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RECRUITING
NCT06636227
PHASE1

Diclofenac Dose Response Study

Sponsor: University of Maryland, Baltimore

View on ClinicalTrials.gov

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. Investigators propose to conduct a human laboratory pilot study to test whether diclofenac can increase KYNA in individuals with AUD, and if so, which of 3 doses (50, 75, or 100 mg) most effectively increases KYNA. Individuals with AUD (n = 24) will complete four sessions where they receive diclofenac (50, 75, or 100 mg) or placebo. Investigators will examine increases in KYA levels and will also assess QUIN levels, alcohol craving, and negative mood.

Official title: Optimal Dosing, Tolerability, and Initial Efficacy of Diclofenac as a KMO Inhibitor in Individuals With Alcohol Use Disorder

Key Details

Gender

All

Age Range

21 Years - 65 Years

Study Type

INTERVENTIONAL

Enrollment

24

Start Date

2024-12-01

Completion Date

2026-08-31

Last Updated

2026-02-09

Healthy Volunteers

No

Interventions

DRUG

Diclofenac 100mg

Diclofenac 100mg

DRUG

Diclofenac 75mg

Diclofenac 75mg

DRUG

Diclofenac 50mg

Diclofenac 50mg

DRUG

Placebo control

Placebo control

Locations (1)

Maryland Psychiatric Research Center

Catonsville, Maryland, United States