Efficacy of mindfulness-based relapse prevention in a sample of veterans in a substance use disorder aftercare program: A randomized controlled trial.

BACKGROUND: Complementary integrative medicine, such as mindfulness-based interventions, (MBI) have demonstrated efficacy in the treatment of depression, anxiety, substance use disorders (SUDs), and pain. Mindfulness-based relapse prevention (MBRP) is an aftercare intervention targeting SUD relapse that integrates cognitive-behavioral relapse prevention and mindfulness meditation practices, raising awareness of substance use triggers and reactive behavioral patterns. This study evaluated the efficacy of MBRP in reducing relapse in veterans following completion of an SUD treatment program. METHODS: This study was a two-site, randomized controlled trial comparing MBRP to 12-step facilitation (TSF) aftercare in military veterans following completion of intensive treatment for SUDs. The 8 weeks of 90-minute, group-based MBRP or TSF sessions were followed by 3-, 6- and 10-month follow-up periods with assessments of alcohol/substance use and secondary outcomes of depression, anxiety, and mindfulness. RESULTS: Forty-seven percent of veterans attended ≥75 % of sessions. Veterans in both the MBRP and TSF aftercare groups maintained reductions in alcohol and illicit substance use during the aftercare treatment. Nineteen participants (11 %; 19/174) reported returning to alcohol use during the study treatment period and the study found no difference between study groups [MBRP: 9 % vs. TSF 13 %; p = 0.42]. Thirteen participants (7.5 %; 13/174) reported a return to illicit substance use during study treatment [MBRP: 5.4 % vs. TSF 10.3 % p = 0.34]. The number of days of drinking and illicit substance use was not different between groups (alcohol, p = 0.53; illicit substance use, p = 0.28). CONCLUSION: Although retention in treatment limits interpretation of the findings, both MBRP and TSF were effective in maintenance of treatment gains following an intensive treatment program for veterans with SUDs. Future studies should focus on strategies to improve treatment participation.

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.

Efficacy of mindfulness-based relapse prevention in veterans with substance use disorders: Design and methodology of a randomized clinical trial.

Mindfulness based interventions have been shown to be efficacious in treating depression, anxiety, pain and substance use disorders (SUDs). Mindfulness-Based Relapse Prevention (MBRP) is an intervention that integrates cognitive-behavioral relapse prevention and mindfulness meditation practices, in an 8-week, manualized group intervention designed to treat SUDs by helping patients regulate negative emotional states and reactive behavior. This paper describes the rationale, study design and methodology of a two-site, randomized controlled trial comparing MBRP to 12-Step Facilitation (TSF) in military Veterans following completion of intensive outpatient treatment for SUDs. The 8 weeks of 90-min, group-based MBRP or TSF sessions are followed by 3-, 6- and 10-month follow-up period with assessments of alcohol/drug use, quality of life, depression, anxiety, mindfulness and other functional outcomes, such as employment. The primary hypothesis is that MBRP will be significantly better than TSF in promoting recovery and prevention of relapse to substance use in a military Veteran population. The secondary hypothesis is that MBRP will lead to greater improvements in quality of life, depression/anxiety, and functional outcomes, such as employment. This study is designed to provide information about the use of group-based MBRP as a relapse prevention strategy for military Veterans who have completed an intensive SUD clinical treatment program. Clinical Trial Identifier: NCT02326363.

Design and methods of a multi-site randomized controlled trial of an integrated care model of long-acting injectable buprenorphine with infectious disease treatment among persons hospitalized with infections and opioid use disorder.

BACKGROUND: Hospitalization with co-occurring opioid use disorder (OUD) and infections presents a critical time to intervene to improve outcomes for these intertwined epidemics that are typically managed separately. A surge in life-threatening infectious diseases associated with injection drug use, including bacterial and fungal infections, HIV, and HCV accounts for substantial healthcare utilization, morbidity, and mortality. Infectious Disease (ID) specialists manage severe infections that require hospitalization and are a logical resource to engage patients in medication treatment for OUD (MOUD). An injectable long-acting monthly formulation of buprenorphine (LAB) has a potential advantage for initiating MOUD within hospital settings and bridging to treatment after discharge. METHODS: A randomized multi-site trial tests a new model of care (ID/LAB) in which OUD and infections are managed by ID specialists and hospitalists using LAB coupled with referrals to community resources for long-term MOUD. A sample of 200 adults admitted to three U.S. hospitals for OUD and infections are randomly assigned 1:1 to ID/LAB or treatment as usual (TAU). The primary outcome measure is the proportion of patients enrolled in effective MOUD at 12 weeks after randomization. Secondary outcomes include relapse to opioid use, adherence to infectious disease treatment, infection morbidity and mortality, and drug overdose. RESULTS: We describe the design, procedures, statistical analysis, and early implementation issues of this randomized trial. CONCLUSIONS: Study findings will provide insight into the feasibility and effectiveness of integrated treatment of OUD and serious infections and have the potential to reduce morbidity and mortality in this vulnerable population.

Efficacy of Ketamine in the Treatment of Substance Use Disorders: A Systematic Review.

Background: Despite advances in behavioral and pharmacotherapy interventions, substance use disorders (SUDs) are frequently refractory to treatment. Glutamatergic dysregulation has received increasing attention as one common neuropathology across multiple substances of abuse. Ketamine is a potent N-methyl-D-aspartate (NMDA) glutamatergic receptor antagonist which has been found to be effective in the treatment of severe depression. Here we review the literature on the efficacy of ketamine in the treatment of SUDs. Methods: A systematic review of the PubMed, Scopus, and ClinicalTrials.gov databases was undertaken to identify completed and ongoing human studies of the effectiveness of ketamine in the treatment of SUDs between January 1997 and January 2018. Results and conclusion: Seven completed studies were identified. Two studies focused on alcohol use disorder, two focused on cocaine use disorder, and three focused on opioid use disorder. Both cocaine studies found improvements in craving, motivation, and decreased cocaine use rates, although studies were limited by small sample sizes, a homogeneous population and short follow-up. Studies of alcohol and opioid use disorders found improvement in abstinence rates in the ketamine group, with significant between-group effects noted for up to two years following a single infusion, although these were not placebo-controlled trials. These results suggest that ketamine may facilitate abstinence across multiple substances of abuse and warrants broader investigation in addiction treatment. We conclude with an overview of the six ongoing studies of ketamine in the treatment of alcohol, cocaine, cannabis, and opioid use disorders and discuss future directions in this emerging area of research.

Individualized real-time fMRI neurofeedback to attenuate craving in nicotine-dependent smokers.

BACKGROUND: Cue-induced craving plays an important role in relapse, and the neural correlates of cue-induced craving have been elucidated using fMRI. This study examined the utility of real-time fMRI (rtfMRI) neurofeedback to strengthen self-regulation of craving-related neural activation and cue-reactivity in cigarette smokers. METHODS: Nicotine-dependent smokers were randomized to rtfMRI neurofeedback or to a no-feedback control group. Participants completed 3 neuroimaging visits. Within each visit, an initial run during which smoking-related cues were used to provoke craving, an individualized craving-related region of interest (ROI) in the prefrontal cortex or anterior cingulate cortex was identified. In the rtfMRI group, activity from the ROI was fed back via a visual display during 3 subsequent runs while participants were instructed to reduce craving during cue exposure. The control group had an identical experience with no feedback provided. RESULTS: Forty-four nicotine-dependent smokers were recruited to participate in our study; data from the 33 participants who completed a 1-week follow-up visit were included in the analysis. Subjective craving ratings and cue-induced brain activation were lower in the rtfMRI group than in the control group. LIMITATIONS: As participants were not seeking treatment, clinical outcomes are lacking. CONCLUSION: Nicotine-dependent smokers receiving rtfMRI feedback from an individualized ROI attenuated smoking cue-elicited neural activation and craving, relative to a control group. Further studies are needed in treatment-seeking smokers to determine if this intervention can translate into a clinically meaningful treatment modality.

Lower subcortical gray matter volume in both younger smokers and established smokers relative to non-smokers.

Although established adult smokers with long histories of nicotine dependence have lower neural tissue volume than non-smokers, it is not clear if lower regional brain volume is also observed in younger, less established smokers. The primary goal of this study was to investigate neural tissue volume in a large group of smokers and non-smokers, with a secondary goal of measuring the impact of age on these effects. We used voxel-based morphometry to compare regional gray matter volume in 118 individuals (59 smokers, 59 age- and gender-matched non-smokers). Younger smokers had significantly lower gray matter volume in the left thalamus and the left amygdala than their non-smoking peers (family-wise error-corrected clusters, P < 0.05). There was no correlation between smoking use variables and tissue volume among younger smokers. Established smokers had significantly lower gray matter volume than age-matched non-smokers in the insula, parahippocampal gyrus and pallidum. Medial prefrontal cortex gray matter volume was negatively correlated with pack-years of smoking among the established smokers, but not the younger smokers. These data reveal that regional tissue volume differences are not limited exclusively to established smokers. Deficits in young adults indicate that cigarette smoking may either be deleterious to the thalamus and amygdala at an earlier age than previously reported, or that pre-existing differences in these areas may predispose individuals to the development of nicotine dependence.

Buspirone treatment of cannabis dependence: A randomized, placebo-controlled trial.

BACKGROUND: The purpose of this study was to evaluate the efficacy of buspirone, a partial 5-HT1A agonist, for treatment of cannabis dependence. METHODS: One hundred seventy-five cannabis-dependent adults were randomized to receive either up to 60mg/day of buspirone (n=88) or placebo (n=87) for 12 weeks combined with a brief motivational enhancement therapy intervention and contingency management to encourage study retention. Cannabis use outcomes were assessed via weekly urine cannabinoid tests. RESULTS: Participants in both groups reported reduced cannabis craving over the course of the study; however, buspirone provided no advantage over placebo in reducing cannabis use. Significant gender by treatment interactions were observed, with women randomized to buspirone having fewer negative urine cannabinoid tests than women randomized to placebo (p=0.007), and men randomized to buspirone having significantly lower creatinine adjusted cannabinoid levels as compared to those randomized to placebo (p=0.023). An evaluation of serotonin allelic variations did not find an association with buspirone treatment response. CONCLUSIONS: Buspirone was not more efficacious than placebo in reducing cannabis use. Important gender differences were noted, with women having worse cannabis use outcomes with buspirone treatment. Considerations for future medication trials in this challenging population are discussed.

Sustained reduction of nicotine craving with real-time neurofeedback: exploring the role of severity of dependence.

BACKGROUND: Neurofeedback delivered via real-time functional magnetic resonance imaging (rtfMRI) is a promising therapeutic technique being explored to facilitate self-regulation of craving in nicotine-dependent cigarette smokers. The current study examined the role of nicotine-dependence severity and the efficacy of multiple visits of neurofeedback from a single region of interest (ROI) in the anterior cingulate cortex (ACC) on craving reduction. METHODS: Nine nicotine-dependent cigarette smokers participated in three rtfMRI visits that examined cue-induced craving and brain activation. Severity of nicotine dependence was assessed with the Fagerström Test for Nicotine Dependence. When viewing smoking-related images with instructions to "crave," patient-tailored ROIs were generated in the vicinity of the ACC. Activity levels from the ROI were fed back while participants viewed smoking cues with the instruction to reduce craving. RESULTS: Neurofeedback from a single ROI in the ACC led to consistent decreases in self-reported craving and activation in the ACC across the three visits. Dependence severity predicted response to neurofeedback at Visit 3. CONCLUSIONS: This study builds upon previous rtfMRI studies on the regulation of nicotine craving in demonstrating that feedback from the ACC can reduce activation to smoking cues across three separate visits. Individuals with lower nicotine-dependence severity were more successful in reducing ACC activation over time. These data highlight the need to consider dependence severity in developing more individualized neurofeedback methods.

Reduction of cue-induced craving through realtime neurofeedback in nicotine users: the role of region of interest selection and multiple visits.

This multi-visit, real-time functional magnetic resonance imaging feedback study demonstrates that treatment-seeking smokers can effectively modulate their behavioral and brain responses to smoking cues. They are more effective at decreasing activity in functionally defined regions involved in "craving" (e.g. ventral anterior cingulate cortex (vACC)) rather than increasing activity in regions involved in "resisting" (e.g. dorsal medial prefrontal cortex (dmPFC)).

Real-time fMRI in the treatment of nicotine dependence: a conceptual review and pilot studies.

Technical advances allowing for the analysis of functional MRI (fMRI) results in real time have led to studies exploring the ability of individuals to use neural feedback signals to modify behavior and regional brain activation. The use of real-time fMRI (rtfMRI) feedback has been explored for therapeutic benefit in a number of disease states, but to our knowledge, the potential therapeutic benefit of rtfMRI feedback in the treatment of addictive disorders has not been explored. This article will provide an overview of the development of rtfMRI and discussion of its potential uses in the treatment of addictions. We also describe a series of pilot studies that highlight some of the technical challenges in developing a rtfMRI feedback paradigm for use in addictions, specifically in nicotine dependence. Because the use of rtfMRI feedback is in its infancy, the work described is focused on establishing some of the basic parameters in optimizing the rtfMRI feedback, such as the type of feedback signal, region of interest for feedback and predicting which subjects are most likely to respond well to training. While rtfMRI feedback remains an intriguing possibility for the treatment of addictions, much work remains to be done in establishing its efficacy.

Volitional reduction of anterior cingulate cortex activity produces decreased cue craving in smoking cessation: a preliminary real-time fMRI study.

Numerous research groups are now using analysis of blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) results and relaying back information about regional activity in their brains to participants in the scanner in 'real time'. In this study, we explored the feasibility of self-regulation of frontal cortical activation using real-time fMRI (rtfMRI) neurofeedback in nicotine-dependent cigarette smokers during exposure to smoking cues. Ten cigarette smokers were shown smoking-related visual cues in a 3 Tesla MRI scanner to induce their nicotine craving. Participants were instructed to modify their craving using rtfMRI feedback with two different approaches. In a 'reduce craving' paradigm, participants were instructed to 'reduce' their craving, and decrease the anterior cingulate cortex (ACC) activity. In a separate 'increase resistance' paradigm, participants were asked to increase their resistance to craving and to increase middle prefrontal cortex (mPFC) activity. We found that participants were able to significantly reduce the BOLD signal in the ACC during the 'reduce craving' task (P=0.028). There was a significant correlation between decreased ACC activation and reduced craving ratings during the 'reduce craving' session (P=0.011). In contrast, there was no modulation of the BOLD signal in mPFC during the 'increase resistance' session. These preliminary results suggest that some smokers may be able to use neurofeedback via rtfMRI to voluntarily regulate ACC activation and temporarily reduce smoking cue-induced craving. Further research is needed to determine the optimal parameters of neurofeedback rtfMRI, and whether it might eventually become a therapeutic tool for nicotine dependence.

A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents.

OBJECTIVE: Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine (NAC), via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy for substance dependence. The authors investigated NAC as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have shown limited efficacy. METHOD: In an 8-week double-blind randomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (ages 15-21 years; N=116) received NAC (1200 mg) or placebo twice daily as well as a contingency management intervention and brief (<10 minutes) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid test results during treatment among participants receiving NAC compared with those receiving placebo, in an intent-to-treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group. RESULTS: Participants receiving NAC had more than twice the odds, compared with those receiving placebo, of having negative urine cannabinoid test results during treatment (odds ratio=2.4, 95% CI=1.1-5.2). Exploratory secondary abstinence outcomes favored NAC but were not statistically significant. NAC was well tolerated, with minimal adverse events. CONCLUSIONS: This is the first randomized controlled trial of pharmacotherapy for cannabis dependence in any age group to yield a positive primary cessation outcome in an intent-to-treat analysis. Findings support NAC as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents.

Contingency management in community programs treating adolescent substance abuse: a feasibility study.

PROBLEM: Adolescent substance abuse remains a public health problem, and more effective treatment approaches are needed. PURPOSE: The study aims to determine the feasibility and preliminary effectiveness of implementing a cost-effective contingency management (CM) intervention in community substance abuse treatment for adolescents with marijuana use disorders. METHODS: Thirty-one adolescents with primary marijuana use disorder enrolled in a community treatment were randomized into either a prize-based CM intervention contingent when submitting negative urine drug screens (UDS) or a noncontingent control group. FINDINGS: There were no significant group differences in percent negative UDS, sustained negative UDS, or retention in treatment. CONCLUSIONS: CM was difficult to integrate into community treatment programs and did not seem to be an effective adjunct to standard community substance abuse treatment for adolescents with marijuana use disorders. Modifying the CM procedure for adolescents, changing staff attitudes toward CM, and/or combining CM with other evidence-based psychosocial treatment may improve outcomes.

Comparative profiles of men and women with opioid dependence: results from a national multisite effectiveness trial.

BACKGROUND: Accumulating evidence indicates important gender differences in substance use disorders. Little is known, however, about gender differences and opioid use disorders. OBJECTIVES: To compare demographic characteristics, substance use severity, and other associated areas of functioning (as measured by the Addiction Severity Index-Lite (ASI-Lite)) among opioid-dependent men and women participating in a multisite effectiveness trial. METHODS: Participants were 892 adults screened for the National Institute on Drug Abuse Clinical Trials Network investigation of the effectiveness of two buprenorphine tapering schedules. RESULTS: The majority of men and women tested positive for oxycodone (68% and 65%, respectively) and morphine (89% each). More women than men tested positive for amphetamines (4% vs. 1%, p < .01), methamphetamine (11% vs. 4%, p < .01), and phencyclidine (8% vs. 4%, p = .02). More men than women tested positive for methadone (11% vs. 6%, p = .05) and marijuana (22% vs. 15%, p = .03). Craving for opioids was significantly higher among women (p < .01). Men evidenced higher alcohol (p < .01) and legal (p = .04) ASI composite scores, whereas women had higher drug (p < .01), employment (p < .01), family (p < .01), medical (p < .01), and psychiatric (p < .01) ASI composite scores. Women endorsed significantly more current and past medical problems. CONCLUSIONS: Important gender differences in the clinical profiles of opioid-dependent individuals were observed with regard to substance use severity, craving, medical conditions, and impairment in associated areas of functioning. The findings enhance understanding of the characteristics of treatment-seeking men and women with opioid dependence, and may be useful in improving identification, prevention, and treatment efforts for this challenging and growing population.

A placebo-controlled trial of atomoxetine in marijuana-dependent individuals with attention deficit hyperactivity disorder.

This study evaluated the effects of atomoxetine on the symptoms of attention deficit hyperactivity disorder (ADHD) and marijuana use in marijuana-dependent adults. In conjunction with motivational interviewing, participants received either atomoxetine (n = 19) or matching placebo (n = 19) for 12 weeks. Participants randomized to atomoxetine had greater improvement in ADHD on the Clinical Global Impression-Improvement scale than participants treated with placebo. No treatment group differences in self-rated ADHD symptoms, overall Wender-Reimherr Adult Attention Deficit Disorder Scale scores, or marijuana use outcomes were noted. These results suggest that atomoxetine may improve some ADHD symptoms but does not reduce marijuana use in this population.

A placebo-controlled trial of buspirone for the treatment of marijuana dependence.

The present study investigated the potential efficacy of buspirone for treating marijuana dependence. Participants received either buspirone (maximum 60mg/day) (n=23) or matching placebo (n=27) for 12 weeks, each in conjunction with motivational interviewing. In the modified intention-to-treat analysis, the percentage of negative UDS results in the buspirone-treatment group was 18 percentage points higher than the placebo-treatment group (95% CI: -2% to 37%, p=0.071). On self-report, participants receiving buspirone reported not using marijuana 45.2% of days and participants receiving placebo reported not using 51.4% of days (p=0.55). An analysis of participants that completed the 12-week trial showed a significant difference in the percentage negative UDS (95% CI: 7-63%, p=0.014) and a trend for participants randomized to the buspirone-treatment group who completed treatment to achieve the first negative UDS result sooner than those participants treated with placebo (p=0.054). Further study with buspirone in this population may be warranted; however, strategies to enhance study retention and improve outcome measurement should be considered in future trials.

Assessment of club drug use in a treatment-seeking sample of individuals with marijuana dependence.

Club drug use is becoming increasingly popular in the United States and has been associated with chronic psychiatric symptoms and neuropsychological abnormalities. Patterns of club drug use and characteristics of club drug users are not homogeneous. Thus, treatment-seeking marijuana-dependent individuals may have a differential pattern of club drug use. Baseline assessments collected from 55 individuals participating in a pharmacological treatment study for marijuana dependence were examined. Individuals completed a 16-item self-report questionnaire assessing club drugs used, frequency and patterns of use, problems associated with use, and reasons for use. Subjects were primarily male (87.3%) and Caucasian (81.8%), with a mean age of 32.1 (+/-9.1 years). As expected, a large number of individuals had used ecstasy (75%). However, LSD and methamphetamine use was also reported by many users (82.5% and 47.5% respectively), with many individuals reporting the use of more than one club drug. Notably, 31.6% of individuals reported tolerance to club drugs. These results emphasize the significant co-occurrence of club drug use in marijuana-dependent individuals. This appears to be the first study to report on club drug use in treatment-seeking marijuana-dependent individuals. Clinical implications and directions for future research are discussed.