Disulfiram (tetraethylthiuram disulfide [TETD]), known by the brand name Antabuse, has been used for more than 50 years as a deterrent to ethanol abuse in the management of alcoholism.
The disulfiram-ethanol reaction (DER) is due to increased serum acetaldehyde concentrations generated by the metabolism of ethanol by alcohol dehydrogenase in the liver. Normally, this acetaldehyde is cleared rapidly by its metabolism to acetate via aldehyde dehydrogenase.[1] Disulfiram blocks this enzyme, irreversibly inhibiting the oxidation of acetaldehyde and causing a marked increase in acetaldehyde concentrations after ethanol consumption. The discomfort associated with this syndrome is intended to serve as a negative stimulus, but the reaction may be severe enough to cause hypotension and death.
Disulfiram has also been proposed as a deterrent to cocaine abuse, and several studies have suggested improved retention rates in treatment programs for cocaine-dependent individuals treated with disulfiram. A study found diminished "high" or "rush" after intravenous (IV) cocaine administration to healthy volunteers pretreated with disulfiram, with no change in cardiovascular parameters.[2]
In considering disulfiram toxicity, a distinction must be made between the clinical manifestations of a DER and the toxic effects of disulfiram itself. Direct disulfiram toxicity may be further divided into acute poisoning versus chronic poisoning. The directly toxic effects of disulfiram include neurologic, cutaneous, and hepatotoxic sequelae in addition to the disulfiram-ethanol reaction.
Emergency department treatment of the DER is primarily supportive. See Treatment and Medication.
Ethanol is mainly metabolized in the liver to acetaldehyde by alcohol dehydrogenase (ADH). Acetaldehyde is then oxidized to acetate by aldehyde dehydrogenase (ALDH). Disulfiram irreversibly inhibits the oxidation of acetaldehyde by competing with the cofactor nicotinamide adenine dinucleotide (NAD) for binding sites on ALDH (see the image below).
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The pathway of ethanol metabolism. Disulfiram reduces the rate of oxidation of acetaldehyde by competing with the cofactor nicotinamide adenine dinucl....
Ultimately, disulfiram reduces the rate of oxidation of acetaldehyde, causing a 5- to 10-fold increase in the concentration of acetaldehyde. An increased serum acetaldehyde concentration is thought to be responsible for the unpleasant side effects associated with the DER.
Disulfiram also directly inhibits hepatic microsomal enzymes (cytochrome P450), in particular CYP2E1. This interferes with the metabolism of certain drugs, most notably that of warfarin, phenytoin, and theophylline. Disulfiram may also decrease the clearance of some benzodiazepines (diazepam, oxazepam, and chlordiazepoxide), caffeine, and some tricyclic antidepressants (desipramine and imipramine). The resulting possible elevation of serum concentrations of these medications has the potential to cause a corresponding toxicity.
Disulfiram is highly lipid soluble (accumulates in adipose tissue, crosses the blood-brain barrier), is highly protein bound, and has 80% bioavailability after an oral dose of 350 mg. Approximately 5-20% is not metabolized and is excreted unchanged in the feces; the remainder is metabolized to toxic and nontoxic metabolites.
The elimination of disulfiram and its numerous metabolites is a very slow process. Approximately 20% of the drug remains in the body for 1-2 weeks post ingestion. Most of these metabolites are then eliminated through the gastrointestinal (GI), renal, and respiratory routes. The prolonged effects of disulfiram occur not only because the drug is slowly eliminated from the body but also because it irreversibly inhibits aldehyde dehydrogenase. In order to regain the ability to metabolize acetaldehyde, the individual must therefore synthesize new stores of the enzyme.
Disulfiram metabolites cause clinically important effects in the body (see the image below).
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Disulfiram, prodrug for active metabolites.
The most important toxic metabolites are diethyldithiocarbamate (DDC) and its metabolite carbon disulfide (CS2). DDC chelates copper, thus impairing the activity of dopamine beta-hydroxylase, an enzyme that catalyzes the metabolism of dopamine to norepinephrine. In this way, DDC causes depletion of presynaptic norepinephrine and accumulation of dopamine. Although hypotension from the DER is mainly attributable to the effects of acetaldehyde, depletion of the potent vasoconstrictor norepinephrine may also be a contributing factor.
Dopamine agonism may be implicated in some of the altered behavior associated with disulfiram toxicity. Hypomania and psychosis have been documented in many reports among people with alcoholism who take high-dose disulfiram (up to 2000 mg/d). It is possible that disulfiram, like L-dopa and amphetamine, unmasks or exacerbates preexisting psychotic symptoms in susceptible individuals by increasing central dopamine levels.
Neurotoxic effects associated with disulfiram include extrapyramidal symptoms, and lesions of the basal ganglia have been described in patients after therapy with disulfiram. Potential mechanisms for disulfiram-associated neurotoxicity include abnormal central nervous system (CNS) metal accumulation from the chelation of copper by DDC, leading to free radical formation and neuronal oxidative stress. In addition, one study found that disulfiram and DDC increase the release of glutamate from striato-cortical synaptic vesicles, both in vitro and in rats, suggesting yet another possible mechanism for DDC-mediated neuronal damage.[3]
Other mechanisms implicated in DDC’s cytotoxic effects include its ability to chelate nickel, to interfere with sulfhydryl groups in cytochrome P-450 enzymes, and to inhibit ADH and ALDH enzymes. Furthermore, DDC inhibits superoxide dismutase, thereby impairing the ability to eliminate free radicals. DDC-induced methemoglobinemia can also occur secondary to impairment of glutathione-dependent methemoglobin reduction.
CS2, another disulfiram metabolite from DDC metabolism, has neurotoxic effects when administered directly. Acute exposure to CS2 causes rapid onset of headache, confusion, nausea, hallucinations, delirium, seizures, coma, and, potentially, death. CS2 may cause seizures by interacting with pyridoxal-5-phosphate, a cofactor in the production of gamma-aminobutyric acid (GABA) from glutamate, thereby depleting GABA levels in the brain and leading to benzodiazepine-resistant seizures; this forms the basis for an important experimental rat model of status epilepticus. In addition to its neurotoxic effects (neurobehavioral toxin), CS2 is hepatotoxic, inhibits cytochrome P-450, and is cardiotoxic.
The mechanism by which chronic disulfiram therapy produces hepatotoxicity is not well understood and may involve hypersensitivity or immunologic reactions in addition to the direct cytotoxic effects of its metabolites.
Disulfiram received US Food and Drug Administration (FDA) approval for use in the treatment of alcoholism in 1951. At that time, it was commonly prescribed in very high doses, up to 3000 mg a day in some cases. This resulted in a relatively high rate of extremely severe or fatal reactions. Currently, much lower doses are used, and the incidence of disulfiram toxicity has waned. According to the 41st Annual Report of the National Poison Data System (NPDS) from America's Poison Centers, in 2023 there were 59 single-substance exposures to disulfiram, with no deaths.[4]
Disulfiram toxicity has a particular classification with significant overlap. The first type of toxicity is the classic DER, known as acetaldehyde syndrome. Secondly, disulfiram has its own associated acute and chronic adverse drug reactions. Finally, disulfiram-like reactions are associated with many other substances that have an ethanol-like mechanism of toxicity with disulfiram.
Disulfiram use is associated with adverse reactions at a rate of approximately 1 per 200-2000 each year. Frequently reported aversive reactions are mainly hepatic, neurologic, dermatologic, and psychiatric.
Drowsiness is the most common side effect and occurs in up to 5% of patients. It generally resolves after 2 weeks of treatment. Other side effects include dyspnea, sweating, alteration of taste, vasodilation, impotence, amblyopia, dizziness, headache, ataxia, polyneuritis, psychosis, and hypertension.
Acute disulfiram overdose is uncommon. In adults, clinical manifestations after acute overdose are rare with doses of less than 3 g. Ingestion of 10-30 g may be lethal. Toxicity in children has been reported after ingestion of 2.5 g of disulfiram. Symptoms of overdose in children are mostly neurologic.
The patient should be advised to carry a medical alert card identifying the medication-assisted treatment, describing potential adverse effects (eg, symptoms of a disulfiram-alcohol reaction), and providing contact information for the treating physician or institution in an emergency.[5]
Patients taking disulfiram should be advised to immediately notify their physician of any early symptoms of hepatitis, including fatigue, weakness, malaise, anorexia, nausea, vomiting, jaundice, or dark urine.[5]
For patient education resources, see Disulfiram - Uses, Side Effects, and More and Alcohol Use Disorder.
The DER is the classic manifestation of patients with disulfiram toxicity. This reaction occurs after the ingestion of even small amounts of ethanol with the concomitant use of disulfiram or disulfiramlike agents. Disulfiram toxicity may also occur in the absence of ethanol exposure. Direct toxic effects are seen with both chronic use and acute massive ingestion.
Ethanol blood levels as low as 5-10 mg/dL can precipitate a DER; 120-150 mg/dL can lead to unconsciousness. Patients may experience DER signs and symptoms after the ingestion of ethanol-containing foods, medications, and products (eg, over-the-counter cough medications, mouthwash, facial-cleaning products, liquid herbal extracts).
In general, the severity and duration of a reaction depend on the amount of ethanol ingested, the dosage and duration of disulfiram therapy, and individual sensitivity. DER symptoms usually occur within 15-30 minutes of ethanol ingestion and last for several hours. Peak effects occur within 8-12 hours. DER may occur within 3 hours of a disulfiram dose and up to 2 weeks following discontinuance of disulfiram.
Lethal DERs have been reported; however, most DER cases are mild, and patients recover without serious sequelae.
Obtain a detailed, organ-specific history for proper diagnosis and management of disulfiram toxicity due to chronic use or acute massive ingestion.
Neurologic toxicity increases with dose and duration of therapy and includes the following:
Central and peripheral sensory motor neuropathy[6]
Diffuse toxic axonopathy
Psychosis - Limbic system stimulation by dopamine
Choreoathetosis - Basal ganglia stimulation by dopamine
Parkinsonism - Caused by low-density lesions in the basal ganglia
Catatonia - Occurs more often with chronic toxicity than with acute toxicity
Movement disorders - From dopamine excess, an enhanced excitotoxic effect of glutamate and calcium-mediated cell death
The link between disulfiram exposure and the development of parkinsonism was supported by an observational cohort study by d’Errico et al. Using a study population of almost 2.5 million people aged 40 years or older, the investigators found 19,072 cases of parkinsonism, with disulfiram having been prescribed in eight of these cases. The report concluded that the risk of parkinsonism is three-fold higher (hazard ratio [HR] 3.10) in association with disulfiram exposure.[7]
Dermatologic manifestations peak at about 2 weeks of treatment and include acneiform eruptions and allergic dermatitis[8]
GI symptoms include the following:
Rotten-egg odor on breath (sulfide metabolites), garliclike or metallic aftertaste in mouth
Hypersensitive or toxic hepatitis - Peaks at about 2 months of therapy and has a fatality rate of approximately 1 in 25,000 cases
Hematologic toxicity - Agranulocytosis, eosinophilia, thrombocytopenia, and methemoglobinemia
A retrospective review of the use of disulfiram among alcoholic patients being treated for active tuberculosis with isoniazid-containing regimens found no increased hepatotoxicity in patients taking both disulfiram and isoniazid. However, conclusions from this report are limited due to the study's retrospective nature and very small sample size (13 patients).[9]
Specific laboratory studies generally have little value in the treatment of acute toxicity. In addition, results are not usually available in a timely fashion.
Computed tomography (CT) scanning of the head and/or magnetic resonance imaging (MRI) studies are valuable in demonstrating CNS involvement (eg, basal ganglia ischemia, infarction) as well as in excluding other causes of altered mental status.
In patients with hypotension and/or tachycardia, an electrocardiogram (ECG) may assist in the assessment of potential end-organ damage as well as the exclusion of other possible causes of the patient's symptoms.[11]
For patients with a possible DER, provide supplemental oxygen, obtain IV access, and place all patients on a monitor. Administer thiamine, glucose, and naloxone to patients with altered mental status, as needed. IV fluids should be instituted if hypotension, tachycardia, or severe vomiting is present.
Patients with coma or a severely altered mental status should be intubated for airway protection. The frequent occurrence of vomiting secondary to a DER places these patients at high risk for aspiration.
Emergency department treatment of a DER is primarily supportive, though fomepizole has the theoretical benefit of blocking ethanol metabolism to acetaldehyde and may be a useful therapy in patients presenting with a DER. Patients with a severely altered mental status or coma should be intubated for airway protection. The risk of aspiration in patients with a DER is high.
Mild sedation with benzodiazepines may be useful in the agitated patient, and benzodiazepines may be used to treat seizures. However, sedation of patients with intractable vomiting increases the risk of aspiration and its sequelae and should be approached with caution. Benzodiazepines also have the potential to exacerbate hypotension.
In cases of intractable vomiting, phenothiazine use must be considered cautiously because their alpha-blockade effect may worsen or induce hypotension. Metoclopramide, ondansetron, or granisetron are considered the antiemetics of choice in these cases.
IV fluids should be given to patients experiencing a DER to replace volume losses from emesis and third spacing of intravascular fluid. IV fluids and vasopressors are indicated to support blood pressure and treat patients who are in shock.
Decontamination procedures are not likely to be beneficial once the reaction begins. Consider gastric emptying only in the hospital setting with cases of massive ethanol ingestion in which a patent and protected airway can be maintained. Inducing emesis with ipecac syrup is not recommended; ipecac syrup contains ethanol, which could precipitate a DER. Also, emesis may delay administration of activated charcoal, worsen the nausea and vomiting associated with disulfiram toxicity, and increase the likelihood of pulmonary aspiration if seizures and coma suddenly occur.
In acute disulfiram overdose, consider the use of activated charcoal (if available and if the patient is alert and able to drink it safely). Use of multiple- dose activated charcoal (MDAC) may be beneficial, as it can increase the rate of elimination of disulfiram and its metabolites that undergo enterohepatic recirculation. Activated charcoal is not indicated for disulfiramlike syndromes, and it is not indicated for the treatment of DERs. The risk-benefit of administering charcoal to a patient with altered mental status and a high likelihood of vomiting and potential aspiration must be carefully weighed.
In a severe DER, hemodialysis may be indicated to enhance the elimination of ethanol and acetaldehyde. Neither hemodialysis nor hemoperfusion has been beneficial for treatment of acute disulfiram overdose.
Fomepizole (Antizol) may be beneficial in cases of severe DERs. Fomepizole is a potent inhibitor of alcohol dehydrogenase; it may limit the metabolism of ethanol by this enzyme and thereby prevent further accumulation of acetaldehyde. A case series by Schicchi et al of 10 patients with DERs found evidence that fomepizole is safe and effective in quickly reversing vasodilation and toxicity induced by DERs.[12]
Monitor all patients with a DER or an acute disulfiram overdose for a minimum of 8-12 hours, even if they lack significant signs or symptoms of toxicity. Admit patients to the intensive care unit (ICU) if they demonstrate signs and symptoms of significant toxicity.
Consult with the local poison control center or a medical toxicologist.
Prompt follow-up care with the primary care physician responsible for treating the patient's alcoholism should be arranged for all patients presenting with a DER or disulfiram toxicity prior to discharge.
Refer patients with alcoholism to an alcoholic detoxification center and advise them not to drink alcohol or consume any medication or product containing alcohol for at least 2 weeks after the last dose of disulfiram.
A psychiatrist should evaluate all patients being treated for overdose before discharge.
Disulfiram is usually prescribed at an initial dose of 500 mg/d for 1-2 weeks, followed by a maintenance dose of 125-500 mg/d. Close monitoring for adverse reactions is required. Liver function should be monitored for hepatotoxicity.[8]
Clinical Context:
An antinauseant and antiemetic available in PO and IV forms for use in severe postoperative and chemotherapy/radiation therapy–induced nausea. Granisetron is a selective antagonist of serotonin 5HT3 receptors. Precise mechanism of action not known; however, thought to block either vagal stimulation of serotonin release in central chemoreceptor trigger zone of area postrema, or a vagally mediated vomiting reflex caused by release of serotonin from enterochromaffin cells of small intestine and stimulation of peripheral 5HT3 receptors.
Clinical Context:
Most useful if administered within 90 minutes of ingestion. Repeat doses may be used, especially with ingestion of sustained-release agents. Limited outcome studies exist, especially when administration is more than 1 h post ingestion.
Administration of charcoal by itself (in aqueous solution), as opposed to coadministration with a cathartic, is becoming the current practice standard. This is because studies have not shown benefit from cathartics, and, while most drugs and toxins are absorbed within 30-90 minutes, laxatives take hours to work. Dangerous fluid and electrolyte shifts have occurred when cathartics are used in small children.
When ingested dose is known, charcoal may be administered at 10 times ingested dose of agent, over one or two doses.
Clinical Context:
Used in protracted hypotension following adequate fluid-volume replacement. Stimulates beta1- and alpha-adrenergic receptors, which, in turn, increases cardiac muscle contractility, heart rate, and vasoconstriction. As a result, systemic blood pressure and coronary blood flow increase.
After obtaining a response, adjust rate of flow to and maintain at a low normal blood pressure (eg, 80-100 mm Hg systolic), sufficient to perfuse vital organs.
Clinical Context:
H2 antagonist that, when combined with an H1 type, may be useful for treating itching and flushing in anaphylaxis, pruritus, urticaria, and contact dermatitis that do not respond to H1 antagonists alone. Use in addition to H1 antihistamines.
Clinical Context:
Inhibits prostaglandin synthesis by decreasing the activity of cyclooxygenase, which results in decreased formation of prostaglandin precursors.
Clinical Context:
A promotility agent that increases gastric contractions, relaxes the pyloric sphincter and duodenal bulb, and increases peristalsis in the duodenum and jejunum. Exact mechanism is unknown, but metoclopramide may increase gastric emptying and decrease intestinal transit time by sensitizing tissues to the effects of acetylcholine. Has little or no effect on gastric, biliary, or pancreatic secretions or on colon or gallbladder motility.
Clinical Context:
Selective antagonist of serotonin 5HT3 receptors generally used to control chemotherapy-associated and postoperative nausea and vomiting. Precise mechanism of action is not known; however, ondansetron is thought to block either vagal stimulation of serotonin release in the central chemoreceptor trigger zone of the area postrema, or a vagally mediated vomiting reflex caused by release of serotonin from enterochromaffin cells of small intestine and stimulation of peripheral 5HT3 receptors, or both.
Samara Soghoian, MD, MA, Clinical Assistant Professor of Emergency Medicine, New York University School of Medicine, Bellevue Hospital Center
Disclosure: Nothing to disclose.
Coauthor(s)
José Eric Díaz-Alcalá, MD, FAAEM, FACMT, Medical and Executive Co-Director, Medical Toxicology Consultant, Administración de Servicios Médicos de Puerto Rico, ASEM Poison Control Center; Chief, Emergency Medicine Unit, Medical Toxicology Consultant, VA Caribbean Healthcare System
Disclosure: Nothing to disclose.
Specialty Editors
John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals
Disclosure: Nothing to disclose.
John G Benitez, MD, MPH, Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center
Disclosure: Nothing to disclose.
Chief Editor
Sage W Wiener, MD, Assistant Professor, Department of Emergency Medicine, State University of New York Downstate Medical Center; Director of Medical Toxicology, Department of Emergency Medicine, Kings County Hospital Center
Disclosure: Nothing to disclose.
Additional Contributors
David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School
Substance Abuse and Mental Health Services Administration and National Institute on Alcohol Abuse and Alcoholism. Medication for the Treatment of Alcohol Use Disorder: A Brief Guide. SAMHSA.gov. Available at https://library.samhsa.gov/product/medication-treatment-alcohol-use-disorder-brief-guide/sma15-4907. 2015; Accessed: April 17, 2025.
The pathway of ethanol metabolism. Disulfiram reduces the rate of oxidation of acetaldehyde by competing with the cofactor nicotinamide adenine dinucleotide (NAD) for binding sites on aldehyde dehydrogenase (ALDH).
Disulfiram, prodrug for active metabolites.
The pathway of ethanol metabolism. Disulfiram reduces the rate of oxidation of acetaldehyde by competing with the cofactor nicotinamide adenine dinucleotide (NAD) for binding sites on aldehyde dehydrogenase (ALDH).
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