Spironolactone in Alcohol Use Disorder (SAUD)

Study Description:

This study will examine pharmacokinetic (PK) and pharmacodynamic (PD) parameters of spironolactone and alcohol, during concomitant oral administration (0, 100, 200, 400 mg/day spironolactone PO), and test the safety and tolerability of spironolactone, co-administered with alcohol, in individuals with alcohol use disorder (AUD).

Objectives:

Our objective is to assess PK and PD parameters during spironolactone-alcohol co-administration, in individuals with AUD. We will also test the safety, tolerability, and potential drug-alcohol interaction.

Endpoints:

Primary Endpoint:

Spironolactone and alcohol PK during concomitant administration (0, 100, 200, and 400 mg/day spironolactone).

Secondary Endpoints:

• Assessment of subjective and cognitive effects of acute alcohol administration during concomitant spironolactone treatment (0, 100, 200, and 400 mg/day).
• Number and severity of adverse events (AEs) experienced, compared between placebo (0 mg/day) and all three spironolactone doses (100, 200, 400 mg/day).
• PK characteristic of spironolactone active metabolites, canrenone, 7-alpha-thiomethylspirolactone (TMS) and 6beta-hydroxy-7alpha-thiomethylspirolactone (HTMS), before and after administration of alcohol.

• INCLUSION CRITERIA:

In order to be eligible to enroll in this study, an individual must meet all of the following criteria:

• At least 21 years old
• Alcohol Use Disorder (minimum 2 symptoms on a validated diagnostic tool, e.g., the Mini- International Neuropsychiatric Interview (MINI) or the Structured Clinical Interview for DSM Disorders (SCID))
• At least four days with >= 4 drinks for females or >= 5 drinks for males during the 28-day period prior to screening, according to alcohol TimeLine Follow Back (TLFB)
• Most recent Clinical Institute Withdrawal Assessment for Alcohol - revised (CIWA-Ar) score is < 10
• Able to speak, read, write, and understand English as demonstrated by their ability to understand and sign the consent for the NIDA screening protocol.
• Female participants must be postmenopausal for at least one year, surgically sterile, or practicing a highly effective method of birth control before entry and throughout the study and must have negative pregnancy tests at each stage. Examples of highly effective methods of birth control include abstinence, hormonal contraceptives (e.g., certain birth control pills, contraceptive patch, vaginal ring, or implants), intrauterine device (IUD), tubal ligation, or vasectomy.

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• Most recent blood tests: potassium > 5.2 mmol/L; creatinine >= 2 mg/dL; eGFR < 60 mL/min/1.73 m^2, hemoglobin A1c (HbA1c) > 6.5 %
• Clinically significant and/or symptomatic hyponatremia, hypomagnesemia, hypocalcemia, and hyperuricemia based on Medical Advisory Investigators (MAI) or designee judgment.
• Known history of clinically significant orthostatic hypotension
• Known history of hypoaldosteronism, hyperaldosteronism, Addison s disease
• Diagnosis of NYHA class III-IV heart failure, or unstable cardiovascular conditions (e.g., arrhythmias, clinically significant ECG abnormalities)
• Current use of any diuretic, angiotensin receptor blocker (ARB), angiotensin converting enzyme inhibitor (ACEI), potassium supplementation, potassium containing salt substitute, heparin and low molecular weight heparin (LMWH), trimethoprim, lithium, digoxin, cholestyramine
• Current use of MR antagonists
• Current use of FDA-approved pharmacotherapy for AUD, or seeking treatment for AUD
• Known history of prior hypersensitivity reaction to spironolactone or other MR antagonists, or any of the product components
• Known history of alcohol withdrawal seizure and delirium tremens.
• Physical and/or mental health conditions that are clinically unstable, as determined by the study clinicians, including (but not limited to) major depressive disorder or generalized anxiety disorder unstable during the past three months or other psychiatric conditions (e.g., schizophrenia, bipolar disorder) unstable during the past twelve months prior to screening.
• Pregnancy, intention to become pregnant, or breastfeeding.
• Any other reason or clinical condition that the Investigators judge would interfere with study participation and/or be unsafe for a participant.