To assess the safety, feasibility and preliminary efficacy of ketamine-enhanced therapy (KET) for alcohol use disorder (AUD) and comorbid major depressive disorder (MDD) in an open-label, single arm, pilot clinical trial.
Moderate to severe AUD according to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-V) criteria
Presence of current Major Depressive Disorder (MDD), according to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-V) criteria
Expressed motivation to reduce or cease alcohol consumption.
Consumed at least 21 standard drinks per week or 2 HDD per week (≥5 standard drinks/day for men; ≥4 for women) in the month prior to screening
DSM-5 diagnosis of current or past psychotic disorder, bipolar I disorder, or substance-induced psychosis.
Current acute suicidality, defined as high risk by the Columbia Suicide Severity Rating Scale (C-SSRS) or clinical judgment or attempts in the past 6 months.
DSM-5 diagnosis of current or past moderate-to-severe ketamine or other dissociative drug use disorder.
Use of ketamine (prescribed or non-prescribed) in the previous 4 weeks.
Single group
Ketamine
DrugSubcutaneous administration of of Ketamine across 3 dosing sessions (at week 2, 4 and 6). Dosing adjustments are permitted based on tolerability, with a minimum dose of 0.7mg/kg and a potential maximum of 1.2 mg/kg, at the discretion of the principal investigator (previous studies have found efficacy at 0.8mg/kg for AUD).
Cognitive Behavioural Therapy
BehavioralThis study uses a manualized CBT program adapted for ketamine-assisted context. It integrates evidence-based CBT for substance use and depression with principles of psychedelic-assisted therapy, including "set and setting." considerations central to psychedelic-assisted therapy. The therapist manual includes guidance on psychological preparation, intention-setting, integration, and therapeutic framing of ketamine experiences. Participants receive six 90-minute sessions over six weeks, delivered by trained health professionals (e.g., psychologists, mental health nurses, social workers) with specific training in the adapted CBT protocol and psychedelic-assisted therapy. Sessions include: Preparation (Week 1): Review of alcohol use, treatment goals, and ketamine orientation. Integration (Weeks 2, 4, 6): Post-dose processing and linking experience to recovery goals occurring 24-48 hours post dose. Continued CBT (Weeks 3, 5): Coping strategies, goal setting, and relapse prevention.
Feasibility will be assessed through recruitment rates, retention to follow-up, session attendance, and treatment adherence.
Feasibility outcomes will be assessed by the traffic light framework may be applied to guide progression decisions for future trials for each of the following variables: (i) time taken to recruit the sample; (ii) proportion of ineligible participants at (a) pre tele-screening and (b) onsite screening; (iii) number of participants who receive (a) at least two doses of ketamine and (b) at least four CBT sessions; (iv) retention rate over the trial. As this is the first study of its kind in this population and pilot studies are not generalisable to other contexts, these will be assessed and reported descriptively. Results will be synthesised in consideration of the feasibility to progress to larger studies, taking into account the measures described above. Specifically, based on our prior trials of CBT, pharmaco-assisted therapy and complex S9 trials, the following would be an estimation of failure to progress to full trial for each variable and when taken together: (i) \> 24 months; (ii)
Safety will be assessed through the frequency, severity, and relatedness of adverse events (AEs), including dissociation, affective destabilisation, and vital sign abnormalities.
Safety outcomes including adverse events (AEs), serious adverse events (SAEs), and vital sign abnormalities, will be summarised descriptively across the study period. Feasibility outcomes (e.g., recruitment and retention rates, session attendance) will be analysed using proportions with corresponding 95% confidence intervals.
Number of Heavy Drinking Days per week (HDDs) (>5 standard drinks/day for men; >4 for women) and total alcohol consumption.
This will be measured by the Timeline Follow Back and corroborated with Phosphatidylethanol (PEth) levels
Change in depressive symptoms measured by MADRS and DASS-21.
MADRS is a clinician-administered rating scale designed to assess the severity of depressive episodes in patients with mood disorders. It is widely used in clinical trials and psychiatric evaluations due to its sensitivity to treatment-related changes. The MADRS will be administered by trained health care professionals. The MADRS total score is calculated by summing the scores of 10 individual items, each rated on a scale from 0 to 6, yielding a total score range of 0 to 60. Higher scores indicate greater severity of depressive symptoms. The 10 items assessed in the MADRS include: Apparent sadness Reported sadness Inner tension Reduced sleep Reduced appetite Concentration difficulties Lassitude/Sluggishness Inability to feel (emotional capacity) Pessimistic thoughts Suicidal thoughts Each item is rated based on clinical judgment following a semi-structured interview, focusing on the past week. Clinically meaningful changes will be reported descriptively, including rates of ≥50%
Changes in suicidal ideation (weekly monitoring) using the Columbia Suicide Severity Rating Scale (C-SSRS).
The C-SSRS is a structured clinician-administered instrument with strong predictive validity for suicidal behavior, used in clinical and research settings to assess the presence, severity, and intensity of suicidal ideation and behavior. The C-SSRS is administered by trained clinicians. C-SSRS scoring includes four subscales: ideation severity (items 1-5, scored by the most severe type endorsed); intensity of ideation (sum of five items including frequency, duration, controllability, deterrents, and reasons for ideation; range 2-25; higher number indicates more intense ideation); suicidal behavior (presence or absence of actual, interrupted, aborted, or preparatory behavior recorded separately); and potential lethality (medical damage rated 0-5, potential lethality rated 0-2). At baseline, this is measured by the baseline version. At each visit following this, this will be recorded on the since last visit. Higher scores indicate more severe suicidality.
Changes in Positive and Negative Mood States
Mood states before/after ketamine sessions assessed by PANAS (Positive and Negative Affect Schedule). This will be measured at integration session 1 (week 2), 2 (week 4) and 3 (week 6). Used to measure an individual's emotional state, assessing two dimensions: Positive Affect (PA; captures feelings like enthusiasm and alertness), and Negative Affect (NA; measures distress and negative emotions like anger and anxiety).
Changes in Depression
Measured by cumulative scores on the DASS-21 Depression Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates greater depression.
Changes in Anxiety
Measured by cumulative scores on the DASS-21 Anxiety Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates more anxiety.
Changes in Stress
Measured by cumulative scores on the DASS-21 Stress Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates more stress.
Change in Alcohol dependence severity
Measured by the Alcohol Dependence Scale. The minimum score is 0 and the maximum score is 47. A higher score indicates more severe dependence.
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South West Sydney Local Health District
Lead sponsor
University of Sydney
Collaborator
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