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Background: Craving is a core clinical feature of cannabis use disorder (CUD) and a predictor of treatment outcomes, yet its temporal course during treatment is not well characterized. This study aimed to identify latent classes of cannabis craving trajectories among adults with CUD and examine associated baseline predictors and cannabis use outcomes.

Methods: This was a secondary analysis of the National Drug Abuse Treatment Clinical Trials Network’s CTN-0053 trial, a 12-week, multisite randomized controlled trial of N-acetylcysteine versus placebo for adults with CUD (N = 302). Cannabis craving was measured using the Marijuana Craving Questionnaire–Short Form at six treatment timepoints (weeks 1–5, 9 and 12) and one 5-week post-treatment follow-up (week 17). Urine cannabinoid tests were conducted twice weekly throughout treatment and follow-up. Latent class growth analysis identified craving trajectories. The present study aimed to identify latent classes of cannabis craving over 12 weeks of treatment and examine baseline predictors of class membership.

Results: A four-class solution provided the best fit: low craving (41%), moderate-decreasing craving (38%), moderate-stable craving (11%), and high craving (10%). Participants in higher craving classes exhibited greater baseline anxiety, depression, and obsessive-compulsive symptoms related to cannabis use. The high craving class had the greatest proportion of cannabis positive urine tests (96%) and the lowest urine test completion rate.

Conclusions: Craving follows heterogeneous trajectories during CUD treatment and is associated with co-occurring mental health symptoms and poorer outcomes. Dynamic craving assessment may support personalized treatment and strategies to prevent return to use.

Related protocols: CTN-0053

Treatments for cannabis use disorder (CUD) have limited efficacy and little is known about who responds to existing treatments. Accurately predicting who will respond to treatment can improve clinical decision-making by allowing clinicians to offer the most appropriate level and type of care. This study aimed to determine whether multivariable/machine learning models can be used to classify CUD treatment responders vs. non-responders.

This secondary analysis used data from National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) multi-site outpatient clinical trial (CTN-0053, Achieving Cannabis Cessation – Evaluating N-Acetylcysteine Treatment (ACCENT)). Adults with CUD (N=302) received 12 weeks of contingency management, brief cessation counseling, and were randomized to receive additionally either 1) N-Acetylcysteine or 2) placebo. Multivariable/machine learning models were used to classify treatment responders (i.e., two consecutive negative urine cannabinoid tests or a 50% reduction in days of use) versus non-responders using baseline demographic, medical, psychiatric, and substance use information.

Prediction performance for various machine learning and regression prediction models yielded area under the curves (AUCs) greater than 0.70 for four models (0.72-0.77), with support vector machine models having the highest overall accuracy (73%; 95% confidence interval [CI]: 68-78%) and AUC (0.77; 95% CI: 0.72, 0.83). Fourteen variables were retained in at least 3 of 4 top models, including demographic (ethnicity, education), medical (diastolic/systolic blood pressure, overall health, neurological diagnosis), psychiatric (depressive symptoms, generalized anxiety disorder, antisocial personality disorder), and substance use (tobacco smoker, baseline cannabinoid level, amphetamine use, age of experimentation with other substances, cannabis withdrawal intensity) characteristics.

Conclusions: Multivariable/machine learning models can improve upon chance prediction of treatment response to outpatient cannabis use disorder treatment, though further improvements in prediction performance are likely necessary for decisions about clinical care.

Related protocols: CTN-0053

Depression is common among individuals with cannabis use disorder (CUD), particularly those who present for CUD treatment. Treatments that consider this comorbidity are essential.

The goal of this secondary analysis was to examine whether N-acetylcysteine (NAC) reduced depressive symptoms among adults (age 8-50) 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.

Data for the analysis were from a NIDA Clinical Trials Network multi-site clinical trial for CUD (CTN-0053). Adults with CUD (N=302) were randomized to receive 2400mg 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- 9-tetrahydrocannabinol) confirmed abstinence. Depressive symptoms were measured by the Hospital Anxiety and Depression Scale.

Results found that 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 they 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 indicate that symptoms of depression may be a barrier to cannabis cessation among adults, regardless of whether NAC is administered. Overall, the findings suggest that depressive symptoms should be considered clinically relevant within cannabis cessation programs for adults, and that more research is needed to explore treatments that could mitigate the impact of depressive symptoms on treatment outcomes. Treatments that address depressive symptoms concurrently with CUD treatment may be particularly beneficial.

Related protocols: CTN-0053

Despite the high prevalence of blunt smoking among cannabis users, very few studies examine the clinical profile of blunt smokers relative to those using more common methods of cannabis use, like joints.

This study uses baseline data from the ACCENT study (Achieving Cannabis Cessation – Evaluating N-acetylcysteine Treatment, CTN-0053), a multi-site randomized pharmacotherapy clinical trial within the NIDA Clinical Trials Network, to predict the association between blunt and joint use frequency and cannabis use characteristics (e.g., grams of cannabis used) and consequences (e.g., withdrawal) among past-month cannabis users (N=377) who were screen for study participation.

After controlling for race, age, gender, other forms of cannabis use (including joint use) and nicotine dependence, multivariable linear regression models indicated that the number of days of blunt use in the past month was a significant predictor of the average amount of cannabis per using day, the estimated average cost of cannabis, and Cannabis Withdrawal scores. Frequency of joint use did not significantly predict any of the cannabis use characteristics or consequences.

Conclusions: Blunt smokers may present to treatment with greater amounts of cannabis smoked and more intense withdrawal symptoms, which may adversely impact their likelihood of successful abstinence. Cannabis-dependent blunt smokers may be more likely to benefit from treatment that targets physiological and mood-related withdrawal symptoms.

Related protocols: CTN-0053

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 of data from NIDA Clinical Trials Network protocol CTN-0053 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.

Participants (N=302, ages 18-50) were randomized to double-blind NAC (1200mg, 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 found that participants in the NAC group, compared to the placebo group, had increased odds of between-visit alcohol abstinence, fewer drinks per week, and fewer drinking days per week. The increase in odds of complete abstinence from alcohol was 37% in the NAC group. The NAC group was 33% less likely to increase their number of drinks, compared to the placebo group, and their drinking days were 31% less than those in the placebo group as well. NAC did not affect the number of binge drinking days, however participants were binge drinking, on average, less than one time per month, so a significant decrease may be hard to detect in this sample. Age, sex, and race did not affect findings.

Conclusions: Though the original study found that NAC was not efficacious in reducing cannabis use in an adult sample, this secondary analysis suggests that NAC may be effective at reducing consumption of alcohol by approximately 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.

Related protocols: CTN-0053

This is the primary outcomes article for CTN-0053.

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. In a 12-week double-blind randomized placebo-controlled trial, treatment-seeking adults ages 18-50 with CUD (N=302), enrolled across six NIDA Clinical Trials Network-affiliated clinical sites, were randomized in a 1:1 ratio to a 12-week course of NAC 1200 mg (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 found 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; however, exploratory analysis within the medication-adherent subgroups revealed no significant differential abstinence outcomes by treatment group.

Conclusions: In contrast with significant 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. In light of these findings, a replication trial of NAC in adolescents with CUD is indicated.

Related protocols: CTN-0053

Recent evidence suggests that women may fare worse than men in cannabis trials with pharmacologic interventions. Identifying baseline clinical profiles of treatment-seeking cannabis-dependent adults could inform gender-specific treatment planning and development. The current study compared baseline demographic, cannabis use, and psychiatric factors between women (n=86) and men (n=216) entering the Achieving Cannabis Cessation-Evaluating N-acetylcysteine Treatment (ACCENT) study, a multi-site randomized controlled trial conducted within the National Drug Abuse Treatment Clinical Trials Network.

Results found that women reported greater withdrawal intensity (p=.001) and negative impact of withdrawal (p=.001), predominantly due to physiological and mood symptoms. Women were more likely to have lifetime panic disorder (p=.038) and current agoraphobia (p=.022), and reported more days of poor physical health (p=.006) and cannabis-related medical problems (p=.023). Women reporting chronic pain had greater mean pain scores than men with chronic pain (p=.006). Men and women did not differ on any measures of baseline cannabis use.

Conclusions: Cannabis-dependent women may present for treatment with more severe and impairing withdrawal symptoms and psychiatric conditions compared to cannabis-dependent men. This might help explain recent evidence suggesting that women fare worse than men in cannabis treatment trials of pharmacologic interventions. Baseline clinical profiles of treatment-seeking adults can inform gender-specific treatment planning and development. Cannabis-dependent women may benefit from integrated treatment focusing on co-occurring psychiatric disorders and targeted treatment of cannabis withdrawal syndrome.

Related protocols: CTN-0053

Despite recent advances in behavioral interventions for cannabis use disorders, effect sizes remain modest, and few individuals achieve long-term abstinence. One strategy to enhance outcomes is the addition of pharmacotherapy to complement behavioral treatment, but to date no efficacious medications targeting cannabis use disorders in adults through large, randomized controlled trials have been identified. The National Drug Abuse Treatment Clinical Trials Network (CTN) is currently conducting a study to test the efficacy of N-acetylcysteine (NAC) versus placebo (PB), added to contingency management, for cannabis cessation in adults (ages 18-50). This study was designed to replicate positive findings from a study in cannabis-dependent adolescents that found greater odds of abstinence with NAC compared to PB. This paper describes the design and implementation of an ongoing 12-week, intent-to-treat, double-blind, randomized, placebo-controlled study with one follow-up visit four weeks post-treatment. Approximately 300 treatment-seeking cannabis-dependent adults will be randomized to NAC or PBO across six study sites in the United States. The primary objective of this 12-week study is to evaluate the efficacy of twice-daily orally-administered NAC (1200mg) versus matched PBO, added to contingency management, on cannabis abstinence. NAC is among the first medications to demonstrate increased odds of abstinence in a randomized controlled study among cannabis users in any age group.

The current study will assess the cannabis cessation efficacy of NAC combined with a behavioral intervention in adults, providing a novel and timely contribution to the evidence base for the treatment of cannabis use disorders. The results from this study have the potential to improve treatment and have a marked impact on clinical practice and public health.

Related protocols: CTN-0053