Matthew J. Carpenter

Both Smoking Reduction With Nicotine Replacement Therapy and Motivational Advice Increase Future Cessation Among Smokers Unmotivated to Quit.

Smokers not currently interested in quitting (N = 616) were randomized to receive telephone-based (a) reduction counseling plus nicotine replacement therapy (NRT) plus brief advice to quit, (b) motivational advice plus brief advice, or (c) no treatment. More smokers in the reduction (43%) and motivational (51%) conditions made a 24-hr quit attempt over 6 months than smokers in the no-treatment condition (16%; p < or = .01), but the 2 active conditions did not differ (p > or = .05). Similarly, 18%, 23%, and 4% of each condition were abstinent (7-day point prevalence) at 6 months (p < or = .01). Results indicate smoking reduction using NRT does not undermine cessation but rather increases the likelihood of quitting to a degree similar to motivational advice.

A Double-Blind Randomized Controlled Trial of N-Acetylcysteine in Cannabis-Dependent Adolescents

OBJECTIVE Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine (NAC), via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy for substance dependence. The authors investigated NAC as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have shown limited efficacy. METHOD In an 8-week double-blind randomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (ages 15-21 years; N=116) received NAC (1200 mg) or placebo twice daily as well as a contingency management intervention and brief (<10 minutes) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid test results during treatment among participants receiving NAC compared with those receiving placebo, in an intent-to-treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group. RESULTS Participants receiving NAC had more than twice the odds, compared with those receiving placebo, of having negative urine cannabinoid test results during treatment (odds ratio=2.4, 95% CI=1.1-5.2). Exploratory secondary abstinence outcomes favored NAC but were not statistically significant. NAC was well tolerated, with minimal adverse events. CONCLUSIONS This is the first randomized controlled trial of pharmacotherapy for cannabis dependence in any age group to yield a positive primary cessation outcome in an intent-to-treat analysis. Findings support NAC as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents.

Menstrual Cycle Phase Effects on Nicotine Withdrawal and Cigarette Craving: A Review

Evidence suggests that women are less likely to quit smoking than are men. This may reflect differences in nicotine dependence and, more specifically perhaps, nicotine withdrawal and craving. However, there is conflicting research on gender differences on the experience of withdrawal and craving. Menstrual cycle effects may moderate this relationship. Given hormonal changes during the menstrual cycle, abstinence-related symptoms such as withdrawal and craving may vary as a function of menstrual phase as well. This qualitative review summarizes the modest but expanding body of research in this area. One of the challenges inherent in interpreting this literature is the difficulty in distinguishing withdrawal symptomatology from premenstrual symptomatology. Methodological variation, including limited sample size and possible selection bias, in which several studies finding null effects excluded women with severe premenstrual dysphoric disorder, may explain some of the inconsistent findings across studies. Nonetheless, some of the 13 studies included in this review found heightened experiences of withdrawal or craving within the latter days of the menstrual cycle (i.e., the luteal phase). Further research is necessary to replicate these findings, but they may suggest the need for focused cessation treatment during the luteal phase or quit attempts that are well timed relative to specific menstrual phases.

Cigarette Warning Label Policy Alternatives and Smoking-Related Health Disparities

BACKGROUND Pictorial health warning labels on cigarette packaging have been proposed for the U.S., but their potential influences among populations that suffer tobacco-related health disparities are unknown. PURPOSE To evaluate pictorial health warning labels, including moderation of their influences by health literacy and race. METHODS From July 2011 to January 2012, field experiments were conducted with 981 adult smokers who were randomized to control (i.e., text-only labels, n=207) and experimental conditions (i.e., pictorial labels, n=774). The experimental condition systematically varied health warning label stimuli by health topic and image type. Linear mixed effects (LME) models estimated the influence of health warning label characteristics and participant characteristics on label ratings. Data were analyzed from January 2012 to April 2012. RESULTS Compared to text-only warning labels, pictorial warning labels were rated as more personally relevant (5.7 vs 6.8, p<0.001) and effective (5.4 vs 6.8, p<0.001), and as more credible, but only among participants with low health literacy (7.6 vs 8.2, p<0.001). Within the experimental condition, pictorial health warning labels with graphic imagery had significantly higher ratings of credibility, personal relevance, and effectiveness than imagery of human suffering and symbolic imagery. Significant interactions indicated that labels with graphic imagery produced minimal differences in ratings across racial groups and levels of health literacy, whereas other imagery produced greater group differences. CONCLUSIONS Pictorial health warning labels with graphic images have the most-pronounced short-term impacts on adult smokers, including smokers from groups that have in the past been hard to reach.

Nicotine therapy sampling to induce quit attempts among smokers unmotivated to quit: a randomized clinical trial.

BACKGROUND Rates of smoking cessation have not changed in a decade, accentuating the need for novel approaches to prompt quit attempts. METHODS Within a nationwide randomized clinical trial (N = 849) to induce further quit attempts and cessation, smokers currently unmotivated to quit were randomized to a practice quit attempt (PQA) alone or to nicotine replacement therapy (hereafter referred to as nicotine therapy), sampling within the context of a PQA. Following a 6-week intervention period, participants were followed up for 6 months to assess outcomes. The PQA intervention was designed to increase motivation, confidence, and coping skills. The combination of a PQA plus nicotine therapy sampling added samples of nicotine lozenges to enhance attitudes toward pharmacotherapy and to promote the use of additional cessation resources. Primary outcomes included the incidence of any ever occurring self-defined quit attempt and 24-hour quit attempt. Secondary measures included 7-day point prevalence abstinence at any time during the study (ie, floating abstinence) and at the final follow-up assessment. RESULTS Compared with PQA intervention, nicotine therapy sampling was associated with a significantly higher incidence of any quit attempt (49% vs 40%; relative risk [RR], 1.2; 95% CI, 1.1-1.4) and any 24-hour quit attempt (43% vs 34%; 1.3; 1.1-1.5). Nicotine therapy sampling was marginally more likely to promote floating abstinence (19% vs 15%; RR, 1.3; 95% CI, 1.0-1.7); 6-month point prevalence abstinence rates were no different between groups (16% vs 14%; 1.2; 0.9-1.6). CONCLUSION Nicotine therapy sampling during a PQA represents a novel strategy to motivate smokers to make a quit attempt. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00706979.

Gender Differences in Craving and Cue Reactivity to Smoking and Negative Affect/Stress Cues

There is evidence that women may be less successful when attempting to quit smoking than men. One potential contributory cause of this gender difference is differential craving and stress reactivity to smoking- and negative affect/stress-related cues. The present human laboratory study investigated the effects of gender on reactivity to smoking and negative affect/stress cues by exposing nicotine dependent women (n = 37) and men (n = 53) smokers to two active cue types, each with an associated control cue: (1) in vivo smoking cues and in vivo neutral control cues, and (2) imagery-based negative affect/stress script and a neutral/relaxing control script. Both before and after each cue/script, participants provided subjective reports of smoking-related craving and affective reactions. Heart rate (HR) and skin conductance (SC) responses were also measured. Results indicated that participants reported greater craving and SC in response to smoking versus neutral cues and greater subjective stress in response to the negative affect/stress versus neutral/relaxing script. With respect to gender differences, women evidenced greater craving, stress and arousal ratings and lower valence ratings (greater negative emotion) in response to the negative affect/stressful script. While there were no gender differences in responses to smoking cues, women trended towards higher arousal ratings. Implications of the findings for treatment and tobacco-related morbidity and mortality are discussed.

N-Acetylcysteine (NAC) in Young Marijuana Users: An Open-Label Pilot Study

Cannabis use disorders (abuse or dependence) are present in 3.6% of adolescents and 5.9% of young adults, compared with only 0.7% of adults over the age of 25 (1). While a small number of large-scale pharmacotherapy clinical trials targeting cannabis dependence have been undertaken, none have demonstrated significant medication effects on marijuana use and none have focused on young marijuana users (2,3). As such, investigation of novel pharmacotherapeutic agents targeting cannabis dependence in young people is an important focus for research. The neurotransmitter glutamate has emerged as a potential target in the treatment of addictions, including cannabis dependence (4). Within animal studies, the anti-oxidant N-acetylcysteine (NAC) has been shown to reverse drug-induced down-regulation of the cystine-glutamate exchanger (5), which presumably allows for regulation of glutamate release, reducing compulsive drug-seeking behaviors. Consistent with this, preliminary studies have demonstrated significant reductions in cocaine craving (6) and cigarette use (7) during NAC treatment. Taken together, these findings implicate NAC as a potential treatment for addictive disorders, including cannabis dependence. Thus, the purpose of this open-label study was to gather tolerability and preliminary efficacy data for NAC in the treatment of cannabis dependence in young people. Participants were 24 cannabis dependent males (n = 18) and females (n = 6), age range 18–21 (mean age 19 ± SE 0.16) interested in cutting down their marijuana use (i.e., without requirements to quit). Twenty-two were White, one African-American, and one Hispanic. They were required to be medically and psychiatrically stable, have no allergy or intolerance to NAC, have no history of seizures or asthma, and be free of medications known to interact with NAC. Participants were enrolled in a four-week open-label trial of NAC 1200 mg twice daily. A baseline visit was followed by four weekly visits (Weeks 1–4) to assess tolerability and clinical effects. Medication was discontinued at the final (Week 4) visit. Participants were encouraged to gradually reduce marijuana use, but no formal cessation instructions or psychosocial treatments were provided. As assessed by medication adherence logs and weekly pill counts, participants took 82.6% ± SE 2.6% of the scheduled NAC doses during the medication trial. Weekly assessments of adverse events (coded as mild, moderate, or severe) revealed that NAC was generally well tolerated. Fifteen participants (63%) reported at least one adverse event, but all were mild to moderate, and none led to discontinuation of medication. The most common adverse events were abdominal discomfort (5/24), muscle pains/aches (5/24), insomnia (4/24), headache (3/24), nasal congestion/runny nose (3/24), nausea (3/24), weight decrease (3/24), restlessness (3/24), and dizziness (3/24). Marijuana use during the month preceding participation was quantified at the baseline visit using timeline follow-back procedures. From the initial assessment visit forward, daily marijuana use diaries were completed by participants and turned in at weekly visits. During the month preceding the trial, participants reported using marijuana 6.1 ± SE 0.24 days per week. A generalized estimating equation (GEE) analysis revealed a reduction in reported days per week of marijuana use over the course of NAC treatment (overall time effect: p = 0.003). Post-hoc pair-wise comparisons (comparator: baseline visit) revealed significant decrease from baseline in days per week of use during the second (5.2 ± SE 0.33; p = 0.006), third (5.2 ± 0.39 p = 0.001), and fourth (5.3 ± 0.32; p = 0.03) week of NAC treatment. During the month preceding the trial, participants reported using an average of 15.9 ± SE 2.4 potency-adjusted “hits” (8) of marijuana per day, and GEE analysis revealed an overall trend-level reduction in “hits” per day over time (p = 0.07). Average “hits” per day decreased to 14.8 ± SE 1.6 at Week 1, 11.6 ± 1.7 at Week 2, 12.4 ± 2.0 at Week 3, and 11.9 ± 2.1 at Week 4. Pair-wise comparison (comparator: baseline visit) revealed significant reduction at the second week of NAC treatment (p = 0.02). In addition to self-report data, semi-quantitative urine cannabinoid levels (quantitative range 0 to 135 ng/dL) and urine creatinine levels, to determine creatinine-normalized urine cannabinoid levels, were collected at each visit to serve as a biomarker of marijuana use (9). In contrast to self reports, semi-quantitative, creatinine-normalized urine cannabinoid levels did not significantly change over the course of the trial. Of note, though, 13 participants remained above the semi-quantitative urine cannabinoid range (0 – 135 ng/mL) throughout the trial, thus limiting the utility of this measure. Craving for marijuana was measured using the 12-item version of Marijuana Craving Questionnaire (MCQ) (10). The four domains of the MCQ represent four constructs characterizing marijuana craving: Compulsivity (inability to control marijuana use), Emotionality (anticipation of using marijuana to relieve withdrawal or negative mood), Expectancy (anticipation of positive outcomes from smoking marijuana), and Purposefulness (intention and planning to use marijuana for positive outcomes). GEE analyses revealed that participants reported significantly reduced ratings on three of the four MCQ domains over the course of NAC treatment (MCQ Emotionality p < 0.001, Purposefulness p = 0.003, and Compulsivity p = 0.008) (Figure 1). Figure 1 Marijuana Craving Questionnaire (MCQ) domain scores (mean ± SE) over the course of treatment. To our knowledge, this is the first study to date investigating the effects of NAC in young people with cannabis dependence. Results from this preliminary open-label study indicate that treatment with NAC was well tolerated and associated with significant decreases in self-report measures of marijuana use and craving. These reductions parallel those noted in prior NAC treatment studies in cocaine and nicotine dependent individuals (6,7). Although the present findings should be interpreted in light of the limitations of this preliminary study (i.e. open-label study without a control group, limited semi-quantitative urine drug testing), data strongly suggest the need for a more rigorous examination of NAC for treatment of cannabis dependence.

Gender Differences in Medication Use and Cigarette Smoking Cessation: Results From the International Tobacco Control Four Country Survey

INTRODUCTION There is conflicting evidence for gender differences in smoking cessation, and there has been little research on gender differences in smoking cessation medication (SCM) use and effectiveness. Using longitudinal data from the International Tobacco Control Four Country Surveys (ITC-4) conducted in the United Kingdom, the United States, Canada, and Australia, we examined gender differences in the incidence of quit attempts, reasons for quitting, use of SCMs, reasons for discontinuing use of SCMs, and rates of smoking cessation. METHODS Data were analyzed from adult smokers participating in the ITC-4, annual waves 2006-2011 (n = 7,825), as well as a subsample of smokers (n = 1,079) who made quit attempts within 2 months of survey. Adjusted modeling utilized generalized estimating equations. RESULTS There were no gender differences in the likelihood of desire to quit, plans to quit, or quit attempts between survey waves. Among quit attempters, women had 31% lower odds of successfully quitting (OR = 0.69; 95% CI = 0.51, 0.94). Stratified by medication use, quit success was lower among women who did not use any SCMs (OR = 0.59; 95% CI = 0.39, 0.90), and it was no different from men when medications were used (OR = 0.73; 95% CI = 0.46, 1.16). In particular, self-selected use of nicotine patch and varenicline contributed to successful quitting among women. CONCLUSIONS Women may have more difficulty quitting than men, and SCMs use may help attenuate this difference.

Do point prevalence and prolonged abstinence measures produce similar results in smoking cessation studies? A systematic review

INTRODUCTION Many smoking cessation trials report either prolonged abstinence (PA) rates (i.e., not smoking since a quit date, with or without a grace period) or point prevalence (PP) abstinence rates (i.e., no smoking one or more days prior to the follow-up), but how these two relate is unclear. METHODS We located 28 pharmacotherapy trials that provided 76 within-study comparisons of PA versus PP. The first two authors independently coded all trials. RESULTS The two measures were highly correlated (r = .88) and PA averaged 0.74 that of PP. Equations for converting PP to PA and vice versa produced estimations that, in 90% of cases, were within 4%-5% of actual PP or PA values. The odds ratio and the relative risk for active versus control were identical when PA and PP were used; however, the difference in proportion abstinent for active versus control was somewhat less when PA was used than when PP was used (8% vs. 10%). DISCUSSION We conclude that PA and PP are closely related and can be interconverted with moderate accuracy. They also produce similar effect sizes when odds ratio and relative risk are used as effect sizes. When absolute difference in percent abstinent is used as an effect size, PA produces a smaller effect size than PP. We believe trials should continue to report both PA and PP outcomes to enhance comparisons across studies.

A placebo-controlled trial of buspirone for the treatment of marijuana dependence.

The present study investigated the potential efficacy of buspirone for treating marijuana dependence. Participants received either buspirone (maximum 60mg/day) (n=23) or matching placebo (n=27) for 12 weeks, each in conjunction with motivational interviewing. In the modified intention-to-treat analysis, the percentage of negative UDS results in the buspirone-treatment group was 18 percentage points higher than the placebo-treatment group (95% CI: -2% to 37%, p=0.071). On self-report, participants receiving buspirone reported not using marijuana 45.2% of days and participants receiving placebo reported not using 51.4% of days (p=0.55). An analysis of participants that completed the 12-week trial showed a significant difference in the percentage negative UDS (95% CI: 7-63%, p=0.014) and a trend for participants randomized to the buspirone-treatment group who completed treatment to achieve the first negative UDS result sooner than those participants treated with placebo (p=0.054). Further study with buspirone in this population may be warranted; however, strategies to enhance study retention and improve outcome measurement should be considered in future trials.