There’s no shortage of info out there about inflammation’s being the root cause of most of what makes people sick and die these days–from arthritis to diabetes to cardiovascular disease to cancer?and what to eat and not eat to put your body into an “anti-inflammatory” state.
But there is a shortage of real knowledge about inflammation itself: What its proper role is in the body and why it is so often out of control. Once you know that, the rest is easy.
Back in the day (some 35 years ago), I studied immunology at NYU Medical School as part of my graduate training in Basic Medical Science. You would think that inflammation, as a major function of the immune system?innate immunity, to be precise?would occupy a substantial proportion of the course material. Nope! Everyone in the field, it seemed, wanted to win the Nobel Prize for figuring out acquired immunity: How does the body figure out how to make a specific antibody against the chemical signature of a microbe it has never encountered before? That was one of the great mysteries of the day; the principle behind vaccination and all manner of specific immunity. Well, that mystery was eventually solved, and I don’t even remember who got the credit. Are we making better vaccines and saving more lives because of it? You be the judge.
But if you go back to the days when infectious disease killed most people; when great plagues swept through human populations with some regularity, it wasn’t acquired immunity that saved most of the survivors. It was innate immunity. After all, acquired immunity takes weeks to develop after the first exposure, and the body can succumb to infection in a few days. So the real life saver is the first response system, the aggressive, non-specific attack against the offending microbes. Of course, such attack can and does do lots of damage to normal tissues in the process, but it might just save your life.
It’s really just like society’s first responders; like the fire department. When your fire alarm detects a fire, the fire department is summoned, and quickly the firemen show up with their axes and their hoses. They put the fire out, all right, but they do lots of damage in the process. Once the fire is out, you bring in the repair contractor to fix the damage. In your body, once the threat of infection has been neutralized, healing begins.
But for some odd reason, inflammation’the basic operation of innate immunity?is still viewed by the medical and scientific community as part of the healing response. In fact, the opposite is true: it inhibits healing quite effectively.
Two years ago, this is how Wendy Weber, A National Center for Complementary and Alternative Medicine (one of the NIH Institutes) program director, was quoted in the Wall Street Journal (wsj.com; the section entitled “The Informed Patient”, article author Laura Landro). ‘”You need to have inflammation when you have a wound and the immune system goes in to heal it. Yet we don’t want too much inflammation in our system causing damage to our arteries” and other harm’.
The prevailing dogma, unfortunately, does not really distinguish the separate roles of immune defense and tissue repair.
To take a simple example, say you sprain your ankle. It gets all swollen and painful and immobilized from what process? Inflammation. In fact, everyone knows that the immediate treatment of choice is to put ice on it. To do what? To suppress inflammation!
Why? Because the inflammation prevents healing from taking place.
OK, so why does inflammation happen at all when you sprain your ankle? Because, it is generally believed, inflammation is the body’s natural response to tissue injury; to distress signals released from damaged cells and tissues. But why? If you sprain your ankle, where is the route of infection? There are no invading microbes to destroy, and if inflammation happens anyway and does more harm than good, why does your body do it? Why do you have to interfere with your body’s natural response to the blunt injury, for optimal healing to occur?
The answer is quite simple: Your body is not acting appropriately, because it is laboring under a nutritional imbalance. Actually, the typical Western diet tends to be deficient and/or imbalanced?in 3 key nutrients: salicylic acid, omega-3 fatty acids (vs. omega 6), and glycine (vs. methionine). The third is the most important and the least well known (although Vladimir Heiskanen’s excellent recent post on this blog gives a pretty good introduction). I’ll get to the specifics of how all this works?down to the cellular and molecular level–in my next post.
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 www.sweetamine.com, which includes his own blog HERE.
“I’ll get to the specifics of how all this works?down to the cellular and molecular level?in my next post.”
Look forward to it. I have had a quick look at the literature and there is little to see re: glycine. The gut microbiome and bacerial metabolites are all the rage though http://www.ncbi.nlm.nih.gov/pubmed/24950203
This abstract seems to emanate from the school of thought that in the western industrialized world, our immune systems are insufficiently exposed to pathogens to function properly. This has even led to therapies that utilize the introduction of live, parasitic worms; parasites which naturally secrete anti-inflammatory substances in order to protect themselves from immune attack by the host. As bizarre as this is, patients suffering from inflammation actually experience improvement, because inflammation is reduced. But the real problem is usually glycine deficiency, and it makes much more sense to just add back the glycine that is usually thrown away with the bones of what we eat. .
More please, inflammation is killing me. Mine results from chronic colitis which is a side effect of the chemo drug Yervoy.
Yervoy side-effects are likely exacerbated by glycine deficiency, so glycine should help.
I’ve tried glycine recently, noticed that it made me constipated (I’m never constipated), and way to mitigate this?
That’s the first time I’ve heard of that effect. I wonder, are you taking it just as a straight powder? Especially if you are taking several grams, it will absorb a lot of water from your GI tract. When I first began researching glycine, I read some clinical trial reports of clinicians who were looking for benefits in major depressive conditions (no real results there: They were hoping for significant effects based on glycine’s action as a neurotransmitter in the CNS). I was struck by how, in these studies, they administered up to 60 grams per day as a dry powder. They did report lots of complaints of GI upset, and that’s what started me on the path to develop palatable formulations for daily use. I think I have succeeded pretty well with sweetamine, and you are the first to report constipation, to my knowledge. It really should be taken with a beverage, hot or cold (although it dissolves more easily in a hot one.)
I took it in pill form. I started with 1 gram, and worked up to three. It was mild with one gram, by three grams I wasn’t going at all for the entire day (very uncommon for me). I took it with a little water right before bed, on a not-so-empty stomach; maybe an hour after eating dinner.
That could explain it: Wherever the capsules dissolved in your GI tract, they took up lots of water. I would suggest you try taking those capsules and opening them up (or if tablets, grinding them up) and just dissolve in your favorite beverage. If that works out OK, try upping the daily serving total to 8 grams (what each serving of my sweetamine contains) for maximum benefit.
Interesting, I’ll try opening them up and see what happens. Not sure I could get to 8 grams though. 2-3 grams actually left me a little sluggish the next day
Oh goody! Just as resistant starch mania is running out of steam, we have a new magic nutrient ready to take it’s place. Let me guess: there’s a tribe in Africa/some Pacific Island that eats a lot of glycine, have perfect health and beauty, no dental cavities, are all ripped and shredded and they bench press elephants for reps? This search for a miracle nutrient/drug that will fix everything is the reason why nutrition science fails to progress.
Oh wait until we start talking about sulfur.
Skeptic, you are correct! Indeed, “This search for a miracle nutrient/drug that will fix everything is the reason why nutrition science fails to progress.” Well, it’s at least one reason for lack of progress where progress is lacking. That is certainly not how I came across glycine. Rather, it was in trying to make sense of reproducible findings (increased health and longevity) in rats when fed a diet severely reduced in the content of methionine. Eventually, reasoned hypothesis connected the dots, bringing together disparate findings among scientists of different disciplines. Self-experimentation (fortunately possible when dealing with simple bulk nutrients) also played a crucial role in testing hypotheses and producing, ultimately, some supremely surprising and satisfying results. Stick with me for the next post and I will connect the dots for you, so you can see, down to the molecular level, exactly what glycine does and how its relative abundance (or not) plays a critical central role in one-carbon metabolism and cellular electrophysiology, which underlies its critical function in the operation of innate immunity.
You have also hinted at a critical flaw in not only nutrition science, but science generally these days: In many ways, scientific investigation has devolved to more and more sophisticated forms of data mining. So we have such disciplines as epidemiology and all the “-omics”: genomics, proteomics, metabolomics, etc. Of course these are wonderful new tools, allowing us to test hypothesis more rapidly and thoroughly than ever before. But it is really a mistake to believe they are scientific disciplines in themselves, and that there is such a thing as “data-driven science” as opposed to “hypothesis-driven” science (the latter being what I call science). The former is rather simplistic; a sort of fishing expedition, looking for the one magical difference we can find (if we measure absolutely everything possible to measure) between an ailing population and a healthy one.
First time i took Glycine i got severe heart palpitations (diagnosed as supraventricular with ekg). They lasted 48hours. I found i unlikely that Glycine was the cause so i took Glycine again and i experienced heart palpitation once again, i also get a feeling of fatigue. The dose was 3-5g. Why is this happening? Is this common?
Glycine as an isolated supplement? It could have been some other ingredient, filler or contaminant in it that you reacted to. Have you tried just using straight Gelatin dissolved in a hot drink etc?
I have never heard of such a reaction. But of course there are idiosynchratic reactions possible to almost anything. What was the form of the supplement? How much was taken? What was the source? All these questions would need to be answered to get a handle on what is happening.
It was just pure Glycine. Ingredients says: 100% Glycine (farmaceutical quality USP28).
Then it does seem like an idiosynchratic reaction. One of the rare genetic diseases is non-ketotic hyperglycinemia (NKH). It results from a defect in the glycine cleavage system (GCS), which is normally the predominant route of glycine clearance. In such cases, glycine builds up to toxic levels, and afflicted individuals do not fare well. At an incidence of about one in 60,000 births, the frequency of carriers of any of the relevant mutations is probably not all that rare (perhaps one in few hundred). Such people are normal, but would likely tend not be glycine-deficient, and glycine supplementation might push glycine up to toxic levels. (In fact, a supplement like SAMe would likely benefit such people.) So that is one possibility you might check out with your doctor.
Joel Im really looking forward to the next part/s of this series. Any link with Methylation/Histamine?
My next post will indeed explain the role of glycine in methylation reactions. Bottom line: almost all of us have too much methylation going on, due to methionine excess. Glycine clears the excess methylation potential by getting methylated by SAMe (S-adenosyl methionine; activated methionine, the universal methylator). Supplements like TMG or SAMe or choline are generally harmful, because they increase the methylation load. Those who recommend such supplementation are exactly wrong, in my view. Yes, sulfur is important, but in further downstream metabolic forms like taurine: not as methionine! Harvard nutritionists cannot figure out why their research links choline (a major methyl source) supplementation with with INCREASED cancer risk, but I believe the connection with excess methylation is clear. In my next post, I’ll also include my own version of the relevant biochemical pathways. You’ll see how–rather than recycling homocysteine to regenerate methionine after a high protein meal–the liver is actually busy getting rid of methionine and its methylation potential as fast as it can. And there is only one pathway for doing this, and it uses up glycine in the process. That should provide some food for thought.
Awesome reply thanks Joel!
How long does it usually take to see improvements in terms of inflammation, e.g., reduced pain for someone with arthritis, with increased glycine intake (8-10g)? Is it a gradual thing?
Very interesting information; I can’t wait for the next part(s)!
Excess inflammation stops as soon as glycine levels get up to healthy levels; usually 2-3 days after starting 8g/day. So any pain or immobility directly caused by inflammation stops within that time. Usually, relief is accompanied by loss of a few pounds, but that’s just the excess water of inflammation.
Once the excess inflammation is gone, healing begins. So often, there are some old aches or places where chronic inflammation has caused damage over months and years, and these conditions gradually improve over many months, once healthy glycine levels are restored and maintained.
I have been a nightly wine drinker for years – over a year ago I discovered that SAMe helped with my long term insomnia (which I had before becoming a wine drinker). I have for the last few weeks been limiting wine to the weekends and now I have insomnia again. Is it now because my liver functions better and before SAMe helped because my liver wasn’t working well? I am very confused about SAMe because for a while it seemed to give me some of my life back.
Most likely the effects of both alcohol and SAMe you describe are directly on the brain. Alcohol’s depressant effects are of course well known. SAMe, by supplying excess substrate to the enzyme COMT (catechol-o-methyl transferase), accelerates the degradation of the neurotransmitters epinephrine, norepinephrine and dopamine, thus also providing a depressive effect.
However, production of methanol-a metabolic by-product of COMT-results in increased production of formaldehyde, which causes lots of damage. In published experiments in lab rats, injection of SAMe into the brain produces the effects I describe above and is actually used to cause.a rat version of Parkinson’s disease.
I’m not big on using drugs to get to sleep, but a glass of wine seems a safer bet.
I have been trying the Sweetamine product for about a week and a half. I can already tell a difference in my “tennis elbow” issue (less pain). Joel’s comment above explains why I suddenly lost a couple of pounds :-)
The same happened to me when I tried glycine recently. Some aches and pains subsiding and dropped some weight as well. I’m going to keep going for a few months as it has been positive so far.
Is sweet amine safe for pregnant or nursing moms? What about children?
Sweetamine is just a food–not a drug–merely replacing the glycine we usually throw away. Nutritionally, it’s the glycine equivalent of about 16 servings of Jell-o (Gelatin is collagen). The difference is that it is not from animal sources and that it requires no digestion, as a mixture of free amino acids.
The only caveat re: pregnancy/nursing, is that you might find you need more, since you need more of every food. I have one client who, while nursing, felt the inflammation that had been bothering her come back late at night after her having had her glycine in the morning. She fixed it by dividing the serving into two; one morning, one evening. Her baby, btw, is very healthy. I think she just has proportionately less sweetamine than her mom.(Although any amount is safe: Before I started selling it I took 40 grams a day and tested my blood every week. No problems). It is noteworthy that this child also had no problems with teething. I mention this because it has always struck me that the typical problems that children have with teething–where the inflammation causing swelling that blocks the eustachian tubes, causing lots of pain and often secondary infection requiring antibiotics, sometimes requiring the surgical implantation of a drain tube–are simply a manifestation of glycine deficiency. Why on earth should an otherwise normal, healthy child develop an excruciating and potentially life-threatening (think of the days before antibiotics) infection from the normal physiological process of cutting teeth? Of course I can’t make any claims in the absence of formal clinical trials, but I strongly doubt a child fed some daily sweetamine would ever have teething pain (in the absence of some real jaw deformity, of course).
This is the only glycine I’m able to source here in Argentina, and it is extraordinarily difficult to get things into the country.
http://www.biovea.com/ar/results.aspx?KW=glicina
Is this a decent source of glycine? Do you think for my two year old I could supplement glycine just by giving him gelatin?
Sure, taking a supplement of glycine is one thing, but what about actively getting less methionine in the food as well, for example? Are there any foods particularly rich in methionine, just as bone broth is rich in glycine?
Just curious :)
Funny you should mention it! I say that because–as I noted in an earlier comment–I was working some years ago on the phenomenon of methionine restriction, and originally started glycine supplementation in lab rats as a strategy for achieving functional methionine restriction. There are even various clinical trials that have been or are being conducted on methionine-restricted diets, but these are very difficult to do. You pretty much have to start with a strict vegan diet, but even then, you have to watch out for such foods as mushrooms and lima beans, which are methionine-rich. Experimentally, clinical trials typically involve all-synthetic foods (originally developed for patients with inborn homocysteinuria), and they are very unpalatable and difficult for people to stick to. The really nice thing about glycine supplementation is that it can be formulated into a single daily serving–like sweetamine–and used like a sweetener in tea or coffee. So it doesn’t require any other dietary changes to make your diet an “anti-inflammatory” diet.
Finally, to answer your second question: Yes, muscle meats are quite methionine-rich, and the worst offender is chicken! Imagine, the official nutrition gurus have been telling us for years that the most nutritious meat to eat is lean, skinless, boneless chicken breast, but it’s really the worst! (It’s also worth mentioning that a level of methionine restriction that produces measurable benefits, at least in lab animals, is one that also severely inhibits growth. So it definitely would not be suitable for kids, whereas glycine supplementation is fine for kids.)
Even with large amounts of glycine I notice that I’m still bothered by eating large amounts of methionine-rich meats. It manifests in greater physical pain and injury proneness.
Yes, of course there is something to be said in favor of moderation, as opposed to viewing glycine as a “magic pill” (like a drug) that can reverse the potential ill effects of excess intake of muscle meats or anything else, for that matter. I certainly do no want to give that impression! My point is rather that what is considered a generally well balanced and sensible diet is really not complete without replacing the glycine that is not consumed with the collagen.
In addition, I should note that in our rat experiments, glycine supplementation did not produce all of the benefits of methionine restriction. For example, it produced a 25% lifespan extension instead of a 40% one. So excess methionine may still produce some ill effects. It could even be classified as a B-vitamin rather than a bulk nutrient, as its minimum daily requirement in the human diet is only about 300-500 mg, far less than any of the other protein-building amino acids.
Perhaps the problem of glycine-rich diet not alleviating excess methionine is that B12 is insufficient (lack of organ meats/shellfish). Or maybe magnesium is deficient (gluten-free diet, or phytate-rich diet).
Since you seem to be touching on the methylation cycle, I guess you’d have to consider the downstream folate cycle, Kreb’s cycle, and transulfuration cycle.
Somehow vitamin A, D, K2 plays are part in all of these critical cell metabolic pathways as well.
Everything always circles back to a Weston Price diet: which provides all the nutrients required for biological function, as well as avoiding the “displacing” processed foods – which he said interferes with repairing and rebuilding mechanism of tissues.
I followed a Weston A. Price diet for 2 years, and it was not only time consuming to adhere to, it made me feel awful and my old sports injuries started bothering me again until I went back to eating my more normal, soul-food, from Grandma’s kitchen diet (and I’m not talking about grandma’s Weston A. Price traditional kitchen either). So now my diet consists of lots of baking with white flour and making things yummy. Me and my family are a lot healthier now.
my grandma’s kitchen had a lot of name brand breakfast cereals as well that I have re-incorporated whole heartedly!
Interesting. A Weston Price diet seems to mean different things to different people. For my daughter, who was crippled with rheumatoid arthritis, it meant 2 liters raw milk per day, cod liver oil, lots of butterfat, fried eggs over easy, bacon, store-bought whole grain sourdough, raw liver, store-bought fermented veggies, stewed meat, cooked/raw veggies/tubers and seafood raw/cooked several times per week. We did not find it overly time-consuming. Replaced cookie-baking time with broth-making.
Took 30 months on this diet from being in too much pain to walk across kitchen floor to “feeling pretty good these days.” Very, very long and arduous process, ups and downs. Now 4 years later she feels great. Still healing minor issues but back to living like a normal healthy young woman.
As I noted in an earlier comment, my next post will include my own version of the key pathways involving methylation, specifically the central role of glycine synthesis and catabolism in the methionine (transmethylation and transulfyration) and folate cycles. It’s worth noting now, however, that B12 is only required for the remethylation of homocysteine to regenerate methionine; the opposite of methionine clearance, which clearance is accomplished by the methylation of glycine via the enzyme glycine-N-methyltransgerase. These opposing processes occur under opposite conditions: remethylation occurs during fasting (or times of low methionine intake), whereas methionine clearance occurs during the absorption of abundant methionine after a high-protein meal.
In terms of dietary effects, it is clear that some of the benefits of methionine restriction are due to glycine sparing, and conversely, some of the benefits of glycine supplementation are due to methionine clearance. The overlap is not absolute.
As to what “interferes with repairing and rebuilding mechanism of tissues”, nothing interferes like inflammation, and nothing fuels inappropriate inflammation like glycine deficiency.
You said in comments above: “Supplements like TMG or SAMe or choline are generally harmful, because they increase the methylation load. Those who recommend such supplementation are exactly wrong, in my view.” I have been prescribed SAMe by a doctor after blood tests showed that I was an ‘undermethylator’. My understanding of this was that the SAMe supplement would restart the methylation cycle. Do you disagree? Could you explain your position further?
Mr. Brind (and Matt) when I go to a site that provides real, measured amounts of methionine and glycine in specific foods, the data strongly contradicts your statements that methionine is unbalanced by glycine – even in chicken breast, the food you listed as “worst”. So…what data source are you using, as it does not seem to be based on actual, usda measured grams of these aminos in specific foods.
Nutritiondata.com provides these measured amounts. Chicken breast, beef muscle meat, and other foods you cite as having bad ratios all have more glycine in them than they do methionine, the opposite of the problem ratio you have stated.
Facts please?
I think Dr. Brind would consider foods that are less than about 10:1 glycine:methionine as high methionine foods. The chicken breast data I just looked up shows 2.8 glycine:methionine. Whereas gelatin is 31.7, helping to get the balance closer to 10:1 if you were to consume some gelatin with your muscle meats. I don’t know if Joel has a theoretical optimal ratio between these two amino acids or not.
macrophages are monocytes not neutrophils (granulocytes)
Does ” Sweetamine ” change a persons PH ?
I have stage 3 Psoriatic Arthritis and hope it help me with my joint inflammation ? Thanks Joe Cannavo