Alcohol and Metronidazole Interaction: Real or Fake?

Douglas S. Paauw, MD


August 21, 2019

For years, we have advised patients to not use alcohol when taking metronidazole because of concern about a disulfiram-like reaction. This concern appears as a precaution in the package insert. Consumer sites, such as Consumer Reports, include it on lists of drugs that should not be taken with alcohol.

My answer, however, would be to inform this patient that he should continue to take the metronidazole even if he plans to drink alcohol at the wedding reception.

How did this concern originate? It began with the theory that because metronidazole blocked hepatic aldehyde dehydrogenase (ALDH) enzyme, it would lead to an accumulation of serum levels of acetaldehyde, the first and major product of alcohol metabolism. Metronidazole was even studied in the 1960s as a potential agent for the treatment of alcohol use disorders.[1,2]

Several cases reported in the literature seemed to suggest that this was indeed a true interaction. However, a review[3] of six cases reported between 1964 and 1999 involving eight patients concluded that there was no convincing evidence that this reaction occurs. Although four of the eight cases were serious, including one death, the authors of all of the case reports presumed the metronidazole-ethanol reaction to be an established pharmacologic fact. In the case involving the patient death, the case report ascribed the death to a metronidazole-alcohol interaction, even though the patient had no recent metronidazole prescription and no metronidazole bottle was found at the scene.

Aside from these early case reports, is there any other evidence supporting the concern about alcohol? A rat model[4] published in 2000 found that metronidazole can increase intracolonic, but not blood, acetaldehyde levels in rats that have received a combination of ethanol and metronidazole. The rats treated with metronidazole had increased growth of Enterobacteriaceae, an alcohol dehydrogenase-containing aerobe, which could be the cause of the higher intracolonic acetaldehyde levels. Of note, the researchers found that the metronidazole did not affect the animals' ability to metabolize hepatic or colon ALDH and did not result in a higher ALDH effect.

Rats aside, human studies were clearly needed to really determine whether the concern about interaction was real.

In a small placebo-controlled, randomized trial[5] involving 12 healthy participants, half received metronidazole three times a day for 5 days and the other half received placebo. All participants were then given ethanol 0.4 g/kg, with serum levels of ethanol and acetaldehyde measured every 20 minutes for the next 4 hours. In addition, blood pressure, pulse, skin temperature, and symptoms were monitored. No difference in blood acetaldehyde levels, vital signs, or symptoms were found between participants in the two groups.

Remember, this single trial was done in young, healthy adults only. That does not describe the majority of patients for whom we provide care. Patients with renal disease, end-stage liver disease, and myriad other chronic conditions may run into trouble with just the alcohol alone.

But for young adults, it appears the risk is very low. In this case, I would offer the patient the same counsel I would for any similar patient regardless of any medications: A drink or two is unlikely to present a problem. Drinking to excess is likely to make him pretty sick and is never recommended.

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