Rachel L. Tomko

A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults

BACKGROUND Cannabis use disorder (CUD) is a prevalent and impairing condition, and established psychosocial treatments convey limited efficacy. In light of recent findings supporting the efficacy of N-acetylcysteine (NAC) for CUD in adolescents, the objective of this trial was to evaluate its efficacy in adults. METHODS In a 12-week double-blind randomized placebo-controlled trial, treatment-seeking adults ages 18-50 with CUD (N=302), enrolled across six National Drug Abuse Treatment Clinical Trials Network-affiliated clinical sites, were randomized in a 1:1 ratio to a 12-week course of NAC 1200mg (n=153) or placebo (n=149) twice daily. All participants received contingency management (CM) and medical management. The primary efficacy measure was the odds of negative urine cannabinoid tests during treatment, compared between NAC and placebo participants. RESULTS There was not statistically significant evidence that the NAC and placebo groups differed in cannabis abstinence (odds ratio=1.00, 95% confidence interval 0.63-1.59, p=0.984). Overall, 22.3% of urine cannabinoid tests in the NAC group were negative, compared with 22.4% in the placebo group. Many participants were medication non-adherent; exploratory analysis within medication-adherent subgroups revealed no significant differential abstinence outcomes by treatment group. CONCLUSIONS In contrast with prior findings in adolescents, there is no evidence that NAC 1200mg twice daily plus CM is differentially efficacious for CUD in adults when compared to placebo plus CM. This discrepant finding between adolescents and adults with CUD may have been influenced by differences in development, cannabis use profiles, responses to embedded behavioral treatment, medication adherence, and other factors.

Countering Craving with Disgust Images: Examining Nicotine Withdrawn Smokers' Motivated Message Processing of Anti-Tobacco Public Service Announcements

There is a lack of research examining whether smoking cues in anti-tobacco advertisements elicit cravings, or whether this effect is moderated by countervailing message attributes, such as disgusting images. Furthermore, no research has examined how these types of messages influence nicotine withdrawn smokers’ cognitive processing and associated behavioral intentions. At a laboratory session, participants (N = 50 nicotine-deprived adults) were tested for cognitive processing and recognition memory of 12 anti-tobacco advertisements varying in depictions of smoking cues and disgust content. Self-report smoking urges and intentions to quit smoking were measured after each message. The results from this experiment indicated that smoking cue messages activated appetitive/approach motivation resulting in enhanced attention and memory, but increased craving and reduced quit intentions. Disgust messages also enhanced attention and memory, but activated aversive/avoid motivation resulting in reduced craving and increased quit intentions. The combination of smoking cues and disgust content resulted in moderate amounts of craving and quit intentions, but also led to heart rate acceleration (indicating defensive processing) and poorer recognition of message content. These data suggest that in order to counter nicotine-deprived smokers’ craving and prolong abstinence, anti-tobacco messages should omit smoking cues but include disgust. Theoretical implications are also discussed.

Reductions in cannabis use are associated with improvements in anxiety, depression, and sleep quality, but not quality of life

AIMS This study examined the longitudinal association between reductions in cannabis use and changes in anxiety, depression, sleep quality, and quality of life. METHODS Secondary analyses were conducted based on data from a cannabis use disorder medication trial in 302 adults (ages 18-50). Changes in symptoms of anxiety and depression, sleep quality, and quality of life were assessed in relation to changes in cannabis use during the 12-week trial of treatment. RESULTS Based on the slope of individual cannabis use trajectory, the sample was classified into two groups (Cannabis Use Reduction, n=152 vs. Cannabis Use Increase, n=150) which was included as a binary covariate in subsequent modeling. Controlling for demographics (age, gender, race/ethnicity), treatment condition, and time-varying tobacco and alcohol use, separate latent growth curve models showed a significant association between the Cannabis Use Reduction group and improvement (i.e., lower values in slope) in anxiety (β=-0.09, SE=0.04; p<0.05), depression (β=-0.11, SE=0.04; p<0.01), and sleep quality (β=-0.07, SE=0.03; p<0.05) over the observation period, but not in quality of life. CONCLUSIONS These results indicate a longitudinal relationship between reductions in cannabis use and improvements in anxiety, depression, and sleep quality. Clinicians treating patients with co-occurring cannabis use and problems with anxiety, depression, or sleep quality should attend to cannabis use reduction as a component of treatment.

Personalizing substance use treatment based on pre-treatment impulsivity and sensation seeking: A review

BACKGROUND Theoretically, substance use disorder (SUD) treatment that matches an individuals etiology and/or maintaining factors should be more effective than a treatment that does not directly address these factors. Impulsivity and sensation/reward seeking may contribute to the development and maintenance of SUDs, and are potential candidate variables for assigning patients to treatment. The goal is to identify whether current research can provide insight into which treatments may be most effective for individuals high in impulsivity or sensation seeking, relative to other treatments. A secondary goal is to provide recommendations for personalizing SUD treatment based on etiology or maintaining factors. METHOD This review summarizes clinical trials that speak to the differential effectiveness of two or more treatments for alcohol, tobacco, and other drug use disorders, based on pre-treatment impulsivity, sensation seeking, or related constructs. RESULTS Few studies examine the differential effectiveness of two or more treatments for individuals high in impulsivity or sensation seeking. Very preliminary evidence suggests that contingency management may hold promise for individuals high in impulsivity. Pharmacological trials were under-represented in the current review, despite evidence that the effectiveness of some pharmacological interventions may be moderated by impulsivity. CONCLUSIONS Potential reasons for slow rate of progress to date are provided. Given slow accumulation of evidence, an alternative method for personalizing treatment based on pre-treatment psychosocial factors, including impulsivity and sensation/reward seeking, is proposed. Future research may explore the role of contingency management for SUD among individuals with high pre-treatment impulsivity or sensation seeking. Finally, novel, technology-enhanced behavioral mechanisms are discussed as an adjunct to SUD treatment for these high-risk populations.

Low Pretreatment Impulsivity and High Medication Adherence Increase the Odds of Abstinence in a Trial of N-Acetylcysteine in Adolescents with Cannabis Use Disorder.

BACKGROUND In light of recent progress toward pharmacologic interventions to treat adolescent cannabis use disorder, it is important to consider which adolescent characteristics may be associated with a favorable response to treatment. This study presents secondary analyses from a parent randomized controlled trial of N-acetylcysteine (NAC) in adolescents with cannabis use disorder. We hypothesized that high pretreatment impulsivity and medication non-adherence would be associated with reduced abstinence rates. METHODS Participants were treatment-seeking adolescents (N=115) who met criteria for cannabis use disorder and were assessed for pretreatment impulsivity. They received 1200 mg NAC or placebo orally twice daily for 8 weeks. An intent-to-treat analysis using a repeated-measures logistic regression model was used to relate pretreatment impulsivity (Barratt Impulsiveness Scale) and treatment group to abstinence rates, measured by urine cannabinoid tests. To explore mechanisms by which NAC may reduce cannabis use, relationships between impulsivity, adherence, and abstinence were assessed in a second statistical model using data from participants with recorded adherence and urine cannabinoid test results (n=54). RESULTS In the intent-to-treat analysis, low pretreatment impulsivity, NAC treatment, and negative baseline urine cannabinoid test results independently increased the odds of having negative urine cannabinoid tests during treatment (OR=2.1, 2.3, and 5.3 respectively). In the sample of participants with adherence data (n=54), adherence tripled the odds of abstinence. Notably, the effect of adherence on abstinence was only observed in the NAC treatment group. Lastly, although the highly impulsive participants had reduced rates of abstinence, highly impulsive individuals adherent to NAC treatment had increased abstinence rates compared to non-adherent individuals. CONCLUSION Low impulsivity, NAC treatment, medication adherence, and baseline negative cannabinoid testing were associated with increased rates of abstinence in adolescents seeking treatment for cannabis use disorder. Efforts to optimize pharmacotherapy adherence may be particularly crucial for highly impulsive individuals. Understanding and addressing factors, such as impulsivity and adherence, which may affect outcomes, may aid in the successful evaluation and development of potentially promising pharmacotherapies.

The effect of N-acetylcysteine on alcohol use during a cannabis cessation trial

BACKGROUND Individuals with alcohol use disorder (AUD) do not always respond to currently available treatments, and evaluation of new candidate pharmacotherapies is indicated. N-acetylcysteine (NAC), an over-the-counter supplement, has shown promise in treating a variety of substance use disorders, but little research has evaluated its merits as a treatment for AUD. This secondary analysis from the National Drug Abuse Treatment Clinical Trials Network examined the effects of NAC versus placebo on alcohol use among participants with cannabis use disorder (CUD) enrolled in a 12-week, multi-site cannabis cessation trial. METHODS Participants (N = 302, ages 18-50) were randomized to double-blind NAC (1200 mg, twice daily) or placebo. Neither alcohol use nor desire for alcohol cessation were requirements for participation. Participants that returned for at least one treatment visit and had recorded alcohol use data (i.e., total drinks per week, drinking days per week, and binge drinking days per week) were included in the analysis (n = 277). RESULTS Compared to the placebo group, participants in the NAC group had increased odds of between-visit alcohol abstinence [OR = 1.37; 95% CI = 1.06-1.78; p = 0.019], fewer drinks per week [RR = 0.67; 95% CI = 0.48-0.99; p = 0.045], and fewer drinking days per week [RR = 0.69; 95% CI = 0.51-0.92; p = 0.014]. Changes in concurrent cannabis use amounts were not correlated to any of the alcohol use variables. DISCUSSION These findings indicate that NAC may be effective at reducing consumption of alcohol by ∼30% among treatment-seeking adults with CUD, suggesting a need for further trials focused on the effects of NAC on alcohol consumption among individuals seeking treatment for AUD.

Alcohol use during a trial of N-acetylcysteine for adolescent marijuana cessation

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.

Incremental validity of estimated cannabis grams as a predictor of problems and cannabinoid biomarkers: Evidence from a clinical trial

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).

Acceptability and compliance with a remote monitoring system to track smoking and abstinence among young smokers

ABSTRACT Background: Similar to adult smokers, quit attempts among younger smokers almost inevitably result in relapse. Unlike adults, less is known about the process of relapse in this younger age group. A technology-based remote monitoring system may allow for detailed and accurate characterization of smoking and abstinence and would help to improve cessation strategies. Objectives: This study describes a mobile system that captures smoking using breath carbon monoxide (CO) and real-time self-reports of smoking behavior. Compliance, feasibility, acceptability, and accuracy of the system were measured during a quit attempt and subsequent monitoring period. Methods: The mobile application (My Mobile Monitor, M3) combined breath CO with ecological momentary assessment, delivered via smartphone. Participants (N = 16; 75% female) were daily smokers between the ages of 19 and 25, who used the app for 11 days during which they agreed to make a quit attempt. Acceptability, compliance, and abstinence were measured. Results: Participants averaged 22.3 ± 2.0 years old and smoked an average of 13.0 ± 6.1 cigarettes per day. Overall session compliance was 69% and during the quit attempt, 56% of participants abstained from smoking for at least 24 hours. Agreement between self-reported smoking compared to breath CO was generally high, when available for comparison, though underreporting of cigarettes was likely. Conclusion: This study demonstrates feasibility of a remote monitoring app with younger smokers, though improvements to promote compliance are needed. Remote monitoring to detect smoking and abstinence represents a step forward in the improvement of cessation strategies, but user experience and personalization are vital.

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

Introduction Some evidence suggests that female smokers may show more context-dependent smoking and that males may show more stereotyped smoking (regardless of stress or cue exposure). The goal of this study was to characterize sex differences in response to stressful and smoking cues ecologically presented in daily life and variability in day-to-day smoking behavior. Methods Adult smokers (N=177) provided ratings of mood and cigarette craving before and after stress and smoking cues were presented 4 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.