From: (Dennis McClain-Furmanski)
Newsgroups: alt.drugs.hard,alt.drugs
Subject: THIQ Hypothesis
Date: 30 Jan 1995 00:48:33 GMT

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
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
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 genome 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
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, not
necessarily in just proving my pet theory.