Optimal Dosing, Tolerability, and Initial Efficacy of Diclofenac as a KMO Inhibitor in Individuals With Alcohol Use Disorder
University of Maryland, Baltimore
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.
Description
Alcohol use disorder (AUD) is a chronic condition for which current pharmacological treatments are only modestly effective \[1,2\]. 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 for AUD \[3,4\]. To that end, 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…
Eligibility
- Age range
- 21–65 years
- Sex
- All
- Healthy volunteers
- No
Inclusion Criteria: * Age 21-65 * Meet DSM-5 diagnostic criteria for current AUD of any severity (Mild, Moderate, or Severe) * In the 30-day period before enrollment, consume \> 14 and \> 7 standard drinks per week for men and women, respectively * In the 30-day period before enrollment, engage in heavy drinking (5 or more drinks for men, 4 or more drinks for women) ≥ 5 times per month Exclusion Criteria: * Currently in treatment, a history of treatment within the 30 days before enrollment, or currently seeking immediate treatment for AUD * Current (last 12 months) DSM-5 diagnosis of SUD fo…
Interventions
- DrugDiclofenac 100mg
Diclofenac 100mg
- DrugDiclofenac 75mg
Diclofenac 75mg
- DrugDiclofenac 50mg
Diclofenac 50mg
- DrugPlacebo control
Placebo control
Location
- Maryland Psychiatric Research CenterCatonsville, Maryland