Choline Sources and Acetylcholine Explained - Mind Nutrition

Published on 5 Sep 2012
We review sources of choline, what choline does and which types are best suited to certain situations.

Beware of companies stuffing their products with choline combinations that have absolutely no benefit to customers. The shotgun approach is becoming increasingly common, as typical customers will see a long list of ingredients on a product label and assume that it must be good, which is mostly not the case.

For more information, subscribe to our channel or visit our website, http://www.mindnutrition.com


Choline as a "smart drug" dietary supplement - Wikipedia

Choline supplements are often taken as a form of 'smart drug' or nootropic, due to the role the neurotransmitter acetylcholine plays in various cognition systems within the brain.  Choline is the precursor molecule for the neurotransmitter acetylcholine, which is involved in many functions including memory and muscle control.

Choline is a chemical precursor or "building block" needed to produce acetylcholine, and research suggests that memory, intelligence, and mood are mediated at least in part by acetylcholine metabolism in the brain.[citation needed] In a study on rats, a correlation was shown between choline intake during pregnancy and mental task performance of the offspring.

The compound's polar groups, the quaternary amine and hydroxyl, render it lipid-insoluble, which might suggest it would be unable to cross the blood–brain barrier. However, a choline transporter that allows transport of choline across the blood–brain barrier exists.[46] The efficacy of these supplements in enhancing cognitive abilities is a topic of continuing debate.

The US Food and Drug Administration requires that infant formula not made from cow's milk be supplemented with choline.[47]

Due to its role in lipid metabolism, choline has also found its way into nutritional supplements that claim to reduce body fat, but little or no evidence proves it has any effect on reducing excess body fat, or that taking high amounts of choline will increase the rate at which fat is metabolised.[citation needed]

Pharmaceutical uses

Choline is used in the treatment of liver disorders,[48][49] Alzheimer's disease,[50] and bipolar disorder.[51]

Some studies show that as a supplement, choline is also used in treating hepatitis, glaucoma,[52] atherosclerosis, and, possibly, neurological disorders.[2]

Choline has also been proven to have a positive effect on those suffering from alcoholism.[53][54]
The current NIH-funded research study COBRIT is gathering data regarding potential benefit of long-term citicoline treatment for recovery after traumatic brain injury.

Groups at risk for choline deficiency

Vegetarians, vegans, endurance athletes, and people who drink a lot of alcohol may be at risk for choline deficiency and may benefit from choline supplements.[citation needed] Studies on a number of different populations have found that the average intake of choline was below the adequate intake.[2][15]
The choline researcher Dr. Steven Zeisel wrote: "A recent analysis of data from NHANES 2003–2004 revealed that for [American] older children, men, women and pregnant women, mean choline intakes are far below the AI. Ten percent or fewer had usual choline intakes at or above the AI."[2]

Food sources of choline

The adequate intake (AI) of choline is 425 milligrams per day for adult women, and higher for pregnant and breastfeeding women. The AI for adult men is 550 mg/day. There are also AIs for children and teens.[16]
Animal and plant foods Choline (mg) Calories
5 ounces (142 g) raw beef liver 473  192 [nb 1]
Large hardboiled egg 113  78 [nb 2]
Half a pound (227 g) cod fish 190  238 [nb 3]
Half a pound of chicken 150  543 [nb 4]
Quart of milk, 1% fat 173  410 [nb 5]
30 gram Brewer's yeast (2 tbsps) 120 116[17]
32 gram sunflower lecithin 544 250[18]
15 gram soy lecithin granules 450 120[19][20]
100 grams of Soybeans dry 116  268[21][22]
A pound (454 grams) of cauliflower 177  104 [nb 6]
A pound of spinach 113  154 [nb 7]
A cup of wheat germ 202  432 [nb 8]
Two cups (0.47 liters) firm tofu 142  353 [nb 9]
Two cups of cooked kidney beans 108  450 . [nb 10]
A cup of uncooked quinoa 119  626 . [nb 11]
A cup of uncooked amaranth 135  716 [nb 12]
A grapefruit 19  103 [nb 13]
Three cups (710 cc) cooked brown rice 54  649 [nb 14]
A cup (146 g) of peanuts 77  828 [nb 15]
A cup (143 g) of almonds 74  822 [nb 16]
Besides cauliflower, other cruciferous vegetables may also be good sources of choline.[23]
Sinapine is an quaternary ammonium alkaloid found in black mustard seeds. It is a choline ester of sinapic acid.[24]
Choline and other nutrient values for many foods can be obtained online.[a 1]

Necessary choline for humans

Here are the daily Adequate Intake Levels and Upper Limits for choline in milligrams, taken from a report published in 2000 by the American Institute of Medicine. [2]

Piracetam The original smart drug

Published on 4 May 2012
Piracetam http://www.antiaging-systems.com/146-... was the first nootropic developed from GABA in the 1960's. It has become famous for its ability to aid learning and memory. It has had many analogues developed from it including Aniracetam: http://www.antiaging-systems.com/42-a... and Pramiracetam: http://www.antiaging-systems.com/154-...

'Smart Pill' A Hit On College Campuses

Uploaded on 30 Mar 2011
Americans are thought of as a society that wants a magic pill to take care of any ill. So why wouldn't American kids look for a pill that makes them smarter?  Ritalin etc

Ten months of research condensed - A total newbies guide to nootropics - Brain Health - LONGECITY

Ten months of research condensed - A total newbies guide to nootropics

You may not be aware of it, but academic steroids are real, completely legal, and clinically proven. I have spent the last 10 months researching, purchasing, and experimenting with nearly every single nootropic available. (http://en.wikipedia.org/wiki/Nootropic)

The effects have been profound. First, with the help of a little caffeine, I am able to study for the bar exam all day with zero mental fatigue. Second, I am able to read vast quantities of information only one time and spit it back with pinpoint precision. It is the closest thing to a photographic memory I have ever experienced. The information is just there on command when needed. When I take practice tests most days I have nearly perfect recall and my only mistakes are analysis.

You can do this for yourself.

The following nootropic regimen is unique in a few regards.

First, the effects of the supplements are synergistic because each of them has a different mechanism of action. If you randomly start taking nootropics, you are likely to take supplements that do not give you a synergistic effect. For instance, acetylcholine is the primary nerotransmitter related to information processing. Acetylcholinerase is responsible for the breakdown of acetylcholine. There are multiple supplements that will increase acetylcholine production, among them CDPCholine, alphaGPC, DMAE, centrophenoxine and Acetyl L Carnitine. If you double up, you simply hit a ceiling on the amount of acetylcholine available. Also, many nootropics such as huperzine A inhibit acetylcholinerase. Inhibiting acetylcholinerase has the same effect as producing more acetylcholine. There are so many supplements whose only mechanism of action is either to increase acetylcholine production or inhibit acetylcholinerase. If you take multiples of these supplements, you will hit a ceiling and will not get a synergistic effect. The synergistic effect of different mechanisms of action is very important to the following regimen.

Second, the effects are cumulative. Caffeine and amphetamines actually deplete your brain over time. They are short-term band-aid solutions that merely shift your brain into overdrive before wearing it out. The supplements here actually enhance the structure and function of your brain. They are proven to be more effective in three months than they are when you first start taking them.

Third, these supplements are non-toxic. They are safe for chronic use.

Forth, if you start with the first three supplements to get a taste of what is available, it is relatively cheap.

If you are just getting started I recommend three supplements.

1) Piracetam
2) CDPCholine
3) Either sulbutiamine or pyritinol

Piracetam is the time honored granddadday of all nootropics. This is a good introduction - http://www.ceri.com/noot.htm When discovered it shocked researchers by being completely non-toxic and also enhancing the performance of normal adults with no forms of mental impairment. Piracetam is proven to increase performance on multiple measures of intelligence. Its effects are cumulative.

It is recommended that you take a source of choline with piracetam. I recommend CDPCholine. Piracetam needs a source of choline because acetylcholine is the primary neurotransmitter related to information processing.

Sulbutiamine prevents mental fatigue. You can be as effective 8 hours in to your day as you are upon waking up. Pyritinol increases alertness, energy and the ability to concentrate. Pick either.

The blood-brain barrier is a threshold that any nutrient must cross in order to be used by your brain. Sulbutiamine is a synthesized version of thiamine that crosses the blood-brain barrier better than regular thiamine. After crossing the blood-brain barrier it is broken down into two parts normal thiamine. It is essentially a brain specific source of thiamine. Thiamine reserves play an important role in mental endurance.

Pyritinol is a neuroenhanced version of vitamin B6. It is one of the oldest and safest nootropics available. Like sulbutiamine, it is essentially a brain specific version of a B vitamin.

I also take the following supplements.

Lion's Mane
Fish Oil

Picamilion is a designer drug. GABA is a neurotransmitter that plays a role in reducing nervous excitement. However, taking GABA orally is ineffective because GABA cannot cross the blood-brain barrier. Picamilion is a synthesis of niacin (vitamin B3) and GABA that was designed to cross the blood-brain barrier. After crossing the blood-brain barrier picamilion is broken down to niacin and GABA.

I especially like the effect of the three neuroenhanced B vitamins. Sulbutiamine is broken down to two thiamine parts (vitamin B1) after crossing the blood-brain barrier. Picamilon is broken down to niacin (vitamin B3) and GABA after it crosses the blood-brain barrier. Pyritinol is enhanced B6. The combination of brain specific B1, B3 and B6 is greater than any of them alone. They are highly synergistic.

Aniracetam is a supplement derived from piracetam. It is much more potent that piracetam and has entirely different types of effects. I take 750 mg of aniracetam and 4000 mg of piracetam daily. The effects are synergistic. Aniracetam is another supplement that you should probably research for yourself. Any supplement in the -racetam family is entirely non-toxic, has cumulative effects, and impacts almost every known measure of mental performance.

Lion's mane is a mushroom that has been used for centuries in the east to enhance the nervous system. Recently it has been discovered that this is because lion's mane increases the production of Nerve Growth Factor. NGF is responsible for determining the rate at which new brain cells are produced. A Nobel Prize was awarded for this discovery because no other substance is known to cross the blood-brain barrier and stimulate the production of NGF. Six months of supplementation with lion's mane is proven to produce a significant improvement in nearly every measure of mental function in people with dementia. In a literal sense, you have more brains when you supplement with lion's mane. NOBEL-FREAKING-PRIZE. Don't underestimate it.

Phosphatidylcholine is synthesized from uridine, choline, and DHA. Fish Oil has two omega-3 fatty acids: EPA and DHA. CDPCholine is broken down and converted into uridine and choline. Thus, phosphatidylcholine can be produced from supplementation with CDPcholine and fish oil. Both phosphatydlcholine and phosphatidylserine are essential components of every nerve cell membrane. Increasing the levels of phosphatidylcholine and phosphatidylserine improve nearly every measure of mental performance.

Bacopa is a herbal supplement long used in India to enhance memory. It has unique chemicals that have a mechanism of action distinct from every other supplement in this regimen. Even alone it has a powerful effect on memory recall. It also repairs old and damaged neurons and dendrites. An interesting side effect is that it is as effective at reducing anxiety as prescription anti-anxiety medicines. This effect cannot be underestimated on stressful tests.

Finally, exercise is crucial. http://well.blogs.ny...ess-anxious/?em Exercise ensures that new neurons produced are able to perform under stress. It gives you a higher level of cognitive function naturally.

This is the holy grail of nootropic supplementation. If you go with the cheapest suppliers on the internet, you shouldn't be set back more than $100 a month. $3 a day is what it costs for limitless mental endurance and the best memory your brain is capable of having. You will surprise yourself. I promise you that you do not know how smart you really are.

As a side note, a doctor diagnosed me with ADHD and prescribed me Adderall. I think most ADHD diagnoses are bogus, but I still took Adderall because it was so effective at helping me to study. I still have a prescription for Adderall but I have stopped taking it. I literally experience almost no effect from it. With this regimen, it is as if I am always on Adderall already. Don't get me wrong. I WISH Adderall worked in conjunction with everything else. But the only effect it has on me now is making me obsessively organize and clean my room.

In addition to increasing performance on a variety of mental tasks, many of these supplements are proven effective at reversing alcohol related cognitive impairment. A year ago my short-term memory and ability to concentrate were impaired from all the drinking I did in law school. Today I can safely say that I am the smartest I have ever been. This will work for anybody.

Do your own research. You will only verify with I have told you.

If you start taking other supplements, the odds are you are only going to compound an effect already produced by one of the supplements on this list. They will not be synergistic. If you are really aggressive about nootropics with synergistic mechanisms of action, you can also look in to deprenyl, hydergine, lithium orotate and ashagandha. I take deprenyl and hydgergine off and on, but they are expensive enough that I do not include them in my usual nootropic stack. I caution against lithium orotate unless you know exactly what you're doing because it can be dangerous.

Good luck.

Note: Every person's brain biochemistry is different. There are a certain number of people who do not respond to Piracetam at all. The effect of any one of these supplements might be different for you. There is ultimately no substitute for researching and experimenting to find out what works for you.
Edited by bmud, 02 January 2010 - 08:52 PM.

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Posted 02 January 2010 - 08:35 PM


Nootropics - The Facts About "Smart Drugs" - Unfinished Man

Nootropics - The Facts About "Smart Drugs" - Unfinished Man

Nootropics – The Facts About “Smart Drugs” Image

I’m excited to bring you something very different than what we usually cover here on Unfinished Man. Today we’re going to talk about drugs. No, not those kinds of drugs, but instead a range of “smart drugs” or Nootropics which a person can use to improve brain function. I’ve been fascinated with them for years, and asked John Holcomb of Brainpower Nutriceuticals if he would mind sharing some information with our readers.

John was kind enough to put together this highly detailed article on what’s available on the market, how each of them works, and why more people haven’t heard of them. It’s a lengthy read, but don’t let the wall of text dissuade you. Once you start reading, I promise you’ll be glued to your screen. 

What are Nootropics?

Nootropics are a topic most have little knowledge of outside of scare articles in mass-market publications, most bemoaning the abuse of Adderall and Ritalin by college students as giving them an unfair advantage. After about a decade of this kind of chatter came the movie Limitless and suddenly nootropics became a topic of interest to a more mainstream audience.

Limitless is a movie about an experimental drug – NZT-48 – that gave users mental superpowers, tunnel vision, and a host of methamphetamine blackout inspired side-effects. It showed the main character transforming from a slacker to a prolific writer overnight simply by taking the pill. He then proceeds to become a stock market prodigy and eventually after some drama becomes a candidate for the US Senate. Many viewers were enchanted by the idea of genius in pill form and started scouring the internet for a similar remedy.

As a supplier of nootropics, I’ve fielded countless inquiries from people looking for the silver bullet that will turn them into a genius without effort. I hate to be the bearer of bad news, but such a product does not and can not ever exist, though with the bad news also comes the good: what does exist on the market does give the majority of users a significant benefit without any of the side-effects that Limitless used as a plot device. Before I get into any more detail on this, let me list some of the various categories of nootropics and how they function.

What’s Available?

Choline: The mother of all nootropics is choline. Choline is a dietary nutrient found primarily in eggs, meat, seafood, and dairy products and over 90% of the population is in a state of deficiency. While the body can produce choline, it requires supplementation from dietary sources for optimal performance.

Choline is used to build and repair cell walls since it is a rate limiting ingredient in the production of phospholipids. It is also a critical part of a neurotransmitter called acetylcholine, which is the primary neurotransmitter that cholinergic nootropics interact with. Acetylcholine (hereafter ACh) is critical for memory recording and retrieval, cognition, and plays a role in mood regulation.

People deficient in choline will find that their memory capacity is poor, their cognition sluggish, and generally that they’re functioning in a fog. Choline can be supplemented in a number of ways, from Alpha-GPC products at the high priced and very effective end of the scale, to choline citrate at the midrange, to choline bitartrate at extremely low prices. Any and all nootropic regimens should focus on ensuring that choline levels are sufficient or they will not be effective.

Reversible acetylcholinesterase inhibitors: Acetylcholinesterase is an enzyme found in the synapses of neurons that mops up acetylcholine after signal transmission. Incidentally, irreversible acetylcholinesterase inhibitors are used as nerve gases since they will prevent a muscle from relaxing after a contraction signal is sent to it by keeping the contraction signal (ACh never is cleared from the synapse, so the signal is seen as constant).

For nootropic purposes we look at reversible inhibitors that slightly increase the length of the neurotransmitter pulse. If you think in terms of the spark plug in a car engine, a reversible acetylcholinesterase inhibitor allows the spark to stay “sparky” for longer thereby ensuring a better rate of fuel burn (incidentally, this is something that many spark plug manufacturers strive to do through adjusting the shape of the plug tip). In terms of nootropic use, it gives the brain a better chance of interpreting signals and can enhance both cognition and memory I/O in a meaningful way. Unlike drugs that increase neurotransmitter production, these mimic that effect by letting the ACh you already have survive in the synaptic cleft longer. The two most common inhibitors are galantamine and huperzine A.

Unfortunately, while you can get a moderate boost from taking these, the limiting factor is that if they were any more potent they could cause you injury (and overdosing on these is a very bad thing to do). These are best used with other cholinergic nootropics rather than by themselves.

Vasodilators and metabolic enhancers: Certain vasodilators and metabolic regulators specialize in increasing blood flow and ATP metabolism in the brain. Most of these are rather mild in their nootropic effects, though to people with certain medical conditions these can have a noticeable effect. Included in this group are Picamilon, Coenzyme q10, and Vinpocetine. Like with acetylcholinesterase inhibitors, overdosing is a real possibility so these are supplements you want to carefully manage the dosing of.

Stimulants: Caffeine, amphetamines, and nicotine all fall into this category. While caffeine’s effect is primarily limited to increasing alertness, the others exert their effects by increasing the amount of neurotransmitters in the neural synapses or by direct receptor stimulation. While this gives a noticeable temporary effect, it also causes a rebound at the end of dosing that decreases cognitive abilities and over time can permanently impair your mental faculties. All of these “supplements” by nature are addictive.

Racetams: This is my personal favorite in terms of nootropic use due to the general effectiveness and tested safety of the chemicals. Generally speaking, the nootropic effects gained are of the same general type that is seen in amphetamines, though the mechanism that they use to achieve their effect is quite different, longer lasting, and without a rebound to subnormal neural efficiency.

While amphetamines flood your synaptic clefts with excess neurotransmitters to get the job done, racetams will lightly bond to the receptors temporarily changing their shape and making them more effective at utilizing the neurotransmitters you already have through allosteric regulation. The beauty of this system is that nothing is irreversibly changed in your body: as easily as it bound to the receptor, the racetam molecule can detach unchanged either to enhance a different receptor or be excreted.

Furthermore, since the body isn’t breaking down or processing the racetam molecule, there are no worries about breakdown byproducts or metabolites causing undesired effects in the system. In the end, you have a potent nootropic effect without the side-effect profiles or safety hazards of other agents such as amphetamines. Since the unique shape of each racetam makes it more likely to bind to certain subsets of neuroreceptors, racetams are often stacked together with great results.

The Racetams

This group has a number of different chemicals each with varying effects. To give a quick breakdown, here is a list:

Piracetam: This is the most common, the best studied, and the most cost effective of the racetams. It can dramatically enhance general cognition, memory I/O, and linguistic skills. Being water soluble, it has a long half life in the system, but can take up to 6 weeks of daily dosing before full effects are apparent. Typical dosing is 2-5g per day.

Oxiracetam: Another water soluble racetam, this can take up to two weeks for full effects to be apparent. Unlike the other racetams there is very little memory enhancement, though there are none that enhance spatial reasoning and logic nearly as much. Many also experience a moderate mental stimulant effect. Typical dosing is 1-2g per day.

Aniracetam: A fat soluble racetam, meaning it is fast acting. Unfortunately, this also means it is fast to exit the system, with typical effectiveness in the 6-7 hour range at typical dosing levels. Of all the racetams this has the greatest effect on memory I/O and creativity. Uniquely, it also exerts a mild anxiolytic effect making it sought after by those seeking stress relief. Typical dosing is 500-800mg every 6-7 hours.

Pramiracetam: Another fat soluble racetam, it gives good general cognitive and memory enhancement, but uniquely it has a focusing and motivating effect that many compare to stimulants. Many people use this as an “as-needed” study aid for cram sessions, exams, or writing papers in much the same way people will use amphetamines. Unfortunately, this is also the most expensive racetam on a per-dose basis. Typical dosing is 200-600mg every 7-8 hours.

Noopept: This is the newest entry to the racetam lineup, and is wildly different in structure when compared to the others. For the longest time it was imported in OTC form from Russia, but in the recent past has become available in bulk. The effects are quite unique, as well, since while it has some of the features from all the other racetams, it has no stand-out feature that sets it above the rest. This is the only racetam that has a reachable overdose level, and since dosing is 20-30mg every 7-8 hours unless you have a precise milligram scale or pre-dosed capsules it is quite feasible to get yourself into to trouble with this. Unlike the other racetams this does require a small level of metabolism before it goes active in the body.

Where to Start?

Common to nearly all the racetams is a very bitter taste that is nearly impossible to wash away. For this reason many opt to either buy their powders pre-encapsulated or purchase a capsule machine and do it themselves. Side-effects from racetams are usually limited to headaches if you are choline deficient, and increased urine odor since they are filtered by your kidneys.

I’m often asked what I recommend for someone wanting to give them a try. For nearly everyone the best start is the most basic: Piracetam with a choline supplement if needed. No other nootropic is as cost-effective or has had as much clinical safety testing to back it up.

The one caveat with racetams: from a wealth of anecdotes about a third of the population is non-responsive or only mildly responsive to one or more types, and about a third are high responders that can experience spectacular results. This is based on your individual brain chemistry and can’t be overcome regardless of dosing. It is vanishingly rare to be a low or non-responder to all types.

Nutritional supplements: There are a wide variety of nutritional supplements that can enhance brain functioning—particularly in the deficient—such as Sulbutiamine (vitamin B1). I could write a novel on this subject, though it is best summed up simply: a balanced healthy diet goes a long way toward improving brain function, and these are best used to fill any deficiencies.
No one Talks About this Stuff!
By now you’re probably asking yourself why you’ve never heard of any of this before, and why it isn’t available at your local health food store. First of all, some of it it: choline, huperzine A, coenzyme q10, and a number of other supplements are out there, though it is rare to see them marketed as nootropics. This isn’t a matter of safety or honesty in labeling so much as politics and big government in action. While there has been a healthy market for many nootropics for decades (after all, piracetam was developed in the 60s), it has never hit the mainstream because it is seen as cheating. While some see it as unlocking their full natural potential, others see the use of nootropics as no different than steroid use in athletics, giving the user an unfair advantage over those that don’t. Unlike in athletics, academics isn’t necessarily a zero sum game. While in a race there is necessarily a winner and a loser, nobody in academics is held back if another student is better able to retain their information. Unlike cheating scenarios that can earn a student academic recognition for material they did not or could not pick up, nootropics enhance a students ability to gain and retain new knowledge. While I would hate to find out that my physician had used crib cards to make it through medical school and then cheated on his licensing exams, I would have no problem trusting one that used nootropics to maximize their learning potential. Unless you are looking from the perspective of the government, there is never any downside to greater intelligence and recall.

That argument aside, the primary reason that you don’t see these products in mainstream production and retail is government regulation. I primarily deal with regulation in the US, though am familiar with the laws in other countries and in most the reasons for a lack of availability are the same. In many nations these are considered to be prescription medications, but unregulated for possession (this is typically the case for the racetams and sometimes some of the others). In the US, some are considered food supplements and are unregulated. Some are considered nutritional supplements and are regulated only in the manner of their production. Some are considered orphan drugs and while there is no law against possession or use, it becomes stickier when it comes to their sales.

In the US, racetams and certain other nootropics can only be sold as research chemicals, not for human consumption. Despite this fact, many companies still market their wares as supplements on various merchant sites such as Amazon and Ebay and as the FDA shuts one down two more pop up. Other companies have relabeled their products as research chemicals in an effort to sidestep the FDA’s jurisdiction. On the customer’s side, it is completely legal to order and possess any amount of racetams if ordered domestically, and up to a three month supply (as defined by Customs) if ordered from overseas. Should anyone desire to spend millions of dollars to apply for OTC drug status for any of the racetams these limitations could be lifted, though since none are patentable the limitations would be lifted for everyone with no way to recoup your costs. It isn’t surprising that nobody is willing to be the one footing the bill.

In Canada, Great Britain, and Australia the situation is a bit different. In all three countries racetams are considered to be prescription drugs. The problem is that they can’t be sold legally in-country since none have proper coding for the medications in their health systems. The only legal way to acquire racetams in these countries is to import them, and you are again limited to a three month supply. Australian customs in particular is known for hassling people about import (technically Piracetam is scheduled, so in rare instances they may request proof of a prescription), though if the products are properly labeled they usually get through.

As with any supplement routine it is best to talk to your health care provider first to ensure that there is no conflict with existing medications or conditions. It is safe to say that the majority of people can improve their academic ability and possibly even their quality of life from a rather modest nootropic regimen. While the idea of enhancing ones intelligence through the equivalent of taking your daily vitamins seems shocking to some, it is a definite possibility for those inclined to try to reach their full potential.

John HolcombBrainpower Nutriceuticals

Cited from: http://www.unfinishedman.com/nootropics-facts-about-smart-drugs/#ixzz2Ovt8Vc00

Oxiracetam W- hat Are Nootropics

Oxiracetam What Are Nootropics


Oxiracetam is a nootropic drug and member of the ‘racetam family. While similar to Piracetam, Oxiracetam is much more potent. It improves many of the same mental processes as Piracetam, and is often taken by those looking for a more powerful alternative.



  • Improves the effectiveness of brain training games such as the ones offered by Lumosity.
  • Increases spatial learning and contextual learning [2]
  • Boosts memory [4][5]
  • Improves general cognitive functions [3]
  • Improves attentiveness, focus, and motivation [3]
  • Effective for the treatment of certain mental disorders including dementia, Alzheimer ’s disease, autism, and schizophrenia. [1]
  • Effective for repairing damage done by excessive alcohol consumption [4]

What Is Oxiracetam?

Oxiracetam is a water-soluble nootropic in the “racetam” family. Its effects are very similar to those of Piracetam and Aniracetam. Comparatively, many users report the effects of Oxiracetam to by much stronger and faster acting then both Piracetam and Aniracetam, however results differ for everyone.

Medical Uses of Oxiracetam

Oxiracetam is not as widely prescribed for treating mental problems as other ‘racetams, however there is still much research being conducted on its potential for treating Alzheimer’s Disease, dementia, and organic solvent abuse.

Oxiracetam is sometimes recommended to help fight cognitive decline due to aging. It’s cognitive benefits work against the symptoms of aging-related cognitive decline while its neuro-protective properties improve the physical health of the brain.

Using Oxiracetam

Like Aniracetam, Oxiracetam is often taken as a more potent alternative to Piracetam. Unlike Aniracetam, however, Oxiracetam is water-soluble. As a result it doesn’t posses the same level of synergy with Piracetam that Aniracetam does. For most, it is best used as a replacement for Piracetam instead of a compliment to it.

How to Take Oxiracetam

The best ways to take Oxiracetam are in either capsules or in a bulk powder form. Capsules are far more convenient, but also more expensive. Like Piracetam, Oxiracetam mixes well with liquids, so mixing a proper dose of powder into a flavored drink such as orange juice is an easy way to take it. An even easier way to take powdered Oxiracetam is to purchase a Of course, if you are willing to invest in a capping machine. This will allow you to create your own Oxiracetam capsules at a much lower price than they can be purchased for.

Dosing Oxiracetam

Oxiracetam is usually sold in 800 mg tablets. It is recommended that you start with one 800 mg dose taken two or three times a day. Like with the other ‘racetams Oxiracetam is safe to take even at very high doses, however it’s effectiveness will decline if taken at too high a dose.

How Does Oxiracetam Work?

Even though the exact mechanism of action is unknown, studies suggest that Oxiracetam affects the production of the neurotransmitters glutamate and acetylcholine.
Acetycholine the only neurotransmitter used in the motor division of the somatic nervous system. It activates muscles in the peripheral nervous system and plays a very important role in our ability to sustain attention in the central nervous system. It also has a variety of effects as a neuromodulator upon plasticity meaning it affects our short-term memory and our ability to learn. [7]
Glutamate is a non-essential amino acid that plays an important role in memory formation, leaning, and sustaining neuron transmissions. [6]

Safety and Side Effects of Oxiracetam

Oxiracetam is regarded as being non-toxic and very safe. It can be taken daily without causing dependence, and use can be stopped without withdrawal symptoms.
There are no known side effects associated with prolonged use of Oxiracetam. Mild side effects that have been reported include insomnia and nausea, as well as mild headaches related to Choline defficiency.

Oxiracetam FAQ
Below are some of the most commonly asked questions about Oxiracetam. If you have a question that’s not on this list, send it to us at questions@whatarenootropics.com and we will answer it for you.

Should I Take Oxiracetam?

How long does it take before I will feel the effects of Oxiracetam?

How does Oxiracetam differ from the other ‘racetams?

Can I take Oxiracetam with other ‘racetams such as Piracetam?

Should I take Choline supplements with Oxiracetam?

How long does a single dose of Oxiracetam last?

Is it possible to overdose on Oxiracetam?

Is it safe to drink alcohol while on Oxiracetam?

Does Oxiracetam make a good study drug?

How can I tell if Oxiracetam is working for me?

Can I take Oxiracetam every day?

What are some good alternatives to Oxiracetam?

Cited Studies
1. http://www.ncbi.nlm.nih.gov/pubmed/1603291
2. http://www.ncbi.nlm.nih.gov/pubmed?term=Enhancement%20of%20hippocampally-mediated%20learning%20and%20protein%20kinase%20C%20activity%20by%20oxiracetam%20in%20learning-impaired%20DBA%2F2%20mice
3. http://www.ncbi.nlm.nih.gov/pubmed?term=Treatment%20of%20cognitive%20impairment%20secondary%20to%20degenerative%20dementia.%20Effectiveness%20of%20oxiracetam%20therapy
4. http://www.ncbi.nlm.nih.gov/pubmed/1559636
5. http://www.sciencedirect.com/science/article/pii/S0166432800002989
6. Robert Sapolsky (2005). “Biology and Human Behavior: The Neurological Origins of Individuality, 2nd edition”. The Teaching Company. “see pages 19 and 20 of Guide Book
7. Himmelheber, AM; Sarter, M; Bruno, JP (2000). “Increases in cortical acetylcholine release during sustained attention performance in rats”. Brain research. Cognitive brain research 9 (3): 313–25. PMID 10808142

[saturated fatty acids led to a reduction in proinflammatory stimuli ] Dietary Saturated Fatty Acids Reverse Inflammatory and Fibrotic Changes in Rat Liver Despite Continued Ethanol Administration

[saturated fatty acids led to a reduction in pro-inflammatory stimuli]  Dietary Saturated Fatty Acids Reverse Inflammatory and Fibrotic Changes in Rat Liver Despite Continued Ethanol Administration

In conclusion, the results of this study clearly demonstrate that dietary saturated fatty acids caused an improvement in pathological changes such as necrosis, inflammation, and fibrosis despite continued ethanol administration. The decrease in lipid peroxidation and endotoxemia in the treatment groups fed saturated fatty acids led to a reduction in proinflammatory stimuli mediated by of NF-κB.

Dietary Saturated Fatty Acids Reverse Inflammatory and Fibrotic Changes in Rat Liver Despite Continued Ethanol Administration

Dietary Saturated Fatty Acids Reverse Inflammatory and Fibrotic Changes in Rat Liver Despite Continued Ethanol Administration

Several lines of investigation indicate that dietary fat can modulate the severity of alcoholic liver injury (Mezey, 1998). In experimental animals, for example, diets enriched with saturated fatty acids protect against alcohol-induced liver injury, whereas diets containing polyunsaturated fatty acids promote liver injury (Nanji and French, 1989; Nanji et al., 1989, 1994a). Saturated fatty acids have also been reported to reverse established alcoholic liver injury (Nanji et al., 1995, 1996, 1997b). Importantly, in previous studies, use of alcohol was discontinued at the time that dietary treatment was initiated. This model represented the alcoholic patient who stopped drinking at the time of hospitalization (French, 1995). 

Alcohol, Oxidative Stress, and Free Radical Damage

Alcohol, Oxidative Stress, and Free Radical Damage

Defeng Wu, Ph.D., and Arthur I. Cederbaum, Ph.D.

Defeng Wu, Ph.D., is a research associate professor, and Arthur I. Cederbaum, Ph.D., is a professor, both in the Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York.

Reactive oxygen species (ROS) are small, highly reactive, oxygen–containing molecules that are naturally generated in small amounts during the body’s metabolic reactions and can react with and damage complex cellular molecules such as fats, proteins, or DNA. Alcohol promotes the generation of ROS and/or interferes with the body’s normal defense mechanisms against these compounds through numerous processes, particularly in the liver. For example, alcohol breakdown in the liver results in the formation of molecules whose further metabolism in the cell leads to ROS production. Alcohol also stimulates the activity of enzymes called cytochrome P450s, which contribute to ROS production. Further, alcohol can alter the levels of certain metals in the body, thereby facilitating ROS production. Finally, alcohol reduces the levels of agents that can eliminate ROS (i.e., antioxidants). The resulting state of the cell, known as oxidative stress, can lead to cell injury. ROS production and oxidative stress in liver cells play a central role in the development of alcoholic liver disease. Key words: alcoholic liver disorder; oxidative stress; free radicals; reactive oxygen species; chronic AODE (alcohol and other drug effects); NAD; NADH oxidoreductases; cytochrome P450; peroxidation; metals; proteins; DNA; lipids; glutathione peroxidase; biochemical mechanism; survey of research

As described throughout the articles in this issue of Alcohol Research & Health, alcohol acts through numerous pathways to affect the liver and other organs and to lead to the development of alcoholic liver disease (ALD) (for summaries of many of these pathways, see Cederbaum 2001; Bondy 1992; Nordmann et al. 1992). No single process or underlying mechanism can account for all the effects of alcohol on an organism or even on one specific organ; instead, many mechanisms act in concert, reflecting the spectrum of the organism’s response to a myriad of direct and indirect actions of alcohol. One factor that has been suggested as playing a central role in many pathways of alcohol–induced damage, and which has been the focus of much research, is the excessive generation of molecules called free radicals, which can result in a state called oxidative stress. (These terms and concepts will be defined and explained in more detail in the following sections.) Particularly important are the actions of a class of oxygen–containing free radicals known as reactive oxygen species (ROS). ROS can damage or cause complete degradation (i.e., peroxidation) of essential complex molecules in the cells, including fat molecules (i.e., lipids), proteins, and DNA. Both acute and chronic alcohol exposure can increase production of ROS and enhance peroxidation of lipids, protein, and DNA, as has been demonstrated in a variety of systems, cells, and species, including humans.

Researchers have learned much about alcohol metabolism and the various enzymes and pathways involved, as well as about the role of lipid peroxidation and oxidative stress in alcohol toxicity. This article summarizes some of these findings. A detailed description of free radicals, ROS, and oxidative stress is followed by a review of the alcohol–related cellular systems involved in ROS production. Next, the article explains why ROS are toxic to cells and what systems have evolved to help cells protect themselves against ROS. Finally, the role of ROS and oxidative stress in alcohol–induced cell injury is discussed, with suggestions about future directions for research in this field. Although this discussion focuses on the role of oxidative stress in alcoholic liver disease, alcohol–induced oxidative stress also occurs in and damages other tissues (e.g., muscle, pancreas, and nerve cells).

What Are Free Radicals and ROS?

A free radical is an atom, molecule, or compound that is highly unstable because of its atomic or molecular structure (i.e., the distribution of electrons within the molecule). As a result, free radicals are very reactive as they attempt to pair up with other molecules, atoms, or even individual electrons to create a stable compound. To achieve a more stable state, free radicals can “steal” a hydrogen atom from another molecule, bind to another molecule, or interact in various ways with other free radicals (see the textbox).


Reactions Involving Free Radicals

Free radicals are highly unstable molecules that attempt to achieve a more stable state by reacting with other atoms or molecules in the cell. The four primary types of chemical reactions that free radicals undergo are:
  • Hydrogen abstraction, in which a radical interacts with another molecule that has a free hydrogen atom (i.e., a hydrogen donor). As a result, the radical binds to the hydrogen atom and becomes stable, whereas the hydrogen donor is converted to a free radical.
  • Addition, in which the radical binds to another, originally stable molecule, converting the combined molecule into a radical.
  • Termination, in which two radicals react with each other to form a stable compound.
  • Disproportionation, in which two identical radicals react with each other, with one of the radicals donating an electron to the other so that two different molecules are formed, each of which is stable.

One chemical element frequently involved in free radical formation is oxygen. Molecular oxygen (O2) is essential for cell function because it plays a pivotal role in a series of biochemical reactions occurring in the respiratory chain, which is responsible for most of the production of adenosine triphosphate (ATP), which provides the energy required for a multitude of cellular reactions and functions. (For more information on the respiratory chain and ATP production, see the article by Cunningham and Van Horn in this issue.)

In the respiratory chain, which takes place in membrane–enclosed cell structures called mitochondria, an electron and a proton (H+) are removed from a helper molecule (i.e., cofactor) called reduced nicotinamide adenine dinucleotide (NADH).1 (1 NADH is generated in the fluid filling the cell [i.e., the cytosol] and then moves to the mitochondria.) The electron is transferred to the first component of the respiratory chain, and the proton is released into the surrounding fluid. Chemically speaking, NADH is oxidized to NAD+ in this reaction, whereas the respiratory chain, component that accepts the electron is reduced.2 (2 Oxidation reactions are those that add oxygen to a molecule or remove hydrogen or an electron from a molecule. The reverse reactions [i.e., removal of oxygen or addition of hydrogen or electrons] are called reductions.) The NAD+ subsequently can be used again to accept new hydrogen atoms that are generated during the metabolism of sugars (e.g., glucose) and other nutrients. The reduced respiratory chain component, in turn, passes the electron on to other molecules in the respiratory chain until it is finally transferred to O2, which then interacts with protons in cells to generate water. This series of electron transfer reactions generates sufficient energy to produce several molecules of ATP for each electron that passes through the respiratory chain.

Molecular oxygen can accept a total of four electrons, one at a time, and the corresponding number of protons to generate two molecules of water. During this process, different oxygen radicals are successively formed as intermediate products, including superoxide (O2•–); peroxide (O2=), which normally exists in cells as hydrogen peroxide (H2O2); and the hydroxyl radical (OH). Superoxide, peroxide, and the hydroxyl radical are considered the primary ROS and have sparked major research on the role of free radicals in biology and medicine.3 (3 Superoxide can react with itself to produce H2O2. Thus, systems producing superoxide also will result in formation of H2O2. Technically, H2O2 is not a free radical, but it is commonly included among the ROS.) However, because they are unstable and rapidly react with additional electrons and protons, most of these ROS are converted to water before they can damage cells. It has been estimated that only about 2 to 3 percent of the O2 consumed by the respiratory chain is converted to ROS (Chance et al. 1979). Nevertheless, the toxic effects of oxygen in biological systems—such as the breakdown (i.e., oxidation) of lipids, inactivation of enzymes, introduction of changes (i.e., mutations) in the DNA, and destruction of cell membranes and, ultimately, cells—are attributable to the reduction of O2 to ROS (Toykuni 1999; de Groot 1994; Nakazawa et al. 1996).

What Is Oxidative Stress?

Because ROS form naturally during many metabolic processes, cells have developed several protective mechanisms to prevent ROS formation or to detoxify the ROS. These mechanisms employ molecules called antioxidants, which will be discussed in more detail in the section “Protection Against ROS Toxicity.” Under certain conditions, such as acute or chronic alcohol exposure, ROS production is enhanced and/or the level or activity of antioxidants is reduced. The resulting state—which is characterized by a disturbance in the balance between ROS production on one hand and ROS removal and repair of damaged complex molecules (such as proteins or DNA) on the other—is called oxidative stress (Halliwell 1999). Oxidative stress is associated with numerous deleterious consequences for the cell (e.g., lipid peroxidation or even cell death), and alcohol–induced oxidative stress may play a significant role in the development of ALD.

Many processes and factors are involved in causing alcohol–induced oxidative stress, including:

  • Changes in the NAD+/NADH ratio in the cell as a result of alcohol metabolism. Alcohol is metabolized in two steps. First, the enzyme alcohol dehydrogenase converts alcohol to acetaldehyde, a toxic and reactive molecule. Next, the enzyme aldehyde dehydrogenase converts the acetaldehyde to acetate. Each of these reactions leads to formation of one molecule of NADH, thereby providing more starting material and thus enhanced activity of the respiratory chain, including heightened O2 use and ROS formation.

  • Production of acetaldehyde during alcohol metabolism, which through its interactions with proteins and lipids also can lead to radical formation and cell damage. (For information on acetaldehyde and its detrimental effects, see the article in this issue by Tuma and Casey.)

  • Damage to the mitochondria resulting in decreased ATP production.

  • Effects on cell structure (e.g., the membranes) and function caused by alcohol’s interactions with either membrane components (i.e., phosphate–containing lipids [phospholipids]) or enzymes and other protein components of the cells.

  • Alcohol–induced oxygen deficiency (i.e., hypoxia) in tissues, especially in certain areas of the liver lobules (i.e., the pericentral region), where extra oxygen is required to metabolize the alcohol. (For more information on alcohol–induced hypoxia in the liver and its consequences, see the article by Cunningham and Van Horn in this issue.)

  • Alcohol’s effects on the immune system, which lead to altered production of certain signaling molecules called cytokines, which in turn lead to the activation of an array of biochemical processes. (For more information on alcohol’s effect on cytokine production and its consequences, see the article in this issue by Neuman.)

  • Alcohol–induced increase in the ability of the bacterial molecule endotoxin to enter the bloodstream and liver, where it can activate certain immune cells. (For more information on the role of endotoxin in liver damage, see the article by Wheeler in this issue.)

  • Alcohol–induced increases in the activity of the enzyme cytochrome P450 2E1 (CYP2E1), which (as described in the section “Systems Producing ROS”) metabolizes alcohol and other molecules and generates ROS in the process.

  • Alcohol–induced increases in the levels of free iron in the cell (i.e., iron that is not bound to various proteins), which can promote ROS generation, as described in the section “Role of Metals.”

  • Effects on antioxidant enzymes and chemicals, particularly a molecule called glutathione (GSH), as described in the section “Protection Against ROS Toxicity.”

  • Biochemical reactions generating an alcohol–derived radical (i.e., the 1–hydroxyethyl radical).

  • Conversion of the enzyme xanthine dehydrogenase into a form called xanthine oxidase, which can generate ROS.
Many of these processes operate concurrently, and it is likely that several, indeed many, systems contribute to the ability of alcohol to induce a state of oxidative stress.

Systems Producing ROS

As implied in the previous section, numerous cellular systems can produce ROS. The major source of ROS production in the cell is the mitochondrial respiratory chain, which, as described earlier, utilizes approximately 80 to 90 percent of the O2 a person consumes. Thus, even though only a small percentage of that oxygen is converted to ROS, the mitochondrial respiratory chain in all cells generates most of the ROS produced in the body.

Another major source of ROS, especially in the liver, is a group of enzymes called the cytochrome P450 mixed–function oxidases. Many different variants of these iron–containing enzymes exist, some of which are responsible for removing or detoxifying a variety of compounds present in our environment and ingested (e.g., foods or drugs), including alcohol. Some cytochrome P450 enzymes also are important for metabolizing substances that naturally occur in the body, such as fatty acids, cholesterol, steroids, or bile acids. The biochemical reactions spurred (i.e., catalyzed) by the cytochrome P450 molecules use molecular oxygen, and during these reactions small amounts of ROS are generated. The extent of ROS generation may vary considerably depending on the compound to be degraded and on the cytochrome P450 molecule involved. One type of cytochrome molecule that is especially active in producing ROS is known as CYP2E1. This enzyme is of particular interest when investigating alcohol–induced oxidative stress because its activity increases after heavy alcohol exposure and because CYP2E1 itself also metabolizes alcohol (Lieber 1997).

ROS also are produced by a variety of oxidative enzymes present in cells, such as the previously mentioned xanthine oxidase. Under normal physiological conditions, xanthine oxidase acts as a dehydrogenase—that is, it removes hydrogen from xanthine or hypoxanthine and attaches it to NAD, thereby generating NADH. However, under certain conditions, such as the disruption of blood flow to a tissue, xanthine dehydrogenase is converted to a ROS–producing oxidase form. Alcohol consumption also may promote the conversion of xanthine dehydrogenase to xanthine oxidase (Sultatos 1988), which can generate ROS, thereby enhancing oxidative stress.

Other sources of ROS in the body are two types of immune cells called macrophages and neutrophils, which help defend the body against invading microorganisms. In this case, however, ROS production is beneficial and even essential to the organism because it plays a central role in destroying foreign pathogens (Rosen et al. 1995). Macrophages and neutrophils contain a group of enzymes called the NADPH oxidase complex, which, when activated, generates superoxide radicals and hydrogen peroxide. Hydrogen peroxide then interacts with chloride ions present in the cells to produce hypochlorite (the active ingredient in bleach), which in turn destroys the pathogen. The NADPH oxidase complex and the resulting ROS production are critical to the body’s defense against all kinds of diseases, as is evident in patients with a condition called chronic granulomatous disease, in which ROS production by the NADPH oxidase complex is drastically reduced. Patients with this condition are highly sensitive to infections and usually die at an early age.

Besides the ROS generation that occurs naturally in the body, humans are constantly exposed to environmental free radicals, including ROS, in the form of radiation, UV light, smog, tobacco smoke, and certain compounds referred to as redox cycling agents, which include some pesticides, but also certain medications used for cancer treatment. The toxicity of these medications against tumor cells (as well as normal body cells) results from the fact that the compounds are modified by cellular enzymes to an unstable intermediate, which then reacts with molecular oxygen to produce the original product plus a superoxide radical. Thus, a vicious cycle of chemical reactions involving these compounds continually produces ROS.

Role of Metals

Most of the systems for the production of ROS described above produce superoxide radicals or hydrogen peroxide. Earlier studies suggested the possibility that these two radicals could interact with each other to produce the most reactive ROS, the hydroxyl radical (OH). Under normal physiological conditions, direct interaction between these two radicals is not likely to play a significant role in generating hydroxyl radicals. However, in the presence of certain metals, particularly free iron or copper ions, a sequence of two reaction steps can occur that results in hydroxyl radical generation. In the first step, hydrogen peroxide can produce the hydroxyl radical by removing an electron from the participating metal ion.4 (4 This reaction can generate other products as well, but the hydroxyl radical appears to be the primary oxidant generated [McCord 1998].) In the second step, involving the superoxide radical (O2•–), the original metal ions are regenerated so that they are again available for reaction with the hydrogen peroxide. This combination of two chemical reactions appears to account for most of the hydroxyl radical production in biological systems and explains, at least in part, why metals such as iron and copper produce oxidative stress and ROS–induced injury in cells.

Because of iron’s critical contribution to hydroxyl radical formation, anything that increases the levels of free iron in the cells promotes ROS generation and oxidative stress. Chronic alcohol consumption has been shown to increase iron levels in the body not only when iron–rich alcoholic beverages, such as red wine, are consumed, but also because chronic alcohol consumption enhances iron absorption from food (see Nanji and Hiller–Sturmhöfel 1997). Similarly, adding iron to alcohol–containing diets has been shown to exacerbate liver injury in animal studies (Tsukamoto et al. 1995), whereas administration of agents that capture free iron can prevent or ameliorate alcohol’s toxic effects on the liver (Sadrzadeh et al. 1994).

Why Are ROS Toxic?

ROS are toxic to cells because they can react with most cellular macromolecules, including proteins, lipids, and DNA.

Proteins perform numerous crucial functions in the cell, primarily in the form of enzymes that mediate most biochemical reactions required for cellular functions. Proteins are made up of approximately 20 different building blocks called amino acids, which differ in their sensitivity to interactions with ROS. For example, the amino acids cysteine, methionine, and histidine are especially sensitive to attack and oxidation by the hydroxyl radical. Accordingly, enzymes in which these amino acids are located at positions that are critical to the enzyme’s activity will become inactivated by the interaction with ROS. Alternatively, the ROS–induced oxidation of proteins can lead to changes in the proteins’ three–dimensional structure as well as to fragmentation, aggregation, or cross–linking of the proteins. Finally, protein oxidation often will make the marked protein more susceptible to degradation by cellular systems responsible for eliminating damaged proteins from the cell.

Lipids that contain phosphate groups (i.e., phospholipids) are essential components of the membranes that surround the cells as well as other cellular structures, such as the nucleus and mitochondria. Consequently, damage to the phospholipids will compromise the viability of the cells. The complete degradation (i.e., peroxidation) of lipids is a hallmark of oxidative damage. The polyunsaturated fatty acids5 present in the membranes’ phospholipids are particularly sensitive to attack by hydroxyl radicals and other oxidants. (5 Unsaturated fatty acids are those that contain a double bond between two of the carbon atoms making up the backbone of the fatty acid molecule. These double bonds can easily be opened in chemical reactions and interact with other substances. Fatty acids containing only one such double bond are called monounsaturated; fatty acids with two or more double bonds are called polyunsaturated.) A single hydroxyl radical can result in the peroxidation of many polyunsaturated fatty acid molecules because the reactions involved in this process are part of a cyclic chain reaction. In addition to damaging cells by destroying membranes, lipid peroxidation can result in the formation of reactive products that themselves can react with and damage proteins and DNA. (For more information regarding the actions of such reactive products, see the article by Tuma and Casey in this issue.)

DNA is the cell’s genetic material, and any permanent damage to the DNA can result in changes (i.e., mutations) in the proteins encoded in the DNA, which may lead to malfunctions or complete inactivation of the affected proteins. Thus it is essential for the viability of individual cells or even the entire organism that the DNA remain intact. The building blocks of DNA molecules are called nucleotides; they consist of a sugar component and an organic base. Each DNA molecule consists of two strands of nucleotides held together by weak chemical bonds. Changes in the nucleotides in one strand can result in mismatches with the nucleotides in the other strand, yielding subsequent mutations. ROS are a major source of DNA damage, causing strand breaks, removal of nucleotides, and a variety of modifications of the organic bases of the nucleotides. Although cells have developed repair mechanisms to correct naturally occurring changes in the DNA, additional or excessive changes caused by ROS or other agents can lead to permanent changes or damage to the DNA, with potentially detrimental effects for the cell.

Protection Against ROS Toxicity

Because ROS production is a naturally occurring process, a variety of enzymatic and nonenzymatic mechanisms have evolved to protect cells against ROS (Yu 1994). At least some of these mechanisms are impaired after long–term alcohol consumption and may therefore contribute to damage to the liver and other organs.

Protective Enzymes

Enzymes involved in the elimination of ROS include superoxide dismutases (SODs), catalase, and glutathione peroxidase. SODs catalyze the rapid removal of superoxide radicals. In mammals there are several types of SODs, which differ with respect to their location in the cells and the metal ions they require for their function. For example, a copper–zinc SOD is present in the fluid filling the cell (i.e., the cytosol) and in the space between the two membranes surrounding the mitochondria. Furthermore, a manganese–containing SOD is present in the mitochondrial interior (i.e., matrix). Both of these enzymes are critical for prevention of ROS–induced toxicity (Fridovich 1997).6 (6 Another type of SOD [EC–SOD] is found outside the cells.) The effects of chronic alcohol exposure on the cellular content or activity of SODs are controversial, with reports of increases, no changes, or decreases, depending on the model, diet, amount, and time of alcohol feeding. Studies employing a commonly used model in which alcohol is administered directly into the stomach of laboratory animals (i.e., the intragastric infusion model, used most commonly with rats and mice) found decreases in SOD activity in the liver (Polavarapu et al. 1998) (see the article by Nanji and French in this issue).

Catalase and the glutathione peroxidase system both help to remove hydrogen peroxide. Catalase is an iron–containing enzyme found primarily in the small membrane–enclosed cell components called peroxisomes; it serves to detoxify hydrogen peroxide and various other molecules. One way that catalase eliminates hydrogen peroxide is by catalyzing a reaction between two hydrogen peroxide molecules, resulting in the formation of water and O2. In addition, catalase can promote the interaction of hydrogen peroxide with compounds that can serve as hydrogen donors so that the hydrogen peroxide can be converted to one molecule of water, and the reduced donor becomes oxidized (a process sometimes called the peroxidatic activity of catalase). Compounds that can provide these hydrogen atoms include beverage alcohol (i.e., ethanol) and methanol.

The glutathione peroxidase system consists of several components, including the enzymes glutathione peroxidase and glutathione reductase and the cofactors glutathione (GSH) and reduced nicotinamide adenosine dinucleotide phosphate (NADPH).7 (7 Glutathione peroxidase contains an amino acid that is modified by addition of a molecule of the metal selenium; therefore, low amounts of selenium are critical for the body’s antioxidant defense.) Together, these molecules effectively remove hydrogen peroxide. GSH, which consists of three amino acids, is an essential component of this system and serves as a cofactor for an enzyme called glutathione transferase, which helps remove certain drugs and chemicals as well as other reactive molecules from the cells. Moreover, GSH can interact directly with certain ROS (e.g., the hydroxyl radical) to detoxify them, as well as performing other critical activities in the cell. 

Nonenzymatic Mechanisms

Because of all its functions, GSH is probably the most important antioxidant present in cells. Therefore, enzymes that help generate GSH are critical to the body’s ability to protect itself against oxidative stress. Alcohol has been shown to deplete GSH levels, particularly in the mitochondria, which normally are characterized by high levels of GSH needed to eliminate the ROS generated during activity of the respiratory chain.

Mitochondria cannot synthesize GSH but import it from the cytosol using a carrier protein embedded in the membrane surrounding the mitochondria. Alcohol appears to interfere with the function of this carrier protein, thereby leading to the depletion of mitochondrial GSH (Fernandez–Checa et al. 1997).

NADPH is involved in a much more diverse range of reactions in the cell than GSH. Nevertheless, because of its role in the glutathione peroxidase system, NADPH or the enzymes that generate this compound are sometimes considered antioxidants. 

In addition to GSH and NADPH, numerous other nonenzymatic antioxidants are present in the cells, most prominently vitamin E (α–tocopherol) and vitamin C (ascorbate). Vitamin E is a major antioxidant found in the lipid phase of membranes and, like other chemically related molecules, acts as a powerful terminator of lipid peroxidation. During the reaction between vitamin E and a lipid radical, the vitamin E radical is formed, from which vitamin E can be regenerated in a reaction involving GSH and ascorbate. Alcohol also appears to interfere with the body’s normal vitamin E content because patients with ALD commonly exhibit reduced vitamin E levels (see Nanji and Hiller–Sturmhöfel 1997).

Alcohol, Oxidative Stress, and Cell Injury

Excess levels of ROS and the resulting oxidative stress have been implicated in a variety of human diseases (see the sidebar). What is the evidence that alcohol–induced oxidative stress plays a role in cell injury, particularly damage to the liver cells? Many studies have demonstrated that alcohol increases lipid peroxidation as well as the modification of proteins; however, it is not always clear if these changes are the causes rather than consequences of alcohol–induced tissue injury. Nevertheless, numerous investigations have found that administering antioxidants, agents that reduce the levels of free iron, or agents that replenish GSH levels can prevent or ameliorate the toxic actions of alcohol. For example, in the intragastric infusion model, the antioxidant vitamin E; the chemical ebselen, which mimics the actions of glutathione peroxidase; the copper–zinc or manganese SODs; or a GSH precursor—all prevented ALD (Iimuro et al. 2000; Nanji et al. 1996; Kono et al. 2001; Wheeler et al. 2001a,b).


Diseases Involving Excessive ROS Levels

In addition to contributing to the development of ALD, ROS have been implicated in many other major diseases that plague humans. A partial listing of these conditions (Knight 1998; Kehrer 1993) includes:
  • The toxic effects of O2 itself, such as the oxidation of lipids and proteins, generation of mutations in the DNA, and destruction of cell membranes.
  • Cardiovascular diseases.
  • Atherosclerosis.
  • Various types of cancer.
  • Diabetes.
  • Neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease.
  • Toxicity of heavy metals (e.g., iron).
  • Radiation injury.
  • Vitamin deficiency.
  • Toxicity of certain medications.
  • Inflammation, such as the destruction of joints, the synovial fluid that lubricates joints and one of its components (i.e., hyaluronic acid), as well as activation of inflammation–promoting signaling molecules called cytokines.
  • Toxic effects of tobacco smoke.
  • Emphysema.
  • Cataracts.
Finally, increasing evidence suggests that aging may be a consequence of the normal, long–term exposure to ROS and the accumulation of oxidized, damaged molecules within the cell—a process that could be likened to a lifetime of “rusting away.”

Accordingly, the health benefits of administering antioxidants such as vitamins E and C or other compounds are the subject of much current research, and clinical trials employing antioxidants in the treatment of various conditions are under way. For example, some therapeutic interventions with antioxidants have shown success or promise in the treatment of Parkinson’s disease and in reducing the toxicity of the cancer medication adriamycin.

Not all instances of ROS production are detrimental to the organism, however. One beneficial effect, as the main article describes, is the production of ROS by certain immune cells in order to destroy invading foreign organisms (Rosen et al. 1995). Furthermore, recent evidence suggests that ROS, especially hydrogen peroxide, may be important in signal transduction mechanisms in cells and thus may be an integral component of cellular physiology and metabolism (Lander 1997).

—Defeng Wu and Arthur I. Cederbaum
Kehrer, J.P. Free radicals as mediators of tissue injury and disease. Critical Reviews in Toxicology 23:21–48, 1993.
Knight, J.A. Free radicals: Their history and current status in aging and disease. Annals of Clinical and Laboratory Science 28:331–346, 1998.
Lander, H.M. An essential role for free radicals and derived species in signal transduction. FASEB Journal 11:118–124, 1997.
Rosen, G.M.; Pou, S.; Ramos, C.L.; et al. Free radicals and phagocytic cells. FASEB Journal 9:200–209, 1995.

The most convincing data indicating that oxidative stress contributes to ALD come from studies using the intragastric infusion model. In these studies, ALD was associated with enhanced lipid peroxidation, protein modification, formation of the 1–hydroxyethyl radical and lipid radicals, and decreases in the hepatic antioxidant defense, particularly GSH levels (Knecht et al. 1995; Tsukamoto and Lu 2001; Iimuro et al. 2000; Nanji et al. 1994; Morimoto et al. 1994). Moreover, changes in the animals’ diets that helped promote or reduce oxidative stress led to corresponding changes in the extent of liver injury. For example, when polyunsaturated fats (which are required for lipid peroxidation to occur) were replaced with saturated fats or other types of fats (i.e., medium–chain triglycerides), lipid peroxidation as well as ALD were reduced or prevented completely, indicating that both alcohol and polyunsaturated fats must be present for ALD to occur. The extent of the ALD was further exacerbated when iron—which, as mentioned earlier, is required for the generation of the hydroxyl radical and therefore promotes oxidative stress—was added to these diets (Tsukamoto et al. 1995). Conversely, the addition of antioxidants such as vitamin E, SOD, or GSH precursors prevented the development of ALD, as mentioned above.

In addition to these studies conducted with intact animals (i.e., in vivo), studies with liver cells (i.e., hepatocytes) grown in culture also showed that alcohol can produce oxidative stress and hepatocyte toxicity. Studies with hepatocytes isolated from control rats or from rats that continuously had been fed alcohol indicated that alcohol metabolism via the enzyme alcohol dehydrogenase results in increased ROS production, hepatocyte injury, and a type of cell death known as apoptosis. Moreover, all of these reactions could be blocked by the administration of antioxidants (Adachi and Ishii 2002; Bailey and Cunningham 2002). Finally, studies using an established hepatocyte cell line that contains the alcohol–metabolizing and ROS–producing enzyme CYP2E1 demonstrated that adding alcohol, polyunsaturated fatty acids, or iron, as well as reducing GSH, resulted in cell toxicity, increased oxidative stress, and mitochondrial damage (Wu and Cederbaum 1999). Furthermore, all of these reactions could be prevented by administering antioxidants. Taken together, these findings indicate that alcohol–induced oxidative stress is a pivotal factor in the development of ALD.

Future Directions for Research

Although researchers already have gained substantial insight into the mechanisms and consequences of alcohol–induced oxidative stress, additional studies are required to further clarify how alcohol produces oxidative stress in various tissues. For example, more detailed information is needed on the mechanisms involved in some of the major proposed pathways (e.g., how alcohol–derived NADH leads to ROS production either directly or during the passage of NADH–derived electrons through the mitochondrial respiratory chain). Other mechanisms remain highly controversial, such as the role of CYP2E1 or of various cytokines in alcohol–induced oxidative stress. Additional analyses need to determine the role of alcohol metabolism and its byproducts (e.g., acetaldehyde) in the production of ROS. Finally, it still is unclear how alcohol–induced oxidative stress is produced in tissues where only limited alcohol metabolism occurs.

Many of these issues can be studied using animal models; however, extrapolation of findings from animals to humans will be a difficult task because ROS production and antioxidant status in humans are affected by numerous nutritional, environmental, and drug influences that are difficult to reproduce in animals. To date, scattered data suggest that the blood of human alcoholics can contain lipids modified by radicals and other reactive molecules as well as immune molecules targeted at such modified lipids and proteins. These data indicate that ROS and other reactive molecules are indeed formed in human alcoholics. (For more information on the presence of such compounds in humans, see the article by Tuma and Casey in this issue.)

Other questions that should be addressed in future research include the following:

  • Do reactive nitrogen species (e.g., nitric oxide) play a role in alcohol–induced oxidative stress in addition to ROS?

  • What is the impact of possible interactions between alcohol and environmental influences such as smoking, use of other drugs or medications, and viral infections (e.g., hepatitis C) on ROS production, oxidative stress, and tissue injury? These interactions must be better defined because most alcoholics are exposed to one or more of these influences in addition to alcohol.

  • How is oxidative stress affected by interactions between alcohol and nutritional factors, such as the levels and specific types of fats ingested? And how much iron is “safe” in a heavy drinker?

  • What are the effects of antioxidants (e.g., vitamin E, vitamin C, or carotenoids) in heavy drinkers? This question is important because some antioxidants can be toxic under certain conditions.
The ability of alcohol to promote oxidative stress and the role of free radicals in alcohol–induced tissue injury clearly are important areas of research in the alcohol field, particularly because such information may be of major therapeutic significance in attempts to prevent or ameliorate alcohol’s toxic effects. As basic information continues to emerge regarding the role of oxidative stress in disease development and the mechanisms underlying ROS–related cellular toxicity, these findings will lead to more rational antioxidant therapeutic approaches. Moreover, these findings could result in the development of more effective and selective new medications capable of blocking the actions of ROS and, consequently, the toxic effects of alcohol.

References (etc)