Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Molecular Psychiatry volume 27, pages 4642–4652 (2022)Cite this article

Subjects

Abstract

Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a sweet solution without alcohol, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity score-matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Spironolactone decreased binge-like alcohol drinking in mice.
Fig. 2: Spironolactone did not affect motor coordination or spontaneous locomotion in mice.
Fig. 3: Spironolactone decreased operant alcohol self-administration in alcohol-dependent (DEP) and nondependent (NON) rats.
Fig. 4: Difference-in-difference estimates and 95% confidence intervals of self-reported changes in Alcohol Use Disorders Identification Test-Consumption-C (AUDIT-C) scores associated with spironolactone exposure, overall, by baseline AUDIT-C score, and by average daily dose of spironolactone.

Similar content being viewed by others

References

  1. Heilig M, MacKillop J, Martinez D, Rehm J, Leggio L, Vanderschuren L. Addiction as a brain disease revised: why it still matters, and the need for consilience. Neuropsychopharmacology 2021;46:1715–1723.

    PubMed  PubMed Central  Google Scholar 

  2. Witkiewitz K, Litten RZ, Leggio L. Advances in the science and treatment of alcohol use disorder. Sci Adv. 2019;5:eaax4043.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Addolorato G, Leggio L, Hillemacher T, Kraus T, Jerlhag E, Bleich S. Hormones and drinking behaviour: new findings on ghrelin, insulin, leptin and volume-regulating hormones. An ESBRA Symposium report. Drug Alcohol Rev. 2009;28:160–165.

    PubMed  Google Scholar 

  4. Kenna GA, Swift RM, Hillemacher T, Leggio L. The relationship of appetitive, reproductive and posterior pituitary hormones to alcoholism and craving in humans. Neuropsychol Rev. 2012;22:211–228.

    PubMed  PubMed Central  Google Scholar 

  5. Funder JW. Mineralocorticoid receptors: distribution and activation. Heart Fail Rev. 2005;10:15–22.

    CAS  PubMed  Google Scholar 

  6. Molinari AM, Machado-Rada MY, Mazaira GI, Erlejman AG, Galigniana MD. Molecular basis of mineralocorticoid receptor action in the nervous system. CNS Neurol Disord Drug Targets. 2013;12:1163–1174.

    CAS  PubMed  Google Scholar 

  7. Kellner M, Wiedemann K. Mineralocorticoid receptors in brain, in health and disease: possibilities for new pharmacotherapy. Eur J Pharmacol. 2008;583:372–378.

    CAS  PubMed  Google Scholar 

  8. Reul JM, Gesing A, Droste S, Stec IS, Weber A, Bachmann C, et al. The brain mineralocorticoid receptor: greedy for ligand, mysterious in function. Eur J Pharmacol. 2000;405:235–249.

    CAS  PubMed  Google Scholar 

  9. Wingenfeld K, Otte C. Mineralocorticoid receptor function and cognition in health and disease. Psychoneuroendocrinology 2019;105:25–35.

    CAS  PubMed  Google Scholar 

  10. de Kloet ER, Rots NY, van den Berg DT, Oitzl MS. Brain mineralocorticoid receptor function. Ann N Y Acad Sci. 1994;746:8–20.

    PubMed  Google Scholar 

  11. Dorey R, Piérard C, Shinkaruk S, Tronche C, Chauveau F, Baudonnat M, et al. Membrane mineralocorticoid but not glucocorticoid receptors of the dorsal hippocampus mediate the rapid effects of corticosterone on memory retrieval. Neuropsychopharmacology 2011;36:2639–2649.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhou M, Kindt M, Joëls M, Krugers HJ. Blocking mineralocorticoid receptors prior to retrieval reduces contextual fear memory in mice. PLoS ONE. 2011;6:e26220.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Gomez-Sanchez E, Gomez-Sanchez CE. The multifaceted mineralocorticoid receptor. Compr Physiol. 2014;4:965–994.

    PubMed  PubMed Central  Google Scholar 

  14. Mitra R, Ferguson D, Sapolsky RM. Mineralocorticoid receptor overexpression in basolateral amygdala reduces corticosterone secretion and anxiety. Biol Psychiatry. 2009;66:686–690.

    CAS  PubMed  Google Scholar 

  15. de Kloet ER, Otte C, Kumsta R, Kok L, Hillegers MH, Hasselmann H, et al. Stress and depression: a crucial role of the mineralocorticoid receptor. J Neuroendocrinol. 2016;28:1–12.

  16. Vogel S, Fernández G, Joëls M, Schwabe L. Cognitive adaptation under stress: a case for the mineralocorticoid receptor. Trends Cogn Sci. 2016;20:192–203.

    PubMed  Google Scholar 

  17. Cannavo A, Bencivenga L, Liccardo D, Elia A, Marzano F, Gambino G, et al. Aldosterone and mineralocorticoid receptor system in cardiovascular physiology and pathophysiology. Oxid Med Cell Longev. 2018;2018:1204598–1204598.

    PubMed  PubMed Central  Google Scholar 

  18. Leggio L, Ferrulli A, Cardone S, Miceli A, Kenna GA, Gasbarrini G, et al. Renin and aldosterone but not the natriuretic peptide correlate with obsessive craving in medium-term abstinent alcohol-dependent patients: a longitudinal study. Alcohol. 2008;42:375–381.

    CAS  PubMed  Google Scholar 

  19. Aoun EG, Jimenez VA, Vendruscolo LF, Walter NAR, Barbier E, Ferrulli A, et al. A relationship between the aldosterone–mineralocorticoid receptor pathway and alcohol drinking: preliminary translational findings across rats, monkeys and humans. Mol Psychiatry. 2018;23:1466–1473.

    CAS  PubMed  Google Scholar 

  20. Fahlke C, Hård E, Eriksson CJ, Engel JA, Hansen S. Consequence of long-term exposure to corticosterone or dexamethasone on ethanol consumption in the adrenalectomized rat, and the effect of type I and type II corticosteroid receptor antagonists. Psychopharmacology 1995;117:216–224.

    CAS  PubMed  Google Scholar 

  21. Fahlke C, Hård E, Hansen S. Facilitation of ethanol consumption by intracerebroventricular infusions of corticosterone. Psychopharmacology 1996;127:133–139.

    CAS  PubMed  Google Scholar 

  22. O’Callaghan MJ, Croft AP, Jacquot C, Little HJ. The hypothalamopituitary-adrenal axis and alcohol preference. Brain Res Bull. 2005;68:171–178.

    PubMed  Google Scholar 

  23. Koenig HN, Olive MF. The glucocorticoid receptor antagonist mifepristone reduces ethanol intake in rats under limited access conditions. Psychoneuroendocrinology. 2004;29:999–1003.

    CAS  PubMed  Google Scholar 

  24. Tunstall BJ, Vendruscolo LF, Allen–Worthington K. Chapter 26 - Rat models of alcohol use disorder. In: Suckow MA, Hankenson FC, Wilson RP, Foley PL, editors. The laboratory rat (3rd Edition). Cambridge, MA, USA: Academic Press; 2020. p. 967–986.

  25. Kashkin VA, Shekunova EV, Egorov AY, Bagrov AY. Marinobufagenin in urine: a potential marker of predisposition to ethanol and a target for spironolactone. Curr Hypertens Rev. 2018;14:35–38.

    CAS  PubMed  Google Scholar 

  26. Makhijani VH, Van Voorhies K, Besheer J. The mineralocorticoid receptor antagonist spironolactone reduces alcohol self-administration in female and male rats. Pharmacol Biochem Behav. 2018;175:10–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Makhijani VH, Irukulapati P, Van Voorhies K, Fortino B, Besheer J. Central amygdala mineralocorticoid receptors modulate alcohol self-administration. Neuropharmacology 2020;181:108337.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Palzes VA, Farokhnia M, Kline-Simon AH, Elson J, Sterling S, Leggio L, et al. Effectiveness of spironolactone dispensation in reducing weekly alcohol use: a retrospective high-dimensional propensity score-matched cohort study. Neuropsychopharmacology. 2021;46:2140–2147.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Rhodes JS, Best K, Belknap JK, Finn DA, Crabbe JC. Evaluation of a simple model of ethanol drinking to intoxication in C57BL/6J mice. Physiol Behav. 2005;84:53–63.

    CAS  PubMed  Google Scholar 

  30. McGinn MA, Tunstall BJ, Schlosburg JE, Gregory-Flores A, George O, de Guglielmo G, et al. Glucocorticoid receptor modulators decrease alcohol self-administration in male rats. Neuropharmacology 2021;188:108510.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7:27–31.

    PubMed  PubMed Central  Google Scholar 

  32. Bush K, Kivlahan DR, McDonell MB, Fihn SD, Bradley KA. The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test. Arch Intern Med. 1998;158:1789–1795.

    CAS  PubMed  Google Scholar 

  33. Fiellin DA, Reid MC, O’Connor PG. Screening for alcohol problems in primary care: a systematic review. Arch Intern Med. 2000;160:1977–1989.

    CAS  PubMed  Google Scholar 

  34. Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Sturmer T. Variable selection for propensity score models. Am J Epidemiol. 2006;163:1149–1156.

    PubMed  Google Scholar 

  35. Pearl J. Invited commentary: understanding bias amplification. Am J Epidemiol. 2011;174:1223–1227.

    PubMed  PubMed Central  Google Scholar 

  36. Cormen TH. Introduction to algorithms. Cambridge, MA: MIT Press; 2009.

  37. Donald SG, Lang K. Inference with difference-in-differences and other panel data. Rev Econ Stat. 2007;89:221–233.

    Google Scholar 

  38. Lechner M. The estimation of causal effects by difference-in-difference methods. Found Trends® Econ. 2011;4:165–224.

    Google Scholar 

  39. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28:3083–3107.

    PubMed  PubMed Central  Google Scholar 

  40. Understanding binge drinking. https://www.niaaa.nih.gov/publications/brochures-and-fact-sheets/binge-drinking.

  41. Berger S, Wolfer DP, Selbach O, Alter H, Erdmann G, Reichardt HM, et al. Loss of the limbic mineralocorticoid receptor impairs behavioral plasticity. Proc Natl Acad Sci USA. 2006;103:195–200.

    CAS  PubMed  Google Scholar 

  42. Grupp LA, Elias J, Perlanski E, Stewart RB. Modification of ethanol-induced motor impairment by diet, diuretic, mineralocorticoid, or prostaglandin synthetase inhibitor. Psychopharmacology 1985;87:20–24.

    CAS  PubMed  Google Scholar 

  43. Vendruscolo LF, Roberts AJ. Operant alcohol self-administration in dependent rats: focus on the vapor model Alcohol. 2014;48:277–286.

    CAS  PubMed  Google Scholar 

  44. Zorrilla EP, Logrip ML, Koob GF. Corticotropin releasing factor: a key role in the neurobiology of addiction. Front Neuroendocrinol. 2014;35:234–244.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Roberto M, Spierling SR, Kirson D, Zorrilla EP. Corticotropin-releasing factor (CRF) and addictive behaviors. Int Rev Neurobiol. 2017;136:5–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Shimonovich M, Pearce A, Thomson H, Keyes K, Katikireddi SV. Assessing causality in epidemiology: revisiting Bradford Hill to incorporate developments in causal thinking. Eur J Epidemiol. 2021;36:873–887.

    PubMed  Google Scholar 

  48. Meeks TW, Bekman NM, Lanouette NM, Yung KA, Vienna RP. Alcohol and alcohol use disorder. In: Ritchie EC, Llorente MD, editors. Veteran psychiatry in the US: optimizing clinical outcomes. Cham: Springer International Publishing; 2019. p. 135–56.

  49. Rubinsky AD, Kivlahan DR, Volk RJ, Maynard C, Bradley KA. Estimating risk of alcohol dependence using alcohol screening scores. Drug Alcohol Depend. 2010;108:29–36.

    PubMed  Google Scholar 

  50. Harris AHS, Bradley KA, Bowe T, Henderson P, Moos R. Associations between AUDIT-C and mortality vary by age and sex. Popul Health Manag. 2010;13:263–268.

    PubMed  PubMed Central  Google Scholar 

  51. Kovács GL. The role of atrial natriuretic peptide in alcohol withdrawal: a peripheral indicator and central modulator? Eur J Pharmacol. 2000;405:103–112.

    PubMed  Google Scholar 

  52. Sonino N, Fallo F, Fava GA. Psychological aspects of primary aldosteronism. Psychother Psychosom. 2006;75:327–330.

    PubMed  Google Scholar 

  53. Sonino N, Tomba E, Genesia ML, Bertello C, Mulatero P, Veglio F, et al. Psychological assessment of primary aldosteronism: a controlled study. J Clin Endocrinol Metab. 2011;96:E878–883.

    CAS  PubMed  Google Scholar 

  54. Hlavacova N, Jezova D. Chronic treatment with the mineralocorticoid hormone aldosterone results in increased anxiety-like behavior. Horm Behav. 2008;54:90–97.

    CAS  PubMed  Google Scholar 

  55. Farokhnia M, Browning BD, Leggio L. Prospects for pharmacotherapies to treat alcohol use disorder: an update on recent human studies. Curr Opin Psychiatry. 2019;32:255–265.

    PubMed  PubMed Central  Google Scholar 

  56. Smythe JW, Murphy D, Timothy C, Costall B. Hippocampal mineralocorticoid, but not glucocorticoid, receptors modulate anxiety-like behavior in rats. Pharm Biochem Behav. 1997;56:507–513.

    CAS  Google Scholar 

  57. Korte SM, de Boer SF, de Kloet ER, Bohus B. Anxiolytic-like effects of selective mineralocorticoid and glucocorticoid antagonists on fear-enhanced behavior in the elevated plus-maze. Psychoneuroendocrinology 1995;20:385–394.

    CAS  PubMed  Google Scholar 

  58. Calvo N, Volosin M. Glucocorticoid and mineralocorticoid receptors are involved in the facilitation of anxiety-like response induced by restraint. Neuroendocrinology 2001;73:261–271.

    CAS  PubMed  Google Scholar 

  59. Ding H, Cui SY, Cui XY, Liu YT, Hu X, Zhao HL, et al. Anti-stress effects of combined block of glucocorticoid and mineralocorticoid receptors in the paraventricular nucleus of the hypothalamus. Br J Pharmacol. 2021;178:3696–3707.

    CAS  PubMed  Google Scholar 

  60. Watts AG, Sanchez-Watts G. Region-specific regulation of neuropeptide mRNAs in rat limbic forebrain neurones by aldosterone and corticosterone. J Physiol. 1995;484:721–736.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. de Guglielmo G, Kallupi M, Pomrenze MB, Crawford E, Simpson S, Schweitzer P, et al. Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats. Nat Commun. 2019;10:1238.

    PubMed  PubMed Central  Google Scholar 

  62. Vendruscolo LF, Koob GF. Alcohol dependence conceptualized as a stress disorder. In: Harkness KL, Hayden EP, editors. The Oxford handbook of stress and mental health. Oxford, United Kingdom: Oxford University Press; 2020.

  63. van Eekelen JA, Bohn MC, de Kloet ER. Postnatal ontogeny of mineralocorticoid and glucocorticoid receptor gene expression in regions of the rat tel- and diencephalon. Brain Res Dev Brain Res. 1991;61:33–43.

    PubMed  Google Scholar 

  64. Yongue BG, Roy EJ. Endogenous aldosterone and corticosterone in brain cell nuclei of adrenal-intact rats: regional distribution and effects of physiological variations in serum steroids. Brain Res. 1987;436:49–61.

    CAS  PubMed  Google Scholar 

  65. Vendruscolo LF, Estey D, Goodell V, Macshane LG, Logrip ML, Schlosburg JE, et al. Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals. J Clin Investig. 2015;125:3193–3197.

    PubMed  PubMed Central  Google Scholar 

  66. Joëls M, de Kloet ER. 30 Years of the mineralocorticoid receptor: the brain mineralocorticoid receptor: a saga in three episodes. J Endocrinol. 2017;234:T49–t66.

    PubMed  Google Scholar 

  67. Yau JL, Noble J, Seckl JR. Continuous blockade of brain mineralocorticoid receptors impairs spatial learning in rats. Neurosci Lett. 1999;277:45–48.

    CAS  PubMed  Google Scholar 

  68. Douma BR, Korte SM, Buwalda B, la Fleur SE, Bohus B, Luiten PG. Repeated blockade of mineralocorticoid receptors, but not of glucocorticoid receptors impairs food rewarded spatial learning. Psychoneuroendocrinology 1998;23:33–44.

    CAS  PubMed  Google Scholar 

  69. Thai CA, Zhang Y, Howland JG. Effects of acute restraint stress on set-shifting and reversal learning in male rats. Cogn Affect Behav Neurosci. 2013;13:164–173.

    PubMed  PubMed Central  Google Scholar 

  70. Otte C, Moritz S, Yassouridis A, Koop M, Madrischewski AM, Wiedemann K, et al. Blockade of the mineralocorticoid receptor in healthy men: effects on experimentally induced panic symptoms, stress hormones, and cognition. Neuropsychopharmacology 2007;32:232–238.

    CAS  PubMed  Google Scholar 

  71. Young KD, Preskorn SH, Victor T, Misaki M, Bodurka J, Drevets WC. The effect of mineralocorticoid and glucocorticoid receptor antagonism on autobiographical memory recall and amygdala response to implicit emotional stimuli. Int J Neuropsychopharmacol 2016;19:pyw036.

  72. Wingenfeld K, Kuehl LK, Dziobek I, Roepke S, Otte C, Hinkelmann K. Effects of mineralocorticoid receptor blockade on empathy in patients with major depressive disorder. Cogn Affect Behav Neurosci. 2016;16:902–910.

    PubMed  Google Scholar 

  73. Klok MD, Alt SR, Irurzun Lafitte AJ, Turner JD, Lakke EA, Huitinga I, et al. Decreased expression of mineralocorticoid receptor mRNA and its splice variants in postmortem brain regions of patients with major depressive disorder. J Psychiatr Res. 2011;45:871–878.

    PubMed  Google Scholar 

  74. Seckl JR, Fink G. Antidepressants increase glucocorticoid and mineralocorticoid receptor mRNA expression in rat hippocampus in vivo. Neuroendocrinology 1992;55:621–626.

    CAS  PubMed  Google Scholar 

  75. Otte C, Hinkelmann K, Moritz S, Yassouridis A, Jahn H, Wiedemann K, et al. Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study. J Psychiatr Res. 2010;44:339–346.

    PubMed  Google Scholar 

  76. Otte C, Wingenfeld K, Kuehl LK, Kaczmarczyk M, Richter S, Quante A, et al. Mineralocorticoid receptor stimulation improves cognitive function and decreases cortisol secretion in depressed patients and healthy individuals. Neuropsychopharmacology 2015;40:386–393.

    CAS  PubMed  Google Scholar 

  77. Vendruscolo LF, Terenina-Rigaldie E, Raba F, Ramos A, Takahashi RN, Mormède P. Evidence for a female-specific effect of a chromosome 4 locus on anxiety-related behaviors and ethanol drinking in rats. Genes Brain Behav. 2006;5:441–450.

    CAS  PubMed  Google Scholar 

  78. de Kloet ER, Meijer OC, de Nicola AF, de Rijk RH, Joëls M. Importance of the brain corticosteroid receptor balance in metaplasticity, cognitive performance and neuro-inflammation. Front Neuroendocrinol. 2018;49:124–145.

    PubMed  Google Scholar 

  79. de Gasparo M, Joss U, Ramjoué HP, Whitebread SE, Haenni H, Schenkel L, et al. Three new epoxy-spirolactone derivatives: characterization in vivo and in vitro. J Pharmacol Exp Ther. 1987;240:650–656.

    PubMed  Google Scholar 

  80. Kolkhof P, Bärfacker L. 30 Years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development. J Endocrinol. 2017;234:T125–T140.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Dinh QN, Young MJ, Evans MA, Drummond GR, Sobey CG, Chrissobolis S. Aldosterone-induced oxidative stress and inflammation in the brain are mediated by the endothelial cell mineralocorticoid receptor. Brain Res. 2016;1637:146–153.

    CAS  PubMed  Google Scholar 

  82. Penuela S, Gehi R, Laird DW. The biochemistry and function of pannexin channels. Biochim Biophys Acta. 2013;1828:15–22.

    CAS  PubMed  Google Scholar 

  83. Good ME, Chiu Y-H, Poon IKH, Medina CB, Butcher JT, Mendu SK, et al. Pannexin 1 channels as an unexpected new target of the anti-hypertensive drug spironolactone. Circ Res. 2018;122:606–615.

    CAS  PubMed  Google Scholar 

  84. Tunstall BJ, Lorrai I, McConnell SA, Gazo KL, Zallar LJ, de Guglielmo G, et al. Probenecid reduces alcohol drinking in rodents. is pannexin1 a novel therapeutic target for alcohol use disorder? Alcohol Alcohol. 2019;54:497–502.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Leggio L, Lee MR. Treatment of alcohol use disorder in patients with alcoholic liver disease. Am J Med. 2017;130:124–134.

    PubMed  Google Scholar 

  86. Farinelli LA, Piacentino D, Browning BD, Brewer BB, Leggio L. Cardiovascular consequences of excessive alcohol drinking via electrocardiogram: a systematic review. J Addict Nurs. 2021;32:39–45.

    PubMed  PubMed Central  Google Scholar 

  87. Vuittonet CL, Halse M, Leggio L, Fricchione SB, Brickley M, Haass-Koffler CL, et al. Pharmacotherapy for alcoholic patients with alcoholic liver disease. Am J Health Syst Pharm. 2014;71:1265–1276.

    CAS  PubMed  Google Scholar 

  88. Mirijello A, Tarli C, Vassallo GA, Sestito L, Antonelli M, d’Angelo C, et al. Alcoholic cardiomyopathy: what is known and what is not known. Eur J Intern Med. 2017;43:1–5.

    PubMed  Google Scholar 

  89. Martinotti G, Di Nicola M, Tedeschi D, Callea A, Di Giannantonio M, Janiri L. Craving Typology Questionnaire (CTQ): a scale for alcohol craving in normal controls and alcoholics. Compr Psychiatry. 2013;54:925–932.

    PubMed  Google Scholar 

  90. Addolorato G, Leggio L, Abenavoli L, Gasbarrini G. Neurobiochemical and clinical aspects of craving in alcohol addiction: a review. Addict Behav. 2005;30:1209–1224.

    PubMed  Google Scholar 

  91. Leggio L, Kenna GA, Fenton M, Bonenfant E, Swift RM. Typologies of alcohol dependence. From Jellinek to genetics and beyond. Neuropsychol Rev. 2009;19:115–129.

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all staff involved in data collection, management, and support at the National Institutes of Health Intramural Research Program (NIH IRP) and the following joint post-baccalaureate fellows in the NIDA/NIAAA Clinical Psychoneuroendocrinology and Neuropsychopharmacology and NIDA Neurobiology of Addiction Sections: Brandon Blank, Adriana Gregory-Flores, Claire Pince, and Lia Zallar. The authors would also like to thank Dr. Kendall Bryant (NIAAA) for providing administrative support and guidance during the initial development of the human pharmacoepidemiology study. Finally, the authors would like to thank Dr. Gail Seabold (NIDA) for professional proofreading and editing the manuscript.

Funding

This work was supported by the NIH intramural funding ZIA-DA-000635 and ZIA-AA000218 (Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section – PI: LL), ZIA-DA000602–06 (Neurobiology of Addiction Section – PI: GFK), and NIAAA extramural funding (R01-AA023733, U24-AA020794, U01-AA020790, and U10-AA013566). The content of this article is solely the responsibility of the authors and does not necessarily represent the official view of the funding agencies.

Author information

Author notes

  1. These authors contributed equally: Mehdi Farokhnia, Christopher T. Rentsch, Vicky Chuong, M. Adrienne McGinn.

  2. These authors jointly supervised this work: Amy C. Justice, Lorenzo Leggio, Leandro F. Vendruscolo.

Authors and Affiliations

  1. Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, MD, USA

    Mehdi Farokhnia, Vicky Chuong, Jenna E. Sanfilippo & Lorenzo Leggio

  2. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Mehdi Farokhnia

  3. VA Connecticut Healthcare System, US Department of Veterans Affairs, West Haven, CT, USA

    Christopher T. Rentsch & Amy C. Justice

  4. Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

    Christopher T. Rentsch, David A. Fiellin & Amy C. Justice

  5. Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK

    Christopher T. Rentsch

  6. Neurobiology of Addiction Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA

    Vicky Chuong, M. Adrienne McGinn, Sophie K. Elvig, Eliza A. Douglass, Luis A. Gonzalez, Renata C. N. Marchette, Brendan J. Tunstall, George F. Koob & Leandro F. Vendruscolo

  7. Department of Pharmacology, Addiction Science, and Toxicology, University of Tennessee Health Science Center, Memphis, TN, USA

    Brendan J. Tunstall

  8. Center for Interdisciplinary Research on AIDS, Yale School of Public Health, New Haven, CT, USA

    David A. Fiellin & Amy C. Justice

  9. Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA

    Lorenzo Leggio

  10. Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA

    Lorenzo Leggio

  11. Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Lorenzo Leggio

  12. Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA

    Lorenzo Leggio

Authors
  1. Mehdi Farokhnia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher T. Rentsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vicky Chuong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Adrienne McGinn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sophie K. Elvig
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eliza A. Douglass
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Luis A. Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jenna E. Sanfilippo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Renata C. N. Marchette
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Brendan J. Tunstall
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. David A. Fiellin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. George F. Koob
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Amy C. Justice
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Lorenzo Leggio
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Leandro F. Vendruscolo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MF and LL conceptualized the study. MF, CTR, VC, MAM, RCNM, BJT, GFK, ACJ, LL, and LFV designed the study and developed the data analysis plan. For the rodent studies, VC, MAM, SKE, EAD, and LAG conducted the experiments and RCNM, BJT, GFK, and LFV provided support. For the pharmacoepidemiology study, CTR managed and analyzed data and DAF and ACJ provided support. MF, CTR, VC, and MAM wrote the first draft of the manuscript and JES, LL, and LFV contributed to the first draft of the manuscript. All authors reviewed, provided feedback, and approved the final manuscript. GFK, ACJ, and LL provided funding for this study.

Corresponding authors

Correspondence to Lorenzo Leggio or Leandro F. Vendruscolo.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Farokhnia, M., Rentsch, C.T., Chuong, V. et al. Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies. Mol Psychiatry 27, 4642–4652 (2022). https://doi.org/10.1038/s41380-022-01736-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-022-01736-y

This article is cited by

Search

Advanced search

Quick links