Who responds to a multi-component treatment for cannabis use disorder? Using multivariable and machine learning models to classify treatment responders and non-responders.

BACKGROUND AND AIMS: 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 versus non-responders. METHODS: This secondary analysis used data from a National Drug Abuse Treatment Clinical Trials Network multi-site outpatient clinical trial in the United States. 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. RESULTS: Prediction performance for various machine learning and regression prediction models yielded area under the curves (AUCs) >0.70 for four models (0.72-0.77), with support vector machine models having the highest overall accuracy (73%; 95% CI = 68-78%) and AUC (0.77; 95% CI = 0.72, 0.83). Fourteen variables were retained in at least three of four 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 on chance prediction of treatment response to outpatient cannabis use disorder treatment, although further improvements in prediction performance are likely necessary for decisions about clinical care.

Determining the impact of cannabis use and severity on tobacco cessation outcomes: study protocol for a prospective tobacco treatment trial.

BACKGROUND: Several evidence-based tobacco cessation treatment strategies exist, though significant barriers to cessation remain which must be addressed to improve abstinence rates for sub-populations of those smoking cigarettes. Cannabis co-use among those who use tobacco is common and appears to be increasing among adults in the United States (US). The literature evaluating the impact of cannabis use on tobacco cessation has been mixed and has several important limitations, which precludes development of treatment recommendations specific to individuals who use tobacco and co-use cannabis. To date, no prospective studies have evaluated the impact of cannabis use and severity on tobacco cessation or quantified cannabis use changes during tobacco treatment to assess for concurrent reductions, abstinence, or compensatory (i.e., increased) cannabis use. This study's aims are to: (1) evaluate tobacco cessation outcomes among participants who co-use cannabis compared to participants only using tobacco, (2) using daily diaries and biochemical verification, assess changes in cannabis use during tobacco treatment, and (3) assess for a dose-dependent impact of cannabis use on tobacco cessation. METHOD: A multi-site, prospective, quasi-experimental 12-week tobacco treatment trial enrolling treatment-seeking adults (ages 18-40; N = 208) from three sites across South Carolina (US) who use tobacco daily and oversampling (2:1) those who co-use cannabis. Participants receive tobacco cessation pharmacotherapy (varenicline) paired with behavioral support, while cannabis use is not addressed as part of treatment. The primary outcome is 7-day point prevalence tobacco abstinence at the week 12 end of treatment visit, measured via biochemical verification and self-report. Secondary outcome measures include changes in cannabis use (via biochemical verification and self-report) during tobacco cessation treatment. DISCUSSION: Results from this trial have the potential to inform tobacco treatment among those co-using cannabis, which may require a tailored approach to address the role of cannabis in quitting tobacco. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov: NCT04228965. January 14th, 2020.

Treatment Implications Associated with Cannabis and Tobacco Co-Use.

PURPOSE OF THE REVIEW: The goal of this article is to summarize the treatment-focused literature on cannabis and tobacco co-use and the treatment implications of co-use. This review will focus on: 1) the impact of co-use on cessation outcomes, 2) compensatory use/substitution of the non-treated substance among co-users, and 3) treatment interventions to address co-use. This article will highlight the limitations to co-use captured in the literature and offer considerations and directives for co-use research and treatment moving forward. RECENT FINDINGS: The degree to which co-use affects cessation for a single, targeted substance remains in question, as the literature is largely mixed. Cannabis treatment trials are better equipped to answer these questions given that they do not typically exclude tobacco users. While the relationship between tobacco use and poorer cannabis outcomes appears to have some evidence, the reverse relationship (cannabis use affecting tobacco outcomes) is not consistently supported. SUMMARY: The co-use of cannabis and tobacco and its impact on single substance cessation and/or compensatory substance use during cessation is generally overlooked in treatment trials, while interventions to address both substances are rare. Capturing co-use adds burden for researchers, clinicians, and participants, but is warranted given the prevalence of co-use and a rapidly changing cannabis and tobacco regulatory environment, which may further complicate co-occurring substance use. Co-users are a heterogeneous population; trials focused on co-users, in addition to better data capture and consistent terminology, will aid in an understanding of nuanced patterns of co-use critical to inform treatment interventions.

Cannabis and Alcohol Co-Use in a Smoking Cessation Pharmacotherapy Trial for Adolescents and Emerging Adults.

INTRODUCTION: The co-use of cannabis and alcohol among tobacco-using youth is common. Alcohol co-use is associated with worse tobacco cessation outcomes, but results are mixed regarding the impact of cannabis on tobacco outcomes and if co-use leads to increased use of non-treated substances. This secondary analysis from a youth smoking cessation trial aimed to (1) evaluate the impact of cannabis or alcohol co-use on smoking cessation, (2) examine changes in co-use during the trial, and (3) explore secondary effects of varenicline on co-use. METHODS: The parent study was a 12-week, randomized clinical trial of varenicline for smoking cessation among youth (ages 14-21, N = 157; Mage = 19, 40% female; 76% White). Daily cigarette, cannabis, and alcohol use data were collected via daily diaries during treatment and Timeline Follow-back for 14 weeks post-treatment. RESULTS: Baseline cannabis co-users (68%) had double the odds of continued cigarette smoking throughout the trial compared with noncannabis users, which was pronounced in males and frequent cannabis users. Continued smoking during treatment was associated with higher probability of concurrent cannabis use. Baseline alcohol co-users (80%) did not have worse smoking outcomes compared with nonalcohol users, but continued smoking was associated with higher probability of concurrent drinking. Varenicline did not affect co-use. CONCLUSIONS: Inconsistent with prior literature, results showed that alcohol co-users did not differ in smoking cessation, whereas cannabis co-users had poorer cessation outcomes. Youth tobacco treatment would benefit from added focus on substance co-use, particularly cannabis, but may need to be tailored appropriately to promote cessation. IMPLICATIONS: Among youth cigarette smokers enrolled in a pharmacotherapy evaluation clinical trial, alcohol and/or cannabis co-use was prevalent. The co-use of cannabis affected smoking cessation outcomes, but more so for males and frequent cannabis users, whereas alcohol co-use did not affect smoking cessation. Reductions in smoking were accompanied by concurrent reductions in alcohol or cannabis use. Substance co-use does not appear to affect all youth smokers in the same manner and treatment strategies may need to be tailored appropriately for those with lower odds of smoking cessation.

Depressive symptoms and cannabis use in a placebo-controlled trial of N-Acetylcysteine for adult cannabis use disorder.

RATIONALE: Depression is common among individuals with cannabis use disorder (CUD), particularly individuals who present to CUD treatment. Treatments that consider this comorbidity are essential. OBJECTIVES: The goal of this secondary analysis was to examine whether N-acetylcysteine (NAC) reduced depressive symptoms among adults (age 18-50) 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. METHODS: Data for this secondary analysis were from a National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) multi-site clinical trial for CUD. Adults with CUD (N = 302) were randomized to receive 2400 mg 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-Δ9-tetrahydrocannabinol) confirmed abstinence. Depressive symptoms were measured by the Hospital Anxiety and Depression Scale. RESULTS: 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 this 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 suggest that depression may be a risk factor for poor CUD treatment outcome and therefore should be addressed in the context of treatment. However, results do not support the use of NAC to concurrently treat co-occurring depressive symptoms and CUD in adults. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01675661.

Pharmacological Treatment of Youth Substance Use Disorders.

While the majority of youth who experiment with alcohol and drugs do not develop problematic levels of use, 5% of adolescents and 15% of young adults meet criteria for a substance use disorder (SUD). Pharmacotherapy, in combination with behavioral interventions, has the potential to increase the likelihood of successful treatment for youth struggling with SUD; however, the literature in this area is limited. To date, there are no Food and Drug Administration (FDA)-approved medications for adolescent SUD, other than buprenorphine, which has been approved down to 16 years of age for opioid use disorder. Despite alcohol and cannabis being the most commonly used substances during adolescence, only three medications have been tested among this demographic, and only two have warranted further study (i.e., naltrexone for alcohol and N-acetylcysteine for cannabis use disorder). Although less common in adolescents and young adults, the most promising pharmacological findings for this age group are for opioid (buprenorphine) and tobacco (bupropion and varenicline) use disorders. In addition, despite the recent marked increases in electronic nicotine delivery systems (i.e., vaping) among youth, treatment strategies are still in their infancy and no recommendation exists for how to promote cessation for youth vaping. Current findings are limited by: small, demographically homogeneous samples; few trials, including a substantial number of youth younger than 18; low retention; medication adherence rates; and minimal information on effective dosing levels and long-term outcomes. Overall, pharmacotherapy may be a potentially effective strategy to increase treatment effects; however, more rigorous research trials are warranted before FDA approval would be granted for any of the potential adjunctive medications in this age group.

Blunts versus joints: Cannabis use characteristics and consequences among treatment-seeking adults.

BACKGROUND: 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, such as joints. METHODS: The current study uses baseline data from the ACCENT (Achieving Cannabis Cessation-Evaluating N-acetylcysteine Treatment) study, a multi-site randomized pharmacotherapy clinical trial within the National Drug Abuse Treatment 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 screened for study participation. RESULTS: 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 (t = 3.04, p < .01), the estimated average cost of cannabis (t = 2.28, p < .05) and Cannabis Withdrawal Scale scores (t = 1.94, p < .05). 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.

Tobacco use during cannabis cessation: Use patterns and impact on abstinence in a National Drug Abuse Treatment Clinical Trials Network study.

BACKGROUND: It is common for cannabis users to also use tobacco. While data suggest that tobacco users have more difficulty achieving cannabis cessation, secondary analyses of clinical trial data sets may provide insight into the moderating variables contributing to this relationship, as well as changes in tobacco use during cannabis treatment. Those were the aims of this secondary analysis. METHODS: The parent study was a multi-site trial of N-acetylcysteine for cannabis dependence conducted within the National Drug Abuse Treatment Clinical Trials Network. Participants were treatment-seeking adults (ages 18-50) who met criteria for cannabis dependence (N = 302). For cigarette smokers (n = 117), tobacco use was assessed via timeline follow-back and nicotine dependence was assessed via the Fagerström Test for Nicotine Dependence (FTND). Outcome measures included: 1) changes in tobacco use based on treatment assignment, nicotine dependence, and concurrent cannabis reduction/abstinence, and 2) independent associations between nicotine dependence and cannabis abstinence. RESULTS: Cigarette smokers accounted for 39% of the sample (117/302), with a median FTND score of 3.0 (10-point scale). Among those with lower baseline nicotine dependence scores, cigarette smoking was reduced in the active treatment group compared to placebo. Those with moderate/high levels of nicotine dependence showed slight increases in smoking following active treatment. Nicotine dependence did not affect cannabis cessation. CONCLUSIONS: Cigarette smoking during cannabis treatment was affected, but depended on baseline nicotine dependence severity, though dependence levels did not impact cannabis abstinence. Interventions that address both tobacco and cannabis are needed, especially due to an increasing prevalence of cannabis use.

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.

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.

Comparing adult cannabis treatment-seekers enrolled in a clinical trial with national samples of cannabis users in the United States.

BACKGROUND: Cannabis use rates are increasing among adults in the United States (US) while the perception of harm is declining. This may result in an increased prevalence of cannabis use disorder and the need for more clinical trials to evaluate efficacious treatment strategies. Clinical trials are the gold standard for evaluating treatment, yet study samples are rarely representative of the target population. This finding has not yet been established for cannabis treatment trials. This study compared demographic and cannabis use characteristics of a cannabis cessation clinical trial sample (run through National Drug Abuse Treatment Clinical Trials Network) with three nationally representative datasets from the US; 1) National Survey on Drug Use and Health, 2) National Epidemiologic Survey on Alcohol and Related Conditions-III, and 3) Treatment: Episodes Data Set - Admissions. METHODS: Comparisons were made between the clinical trial sample and appropriate cannabis using sub-samples from the national datasets, and propensity scores were calculated to determine the degree of similarity between samples. RESULTS: showed that the clinical trial sample was significantly different from all three national datasets, with the clinical trial sample having greater representation among older adults, African Americans, Hispanic/Latinos, adults with more education, non-tobacco users, and daily and almost daily cannabis users. CONCLUSIONS: These results are consistent with previous studies of other substance use disorder populations and extend sample representation issues to a cannabis use disorder population. This illustrates the need to ensure representative samples within cannabis treatment clinical trials to improve the generalizability of promising findings.

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.

Gender Differences in Internalizing Symptoms and Suicide Risk Among Men and Women Seeking Treatment for Cannabis Use Disorder from Late Adolescence to Middle Adulthood.

Cannabis continues to rise in popularity as the perception of its harmfulness decreases and evidence of its deleterious developmental effect increases. While internalizing distress and suicide risk have been linked with cannabis use problems [DSM-5 cannabis use disorder (CUD); DSM-IV cannabis abuse and dependence] it remains unclear how this association varies over the course of development in treatment-seeking men and women. The current study utilized the National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) to conduct a cross-sectional comparison of internalizing distress and suicide risk among men (n=437) and women (n=163) spanning ages 18-50 who met DSM-5 criteria for CUD. Interactions between gender and developmental stage (i.e., late adolescence, early adulthood, and middle adulthood) were observed for suicide risk and anxiety but not depression problems. Specifically, women seeking CUD treatment in late adolescence and middle adulthood exhibited significantly higher rates of anxiety and suicide risk compared to men seeking treatment during the same developmental stages. Internalizing distress and suicide risk did not differ between treatment-seeking men and women in the early adult stage. Overall, results suggest that the structure of risk for CUD may differ in men and women across the lifespan and that women presenting for CUD treatment during late adolescence and middle adulthood may uniquely benefit from intervention designed to address these elevations in anxiety and suicide risk.

Achieving cannabis cessation -- evaluating N-acetylcysteine treatment (ACCENT): design and implementation of a multi-site, randomized controlled study in the National Institute on Drug Abuse Clinical Trials Network.

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 Institute on Drug Abuse Clinical Trials Network (NIDA CTN) is currently conducting a study to test the efficacy of N-acetylcysteine (NAC) versus placebo (PBO), 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 PBO. 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 (1200 mg) 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.

Cigarette smoking during an N-acetylcysteine-assisted cannabis cessation trial in adolescents.

BACKGROUND AND OBJECTIVES: Tobacco and cannabis use are both highly prevalent worldwide. Their co-use is also common in adults and adolescents. Despite this frequent co-occurrence, cessation from both substances is rarely addressed in randomized clinical trials. Given evidence that tobacco use may increase during cannabis cessation attempts, and additionally that tobacco users have poorer cannabis cessation outcomes, we explored tobacco outcomes, specifically cigarette smoking, from an adolescent cannabis cessation trial that tested the efficacy of N-acetylesteine (NAC). METHODS: Cannabis-dependent adolescents (ages 15-21; n = 116) interested in cannabis treatment were randomized to NAC (1200 mg bid) or matched placebo for 8 weeks. Participants did not need to be cigarette smokers or be interested in smoking cessation to qualify for inclusion. RESULTS: Approximately 59% of enrolled participants were daily and non-daily cigarette smokers, and only differed from non-smoking participants on the compulsion sub-scale of the Marijuana Craving Questionnaire. Among cigarette smokers who were retained in the study, there was no change in cigarettes per day for either NAC or placebo groups during the eight-week treatment phase. Being a cigarette smoker did not appear to influence the effects of NAC on cannabis abstinence, though there was a trend in the placebo group of poorer cannabis outcomes for cigarette smokers vs. non-smokers. CONCLUSIONS: No evidence was found of compensatory cigarette smoking during this cannabis cessation trial in adolescents. Further work assessing interventions to reduce both cannabis and tobacco use in this population is greatly needed.

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.

Characteristics of an outpatient treatment sample by primary substance of abuse.

OBJECTIVE: This study examines sociodemographic and clinical characteristics, as a function of primary substance of abuse, among clients approached, screened, and assessed for eligibility in a 10-site effectiveness trial of a Web-based psychosocial intervention for substance use disorders. Consistent with the design of effectiveness trials, eligibility criteria were broad and exclusion criteria minimal; thus, the recruited sample may be viewed as relatively representative of patients seeking treatment throughout the United States. METHODS: χ tests for categorical variables and F tests for continuous variables were used to analyze demographic, substance use, physical and mental health, and sexual risk data collected at screening and baseline; pairwise comparisons between primary substance subgroups for baseline data were conducted if the test statistic P value was 0.01 or less. RESULTS: Few participants expressed disinterest in the study at screening because of the computer-assisted intervention. A diverse sample of substance users completed baseline and were enrolled: 22.9% marijuana; 21.7% opiates; 20.9% alcohol; 20.5% cocaine; and 13.9% stimulants users. Marijuana users demonstrated the greatest differences across primary substances: they were younger, less likely to be married or attend 12-step meetings, and more likely to be in treatment as a result of criminal justice involvement. All patients, even marijuana users, reported comparable rates of co-occurring mental health disorders and sexual risk and substantial rates of polysubstance use disorders. CONCLUSIONS: Primary substance of abuse may be a less important indicator of overall severity compared with co-occurring disorders and other factors common across treatment seekers, further demonstrating the need for integrated treatment services and care and comprehensive pretreatment assessment.