# Proof of concept: diclofenac as a KMO inhibitor in AUD

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $223,531

## Abstract

Summary
 The development of efficacious medications for AUD remains a high research priority with current emphases
on identifying novel molecular targets and efficiently screening new compounds. Pharmacological modulation of the
kynurenine pathway (KP) represents a promising novel target for AUD. The KP is a complex enzymatic cascade with
each step producing biologically active metabolites that are critically involved in diverse physiological and pathological
processes. Chronic alcohol exposure produces dysregulation of the KP, particularly as evidenced by decreased levels
of the neuroprotective metabolite kynurenic acid (KYNA) and increased levels of the neurotoxic metabolite quinolinic
acid (QUIN). This metabolic shift is associated with various alcohol-related pathologies in animals and humans. Thus,
a medication that targets the KP to restore KYNA and attenuate QUIN levels may be an effective treatment for AUD.
The enzyme kynurenine 3-monooxygenase (KMO) is a major gatekeeper of the KP and resultant KYNA levels. KMO
inhibition shifts the KP towards KYNA production in brain and away from QUIN production. Critically, KMO inhibition in
rodents, through its increase in brain KYNA levels, decreases alcohol self-administration, preference, cue-reactivity,
and relapse behaviors. However, KMO-inhibitors have not been tested in humans because of presumed lack of
availability. Diclofenac is an FDA-approved Non-Steroidal Anti-Inflammatory Drug that was recently discovered to
inhibit KMO activity. Consistent with KMO inhibition, diclofenac increases KYNA levels in the brain and periphery of
rodents. However, it remains unknown whether diclofenac increases KYNA levels and affects alcohol-related
behaviors in humans at approved, safe dosages. In a Phase Ia/b proof of concept study, we will test the
pharmacological mechanism, optimal dosing, tolerability, and initial efficacy of diclofenac as a potential novel
treatment for AUD. We will conduct a randomized, double-blind, dose-escalating, placebo-controlled, cross-over study
in which individuals with AUD (n=24) complete four sessions where they receive diclofenac (25 mg, 50 mg, or 75 mg)
or placebo. Our primary aim is to identify the dose by which diclofenac, vs. placebo, produces changes to the KP
indicative of KMO inhibition (e.g., increasing KYNA levels). We will also assess whether diclofenac, vs. placebo,
decreases tonic alcohol craving and negative mood, attenuates alcohol cue-reactivity, and improves cognitive
function. Findings will inform subsequent studies testing diclofenac for AUD as well as other disorders for which KMO
inhibition has been identified as a pharmacological target of interest.

## Key facts

- **NIH application ID:** 10951718
- **Project number:** 1R21AA031776-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Daniel Roche
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $223,531
- **Award type:** 1
- **Project period:** 2024-09-20 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10951718

## Citation

> US National Institutes of Health, RePORTER application 10951718, Proof of concept: diclofenac as a KMO inhibitor in AUD (1R21AA031776-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10951718. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*