How Antabuse (Disulfiram) Works
Disulfiram blocks the enzyme aldehyde dehydrogenase (ALDH), causing acetaldehyde to accumulate in the blood after alcohol consumption, which produces intensely unpleasant physical symptoms that deter drinking. 1, 2
Mechanism of Action
Disulfiram irreversibly inhibits aldehyde dehydrogenase-2 (ALDH2), the enzyme responsible for converting acetaldehyde into acetic acid during the second step of alcohol metabolism. 2, 3, 4
When alcohol is consumed after taking disulfiram, acetaldehyde concentrations in the blood rise to 5–10 times higher than would occur with alcohol alone. 2
This acetaldehyde buildup triggers what is called the "disulfiram-alcohol reaction" or "acetaldehyde syndrome," creating an aversive experience that conditions patients to avoid alcohol. 1, 2, 3
The Disulfiram-Alcohol Reaction
The accumulated acetaldehyde produces a constellation of highly unpleasant symptoms:
Cardiovascular effects: flushing, arrhythmias, tachycardia, and hypotension 1, 5
Neurological effects: dizziness and headache 1
The severity of this reaction is proportional to both the dose of disulfiram and the amount of alcohol consumed. 2
The reaction persists as long as alcohol is being metabolized; disulfiram does not speed up alcohol elimination. 2
Pharmacokinetics and Duration of Effect
Disulfiram is absorbed slowly from the gastrointestinal tract and eliminated slowly from the body. 2
The drug's effects persist for 1–2 weeks after the last dose, meaning alcohol consumption can still trigger unpleasant symptoms even a week or more after stopping disulfiram. 2
Prolonged use does not produce tolerance; instead, patients become progressively more sensitive to alcohol the longer they remain on therapy. 2
The irreversible nature of ALDH inhibition means new enzyme must be synthesized before normal alcohol metabolism can resume. 4, 6
Active Metabolites
Disulfiram itself is converted through three metabolic steps into diethylthiomethylcarbamate (Me-DTC), which along with two further oxidized metabolites appears to be the active form that inhibits ALDH. 4
One metabolite, methyl diethylthiocarbamoyl-sulfoxide (MeDTC-SO), forms a covalent adduct with the ALDH enzyme, completely abolishing its activity. 6
Critical Safety Considerations
Disulfiram is contraindicated in patients with any degree of alcoholic liver disease, acute hepatitis, or elevated liver enzymes due to documented hepatotoxicity risk. 1, 7, 8
European and French hepatology guidelines explicitly contraindicate disulfiram in hepatic insufficiency. 7
For patients with liver disease requiring pharmacotherapy for alcohol use disorder, baclofen is the only medication with proven safety and efficacy in cirrhotic patients and should be used instead. 7, 8
Acamprosate is another safe alternative in liver disease because it undergoes no hepatic metabolism and carries zero hepatotoxicity risk. 7, 8
Clinical Context
Disulfiram functions as "aversive therapy"—the threat and experience of severe physical discomfort creates a psychological deterrent to drinking. 1
This mechanism differs fundamentally from other alcohol use disorder medications: naltrexone blocks opioid receptors to reduce reward, while acamprosate modulates glutamate to reduce cravings and withdrawal. 7
Because of its hepatotoxic potential and the availability of safer alternatives, disulfiram is currently not commonly used in modern practice. 1