Therapeutic potential of ketamine for alcohol use disorder

The paper is a narrative review integrating preclinical data, mechanistic studies and clinical-trial evidence rather than a quantitative meta-analysis. To identify human clinical trials, the researchers searched ClinicalTrials.gov for trials related to ketamine and then applied topic restrictions for substance-related disorders and alcohol-related disorders. The initial ClinicalTrials.gov search for all ketamine trials yielded 1,011 studies; narrowing to substance-related disorders produced 34 results and restricting further to alcohol-related disorders produced 11 results. Of those 11, four trials were completed and seven were active, recruiting, or not yet recruiting. One completed trial was excluded as non-interventional, and another completed trial lacked posted results and was grouped with incomplete studies. That left two completed trials specifically related to AUD or comorbid AUD and depression for detailed consideration, with a further six incomplete alcohol-related trials included in the review. The authors complemented the registry search with a PubMed search using the terms “ketamine” and “alcohol” restricted to the previous ten years, which initially yielded 461 results; filtering to clinical trials produced 42 items and yielded one additional completed study relevant to ketamine as an interventional therapy for alcohol-related disorders. They also searched ClinicalTrials.gov for ketamine trials focused on other SUDs (cocaine, cannabis, opioids) and incorporated five completed interventional studies for other substances into the synthesis. For preclinical, mechanistic and biomarker sections the authors reviewed animal studies and human mechanistic work identified in the literature. The review reports trial characteristics (dose ranges, routes) and summarises outcomes qualitatively; it does not report a systematic risk-of-bias assessment or a pooled quantitative synthesis.

Neurobiology and rationale: The authors summarise evidence that AUD involves multi-system neurotransmitter dysregulation and circuit-level changes. Dopaminergic dysfunction in the ventral tegmental area–nucleus accumbens axis is implicated in reward and withdrawal-related anhedonia. Nicotinic acetylcholine receptors, noradrenergic and serotonergic systems modulate alcohol-related reinforcement and withdrawal-related negative affect. Opioid receptors (μ and κ) contribute to alcohol reinforcement and withdrawal processes and are targets of existing AUD pharmacotherapies such as naltrexone. Chronic alcohol produces GABAergic suppression and a hyper-glutamatergic state on withdrawal, with NMDA receptor upregulation implicated in excitability, seizures and maladaptive plasticity. Alcohol-associated reductions in hippocampal neurogenesis and altered synaptic plasticity likely contribute to maladaptive memory and relapse vulnerability. Mechanisms of ketamine relevant to AUD: Ketamine is primarily an NMDA receptor antagonist but has pleiotropic effects, including modulation of GABA A receptor subtypes, increases in brain-derived neurotrophic factor (BDNF), inhibition of eEF2 kinase, mTOR signalling activation, and effects on dopaminergic, cholinergic and opioid signalling. Through these mechanisms ketamine can enhance synaptic plasticity, stimulate neurogenesis and alter resting-state functional connectivity (rsFC) in networks implicated in addiction, depression and PTSD (for example, reductions in salience network connectivity and sgACC coupling). These actions provide a mechanistic rationale for reducing negative affect, disrupting maladaptive reward memories and attenuating relapse-driving circuitry in AUD. Clinical-trial evidence: The review summarises completed human trials and ongoing studies. Among completed alcohol-related interventional studies, one trial combining a single ketamine infusion (0.71 mg/kg) with motivational enhancement therapy (MET) reported increased likelihood of abstinence, longer time to relapse and fewer heavy-drinking days compared with benzodiazepine + MET control. Another completed study found that naltrexone (380 mg) followed by multiple ketamine infusions (0.5 mg/kg) maintained antidepressant effects and reduced alcohol craving in participants with comorbid AUD and depression. A trial delivering ketamine infusions after alcohol consumption (350 ng/ml over 30 min) reported reduced maladaptive reward memories and reduced reinforcing effects of alcohol and long-term drinking versus saline. Trials in other SUDs show broadly consistent findings: in cocaine dependence, ketamine infusions (0.41–0.71 mg/kg) increased motivation to quit and reduced cue-induced craving, with higher doses producing greater reductions. In cannabis use disorder, ketamine (0.41–0.71 mg/kg) combined with MET or mindfulness-based relapse prevention decreased use and increased confidence to abstain. In opioid withdrawal, a single ketamine infusion enabled 91.7% of participants to initiate extended-release naltrexone and reduced Subjective Opioid Withdrawal Scale scores by a mean of 34 points. Ongoing trials: Several larger randomized trials are in progress. NCT04084860 (E. Dakwar) is a 120-participant RCT of two ketamine infusions (0.71 mg/kg at weeks 1 and 6) with or without psychotherapy versus benzodiazepine control, with primary outcome of heavy drinking days at 12 weeks. NCT02649231 (C. Morgan) is a 96-participant RCT testing three ketamine infusions (0.8 mg/kg) combined with relapse-prevention CBT versus control arms, with relapse rates and percentage abstinent days as primary outcomes. Other trials include comparisons of ketamine versus extended-release naltrexone for preventing readmission (NCT04562779) and trials exploring intranasal ketamine for rapid reduction of suicidal ideation in the context of alcohol abuse (NCT03539887) and ketamine combined with naltrexone for comorbid AUD and depression (NCT02461927). Dosing and routes: Completed AUD/SUD trials have used intravenous ketamine at doses from 0.11 mg/kg to 0.71 mg/kg; ongoing AUD trials commonly use 0.5–0.8 mg/kg IV. One ongoing AUD trial tests intranasal administration (estimated 50 mg over 15 minutes, ~0.5–1 mg/kg equivalent). The authors note that most AUD trials so far use IV delivery, whereas an FDA-approved intranasal formulation exists for treatment-resistant depression, raising questions about accessibility and monitoring. Preclinical and sex-specific findings: Animal studies show ketamine and AMPA/kainate antagonists can reduce alcohol consumption, ameliorate withdrawal-induced depressive and anxiety-like behaviours, and increase BDNF. Several rodent studies report sex-specific effects: in some models female animals showed greater sensitivity to ketamine’s reduction of alcohol intake or binge-like drinking, while other studies reported mixed or opposite patterns depending on baseline alcohol preference and measurement. The authors highlight that human AUD populations show sex differences in comorbidity and drinking motives, suggesting the need for sex-balanced clinical research. Biomarkers and predictors of response: Candidate biomarkers that emerged from depression/PTSD work and may be relevant to AUD include family history of alcoholism (associated with extended antidepressant response to ketamine), plasma BDNF increases post-treatment (correlated with response), BDNF Val66Met polymorphism (Met allele attenuated ketamine’s effect in mice), baseline plasma d-serine (negatively correlated with duration of response in PTSD), pretreatment rACC activity (predictive by MEG), Glx/Glutamate ratios by proton-MRS (negative correlation with antidepressant response), and EEG measures of slow-wave activity and delta sleep ratio as indicators of synaptic-plasticity changes associated with response. Genetic polymorphisms in GRIN2B and NOS1 have been associated with chronic ketamine use, suggesting potential markers for abuse liability, though evidence is preliminary and predominantly in male ketamine users. Addiction liability and safety: Ketamine has abuse potential; preclinical self-administration models and population data indicate illicit use. Acute ketamine toxicity can include delirium, memory impairment, tachycardia and other physiological effects; chronic use has been linked to urinary tract damage and withdrawal symptoms of craving, anxiety and dysphoria. The authors emphasise that any clinical implementation must weigh therapeutic benefit against abuse risk and identify patient-selection criteria and monitoring strategies.

Worrell and colleagues interpret the assembled evidence as providing a plausible mechanistic and preliminary clinical rationale for evaluating ketamine as a treatment for certain forms of AUD. They argue that ketamine’s ability to antagonise NMDA receptors, increase BDNF and promote synaptic plasticity and neurogenesis, and to modulate functional connectivity in networks implicated in negative affect may target core processes that drive relapse, particularly negative reinforcement linked to depression, stress and PTSD. Clinical data from small completed trials and trials in other SUDs are described as promising, showing effects on abstinence, craving, motivation to quit and reduced maladaptive reward memories, but the authors stress that evidence in AUD is still limited. The authors position these findings relative to existing treatments by noting that approved pharmacotherapies for AUD (disulfiram, naltrexone, acamprosate) have modest effect sizes and limitations, and that ketamine—already approved for treatment-resistant depression—could be repurposed more rapidly than novel compounds. They caution, however, that the therapeutic profile and mechanisms of ketamine are complex, with possible opioid-system involvement and interactions with naltrexone reported inconsistently across studies; therefore the clinical ramifications of combining ketamine with opioid antagonists require further study. Key limitations and uncertainties highlighted by the authors include the small number of completed AUD-specific clinical trials and incomplete reporting for some studies, heterogeneity in dosing and delivery routes, limited sample sizes, and an incomplete biomarker and genetic understanding to predict response or abuse risk. Sex-specific preclinical findings and sex differences in AUD epidemiology and comorbidity are noted as important but insufficiently explored in human trials. The authors also acknowledge the abuse liability of ketamine, acute and chronic adverse effects, and the need to identify patients for whom benefits outweigh risks. Implications for future research and clinical implementation emphasised by the authors include the need for larger randomized controlled trials to define efficacy, optimal dosing and delivery routes (IV versus intranasal), and the value of combining ketamine with psychotherapy (e.g. MET, CBT, mindfulness-based relapse prevention). They recommend integrating biomarker assessments (BDNF, d-serine, neuroimaging and EEG measures) and genetic screening (GRIN2B, NOS1 and related loci) into trials to predict therapeutic response and minimise abuse risk. Finally, the authors call for attention to sex differences in trial design and for careful monitoring and guidelines addressing ketamine’s abuse potential if clinical use for AUD is pursued.