Following adjustment for DCCT baseline retinopathy status, age, sex, HbA1c, and duration of diabetes, significant associations remained for sE-selectin and TNFR-1 and -2 but not for IL-6 or PAI-1. CONCLUSIONS--Our study indicates that high levels of inflammatory markers, mainly E-selectin and sTNRF-1 and -2, are important predictors of macroalbuminuria in patients with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Marijuana is the most widely used illicit substance among youths and recent epidemiological data indicate that rates of marijuana use are on the rise. The purpose of this study was to examine marijuana craving trajectories among adolescents in an eight-week, placebo-controlled pharmacotherapy trial targeting marijuana cessation. All participants received contingency management and cessation counseling, and were randomized to either N-acetylcysteine (1200mg NAC twice daily; n =45) or placebo (n =44). Craving for marijuana was measured using the short-form of the Marijuana Craving Questionnaire (MCQ). Results demonstrated a significant decrease in MCQ scores over time for the total sample, but no significant differential change in scores between the NAC and placebo groups. This lack of significant difference is in the setting of NAC participants submitting significantly more negative urine cannabinoid tests as compared to placebo participants. This suggests that cessation effects associated with NAC may be mediated by effects other than marijuana craving. [Copyright &y& Elsevier]

OBJECTIVE - To determine whether immunocomplexes (ICs) containing advanced glycation end product (AGE)-LDL (AGE-LDL) and oxidized LDL (oxLDL) contribute to the development of retinopathy over a 16-year period in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS - Levels of AGE-LDL and oxLDL in ICs were measured in 517 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Retinopathy was assessed by stereoscopic fundus photography. Cox proportional hazards models were used to assess the effect of AGE-LDL-ICs and oxLDL-ICs on retinopathy progression. RESULTS - In unadjusted models, higher baseline levels of AGE-LDL-ICs and oxLDL-ICs significantly predicted progression of diabetic retinopathy outcomes. After adjustment by study-design variables (treatment group, retinopathy cohort, duration of type 1 diabetes, and baseline albumin excretion rate [AER], hemoglobin A1c (HbA1c), and Early Treatment Diabetic Retinopathy Study [ETDRS] score), one SD increase in IC levels was associated with 47% (hazard ratio [HR] 1.47 [95% CI 1.19-1.81]; AGE-LDL-IC) and 45% (1.45 [1.17-1.80]; oxLDL-IC) increased risk of developing proliferative diabetic retinopathy (PDR) and 37% (1.37 [1.12-1.66]; to both ICs) increased risk of progressing to severe nonproliferative retinopathy. Analyses were stratified by retinopathy cohort because results differed between primary and secondary cohorts. For AGE-LDL-ICs, HR for progression to PDR was 2.38 (95%CI 1.30-4.34) in the primary cohort and attenuated in the secondary cohort (1.29 [1.03-1.62]). Similar results were observed for oxLDL-ICs. CONCLUSIONS - Increased levels of AGE-LDL and oxLDL in ICs are associated with increased risk for progression to advanced retinopathy in patients with type 1 diabetes, indicating that the antibody response to modified LDL plays a significant role in retinopathy progression. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to examine the modifying effect of gender on the association between early life trauma and the hypothalamic-pituitary-adrenal (HPA) axis response to a pharmacologic challenge and a social stress task in men and women. Participants (16 men, 23 women) were the control sample of a larger study examining HPA axis function. Individuals with major depressive disorder, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded. Methods: In two test sessions, subjects received 1 µg/kg of corticotropin-releasing hormone (CRH) intravenously and participated in the Trier Social Stress Test (TSST). Primary outcomes included plasma cortisol and corticotropin levels measured at baseline and more than five time points following the challenges. Predictors included gender and early life trauma, as measured by the Early Trauma Index. Using factor analysis, the domains general trauma, severe trauma, and the effects of trauma were established. Using regression, these constructs were used to predict differential HPA reactivity in men and women following the challenges. Results: The three factors accounted for the majority of the variance in the ETI. Following the CRH challenge, women had higher overall corticotropin response as dictated by the area under the curve analysis. There were no significant associations between trauma and neuroendocrine response to the TSST. Conclusions: CRH challenge results indicate that gender differences in the impact of early trauma may help explain the differential gender susceptibility to psychopathology following adverse childhood events. This may help explain gender differences in some stress-sensitive psychiatric disorders. Depression and Anxiety, 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Oxidized LDL (oxLDL) and oxLDL antibodies form immune complexes (IC) that reflect essential components in the development of atherosclerosis: dyslipidemia, oxidative stress and induction of a pro-inflammatory humoral immune response. We measured oxLDL in IC (oxLDL-IC) isolated from patients with type 1 diabetes to assess the relationship between oxLDL-IC and coronary artery calcification (CAC). Methods: OxLDL was measured in IC isolated from baseline samples from a subgroup of 476 patients of the Diabetes Control and Complications Trial (DCCT). CAC was determined by computed tomography (CT) 11–20 years later. Multivariable log-binomial regression models were used to estimate the risk ratios associated with having a high CAC score with an increase of 1 standard deviation (SD) of the natural logarithm of oxLDL-IC. Results: Multivariable regression models indicate that a 1 SD increase in the levels of oxLDL-IC was associated with a 37% increase in the risk of having high CAC score (RR=1.36; 95% CI: 1.12–1.67) at follow-up after adjustment for DCCT treatment group, retinopathy/AER groups, gender and CT scanning site as well as baseline age, diabetes duration and HbA1C %. Further adjustment for smoking status, blood pressure and LDL resulted in a risk ratio of 1.23 (95% CI: 1.01–1.50) which remained statistically significant indicating that baseline oxLDL-IC is independently associated with the development of CAC. Discussion: Increased levels of oxLDL-IC are associated with the development of coronary calcification. This observation reinforces previously published clinical and experimental data demonstrating that oxLD-IC has pro-inflammatory and proatherogenic properties. [Copyright &y& Elsevier]

Abstract: Introduction: Tobacco use often starts in adolescence, yet assessment of dependence among adolescent smokers remains a challenge, particularly given the potential discord between self-reports of smoking behavior and actual use. We could find no prior study, among adolescents, that directly compares the association between objective biomarkers of tobacco exposure (e.g., cotinine) and multiple measures of dependence. This study examined the concurrent validity of two common dependence measures: the Fagerström Test for Nicotine Dependence (FTND) and the Hooked on Nicotine Checklist (HONC). We further examined the FTND by removing the one item on cigarettes smoked per day. Methods: Based within a parent clinical trial for adolescent smoking cessation, eligible participants were 12–21years old, smoking ≥5cigarettes per day on average, and with urine cotinine >100ng/ml at baseline. Results are based on participants who completed each measure and who provided a urine cotinine sample at baseline (N=73). Results: Results showed that the FTND was associated with cotinine (p<0.001; R2 =0.25), and that this relationship held true for the revised FTND as well (p<0.001; R2 =0.18). However, the HONC was only marginally associated with cotinine (p=0.06; R2 =0.09). Discussion: Our results suggest that the FTND may be better associated with actual smoking behavior in adolescents as compared to the HONC. Pending replication, our data provide caution with regard to assessment of nicotine dependence at least among established adolescent smokers who have more entrenched smoking behavior. [ABSTRACT FROM AUTHOR]

Individuals with attention-deficit/hyperactivity disorder (ADHD) are more likely than those without ADHD to initiate smoking and develop nicotine dependence. Recent research indicates that adults with ADHD experience more severe nicotine withdrawal symptoms than those without ADHD. However, little is known about nicotine withdrawal in adolescent smokers with history of ADHD. Among a sample of 134 nicotine-dependent adolescents entering a smoking cessation research study, participants completed the Minnesota Nicotine Withdrawal Scale (MNWS) and lifetime diagnostic assessment for ADHD during the baseline visit. Responses on individual items and MNWS total score were compared between participants with and without history of ADHD. In addition, correlations between MNWS responses and current ADHD symptoms were investigated among participants with history of ADHD. Forty-eight participants (36%) met lifetime ADHD criteria. Adolescent smokers with history of ADHD scored significantly higher on MNWS than those without history of ADHD. Among participants with history of ADHD, responses on the MNWS difficulty concentrating, restlessness/impatience, and anxiety/nervousness items each correlated positively with several current ADHD symptoms. Treatment-seeking adolescent smokers with history of ADHD are more likely to endorse nicotine withdrawal symptoms than those without history of ADHD. However, it does not appear that the symptoms reported in this sample represent a valid 'withdrawal syndrome,' particularly because these smokers had not yet formally attempted to quit. Rather, the data likely reflect common features between ADHD and nicotine withdrawal. Smoking research, particularly among adolescents in whom ADHD is so common, should carefully consider the complex issue of comorbid ADHD and nicotine dependence. (Am J Addict 2010;00:1-7) [ABSTRACT FROM AUTHOR]

Background: Time from first cannabis use to cannabis dependence (latency) may be an important prognostic indicator of cannabis-related problems and treatment outcomes. Gender differences in latency have been found; however, research in this general area is limited. As cannabis use increases and perceived risk declines, a better understanding of how these factors interact in predicting treatment outcomes is critical.Methods: A secondary data analysis of a randomized, double-blind, placebo-controlled pharmacotherapy trial for cannabis dependence (N = 302) examined the associations between age of cannabis use onset, time to cannabis dependence (latency), and gender on cannabis use during the trial. Mediation analysis tested whether the association between age of onset and cannabis use during the trial was mediated by latency to cannabis dependence differentially for men and women.Results: Age of use initiation was inversely correlated with latency to dependence prior to treatment [HR(95% CI) = 1.18 (1.06, 1.30); p = .002] and cannabis use during treatment (β=-1.27; SE = 0.37; p < .001). There was a significant mediation effect between age of onset, latency, and cannabis use that varied by gender. Earlier age of onset predicted longer latency, and subsequently, greater cannabis use during the trial in men (21.4% mediated; p < .05), but not women. Other substance use, race, and past psychiatric diagnosis did not predict latency either independently or in interaction models.Conclusion: Findings support existing evidence that early cannabis use onset is associated with worse outcomes and add new knowledge on the differential associations between age of onset, latency to cannabis dependence, and treatment outcomes for men and women. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of this study was to evaluate a pilot preoperative contingency management (CM) intervention for smoking abstinence.Aims and Methods: This multisite pilot study was conducted at two cancer center-based tobacco treatment programs. Participants who were smoking, diagnosed with or suspected to have any type of operable cancer, and had a surgical procedure scheduled in the next 10 days to 5 weeks (N = 40) were randomized to receive standard care plus monitoring only (MO) or CM prior to surgery. All patients received breath carbon monoxide (CO) tests 3 times per week, nicotine patches, and counseling. The CM group also earned payments for self-reported smoking abstinence confirmed by CO breath test ≤6 ppm on an escalating schedule of reinforcement (with a reset if they smoked). Seven-day point prevalence abstinence rates on the day of surgery and at 3-month follow-up were compared between groups using repeated measures log-linear regression models utilizing generalized estimating equations. Participants lost to follow-up are assumed to have returned to smoking.Results: The sample was 50% female and 75% White. In covariate adjusted models, patients in the CM group had a greater probability of reported abstinence. On the day of surgery (end of treatment), 52% of CM patients were abstinent compared with 16% of patients in MO (risk ratio = 3.2 [1.1-9.3]; p = .03). At the 3-month follow-up, 43% of CM patients were abstinent compared with 5% in MO (risk ratio = 8.4 [1.5-48.3]; p = .02).Conclusions: Providing monetary incentives contingent on abstinence prior to cancer surgery may produce significant improvements in smoking abstinence rates relative to breath CO MO.Implications: In this pilot preoperative CM intervention for smoking abstinence, patients receiving a CM intervention prior to cancer surgery had a greater probability of smoking abstinence at the end of treatment compared with a breath MO group (52% vs. 16%, respectively). Thus, providing monetary incentives contingent on abstinence may produce significant improvements in smoking abstinence rates prior to cancer surgery relative to breath CO monitoring. [ABSTRACT FROM AUTHOR]

Cannabis use disorder (CUD) is a common and consequential disorder. When applied to the dorsolateral prefrontal cortex (DLPFC), repetitive transcranial magnetic stimulation (rTMS) reduces craving across substance use disorders and may have therapeutic clinical effects when applied in serial-sessions. The present study sought to preliminarily determine whether serial-sessions of rTMS applied to the DLPFC had a therapeutic effect in CUD. This study was a two-site, phase-2, double-blind, randomized-controlled-trial. Seventy-two treatment-seeking participants (37.5% Women, mean age 30.2±9.9 SD) with ≥moderate-CUD were randomized to active or sham rTMS (Beam-F3, 10 Hz, 20-total-sessions, two-sessions-per-visit, two-visits-per-week, with cannabis cues) while undergoing a three-session motivational enhancement therapy intervention. The primary outcome was the change in craving between pre- and post- treatment (Marijuana Craving Questionnaire Short-Form—MCQ-SF). Secondary outcomes included the number of weeks of abstinence and the number of days-per-week of cannabis use during 4-weeks of follow-up. There were no significant differences in craving between conditions. Participants who received active-rTMS reported numerically, but not significantly, more weeks of abstinence in the follow-up period than those who received sham-rTMS (15.5%-Active; 9.3%-Sham; rate ratio = 1.66 [95% CI: 0.84, 3.28]; p =0.14). Participants who received active-rTMS reported fewer days-per-week of cannabis use over the final two-weeks of the follow-up period than those receiving sham-rTMS (Active vs. Sham: −0.72; Z=−2.33, p =0.02). This trial suggests rTMS is safe and feasible in individuals with CUD and may have a therapeutic effect on frequency of cannabis use, though further study is needed with additional rTMS-sessions and a longer follow-up period. • This phase-2 RCT tested the efficacy of prefrontal rTMS for cannabis use disorder. • The study paradigm was safe and feasible, and participants tolerated rTMS well. • The active-group had numerically more weeks of abstinence during follow-up. • The active-group had fewer days-per-week of cannabis use during follow-up. • More rTMS and a longer follow-up may result in a larger effect in future studies.. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Hedonic dysregulation is a core mechanism of addiction. There is a dearth of research on hedonic dysregulation in cannabis use disorder (CUD). The current study tested whether personalized scripted imagery may be an efficacious approach to remediate reward functioning in adults with CUD. Adults with CUD (n=10) and non-CUD controls (n=12) completed a single session personalized scripted imagery procedure. Non-drug (i.e. natural) reward and neutral scripts were transcribed and participants listened to the scripts in counterbalanced order. Primary outcomes included positive affect (PA), galvanic skin response (GSR), and cortisol and were assessed at four timepoints. Mixed effects models were used to compare between and within subject effects. Mixed effects models revealed a Condition (reward vs. neutral) X Group (CUD vs. control) interaction (p=0.01) on PA response, indicating blunted PA response to the neutral script relative to the reward script in CUD participants. Likewise, GSR response in CUD participants was decreased in response to the neutral script relative to the reward script (p=0.034; interaction n.s.). An interaction effect of Group X PA on cortisol response was found (p=.036) indicating that cortisol was positively correlated with PA in healthy control participants, but not CUD participants. Adults with CUD may demonstrate acute deficits in hedonic tone under neutral conditions relative to healthy controls. Personalized scripted imagery may be an efficacious tool to remediate hedonic dysregulation in CUD. Cortisol may play a role in healthy positive affect regulation warranting further investigation. • Natural reward processing in adults with cannabis use disorder (CUD) was investigated. • Adults with CUD showed blunted positive affect (PA) under neutral conditions. • Adults with CUD showed blunted galvanic skin response (GSR) under neutral conditions. • Cortisol and PA were positively correlated in healthy controls but not adults with CUD. [ABSTRACT FROM AUTHOR]

Primary care visits present an opportune time to assess behaviors that contribute to patient health. Smoking, alcohol use, and illicit drugs are routinely documented in electronic health records, but less is known about screening for E-cigarette use and the prevalence of E-cigarette use in primary care settings. Data include 134,931 adult patients who visited 1 of 41 primary care clinics within a 12-month period (June 1, 2021–June 1, 2022). Data on demographics, combustible tobacco, alcohol, illicit drug, and E-cigarette use were extracted from electronic medical records. Logistic regression was utilized to examine the variables associated with differential odds of being screened for E-cigarette use. Rates of E-cigarette screening (n =46,997; 34.8%) were significantly lower than that of tobacco (n =134,196; 99.5%), alcohol (n =129,766; 96.2%), and illicit drug (n =129,766; 92.6%) use. Of those assessed for E-cigarette use, 3.6% (n =1,669) reported current use. Of those with documented nicotine use (n =7,032), 17.2% (n =1,207) used mono E-cigarettes exclusively, 76.3% (n =5,364) used combustible tobacco exclusively, and 6.6% (n =461) reported dual use (both E-cigarette use and combustible tobacco use). Those who used combustible tobacco or illicit substances as well as younger patients were more likely to have been screened for E-cigarette use. Overall rates of E-cigarette screening were significantly lower than those of other substances. The use of combustible tobacco or illicit substances was associated with an increased likelihood of being screened. This finding may be because of the relatively recent proliferation of E-cigarettes, the recent addition of E-cigarette documentation to the electronic health record, or a lack of training on screening for E-cigarette use. [ABSTRACT FROM AUTHOR]

Introduction Contingency management (CM) interventions deliver monetary reinforcers contingent upon biochemically verified abstinence from smoking. CM has been found to be effective, however, individual participant, analyses are warranted to further elucidate how individual-level behavior patterns vary during the intervention period, both within and across treatment groups. Aims and Methods This is a secondary analysis of a randomized controlled pilot trial of presurgical cancer patients who smoke (RCT N = 40). All participants were current everyday smokers and were enrolled in cessation counseling, offered nicotine replacement therapy, and submitted breath CO testing 3 times per week for 2–5 weeks. Participants randomized to CM received monetary reinforcers for breath CO ≤6 ppm on an escalating schedule of reinforcement with a reset for positive samples. Sufficient breath CO data exist for 28 participants (CM = 14; monitoring only [MO] = 14). Effect size was calculated for differences in negative CO tests. Time to first negative test was tested using survival analysis. Fisher's exact test was used to assess relapse. Results The CM group achieved abstinence more quickly (p <.05), had a lower percentage of positive tests (h = 0.80), and experienced fewer lapses following abstinence (p =.00). While 11 of 14 participants in the CM group achieved and sustained abstinence by their third breath test, this was only true for 2 of the 14 MO participants. Conclusions Those in CM achieved abstinence quicker and with fewer lapses than those engaged in MO speaking to the efficacy of the schedule of financial reinforcement. This is particularly important within presurgical populations given the potential benefits to postoperative cardiovascular and wound infection risk. Implications While the efficacy of CM as an intervention is well established, this secondary analysis provides insight into the individual behavior patterns underlying successful abstinence. Those assigned to CM were not only more likely to achieve abstinence, but did so more quickly and with fewer instances of relapse. This is of particular importance to those scheduled for surgery where achieving abstinence as early as possible impacts on the risk of postoperative complications. CM interventions may be particularly well suited for critical windows in which timely and sustained abstinence is advantageous. [ABSTRACT FROM AUTHOR]

Background: Understanding the relationship between tobacco use and symptom burden may inform tobacco treatment interventions tailored to the needs of individuals with cancer. Methods: The study included 1409 adult cancer survivors from Wave 5 of the US Food and Drug Administration Population Assessment of Tobacco and Health (PATH) Study. A multivariate analysis of variance controlling for age, sex, and race/ethnicity assessed the association of cigarette smoking and vaping on cancer‐related symptom burden (fatigue, pain, emotional problems) and quality of life (QoL). Generalized linear mixed models controlling for the same factors were used to assess associations among symptom burden, QoL, and quit‐smoking intentions, quit‐smoking likelihood, and past 12‐month smoking quit attempts. Results: Weighted rates of current cigarette smoking and vaping were 14.21% and 2.88%, respectively. Current smoking was associated with greater fatigue (p <.0001; partial η2 =.02), pain (p <.0001; partial η2 =.08), emotional problems (p <.0001; partial η2 =.02), and worse QoL (p <.0001; partial η2 =.08). Current vaping was associated with greater fatigue (p =.001; partial η2 =.008), pain (p =.009; partial η2 =.005), and emotional problems (p =.04; partial η2 =.003), but not worse QoL (p =.17). Higher cancer symptom burden was not associated with reduced interest in quitting, likelihood of quitting, or odds of past year quit attempts (p >.05 for each). Conclusions: Among adults with cancer, current smoking and vaping were associated with greater symptom burden. Survivors' interest in and intentions to quit smoking were not related to symptom burden. Future research should examine the role of tobacco cessation in improving symptom burden and QoL. Among adults with cancer, current smoking and current vaping were associated with greater symptom burden, but interest in and intentions to quit smoking were not related to symptom burden or quality of life. Future research should examine the role of tobacco cessation in improving symptom burden and quality of life. [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Baseline Markers of Inflammation Are Associated With Progression to Macroalbuminuria in Type 1 Diabetic Subjects" in the 2013 issue is presented.