# A Novel Drug Combination for Alcohol-Use Disorders: A Human Laboratory Study

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $622,574

## Abstract

ABSTRACT/SUMMARY
 Alcohol-use disorder (AUD) is an unrelenting public-health concern. AUD is characterized by perturbations
of central monoamine (i.e., dopamine [DA], serotonin [5HT], and norepinephrine [NE]) systems making them a
logical target for medications development. Individual monoamine-uptake inhibitors were moderately effective
in a majority of the trials in which they were tested for managing AUD. Continuing to target monoamine-uptake
inhibition for AUD is warranted, but novel strategies are needed to identify a highly efficacious
pharmacotherapy. We propose to demonstrate the initial efficacy of an innovative pharmacological strategy for
managing AUD: Triple Monoamine-Uptake Inhibition. Triple monoamine-uptake inhibitors are under
development, but are not yet available commercially for human use. Combining available medications,
however, makes it possible to achieve triple monoamine-uptake inhibition. Duloxetine (DUL), an
antidepressant, has high affinity for the 5HT (ki = 0.8 nM) and NE (ki = 7.5 nM) transporters, but lower affinity
for the DA transporter (ki = 240 nM). Methylphenidate (MTH) has high affinity for the DA transporter (ki = 34
nM), but lower affinity for the 5HT (ki = >10,000 nM) and NE (ki = 339 nM) transporters. We will combine DUL
and MTH to functionally produce a triple monoamine-uptake inhibitor. A mixed-model study will be conducted
in which separate cohorts of non-treatment-seeking AUD participants will be randomized to different
maintenance doses of delayed-release DUL (i.e., DUL dose is a between-subject factor). Participants (N=16)
in each DUL cohort will be maintained concurrently on increasing doses of long-acting MTH (i.e., MTH dose is
a within-subject factor). Alcohol (ALC) self-administration will be determined after participants in each DUL
cohort are maintained for 6 days on each MTH dose. A reverse-engineered ALC self-administration (ALC SA)
procedure with good predictive validity for clinical efficacy will be used to demonstrate the initial efficacy of
DUL-MTH combinations. ALC craving will also be assessed. We hypothesize DUL-MTH combinations will
produce an additive or supra-additive reduction in ALC SA relative to the constituent drugs alone. Innovations
include: 1) testing a novel pharmacological strategy, triple monoamine-uptake inhibition, for AUD; 2) testing a
combination of marketed drugs as opposed to waiting for compounds under development to be available for
testing in humans, thereby impacting clinical research and practice more quickly; 3) the use of once daily
dosing formulations of the constituent compounds which will improve compliance when advanced to clinical
trials or practice; 4) the use of a sophisticated ALC SA procedure; 5) testing multiple doses of DUL and MTH
alone and in combination to identify the most effective, safe and tolerable dose combination which will enhance
the probability of success when advanced to a clinical trial or practice; and 6) providing the impetus for th...

## Key facts

- **NIH application ID:** 9970160
- **Project number:** 5R01AA026255-03
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** CRAIG R RUSH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $622,574
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970160

## Citation

> US National Institutes of Health, RePORTER application 9970160, A Novel Drug Combination for Alcohol-Use Disorders: A Human Laboratory Study (5R01AA026255-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9970160. Licensed CC0.

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