# The role of brief potent glutamatergic modulation in addressing problem drinking: a randomized, controlled trial

> **NIH NIH R01** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2021 · $708,284

## Abstract

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.
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## Key facts

- **NIH application ID:** 10241426
- **Project number:** 5R01AA027509-03
- **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
- **Principal Investigator:** Elias Dakwar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $708,284
- **Award type:** 5
- **Project period:** 2019-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241426

## Citation

> US National Institutes of Health, RePORTER application 10241426, The role of brief potent glutamatergic modulation in addressing problem drinking: a randomized, controlled trial (5R01AA027509-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241426. Licensed CC0.

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