Disulfiram: Definition, Mechanism of Action, Uses, Dosage, Side Effects, Alternatives

Disulfiram, also known as Antabuse, is a medication used to treat alcohol dependence by creating an adverse reaction when alcohol is consumed. The drug is primarily prescribed for individuals with alcohol use disorder (AUD) as part of medication-assisted treatment (MAT). 

The mechanism of action of Disulfirum is that it inhibits aldehyde dehydrogenase (ALDH), leading to a buildup of acetaldehyde. This causes nausea, vomiting, and cardiovascular effects and deters alcohol consumption. Following oral administration, 80–90% of Disulfiram is absorbed in the gastrointestinal tract, as Lanz et al. 2023 detailed in “Disulfiram: Mechanisms, Applications, and Challenges.”

Standard dosage begins at 500 mg daily for 1-2 weeks, followed by a maintenance dose of 250 mg per day. Side effects range from mild reactions like headache, drowsiness, and a metallic taste to severe complications such as liver toxicity, psychosis, and cardiovascular distress. A systematic review of randomized clinical trials assessing pharmacotherapy for alcohol use disorder (AUD) found that Disulfiram significantly increased abstinence, with a relative risk (RR) of 1.77, and reduced heavy drinking, with a relative risk of 0.19, compared to placebo. These findings were highlighted by Bahji et al. 2022 in “Pharmacotherapies for Adults With Alcohol Use Disorders: A Systematic Review and Network Meta-analysis.”

Common side effects include headache, drowsiness, nausea, vomiting, and skin rashes, while severe reactions involve liver toxicity, psychotic episodes, cardiovascular complications, and peripheral neuropathy.

Alternative medications for alcohol addiction include Naltrexone, Acamprosate, Nalmefene, Topiramate, and Gabapentin, each targeting different mechanisms to reduce cravings and prevent relapse. Behavioral therapy and support groups further enhance treatment effectiveness when combined with Disulfiram.

What Is Disulfiram?

Disulfiram is an FDA-approved prescription drug used to treat alcohol dependence by creating an aversive reaction when alcohol is consumed. Chemically known as tetraethylthiuram disulfide, it inhibits aldehyde dehydrogenase (ALDH), leading to the buildup of acetaldehyde, a toxic byproduct of alcohol metabolism. This reaction discourages alcohol consumption, reinforcing abstinence. Marketed under the brand name Antabuse, Disulfiram is a key component of medication-assisted treatment (MAT) for individuals recovering from alcohol dependence.

What Is the Mechanism of Action of Disulfiram?

The mechanism of action of Disulfiram involves the inhibition of aldehyde dehydrogenase, an enzyme essential for alcohol metabolism. When someone consumes alcohol, it is first converted into acetaldehyde, a toxic compound. Normally, aldehyde dehydrogenase breaks down acetaldehyde into a less harmful substance. Disulfiram blocks this enzyme, causing acetaldehyde to accumulate in the bloodstream. This buildup results in unpleasant effects such as nausea, vomiting, headache, and palpitations.

How Does Disulfiram Work for Alcohol Addiction?

Disulfiram works for alcohol addiction by inhibiting aldehyde dehydrogenase (ALDH), an enzyme crucial for metabolizing alcohol. When alcohol is consumed, it is first converted into acetaldehyde, a toxic compound. Normally, ALDH breaks down acetaldehyde into harmless substances. Disulfiram blocks ALDH, leading to an accumulation of acetaldehyde in the body. This buildup causes unpleasant reactions such as nausea, vomiting, headache, and palpitations, which deter individuals from consuming alcohol. ​

In New Hampshire, excessive alcohol consumption is a significant concern. Approximately 18.0% of adults reported binge drinking or heavy drinking in 2023, as revealed by America’s Health Rankings. Furthermore, the state experiences an average of 661 annual deaths attributable to alcohol addiction. Implementing treatments like disulfiram, alongside counseling and support, can be instrumental in addressing alcohol addiction within the state.

What Are the Uses of Disulfiram?

The uses of Disulfiram are primarily centered on its role in treating alcohol use disorder (AUD) as part of a medication-assisted treatment plan. This FDA-approved drug is prescribed to discourage alcohol consumption by triggering adverse physical reactions when alcohol is ingested. Its deterrent mechanism makes it particularly effective in supporting long-term abstinence. Clinical data show that Disulfiram significantly reduces the risk of relapse.

In a systematic review, patients receiving Disulfiram had a higher rate of abstinence (relative risk = 1.77) and lower rates of heavy drinking (relative risk = 0.19) compared to those on placebo (Bahji et al., “Pharmacotherapies for Adults With Alcohol Use Disorders: A Systematic Review and Network Meta-analysis,” 2022). Beyond alcohol dependence, emerging research is exploring Disulfiram’s potential in treating other conditions such as cocaine addiction, Lyme disease, and certain cancers, though these are not yet FDA-approved.

Are There Off-Label Uses for Disulfiram?

Yes, there are off-label uses for Disulfiram. Beyond its FDA-approved application for alcohol dependence, Disulfiram has been explored in the treatment of cocaine addiction, Lyme disease, and certain cancers. Disulfiram aids in reducing cocaine use among individuals with concurrent opioid dependence, as suggested by Grout M. and Mitchell K. 2023. In Lyme disease, research suggests Disulfiram’s potential effectiveness against Borrelia burgdorferi, the causative agent, with some patients experiencing symptom improvement. Additionally, preclinical studies have demonstrated Disulfiram’s anticancer properties, including the inhibition of tumor growth and metastasis, as explored by Luo et al. 2023 in “Safety Assessment of disulfiram: Real-world Adverse Event Analysis Based on FAERS Database.”

What Is a Typical Dose of Disulfiram?

The recommended starting dose of Disulfiram is 500 mg per day for one to two weeks, typically administered once daily in the morning. This initial dose helps establish therapeutic levels and ensure patient compliance. After this period, a maintenance dose of 250 mg per day is generally prescribed, though doses may range between 125 mg and 500 mg depending on individual tolerance, body weight, and preexisting medical conditions. Clinical guidelines from the Substance Abuse and Mental Health Services Administration (SAMHSA) recommend tailoring the dosage based on liver function and the patient’s ability to adhere to alcohol abstinence. Disulfiram is most effective when used as part of a structured medication-assisted treatment plan.

What Should You Do If You Miss a Dose of Disulfiram?

Do not take a double dose to make up for a missed dose. If you miss a dose of Disulfiram, take it as soon as you remember. If it is close to the next scheduled dose, skip the missed one and continue with the regular schedule to avoid overdose risks.

What Are the Side Effects of Disulfiram?

The side effects of Disulfiram are both common and potentially serious, depending on dosage, duration, and individual health status, with common side effects being drowsiness, fatigue, skin rash, headache, and a metallic or garlic-like taste in the mouth. More serious reactions are hepatitis, liver failure, optic neuritis, or peripheral neuropathy, especially with prolonged use or in individuals with preexisting liver conditions. In rare cases, psychotic reactions and cardiovascular complications have been reported. Patients must also avoid all alcohol-containing products, as combining alcohol with disulfiram may trigger severe reactions such as nausea, flushing, chest pain, and respiratory distress.

Common Side Effects of Disulfiram

The common side effects of disulfiram include:

• Drowsiness: Approximately 5% of patients experience drowsiness, typically resolving after two weeks of treatment. ​
  
• Headache: Headaches are commonly reported during disulfiram therapy, as investigated in a pilot study by Tanabe J et al. 2019, titled “Effects of Alcohol and Acetate on Cerebral Blood Flow: A Pilot Study.” Out of 138 user reviews on Drugs.com, 12 (8.7%) mention headaches.
  
• Fatigue: Some individuals experience unusual tiredness or fatigue while on disulfiram. ​
  
• Metallic or Garlic-like Taste: A metallic or garlic-like aftertaste is a frequently reported side effect, occurring within the first two weeks of treatment. ​
  
• Skin Rash: Skin eruptions, including rashes and acneiform eruptions, have been observed in patients taking disulfiram
  
• Decreased Sexual Ability in Males: Some male patients have reported a decrease in sexual ability during disulfiram therapy. ​
  
• Nausea and Vomiting: Gastrointestinal disturbances such as nausea and vomiting are possible side effects of disulfiram. ​
  
• Liver Function Abnormalities: Altered liver function tests and, in rare cases, hepatitis have been associated with disulfiram use.

Severe Side Effects of Disulfiram

Some serious side effects of disulfiram include:

• Hepatotoxicity: Disulfiram has been linked to severe liver damage, including fulminant hepatitis and liver failure, sometimes requiring transplantation. Hepatic reactions typically appear within 2–12 weeks of starting treatment.
  
• Peripheral Neuropathy: Long-term use may cause nerve damage, leading to tingling, burning, or numbness in the hands and feet. This condition may persist after discontinuation.
  
• Psychosis: Acute toxic psychosis, including confusion, paranoia, or hallucinations, has been reported, particularly at high doses or in combination with alcohol.
  
• Optic Neuritis: Inflammation of the optic nerve results in blurred vision, eye pain, or even vision loss, though this is rare.
  
• Seizures: Seizure activity, including tonic-clonic seizures, has been documented in patients using disulfiram, especially in the context of liver impairment (Medscape Drug Reference).
  
• Severe Allergic Reactions: Anaphylaxis and angioedema, though rare, occur and require emergency medical attention.
  
• Cardiovascular Complications: Tachycardia, hypotension, and cardiovascular collapse have been reported, particularly if alcohol is consumed during treatment. A clinical study by Kumaraswamy et al. 2013, in “A Study of Cardiovascular Complications of Disulfiram-Ethanol Reaction,” found that 15 to 30% of Disulfiram users experience symptoms resembling severe cardiac conditions, often triggering anxiety or panic attacks. In grave cases, these severe cardiovascular reactions necessitate immediate medical intervention.
  
• Respiratory Depression: In extreme cases, disulfiram-alcohol reactions may trigger breathing difficulties or respiratory arrest.

What Are the Alternatives to Disulfiram for Treating Alcohol Addiction?

The alternatives to Disulfiram for treating alcohol use disorder (AUD) are naltrexone, acamprosate, nalmefene, topiramate, and gabapentin. These medications are designed to aid relapse prevention and support recovery by targeting various biological mechanisms associated with alcohol dependence.

The alternatives to Disulfiram for treating alcohol addiction are explained below:

Naltrexone

Naltrexone blocks opioid receptors to reduce the pleasurable effects of alcohol. A clinical study by Streetonet al. 2001, “Naltrexone, A Relapse Prevention Maintenance Treatment Of Alcohol Dependence: A Meta-Analysis Of Randomized Controlled Trials,” shows that Naltrexone cuts relapse rates by up to 36%.

Acamprosate

Acamprosate stabilizes neurotransmitter balance disrupted by alcohol dependence.  A meta-analysis by Mason BJ, Lehert P., et al. 2012, titled “Acamprosate for alcohol dependence: a sex-specific meta-analysis based on individual patient data,” found that Acamprosate increases abstinence rates by 11% compared to placebo. Unlike Disulfiram, it does not interact with alcohol but precipitates diarrhea or anxiety.

Nalmefene

Nalmefene, like Naltrexone, modulates opioid receptors to reduce alcohol cravings. Research highlights its effectiveness in promoting controlled drinking behaviors. [Read more about Nalmefene.]

Topiramate

Topiramate affects GABA and glutamate pathways, reducing alcohol cravings and withdrawal symptoms.

Gabapentin

Gabapentin stabilizes neural excitability and mitigates withdrawal effects, showing promise in alcohol addiction treatment.

Is Disulfiram a Standalone Treatment for Alcohol Addiction?

No, Disulfiram is not a standalone treatment for alcohol addiction. Behavioral therapy, support groups, and psychological treatment enhance recovery outcomes when combined with Disulfiram. Cognitive Behavioral Therapy (CBT), 12-step programs, and motivational interviewing majorly improve alcohol addiction treatment rates when integrated with medication-assisted treatment. Cognitive Behavioral Therapy (CBT) has an effectiveness rate of 50-75%, as elaborated by Pybis, Jo, et al. 2017 in “The Comparative Effectiveness and Efficiency of Cognitive Behaviour Therapy and Generic Counselling in the Treatment of Depression: Evidence from the 2nd UK National Audit of Psychological Therapies.”

What Drugs Interact with Disulfiram?

​Drugs that interact with Disulfiram are alcohol, metronidazole, isoniazid, and warfarin. These interactions can lead to dangerous reactions and increased toxicity, particularly affecting the central nervous system (CNS) and liver function.

Here’s a closer look at each:

• Alcohol: Combining Disulfiram with alcohol leads to toxicity and causes symptoms like flushing, nausea, vomiting, and severe cardiovascular reactions. This is because Disulfiram inhibits the breakdown of acetaldehyde, a byproduct of alcohol metabolism.
  
• Metronidazole: Disulfiram and metronidazole both cause disulfiram-like reactions, leading to acute psychosis, nausea, and vomiting when taken together. Metronidazole induces psychiatric side effects such as dizziness, tremors, and hallucinations in 9% to 11% of patients, with adverse drug reactions accounting for nearly 3% to 5% of hospital admissions, as noted by Khandheria M. et al. 2014 in their study “Psychotic Episode Secondary to Metronidazole Use.”
  
• Isoniazid: When used alongside Disulfiram, isoniazid accelerates the risk of liver toxicity, leading to hepatotoxicity and other severe side effects. Therapy with isoniazid causes transient serum aminotransferase elevations in 10% to 20% of patients, with 3% to 5% experiencing levels exceeding five times the upper limit of normal (ULN), as mentioned in LiverTox: Clinical and Research Information on Drug-Induced Liver Injury.
  
• Warfarin: Disulfiram augments the anticoagulant effects of warfarin, increasing the peril of bleeding.
  

Given these potential drug interactions, consult with a healthcare provider before starting disulfiram to ensure it’s appropriate for your situation and to discuss any possible contraindications.

Are There Foods to Avoid When Taking Disulfiram?

Yes, foods to avoid when taking Disulfiram are those that contain hidden alcohol or undergo fermentation. These foods trigger adverse reactions when combined with the medication, as they elicit similar symptoms to drinking alcohol.

• Vinegar: Made through fermentation, vinegar contains small amounts of alcohol and sparks a reaction.
  
• Fermented foods: These are items like soy sauce, sauerkraut, and kimchi, which undergo fermentation and contain trace alcohol levels.
  
• Certain sauces: Some sauces, particularly those used in cooking, contain hidden alcohol, which interact with Disulfiram.
  
• Cough syrups with alcohol: Many over-the-counter cough syrups contain alcohol, which provoke adverse reactions when combined with Disulfiram.
  

What Happens If You Take Disulfiram with Alcohol?

Taking disulfiram with alcohol has a severe and unpleasant reaction. When disulfiram is amalgamated with alcohol, it inhibits the enzyme aldehyde dehydrogenase, which is responsible for breaking down acetaldehyde, a byproduct of alcohol metabolism. As a result, acetaldehyde accumulates in the body, evoking symptoms such as flushing, sweating, nausea, vomiting, headache, chest pain, and difficulty breathing. These reactions are intense and potentially dangerous, making  individuals to associate alcohol consumption with these unpleasant effects. This deterrent effect helps in the treatment of alcohol use disorder (AUD) by minimizing the likelihood of relapse.

How Long After Disulfiram Can You Drink Alcohol?

You can wait at least 14 days after stopping disulfiram before consuming alcohol. The medication’s effects last up to two weeks after discontinuation, so drinking alcohol too soon spawns severe reactions, covering nausea, vomiting, chest pain, and hazardously low blood pressure. To avoid serious health risks, iwait the full 14 days before drinking again.

Is Disulfiram Safe for Long-Term Use?

Yes, taking Disulfiram for long-term use is safe under medical supervision, but it prompts careful monitoring for potential risks. Long-term use of Disulfiram has adverse effects such as liver toxicity, neurological issues, and psychological side effects like depression or confusion. In a Swedish registry spanning 36 years, 82 cases of disulfiram-induced liver injury were reported, equating to approximately 1 case per 1.3 million average daily doses, as established by Ramer et al. 2020 in “Disulfiram-Induced Acute Liver Injury.”

How Long Does Disulfiram Stay in Your System?

Disulfiram stays in your system for up to two weeks after discontinuation. This is because its effects, caused by irreversible inhibition of aldehyde dehydrogenase, persist for up to 14 days. The half-life of Disulfiram is approximately 60 to 120 hours, depending on individual factors such as metabolism. Even after stopping the medication, its impact on alcohol metabolism remains substantial, leading to potential adverse reactions if alcohol is consumed.