This double-blind, placebo-controlled study (n=55) investigated the use of ketamine (35mg/70kg) versus midazolam (an anesthetic), plus mindfulness-based therapy (5-week program) for cocaine dependence. The ketamine group scored significantly better and were 53% less likely to relapse.
Papers cited by this study that are also in Blossom
Objective
Research has suggested that subanesthetic doses of ketamine may work to improve cocaine-related vulnerabilities and facilitate efforts at behavioral modification. The purpose of this trial was to test whether a single ketamine infusion improved treatment outcomes in cocaine-dependent adults engaged in mindfulness-based relapse prevention.
Methods
Fifty-five cocaine-dependent individuals were randomly assigned to receive a 40-minute intravenous infusion of ketamine (0.5 mg/kg) or midazolam (the control condition) during a 5-day inpatient stay, during which they also initiated a 5-week course of mindfulness-based relapse prevention. Cocaine use was assessed through self-report and urine toxicology. The primary outcomes were end-of-study abstinence and time to relapse (defined as first use or dropout).
Results
Overall, 48.2% of individuals in the ketamine group maintained abstinence over the last 2 weeks of the trial, compared with 10.7% in the midazolam group (intent-to-treat analysis). The ketamine group was 53% less likely (hazard ratio=0.47; 95% CI=0.24, 0.92) to relapse (dropout or use cocaine) compared with the midazolam group, and craving scores were 58.1% lower in the ketamine group throughout the trial (95% CI=18.6, 78.6); both differences were statistically significant. Infusions were well tolerated, and no participants were removed from the study as a result of adverse events.
Conclusions
A single ketamine infusion improved a range of important treatment outcomes in cocaine-dependent adults engaged in mindfulness-based behavioral modification, including promoting abstinence, diminishing craving, and reducing risk of relapse. Further research is needed to replicate these promising results in a larger sample.
Cocaine use disorder remains a major public health problem with no FDA‑approved pharmacotherapies and limited success of standard behavioural treatments. Previous preclinical and human laboratory work has suggested that modulation of glutamate neurotransmission, and specifically N‑methyl‑D‑aspartate receptor (NMDAR) modulation, may affect cocaine‑related learning and reinforcement. Ketamine, a dissociative anaesthetic given at subanesthetic doses, has shown robust antidepressant effects and in laboratory studies in people with cocaine dependence it has been reported to increase motivation to quit, reduce craving, and decrease cocaine use over short periods. However, those benefits have typically been transient, and it has been proposed that combining ketamine with a behavioural intervention might extend and translate its effects into clinically meaningful, sustained change. Dakwar and colleagues designed this randomised clinical trial to test whether a single subanesthetic intravenous ketamine infusion (0.5 mg/kg over 40 minutes), given to adults with cocaine dependence initiating mindfulness‑based relapse prevention (MBRP), would improve clinically relevant outcomes compared with an active control (midazolam). The primary endpoints were end‑of‑study abstinence (two weeks confirmed by urine toxicology) and time to relapse (first use or dropout); secondary aims included effects on weekly cocaine use, craving, and safety/tolerability. The trial therefore evaluated ketamine as an adjunct to a manualised mindfulness‑oriented behavioural platform rather than as a stand‑alone medication.
This was a randomised, double‑blind, parallel‑group trial conducted at the New York State Psychiatric Institute between September 2011 and December 2016. Fifty‑five treatment‑seeking adults who met DSM‑IV criteria for cocaine dependence and met prespecified recent‑use thresholds were enrolled. Key exclusions included current DSM‑IV depressive or anxiety disorders, psychotic or dissociative history, and benzodiazepine or opioid use disorder; participants were required to be medically healthy and under age 70. Screening included structured diagnostic interview, medical assessment, serum tests, and scales for depression and dissociation. Participants were hospitalised for a 5‑day inpatient phase during which they initiated an adapted 5‑week course of MBRP. On day 2 they received a single 40‑minute intravenous infusion of either ketamine hydrochloride 0.5 mg/kg or active control midazolam 0.025 mg/kg; infusions were prepared and administered by blinded staff. To preserve blinding and minimise expectancy effects, participants were told they might receive one of several possible medications. Vital signs were continuously monitored, and dissociative symptoms were assessed immediately postinfusion using the Clinician‑Administered Dissociative States Scale (CADSS). A morning MBRP session occurred about 2 hours postinfusion, with further high‑density MBRP sessions on days 2–5 and outpatient MBRP once weekly during weeks 2–5; participants returned twice weekly during weeks 2–5 for MBRP, physician visits and measures, and urine toxicology. A telephone follow‑up interview occurred at 6 months. The prespecified primary outcome was two weeks of end‑of‑study abstinence confirmed by urine toxicology. Time to relapse (first use or dropout after the inpatient phase) was analysed as a secondary primary outcome. Weekly cocaine use and weekly craving were analysed as secondary outcomes. Statistical methods included logistic regression for the primary abstinence outcome, Cox proportional hazards models for time to relapse (hazard ratios reported; a hazard ratio below 1 indicates reduced risk in the ketamine group), and longitudinal mixed‑effects models for weekly binary cocaine use and continuous craving scores (random intercepts; route of use included as a covariate). The investigators planned for a sample of 60 but stopped enrollment at 55 after an interim analysis indicated a robust difference that would remain significant under a conservative algorithm. Analyses were two‑sided with α=0.05 and were performed in SAS 9.4.
Baseline demographic characteristics, side effects, and adverse events were tabulated and summarized using means and standard error (or median and interquartile range for nonnormally distributed outcomes). Differences between groups on dissociative symptoms (as assessed with the CADSS) were analyzed using the Wilcoxon rank-sum test. The between-group difference in change from baseline to postinfusion assessment on the Dissociative Experiences Scale and in peak systolic blood pressure were also analyzed using Wilcoxon nonparametric rank-sum tests. The primary outcome was 2 weeks of end-of-study abstinence, confirmed by urine toxicology; if participants denied use between visits and yet provided urine samples indicative of recent cocaine use, they were designated as not abstinent for that self-report period. The proposed sample size was 60 individuals, although the research was stopped after an interim analysis (N=55) requested by the National Institute on Drug Abuse demonstrated a difference that would remain significant even if the trial finished according to a "worst-case" algorithm. Logistic regression was used to analyze the effect of treatment on the primary outcome in the interim and present analyses. Time to relapse (defined as first use or dropout after the inpatient phase) was analyzed using the Cox proportional hazard model. The secondary outcomes of weekly cocaine use (during weeks 2 through 5) and weekly craving scores (during weeks 1-5) were analyzed using longitudinal mixed-effect models with the effect of study week, treatment, study week-bytreatment two-way interaction, and the corresponding outcome measured at baseline (when appropriate). A random intercept was used to account for the between-subject variances. The logit link function was used to model binary cocaine use, and the log link function was used to model craving scores to account for their nonnormal distribution. Consistent with previous cocaine use disorder trials, route of use was included as a covariate in all analyses. Analyses were performed using SAS, version 9.4, with all tests two-sided at a 5% level of significance.
This is, to our knowledge, the first clinical trial to investigate a subanesthetic dose of ketamine in cocaine-dependent individuals, as well as the first to investigate a single intravenous infusion in the context of behavioral treatment. We found that ketamine was well tolerated and promoted abstinence. We also found that, compared with midazolam, ketamine was associated with a lower likelihood of cocaine use, lower levels of cocaine craving, and longer time to relapse. A single ketamine infusion also led to a greater proportion of individuals remaining cocaine free at the 6-month telephone followup interview. These results suggest that ketamine, in combination with mindfulnessbased behavioral modification, may be an effective pharmacotherapy for cocaine use disorder. Previous studies with ketamine in cocaine-dependent individuals were laboratorybased trials investigating the subacute effects of ketamine (24-48 hours after infusion) on cocaine-related vulnerabilities in the absence of any behavioral treatment. Any improvements that were observed, such as reductions in use and craving, were typically transient, subsiding after several days. These preclinical data indicated that the benefits of ketamine are generally brief and would need to be extended in some manner to have a clinical impact. One strategy for sustaining these effects is to embed ketamine infusions into an addiction-oriented behavioral framework. Such a combination might leverage the impact of ketamine into longer-lasting changes, especially in perspective, decision making, and relapse prevention skills. Early trials evaluating "ketamine psychedelic therapy" also employed an integrated approach, with intramuscular ketamine combined with existentially oriented psychotherapy to treat alcohol and opioid use disorders. We designated MBRP as the behavioral platform for ketamine because the two interventions share hypothesized neural mechanisms and have comparable effects on dependence-related vulnerabilities, such as reactivity and craving. Also, the psychoactive effects of ketamine, specifically its mysticaltype phenomena, suggest some similarities with the meditative experienceand might work to provide an experiential stepping-stone toward deepening mindfulness training. While this trial was not designed to evaluate synergy between ketamine and MBRP, it served to evaluate whether ketamine provides additional benefit to individuals engaged in this behavioral treatment. The group receiving ketamine demonstrated higher rates of retention, consistent with the previous finding that ketamine enhances motivation to change drug use and supporting the hypothesis that it might serve to facilitate engagement with behavioral treatment. MBRP also appeared to be helpful in carrying forward the effects of ketamine beyond what has been observed in previous research, with participants maintaining abstinence and experiencing sustained craving reduction through several weeks. It is not possible, however, to conclude whether MBRP was necessary for sustaining the benefits of ketamine because our study did not include a treatment Diploma; PTSD=posttraumatic stress disorder. b Information on race was missing for four participants in the ketamine group. c Information on ethnicity was missing for one participant in the ketamine group. d Information on employment was missing for one participant in the ketamine group. e Information on education was missing for one participant in each group. f Information on comorbidity was missing for one participant in the ketamine group and three in the midazolam group. g Hamilton Depression Rating Scale scores were missing for two participants in the ketamine group and four in the midazolam group. Am J Psychiatry 176:11, November 2019 ajp.psychiatryonline.org 927 group that received medication without MBRP; it is conceivable, although unlikely based on previous work, that ketamine might have led to these results in the absence of any behavioral treatment. Similarly, another psychosocial framework might have been just as helpful a behavioral counterpart, as we did not compare different behavioral treatment and medication combinations. This trial suggests, in any case, that the effects of ketamine might be sustained when integrated into behavioral treatment; future research can examine this hypothesis more rigorously. Further clarification of the therapeutic mechanisms of ketamine can assist in our understanding of how best to harness its clinical potential. A range of pathways have been hypothesized to account for the antidepressant efficacy of ketamine, from receptor-specific changes to neurotrophic, modulatory, and even psychological mechanisms. Some of these mechanisms are relevant to substance use disorders as well and suggest innovative strategies for enhancing or replacing ketamine. For example, preclinical research indicates that an infusion of brain-derived neurotrophic factor (BDNF), which has also been shown to be elaborated by ketamine, into the brains of rodents disrupts cocaine self-administration. This suggests that pharmacotherapy supplementing the BDNF-related effects of ketamine may serve to sustain efficacy. A recent small study suggested that opioid-related mechanisms may be involved in the antidepressant effects of ketamine. Although these findings are preliminary, they call attention to why ketamine might be abused and to the importance of appropriately addressing this abuse liability in clinical settings. As in other clinical procedures involving substances of abuse liability (e.g., provision of postoperative opioids), there are various safeguards that work to minimize these risks, such as careful patient selection, preparation, monitoring, and postintervention support. These safeguards were incorporated into the present study as well as into the studies of ketamine in depressive and anxiety disorders; there has been no incidence of ketamine misuse in any of the research to date, suggesting that this risk can be effectively managed even when this agent is given to substance users. The behavioral and mindfulnessbased framework may have also worked to guide participants to engage with the infusions in a therapeutic manner, cultivating a perspective that is not grasping of any particular sensation or experience, but that is accepting, deliberate, and nonreactive. This trial has several limitations. The sample was relatively small, and there were minor discrepancies between treatment arms in demographic characteristics and preferred route of use. Future trials with larger samples and with randomization stratified by route of use should work to address this limitation. Furthermore, a larger sample may provide sufficient power to evaluate the impact of ketamine on the use of other substances that may be related to cocaine, such as tobacco and alcohol. Second, the study procedures were highly monitored, including an inpatient phase. Inpatient treatment of cocaine use disorders is uncommon, and the level of monitoring provided is unusual in standard practice. Third, the sample was relatively homogeneous, with a majority of participants African American and male, and with minimal psychiatric comorbidity. While the selection of patients with no comorbidities might hamper the extension of our findings to a more psychiatrically complicated population, it is likely that cocainedependent individuals with depression or anxiety would respond even more robustly to ketamine given evidence supporting its psychiatric efficacy. Future trials can examine the effect of ketamine on individuals with drug dependence and psychiatric comorbidity, as well as examine sex differences in the response to ketamine.
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Fifty‑five participants were randomised (ketamine N=27; midazolam N=28). Baseline median daily cocaine expenditure was similar between groups (ketamine $32.86; midazolam $36.43). The proportion of freebase (smoked) users differed modestly between groups (55.6% in ketamine; 71.4% in midazolam). The infusion produced greater acute dissociative effects in the ketamine arm: median CADSS score postinfusion was 22 (IQR=13–34) versus 7 (IQR=4–10) for midazolam (p<0.001); psychoactive effects resolved within 30 minutes, and there was no persistent dissociation on postinfusion measures. On the primary abstinence outcome (intent‑to‑treat), 48.2% of participants in the ketamine group maintained abstinence over the last two weeks of the trial compared with 10.7% in the midazolam group. Time‑to‑event analysis showed the ketamine group had a reduced risk of relapse (first use or dropout) with a hazard ratio of 0.47 (95% CI=0.24, 0.92), indicating a 53% lower likelihood of relapse compared with midazolam. In longitudinal analyses controlling for route of use, odds of cocaine use in the midazolam group were 7.8 times those in the ketamine group (odds ratio=7.8; 95% CI=1.5, 39.9; p=0.01). There was no significant time-by‑treatment interaction for cocaine use, and no overall change in use over study weeks, consistent with maintenance of early gains in the ketamine arm. Craving scores were substantially lower in the ketamine group across the trial: the main‑effects model estimated craving to be 58.1% lower in ketamine than in midazolam (95% CI=18.6, 78.6; p=0.01), with no significant week‑by‑treatment interaction. Measures of perceived stress and mindfulness did not differ between groups over time. At the 6‑month telephone follow‑up, 44% (12/27) of ketamine recipients reported abstinence, versus 0% in the midazolam group (χ2=15.92, p<0.001). Infusions were reported to be well tolerated and no participants were withdrawn due to adverse events.
Dakwar and colleagues report that a single subanesthetic ketamine infusion, administered within a structured mindfulness‑based relapse prevention programme, was well tolerated and associated with improved cocaine‑related outcomes relative to an active control. The ketamine arm showed higher end‑of‑study abstinence rates, reduced risk of relapse (hazard ratio=0.47), markedly lower craving throughout follow‑up, greater retention and a higher self‑reported abstinence rate at 6 months. The investigators interpret these results as consistent with the hypothesis that ketamine can temporarily reduce craving, increase motivation, and decrease behavioural reactivity, and that embedding the drug within a behavioural framework such as MBRP may leverage these transient effects into more durable clinical gains. The authors situate their findings against prior laboratory studies that found short‑lived benefits of ketamine in cocaine‑dependent volunteers and argue that combining pharmacological and psychological interventions may extend benefits. They note possible mechanistic pathways relevant to both ketamine and mindfulness training (for example, modulation of mesolimbic function, promotion of prefrontal plasticity and synaptogenesis, and changes in default‑mode network connectivity). Potential biological mediators discussed include brain‑derived neurotrophic factor and, preliminarily, opioid‑related mechanisms; the investigators also raise the issue of ketamine’s abuse liability and describe safeguards used in the trial (careful patient selection, monitoring and postintervention support). Key limitations acknowledged by the authors include the relatively small sample size and some baseline imbalances (including route of use), the highly monitored inpatient initiation phase that limits generalisability to usual outpatient care, and the homogeneous sample composition (majority male and African American with minimal psychiatric comorbidity). They also note that the trial did not include a medication‑only arm, so it is not possible to determine whether MBRP was necessary to sustain benefits, nor was the integrity of the blind formally tested; informing participants that they might receive several different medications constituted deliberate deception to protect blinding but would not be practicable in routine clinical settings. The authors conclude that the results are promising but require replication in larger, more diverse samples, with study designs able to test the hypothesised synergy between ketamine and behavioural treatments and to clarify mechanisms and risks.
Greenway, K. T., Garel, N., Jerome, L. et al. · Expert Review of Clinical Pharmacology (2020)
Dakwar, E., Levin, F. R., Hart, C. L. et al. · American Journal of Psychiatry (2020)