By Joel Brind, Ph.D.
The subject of glutathione (GSH) came up in my last post on diet and inflammation, some of the comments reflecting the popularity of GSH as some sort of miracle molecule among alternative health purveyors and practitioners. Among the commenters, Sarah said: “Is this total BS? Is glutathione really the miracle substance some alternative med doctors say that it is?”
The short answer to the second question is yes: I would agree that GSH can be called–as one popular alternative physician (Mark Hyman) puts it?”the mother of all antioxidants.” After all, GSH is a universal and tremendously versatile intracellular antioxidant and detoxifier of other reactive chemical stressors (like formaldehyde and acetaminophen). GSH is, in fact, both reusable and indispensable. It is made in the liver, although in highest concentration in red blood cells (where oxidative stress is naturally highest), but important in the liver itself, as well as other organs, including the brain.
But I also have to say that there is a lot of BS out there about GSH, because of the type of simplistic thinking that is all too common among scientists and health gurus these days. So the simplistic story typically goes something like this:
- GSH is a good thing, the body’s most important endogenous (non-essential, made by the body itself) antioxidant/detoxification molecule.
- Studies show that GSH is highest in the young and the healthy, and lowest in the old and the sick. Therefore, raising blood levels of GSH is a good thing.
- We can raise blood levels of GSH by directly adding GSH (although this is often not practical, as it does not survive the digestive system well).
- We can raise blood levels of GSH by adding the limiting precursor’the amino acid cysteine’to the diet as a supplement.
- Therefore, we can improve health status by cysteine supplementation.
Now, let’s actually think this through:
- GSH is a good thing, the body’s most important endogenous antioxidant/detoxification molecule.
- The liver makes more GSH in response to oxidative/toxic chemical stress.
- Substances which raise blood levels of GSH?even a precursor like cysteine?may do so because they increase (or reflect an increase in) oxidative/toxic chemical stress, the body making more GSH to neutralize the increased stress.
- Therefore, we might actually make things worse with cysteine supplementation.
So it’s possible that adding a supplement that increases GSH might do more harm than good, if we fail to consider the body’s exquisite natural system of checks and balances.
Let’s consider an analogous situation: Red blood cells are the indispensable oxygen carriers in the blood. If you don’t have enough of them, you have anemia. The body will compensate and make more of them if you deprive it of oxygen. You can do this by, say, moving from New York (close to sea level) to Denver (a mile high), where the oxygen content of the air is lower, and it works. You can also do it by smoking cigarettes, subjecting your body to chronic carbon monoxide poisoning. Ergo, smoking cigarettes can cure anemia!
Getting back to GSH, let’s go back to the metabolic diagram?Figure b from my last post (reprinted below) on diet and inflammation?which shows how the liver handles (i.e., gets rid of) excess methionine coming in from a typical high protein (e.g., muscle meat) meal:
In this diagram (active pathways shown by green arrows), methionine comes in at the lower left. As shown by the first star-pointed yellow arrow, the presence of methionine literally turns on the activity of the enzyme (called MAT) which turns methionine into SAMe (a necessary activation step, either to use the methionine as an important methylator or to get rid of it). SAMe is a very reactive (and therefore, potentially toxic) compound, and the liver gets rid of it by harmlessly giving the methyl group to a molecule of glycine (a step called transmethylation, performed by the enzyme GNMT).
That takes care of the “meth” part of methionine, so now the liver has to deal with the “thionine” part, by a process called transulfuration. When methionine gives up its methyl group, it becomes the amino acid homocysteine (Hcy; see lower right of figure). Hcy can be remethylated to methionine, but that process is turned off when methionine (and therefore, SAMe) is abundant (see black dashed arrow from right to left near bottom of figure).
That’s where GSH synthesis comes in. As indicated by the long yellow star-pointed arrow, the presence of increased SAMe literally turns on the enzyme CBS, which combines the amino acids Hcy and serine, to form cystathionine. This is the key committed step in the synthesis of cysteine. In turn the availability of cysteine determines how much GSH is made. Add more cysteine, and you get more GSH, assuming there is enough glycine around, of course: If glycine is inadequate, you can’t make more GSH, because each molecule of GSH has the same amount of glycine as cysteine (and the same amount as gelatin, for that matter). Meanwhile, adding more cysteine makes things worse, by decreasing the amount of methionine needed to make cysteine for making proteins, thus exacerbating the excess of methionine.
So the bottom line is that the liver makes more GSH as a response to excess levels of methionine and its unstable derivative, SAMe, so that toxic downstream products of SAMe can be detoxified. If glycine is deficient, adding more cysteine won’t help.
Note also that, when we consider the entire process of detoxifying a single molecule of excess methionine, one molecule of glycine is used up in transmethylation (by GNMT), a molecule of serine (which is made in one step from glycine) and another molecule of glycine is used up in making one molecule of GSH. Thus, 3 glycine equivalents are used in order to dispose of one excess molecule of methionine. Although glycine is nonessential, the liver can not keep up if the diet is methionine-loaded (with muscle meats) and glycine-deficient (with the glycine-rich bones and connective tissues discarded).
So much for theory, and experiments in laboratory animals. After all, the information presented here is mainly derived from experiments in rats. Human studies must provide the proof of the pudding.
Accordingly, a landmark 2010 study by Gall et al., looking at 485 different metabolites in the plasma of 399 non-diabetic Americans, found the following: In the 138 subjects with insulin resistance (a prediabetic state, compared to the 261 subjects with normal glucose tolerance), the single most reduced substance was (drum roll, please) glycine! (Serine was also significantly reduced.) Meanwhile, 3 of the top 10 metabolites with increased concentrations in the insulin resistant subjects were alpha hydroxybutyrate (a direct product of alpha ketobutyrate), alpha ketobutyrate and cysteine. In other words (looking back at the figure), there was a back-up of biochemical metabolites on the pathway for making GSH, fitting in perfectly with the observed deficiencies in glycine and serine.
In terms of a placebo-controlled clinical trial, a 2008 study by Cruz et al. of 74 Type 2 diabetic patients in greater Mexico City’tested a 3-month course of glycine supplementation (15 grams/day). Patients who received the glycine showed significant reductions in blood inflammatory markers, and enjoyed reductions of fasting glucose from 183 to 140 and of Hemoglobin A1C (the standard marker for long-term blood glucose control) from 8.3 to 6.9, right down to the threshold values for diabetes.
Data like these, which so clearly confirm the theory, put glutathione and its precursors in proper perspective, and helped drive me to formulate and sell the glycine supplement Sweetamine. And btw, feeding rats supplemental glycine makes them live longer, even as it reduces the GSH in their livers by more than fourfold. So the answer is no: More GSH is not necessarily better.
About the Author
Joel Brind, Ph.D. has been a Professor of Biology and Endocrinology at Baruch College of the City University of New York for 28 years and a medical research biochemist since 1981. Long specializing in steroid biosynthesis and metabolism and endocrine-related cancers, he has specialized in amino acid metabolism in recent years, particularly in relation to glycine and one-carbon metabolism. In 2010 he founded Natural Food Science, LLC to make and market glycine supplement products via http://sweetamine.com , which includes his own blog HERE.
So does this mean best thing is to up Glycine? How about DMG?
Or TMG?
Yes, no and no. TMG (trimethylglycine) and DMG (dimethylglycine) already have excess methyl groups attached, and would need to be demethylated to generate usable glycine that could then serve as a place to dump the excess methyl groups generated by the excess methionine. So glycine clears out the backlog of intermediates on the road to making GSH, GSH being needed to detoxify downstream products of the excess methylation capacity, like formaldehyde. Restoration of adequate quantities of glycine then allows the excess methylation to be nipped in the bud (by GNMT), so less GSH is then actually needed.
My brain is way too low functioning right now to digest most of that biochemistry stuff. I’ve just finished off a pound of glycine, taking 10 grams most days. Before that I was taking about 6 grams of gelatin for a few weeks. I have noted zero improvement in inflammation. For a couple of weeks now I’ve also been using One World Whey un-denatured whey protein powder for boosting glutathione levels. I’m taking so many other supplements now that it’s hard to say what is doing what. I have noticed some improvement in brainfog, taking other stuff, but that’s about it. Now I have a case of Iritis that seems more resistant to steroid drops than usual and some increased connective tissue inflammation to go with it, but not a lot more than usual. I have some sort of autoimmune condition, but no official diagnosis. I think the Iritis is probably due to stirring the biochemical pot, but all bets are off as to just what. I did find a testimonial of a guy who said that his recurring Iritis flared when he started taking immunocal (undenatured whey product), but resolved afterward. I was starting to follow Chris Shade’s mercury detox protocol. It uses small amounts of liposomal glutathione, but he says the more limiting factor in detoxification via the glutathione detox system is the enzymes that keep the glutathione production and elimination pathways working. For that he uses mostly plant extracts. If I understood right, these work by sort of challenging the system, in other words, they provide a stressor causing an up-regulation of the glutathione detoxification system via enzyme production. I’m wondering lately if viewing stress/anti-stress – oxidant/antioxidant as good/evil is not misguided. It seems like more of an issue of balance where stress drives it’s own management and is a by-product of just functioning and being alive. Anyway, I’m running on here, but my main message is that glycine hasn’t done a thing for me that I can tell. I haven’t monitored my blood sugar much during that time unfortunately, except right after starting iodine, at which time it seemed slightly improved, but that’s with a very small sampling and not much to compare it to. I remember you saying in a comment that you’ve noticed decreased inflammation while taking glycine and so has everyone else (I’m paraphrasing). I thought that was a rather bold statement. Now you have one example (me) in which that isn’t true, so you shouldn’t say that. Unless I just have to eat my way through more to see any results.
BTW, I also always eat the whole animal. I butcher most of my own meat and always make stock out of bones. And just a side note, being very familiar with primitive cooking, I don’t think it was common for people to cook animals into total mush like paleo and WAPF people are always advocating. You can cook in a pit in the ground and get that effect, but boiling for that long by primitive means is pretty much limited to cooking in clay pots, which a lot of people didn’t make. I think more likely explanations for higher glycine intake (if that is assumed) would be eating whole small animals and insects, and just chewing away at stuff that we would be too lazy or spoiled to eat, like connective tissue on the ends of bones.
I’m cutting back on the whey protein and a lot of other supplements in hopes that my Iritis will improve before resuming. I guess that considering my lack of apparent benefits while supplementing with glycine, that I’ll have a hard time talking myself into buying another pound. Any input is appreciated. I don’t mean to be a dick or anything, but bottom line for me, as with so many other supplement experiments, is bank account 0, supplement companies 3. Pretty much what I expected but, like so many people, I’m desperate enough to keep throwing money out there.
BTW, for you glycine experimenters out there, I got mine from pipingrock pretty cheap and it doesn’t taste bad at all, just gritty and a little sweet. Has anyone seen any benefits from taking supplemental glycine or gelatin?
Thanks for the detailed comment, Steven. Every time you write you reveal more important information, as in: “BTW, I also always eat the whole animal. I butcher most of my own meat and always make stock out of bones.” That tells me that you are not likely glycine-deficient in the first place, so I would not expect glycine supplementation to do much for you. And it isn’t that glycine stops all inflammation; just inappropriate inflammation. Inflammation is a natural function of the immune system, so it seems that either some autoimmune or allergic or perhaps even true chronic infection is going on, rather than the typical inappropriate response to tissue injury that results from glycine deficiency. It is widely believed that at least some autoimmune disease is the result of a true infection that may be gone, but the immune system has been tricked into attacking some normal tissues. I’m not a medical practitioner of any kind, so I think there’s probably no more info I can offer that might help.
OK I think I’m starting to get it. I feel that a person would be unlikely to see significant improvements in autoimmune or allergic disorders with glycine, simply because in that case, as far as the immune system is concerned, it is acting appropriately. That’s the whole basis of that kind of immune dysfunction. You can even argue things like sunburn are appropriate inflammation to a point. What glycine might actually help however is in processes that we don’t necessarily notice, i.e. the low-grade “chronic inflammation” or “metabolic inflammation” we always hear about being so damaging. So showing glycine’s effectiveness becomes very tricky because we are talking about long-term effects that bubble under the surface. If you buy a tub of glycine and take it all in a few months, surprise, you will not notice anything. It’s having sufficient glycine in the diet over a period of many many years that probably has beneficial effects, on degenerative “meta-inflammation” diseases such as atherosclerosis, type 2 diabetes, alzheimers Etc. So in light of all the theorizing it’s a sensible wager to balance the glycine in your diet now, for prevention. I guess only really big long expensive studies will be able to tell us for sure if it does help or not. It is actually as you say very reminiscent of the Omega-3 hype we currently enjoy. Maybe amino-acid balancing supplements will fill the pharmacy shelves of 2034
Yes and no, I would say. I agree that effects may be subtle and take a long time to manifest, and that the extraordinary safety, convenience and low cost make taking daily glycine a “sensible wager”, even if one doesn’t notice any difference (as indeed, I noticed no difference on 40 grams per day for a month).
But how can you say that “having sufficient glycine in the diet over a period of many many years that probably has beneficial effects, on degenerative ?meta-inflammation? diseases such as atherosclerosis, type 2 diabetes,” such that “only really big long expensive studies will be able to tell us for sure if it does help or not.”, when such dramatic results as I cited in my post from the 3-month study on type 2 diabetes have been reported? And btw, I have also had customers of mine report that they no longer need medication to treat their type 2 diabetes after a few months on sweetamine.
I’m also planning some clinical trials of my own with type 2 diabetes patients, and expect to see changes in important blood parameters in 3 months (You need that long to see real differences in Hemoglobin A1C.) on sweetamine v. placebo.
Thanks Joel. Maybe that thing about appropriate v.s. inappropriate inflammation should have been clear from your previous posts, but I’ve had pretty severe brainfog until recently when it improved just a little, so I don’t always comprehend challenging material. I have had Lyme, but at this point I think it’s the least of my problems. Whether the infection is still active or not, the question to me is more why some of us go into a full tailspin and get locked into a cycle of chronic illness when we get (insert microbe of choice) while other people can recover. There is clearly a genetic component. I have HLA-B27, but not everyone with that gets an autoimmune disease. Iritis may be caused by, or certainly aggravated by, infection, but there is obviously a lot more going on. I’m going after detoxification since it’s something that I can actually do which might have far reaching effects. At the very least, mercury can’t be helping and may drive autoimmune reactions. It looks like mercury may be part of Iritis picture too. Unfortunately, It’s sort of like poking a hornets nest with a stick.
I would not be so quick to assume that Lyme is the “least of” your problems. Lyme bacteria are known to take up long-term residence in the nervous system and the infection can flare up in different ways. As I’ve pointed out in comment on an earlier post, I have one friend with chronic Lyme who has been taking sweetamine for years, and he notices it helps with his memory. So it is conceivable that all the gelatin and glycine supplementation has been helping you also clear the “brainfog”. Other aspects of the disease don’t seem to be affected.
I just think that it’s more a disease of susceptibility. I respect it’s tenacious and adaptive nature, but the question to me is why do some of us go into a full tailspin while others can recover. And people don’t often recover by treating the organism, it’s usually something else that seems to put them over the top. Who knows if I’m infected, or what would happen if I could eliminate it completely. My intuition says I’d still be sick, still stuck in some kind of vicious cycle or rut. I’m not totally ruling it out, but I don’t even think about treating the infection anymore. When I finally stopped trying to treat it, I didn’t get any worse. In fact, I probably improved a little for a while.
The brainfog improvement was pretty well into the glycine experiment. I think it was probably liposomal vitamin C or iodine or both. The effect does seem to have fled now, but I’m not taking much C now and no iodine.
Been tested for lyme? Lyme disease can cause iritis.
Why not just use gelatin instead of separating out glycine? Or better yet just practice nose to tail eating like many cultures to naturally balance amino acids. Reductionism can have unintended consequences.
That is correct, Summer. The advantage of a glycine supplement (although my sweetamine also contains L-proline, another major component of collagen) is simplicity: You don’t need to make any other dietary changes to get the benefits. You also don’t need to eat any animal flesh or animal products, since glycine is such a simple compound it is easily made inorganically, as in sweetamine. (Even your liver can make it from carbon dioxide, formaldehyde and ammonia!) I would only object to the term “reductionism”, which is not how I arrived at the glycine solution anyway. Sure, there can be unintended consequences to any course of action, including “nose to tail eating”, although that is the purest “whole food” approach.
I used the term reductionist only because I interpreted your argument as a warning against reductionism(though I am probably misusing the term) in regards to thinking glutathione is only good so more would have only good effects. But reality is always more complicated. We can rarely anticipate all the effects of supplementation. But frequently there are natural safeguards within a “whole” product. So my question is genuine. Why glicine over gelatin?
Sorry, I thought I answered your question: It’s a matter of convenience, really. For example, I formulated sweetamine such that one serving of a sweetener per day delivers 8 grams of glycine, which is the glycine equivalent of about 16 servings of jell-o. So it’s much more convenient than gelatin, and cheaper too. The other reason is important for some people, i.e., the avoidance of animal products.
But I don’t necessarily agree that “reality is always more complicated.” Often the great discovery–such as the central role of glycine in metabolism and its ramifications re: everything (cancer, heart disease, diabetes, you name it) related to chronic inflammation–turns out to be astonishingly simple. In fact, I would say that, as a general rule, when I see in a scientific paper a statement like: “The system is quite complex”, it’s just a way of saying: “We don’t know WTF we’re talking about”. Put another way, the allegation of complexity is the last refuge of the ignorant. It closes off the mind and the result is that one is prevented from ever discovering real knowledge. There is a huge difference between simple and simplistic.
Making the argument that supplementing glycine(as opposed to gelatin) for achieving greater dosages or for vegetarians is a reasonable argument. I don’t feel implying someone is”ignorant” is a reasonable argument. It is not ignorant to suggest that we may not know the full effects of supplementing just glycine. I think it is reasonable to question any supplement.
Sorry, Summer, I did not mean to imply that it is ignorant to be skeptical at all. I was referring to the way scientists often punt on a question of interpretation of data with the claim of complexity, rather than simply admitting that they do not understand. Typically, real discovery renders a previously “complex” issue quite simple.
I used to work with an old dermatologist who was trained in the days where the specialty was called “dermatology and syphilology”, because the cause and course of syphilis was such a “complex” mystery. So the field was populated by all sorts of “experts” (much as we have now in the cancer field). As my colleague pointed out, when penicillin came on the scene, the “experts” disappeared.
Perhaps a better known example is in the field of astronomy. Back in the 16th century, all the “experts” in astronomy followed the Ptolemaic system, Ptolemy having devised the very complex “epicycles” to describe the movements of the planets. But once Copernicus reoriented the thinking by putting the sun–instead of the earth–at the center of the solar system, the complex “epicycles” disappeared, and the simple eliptical orbits of all the planets became clear.
What about organic sulfur/100% pure MSM?? Read that will help increase glutathione?? Is that a good way to increase it?
MSM is a downstream sulfur metabolite which is also a useful anti-oxidant (I take it myself.) But it has no effect on levels of glutathione. Here are two recent human experimental studies which demonstrate this:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507661/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920715/
Dr. Brind. I enjoyed your post, and I find your view refreshing amid all the glutathione hype. I have a comment with a few questions and I would appreciate your response if you have a moment.
I have researched glutathione a fair amount, and I have made some similar observations as you have. However, there are a few points that I would like to investigate.
You suggest that cysteine is elevated in those with insulin resistance and further suggest that may be evidence that cysteine is potentially toxic and that supplementation with cysteine might be a bad idea. That is certainly interesting, but how does that explain the successful use of NAC in cases of, for example, acetaminophen poisoning? Is it not fairly well accepted that acetaminophen poisoning is due to GSH depletion and that NAC replenishes GSH to prevent liver damage? If that is not how it works, then do you propose another explanation?
I’m also not convinced that cysteine is necessarily problematic on account of mammal milk contains cysteine in the covalent bonded form designed to survive stomach acid degradation. If cysteine is, in fact, a toxin, why would that be the case that mammal infants drink a bioavailable form of the amino acid?
Regarding glycine, I have read the rat studies, and I agree that there is reason to suspect that glycine has similarly protective effects in humans. However, I don’t know of any studies that show the same benefits in humans. I do have to admit, the Mexican study you cite lends credence to the notion. And, I have written about the possible benefits of glycine (whether from free-form amino acids or from gelatin) in the context of its *potential* to counter the inflammatory effects of complete protein (specifically methionine). But do you know of any conclusive evidence that glycine is beneficial in humans in the same ways as in rats? If so, I am interested in knowing because that would be useful information that I would like to pass along to people.
Thank you.
Sincerely,
Joey
I’ll let Joel reply to this Joey, but I know that he has made the point in the past that amino acids like cysteine are great for growth specifically, and that they become unpreferable the moment growth stops.
Thanks for the thoughtful comment, Joey.
Re: the idea of cysteine’s being a toxin: It’s all a matter of degree. It’s an important amino acid nutrient. It becomes a toxin when there is too much relative the the body’s needs. As Matt suggested, the needs are greater for all the amino acids during periods of growth than in full grown people. And in most people, cysteine just adds to the methionine load, so you could say it acts more like a toxin.
Re: the use of N-acetyl cysteine in acetaminophen poisoning, animal studies suggest glycine is even better at preventing the damage (i.e., cell death) resulting from acetaminophen toxicity. (Here’s a link to one such study: http://www.ncbi.nlm.nih.gov/pubmed/17567465). Likely, adding both amino acids can really boost GSH as an acute drug type of therapy for such a condition. However, it is also suggested that the main effect of glycine is the direct membrane stabilization via the operation of glycine-gated chloride channels and resulting hyperpolarization from chloride entry.
That brings us to the question of translation to the human condition. True, there have been remarkably few human trials in the peer-reviewed literature, save for a few high-dose trials for major depression, and these have had largely mixed and undramatic results. Here I invoke largely my own experience and that of friends and family and more recently, customers, with many, many anecdotal reports (you can find some on the pages of this blog) of inappropriate inflammation disappearing (fibromyalgia, arthritis, psoriasis, asthma, etc.) Indeed, as I have noted before on these pages, the most important discovery is that even what was considered “normal” inflammation (e.g., after blunt injury) is not appropriate. Inflammation’s sole purpose, I am convinced, is to fight infection. Beyond that it just impedes healing and does damage. Peer-reviewed clinical trials take time to be amassed in the literature, and I’m sure we will see many in the literature in the years to come (some of my own included).
But there’s also a good reason to expect the results in lab animals to translate to human beings, and that is the extremely fundamental nature of glycine. It is the simplest amino acid there is, and its fundamental role in stabilizing biological membranes probably applies to even very primitive living beings. And perhaps the most compelling reason of all to try glycine supplementation is its extraordinary–we might even say nearly absolute–safety. The website of the prestigious NYU Langone Medical Center in New York City has a page on glycine, on which you find the following:
“Safety Issues
No serious adverse effects from using glycine have been reported, even at doses as high as 60 g per day. One participant in the 22-person trial described above developed stomach upset and vomiting, but it ceased when the glycine was discontinued.”
So as I’ve said before, it doesn’t hurt to try it. And for me, trying it opened an important portal of discovery.
the study did say also that the glycine(with fructose) did increased
apoptosis which is rather a bad news.
I am taking NAC since a week, quite impressive as a result.
What study are you referring to? The page to which I referred (http://www.med.nyu.edu/content?ChunkIID=21751) reported clinical benefits and that only “theoretical concerns” had been raised. But unfortunately, the citations were by number and reference list was only by authors’ names.
Thank you for the thoughtful and helpful response.
I suspect, as you suggest, context matters. I think the GSH craze is probably like a lot of things where in the right context a GSH boost by whatever means – be that NAC or covalent bonded cystine or whatever – can be exactly what is needed. But that doesn’t translate into “everyone should be downing bottles of NAC every day” as many would suggest.
I also wonder if NAC and things like undenatured whey protein might offer other benefits apart from providing cysteine in a usable form. Wouldn’t be the first time people attribute the health benefits of things to the wrong property.
Anecdotally I do know at least one person who has experienced great benefits from ImmunoCal, which is supposed to increase GSH. Interestingly, however, I know of at least one study that found ImmunoCal contained no covalent bonded cystine. So the benefits of ImmunoCal could be a) due to something else entirely or b) placebo.
I do see a great deal of potential in glycine and have for a while. I find it interesting that some people are supplementing with up to 60 grams a day. I wonder, are there any reported benefits at such high doses?
Thanks.
Joey, I looked further into the acetaminophen toxicity situation in responding to Stella Bright’s recent comment below, and have given a more complete and clear response. In short, the acetaminophen poisoning condition is rather unique, since it irreversibly destroys both GSH and cysteine, thus causing an immediate cysteine deficit, as well as the generally prevailing glycine deficiency. As I noted earlier, adding glycine not only helps supply more substrate for making GSH, but it lowers the GSH requirement. I suspect therefore that the combination of glycine and cysteine has been siezed upon as generally a good thing to raise GSH and optimize health status, but it is really only applicable to the specific acetaminophen situation (or in regard to similar toxins). On the other hand, acetaminophen use is really widespread, so it may be a more common situation than one might think.
Thank you for this response. That is very useful information.
This is great information, thank-you Joel – and Matt for channeling Joel’s information our way. I’ve been using glycine and gelatin but recently just gelatin. I’m wondering what amount of gelatin would be the equivalent of 8 grams of glycine supplement? I use 1 tablespoon of gelatin a day for sure and sometimes more.
One 4-ounce serving of a gelatin dessert like jell-o contains about half a gram of glycine. So 8 grams is equivalent to about 16 servings of jell-o. If you go by weight, dry gelatin is about 22% glycine. As I noted above, a glycine supplement like sweetamine is basically more convenient.
great, thanks Joel.
Always selling, aren’t you Dr. Brind?
Can anyone say “conflict of interest”?
Hey Deb. I use Vital Proteins gelatin and 1 tablespoon equals out to about 3.8g of glycine. I’m sure it’s similar with all supplemental gelatin.
thanks, Tyler!
Does this apply to autistic people? Or just healthy people who want to try supplementation because they saw it on Dr. Oz?
I’ve been reading a lot lately about how glutathione levels are low and methylation is severely impaired in autistics and people with chronic fatigue. I have both. My blood tests showed low levels of B12, folate and high levels of homocysteine. I used to get 1cc a week of intramuscular B-vitamin injections. It brought my homocysteine levels down but didn’t improve my fatigue at all so I quit the shots (they were a pain in the ass) and started supplementing B12 orally, instead.
After reading about the benefits I started taking N-acetylcysteine a few weeks ago. I wouldn’t call it miraculous but for the first time in about 13 years I could maintain something approaching a normal circadian rhythm. I have terrible insomnia and in the mornings I felt sick and tired whether I slept or not. It’s hell. On NAC I feel a lot better in that respect. The problem is it’s hell on my digestion. NAC gives me the runs like nothing else.
Any advice? Try as I might, I can’t really wrap my head around the methylation cycle. I’m a computer science major, not a biology major. I’d like to know how to troubleshoot the problem properly.
P.S. I was wondering when the subject of methylation would come up. You’d think on a site about metabolism, it would have come up sooner.
The subject of methylation came up prior to this when Dr Brind wrote about the methionine and glycine pathways in the liver.
I can’t pretend to know anywhere near as much as Dr Brind on this subject but I can tell you with certainty that glycine would benefit anyone whether they are normal or dealing with a severe illness such as autism.
After reading his last few posts it strikes me as odd that so many physicians treat high homocysteine with more methyl groups instead of glycine since, as Dr Brind has made clear, glycine is what is needed to bread down homocysteine.
I would be interested to hear his response as to how a supplement like n-acetyl cysteine would give someone so much symptom relief (such as in your case)
What if you’re an under-methylator? Would glycine still be indicated? And what is the best test to determine whether you’re over or under methylating?
It seems like the entire concept of being an “under methylator” is bogus unless you suffer from a real and severe protein deficiency. The “under-methylation” diagnosis, usually part of the MTHFR diagnosis seems bogus after reading these posts about the methylation and glycine pathways.
Can I ask how you were diagnosed with this? I was told for years that i am an under-methylator. Turns out I needed glycine not more methionine or methyl groups
As you’ll note from my reply to Angela, I think the “under-methylator” diagnosis might be accurate for some people (obviously not you, Sarah), but is likely much overused. I’m going to take a closer look at the varius issues involved, e.g., genetic variation in COMT (See my reply below to darius) and see just how widespread it might be. If the methionine cycle is not working properly, then there could be functional methylation deficiencies which become important during fasting periods, even though lots of methionine comes in with meals. After all, we know that people can suffer from hypoglycemia even though lots of carbs are taken in with meals, right? And as I’ve pointed out, the main aspect of the methionine cycle that is generally missed is the fact that the body treats methionine in a biphasic way, similar to the way it treats glucose. That’s exactly why I suggested that, if someone really is an under-methylator, a methylation recharge may be needed in between meals, even though the meals be loaded with methionine.
But regardless of how often under-methylation is a correct diagnosis, glycine is still crucial to keep the methylation load from being excessive, and if anything, one needs more glycine if one supplements with methionine or something (TMG being the most potent) that recharges it with methyl groups. So you are certainly right about that, Sarah.
A key–but subtle–point in all this biochemical regulation may be missed in viewing the reciprocal relationship between glycine and methionine: While excess methionine will deplete glycine to pathologically low (even if considered “normal”) levels, excess glycine (unless you eat hundreds of grams per day!) does not deplete methionine below optimal functional levels. The reason for this is actually clear in the metabolic diagrams (Both figure “a” and figure “b” appear in my part 4 on diet and inflammation post on this blog). In these figures, the biochemical switches that turn key enzymes on or off are indicated by yellow star-pointed arrows and dashed red ball-pointed arrows respectively. The molecules that act as such metabolic switches are methionine, SAMe, and methylfolate (MeTHF). As such, these substances act as drugs. But glycine does not turn anything on or off; rather, merely acting strictly as a nutrient, providing material (substrate) for several of the key reactions. Too much glycine is therefore only a problem in the rare case of a genetic abnormality like NKH, where a normal pathway for processing glycine is non-functional.
I didn’t think it would take too long for the subject of “under-methylation” to come up! (And btw, sa230e, I have been writing about methylation for some time. You can look at my recent post on this blog, part 4 on diet and inflammation, where I detail the pathways involving methionine and glycine in both methionine rich–as after a high protein meal–and methionine-poor–as during fasting–situations. During fasting is when the methionine cycle works. In the high methionine condition, methionine is cleared rather than recycled. This is the situation illustrated in the figure in the present post.)
Those who have been following my posts here know that my view is that we are generally over-methylated; eating a diet way too rich in methionine and poor in glycine, which is needed to get rid of the excess methionine.
However, it is an important question as whether under-methylation is a real problem for many people, and if so, how does that square with the generally high methionine diet and the excess of methionine (and methylation) thus produced? After all, under-methylation is a rather popular diagnosis these days, at least among alternative health practitioners. It is offered as an explanation for such conditions as compulsive disorders, seasonal depression, allergic disorders, asthma; in short, a host of diverse problems attributed to chronically high levels of histamine. Histamine is high because its degradation is dependent upon the presence of methionine (as active SAMe, which actually does the methylating). The reason for under-methylation is often thought to be a hypoactive variant of the enzyme MTHFR, which produces the methylated form of folic acid that is required to regenerate (i.e., recycle) methionine. (I discussed this at some length in the comments after my part 4 of diet and inflammation post on this blog.)
So, assuming under-methylation is a genuine condition suffered by some (or many), we go back to the question: How do we square under-methylation with a typically high-methionine diet, and what sort of dietary strategy should be employed to deal with this apparently contradictory situation? I think the answer is to consider the idea that one can be in a condition of hypermethylation after a high-protein meal, but sink into a hypomethylation condition during the hours between meals, if the methionine cycle does not work optimally (as in some MTHFR variants) and/or histamine excess and/or the presence of certain drugs puts a strain on available SAMe during that time.
But what about glycine? Won’t that interfere with necessary methylation or regeneration of methionine? Actually, no. You can keep taking supplemental glycine, because, again, we add it as a nutrient so that it is always properly abundant. It only helps to clear EXCESS methionine, but it does not turn off the methionine cycle when methionine is low and needs to be regenerated.
So my nutritional suggestion is this: If you have been diagnosed as an “under-methylator” and take supplements to increase methylation (methionine itself being probably the safest and most efficient), that can be pursued, if the supplements are taken between meals. (Methionine-supplements are typically supposed to be taken with food, according to the label, so it can be taken with a small snack. Better yet, methionine can be taken as a snack, in the form of brazil nuts, for example, which are 1% methionine all by themselves, a very rich source. It makes no sense to me at all to take a methionine supplement along with a high-methionine meal.) And keep up the 8 grams/day of glycine, taken once a day, whenever you like.
As always, one can try this sort of regimen for a month and see if things get better or not.
One thing people don’t realize is that reactive oxygen species (ROS), while they cause oxidative damage to the body, is also used by the body for this very same reason to fight disease. If your white blood cells are the soldiers in your body that fight your enemies, ROS are the bullets they shoot. This is why many believe that over-doing it with anti-oxidants can actually impair your ability to fight off illness. Dr James Watson, who won the Nobel with Crick for mapping the human genome, has said free radicals “may be key to preventing and treating cancer ? and depleting the body of them may be counter-productive.”http://www.dailymail.co.uk/health/article-2259280/Superfoods-make-cancer-MORE-likely-says-pioneer-DNA-study.html
He goes on to say that taking too many supplements increases your chances of getting cancer, and prevents cancer therapies from working if you do get cancer. So, as is usually the case in nutrition, “X is good, therefore more X must be better!” is wrong.
You raise an interesting point as usual, skeptic. In fact you seem to be echoing my point about simplistic thinking usually ending up wrong. However, you seem to be applying this view to supplements in general, and painting all supplements with such a broad brush risks your sliding into simplistic territory yourself.
But you are certainly correct in speaking of anti-oxidants as useful chemical species in fighting disease, and the possibility that taking too many anti-oxidants may inhibit important bodily defenses against infection and even cancer. Indeed, I find it interesting that, even as we may topically apply the ROS hydrogen peroxide to a wound on the outside, our own immune system is applying the same hydrogen peroxide on the inside for the same purpose: to kill any invading pathogens.
How that is relevant to GSH, and its precursors glycine, cysteine and methionine is that glycine is the natural regulator of the activation of the cells that make the ROS and cause inflammation. It is, in my view (and as my several recent posts on this blog attest) a deficiency in glycine which makes these cells hyper-reactive, making all these ROS to kill bugs that aren’t there, such as in tissue damage resulting from blunt injury, or the ordinary micro-injuries that occur due to normal turbulence in the arteries. It is also my view that anti-oxidants are so popular and useful because they help to mitigate the damage caused by ROS. But much better to stop the excessive ROS production in the first place by supplementing with glycine.
But importantly, remember that I do not advocate any sort of “mega-dosing” with glycine, or even using glycine as any sort of drug at all. Rather, I believe that the moderate intake of about 8 grams per day, as a supplement to a typical diet, is about right to replace the glycine missing from the diet because we throw it away with the bones and connective tissues of the meat, fish and poultry we eat. Perhaps it would help if we stopped calling it “glycine supplementation” and called it “glycine replacement” instead?
Firstly thank you Joel for these articles. It sheds light on some of the conflicting information out there regarding the healthiness or otherwise of different diets (e.g. vegans and wapf-folks both probably achieve a more favourable glycine: methionine ratio than vegetarians or steak-and-salad paleos).
My question is, in the context of a glycine abundant diet, would supplimenting with NAC be beneficial? Or would it simply be redundant, because with such a diet one would be producing plenty of cysteine ( assuming a sufficient methione intake)? Secondly, would sublingual glutathione ever be helpful? i.e. Are there benefits to raising GSH levels beyond what the body naturally makes given plenty of glycine and sufficient methionine/ cysteine?
Why would taking a gram of tmg give me an increased feeling of wellbeing and give me energy, in a similar way to how 100mg of caffeine feels?
Sorry I missed your comment earlier. TMG (aka glycine-betaine) provides a short-cut to regenerate methionine from homocysteine, an alternative pathway to methionine synthase, the enzyme which uses methyl-folate to regenerate methionine. The methionine is then quickly activated to SAMe, which likely acts to accelerate the degradation of certain neurotransmitters in the brain, especially dopamine, via the enzyme COMT, which methylates–thereby inactivating–dopamine. There is a great deal of research on this pathway due to its involvement in emotional processing and sensations of well being, and people with different genetic variants of this enzyme show differences in emotional processing.
So you might then ask, why don’t you get the same effect (no pun intended) from SAMe? The answer to that is in the dosage. The typical dose of SAMe is 200 mg. The methyl group of the SAMe molecule makes up only 3.8% of the molecule by weight. In contrast, the methyl group donated by TMG to regenerate a SAMe molecule in the body constitutes 12.8% of the TMG molecule. So let’s do the math, comparing a 1 gram capsule of TMG to a 200 mg capsule of SAMe: 1,000 is 5 times 200 mg, times 12.8/3.8. That comes out to 5 x 3.37 = 16.8. In other words, a 1 gram dose of TMG gives you 16.8 times the dose of available methyl groups as 200 mg of SAMe. There’s your rush!
But watch out: You’d better have lots of glycine around to metabolise that SAMe that is formed (and to make adequate GSH) Otherwise it might do damage. Experimentally, brain damage mimicking Parkinsons disease has been demonstrated from injecting SAMe into the brains of rats. What happens specifically in that case is that the methylated neurotransmitters generated by the burst of COMT activity, degenerate by releasing methyl alcohol, which turns into formaldehyde. The formaldehyde does the cellular damage (and requires lots of GSH to neutralize it).
On the human side, there appear to be no peer-reviewed studies that indicate any ill effects of TMG. Of course, since it increases the methylation load, the abundance of glycine becomes more important to keep everything in balance.
A side note: this gets at the conundrum, so familiar to those of us who have been mysteriously sick for a long time, of how to distinguish “healing reactions” or “detox” from true harm.
I get Parkinsonian symptoms from 5-MTHF and TMG. I have had many people tell me that I should push through this, as this is my brain and nerves “waking up.”
(I should say that I have never tried these methylation-boosting supplements against a background of abundant glycine.)
I would be less inclined to “push through”, with symptoms that mimic experimentally induced damage with essentially the same chemical insult (a burst of SAMe in the brain). Assuming the same ability to cross the blood-brain barrier (although it might cross more easily), 5-MTHF has about the same methylation potential as SAMe itself. If you really want to pursue the increase in methylation potential, you might just try the strategy of a few Brazil nuts in between meals. (And of course, you should have adequate glycine in your system as well.)
Oh, I wonder if this explains the unpleasant effects I get from methyl-B12 (1mg sublingual): sinus pain, sneezing, feeling blah? I don’t notice anything from methyl-folate (800mcg) though…
Hard to say, Amy. If B12 is deficient, methylfolate will have no effect, as that methyl group is trapped. If B12 is not deficient, but methylfolate is (due to inadequate activity of MTHFR), B12 will have no effect. But TMG will show the effect of increased SAMe, as it recharges homocysteine by an alternate mechanism.
Okay, this is helping immensely. Thank you.
I have read that the use of NAC, Glutamine and Glycine in a 4:2:1 ratio naturally boosting GSH. It doesn’t sound like a very good protocol in this light.
Prof. Brind,
You’ve persuaded me to question the wisdom of boosting GSH through whey protein and NAC, but what about supplementing GSH itself? Absorption issues aside — let’s say we’re talking about IV or liposomal GSH — can you see any downside?
When I experimented with liposomal GSH, I felt awful. Some people would say that this was detox — a good thing and a green light to continue with GSH. I was not so sure.
As an answer to the last 3 comments (which are pretty closely related), I would say that strategies to increase GSH which don’t load up with cysteine specifically (e.g., the strategy reported by ML) or which involve just taking GSH itself, likely will not do either much good or much harm. I think the important point is that when glycine is deficient and methylation is in excess, the need for GSH is elevated, even as the body’s ability to make it is diminished. But when glycine is abundant, excess methionine is cleared, reducing the need for GSH on the one hand, and providing the material to make as much GSH as might be needed (i.e., the ability to make GSH no longer limited by the availability of glycine).
Thanks for your response, Prof. Brind.
But I am surprised that you say that supplemental glutathione is unlikely to help or harm. Regarding IV glutathione specifically, the internet abounds with stories of dramatic responses — positive and negative.
The negative responses are what I want to understand. Doctors who advocate IV glutathione tend to argue that all negative responses are merely detox — an argument for proceeding slowly, to be sure, but ultimately an argument strongly pro, rather than contra, supplemental glutathione.
However, there are dissenting views. For example, in the CFS community, one often hears the argument that supplemental glutathione flushes active B12 from the body, leading to folate trapping. If this is true, the argument goes, negative reactions to glutathione/NAC are not beneficial detox but dangerous B12/folate deficiencies.
I should stress that in all of this I am talking about people who are very sick. For my own part, if I were healthy, I wouldn’t be messing around with any of this stuff!
All I know for certain is that 500mg per day of liposomal glutathione took me to an extremely unpleasant place in less than a week.
I must confess here to some ignorance myself–not really familiar with the stories of GSH side-effects. What I’ve found on the internet are mainly infomercials by suppliers and treatment centers, and the peer-reviewed literature has almost nothing on treatment of people (I found one article on neanatal premies receiving liposomal GSH, and they apparently did not complain:-). My supposition that GSH would not make much difference was really based on the fact that a total of around 500 mg/day of GSH is really not much for a human body. I know of trials of for example, of 6 grams/day making a significant positive impact for patients with cystic fibrosis, but I am still surprised at the kind of dramatic effects you and others have reported.
However, the argument that GSH flushes B12 from the body is interesting, although I do not know if it has merit. Of course, if it does deplete B12 it would result in methyl trapping (folate trap), which could lead to serious consequences due to the resulting folate deficiency. This hypothesis could be tested, however, by seeing if simultaneous administration of B12 abolishes the negative reaction to GSH.
So what is your explanation for why young people have higher levels of GSH than old people?
Lots of things go down with advancing age, as a generalized phenomenon, and it’s hard to differentiate what is due to aging per se, or to a gradual disease process like chronic inflammation. I do not have a specific mechanism to suggest, however, nor do I think it necessarily has any real significance. Remember that a major dietary change like lowering methionine consumption or raising glycine consumption reduce hepatic GSH many fold, yet slow the aging process.
Dr Brind- I’m veering of course here somewhat, but will add some thoughts nonetheless. Thank you for providing more compelling evidence for us to add glycine into our diets than the often trumpeted “because our ancestors used to eat nose to tail”. I have my doubts on this arguement due to my limited observations made while butchering beeves. But basically, it seems that its a whole lot easier to extract and eat the muscle meat than the “high glycine” cuts! My wild guess is that our ancestors had the same out of wack ratios during times of plenty. But I’m curious on how you arrived at the general ballpark recommendation of 8 grams per day? I’m sorry if this has already been addressed in a previous article or comment thread, as I have not read them in entirely (yet).
Thanks for your question, Jake, which I have not answered it earlier.
A Spanish research team in the Canary Islands (Enrique Melendez-Hevia, et al.) published their estimation of 10 a gram average daily glycine deficit 5 years ago, based on their conclusions re: what they consider “a weak link” in human metabolism, i.e., the inability to make sufficient glycine for collagen synthesis. (Incidentally, I think they are wrong about their being such a weak link.) They found great results in (unpublished) clinical trials on hundreds of patients with arthritis, and believe that the benefits of glycine supplementation are that it enables sufficient collagen synthesis for tissue repair. (And they seem unaware of glycine’s crucial role in regulating inflammation, which is where I believe the benefit lay.) At any rate, I started my own self-experimentation with 10 g/day (after trying 40g/day for a month, testing my blood weekly, to make sure it was safe). After trying a few different levels, I settled at 8 grams. 8 grams was adequate to keep inflammation totally down (generally experienced as soreness after exercise) and also easy to formulate into a once per day drink or additive to a drink. The experience of sweetamine customers appears to confirm that 8 grams make a suitable daily serving.
Thank you for writing another incredibly well-written and information-rich post. I hope you will continue to post things here on the 180degree sight. You’ve really shed light on some questions that have been nagging at me for a very long time!!! Thank you!!
I wanted to mention one thing regarding the supplementation of straight GSH in sublingual or IV form. I once engaged in this therapy, receiving glutathione “pushes” after a spectra-cell analysis said that I had low levels of it. I cannot say that it helped me at all and it’s VERY EXPENSIVE. I’m sure that the physicians who suggested that I needed these treatments had good intentions. But it’s a little annoying to later find out that there is such misunderstanding about GSH in the alternative medicine community and that likely, I would have benefited more from taking glycine. Oh well! I figured it out on my own a few years later…
If people try to give you a hard time because you sell a Glycine (and proline) supplement, just refer them to the relative cost of what you are selling vs the extremely high cost of most other supplements and protocols being forced on people!
Thanks for your kind comment Sarah. Actually, I like to tell people that my sweetamine has the glycine equivalent of about 16 servings of Jell-O, and it’s a lot cheaper than that! (around $1 per day, depending on how much you buy at a time). I also get the feeling that most readers of the 180health blog have already confronted the massive ignorance that is rampant in both the traditional and alternative health fields (just like in other fields of endeavor), and are hungry for answers that are well thought through and actually provide solutions to long-standing problems (and they are used to finding honest answers here). You can probably tell that I am thoroughly enjoying the dialog that has developed with this well informed readership, and I also hope to continue posting on this blog.
Guilty as charged! I do have trust issues with supplements. Perhaps I’m being more superstitious than scientific, but most supplements usually prove either hilariously ineffective or tragically dangerous. My wait-and-see approach in the past in regards to new and popular supplements has always served me well (Vitamin E everyone?) Although I do concede that you indeed are not advising mega-dosing, and you are starting to convince me :)
Hi Joel,
In some studies, the researchers have used quite high doses of glycine AND cysteine (100mg/kg/day of both, I think) and the combination seems to be quite effective.
http://www.ncbi.nlm.nih.gov/pubmed/23534396
http://www.ncbi.nlm.nih.gov/pubmed/21795440
http://www.ncbi.nlm.nih.gov/pubmed/24081740
So there might be a reason to think that in the context of high glycine intake, even several grams of cysteine isn’t something one should be very cautious of (maybe). Maybe there is even some net benefit.
BTW Joel, what do you think about these studies:
1) http://www.ncbi.nlm.nih.gov/pubmed/22236003 In this study, quite low concentrations of histidine, and especially cysteine, had quite significant anti-NF-kB effects on the endothelial cells.
2) http://www.ncbi.nlm.nih.gov/pubmed/23361591 In this large study (n=100), histidine supplementation (4g/day for 3 months) was very useful for the obese women: 30% reduction in TNF-alpha and CRP, 2.7kg reduction in fat mass and other beneficial changes in HOMA-IR, NEFA and oxidative stress markers.
In some other studies, histidine or histidine-containing peptides (carnosine, anserine) have had similar effects on rats and humans.
Maybe it would be beneficial to focus on histidine/carnosine/anserine as well, especially if we have metabolic syndrome? Some studies also show that people with diabetes have low plasma histidine, so maybe that also would be called “replacement” instead of “supplementation”: http://www.ncbi.nlm.nih.gov/pubmed/21996294
“Among the amino acids determined, serum histidine, arginine, threonine, glycine, lysine and serine were found to be significantly lower in obese women as compared to non-obese controls (P < 0?001). The difference was the greatest for histidine (P < 0?001). In obese women, both histidine and arginine were negatively associated with inflammation and oxidative stress. In non-obese controls, histidine was negatively associated with oxidative stress."
Hi Vladimir, and thanks for the amino acid-rich meal! It will take me some time to “digest” it and respond! (Of course, I really mean time to absorb it, as amino acids are absorbed without further digestion from protein foods:-)
OK, Vladimir, I’ve gone through the first 3 studies you cited, and it appears that the work of this group headed by RV Sekhar at Baylor in Houston, Texas, exemplifies almost exactly the kind of simplistic thinking I criticized in the text of the current post, specifically, their reasoning essentially is:
1. GSH is a good thing, the body’s most important endogenous antioxidant/detoxification molecule.
2. Studies show that GSH is highest in the young and the healthy, and lowest in the old and the sick. Therefore, raising blood levels of GSH is a good thing.
3. We can raise blood levels of GSH by adding the precursors’the amino acids cysteine and glycine’to the diet as a supplement.
4. Therefore, we can improve health status by increasing GSH through cysteine and glycine supplementation.
So they worked both with mice and people (normal human subjects in two studies and HIV-infected subjects in the third), and did indeed demonstrate higher levels of GSH in the young v. the “elderly” (Age 60-75: not so elderly in my book, as I’m almost 64!), as well as impaired glucose tolerance (i.e., insulin resistance or pre-diabetes) and fat-burning ability in the elderly. Then they fed the subjects both glycine and cysteine (the same amount of each, in fact, about the same 8 grams/day of glycine as I put in sweetamine), and found that indeed, GSH went up to youthful levels and both insulin sensitivity and fat burning ability were normalized. In addition, with isotopic infusion experiments, they demonstrated that the treatment was directly responsible for the increase in GSH. Ergo, glycine + cysteine is a good thing to do, because it restores healthy youthful function by restoring higher, youthful levels of GSH. As you said, Vladimir, “the combination (of glycine and cysteine) seems to be quite effective.” Great science, right?
Not so fast. A proper controlled experiment would have included both a “glycine only” group and a “cysteine only” group. But the investigators apparently assumed that an increase in GSH was needed in order to improve the health status of the subjects.
But suppose that the supplementation with glycine alone would have normalized the handling of sugar and fat, without any cysteine? This very outcome would be suggested by, for example, the Cruz study on diabetics in Mexico City which I cited (wherein they supplemented with glycine alone). That would have shot down the idea that cysteine was necessary at all. Of course, without supplying the cysteine supplementation, GSH would probably not have gone up either, and that would have shot down the theory that the observed improvements had anything to do with GSH at all, but were rather due entirely due to the supplementation with glycine! (I would argue–as indeed I did in the text of this post–that the increase in GSH is only necessary to deal with the increased methylation stress induced by the supplemental cysteine.)
Finally, I (sadly) note the impact of such flawed science as exemplified by the Baylor team: These three studies were published in a top-notch nutritional journal, a top-notch aging journal and a top-notch endocrinology journal, respectively. Hence they are sure to burnish the image of GSH in the biomedical world. Looks like the GSH fad has some time yet to run.
But give me another day to go over those papers on histidine and other amino acids.
Thanks for checking those papers :)
I have been collecting other histidine/carnosine/anserine papers here (without reading them carefully, though): https://docs.google.com/document/d/16EyUEgK_jGCpyDYDe7dLJSHBypaPEi1gqACrA4RvC0Y/edit?usp=docslist_api
The first three links in the document are human trials. However, most of the studies have been conducted in rats, often with 0.1% addition of histidine to drinking water.
1) http://www.ncbi.nlm.nih.gov/pubmed/22236003 In this study, quite low concentrations of histidine, and especially cysteine, had quite significant anti-NF-kB effects on the endothelial cells.
The glycine and histidine at 0.2 mM may be real, although that’s 4x physiological for cysteine. But 2 mM and 20 mM for any of those amino acids? Seriously? So I would agree that histidine is worth looking into (as well as the histidine dipeptides carnosine and anserine, as you suggest, especially in light of the Feng clinical trial you cite, which was of very modest supplementation with histidine. While it might be possible to get the same anti-inflammatory effects with glycine, it is certainly intriguing that the histidine supplementation (or maybe, replacement, as you suggest) resulted in significant weight loss as well. Glycine doesn’t cause weight loss, except for an initial loss of the excess water weight attributable to the inflammation.
On second thought, I have calculated that, even at the minimum BMI for the obese women in the Feng study, an average loss of BMI of only 0.86 kg/sq. meter comes out to only about 5 pounds (2.3 kg). Hence, the significant but very modest weight loss may be attributable to the loss of water of inflammation, rather than fat mass. It would certainly be interesting if the same effect could be obtained with glycine rather than histidine, or whether their might be an additive or synergistic effect.
According to the full text, they didn’t measure only BMI. They also measured fat mass: “Fat mass (FM) was measured using the electric impedance method with a body fat mass analyser (ioi 353; Janex Medical, Seoul, Korea).”
Do you think that this measured decrease of fat mass (-2.71kg) could partially be explained by loss of water?
I think that loss of 5 pounds in 3 months is quite a good result, and there’s the possibility that the fat loss could continue if one supplemented histidine for a longer time (e.g. 1 year).
If we extrapolate (might not be appropriate), the loss of 10kg/year would be a lot. Though I don’t know whether that’s a realistic scenario.
I recall watching this lecture by obesity researcher Stephan Guyenet, who showed that usually dieting doesn’t even lead to significant sustained weight loss. So if we could achieve some permanent weight loss without even dieting, that might be quite a huge thing.
https://www.youtube.com/watch?v=WMdSHNnRbEs (the beginning of the lecture)
I don’t have the full paper, but assuming they confirmed it was a real loss of fat mass, that would be significant. However, a loss of 5 pounds is typical within one week when people who are glycine-deficient and have significant inflammation (like swollen knees, etc.). The loss of a few litres of water is enough to account for the acute weight loss, which does not continue.
Moreover, I am interested in the relationship between glycine, histidine (and histiding dipeptides, carnosine and anserine) and inflammation. For one thing, Gall et al 2010 did not indicate any substantial reduction in histamine in insulin-resistant v. normal subjects (although they did not show all their data, so there might have been some reduction.) For another thing, the mechanism of histidine depletion would likely be through excessive histamine synthesis and secretion. This sort of problem is typical of chronic inflammatory conditions such as asthma, which are often ameliorated by glycine alone. So if the membrane stabilizing effects of glycine prevents excessive histamine release (and resynthesis), it could be that histidine deficiency is secondary to glycine deficiency. This hypothesis could be easily tested by running such a study as Feng et al. did, but with glycine instead of histidine. They could test for the same effects as with histidine alone, and also for levels of histidine as well. In addition, they might perhaps (if they have some plasma or serum samples left over from their histidine study) check to see what changes their may have been in levels of glycine in the subjects who took histidine v. placebo. That could establish which effect is primary.
I must say that it puzzles me why all those investigators who run trials with various amino acid do not run full amino acid profiles on the subjects’ plasma or serum. These days, that is not very difficult to do with very small volumes of blood, and it would answer so many important questions simultaneously.
I think the Feng 2013 paper is a “free full text”. I can access it without a VPN connection to my university. It’s an interesting paper. The reported decreases in CRP and TNF-alpha seem quite huge…
I think that many “glucogenic” amino acids are decreased in diabetic patients. Maybe diabetics waste glycine and histidine to glucose production, because of inflammation?
In HFD-fed rats, histidine levels are lowered and I suspect that inflammation is the cause. So I guess that glycine would spare histidine.
Personally I’m eating both: 1-2g histidine and 6-8g glycine.
It’s stupid that they measure so few things in those studies… :(
The diabetic wasting of amino acids–diverting them to gluconeogenesis–is due to the lack of insulin action. Insulin switches the metabolic machinery away from glucogenesis (from glycogen) and gluconeogenesis (from amino acids and glycerol and pyruvate) to glucose utilization and storage. Where inflammation comes in, I believe, is via a chronic attack on beta cells in the pancreatic islets, leading eventually to diabetes and ultimately to insulin-dependent diabetes, once the beta cells are destroyed.
Thank you for sharing all you knowledge on glycine and its potential healing effects, Dr. Brind.
I have many questions but my first, and main one is, is it possible for glycine to cause depressive affects? It may be happenstance, but by the end of the first day of taking 3gms I was feeling depressed. (Taurine does the same thing to me sadly, as I was getting some good benefits from it.)
I bought a magnesium/glycine powder (200mg mag and 900mg glycine) and the first dose caused stomach distress as you mentioned it might. (Not a normal malady for me.) Since your product comes in a powder form as well, what keeps it from causing upset stomach?
I really want to give the glycine a fair trial as I know I am plagued with chronic inflammation. (Elevated HSCRP and elevated ferritin. Also, some painful muscles and arthritic finger joint.) I will add though, tart cherry juice has helped tremendously but I think this is a completely different pathway of healing.
I’ve tested for MTHFR, COMT, CBS, etc. snps. (+/+ and +/- for many.) I’ve struggled with depression off and on over the years and obviously I don’t want to add to this potential problem. Inflammation is probably my worst health issue but if the treatment would cause depression, I’m not sure which is worse.
Thanks in advance for your response.
Sorry glycine is depressive for you, Diane. I suppose it can act that way as an inhibitory transmitter in the brain, which is why it is supposed to be an effective sleep aid. (And btw, taurine can act via the same receptors, so that’s not surprising.)
You might have a look at some of my earlier comments above, as it occurred to me that some people may experience under-methylation in the periods between meals, even if the usual predominance of methionine in meals causes an overall glycine deficiency. Remember the main difference in the way I look at the methylation cycle is the difference between after high-protein meals and during fasting. And just like people can be prone to hypoglycemia between meals–even though there are plenty of carbs consumed during the meal–it makes sense to me that one can be methylation deficient in between, if methione (SAMe) is not regenerated at an adequate rate (like if MTFR is not performing adequately). So what you might try is, in addition to daily glycine, a methylation supplement in between meals. It could be methionine itself (from a rich source such as Brazil nuts), or SAMe or methyl folate, to the most potent methionine regenerator, trimethylglycine. As long as there is ample glycine around, this might avoid depression while also avoiding inflammation. And I would guess you would know within a day or two if this sort of regimen works or not. As a preliminary indication, do you find that, when you are taking daily glycine supplementation, the depressive effect hits in between meals, say, 2-3 hours or more after a meal?
Glycine and Taurine are actually neurotransmitters in their own right. There are both Glycine and Taurine receptors in the brain. So yes it could affect your mood. Many people use Taurine specifically to treat anxiety. It helps to inhibit glutamate excitability.
I think you are saying that the depressive effects of glycine might only become apparent when methionine is scarce. Is this because then glycine would be more abundant, since it would not be required to ‘waste’ methionine? But the abundance of glycine must also depend on when the last dose was taken; in the wikipedia article on glycine it says its half life in the body is dosage dependent, between 0.5hrs and 4 hrs in the study cited. So it seems to me that, both to maximize the positive effects (anti-inflamatory etc) and to minimise potential negative effects (depression) it would be a good idea to divide up the daily dose and maybe take some with each (methionine rich) meal?
In my experience, the positive effects of glycine last for 2-3 days, so I would think the half-life is a bit longer than 4 hours (especially after building up the steady-state levels for several days). No question that dividing the daily intake would make for a more even steady state level. So what you say, Amy makes perfect sense. Of course, it is most natural to take the glycine with a methionine-rich meal–as in bone broth or other form of the gelatin that naturally occurs with the muscle meat. For most people, the effects on the brain are not so immediate and dramatic. However, for those people for whom they are, a bit of self-experimentation on the timing should easily establish an optimal regimen.
Ok, this is a topic a would have loved to approach since a while.
Glutathione does not work for me. High or low doses, no matter.
NAC does on a very impressive way, the result is much higher glutathione
in my blood test then the glutathione supplement in any doses.
My opinion and observations are till now that precursors taken orally
do work while the desired compound taken in the exact form as desired
almost(Never in my case) work.
Injections are another story, my personal knowledge is low.
How i came to NAC.. I was unfortunately taking large dose of paracetamol,
Tylenol for US. Long periods. Of course it had a disastrous impact on my liver.
I started having alcohol induced migraines to the degree that i couldnt drink without having one. the vomiting, the blindness, almost delirious.
Zolmitriptan was working, but the secondary effects were hell.
I met a doctor who demanded me to take NAC for a while.
I checked before taking and decided to go directly for Glutathione.
Nothing. I took quite a doses, 3,4 grams.. Then i decided to follow the primary proposition. NAC.
My migraines stopped. No matter the quantity of alcohol consumed i could just suffer a slightly unpleasant state due to drinking but no more.
Energy, great . I use to suffer some stomach pains that has disappeared entirely. Physical state, better then a long while.
NAC does work better then Glutathione. For me, but it seem not only as i checked few forums before writing that..
I don’t know why of course, is it the body refusing to use anything not coming straightly from the live or directly from injection in the blood(which skips the
liver barrier).. No idea. Sizes of molecules, dunno..
But again, precursors go a way further for me.
I cannot not be tempted by the idea that as the grandiose factory
the body is, having a formula imposed which probably most of the time
isn’t the exact one it uses
does get rejected.
It also corresponds to your basic line Matt, feed your body with food and not supplements. Let it extract and digest what it needs instead of imposing
a ready chemicals.
Yes, Stella, the body is a “grandiose factory” and more, but it is understandable if we think through what is going on. Yes, intravenous administration bypasses the liver, but in terms of GSH, a lot needs to be infused because it gets diluted by the plasma and the blood cells before it gets to the liver. So, if you want to get something to the liver specifically–such as to reverse paracetamol (acetaminophen) toxicity–you have to eat it. Trouble is, GSH–even though it resists digestion because of the particular linkage of the amino acids–is very poorly absorbed. Hence, the best way to crank up hepatic GSH is it eat precursors. In general, glycine is more limiting, in my view, except when there is a particular stress like paracetamol. What is unique about this situation is that the toxic metabolite of paracetamol (a benzoquinoneimine) is irreversibly bound to the sulfur atom of GSH, rendering the GSH non-reusable. Even worse, it renders the cysteine part of the GSH non-reusable, thus radically depleting cysteine. Ergo, the most effective way to deal with toxins that deplete GSH in this way is to eat cysteine or NAC (essentially the same thing). So that’s an effective strategy at which you have arrived, and I would only add that maintaining ample glycine avoids exacerbating a glycine deficiency.
Thank you Dr. Rind for your response to my comment. And Amy, good find.
The first day I took the glycine in powder form in water, it was on an empty stomach. Bad. The past couple of days I’ve done much better since making sure I have some food in my stomach before drinking. This evening I’m feeling a touch of depression. I bought some Brazil nuts at your suggestion, but could only find them in the shell. Tonight, I went in the garage and cracked one in a vise to enjoy. ;D
In response to the comment above, I’ve wondered when taking the taurine (and if it might be the same for glycine) if I became depressed because it had built up in my system or if I was having a period of slow methylation. I hope the later. I’m paying more attention to the effects I feel and when, so I can hopefully figure out what is what and try to keep it all in check.
I do have a question, if it’s not too off topic and if you don’t mind. How/where do MAOA and MAOB fit in the methylation cycle? I have a lot of these snps.
Thanks, again.
As I mentioned earlier, taurine actually binds to glycine receptors, and both compounds cycle through the body rather quickly. (BTW sweetamine also contains a gram of taurine per serving, in addition to 8 grams of glycine.) Re MAOs: These enzymes have nothing to do with the methylation cycle.
Thank you, Dr. Brind.
(Sorry for misspelling your name earlier.) I understand your comments above. I’m tweaking the timing and amount of my intake of glycine and it seems to be working. And, when I get too much for my methylation to handle, I now know what to do. Appreciate it.
Matt Stone, is there a way to contact you directly, for a personal talk with you (like a consultation)? We have a very unfortunate situation in our family and would like your help.
I think you’re better off working with Dr. Smith. drsmith@180degreehealth.com
When would be the best time to take glycine?
I take taurine to help bile flow. Can I take these together?
I think I have read that glycine is stimulating while taurine is relaxing? I don’t fully understand the implications but I find that taurine and gaba have a very good effect on me. I tend towards very high sympathetic dominance.
I take my glycine–my sweetamine product–first thing in the morning; a whole 8 grams for the day. Sweetamine also contains a gram of taurine, so of course they go well together. Taurine can also activate glycine receptors. Hence, both should have a relaxing effect as neurotransmitters.
Hi,
I am taking NAC for 12 months (1,8g/day) after 20 years of therapy-resistance in a severe OCD (even had to give up my clinical career as a physician). I am aware of the promising studies, eg. in bipolar disease or other neuropsychiatric disorders and therefore decided to give it a try. I had an surprisingly excellent response and tolerated NAC well. Because of a gastric ulceration I had to abruptly terminate NAC treatment. I am now worried, that this rapid “NAC deprivation” may have adverse effects, because the metabolism has adapted. Do you think some kind of “rebound oxidative stress” with permanent neurological damage may occur under this circumstances? I am really worried. I am aware, that almost all NAC supplementation studies (especiall the crossover-designs) seem to treminate traetment from one day to the other. Your expert opinion is highly appreciated.
Many thanks in progress!
Hi JG,
Can’t say I know much about NAC in such conditions. However, I’m a bit surprised that a gastric ulcer would preclude NAC therapy. I should think there would be an appropriate form in which it could be taken orally without exacerbating a gastric ulcer, so that its benefits would continue for you. There is even some evidence that NAC is of benefit to such conditions: http://www.currenttherapeuticres.com/article/S0011-393X(97)80106-3/abstract
I’ve been taking Sweetamine a few times a week for the past couple months. The only thing I notice is that it makes me incredibly tired a couple hours after. (Or at least there seems to be an uncanny correlation between my becoming very tired on the days I take Sweetamine.)
Any explanation for that?
I would think that would be a sign that it is relaxing your nervous system. Do you have tendencies to feel anxious, hyperactive, strung out, and stressed with bouts of insomnia at various points in your life? If so, the tiredness is probably a very good sign, and may be something you should seek out more of. Otherwise, I don’t know the significance.
What you mentioned at the end of the post about how rats given supplemental glycine have LESS glutathione contradicts your explanation of the methylation cycle. According to my understanding, glycine (along with cysteine and glutamine) are needed for the body to produce glutathione. So how is it reduced in those rats? Could you please explain?
How about pairing NAC/Iv Glutathione, broth and glycine supplementation together? How would that work out? Isn’t Glutathione supplementation necessary if you have MTHFR?
Hello Dr Brind
In this post you mention two studies that show a correlation between low glycine and insulin resistance, a prediabetic state, and diabetes respectively. It is interesting to note that in neither case could the authors distinguish which was cause and which was effect. It is tempting to draw the conclusion that there is a deficiency of glycine, given that protein is largely supplied by muscle rather than with the rest of the animal. However, more recent research suggests it isn’t a lack of glycine which is responsible for these states but that it is depleted by the need to metabolise an excess of glucose provided in the diet. It seems, therefore, that while glycine supplementation has been shown to be useful to ameliorate the effect of raised blood glucose and lowered glycine levels, fundamental changes in diet are necessary to meet the underlying cause of the problem.
David
PS In the 2008 trial in Mexico city, you say the participants were given 15g of glycine per day. Actually, the amount was 5g. The reason the figure of 15g arises is because the glycine was administered as a dose combined with 10g of water.