Cannabinoids for the treatment of cannabis use disorder: New avenues for reaching and helping youth?

Cannabis use peaks during adolescence and emerging adulthood, and cannabis use disorder (CUD) is associated with a wide range of adverse outcomes. This is particularly pertinent in youth, because the developing brain may be more vulnerable to adverse effects of frequent cannabis use. Combining evidence-based psychosocial interventions with safe and effective pharmacotherapy is a potential avenue to improve youth outcomes, but we lack approved CUD pharmacotherapies. Here, we review new potential avenues for helping youth with CUD, with a particular focus on cannabinoid-based treatments. Evidence from placebo-controlled RCTs suggests synthetic delta-9-tetrahydrocannabinol (THC) decreases withdrawal symptoms, but not cannabis use, in adults with daily cannabis use/CUD, while findings regarding formulations containing THC combined with cannabidiol (CBD) are mixed. Preliminary evidence from two placebo-controlled RCTs in adults with CUD suggests that both Fatty Acid Amide Hydrolase inhibitors and CBD can reduce cannabis use. However, larger trials are needed to strengthen the evidence. Findings from adults point to cannabinoid-based treatments as a potential strategy that should be examined in youth with CUD.

Cannabidiol versus risperidone for treatment of recent-onset psychosis with comorbid cannabis use: study protocol for a randomized controlled clinical trial.

BACKGROUND: Cannabis use is an important risk factor for development of psychosis and further transition to schizophrenia. The prevalence of patients with psychosis and comorbid cannabis use (dual diagnosis) is rising with no approved specialized pharmacological treatment option. Cannabidiol, a constituent of the Cannabis sativa plant, has potential both as an antipsychotic and as a cannabis substituting agent. The aim of this study is to evaluate the efficacy of cannabidiol versus a first-choice second-generation antipsychotic (risperidone) in patients with early psychosis and comorbid cannabis use. METHODS: The study is a phase II randomized, double-blinded, parallel-group, active-comparator clinical trial. We plan to include 130 patients aged between 18 and 64 years with a recent diagnosis of psychosis, comorbid cannabis use, and currently not treated with antipsychotics. The participants will be randomized to seven weeks of treatment with either cannabidiol 600 mg (300 mg BID) or risperidone 4 mg (2 mg BID). Participants will undergo clinical assessment after 1, 3, 5 and 7 weeks, telephone assessment the weeks in between, and a safety visit two weeks after end of treatment. The primary outcomes are cessation of cannabis use (self-reported) and psychotic symptom severity. The secondary outcomes include frequency and quantity of cannabis use, global illness severity, psychosocial functioning, subjective well-being, cognition, sleep, circadian rhythmicity, and metabolomics. DISCUSSION: The results of this trial can potentially contribute with a new treatment paradigm for patients suffering from dual diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov , NCT04105231 , registered April 23rd, 2021.

Imagery rehearsal therapy and/or mianserin in treatment of refugees diagnosed with PTSD: Results from a randomized controlled trial.

Sleep disturbances are frequently part of the symptomatology in refugees with post-traumatic stress disorder (PTSD). It has been suggested that targeting sleep disturbances may enhance the outcome of PTSD treatment. However, randomized studies on the effect of treatment focusing on sleep disturbances in refugees with PTSD are lacking. The aim of this study was to examine add-on treatment with imagery rehearsal therapy (IRT) and/or mianserin against treatment as usual (TAU) alone in a sample of trauma-affected refugees with PTSD at 8-12 months follow-up. In a randomized controlled trial, 219 adult refugees diagnosed with PTSD and suffering from sleep disturbances were randomized to four groups (1:1:1:1) receiving, respectively, TAU, TAU + mianserin, TAU + IRT, and TAU + IRT + mianserin. The primary outcome was subjective sleep quality (Pittsburgh Sleep Quality Index) and the secondary outcomes included PTSD and depression symptoms, level of functioning and subjective well-being. The data were analysed using mixed models. The only significant effect of IRT was on level of functioning (p = .040, ES 0.44), whereas there was no significant effect of mianserin on any of the measured outcomes. Low adherence to both IRT (39%) and mianserin (20%) was observed. Contrary to our hypothesis, we did not find IRT or mianserin to be superior to TAU. The low adherence may potentially cause an underestimation of the effect of IRT and mianserin and indicates a necessity to further analyse the complex factors that may impact the motivation and ability of trauma-affected refugees to participate in and profit from available treatment options.

Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users.

BACKGROUND: Prolonged treatment with benzodiazepines is common practice despite clinical recommendations of short-term use. Benzodiazepines are used by approximately 4% of the general population, with increased prevalence in psychiatric populations and the elderly. After long-term use it is often difficult to discontinue benzodiazepines due to psychological and physiological dependence. This review investigated if pharmacological interventions can facilitate benzodiazepine tapering. OBJECTIVES: To assess the benefits and harms of pharmacological interventions to facilitate discontinuation of chronic benzodiazepine use. SEARCH METHODS: We searched the following electronic databases up to October 2017: Cochrane Drugs and Alcohol Group's Specialised Register of Trials, CENTRAL, PubMed, Embase, CINAHL, and ISI Web of Science. We also searched ClinicalTrials.gov, the WHO ICTRP, and ISRCTN registry, and checked the reference lists of included studies for further references to relevant randomised controlled trials. SELECTION CRITERIA: We included randomised controlled trials comparing pharmacological treatment versus placebo or no intervention or versus another pharmacological intervention in adults who had been treated with benzodiazepines for at least two months and/or fulfilled criteria for benzodiazepine dependence (any criteria). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 38 trials (involving 2543 participants), but we could only extract data from 35 trials with 2295 participants. Many different interventions were studied, and no single intervention was assessed in more than four trials. We extracted data on 18 different comparisons. The risk of bias was high in all trials but one. Trial Sequential Analysis showed imprecision for all comparisons.For benzodiazepine discontinuation, we found a potential benefit of valproate at end of intervention (1 study, 27 participants; risk ratio (RR) 2.55, 95% confidence interval (CI) 1.08 to 6.03; very low-quality evidence) and of tricyclic antidepressants at longest follow-up (1 study, 47 participants; RR 2.20, 95% CI 1.27 to 3.82; low-quality evidence).We found potentially positive effects on benzodiazepine withdrawal symptoms of pregabalin (1 study, 106 participants; mean difference (MD) -3.10 points, 95% CI -3.51 to -2.69; very low-quality evidence), captodiame (1 study, 81 participants; MD -1.00 points, 95% CI -1.13 to -0.87; very low-quality evidence), paroxetine (2 studies, 99 participants; MD -3.57 points, 95% CI -5.34 to -1.80; very low-quality evidence), tricyclic antidepressants (1 study, 38 participants; MD -19.78 points, 95% CI -20.25 to -19.31; very low-quality evidence), and flumazenil (3 studies, 58 participants; standardised mean difference -0.95, 95% CI -1.71 to -0.19; very low-quality evidence) at end of intervention. However, the positive effect of paroxetine on benzodiazepine withdrawal symptoms did not persist until longest follow-up (1 study, 54 participants; MD -0.13 points, 95% CI -4.03 to 3.77; very low-quality evidence).The following pharmacological interventions reduced symptoms of anxiety at end of intervention: carbamazepine (1 study, 36 participants; MD -6.00 points, 95% CI -9.58 to -2.42; very low-quality evidence), pregabalin (1 study, 106 participants; MD -4.80 points, 95% CI -5.28 to -4.32; very low-quality evidence), captodiame (1 study, 81 participants; MD -5.70 points, 95% CI -6.05 to -5.35; very low-quality evidence), paroxetine (2 studies, 99 participants; MD -6.75 points, 95% CI -9.64 to -3.86; very low-quality evidence), and flumazenil (1 study, 18 participants; MD -1.30 points, 95% CI -2.28 to -0.32; very low-quality evidence).Two pharmacological treatments seemed to reduce the proportion of participants that relapsed to benzodiazepine use: valproate (1 study, 27 participants; RR 0.31, 95% CI 0.11 to 0.90; very low-quality evidence) and cyamemazine (1 study, 124 participants; RR 0.33, 95% CI 0.14 to 0.78; very low-quality evidence). Alpidem decreased the proportion of participants with benzodiazepine discontinuation (1 study, 25 participants; RR 0.41, 95% CI 0.17 to 0.99; number needed to treat for an additional harmful outcome (NNTH) 2.3 participants; low-quality evidence) and increased the occurrence of withdrawal syndrome (1 study, 145 participants; RR 4.86, 95% CI 1.12 to 21.14; NNTH 5.9 participants; low-quality evidence). Likewise, magnesium aspartate decreased the proportion of participants discontinuing benzodiazepines (1 study, 144 participants; RR 0.80, 95% CI 0.66 to 0.96; NNTH 5.8; very low-quality evidence).Generally, adverse events were insufficiently reported. Specifically, one of the flumazenil trials was discontinued due to severe panic reactions. AUTHORS' CONCLUSIONS: Given the low or very low quality of the evidence for the reported outcomes, and the small number of trials identified with a limited number of participants for each comparison, it is not possible to draw firm conclusions regarding pharmacological interventions to facilitate benzodiazepine discontinuation in chronic benzodiazepine users. Due to poor reporting, adverse events could not be reliably assessed across trials. More randomised controlled trials are required with less risk of systematic errors ('bias') and of random errors ('play of chance') and better and full reporting of patient-centred and long-term clinical outcomes. Such trials ought to be conducted independently of industry involvement.

Treatment of sleep disturbances in trauma-affected refugees: Study protocol for a randomised controlled trial.

BACKGROUND: Sleep disturbances are often referred to as a hallmark and as core symptoms of post-traumatic stress disorder (PTSD). Untreated sleep disturbances can contribute to the maintenance and exacerbation of PTSD symptoms, which may diminish treatment response and constitute a risk factor for poor treatment outcome. Controlled trials on treatment of sleep disturbances in refugees suffering from PTSD are scarce. The present study aims to examine sleep-enhancing treatment in refugees with PTSD. We aim to assess if add-on treatment with mianserin and/or Imagery Rehearsal Therapy (IRT) to treatment as usual (TAU) for PTSD improves sleep disturbances. We will study the relation between sleep disturbances, PTSD symptoms, psychosocial functioning and quality of life. METHODS: The study is a randomised controlled superiority trial with a 2 × 2 factorial design. The study will include 230 trauma-affected refugees. The patients are randomised into four groups. All four groups receive TAU - an interdisciplinary treatment approach covering a period of 6-8 months with pharmacological treatment, physiotherapy, psychoeducation and manual-based cognitive behavioural therapy within a framework of weekly sessions with a physician, physiotherapist or psychologist. One group receives solely TAU, serving as a control group, while the three remaining groups are active-treatment groups receiving add-on treatment with either mianserin, IRT or a combination of both. Treatment outcome is evaluated using self-administered rating scales, observer ratings and actigraph measurements at baseline, during treatment and post treatment. The primary outcome is subjective sleep quality using the Pittsburgh Sleep Quality Index. Secondary outcome measures are objective sleep length, nightmares, PTSD severity, symptoms of depression and anxiety, pain, quality of life and psychosocial functioning. DISCUSSION: This trial will be the first randomised controlled trial to examine sleep-enhancing treatment in trauma-affected refugees, as well as the first trial to investigate the effect of IRT and mianserin in this population. Therefore, this trial may optimise treatment recommendations for sleep disturbances in trauma-affected refugees. Based on our findings, we expect to discuss the effect of treatment, focussing on sleep disturbances. Furthermore, the results will provide new information regarding the association between sleep disturbances, PTSD symptoms, psychosocial functioning and quality of life in trauma-affected refugees. TRIAL REGISTRATION: EudraCT registration under the name 'Treatment of sleep disturbances in trauma-affected refugees - a randomised controlled trial', registration number: 2015-004153-40 , registered on 13 November 2015. ClinicalTrials.gov, ID: NCT02761161. Registered on 27 April 2016.

Treatment of adult patients with schizophrenia and complex mental health needs - A national clinical guideline.

BACKGROUND AND AIM: The Danish Health and Medicines Authority assembled a group of experts to develop a national clinical guideline for patients with schizophrenia and complex mental health needs. Within this context, ten explicit review questions were formulated, covering several identified key issues. METHODS: Systematic literature searches were performed stepwise for each review question to identify relevant guidelines, systematic reviews/meta-analyses, and randomized controlled trials. The quality of the body of evidence for each review question was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Clinical recommendations were developed on the basis of the evidence, assessment of the risk-benefit ratio, and perceived patient preferences. RESULTS: Based on the identified evidence, a guideline development group (GDG) recommended that the following interventions should be offered routinely: antipsychotic maintenance therapy, family intervention and assertive community treatment. The following interventions should be considered: long-acting injectable antipsychotics, neurocognitive training, social cognitive training, cognitive behavioural therapy for persistent positive and/or negative symptoms, and the combination of cognitive behavioural therapy and motivational interviewing for cannabis and/or central stimulant abuse. SSRI or SNRI add-on treatment for persistent negative symptoms should be used only cautiously. Where no evidence was available, the GDG agreed on a good practice recommendation. CONCLUSIONS: The implementation of this guideline in daily clinical practice can facilitate good treatment outcomes within the population of patients with schizophrenia and complex mental health needs. The guideline does not cover all available interventions and should be used in conjunction with other relevant guidelines.