INSPIRATIONS FROM HISTORY
Year : 2015 | Volume
: 20 | Issue : 1 | Page : 41--43
Tracing the journey of disulfiram: From an unintended discovery to a treatment option for alcoholism
Arghya Pal, Raman Deep Pattanayak, Rajesh Sagar
Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India
Raman Deep Pattanayak
Department of Psychiatry, All India Institute of Medical Sciences, New Delhi
Disulfiram is a drug that has been used as a deterrent agent in the treatment of alcohol use disorders. This section ventures into the journey of the discovery of the molecule, starting from the accidental discovery of its potential pathophysiological effects, thereafter becoming obscure due to lack of indications (alcohol use was not considered a problem!); and finally making a comeback and standing the rigorous test of time due to the determination of a few researchers, which makes it a story worth revisiting.
|How to cite this article:|
Pal A, Pattanayak RD, Sagar R. Tracing the journey of disulfiram: From an unintended discovery to a treatment option for alcoholism.J Mental Health Hum Behav 2015;20:41-43
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Pal A, Pattanayak RD, Sagar R. Tracing the journey of disulfiram: From an unintended discovery to a treatment option for alcoholism. J Mental Health Hum Behav [serial online] 2015 [cited 2020 Feb 26 ];20:41-43
Available from: http://www.jmhhb.org/text.asp?2015/20/1/41/164826
The Nobel Laureate Dr. Albert Szent-Gyorgyi stated that " discovery is said to be an accident meeting a prepared mind." The story of disulfiram illustrates the fantastic journey of a molecule from being discovered accidentally, going into obscurity due to lack of indications, bounced back due to the bravado of a few determined researchers and stood the test of time.
Disulfiram or tetraethylthiuram disulfide (Antabuse; ) is used as a deterrent agent for patients with alcohol use disorders, thereby supporting the patients in their effort to maintain abstinence. Unlike the popular lay beliefs that it is used to deter the unwilling or unmotivated patients from using alcohol, its medical use is always done with informed consent of the patient, and the idea is to facilitate abstinence in a client or patient who is otherwise motivated to quit, but finds it difficult to resist. The drug leads to an irreversible inactivation of aldehyde dehydrogenase leading to the cessation of alcohol metabolism at the acetaldehyde state, leading to its accumulation in the blood leading to the unpleasant sensation.
Historical Aspect: Tracing the Journey
The first reports of synthesis of disulfiram as a compound dates back to 1881 when a German Chemist M. Grodzki synthesized it like many of other newer compounds during that time.  The then apparently insignificant discovery made it back to the limelight by finding its use in rubber industry in order to hasten vulcanization (i.e., the process of stiffening rubber). It was here that the watchful eyes of E. E. Williams caught the distress among the workers involved in the processing of the substances after ingesting alcohol. 
However, the lead character of the disulfiram story was Dr. Erik Jacobsen (1903-1985) who was a Professor of Pharmacology at the University of Copenhagen. In the 1940s, he along with Dr. Jens Hald started working on the copper metabolism of the intestinal parasites, which is the prime metal in the respiratory pigment in the helminthes. They discovered that disulfiram could form chelates with copper leading to the death of the organisms. During these years Dr. Jacobsen assumed the post of head of the Biochemistry Laboratory of a Danish Pharmaceutical Company Medicinal Co. Inc., which took an immediate interest in these results. At that time, courtesy of the damage due to the Second World War, Scabies and intestinal worm infections were major public health problems and thus, disulfiram was rapidly hoisted to the peak of popularity.
Then came the positive results of its vermicidal action in rabbits, and Dr. Jacobsen, with a habit of trying out the new drugs on himself, decided to expose himself to disulfiram. Very quickly, he could realize that "disulfiram tablets really changed the effect of alcohol in a most unpleasant direction."  When similar results also came from his partner Dr. Hald, they thought of using the substance in treating patients with alcohol use disorder. However, the idea received lukewarm interest because alcohol dependence was not considered to be a big enough problem!
Later, on the insistence of Dr. Oluf Martensen-Larsen, an expert in treating patients with alcohol use and who pointed out the immense potential of the drug as an alcohol-deterrent agent, the interest in the drug was sustained again. Another accidental mixing of a sample of disulfiram with copper led to the obtainment of a better molecule with a larger surface and being easily absorbed in the organisms. This molecule was later patented under the Danish name of "Antabus" in 1952, but was soon anglicized as "Antabuse" - a name that not only bore evidence to its gaining popularity, but was also a tell-tale of its purpose.
The story had another breakthrough which occurred quite by chance when one of their colleagues had suddenly entered their laboratory to the "smell of Acetaldehyde," to which the Dr. Jacobsen was oblivious being occupied in the room for ages, pondering over the mechanism of action. Later on Hald and Jacobsen were able to demonstrate increased level of acetaldehyde in the blood and also in the expired air. By this time, due to the previous work of Dr. Erik Widmark, it was well known that ethanol was metabolized in the liver by successive conversion acetaldehyde and then to acetic acid by the enzyme alcohol and aldehyde dehydrogenase respectively. After this, they were able to derive that the drug acts by inhibiting the aldehyde dehydrogenase, leading to the accumulation of acetaldehyde.
Following this, came a series of papers, initially in the Scandinavian Journals followed by publications in the European  and American community. Other researchers with interest also started using the drug with promising results. Dr. Martensen-Larsen reported the use of disulfiram on 83 patients with approximately 50% being able "benefit markedly."  Researchers like Dr. Erik Glud also pointed out the need to optimize the pattern of using disulfiram considering the difference in the pattern of drinking among the American and Scandinavian community. 
Later, the research on the molecule started to diversify ranging from the disulfiram-ethanol interaction to the pathophysiological effects of the produced Acetaldehyde. The research on disulfiram not only stimulated research on alcohol metabolism, but also related chemical and pharmacological aspects leading to the discovery of certain other substances that can cause reaction with alcohol like tetramethylthiuram monosulfide, which were very similar to disulfiram.
Clinical Use from the Mid-20 th Century Till Date
By the early 1950s, disulfiram started to come in clinical use in full fledge. It was approved to be used in Denmark in 1949 and the United States in 1951. However, the drug also fell into disrepute due to the fatal reactions caused due to the use of exorbitant high dosages (up to 3000 mg). The drug also became notorious due to the reports of the neurological, hepatic, and cutaneous side-effects which later on were attributed to diethyldithiocarbamate, one its metabolites. Soon, the dosage came down significantly and after reduction of dose-related toxicity, there was a renewed interest in its prospect.
The drug remains a case of being thrust into clinical action without the rigorous preclinical trials. However, about 60% of the later published studies showed acceptable abstinence rates. In a recent meta-analysis, disulfiram was found to be a safe and efficacious treatment compared to other abstinence supportive pharmacological treatments or to no disulfiram.  A prospective open treatment study evaluated the long-term course of drinking outcomes and impact of deterrent agents in 180 chronic alcohol-dependent users consecutively admitted over 9 years and found the abstinence rate of >50% over a period of follow-up until 7 years. The cumulative probability of not having relapsed was 0.52, and that of not having consumed any alcohol was 0.26.  Despite long-term use, disulfiram/calcium carbimide were well tolerated.
Even after seven decades of being in vogue, disulfiram remains one of the most frequently prescribed medications in alcohol dependence, with a higher trend of use in the Scandinavian countries. It is frequently used as a deterrent agent in the specialist substance use treatment settings in India as well. Further, disulfiram is an economical and low-cost drug, which makes it affordable for patients. The treatment of alcohol dependence remains a challenging issue, and no single option can cater to all the diverse cases of alcohol use disorders. Nonetheless, it is useful to have the therapeutic options available from which the client and clinicians can consider the best-fit for a particular clinical situation.
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Conflicts of interest
There are no conflicts of interest.
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