University of Wisconsin–Madison Medical College of Wisconsin

Comment on ‘Can Metronidazole Cause a Disulfiram-Like Reaction? A Case-Control Study Propensity Matched By Age, Sex and Ethanol Concentration’

Petros N. Karamanakos, MD, MSc, PhD; Eleftheria S. Panteli, MD, MSc, PhD, DESA; Marios Marselos, MD, PhD

WMJ. 2024;123(1):3-4.

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Dear Editor:

We read with great interest the recently published article by Feldman and Jaszczenski regarding the possibility of a disulfiram-like reaction brought about by the use of metronidazole.1 According to their results, there were no patients who experienced such a reaction after concomitant use of alcohol and metronidazole. Based on this finding, they suggest that metronidazole should not be avoided due to concern about an interaction with ethanol. Because of our continuous research on disulfiram, we find the issue very interesting and we would like to comment briefly on this report.

In a previous work of our laboratory team published in 2007, we clearly showed that metronidazole does not provoke a disulfiram-like reaction, because it does not inhibit the hepatic aldehyde dehydrogenase nor increase blood acetaldehyde in the Wistar rat.2 In addition, in this study, we demonstrated for the first time that metronidazole produces a tremendous increase in the levels of brain serotonin, while the enhancing effects of ethanol on the central levels of serotonin are well established.3 Likewise, we concluded that the reaction to ethanol exhibited by metronidazole may be the result of an interaction in the context of a type of a serotonin syndrome (SS), as in the case of the concomitant administration of agents possessing serotonergic activity. In support of this notion, it has been demonstrated that the combination of ethanol with serotonergic agents may induce a SS.4

The clinical manifestations of SS are a triad of altered conscious state, autonomic dysfunction, and neuromuscular excitability. However, in a retrospective study by Radomski et al,5 it was shown that the clinical picture of SS may be highly variable, and, in fact, all the symptoms observed during a “disulfiram reaction” are included in the detailed list of symptoms provided by this study.

In conclusion, we suggest that the authors should be aware of the serotonergic properties of metronidazole and ethanol, the combination of which might lead, at least in theory, to a SS, with symptoms very similar to those of a disulfiram-like reaction. Hence, we believe that they might reconsider their suggestion that patients under treatment with metronidazole can safely use alcohol due to lack of interaction between these two agents. Given the low incidence of SS, the fact that none of the 18 patients of the study who received metronidazole and ethanol had a suspected disulfiram-like reaction cannot rule out the possibility of alcohol intolerance produced by metronidazole.

  1. Feldman R, Jaszczenski R. Can metronidazole cause a disulfiram-like reaction? a case-control study propensity matched by age, sex, and ethanol concentration. WMJ. 2023;122(3):171-177.
  2. Karamanakos PN, Pappas P, Boumba VA, et al. Pharmaceutical agents known to produce disulfiram-like reaction: effects on hepatic ethanol metabolism and brain monoamines. Int J Toxicol. 2007;26(5):423-432.
  3. Daws LC, Montañez S, Munn JL, et al. Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism. J Neurosci. 2006;26(24):6431-6438. doi:10.1523/JNEUROSCI.4050-05.2006
  4. Velez LI, Shepherd G, Roth BA, Benitez FL. Serotonin syndrome with elevated paroxetine concentrations. Ann Pharmacother. 2004;38(2):269-272. doi:10.1345/aph.1D352
  5. Radomski JW, Dursun SM, Reveley MA, Kutcher SP. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypoth. 2000;55(3):218-224. doi:10.1054/mehy.2000.1047

Author Affiliations: Department of Neurosurgery, Olympion General Hospital and Rehabilitation Center, 26443, Patras, Greece (Karamanakos); Department of Anesthesiology and Critical Care Medicine, University Hospital of Patras, School of Medicine, University of Patras, Rion-Patras, Greece (Panteli); Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece (Karamanakos, Marselos).
Corresponding Author: Petros N. Karamanakos, MD, MSc, PhD, Department of Neurosurgery, Olympion General Hospital and Rehabilitation Center, Volou and Milihou, 26443, Patras, Greece; email; ORCID ID 0000-0002-5445-9680
Funding/Support: None declared.
Financial Disclosures: None declared.
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