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How is alcohol neurotoxic?

Doodle

Bluelighter
Joined
Nov 17, 2003
Messages
1,256
Location
Melbourne, Australia
Okay I've seached all over the shop about this but haven't found anything. Learnt heaps about other stuff - now my head hurts :)

I know alcohol is neurotoxic (i.e. it damages brain neurons) but what I don't understand is how it is neurotoxic.

For example I do understand how MDMA possibly leads neurotoxicity because of dopamine being picked up by serotonin reuptakers and MAO converting this to hydrogen peroxicde which is toxic to the brain.

So whats the process which causes alcohol to be neurotoxic?

Hope this makes sense - thanks for your help.
 
Wow, I didn't know alcohol was neurotoxic. I googled 'alcohol neurotoxicty' and while it brings up references to it, there's no pages explaining it.

I second Doodle's request.

:)
 
The dopamine uptake via the serotonin transporter theory seems to have been significantly discredited these days.

Take a look at the metabolites of alcohol - acetyldehyde, which is toxic. This metabolism is intracellular, and so presumably stresses the relevant cell.

Moreover high levels of alcohol seem to reduce levels of key vitamins, though I've only a had a quick glance around the web and so haven't really looked for much detail related to this.
 
Take a look at the metabolites of alcohol - acetyldehyde, which is toxic.

Absolutely. This stuff is nasty. This is why us westerners tolerate alcohol so well. We evolved, that is after deciding the only way to sterilize water was to add yeast and brew it 8) The Chinese on the other hand found that boiling water had the same effect 8o

As time went on we developed a response to alcohol - the toxin - by producing extra oxidative enzymes to allow quick conversion of acetaldehyde to acetic acid.

Although there are undoubtedly other mechanisms at play, and alcohol can be metabolised in the brain, it is this toxin which no doubt causes many of the degenerative disorder which accompany long term high levels of alcohol abuse. What's amazing is to look at the lobotomised brain of a serious long term alcoholic. The grey matter not only turns white, but disappears altogether leaving a big hole!!

So what should we to do with all the extra oxidative RNA and enzymes floating around, if not feel like a drink? ;)
 
taken from the DXM faq

Excitotoxic rebound is a process by which brain cells, accustomed to a lower level of activity, essentially "burn themselves out" when a depressant drug is removed. Alcohol, benzodiazepines (tranquilizers, e.g., ValiumTM), and barbiturates (sedative-hypnotics or "downers") are well known for causing severe excitotoxic rebound

probably only applies to alcoholics... avoided by 'tapering down' your dose
 
phase_dancer said:
So what should we to do with all the extra oxidative RNA and enzymes floating around, if not feel like a drink? ;)

Take pills? Oh woops, wrong enzyme :p
 
^ I dunno, there could be a few places where increased oxidation rates via 2D6 or other enzymes might be preferable over the alternative: that villain MAO ;)

MDMA_metabolism.gif
 
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woah hectic diagram. nice one.

I'll admit that I know much less than you about mdma pharmacology, but the more evidence I hear dropped by people around this forum "in the know" the more I come to think MAO-B seems to be mostly responsible for the problems with MDMA.

Nice website too phase_dancer :)
anyway, back on topic.
 
just to digress a little bit further im fascinated to see that when u take MDMA your also getting exposed to a host of other metabolites... i knew metabolites were formed but i thought it was just a single inactive molecule or something... that diagram is crazy... DMDA, HO-MDA, etc ... wow
 
I've always had the feeling that alcohol 'shuts things off' so to speak. I too have been wondering about alcohols neurotoxic effect. I have looked around at what happens with long term and heavy alcoholism, and was not suprised in the least at what happens to the brain. I have especially been interested with the DT's because it is not always reversable (though most cases are), and it is guaranteed to cause some type of permanant damage in the brain... just like heavy E or amphetamine useage leaves its trace on the brain.
"Alcohol withdrawal syndrome is mediated by a variety of mechanisms. The brain maintains neurochemical balance through inhibitory and excitatory neurotransmitters. The main inhibitory neurotransmitter is gamma-aminobutyric acid (GABA), which acts through the GABA-alpha (GABA-A) neuroreceptor. One of the major excitatory neurotransmitters is glutamate, which acts through the N-methyl-D-aspartate (NMDA) neuroreceptor.

Alcohol enhances the effect of GABA on GABA-A neuroreceptors, resulting in decreased overall brain excitability. Chronic exposure to alcohol results in a compensatory decrease of GABA-A neuroreceptor response to GABA, evidenced by increasing tolerance of the effects of alcohol.

Alcohol inhibits NMDA neuroreceptors, and chronic alcohol exposure results in up-regulation of these receptors. Abrupt cessation of alcohol exposure results in brain hyperexcitability, because receptors previously inhibited by alcohol are no longer inhibited. Brain hyperexcitability manifests clinically as anxiety, irritability, agitation, and tremors. Severe manifestations include alcohol withdrawal seizures and delirium tremens."
Alcohol Withdrawal Syndrome - March 15, 2004 - American Family Physician

I will look around some more to find some case studies and papers regarding permanant damage, might go check out a psychology book of mine by Glassman... the biological perspective might have something.
 
I thought one of the main ways alcohol was neurotoxic was through dehydration?

Draining the fluid that your brain floats in causing physical damage to the brain?
 
I don't have any sources, I just read it on bluelight somewhere...

And I don't think that it would be all the fluid around your brain, just a little might cause enough of a disturbance...

Does anyone know if the neurotoxic because of dehydration thing is true?
 
I seriously doubt it... there's plenty of fluid there, and it's replenished pretty fast in case of loss. Besides, unless you're drinking 100% alcohol (and I DO mean 100%, and you're talking about a lab to get that) alcohol probably isn't going to dehydrate anything, since most drinks are 40% tops, and ethyl alcohol, while completely miscible with water, will only actively absorb about 6% of its volume before reaching an equilibrium.

I think it has (at least partly) something to do with disruption of cell membranes... I know that's how it kills bacteria! I'm pretty sure I remember reading it somewhere; I cant remember the details, though..

Some old lecture notes (I'm suddenly realising just how distracting this place is... I'm supposed to be studying third year chemistry, not second year pharmacology!! ;)) suggest that long-term alcohol neurotoxicity includes visual impariment, paresthesis of hands and feet, Wernike's ecephalopathy (including brain lesions and characterised by ataxia, confusion and paralysis), cerebral atrophy, enlarged ventricles and memory disorders such as Korsahoff's syndrome (good god... remind me never to drink again...!!). Anyway, other than that, I know little... my pharmacology textbook references the following, which I can't get online, but someone might have at a library (no time to look, but if someone's really keen, I can go over and have a browse in a week or two):

Charness, M. E., Simon, R. P., Greenberg, D. A., "Ethanol and the nervous system", N Engl J Med 321:442-454.

If someone finds it, perhaps they could scan and upload it? I'd be interested to read it myself... Someone could also try a literature search, see what they can find, if they have more time than me? Else it'll give me something to do in my upcoming break :D
 
I'm supposed to be studying third year chemistry

Oh that makes me feel all warm and fuzzy inside ;)

Great to hear there may be another critical voice in the chem department? I need some disagreement and argument with some of my outlandish postulations, and we have so few chemist students/ graduates who regularly post on this forum. Nice to see the number is growing :)

Thanks for your comments and the reference phantasmal. Sadly I don't have access to that database, but if anyone want's to buy me a subscription.... =D

I'll look on a few hosting databases I do have access to, but from what I've seen so far, there's very few NEJM papers
 
i like to view alcohol as exercising the brain. through neurotoxicity, you're mearly killing off the lazy cells. when glutamate receptors, then transmiters up-regulate, you'll light up the pet-scans like its christmas!
 
Resilience to Alcohol

Resilience

Like most of you, I've known a few drinkers who couldn't be classed as anything other than alcoholics. Take 30 or more years of hard drinking, and add that to the same number of years (or more) smoking cigarettes, and the overall deterioration of health becomes more than apparent after ~ age 50.

But in respect to giving up at a later age, it's also amazing to discover just how resilient and repairable the body is, even at age 60.

During my teens - after my father had departed for a brighter future - an old school friend of my mums (Len) made our place his second home for a few years. Mum was a social drinker and occasional smoker and never had a problem giving up either drink or cigs when she felt she was developing a smokers cough. But as I said, she was not hardcore at either.

So I never saw any detrimental health effects from her lifestyle. Quite different was Len who drank copious amounts of beer and smoked 80+ 16mg cigs a day. Len was an ex-serviceman who worked at a prison farm. His day consisted of being up at 4:00am to round up the boys to milk cows. By 8:00am he was finished till 4:00pm when he returned to supervise the afternoon milking.

His time in between was spent at the RSA (NZ RSL equivalent) drinking with his mates. After evening knock off he'd usually go back to the RSA, then at some point arrive at our place for something to eat - with more beer. Len would smoke ~ a 20 pkt after dinner and on the way home.

Len had a smokers cough that would raise the dead. It was hideous. If he felt a coughing fit coming on he'd disappear into the bathroom where he'd gasp and wheeze, cough a splutter. When he caught my bro and I pressed ear to the bathroom door, he said nothing and walked past. I wondered how the fuck he was still alive - it was that bad and both my bro and I have never since heard a cough like it.

After almost a year of knowing Len I asked mum how she knew Len at school. She said Len was in the 1st 15 rugby team, and was every girls' dream date. He was strong, feisty, quick witted and a smooth dude. She dug out a couple of old photo's which left me stunned.

I couldn't believe it; that this shadow of a man, the frail and awkward Len, once was a top football player? Fuck, I thought! what had changed?

I brewed on this long and hard, lying awake at night wondering how and when the changes in this man had taken place. He was 3 years younger than mum yet looked 20 years older. Finally, after quitting cigs myself at 20, I suggested he might like to try the Herbal Tobacco (no not pot) I used to wean off the nicotine. Surprisingly he agreed to give them a go. It lasted almost a week, where for 2 days he got down to less than 10 cigs, while smoking the herbal inbetween. Then he went back to cigs saying the herbals were too awkward to roll. So I rolled up a few ounces and off he went. A few months later he gave up altogether.

Now, with all that beer, you'd think this man would have a big healthy [sic] pot belly. But he didn't - he was skinny as a rake. However, after a couple of months off the ciggies, his tummy started to grow. When I returned to NZ in 83 after being away 2 years, Len was a big belly beer drinker, but despite that he looked so much more healthy.

I had a lot of distaste for Len during the first years I knew him. He gave my mates and my bro and I shit all the time. He'd wave a finger at my friends saying something like "I'll see you in Waikeria [Prison]. You'll all end up there...good for nothing fuckin kids... " He was also the one who took all my chem gear and buried it to make more room in the shed. I won't go into details which followed other than to say I never spoke to either him or my mum for over a year. So I really had reason to dislike this man. But over time pity had taken place of vengeance.

The next time I returned home, some 6 years later, I was absolutely blown away. I couldn't get over how he looked. He'd been off the booze for nearly a year and looked years younger. He was sharp and quick witted, happy faced; a completely different person. I was instantly flooded with a deep admiration for this man who's eyes sparkled in a way I can't describe. He was a hero afterall. Not only did he banish his 2 massive monkeys, but he stood taller, like an older version of the champ I'd seen in those photos.


Presently in his late 70's, ol Len achieved more in the 10 years post-drinking than he had in much of his earlier life. Although his mind has remained sharp, he has suffered from what was probably other alcohol related illness. He did end up having had a heart attack, - probably from a new young bride of 65 ;) - but a triple bypass seemed to fix that. Diabetes and Arthritis have plagued him recently, but all the same, he had 10 years where his quality of life soared.


But if I'd had to guess his life expectancy when I first met Len, I would have said he wouldn't have lasted more than a couple of years. My conclusion was that while alcohol may damage the brain and organs - beyond repair even - it obviously - at least for some people - takes a lot to damage the brain beyond recovery.
 
Thanks all for your input.

Here is an interesting but long read regarding how acetaldehyde may/does affect the brain.

Seeing it is long I have put the most relevant part in bold.

From "Alcoholism--the Biochemical Connection" by Joan Larson, PhD:

Discoveries about the way alcohol is processed in the body
have provided further evidence of a genetic link. For example,
Harvard scientists (L. Tunglai et al. 1977) recently came upon a
previously unknown liver enzyme responsible for metabolizing
alcohol. This enzyme, alcohol dehydrogenase II (II ADH), can
process or oxidize alcohol up to 40 percent more efficiently than
the liver enzymes most of us have. People who have this enzyme--
and most of us do not--have an inborn ability to drink very large
amounts of alcohol without becoming intoxicated. These are the
folks who can drink many of us under the table without getting
the least bit tipsy and or feeling hung over the next morning.
Researchers have also discovered that the absence of a
crucial liver enzyme accounts for the fact that very few
Orientals become alcoholics. In fact, many Asians get sick
whenever they drink. Their pulses race and they feel dizzy and
nauseated. The explanation for this peculiar reaction is the fact
that many Orientals have only one liver enzyme that processes
alcohol, rather than the two found in people from other parts of
the world. About half the Oriental population is missing this
second crucial enzyme.
Alcoholics and nonalcoholics process alcohol differently.
When alcohol reaches the liver, it is changed into acetaldehyde,
a harmful byproduct of alcohol metabolism that can damage liver
cells. Normally, the liver rapidly transforms the harmful
acetaldehyde into a neutral substance called acetic acid or
acetate. The acetic acid is then converted into carbon dioxide
and water. We expel the carbon dioxide through respiration and
the water through urination.
Until recently, it was believed that the liver always
handles alcohol in the same way. But new research shows that a
different scenario occurs among certain alcoholics and children
of alcoholics with no drinking experience. Their livers change
alcohol into acetaldehyde at twice the normal rate, while the
subsequent conversion of acetaldehyde into acetic acid is
abnormally slow and takes twice as long as usual. The
accumulation of acetaldehyde damages liver cells, which become
abnormally large as they strive to get rid of the accumulated
acetaldehyde. This damage affects the liver's ability to absorb
and utilize the nutrients needed for good health. To make matters
worse, excess acetaldehyde escapes the liver and travels through
the bloodstream to the heart, where it can be very damaging (it
interferes with the protein synthesis of the heart muscle).

It (acetaldehyde)
also reaches the brain, where it blocks proper neurotransmitter
action in creating normal feelings, behavior, and memory. The
unused natural neurotransmitters begin to build up and combine
with the acetaldehyde to form potent psychoactive compounds
called tetrahydroisoquinolines (THIQs), which are remarkable
similar to opiates. THIQs fit in the same receptor sites in the
brain as natural pain killing chemicals called endorphins and
such narcotics as morphine and heroin.



The Chemistry of Addiction

Two decades ago, Texas researcher Virginia Davis noticed
during autopsies of skid row alcoholics that their brains
contained an opiate that she first mistook for heroin. This was
puzzling because these indigents did not have the money needed to
support such an expensive drug habit. The heroin like substance
turned out to be THIQs that had been manufactured inside their
brains when acetaldehyde from the breakdown of alcohol had
combined with natural neurotransmitters. Davis's data support the
concept of alcoholism as a true addiction stemming from specific
biochemical events leading to the formation of an addictive
substance similar to opiates such as heroin.
We now know that in heavy drinkers, THIQs displace
endorphins and bind with the opiate receptors in the brain. In
doing so, they signal the brain to stop producing endorphins. As
the natural endorphin supply declines, more and more alcohol is
needed to produce more THIQs to replace the natural endorphins
and bind with opiate receptors to create feelings of well-being.
At the University of Texas, researcher Kenneth Blum, M.D.,
found that restoring these natural endorphins and
neurotransmitters destroyed or depleted by alcohol will reduce
cravings for alcohol and restore normal moods.
Some pertinent findings emerged from a study of the
reactions to alcohol among two groups of college students. One
group was composed of students who had a family history of
alcoholism; those in the second group had no alcoholism in their
backgrounds. After four drinks, the students from alcoholic
families produced much higher levels of acetaldehyde, and they
could perform a variety of mental and physical tests better under
the influence of four drinks than when they had not been
drinking. The students with no family history of alcoholism
reported feeling moderately intoxicated and showed impaired
physical dexterity, reflexes, mental ability after four drinks.


Is this change in the brain considered to be the result of neurotoxicity?

Apparently acetaldehyde is also found in:

- Yoghurt
- Cigarette smoke
- Marijuana Smoke

Also for the simple folk like me here is a basic explanation of the how alcohol affects the human body.

How alcohol works
http://science.howstuffworks.com/alcohol.htm
 
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