Disulfiram (sold under the trade names Antabuse) is a drug used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, causing many of the effects of a hangover to be felt immediately following alcohol consumption. Disulfiram plus alcohol, even small amounts, produce flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, fast heart rate, low blood pressure, fainting, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, abnormal heart rhythms, heart attack, acute congestive heart failure, unconsciousness, convulsions, and death.
In the body, alcohol is converted to acetaldehyde, which is then broken down by acetaldehyde dehydrogenase. When dehydrogenase enzyme is inhibited, acetaldehyde builds up, causing the unpleasant effects. Disulfiram should be used in conjunction with counseling and support.
Disulfiram has been studied as a possible treatment for cancer and latent HIV infection.
The synthesis of disulfiram, originally known as tetraethylthiuram disulfide, was first reported in 1881. By around 1900, it was introduced to the industrial process of Sulfur vulcanization of rubber and became widely used. In 1937 a rubber factory doctor in the US published a paper noting that workers exposed to disulfiram had negative reactions to alcohol and could be used as a drug for alcoholism; the effects were also noticed in workers at Swedish rubber boot factory.
In the early 1940s it had been tested as a treatment for scabies, a parasitic skin infection, as well as intestinal worms.
Around that time, during the German occupation of Denmark, Erik Jacobsen and Jens Hald at the Danish drug company Medicinalco picked up on that research and began exploring the use of disulfiram to treat intestinal parasites. The company had a group of enthusiastic self-experimenters that called itself the “Death Battalion”, and in the course of testing the drug on themselves, accidentally discovered that drinking alcohol while the drug was still in their bodies made them mildly sick.
They made that discovery in 1945, and did nothing with it until two years later, when Jacobsen gave an impromptu talk and mentioned this self-experimental work and Disulframs nausea inducing effects when combined with alcohol, this talk which was discussed afterwards in newspapers at the time, lead them to further explore the use of the drug for aversive-reaction based therapy for the treatment of alcohol abuse. That work included small clinical trials with Oluf Martensen-Larsen, a doctor who worked with alcoholics. They published their work starting in 1948.
The chemists at Medicinalco discovered a new form of disulfiram while trying to purify a batch that had been contaminated with copper. This form turned out to have better pharmacological properties, and the company patented it and used that form for the product that was introduced as Antabus (later anglicized to Antabuse).
This work led to renewed study of the human metabolism of ethanol. It was already known that ethanol was mostly metabolized in the liver, with it being converted first acetaldehyde and then acetaldehyde to acetic acid and carbon dioxide, but the enzymes involved were not known. By 1950 the work led to the knowledge that ethanol is oxidized to acetaldehyde by alcohol dehydrogenase and acetaldehyde is oxidized to acetic acid by aldehyde dehydrogenase (ALDH), and that disulfiram works by inhibiting ALDH, leading to a buildup of acetaldehyde, which is what causes the negative effects in the body.
The drug was first marketed in Denmark and as of 2008 Denmark was the country where it was most widely prescribed. It was approved by the FDA in 1951. The FDA later approved other drugs for treatment of alcohol use disorder, namely naltrexone in 1994 and acamprosate in 2004.
When disulfiram creates complexes with metals (dithiocarbamate complexes), it is a proteasome inhibitor and as of 2016 it had been studied in in vitro experiments, model animals, and small clinical trials as a possible treatment for liver metastasis, metastatic melanoma, glioblastoma, non-small cell lung cancer, and prostate cancer. Various clinical trials of copper depletion agents have been carried out.
Disulfiram has also been identified by systematic high-throughput screening as a potential HIV latency reversing agent (LRA). Reactivation of latent HIV infection in patients is part of an investigational strategy known as “shock and kill” which may be able to reduce or eliminate the HIV reservoir. Recent phase II dose-escalation studies in patients with HIV who are controlled on antiretroviral therapy have observed an increase in cell-associated unspliced HIV RNA with increasing exposure to disulfiram and its metabolites. Disulfiram is also being investigated in combination with vorinostat, another investigational latency reversing agent, to treat HIV.