OBJECTIVE:Early evidence suggests that ketamine may be an effective treatment to sustain abstinence from alcohol. The authors investigated the safety and efficacy of ketamine compared with placebo in increasing abstinence in patients with alcohol use disorder. An additional aim was to pilot ketamine combined with mindfulness-based relapse prevention therapy compared with ketamine and alcohol education as a therapy control.METHODS:In a double-blind placebo-controlled phase 2 clinical trial, 96 patients with severe alcohol use disorder were randomly assigned to one of four conditions: 1) three weekly ketamine infusions (0.8 mg/kg i.v. over 40 minutes) plus psychological therapy, 2) three saline infusions plus psychological therapy, 3) three ketamine infusions plus alcohol education, or 4) three saline infusions plus alcohol education. The primary outcomes were self-reported percentage of days abstinent and confirmed alcohol relapse at 6-month follow-up.RESULTS:Ninety-six participants (35 women; mean age, 44.07 years [SD=10.59]) were included in the intention-to-treat analysis. The treatment was well tolerated, and no serious adverse events were associated with the study drug. Although confidence intervals were wide, consistent with a proof-of-concept study, there were a significantly greater number of days abstinent from alcohol in the ketamine group compared with the placebo group at 6-month follow-up (mean difference=10.1%, 95% CI=1.1, 19.0), with the greatest reduction in the ketamine plus therapy group compared with the saline plus education group (15.9%, 95% CI=3.8, 28.1). There was no significant difference in relapse rate between the ketamine and placebo groups.CONCLUSIONS:This study demonstrated that treatment with three infusions of ketamine was well tolerated in patients with alcohol use disorder and was associated with more days of abstinence from alcohol at 6-month follow-up. The findings suggest a possible beneficial effect of adding psychological therapy alongside ketamine treatment.

Background In the past two decades, subanaesthetic doses of ketamine have been demonstrated to have rapid and sustained antidepressant effects, and accumulating research has demonstrated ketamine's therapeutic effects for a range of psychiatric conditions. Aims In light of these findings surrounding ketamine's psychotherapeutic potential, we systematically review the extant evidence on ketamine's effects in treating mental health disorders. Method The systematic review protocol was registered in PROSPERO (identifier CRD42019130636). Human studies investigating the therapeutic effects of ketamine in the treatment of mental health disorders were included. Because of the extensive research in depression, bipolar disorder and suicidal ideation, only systematic reviews and meta-analyses were included. We searched Medline and PsycINFO on 21 October 2020. Risk-of-bias analysis was assessed with the Cochrane Risk of Bias tools and A Measurement Tool to Assess Systematic Reviews (AMSTAR) Checklist. Results We included 83 published reports in the final review: 33 systematic reviews, 29 randomised controlled trials, two randomised trials without placebo, three non-randomised trials with controls, six open-label trials and ten retrospective reviews. The results were presented via narrative synthesis. Conclusions Systematic reviews and meta-analyses provide support for robust, rapid and transient antidepressant and anti-suicidal effects of ketamine. Evidence for other indications is less robust, but suggests similarly positive and short-lived effects. The conclusions should be interpreted with caution because of the high risk of bias of included studies. Optimal dosing, modes of administration and the most effective forms of adjunctive psychotherapeutic support should be examined further.

Esketamine was recently licensed by the US Food and Drug Administration (FDA) and European Drug Agency (EDA) for use in treatment resistant depression (TRD), and further research indicates ketamine as a possible treatment in other mental health conditions. While the underlying mechanisms remain unclear, it has been hypothesised that ketamine's acute psychoactive effects may be associated with psychiatric treatment efficacy. We systematically reviewed the evidence for this association. The databases Medline, Embase and PsychInfo were searched up to June 2019. Studies were included if they enrolled adults with a psychiatric diagnosis, assessed acute psychoactive effects using a quantitative measure, and reported on the relationship between acute effects and treatment outcome. We included 21 studies, involving 891 patients. Seventeen studies assessed patients with depression (TRD [k = 14]), three assessed substance use disorders, and one assessed social anxiety disorder. Overall, 41 associations were assessed, of which 26 % were significant. The studies reviewed displayed great variability in terms of methodology and quality of reporting. The most commonly assessed effect was dissociation, measured by the CADSS. Our results suggest that the CADSS total is not consistently associated with antidepressant outcomes. Apart from this, the current literature is too limited to draw definite conclusions on the presence of an association between acute psychoactive effects and mental health outcomes. The field would benefit from consistently employing a priori hypotheses, more transparent reporting and sufficiently powered statistical analyses. Furthermore, the use of a broader range of assessments tools of acute psychoactive effects during ketamine administration would be beneficial.

Opioid use disorder (OUD) is reaching epidemic proportions worldwide, and is notoriously difficult to treat. Compassion focused therapy (CFT) has emerged as therapeutic tool for treating individuals exhibiting high levels of self-criticism and low self-esteem, both of which are common in OUD. Until now, however, there had been no research investigating this therapy in patients with OUD. Before running a premature clinical trial, it is important to fully assess the feasibility and acceptability of this treatment in this group of individuals. We aimed to assess the feasibility of CFT treatment in individuals with OUD in a short group intervention, which was co-created by the research team, service users and a local drugs service. The intervention involved three 2-hour sessions held over 3 weeks, where participants engaged in compassion-orientated psychoeducation and self-compassionate exercises. Individuals were randomly assigned to either the CFT group (n = 15), the active control (relaxation) group (n = 12) or the waitlist control group (n = 11). Of 103 individuals approached, 45% attended a baseline visit suggesting the treatment was acceptable to this group. A relatively low attrition rate across the 3 groups was found for CFT (21.1%), with no difference in drop-out between the groups. Qualitative analysis of interviews with participants identified a desire for more sessions. Compassion focused therapy was thus feasible and well-tolerated in those with OUD, and a further trial to evaluate any clinical differences may be warranted.

Social anxiety disorder (SAD) has been related to alcohol use disorder (AUD). Shyness can be considered a subclinical analogue of SAD, yet there is little research into the effect of alcohol on anxiety levels in highly-shy individuals. This naturalistic study investigated acute and sub-acute effects of alcohol in high and low shy social drinkers. 97 individuals were tested at home and assigned to either consume alcohol to normal levels (n=50) or to remain sober (n=47). Baseline measures of AUD symptoms, shyness and social phobia were taken. Measures of state anxiety were taken at baseline, following a period of alcohol consumption or sobriety, and the following morning. Marginally decreased acute anxiety resulting from alcohol consumption in high shyness was observed. A significant increase in anxiety the day following drinking was observed in highly-shy participants. There was a significant correlation between anxiety elevation on the second day and AUDIT scores in highly-shy participants. This study suggests anxiety during hangover is linked to AUD symptoms in highly-shy individuals, providing a potential marker for increased AUD risk, which could inform prevention and treatment. This naturalistic study investigated whether the effects of alcohol on anxiety during intoxication and hangover differ as a function of shyness, exploring possible links to Alcohol Use Disorder (AUD) symptoms. Increased anxiety was observed during alcohol hangover among those scoring more highly on the shyness scale. There was a trend towards a positive association between hangxiety and AUD symptoms among high-shy participants in the alcohol group. Contrary to prediction, there was no significant reduction in anxiety during intoxication in the alcohol group, and this effect did not differ as a function of shyness. We did not find evidence in favour of an association between reduction in anxiety during intoxication and AUD symptoms among high or low shy participants. observed decrease in anxiety among participants in the high shy sober condition from baseline to hangover. The findings of this study support the withdrawal-relief model of problematic alcohol use among shy individuals. This research therefore indicates possible motives and high risk situations for shy individuals with AUD symptoms, which may be usefully considered in group and individualized addiction treatments. These findings also suggest benefit in targeting shy individuals for instance through awareness raising during campaigns like ‘Dry January’ which encourage individuals to re-evaluate their relationship with alcohol (Ballard, 2015). Future research should clarify the mechanisms underlying the hangxiety effect observed, for instance the potential role of rumination and post-event processing (Clark & Wells, 1995), and the role of coping motivated drinking, which was not directly assessed here, and may mediate the relationship between hanxiety and AUD symptoms among shy individuals.

Social anxiety disorder (SAD) has been related to alcohol use disorder (AUD). Shyness can be considered a subclinical analogue of SAD, yet there is little research into the effect of alcohol on anxiety levels in highly-shy individuals. This naturalistic study investigated acute and sub-acute effects of alcohol in high and low shy social drinkers. 97 individuals were tested at home and assigned to either consume alcohol to normal levels (n = 50) or to remain sober (n = 47). Baseline measures of AUD symptoms, shyness and social phobia were taken. Measures of state anxiety were taken at baseline, following a period of alcohol consumption or sobriety, and the following morning. Marginally decreased acute anxiety resulting from alcohol consumption in high shyness was observed. A significant increase in anxiety the day following drinking was observed in highly-shy participants. There was a significant correlation between anxiety elevation on the second day and AUDIT scores in highly-shy participants. This study suggests anxiety during hangover is linked to AUD symptoms in highly-shy individuals, providing a potential marker for increased AUD risk, which could inform prevention and treatment.

Background: 3,4-Methylenedioxymethamphetamine (MDMA) is widely known for its positive acute effects on social behaviour, such as increasing empathy, whilst also attenuating the negative impact of social exclusion. However there is a scarcity of research that investigates the long-term impact of recreational MDMA use on these fundamental social processes. Method: Sixty-seven individuals were split into three groups based on their drug-use history: poly-drug MDMA users (n=25), poly-drug users who do not use MDMA (n=19), alcohol-only users (n=23), and were tested in an independent groups design. Participants completed both a self-report measure of emotional and cognitive empathy, along with the Multifaceted Empathy Task - a computerised assessment of empathy - and the Cyberball Game - a social exclusion paradigm. Results: MDMA users had significantly greater subjective emotional empathy, and greater cognitive empathy on the computer task compared with the poly-drug users who do not use MDMA. There were no significant differences in subjective responses to social exclusion between the groups. Indices of MDMA use did not correlate with empathy. Conclusions: Long-term MDMA users in this sample exhibited normal psychosocial functioning in regard to empathy and social pain and had higher subjective emotional empathy. This conflicts with previous suggestions that moderate, long-term MDMA use may cause heightened social distress, and is further evidence of the safety of the drug, which is relevant to considerations of its therapeutic use.

Supplemental material, JOP826594_supplemental_material for Greater empathy in MDMA users by Molly Carlyle, Tobias Stevens, Leah Fawaz, Beth Marsh, Sophia Kosmider and Celia JA Morgan in Journal of Psychopharmacology