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04. Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations

Published on August 1, 2025 Certification expiration date: August 1, 2028

Kevin A. Sevarino, M.D.C.M., Ph.D.

Associate Clinical Professor of Psychiatry - Yale School of Medicine

Key Points

  • Disulfiram is most effective for patients committed to abstinence. It is contraindicated in medication non-compliant patients or those with cognitive impairment.
  • The disulfiram-alcohol reaction can be triggered by alcohol-containing products like mouthwash or hand sanitizers. Symptoms appear 10-30 minutes after exposure.
  • Disulfiram may cause serious adverse effects including hepatotoxicity, optic neuritis, and peripheral neuropathy. Discontinue immediately if liver injury signs appear.

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Slides and Transcript

Slide 1 of 24

Now, let’s talk about the role of disulfiram in treating alcohol use disorder. Many know this agent as Antabuse.
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 1 of 24

Slide 2 of 24

So Antabuse or disulfiram was discovered in 1920 and it was FDA approved way back in 1951. It’s used in selected alcohol use disorder patients who could benefit from what we call enforced sobriety, so that supportive and psychotherapeutic treatment may be applied to best advantage. It discourages drinking by making the patient physically ill when alcohol is consumed, and that illness can be quite severe.
References:
  • Skinner, M. D., Lahmek, P., Pham, H., & Aubin, H. J. (2014). Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PloS One, 9(2), e87366. https://doi.org/10.1371/journal.pone.0087366
  • Jørgensen, C. H., Pedersen, B., & Tønnesen, H. (2011). The efficacy of disulfiram for the treatment of alcohol use disorder. Alcoholism, Clinical and Experimental Research, 35(10), 1749–1758. https://doi.org/10.1111/j.1530-0277.2011.01523.x
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Slide 3 of 24

Starting dose is 250 mg a day. There are some people that stay there but if patients get somewhat exposed to alcohol and have no reaction, you pretty easily go up to 500 mg a day. And sometimes, you need to go as high as 1000 mg a day. Remember, because this disulfiram-alcohol reaction is severe, you need to take it at least 12 hours after the last alcohol use.
References:
  • Jørgensen, C. H., Pedersen, B., & Tønnesen, H. (2011). The efficacy of disulfiram for the treatment of alcohol use disorder. Alcoholism, Clinical and Experimental Research, 35(10), 1749–1758. https://doi.org/10.1111/j.1530-0277.2011.01523.x
  • Lanz, J., Biniaz-Harris, N., Kuvaldina, M., Jain, S., Lewis, K., & Fallon, B. A. (2023). Disulfiram: Mechanisms, applications, and challenges. Antibiotics, 12(3), 524. https://doi.org/10.3390/antibiotics12030524
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 3 of 24

Slide 4 of 24

The disulfiram-alcohol reaction can be triggered when alcohol is consumed one to two weeks after the last dose of disulfiram. So it is an irreversible inhibitor of the enzyme acetaldehyde dehydrogenase and so the body has got to build that enzyme back up. Usually though within a week, somebody could consume alcohol again without a reaction.
References:
  • Jørgensen, C. H., Pedersen, B., & Tønnesen, H. (2011). The efficacy of disulfiram for the treatment of alcohol use disorder. Alcoholism, Clinical and Experimental Research, 35(10), 1749–1758. https://doi.org/10.1111/j.1530-0277.2011.01523.x
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Slide 5 of 24

If there’s a reaction, the reaction can be immediate but usually is 10 to 30 minutes after alcohol is consumed. The symptoms can be triggered by exposure to all sorts of things – alcohol-containing mouthwash, cooking wine that isn’t heavily cooked off, alcohol-containing hand sanitizers. In the old days, there was Aqua Velva which was an aftershave that was alcohol containing.
References:
  • Jørgensen, C. H., Pedersen, B., & Tønnesen, H. (2011). The efficacy of disulfiram for the treatment of alcohol use disorder. Alcoholism, Clinical and Experimental Research, 35(10), 1749–1758. https://doi.org/10.1111/j.1530-0277.2011.01523.x
  • Lanz, J., Biniaz-Harris, N., Kuvaldina, M., Jain, S., Lewis, K., & Fallon, B. A. (2023). Disulfiram: Mechanisms, applications, and challenges. Antibiotics, 12(3), 524. https://doi.org/10.3390/antibiotics12030524
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 5 of 24

Slide 6 of 24

Adverse effects even in the absence of the disulfiram-alcohol reaction, a metallic taste in the mouth, there can be hepatotoxicity, optic neuritis and peripheral neuropathy.
References:
  • Jørgensen, C. H., Pedersen, B., & Tønnesen, H. (2011). The efficacy of disulfiram for the treatment of alcohol use disorder. Alcoholism, Clinical and Experimental Research, 35(10), 1749–1758. https://doi.org/10.1111/j.1530-0277.2011.01523.x
  • Lanz, J., Biniaz-Harris, N., Kuvaldina, M., Jain, S., Lewis, K., & Fallon, B. A. (2023). Disulfiram: Mechanisms, applications, and challenges. Antibiotics, 12(3), 524. https://doi.org/10.3390/antibiotics12030524
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 6 of 24
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Slide 7 of 24

So normally, alcohol is first in the gastric lining and the liver metabolized to acetaldehyde by alcohol dehydrogenase. Acetaldehyde is a very short-lived intermediate because acetaldehyde dehydrogenase then very quickly breaks it down into acetate and water. So it’s not present in very high concentrations because if it was you get sick.
References:
  • Lanz, J., Biniaz-Harris, N., Kuvaldina, M., Jain, S., Lewis, K., & Fallon, B. A. (2023). Disulfiram: Mechanisms, applications, and challenges. Antibiotics, 12(3), 524. https://doi.org/10.3390/antibiotics12030524
  • Barth, K., & Malcolm, R. (2010). Disulfiram: An old therapeutic with new applications. CNS & Neurological Disorders – Drug Targets, 9(1), 5–12. https://doi.org/10.2174/187152710790966678
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 7 of 24

Slide 8 of 24

Now, in the mitochondria, those little powerhouses of the cell, you have acetaldehyde dehydrogenase, principally acetaldehyde dehydrogenase 2. That is the major enzyme that clears acetaldehyde. If you have either a genetic predisposition to a slow acetaldehyde dehydrogenase, that’s ALDH2*2, or you block it with disulfiram, acetaldehyde builds up and you get really sick.
References:
  • Lanz, J., Biniaz-Harris, N., Kuvaldina, M., Jain, S., Lewis, K., & Fallon, B. A. (2023). Disulfiram: Mechanisms, applications, and challenges. Antibiotics, 12(3), 524. https://doi.org/10.3390/antibiotics12030524
  • Barth, K., & Malcolm, R. (2010). Disulfiram: An old therapeutic with new applications. CNS & Neurological Disorders – Drug Targets, 9(1), 5–12. https://doi.org/10.2174/187152710790966678
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 8 of 24
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Slide 9 of 24

You get throbbing in your head and neck. You may lose consciousness. Your blood pressure drops which is one of the primary reasons it could be so dangerous ’cause you can actually have a stroke during the reaction. You’re very uneasy. You vomit. You have flushing. That’s a key sign. Sweating, thirst, weakness, palpitation. It’s like your first date. Hyperventilation.
References:
  • Lanz, J., Biniaz-Harris, N., Kuvaldina, M., Jain, S., Lewis, K., & Fallon, B. A. (2023). Disulfiram: Mechanisms, applications, and challenges. Antibiotics, 12(3), 524. https://doi.org/10.3390/antibiotics12030524
  • Stokes, M., Patel, P., & Abdijadid, S. (2025). Disulfiram. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK459340/
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 9 of 24

Slide 10 of 24

Respiratory depression, cardiovascular collapse, myocardial infarction, congestive heart failure, seizures, death. This is not something to be toyed with and you want to give that warning to your patients.
References:
  • Lanz, J., Biniaz-Harris, N., Kuvaldina, M., Jain, S., Lewis, K., & Fallon, B. A. (2023). Disulfiram: Mechanisms, applications, and challenges. Antibiotics, 12(3), 524. https://doi.org/10.3390/antibiotics12030524
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 10 of 24
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Slide 11 of 24

Therefore, I don’t use it especially in two groups of patients, those that have shown noncompliance to medications and especially very impulsive relapses to drinking and those that have cognitive impairment because they can’t really understand the consequences of what would happen when they drink.
References:
  • Lanz, J., Biniaz-Harris, N., Kuvaldina, M., Jain, S., Lewis, K., & Fallon, B. A. (2023). Disulfiram: Mechanisms, applications, and challenges. Antibiotics, 12(3), 524. https://doi.org/10.3390/antibiotics12030524
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 11 of 24

Slide 12 of 24

If we look at a meta-analysis from the McPheeters, you can see that disulfiram has efficacy for abstinence, and importantly open-label studies show far greater efficacy. So why would that be? That’s because the person knows they’re taking a medication that can make them sick, and I think a powerful driver, not only a placebo effect but real effect, is the belief that a medication will work. As well, it shows that those that are committed to abstinence, and may have supervised administration. In other words, a loved one, a partner, is instructed to call if the person doesn’t take their medication. That’s called network therapy and that can really help the efficacy of disulfiram.
References:
  • McPheeters, M., O'Connor, E. A., Riley, S., Kennedy, S. M., Voisin, C., Kuznacic, K., Coffey, C. P., Edlund, M. D., Bobashev, G., & Jonas, D. E. (2023). Pharmacotherapy for alcohol use disorder: A systematic review and meta-analysis. JAMA, 330(17), 1653–1665. https://doi.org/10.1001/jama.2023.19761
  • Skinner, M. D., Lahmek, P., Pham, H., & Aubin, H. J. (2014). Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PloS One, 9(2), e87366. https://doi.org/10.1371/journal.pone.0087366
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Slide 13 of 24

If you look at the meta-analysis, disulfiram compared to control had an odds ratio, here they called it a G of 0.77 compared to naltrexone, 0.76 compared to acamprosate, 0.43 compared to placebo. So when you can ensure compliance, this is a very effective agent.
References:
  • McPheeters, M., O'Connor, E. A., Riley, S., Kennedy, S. M., Voisin, C., Kuznacic, K., Coffey, C. P., Edlund, M. D., Bobashev, G., & Jonas, D. E. (2023). Pharmacotherapy for alcohol use disorder: A systematic review and meta-analysis. JAMA, 330(17), 1653–1665. https://doi.org/10.1001/jama.2023.19761
  • Skinner, M. D., Lahmek, P., Pham, H., & Aubin, H. J. (2014). Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PloS One, 9(2), e87366. https://doi.org/10.1371/journal.pone.0087366
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 13 of 24

Slide 14 of 24

It’s often used in those that face severe consequences if they resume drinking, maybe in impaired professionals program. It may be someone under the risk of divorce or job loss if they drink again or somebody that firmly now believes that they will die if they drink again.
References:
  • Skinner, M. D., Lahmek, P., Pham, H., & Aubin, H. J. (2014). Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PloS One, 9(2), e87366. https://doi.org/10.1371/journal.pone.0087366
  • Lanz, J., Biniaz-Harris, N., Kuvaldina, M., Jain, S., Lewis, K., & Fallon, B. A. (2023). Disulfiram: Mechanisms, applications, and challenges. Antibiotics, 12(3), 524. https://doi.org/10.3390/antibiotics12030524
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 14 of 24
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Slide 15 of 24

Let’s talk about hepatic disease ’cause this is quite important here with disulfiram. The American College of Gastroenterology Guidelines says, and I quote: “Disulfiram should not be used in the treatment of alcohol use disorder along any spectrum of alcoholic liver disease.” They say this is a conditional recommendation of very low level of evidence.
References:
  • Jophlin, L. L., Singal, A. K., Bataller, R., Wong, R. J., Sauer, B. G., Terrault, N. A., & Shah, V. H. (2024). ACG Clinical Guideline: Alcohol-Associated Liver Disease. The American Journal of Gastroenterology, 119(1), 30–54. https://doi.org/10.14309/ajg.0000000000002572
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 15 of 24

Slide 16 of 24

So that would say that if you have any evidence of alcoholic liver disease, you don’t use disulfiram. What happens if in fact everything else has failed – naltrexone, acamprosate, other agents along with your behavioral treatments – but you have seen some evidence that disulfiram has worked in the past, or this is the first time you’re trying it but they can’t get a liver transplant unless they show six months of abstinence? Well, with very careful monitoring, you might consider using this agent.
References:
  • Jophlin, L. L., Singal, A. K., Bataller, R., Wong, R. J., Sauer, B. G., Terrault, N. A., & Shah, V. H. (2024). ACG Clinical Guideline: Alcohol-Associated Liver Disease. The American Journal of Gastroenterology, 119(1), 30–54. https://doi.org/10.14309/ajg.0000000000002572
  • Vanjak, D., Samuel, D., Gosset, F., Derrida, S., Moreau, R., Soupison, T., Soulier, A., Bismuth, H., & Sicot, C. (1989). Hépatite fulminante au disulfirame chez un malade atteint de cirrhose alcoolique. Survie après transplantation hépatique [Fulminant hepatitis induced by disulfiram in a patient with alcoholic cirrhosis. Survival after liver transplantation]. Gastroenterologie clinique et biologique, 13(12), 1075–1078.
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Slide 17 of 24

Nonetheless, be aware that the guidelines from the American College of Gastroenterology say don’t use it. The mechanism of hepatotoxicity is most likely an idiosyncratic hypersensitivity. You, then you’d see eosinophilia, a rash and a fever. And the hepatotoxicity can range from asymptomatic transaminitis all the way to symptomatic liver injury with jaundice or acute liver failure or death. So it’s nothing to be played with.
References:
  • Jophlin, L. L., Singal, A. K., Bataller, R., Wong, R. J., Sauer, B. G., Terrault, N. A., & Shah, V. H. (2024). ACG Clinical Guideline: Alcohol-Associated Liver Disease. The American Journal of Gastroenterology, 119(1), 30–54. https://doi.org/10.14309/ajg.0000000000002572
  • LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. (2012). National Institute of Diabetes and Digestive and Kidney Diseases. https://doi.org/10.56344/LIVERDOC
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 17 of 24

Slide 18 of 24

Hepatitis with disulfiram therapy may develop even after months of therapy so don’t let your guard down in those that are on it. Disulfiram-induced hepatitis may be more common in those with preexisting alcoholic liver disease or continuing it once jaundice is seen. So this is some of what’s behind the American College of Gastroenterology’s recommendations.
References:
  • Jophlin, L. L., Singal, A. K., Bataller, R., Wong, R. J., Sauer, B. G., Terrault, N. A., & Shah, V. H. (2024). ACG Clinical Guideline: Alcohol-Associated Liver Disease. The American Journal of Gastroenterology, 119(1), 30–54. https://doi.org/10.14309/ajg.0000000000002572
  • Vanjak, D., Samuel, D., Gosset, F., Derrida, S., Moreau, R., Soupison, T., Soulier, A., Bismuth, H., & Sicot, C. (1989). Hépatite fulminante au disulfirame chez un malade atteint de cirrhose alcoolique. Survie après transplantation hépatique [Fulminant hepatitis induced by disulfiram in a patient with alcoholic cirrhosis. Survival after liver transplantation]. Gastroenterologie clinique et biologique, 13(12), 1075–1078.
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Slide 19 of 24

Without preexisting alcoholic liver disease, disulfiram did not show progression to alcoholic liver disease, and that’s a study by Vanjak. And in those with cirrhosis, it showed a trend to increase risk of decompensation. So that might say that you can have alcoholic liver disease, and probably still use it, but once you pass into a documented cirrhosis you need to be more careful. There’s no cross-sensitivity to liver injury between disulfiram and the other MAUD agents.
References:
  • Vanjak, D., Samuel, D., Gosset, F., Derrida, S., Moreau, R., Soupison, T., Soulier, A., Bismuth, H., & Sicot, C. (1989). Hépatite fulminante au disulfirame chez un malade atteint de cirrhose alcoolique. Survie après transplantation hépatique [Fulminant hepatitis induced by disulfiram in a patient with alcoholic cirrhosis. Survival after liver transplantation]. Gastroenterologie clinique et biologique, 13(12), 1075–1078.
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 19 of 24

Slide 20 of 24

What adjustments do you make in the presence of hepatic disease with disulfiram? Any appearance of signs or symptoms of liver injury should lead to immediate discontinuation. So assuming you’re not on a subtherapeutic dose and the person is not drinking and that results in worsening liver function tests, you would discontinue if you saw those go up.
References:
  • Stokes, M., Patel, P., & Abdijadid, S. (2025). Disulfiram. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK459340/
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Slide 21 of 24

Advise the patient immediately to notify you or an ED, emergency department, if there are signs of hepatitis. And that can be pretty vague things like fatigue and weakness that’s a little hard to follow. But jaundice, dark urine, vomiting, definitely that’s a red flag. If stopped early, complete recovery of the liver changes is expected within four to six weeks. Rechallenge leads to rapid reoccurrence and you shouldn’t do it.
References:
  • Stokes, M., Patel, P., & Abdijadid, S. (2025). Disulfiram. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK459340/
  • LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. (2012). National Institute of Diabetes and Digestive and Kidney Diseases. https://doi.org/10.56344/LIVERDOC
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 21 of 24

Slide 22 of 24

Baseline and followup liver function tests which should be within two weeks are suggested to detect hepatic dysfunction resulting from disulfiram initiation. And for maintenance, consider up to monthly testing based on your assessment of liver abnormality. So in other words, initially if you saw a slight bump in transaminitis and you didn’t stop it, then I would do monthly testing thereafter. If in fact the person’s liver seems to be functioning normally, you may not do monthly testing although in my case I probably would.
References:
  • Stokes, M., Patel, P., & Abdijadid, S. (2025). Disulfiram. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK459340/
  • LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. (2012). National Institute of Diabetes and Digestive and Kidney Diseases. https://doi.org/10.56344/LIVERDOC
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Slide 23 of 24

Key points here for disulfiram. I hope I didn’t scare you away from considering it because it can be a very effective agent. Disulfiram is the oldest of the FDA-approved MAUDs. It inhibits mitochondrial aldehyde dehydrogenase so that the intermediate acetaldehyde builds up and it produces the alcohol-disulfiram reaction.
Disulfiram for Alcohol Use Disorder: Mechanisms, Efficacy, and Hepatic Safety Considerations Slide 23 of 24

Slide 24 of 24

Disulfiram is to be used in selected alcohol use disorder patients who can benefit from enforced sobriety so that supportive and psychotherapeutic interventions can be used to best advantage. And finally, disulfiram must not be used in those with alcoholic liver disease unless all other treatments have failed and reuse of alcohol would be catastrophic.
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05. Gabapentin, Topiramate, and Baclofen for Alcohol Use Disorder

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CME Information

Learning Objectives:

After completing this activity, the learner will be able to:

  1. Select appropriate medications for alcohol use disorder based on patient-specific factors including hepatic function, treatment goals, and comorbid medical conditions.
  2. Monitor and manage potential adverse effects of medications for alcohol use disorder, including hepatotoxicity with naltrexone and disulfiram, and metabolic acidosis with topiramate.
  3. Implement evidence-based combination therapy using medications for alcohol use disorder with behavioral interventions to optimize treatment outcomes in patients with varying degrees of liver disease.

Original Release Date: August 1, 2025

Expiration Date: August 1, 2028

Expert: Kevin A. Sevarino, M.D.

Medical Editor: Flavio Guzmán, M.D. 

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