Spironolactone for alcohol use disorder

The heart failure medicine has showed some promise in treating alcohol use disorder, through a different mechanism than existing treatments.

Alcohol intake is often intertwined with much of people’s social life – so the line between casual or occasional drinking, and unhealthy alcohol intake that causes social or health problems can at times be difficult for people to identify.¹ To reduce risk of alcohol-related disease or injury, Australian guidelines recommend healthy adults limit alcohol intake to no more than 10 standard drinks a week, and no more than four standard drinks on any one day.²

Though they may not fit the definition, people engaging in risky and/or binge drinking are at increased risk for alcohol use disorder – previously referred to as alcoholism. Alcohol use disorder is a chronic brain condition from which people can recover with appropriate management, but it cannot be cured.¹ Management centers around counselling and behavioural therapies.

Pharmacological therapy alone is relatively ineffective, and may be used to help improve the chances of maintaining abstinence depending on the person’s circumstances (e.g. motivation and goals, adherence to pharmacological treatment), and concurrent medicines (e.g. use of opioids, and co-existing medical conditions such as renal or hepatic impairment).^1,3,4

Acamprosate and naltrexone are used to reduce alcohol cravings. Acamprosate is thought to reduce neuronal hyperexcitability characteristics of alcohol withdrawal, while naltrexone is an opioid antagonist, and thought to reduce the pleasurable effects of alcohol by blocking the effects of endogenous opioids released after alcohol intake.^3,4 Disulfiram deters alcohol intake by irreversibly inhibiting aldehyde dehydrogenase, which prevents the usual metabolism of alcohol. This causes raised acetaldehyde levels, leading to a range of unpleasant and potentially serious effects when alcohol is consumed eg. flushing, sweating, nausea, vomiting, palpitations, headache, dyspnoea, chest pain, hypotension, cardiovascular collapse, seizures or arrhythmias.^3,4

Given the significant burden of disease associated with alcohol use disorder, increasing treatment options in this space are warranted. Research has found promising drug targets in the neuroendocrine systems – particularly aldosterone and its mineralocorticoid receptor which regulates fluid and electrolyte homeostasis.⁵ Mineralocorticoid receptors are also found in the parts of the brain involved in alcohol use disorder, and are thought to play a role in alcohol seeking and intake – with aldosterone (the main mineralocorticoid hormone) levels positively correlated with self-reported alcohol craving and anxiety.⁵ Accordingly, this suggests medicines that block mineralocorticoid receptors may be a promising approach. One such medicine is spironolactone, an aldosterone antagonist, now commonly used in heart failure.⁶

Previous work with spironolactone has found promising but inconsistent results.⁵ Therefore, recent work looked to further explore the potential use of spironolactone, including its impacts on locomotion and motor coordination, and alcohol pharmacokinetics using rodents; alongside a pharmacoepidemiologic study using electronic health records.⁵ In the mice and rats treated with spironolactone, there was a dose-dependent reduction in the intake of alcohol, and spironolactone was not observed to affect locomotion and motor coordination, nor impact upon food and water intake.

The pharmacoepidemiologic studies looking at spironolactone use for at least 60 days (n = 10,726) found a reduction in self-reported alcohol consumption as measured using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), compared to a matched cohort who were not exposed to spironolactone (n = 34,461) (Diff-in-Diff: −0.17 points, 95% confidence interval (CI): −0.09, −0.25; p<0.0001). The largest effects were seen in the group with the highest alcohol use at baseline (AUDIT-C scores of ≥8; decreased 0.47 points (95% CI: −0.29, −0.66; p<0.0001); and similarly in individuals taking ≥50 mg spironolactone per day (Diff-in-Diff: −0.69 points, 95% CI: −0.50, −0.89; p<0.0001).

These findings throw more weight behind the use of spironolactone and support the need for more work to better understand the role of the mineralocorticoid receptors, and the mechanism by which spironolactone works in alcohol use disorder. Studies with larger sample sizes, and due consideration with concurrent conditions that may impact on alcohol use disorder and its management (e.g. depression, and other associated aspects such as craving and relapse, reward and stress function), will be useful for better understanding of the clinical utility of spironolactone in this space.