The Glycine-Oxalate Connection Your Doctor Isn't Testing For

Glycine is necessary for a long life, smooth movement, a calm mind, and stable blood sugar, but how would you know if it's too much?

3 grams of glycine one hour before bed has been shown to reduce daytime sleepiness, help people fall asleep faster, and help people feel more rested and perform better cognitively during the day, and 15 grams of collagen peptides (which are rich in glycine) taken one hour before bed has been shown to help people stay asleep without waking up in the middle of the night.

5 grams of glycine cuts the blood sugar response in half when it is taken alongside 25 grams of glucose.

Glycine-rich collagen promotes collagen synthesis, and 1000 Calories of collagen for four weeks has been shown to help severe burn victims heal nearly four times faster.

Glycine is an inhibitory neurotransmitter, which is why it helps sleep, and disorders of glycine synthesis or signaling cause increased muscle tension, excessive startle response, and joint dislocations. The joint dislocations are probably a result of the muscles being too stiff to keep joints in correct alignment, so we might suppose that general muscular stiffness and poor joint alignment is in part driven by suboptimal glycine status in most of us who have such problems.

Despite its role as an inhibitory neurotransmitter, glycine is also needed to enable excitatory NMDA-type glutamate receptors to be activated by glutamate. Thus, deficiencies in glycine could impair neuronal excitation, which could hurt alertness, learning, and executive function. Poor function of NMDA receptors has been implicated in schizophrenia. 11 trials using between 30 and 60 grams per day of glycine for six to 28 weeks suggest glycine could cut schizophrenia symptoms on the order of 20-35%. The most common side effects of high-dose glycine in these trials were nausea and dry mouth.

Glycine may even help you live longer, as it does in mice.

All of this makes glycine look GREAT.

The problem is that excesses of glycine can be removed in one of two ways:

• One is to break glycine down to CO2 and ammonia in the glycine cleavage system, which is a mitochondrial multi-enzyme system dependent on magnesium, lipoic acid, vitamin B6 as pyridoxal 5’-phosphate (PLP or P5P), folate in the form of tetrahydrofolate (THF), riboflavin in the form of FAD, and niacin in the form of NAD+. The energy in the chemical bonds is carried away to the mitochondrial respiratory chain in the form of NADH.
  

• The second is to break glycine down via D-amino acid oxidase in peroxisomes to glyoxalate. Peroxisomes assist mitochondria with energy metabolism and serve specialized lipid synthesis and broad detoxification roles. D-amino acid oxidase uses molecular oxygen and riboflavin in the form of FAD, and when it converts glycine to glyoxalate it releases ammonia and hydrogen peroxide as byproducts. Glyoxalate can then be converted by L-lactate dehydrogenase using NAD+ to oxalate. However, formation of oxalate can be avoided if alanine-glyoxalate aminotransferase (AGT, encoded by the AGXT gene, which is defective in the genetic disorder primary hyperoxaluria type 1) converts the glyoxalate back to glycine, which requires vitamin B6 and the simultaneous conversion of the amino acid alanine to pyruvate.

Notably, glycine can be converted to serine using B6 and the 5,10-methylene-THF form of folate, and serine can be converted to pyruvate using B6, magnesium, and potassium. This could be an alternative way of clearing excess glycine that is largely similar to burning glucose for energy.

All excesses of glycine are likely to contribute to some type of harm: carbon for carbon, calorie for calorie, glycine generates more NADH through the glycine cleavage system than any other molecule that can be burned for energy, which can stress complex I of the respiratory chain and impair NAD+-dependent reactions throughout the cell; when excess glycine generates oxalate, it is generating a molecule that not only forms crystals in the kidneys, joints, and brain, but also poisons energy metabolism by inhibiting glycolysis, gluconeogenesis, the citric acid cycle, and the clearance of the potentially neurotoxic D-lactate.

Just because a biochemical pathway shows something can happen doesn’t mean that it does and doesn’t tell us how quantitatively important it is. So, let’s look at the evidence that glycine is converted to oxalate in humans.

But first, the short answer.

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The Short Answer

Measure your glucose and lactate upon waking after an overnight fast and/or one-hour postprandially on a day-to-day basis after a relatively standardized test meal. Test how this changes in response to different regimes of glycine supplementation. If glucose and lactate rise, glycine is likely overriding your respiratory chain; if glucose rises and lactate falls, glycine is likely being converted to oxalate. Run the Comprehensive Nutritional Screening and focus on fixing deficiencies of thiamin, B6, total folate, tetrahydrofolate, magnesium, potassium, lipoic acid, riboflavin, or niacin; or, cut back on the dose of glycine until glucose and lactate normalize.

Glycine Is Converted to Oxalate In Humans

Isotopic labeling is a technique to allow the tracing of an administered molecule through a biochemical pathway. The technique involves altering the weight of an atom within a molecule so that atomic weight signature can be monitored in the end products one is looking for. So, to test whether glycine is converted to oxalate, scientists have modified the weight of one or another carbon on the glycine molecule to look for the modified atoms showing up in urinary oxalate.

Early studies from the 1950s and 60s (here, here, and here) indicated that when just under 200 milligrams of isotopically labeled glycine were administered orally every six hours over the course of two to four days to human subjects consuming low-oxalate diets, between 20-50% of urinary oxalate could be accounted for by the glycine.

In subjects with primary hyperoxaluria, a set of genetic disorders that increase endogenous oxalate generation, the proportion of glycine that became oxalate was several times higher than in healthy subjects, but this was reflected in proportionally higher urinary oxalate, so the percentage of urinary oxalate accounted for by the glycine was not actually different.

A 2010 paper infused about 32 milligrams of labeled glycine per hour for five hours and found no label in urinary oxalate. When they infused ten times this amount, plasma glycine increased 29%, whole-body glycine flux increased 72%, and glycine accounted for 16% of urinary oxalate.

This was on a background diet containing 50 milligrams of oxalate and 1000 milligrams of calcium.

The authors of this paper argued that the older studies grossly overestimated the contribution of glycine due to outdated methodology for isotopic labeling and for urinary oxalate detection, and that their use of oral glycine instead of infused glycine complicated their analysis. However, one could also argue this study was too short, since the older studies found that the glycine label took a day or two to maximize its abundance in the urinary oxalate, and one could further argue that oral glycine is far more relevant to nearly any real-world use of this amino acid.

More importantly, however, the larger amount of glycine that accounted for 16% of urinary oxalate was only about 1.6 grams of glycine.

This indicates that supplemental doses of glycine between 3 grams and 60 grams are likely to generate plenty of oxalate.

Further, the oxalate values in the urine suggest a dose-response with the glycine infusion: the low dose was associated with a urinary oxalate of 0.89 milligrams per urine spot collection instead of 0.82, and the high dose was associated with a urinary oxalate of 1.02 instead of 0.8. These differences were not statistically significant, but the yield of oxalate from glycine at the higher dose was demonstrated robustly with isotopic labeling, making it clear that glycine was in fact converted to oxalate. If we average the baseline of 0.8 and 0.82 to yield 0.81, oxalate was 10% higher with the lower dose and 26% higher with the higher dose. These overall are consistent in magnitude with the labeling estimate that ~1.6 grams of glycine accounted for 16% of urinary oxalate.

These studies had between one and seven people each, and none of them demonstrated a statistically significant rise in total oxalate.

They provide proof of principle that glycine is on average partially converted to oxalate and that it can be a major source of urinary oxalate, but they do not make it clear how much glycine generates oxalate under what circumstances and whether supplementing with glycine will increase the total oxalate burden.

However, the balance of the existing evidence does favor glycine as a cause of increased oxalate.

I do not know of any randomized controlled trials of glycine supplementation that looked for changes in total urinary oxalate as an outcome.

How Can You Tell If You Have Too Much Glycine?

The following methods have not been vetted in randomized controlled trials, and are instead derived from biochemical reasoning.

If NADH accumulates beyond the capacity for it to be cleared by the mitochondrial respiratory chain, it will inhibit glycolysis and favor the accumulation of lactate at the expense of pyruvate. The primary signature of this will be an increase in lactate with a likely rise in glucose alongside it.

Oxalate inhibits glycolysis at the step of pyruvate kinase, which inhibits pyruvate production and therefore inhibits lactate production. The primary signature of this will be an increase in the ratio of glucose to lactate. If glucose goes up and lactate goes down this would be a strong signature of this occurring.

While you could test 24-hour urine oxalate on a certain long-term dose of glycine, measuring fasting levels of glucose and lactate at home, and/or measuring one-hour postprandial levels from day to day after a relatively controlled test meal, can give more real-time feedback and can allow you to do more tests on different doses and make decisions much more quickly.

The equipment I use for this: ​KetoMojo meter and strips​, Novabiomedical Lactate Plus ​meter​, Novabiomedical Lactate Plus ​strips​, ​alcohol pads​; If you plan to do a LOT of testing, ​extra KetoMojo strips​, extra ​lactate strips​, and ​extra 30g lancets.

Glycine has been shown to lower postprandial glucose responses, if glycine raises glucose this is a strong signal the dose is going beyond your tolerance.

If you are not getting an empirical benefit to the dose of glycine you are using, the most sensible thing is to cut back on the dose.

However, if you want to increase your tolerance, you need to run the Comprehensive Nutritional Screening and use the Cheat Sheet for interpreting the results, looking for deficiencies in the following:

• Deficiencies of B6, folate, magnesium, and potassium could prevent clean conversion of glycine to glucose or energy without overloading the respiratory chain.

• Additional deficiencies of tetrahydrofolate, lipoic acid, riboflavin, or niacin could be hurting the glycine cleavage system and encouraging use of D-amino acid oxidase in its place.

Notably, the need for tetrahydrofolate could explain the need for supplemental glycine in the first place, since it is the form of folate needed to synthesize glycine from glucose. This was covered in Why You Need to Start Juicing Tonight and Why Your Folate Supplement May Be Working Against You.

Thiamin deficiency raises oxalate in animals, and this is probably because it prevents pyruvate clearance, which would be expected to backup the AGXT reaction and to prevent the clean clearance of serine. Thus, thiamin deficiency should also be fixed if found.

Due to the complexity of biochemistry, increased oxalate could be a second- or third-order effect of many other deficiencies, which is why it is always with zero exceptions best to be comprehensive about nutritional screening and fix any problems that are found.

What is your experience with glycine? Let me know in the comments!