This randomised, double-blind, active placebo-controlled pilot study (n=40) examined the effects of ketamine (49.7mg/70kg, n=17) or the active control midazolam (1.75mg/70kg, n=23) combined with motivational enhancement therapy to treat patients with alcohol use disorder. The preliminary data showed that a single ketamine infusion in combination with motivational enhancement therapy improves measures of drinking in patients with alcohol use disorder.
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Objective
Pharmacotherapy and behavioral treatments for alcohol use disorder are limited in their effectiveness, and new treatments with innovative mechanisms would be valuable. In this pilot study, the authors tested whether a single subanesthetic infusion of ketamine administered to adults with alcohol dependence and engaged in motivational enhancement therapy affects drinking outcomes.
Methods
Participants were randomly assigned to a 52-minute intravenous administration of ketamine (0.71 mg/kg, N=17) or the active control midazolam (0.025 mg/kg, N=23), provided during the second week of a 5-week outpatient regimen of motivational enhancement therapy. Alcohol use following the infusion was assessed with timeline followback method, with abstinence confirmed by urine ethyl glucuronide testing. A longitudinal logistic mixed-effects model was used to model daily abstinence from alcohol over the 21 days after ketamine infusion.
Results
Participants (N=40) were mostly middle-aged (mean age=53 years [SD=9.8]), predominantly white (70.3%), and largely employed (71.8%) and consumed an average of five drinks per day prior to entering the study. Ketamine significantly increased the likelihood of abstinence, delayed the time to relapse, and reduced the likelihood of heavy drinking days compared with midazolam. Infusions were well tolerated, with no participants removed from the study as a result of adverse events.
Conclusions
A single ketamine infusion was found to improve measures of drinking in persons with alcohol dependence engaged in motivational enhancement therapy. These preliminary data suggest new directions in integrated pharmacotherapy-behavioral treatments for alcohol use disorder. Further research is needed to replicate these promising results in a larger sample.
Pathological alcohol use causes substantial global mortality and economic burden, yet most affected individuals are not in treatment and many who enter care do not respond to existing pharmacotherapies or behavioural interventions. The investigators frame problematic drinking as maintained both by preexisting vulnerabilities and by neural adaptations that undermine motivation, increase stress sensitivity, and reduce interest in nonalcohol pursuits. Earlier work in cocaine dependence by Dakwar and colleagues suggested that a single subanesthetic ketamine infusion can produce rapid effects on such vulnerabilities and, when paired with a behavioural intervention, increase rates of abstinence compared with an active control. This pilot trial set out to test whether a single intravenous ketamine infusion, administered on a therapist-designated quit day during the second week of a 5-week outpatient motivational enhancement therapy (MET) programme, would improve drinking outcomes relative to an active control (midazolam) in adults with alcohol dependence. Primary and secondary aims were to evaluate short-term abstinence, heavy drinking days, and time to relapse or study dropout, and to assess tolerability and safety in this clinical sample.
This was a randomized, midazolam-controlled outpatient pilot trial conducted from September 2014 to September 2017. Treatment-seeking adults meeting criteria for alcohol dependence were recruited; 95 were screened, 50 enrolled, and 40 were randomly assigned in an intent-to-treat sample. Participants were required to abstain from alcohol for at least 24 hours before the infusion and to fast overnight. The infusion was delivered on a predesignated quit day during week 2 of a 5-week MET programme. Participants were randomised by a statistician in randomly sized blocks to receive either ketamine (total nominal dose 0.71 mg/kg given as a 2-minute 0.11 mg/kg bolus followed by a 50-minute 0.6 mg/kg slow drip; N=17) or an active control of midazolam (2-minute saline bolus then 50-minute slow-drip midazolam at 0.025 mg/kg; N=23). Medication preparation and assignment were handled by the study pharmacy. Blinding included a minor deception: participants were told they might receive a variety of psychoactive compounds to reduce expectancy effects. Vital signs were continuously monitored, medical coverage was provided for up to 3 hours postinfusion, and relaxation/mindfulness exercises were used before and during infusions. All participants received six MET sessions over 5 weeks (initial session in week 1 to set goals, weekly sessions in weeks 2–5, plus an additional MET session 24 hours after infusion to capitalise on hypothesised short-term motivational effects). Alcohol use was measured at each visit using the timeline followback method with urine ethyl glucuronide testing to confirm abstinence; a positive urine test overrode self-reported abstinence. Secondary measures assessed craving, arousal, withdrawal, self-efficacy, perceived stress, mindfulness, and impulsivity, and urine toxicology was collected repeatedly. A six‑month telephone follow-up was attempted. The prespecified primary outcome was daily abstinence (0 drinks) over the 21 days following infusion, dichotomised for each calendar day. Days with missing data were treated as nonabstinent in the main analysis; sensitivity analyses treated missing days as missing. A longitudinal logistic mixed-effects model (logit link, random intercept) tested the effects of time (including quadratic terms), treatment, and time-by-treatment interaction, adjusted for baseline total drinks. Heavy drinking days and other secondary outcomes were analysed using longitudinal mixed-effects models with appropriate link functions (logit for binary outcomes, log link for right-skewed outcomes) and an autoregressive correlation structure. Time-to-event outcomes (time to relapse, first use, first heavy drinking day) were analysed with Kaplan-Meier curves and log-rank tests. Analyses were conducted in SAS v9.4 with two-sided tests at the 5% significance level.
The study participants' baseline demographic characteristics are summarized in Table. The primary outcome of self-reported drinking days by timeline followback after the infusion was dichotomized so that each day was defined as abstinent (0 drinks) or nonabstinent (at least one drink). Days with missing data were treated as nonabstinent days. A longitudinal logistic mixedeffects model with a logit link and a random intercept was used to account for between-subject variances. The fixed effect of time (days postinfusion), treatment, and time-bytreatment interaction, adjusted by baseline total drinks, was used to analyze the longitudinal primary outcome: abstinent days during the 21 days postinfusion. Additionally, because the observed data do not follow a linear trend, time was also tested as a quadratic effect by testing whether the effect of time squared was significant. The Akaike information criterion and Bayesian information criterion summary fit statistics were used to identify which model best fit the observed data. Reduction in heavy drinking days and other secondary measures were analyzed with longitudinal mixed-effects models, with the effect of study week, treatment, and study week-by-treatment two-way interaction adjusted by the corresponding outcome measures at baseline. A random intercept was used to account for between-subject variances, and a generalized estimating equation structure was included to account for within-subject correlations over time as an autoregressive (AR) process. We used the logit link to model binary outcomes (i.e., heavy drinking day) and the log link function to model outcomes (i.e., craving, arousal, and withdrawal) with rightskewed distributions. All other secondary outcomes were approximately normally distributed and modeled with identitylink functions. The secondary outcome, time to relapse, was defined as time to the first heavy drinking day or time to dropout, whichever came first, and was analyzed by using Kaplan-Meier survival curves and the log-rank test. Time to first alcohol use and time to first heavy drinking day were similarly analyzed. All analyses were performed in SAS, version 9.4, with all tests two-sided at a 5% level of significance.
To our knowledge, this is the first trial to investigate the efficacy of a single ketamine infusion for alcohol use disorder. These preliminary data indicate that, compared with midazolam, ketamine led to a lower likelihood of alcohol use over a 21-day period after infusion, as well as a lower likelihood of heavy alcohol use and longer time to relapse. This suggests that ketamine in combination with motivational enhancement therapy may be an effective pharmacotherapy for initiating and sustaining abstinence from alcohol. These data expand on previous findings on ketamine infusions in individuals with cocaine dependence. In the laboratory setting, any improvements (i.e., reductions in use and craving) that were observed from a single infusion were typically transient, subsiding after several days. A subsequent trial embedding a single infusion into a mindfulnessbased framework demonstrated more persistent effects, suggesting that an integrated model might work to promote synergy between the behavioral treatment and ketamine. Early trials evaluating so-called ketamine psychedelic therapy also employed an integrated approach, with intramuscular ketamine combined with existentially oriented psychotherapy to treat alcohol and opioid use disorders. Building on these previous findings, we paired motivational enhancement therapy and ketamine in this trial with the assumption that they might work together to marshal motivation toward initiating and sustaining abstinence. In previous studies, psychological mechanisms have been implicated in the impact of ketamine on the motivation to quit and other dependence-related vulnerabilities, perhaps through shifts in perspective. A psychotherapy framework aimed at further enhancing motivation, such as motivational enhancement therapy, may serve to focus these perspectival shifts toward deepening commitment and readiness for change. This dovetails with early research examining comparable compounds integrated into addictionoriented psychotherapy, such as psilocybin and LSD (lysergic acid diethylamide), whereby certain psychoactive effects were intended to facilitate a reappraisal of personal values and existential meaning, as well as a deliberate restructuring of commitments and behavior. In this trial, no participants dropped out of the ketamine group, but six dropped out of the control (midazolam) group, with four resuming heavy alcohol use before dropping out. Although the sample size was small, this suggests that ketamine may be helpful in promoting engagement with behavioral treatment, as hypothesized. In turn, motivational enhancement therapy may be helpful in carrying forward the apparent effects of ketamine on reduction in substance use beyond what has been observed in previous laboratory-based research without a supportive or behavioral framework during follow-up. It is not possible, however, to conclude from this trial whether motivational enhancement therapy was necessary for these persistent effects in the absence of a twoby-two factorial design (e.g., participants receiving infusions without motivational enhancement therapy). Surprising findings were the high rates of abstinence initiation irrespective of medication assignment, with most participants in both treatment groups able to stop drinking for a brief period after the designated quit day. Similarly, there was no significant difference between groups in time to first use or first heavy use. Yet, there were significant differences between groups over time in the proportion of both drinking days and heavy drinking days, with participants assigned to the control (midazolam) group significantly more likely both to drink and to drink heavily. Taken together, these findings suggest that ketamine provided protection against a lapse evolving into continued use (relapse) or into dropout from treatment. This may stem from ketamine minimizing the abstinence violation response (i.e., individuals losing hope after using and consequently relapsing or disengaging from treatment). These findings suggest a new usefulness for ketamine in facilitating addiction treatment and reducing the risk of relapse, namely, by maintaining motivation for sobriety even in the face of stressors, challenges, and lapses. An issue in studying treatment with ketamine (similar to those emerging in studies of psychedelics, such as psilocybin, or in studies of MDMA) is the problem of blinding participants and investigators, given the distinctive psychoactive effects of these agents. The substantial dissociative effects of ketamine may lead patients to feel that they received the active medication and engender placebo effects. We aimed to address this issue by using an active control (midazolam) and employing a minor deception whereby participants were informed that they may receive any of a variety of psychoactive compounds (as opposed to a binary randomization between midazolam and ketamine). However, we did not test the integrity of the blind by ascertaining what participants or staff believed was received during infusions. Additionally, even though a history of ketamine or benzodiazepine misuse was exclusionary, we did not determine the extent to which previous exposure to ketamine or midazolam may have enabled participants to identify what they received. The findings that participants in the control group sustained abstinence for the first 7-10 days after the infusion, with overall abstinence rates higher than the modest response observed in previous trials that tested motivational enhancement therapy alone (e.g., 28% in Project MATCH), are of interest. These data suggest that midazolam may indeed have functioned as a good placebo or that there may be some transient benefit to a low-dose midazolam infusion. Heavy drinkers making a quit attempt may experience some degree of alcohol withdrawal or craving that could be relieved with midazolam. It is possible, therefore, that the impact of ketamine observed in this trial might have been more pronounced if an inactive control without beneficial effects (such as saline) had been used as the comparator. Greater clarification of the therapeutic mechanisms of ketamine, as well as of its possible neurotoxicity and bladder complications with repeated administrations, can aid clinicians in understanding how to best harness its clinical potential while minimizing potential risks. As in a previous trial with cocaine users, these data suggest that a single dose may have enduring benefits, especially when integrated into a behavioral treatment. The persistence of these effects, well after ketamine and its metabolites are expected to have cleared, indicates that its therapeutic activity extends beyond direct neural activation (as in an agonist model of addiction treatment) to include sustained effects on decision making and behavior. Neurotrophic, modulatory, and even psychological mechanisms have all been proposed to account for the sustained antidepressant effect of a single dose of ketamine. These downstream effects on diverse neural circuits may have relevance to addiction treatment as well. Preclinical research suggests that neurotrophic mechanisms involving mTOR (mammalian target of rapamycin) may be involved in the antidipsotropic effects of ketamine in rodentsand that ketamine modulates prefrontal functional connectivity to disrupt drug reinstatement in monkeys. Several studies indicate that individuals with a first-degree family history of alcoholism may have a heightened and more prolonged antidepressant response to ketamine, perhaps as a result of epigenetic changes, glutamate subreceptor variations, and environmental factors. The neural changes associated with a predisposition to alcohol use disorder, and perhaps with disordered use itself, may therefore work to optimize the efficacy of ketamine. It is possible that the activity of ketamine may have been similarly enhanced by such factors in our sample, with the majority of participants endorsing a first-degree family history of alcoholism (Table), even though this was not an antidepressant response because individuals with depressive symptoms were excluded. The inherited and acquired neural vulnerabilities associated with problematic substance use are shared for different substance use disorders, including cocaine, alcohol, and opioids. As suggested by findings from this trial and from previous research with both cocaine and opioid users, dependence-related vulnerabilities across different substance use disorders may be equally susceptible to the therapeutic effect of ketamine, which may include changes in functional connectivity as well as alterations in glutamatergic, opioid, and dopaminergic signaling. For example, a recent small study suggested that there may be opioid-related mechanisms behind the antidepressant response, although this finding is preliminary, and other data suggest otherwise. Given emerging data indicating the effect of certain ketamine enantiomers and metabolites, such as (R)-ketamine and (2R,6R)-hydroxynorketamine, on glutamate and dopamine neurotransmission, future studies examining serum levels of ketamine and of its metabolites may be helpful in clarifying ketamine's mechanism of action.
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The intent-to-treat sample comprised 40 participants, who were mostly middle-aged (mean age 53 years, SD=9.8), predominantly white (70.3%), and largely employed (71.8%), reporting an average of five drinks per day before study entry. Across groups, infusions were generally well tolerated. The most common adverse effects were sedation (midazolam: N=12; ketamine: N=8) and headache (midazolam: N=4; ketamine: N=6), typically lasting about 12 hours postinfusion. Dissociative symptoms measured by the Clinician-Administered Dissociative States Scale were significantly higher immediately after ketamine (median=19, IQR 9–30.75) than after midazolam (median=2, IQR 0.25–9.25; χ2=7.87, p=0.005). Two ketamine-treated participants had brief mild agitation; there were no reports of persistent psychoactive effects or initiation of benzodiazepine, opioid, or ketamine misuse. On the primary outcome of daily abstinence over the 21 days after infusion, the longitudinal logistic mixed-effects model (with time treated as a quadratic term) indicated that ketamine significantly increased the likelihood of abstinence compared with midazolam. Sensitivity analyses treating missing days as missing, and analyses without adjustment for baseline drinks, yielded similar results, suggesting robustness to these assumptions. Across the 21 days, 47.1% (8/17) of ketamine participants used alcohol and 17.6% (3/17) had a heavy drinking day; corresponding figures in the midazolam arm were 59.1% (13/22) using alcohol, 40.9% (9/22) with a heavy drinking day, and 52.2% (12/23) who met the study definition of relapse at some point. Six participants dropped out of the midazolam group (one immediately after infusion, five after the first week); no participants dropped out of the ketamine group. For the secondary outcome of heavy drinking days, there was a significant study week-by-treatment interaction (F=12.34, df=1,798, p<0.001). In the midazolam group the odds of a heavy drinking day increased with each postinfusion day (odds ratio=1.19, 95% CI=1.14–1.25, p<0.001), whereas the odds did not change significantly over time in the ketamine group (odds ratio=0.98, 95% CI=0.89–1.08, p=0.74). The two-way interaction of study week-by-treatment was not significant for the other secondary measures (craving, withdrawal, mindfulness, impulsivity, stress sensitivity, self-efficacy). Time-to-event analyses showed a longer time to relapse (defined as first heavy drinking day or dropout) in the ketamine group by log-rank test (χ2=4.2, p=0.04), but no significant differences in time to first alcohol use or time to first heavy drinking day. At six-month telephone follow-up 19 of 40 participants were reached (47.5%); among respondents, 75% (6/8) in the ketamine group reported abstinence versus 27% (3/11) in the midazolam group.
Dakwar and colleagues interpret these preliminary data as evidence that a single subanesthetic ketamine infusion, given on a planned quit day and combined with motivational enhancement therapy, reduced short-term alcohol use and heavy drinking and prolonged time to relapse relative to an active control. They situate these findings within prior work showing transient laboratory effects of ketamine and longer-lasting benefits when an infusion is embedded within a psychosocial framework, proposing that an integrated pharmacotherapy–behavioural model may produce synergy. The investigators suggest psychological mechanisms—such as perspectival shifts that increase motivation to change—may interact with neurobiological effects (neurotrophic and modulatory changes, potential mTOR involvement, altered prefrontal connectivity) to support sustained behaviour change beyond the pharmacokinetic clearance of ketamine and its metabolites. The authors acknowledge several important limitations. The sample was small and relatively homogeneous, limiting statistical power and generalisability; treatment duration and follow-up were brief, with only 21 days of detailed alcohol monitoring after infusion and incomplete six-month follow-up. More than a quarter of control participants dropped out, and the standard assumption of treating dropout as relapse could bias results despite sensitivity checks that produced similar findings. Blinding remains a concern given ketamine's distinctive dissociative effects; although an active control and limited deception were used, the integrity of the blind was not formally assessed. The comparator (low-dose midazolam) may have had some transient benefit for withdrawal or craving, which could have reduced the apparent effect size of ketamine compared with an inert placebo. Safety considerations for repeated administration—neurotoxicity and bladder complications—are highlighted as areas requiring further study, particularly outside specialised research settings. Finally, the investigators emphasise that these results are a first step. They recommend replication in larger, more diverse samples with longer follow-up, more frequent assessments, and design features (for example, factorial designs and measurement of ketamine metabolites) that can clarify whether ketamine's clinical benefits depend on concurrent behavioural therapy and elucidate underlying mechanisms.
In this pilot randomised trial, a single ketamine infusion administered on a designated quit day and combined with motivational enhancement therapy was associated with greater short-term odds of alcohol abstinence, fewer heavy drinking days, and longer time to relapse compared with an active midazolam control. The findings support further research to determine durability of effect, safety with repeated use, and whether there is true synergy between ketamine and behavioural treatments, ideally tested in larger samples with longer follow-up and mechanistic assessments.
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