Researchers at the National Institute on Drug Abuse (NIDA), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and Yale University School of Medicine investigated the impact of spironolactone on AUD.
Initially, they studied rodents and found that spironolactone reduced binge drinking in mice and reduced self-administration of alcohol in rats without adversely affecting food or water intake or causing motor or coordination problems.
They also analyzed electronic health records (EHRs) of patients drawn from the United States Veterans Affairs healthcare system to explore potential changes in alcohol use after spironolactone treatment was initiated for other conditions and found a significant link between spironolactone treatment and reduction in self-reported alcohol consumption, with the largest effects observed among those who reported hazardous/heavy episodic alcohol use prior to starting spironolactone treatment.
"Combining findings across three species and different types of research studies, and then seeing similarities in these data, gives us confidence that we are onto something potentially important scientifically and clinically," senior co-author Lorenzo Leggio, MD, PhD, senior investigator in the Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN) Section, a joint NIDA and NIAAA laboratory, said in a news release.
The study was published online September 20 in Molecular Psychiatry.
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There is a "critical need to increase the armamentarium of pharmacotherapies to treat individuals with AUD," the authors note, adding that neuroendocrine systems involved in alcohol craving and drinking "offer promising pharmacologic targets in this regard."
"Both our team and others have observed that patients with AUD often present with changes in peripheral hormones, including aldosterone, which plays a key role in regulating blood pressure and electrolytes," Leggio told Medscape Medical News.
Spironolactone is a nonselective mineralocorticoid receptor (MT) antagonist. In studies in animal models, investigators said they found "an inverse correlation between alcohol drinking and the expression of the MR in the amygdala, a key brain region in the development and maintenance of AUD and addiction in general."
Taken together, this led them to hypothesize that blocking the MR, which is the mechanism of action of spironolactone, "could be a novel pharmacotherapeutic approach for AUD," he said.
Previous research by the same group of researchers suggested spironolactone "may be a potential new medication to treat patients with AUD." The present study expanded on those findings and consisted of a three-part investigation.
In the current study, the investigators tested different dosages of spironolactone on binge-like alcohol consumption in male and female mice and assessed food and water intake, blood alcohol levels, motor coordination, and spontaneous locomotion.
They then tested the effects of different dosages of spironolactone injections on operant alcohol self-administration in alcohol-dependent and nondependent male and female rats, also testing blood alcohol levels and motor coordination.
Finally, they analyzed health records of veterans to examine the association between at least 60 continuous days of spironolactone treatment and self-reported alcohol consumption (measured by the Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]).
Each of the spironolactone-exposed patients was matched using propensity scores with up to five unexposed patients who had reported alcohol consumption in the 2 years prior to the index date.
The final analysis included a matched cohort of 10,726 spironolactone-exposed individuals who were matched to 34,461 unexposed individuals.
Spironolactone reduced alcohol intake in mice drinking a sweetened alcohol solution; a 2-way ANOVA revealed a main effect of dose (F 4,52 = 9.09, P < .0001) and sex, with female mice drinking more alcohol, compared to male mice (F 1,13 = 6.05, P = .02).
Post hoc comparisons showed that spironolactone at doses of 50, 100, and 200 mg/kg significantly reduced alcohol intake (Ps = .007, .002, and .0001, respectively).
In mice drinking an unsweetened alcohol solution, the 2-way repeated measures ANOVA similarly found a main effect of dose (F 4,52 = 5.77, P = .0006), but not of sex (F 1,13 = 1.41, P = .25).
Spironolactone had no effect on the mice's intake of a sweet solution without alcohol and had no impact on the consumption of food and water or on locomotion and coordination.
In rats, a 2-way ANOVA revealed a significant spironolactone effect of dose (F 3,66 = 43.95, P < .001), with a post hoc test indicating that spironolactone at 25, 50, and 75 mg/kg reduced alcohol self-administration in alcohol-dependent and nondependent rats (all Ps = .0001).
In humans, among the exposed individuals in the matched cohort, 25%, 57%, and 18% received daily doses of spironolactone of < 25 mg/day, 25-49 mg/day, and ≥ 50 mg/day, respectively, with a median follow-up time of 542 (IQR 337 – 730) days.
The AUDIT-C scores decreased during the study period in both treatment groups, with a larger decrease in average AUDIT-C scores among the exposed vs unexposed individuals.
|Category of Patient||Change in AUDIT-C Score|
|Exposed||3.07 (SD .02) to 2.16 (SD .02)|
|Unexposed||2.96 (SD .01) to 2.22 (SD .01)|
"Therefore, on average, AUDIT-C scores decreased 0.17 points more among spironolactone-exposed individuals, compared to the unexposed individuals," the authors summarize (P < .0001).
When the analysis was stratified by baseline AUDIT-C score, the average scores decreased more dramatically among those with the highest severity of alcohol use at baseline.
|AUDIT-C Baseline Score||Decrease in AUDIT-C Score (95% CI)||P Value|
|1-3||0.07 points (-0.01, to -0.14)||.02|
|4-7||0.13 points (-0.02 to -0.24)||.02|
|≥ 8||0.47 points (-0.29 to -0.66)||< .0001|
"These are very exciting times because, thanks to the progress in the addiction biomedical research field, we are increasing our understanding of the mechanisms how some people develop AUD; hence we can use this knowledge to identify new targets." The current study "is an example of these ongoing efforts," said Leggio.
"It is important to note that [these results] are important but preliminary." At this juncture, "it would be too premature to think about prescribing spironolactone to treat AUD," he added.
Commenting for Medscape Medical News, Joyce Besheer, PhD, professor, Department of Psychiatry and Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, called the study an "elegant demonstration of translational science."
"While clinical trials will be needed to determine whether this medication is effective at reducing drinking in patients with AUD, these findings are exciting as they suggest that spironolactone may be a promising compound and new treatment options for AUD are much needed," said Besheer, who was not involved with the current study.
Leggio agreed. "We now need prospective, placebo-controlled studies to assess the potential safety and efficacy of spironolactone in people with AUD," he said.
This work was supported by the National Institutes of Health (NIH) and the NIAAA. Leggio, study co-authors, and Besheer declare no relevant financial relationships.
Mol Psychiatry. Published online September 20, 2022. Abstract
Batya Swift Yasgur MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).
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