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Topiramate has been found to be effective in reducing alcohol use and may also attenuate anxiety severity in patients with alcohol use disorder (AUD). This study compared the neural response of treatment-seeking patients with AUD on either topiramate or naltrexone during an anticipatory anxiety task. Participants were 42 patients with AUD who were randomized to receive either topiramate (n = 23; titrated dose up to 200 mg/day) or naltrexone (n = 19; 50 mg/day) for 12-weeks as part of a larger randomized controlled trial. Following 6 weeks of treatment, participants completed an anticipatory anxiety task during a functional magnetic resonance imaging (fMRI) session. The task presented a series of high-threat and low-threat stimuli followed by an unpleasant or pleasant image, respectively. Primary whole-brain analyses revealed no significant differences in neural activation between the topiramate and naltrexone groups. Deactivation for safe cues relative to threat cues was observed within the precuneus, inferior parietal lobule and the cingulate gyrus. In the precentral and middle frontal gyri, threat cues elicited greater activation. Exploratory analyses revealed an effect of change in anxiety from baseline to week 6, with a greater reduction associated with a reduced response to threat cues relative to safe cues in the cuneus and lingual gyrus. The current study is the first to examine and compare neural activation during anticipatory anxiety in treatment-seeking individuals on topiramate and naltrexone. This preliminary research contributes to our understanding of the therapeutic mechanisms of these alcohol pharmacotherapies., (© The Author(s) 2024. Medical Council on Alcohol and Oxford University Press.)

Background: Insomnia and excessive daytime sleepiness (EDS) are reported to be common in methadone maintenance treatment (MMT) but much less is known about these symptoms in buprenorphine maintenance treatment (BMT) and in women compared with men. Methods: Cross sectional study of recipients of BMT ( n  = 113, 47 women), MMT ( n  = 184, 94 women), people using opioids nonmedically (nonopioid agonist treatment, non-OAT: n  = 87, 31 women) and a reference group with no opioid use (RG; n  = 105, 53 women) in Australia. Measures included Athens Insomnia Scale, Epworth Sleepiness Scale, the Hospital Anxiety and Depression Scale, and other substance use. Results: Insomnia (Athens Insomnia Scale, total ≥10) was highly prevalent among all people who use opioids (BMT 46.0-68.1%; MMT 55.4-69.6%; non-OAT 58.6-80.5%), did not differ significantly among these groups, and was significantly associated with anxiety and depression. EDS (Epworth score >10) was found in 14.2% of BMT, 22.8% of MMT, 35.6% of non-OAT groups, and 11.4% of the RG, and was significantly associated with depression overall. Fewer people had Epworth score >15 indicating more severe EDS (BMT 4.4%, MMT 6.0%; non-OAT 13.8%; RG 1.9%). Insomnia and EDS did not differ by sex or by opioid dose, nor were they significantly associated with other drug use, housing stress or social security status. Conclusions: Insomnia was common in people receiving OAT and using opioids non-medically, and associated with anxiety and depression. Clinicians should consider the possibility of daytime sleepiness in people receiving BMT and MMT, and in people using opioids nonmedically.

Aim: To assess the effectiveness of a 12 week specialized, integrated intervention for alcohol dependence with comorbid anxiety and/or mood disorder using a randomized design in an outpatient hospital setting., Methods: Out of 86 patients meeting the inclusion criteria for alcohol dependence with suspicion of comorbid anxiety and/or depressive disorder, 57 completed a 3-week stabilization period (abstinence or significantly reduced consumption). Of these patients, 37 (65%) met a formal diagnostic assessment of an anxiety and/or depressive disorder and were randomized to either (a) integrated intervention (cognitive behavioural therapy) for alcohol, anxiety and/or depression, or (b) usual counselling care for alcohol problems., Results: Intention-to-treat analyses revealed a beneficial treatment effect of integrated treatment relative to usual counselling care for the number of days to relapse (χ(2) = 6.42, P < 0.05) and lapse (χ(2) = 10.73, P < 0.01). In addition, there was a significant interaction effect of treatment and time for percentage days of abstinence (P < 0.05). For heavy drinking days, the treatment effect was mediated by changes in DASS anxiety (P < 0.05). There were no significant treatment interaction effects for DASS depression or anxiety symptoms., Conclusions: These results provide support for integrated care in improving drinking outcomes for patients with alcohol dependence and comorbid depression/anxiety disorder., Trial Registration: ClinicalTrials.gov Identifier: NCT01941693., (© The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

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., (© The Author 2014. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Rationale: There is some uncertainty whether the acute hyperthermia caused by MDMA (ecstasy) plays a significant role in determining the long-term neurotoxic effects on brain 5-HT systems and associated changes in mood and behaviour., Objective: The present study assessed whether long-term behavioural and cognitive changes seen in MDMA-treated rats are affected by hyperthermia at the time of drug administration., Method: Male Wistar rats were treated with MDMA (4x5 mg/kg i.p. over 4 h on 2 consecutive days) or vehicle at either a high ambient temperature (28 degrees C) or a low ambient temperature (16 degrees C). Eight to 18 weeks later, rats were tested in behavioural measures of anxiety (social interaction and emergence tests), a test of cognition (object recognition test) and the forced swim test of depression. At the conclusion of behavioural testing the rats were killed and their brains analysed using HPLC., Results: MDMA treatment caused a clear and consistent hyperthermia at 28 degrees C and hypothermia at 16 degrees C. Months later, rats pre-treated with MDMA at either 16 or 28 degrees C displayed increased anxiety in the social interaction and emergence tests and reduced escape attempts and increased immobility in the forced swim test. MDMA pre-treatment was also associated with poorer memory on the object recognition test, but only in rats given the drug at 28 degrees C. Rats pre-treated with MDMA showed loss of 5-HT in the hippocampus, striatum, amygdala and cortex, regardless of body temperature at the time of dosing. However, 5-HIAA loss in the amygdala and hippocampus was greater in rats pre-treated at 28 degrees C. Dopamine in the striatum was also depleted in rats given MDMA., Conclusions: These results indicate that hyperthermia at the time of dosing with MDMA is not necessary to produce subsequent 5-HT depletion and anxiety in rats. They also extend previous findings of long-term effects of brief exposure to MDMA in rats to include apparent "depressive" symptoms in the forced swim model.

Rationale: Rats avidly consume standard off-the-shelf beer; however, the behavioural consequences of beer consumption in rodents have hardly been studied., Objectives: The present study examined the acute anxiolytic and ataxic effects of beer consumption in rats and the anxiogenic effects of withdrawal from free access to beer., Method: In experiment 1, male Wistar rats received 30 min access to "near-beer" each day (a malt beverage that looks and tastes like beer but which contains <0.5% ethanol). On the test day, for some rats, ethanol (either 2% or 4% v/v) was added to the near-beer to make it resemble standard (ethanol-containing) beer of "light" (2.5% beer) or full strength (4.5% beer). Immediately after this, rats were tested on their response to a predatory cue (a fabric collar that had been worn by a cat) and on an accelerating rotarod. In experiment 2, rats were trained in the same drinking paradigm as above and then tested on a further battery of anxiety tests. In experiment 3, rats were given continuous home cage access to either 4.5% beer or near-beer for 35 days. Half of the rats were then denied access to beer or near-beer for 24 h and then tested on the same anxiety test battery as in experiment 2., Results: Rats drinking 4.5% beer approached a predatory cue significantly more than those given near-beer, indicating an anxiolytic effect. In experiment 2, rats drinking 4.5% beer displayed less anxiety-like behaviour in the elevated plus maze and emergence tests but not in the social interaction test. Rats given 4.5% beer fell off the rotarod significantly faster than rats given near-beer, indicating an ataxic effect. Rats previously given 4.5% beer drank significantly less near-beer the following day, suggesting a moderate aversion the day after beer consumption. In experiment 3, rats denied access to 4.5% beer showed significantly less social interaction and took longer to emerge into an open field than controls., Conclusion: These results are the first to our knowledge to show that rats will consume beer at levels that produce clear effects on anxiety and on motor co-ordination, and that will eventually produce behavioural signs of withdrawal.

The long-term behavioural and neurotoxic effects of 3,4-methlyenedioxymethampthetamine (MDMA, "Ecstasy") were examined in rats. Rats were given MDMA (5 mg/kg i.p. once per hour for 4 h) or vehicle injections on each of two consecutive days at an ambient temparature of 28 degrees C. MDMA caused acute hyperthermia and locomotor hyperactivity on both days. Four and six weeks after drug administration the rats previously treated with MDMA showed elevated levels of anxiety-like behaviour in the emergence and social interaction tests, respectively. At 9 weeks post-MDMA, the rats displayed an increase in anxiety on the elevated plus-maze test relative to controls. Ten weeks following treatment the rats were killed and their brains dissected and neurotramitter content analysed using High Performance Liquid Chromotography (HPLC). Rats previously given MDMA showed significantly decreased 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the amygdala, hippocampus and striatum relative to controls. This 5-HT depletion may have a causal role in producing increased anxiety-like behaviours in MDMA-treated rats. These results are consistent with human studies suggesting that exposure to high doses of MDMA may predispose to long-term psychological problems such as anxiety and depression.

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.