Fear and Loathing in Clinical Nutrition – Part II

A Perspective on Glutamate, Glutamic Acid, Glutamine and Neurotoxicity

“Fear always springs from ignorance.”

– Ralph Waldo Emerson (1803-1882), American lecturer, poet, and essayist 

“Rule one: Never allow a crisis to go to waste; they are opportunities to do big things.”

– Rahm Emanuel – Chief of Staff for Barack Obama as quoted on “Face the Nation” November 9, 2008

Before continuing my discussion on glutamate biochemistry and physiology, I would like to delve more deeply into my exploration of the nature of fear, which I believe is profoundly shaping the way many employ clinical nutrition today (As exemplified by current attitudes on dietary glutamate and iodine).  As I mentioned in the part I of this series, what we dread and whether we decide to stand and fight or flee the scene is based on a number of sometimes less than totally rational thought processes.  In turn, we as humans, on one hand, sometimes tend to fear that which warrants none and, conversely, readily accept that which, in reality, often poses significant danger.  In terms of the practice of clinical nutrition, you may recall that differing attitudes on glutamate and iodine exemplified this dichotomy perfectly.  For, it seems to me that dietary glutamate/glutamic acid/glutamine is generating much more fear than it deserves and iodine, in contrast, is generating much less fear than it deserves.

With the assumption that continuous misinterpretation of the risk/benefit ratio of various substances with which we work everyday does not serve our overall goal of creating better health for our patients and creating successful practices, what can we do to improve our ability to correctly determine risk/benefit ratio?  I would suggest that the first step in answering this question is accepting that the first quote above by Emerson is correct.  If we are ever going to become more accurate in determining whether administration of a substance to a patient presents more opportunities for success than failure, we must recognize that true knowledge of the facts is key.  Furthermore, we must accept the reality that, just because we fervently believe something does not make it true.  For, as expressed in the following quote, belief in what we already know is often the number one deterrent to increasing true knowledge of facts.

“It is what we think we know already that prevents us from learning.”

– Claude Bernard

Of course, I realize that many of you may feel that your level of knowledge renders this discourse completely unnecessary.  Furthermore, I certainly recognize the feeling I, personally, sometimes have that all my actions in clinical nutrition are based on a dispassionate analysis of clinical and research data rather than on unrealistic fear or optimism that ultimately has its genesis in ignorance.  How correct are we in determining whether our actions with patients are based on knowledge and dispassionate analysis of the facts rather than on beliefs based on irrational fear or optimism?  Interestingly, this question has been examined by others.   As you may recall, I first explored how fear can affect the quality of health care in the Mercury Revisited series.  In that series, my window into this issue was a fictional account of how fear might affect health care from a large population perspective.  How large?  How about the future existence of mankind?  In the literary classic, War of the Worlds, H.G. Wells discusses how fear kept humans from predicting that our bacterial allies would ultimately cause the demise of the Martians:

“For so it had come about, as indeed I and many men might have foreseen had not terror and disaster blinded our minds.”

Why did I use this quote in the context of a review of the literature on mercury?  As I explained in that series, I felt that I had very good reasons to believe that fear of mercury was leading to ignorance-based actions that are often less than optimal in terms of maximizing patient health.

Of course, I readily understand that an allegory such as War of the Worlds leaves a bit to be desired in terms of supporting my contention that our beliefs and fears about health care are often, to our detriment, in conflict with reality.  Therefore, please consider another, somewhat lighthearted consideration of our ability to use evidenced-based data when making treatment decisions.  In a bipartisan examination of the nation’s healthcare system by Billy Beane, Newt Gingrich, and John Kerry entitled “How to take American health care from worst to first” that appeared in the October 24, 2008 edition of The New York Times, the authors make an interesting point that our health care system would be much improved if the participants conducted their affairs in a way that they are conducted in baseball.  The first quote I would like to present relates to availability of reliable data in baseball compared to health care:

“Remarkably, a doctor today can get more data on the starting third baseman on his fantasy baseball team than on the effectiveness of life and death procedures.  Studies have shown that most health care is not based on clinical studies of what works best and what does not – be it a test, treatment, drug, or technology.  Instead, most health care is based on informed opinion, personal observation or tradition.”

In contrast, baseball now makes key decisions using a statistics-based paradigm called sabermetrics.  What is sabermetrics?  The authors state:

“These are not the stats we studied as children on the backs of baseball cards.  Sabermetrics relies on obscure statistics like WHIP (walks and hits per inning pitched), VORP (value over replacement player) or runs created – a number derived from the formula [(hits + walks) x total bases]/(at bats + walks).  Franchises have used this data to answer some of the key questions in baseball: When is an attempted steal worth the risk?  Whom should we draft, and in what order?  Should we re-sign an aging star player and run the risk of paying for past performance rather than future results? 

How might this statistics-based approach be used in health care?  The authors surmise:

“Similarly, a health care system that is driven by robust comparative clinical evidence will save lives and money.  One success story is Cochrane Collaboration, a nonprofit group that evaluates medical research.  Cochrane performs systematic, evidence-based reviews of medical literature.  In 1992, a Cochrane review found that many women at risk of premature delivery were not getting corticosteroids, which improve the lung function of premature babies.

Based on this evidence, the use of corticosteroids tripled.  The result?  A nearly 10 percentage point drop in the deaths of low-birth-weight babies and millions of dollars in savings by avoiding the cost of treating complications.”

While I realize that you may not agree with the decision to use corticosteroids, hopefully you will agree that the methodology used not only makes sense for a critical care situation involving premature babies but for the practice of clinical nutrition.

By now I would suspect that you would like to see something more definitive than an allegorical novel or a newspaper commentary that supports my position that, all too often, our methodology for patient treatment is based more on beliefs derived from ignorance-based, unrealistic fear or optimism rather than dispassionate, evidence-based objective evaluation.   Therefore, I would now like to review one of the most fascinating studies I have read in a long time that addresses a very simple but very important question, “How effective are we as health care practitioners in ascertaining our own knowledge level and competence?”  How important is this question?  To me, it cannot be over emphasized.  Why?  If the root cause of unrealistic fear and optimism is ignorance, then unrealistic fear and optimism can never be eliminated unless both of the following occur:  (1) We must accept the fact that we are ignorant about certain issues and (2) We need to have sufficient clarity and objectivity so that we can readily learn the issues about which we are ignorant.

In “Accuracy of physician self-assessment compared with observed measures of competence” Davis et al (1) tried to determine whether we as health care professionals can reliably determine our own levels of knowledge.  In the following quote the authors discuss in more detail the issue being addressed and the methodology used:

“While the term self-assessment is used to describe many types of activities, we were interested in considering the aspects of ‘self-rating’ or ‘self-audit’ in contrast to the use of self-administered examination of knowledge or clinical performance.  To our knowledge, no systematic reviews of studies of this type of physician self-assessment compared with external observation as a reference standard exist.  We, therefore, reviewed the literature to determine how accurately physicians self-assess compared with external observations of their competence.”

How was the study conducted?  Various electronic databases were searched for relevant studies.  Ultimately, what was included?

“The search yielded 725 articles, of which 17 met all inclusion criteria.  The studies included a wide range of domains, comparisons, measures, and methodological rigor.”

What were the findings of this search?  The authors note:

“Of the 20 comparisons between self and external assessment, 13 demonstrated little, no, or an inverse relationship and 7 demonstrated positive associations.”

In particular, though, please note these important findings of the study:

“A number of studies found the worst accuracy in self-assessment among physicians who were the least skilled and those who were the most confident.  These results are consistent with those found in other professions.”

These findings led Davis et al (1) to conclude:

“While suboptimal in quality, the preponderance of evidence suggests that physicians have a limited ability to accurately self-assess.”

As I hope you can see, the results of this study have tremendous implications in terms of moving beyond irrational fear and optimism in making treatment decisions with our patients.  In particular, they suggest that those “experts” who are most confident and vocal that iodine is a totally benign cure-all for everyone and that glutamate/glutamic acid/glutamine is a pariah that everyone needs to avoid in any amount may, in reality, be those “experts” for whom we need to regard with the greatest amount of healthy, well placed skepticism.  In an interview with the lead author of the study, David Davis, MD, that appeared in the October 2008 edition of Clinical Laboratory News (2) these implications are discussed in more detail.  First, the author summaries the findings of the study:

“There are three fundamental findings: 1. Over a broad range of intellectual tasks, healthcare workers overrate their ability.  2. The relationship between the actual competence of healthcare workers and their self-assessment of competence is unreliable.  Often, there is no relationship, and occasionally there is even an inverse relationship.  3. The most incompetent workers show the greatest gap between self-assessment and actual competence.”

In turn, Davis (2) points out that this level of incompetence can self-perpetuate:

“The main problem caused by inflated self-assessment is that healthcare workers tend to choose continuing education topics they like but not what they need.  Continuing education requirement should actually be based on the results of objective competency assessment.  In addition, it is helpful to incorporate the opinions of experts familiar with an individual’s work.”

Davis (2) then goes to elaborate how health care professionals often make poor choices concerning continuing education:

“Physicians and most other healthcare professionals are currently asked to pick their own continuing education activities.  Essentially, we are asking healthcare workers to determine their own learning needs.  Unfortunately, the general tendency of people to inaccurately self-assess means that they often do not pick the topics on which they need the most education.”

What can be done to remedy the situation?  Davis (2) suggests:

“Yes, they can improve self-assessment by improving competency and by accepting accurate objective assessments as feedback.  As people become more knowledgeable about their performance, and/or competent regarding a particular task or characteristic, their self-assessment tends to become more accurate.  In addition, their morale usually improves.”

Before leaving this discussion on causes of ignorance that can lead to irrational fear or optimism, I would like to make what I consider to be a reasonable extrapolation of the work by Davis (1, 2).  Could it be that many of those who profess to be the most knowledgeable on a subject, in reality, know the least?  My experience with the hundreds of articles I have read and lectures I have attended over the years on nutrition and alternative medicine leads me to believe this may be true in many instances.  This is why, over the years, I have placed my trust most often in statements made by those who reference all key points.  For, by doing so, these individuals are openly stating that they are not “the smartest people in the room” so to speak.  Rather, they are making it clear that their knowledge is based on the knowledge of others who may be just as intelligent, if not more so, than they are.  For me, the “experts” I trust the most are not those who arrogantly profess ultimate knowledge of any particular subject but those with, obvious humility, profess that their sometimes considerable knowledge has been derived as a result of “standing on the shoulders” of those possessing equal or superior knowledge.  Furthermore, again, with obvious humility, they profess to be ongoing students who have a never ending thirst to learn from others.  For me, over the years, “experts” in this category have been my most valued teachers.

Lastly, I would like to offer some thoughts on how we can use the above information most effectively in this new world of fear about costs and cost effectiveness where “change” has become the buzzword of the day.  For, even though you may not agree with his politics, hopefully you can agree with Rahm Emanuel’s quote that can be found in the beginning of this issue that suggests even major crises can be seen with a “glass half full” point of view where, along with the sometimes inevitable hardships, opportunities are also presented.   Therefore, with this frame of reference in mind, I would like to ask, in this world where patients are seeing crises and demanding changes in health care in relationship to cost and cost effectiveness, how can we use these crises to our advantage by changing to meet these demands?  First, in line with the comments quoted above by Davis (2), I feel we need to state in no uncertain terms to those who teach the continuing education seminars we attend that any claims about expertise in a certain area must be substantiated.  When they say “Magnesium stearate in supplements is a major toxin,” we need to say “PROVE IT!! – BY SHOWING LEGITIMATE RESEARCH OR CLINICAL DATA.”  If they say “Magnesium stearate in supplements is totally safe,” we need to say “PROVE IT!! – BY SHOWING LEGITIMATE RESEARCH OR CLINICAL DATA.”  And when they say “Glutamate/iodine is totally safe/unsafe for everyone/no one at virtually any dose,” we need to say…well, I think you get the point.  By doing this, we can take the information we have gained back to our patients and begin to douse the flames of ignorance-induced unrealistic fear and optimism that are continually being fanned by the Internet and the mass media.

How else can we change in a country that now demands it?  I feel we need to openly admit to all that, no matter what our level of knowledge, we will always be students not only ready but anxious to not only accept legitimate new information but to forsake old beliefs and agendas if they prove to be incorrect.  Next, we need to get rid of our insecurities that lead us to believe that if we admit previous assumptions and beliefs were incorrect even though they were based on the best information available at the time, we will be criticized as being less than credible.  In my experience, I found that those who continue to strive for excellence, even when it means renunciation of long held beliefs based on dated information, are universally lauded for their integrity and passion for truth, even when it turns out that what they passionately believed in the past was not true.

What might be the net result if we demanded these changes from both ourselves and those who teach us?  First, I would suggest that we would be a whole lot smarter, making us less prone to make statements that we think are true, but in reality are statements of either unrealistic fear or optimism.  In turn, our credibility would be increased in the eyes of our patients and the public in general.  Then, in my opinion, with increased credibility, fewer patients will say “It’s too expensive!!”  Why?  In my experience, when some patients are saying “It’s too expensive!!” it is true that they are saying “I don’t have enough money!!”  However, in my experience, many others are saying when they balk at the cost “You have not convinced me that my money is being well spent in terms of addressing my needs and concerns!!”  For, I would suggest that it is true not only for patients but for all of us that if we are uncertain due to suspicions of questionable credibility that the money we are spending will bring us something in return that will address what is important to us, one penny is too much to spend.

With this change in the way we think and act in mind, I would like to present a real life scenario on how we might respond when adversity comes our way as nutritional practitioners.  Consider the headline that appeared in the November 10, 2008 edition of USA Today:

“Study: Vitamin E doesn’t prevent heart ‘events'”

This headline was based on the study “Vitamins E and C in the prevention of cardiovascular disease in men” by Sesso et al (3) that concluded:

“In this large, long-term trial of male physicians, neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events.  These data provide no support for the use of these supplements for the prevention of cardiovascular disease in middle-aged and older men.”

Of course, this is just another in a long line of studies that have demonstrated poor results when supplementing isolated nutrients with no other lifestyle modifications, despite positive results in epidemiologic, population-based studies on foods that contain these nutrients. Interestingly, our reaction as an industry in the past to these negative studies has often revolved around claims of journal or author bias, FDA/pharmaceutical company conspiracy, or methodological incompetence on the part of the researchers.  Could these responses suggest a situation where unrealistic fear and optimism has ruled?  I believe it is quite possible.    However, what if we went beyond our fears and agendas revolving around unrealistic optimism and just spoke what I feel is the truth based on a host of studies; “When middle-aged men wash down supplemental forms of vitamins C and E with a Coke in the middle of their “happy meal” at the local fast food restaurant, they are unlikely to see any benefit in terms of the health concerns that matter to them the most.  This does not make supplemental vitamins C and E bad.  It just means that they do not work like drugs and thus, alone, cannot counteract the effects of a self destructive lifestyle.”  In agreement, one of the authors of the study who could have easily condemned all use of these supplements, instead stated the following in a news release dated November 13, 2008 from Voice of America:

“Dr. Graziano says the findings demonstrate that taking care of your body involves more than taking a capsule.”

Then, what if we stated; “Let me show you how to use supplemental forms of vitamins C and E so that you can get benefit in relationship to your major health concerns and thereby get your money’s worth.”  Would fewer patients now complain that the supplements are “too expensive?”  I would suggest, yes.

Glutamate/glutamic acid/glutamine – Why do we fear it so much?

John Olney and his research on the “excitotoxic” effects of dietary glutamate

Now that, hopefully, I have further reinforced the idea that unrealistic fear and optimism are major forces in shaping our current beliefs and attitudes about clinical nutrition, and have reinforced the idea that true learning and clinical advancement can only occur if we free ourselves of these ignorance-based forces, I would like to continue my examination of the realities of dietary glutamate/glutamic acid/glutamine based on published research.  In part I of this series I explored the basic biochemistry and physiology of glutamate.  Now I would like to explore why so much controversy exists by initially discussing papers published by John Olney back in the 1970s and 1980s.  As you will see, Olney was the first major researcher to suggest that dietary glutamate may pose a significant threat to neurologic health.  Many years later, Dr. Russell Blaylock, as many of you are aware, continued Olney’s crusade to educate the American public about the dangers of dietary glutamate.  However, given that much of Blaylock’s writings are based on Olney’s papers, I would like to begin my discussion in this issue with his publications.

To highlight Olney’s large body of work on glutamate, I would like to review one of the major reviews of the literature that the author published entitled “Excitotoxic amino acids: Research applications and safety implications” (4).  In this paper, Olney (4) first points out what I discussed in part I, that glutamate is very prevalent in the central nervous system and presents a significant potential for adverse effects:

“It has been demonstrated repeatedly in recent years that glutamate (Glu), putative excitatory transmitter and the most abundant amino acid in the mammalian central nervous system, has striking neurotoxic properties.  Moreover, it is clear from molecular specificity studies that certain structural analogs of Glu mimic both the neuroexcitatory and neurotoxic effects of Glu and have the same orders of potency for their excitatory and toxic activities.  For convenience, in referring to those structural analogs of Glu having both neuroexcitatory and neurotoxic activity, we have proposed the term ‘excitotoxic’ amino acids.” 

However, as I have been discussing Olney’s (4) major concern about glutamate does not relate to that which is found endogenously in the CNS but that which is derived from dietary sources.  In particular, he was concerned about glutamate that was being added to baby foods:

“Glu has long been used as a food-flavoring agent and currently remains among the additives listed by the Food and Drug Administration (FDA) as GRAS (generally regarded as safe).  In the absence of regulatory restrictions, Glu was added liberally to processed infant foods for many years. In 1969, when the potential of Glu to induce brain damage in infant animals following oral administration was demonstrated, baby food manufacturers voluntarily stopped adding Glu to baby foods.  About the same time, however, they began adding protein hydrolysates (rich in Glu and aspartate) in concentrations sufficient to maintain the free Glu content in baby foods at flavor levels to which the maternal palate had been conditioned.  In addition, babies continued to be fed Glu-supplemented processed foods from the adult table.  In 1973, at FDA request, the Federated American Societies for Experimental Biology (FASEB) formed an 11-member scientific advisory committee to review the safety of GRAS food additives.  In 1976 this Committee advised FDA that neither Glu nor protein hydrolysates could be considered safe for use in baby or junior foods.”

Olney (4) then offers some thoughts about the clinical implications of adding glutamate to baby food:

“I agree with the tentative conclusion of the FASEB Committee that Glu cannot be considered safe for use in infant or junior foods.  If the amounts of Glu added to foods ingested by immature humans were in the range of those found naturally in human milk, no safety issue would have risen.  However, it is quite predictable that the concentrations used for food flavoring will always be excessive compared to concentrations in human milk because no flavor effect is achieved from Glu in the concentration range found in milk.  For example, to achieve the desired flavoring effect baby food manufacturers have used Glu in levels up to 0.6% (>750 mg Glu per 4.5-oz. jar of strained baby food).  Since human breast milk contains free Glu in the range of 30 to 35 mg/150 ml, one jar of the above baby food would contain 20 to 25 times more free Glu than is found in one feeding of human milk and would provide a human infant with more than 125 mg Glu/kg body weight, which is 25% of the oral load (500 mg/kg) known to destroy hypothalamic neurons in infant animal brain.  Although blood-brain barriers protect most central neurons from Glu, it must be recognized that (a) certain brain regions lack such protection; (b) it requires only a transient increase in blood Glu levels for neurons in such regions to be destroyed; (c) mechanisms for preventing transient blood Glu elevations may be ineffective in youth or disease; (d) the addition of Glu to foods ingested by immature humans entails risk without benefit (meets no health or nutritional needs).”

In a later review of the literature entitled “Excitotoxic food additives: functional teratological aspects,” Olney (5) discusses the very controversial issue of dietary glutamate absorption:

“Glu, the only excitotoxin for which extensive data are available, is absorbed from the gastrointestinal tract into blood more efficiently in humans than in any other species studied to date.”

However, with that stated, Olney (5) points out the following:

“It should be mentioned that gastrointestinal absorption of Glu in human adults is characterized by extreme individual variation, with some individuals displaying much higher plasma Glu elevations than others following the same loading dose.  Since human are often exposed to acute Glu intake loads in the range 100-150 mg/kg, it is instructive to note that this amount of Glu (150 mg/kg) results in a 20-fold mean plasma Glu elevation in adult humans compared to a 4-fold and 0-fold elevation in adult mice and monkeys, respectively.”

I will present more recent research on this very clinically important and controversial aspect of glutamate physiology shortly that suggests Olney may be less than totally accurate concerning absorption of glutamate.

As I hope you can see, Olney makes a very strong case that humans can, through the use of foods that use glutamate as a flavoring agent, ingest excessive amounts of glutamate that, in turn, can have an adverse effect on neurologic function.  Furthermore, infants are especially prone to experiencing adverse effects when ingesting baby foods that contain glutamate as a flavoring agent.

Russell Blaylock, MD – Continuing Olney’s efforts to publicize the excitotoxic effects of dietary glutamate

As I mentioned, Olney’s papers were primarily published in the 1970s and 80s.  More recently, Russell Blaylock, MD has been responsible for creating the vast majority of public awareness on this issue.  Much of this current awareness occurred as the result of the publication of Blaylock’s book, Excitotoxins: The Taste that Kills (6).  In his most current book, Health and Nutrition Secrets that can save your life, Revised Edition (7)Dr. Blaylock presents his most current thoughts on dietary glutamate and brain function.  What follows are some of the key highlights from the section of the book on dietary glutamate.  First, one of Blaylock’s primary points is that there is a difference between glutamate that is found naturally in whole foods and that which is added to processed foods as a flavor enhancer:

“Monosodium glutamate is the sodium salt of glutamic acid, a form of glutamate, the (under normal circumstances) carefully regulated neurotransmitter I have already discussed.  Glutamic acid is an amino acid that occurs naturally in many foods.  In nature, it is bound by peptide linkages, which are broken down slowly during the digestive process, thereby preventing the sudden surges that are associated with the pure, processed additive, MSG.”

In part I of this series, I discussed the paper by Mallick (8) which indicated whole foods high in glutamate.  Currently, from which food is the glutamate that is added to processed food derived?  Blaylock (7) states:

“The MSG added to food these days is produced by fermenting sugar beet molasses.  The processed form is a white crystal that looks very much like salt or sugar.  While it does not have its own taste, it is used as a ubiquitous flavor enhancer in virtually every canned, packaged, or otherwise processed food sold in stores.”

Blaylock (7) then presents a simplified explanation of how dietary glutamate can adversely affect brain function:

“Glutamate only causes toxicity when it is found floating free outside the neuron, and the brain possesses several safety measures to protect itself.  One is based on quickly removing glutamate once it is secreted from a synaptic terminal, whisking it away to be stored safely in a nearby cell called an astrocyte.  The whisking away process is carried out by special carrier proteins, which can be thought of as escorts.”

A second safety measure is to protect the brain from glutamate floating free in the blood stream.  Glutamate is normally found in many foods, including vegetables and meats.  To prevent this glutamate from entering the brain and setting off destructive excitotoxicity, God created a special boundary called the blood-brain barrier that prevents most harmful substances in the blood from entering the interior of the brain.  It can be thought of as a gatekeeper.

Under normal circumstances this gatekeeper is very efficient.  Unfortunately, persistent manipulation of the foods we consume has endangered the balance necessary for this protective mechanism to operate correctly.  By artificially adding very high concentrations of free glutamate to food, blood glutamate levels in most people are far higher than ever intended, taxing the ability of the protective gatekeeper.  If blood levels remain high, the glutamate can gradually seep into the brain past the gatekeeper, creating havoc.”

Before continuing, please note again that Blaylock (7) makes it clear that the amino acid glutamate, as found in natural foods, does not pose a danger to neurologic health.  Rather, very specifically, glutamate in the form of MSG when added to processed foods is the issue.  However, as noted by Blaylock (6) in his first book “Excitotoxins: The Taste that Kills,” the solution to the problem is not nearly as simple as eliminating all labeled MSG from processed foods.  For, according to the author, other food additives with different names can contain MSG.  One in particular that is given special emphasis by Blaylock (6) is hydrolyzed vegetable protein.  According to the author:

“Hydrolyzed vegetable protein is a special case and deserves a closer look.  If you will recall, the manufacturing process…is a series of chemical processes; first boiling vegetables in sulfuric acid for several hours, then neutralizing the acid with a caustic soda (an alkalizing agent often used to make soap), and then drying the resulting brown sludge.  Additional MSG may be added as well to the fine brown powder.  The result is marketed as hydrolyzed vegetable protein.”

With the above in mind, Blaylock (6) provides a list of food additives in the appendix that either always contain MSG, frequently contain MSG, or may contain MSG or excitotoxins.   Virtually all are additives used in processed foods with three exceptions, soy protein concentrate, soy protein isolate, and whey protein concentrate.  As you may know, these are often used as constituents of functional food products provided by several professional supplement companies, including many sold by Moss Nutrition.  Should we be concerned that functional foods containing soy or whey protein may cause adverse neurologic effects?  I will address this question shortly.  However, I would first like to comment on the fact that so many processed foods contain either MSG or additives that contain MSG.  For me, whether or not processed foods contain MSG is a non-issue in terms of dietary advice I provide.  Why?  Debating whether or not processed foods should contain MSG is like debating whether the contents of the paper wrapper for cigarettes should be changed.  For no matter what the content of the paper, I will still advise avoidance of cigarettes under all circumstances.  Similarly, as part of a clinical nutrition community that has long advocated ingestion of a Paleolithic type diet containing only fresh, whole foods, I will continue to advocate avoidance of processed foods whether or not they contain MSG.

Glutamate/glutamic acid and the Internet

If the controversy relating to glutamate/glutamic acid and neurologic function were limited to the excellent research and commentaries by Olney and Blaylock relating to MSG and its inclusion in processed foods, I feel there would be little more to say except, as I suggested above, that the issue of MSG presents still one more reason to avoid the processed, refined foods found in most supermarkets and fast food outlets.  However, as I have been suggesting in this series, the fear that is generated by people who think they have extensive knowledge of a subject but, in reality, are less than fully informed, can lead to claims that are sometimes questionable from a logic-based, scientific standpoint.  Where might we find such dubious claims?  As you might expect, on the Internet.  On the website, www.truthinlabeling.org, that is getting increased attention among both lay and professional groups, several unreferenced claims are made about MSG and glutamate/glutamic acid that go way beyond those research based claims made by Olney and Blaylock.

On this site, it is claimed that many protein containing foods that undergo any type of processing, including those found in supplements, will contain free glutamic acid.  In turn, since, according to the website, this “processed free glutamic acid” is the same as MSG, it presents the same neurologic threat as MSG and should be avoided.   Specifically, the site states:

“MSG is shorthand for processed free glutamic acid, i.e., glutamic acid that has been manufactured or freed from protein through processing or bacterial fermentation.  It is a toxic substance.”

The site goes on to make unreferenced claims about how MSG and processed free glutamic acid (Which, according to the site, are one and the same) are produced:

“The second way of producing MSG is through breakdown of protein, i.e., processed free glutamic acid (MSG) is created when protein is either partially or fully broken apart into its constituent amino acids.  A protein can be broken into its constituent amino acids in a number of ways (autolysis, hydrolysis, enzymolysis, and/or fermentation).  When a protein is subject to autolysis, hydrolysis, enzymolysis, and/or fermentation, the amino acid chains in the protein are broken, and the amino acids are freed.  Acids, enzymes, and/or fermentation processes may be used to create MSG in this way.”

Interestingly, as you may have noticed, what has just been described in the above quote not only can happen during the process of creating certain substances found in the American diet but also happens in the human digestive tract when any dietary protein is consumed.  Therefore, by extension, not only must protein-containing foods exposed to these processes during manufacture be avoided but any protein-containing foods.  For, not only will the methods of food preparation mentioned above cause the formation of MSG (free glutamic acid) but so will basic digestive processes that occur in the mammalian GI tract.  In turn, if we are to adhere to this logic, the only way to avoid MSG (free glutamic acid) is to ingest a diet that contains no glutamic acid.  However, since all proteins contain a certain amount of glutamic acid, the only way to avoid MSG (free glutamic acid), according to www.truthinlabeling.org, is to ingest a diet containing absolutely no protein.

While the site does not go so far as to issue absolute prohibitions on dietary protein because of the ubiquitous presence of free glutamic acid, it does suggest avoidance of the following by those who have a history of adverse reactions to MSG:

“Dietary supplements”

“Protein drinks often recommended for seniors”

“Protein bars and protein powders”

“Kosher food”

“Protein powders sold in health food stores”

“Food that is labeled ‘organic.'”

Hopefully, we can all agree that common sense and clinical experience suggests that, even though the above foods contain free glutamate, recommendations for total avoidance by those who have experienced adverse reactions to MSG represent more of a fear-based agenda expressed by those self-proclaimed experts who, as suggested by Davis (2), may know less than they think they do.  Therefore, I hope we can also agree that even though MSG is a form of free glutamate, the answer to the MSG problem from a patient management standpoint is not simply a matter of recommending any and all foods that either contain free glutamate or form free glutamate after digestion, which includes virtually every protein source on earth, be avoided.  In contrast, could the answer to the problem revolve less around the idea that free glutamate is being ingested and more around the following?

  • What is the amount of free glutamate that is being ingested at any one time?
  • How much of this free glutamate is actually absorbed?
  • How fast is the free glutamate absorbed?
  • In line with the Davis hypotheses, could the placebo effect be coming into play where people who are the most certain about their reactivity to free glutamate actually know the least?

To determine whether the hypotheses I have just suggested has validity, I will examine these questions and re-examine the claims made by www.truthinlabeling.org, Olney, and Blaylock to determine if they are consistent with the findings of some of the most current research on MSG and glutamate/glutamic acid.  Does this research I am about to consider and the researchers who performed it have credibility?  In my opinion, based on the findings of Davis discussed earlier in this monograph, the fact that the claims of expertise made by the authors of these papers are fairly reserved and fully referenced would suggest that the answer to this question is “Yes”.

From an overall standpoint, do published papers exist that suggest reactivity to free glutamate is not merely an issue of whether free glutamate is present in the diet but an issue of the presence of a host of other factors?

In “Monosodium glutamate: A safety assessment by Food Standards Australia New Zealand” by Food Standards Australia New Zealand (9), the following is stated:

“Overall, the evidence indicates that the extent of the rise in plasma concentrations of glutamate is affected by a number of factors including the size of the dose (increases with rising dose); the nature of the dosing vehicle (e.g. water causes greater rise than a mixed meal); the temporal proximity of food consumption (fasted subjects exhibit a greater response than those dosed with a meal); and macronutrient composition of the concurrent food (carbohydrate and mixed meals have an attenuating effect compared with fasting or protein).”

With the assumption that this quote has validity, I would now like to explore some of its individual components in more depth.

As suggested by www.truthinlabeling.org, is all dietary free glutamate fundamentally the same no mater what the source?

In fact, as suggested by Geha et al(10), this claim, indeed, is true:

“Regardless of the dietary source (protein, protein, hydrolysates or salts of free glutamic acid, including the monosodium salt MSG), all glutamate molecules entering the circulation from the gastrointestinal tract are structurally identical.”

As suggested by www.truthinlabeling.org, does the mere presence of free glutamate in a dietary source represent a legitimate concern in terms of optimal CNS function?

Truthfully answering this question is not only important in terms of the dietary recommendations we make to patients but in terms of our recommendations concerning whey-, rice-, and soy-based protein supplements.  In discussing these protein sources, though, please keep in mind that I am excluding those products, as suggested above by Blaylock, where the manufacturers have added purified MSG without indicating such on the label.  To me, these adulterated products, as with the processed foods I discussed above, should be avoided due to their MSG and content and a host of other reasons.  However, what of the excellent functional food products supplied by many professional supplement manufacturers where free glutamate is a natural constituent of the protein?  The following discussion is also designed to address this question.

To begin, I would first like to point out a quote that was initially presented in part I of this series.  Mallick (8) points out:

“It was reported that glutamate is the most abundant amino acid in mother’s milk in all the species analyzed.  The total glutamate content (free and protein bound) in human milk is 161.5 mg/dl to 230.0 mg/dl.  However, human breast milk contains rather high amounts of free glutamate; ten times as high as cow’s milk.  Interestingly, this high level of free glutamate is found only in the milk of humans and higher primates such as chimpanzees, and the milk of other species has much lower free glutamate levels.  The reason for this difference in unclear, but the amount of glutamate is enough to give a taste, so that human infants may experience ‘unami’ as one of the first tastes after birth.”

With this information in mind, what is the typical intake of glutamate for breast-fed infants?  The author notes:

“The daily intake of free glutamate in a breast fed infant is about 36.0 mg/kg body weight while the daily intake of protein bound glutamate is approximately 357.0 mg/kg body weight.  Human infants ingest more glutamate than human adults on a body weight basis and they have the clear ability to metabolize large amounts of glutamate.”

With the assumption that we can all agree that breast milk is the optimal food for babies, these quotes would seem to suggest that not only does the mere presence of free glutamate not constitute a threat to CNS health but actually promotes CNS health.  This latter suggestion is supported by Agostini et al (11) in their study “Free glutamine and glutamic acid increase in human milk through a three-month lactation period.”  In their conclusion, the authors discuss the importance of free glutamic acid to optimal development:

“We found that taurine, glutamic acid, and glutamine were the most abundant free amino acids in human milk throughout the first trimester of lactation.  Although taurine remained stable, glutamic acid (the prevalent free amino acid) and glutamine increased approximately 2.5 and 20 times, respectively, with progressing lactation, representing more than 50% of total free amino acids at 3 months.  The content of essential free amino acids was also stable, so the change in total free amino acid content was almost entirely due to the changes in glutamic acid and glutamine.”

What is the purpose for placing such a priority on these two free amino acids in breast milk?  The authors suggest:

“We could then speculate that the major free amino acids of human milk, particularly glutamic acid and glutamine, might have a double role: protection of intestinal growth and integrity, and supply of functional substrates to the nervous tissues.” 

Finally, please recall from above the quote by Olney (4) that suggests that the problem is not the presence of free glutamate per se in baby food but the presence of “excessive” amounts compared to the amounts found in human breast milk.

As I suggested above, could rate of absorption of free glutamate be a determining factor in terms of reactivity?

Geha et al (10) suggests that this may be true in their studies where participants ingested a large dose of MSG alone and with food:

“The responses were not observed when MSG was given with food.”

Of course, these findings are in direct conflict with the reality that many patients react when they ingest foods containing MSG.  Therefore, while rate of absorption may be an important factor, other factors, as I suggesting, must also be coming into play.  Could one of these factors be the health of the gut lining?  As you are undoubtedly well aware, a healthy gut lining does an excellent job of limiting absorption of food factors to amounts that promote optimal physiologic function, even when large amounts are consumed.  In contrast, an unhealthy gut can become hyperpermeable and allow passage of potentially harmful amounts of food constituents into the general circulation.  Could this be true for free glutamate?  In fact, this appears to be the case since current research shows, contrary to what was suggested by Olney {Olney JW, 1988 #993}, that most dietary glutamate is taken up by the gut lining and never released into the general circulation.  In their paper “Emerging aspects of dietary glutamate metabolism in the developing gut,” Burrin et al (12) state the following:

“The importance of glutamate as a gut oxidative fuel has also been shown in studies in premature infants and adults.  These studies indicate that ~75-80% of the dietary glutamate intake is metabolized in first-pass by splanchnic tissues and that a large portion >80% of this glutamate is oxidized to CO2.”

Therefore, when encountering patients who appear to be reactive to dietary free glutamate, addressing gut health may be an important aspect of our comprehensive program that is designed to address all the issues I am discussing.

As I suggested above, could the placebo effect in people who think they know the most about free glutamate reactivity be one of those factors?

To answer this question, consider this quote by Geha et al (10):

“A drink vehicle with a novel taste that could effectively mask the taste of MSG was used to challenge individuals who believed themselves to be MSG sensitive.  Of >30 such individuals with whom contacts were made, only six agreed to be tested.  When these individuals were challenged with 6 g of MSG in a double-blind, placebo controlled manner, it was found that four of the six did not react to either substance, whereas two reacted to both MSG and placebo.  Of the subjects who reacted, one reported tingling of hands and warmth behind the ears after both MSG and placebo; the other subject experienced tightness of the face after ingesting either substance.  The remaining four individuals who had ascribed their previous symptoms such as headache, nausea, tongue swelling and uncontrollable coughing to MSG ingestion, did not react to either substance.”

Given that www.truthinlabeling.org singled out whey protein as a threat for patients who react to MSG, does research exist that suggests whey protein may be beneficial for neurologic function?

Before answering this question, please note again that I am excluding inferior products where purified MSG has been added in a clandestine manner.  In contrast, I am referring to the high quality whey protein concentrates employed by the most quality conscious professional manufacturers.  With this qualifier in mind, consider this conclusion from a study by Markus et al (13)where stress-vulnerable participants ingested whey protein fortified with an additional amount of a factor naturally found in whey protein, α-lactalbumin:

“Because an increase in the plasma tryptophan-large neutral amino acid ratio is considered to be an indirect indication of increased brain serotonin function, the results suggest that dietary protein rich in α-lactalbumin improves cognitive performance in stress vulnerable subjects via increased brain tryptophan and serotonin activities.”

With all of the above in mind, I hope we can now agree that when we find that patients are reactive to glutamate/glutamic acid, we need to consider much more than just the mere presence of glutamate/glutamic acid in the diet when making recommendations.

Can supplemental glutamine act as an excitotoxin by converting to free glutamate?

As I expect you noticed, the title of this series also contains the word “glutamine,” which I have not addressed to a significant extent up to this point.  Why?  As I hope you have seen, it is a peripheral issue in this glutamate controversy.  Nevertheless, I feel it must be addressed since comments from many of you over the years suggests that there is a somewhat common belief that supplemental glutamine should be avoided because of the fact that it can be converted to glutamate.  As you might expect, the source of this concern is almost always suggested to be either websites on the Internet or information released by Dr. Blaylock.  Before, delving into the specific biochemistry of an issue which is more complicated than this simplistic belief might suggest, I would like to discuss the realities about the sources of this belief.  First, could the Internet truly be the source?  As the quote below from www.worldhealth.net suggests, the answer appears to be “Yes”:

“People who are hypersensitive to monosodium glutamate (MSG) should use glutamine with caution, as the body metabolises glutamine into glutamate.”

Is Dr. Blaylock truly behind this belief?  The following quote from his latest text (7) suggests that some of his statements are being taken out of context by those who have an anti-glutamine agenda.  For, while Blaylock does not generally recommend glutamine supplementation, he does feel that certain circumstances may warrant its use:

“Glutamine is an amino acid that acts as a major fuel for the small intestine.  Biochemically, it is converted to glutamic acid and then to alpha-ketogluterate, which goes on to form ATP for energy.  Normally, I do not advise supplementing with glutamine because in the brain it is also converted to glutamic acid, where it can contribute to excitotoxicity, but because of the severity of the leaky gut problem, a short-term course of glutamine is less dangerous than the problems associated with this disorder.”

However, does a body of research suggest that even this qualified warning is unwarranted?  As you will see, the answer is “Yes”.  However, to fully appreciate what I am about to present, I would first like to review a basic principle I have been emphasizing repeatedly in this series: “The dose makes the poison.”  Like everything else on earth, there is no question that excessive dosing of glutamine could create adverse effects on neurologic function.  Therefore, I would certainly agree that glutamine supplementation is not advisable for individuals who do not demonstrate deficiency of this amino acid.  In turn, I would strongly recommend that the public not start ingesting large amounts of glutamine just because a self-proclaimed “expert,” who we now know has less knowledge than what he or she professes, is preaching that glutamine represents a benign panacea which, as I hope I have convinced you, does not exist.  In contrast, I hope we can all agree that glutamine supplementation would certainly be advisable for those who are deficient and need to be repleted to optimal levels.  If this is true, we need to rephrase our question from “Can glutamine supplementation increase glutamate formation?” to “Can glutamine supplementation at levels needed to optimally replete endogenous stores increase glutamate formation in those patients determined to be deficient in glutamine?  With the assumption that we are only going to supplement patients who are deficient in glutamine with optimal levels necessary for repletion, does a risk of glutamate formation exist in these patients?

Is the claim that glutamine can be converted to glutamate correct?

As stated by Chwals (14), this is indeed true:

“Glutamine and glutamate share a number of functions that can be fulfilled by either substrate, since they are metabolically interconvertable.”

Will supplemental glutamine be converted to glutamate in ailing patients determined to be deficient?

As you will see, several studies strongly suggest that the answer to this question is an emphatic “No!”.  First, consider this study performed on what most would agree is an ailing population, very low birth weight infants.  In “A randomized controlled trial of Enteral glutamine supplementation in very low birth weight infants: Plasma amino acid concentrations,” van den Berg et al (15) supplemented glutamine at a level of 0.3 g/kg body weight (Approximately 20 g per day for a 150 lb. individual) to 52 very low birth weight infants.  What were the findings of this study?

“Enteral glutamine supplementation in VLBW infants does not alter plasma concentrations of glutamine, glutamate or other amino acids.  Enteral supplementation in a dose of 0.3g/kg per day seems safe in VLBW infants.”

The authors then suggest the following to explain their findings.  In particular, please note the statements on glutamate formation:

“In the studies on enteral glutamine supplementation, including our study, plasma glutamine concentrations did not change, whereas in three of four studies on parenteral supplementation, plasma glutamine concentrations were increased in the glutamine-supplemented group.  This difference can be attributed to the fact that enterally administered glutamine is almost entirely metabolized by the gut and does not reach the systemic circulation.  Therefore, it is unlikely that enteral glutamine supplementation has direct adverse effects as a consequence of an elevated plasma glutamine concentration.

We found that enteral glutamine supplementation did not alter plasma concentrations of glutamate, a glutamine metabolite that is potentially neurotoxic.  This is in line with previous studies on enteral and parenteral glutamine supplementation in VLBW infants.  As a consequence, neurotoxicity caused by an elevated plasma glutamate concentration in VLBW infants receiving glutamine supplementation seems unlikely.”

From this extreme situation, I would like to go to another extreme situation, patients with head trauma.  Based on what has been suggested by certain websites and Dr. Blaylock, it can certainly be expected that head trauma patients supplemented with IV glutamine, thus bypassing a gut-related utilization, will demonstrate elevated glutamate levels.  However, in contrast, a recently published paper examining fifteen head trauma patients by Berg et al (16) suggests otherwise:

“In summary, the present study demonstrated a continuous efflux of glutamine from the brain independent of i.v. exogenous glutamine supplementation normalising plasma glutamine concentration.  Furthermore, a zero glutamate balance across the head was also maintained during the period of exogenous glutamine supplementation.  The low plasma glutamine concentrations together with an endogenous glutamine production on the normal level were suggestive of a high level of catabolism with increased glutamine demand following head trauma.”

Thus, as I hope you can see, as I have been suggesting, patients who are supplemented with glutamine to correct a glutamine deficiency will not demonstrate elevated glutamate levels even when given intravenously to head trauma patients where compromise of the blood-brain barrier is possible.

Of course, I would assume that most of you are not seeing patients who fall into these extreme categories.  Therefore, we now need to ask whether glutamine deficiency is common in the routine chronically ill patient experiencing catabolic stress.  To answer this concern, consider this quote by Miller (17):

“During catabolic stress…intracellular glutamine levels can drop more than 50 percent, and plasma concentration falls 30 percent.  It is under these circumstances that supplemental glutamine becomes necessary.”

Furthermore, the presence of inflammation, which is now being demonstrated to be almost a constant in chronically ill patients, can adversely affect glutamine levels as suggested by Hulsewe et al (18):

“The presence of inflammatory activity had significant negative effects on glutamine concentrations…”

With the above research in mind, it seems clear to me that, in contrast to the suggestions of certain websites and Dr. Blaylock, optimal levels of glutamine supplementation designed to eliminate systemic glutamine deficiencies in ailing populations present virtually no risk of unwanted glutamate formation, even in patients where a compromise of the blood-brain barrier is possible.

SOME FINAL THOUGHTS ON FEAR AND LOATHING AS THEY RELATE TO GLUTAMATE/GLUTAMIC ACID/ GLUTAMINE

Does the presence of large amounts of free glutamate in processed foods represent a risk to the health of the population at large?  Certainly we can thank Drs. Olney and Blaylock for bringing to our attention the fact that this risk is real.  However, I have a genuine concern that the ever increasing level of fear that is now consuming our society has elevated a legitimate concern about ingestion of processed foods containing MSG that is directly added or formed during processing procedures to a fear that virtually any supplement or any protein on our dinner plate will contain dreaded excitotoxins.  As I hope I have demonstrated, the reality is that many of the warnings on this subject that suggest a dietary apocalypse are overstatements that almost always are the result of a toxic soup of ignorance and the inevitable fear that follows.  In turn, this fear affects our ability to accurately discern who the real experts are.  The end result is that we too often assume great knowledge among those who most loudly proclaim expertise and absolute knowledge when, in fact, compelling research suggests that, in reality, they know the least.

An even larger concern for me, though, is that this cautionary tale about glutamate/glutamic acid/glutamine is not just an isolated issue but an allegory for a much larger problem.  More and more, we hear “experts” proclaiming that the foods on our table and the supplements on our countertop contain substances that are either panaceas or poisons.  As I hope I have demonstrated, all evidence suggests that these proclamations virtually never come from minds that are functioning in a rational, scientific manner.  Rather they often come from minds that are either ignorant, fearful, overconfident, or a combination of any of the three, leading to offerings of information that, while they may often contain certain kernels of truth, actually, from an overall standpoint, are sometimes dangerous distortions of truth.

During these times that present economic, political, and environmental conditions that have never been seen before in our lives, fear will inevitably increase for very good reasons.  However, fear, as I have suggested, can easily and rapidly become malignant in the presence of ignorance.  Nevertheless, as suggested by Emanuel at the beginning of this commentary, great crises can lead to great opportunities to make major improvements.  If we can educate our patients and the world at large from a position of dispassionate knowledge of the facts that comes from constant learning from both “true” experts and clinical observations in an environment where we have freed ourselves as best as possible from our hidden fears and agendas, I feel we will be part of the solution.  However, if we allow ourselves to be hypnotized by the fear generated by those “know-it-all experts” that seem ever more prevalent in the field of clinical nutrition, then I feel we cannot help but be an ongoing part of the problem.

In the next issue I will present some final thoughts and information on fear and loathing in clinical nutrition.  In addition, I will use this precautionary tale on fear and loathing as a springboard to continue my examination of what I consider to be sometimes dangerous overconfidence and lack of fear on the issue of supplemental iodine.

Moss Nutrition Report #224 – 12/01/2008

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