AIDS 
Treatment Information

 Article: NAC, Glutamine, and Alpha Lipoic Acid--reprinted with permission of AIDS.org.

Date: 04/04/97

Issue: 268

Author: Lark Lands

[Note, by John S. James: Lark Lands, Ph.D., a well-known health educator and consultant, is the author of POSITIVELY WELL: LIVING WITH HIV AS A CHRONIC, MANAGEABLE SURVIVABLE DISEASE, an 800-page book which will be published later this year. AIDS TREATMENT NEWS published her article "Neuropathy: Nutrient Therapies," in issue #250, July 5, 1996.

[Two issues ago, AIDS TREATMENT NEWS described the results of a clinical trial of n-acetylcysteine "Stanford NAC Study: Glutathione Level Predicts Survival," issue #266, March 7, 1997). Dr. Lands believes that NAC may work better if combined with other supplements, especially glutamine, alpha lipoic acid, and vitamin C, within a healthy overall diet. We did not mention these supplements in our earlier article, as they were not used in the study we were reporting. Instead we interviewed Dr. Lands, who gave us permission to reprint material from her book (below).

Note that all of these supplements -- including NAC -- are unlikely to be suggested by mainstream physicians. The reason is that there is nowhere near the evidence supporting them as there is supporting FDA-approved drugs (such as the new protease inhibitors). There is no good evidence against most supplements, either. But there can be risks for persons with certain medical conditions; therefore it is important that anyone receiving medical care let their physician know about any treatments they are using or considering.

The problem is that research is needed, but there is little money for research on treatments which are inexpensive and generally available. While mainstream drugs are approved based on trials with hundreds of volunteers, what trials there may be for a nutritional supplement treatment may include only a handful of volunteers. And sometimes there are only laboratory and animal studies, and informed guesses based on possible mechanisms of action. That is why such treatments are "alternative" in the first place. (We prefer the term "complementary" to "alternative," meaning nutritional and other treatment approaches which may be used with -- not instead of -- standard medical care.)

What people do with complementary treatments usually depends on their personal philosophies; some have nothing to do with them, others build their medical care around them. We suggest considering a middle course. People with HIV respond very differently to different treatments, mainstream and otherwise. We suspect that complementary treatments which are well thought out might significantly benefit some people, but not others. One approach, then, is to view proposed complementary treatments -- when they are reasonably safe and have some plausibility -- as suggestions for strategies one could try to see if they seem to be helping.

Aside from the book excerpts published below, we asked Dr. Lands the following questions:

AIDS TREATMENT NEWS: How many people do you know who have combined NAC with glutamine and other supplements you suggest? In other words, to what extent are your recommendations based on peoples' experiences, and to what extent are they based on the published literature (which is limited here, since many important studies have not been done)?

Lark Lands: I personally know and have worked with many hundreds of people who have combined multiple antioxidants to help combat the oxidative stress of this disease. In order to maintain optimal glutathione levels, this has usually included NAC, vitamin C, L-glutamine, and alpha-lipoic acid. In addition, at almost every one of the 40-50 conferences where I speak each year people will come up to tell me that they have been including such nutrients as parts of their programs for years. Both they and my own clients make it clear that they believe strongly that using supplements in this way is a very important part of their long-term programs for living long and well with HIV. Many have reported what appears to be significant disease stabilization and even, in some cases, significant increases in CD4s after beginning comprehensive supplementation programs, as well as very significant symptom reduction. And the research to date certainly seems to support this, with multiple studies showing slower disease progression with higher levels of nutrients, in general, and, of course, the Herzenberg study suggesting the much higher level of survival in those with higher glutathione levels.

ATN: If someone tries combining NAC with the other supplements you suggest, what could they look for as an indicator of how well it may be working for them?

LL: It would depend on the particular supplement and on the prior existence of symptoms that might be related to nutrient deficiencies. In other words, if someone has a symptom that obviously improves when a nutrient or combination of nutrients is tried, then it may be obvious that there had previously been one or more nutrient deficiencies which, when corrected, resulted in symptomatic improvement. For example, if you have neuropathy and find that the numbness or pain is lessened or eliminated when you use alpha-lipoic acid, then you can reasonably assume that the lipoic acid is helping you. If you have lost muscle tissue and find that taking L-glutamine seems to help restore the muscles, or you have diarrhea and find that using L-glutamine seems to improve it, then you can reasonably assume that your glutamine levels were too low for all your body's needs and that supplementation with it is helping you.

Unfortunately, there are no such obvious signs of improvement when you're simply taking multiple nutrients in order to try to maintain optimal antioxidant status in the body and, thus, slow disease progression. There is, however, a theoretical support for this, based on the work of many different researchers, including the Herzenbergs. I feel very strongly that long-term use of such supplements is important for those who wish to (1) protect their bodies from the oxidative stress known to be caused by HIV disease and the internal body damage and inflammation that can result from that, and (2) maintain the higher levels of antioxidant compounds in their bodies that seem to be tied to slower disease progression.

ATN: What could you say about the importance of a balanced diet overall?

LL: It is essential to have a healthful, whole-foods diet as the base that underlies any supplementation program. Such a diet should be the foundation upon which you place additional supplements. Pills alone simply cannot suffice. For anyone, the basic rule here is simple: get all the nutrients you can with a fork and spoon. In that way, you will be getting at least some of the whole broad spectrum of nutrients that are important to human health, along with their cofactors. And this will include the nutrients we have not yet discovered; you cannot get those in a pill. Unfortunately, because of the extraordinary demands for nutrients created by this disease, I do not believe that it is possible to get an optimal level of all the nutrients needed for living long and well with HIV from food alone. Several studies support this view, including one from the University of California at Berkeley which found that only the higher levels of nutrients that could only be achieved by supplementation were linked to a reduced hazard of AIDS and increased CD4 levels. They did not find an association between the level of nutrients that was obtained from food alone and any reduced risk of AIDS. This does not mean that eating well and obtaining nutrients from food is not important. It only means that it is apparently insufficient to obtain the level of nutrients needed to support immune function and protect the body in someone living with HIV. The demand for certain nutrients, including L-glutamine and multiple antioxidants, is just too great. However, if purchasing supplements is out of the question, then at least careful food choices can optimize your intake from your daily diet.

***

The following is from Dr. Lands' forthcoming book, POSITIVELY WELL: LIVING WITH HIV AS A CHRONIC, MANAGEABLE SURVIVABLE DISEASE.

Glutamine

Glutamine is an amino acid which is normally found in greater abundance in the body than any other free amino acid. It is crucial for many aspects of healthy body function, including maintenance of optimal antioxidant status, building and maintenance of muscle tissue, maintenance of optimal immune function, and repair and maintenance of intestinal tissue. Because it has long been classified as "non-essential" -- meaning that the body can normally synthesize what it needs -- little attention has been paid to its importance in HIV disease. Luckily, the work of Judy Shabert, M.D., M.P.H., is changing that. She has shown that glutamine deficiency may cause many serious problems, including inadequate antioxidant status in the body, wasting, and loss of both intestinal and immune function. Dr. Shabert points to the research showing that during the stress of infection or injury, the demand for glutamine is very high. The muscles respond to this demand by releasing their stored glutamine. In fact, the rate of release of glutamine from the muscles is dramatically increased, to levels 3-4 times normal. According to Dr. Shabert, the body does this in order to provide glutamine to the intestinal tract, liver, kidneys, and immune system cells.

With the short-term metabolic stress that is created by acute infections, the body can soon return to normal rates of glutamine use. The muscle glutamine levels are quickly restored and the muscles are not damaged. Unfortunately, with the continuous metabolic stress that results from the chronic infection of HIV disease, the demand for glutamine continues and the concentration of this amino acid in the muscles falls rather rapidly. This results in a decline in the synthesis of muscle tissue and, eventually, a wasting away of the muscles. Since the muscles can no longer provide sufficient glutamine, blood levels will also stay chronically low. Only when glutamine levels are restored to normal will muscle synthesis be able to work normally in order to restore the muscle tissue. Thus, supplementation of this amino acid at levels sufficient to restore normal status in the body is vitally important. Muscle loss may be restored or, better yet, muscle wasting may be prevented in the first place. This, of course, makes glutamine crucial for the prevention of internal decline and wasting.

In addition, glutamine is very important for the maintenance of immune function. It is the primary fuel source for lymphocytes and macrophages. These cells consume glutamine at high rates even when there are no special demands for immune system response to an infection. During an immune response when the immune cells have to increase in number and do their work of destroying pathogens, the rate at which glutamine is used increases dramatically. When the body's supply of glutamine runs short, immune function is compromised. Dr. Shabert notes that both the speed at which T cells mature and the proliferative responses of T cells have been shown to be positively affected by supplementation with L-glutamine. Glutamine also increases the activity of natural killer cells and improves the function of neutrophils. In addition, glutamine is critical for the immune function of the respiratory tract, the genitourinary tract, and the intestinal tract. The linings of these tracts produce secretory immunoglobulin A (sIg-A), a type of antibody which works in and on the linings to provide immune defense. Glutamine is a required nutrient for sIg-A-producing cells. This antibody provides the primary immunological defense of the intestinal tract. Thus, supplementation with L-glutamine may help restore sIg-A production in a way that will improve the immune defense of the gut lining and help prevent infections... It may also help to restore the immune function of the respiratory tract... For all these reasons, giving the body sufficient L-glutamine to help restore adequate amounts of sIg-A to the linings of the body might significantly boost immune defenses.

Glutamine is also critical for maintaining the health of the intestinal tract since it is required for the constant rebuilding of intestinal cells. The cells lining the intestine function to absorb nutrients and to block the uptake of pathogens. These cells are regenerated every 3-4 days. The energy which allows this process to occur comes from glutamine. If glutamine concentrations are low, the result is intestinal tissue atrophy and decreased absorption, with resulting lack of uptake of nutrients vital to the body's function. Glutamine is also necessary to maintain the barrier function of the intestines, the body's ability to block the uptake of pathogens, improperly digested food particles, and so on. As is readily apparent, glutamine's ability to help repair the intestines is among its most important benefits for people living with HIV.

For those on intravenous nutrition (total parenteral nutrition/TPN), it may be important to add glutamine to the IV solution. In an extensive review article on the role of glutamine in critically ill hospitalized patients, it is suggested that supplemental glutamine in either enteral or parenteral feedings may greatly improve nutrition management and increase the speed of recovery, thus shortening hospital stays. In part, this is almost certainly due to its capacity to heal the intestines or prevent their atrophy. Dr. Shabert points out that the usual failure to replete lean tissue that is seen when standard TPN or most oral nutritional formulas are used in an attempt to address wasting is due to the fact that most such formulas fail to provide the rate-limiting amino acid for muscle tissue building, L- glutamine.

Restoring glutamine sufficiently to achieve optimal blood levels can also be critically important for maintaining the antioxidant status in the body. Glutathione is one of the body's best antioxidant defenses against the oxidative damage of HIV disease. The reason that L-glutamine is important to maintain glutathione levels is somewhat complicated but the simple version is this. The amino acid cysteine is generally the rate-limiting factor in the production of glutathione in the body. In other words, the amount of glutathione that you can produce will be dependent on the amount of cysteine that is available for that process. That's why N-acetylcysteine (NAC), discussed below, is important for glutathione synthesis. However, once you've provided all the cysteine that's necessary, glutamine becomes the rate-limiting factor in the production of glutathione. Thus, in a body depleted of glutamine, glutathione production will never be optimal. Supplementing with both NAC and L-glutamine can greatly improve the chances for full glutathione replenishment, with all the benefits that come from that. It will also help to ensure that your body remains capable of properly breaking down all the drugs you may be taking. The liver uses glutathione for the detoxification of drugs. When levels of glutathione in the liver are too low, its ability to properly break drugs down may be compromised.

Dr. Shabert believes that the combination of all these needs for glutamine results in a demand for it that is well beyond what the body can possibly provide for itself. Thus, supplementation with sufficient amounts of L-glutamine to provide the body what it needs for all these important functions is very crucial. The L-glutamine can be given either orally or intravenously to accomplish this. Glutamine normally makes up 5-8% of dietary protein so the average person eating approximately 100 grams of protein per day is getting around 5-8 grams daily. However, this level appears to be inadequate even for maintenance of glutamine levels in someone living with HIV who is asymptomatic. For someone in more advanced disease stages or in need of intestinal repair or muscle rebuilding, it is hopelessly insufficient. It appears that even those in early, asymptomatic disease stages may need approximately 10 grams per day to protect their bodies. As the disease progresses, moving toward 15 grams per day is probably appropriate. When there are already existing problems, increasing to even higher doses may be necessary.

Charlie Smigelski, R.D., a registered dietitian and researcher at Harvard University, has suggested that doses of 40 grams per day may be useful for those who need to repair the intestines or gain weight and muscle tissue. Based on his work and that of other researchers, it appears that doses of 30-40 grams per day (30,000- 40,000 mg), spread out over five doses of 6-8 grams each (6,000-8,000 mg), continued for at least 7-10 days may be helpful. Lengthier periods on this higher dosage may be necessary for some, especially if the need for intestinal repair coincides with the need to restore wasted muscles. Substantial amounts of L-glutamine are necessary for both of these so when these two problems coincide, it may be necessary to continue higher dosage levels until both the intestines and the muscles are well restored. It is only when all the extraordinary demands for glutamine needed to effect intestinal and muscle repair are met that the body will be able to return to meeting day-to-day needs for maintenance of those tissues and of proper antioxidant status in the body with lower levels of L-glutamine.

There is a blood test available that can measure glutamine levels as part of an assay of amino acids in plasma. Unfortunately, blood levels can be somewhat misleading because the body will attempt to keep blood levels normal even when the level in the muscles is low...

Glutamine is available in both capsules (usually 500 mg each) and powdered form. However, in general, the powdered form is preferable since far too many capsules would be required to meet the dosage levels necessary for the best results. For those in need of higher dosages, the powdered form is a must. It will be much easier to take and is considerably less expensive than the encapsulated forms. In addition, you'd never want to take 80 gelatin capsules per day of anything. The gelatin in the capsules could cause diarrhea. With most products, each teaspoon of L-glutamine powder contains approximately 4 grams. If you're doing the higher dose of 40 g per day, this would mean taking approximately 2 teaspoons, five times per day. After the intensive therapy period, the dosage can be reduced to 3/4 to one teaspoon (3-4 grams), 3-4 times per day. The powder can be mixed in a half a cup of water or juice or, if you prefer, in a warm liquid such as soup or tea. Do not, however, add it to hot liquids.

Individuals who are on protein-restricted diets because of advanced liver or kidney disease should not take glutamine without their physician's approval since it would have to be considered part of the limited amount of protein allowed.

Lipoic Acid (Thioctic Acid)

Alpha-lipoic acid (also known as thioctic acid) is an important antioxidant which quenches many different reactive oxygen species, including hydroxyl radicals, hypochlorous acid, and singlet oxygen. It readily crosses cell membranes and works as an antioxidant in both lipid and aqueous parts of the body. In other words, it can counter many different forms of oxidative stress and prevent the cellular damage they might cause. It both directly reduces oxidative stress in the body and indirectly spares or recycles or regenerates the other major antioxidants, raising their levels in the bloodstream. It can recycle vitamin E from its oxidized form back to its reduced form (in which it again becomes an antioxidant), thus helping to protect cell membranes. Vitamin C can also be regenerated through reaction with alpha-lipoic acid, as can glutathione. In fact, alpha-lipoic acid has been shown to protect against the symptoms of vitamin E or vitamin C deficiency in animals fed diets deficient in those nutrients. One small study (10 HIV+'s in CDC Stage 4) showed a combination of effects from supplementation with alpha-lipoic acid including increases in blood levels of vitamin C and glutathione, increases in CD4 cells, and decreases in the body compounds that result from oxidative stress. The latter shows that it was indeed working well as an antioxidant. Although most of the HIV community has focused in the past on NAC as a way to raise glutathione, research carried out by Dr. Lester Packer at the University of California at Berkeley has shown that alpha-lipoic acid may be the best way to raise glutathione levels in people living with HIV.

Alpha-lipoic acid is very important to the liver cell metabolic pathways and can be rapidly depleted when the liver is under stress. In Europe, it has long been used in the treatment of hepatic disorders because of its liver-sparing effects which can help the liver repair. Although later research has shown that it is not specifically helpful for mushroom poisoning or alcoholic liver degeneration (two things for which it had been used in the past), there are other causes of liver damage for which it may be quite useful. Its effectiveness in raising cellular glutathione levels is probably very important for liver repair with a disease like HIV that induces glutathione deficiency. Especially when used in combination with silymarin, I have seen it work quite well to reduce elevated liver enzymes, even in some people in whom the levels had been elevated for quite some time. Some of my clients, in fact, have successfully used this combination to lower enzymes sufficiently to get into clinical trials of various drugs, where too-high liver enzymes would have otherwise excluded them. Its combined usefulness in repairing the liver and working as an antioxidant has led to its extensive use in Europe for radiation sickness, drug poisonings, and chemical overdoses. It may provide some protection against the damage induced by radiation therapy during cancer treatment.

In addition, both in vivo and in vitro research has shown potential for alpha-lipoic acid to serve as an antiretroviral agent. It has been shown to inhibit replication of HIV in both acutely and chronically infected cells by a mode of action different than that of nucleoside analogues. In vitro, alpha-lipoic acid has been shown to have synergistic effects when combined with AZT, with the combination of the two showing stronger inhibition of HIV replication than either had when used alone. In vitro research done at Kumamoto University in Japan has shown that alpha-lipoic acid significantly depresses both HIV tat gene activity and HIV infectivity, and is active in both acute and chronically infected cells. Other in vitro research done in the Department of Molecular and Cell Biology at the University of California, Berkeley, has shown that alpha-lipoic acid inhibits NF-kappa B activity. German in vitro research has also shown that alpha-lipoic acid inhibits the infectivity of virus particles and suppresses viral replication, and follow-up in vivo studies by the same researchers showed that it does have antiviral effects in HIV+'s, reducing viral titers just as had been predicted by the in vitro research. Since NF-kappa B is, in essence, an on-off switch for the activation of HIV, and tat inhibition is considered a promising antiviral approach, and anything non-toxic that effectively suppresses viral replication and reduces infectivity is immensely desirable, alpha lipoic acid may be a very important part of a comprehensive antiviral approach. So why haven't other researchers been rushing to pursue its antiviral possibilities? Gee, it couldn't be because it's unpatentable and, thus, unlikely to be profitable, do you think?

Alpha-lipoic acid has long been used in Europe for the treatment of peripheral neuropathy in diabetics. A number of controlled clinical trials have shown its usefulness for reducing both the pain and numbness suffered by those with diabetic neuropathy, and its use for this condition is approved in Germany. Its antioxidant properties may help protect the nerves from the inflammation and oxidative damage that HIV induces, as has been shown to be true with diabetic neuropathy. Alpha- lipoic acid is also a true oral chelating agent that has been widely used in Europe in the treatment of heavy metal toxicity caused by chemicals such as arsenobenzoles, mercuric chloride, and carbon tetrachloride. Thus, it is possible that it might be removing something that is toxic to nerves. Because of its liver protective and antioxidant benefits, it has been included as a component of the programs of many of my clients for several years now. It may have contributed to the success of the multi-nutrient neuropathy elimination programs some of them have used.

Alpha-lipoic acid may also be useful for cognitive dysfunction in HIV disease. Tissues of the central nervous system are known to be particularly vulnerable to oxidative stress because of their high rate of oxygen consumption and high mitochondrial density. The mitochondria produce lots of free radicals during normal oxidative metabolism and, especially without sufficient antioxidant protection, the mitochondrial tissue may be damaged. It is believed that this sort of oxidative stress damage may be partially responsible for neurodegenerative diseases. In animal studies, alpha-lipoic acid has been shown to improve memory, apparently by reversing the damage that had been induced by oxidative stress. Although no research has been done to look at the possible usefulness of alpha-lipoic acid for neurocognitive degeneration in people living with HIV, it is certainly an interesting possibility.

Because it not only appears to be non-toxic but also may improve T-cell function, while helping keep the liver healthy (especially where there is long-term drug usage that may adversely affect the liver), serving as a powerful antioxidant, and possibly protecting the nerves, it seems like an extremely useful part of a total integrated approach. If it also has an antiviral effect, so much the better.

Many people take 100-200 mg, three times per day with meals, sometimes increasing the amounts when liver enzymes are elevated or neuropathy is present. There is no known toxicity, but one report shows possibility of thrombocytopenia (decreased platelets) from higher doses. Because it is an effective mineral chelating agent, some writers have raised the question of whether alpha lipoic acid might remove important minerals; although no problems have been observed at the doses listed here, to err on the side of safety, its use could be accompanied by the daily intake of a good multiple vitamin/mineral supplement and an iron supplement, and blood cell tests (RBC and platelets) could be monitored while it's being taken.