Psychiatry Classics #4: Disulfiram for alcohol addiction

In the 1940s two Danish researchers, Erik Jacobsen and Jens Hald, tested a series of substances in an attempt to identify drugs that might rid the body of intestinal worms. After one of them worked in rabbits, Jacobsen tried it on himself, as he had a fun little habit of trying all of his invented drugs on himself.

“During the course of self-experimentation” as Larimer reports, both Jacobsen and Hald noted this substance — called disulfiram — led to a substantial increase in their sensitivity to the toxic effects of alcohol.

In late 1947 and 1948, Oluf Martensen-Larsen, an expert on the treatment of alcoholism, was able to convince his colleagues to allow him to try disulfiram in the treatment of alcohol abuse. In this classic paper, he reported on 83 patients that he had treated with disulfiram (also called Antabuse) for the treatment of their alcohol addiction.

At the time the mechanism was not known, but it was known that giving the drug prophylactically led people to become violently ill with hangover-like effects of alcohol. It is now almost certain that its effects are due to the inhibition of aldehyde dehydrogenase, which causes acetaldehyde to build up in the blood stream following alcohol consumption and cause all sorts of unpleasant toxicity.

In cultured cortical neurons, acetaldehyde causes a substantial loss of MAP2-positive neuronal processes, indicative of the fact that the toxicity of acetaldehyde does not spare the CNS:

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PMID: 11132090

One of the patients he described as having a successful reaction to the treatment was a middle-aged woman. After starting on disulfiram, she began to blush after taking only a mouthful of liquor. As Martensen-Larsen reports, “Her abstinence might be explained by her desire to avoid the humiliation associated with the blushing, but she insists that this is not the deciding factor, and that she has lost the taste for wine and spirits.”

Overall, he classifies 32/83 (39%) of patients as successes, 29/83 (35%) as partial successes as long as their blood and urine checks indicated that they will still on the drug, 13/83 (16%) as successes only as long as the physician can successfully encourage them to stay on the drug, and 9/83 (11%) as not responding to the drug, at least in because they refused to continue on it.

Disulfiram is still used today as a part of a comprehensive treatment for alcohol addiction that includes psychosocial factors as well.

References

Larimer R 1952 JAMA Treatment Of Alcoholism with Antabuse. doi:10.1001/jama.1952.03680020013004

Arghya Pal, Raman Deep Pattanayak, Rajesh Sagar. (2015) “Tracing the journey of disulfiram: From an unintended discovery to a treatment option for alcoholism.” Journal of Mental Health and Human Behavior. DOI: 10.4103/0971-8990.164826

Martensen-Larsen O. Treatment of alcoholism with a sensitizing drug. Lancet 1948;2:1004. Back to cited text no.

Wan JY, Wang JY, Wang Y, Wang JY. A comparison between acute exposures to ethanol and acetaldehyde on neurotoxicity, nitric oxide production and NMDA-induced excitotoxicity in primary cultures of cortical neurons. Chin J Physiol. 2000;43(3):131-8.