Alcohol addiction and the THIQ Hypothesis

This is a summary of research results, a compilation of observations of mine, all tossed together with speculations based on my education and expertise. Frankly, I’m quite convinced of the conclusions, enough so that I intend to pursue biochemical and genetic research on this. There’s enough here to spend a life time on, and I intend to, unless I can get real results sooner. I find it a fascinating study in the operation of science, as much as in addictions.

It starts some years ago with dead people. In a fairly well known (among those in the addiction field) story, a researcher was looking into brain structures using dead people at a coroner’s office. She knew about the particular changes that occur with chronic opiate use. While examining the brains in question, she remarked to the coroner that it was surprising that so many of their subjects were junkies. The coroner replied that these were in fact winos who suffered from all the signs of chronic alcoholism in all their body tissues, and none were shown to be addicted to opiates. So began the research into the chemical similarities between alcohol and heroin addiction. Among the results of this was the fact that there was a general atrophy of endorphin receptors. Somehow, these receptors,those stimulated by either endorphins (endogenous morphine) or the plant kingdom’s real stuff, were getting wiped out. Examining them showed that they were being plugged by a molecule which fit into the receptor, but was dissimilar enough that it was not being removed.

This chemical is tetrahydro isoquinilone. It is a normally formed breakdown product of the monoamine neurotransmitters. Monoamine oxidase attacks these neurotransmitters once they’ve done their job, removes them from the receptors, and disassembles them for reuptake into the neuron for recycling. These are normal, but only in very small amounts. In the presence of acetaldehyde, the first breakdown product of ethyl alcohol, and in fact a product of burning tobacco, monoamines break down much more frequently into this chemical.

THIQ - tetrahydro isoquinilone

When acetaldehyde is present, THIQ forms. It gets plugged into endorphin receptors, and stimulates them. This is a primary agonist action. However, the part of the molecule which protrudes from the receptor is *not* shaped like the neurotransmitter it acts as, and the monoamine oxidase cannot remove it or break it down. It gets stuck in the receptor, preventing it from being used again. This is a secondary antagonist action — a permanent one. With more and more endorphin receptors being taken out of action, the person begins to feel the lack. They feel the need to return to the previous balance. They have already trained their brain to know that using alcohol (or tobacco) relieves this need. So they use some more. Once enough receptors are taken out by THIQ, and the person attempts to correct it, an escalating spiral has started.

This THIQ hypothesis made big noise when it was first introduced, a little over 5 years ago. At first, there were studies which showed that the hypothesis was flawed. It fell out of favor. Then, more studies showed that the reaction would in fact take place, and it came back in. Finally, in the absence of corroborating evidence in biological systems, it fell out of favor again.

Last summer, out comes a claim from a researcher named Mele. He had been hired by a tobacco company to do studies on, well, I’m not really sure. But what he ended up doing was showing that rats preferred to take acetaldehyde. Since it’s nasty stuff, they won’t drink it, so the apparatus used included IV injection. Once habituated to nicotine, rats would press a bar 12 times on average for water. They would press 4 times that for water and nicotine. But they would press it 10 times 40 times that for water, nicotine and acetaldehyde. Since this appeared to substantiate the fact that tobacco was addictive (recall acetaldehyde is in tobacco smoke) the company decided not to publish his results (so goes his fairly well substantiated claim). The corroborating evidence for acetaldehyde’s role in mediating *some forms* of addiction apparently exists, and in fact existed 10 years ago, when he did this work.

What else supports this? The long standing claim that genetics plays a part. Alcohol breaks down by the action of alcohol dehydrogenase on the alcohol, removing a hydrogen, forming acetaldehyde. This toxin is supposed to be removed quickly by the action of acetaldehyde dehydrogenase (away with another hydrogen) forming acetate and water. If, in this two step process, there is either relatively too much alcohol dehydrogenase, or relatively too little acetaldehyde dehydrogenase, a build up of acetaldehyde will occur. The levels of both of these enzymes are genetically determined. It would seem that if the gap between these were too large the person would be more prone to addiction.

Yet the Japanese are very often extremely deficient in aldehyde dehydrogenase, hence their tendency to turn red, sweat, get cramps, etc., when they take alcohol. This effect is so common that it’s called the ‘oriental flush’. This is precisely the effect seen when someone drinks on Antabuse – disulfarim – which blocks the action of aldehyde dehydrogenase. It appears there is a range of disparity between the enzymes which allows the acetaldehyde build up to the point that THIQ is formed, but not so much that the person suffers too much of this effect when they drink.

Many studies have been done on alcohol metabolism. Most have shown that the metabolism of alcohol does not correlate with incidence of alcoholism. Not in racial groups, and not in individuals. My contention is that they’ve studied the wrong thing. They looked at the metabolism of alcohol, *not* the metabolism of acetaldehyde. Alcohol provides the primary action sought by users, and may in itself be habit forming, but I claim that it is the acetaldehyde which mediates the addiction. My field of personal interest is in studying what appears to be an extremely high rate of alcoholism in Native Americans. Incidence rates in 1980 were estimated at 70%. Those that had it suffered adverse consequences in all body systems more so than most other groups, and much sooner.

Native Americans are a genetic group coming from three separate ancestral groups from the orient. It is likely they have a genetic make up for the markers for acetaldehyde production, which falls pretty much at the optimum for THIQ production. What’s it going to take to prove this? First, following up on Mele’s work to substantiate it. Ksir at Wyoming (co-author of probably the best drug use and abuse textbook on the market) is in the process of doing this. Getting the rats to take acetaldehyde is apparently the sticking point.

Second, redoing the alcohol metabolism studies with measurement of acetaldehyde levels over time. Last, determining the genetic markers for acetaldehyde production, and correlating them with incidence rates in genetic groups, and with individuals who have been shown to be particularly susceptible to alcohol addiction. #1 being under way, I intend to work on #2. #3 will come once report comes from the human gnome project that they have isolated the genotypes which determine acetaldehyde dehydrogenase production. We know the specific enzymes and locations of production, so it won’t be too tough a job. Getting it past the ethics committees will be tougher.

As I said, some of this is speculative. But too many pieces of the puzzle fit too well for it to be entirely wrong. If it all turns out, it will give us a genetic marker for testing to determine if a person is at high risk to develop addiction to anything which produces acetaldehyde. This will give the person the chance at informed decision making. And given the expected advances in genetic medicine, it should be possible to correct the enzyme levels if not in individuals, then in their offspring, and so reduce their risk. Addiction would still exist. But some cases of it could be prevented either by high risk persons choosing not to use, or physical reduction of the risk factor. I welcome comments, particular thoughtful comments, regarding the background, logic and conclusions here. I am, at the root of it all, interested in discovering the true nature of addictions, or as much as possible. This is the end of Dynasor’s writing

The short story is: Rats were placed in one cage with water and an alcohol mixture. The rats chose to drink the water, completely ignoring the alcohol mixture.

The rats were taken out of the cage. THIQ was surgically implanted in their brains and they were placed back in the cage. Now they drank the alcohol, completely ignoring the pure water, until they died.

Such is the nature of our disease. Surgically implanting the THIQ completely bypasses all social factors so that whether or not we went to church, got potty trained, came from a split family, were sexually abused, or any other number of social factors matter not one whit. It is completely a matter of whether or not the brain manufactors THIQ. If it does. (and we drink at all) we become alcoholic.

If the brain does not manufactor THIQ we cannot become alcoholic, even if we drink a freight train load.

by Dennis McClain-Furmanski,

1 Comment

  1. melissa

    I enjoyed reading and understanding your thought process, I am in college now, to be an addiction counselor, and also am in recovery. I am an alcoholic who has remained sober for 5 years with the help of AA. I believe you are on the right track! I look forward to hearing more.

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