Cannabis use and trauma-focused treatment for co-occurring posttraumatic stress disorder and substance use disorders: A meta-analysis of individual patient data.

High rates of cannabis use among people with posttraumatic stress disorder (PTSD) have raised questions about the efficacy of evidence-based PTSD treatments for individuals reporting cannabis use, particularly those with co-occurring alcohol or other substance use disorders (SUDs). Using a subset of four randomized clinical trials (RCTs) included in Project Harmony, an individual patient meta-analysis of 36 RCTs (total N = 4046) of treatments for co-occurring PTSD+SUD, we examined differences in trauma-focused (TF) and non-trauma-focused (non-TF) treatment outcomes for individuals who did and did not endorse baseline cannabis use (N = 410; 70% male; 33.2% endorsed cannabis use). Propensity score-weighted mixed effects modeling evaluated main and interactive effects of treatment assignment (TF versus non-TF) and baseline cannabis use (yes/no) on attendance rates and within-treatment changes in PTSD, alcohol, and non-cannabis drug use severity. Results revealed significant improvements across outcomes among participants in all conditions, with larger PTSD symptom reductions but lower attendance among individuals receiving TF versus non-TF treatment in both cannabis groups. Participants achieved similar reductions in alcohol and drug use across all conditions. TF outperformed non-TF treatments regardless of recent cannabis use, underscoring the importance of reducing barriers to accessing TF treatments for individuals reporting cannabis use.

A multi-centre, double-blind, 12-week, randomized, placebo-controlled trial of adjunctive N-Acetylcysteine for treatment-resistant PTSD.

BACKGROUND: PTSD may involve oxidative stress, and N-acetylcysteine (NAC) may reduce the impact of oxidative stress in the brain. This study aims to investigate the efficacy of adjuvant NAC in people with treatment-resistant PTSD. METHODS: A multicentre, randomised, double-blind, placebo-controlled trial for adults with PTSD unresponsive to first-line treatment. The intervention was either oral NAC 2.7 g/day or placebo for 12 weeks. The primary outcome was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) at 12 weeks compared with baseline. Secondary outcomes included depression and substance craving. Follow-up measures were obtained at 16 and 64-weeks. RESULTS: 133 patients were assessed, with 105 randomised; 81 participants completed the 12-week trial, 79 completed week-16 follow-up, and 21 completed week-64 follow-up. There were no significant differences between those taking NAC and those taking placebo in CAPS-5 scores at week 12, nor in secondary outcomes. Significant between-group differences were observed at week 64 in craving duration (Cohen's d = 1.61) and craving resistance (Cohen's d = 1.03), both in favour of NAC. CONCLUSION: This was the first multicentre, double-blind, randomised, placebo-controlled trial of adjunctive NAC for treatment-resistant PTSD. No benefit of NAC was observed in this group beyond that provided by placebo at end of the trial. TRIAL REGISTRATION: ACTRN12618001784202, retrospectively registered 31/10/2018, URL: http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376004.

The Potential of N-Acetyl-L-Cysteine (NAC) in the Treatment of Psychiatric Disorders.

N-acetyl-L-cysteine (NAC) is a compound of increasing interest in the treatment of psychiatric disorders. Primarily through its antioxidant, anti-inflammatory, and glutamate modulation activity, NAC has been investigated in the treatment of neurodevelopmental disorders, schizophrenia spectrum disorders, bipolar-related disorders, depressive disorders, anxiety disorders, obsessive compulsive-related disorders, substance-use disorders, neurocognitive disorders, and chronic pain. Whilst there is ample preclinical evidence and theoretical justification for the use of NAC in the treatment of multiple psychiatric disorders, clinical trials in most disorders have yielded mixed results. However, most studies have been underpowered and perhaps too brief, with some evidence of benefit only after months of treatment with NAC. Currently NAC has the most evidence of having a beneficial effect as an adjuvant agent in the negative symptoms of schizophrenia, severe autism, depression, and obsessive compulsive and related disorders. Future research with well-powered studies that are of sufficient length will be critical to better understand the utility of NAC in the treatment of psychiatric disorders.

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.

Behavioral Treatments for Alcohol Use Disorder and Post-Traumatic Stress Disorder.

Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are highly prevalent and debilitating psychiatric conditions that commonly co-occur. Individuals with comorbid AUD and PTSD incur heightened risk for other psychiatric problems (e.g., depression and anxiety), impaired vocational and social functioning, and poor treatment outcomes. This review describes evidence-supported behavioral interventions for treating AUD alone, PTSD alone, and comorbid AUD and PTSD. Evidence-based behavioral interventions for AUD include relapse prevention, contingency management, motivational enhancement, couples therapy, 12-step facilitation, community reinforcement, and mindfulness. Evidence-based PTSD interventions include prolonged exposure therapy, cognitive processing therapy, eye movement desensitization and reprocessing, psychotherapy incorporating narrative exposure, and present-centered therapy. The differing theories behind sequential versus integrated treatment of comorbid AUD and PTSD are presented, as is evidence supporting the use of integrated treatment models. Future research on this complex, dual-diagnosis population is necessary to improve understanding of how individual characteristics, such as gender and treatment goals, affect treatment outcome.

The Role of Relationship Adjustment in an Integrated Individual Treatment for PTSD and Substance Use Disorders Among Veterans: An Exploratory Study.

OBJECTIVE: Identifying factors that influence treatment outcomes of emerging integrated interventions for co-occurring posttraumatic stress disorder (PTSD) and substance use disorder is crucial to maximize veterans' health. Dyadic adjustment suffers among individuals with PTSD and substance use disorder and may be an important mechanism of change in treatment. This exploratory study examined the association between dyadic adjustment and treatment outcomes in individual integrated treatment for co-occurring PTSD and substance use disorder. METHODS: Participants were treatment-seeking veterans (N = 15) participating in a larger randomized controlled trial examining the efficacy of a novel integrated treatment for co-occurring PTSD and substance use disorder. Multiple regression analyses controlling for baseline symptom severity and independent sample t-tests were used to examine the relation between dyadic adjustment and treatment outcome variables including PTSD, substance use disorder, and depression symptom severity. RESULTS: Baseline dyadic adjustment was associated with session 12 PTSD symptom severity as measured by both the Clinician-Administered PTSD Scale (CAPS) and PTSD Checklist (PCL), such that participants with high dyadic adjustment had significantly lower session 12 CAPS and PCL scores compared to participants with low dyadic adjustment. Baseline dyadic adjustment was not associated with session 12 depression symptoms or frequency of substance use. CONCLUSIONS: These findings suggest that while the primary determinant of treatment outcome in this sample is the application of an evidence-based intervention, dyadic adjustment may play a role in individual treatment outcome for some treatment-seeking veterans. Data from this study were derived from clinical trial NCT01365247.

Posttraumatic Stress Disorder: Overview of Evidence-Based Assessment and Treatment.

Posttraumatic stress disorder (PTSD) is a chronic psychological disorder that can develop after exposure to a traumatic event. This review summarizes the literature on the epidemiology, assessment, and treatment of PTSD. We provide a review of the characteristics of PTSD along with associated risk factors, and describe brief, evidence-based measures that can be used to screen for PTSD and monitor symptom changes over time. In regard to treatment, we highlight commonly used, evidence-based psychotherapies and pharmacotherapies for PTSD. Among psychotherapeutic approaches, evidence-based approaches include cognitive-behavioral therapies (e.g., Prolonged Exposure and Cognitive Processing Therapy) and Eye Movement Desensitization and Reprocessing. A wide variety of pharmacotherapies have received some level of research support for PTSD symptom alleviation, although selective serotonin reuptake inhibitors have the largest evidence base to date. However, relapse may occur after the discontinuation of pharmacotherapy, whereas PTSD symptoms typically remain stable or continue to improve after completion of evidence-based psychotherapy. After reviewing treatment recommendations, we conclude by describing critical areas for future research.

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.

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.

Cold pressor task reactivity: predictors of alcohol use among alcohol-dependent individuals with and without comorbid posttraumatic stress disorder.

BACKGROUND: The association between stress and alcohol dependence has been well established. Abnormalities in stress reactivity and hypothalamic-pituitary-adrenal axis (HPA) function may be involved in the mechanistic connection between stress and the initiation, development, and/or maintenance of alcohol dependence. Posttraumatic stress disorder (PTSD) commonly co-occurs with alcohol dependence and is characterized by HPA axis abnormalities. This study investigated the relationship between subjective and neuroendocrine stress reactivity to the cold pressor task (CPT) and prospective alcohol use among individuals with alcohol dependence, with and without comorbid PTSD. METHODS: Participants were 63 individuals with (a) alcohol dependence only (n=35) or (b) comorbid alcohol dependence and PTSD (n=28). Participants completed the CPT, a widely used physical laboratory stressor. Subjective stress, craving, adrenocorticotrophin (ACTH), and cortisol were measured before, immediately after, and at 5, 30, 60, and 120 minutes after the CPT. Alcohol use during 1 month following testing was also assessed. RESULTS: For the alcohol-only group, change in craving immediately following the CPT and craving during the 120-minute recovery phase were predictive of follow-up alcohol use. For the alcohol/PTSD group, change in craving was not predictive of follow-up use. Baseline drinking was, however, predictive of followup alcohol use for the alcohol/PTSD group. For the alcohol-only group, a blunted ACTH response coupled with a higher change in craving following the CPT was associated with significantly greater frequency and intensity of drinking during the follow-up phase. CONCLUSIONS: These preliminary findings demonstrate significant differences between the alcohol-only and the alcohol/PTSD group in predictors of relapse. For the alcohol-only group, reactivity to an acute laboratory stressor may be predictive of subsequent alcohol use. This was not true for the alcohol/PTSD group. Although preliminary, the findings may help shed light on the mechanistic relationship between stress reactivity and increased risk for alcohol relapse and dependence in individuals with and without other Axis I comorbidity.