Elias Dakwar - US grants

DESCRIPTION (provided by applicant): Cocaine dependence remains a significant health problem for which effective pharmacotherapy treatments are lacking. In this application for a K23 Mentored Patient Oriented Research Career Development Award, Dr. Elias Dakwar proposes a comprehensive plan towards becoming an independent researcher of innovative treatments for drug dependence. Specifically, this proposal will focus on treating cocaine dependence with sub-anesthetic infusions of ketamine, a high-affinity non-competitive N- methyl-D-aspartate receptor (NMDAR) antagonist, which has recently emerged as a novel antidepressant strategy. Purported mechanisms of its antidepressant action - modulation of the anterior cingulated cortex (ACC), increased neural plasticity in the prefrontal regions of the brain - suggest that ketamine may have a role in the treatment of cocaine dependence as well. Prefrontal dysfunction is believed to be highly associated with the development and maintenance of drug dependence, and ACC dysfunction in particular has been implicated in arousal, impulsivity, and stress sensitivity, as well as in cue reactivity and increased risk of relapse in cocaine users. Disruptions in the glutamate system are hypothesized to underlie these clinically significant impairments in prefrontal functioning, and NMDAR antagonism, via modulation of glutamate, has been proposed as a way to address these deficits. However, the only specific antagonist studied, memantine, failed to show an effect in humans. As recent studies demonstrate, the robust, unique and sustained activity of sub-anesthetic dose ketamine on human brain systems suggest that it may be able to restore normal brain function in a way not observed with memantine, and potentially produce the effects on cocaine dependence that preclinical and animal studies with NMDAR antagonists have been predicting. This trial therefore aims to investigate in a randomized, placebo-controlled trial the effect of ketamine on risk of relapse (time to first cocaine use) in newly abstinent cocaine dependent individuals, as well as to investigate mechanisms of action in regards to stress sensitivity, mindfulness, and impulsivity. Even in the absence of positive findings, the proposed project stands to advance the field by elucidating the role of NMDAR blockade as a treatment strategy for drug dependence. Also, it can contribute more generally to understanding how targeting certain vulnerabilities, such as stress sensitivity and mindfulness impairment, might impact addiction. While pursuing this line of research with the expertise of his mentor (Dr. Frances R. Levin) and preceptors (Drs. Carl Hart and Sanjay Mathew), Dr. Dakwar will concurrently engage in an individualized training program so as to develop in the following important areas: 1) human laboratory and clinical trial study design, methodology, and logistics, 2) advanced biostatistics, 3) responsible conduct of research, 4) manuscript preparation, 5) grant-writing and grant-management skills, and 6) behavioral and translational neurobiology. Overall, this award will ensure Dr. Dakwar's successful transition to an independent investigator of innovative treatments for drug dependence. PUBLIC HEALTH RELEVANCE: Cocaine dependence remains a significant public health issue for which effective medications are lacking. The overall goal of this K23 proposal is to launch the career of Elias Dakwar, MD as a researcher of innovative treatments for drug dependence. In the proposed project, he will investigate the effect of a single dose of sub- anesthetic ketamine on risk of relapse among cocaine dependent individuals. Alongside a training plan, this project will allow him to develop into a researcher targeting vulnerabilities that may perpetuate problematic cocaine use, such as stress sensitivity, disruptions in the glutamate system, and impaired self-regulation.

DESCRIPTION (provided by applicant): Disruptions in the glutamatergic system represent an innovative target of medications development for cocaine dependence. Our preliminary investigations with ketamine, a glutamatergic modulator with potent prefrontal effects, suggest that it represents a promising Candidate. Alongside being safely administered, with no development of psychosis or ketamine misuse, we found that sub-anesthetic ketamine led to significant changes in measures of motivation to stop cocaine use, when compared to an active control (n=8). Further, ketamine had promising effects on cue-induced craving. This project aims to examine whether these promising effects extend to cocaine self- administration. We will evaluate the effect of a single sub-anesthetic dose of ketamine (0.11 mg/kg over 2 minutes, followed by 0.60 mg/kg over 50 minutes) on cocaine self- administration in 20 non-treatment seeking non-depressed cocaine-dependent individuals who complete a 9-week combined laboratory-inpatient and outpatient double- blind, cross-over, randomized, controlled study. Participants will be provided a choice session of five cocaine choices 24 hours following each active infusion. We predict that, compared to midazolam, ketamine will significantly reduce the number of cocaine choices during the choice session. Secondary aims pertain to the effect of ketamine on cocaine-related deficits that implicate prefrontal dysfunction, such as stress sensitivity, craving, impulsivity, low motivation, low self-efficacy, and low mindfulness. Thus, we aim to evaluate a highly innovative intervention in a manner that has the capacity to make important and unprecedented contributions to the field. An effect of ketamine on cocaine self-administration would suggest that brief potent glutamatergic modulation represents a possible treatment strategy for cocaine dependence that merits further investigation.

DESCRIPTION (provided by applicant): Alterations in glutamate neurotransmission are recognized as an important target of pharmacotherapy for alcohol dependence. Our preliminary investigations with ketamine, a glutamate modulator with potent prefrontal effects, suggest that it uniquely addresses neuroadaptations related to problematic drug and alcohol use. Alongside being safely administered to active drug users, we found that sub-anesthetic ketamine significantly increased motivation to stop cocaine use and decreased cue-induced craving when compared to an active control, 24 hours post-infusion. An ongoing clinical trial also indicates that ketamine can be feasibly administered in the setting of outpatient addiction treatment. Expanding on these findings, this project aims to examine whether ketamine will benefit problematic alcohol use in clinical settings. We will evaluate the effect of a single sub-anestheti dose of ketamine (0.11 mg/kg over 2 minutes, followed by 0.60 mg/kg over 50 minutes) on alcohol dependence in 40 non-depressed alcohol-dependent individuals engaged in Motivational Enhancement Therapy (MET). We predict that, compared to the active control midazolam, ketamine will significantly reduce percentage heavy drinking days. Secondary aims pertain to the effect of ketamine on alcohol-related deficits that implicate prefrontal dysfunction or glutamate abnormalities, such as stress sensitivity, craving, withdrawal, impulsivity, low self-efficacy, and low mindfulness. Thus, we aim to evaluate a highly innovative intervention in a manner that has the capacity to make important contributions to the field. An effect of ketamine on these outcomes would suggest that brief potent glutamatergic modulation represents a possible treatment strategy for alcohol dependence that merits further investigation.

Project Summary The incidence of opioid use disorders (OUDs) has increased to near-epidemic proportions. Clinical researchers have a clear responsibility to improve access to long-term treatment in order to avoid the pattern of relapse, recurrent detoxification admissions, or overdose characteristic of present treatment efforts. While agonist maintenance with methadone or buprenorphine represents an effective long-term treatment strategy, it may be unacceptable to many individuals; this may compromise treatment seeking or prevent the initiation of maintenance treatment following detoxification. Long-acting injectable naltrexone (XR-NTX) robustly blocks the effects of opioids for at least 4 weeks and is now indicated for relapse prevention following detoxification. XR-NTX therefore represents an effective alternative to agonist treatment, but it is significantly underutilized due to hurdles associated with rapidly and tolerably transitioning active users. Indeed, about half of individuals fail to initiate XR-NTX in existing naltrexone titration protocols. Our data suggest that the N-methyl-D-aspartate receptor antagonist ketamine may be feasibly integrated into a 3-day rapid non-opioid based naltrexone titration, with sub-anesthetic infusions exerting apparent effects on spontaneous and precipitated withdrawal as well as on retention. In the proposed investigation, we aim to evaluate whether two 90-minute sub-anesthetic ketamine infusions (1.41 mg/kg), compared to 2 infusions of the control midazolam (0.04 mg/kg), improve outcomes in opioid dependent individuals engaged in a rapid non-opioid based oral naltrexone titration, followed by XR-NTX maintenance. The primary outcome will be the proportion of participants to initiate XR-NTX. Secondary outcomes include abstinence rates, 3-month retention, and withdrawal severity. The investigators' extensive experience with sub-anesthetic ketamine infusions and with antagonist-based treatment of opioid dependence supports the feasibility of this novel protocol. If successful, this trial would represent a major advance in efforts to identify novel pharmacotherapies for OUD management, and for addressing a critical hurdle in XR-NTX utilization. Thus it may pave the way for research into analogous compounds, such as ketamine- like antidepressants currently in development. This may ultimately serve to broaden access to effective maintenance treatment options for active users, and to reposition detoxification as a stepping-stone to long-term treatment. These data may therefore advance treatment efforts for OUDs and increase access to a larger repertoire of first-line treatments.

Project Summary Alterations in glutamate neurotransmission are recognized as an important target of pharmacotherapy for cocaine use disorders (CUDs). Our preliminary investigations with ketamine, a glutamate modulator with potent prefrontal effects, suggest sub-anesthetic infusions may work to facilitate behavioral modification by addressing critical CUD- related vulnerabilities. Alongside being safely administered to active cocaine users, we have found that sub-anesthetic ketamine, 24 hours post-infusion, significantly increases motivation to stop cocaine use by 60%, decreases cue-induced craving by a similar magnitude, and reduces the choice for cocaine now vs. money later by 67% when compared to an active control. A pilot efficacy trial also indicates that a single infusion of ketamine facilitates mindfulness-based relapse prevention (MBRP) and promotes abstinence (53% ketamine vs. 11% midazolam). Expanding on these promising but preliminary findings, this trial aims to evaluate whether ketamine promotes abstinence by facilitating behavioral modification in a treatment model approximating a general clinical setting. We will evaluate the effect of up to two outpatient sub-anesthetic doses of ketamine (0.11 mg/kg over 2 minutes, followed by 0.60 mg/kg over 50 minutes) on CUDs in 110 non-depressed individuals engaged in motivation enhancement therapy followed by MBRP. We predict that, compared to the control midazolam, ketamine will significantly promote 3 weeks of end-of-study abstinence in this 7-week trial. Secondary aims pertain to the effects of ketamine on other drug use outcomes, such as reduction in number of cocaine use days; and the evaluation of behavioral and biological mediators of ketamine efficacy, such as serum brain-derived neurotrophic factor (BDNF) levels and measures of behavioral non-reactivity. If successful, this project stands to contribute significantly to the treatment of CUDs, for which there are no clearly effective pharmacotherapies at present, and has the potential to lead the field in new directions of combined medication-behavioral treatment development. Future studies might test other medications using the design introduced in this proposal, as well as focus on clarifying the mechanisms by which ketamine addresses CUDs.

Project Summary: Alterations in glutamate neurotransmission are recognized as an important target of pharmacotherapy for alcohol use disorder (AUD). Preliminary investigations with ketamine, a glutamate modulator with potent prefrontal effects, suggest sub-anesthetic infusions may work to facilitate behavioral modification by addressing critical vulnerabilities for a variety of substance use disorders, including AUD. Expanding on a preliminary study suggesting that ketamine reduces number of heavy drinking days (HDD) when combined with motivational enhancement therapy (MET), this 12-week trial powered to detect proportional differences consistent with our prior data (n=120) aims to evaluate whether ketamine promotes a reduction in HDDs relative to an active control (midazolam). We will randomize (1:1) 120 participants seeking treatment for AUD and demonstrating high baseline problem drinking to 2 infusions of ketamine or midazolam separated by 5 weeks (0.71 mg/kg ketamine or 0.025 m/kg midazolam over 52 min). Further, in order to more rigorously assess the impact of behavioral treatment on the efficacy of ketamine, we will employ a two by two factorial (2x2) design, with participants in each medication arm randomized (1:1) either to standard medication management, or to a manualized sequence of motivational enhancement therapy (MET) followed by mindfulness-based relapse prevention (MBRP). MBRP is expected to facilitate relapse prevention after individuals have reduced use or initiated abstinence during MET. We predict that, compared to the control midazolam, ketamine will significantly reduce the proportion of individuals with HDDs. An important secondary hypothesis is that those receiving ketamine and behavioral treatment will demonstrate significantly better outcomes than individuals receiving ketamine alone. Other aims pertain to the effects of ketamine on number of daily drinks, and number of drinking days; the impact of ketamine on time to first HDD or drop-out; and the evaluation of added effectiveness when ketamine is combined with MET/MBRP. If successful, this project stands to contribute significantly to the treatment of AUD, for which new pharmacotherapy strategies are needed. Future studies might test other medications using the design introduced here, as well as focus on clarifying the mechanisms by which ketamine addresses AUD. !