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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

Objectives: The accelerated development of additive pharmacotherapy treatment (ADAPT-2) for methamphetamine use disorder (MUD) trial demonstrated the efficacy of extended-release injectable naltrexone (NTX) and oral bupropion (BUP). In this secondary analysis, we determined whether craving and impulsivity levels could predict subsequent use of methamphetamine.

Methods: Participants (N = 357) of the ADAPT-2 trial with at least one transition point [transition from positive-to-negative urine drug screen (UDS) or vice versa] during stage 1 (baseline through week-6) were included in this secondary analysis. Craving was assessed using the Visual Analog Scale (VAS). Impulsivity was assessed using the 2-item impulsivity factor of the Concise Health Risk Tracking (CHRT) Scale.

Results: A significant treatment by craving by time interaction was noted (P = 0.018), where higher craving levels were consistently associated with a lower likelihood positive-to-negative UDS transition at the next visit in both NTX-BUP and placebo groups. However, no such effect was present by week 6 of treatment in the placebo group. CHRT Impulsivity also had a significant effect on the probability of a positive-to-negative UDS transition (P = 0.019) in addition to the 3-way interaction of VAS, week, and treatment group. Individuals with lower craving levels but higher impulsivity exhibited a lower probability of transitioning to negative UDS at the next visit. Higher craving, but not impulsivity, was associated with a higher likelihood of negative-to-positive UDS transition at the next visit in both treatment groups.

Conclusions: Further investigations are necessary to optimize NTX-BUP treatment, focusing on the impact of craving and impulsivity on outcomes.

Related protocols: CTN-0068

The Treatment Effectiveness Assessment (TEA) score is derived from a 4-item self-administered assessment utilizing a Likert scale to evaluate changes across four life domains: substance use, personal responsibilities, health, and citizenship. The World Health Organization Quality of Life Brief (WHOQOL-BREF) scale is a shortened version of the original instrument that may be more convenient for use in large research studies or clinical trials. It assesses the individual’s perceptions in the context of their culture and value systems, and their personal goals, standards, and concerns. Cocaine craving is a core symptom of cocaine use disorder and remains a consistent obstacle to achieving sustained reductions in use and relapse prevention.

This secondary analysis of data from CTN-0048 aimed to examine relationships between quality of life and health satisfaction (using the WHO-QOL scale), cocaine use (urine drug screens), and patient ratings of treatment effectiveness, as measured by the TEA over 8 weeks of treatment.

Results found significant negative relationships between cocaine craving and TEA and significant positive relationships between patient quality of life and satisfaction with health. A model including 4 health domains also indicated that there were significant positive relationships between health domains and TEA as well. TEA was not significantly related to longest duration of abstinence (LDA) for cocaine verified by urine drug screens.

Conclusions: Self-reported treatment effectiveness was integrally related to patient level factors, over time, while in treatment for cocaine use disorder and receiving placebo or buprenorphine and extended-release naltrexone, however TEA was not predictive of LDA. Recognizing and providing parallel intervention for these patient level factors during substance use disorder treatment may enhance patient reports of treatment effectiveness, indicating improvement across the patient reported domains of substance use, life satisfaction, health, and community.

Related protocols: CTN-0048

Cocaine craving is a core symptom of cocaine use disorder (CUD) and remains a consistent obstacle to achieving sustained reductions in use and relapse prevention. A systematic review examining pharmacological treatment for cocaine craving reported that in their review of 130 clinical trials, there was an association between craving and multiple cocaine use outcomes in most studies, including both self-report and biochemical evidence of use (i.e., urinary benzoylecgonine). Some studies have examined relationships between craving and treatment efficacy with opioid agonists and shown more mixed results.

This study aimed to examine the relationship between self-reported cocaine craving over time (i.e., 100mm Visual Analog Scale) and cocaine use over time (measured via urine drug screen and self-report) in a sample of patients receiving medication treatment for cocaine use disorder (from CTN-0148).

Results from the urine drug screen model found that there was a significant relationship between cocaine craving and urine drug screens for cocaine use (OR=0.98, p<0.01), such that lower cocaine craving was associated with higher percentages of negative urine drug screens, while holding treatment assignment constant. Results from the self-reported use model found that there was a significant impact of time on self-reported cocaine use, and when examining the time by craving interaction (B=0.0008, p<0.01), such that lower cocaine craving was associated with higher percentages of negative self-reported cocaine use, while holding treatment assignment constant.

Conclusions: Low craving is significantly associated with decreased cocaine use over time while receiving placebo or buprenorphine and extended-release naltrexone. This therapeutic may represent a promising treatment to build on for the medical treatment for cocaine use disorder.

Related protocols: CTN-0148

Polysubstance use may complicate treatment outcomes for individuals who use opioids. This research aimed to examine the prevalence of polysubstance use in an opioid use disorder treatment trial population and polysubstance use’s association with opioid relapse and craving.

This study is a secondary data analysis of individuals with opioid use disorder who received at least one dose of medication (n=474) as part of a 24-week, multi-site, open label, randomized Clinical Trials Network study (CTN-0051, X:BOT) comparing the effectiveness of extended-release naltrexone versus buprenorphine. Models examined pretreatment polysubstance use and polysubstance use during the initial 4 weeks of treatment on outcomes of relapse by week 24 of the treatment trial and opioid craving.

Polysubstance use was generally not associated with treatment outcomes of opioid relapse and craving. Proportion of days of pretreatment sedative use was associated with increased likelihood of opioid relapse (OR: 1.01, 95% CI: 1.00–1.02). Proportion of days of cocaine use during the initial 4 weeks of treatment was associated with increased likelihood of opioid relapse (OR: 1.05, 95% CI: 1.01–1.09) but this effect was no longer significant once the potential of confounding by opioid use was considered. Sedative use during initial 4 weeks of treatment was associated with increased opioid craving (b: 0.77, 95% CI: 0.01–1.52). The study found no other significant relationships.

Conclusions: In the current study population, polysubstance use was only marginally associated with 24-week treatment outcomes.

Related protocols: CTN-0051

Sleep disturbance may play a role in cocaine use outcomes and, hence, may be a potential therapeutic target for cocaine use disorder (CUD). Research in this area, which has largely relied on resource-intensive polysomnography, would be facilitated by identifying a self-report sleep measure predictive of CUD outcomes and by a better understanding of the mechanisms by which sleep may impact CUD outcomes.

This study, a secondary analysis of CTN-0046 (Smoking Cessation and Stimulant Treatment), tested the predictive validity of the Pittsburgh Sleep Quality Index (PSQI), a self-report assessment of past-month sleep quality. To better understand potential mechanisms, mediation models relating sleep disturbance to CUD outcomes were evaluated.

The PSQI was collected at baseline; the outcomes of interest were cocaine and drug abstinence at end-of-treatment (weeks 9-10). Potential mediators, measured in weeks 1-8, were: cocaine craving (Brief Substance Craving Scale); and anxiety and depression symptoms (Hospital Anxiety and Depression Scale). Mediation techniques were used to evaluate mediation effects separately and jointly.

The majority of participants (58.3%) had baseline sleep disturbance. Sleep disturbance was not a significant predictor of end-of-treatment abstinence when regressed without consideration of mediators. Cocaine craving, anxiety, and depression were significant mediators, both separately and jointly, of an effect of baseline sleep disturbance on end-of-treatment abstinence.

Conclusions: This exploratory analysis suggests that there may be an indirect relationship between self-reported sleep quality and substance use outcomes in cocaine-dependent patients, mediated by craving, anxiety, and depression.

Related protocols: CTN-0046

A double blind, placebo-controlled randomized trial evaluation osmotic-release oral system methylphenidate (OROS-MPH) for smoking cessation revealed a significant interaction effect in which participants with higher baseline ADHD severity had better abstinence outcomes with OROS-MPH while participants with lower baseline ADHD severity had worse outcomes (CTN-0029). This study examined secondary outcomes that might bear on the mechanism for this differential effect treatment effect. Longitudinal analyses were conducted to evaluate the effect of OROS-MPH on three secondary outcomes (ADHD symptom severity, nicotine craving, and withdrawal) in the total sample (N=255, 56% male) and in the high (N=134) and low (N=121) baseline ADHD severity groups.

Results found that OROS-MPH significantly improved ADHD symptoms and nicotine withdrawal symptoms in the total sample, and exploratory analyses showed that in both higher and lower baseline severity groups, OROS-MPH statistically significantly improved these two outcomes. No effect on craving overall was detected, though exploratory analyses showed statistically significantly decreased craving in the high ADHD severity participants on OROS-MPH. No treatment by ADHD baseline severity interaction was detected for the outcomes.

Conclusions: Methylphenidate improved secondary outcomes during smoking cessation independent of baseline ADHD severity, with no evident treatment-baseline severity interaction. Results suggest divergent responses to smoking cessation treatment in the higher and lower severity groups cannot be explained by concordant divergence in craving, withdrawal, and ADHD symptoms severity, and alternative hypotheses may need to be identified.

Related protocols: CTN-0029

Smoking prevalence is high among substance abusers, making it important to understand when nicotine abstinence will aid, impair, or not affect abstinence from other substances. This study tested novel hypotheses about the coupling of nicotine and stimulant craving over time during stimulant dependence treatment. Adults (N=538) with cocaine and/or methamphetamine dependence completed a 10-week randomized controlled trial of substance use treatment with or without smoking cessation treatment (NIDA Clinical Trials protocol CTN-0046, Smoking Cessation and Stimulant Treatment, S-CAST). Participants reported nicotine and stimulant craving weekly and use twice per week. Latent change score modeling tested the association between weekly increases in nicotine craving and subsequent weekly changes in stimulant craving. Interestingly, results revealed a “substitution” effect: increases in nicotine craving predicted subsequent decreases in stimulant craving. Additionally, increases in nicotine craving predicted subsequent increases in nicotine use, and decreases in stimulant use. As expected, the substitution effect between nicotine and stimulant craving was stronger when stimulants were administered through the same route as nicotine (i.e., smoking), versus other routes. Finally, smoking cessation treatment eliminated the coupling between nicotine craving and stimulant craving.

Conclusions: Contrary to concerns about nicotine abstinence during substance dependence treatment, increases in nicotine craving may be associated with later reductions in stimulant craving and use, and unrelated when smoking cessation treatment is introduced. Weekly changes in nicotine craving convey information that can help clinicians to predict and understand shifts in stimulant craving and use during substance use disorder treatment. This research improves the understanding of how the ebb and flow of craving relates across substances and holds promise for treatments that harness these interrelationships to improve abstinence from co-occurring substance use problems.

Related protocols: CTN-0046

Smoking is highly prevalent in substance dependence, but smoking-cessation treatment (SCT) is more challenging in this population. To increase the success of smoking cessation services, it is important to understand potential therapeutic targets, like nicotine craving, that have meaningful but highly variable relationships with smoking outcomes. This secondary analysis of data from National Drug Abuse Treatment Clinical Trials Network protocol CTN-0046 (Smoking Cessation and Stimulant Treatment) characterized the presence, magnitude, and specificity of nicotine craving as a mediator of the relationship between SCT and smoking abstinence in the context of stimulant-dependence treatment. The original trial was a randomized, 10-week study conducted at 12 outpatient substance use disorder (SUD) treatment programs. Adults with cocaine and/or methamphetamine dependence (n=538) were randomized to SUD treatment as usual (TAU) or TAU+SCT. Participants reported nicotine craving, nicotine withdrawal symptoms, and substance use in the week following a uniform quit attempt of the TAU+SCT group, and self-reported smoking 7-day point prevalence abstinence (verified by carbon monoxide) at end-of-treatment.

Bootstrapped regression models indicated that, as expected, nicotine craving in the week following a quit attempt was a significant mediator between SCT and smoking abstinence, accounting for 14% of the total effect. Nicotine withdrawal symptoms and substance use were not significant mediators. This pattern held for separate examinations of cocaine and methamphetamine dependence.

Conclusions: Nicotine craving accounts for a small but meaningful portion of the relationship between smoking-cessation treatment and smoking-abstinence during SUD treatment. Nicotine craving, particularly during the week following a quit attempt, may be a useful therapeutic target for increasing the effectiveness of smoking-cessation treatment in substance dependence. This timing is useful for clinicians and researchers attempting to predict outcomes within SUD treatment, as the increased variability and intensity of craving after a quit attempt may produce a clearer relationship between craving and nicotine outcomes.

Related protocols: CTN-0046

The rapid rise in the number of methamphetamine users, relative to cocaine users, has brought the number of each to nearly equal levels, making research on similarities and differences across these groups a needed area of exploration. Craving is postulated to play a significant role in relapse for both users types, yet group differences on observed scale scores have been reported without first assessing the prerequisite measurement equivalence (invariance) of the items, which is essential for meaningful group comparisons. A brief, practical measure of cocaine craving exists (the 10-item Cocaine Craving Questionnaire-Brief [CCQ-Brief]), however, the data were collected over a decade ago at one site, excluded individuals under age 26 and individuals dependent on stimulants other than cocaine, and only 3% were female. For this study, the CCQ-Brief was adapted to broaden it to include “cocaine, methamphetamine or other stimulants,” instead of just cocaine. The aim of this research was to psychometrically assess the resultant measure, the Stimulant Craving Questionnaire (STCQ).

Baseline data from stimulant users in residential treatment participating in CTN-0037 (Stimulant Reduction Intervention Using Dosed Exercise [STRIDE]) were used to assess the measurement invariance of the STCQ (N=301, n=177 cocaine, 124 methamphetamine). The unifactorial scale demonstrated measurement invariance across cocaine and methamphetamine users for factor loadings (metric), common residual covariances between item pairs, and item intercepts (scalar), as determined by fit indices. The latent mean, as well as 5 (out of 10) item means and the overall composite scale score, was significantly greater for methamphetamine users compared to cocaine users.

Conclusions: Results indicate that the STCQ is an invariant tool for the assessment of stimulant craving across the two most prevalent user types. Methamphetamine users had significantly higher levels of observed and latent craving than cocaine users, demonstrating a potentially meaningful difference in craving between users of these two stimulants. Future research will determine if treatments and statistical models need to account for craving variations across methamphetamine and cocaine users.

Related protocols: CTN-0037

Most patients relapse to opioids within one month of opioid agonist detoxification, making the antecedents and parallel processes of first use critical for investigation. Craving and withdrawal are often studied in relationship to opioid outcomes, and a novel analytic strategy applied to these two phenomena may indicate targeted intervention strategies. Specifically, this secondary data analysis of the National Drug Abuse Treatment Clinical Trials Network Prescription Opioid Addiction Treatment Study (POATS, CTN-0030) used a discrete-time mixture analysis with time-to-first opioid use (survival) simultaneously predicted by craving and withdrawal growth trajectories. This analysis characterized heterogeneity among prescription opioid-dependent individuals (N=653) into latent classes (i.e., latent class analysis [LCA]) during and after buprenorphine/naloxone stabilization and taper. A 4-latent class solution was selected for overall model fit and clinical parsimony. In order of shortest to longest time-to-first use, the 4 classes were characterized as 1) high craving and withdrawal; 2) intermediate craving and withdrawal; 3) high initial craving with low craving and withdrawal trajectories; and 4) a low initial craving with low craving and withdrawal trajectories. Odds ratio calculations showed statistically significant differences in time-to-first use across classes.

Conclusions: Generally, participants with lower baseline levels and greater decreases in craving and withdrawal during stabilization combined with slower craving and withdrawal rebound during buprenorphine taper remained opioid-free longer. This exploratory work expanded on the importance of monitoring craving and withdrawal during buprenorphine induction, stabilization, and taper. Future research may allow individually tailored and timely interventions to be developed to extent time-to-first opioid use.

Related protocols: CTN-0030

Craving is viewed as a core feature of substance use disorders and has been shown to predict future drug use, particularly over the short term. Accordingly, craving is often assessed in treatment settings as a marker of risk for subsequent drug use. The identification of the briefest measure that maintains predictive validity is of particular value for both clinical and research settings to minimize assessment burden while maintaining utility for the prediction of use. Data from a National Drug Abuse Treatment Clinical Trials Network multi-site clinical trial of treatment for prescription opioid dependence (CTN-0030) were examined to evaluate whether a brief, 3-item craving scale, the Opioid Craving Scale, administered each week predicted urine-confirmed self-report of prescription opioid use in the subsequent week. Logistic regression models examining the association between craving and presence or absence of opioid use in the following week were conducted, controlling for opioid use in the previous week, treatment condition, and lifetime history of heroin use. Greater craving was associated with higher odds of prescription opioid use in the following week. For each one-unit increase on this 10-point scale, the odds of using opioids in the subsequent week was 17% higher. In addition to an item assessing urges, items assessing cue-induced craving and perceived likelihood of relapse in an environment where drugs were previously used contributed uniquely to this association.

Conclusions: A brief measure of prescription opioid craving predicted prescription opioid use among individuals in treatment and demonstrated internal consistency, reliability, and concurrent and predictive validity. This measure offers an efficient strategy to inform the assessment of risk for use in this population and may be a valuable tool in both clinical and research settings.

Related protocols: CTN-0030

This study aimed to quantify the relations between craving and withdrawal symptoms and time to first opioid use among prescription opioid (PO) abusers undergoing buprenorphine detoxification. Higher indicators of craving and withdrawal at the outset of the taper were hypothesized to predict earlier user. Data from 653 PO-dependent individuals initiating a 14-day taper from buprenorphine/naloxone, recruited for the National Drug Abuse Treatment Clinical Trials Network protocol CTN-0030, were analyzed using survival analysis to explore time to first use as a function of opioid craving and withdrawal. Participants were collapsed across condition and measurements taken at the start of the taper were used. Participants were followed for 10 weeks after the taper began. PO craving was measured by 3 items on the Visual Analog Scale (VAS; e.g. “How much do you currently crave opiates?”) and opioid withdrawal was measured by the Clinical Opiate Withdrawal Scale and 1 item on the VAS. Withdrawal significantly predicted time to first use, such that each withdrawal unit increase led to a 1.0% decrease in time to first use. Craving items significantly predicted time to first use. Each unit increase on the craving item response scales was associated with a 1.7% to 1.9% decrease in time to first use, depending on the item. Further analyses revealed differences among individuals who terminated study involvement after the first taper and those willing to take part in a second taper.

Conclusions: Higher reports of withdrawal and craving at the outset of a buprenorphine taper are important clinical indicators of earlier lapse to opioids. Novel therapies to attenuate these effects are needed.

Related protocols: CTN-0030

Novel approaches to the treatment of stimulant abuse and dependence are needed. Clinical data examining the use of exercise as a treatment for the abuse of nicotine, alcohol, and other substances suggest that exercise may be a beneficial treatment for stimulant abuse. In addition, exercise has been associated with improvements in many other health-related areas that may be adversely affected by stimulant use or its treatment, such as sleep disturbance, cognitive function, mood, weight, quality of life, and anhedonia. Neurobiological evidence provides plausible mechanisms by which exercise could positively affect treatment outcomes in stimulant abuse. National Drug Abuse Treatment Clinical Trials Network protocol CTN-0037, Stimulant Reduction Intervention using Dosed Exercise (STRIDE), is a multisite randomized clinical trial that compares exercise to health education as potential treatments for stimulant abuse or dependence. If exercise were to have an impact on acute and longer-term outcomes when added to usual substance abuse treatment, this would be of substantial public health importance. Exercise has limited side effects compared with medications, is not likely to interact with concurrent pharmacotherapy, is lower in cost, can be performed at home, can be continued indefinitely if effective in diverting relapse, and may be useful with vulnerable populations such as pregnant women. Exercise may also improve overall health and functional status, and reduce the cost burden associated with substance use disorders.

Related protocols: CTN-0037

The Patient Feedback Survey, developed and evaluated in National Drug Abuse Treatment Clinical Trials Network protocol CTN-0016, is a performance improvement measure designed to assess the quality of outpatient substance abuse treatment. In this study, researchers modified and administered this measure to 500 individuals at AdCare Hospital, one of the New England Consortium Node’s community treatment providers (CTPs). Although the feedback scores were high in general, analyses of variance showed score variability in relation to type and length of treatment. Moreover, respondents who reported any use of marijuana, cravings for substances, or mutual-support group attendance (i.e., Alcoholics Anonymous or Narcotics Anonymous) had lower feedback scores than respondents without these experiences.

Conclusions: The results of the PFS study show that patients seeking outpatient services at a multisite community treatment program report positive evaluations of their treatment sessions. These findings are similar to the results of the original CTN study. The modified PFS appears to be an efficient measure that has the potential to gain broader applicability. This article highlights the importance of investigating treatment evaluations in the context of other recovery experiences.

Related protocols: CTN-0016