Background: in the last 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.
Methods: the systematic review protocol was registered in PROSPERO (CRD42019130636). Human studies investigating the therapeutic effects of ketamine in the treatment of mental health disorders were included. Due to the extensive research in depression, bipolar disorder and suicidal ideation, only systematic reviews & meta-analyses were included. We searched Medline and PsychInfo on the 21st of October 2020. Risk of Bias analysis was assessed using the Cochrane Risk of Bias tools and a Measurement Tool to Assess Systematic Reviews (AMSTAR) Checklist.
Results: 83 published reports were included in the final review, consisting of 33 systematic reviews, 29 RCTs, two-randomised trials without placebo, two non-randomised trials with controls, six open label trials and ten retrospective reviews. The results were presented using 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 due to the high risk of bias of included studies. Optimal dosing, modes of administration and the most effective forms of adjunctive psychotherapeutic support needs to be further examined.

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.

Alcohol use disorder (AUD) is associated with detrimental physical and mental health consequences, as well as societal costs. Repetitive negative thinking (RNT), characterised by recurrent, uncontrollable thoughts on negative themes, is proposed to contribute to AUD by amplifying negative mood which triggers alcohol consumption as a coping mechanism. However, the acute effects of alcohol consumption on RNT have not been empirically examined. Moreover, little is known about the nature of RNT among people with AUD. The first aim of this thesis was to examine the reciprocal relationship between RNT and alcohol consumption. In Chapter 2, I report the acute effects of low or high dose alcohol consumption on state rumination compared to placebo among hazardous and harmful drinkers. These findings indicated that low dose alcohol intake may temporarily terminate ruminative thinking patterns by improving negative mood. In Chapter 3, I explore the subjective experiences of rumination among individuals with AUD. This revealed a self-perpetuating cycle between drinking and rumination, potentially mediated by alcohol focused rumination, negative mood and feelings of shame associated with drinking. Following from this, I examine ketamine combined with psychological therapy as a novel treatment for AUD, and explore potential mechanisms of this treatment. In Chapter 4, I present a systematic review on the evidence base for ketamine treatment for mental health and substance use disorders. This demonstrated that ketamine has the strongest evidence base in depressive disorders, with some evidence of short term decreases in craving and substance use, and increases in abstinence in alcohol and substance use disorders. In Chapter 5, I examine the potential mechanisms of ketamine’s therapeutic effects in AUD, using data from the Ketamine for the Reduction of Alcoholic Relapse (KARE) trial. The results did not support RNT nor the acute subjective effects of ketamine as mediators of treatment effects on abstinence from alcohol. Following from this, in Chapter 6, I present qualitative data from subjective reports of participants from the KARE trial. This indicated a potential role for ketamine induced dissociation and feelings of connectedness in changing their relationship with alcohol. In Chapter 7, I discuss the interpretation and implications of the findings, as well as strengths and limitations of the thesis and suggestions for future research.

Experiences of childhood trauma (abuse and neglect) are disproportionately higher in those with opioid use disorder (OUD). Childhood trauma may affect the reinforcing and rewarding properties of opioid drugs and responses to pain, potentially via developmental changes to the endogenous opioid system. This has been supported by preclinical research, yet this has not been investigated in non-addicted humans. Physically healthy participants with either a history of severe childhood trauma or no previous history of childhood trauma attended two sessions where they received either an intramuscular active dose of morphine (0.15 mg/kg) or a very low dose control (0.01 mg/kg) in a randomised, double-blind crossover design. Sessions were held 1 week apart. Participants' physical pain threshold and tolerance were measured pre- and post-drug administration using the cold water pressor test, alongside acute subjective and behavioural responses over 2.5 h. The trauma group reported liking the effects of morphine, feeling more euphoric and wanting more of the drug over the session, as well as feeling less nauseous, dizzy, and dislike of the effects of morphine compared to the non-trauma comparison group. Morphine increased pain threshold and tolerance, yet this did not differ between the groups. Childhood trauma may therefore sensitise individuals to the pleasurable and motivational effects of opioids and reduce sensitivity to the negative effects, providing compelling evidence for individual differences in opioid reward sensitivity. This may explain the link between childhood trauma and vulnerability to OUD, with consequent implications on interventions for OUD, the prescribing of opioids, and reducing stigmas surrounding OUD.

This includes the study eligibility form which was used to assess the eligibility of articles to be included in the systematic review at the full text screening stage. The data extraction forms were then used to collect the necessary data for the narrative synthesis from articles that were included in the systematic review. There are two data extraction forms. One relates to data extraction from studies which analysed primary data and the other one is for collecting data from systematic reviews/meta-analyses.

RATIONALE: Rumination is a repetitive, negative, self-focused thinking style associated with various forms of psychopathology. Recent studies suggest that rumination increases craving for alcohol and predicts harmful drinking and alcohol-related problems. However, the acute effects of alcohol on rumination have not been previously studied. It is proposed that alcohol may reduce ruminative thinking through decreasing negative mood. OBJECTIVES: in the present study, we aimed to test the previously unexplored effects of acute alcohol consumption on rumination in a hazardous drinking population. METHODS: We conducted a randomised placebo-controlled laboratory study to examine the effect of low (0.4 g kg-1) and high doses (0.8 g kg-1) of alcohol on state rumination compared to placebo. Participants completed a rumination induction task prior to receiving drinks. We then measured state rumination and mood at repeated time points; 30 min, 60 min and 90 min post-drinks consumption. RESULTS: We found a significant decrease in state rumination in the low-dose alcohol group compared to placebo at 30 min post-alcohol consumption, but no difference was observed between the high-dose alcohol and placebo groups. Mediation analysis provided evidence for an indirect effect of alcohol on state rumination through concurrent changes in negative mood. CONCLUSIONS: These findings suggest that acute alcohol consumption can regulate negative mood and concurrently rumination, providing preliminary evidence for the role of rumination in alcohol use disorders. Rumination may be a treatment target in alcohol use disorders.