Distinguished Faculty award winner, Professor of Human Medicine James Galligan.by James J. Galligan, Ph.D.,
Professor of Pharmacology and Toxicology
and Neuroscience Program Director

Alcoholism is difficult to treat as alcohol can change brain function in an almost permanent way such that cravings for the drug never go away even when the alcoholic is sober. There are many treatment plans which have varying degrees of success but even in alcoholics who have been sober for years, there is always a risk of relapse.

There are several drugs used for the treatment of alcoholism with varying degrees of success. One drug that is very effective in reducing the cravings for alcohol is disulfiram. To understand how this drug works, we need to understand how the body metabolizes alcohol. Alcohol is metabolized in the liver. There are two enzymes responsible for this process: alcohol dehydrogenase and aldehyde dehydrogenase (see figure below). Alcohol dehydrogenase takes one molecule of alcohol and converts it to acetaldehyde. Acetaldehyde is “toxic” as it is responsible for the effects we associate with a hangover (headache, nausea, vomiting). When most people drink moderate amounts of alcohol they do not experience a hangover as the enzyme aldehyde dehydrogenase converts acetaldehyde to acetic acid which is quickly excreted from the body by the kidney. However, when a person consumes large amounts of alcohol, aldehyde dehydrogenase cannot keep up with the amount of acetaldehyde that accumulates and a hangover results. Disulfiram is a drug that inhibits aldehyde dehydrogenase and is used to treat alcoholism. When a person takes disulfiram and drinks alcohol, aldehyde dehydrogenase cannot convert acetaldehyde to acetic acid and acetaldehyde levels build up even with moderate amounts of alcohol consumption. The drinker immediately feels nauseous with a headache and vomiting to follow. This person does not experience any of the “good” effects of alcohol and goes immediately to a hangover. Disulfiram works well in alcoholics trying to stay sober. However, if the alcoholic chooses to stop taking disulfiram it no longer works.

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Perhaps if aldehyde dehydrogenase could be inhibited permanently, this shortcoming could be overcome. This is the strategy being tested by a research group working in Chile in South America. The group led by Dr Juan Asenjo (Director of the Institute for Cell Dynamics and Biotechnology at Universidad de Chile) is preparing to test a “vaccine” that will produce long term inhibition of aldehyde dehydrogenase in an early clinical trial in human subjects. This is not the typical vaccine though. Conventional vaccines are injections of a virus or bacteria that will activate your immune system to produce antibodies against that invader. Usually only small amounts or an inactive form of the virus or bacteria is used. Now your body has an immune memory so that when you are exposed to that invader again, your immune system is prepared to fight off the infection. The Chilean group is proposing a different strategy. They will use a modern molecular biology technique in which a virus containing genetic material that will “knock down” the gene that encodes the aldehyde dehydrogenase protein. The Chilean group reports that this gene knockdown can last up to 9 months. Booster shots would likely be required to maintain the gene knockdown for continued protection against alcoholic relapses.

No data are available in the peer reviewed scientific literature to document the potential effectiveness of the gene knockdown strategy in the treatment of alcoholism. For example, there are no published studies of using this strategy in animal models of chronic alcohol consumption. We await the findings of the early trials of this exciting and hopefully life changing treatment for recovering alcoholics.