Spironolactone for Alcoholism

Overseen By NIDA IRP Screening Team

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute on Drug Abuse (NIDA)

Must not be taking: Diuretics, ARBs, ACEIs, others

Disqualifiers: Heart failure, Unstable cardiovascular, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 8 weeks

20 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including diuretics, angiotensin receptor blockers, ACE inhibitors, potassium supplements, and some others. If you are on any of these, you would need to stop them to participate in the study.

What evidence supports the effectiveness of the drug spironolactone for reducing alcohol consumption?

Research shows that spironolactone, a drug that blocks certain hormone receptors, can reduce alcohol consumption in both animals and humans. In studies, people who took spironolactone reported drinking less alcohol compared to those who did not take the drug, especially among those who drank heavily at the start. ^{1 2 3 4 5}

Is spironolactone safe for humans?

Spironolactone has been studied in both animals and humans, showing it can reduce alcohol consumption without affecting food or water intake, motor coordination, or blood alcohol levels. However, more research is needed to confirm its safety specifically for treating alcohol use disorder. ^{1 2 4 6 7}

How is the drug Spironolactone unique in treating alcoholism?

Spironolactone is unique in treating alcoholism because it is primarily known as a medication for conditions like heart failure and high blood pressure, and its use for alcoholism is novel, potentially offering a different mechanism of action compared to traditional treatments for alcohol dependence. ^{8 9 10 11 12}

What is the purpose of this trial?

Background: Alcohol use disorder (AUD) affects about 29.5 million people in the United States. Only 3 medicines have been approved by Food and Drug Administration to treat AUD. Researchers want to find better treatments for AUD. Animal studies found that a medicine called spironolactone, may decrease the amount of alcohol the animals drank. Spironolactone is approved to treat high blood pressure, or heart failure in people. It is not approved to treat AUD. Objective: To test a medicine (spironolactone) in people who sometimes drink excessive alcohol in order to understand how the body breaks down spironolactone and if there are any side effects in people who drink alcohol while taking this medicine. Eligibility: People aged 21 and older with AUD. Design: Participants will have 4 separate 7-day stays at a clinic in Baltimore over 2 months. Spironolactone is a capsule you swallow. Participants will take a capsule twice a day for 5 days during each clinic stay. During 1 of their 4 stays, they will take a placebo instead of the medicine. The placebo capsule looks just like the spironolactone capsule but contains no medicine. Participants will not know when they are taking the medicine or the placebo. Participants will not drink alcohol until day 6 of each clinic stay. Then they will be asked to drink alcohol in a bar-like area in the clinic. Their breath and blood alcohol levels and their well-being will be measured. Participants will undergo other tests in the clinic: A DEXA (dual energy X-ray absorptiometry) scan uses X-rays to measure bone density and muscle mass. Participants will lie on an open-top, padded table, then a small arm will scan the full length of their body. The radiation participants will get in this study is about the same as from one regular x-ray. Blood tests. Participants may feel some discomfort at the site of needle entry. Electrocardiogram. This test records the heart activity. Sensors are attached to the skin with stickers and removed after a few minutes. Urine tests. All urine will be collected over a 3-day period during each stay. We will measure the amount of urine, and different hormones and salts in the urine. Questionnaires and tasks. Participants will answer questions about their alcohol use. They will perform tasks to test mood, craving, mental and physical coordination, and how much they feel an effect from alcohol after drinking.

Research Team

Lorenzo Leggio, M.D.

Principal Investigator

National Institute on Drug Abuse (NIDA)

Eligibility Criteria

Adults aged 21+ with Alcohol Use Disorder who drink heavily are eligible for this trial. They must be in good general health, not pregnant or breastfeeding, and using effective birth control if applicable. Participants cannot have certain medical conditions like heart failure or unstable mental health issues, nor can they be on specific medications that could interfere with the study.

Inclusion Criteria

Self-reported drinking according to alcohol TimeLine Follow Back

Most recent Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA-Ar) score is < 10

Alcohol Use Disorder (minimum 2 symptoms on a validated diagnostic tool)

Exclusion Criteria

I am currently taking medications such as water pills or blood pressure drugs.

Pregnancy, intention to become pregnant, or breastfeeding

Current use of certain pharmacotherapy for AUD, or seeking treatment for AUD

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo 4 separate 7-day stays at a clinic, taking spironolactone or placebo, with alcohol administration on day 6.

8 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Placebo
• Spironolactone

Trial Overview The trial is testing Spironolactone, a drug normally used for blood pressure and heart failure, to see if it helps people with AUD drink less alcohol. Participants will stay at a clinic multiple times taking either Spironolactone or a placebo without knowing which one they're getting. They'll also undergo tests and answer questions about their alcohol use.

Participant Groups

Group I: Placebo 4th visit Experimental Treatment 2 Interventions

Stage1: 2x50 mg/day spironolactoneStage 2: 2x100 mg/day spironolactonestage 3: 2x200 mg/day spironolactonestage 4: Placebo

Group II: Placebo 3rd visit Experimental Treatment 2 Interventions

stage1: 2x50 mg/day spironolactonestage 2: 2x100 mg/day spironolactonestage 3: Placebostage4: 2x200 mg/day spironolactone

Group III: Placebo 2nd visit Experimental Treatment 2 Interventions

stage 1: 2x50 mg/day spironolactonestage 2: Placebostage3: 2x100 mg/day spironolactonestage 4: 2x200 mg/day spironolactone

Group IV: Placebo 1st visit Experimental Treatment 2 Interventions

stage 1: Placebostage 2: 2x50 mg/day spironolactonestage 3: 2x100 mg/day spironolactonestage4: 2x200 mg/day spironolactone

Spironolactone is already approved in United States, European Union for the following indications:

Approved in United States as Aldactone for:

• High blood pressure
• Heart failure
• Liver scarring
• Kidney disease
• Low blood potassium
• Early puberty in boys
• Acne
• Excessive hair growth in women

Approved in European Union as Aldactone for:

• Fluid retention due to heart failure
• Liver scarring
• Kidney disease
• High blood pressure
• Low blood potassium

Who Is Running the Clinical Trial?

National Institute on Drug Abuse (NIDA)

Lead Sponsor

Trials

2,658

Recruited

3,409,000+

Findings from Research

In both mouse and rat models, spironolactone significantly reduced alcohol consumption without affecting the intake of non-alcoholic sweet solutions or other behaviors, indicating its specific action on alcohol use.

In a human study, individuals taking spironolactone for at least 60 days reported a greater reduction in alcohol consumption, especially among those with higher baseline alcohol use, suggesting its potential as a novel treatment for alcohol use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies. Farokhnia, M., Rentsch, CT., Chuong, V., et al.[2023]

A study involving 523 adults treated with spironolactone for at least 90 days showed a significant reduction in weekly alcohol consumption, with treated patients reducing their intake by 3.50 drinks compared to 2.74 drinks in untreated patients, indicating spironolactone may be effective for alcohol use disorder (AUD).

Among heavy drinkers (those consuming more than 7 drinks per week), those treated with spironolactone experienced an even greater reduction of 4.18 drinks per week, suggesting that higher doses of spironolactone could lead to more significant improvements in alcohol consumption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of spironolactone dispensation in reducing weekly alcohol use: a retrospective high-dimensional propensity score-matched cohort study. Palzes, VA., Farokhnia, M., Kline-Simon, AH., et al.[2022]

Acamprosate and naltrexone are effective pharmacotherapies for severe alcohol dependence, significantly reducing alcohol intake and increasing the chances of prolonged abstinence, supported by Level I evidence from multiple studies.

Acamprosate has shown sustained benefits over time and is well tolerated without known interactions with alcohol, while naltrexone can block opioid analgesics and requires adjunctive psychosocial treatment for optimal results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New pharmacotherapies for alcohol dependence. Graham, R., Wodak, AD., Whelan, G.[2020]

The study found that blocking the mineralocorticoid receptor (MR) with spironolactone significantly reduced alcohol self-administration in both male and female Long-Evans rats, indicating that MR signaling plays a role in alcohol consumption behaviors.

In female rats, spironolactone not only decreased alcohol intake but also reduced the persistence of seeking alcohol when it was no longer available, suggesting a stronger impact of MR antagonism on alcohol-related behaviors in females compared to males.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The mineralocorticoid receptor antagonist spironolactone reduces alcohol self-administration in female and male rats. Makhijani, VH., Van Voorhies, K., Besheer, J.[2019]

This study is the first to identify genetic variants that may predict treatment outcomes for alcohol use disorder (AUD) based on data from 1,083 participants, revealing that SNPs in the BRE gene are linked to relapse to heavy drinking.

Specific genetic markers were found to be associated with the effectiveness of naltrexone and acamprosate, suggesting that genetic testing could help tailor AUD treatments to individual patients for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic contributions to alcohol use disorder treatment outcomes: a genome-wide pharmacogenomics study. Biernacka, JM., Coombes, BJ., Batzler, A., et al.[2022]

The glucocorticoid receptor antagonist mifepristone significantly reduced ethanol intake in rats under limited access conditions, with a maximum suppression of 40% at the highest dose (20 mg/kg).

In contrast, the mineralocorticoid receptor antagonist spironolactone did not affect ethanol consumption, highlighting the specific role of glucocorticoid receptors in regulating voluntary alcohol intake.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The glucocorticoid receptor antagonist mifepristone reduces ethanol intake in rats under limited access conditions. Koenig, HN., Olive, MF.[2013]

Allopregnanolone, a neuroactive steroid, shows promise as a therapeutic option for treating symptoms of alcohol use disorders (AUDs), supported by both basic science and clinical evidence.

The review highlights the importance of understanding how allopregnanolone and its precursor, pregnenolone, may help regulate stress and immune responses related to AUDs, while also addressing potential risks and management strategies for therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies. Morrow, AL., Boero, G., Porcu, P.[2021]

Intravitreal injection of 4 mg triamcinolone acetonide significantly improved visual acuity in diabetic patients with massive macular hard exudates, with improvements noted at multiple follow-up points over an average of 8.25 months.

The treatment led to complete resolution of hard exudates in 50% of cases and decreased fluorescein leakage, although 25% of patients experienced elevated intraocular pressure, which was manageable with topical medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary intravitreal triamcinolone acetonide for diabetic massive macular hard exudates. Khairallah, M., Zeghidi, H., Ladjimi, A., et al.[2022]

Intravitreal triamcinolone acetonide (TA) injections significantly improved vision in 56% of treated eyes after 2 years, compared to only 26% in the placebo group, indicating its efficacy in managing diabetic macular edema.

While TA treatment led to a higher incidence of increased intraocular pressure and cataract progression, these side effects were manageable, suggesting that the benefits of improved vision may outweigh the risks for patients with refractory diabetic macular edema.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial. Gillies, MC., Sutter, FK., Simpson, JM., et al.[2022]

In a study of 16 patients with persistent serous choroidal detachment (SCD) after glaucoma surgery, a subtenon injection of triamcinolone acetonide (TA) led to complete resolution of SCD within 1 to 4 weeks.

The treatment was found to be safe, with no recurrence of SCD observed in any patient during the 6-month follow-up period, indicating its efficacy as a therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subtenon triamcinolone injection to treat serous choroidal detachment after glaucoma surgery: A case series. Nilforushan, N., Abolfathzadeh, N., Najafzadeh, F., et al.[2023]

In a study of 22 patients with birdshot chorioretinopathy, implantation of a fluocinolone acetonide drug delivery device led to significant improvements in median visual acuity and complete resolution of vitreous haze in all eyes by 12 months.

While the treatment effectively controlled inflammation and reduced the need for systemic immunosuppressive therapy, it was associated with a high incidence of cataract progression and intraocular hypertension or glaucoma, necessitating additional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of birdshot chorioretinopathy treated with an intravitreal sustained-release fluocinolone acetonide-containing device. Rush, RB., Goldstein, DA., Callanan, DG., et al.[2022]

Benzyl alcohol (BA), a preservative in triamcinolone acetonide (TA) suspensions, was found to be toxic to retinal pigment epithelial (RPE) cells in a dose- and time-dependent manner, with concentrations as low as 0.225 mg/mL causing significant damage after just 2 hours.

The study suggests that the use of commercial TA solutions containing BA for intravitreal injections can harm RPE cells, highlighting the need for preservative-free formulations to protect retinal health, especially during procedures like macular hole surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro benzyl alcohol cytotoxicity: implications for intravitreal use of triamcinolone acetonide. Chang, YS., Wu, CL., Tseng, SH., et al.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Effectiveness of spironolactone dispensation in reducing weekly alcohol use: a retrospective high-dimensional propensity score-matched cohort study. [2022]

3. Australia pubmed.ncbi.nlm.nih.gov

New pharmacotherapies for alcohol dependence. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

The mineralocorticoid receptor antagonist spironolactone reduces alcohol self-administration in female and male rats. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Genetic contributions to alcohol use disorder treatment outcomes: a genome-wide pharmacogenomics study. [2022]

6. England pubmed.ncbi.nlm.nih.gov

The glucocorticoid receptor antagonist mifepristone reduces ethanol intake in rats under limited access conditions. [2013]

7. England pubmed.ncbi.nlm.nih.gov

A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Primary intravitreal triamcinolone acetonide for diabetic massive macular hard exudates. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Subtenon triamcinolone injection to treat serous choroidal detachment after glaucoma surgery: A case series. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Outcomes of birdshot chorioretinopathy treated with an intravitreal sustained-release fluocinolone acetonide-containing device. [2022]

12. England pubmed.ncbi.nlm.nih.gov

In vitro benzyl alcohol cytotoxicity: implications for intravitreal use of triamcinolone acetonide. [2013]