Kirsten C. Morley

Increased anxiety and impaired memory in rats 3 months after administration of 3,4-methylenedioxymethamphetamine ("ecstasy").

Male Wistar rats were administered either (a) a high dose regime of 3,4-methylenedioxymethamphetamine (MDMA) (4 x 5 mg/kg, i.p. over 4 h on each of 2 consecutive days), (b) a moderate dose regime of MDMA (1 x 5 mg/kg on each of 2 consecutive days), (c) D-amphetamine (4 x 1 mg/kg over 4 h on each of 2 days), or (d) vehicle injections. The high MDMA dose regime and the amphetamine treatment both produced acute hyperactivity and hyperthermia. Twelve weeks later, all rats were tested in the drug-free state on a battery of anxiety tests (elevated plus maze, emergence and social interaction tests). A further 2 weeks later they were tested on a novel object recognition memory task. Rats previously given the neurotoxic dose of MDMA showed greater anxiety-like behaviour on all three anxiety tests relative to both controls and D-amphetamine-treated rats. Rats given the moderate MDMA dose regime also showed increased anxiety-like behaviour on all three tests, although to a lesser extent than rats in the high dose group. In the object recognition task, rats given the high MDMA dose regime showed impaired memory relative to all other groups when tested at a 15-min delay but not at a 60-min delay. Rats previously exposed to amphetamine did not differ from saline controls in the anxiety or memory tests. These data suggest that moderate to heavy MDMA exposure over 48 h may lead to increased anxiety and memory impairment 3 months later, possibly through a neurotoxic effect on brain serotonin systems.

Cannabinoids prevent the acute hyperthermia and partially protect against the 5-HT depleting effects of MDMA (“Ecstasy”) in rats

Cannabinoid-MDMA interactions were examined in male Wistar rats. MDMA (4 x 5 mg/kg or 2 x 10 mg/kg over 4 h on each of 2 days) was administered with or without Delta 9-tetrahydrocannabinol (THC) (4 x 2.5 mg/kg), the synthetic cannabinoid receptor agonist CP 55,940 (2 x 0.1 or 0.2 mg/kg) or the cannabinoid receptor antagonist SR 141716 (2 x 5 mg/kg). Co-administered Delta 9-THC and CP 55,940 but not SR 141716 prevented MDMA-induced hyperthermia, causing a powerful hypothermia. Co-administered Delta 9-THC, CP 55,940 and SR 141716 all tended to decrease MDMA-induced hyperactivity. Co-administered Delta 9-THC provided protection against the long-term increases in anxiety seen in the emergence test, but not the social interaction test, 6 weeks after MDMA treatment. Co-administered Delta 9-THC and CP 55,940, but not SR 141716, partly prevented the long-term 5-HT and 5-HIAA depletion caused by MDMA in various brain regions. SR 141716 administered with CP 55,940 and MDMA prevented the hypothermic response to the CP 55,940/MDMA combination but did not alter the CP 55,940 attenuation of MDMA-induced 5-HT depletion. These results suggest a partial protective effect of co-administered cannabinoid receptor agonists on MDMA-induced 5-HT depletion and long-term anxiety. This action appears to operate independently of cannabinoid CB1 receptors.

Baclofen for the Treatment of Alcohol Dependence and Possible Role of Comorbid Anxiety

AIM To conduct a double-blind, placebo-controlled randomized clinical trial of baclofen in the treatment of alcohol dependence. METHODS Out of 69 participants consecutively screened, 42 alcohol-dependent patients were randomized to receive placebo, baclofen 30 mg/day or baclofen 60 mg/day for 12 weeks. All subjects were offered BRENDA, a structured psychosocial therapy for alcohol dependence that seeks to improve motivation for change, enhance strategies to prevent relapse and encourage compliance with treatment. RESULTS Intention-to-treat analyses revealed that alcohol consumption (heavy drinking days, drinks per drinking day) significantly reduced across all three groups during the treatment period. There were no statistically significant advantages to treatment on time to first heavy drinking day (relapse) (P = 0.08), nor time to first drink (lapse) (P = 0.18). A post hoc analysis stratifying according to whether there had been a comorbid anxiety disorder, revealed a beneficial effect of baclofen 30 mg/day versus placebo on time to lapse and relapse (P < 0.05). There was also a beneficial effect for baclofen 60 mg/day relative to placebo on time to relapse in this comorbid group (P < 0.05). Both doses of baclofen were well tolerated. There were no serious adverse events. CONCLUSIONS In spite of the small sample for a 3-arm clinical trial, this study suggests a specific role of baclofen in alcohol-dependent individuals with comorbid anxiety. Replication in larger, fully-powered studies is required.

Do acamprosate or naltrexone have an effect on daily drinking by reducing craving for alcohol

AIM To explore the effect of acamprosate and naltrexone on craving and alcohol consumption in the treatment of alcohol dependence. DESIGN A randomized, double-blind, single-dummy, placebo-controlled trial. SETTING Three treatment centres in Sydney, Australia. PARTICIPANTS A total of 169 alcohol-dependent subjects were given naltrexone (50 mg/day), acamprosate (1998 mg/day) or placebo for 12 weeks, in conjunction with manualized medication compliance therapy. INTERVENTION During the course of the trial, participants kept a daily diary which included the number of standard drinks they consumed and their peak craving for alcohol that day rated on a 0-10 scale. MEASUREMENTS Subjective ratings of daily craving and daily drinking for the first 6 weeks of treatment. FINDINGS Mixed/hierarchical linear models were employed on an intention-to-treat basis. Analyses revealed that craving was a significant predictor of daily drinking and baseline levels of depression were the best predictor of daily craving. There was no significant improvement in model fit when treatment group was added both in models of daily craving and daily drinking. Daily alcohol consumption was best predicted by a model incorporating baseline dependence and depression scores, and daily craving, entered as a time-varying covariate. However, there was a significant craving x time x treatment interaction (t = -3.365, df = 4413.712, P < 0.001), suggesting that at higher levels of craving drinking was reduced at a significantly greater rate with naltrexone compared to acamprosate. CONCLUSIONS Naltrexone had a greater effect on drinking when craving was high. These results support the role of naltrexone in reducing craving when that craving is highly salient. The role of acamprosate in reducing craving was not supported by these findings.

Psychosocial interventions for people with both severe mental illness and substance misuse

Over 50% of people with a severe mental illness also use illicit drugs and/or alcohol at hazardous levels. This review is based on the findings of 32 randomized controlled trials which assessed the effectiveness of psychosocial interventions, offered either as one-off treatments or as an integrated or nonintegrated program, to reduce substance use by people with a severe mental illness. The findings showed that there was no consistent evidence to support any one psychosocial treatment over another. Differences across trials with regard to outcome measures, sample characteristics, type of mental illness and substance used, settings, levels of adherence to treatment guidelines, and standard care all made pooling results difficult. More quality trials are required that adhere to proper randomization methods; use clinically valuable, reliable, and validated measurement scales; and clearly report data, including retention in treatment, relapse, and abstinence rates. Future trials of this quality will allow a more thorough assessment of the efficacy of psychosocial interventions for reducing substance use in this challenging population.

Expectancy in Double-Blind Placebo-Controlled Trials: An Example from Alcohol Dependence

Background: Double-blind placebo-controlled trials are intended to control for the impact of expectancy on outcomes. Whether they always achieve this is, however, questionable. Methods: Reanalysis of a clinical trial of naltrexone and acamprosate for alcohol dependence investigated this issue further. In this trial, 169 alcohol-dependent patients received naltrexone, acamprosate or placebo for 12 weeks. In addition to being assessed on various indices of alcohol dependence, they were asked whether they believed they received active medication or placebo. Results: While there were no differences in outcomes between treatment groups, those who believed they had been taking active medication consumed fewer alcoholic drinks and reported less alcohol dependence and cravings. That is, irrespective of actual treatment, perceived medication allocation predicted health outcomes. Conclusions: These results highlight the differences between treatment administration in clinical trials and standard medical practice, a discrepancy that may sometimes decrease the validity of these types of trials.

Issues with recruitment to randomised controlled trials in the drug and alcohol field: a literature review and Australian case study.

ISSUES The randomised control trial (RCT) is a widely used tool for measuring the effectiveness of health treatments and services. However, subject recruitment is an ongoing challenge for those conducting RCTs and may have a serious impact on the success of the study and the reliability of the outcomes. APPROACH In this review we present an examination of the problems and strategies associated with recruitment to RCTs, with particular reference to studies conducted in the drug and alcohol field. A case study of recruitment to an RCT for the treatment of alcohol dependence is presented, supplemented by PubMed, Current Contents and Medline searches to identify relevant publications. KEY FINDINGS The literature suggests that the most common barriers to patient participation involve fears of assignment to placebo treatment, insufficient compensation and poor attendance at initial appointments. Moreover, subject referrals from staff may be a greater problem than reluctance of patients. Referrals are inhibited by complicated entry criteria, time constraints due to busy work schedules or a limited research culture. IMPLICATIONS Subject recruitment may be promoted by financial reimbursement, close partnerships between research and referral staff; increasing the treatment group ratio in multi-drug trials to minimise randomisation to placebo; addressing negative staff attitudes; and simplifying the referral process. CONCLUSION The need for multi-centre sites in Australian drug and alcohol treatment studies is highlighted.

Some new directions for research on psychological interventions for comorbid anxiety and substance use disorders

ISSUES Comorbidity between anxiety and substance use disorders is common, yet it is poorly understood and poorly treated. APPROACH Narrative literature review. PsycINFO and Medline databases were searched for clinical trials of anxiety and substance use disorders using clinical queries for 2005-2009. KEY FINDINGS There are few well-conducted treatment outcome trials for comorbid anxiety and substance use disorders. Some recent (2005-2009) outcome literature has focused on specific mechanisms (anxiety sensitivity and tension reduction alcohol expectancies) that may underlie comorbidity between anxiety and substance use disorders and may lead to more targeted intervention. IMPLICATIONS AND CONCLUSION: The research base for understanding and treating comorbid anxiety and substance use disorders needs to be broadened. In particular research is needed with a focus on: (i) specifying particular comorbid relationships between anxiety and substance use disorders; (ii) the mechanisms that may underlie and maintain those relationships; and (iii) well-conducted evaluations of treatments that target those mechanisms.

The efficacy and biobehavioural basis of baclofen in the treatment of alcoholic liver disease (BacALD): Study protocol for a randomised controlled trial

BACKGROUND Effective treatments for alcohol use disorders in those with significant liver disease are critically lacking. The primary aim of the current study is to explore the effectiveness and biobehavioural basis of low and high dose baclofen in improving treatment outcomes for alcohol dependence in people with alcoholic liver disease (The BacALD study). METHODS This double-blind, placebo-controlled study will randomize 180 participants to a 12-week regime of either baclofen (30 mg/day baclofen, 75 mg/day baclofen) or placebo. Participants must meet the ICD-10 criteria for alcohol dependence in addition to alcoholic liver disease (ALD) defined as the presence of symptoms and/or signs referable to liver disease or its complications with or without cirrhosis. Primary outcome measures will include total abstinence duration, and time to lapse and relapse. Furthermore, 60 of the ALD patients enrolled in the trial will also participate in a pharmacokinetic and cue-reactivity component, along with an additional 30 healthy volunteers matched for age and gender randomised to a 1 week regime of either 30 mg/day baclofen or 75 mg/day baclofen. At week 1, plasma levels of baclofen and β-p-chlorophenol-γ-hydroxybutric acid will be measured at 0, 1 and 4 h following baclofen administration and psychophysiological responses to alcohol-associated stimuli will be assessed in a cue reactivity paradigm. Recruitment commenced in late March 2013. CONCLUSIONS This trial will demonstrate the efficacy and safety of two doses of baclofen in patients with alcoholic liver disease and will explore the biobehavioural mechanisms of the treatment effect.

Pharmacotherapeutic agents in the treatment of methamphetamine dependence

ABSTRACT Introduction: Methamphetamine use is a serious public health concern in many countries and is second to cannabis as the most widely abused illicit drug in the world. Effective management for methamphetamine dependence remains elusive and the large majority of methamphetamine users relapse following treatment. Areas covered: Progression in the understanding of the pharmacological basis of methamphetamine use has provided us with innovative opportunities to develop agents to treat dependence. The current review summarizes relevant literature on the neurobiological and clinical correlates associated with methamphetamine use. We then outline agents that have been explored for potential treatments in preclinical studies, human laboratory phase I and phase II trials over the last ten years. Expert opinion: No agent has demonstrated a broad and strong effect in achieving MA abstinence in Phase II trials. Agents with novel therapeutic targets appear promising. Advancement in MA treatment, including translation into practice, faces several clinical challenges.