Kevin M. Gray

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.

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.

Potential Role of N-Acetylcysteine in the Management of Substance Use Disorders

There is a clear and pressing need to expand pharmacotherapy options for substance use disorders (SUDs) in order to improve sustained abstinence outcomes. Preclinical literature has demonstrated the role of glutamate in addiction, suggesting that new targets for pharmacotherapy should focus on the restoration of glutamatergic function. Glutamatergic agents for SUDs may span multiple addictive behaviors and help demonstrate potentially overlapping mechanisms in addiction. The current review will focus specifically on N-acetylcysteine (NAC), a safe and well-tolerated glutamatergic agent, as a promising potential pharmacotherapy for the treatment of SUDs across several substances of abuse. Building on recently published reviews of the clinical efficacy of NAC across a broad range of conditions, this review will more specifically discuss NAC as a pharmacotherapy for SUDs, devoting particular attention to the safety and tolerability profile of NAC, the wealth of preclinical evidence that has demonstrated the role of glutamate dysregulation in addiction, and the limited but growing clinical literature that has assessed the efficacy of NAC across multiple substances of abuse. Preliminary clinical studies show the promise of NAC in terms of safety, tolerability, and potential efficacy for promoting abstinence from cocaine, nicotine, and cannabis. Results from randomized clinical trials have been mixed, but several mechanistic and methodological factors are discussed to refine the use of NAC in promoting abstinence and relapse prevention across several substances of abuse. Further preclinical and clinical investigation into the use of NAC for SUDs will be vital in addressing current deficits in the treatment of SUDs.

Cognitive enhancers in the treatment of substance use disorders: Clinical evidence

Attenuation of drug reward has been the major focus of medication development in the addiction area to date. With the growth of research in the area of cognitive neuroscience, the importance of executive function and inhibitory cognitive control in addictive disorders is becoming increasingly apparent. An emerging strategy in the pharmacotherapy of addictions and other psychiatric disorders involves the use of medications that improve cognitive function. In particular, agents that facilitate inhibitory and attentional control, improve abstraction, planning and mental flexibility could be beneficial in the treatment of substance use disorders. Because there are multiple neurotransmitter systems involved in the regulation of cognitive function, agents from a number of drug classes have been tested. In particular, agents acting through the cholinergic, adrenergic and glutamatergic systems have shown potential for improving cognitive function in a number of psychiatric and neurologic disorders, but most of these agents have not been tested in the treatment of individuals with substance use disorders. This manuscript provides a review of clinical data supporting the use of the major classes of cognitive enhancing agents in substance use disorders. Agents that have shown promise in cognitive enhancement in other disorders, and have a theoretical or mechanistic rationale for application to substance use disorders are also highlighted.

Bupropion SR and contingency management for adolescent smoking cessation

There is a significant need for evidence-based treatments for adolescent smoking cessation. Prior research, although limited, has suggested potential roles for bupropion sustained-release (SR) and contingency management (CM), but no previous studies have assessed their combined effect. In a double-blind, placebo-controlled design, 134 adolescent smokers were randomized to receive a 6-week course of bupropion SR + CM, bupropion SR + non-CM, placebo + CM, or placebo + non-CM, with final follow-up at 12 weeks. The primary outcome was 7-day cotinine-verified point prevalence abstinence, allowing for a 2-week grace period. Combined bupropion SR + CM treatment yielded significantly superior abstinence rates during active treatment when compared with placebo + non-CM treatment. In addition, combined treatment showed greater efficacy at multiple time points than did either bupropion SR + non-CM or placebo + CM treatment. Combined bupropion SR and CM appears efficacious, at least in the short-term, for adolescent smoking cessation and may be superior to either intervention alone.

Cue reactivity in young marijuana smokers: A preliminary investigation.

To develop and evaluate the feasibility of a cue reactivity paradigm for young marijuana smokers, the authors set up a laboratory procedure involving neutral and marijuana-related imagery, video, and in vivo cues. Fifteen adolescents and young adults with cannabis use disorders completed the procedure, which included continuous measurement of skin conductance and heart rate. Participants also completed questionnaires regarding marijuana craving before, during, and after cue presentations. Higher levels of craving and skin conductance were observed during marijuana cue presentations. The procedure appears to elicit cue reactivity among adolescents and young adults with cannabis use disorders and should be further evaluated and refined with a larger sample. Implications for future studies are discussed.

Laboratory-based, cue-elicited craving and cue reactivity as predictors of naturally occurring smoking behavior

Cigarette craving, one hallmark sign of nicotine dependence, is often measured in laboratory settings using cue reactivity methods. How lab measures of cue reactivity relate to real world smoking behavior is unclear, particularly among non-treatment seeking smokers. Within a larger study of hormonal effects on cue reactivity (N=78), we examined the predictive relationship of cue reactivity to smoking, each measured in several ways. Results indicated that cue-evoked craving in response to stressful imagery, and to a lesser extent, in vivo smoking cues, significantly predicted smoking behavior during the week following testing. However, this predictive relationship was absent upon controlling for reactivity to neutral cues. Nicotine dependence may moderate the relationship between cue reactivity and actual smoking, such that this predictive relationship is less robust among highly dependent smokers than among smokers low in nicotine dependence. The question of whether cue-elicited craving predicts smoking among smokers not in treatment is best answered with a qualified yes, depending on how craving is manipulated and measured. Our findings highlight important methodological and theoretical considerations for cue reactivity research.