Introduction

While cannabis use is increasingly prevalent across age groups, adolescents and young adults represent an age range of particular concern regarding cannabis-related adverse outcomes. Adolescent-onset cannabis use is more than twice as likely as adult-onset use to progress to an impairing pattern of use defined as cannabis use disorder. Moreover, youth who use cannabis regularly are particularly prone to adverse educational, occupational, and mental health outcomes associated with cannabis use.

The current evidence base for addressing cannabis use disorder in youth includes psychosocial, behavioral, and family-based interventions. While this array of interventions may be helpful for many young people presenting with cannabis use disorder, effect sizes are small to modest and long-term outcomes are limited. Efforts are afoot to yield improved outcomes, both via bolstering these interventions and via examination of potential pharmacological approaches to complement them. To date, there are no United States Food and Drug Administration approved medications for cannabis use disorder in adolescents or adults. However, amid increased rates of cannabis use disorder, there has been a focus on developing and testing candidate medications for this condition.

Among candidate medications for cannabis use disorder is N-acetylcysteine, a compound that has demonstrated amelioration of substance use-induced dysregulation of the neurotransmitter glutamate in the nucleus accumbens in rodent models, as well as associated reductions in substance self-administration. Given that N-acetylcysteine is readily available as an over-the-counter supplement and has demonstrated tolerability across age groups even at high doses when administered to address acetaminophen toxicity, it has been considered a medication with strong potential for broad dissemination and implementation if preclinical findings translate to human substance use disorders.

A prior randomized, placebo-controlled trial in youth ages 14–21 evaluated N-acetylcysteine added to brief weekly counseling and a twice-weekly contingency management intervention, in which visit attendance and negative urine cannabinoid test results were monetarily reinforced. Participants receiving N-acetylcysteine had more than double the odds, compared to placebo participants, of achieving cannabis abstinence reflected in negative urine cannabinoid tests. A subsequent similarly designed trial in adults ages 18–50 yielded null findings, with no difference in cannabis use outcomes between N-acetylcysteine and placebo groups, suggesting that N-acetylcysteine’s effect on cannabis use disorder may be developmentally specific to youth. This assertion was further supported by a post hoc analysis of participants ages 18–21 in the adult trial, indicating an effect size favoring N-acetylcysteine over placebo comparable to that observed in the prior youth-focused trial. These discrepant findings across youth versus adult participants may potentially reflect differential effects of N-acetylcysteine based on developmental stage, or may be owing to developmental differences in the course, context, and phenomenology of cannabis use disorder. Of note, given that these trials included contingency management as a robust platform behavioral intervention, questions remained regarding the context in which N-acetylcysteine might be effectively delivered to youth in clinical practice. Specifically, it was unclear whether N-acetylcysteine would yield a positive effect if not paired with contingency management. This is an important consideration, particularly given prior evidence of synergy between pharmacotherapy and contingency management in interventions for youth substance use disorders.

The present trial was conducted to evaluate N-acetylcysteine’s efficacy for youth cannabis use disorder when paired with brief medical clinician-delivered cessation counseling and medical management. Findings were deemed relevant for clinical practice, particularly to distinguish whether contingency management—included in a prior youth trial with positive findings, but not in the present trial—is a necessary platform treatment to facilitate N-acetylcysteine’s efficacy for youth cannabis use disorder.

Participants and methods

Study design and participants

This randomized, double-blind, placebo-controlled, parallel-group study included a screening period of up to 4 weeks, a 12-week treatment course, and follow-up through week 26 from randomization, with post-treatment visits at approximately weeks 16 and 26. The study received Medical University of South Carolina Institutional Review Board approval and was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice guidelines. Study outcomes were pre-registered on clinicaltrials.gov (NCT 03055377). The 2400 mg/day dosage of oral N-acetylcysteine, administered as 1200 mg twice daily, was selected based on prior positive findings with this dosage combined with contingency management. Participants ages ≥18 provided written informed consent. Written parental consent and participant assent were obtained for those <18 years old. Eligible participants were ages 14–21, met DSM-5 criteria for cannabis use disorder within the last 30 days, expressed interest in cannabis use disorder treatment, and submitted a urine sample positive for cannabinoids (> 50 ng/mL). Individuals currently enrolled in cannabis use disorder treatment, with moderate or severe substance use disorders aside from cannabis or nicotine/tobacco, with current (past 30 days) or planned synthetic cannabinoid use, pregnant or lactating, currently prescribed carbamazepine or nitroglycerin, with seizure disorder or uncontrolled severe asthma, or with acutely unstable medical or psychiatric disorders were excluded.

Participants self-reported baseline motivation, readiness, and confidence to quit using cannabis (all on a 1–10 scale, with 1 = “not” and 10 = “extremely”) and were randomized in 1:1 ratio to N-acetylcysteine or placebo, stratified by age (≤18 versus ≥19) and by nicotine use status (assessed via Clinical Laboratory Improvement Amendments of 1988 [CLIA]-waived point-of-care urine cotinine test, with cutoff of <50 ng/mL signifying a cotinine-negative sample and thus categorizing into the non-nicotine-use group). A stratified random block design was utilized with random block sizes of 4 and 6. The randomization schedule was developed by the study statistician prior to initiation of enrollment, using a blinded allocation (A/B), and the investigational pharmacy randomly assigned active NAC and placebo treatment to A/B assignments. Participants, clinicians, and study personnel were blind to treatment allocation throughout the study.

Procedures

United States Pharmacopeia (USP) grade N-acetylcysteine powder was encapsulated in 600 mg quantities (two 600 mg capsules per dose). Matched placebo capsules were also prepared. All capsules were packaged and dispensed in blister packs, with individual labels for time/date of each dose. Participants were instructed to take two capsules (1200 mg) twice daily (total of 2400 mg per day), in approximately 12-h intervals; in the event of issues with tolerability, dose adjustments in increments of 600 mg were permitted at the discretion of the study medical clinician. Text messages prompted participants at the scheduled time for each dose, including a secure link for participants to upload a video recording of their medication-taking; study personnel reviewed participants’ uploaded videos to confirm adherence.

All participants received brief (typically <10 min) weekly medical clinician-delivered medical management and non-manualized skills-based cannabis cessation counseling (designed to match the intervention provided in the prior youth N-acetylcysteine trial, and to mimic what may be feasibly conducted in a busy clinical practice setting). The study, which included a hybrid of in-person and virtual visits, was conducted via a dedicated research clinic at the Medical University of South Carolina in Charleston, South Carolina.

Outcome measures

Urine cannabinoid testing at baseline, during weekly visits, and at post-treatment follow-up visits, was conducted as the primary biological measure of cannabis use. Participants self-reported cannabis use throughout the study via mobile technology-delivered daily surveys, including quantification of daily cannabis and other substance use. Missing daily substance use data were filled via Timeline Follow-Back-like procedures at study visits.

Weekly urine samples were tested qualitatively with CLIA-waived point-of-care cannabinoid tests (cutoff of <50 ng/mL signifying a cannabinoid-negative urine sample) and sent to the laboratory for quantitative cannabinoid and creatinine testing to allow for evaluation of creatinine-normalized cannabinoid levels. For virtual visits, necessitated as an option due to COVID-19 related restrictions to in-person visits, qualitative urine cannabinoid tests were conducted remotely but laboratory quantification was not performed.

Primary efficacy was assessed as self-reported abstinence from cannabis use confirmed by urine cannabinoid testing (<50 ng/mL) during the 12 weeks of treatment, measured at weekly study visits. In addition to abstinence, weekly proportion of days using cannabis (frequency) and grams of cannabis used per using day (amount) were compared between study treatment groups.

Adverse events were assessed for severity and relatedness to study treatment by the medical clinician at all visits and coded in Medical Dictionary for Regulatory Activities (MedDRA) terminology by body system.

Study personnel reviewed participants’ uploaded medication-taking videos to confirm adherence; as part of medical management, the medical clinician addressed medication adherence during weekly visits throughout treatment. Adherence was assessed as the percentage of video-verified doses compared with the expected number of doses taken, summarized at each weekly visit (range 0–100%). A participant was considered medication compliant when taking at least 80% of prescribed doses.

Statistical analysis

A sample size of 67 participants per treatment group would provide 80% power with two-sided α = 0.05 to detect a group difference on the primary endpoint (proportion of negative urine cannabinoid tests); accounting for an anticipated 30% attrition rate, a sample size of 96 per group was deemed adequate for statistical power.

Participant baseline characteristics found to be significantly associated with cannabis use outcomes were included as covariates in adjusted model development. Self-reported 7-day point prevalence abstinence, cannabis use days, and cannabis use amounts were summarized at each weekly study visit as well as follow up visits. The main effect of N-acetylcysteine on negative weekly urine cannabinoid tests was assessed with a repeated measure log-linear regression using a general estimating equations framework (GEE). Models were computed using design covariates, including study treatment assignment, visit week, baseline cannabis use rates, and characteristics utilized in the stratification at randomization (age, urine cotinine resulting indicating nicotine use status). Working correlation structures were independently compared using the quasi-likelihood under the independence model criterion statistic. All randomized participants were included in the primary analysis and assessed (1) using all available data and (2) with participants deemed non-abstinent at any missed visit (drop-out/loss-to-follow up included). Model based means were used to construct the pairwise comparisons of treatment groups. In addition to the longitudinal analysis of negative urine cannabinoid tests and 7-day point prevalence abstinence rates during treatment, rates were compared between treatment groups at each post-treatment follow-up visit using logistic regression models. Summary results are presented as means and standard deviations, while model-based results are presented as risk ratios (RR) and associated 95% confidence intervals. Secondary cannabis use outcomes were (1) percentage of days using cannabis (frequency) and (2) grams of cannabis per using day (amount) between study visits during treatment, and were compared between study groups using linear mixed effects regression models. Assumptions of residual normality were assessed using QQ plots, and when deviations from normality were determined, data transformations were made (e.g. natural logarithm, square root). In addition to the primary analysis, modifying effects of sex assigned at birth on treatment efficacy were examined. When significant, stratified treatment efficacy estimates were estimated.

Penetration of the medication blind was assessed at the end of study treatment. Between groups assessment of blinding efficacy was conducted using Pearson’s Chi-Square test statistic, and data are reported as proportions correctly identifying their actual treatment assignment.

Treatment emergent adverse events are reported as the total number of events and frequencies for the whole cohort, as well as stratified by treatment assignment for all events that occur during study treatment.

Adherence (proportion of participants taking ≥80% of medication doses) was compared between randomized treatment groups using generalized linear mixed effects models with outcome specific distributions (logistic). Overall group differences, as well as differential adherence over time, were assessed through inclusion of a treatment group factor, a linear time factor, and the appropriate interaction.

All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results

Baseline characteristics and trial retention

Participants were enrolled and data collected between August 2017 and January 2024. Among 217 participants consented and assessed for inclusion, 192 were randomized and initiated treatment (N-acetylcysteine n = 98 and placebo n = 94), and 140 attended the week 12 end-of-treatment visit (72.9%) (Fig. 1). Retention to end of treatment was similar between groups (N-acetylcysteine 71.4%, 70/98 and placebo 74.5%, 70/94). Of the 2304 possible weekly treatment visits (192 participant × 12 weekly visits), 1548 (67.2%) urine cannabinoid test results (1061 quantitative from in-person visits and 487 qualitative-only from virtual visits) and 1785 (77.5%) self-reported cannabis use summary measures were available for analysis. Further, 110 (57.3%) participants had data available at the 16-week follow-up and 93 (48.4%) at the 26-week follow-up visits. Demographic, clinical, and substance use history variables were summarized for the entire randomized cohort as well as stratified by randomized treatment assignment (Table 1). Participants were on average 19.2 years old (SD = 1.5), primarily female (52.6%), and white (78.5%); 14.1% were Hispanic and 10.4% were Black. In the 30 days prior to initial assessment, participants averaged 23.6 (SD = 7.6) cannabis use days. Additionally, 87.0% of participants had at least 1 alcohol use day and 71.4% used nicotine products; those who used nicotine averaged 17.4 nicotine use days in the 30 days prior to baseline (SD = 12.0).

Fig. 1: Recruitment and enrollment flowchart.

_{Summary of participant engagement at all stages of the trial.}

Table 1. Demographics and clinical characteristics. Data are shown as means and associated standard deviations for continuous characteristics and count and percentages for categorical characteristics.

Baseline correlates of study outcome

Higher baseline cannabis use days (RR = 0.81 95% CI: 0.86, 0.91; p = 0.002) as well as daily cannabis use (yes/no) were both negatively associated with abstinence during treatment (RR = 0.18 95% CI: 0.09, 0.35; p < 0.001); baseline nicotine use status (RR = 0.29 95% CI: 0.13, 0.63; p = 0.01) was associated with decreased probability of weekly cannabis abstinence during treatment. Higher self-reported readiness (RR = 1.20 95% CI: 1.03, 1.39; p = 0.021) and confidence to quit (RR = 1.38 95% CI: 1.13, 1.68; p = 0.002) were significantly associated with higher likelihood of study abstinence, while baseline motivation was not (RR = 1.17 95% CI: 0.96, 1.42; p = 0.13). Sex assigned at birth, age, race, nicotine and alcohol use frequency, age at initiation of self-defined regular cannabis use, any prior cannabis quit attempts, self-defined regular e-cigarette use, and cannabis use disorder severity were not associated with study abstinence (all p > 0.05).

Primary cannabis abstinence outcomes

During study treatment, 182 (11.8%) urine samples were negative for cannabinoids (N-acetylcysteine 72/763, 9.4%; placebo 110/785, 14.0%) (Fig. 2). In design adjusted models (baseline cannabis use days, age, nicotine use status), there was no statistical difference in the rate of negative urine cannabinoid tests between N-acetylcysteine and placebo participants (RR = 0.93, 95% CI =0.53, 1.64; p = 0.80). When imputing missing data to positive for urine cannabinoids, results were consistent with available data (RR = 0.85, 95% CI = 0.46, 1.55; p = 0.59). At the 16-week follow-up visit, n = 72 of 192 randomized participants had urine cannabinoid data available with 10 negative urine cannabinoid tests; 5 in the N-acetylcysteine group (5/34, 14.7%) and 5 in the placebo group (5/38, 13.2%). Similarly at the 26-week follow up time point, n = 85 participants had available urine data with 15 negative urine tests; 6 in the N-acetylcysteine group (6/38, 15.8%) and 9 in the placebo group (9/47, 19.2%) (overall RR = 0.94, 95% CI: 0.39, 2.24, p = 0.88).

Fig. 2: Abstinence rates stratified by treatment assignment.

_{Data are shown as the percentage of negative urine cannabinoid tests (UCT) and self-reported 7-day point prevalence abstinence measured during 12 weeks of study treatment. NAC = N-acetylcysteine.}

There was no evidence that participant sex assigned at birth modified treatment efficacy for urine cannabinoid test results (p > 0.70). Baseline confidence to quit showed evidence of differential relationship between the N-acetylcysteine and placebo participants (confidence × treatment interaction; χ²₁ = 6.2; p = 0.013) with a significant association between higher confidence and increased abstinence in the participants randomized to receive N-acetylcysteine (RR = 1.66 95% CI: 1.40, 2.00; p = 0.001) but non-significant in participants randomized to receive placebo (RR = 1.08 95% CI: 0.94, 1.24; p = 0.27). A similar but statistically non-significant result was seen in baseline readiness to quit (readiness × treatment interaction; χ²₁ = 3.3; p = 0.07) with a significant association between higher readiness and increased abstinence in the participants randomized to receive N-acetylcysteine (RR = 1.24 95% CI: 1.08, 1.43; p = 0.002) but non-significant in participants randomized to receive placebo (RR = 1.08 95% CI: 0.94, 1.24; p = 0.26).

Secondary cannabis use outcomes

During study treatment, 208 (11.7%) weekly self-reports were negative for cannabis use (N-acetylcysteine 93/888, 10.5%; placebo 115/897, 12.8%) (Fig. 2). Self-reported weekly abstinence taken at each study visit during treatment showed no difference between groups in design adjusted models (RR = 1.02, 95% CI = 0.63, 1.65; p = 0.93) or imputed models (RR = 0.96, 95% CI = 0.57, 1.62; p = 0.89). There was no evidence that participant sex modified treatment efficacy for self-reported weekly abstinence (p > 0.20).

The mean percentage of cannabis use days decreased over time during study treatment (β = –0.01, SE = 0.003, F_1,144 = 19.4, p < 0.001) but no differences were noted between study treatment groups (β = −0.01, SE = 0.039, F_1,180 = 0.1, p = 0.78, Fig. 3a). Similarly, grams of cannabis used per using day decreased over time during study treatment (β = −0.03, SE = 0.009, F_1,667 = 10.0, p = 0.002) but no differences were noted between groups (β = 0.00, SE = 0.08, F_1,315 = 0.00, p = 0.99, Fig. 3b).

Fig. 3: Self-reported cannabis use outcomes.

_{Weekly average self-reported (a) percentage of cannabis using day (b) and grams of cannabis use per using day. Data are shown as model-based means and associated standard errors. NAC = N-acetylcysteine.}

Blinding efficacy

At the end of treatment, 128 participants responded to the penetration of the blind questionnaire; 53.2% (n = 33/62) of N-acetylcysteine participants and 69.7% (n = 46/66) of placebo participants correctly identified their treatment assignment (χ²₁ = 3.7, p = 0.06).

Safety/adverse events

Study medication was generally well tolerated. A total of 616 adverse events were reported by 159 participants (83%) across 12 weeks of study treatment (86/98 N-acetylcysteine participants and 73/94 placebo participants). Most reported events were considered “definitely not related to study treatment” (436/616, 70.8%) and only 14 (2.3%) reported events were considered severe (N-acetylcysteine 10/347 [2.9%] and placebo 4/269 [1.5%]). The most common adverse event category across both treatment groups was gastrointestinal (63/98 N-acetylcysteine and 37/94 placebo participants, χ²₁ = 11.9, p < 0.001) followed by infections (mostly upper respiratory) (35/98 N-acetylcysteine and 38/94 placebo participants, χ²₁ = 0.5, p = 0.50). Adverse events reported by ≥5% of participants in the overall sample and/or in either the N-acetylcysteine or placebo group are summarized in Table 2. Medication dose adjustment was made in 18 (9.4%) participants during treatment, with more made in the N-acetylcysteine group (14/98, 14.3%) than the placebo group (4/94, 4.3%; p = 0.02).

Table 2. Adverse events reported by ≥5% of participants in the overall sample and/or in either the N-acetylcysteine or placebo group. Data are shown as number and percentage of participants in each group.

Medication adherence

By treatment group, 75.3% (889/1176) of N-acetylcysteine and 80.3% (896/1116) of placebo weekly reports were categorized as adherent (RR = 0.98; 95% CI = 0.91, 1.05; p = 0.56), defined as taking ≥80% of doses. Further, medication adherence was not significantly associated with negative urine cannabinoid tests during treatment (RR = 0.98; 95% CI = 0.91, 1.05; p = 0.56).

Discussion

In this randomized, placebo-controlled trial of N-acetylcysteine added to weekly medical clinician-administered brief cessation counseling and medical management for youth cannabis use disorder, demographic variables were well balanced between treatment groups, and participant retention and medication adherence rates indicated adequate power to test clinical outcomes. Across all participants, the percentage of cannabis using days and grams of cannabis used per using day decreased over time during study treatment; however, no difference in cannabis use reduction or cessation outcomes was noted between participants in the N-acetylcysteine and placebo groups. N-acetylcysteine was generally well-tolerated, differing from placebo only in the frequency of gastrointestinal adverse events; most events were rated as mild or moderate.

Efficacy findings differ from those of a similarly designed prior randomized, placebo-controlled trial of N-acetylcysteine for youth cannabis use disorder, which demonstrated more than doubled odds of negative urine cannabinoid tests during treatment in the N-acetylcysteine group compared to the placebo group. While it is possible to interpret the present findings as a replication failure, the prior study’s design and execution differed from the present trial in two key ways: (1) inclusion of contingency management as a platform behavioral treatment to promote abstinence from cannabis and attendance at study visits, and (2) participant enrollment between 2009 and 2011, contrasted with the present trial’s enrollment spanning 2017–2023.

Contingency management is a robust behavioral treatment, providing salient reinforcers for evidence of desired behavior that may be particularly pertinent for youth who use cannabis; in the case of the prior N-acetylcysteine trial, this included an escalating schedule of monetary incentives for visit attendance and for negative urine cannabinoid tests. When treatment motivation is fleeting or limited, as often occurs with adolescents and emerging adults, contingency management may provide a key extrinsic reinforcer to motivate treatment engagement and bolster efforts to achieve substance abstinence. In the present study, baseline self-reported confidence and readiness—but not motivation—to quit cannabis were predictive of treatment success, indicating the importance of factors beyond motivation. Given prior evidence of synergy between contingency management and pharmacotherapy for youth substance use disorder treatment, the platform of behavioral incentives may have played a key role in facilitating the prior trial’s demonstration of N-acetylcysteine efficacy, contrasting with the present findings in the absence of contingency management.

The years between the prior and present N-acetylcysteine trials have seen substantial changes in cannabis-related policies across much of the US, associated with decreased perception of cannabis-related harm among youth. Additionally, cannabis preparations have included higher concentrations of delta-9-tetrahydrocannabinol, the main psychoactive component in cannabis that drives its addictive potential. While rates of youth cannabis use and cannabis use disorder have risen over that time span, recent findings highlight a paradoxical concurrent decrease in treatment admissions. Though evidence is clear that youth-onset cannabis use disorder is impairing and associated with an array of adverse outcomes, in an environment of increasingly positive and permissive messaging related to cannabis, engagement in and response to cannabis use disorder treatment may be less robust. Even with the present study’s treatment-seeking sample, cannabis abstinence rates during treatment were low, averaging below 15% across both treatment groups. Additionally, amid increases in co-occurring mental health symptoms among youth, coping motives for cannabis are increasingly common, suggesting increased clinical complexity. This indicates the need for enhanced approaches to tailoring treatment that are accessible and acceptable to youth and responsive to their clinical presentations.

N-acetylcysteine’s role in substance use disorder pharmacotherapy remains unclear. While preclinical models indicate robust mechanistic and behavioral responses across substances, human laboratory and clinical trials have yielded a far less consistent picture. This translational gap may be owing to an array of factors, including details of trial design, such as inclusion criteria, dosing and duration, and embedded behavioral treatment; bridging these translational steps in substance use disorder pharmacotherapy development remains an overarching challenge to the field. Additionally, given the complexity of biological, psychological, and social contributions to substance use disorders, other factors may maintain continued use even when a pharmacological intervention demonstrates a desired mechanistic response. This highlights the importance of developing integrated behavioral and pharmacological interventions that are complementary or synergistic in addressing factors that maintain addictive behaviors. It is possible that incentives to motivate change are necessary to complement N-acetylcysteine in promoting abstinence. Additionally, the finding that confidence and readiness to quit cannabis predicted treatment success in the present study—significantly so in the N-acetylcysteine group and not in the placebo group—indicates a potential pathway for tailoring N-acetylcysteine treatment for those most likely to respond.

Strengths of the present trial include its rigorous design and adequate sample size with similar representation across sexes, participant retention, and medication adherence to test clinical outcomes. Limitations include modest racial diversity in the enrolled participant sample, as well as reduced capacity for quantitative laboratory analysis of urine cannabinoids amid COVID-19 pandemic-related reliance on virtual visits; point-of-care qualitative testing is not considered as rigorous as quantitative laboratory analysis. Additionally, the study’s lack of mechanistic data on pharmacological target engagement significantly limits interpretation of null findings. Also of note, the two-group design (N-acetylcysteine versus placebo) without inclusion of contingency management elements allowed for only indirect comparison with the prior trial’s findings. Nonetheless, present findings indicate that N-acetylcysteine is not efficacious for youth cannabis use disorder when not paired with contingency management, highlighting the important role of behavioral incentives in facilitating N-acetylcysteine’s efficacy. Given the high prevalence and adverse outcomes associated with youth cannabis use disorder, more work is needed to develop and tailor behavioral and pharmacological treatments that are accessible to and effective for youth.

Introduction

Cannabis use has become more common across all age groups, but adolescents and young adults face particular risks for negative outcomes related to it. When cannabis use begins during adolescence, individuals are more than twice as likely to develop cannabis use disorder (CUD) compared to those who start using as adults. Additionally, young people who use cannabis regularly are especially prone to adverse effects on their education, employment, and mental health.

Current treatments for CUD in youth include various counseling, behavioral, and family-based interventions. While these approaches can be helpful for many young individuals with CUD, their overall effectiveness is modest, and long-term results are often limited. Researchers are actively working to improve these interventions and explore potential medications to complement them. Presently, no medications are approved by the United States Food and Drug Administration for treating CUD in adolescents or adults. However, with rising rates of CUD, there has been an increased focus on developing and testing new medications for this condition.

One medication being considered for CUD is N-acetylcysteine (NAC). In animal studies, NAC has shown promise in correcting brain chemical imbalances linked to substance use and reducing self-administration of substances. NAC is readily available as an over-the-counter supplement and has demonstrated good safety across all age groups, even at high doses used for other medical conditions. These characteristics suggest NAC could be widely used if its early research findings prove true for human substance use disorders.

A previous study, a randomized, placebo-controlled trial in youth aged 14–21, evaluated NAC when combined with weekly counseling and a contingency management program. In that program, participants received financial rewards for attending visits and for submitting urine tests negative for cannabis. Participants who received NAC were more than twice as likely to achieve cannabis abstinence, confirmed by urine tests, compared to those who received a placebo. However, a later, similar study in adults aged 18–50 found no difference in cannabis use outcomes between NAC and placebo groups. This suggested that NAC's effect on CUD might be specific to youth, a notion supported by an analysis of the 18–21-year-olds in the adult trial, which showed a similar benefit to the youth-focused study. These differing results between youth and adult participants could be due to developmental differences in how NAC affects the brain or how CUD progresses and presents at different ages. Since both earlier trials included contingency management, a strong behavioral intervention, questions remained about whether NAC would be effective in clinical practice without it, especially given prior evidence of a combined benefit between medication and contingency management for youth substance use disorders.

The current trial aimed to assess NAC's effectiveness for youth CUD when combined with brief cessation counseling and medical management delivered by a medical clinician, but without contingency management. The findings from this study are important for clinical practice, as they help determine if contingency management is a necessary component for NAC to be effective in treating CUD in youth.

Participants and methods

This study was a randomized, double-blind, placebo-controlled trial involving two groups of participants. It included a screening period of up to four weeks, a 12-week treatment phase, and follow-up visits through week 26. The study received approval from the Medical University of South Carolina Institutional Review Board and adhered to ethical guidelines. The chosen dosage of oral NAC was 2400 mg per day, given as 1200 mg twice daily, based on successful outcomes from previous studies using this dosage with contingency management. Participants aged 18 and older provided written informed consent, while those under 18 provided assent, with parental consent also obtained. Eligible participants were 14–21 years old, met criteria for cannabis use disorder within the previous 30 days, expressed interest in treatment, and had a urine sample positive for cannabinoids. Individuals with other significant substance use disorders (besides cannabis or nicotine), synthetic cannabinoid use, pregnancy, certain medical conditions (e.g., seizure disorder), or severe unstable medical or psychiatric disorders were excluded.

Participants reported their baseline motivation, readiness, and confidence to quit cannabis on a 1–10 scale. They were then randomly assigned, in equal numbers, to either the NAC or placebo group. This assignment was stratified by age (under 19 versus 19 and older) and nicotine use status. A statistician created the randomization schedule to ensure blinding, and the study pharmacy assigned the active drug or placebo to coded labels (A/B). Participants, clinicians, and study staff remained unaware of treatment assignments throughout the study.

NAC powder, meeting United States Pharmacopeia (USP) standards, was encapsulated in 600 mg doses, and identical placebo capsules were prepared. All capsules were packaged in blister packs with dose timings. Participants were instructed to take two capsules (1200 mg) twice daily, roughly 12 hours apart. Dose adjustments were allowed if tolerability issues arose. Text messages prompted participants to take their medication, with a link to upload a video recording to confirm adherence. Study personnel reviewed these videos. All participants received brief (typically under 10 minutes) weekly medical management and skills-based cannabis cessation counseling from a medical clinician. This counseling was designed to be similar to the intervention in the prior youth NAC trial and to be practical for a busy clinical setting. The study was conducted at a research clinic in Charleston, South Carolina, offering both in-person and virtual visits.

Cannabis use was primarily measured through urine cannabinoid testing at baseline, weekly visits, and follow-up appointments. Participants also reported their daily cannabis and other substance use via mobile surveys. Missing daily data were collected during study visits using a recall method. Weekly urine samples were initially tested qualitatively at the point of care, then sent to a laboratory for quantitative cannabinoid and creatinine testing for more precise analysis. During virtual visits (due to COVID-19 restrictions), only qualitative urine tests were performed remotely, not quantitative laboratory analysis. The main measure of treatment success was self-reported cannabis abstinence confirmed by negative urine tests during the 12 weeks of treatment. Additionally, the weekly proportion of days using cannabis (frequency) and grams of cannabis used per using day (amount) were compared between the groups. Adverse events, or side effects, were assessed by the medical clinician at every visit for severity and relatedness to the study medication. Medication adherence was determined by the percentage of video-verified doses taken compared to the prescribed number, with participants taking at least 80% of doses considered compliant.

The study aimed for 67 participants per group to have enough statistical power to detect a difference in negative urine cannabinoid tests, accounting for a 30% dropout rate, leading to a target of 96 participants per group. Baseline characteristics linked to cannabis use outcomes were included in statistical models. Data on self-reported abstinence and cannabis use frequency/amount were summarized weekly. The effect of NAC on negative weekly urine tests was analyzed using specific statistical models that adjusted for factors like treatment assignment, visit week, baseline cannabis use, age, and nicotine use. All randomized participants were included in the main analysis, with outcomes assessed using available data and also by assuming missed visits indicated continued cannabis use. Comparisons between groups were made using model-based means. Follow-up abstinence rates were also compared using logistic regression. Secondary outcomes, such as cannabis use frequency and amount, were compared using linear mixed effects models. Potential modifying effects of sex on treatment efficacy were also examined. The effectiveness of the study's blinding was assessed at the end of treatment by asking participants to guess their assignment. Adverse events and medication adherence rates were also analyzed for differences between the treatment groups. All statistical analyses were performed using SAS software.

Results

Participant enrollment and data collection occurred between August 2017 and January 2024. Of 217 participants assessed, 192 were randomized (98 to NAC, 94 to placebo) and began treatment. Retention at the 12-week end-of-treatment visit was 72.9% overall (140 participants), with similar rates between groups (NAC: 71.4%; placebo: 74.5%). Out of all possible weekly treatment visits, 67.2% of urine cannabinoid test results and 77.5% of self-reported cannabis use measures were available for analysis. Follow-up data were available for 57.3% of participants at 16 weeks and 48.4% at 26 weeks. Participants were, on average, 19.2 years old, predominantly female (52.6%), and white (78.5%), with 14.1% Hispanic and 10.4% Black individuals. In the month before the study, participants reported an average of 23.6 days of cannabis use. Additionally, most participants reported using alcohol (87.0%) and nicotine (71.4%).

At baseline, higher cannabis use frequency and daily use were associated with a lower likelihood of achieving abstinence during treatment. Baseline nicotine use was also linked to a decreased chance of weekly cannabis abstinence. Conversely, higher self-reported readiness and confidence to quit cannabis at the start of the study were significantly associated with a greater likelihood of abstinence, while overall motivation was not. Factors such as sex, age, race, alcohol use frequency, age of regular cannabis use initiation, prior quit attempts, e-cigarette use, and CUD severity were not associated with abstinence.

During the 12-week treatment period, 11.8% of all urine samples were negative for cannabinoids (9.4% in the NAC group and 14.0% in the placebo group). Statistical analysis, accounting for baseline cannabis use, age, and nicotine use, showed no significant difference in the rate of negative urine cannabinoid tests between the NAC and placebo groups. These findings remained consistent even when missing data were assumed to be positive for cannabinoids. Similar results were observed at the 16-week and 26-week follow-up visits, with no significant difference in negative urine test rates between the groups.

The participant's sex did not influence the effectiveness of treatment regarding urine cannabinoid test results. However, baseline confidence in quitting showed a different relationship between the NAC and placebo groups. Participants in the NAC group who reported higher confidence at baseline were significantly more likely to achieve abstinence. A similar, though not statistically significant, trend was observed for baseline readiness to quit in the NAC group, where higher readiness was associated with increased abstinence.

For secondary outcomes, self-reported weekly cannabis abstinence rates during treatment did not differ between the NAC and placebo groups. Participant sex also did not modify treatment efficacy for self-reported abstinence. While the average percentage of cannabis use days and the grams of cannabis used per day decreased over time across all participants during treatment, there were no significant differences in these reductions between the NAC and placebo groups.

At the end of treatment, 128 participants guessed their treatment assignment. A slightly higher percentage of placebo participants (69.7%) correctly identified their assignment compared to NAC participants (53.2%), but this difference was not statistically significant. Study medication was generally well-tolerated, with 83% of participants reporting at least one adverse event, though most were considered unrelated to the study drug (70.8%) and mild or moderate in severity. Only 2.3% of reported events were severe. Gastrointestinal issues were the most common adverse event and were significantly more frequent in the NAC group compared to the placebo group. Medication dose adjustments due to tolerability issues were more common in the NAC group (14.3%) than the placebo group (4.3%). Medication adherence, defined as taking at least 80% of prescribed doses, was high and similar between both groups (75.3% for NAC, 80.3% for placebo) and was not linked to negative urine cannabinoid tests.

Discussion

This randomized, placebo-controlled trial evaluating N-acetylcysteine (NAC) combined with weekly brief counseling and medical management for youth cannabis use disorder (CUD) found no significant difference in cannabis use reduction or cessation outcomes between the NAC and placebo groups. Participant demographics were well-balanced, and retention and medication adherence rates were sufficient for robust testing of clinical outcomes. While both groups experienced a decrease in cannabis use over time, NAC did not provide an added benefit. NAC was generally well-tolerated, with gastrointestinal issues being the only notable difference from placebo, and most adverse events were mild or moderate.

These findings differ from a previous, similarly designed trial of NAC for youth CUD, which showed NAC significantly increased the odds of negative urine cannabinoid tests. While the current results might be seen as a failure to replicate, two key differences in the prior study's design and execution could explain the discrepancy: first, the inclusion of contingency management (financial incentives for abstinence and visit attendance) in the previous trial, and second, the different time periods of participant enrollment (2009–2011 versus 2017–2023 for the present trial).

Contingency management is a powerful behavioral treatment that provides concrete rewards for desired behaviors, which can be particularly relevant for youth who use cannabis. In the earlier NAC trial, escalating monetary incentives likely motivated participants to engage in treatment and achieve abstinence. For adolescents and emerging adults, whose motivation for treatment can fluctuate, contingency management may offer crucial external reinforcement. In the present study, participants' baseline self-reported confidence and readiness to quit cannabis predicted treatment success (though motivation did not), emphasizing the importance of factors beyond simple motivation. Given evidence that contingency management and medication can work together synergistically for youth substance use disorders, the behavioral incentives in the prior trial may have been essential for NAC's observed efficacy, unlike in the present study without contingency management.

The years between the two NAC trials have seen significant shifts in cannabis policies across the United States, leading to a reduced perception of harm among youth regarding cannabis. Furthermore, cannabis products now often contain much higher concentrations of delta-9-tetrahydrocannabinol, the primary psychoactive component responsible for its addictive potential. Although youth cannabis use and CUD rates have increased, there has been a paradoxical decrease in treatment admissions. This suggests that in an environment with increasingly positive and permissive messages about cannabis, youth may be less likely to engage with or respond to CUD treatment. Even within this study's sample of treatment-seeking youth, cannabis abstinence rates remained low (under 15%) across both groups. Additionally, with a rise in co-occurring mental health symptoms among youth, cannabis use is often motivated by coping, indicating greater clinical complexity. This highlights the urgent need for enhanced, tailored treatment approaches that are accessible and acceptable to youth and responsive to their diverse clinical presentations.

N-acetylcysteine's overall role in treating substance use disorders remains unclear. While laboratory studies indicate strong biological and behavioral effects across various substances, human clinical trials have yielded much less consistent results. This gap between preclinical and clinical findings may be due to differences in trial design, such as participant selection, dosing strategies, and the behavioral treatments included. Bridging this translational gap remains a significant challenge in developing new medications for substance use disorders. Given the complex interplay of biological, psychological, and social factors in addiction, other elements may sustain substance use even when a medication shows a desired biological effect. This underscores the importance of developing integrated behavioral and pharmacological interventions that complement each other in addressing the multifaceted reasons for addictive behaviors. It is possible that external incentives are necessary to enhance NAC's ability to promote abstinence. Furthermore, the finding that confidence and readiness to quit cannabis predicted treatment success in the NAC group suggests a potential path for tailoring NAC treatment to those most likely to benefit. The strengths of this study include its rigorous design, sufficient sample size, balanced representation across sexes, good participant retention, and high medication adherence. Limitations include modest racial diversity in the enrolled participants and reduced capacity for quantitative urine cannabinoid analysis during the COVID-19 pandemic due to reliance on virtual visits; qualitative point-of-care testing is considered less precise than laboratory analysis. Additionally, the study's lack of data on how the medication affected its biological targets limits the interpretation of the null findings. The two-group design (NAC versus placebo) without a contingency management arm also only allowed for indirect comparison with the prior trial. Nevertheless, the present findings suggest that NAC alone is not effective for youth CUD when not combined with contingency management, emphasizing the critical role of behavioral incentives in facilitating NAC's efficacy. Given the high prevalence and negative consequences of youth CUD, further research is needed to develop accessible and effective behavioral and pharmacological treatments for young people.

Introduction

Cannabis use is common among many age groups, but it raises particular concerns for adolescents and young adults. Cannabis use that begins in adolescence is more than twice as likely to develop into a cannabis use disorder compared to use that starts in adulthood. Furthermore, young people who use cannabis regularly are especially vulnerable to negative effects on their education, work, and mental health.

Current treatments for cannabis use disorder in young people include various psychological, behavioral, and family-focused therapies. While these interventions can be helpful, their effects are often small to moderate, and long-term results are limited. Researchers are actively working to improve these treatments and explore potential medications to enhance them. Currently, there are no medications approved by the United States Food and Drug Administration (FDA) for cannabis use disorder in adolescents or adults. However, with increasing rates of cannabis use disorder, there is a strong focus on developing and testing new medications for this condition.

One potential medication for cannabis use disorder is N-acetylcysteine (NAC). Studies in animal models have shown that NAC can help correct imbalances of a brain chemical called glutamate, which are caused by substance use. This correction has also been linked to a reduction in the animals' self-administration of substances. NAC is easily available as an over-the-counter supplement and has been shown to be well-tolerated in people of all ages, even at high doses used for acetaminophen poisoning. This makes it a promising candidate for widespread use if its effects observed in animal studies can be replicated in human substance use disorders.

A previous study on youth aged 14–21 found that NAC, when combined with brief weekly counseling and a reward-based intervention (contingency management), more than doubled the chances of participants achieving cannabis abstinence compared to a placebo group. However, a similar study in adults aged 18–50 found no difference in cannabis use outcomes between NAC and placebo groups, suggesting that NAC's effect might be specific to younger individuals. This idea was supported by a later analysis of the adult study participants aged 18–21, who showed an effect similar to that seen in the youth study. It remained unclear whether NAC would be effective for youth without the strong behavioral support of contingency management.

The current study was conducted to determine if NAC is effective for youth cannabis use disorder when combined only with brief counseling and medical management from a clinician, without contingency management. The findings are important for clinical practice to understand if contingency management is a necessary component for NAC to be effective in treating cannabis use disorder in young people.

Participants and methods

This study was a randomized, double-blind, placebo-controlled trial. It involved a screening period of up to four weeks, a 12-week treatment period, and follow-up visits through week 26. The study was approved by the Medical University of South Carolina Institutional Review Board and followed ethical guidelines. The chosen NAC dosage was 2400 mg/day, taken as 1200 mg twice daily, based on previous positive findings with this dosage. Participants aged 18 or older provided their own informed consent, while those under 18 provided assent along with parental consent.

Eligible participants were between 14 and 21 years old, met criteria for cannabis use disorder in the past 30 days, expressed interest in treatment, and had a positive urine test for cannabinoids. Individuals with other significant substance use disorders (besides cannabis or nicotine), current or planned synthetic cannabinoid use, pregnancy, certain medical conditions, or unstable psychiatric disorders were excluded. Participants reported their baseline motivation, readiness, and confidence to quit cannabis on a scale of 1 to 10. They were then randomly assigned in a 1:1 ratio to receive either NAC or a placebo, with the assignments blinded to participants, clinicians, and study staff throughout the study.

Participants received either NAC or matched placebo capsules, packaged to be taken twice daily. Text messages prompted participants to take their doses and upload video recordings to confirm adherence. All participants also received brief (typically less than 10 minutes) weekly medical management and skills-based cannabis cessation counseling from a medical clinician. This counseling was designed to be similar to that in the previous youth NAC study and to be feasible in a busy clinical setting. The study was conducted both in-person and virtually at a dedicated research clinic.

The main measure of treatment effectiveness was self-reported abstinence from cannabis, confirmed by negative urine cannabinoid tests, during the 12 weeks of treatment. Other measures included the weekly percentage of days participants used cannabis and the amount of cannabis used per day. Any negative effects were assessed by the medical clinician and categorized. Medication adherence was tracked by reviewing participants' video recordings of medication-taking, with adherence defined as taking at least 80% of prescribed doses.

For statistical analysis, a sample size of 67 participants per group was estimated to be sufficient to detect a difference, with 96 participants per group planned to account for potential dropouts. Baseline characteristics associated with cannabis use outcomes were included in the statistical models. The main effect of NAC on negative urine cannabinoid tests was analyzed using a statistical method called generalized estimating equations (GEE). Missing data were handled by assuming participants were not abstinent during missed visits. Secondary outcomes, such as cannabis use frequency and amount, were compared using linear mixed effects models. The study also examined if sex at birth influenced treatment efficacy and assessed how well the blinding was maintained.

Results

Participants were enrolled and data collected between August 2017 and January 2024. Out of 217 participants assessed, 192 were randomized and began treatment (98 in the NAC group and 94 in the placebo group). Retention at the end of the 12-week treatment was similar between groups, with 72.9% of participants attending the final visit. The study cohort averaged 19.2 years old, with slightly more females (52.6%) and a majority being white (78.5%). Before the study, participants reported using cannabis on average 23.6 days out of the previous 30, and many also reported using alcohol (87.0%) and nicotine products (71.4%).

Factors at the start of the study that were associated with lower rates of cannabis abstinence during treatment included higher baseline cannabis use days and daily cannabis use, as well as baseline nicotine use. Conversely, higher self-reported readiness and confidence to quit cannabis were significantly linked to a greater likelihood of abstinence. Other demographic factors, such as sex, age, race, or severity of cannabis use disorder, were not significantly associated with abstinence.

During the 12-week treatment, only 11.8% of all urine samples were negative for cannabinoids (9.4% in the NAC group and 14.0% in the placebo group). Statistical analysis showed no significant difference in the rate of negative urine cannabinoid tests between the NAC and placebo groups, even when accounting for missing data. Similar results were found at follow-up visits 16 and 26 weeks after randomization, with no notable difference in abstinence rates between the groups. There was no evidence that a participant's sex at birth changed how effective the treatment was. However, higher baseline confidence to quit was strongly linked to increased abstinence in the NAC group but not in the placebo group. A similar, but not statistically significant, trend was observed for baseline readiness to quit.

Regarding secondary outcomes, there was no difference between the NAC and placebo groups in self-reported weekly abstinence rates. Both groups showed a decrease over time in the average percentage of days using cannabis and the average grams of cannabis used per using day during the study treatment, but these improvements did not differ between the treatment groups.

At the end of the study, 53.2% of participants in the NAC group and 69.7% of participants in the placebo group correctly guessed their treatment assignment, suggesting that the blinding was not completely effective.

Study medication was generally well tolerated. A total of 616 adverse events were reported by 83% of participants across both groups. Most events were considered "definitely not related to study treatment" (70.8%) and only a small percentage (2.3%) were severe. The most common adverse event category was gastrointestinal issues, which were reported more often in the NAC group compared to the placebo group. Medication dose adjustments were made for a small percentage of participants, more frequently in the NAC group.

Adherence, defined as taking at least 80% of doses, was high and similar in both groups (75.3% in NAC and 80.3% in placebo) and was not significantly associated with negative urine cannabinoid tests during treatment.

Discussion

This study evaluated N-acetylcysteine (NAC) as an addition to weekly medical counseling and management for youth cannabis use disorder. The participant groups were well-matched, and retention and medication adherence rates were sufficient to assess clinical outcomes. While participants across both groups reduced their cannabis use over time, no significant difference in cannabis use reduction or cessation was observed between those receiving NAC and those receiving placebo. NAC was generally well-tolerated, with only a minor increase in gastrointestinal side effects compared to placebo; most adverse events were mild or moderate.

The findings of this study differ from a previous, similarly designed trial of NAC for youth cannabis use disorder, which showed that NAC significantly increased the odds of achieving cannabis abstinence. This difference might be explained by two main factors: first, the previous study included contingency management—a strong behavioral treatment that provides rewards for desired behaviors like abstinence and visit attendance—whereas the current study did not. Second, the previous study enrolled participants between 2009 and 2011, while the current study took place from 2017 to 2023.

Contingency management provides significant external motivators that can be especially important for young people with fluctuating motivation. In the prior study, monetary incentives likely played a key role in encouraging engagement and supporting abstinence. In the present study, only baseline self-reported confidence and readiness to quit cannabis, not motivation, predicted treatment success. Given past evidence of combined benefits between medication and behavioral incentives for youth substance use disorders, the absence of contingency management in this trial may explain why NAC did not show effectiveness.

Over the years between these two trials, there have been significant changes in cannabis policies across the US, leading to a reduced perception of harm among young people. Additionally, cannabis products now often contain higher concentrations of delta-9-tetrahydrocannabinol (THC), the main psychoactive component. Despite a rise in youth cannabis use and cannabis use disorder during this period, there has been a puzzling decline in treatment admissions. Even in this study's group of participants seeking treatment, cannabis abstinence rates were low, typically below 15% across both groups. This suggests that in an environment with increasingly positive views on cannabis, engagement with and response to treatment may be less robust, highlighting the need for more tailored and accessible treatment approaches for young people.

The overall role of NAC in treating substance use disorders remains uncertain. While animal studies show clear benefits, human trials have yielded inconsistent results. This gap between preclinical and human findings may be due to differences in study design, such as participant selection, medication dosing and duration, and the type of behavioral treatment provided. The complexity of biological, psychological, and social factors contributing to substance use disorders means that even if a medication has a desired effect on brain chemistry, other factors might still maintain drug use. This underscores the importance of developing integrated treatments that combine behavioral and pharmacological strategies to address the various factors driving addictive behaviors. It is possible that incentives are necessary to complement NAC's effects in promoting abstinence. The finding that confidence and readiness to quit predicted success in the NAC group suggests a potential way to identify young people who might benefit most from NAC treatment.

Strengths of this study include its rigorous design, adequate sample size, and high rates of participant retention and medication adherence. However, limitations include a modest diversity in racial representation among participants and challenges with quantitative urine analysis due to virtual visits during the COVID-19 pandemic. The study also lacked data on the medication's direct effect on biological targets, which limits the interpretation of the null findings. Furthermore, by not including a contingency management group, the study could only indirectly compare its findings with the previous trial. Nevertheless, the current findings suggest that NAC is not effective for youth cannabis use disorder when it is not paired with contingency management, emphasizing the critical role of behavioral incentives. Given the high prevalence and negative consequences of youth cannabis use disorder, continued efforts are needed to develop effective and accessible behavioral and pharmacological treatments for young people.

Introduction

Cannabis use is common among people of all ages, but there is special concern about its effects on adolescents and young adults. When individuals begin using cannabis in their teenage years, they are more than twice as likely to develop a problematic use pattern, known as cannabis use disorder, compared to those who start using as adults. Furthermore, young people who use cannabis regularly often experience negative effects on their education, jobs, and mental health.

Current treatments for cannabis use disorder in young people include counseling, behavioral therapies, and family-based approaches. While these methods can help many young people, their success rates are often modest, and long-term results are limited. Researchers are working to improve these treatments and are also looking into medications that could help. As of now, the United States Food and Drug Administration (FDA) has not approved any medications for cannabis use disorder in adolescents or adults. However, with the rising rates of cannabis use disorder, there is a strong focus on finding and testing potential drug treatments.

One medication being considered for cannabis use disorder is N-acetylcysteine (NAC). Studies in animals have shown that NAC can help correct imbalances in brain chemicals caused by substance use, which also leads to a reduction in self-administering substances. Because NAC is available over-the-counter and has been shown to be safe for various age groups, even at high doses when used for other conditions, it is seen as a promising treatment that could be widely used if research findings translate to people with substance use disorders.

A previous study in young people aged 14–21 tested NAC combined with weekly counseling and a reward-based program (contingency management) that gave participants money for attending visits and for submitting urine samples that tested negative for cannabis. Participants who received NAC were more than twice as likely to stay abstinent from cannabis compared to those who received a placebo. However, a similar study in adults aged 18–50 showed no difference between NAC and placebo groups, suggesting that NAC's effect on cannabis use disorder might be specific to younger individuals. Further analysis of the 18–21 age group in the adult study supported this idea, showing a similar positive effect for NAC as seen in the youth study. These different findings between youth and adult participants might mean that NAC works differently depending on a person's developmental stage, or because cannabis use disorder progresses and presents differently at different ages. An important question remained: would NAC still be effective for youth if not combined with contingency management? This was a key question because prior research suggested that medication and contingency management could work together to improve outcomes for young people with substance use disorders.

The current study was conducted to see how well N-acetylcysteine works for cannabis use disorder in young people when paired only with brief counseling and medical management from a doctor, without the use of contingency management. The findings are important for clinical practice, especially to determine if contingency management—which was part of the previous successful youth trial but not this one—is a necessary component for N-acetylcysteine to be effective for youth cannabis use disorder.

Participants and Methods

This study was designed as a randomized, double-blind, placebo-controlled trial, meaning participants were randomly assigned to receive either NAC or a placebo, and neither they nor the researchers knew which treatment they were getting. The study involved a screening period of up to four weeks, a 12-week treatment period, and follow-up visits until 26 weeks after randomization. The study followed ethical guidelines and was approved by the Medical University of South Carolina Institutional Review Board.

Participants were young people aged 14–21 who met the criteria for cannabis use disorder, expressed interest in treatment, and had a positive urine test for cannabis. Individuals with other severe substance use disorders, certain medical conditions, or who were pregnant were not included. All participants aged 18 and older provided their written consent, while those under 18 provided their agreement along with parental consent. The NAC dosage used was 2400 mg per day, given as two 1200 mg doses, based on previous positive results with this amount.

Participants were instructed to take two capsules (1200 mg) twice daily, about 12 hours apart. They were prompted by text messages and asked to upload video recordings of themselves taking the medication to confirm adherence. Researchers reviewed these videos. All participants received brief (less than 10 minutes) weekly counseling from a medical professional, focused on quitting cannabis. This counseling was designed to be similar to what could be done in a busy clinical setting. Visits were conducted both in person and virtually.

The main way researchers measured success was by checking for self-reported cannabis abstinence confirmed by weekly urine tests that were negative for cannabis. In addition to abstinence, researchers also compared the weekly percentage of days participants used cannabis and the amount of cannabis used per day between the treatment groups. Side effects were monitored by medical staff at every visit, and how closely participants followed their medication schedule was also tracked. Adherence was measured as the percentage of video-verified doses taken, with taking at least 80% of doses considered compliant.

Statistical methods were used to analyze the data. Researchers determined that 67 participants per group would provide enough statistical power for the study, and they aimed for 96 participants per group to account for potential dropouts. Baseline characteristics of participants that were linked to cannabis use outcomes were considered in the analysis. Various statistical models were used to compare rates of negative urine tests and self-reported abstinence between the groups over time and at follow-up visits. They also examined how other factors, like gender, might influence treatment effectiveness. The effectiveness of blinding (whether participants could guess if they were receiving NAC or placebo) was also assessed.

Results

Participants were enrolled and data collected between August 2017 and January 2024. Out of 217 individuals assessed, 192 were randomly assigned to a group and started treatment (98 in the NAC group and 94 in the placebo group). About 73% (140 participants) completed the 12-week treatment period, with similar retention rates between both groups. Data on urine cannabinoid tests were available for about 67% of possible weekly visits, and self-reported cannabis use data for about 77.5%. At the 26-week follow-up, about 48% of participants had data available.

Participants were, on average, 19.2 years old, mostly female (52.6%) and white (78.5%). Before the study, participants reported using cannabis on average 23.6 days out of the previous 30. Most also used alcohol (87%) and nicotine products (71.4%). Factors associated with a lower chance of cannabis abstinence during treatment included higher baseline cannabis use and nicotine use. On the other hand, higher self-reported readiness and confidence to quit cannabis were linked to a greater chance of abstinence.

During the 12 weeks of treatment, about 11.8% of all urine samples tested negative for cannabis. There was no statistically significant difference in the rate of negative urine tests between the NAC group (9.4%) and the placebo group (14.0%). These results remained consistent even when missing data were assumed to be positive for cannabis. Similarly, at the 16-week and 26-week follow-up visits, there was no overall difference in negative urine test rates between the groups. However, there was an interesting finding: participants in the NAC group who reported higher confidence to quit at the start of the study were significantly more likely to achieve abstinence. A similar, though not statistically significant, trend was observed for baseline readiness to quit.

Regarding secondary outcomes, the average percentage of days participants used cannabis and the amount of cannabis used per day decreased over time for all participants during the study. However, there were no differences in these reductions between the NAC and placebo groups.

At the end of the study, when participants were asked to guess their treatment assignment, about 53% in the NAC group and 70% in the placebo group guessed correctly. This difference was close to being statistically significant.

Overall, the study medication was well tolerated. Out of 192 participants, 159 (83%) reported at least one side effect during the 12 weeks of treatment. Most of these events were considered unrelated to the study medication and were mild or moderate. The most common side effect category for both groups was gastrointestinal issues, which were more frequent in the NAC group. Medication dosage adjustments were more common in the NAC group (14.3%) than in the placebo group (4.3%).

Medication adherence was similar between groups, with about 75% of NAC reports and 80% of placebo reports categorized as adherent (taking at least 80% of doses). Importantly, medication adherence was not linked to having negative urine cannabis tests during treatment.

Discussion

This study, which tested N-acetylcysteine with weekly brief counseling for cannabis use disorder in youth, found no difference in outcomes between the NAC and placebo groups. While cannabis use generally decreased over time for all participants, NAC did not prove more effective than placebo in reducing or stopping cannabis use. NAC was generally well-tolerated, with the main difference from placebo being more gastrointestinal side effects, most of which were mild or moderate.

These findings differ from a previous study of NAC for youth cannabis use disorder, which showed that NAC more than doubled the chances of negative cannabis urine tests. It is possible these results differ for two main reasons: first, the previous study included "contingency management" (a system of rewards for staying sober and attending visits), which was absent in the current trial. Second, participants in the prior study were enrolled between 2009 and 2011, while the current study enrolled participants from 2017 to 2023.

Contingency management is a strong behavioral treatment that provides clear rewards for desired behaviors. This approach can be especially helpful for young people who use cannabis, as it can provide motivation to engage in treatment and work towards abstinence, particularly when their own motivation might be inconsistent. In the current study, only baseline self-reported confidence and readiness to quit cannabis (but not motivation itself) predicted treatment success. This suggests that factors beyond initial motivation are important. Given that previous evidence shows medication and contingency management can work together effectively for youth substance use disorders, the reward system in the earlier trial might have been key to NAC's success.

The years between the two NAC studies have seen significant changes in cannabis policies across the U.S., which have led to young people perceiving cannabis as less harmful. Additionally, cannabis products now often contain much higher concentrations of THC, the main psychoactive component that contributes to addiction. Although rates of youth cannabis use and cannabis use disorder have increased, paradoxically, treatment admissions have decreased. Even though it is clear that cannabis use disorder starting in youth can cause many problems, the increasingly positive and permissive messages about cannabis in society may make young people less engaged in or responsive to treatment. Even in this study's sample of treatment-seeking youth, cannabis abstinence rates were low in both groups. With more young people experiencing mental health symptoms, using cannabis to cope is also more common, suggesting increased clinical complexity. This highlights the need for better tailored treatments that are accessible and appealing to young people, and that respond to their specific needs.

The overall role of N-acetylcysteine in treating substance use disorders remains unclear. While laboratory studies suggest strong effects in animals, human clinical trials have shown much less consistent results. This gap between animal and human studies might be due to various factors, such as differences in study design, participant selection, dosage, and the type of behavioral treatment provided. Bridging this gap remains a major challenge in developing new drug treatments for substance use disorders. Also, the complex interplay of biological, psychological, and social factors in substance use disorders means that other elements might keep someone using, even if a medication addresses a specific biological process. This emphasizes the importance of developing combined behavioral and drug treatments that work together to address the various factors that maintain addictive behaviors. It is possible that incentives to motivate change are needed to complement NAC in promoting abstinence. The finding that confidence and readiness to quit cannabis predicted treatment success in this study—significantly so in the NAC group—suggests a way to identify individuals who might respond best to NAC treatment.

Strengths of this study include its rigorous design, appropriate sample size with balanced gender representation, and good participant retention and medication adherence, allowing for a proper evaluation of clinical outcomes. Limitations include limited racial diversity in the participant group and reduced capacity for detailed laboratory analysis of urine cannabis levels due to COVID-19 related virtual visits, as basic point-of-care testing is not as precise as laboratory analysis. Additionally, the study did not include data on how the medication affected brain mechanisms, which limits the interpretation of the negative findings. Also, because this study did not include contingency management, it only allowed for an indirect comparison with the previous trial that did. Nevertheless, these findings suggest that NAC is not effective for youth cannabis use disorder when it is not combined with contingency management. This highlights the important role that behavioral incentives may play in helping NAC work. Given the widespread nature and negative effects of cannabis use disorder in young people, more research is needed to develop and adapt behavioral and drug treatments that are both accessible and effective for youth.

Introduction

Cannabis use is common for many people, but it is especially concerning for teenagers and young adults. When young people start using cannabis, they are more than twice as likely as adults to develop a harmful pattern of use, known as cannabis use disorder. Also, young people who use cannabis regularly often face problems with their schooling, jobs, and mental well-being.

Current ways to help young people with cannabis use disorder include different types of therapy that involve talking, changing behaviors, or working with families. While these methods can be helpful, their effects are often small and do not last long. Researchers are trying to find better ways to help, including looking at new medicines. Right now, no medicine is officially approved to treat cannabis use disorder in teens or adults. However, because cannabis use disorder is becoming more common, there is a focus on testing new medicines for this condition.

One medicine being tested for cannabis use disorder is N-acetylcysteine, or NAC. Studies in animals have shown that NAC can help fix brain chemistry problems caused by substance use, which then led to the animals using less of the substance. NAC is easy to buy as a supplement without a prescription and has been shown to be safe, even in large amounts used for other health issues. Because of this, many thought NAC could be a widely used medicine if it worked in people like it did in animals.

Before this study, an earlier study with young people (ages 14–21) looked at NAC. In that study, NAC was given along with weekly talks and a reward system where teens earned money for attending visits and having clean urine tests. Young people who took NAC were more than twice as likely to stop using cannabis compared to those who received a fake pill. However, a similar study in adults (ages 18–50) found that NAC did not help them stop using cannabis. This suggested that NAC's helpful effects might only apply to young people. This idea was further supported by a closer look at the data from the adult study, which showed that NAC did help participants aged 18–21 in a similar way to the earlier youth study.

These different findings between young people and adults might mean that NAC works differently depending on a person's age or how their cannabis use problem develops. It was also unclear if NAC would still work if it was not combined with a reward system, which was part of the successful youth study. This new study aimed to find out if NAC helps young people with cannabis use disorder when given with only brief talks from a doctor and health support, without the reward system.

Participants and methods

This study was designed as a blind trial, meaning neither the participants nor the study staff knew who was getting the real medicine (NAC) and who was getting a fake pill (placebo). The study included a check-in period of up to 4 weeks, a 12-week treatment period, and follow-up visits later. It was approved by a medical review board and followed strict rules for medical studies. The dose of NAC used was 2400 mg per day, given as 1200 mg twice daily, based on earlier studies that showed good results with this amount.

People who joined the study were between 14 and 21 years old. They had to meet the criteria for cannabis use disorder within the last 30 days, want to get help, and have cannabis show up in their urine. People were not allowed to join if they were already in cannabis treatment, had serious problems with other substances (besides cannabis or nicotine), used or planned to use synthetic cannabis, were pregnant or breastfeeding, or had certain serious health or mental health conditions. Before the study started, participants reported how motivated, ready, and confident they felt about quitting cannabis. They were then randomly put into either the NAC group or the fake pill group, making sure the groups were balanced by age and whether they used nicotine.

Participants were given NAC or fake pills that looked the same. They were told to take two capsules (1200 mg) twice a day, about 12 hours apart. If they had problems taking the medicine, the dose could be changed by the study doctor. Participants received text messages reminding them to take their medicine and could send videos to show they were taking their pills. Study staff checked these videos to make sure participants were taking their medicine as told.

All participants received short weekly talks with a doctor, usually less than 10 minutes. These talks offered advice on how to stop using cannabis and provided general health care. This type of counseling was designed to be similar to what a doctor could realistically do in a busy clinic. The study took place at a research clinic, and visits were held both in person and online.

To measure how well the treatment worked, urine tests for cannabis were done every week. Participants also reported their cannabis use daily using surveys on their phones, including how much and how often they used. The main goal was to see how many people stopped using cannabis, which was confirmed by their weekly urine tests. We also compared how often people used cannabis and how much cannabis they used between the two groups. Any side effects were recorded, and we checked how well participants took their medication.

Results

The study ran from August 2017 to January 2024. Out of 217 people who were checked for the study, 192 were randomly assigned to a group and started treatment (98 in the NAC group and 94 in the fake pill group). By the end of the 12-week treatment, 140 participants were still in the study (about 73%), and this rate was similar for both groups. Participants were, on average, 19.2 years old, slightly more than half were female (52.6%), and most were white (78.5%). Before the study, participants used cannabis on average 23.6 days out of the previous 30 days. Many also used alcohol (87%) and nicotine (71.4%).

Certain factors at the start of the study were linked to how well participants did. For example, people who used cannabis more often at the beginning were less likely to stop using it during the study. Also, if a participant used nicotine at the start, they were less likely to stop using cannabis. On the other hand, participants who reported feeling more ready and confident to quit cannabis at the beginning were more likely to stop during the study. Age, sex, race, and how severe their cannabis use problem was did not seem to affect whether they stopped using cannabis.

During the 12 weeks of treatment, a small number of urine samples were negative for cannabis (about 12%). There was no meaningful difference in the number of negative urine tests between the NAC group and the fake pill group. This means NAC did not help people stop using cannabis more than the fake pill did. This finding remained the same even when considering missing data. At follow-up visits after treatment ended (at 16 and 26 weeks), there was still no difference in cannabis abstinence rates between the two groups.

While there was no overall benefit of NAC, participants in the NAC group who reported higher confidence in their ability to quit were more likely to stop using cannabis. This link between confidence and stopping cannabis was not seen in the fake pill group. A similar, but not statistically significant, trend was observed for readiness to quit. This suggests that NAC might be more helpful for individuals who are already confident in their desire to stop using cannabis.

Both groups, over time, reduced the percentage of days they used cannabis and the amount of cannabis they used on the days they did use. However, there was no difference in these reductions between the NAC group and the fake pill group. This means NAC did not help participants reduce their cannabis use more than the fake pill.

The study medicine was generally safe. Out of 192 participants, 159 reported a total of 616 side effects, but most were not related to the study medicine (70.8%) and only a few were severe (2.3%). The most common side effects for both groups were stomach problems, which happened more often in the NAC group. About 9% of participants had their dose adjusted, more so in the NAC group than the fake pill group. Participants in both groups took their medicine well, with about 75-80% of weekly reports showing they took at least 80% of their doses. Taking the medicine consistently did not appear to be linked to negative cannabis urine tests.

Discussion

In this study, which involved giving N-acetylcysteine (NAC) along with weekly counseling and health support to young people with cannabis use disorder, the study groups were well-matched, and most participants stayed in the study and took their medicine as instructed. We found that while participants generally reduced their cannabis use over time, there was no difference in how much they reduced use or whether they stopped using cannabis between those who took NAC and those who took a fake pill. NAC was mostly safe, with stomach problems being the main side effect that occurred more often than with the fake pill.

These findings are different from an earlier study that also looked at NAC for young people with cannabis use disorder, which showed that NAC helped reduce cannabis use. It is possible that our current findings do not mean that NAC fails to work, but rather that the study designs were different in two key ways: first, the earlier study included a reward system that paid participants for not using cannabis and attending visits, which this study did not. Second, the earlier study was conducted between 2009 and 2011, while this study was conducted more recently, from 2017 to 2023.

A reward system is a very strong way to encourage desired behaviors, especially for young people who use cannabis. In the earlier NAC study, this system offered clear rewards that could help motivate young people to stay in treatment and try to stop using cannabis. In our study, we found that a participant's self-reported confidence and readiness to quit cannabis at the start of the study predicted their success, suggesting that factors beyond just motivation are important. This indicates that the reward system in the earlier study might have been a key part of why NAC worked then, but not in our study without it.

The years between the two studies have also seen big changes in cannabis laws across the United States. This has led to young people seeing cannabis as less harmful. Also, cannabis products now often have much higher amounts of the psychoactive ingredient, THC. While it is clear that cannabis use disorder in young people can cause many problems, it might be harder for young people to engage with and respond to treatment when there is more positive and accepting messaging about cannabis in society.

The overall role of NAC in treating substance use problems is still not clear. While animal studies show strong effects, human studies often give mixed results. This gap between animal and human findings might be due to many things, such as how a study is designed, the dose of medicine used, how long it's given, and what other treatments are included. It also highlights that many factors contribute to substance use problems, even when a medicine works on a biological level. This means it is important to develop treatments that combine both medicines and behavioral help in ways that support each other. Our study suggests that rewards might be needed to help NAC work in encouraging young people to stop using cannabis. Additionally, the finding that confidence and readiness to quit predicted success in the NAC group suggests that NAC treatment might be best for those who are already confident in their ability to quit.

This study had strong points, including a careful design, enough participants, good participant retention, and consistent medication-taking. However, there were some limits, such as not having a lot of racial diversity among participants. Also, because of COVID-19, some urine tests were only quick qualitative tests rather than more detailed lab analyses. The study also did not collect data on how NAC affected brain chemistry, which limits our understanding of why it did not work. Despite these limitations, our findings suggest that NAC is not effective for young people with cannabis use disorder when it is not combined with a reward system. This highlights how important behavioral rewards can be in helping NAC work. More research is needed to find accessible and effective treatments for young people struggling with cannabis use disorder.