Exploring the Utility of a Functional Magnetic Resonance Imaging (fMRI) Cannabis Cue-Reactivity Paradigm in Treatment Seeking Adults with Cannabis Use Disorder.

Introduction: Functional magnetic resonance imaging (fMRI) studies examining cue-reactivity in cannabis use disorder (CUD) to date have either involved non-treatment seeking participants or been small. We addressed this gap by administering an fMRI cue-reactivity task to CUD participants entering two separate clinical trials. Methods: Treatment-seeking participants with moderate or severe CUD had behavioral craving measured at baseline via the Marijuana Craving Questionnaire (MCQ-SF). They additionally completed a visual cannabis cue-reactivity paradigm during fMRI following 24-hours of abstinence from cannabis. During fMRI, the Blood Oxygen Level Dependent (BOLD) signal was acquired while participants viewed cannabis-images or matched-neutral-images. BOLD responses were correlated with the MCQ-SF using a General Linear Model. Results: N=65 participants (32% female; mean age 30.4±9.9SD) averaged 46.3±15.5SD on the MCQ-SF. When contrasting cannabis-images vs. matched-neutral-images, participants showed greater BOLD response in bilateral ventromedial prefrontal, dorsolateral prefrontal, anterior cingulate, and visual cortices, as well as the striatum. Similarly, there was stronger task-based functional-connectivity (tbFC) between the medial prefrontal cortex and both the amygdala and the visual cortex. There were no significant differences in either activation or tbFC between studies or between sexes. Craving negatively correlated with BOLD response in the left ventral striatum (R 2 =-0.25; p =0.01). Conclusions: We found that, among two separate treatment-seeking CUD groups, cannabis cue-reactivity was evidenced by greater activation and tbFC in regions related to executive function and reward processing, and craving was negatively associated with cue-reactivity in the ventral striatum. Future directions include examining if pharmacological, neuromodulatory, or psychosocial interventions can alter corticostriatal cue-reactivity.

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.

N-acetylcysteine does not alter neurometabolite levels in non-treatment seeking adolescents who use alcohol heavily: A preliminary randomized clinical trial.

Current treatments for adolescent alcohol use disorder (AUD) are mainly psychosocial and limited in their efficacy. As such, pharmacotherapies are being investigated as potential adjunctive treatments to bolster treatment outcomes. N-acetylcysteine is a promising candidate pharmacotherapy for adolescent AUD because of its tolerability and demonstrated ability to modulate glutamatergic, GABAergic, and glutathione systems. The primary objective of this double-blind, placebo-controlled, within-subjects crossover preliminary investigation was to measure potential changes within glutamate + glutamine (Glx), GABA, and glutathione levels in the dorsal anterior cingulate cortex (dACC) using proton magnetic resonance spectroscopy during 10-days of N-acetylcysteine (1200 mg twice daily) compared to 10-days of placebo in non-treatment seeking adolescents who use alcohol heavily (N = 31; 55% female). Medication adherence was confirmed via video. Effects on alcohol use were measured using Timeline Follow-Back as an exploratory aim. Linear mixed effects models controlling for baseline metabolite levels, brain tissue composition, alcohol use, cannabis use, and medication adherence found no significant differences in Glx, GABA, or glutathione levels in the dACC after N-acetylcysteine compared to placebo. There were also no measurable effects on alcohol use; however, this finding was underpowered. Findings were consistent in the subsample of participants who met criteria for AUD (n = 19). The preliminary null findings in brain metabolite levels may be due to the young age of participants, relatively low severity of alcohol use, and non-treatment seeking status of the population investigated. Future studies can use these findings to conduct larger, well-powered studies within adolescents with AUD.

Results from a randomized, double-blind, placebo-controlled, crossover, multimodal-MRI pilot study of gabapentin for co-occurring bipolar and cannabis use disorders.

Disrupted brain gamma-aminobutyric acid (GABA)/glutamate homeostasis is a promising target for pharmacological intervention in co-occurring bipolar disorder (BD) and cannabis use disorder (CUD). Gabapentin is a safe and well-tolerated medication, FDA-approved to treat other neurological diseases, that restores GABA/glutamate homeostasis, with treatment studies supporting efficacy in treating CUD, as well as anxiety and sleep disorders that are common to both BD and CUD. The present manuscript represents the primary report of a randomized, double-blind, placebo-controlled, crossover (1-week/condition), multimodal-MRI (proton-MR spectroscopy, functional MRI) pilot study of gabapentin (1200 mg/day) in BD + CUD (n = 22). Primary analyses revealed that (1) gabapentin was well tolerated and adherence and retention were high, (2) gabapentin increased dorsal anterior cingulate cortex (dACC) and right basal ganglia (rBG) glutamate levels and (3) gabapentin increased activation to visual cannabis cues in the posterior midcingulate cortex (pMCC, a region involved in response inhibition to rewarding stimuli). Exploratory evaluation of clinical outcomes further found that in participants taking gabapentin versus placebo, (1) elevations of dACC GABA levels were associated with lower manic/mixed and depressive symptoms and (2) elevations of rBG glutamate levels and pMCC activation to cannabis cues were associated with lower cannabis use. Though promising, the findings from this study should be interpreted with caution due to observed randomization order effects on dACC glutamate levels and identification of statistical moderators that differed by randomization order (i.e. cigarette-smoking status on rBG glutamate levels and pMCC cue activation). Nonetheless, they provide the necessary foundation for a more robustly designed (urn-randomized, parallel-group) future study of adjuvant gabapentin for BD + CUD.

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.

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.

Adolescent Substance Use Disorder Treatment: an Update on Evidence-Based Strategies.

PURPOSE OF REVIEW: To examine the most recent published evidence (2016-2019) regarding the treatment of adolescent substance use disorders and to provide an update on evidence-based strategies, adjunctive interventions, and methods to improve currently established treatment approaches. RECENT FINDINGS: Recent evidence suggests that psychosocial treatments such as family-based therapy, cognitive behavioral therapy, and multicomponent approaches remain the most effective methods of treatment; however, innovative ways of improving these treatment strategies may include digital and culturally based interventions. New advances in adjunctive treatments such as pharmacotherapy, exercise, mindfulness, and recovery-oriented educational centers may have some clinical utility. Well-established psychosocial interventions remain the primary modality of treatment. Promising new adjunctive treatments and improvements in our currently established treatments may yield significant improvements.

Preliminary evidence that computerized approach avoidance training is not associated with changes in fMRI cannabis cue reactivity in non-treatment-seeking adolescent cannabis users.

BACKGROUND: Cognitive Bias Modification (CBM) has garnered interest as a potential addiction treatment. CBM interventions such as Approach Avoidance Training (AAT) are designed to alter automatic tendencies to approach drugs or drug-related cues. In our previous work, the cannabis AAT (CAAT) reduced cannabis approach bias, which was related to reduced cannabis use, among 80 non-treatment-seeking cannabis-using youth (Jacobus et al., 2018). In this preliminary examination, a subsample of these youth underwent neuroimaging to explore CAAT's effect on cannabis cue-related neural activation. METHODS: Sub-study participants were 41 cannabis-using youth ages 17-21 (mean age = 18.83; 47.5% female). Participants completed a cannabis cue-reactivity task during a functional MRI scan pre- and post CAAT-training or CAAT-sham to examine CAAT-related neural changes. RESULTS: Thirty-seven youth completed all six CAAT (n = 19) or CAAT-sham (n = 18) training sessions and had usable neuroimaging data. The group*time interaction on cannabis approach bias reached trend-level significance (p = .055). Change in approach bias slopes from pre-to post-treatment was positive for CAAT-sham (increased approach bias) and negative for CAAT-training (change to avoidance bias), consistent with the larger study. No significant changes emerged for cannabis cue-induced activation following CAAT-training or CAAT-sham in whole brain or region of interest analyses. However, active CAAT-training was associated with small-to-medium decreases in amygdala (Cohen's dz = 0.36) and medial prefrontal cortex (Cohen's dz = 0.48) activation to cannabis cues. CONCLUSIONS: Despite reducing cannabis use in the larger sample, CAAT-training did not alter neural cannabis cue-reactivity in the sub-study compared to CAAT-sham. More research is needed to understand neural mechanisms underlying AAT-related changes in substance use.

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.

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

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

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

AIMS: Current adolescent alcohol treatments have modest effects and high relapse rates. Evaluation of novel pharmacotherapy treatment is warranted. N-acetylcysteine (NAC), an over-the-counter antioxidant supplement with glutamatergic properties, is a promising treatment for marijuana cessation in adolescents; however, its effects on adolescent drinking have not been examined. To that end, this secondary analysis evaluated: (1) the effect of NAC vs. placebo on alcohol use over an eight-week adolescent marijuana cessation trial and (2) the role of marijuana cessation and reduction on subsequent alcohol use. METHODS: Marijuana-dependent adolescents (ages 15-21; N=116) interested in treatment were randomized to NAC 1200mg or matched placebo twice daily for eightweeks. Participants were not required to be alcohol users or interested in alcohol cessation to qualify. RESULTS: There were no demographic or baseline alcohol use differences between participants randomized to NAC vs. placebo (ps>0.05). Of the 89 participants returning for ≥one visit following randomization, 77 reported ≥one alcoholic drink in the 30days prior to study entry and averaged 1.3 (SD=1.4) binge drinking days per week. During treatment, less marijuana use (measured via urine cannabinoid levels) was associated with less alcohol use in the NAC-treated group but not in the placebo-treated group (p=0.016). CONCLUSIONS: There was no evidence of compensatory alcohol use during marijuana treatment. In fact, in the NAC group, lower levels of marijuana use were associated with less alcohol use, suggesting NAC effects may generalize to other substances and could be useful in decreasing adolescent alcohol use. NAC trials specifically focused on alcohol-using adolescents are warranted.